www.eopenaccess.com/index.php/chd e1 cancer health disparities editorial introducing cancer health disparities journal keshav k. singh, ph.d editor-in-chief in today’s world, understanding, preventing and curing cancer remains the top most challenge. over the past several decades, there has been a substantial advancement in screening, diagnosis, prevention, and treatment of cancer. nevertheless, disparities in the incidence, penetrance, social factors, genetic background, and environmental influence all affect the time of diagnosis, the course of prognosis and successful treatment of cancer. a recent study reports the higher incidence of prostate cancer in american populations, which is relatively much lesser in asian populations. among americans, its incidence is higher in african-americans in comparison to caucasians. similarly, cancer chemotherapy success varies widely across different ethnic populations. these observations make cancer health disparities research an important field of investigation. disparities research would give way to personalized medicine for treatment of cancer in different populations. the goal of the cancer health disparities is to cover all aspects of disparities including social, cultural, environmental, and genetic determinants contributing to differences in cancer incidence, prevalence, death, survivorship, and burden of cancer that exist among different population around the world. the overall aim is to publish high quality, high impact, and innovative research articles in all areas related to cancer health disparities. cancer health disparities will publish case report, multidisciplinary editorial, commentary, hypothesis, short and full-length reviews, fulllength original, clinical or basic science research articles and short articles of immediate scientific or clinical significance. these include disparities at the population, epidemiological, metabolic, molecular, genetic, physiological, clinical, diagnostic and therapeutic levels. cancer health disparities would provide a common dedicated platform to clinicians, epidemiologists, population and prevention scientists, molecular biologists, physician scientists and others for publishing multidisciplinary research on cancer disparities that would accelerate research in this important field. this would pave the way to efficient and targeted personalized cancer care for diverse ethnic populations. the editorial team is excited about the launch of this journal and looking forward to your participation. keywords: cancer health disparities, issn: 25739530 citation: singh kk. (2017). introducing cancer health disparities journal. cancer health disparities;1:e1. doi:10.9777/chd.2017.10001 www.companyofscientists.com/index.php/chd e1 cancer health disparities commentry first strike: a vietnam war veteran and prostate cancer survivor bill ward corresponding author’s email: lamar2@cox.net abstract mr. bill ward is native community health advocate with a personal goal of enhancing cancer knowledge among american indian men regarding screening. as a cancer survivor and a veteran, mr. ward provides essential stories in creating a supportive environment in both prevention and survivorship. bill’s story in his own words that follow were intended to share as an outreach activity supported by spirit of eagles, community networks program (nci u54 153605). keywords: prostate, cancer, survivor, veterans citation: ward b (2018) first strike: the voice of a prostate cancer survivor. cancer health disparities 2: e1e2. doi:10.9777/chd.2018.10010 www.companyofscientists.com/index.php/chd e2 cancer health disparities commentry the first strike: i like to use the frist strike analogy from a military perspective to define my battle with prostate cancer. i do this in my way, my words, to share a difficult story that i hope resonates with others. reconnaissance: at the start of my battle with prostate cancer, i noticed some pain in the most sacred part of my body. my training as a soldier has never allowed the enemy the first shot at taking me out. by instinct, i preferred to be the aggressor as opposed to sitting back and being the defender. this is where my first strike occurredgetting checked by the doctor. i would relate my next steps of further investigation of this pain and its cause to a reconnaissance (recon) phase. it was during recon that i began to understand and strategize against my enemy. this first strike was a pro-active move intended to subvert the enemy’s attempt to succeed by using the element of surprise, all the while, advancing slowly in order to make it difficult for me to win this long battle. preparing for combat: conferring with my allies and ultimately getting a prostate biopsy based on the psa (prostatespecific antigen) blood test reading, i was able to catch my enemy at an early stage. with further research and consultation with my recon team that included experts and those i trusted, i.e., doctors and family; i was presented with all available weapons of choice in terms of helping me win this battle. all this information, while overwhelming, increased my confidence as i prepared to go into combat. from the onset, my training and personality prevented me from implementing a “watch and wait” approach. i had no interest in gauging how aggressive the enemy was going to be, or if it would retreat. going into battle: in fact, it was of little interest to me to engage in the equivalent of a “fire fight” by using radioactive treatment options. that was a personal choice, for i knew i had to do something that would give me complete peach of mind. therefore i opted to use my own choice of weapon, a bomb called the davinci robotic-assisted surgical machine for a radical prostatectomy. after the “bomb” was dropped, the radical surgery tissue samples were sent to the hospital’s department of pathology to evaluate and assess for the presence of cancer cells “my enemy” outside the prostate gland. upon analysis, it was determined that indeed there were no cancer cells outside of territory-the prostate. when you are engaged in a battle for life, superior firepower is a game changer and is exactly what i chose to use in order to win this battle against the prostate cancer. debriefing highlights: early detection of the disease allowed me to catch and defeat the enemy before it spread to a larger area and possibly outside of my prostate. remaining alert to changes in my body, and ready to act when threatened, and entering my battle with a skilled and supportive recon team proved essential” that victory is now 13 years old. don’t let the enemy catch you sleeping! man-up and get yourself checked. “nothing comes to a sleeper but a dream, and sometimes it’s a bad dream.” get checked!! editor comment: the voice of survivors is crucial to improving cancer awareness, early detection and successful treatment for native american cancer patients. bill ward is a wonderful advocate. his take-home message is to seek out the best information and choose a treatment that fits your personal situation and goals. his choice may not be every man’s nor every native man’s choice but the story is supportive of doing what is necessary to become a strong fighter “survivor”. jskaur, guest editor www.companyofscientists.com/index.php/chd e1 cancer health disparities commentry the evolution of palliative care within the american indian health system judith salmon kaur and blythe winchester *corresponding author’s email: kaur.judith@mayo.edu abstract palliative care is now considered an important quality component within cancer care and essential to the continuum of cancer care programs nationwide. american indian and alaska native patients have significant differences in mortality from various cancers, and therefore palliative care is very important while working in parallel towards improved survival overall. in fact, palliative care has in some circumstances even contributed to improved survival (annual report to the nation on the status of cancer 1975-2009. doi:10.1093/jnci/djs491). this article recounts the efforts made over many years to institute quality palliative care programs that are culturally acceptable to native populations and outlines “next steps”. keywords: palliative care, american indians, alaska natives citation: kaur js and winchester b (2018) the evolution of palliative care within the indian health system. research reports 2:e1-4. doi:10.9777/chd.2018.10006 www.companyofscientists.com/index.php/chd e2 cancer health disparities commentry introduction the institute of medicine produced two substantive reports, one in 1997 and the other in 2001, which outlined deficiencies in the provision of palliative care for persons with life-threatening illness, including persons suffering with cancer (national academy of science, 1997; institute of medicine and national research council national cancer policy board, 2001). both iom reports highlighted the fact that minorities suffer disproportionately from the lack of provision of quality palliative care. within the american indian and alaska native (ai/an) populations the incidence of chronic diseases such as cancer, heart disease, cerebrovascular disease and diabetes mellitus are rising rapidly, and are now the leading causes of disability and mortality in this population (indian health service, 2005). ai/an populations have access problems to health care related to high rates of living in primarily isolated rural communities and having high rates of being uninsured. it is poorly understood that the indian health system (ihs) is not actually insurance (kitzes and domer, 2003; gorospe, 2006). due to these issues and others, ai/an’s with cancer often present to the health care system at a later stage than do nhw’s, and those ai/an’s diagnosed with cancer suffer the poorest survival of any ethnic group (national cancer institute, 2018; national cancer institute, 2016). beginning in 2001, several national and regional seminars in palliative care have been offered to practitioners who care for the ai/an population. the indian health service sponsored 3 national palliative care conferences, from 2001 through 2003, at which one team of health care providers (consisting of physician, nurse and one of the following: social service, psychologist, spiritual counselor, or pharmacist) from each ihs area attended with the expectation that they, in turn, would train their colleagues. the alaska palliative care symposium, sponsored by the alaska native tribal health consortium held annual events since 2005. additionally, palliative care content has been incorporated into several conferences sponsored by the spirit of eagles program, including the cdc comprehensive cancer leadership institutes for tribes. in 2004, the spirit of eagles program (an nci funded special population network), under the leadership of a native medical oncologist who also was board certified in palliative care and hospice (co-author jsk), performed a needs assessment for palliative care within the indian health system (michalek, et al., 2005). among the 10 suggestions related to the findings of the report were: “education programs should be instituted and sustained, especially in pain management.” as a part of this needs assessment, a survey of tribal health directors was commissioned by the spirit of eagles to assess available and desired services related to palliative care. over 50% of responding tribal health directors reported an urgent level of need for palliative services such as pain management (70%), advanced care planning (58%), care for the dying (53%), hospice contracts (54%), and bereavement support (52%). conversely, a high percent of palliative care services were either not available, or available only outside of the local community (e.g., care for dying 53%; pain management 44%; respite care 48%; advanced care planning 44%; hospice services 42%) (indian health service, 2006). in a national survey undertaken by the national indian council on aging (nicoa) and the national senior www.companyofscientists.com/index.php/chd e3 cancer health disparities commentry citizens law center (nsclc), among the least available long term care services reported by the tribes was hospice care, and chronically ill elders were frequently reported as not having home care needs met adequately (petersen, et al., 2006). in response to the documented need for improvement in access and quality of palliative care within the indian health system, the indian health service (ihs) has undertaken a multipronged approach to foster positive change. one component of the effort is to educate health care providers within the indian health system to improve knowledge, attitudes, and skills in the provision of palliative care. the dvd sponsored by the national cancer institute is known as epeco (education in palliative and end-of-life care for oncology) with american indian and alaska native cultural considerations) was used for multiple trainings of indian health service teams at mayo clinic with an “intensive case-based training for indian health” from 20102012. in 2014 a webinar series was hosted by blythe winchester, m.d. with over 500 participants including physicians, nurses and allied health professionals. these programs were designed to fill gaps between current and desired practice to relieve suffering. the overwhelming response to the webinar series shows the perception that education in palliative care is recognized as a need to improve overall quality care within the indian health system. also, cross cultural approaches involving traditional healers have been valuable since indigenous patients will often consult with their traditional people for ceremonies and medicine to help them heal or cope with their illness. a traditional health model helps the person focus on their cultural roots for meaning, purpose, and acceptance of health and wellbeing. with a renewed sense of empowerment, the holistic approach becomes a selfdetermined end of life care plan. approaches using traditional approaches were presented at the spirit of eagles national conference held in niagara falls, ny on sept. 21-24, 2017. a pre-conference workshop was also held in niagara falls dedicated to palliative care issues across aian populations. over 60 multidisciplinary specialists and students attended. as noted previously, alaska has been a true leader in the endeavor to provide palliative care to the alaska native population to overcome barriers associated with the huge geography and remote nature of villages there. a team from alaska shared models of services to underserved patients with advanced serious illness, including cancer. tools and resources were provided to educate and equip a broad variety of healthcare providers through the alaska tribal health system particularly where palliative care resources are limited. the anthc group has also developed a framework on advance care planning tools for culturally diverse populations in urban and rural regions. project echo ( (extension for community care outcomes) is funded by the agency for health care research quality (ahrq) funding has included telehealth to train in palliative care best practices and involves several indian health service sites including alaska and new mexico. (https:healthit.ahrq.gov/ahrq-funded-projects/) next steps: 1. now that palliative care is recognized within ihs as an educational and clinical need within the system, ongoing programs should be available www.companyofscientists.com/index.php/chd e4 cancer health disparities commentry 2. dr. winchester will report to ihs and provide an internal review of how those perceived needs have changed and improved over the past decade. 3. data from project echo and other programs should be disseminated widely within the indian health system and new programs identified and modified to meet local and regional needs. acknowledgements we thank lisa baethke, coordinator for native circle for disseminating palliative care across tribes. conflict of interest the authors declare that no competing or conflict of interests exists. the funders had no role in study design, writing of the manuscript, or decision to publish. authors’ contributions judith salmon kaur: literature review and manuscript preparation. blythe winchester: a review of the indian health service training to date and copresenter at the spirit of eagles palliative care preconference workshop mentioned in this manuscript. references gorospe, e. (2006). establishing palliative care for american indians as a public health agenda. internet journal of pain, symptom control and palliative care. 4, 2. indian health service (2005). the first 50 years of the indian health service: caring and curing (washington, dc: department of health and human services). indian health service (2006). guidelines for palliative care services in the indian health system. https://www.uaa.alaska.edu/academics/college-ofhealth/nrc-alaska-nativeelders/_documents/ihs_palliative-care-services.pdf. accessed july 16, 2018. institute of medicine and national research council national cancer policy board (2001). improving palliative care for cancer: summary and recommendations (washington, dc: national academies press). kitzes, j. and domer, t. (2003). palliative care: an emerging issue for american indians and alaskan natives. j pain palliat care pharmacother. 17, 201–210. michalek, a., mahoney, m.c., and kaur, j. (2005). palliative care services: a survey of tribal health directors. the ihs provider. may, 118–119. national academy of science (1997). approaching death: improving care at the end of lifea report of the institute of medicine (washington, dc: national academies press). national cancer institute (2016). building on opportunities in cancer research. https://www.cancer.gov/aboutnci/budget/about-annual-plan/nci-plan-2016.pdf. accessed july 16, 2018. national cancer institute. center to reduce cancer health disparities: examples of cancer health disparities. https://www.cancer.gov/aboutnci/organization/crchd/ about-health-disparities/examples. accessed july 16, 2018. petersen, w.o., kaur, j.s., finke, b., et al (2006). palliative and end of life care: perspectives on care within the indian health system. j psychosoc oncol. 15, s25. www.companyofscientists.com/index.php/chd e1 cancer health disparities research community cancer screening: reducing health disparities among native americans in rural, tribal communities pat conway1*, jennifer boeckel1, colleen buckley2, jodie fetsch3, margaret gates4, danielle myers wilson1, jesse tran5, joyce sayler5 1essentia institute of rural health, 502 east 2nd st, duluth, mn 55805, 2indian health service, 10 river road, fort yates, nd 58538; 3custer health, 403 burlington street se, mandan, nd 58554; 4standing rock sioux tribe tribal health, p.o. box d, fort yates, nd 58538; 5north dakota department of health, 600 e. boulevard avenue, bismarck, nd 58505 *corresponding author e-mail: pat.conway@essentiahealth.org abstract native americans have higher cancer morbidity and mortality rates than non-native americans and cancer screening rates are lower. this qualitative case study used community-based participatory research principles to identify individual, family, community, and environmental factors that positively influenced screening rates in a rural, native american community. over a two-year period, 90 people participated in 11 focus groups to inform the evaluation of the standing rock reservation men’s and women’s health days program. focus group interviews were digitally recorded, transcribed, and saved into nvivo for analysis. categories and themes were developed using a modified grounded theory approach, leading to a comprehensive model that allowed coding of all comments. the evaluation confirmed that many components of the screening were valuable, such as the advantages of holistic, culturally appropriate approaches within a social setting. individual experience with cancer and other chronic diseases, family experience with cancer and family support, and friends and exposure to toxins in the community influenced participation in cancer screening. collaboration between organizations, intensive outreach and recruitment, multiple services provided in one location, consistency of staff, incentives, and the opportunity to socialize and share a meal increased participation. barriers to screening, such as transportation, changing funding and criteria for screenings, reductions in other services, and unpleasant screening procedures, have required ongoing patience and problem solving on the part of the community team to ensure that high rate of screenings continue. these findings led to recommendations for program development in the target community and other similar communities nationally. keywords: cancer screening; health disparities; native americans; community health citation: conway p, boeckel j, buckley c, fetsch j, gates m, wilson dm, tran j, sayler j (2018). community cancer screening: reducing health disparities among native americans in rural, tribal communities. cancer health disparities 2:e1-e8. doi:10.9777/chd.2018.10005 www.companyofscientists.com/index.php/chd e2 cancer health disparities research introduction native americans in north dakota and nationally have higher cancer morbidity and mortality rates than non-american indians (white et al., 2014; north dakota department of health, 2012). cancer screening rates are also low. one community increased cancer screening numbers and the number of screening days annually through the standing rock reservation health days program. this intersectoral approach (rantala, 2014) to community health screening included diverse partners: custer health, the local public health organization; standing rock tribal health; indian health service (ihs); the north dakota breast and cervical cancer early detection program; avon foundation; susan g. komen affiliates; north dakota department of health (nd doh); and the great plains tribal chairman’s health board. it had two components: women’s health days which began in 1997 and men’s health days, introduced in 2003. standing rock sioux tribe, located in south central north dakota and north central south dakota, has 6,171 residents. the sparsely populated reservation spans mountain and central time zones. to resolve complications resulting from differences in legislation across the two states, north and south dakota formally agreed that the entire standing rock community would be served by the nd women’s way program. initially, custer health used screening resources available through the women’s way program to implement the program; ihs provided clinic space and staff for screening; community health representatives (chrs) recruited participants. other organizations joined to increase community participation in screening days; for instance, the casino provided food; community providers set up diabetes, dental, and nutrition education stations. the men’s and women’s screening days program has been recognized regionally and nationally as a successful screening program (http://archived.naccho.org/topics/modelpractices/ database/practice.cfm?practiceid=63). this paper describes driving forces that motivated tribal members to participate in screening initially and to return in future years, as well as individual, family, community, and environmental supports for and challenges to screening. two evaluation questions guided interviews with community members to identify those factors that contributed to successful programming and increased rates of cancer screening: 1. how do individual, family, and community factors influence screening for chronic diseases, including cancer, diabetes and heart disease? 2. how do characteristics of the screening program and other health care programs influence screening for chronic diseases? materials and methods interviews with community members and providers this qualitative case study (yin, 2017) was guided by community based participatory action (cbpr) research principles; cbpr principles guided planning and implementation of the enhanced evaluation of standing rock men’s and women’s health days programs, ensuring that data collection and dissemination of results occurred in a manner appropriate for this community (minkler et al., 2008; israel et al. 1998). representatives from organizations engaged in the screening program formed an evaluation workgroup overseeing planning, implementation, analysis, and dissemination of information. a tribal resolution; irb approval through sitting bull college, aberdeen area ihs, and essentia health; and approval by the nd doh were obtained. sample and data collection process standing rock tribal members who were 40 years of age and older were recruited to participate in focus groups. tribal members representing people who screen regularly, those who rarely participated in cancer screening, and members www.companyofscientists.com/index.php/chd e3 cancer health disparities research who had never participated in the men’s and women’s health days screenings were invited to participate. chrs, in consultation with custer health, identified participants, reminded them about the focus groups, and arranged transportation for those with no means to travel independently. ninety people participated in 11 focus groups in five of the eight standing rock communities. men’s and women’s groups were held separately, which the workgroup determined was culturally appropriate in this community. focus groups were conducted at the casino and in public buildings in each community, to ensure greater access for community members. data collection occurred over a two-year period. after review of initial evaluation results, the workgroup identified a gap resulting from lack of data collection in one community; therefore, additional focus groups were conducted. members of the workgroup participated in focus group training prior to conducting the focus groups. when participants arrived for each focus group, a workgroup member asked them to sign in; at the conclusion, that person provided each participant with incentives, thanking them for participating. each focus group was managed by a facilitator who led the focus group; a co-facilitator who was available for support in the group and to assist any member who needed to leave the meeting during the interviews. a note taker typed verbatim comments. each focus group began with a prayer and the facilitator’s explanation about the purpose of the meeting and a review of the informed consent form. members who wished to participate signed the informed consent form and received a copy of the form. interviews were guided by a semi-structured interview schedule which was created by the evaluation work team and revised following the first two focus groups. data analysis interviews was digitally recorded and transcribed for analysis. transcripts were then saved into nvivo for development of categories and themes using a modified grounded theory approach. the categories were created through an iterative process, where two researchers working independently coded a sample of comments, compared their results, revised the categories, and presented the categories to the evaluation team for further revisions. existing theory and research also guided the development of categories, especially the ecological perspective (markus, 2012). this led to a comprehensive model that allowed coding of all comments. individual interviews were also conducted with individuals representing organizations who participated in the screening days, to augment understanding about the program. results evaluation question 1. how do individual, family, and community factors influence screening for chronic diseases, including cancer, diabetes and heart disease? men’s and women’s comments fell into four categories: 1. individual factors that influence participation in screening, 2. family factors that influence participation in screening, 3. community factors that influence participation in screening, and 4. characteristics of health screening days that influence participation in screening (see table 1 for all categories and frequencies.) www.companyofscientists.com/index.php/chd e4 cancer health disparities research table 1. individual, family, community and health screening days factors influencing screening. factors influencing screening categories number: phrases individual factors age of individual 5 experience with cancer and knowing whether have cancer 43 currently screening yes or no 36 health other than cancer 13 lack of time 5 stubborn 2 risk factors for cancer 5 family factors family member experience with cancer 39 knowledgeable about screening and supports person in participating 15 community factors environmental risk factors 4 friend supports 12 gossip 4 interventions to increase awareness about screening 4 referral to screening program by health care provider 1 health screening days funding 11 criteria for eligibility for screening 32 health care provider 9 incentives, such as knives, beads, meal, and socialization 49 other activities, providers at the screening, ie diabetes, eye, heart, mental health, nutrition. 22 process flow of activities during health screening day 6 recruitment 35 transportation 32 location 9 scheduling 18 the screening itself, screening results, and screening days overall 39 individual factors that influence participation in screening. fear of having cancer was both a motivator and barrier to screening. having had cancer motivated some to continue screening and to encourage others to screen; on the other hand, some were fearful of learning that they had cancer. having other health issues such as diabetes and risk factors such as obesity and smoking motivated some to participate. when they found out i did have cancer, i went through the procedures and everything else. because i am cancer free, i thought i’d try to be an advocate for anyone with cancer or refer anybody [for screening]. i contacted my nephews, anybody, www.companyofscientists.com/index.php/chd e5 cancer health disparities research my three sons, anyone that was over forty and i encouraged them to go to the men’s clinic and they did. “i just don't want to hear the bad news. if i have cancer i don't know; how i would deal with it?” lack of time and other responsibilities were a common barrier. “i know, i always tell my daughters; you better get over there. she says, ‘well i can't, mom, i got no leave or whose going to watch my kids?’” family factors. the most commonly mentioned reason for participating in screening was having experience with a family member with cancer. the first cancer that my mom had was colon cancer; i had to have that colonoscopy done. it was my grandmother, my mother, and my sisters that i lost to cancer. i don’t know how many cards i filled out with a lot of my friends and relatives on them; but i just had one go to the last women’s day in september. she hit me in the arm and she said, “oh, i’m really glad you signed me up.” i said why and she has cervical cancer. family members frequently encouraged other members to participate in screening. community factors. community factors influencing participation in screening included friends in the community, and environmental factors. “my coworker, she goes every year too and she said, “i went to women's way. “i said, “good for you, we got to go every year.” “yes we do,” she said. on the other hand, fear of gossip kept some from participating in health screening events. “gossip is one of the biggest things on the reservation, so there’s another fear there. they think someone’s going to say, so and so went to women’s way, i wonder what’s wrong with her?.” exposure to environmental risk factors, such as agent orange, asbestos, and carbon monoxide, were identified as community factors that might influence the decision to be screened for cancer. evaluation question 2. how do characteristics of the screening program and other health care programs influence screening for chronic diseases? a combination of factors regarding the program influenced participation in screening, including: 1. policies and procedures for funding and the criteria for eligibility for screening, 2. access to health screening days (scheduling, transportation), 3. incentives (food, gifts such as multifunction tools, other activities such as diabetes counseling and nutrition), 4. characteristics of the screening itself, including the provider, workflow, and the screening itself. policies and procedures. a common barrier for participating in screening by tribal members was complexity of funding, with multiple payors such as women’s way, insurance, the va, ihs, co-pays, and out of pocket costs. “when i got that billing, that’s why i didn’t go back. i know they called me and said, “are you coming to the next women’s way?” and i was kind of hesitant. my husband said, “well, you’ve been going all this time. why are you going to stop?” i said, “look at this bill, i can’t pay this.” cancer screening criteria. confusion about criteria for cancer screening at the national and local level impeded participation; a question that comes to mind: is there different age brackets for different cancers? do you know what i mean? like what he said for the prostate; is that 30s, pancreatic cancer is that like in the 50s? access to health screening days. multiple methods of outreach, including flyers, word of mouth from family and friends, the local radio and newspaper, www.companyofscientists.com/index.php/chd e6 cancer health disparities research a phone call inviting one to participate, district meetings, posters at the store, post office and district building, chrs, letters with an appointment time, stories by survivors of cancer, increased knowledge about and participation in screening. “i keep hearing about this maybe i should go check it out.” existing transportation is available and has additional benefits; “i get a big kick out of the men because around the first, here comes the shuttle picking them up and out they go and i think it’s fun for them because they get to visit in their own language.” it is problematic, though, in terms of flexibility, availability, and scheduling, and may not be appropriate for someone who has compromised health issues. access is enhanced by extending screening to several locations. incentives. “offering meals” was the most common incentive. “maybe a small meal. that small meal doesn't see much to everybody but those of us who can't afford a meal at lunch…i'm here i'm getting a free meal.” gifts such as tools and gas cards were appreciated. holding other activities during the day also increased participation: breast self-exam, dental care, diabetes, domestic violence, eyes, heart, mental health, and nutrition. they also check your blood pressure, check your blood, make sure you have your doctor’s appointment and they have the new jelly things now where you can actually feel one of those things. yeah, a breast with a bead in it and you has to like put it on and try to find it. and the diabetic and the eye, if you need to go to the eye clinic and the dental if you need to go to the dental. i think as you go into the different departments, you go into this one. they check your cholesterol, you go into this one they check your diabetes and so forth. what i feel about that is that it gives me a chance to sit down there, not only to be checked but to ask questions or make comments and so forth and that’s the only way you learn. the screening itself. the flow of activities, screening staff, the screening itself, and screening results influenced participation. participants described the process in a matter-of-fact way and as positive. you just go there and you sit down with one individual and they talk about this and that and then you sign a form or you do this and then you go onto the next one which maybe takes care of the cholesterol and maybe the other one takes care of diabetes and finally you get to the doctor and then he checks you out and that’s the important part. having consistent screening staff who were engaged in the community positively influenced screening. the rapid turnover among physicians was a barrier to participation. but when they are in town they remember us. you know they know our names, they call us and ask how are you doing and everything like that. and a lot of the doctors are even friendly. if you have a certain doctor, mine’s [nurse practitioner with? years’ service in the community], because he's always been there. i'd rather go to him. doctors are so hard to recruit and keep on the reservation, because we don't have nothing that attracts them here and they have to travel 90 miles to bismarck and so many miles to rapid city. so it's hard to recruit them and retain them. i know that's a problem that we have. they don't like our school; they don't like their kids in our schools so that's a big problem that we have. the most common reason to avoid the screening itself was because it was unpleasant, especially rectal exams, colonoscopies, prostate exams, and mammograms. fear of the glove (laugh), the exam part of it. i think a lot of people fear that the most, the exam part. i think the problem with that kit is it has to be private. because people see you with that and they say oh, you’re playing with your poop. my brother was very ashamed of doing one of those, my www.companyofscientists.com/index.php/chd e7 cancer health disparities research youngest brother, and i got very upset with him and i told him you have to do it there’s a lot of things that they can find out with that screening that may save your life so just do it. discussion the standing rock men’s and women’s health screening days, guided by an active workgroup of community members, health care providers, and other community organizations, have increased men’s and women’s screening rates for colorectal, prostate, breast, and cervical cancer. individual experience with cancer and other chronic diseases, family experience with cancer and family support, and friends and exposure to toxins in the community influenced individuals to participate in cancer screening. characteristics of the screening that increased screening rates were collaboration between organizations, intensive outreach and recruitment, multiple services provided in one location, consistency of staff, incentives, and the opportunity to socialize and share a meal. barriers to screening, such as transportation, changing funding and criteria for screenings, reductions in other services, and unpleasantness of some screening procedures, have required ongoing patience and problem solving on the part of the community team to ensure that the high rate of screenings is maintained. following the evaluation, the number of field clinics was increased to increase access in remote regions of the reservation. education regarding screening recommendations has increased. where possible, screenings have been integrated into ihs clinics’ regular routine, with providers recommending screening. screening tools have changed to reduce unpleasantness. referrals and post card notices of annual screening dates and locations are managed centrally to ensure that no one falls through the cracks. the evaluation confirmed that many components of the screening were valuable, such as the advantages of a holistic, culturally appropriate approach to health screenings within a social setting. overall, community members expressed strong support: they take interest, “come in here and sit down and we’ll work with you.” i can sit down and talk face to face with an individual that has expertise in this area and it gives me a chance to interact with them and get my questions answered. an unintended consequence of the evaluation was increased commitment to continue the process, unifying community organizations. collaboration between partners continues, to address some ongoing issues such as differences of opinions about screening criteria and fear surrounding cancer screening and treatment; and new issues arise. recommendations for implementation in other communities recommendations to increase cancer screening rates, especially in rural, tribal communities, include: 1. develop and nurture robust community partnerships and trusting relationships with community members through transparency, patience, persistence, and flexibility as demonstrated by adapting programs to fit diverse communities. 2. create cancer screening events that provide opportunities for other screenings, health education, and socialization. 3. support independence for health clinics with already established culture and procedures. 4. seek funding to support local programs, adding resources. 5. recognize that cancer screening might not be a community’s first priority. family and community events take priority. for instance, if a funeral occurs on a screening day, the screening event will not be successful. www.companyofscientists.com/index.php/chd e8 cancer health disparities research 6. use feedback to develop, implement, and adapt programs to accommodate constantly changing environments. 7. advocate for increased funding from local, state and national sources that support cancer screening and prevention activities across organizations. acknowledgements we thank community health representative(s), community partners, and community members who participated in the study. conflict of interest statement the author has declared that no competing or conflict of interests exists. the funders had no role in study design, writing of the manuscript and decision to publish. authors’ contributions pc conceived, planned and executed the study; jb, cb, jf, mg and dmw participated in planning, data collection, analysis and writing; pc, jt, js participated in planning, execution and writing. references israel, b.a., coombe, c.m., cheezum, r.r., schulz, a.j., mcgranaghan, r.j., lichtenstein, r., reyes, a.g., clement, j., & burris, a. (2010). community-based participatory research: a capacity-building approach for policy advocacy aimed at eliminating health disparities. american journal of public health 100(11), 2094-2102. israel, b.a., schulz, a.j., parker, e.a., and becker, a.b. (1998). review of community-based research: assessing partnership approaches to improve public health. annual review of public health 19, 173-202. marcus, s.f. (2012). photovoice for healthy relationships: community-based participatory hiv prevention in a rural american indian community. american indian and alaska native mental health research 19(1), 102-123. minkler, m., and wallerstein, n. (eds.). (2008). communitybased participatory research for health: from process to outcomes (2 nd ed.). san francisco, ca: jossey-bass. north dakota department of health. (2012). north dakota american indian health profile. https://www.ndhealth.gov/healthdata/communityhealth profiles/american%20indian%20community%20profile.p df rantala, r., bortz, m., and armada, f. (2014). intersectoral action: local governments promoting health. health promot. int. 29 suppl 1, i92-i102. doi: 10.1093/heapro/dau047 white, m.c., espey, d.k., swan, j., wiggins, c.l., eheman, c., and kaur, j.s. (2014). disparities in cancer mortality and incidence among american indians and alaska natives in the united states. american journal of public health 104 suppl 3, s377-s387. yin, r.k. (2017). case study research and applications: design and methods. sage publications, inc. https://www.ndhealth.gov/healthdata/communityhealthprofiles/american%20indian%20community%20profile.pdf https://www.ndhealth.gov/healthdata/communityhealthprofiles/american%20indian%20community%20profile.pdf https://www.ndhealth.gov/healthdata/communityhealthprofiles/american%20indian%20community%20profile.pdf http://heapro.oxfordjournals.org/search?author1=riikka+rantala&sortspec=date&submit=submit http://heapro.oxfordjournals.org/search?author1=martin+bortz&sortspec=date&submit=submit http://heapro.oxfordjournals.org/search?author1=francisco+armada&sortspec=date&submit=submit http://www.ncbi.nlm.nih.gov/pubmed/24754660 http://www.ncbi.nlm.nih.gov/pubmed/24754660 http://www.ncbi.nlm.nih.gov/pubmed/24754660 www.companyofscientists.com/index.php/chd e1 cancer health disparities research relationship between the tp53 snp rs1800371 and lung cancer in african americans noah nichols1, khadijah mitchell1, adriana zingone1, claire meaney1, elise d. bowman1, bríd m. ryan1 1laboratory of human carcinogenesis, centre for cancer research, nci, building 37, room 3060c, bethesda, md, 20892, *corresponding author e-mail: brid.ryan@nih.gov abstract germline and somatic mutations in tp53 have been investigated and intensely catalogued. one of these germline mutations, tp53 p47s snp is only found in populations with african ancestry. the s47 variant was associated with an impaired ability to induce cell death following cisplatin treatment, and with a high rate of spontaneous cancer formation in mice engineered to carry s47. lung cancer incidence is higher among men of african descent. we therefore tested the hypothesis that p47s was associated with increased risk of lung cancer. we included 926 controls and 425 cases, all of whom were african americans. we genotyped rs1800371 using a predesigned taqman assay. no serine/serine genotypes were detected in the population. the proline/serine genotype was detected in 42 individuals (32/891 controls (3.5%) and 10/434 cases (2.3%). the serine allele was not associated with risk of lung cancer (or: 0.65, 95% c.i. 0.28-1.48). rs1800371 is not associated with risk of lung cancer among african americans. keywords: tp53, snp, health disparities citation: nicholas n et al (2019) relationship between the tp53 snp rs1800371 and lung cancer in african americans. cancer health disparities 3: e1-e9. doi:10.9777/chd.2019.1005. www.companyofscientists.com/index.php/chd e2 cancer health disparities research introduction lung cancer is the leading cause of cancer-related death in the united states and the second most common form of cancer in both men and women (siegel et al., 2017). several studies have demonstrated an increased lung cancer burden in african americans (aa) (siegel et al., 2016). smoking is the major etiological cause of lung cancer (doll and peto, 1976; peto, 2001); however, a combination of environmental and genetic factors could predispose an individual to lung cancer. the p53 tumor suppressor (tp53) is widely studied and its importance in tumorigenesis is underpinned by the fact that it is the most frequently mutated gene in human cancers (olivier et al., 2010). somatic mutations in tp53 have been investigated and intensely catalogued. additionally, individuals with li-fraumeni syndrome, who carry germline mutations in tp53, have an increased risk of developing cancer (malkin, 1993). acting as a transcription factor, p53 binds regulatory elements in dna and facilitates the transcription of genes that protect against tumor growth. pathways activated by p53 include cell cycle arrest, apoptosis, and angiogenesis inhibition (whibley et al., 2009). harris and colleagues first identified the tp53 p47s snp (rs1800371) in 1992 (felley-bosco et al., 1993; gerwin et al., 1992). this polymorphism, characterized by a c>t transition at position 1 of codon 47 (ccg-tcg), causes a non-synonymous amino acid change from proline to serine. felleybosco et al., noted that the individuals in that study, who identified as caucasian american, were homozygous for the proline allele. however, the ct genotype was observed in 3/37 african americans. in a functional analysis of this polymorphism, the authors concluded that, in their model, the s47 allele functioned similar to wildtype p53. phosphorylation of the n-terminal domain of p53 facilitates its transactivation activity of proapoptotic genes (kurihara et al., 2007). for example, p38 mapk and hipk2 transactivation by p53 occurs through proline-directed phosphorylation of codon 46 at the n-terminal domain. therefore, it was hypothesized that loss of the adjacent proline residue at position 47 could impair apoptotic activation. indeed, li et al. demonstrated that the s47 variant is an inferior substrate for p38 mapk and exhibited a decreased ability to induce apoptosis in vivo compared with wild-type p53 (li et al., 2005). the s47 variant was also associated with an impaired ability to induce cell death following cisplatin treatment (jennis et al., 2016). furthermore, the serine variant was associated with decreased transcription of a subset of target genes involved in metabolism and proapoptotic signaling (jennis et al., 2016). mice engineered to carry s47 had a high rate of spontaneous cancer formation, as 80% of s47 homozygous mice developed hepatocellular carcinoma, b-cell lymphoma, and other tumor types (jennis et al., 2016). previous work has established the increased frequency of the s47 allele in african americans and other populations with west african ancestry. despite convincing evidence from mouse models and cell culture experiments suggesting that the s47 variant is functionally significant and mechanistically differs from the proline variant, several studies have failed to show an association with cancer risk or survival (alawadi et al., 2011; almeida et al., 2009; jaiswal et al., 2011; kaur et al., 2014; mostaid et al., 2014; sameer et al., 2010; www.companyofscientists.com/index.php/chd e3 cancer health disparities research santos et al., 2011; singamsetty et al., 2014), though many of these studies included small sample sizes. herein, we genotyped 425 lung cancer cases and 926 controls. the objective of this study is to determine whether rs1800371 is associated with lung cancer risk and survival in african americans and admixed european americans. methods and materials patient population participants were selected from the ongoing national cancer institute-maryland case-control study. we included 926 controls and 425 cases for whom dna was available (all african american). the nci-maryland lung cancer case-control study is an ongoing study that started in 1998 and includes participants recruited from the greater baltimore and eastern shore regions of maryland (mechanic et al., 2007).. cases, recruited from seven hospitals in the greater baltimore metropolitan area, were diagnosed with histologically confirmed nsclc (of any stage). population controls, frequency matched to cases on age, race, and sex, were recruited from maryland department of motor vehicles records. general inclusion criteria included having been born in the united states, an ability to speak english well enough to be interviewed, being in good health and not residing in an institution. trained interviewers administered a standardized questionnaire to capture information regarding demographics, socioeconomic characteristics, tobacco smoking history (current, former [those who reported to have quit smoking one year prior to the interview], or never [those who smoked less than 100 cigarettes over their lifetime]), as well as pack-years of smoked cigarettes, alcohol history, medical history, family cancer history, reproductive history, and occupational history. body mass index (bmi) was determined using reported measures of height and weight by the participant. table 1. demographic characteristics of the cases and controls. african americans controls n=926 cases n=445 p-value age (mean, sd) 64.6 (8.8) 63.6 (9.9) 0.06 gender (n, %) <0.0001 males 615 (66.4) 231 (51.9) females 311 (33.6) 214 (48.1) smoking (n, %) <0.0001 never 321 (34.7) 31 (7.0) former 397 (42.8) 156 (35.1) current 185 (20.0) 193 (43.4) former smoker: quit within 1 year of interview 23 (2.5) 65 (14.6) pack-years of smoking (median, iqr) 7.4 (0-25.0) 29.7 (15.0-45.5) <0.0001 family history of lung cancer (n, %) 0.003 www.companyofscientists.com/index.php/chd e4 cancer health disparities research no 628 (67.8) 260 (58.4) yes 177 (19.1) 112 (25.2) missing 121 73 histology (n, %) adenocarcinoma 198 (44.5) squamous cell carcinoma 123 (27.6) nsclc* 67 (15.1) other 32 (7.2) missing 25 genotyping genomic dna was isolated from cheek cells or buffy coat samples containing white blood cells from patients in the case–control study using flexigene dna kit (qiagen), according to the manufacturer's instructions. case, control, and duplicate samples (10%) were randomized and blinded for processing. genotypes were obtained using a standard taqman snp genotyping assay for rs1800391 and followed the manufacturer’s protocol. genotyping failed for 4 individuals. cases and controls were randomized across all the plates. duplicate concordance was 100%. we also genotyped a series of european americans (n=1349). all were homozygous wild-type for the snp (cc). global genetic ancestry global genetic ancestry analysis was performed as previously described (al-alem et al., 2014). briefly, dna from blood was genotyped for 100 ancestry informative markers (aims) using the sequenom massarray iplex platform. the aims panel consisted of carefully selected autosomal markers that were previously identified and validated for estimating continental ancestry information in admixed populations (kosoy et al., 2009; nassir et al., 2009). individual snp genotype calls were generated using sequenom typer software. a genotype concordance rate of 99.5% was observed for all markers. genotyping call rates exceeded 97% for all individuals included in the analyses. individual admixture estimates for each study participant were calculated using a modelbased clustering method as implemented in the program structure v2.3 (falush et al., 2003). structure 2.3 was run using parental population genotypes from west africans, europeans, and native americans (kosoy et al., 2009) under the admixture model using the bayesian markov chain monte carlo method (k = 3, assuming three founding populations) and a burn-in length of 30,000 for 70,000 repetitions. statistical analysis chi-square tests were used to compare categorical variables between cases and controls. a logistic regression model was used to estimate odds ratios and 95% confidence interval (ci), before and after adjustment for known and potential confounders, including age, gender, smoking status, pack-years of smoking and bmi. cox proportional hazard models were used to estimate hazard ratios (hr) and 95% ci for disease-free survival after adjustment for age, gender, smoking status, packyears, tumor stage and histological subtype. survival was calculated using the difference in time www.companyofscientists.com/index.php/chd e5 cancer health disparities research between the date of surgery or diagnosis and the date of last known follow-up or death from lung cancer. all statistical tests were two-sided, and a pvalue of 0.05 was used to assess significance. we used stata version 14 to perform all analyses. results frequency of rs1800371 genotypes the proline/serine genotype was detected in 42 individuals (3.1%), giving an allele frequency of 1.5%. of these, 32 (3.5%) were controls and 10 (2.3%) were cases (table 2). no serine/serine genotypes were reported. also, the proline/serine genotype was only detected in african americans, which is consistent with the ancestral origin of the serine allele. table 2. frequency of rs1800371 in cases and controls. european american african american rs1800371 control case control case proline/proline 717 (100%) 632 (100%) 891 (96.5%) 434 (97.8%) proline/serine 32 (3.5%) 10 (2.3%) serine/serine relationship between rs1900371 with lung cancer risk as the serine allele was only detected in african americans, we restricted our analysis to this subgroup of the population. we observed a nonsignificant association between the snp and lung cancer risk both before (or: 0.64, 95% c.i. 0.311.32) and after adjustment for potential confounders (or: 0.55, 95% c.i. 0.28-1.48) (table 3). as african americans are an admixed population, we also adjusted our analysis for global genetic ancestry, however, this adjustment did not alter the coefficients (table 3). table 3. relationship between rs1800371 with lung cancer risk among african americans. rs1800371 or (95% c.i.) a p-value or (95% c.i.) b p-value or (95% c.i.) c p-value proline/proline reference reference reference proline/serine 0.64 (0.31-1.32) 0.23 0.65 (0.28-1.48) 0.30 0.65 (0.28-1.50) 0.32 serine/serine na na na a unadjusted b adjusted for age at diagnosis, gender, smoking status, pack-years of smoking, bmi c adjusted for age at diagnosis, gender, smoking status, pack-years of smoking, bmi, west african ancestry, european ancestry and native american ancestry www.companyofscientists.com/index.php/chd e6 cancer health disparities research relationship between rs1800371 with lung cancer survival we tested the relationship between rs1800371 with lung cancer specific survival among the african american cases for whom we had survival data (n=439). we observed a non-significant relationship between the serine allele with prognosis (hr: 0.82, 95% c.i. 0.34-2.00). table 4. relationship between rs1800371 and lung cancer survival among african americans. rs1800371 hr (95% c.i.) a n=439 p-value hr (95% c.i.) b n=360 p-value proline/proline reference reference proline/serine 0.82 (0.34-2.00) 0.67 0.56 (0.23-1.38) 0.21 serine/serine na na discussion animal and experimental studies using human cells have suggested that the serine allele of rs1800371 predisposes individuals to risk of cancer (basu et al., 2016; jennis et al., 2016). in this study, we examined whether carriers of the serine allele had an increased risk of lung cancer. however, we did not find evidence for an association, neither did we find an association with survival. mostaid et al. did not find an association between s47 and lung cancer risk in a bangladeshi population. (mostaid et al., 2014). similarly, no risk associations were observed in esophageal, breast, colorectal and bladder cancer studies (alawadi et al., 2011; jaiswal et al., 2011; kaur et al., 2014; sameer et al., 2010; santos et al., 2011). in contrast, singamsetty et al., focusing on a south indian population, observed a significant difference in the proportion of s47 alleles in cases which had a protective effect on crc risk (singamsetty et al., 2014). furthermore, one study has demonstrated an association with increased risk and the s47 variant. in 2013, an extra-axial brain tumor study revealed a small increase in risk for tumor development in a brazilian population (almeida et al., 2009). in breast cancer, particularly among premenopausal women, the serine allele is associated with increased risk among african americans (murphy et al., 2017). the ct genotype, conferring one copy of the serine allele and one copy of the proline allele, was observed in 42/1435 (2.9%) of african americans. this frequency is somewhat lower than the occurrence of the ct genotype in african populations (~6-8%) previously reported, but the lower frequency in our cohort could reflect genetic admixture. of note, the minor allele frequency of the t allele in this study (1.5%) is similar to that reported in a recent report of african american women (~1.4%) (murphy et al., 2017). p53 mediates its tumor suppressive function by inhibiting cell growth, inducing senescence and modulating cell metabolism. it accomplishes these functions via transcriptional activation of target genes, some of which is driven by posttranslational modifications such as phosphorylation. for example, phosphorylation of serine 46, the amino acid next to proline 47 is required for efficient p53-mediated cell death in several cell line systems and in mice (bulavin et al., 1999; jennis et al., 2016). phosphorylation of serine 46 requires the presence of a proline at 47, thus www.companyofscientists.com/index.php/chd e7 cancer health disparities research serine 47 significantly impairs the induction of cell death in cell line models (li et al., 2005). however, the impact of this variant on the p53 signaling pathway and cancer risk in an intact animal has never been assessed. in a follow up study, jennis and colleagues found that the s47 variant is modestly impaired for most p53 functions, and that it is significantly impaired for the ability to transactivate a subset of p53 target genes to induce cell death following cisplatin or ferroptosis in a mouse model (jennis et al., 2016). we had hypothesized that rs1800371 would be associated with increased risk of lung cancer. this hypothesis was primarily based on the observation that 80% of mice carrying two copies of the serine allele developed spontaneous cancers. there are several possible reasons why an observation with cancer risk was not observed in our study. first, it is possible that this snp is not associated with lung cancer. in the mouse study, the main tumor type observed was hepatocellular carcinoma. this is possibly related to the fact that one of the main gene targets disrupted by serine 47 is gls2 (jennis et al., 2016). while some penetrance of spontaneous tumors was observed among mice carrying one serine allele, the frequency was lower. also, our study population did not identify any individuals carrying two serine alleles and it is possible that both alleles are needed for higher disease penetrance. moreover, smoking is the main etiological cause of lung cancer in our population and it is possible that the mechanism of smoking-induced lung carcinogenesis does not involve ferroptosis. tp53 has many splice variants, and one key difference between the human and mouse is the presence and absence of the dominant negative delta133 isoform in human and mice, respectively. however, given that this variant occurs in codon 47, and delta133 is missing the first 133 codons of the full-length gene, it seems unlikely that these differences in isoform expression could impact function. finally, as shown in previous studies, tp53-related variants do not always function in isolation. for example, the two promoter variants snp309 and snp285 of the mdm2 gene, negative regulator of p53, functionally interact; snp285 acts as an antagonist to snp309 by overriding the effect of snp309 on sp1-mediated transcription (knappskog et al., 2011; ryan et al., 2012). therefore, it is possible that the tumor suppressive function of serine 47 interacts with another human polymorphism in the tp53 pathway. our study suggests that rs1800371 is not associated with increased lung cancer risk among african americans, but we cannot rule out the possibility that carriers of two serine alleles would have increased susceptibility. however, given the penetrance of hepatocellular carcinoma in mice carrying the serine allele, and disparities in liver cancer incidence in the us (islami et al., 2017), case control studies of this cancer type and rs1800371 should be considered. acknowledgements community health representative(s), community partners, and community members who participated in the study. this work was supported by the intramural research program of the center for cancer research, national cancer institute. conflict of interest statement the author has declared that no competing or conflict of interests exists. the funders had no role in study design, writing of the manuscript and decision to publish. www.companyofscientists.com/index.php/chd e8 cancer health disparities research authors’ contributions conceptualization: bmr, formal analysis: nn, az, bmr, km, cm methodology: az, nn, ebsupervision: az, bmr writing ± original draft: nn, bmr writing ± review & editing: nn, km, bmr, az, eb, cm, references al-alem, u., rauscher, g., shah, e., batai, k., mahmoud, a., beisner, e., silva, a., peterson, c., and kittles, r. 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(2009). p53 polymorphisms: cancer implications. nat rev cancer 9, 95-107. www.companyofscientists.com/index.php/chd e1 cancer health disparities research regional disparities in ovarian cancer in the united states zhixin wang1, sarah dilley2, hyounkyoung g park3, alfred a. bartolucci4, chenguang wang5, warner k. huh2,6, sejong bae1,6 1 division of preventive medicine, department of medicine, school of medicine, university of alabama at birmingham, birmingham, al 2 division of gynecology oncology, department of obstetrics and gynecology, school of medicine, university of alabama at birmingham, birmingham, al 3 university of liverpool, uk 4 department of biostatistics, school of public health, university of alabama at birmingham, birmingham, al 5 division of biostatistics and bioinformatics, sidney kimmel comprehensive cancer center, the johns hopkins university, baltimore, md 6 comprehensive cancer center, university of alabama at birmingham, birmingham, al corresponding author: sbae@uabmc.edu abstract the aim of this study was to investigate the association between geographic regions and ovarian cancer disparities in the united states. data from the surveillance, epidemiology, and end results (seer) program was used to identify women diagnosed with ovarian cancer. 18 registries were divided into two groups: south region and us14 region. chi-square tests were used to compare proportions, the logistic regression model to evaluate the association between 5-year survival and other variables, and the cox proportional hazards model to estimate hazard ratios. the south region had a lower incidence rate than the us14 region (12.0 vs. 13.4 per 100,000), and a lower 5-year observed survival rate (37.5% vs. 39.8%). white women living in the us14 region had the best overall survival, compared to white women living in the south region, and black women living in both regions. women in the south region were less likely to have insurance (6.6% vs. 2.7%, p<0.0001) and surgery (73.4% vs. 76.2%, p<0.0001). women living in the south were 1.4 times more likely to die after five years of diagnosis than women living in the us14 region. the data confirmed regional disparities in ovarian cancer in the united states, showing women living in the south region were disadvantaged in ovarian cancer survival regardless of race, black or white. future research focusing on the identification of contributing factors to regional disparity in ovarian cancer is necessary to develop practical approaches to improve health outcomes related to this lethal disease. keywords: ovarian cancer, geographic health disparities, survival citation: wang z et al. (2019) regional disparities in ovarian cancer in the united states. cancer health disparities 3:e1-e12. doi:10.9777/chd.2019.1002. www.companyofscientists.com/index.php/chd e2 cancer health disparities research introduction ovarian cancer is the tenth most common cancer and the fifth most lethal cancer among women in the united states. in 2017, there will be an estimated 22,440 new cases and 14,080 cancer deaths (acs, 2014). a woman’s risk of getting invasive ovarian cancer during her lifetime is about 1 in 75, and the risk of dying from invasive ovarian cancer is about 1 in 100 (ocrfa). racial disparities in ovarian cancer have been well documented in the united states. for example, white women had higher incidence rates and higher mortality rates compared to black women. however, 5-year relative survival rate was lower in black women than in white women. the incidence of ovarian cancer was 12.2 in white women, and 9.4 in black women, and the number of deaths was 7.7 in white women and 6.4 in black women (per 100,000 women, 2010-2014) (ocrfa). the five-year relative survival rate in black women was 38%, compared with 46% in white women (20062012) (acs, 2014). from 2003 to 2012, the incidence rate decreased by 2.1% per year among white women, while it only decreased by 1.3% among black women (cdc). during the same time period, the mortality rate decreased by 2.1% per year among white women comparing to 1.6% among black women(cdc). the five-year relative survival rate of ovarian cancer among white women increased from 35% (1975-1977) to 46% (2006-2012). however, the survival rate among black women decreased from 42% to 38%. studies about racial disparities in ovarian cancer have shown that the racial difference in survival rate is affected by multiple factors, such as receiving of guideline care, socioeconomic status, medical comorbidities, genetic differences, lifestyle, diet and more. it has been reported that black women are more likely to be diagnosed at advanced stages, less likely to receive guideline care (surgery and chemotherapy), and more likely to have comorbidities (bristow et al., 2013), (long et al., 2015), (howell et al., 2013), (srivastava et al., 2017), (chase et al., 2012). however, after controlling for access to quality care, socioeconomic status, cancer stage and treatment, there was no difference in ovarian cancer survival between black and white women (collins et al., 2014), (terplan et al., 2008). contrary to well-studied racial disparities, there are few studies on regional differences in ovarian cancer that may be considered as a critical moderator to explain the unequal outcomes of the healthcare system. one study reported that ovarian cancer incidence rates were different among the four regions in the united states (northeast, midwest, west and south), showing the lower incidence rate for all races combined in the south than in any of the other 3 regions (hall et al., 2003). another study reported that the areas with the lowest rates of cancer-directed surgery were likely to be in more remote locations, addressing some relevance of the regional disparities to ovarian cancer mortality (fairfield et al., 2010). also, geographic proximity to high volume hospitals and travel distance to receive treatment were significantly associated with adherence to guideline care for advanced-stage ovarian cancer patients (bristow et al., 2014a). bristow, et al, reported the relationship between low ses and more limited access to high volume of healthcare and assumed disparities in ovarian cancer survival associated with race and ses resulted from unequal access to care (bristow et al., 2014a). hodeib and colleagues (hodeib et al., 2015) also found the low ses was a significant and independent predictor of deviation from the nccn guidelines for surgery, chemotherapy, and overall treatment in their study on patients with early-stage ovarian cancer. regional and racial/ethnic disparities in health outcomes are often associated with socioeconomic factors(long et al., 2015), (chase et al., 2012), (collins et al., 2014). black race and low ses were independently associated with an www.companyofscientists.com/index.php/chd e3 cancer health disparities research increased likelihood of treatment non-adherent to guidelines (bristow et al., 2014b) (bristow et al., 2015). the us census bureau reported in its annual population report on income and poverty that the south region continues to have the lowest median income and the highest poverty rate relative to the other regions (chase et al., 2012). considering the disproportionate number of african americans in the south, geographic variations may be resulted from the combined effects of race and region on the outcomes of ovarian cancer that specifically living in the south is associated with greater racial disparity in ovarian cancer incidence and survival. therefore, this study aimed to investigate the association between geographic regions and ovarian cancer disparities in the united states. materials and methods data from the surveillance, epidemiology, and end results (seer) 18 program (2000-2014) was used that covered 28% of the us population. the seer program collects data on patient demographics, primary tumor site, tumor morphology and stage at diagnosis, first course of treatment, and followup for vital status, supported by the national cancer institute. seer 18 registries cover approximately 28% of the newly diagnosed cancer patients in the united states. to compare regional differences, we divided the 18 registries into two groups: south region and us14 region. the registries included in the south region are: louisiana; metropolitan atlanta, georgia; rural georgia; and greater georgia. the registries included in the us14 region are: connecticut; hawaii; iowa; new mexico; utah; california excluding san francisco, san josemonterey, and los angeles; kentucky; new jersey; san francisco-oakland metropolitan statistical area, california; metropolitan detroit, michigan; seattle (puget sound), washington; san josemonterey, california; los angeles, california; and alaska natives. only non-hispanic white (nhw) and non-hispanic black (nhb) women were included in this analysis. ovarian cancer stages were identified according to the 3rd and 6th editions of staging manual of american joint committee on cancer (ajcc) and compared at stages: 0, i, ii, iii, iv, and unstaged. the stages were also combined into three groups: stage 0-ii (non-advanced stage), stage iii-iv (advanced stage), and unstaged. insurance status includes two categories: insured (including any medicaid and insured) and uninsured. ageadjusted incidence rates and mortality rates were calculated by seer*stat. incidence under 25 cases and mortality under 15 cases are suppressed. five-year survival rates were calculated by sas 9.2. chi-square tests were performed when comparing proportions. a logistic regression model was built to evaluate the association between 5-year survival and other variables: age, cancer stage, and health insurance. the sidak adjusted log-rank test was applied to compare multiple survival curves. the cox proportional hazards model was used to estimate hazard ratios. results a total of 43,637 women with ovarian cancer were included in this study. 36,182 were in us14 region and 7,455 were in the south region (table 1). among the women in the us14 region, 33,813 (93.4%) were non-hispanic white (us14-nhw) and 2,369 (6.6 %) were non-hispanic black (us14nhb). in the south region, 5,834 (78.3%) were non-hispanic white (south-nhw) and 1,621 (31.7%) were non-hispanic black (south-nhb) (table 2). average age at diagnosis in the us14 region was 63.4, which was older than 62.5 in the south region (p<0.0001). there was no significant difference between age at diagnosis for both races living in the us14 or the south region (nhw: p=0.15 and nhb: p=0.22). www.companyofscientists.com/index.php/chd e4 cancer health disparities research table 1. patient characteristics by region. characteristics total (n=43,637) region p-value us14 (n=36,182) south (n=7,455) age at diagnosis (%) mean (sd) 63.3 (15.8) 63.4 (15.7) 62.5 (15.9) <0.0001 median (iqr) 64.0 (53,76) 64 (53, 76) 63 (52, 75) ≥ 65 21,034 (48.2) 48.4% 47.0% 0.03 < 65 22,603 (51.8) 51.6% 53.0% cancer stage (%) <0.0001 0 81 (0.2) 68 (0.2) 13 (0.2) i 8,447 (19.6) 7,062 (19.8) 1,385 (18.9) ii 3,001 (7.0) 2,441 (6.8) 560 (7.6) iii 13,008 (30.2) 10,779 (25.3) 2,229 (30.4) iv 11,036 (25.7) 9,028 (25.3) 2,008 (27.4) unstaged 7,445 (17.3) 6,302 (17.7) 1,143 (15.6) grouped cancer stage (%) <0.0001 stage 0-ii 11,529 (26.8) 9,571 (26.8) 1,958 (26.7) stage iii-iv 24,044 (55.9) 19,807 (55.5) 4,237 (57.7) unstaged 7,445 (17.3) 6,302 (17.7) 1,143 (15.6) surgery <0.0001 yes 32,786 (75.7) 27,347 (76.2) 5,439 (73.4) no 10,529 (24.3) 8,558 (23.8) 1,971 (26.6) insurance (%)ⱡ www.companyofscientists.com/index.php/chd e5 cancer health disparities research insured 8,703 (96.6) 7,154 (97.3) 1,549(93.4) uninsured 306 (3.4) 197 (2.7) 109 (6.6) 5-year survival◊ <0.0001 yes 17,331 (39.7) 14,575 (40.3) 2,756 (37.0) no 26,306 (60.3) 21,607 (59.7) 4,699 (63.0) ⱡ only available for cases diagnosed after 2007 table 2. patient characteristics by region and race (2000-2008). characteristics total (n=43,637) white (n=39,647) black (n=3,990) us14 (n=33,813) south (n=5,834) p-value us14 (n=2,369) south (n=1,621) p-value age at diagnosis (%) mean (sd) 63.3 (15.8) 63.6 (15.6) 63.3 (15.2) 0.15 60.2 (16.8) 59.5 (17.6) 0.22 median (iqr) 64.0 (53,76) 64 (53, 76) 64 (54, 75) 61 (49, 73) 60 (49, 73) ≥ 65 21,034 (48.2) 16,521 (48.9) 2,847 (48.8) 0.93 1,006 (42.5) 660 (40.7) 0.27 < 65 22,603 (51.8) 17,292 (51.1) 2,987 (51.2) 1,363 (57.5) 961 (59.3) cancer stage (%) 0.0009 0.01 0 81 (0.2) 65 (0.2) 9 (0.2) 3 (0.1) 4 (0.3) i 8,447 (19.6) 6,648 (19.9) 1,104 (19.2) 414 (17.9) 281 (17.7) ii 3,001 (7.0) 2,298 (6.9) 450 (7.8) 143 (6.2) 110 (6.9) iii 13,008 (30.2) 10,220 (30.6) 1,795 (31.2) 559 (24.2) 434 (27.4) iv 11,036 (25.7) 8,283 (24.8) 1,493 (26.0) 745 (32.3) 515 (32.5) unstaged 7,445 (17.3) 5,856 (17.6) 902 (15.7) 446 (19.3) 241 (15.2) www.companyofscientists.com/index.php/chd e6 cancer health disparities research grouped cancer stage (%) 0.002 0.004 stage 0-ii 11,529 (26.8) 9,011 (27.0) 1,563 (27.2) 560 (24.2) 395 (24.9) stage iii-iv 24,044 (55.9) 18,503 (55.5) 3,288 (57.2) 1,304 (56.5) 949 (59.9) unstaged 7,445 (17.3) 5,856 (17.6) 902 (15.7) 446 (19.3) 241 (15.2) surgery 0.13 0.51 yes 32,786 (75.7) 25,822 (77.0) 4,413 (76.1) 1,525 (64.8) 1,026 (63.8) no 10,529 (24.3) 7,731 (23.0) 1,389 (23.9) 827 (35.2) 528 (36.2) insurance (%)ⱡ <0.0001 0.02 insured 8,703 (96.6) 6,654 (97.6) 1,229 (94.6) 500 (93.6) 320 (89.1) uninsured 306 (3.4) 163 (2.4) 70 (5.4) 34 (6.37) 39 (10.9) 5-year survival◊ 0.0004 0.5 yes 17,331 (39.7) 13,787 (40.8) 2,235 (38.3) 788 (33.3) 521 (32.1) no 26,306 (60.3) 20,026 (59.2) 3,599 (61.7) 1,581 (66.7) 1,100 (67.9) ⱡ only available for cases diagnosed after 2007 www.companyofscientists.com/index.php/chd e7 cancer health disparities research over half of the women in this data (55.9%) were diagnosed with advanced ovarian cancer stage (stage iii and iv). women in the south region were more likely to be diagnosed at an advanced stage (57.7% vs. 55.5%, p<0.0001). this result was consistent within each race (57.2% vs. 55.5% for nhw, p=0.0002; 59.9% vs. 56.5% for nhb, p=0.004). nhw and nhb had different regional differences in cancer stage distributions: south nhw had higher proportion in stage iv compared to us14-nhw (26.0% vs. 24.8%), whereas south nhb had higher proportion in stage iii compared to us14-nhb (27.4% vs. 24.2%). in addition, the south region had lower proportion of unstaged patients (15.7% vs. 17.6 for nhw and 15.2% vs. 19.3% for nhb). overall, there were 75.7% ovarian cancer patients who had any surgery on the primary cancer site. women in the us14 region were more likely to have surgery compared to women in south region (76.2% vs. 73.4%, p<0.0001). there were no significant regional differences comparing the us14 region with the south region within each race, (nhw: 76.1% vs. 77.0%, p=0.13; nhb: 64.8% vs. 63.8%, p=0.51). in seer data, insurance information was only available for patients diagnosed in 2007 and after. among a total of 96.6% women who were insured, women in the south region were less likely to have insurance (93.4% vs. 97.3%, p<0.0001). us14-nhw and us14-nhb had a higher proportion of being insured than south-nhw and south-nhb (97.6% vs. 94.6%, p<0.0001; 93.6% vs. 89.1%, p=0.02, respectively). the overall 5-year survival rate was 39.7% from 2000-2008. the south region had a significantly lower 5-year survival rate than the us14 region (37.0% vs. 40.3%, p<0.0001). the 5year survival rate of south-nhw was significantly lower than that of us14-nhw (38.3% vs. 40.8%, p=0.0004). south-nhb had the lowest 5-year survival rate (32.1%). the south region constantly had lower ageadjusted incidence rates than the us14 region during the study period 2000-2014 (2000: 12.7 vs. 15.4, per 100,000; 2014: 10.6 vs. 11.7, per 100,000) (figure 1). white women (us14-nhw and southnhw) had higher incidence rates than black women (us14-nhb and south-nhb) (figure 2). while nhw in us14 had higher incidence rates than nhw in south, nhb in us14 region and nhb in the south region had similar incidence rates except for years after 2010, when nhb in the us14 started to have higher incidence rates than nhb in the south region. figure 1. incidence rate comparison between us14 and south region. figure 2. incidence rate comparison between us14 and south region by race. regional differences in mortality rates were observed in years 2000 to 2004 and years 2010 to 2014, when the us14 region had higher mortality rates than the south region (figure 3). nhw 0 2 4 6 8 10 12 14 16 18 2000 2002 2004 2006 2008 2010 2012 2014 in ci d e n ce ( p e r 10 0 ,0 0 0 ) us14 south 0 2 4 6 8 10 12 14 16 18 2000 2002 2004 2006 2008 2010 2012 2014 in ci d e n ce ( p e r 10 0 ,0 0 0 ) us14-nhw us14-nhb south-nhw south-nhb www.companyofscientists.com/index.php/chd e8 cancer health disparities research women had higher mortality rates than nhb women over all years (figure 4). figure 3. mortality rate comparison between us14 and south region. figure 4. mortality rate comparison between us14 and south region by race. the us14 region had higher 5-year survival than the south region (figure 5). compared with the us14 region, 5-year survival rates in the south region were very unsteady. nhw women had higher 5-year observed survival rates than nhb women (figure 6). a logistic regression model showed that after controlling for surgery, women in the south region were still 1.4 times more likely to die 5-years after diagnosis (95% ci: 1.2-1.6). controlling for age, race, cancer stage and insurance, women in the south region were 1.2 times less likely to receive surgery (95% ci: 1.031.4). figure 5. five-year survival rate comparison between us14 and south region. figure 6. five-year survival rate comparison between us14 and south region by race. women in the south region had significantly shorter survival times than women in the us14 region (figure 7). nhw in the us14 region had significantly longer survival time compared to nhw in the south region, nhb in the us14 region, and nhb in south region (p<0.0001 for all three comparisons, figure 8). after adjusting for surgery, compared with the us14 region, the hazard ratio of death for the south region was 2.6 times higher for age group 20-34 (95% ci: 1.4-4.9), 1.5 times higher for age group 45-54 (95% ci: 1.2-1.8), 1.4 times higher for age group 75-84 (95% ci: 1.2-1.6), and 1.3 times higher for women older than 84 years old (95% ci: 1.1-1.7) (table 3). 0 2 4 6 8 10 2000 2002 2004 2006 2008 2010 2012 2014 m o rt a lit y (p e r 10 0 ,0 0 0 ) us14 south 0 2 4 6 8 10 2000 2002 2004 2006 2008 2010 2012 2014 m o rt a lit y (p e r 10 0 ,0 0 0 ) us14-nhw us14-nhb south-nhw south-nhb 32% 34% 36% 38% 40% 42% 44% 2000 2001 2002 2003 2004 2005 2006 2007 2008 5 -y e a r su rv iv a l r a te us14 south 0% 5% 10% 15% 20% 25% 30% 35% 40% 45% 2000 2001 2002 2003 2004 2005 2006 2007 2008 5 -y e a r su rv iv a l r a te us14-nhw us14-nhb south-nhw south-nhb www.companyofscientists.com/index.php/chd e9 cancer health disparities research figure 7. overall survival comparison between us14 and south region. figure 8. overall survival comparison between us14 and south region by race. table 3. hazard ratio of death comparing the south region to the us14 region for patients who had surgery. hr 95% ci age ≤ 20 2.076 (0.106, 40.485) 20-34 2.567* (1.351, 4.879) 35-44 1.304 (0.945, 1.789) 45-54 1.472* (1.223, 1.771) 55-64 1.048 (0.908, 1.208) 65-74 1.054 (0.911, 1.220) 75-84 1.363* (1.162, 1.599) ≥ 84 1.341* (1.052, 1.709) * p<0.05 discussion the racial disparities among women with ovarian cancer in the united states are well-known. however, not much research has been done on the regional differences of this lethal disease. one study published in 2003 confirmed that the ovarian cancer incidence rate varied among the four regions in the united states: northeast, midwest, west and south (hall et al., 2003). they found that black women in the south region had the second lowest incidence rates (10 per 100,000), compared with 9.7 for the black women in the west region. their comparisons were limited to incidence rates only. results from this study confirmed that regional differences existed in incidence rates, with the south region having the lower incidence rate (12.0 vs. 13.4, per 100,000 2000-2014) compared to the us14 region (data not shown). additionally, regional variation in 5-year survival (37.5% vs. 39.8%, 2000-2014) and overall survival (figure 5) was identified. the association between survival and age at diagnosis, race, region, cancer stage, surgery and health insurance was further analyzed. the results indicated that women with ovarian cancer in the south region had significantly poorer survival compared to the us14 region. especially, among white women, those who live in the south region had worse survival outcome. black women were known to have lower incidence rates, lower mortality rates, and lower survival than white women (howell et al., 2013; srivastava et al., 2017); (moorman et al., 2009); (kim et al., 2010); (chan et al., 2008); (terplan, 2012);(park et al., 2017; stewart et al., 2017). ross and colleagues reported a survival disadvantage was still observed in black women with ovarian cancer in the deep south after controlling for clinical and environmental factors (ross et al., 2017). rationale behind these racial disparities is acknowledged to be multifaceted and intertwined. black women tend to be diagnosed at advanced 0.2 0.4 0.6 0.8 1.0 0 12 24 36 48 60 72 84 96 survival time, months s u rv iv a l p ro b a b il it y south us14 0.2 0.4 0.6 0.8 1.0 0 12 24 36 48 60 72 84 96 survival time, months s u rv iv a l p ro b a b ili ty south-nhb south-nhw us14-nhb us14-nhw www.companyofscientists.com/index.php/chd e10 cancer health disparities research cancer stages, and were less likely to receive standard treatment, including surgery and chemotherapy, according to the guideline (barber et al., 2017; bristow et al., 2013; howell et al., 2013; kim et al., 2010; terplan et al., 2012). disparities in ovarian cancer treatment and survival persisted, resulting in black women, even among women with equal access to care, experiencing poorer survival (bandera et al., 2016). therefore, the higher proportion of black population in the south region (21.7% in the south, 6.5% in the us14 region) may partially contribute to the regional differences in incidence and mortality rates, and survival. however, region was identified as an independent predictor of ovarian cancer survival, too. for example, after accounting for race, age, cancer stage, insurance and surgery, women in the south region were still 1.4 times more likely to die 5-years after diagnosis. also women in the south region were 1.2 times less likely to receive surgery. socioeconomic status (ses) is also important factor which affects health outcomes. according to the 2014 report of income and poverty in the united states from the us department of commerce, the south region (including georgia and louisiana) had the lowest income and highest poverty rate among the regions in the united states (northeast, midwest, west and south). studies have shown that lower ses status is associated with lower insurance participating rates, limited access to high volume hospitals, and poorer survival in ovarian cancer (brewer et al., 2015; bristow et al., 2015). we identified the south region had lower insurance participating rate and lower surgery rate, compared to the us14 region, which are consistent with these findings resulting in worse survival. as another factor that may contribute to these regional disparities, regional differences in numbers and distributions of high volume hospitals and surgeons need to be considered. for example, density of oncology hospitals could affect chemotherapy use (polsky et al., 2006). further study is needed to identify possible reasons for unsteady 5-year survival rates in the south region, especially what factors contribute to increasing 5-survival rates in this region. this may help identify possible solutions to decrease regional disparities in ovarian cancer in the united states. this study has some limitations related to data used for analysis. the seer research data did not provide the information on insurance and ses, thus the analysis in this study was limited and could not be done to analyze the impact of insurance status in detail and the association between ses status and other variables. acknowledgements this article was partially supported by the national cancer institute (p30 ca013148, 2u54 ca118948), national institute on minority health and health disparities (u54md008176) the contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the funding agency, nih. conflict of interest statement the author has declared that no competing or conflict of interests exist. the funders had no role in study design, writing of the manuscript and decision to publish. authors’ contributions conceptualization: sd ab mf wh sb. formal analysis: zw sb. methodology: zw ab sb. supervision: ab sb. writing ± original draft: zw sd ab hp. writing ± review & editing: zw sd ab hp mf wh sb. www.companyofscientists.com/index.php/chd e11 cancer health disparities research references 1. acs (2014). cancer facts & figures 2014 (atlanta: american cancer society). 2. bandera, e.v., lee, v.s., rodriguez-rodriguez, l., powell, c.b., and kushi, l.h. (2016). racial/ethnic disparities in ovarian cancer treatment and surviva. clin cancer res 22, 5909-5914. 3. barber, e.l., dusetzina, s.b., stitzenberg, k.b., rossi, e.c., gehrig, p.a., boggess, j.f., and garrett, j.m. (2017). variation in neoadjuvant chemotherapy utilization for epithelial ovarian cancer at high volume hospitals in the united states and associated survival. gynecologic oncology 145, 500-507. 4. brewer, k.c., peterson, c.e., davis, f.g., hoskins, k., pauls, h., and joslin, c.e. (2015). the influence of neighborhood socioeconomic status and race on survival from ovarian cancer: a population-based analysis of cook county, illinois. annals of epidemiology 25, 556-563. 5. bristow, r.e., chang, j., ziogas, a., anton-culver, h., and vieira, v.m. (2014a). spatial analysis of adherence to treatment guidelines for advanced-stage ovarian cancer and the impact of race and socioeconomic status. gynecologic oncology 134, 60-67. 6. bristow, r.e., chang, j., ziogas, a., campos, b., chavez, l.r., and anton-culver, h. (2015). sociodemographic disparities in advanced ovarian cancer survival and adherence to treatment guidelines. obstetrics and gynecology 125, 833-842. 7. bristow, r.e., chang, j., ziogas, a., randall, l.m., and anton-culver, h. (2014b). high-volume ovarian cancer care: survival impact and disparities in access for advanced-stage disease. gynecol oncol 132, 403-410. 8. bristow, r.e., powell, m.a., al-hammadi, n., chen, l., miller, j.p., roland, p.y., mutch, d.g., and cliby, w.a. (2013). disparities in ovarian cancer care quality and survival according to race and socioeconomic status. journal of the national cancer institute 105, 823-832. 9. cdc. ovarian cancer trends (centers for disease control and prevention). 10. chan, j.k., zhang, m., hu, j.m., shin, j.y., osann, k., and kapp, d.s. (2008). racial disparities in surgical treatment and survival of epithelial ovarian cancer in united states. journal of surgical oncology 97, 103-107. 11. chase, d.m., fedewa, s., chou, t.s., chen, a., ward, e., and brewster, w.r. (2012). disparities in the allocation of treatment in advanced ovarian cancer: are there certain patient characteristics associated with nonstandard therapy? obstetrics and gynecology 119, 68-77. 12. collins, y., holcomb, k., chapman-davis, e., khabele, d., and farley, j.h. (2014). gynecologic cancer disparities: a report from the health disparities taskforce of the society of gynecologic oncology. gynecologic oncology 133. 13. fairfield, k.m., lucas, f.l., earle, c.c., small, l., trimble, e.l., and warren, j.l. (2010). regional variation in cancerdirected surgery and mortality among women with epithelial ovarian cancer in the medicare population. cancer 116, 4840-4848. 14. hall, h.i., tung, k.h., hotes, j., and logan, p. (2003). regional variations in ovarian cancer incidence in the united states, 1992-1997. cancer 97, 2701-2706. 15. hodeib, m., chang, j., liu, f., ziogas, a., dilley, s., randall, l.m., anton-culver, h., and bristow, r.e. (2015). socioeconomic status as a predictor of adherence to treatment guidelines for early-stage ovarian cancer. gynecol oncol 138, 121-127. 16. howell, e.a., egorova, n., hayes, m.p., wisnivesky, j., franco, r., and bickell, n. (2013). racial disparities in the treatment of advanced epithelial ovarian cancer. obstetrics and gynecology 122, 1025-1032. 17. kim, s., dolecek, t.a., and davis, f.g. (2010). racial differences in stage at diagnosis and survival from epithelial ovarian cancer: a fundamental cause of disease approach. social science & medicine 71, 274-281. 18. long, b., chang, j., ziogas, a., tewari, k.s., anton-culver, h., and bristow, r.e. (2015). impact of race, socioeconomic status, and the health care system on the treatment of advanced-stage ovarian cancer in california. american journal of obstetrics and gynecology 212, e461469. 19. moorman, p.g., palmieri, r.t., akushevich, l., berchuck, a., and schildkraut, j.m. (2009). ovarian cancer risk factors in african american and white women. american journal of epidemiology 170, 598-606. 20. ocrfa. statistics (ovarian cancer research fund alliance). 21. park, h.k., ruterbusch, j.j., and cote, m.l. (2017). recent trends in ovarian cancer incidence and relative survival in the united states by race/ethnicity and histologic subtypes. cancer epidemiol biomarkers prev 26. 22. polsky, d., armstrong, k.a., randall, t.c., ross, r.n., evenshoshan, o., rosenbaum, p.r., and silber, j.h. (2006). variation in chemotherapy utilization in ovarian cancer: the relative contribution of geography. health services research 41, 2201-2218. 23. ross, j., braswell, k.v., madeira da silva, l., mujica, f., stutsman, s., finan, m.a., nicolson, w., harmon, m.d., missanelli, m., cohen, a., et al. (2017). unraveling the etiology of ovarian cancer racial disparity in the deep south: is it nature or nurture? . gynecol oncol 145, 329333. 24. srivastava, s.k., ahmad, a., miree, o., patel, g.k., singh, s., rocconi, r.p., and singh, a.p. (2017). racial health disparities in ovarian cancer: not just black and white. journal of ovarian research 10, 58. 25. stewart, s.l., harewood, r., matz, m., rim, s.h., sabatino, s.a., ward, k.c., and weir, h. (2017). disparities in ovarian www.companyofscientists.com/index.php/chd e12 cancer health disparities research cancer survival in the united states (2001-2009): findings from the concord-2 study. cancer 123, 5138-5159. 26. terplan, m., schluterman, n., mcnamara, e.j., tracy, j.k., and temkin, s.m. (2012). have racial disparities in ovarian cancer increased over time? an analysis of seer data. gynecologic oncology 125, 19-24. 27. terplan, m., temkin, s., tergas, a., and lengyel, e. (2008). does equal treatment yield equal outcomes? the impact of race on survival in epithelial ovarian cancer. gynecologic oncology 111, 173-178.           www.companyofscientists.com/index.php/chd e1 cancer health disparities  research androgen metabolism genes in prostate cancer health disparities wei liu1,2, runhua liu2,3, lizhong wang2,3* 1provincial key laboratory on molecular and chemical genetic, the second hospital of jilin university, changchun 130041, pr china 2department of genetics, university of alabama at birmingham, birmingham, al 35294 3comprehensive cancer center, university of alabama at birmingham, birmingham, al 35294 *corresponding author e-mail: lwang12@uab.edu abstract for men in the united states, prostate cancer is common, and newly diagnosed cases of prostate cancer outnumber those of all other cancer types. for prostate cancer, there are racial disparities between caucasian americans and african americans. androgens and androgen metabolism may be involved in these disparities as well as in the initiation and progression of prostate cancer. here, we analyzed, in the cancer genome atlas (tcga) database, the mrna expression of genes involved in androgen metabolism in prostate cancer based on the patient’s race. the results revealed that expressions of ugt2b15 and cyp3a5 are higher but that srd5a2, cyp17a1, hsd3b2, and akr1c3 are lower in african american prostate cancers than in those of caucasian americans. these genes may relate to the racial disparities associated with prostate cancer. however, the evidence require validation and functional analysis. keywords: prostate cancer; racial disparity; androgen; metabolism; gene expression citation: liu w. liu r, wang l (2017). androgen metabolism genes in prostate cancer health disparities cancer health disparities;1:e1-e6. doi:10.9777/rr.2017.10003           www.companyofscientists.com/index.php/chd e2 cancer health disparities  research introduction according to the latest statistics provided by the american cancer society (acs), there are 161,360 incident cases newly diagnosed with prostate cancer, accounting for 19% of all new cancer cases in 2017 and, for males, leading all other cancers (siegel et al., 2017). the incidence varies with race. the rate for african american (aa) men is 198.4/100,000, higher than 114.8/100,000 for caucasian american (ca) men. although the racial disparities in prostate cancer are related to lifestyle, dietary, socioeconomic, and clinical factors, genetic factors are also substantial (chang et al., 2014; cooper and page, 2014; plata bello and concepcion masip, 2014; schaid, 2004; singh et al., 2017). for most prostate cancers, which are generally androgen-sensitive, androgen withdrawal can produce initial regressions (cooper and page, 2014). lower levels of intraprostatic androgens are associated with a lower incidence of prostate cancer (cooper and page, 2014). androgen deprivation therapy, a common treatment, can block progression of metastatic prostate cancer (welsh and hentz, 2017; yang et al., 2017; young et al., 2017). further, differences in androgen metabolism may relate to the racial disparities in this disease (singh et al., 2017). thus, for prostate cancer, androgen metabolism may be involved in racial disparities as well as in tumor imitation and progression. for ca and aa men in the united states, there are differences in androgen levels. serum testosterone levels of aa men (aged 31 to 50) are about 15% higher than those of ca men (ellis and nyborg, 1992; singh et al., 2017). in prostate tissues of aa men, androgens, androstenedione, and sex hormone-binding globulin levels are greater than those in tissues of ca men (singh et al., 2017). likewise, for aa men, expression of the androgen receptor (ar) protein is 22% higher in benign prostate tissue and 81% higher in prostate cancer tissue relative to ca men (gaston et al., 2003). these differences may contribute to racial disparities for prostate cancer. other factors, such as age, body mass index, prostate specific antigen, and pathologic gleason grade, may be involved in these disparities (plata bello and concepcion masip, 2014; schaid, 2004). however, whether genes involved in androgen metabolism are primary factors for these racial disparities is not known. therefore, with the cancer genome atlas (tcga) database, we conducted an expression analysis of genes involved in androgen metabolism in prostate cancer based on the patient’s race. from the findings, we have presented a potential mechanism underlying androgen metabolism in racial disparities for prostate cancer. results and discussion we analyzed the mrna expression of 20 genes involved in androgen metabolism, including akr1c2, akr1c3, cyp3a4, cyp3a5, cyp7b1, cyp11a1, cyp17a1, cyp19a1, hsd3b1, hsd3b2, hsd17b3, hsd17b6, hsd17b10, rdh5, rdh16, srd5a1, srd5a2, srd5a3, ugt2b7, and ugt2b15, by use of a web-portal ualcan tool (chandrashekar et al., 2017) for analyses of tcga gene expression data in 52 normal prostate tissues, 147 ca prostate cancer tissues, and 6 aa prostate cancer tissues. for aa tissues, there were significantly higher expressions of 5 genes, including hsd3b2 (cancer/normal fold change = 1.11; p = 4.31x10-2), hsd17b3 (fold change = 3.22; p = 1.11x10-16), hsd17b10 (fold change = 1.27; p = 1.79x10-12), srd5a1 (fold change = 1.27; p = 4.02x10-5), and srd5a3 (fold change = 1.14; p = 2.58x10-3), but significantly lower expressions of 9 genes, including akr1c2 (fold change = 0.32; p = 9.42x10-3), cyp3a5 (fold change = 0.14; p = 1.32x10-3), cyp11a1 (fold change = 0.21; p = 3.85x10-8), cyp19a1 (fold change = 0.27; p = 4.32x10-2), cyp7b1 (fold change = 0.52; p = 2.20x10-4), hsd17b6 (fold change = 0.59; p = 6.56x10-4), rdh5 (fold change = 0.50; p = 5.76x105), srd5a2 (fold change = 0.23; p = 5.73x10-10), and ugt2b7 (fold change = 0.00; p = 1.83x10-2). of note, expressions of akr1c3, cyp3a5, cyp17a1,           www.companyofscientists.com/index.php/chd e3 cancer health disparities  research hsd3b2, srd5a2, and ugt2b15 showed significant differences in prostate cancer tissues between ca men and aa men (figure 1). expressions of cyp3a5 (fold change = 1.38; p = 4.32x10-2) and ugt2b15 (fold change = 1.87; p = 4.32x10-2) in aa prostate cancers were higher than those for ca prostate cancers, but expressions of akr1c3 (fold change = 0.58; p = 4.32x10-2), cyp17a1 (fold change = 0.50; p = 4.32x10-2), hsd3b2 (fold change = 0.77; p = 4.32x10-2), and srd5a2 (fold change = 0.71; p = 4.32x10-2) were lower in aa prostate cancers than in ca prostate cancers (figure 1). figure 1. mrna expression of genes involved in androgen metabolism in normal prostate tissues and prostate cancers based on the race of patients as determined with the tcga database. ca, caucasian american; aa, african american. akr1c3 is associated with a reduction of androstenedione and lower (mostaghel and nelson, 2008) production of testosterone and dihydrotestosterone (dht) (yepuru et al., 2013). higher expression of akr1c3 enhances survival of prostate cancer cells and formation of endothelial cell tubes, and is positively correlated with a higher gleason score (dozmorov et al., 2010). however, there were lower expressions of akr1c3 in aa prostate cancers than in ca prostate cancers, which suggests a contradictory function of akr1c3 in racial disparities between aa and ca men. cyp3a5, which is involved in hydroxylation of testosterone and dehydroepiandrosterone (zeigler-johnson et al., 2013), enhances growth of prostate cancer cells through facilitating the nuclear translocation of ar (mitra and goodman, 2015). the higher expression cyp3a5 in aa men may be associated with higher ar levels and a higher risk of prostate cancer (singh et al., 2017). as shown here, there were higher expression levels           www.companyofscientists.com/index.php/chd e4 cancer health disparities  research of cyp3a5 in aa prostate cancers compared with ca prostate cancers, supporting the previous observation and hypothesis. in the gonads and adrenals, cyp17a1 is involved in various pathways of androgen biosynthesis (bremmer et al., 2014). although greater expression of cyp17a1 appears to correlate with higher stages and shorter relapse-free times in prostate cancer (bremmer et al., 2014; gomez et al., 2015; salvi et al., 2016), expression of the cyp17a1 gene was lower in primary prostate cancers than in normal prostate tissue and was lower in aa prostate cancers than in ca prostate cancers. although, for aa men, a dysfunction of cyp17a1 may affect the susceptibility to prostate cancer, the present data do not support the concept that cyp17a1 is a regulator for racial disparities between aa men and ca men. hsd3b2 is involved in catalyzing androstendione and dht metabolites (simard et al., 1996). higher expression of hsd3b2 accelerates the degradation of dht metabolites and leads to lower dht levels (simard et al., 1996). however, the relationship between high dht levels and prostate cancer risk is controversial. for ca men and aa men, there are no significant differences in dht levels in sera and tissues (singh et al., 2017). the present data also showed higher expression of hsd3b2 in aa prostate cancers compared with ca prostate cancers, results that are inconsistent with racial disparities between aa and ca men. srd5a2 is responsible for the conversion of testosterone into dht (fang et al., 2017). genetic analyses suggest that there are srd5a2 ta repeat alleles in aa men at high risk for prostate cancer but not in ca men (singh et al., 2017), indicating that genetic variants of srd5a2 may be associated with racial disparities. variants of the enzyme may enhance the activity and result in higher levels of dht, leading to cancer progression. however, higher expression of srd5a2 appears to be inconsistent with higher levels of dht (singh et al., 2017). the present data showed that expression of srd5a2 was lower in aa prostate cancers compared with those of cas, which does not support a role of srd5a2 in the racial disparities between aa men and ca men. in the androgen biosynthesis pathway, ugt2b15 is a regulator for androstenedione glucuronidate (gauthier-landry et al., 2015). high androstenedione levels may require more glucuronosyltransferases encoded by ugt2b15 (singh et al., 2017). of note, there are higher androstenedione levels in normal prostate tissues and greater expression of ugt2b15 in aa prostate cancers than in those of cas (singh et al., 2017). as shown here, there was higher expression of ugt2b15 in aa prostate cancers compared with ca prostate cancers, supporting a function of ugt2b15 in racial disparities of prostate cancers. since prostate cancer is a pathophysiologic disease involving a variety of genetic factors (chang et al., 2014; cooper and page, 2014), the change of a single gene may be insufficient to produce racial disparities. further, the functions of genes in racial disparities in prostate cancer are associated with mrna and protein expression. moreover, the aa cohort of prostate cancers in this tcga database includes only six cases, which limits the statistical power to detect significant differences in our analysis. therefore, a larger sample cohort is needed to establish the relationship between the genes and racial disparities in prostate cancer. in summary, in the united states, the incidences of prostate cancer are different for ca and aa men. genes, such as cyp3a5 and ugt2b15, which are involved in androgen metabolism, appear to be associated with racial disparities between aa and ca prostate cancers. due to a limitation of sample size, however, the results need to be validated in further studies. acknowledgements we thank dr. donald l. hill for editorial assistance in preparing this manuscript. this work was supported by the national institutes of health/national cancer institute (ca179282 and           www.companyofscientists.com/index.php/chd e5 cancer health disparities  research ca118948) and the department of defense (pc130594 and pc140308). conflict of interest statement the author has declared that no competing or conflict of interests exist. the funders had no role in study design, writing of the manuscript and decision to publish. authors’ contributions wl performed the analyses. rl and lw wrote the manuscript. references bremmer, f., jarry, h., strauss, a., behnes, c.l., trojan, l., and thelen, p. 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(2013). relationship of early-onset baldness to prostate cancer in african-american men. cancer epidemiol biomarkers prev 22, 589596. www.companyofscientists.com/index.php/chd e1 cancer health disparities research indigenous writing retreats: native american community members and scholars in action! rodney c. haring1,2, iehnhotonkwas bonnie jane maracle 5, priscilla r. sanderson1,3, whitney ann e. henry2, donna grandbois1,4, erik brodt1, pete hill6 hampton faculty fellow, spirit of eagles, mayo clinic comprehensive cancer center, rochester,mn1, roswell park comprehensive cancer center, cancer prevention and population sciences, office of cancer health disparities research 2, northern arizona university, college of health and human services, health sciences department1, 3, north dakota state university, college of health professionals, department of public health4 kanatsiohareke mohawk community5, native american community services, inc. 6 * corresponding author email: rodney.haring@roswellpark.org abstract writing retreats provide time away from distractions to write manuscripts, grant applications, books, or dissertations. a unique characteristic of writing retreats is that they form a “community of scholars,” which is culturally congruent with indigenous intellectuals, who are familiar with community as an essential way of life. this perspective piece presents experiences from a national cohort of indigenous scholars (n=6) and viewpoints from a series of indigenous writing retreats (n=22). feedback from aggregated writing retreats endorses the feasibility, growth, and advocacy of future writing retreats and study. shared outlooks included protected writing times, which produced increased productivity, mentorship, traditional advisement, blended with core values related to a community-based participatory research framework. keywords: writing retreat, indigenous, american indians, native american, haudenosaunee, education, minority, community based participatory research, cbpr, public health citation: haring rc et al (2018) indigenous writing retreats. cancer health disparities 2:e1-e10. doi:10.9777/chd.2018.10008. mailto:rodney.haring@roswellpark.org www.companyofscientists.com/index.php/chd e2 cancer health disparities research introduction writing retreats are becoming an integral part of academic literature. retreats often provide a period away from distractions and are dedicated to writing papers, manuscripts, grant applications, books, or putting the finishing touches on a project (rosser, rugg, & ross, 2001; cable, boyer, colbert, & boyer, 2013). this dedication includes investigators writing research proposals that cycle from one project to another quickly, making it challenging to find productive time to produce manuscripts (rosser, rugg, & ross, 2001). one unique characteristic of writing retreats is the composition of diverse learners, their educational backgrounds, creativity, and community members’ participation. writing retreats often include on-site mentorship and writing tutors, who play a critical role in providing the on-demand guidance and support needed to finish projects (jackson, 2009; cable, boyer, colbert, & boyer, 2013). community is essential to american indian culture and a way of life for many american indian, first nations, or native american peoples, who will be noted in this article as indigenous. therefore, creating a community within a writing retreat is a significant aspect of planning these gatherings. the notion of a “community of scholars” (spears, 2004 in jackson, 2009) creates an ideal atmosphere for indigenous scholars, bringing together traditional and scientific means to complete projects. further, organized indigenousspecific writing retreats are a relatively new phenomenon in academia and are increasingly becoming a much-needed element in indigenous landscapes. with the growing number of indigenous people throughout north america pursuing higher levels of education (national center for educational statistics (2016). retrieved from http://nces.ed.gov/pubs2008/nativetrends/ ind_6_1.asp) and being involved in proposaland report-writing, developing business plans, writing books and articles, it has become more and more important that time and an appropriate place be prepared purposely so that writing tasks can be worked on without unwarranted distraction. because indigenous people are hereditarily communal beings, it stands to reason that they would instinctively be empowered to complete their tasks when working together in a modern shared working-living environment (haring, hudson, erickson, taualii, & freeman, 2014). the indigenous-based retreat becomes a cooperative venture in writing, regardless of the required product itself. an inspired production process is a result of the writing members in a short-term community having the opportunity to share ideas and concerns about their present tasks, listen to each other’s stories of struggles and good fortune regarding their work and, most importantly, gain advice from others’ experiences in navigating and completing similar writing tasks. indigenous writing retreats are also a means to socialize, interact, and learn with communities during down times. modeling is parallel to what is perceived as social learning theory. social learning theory shares that individuals acquire beliefs from role models, close friends, social environmental situations, and their parents (bandura, as cited in petraitis, flay, & miller, 1995). in relation to cultural sharing, social learning theory would predict that experience with cultural peers, families, environmental situations, parents, and extended family members may shape a person’s or child’s reason for learning his or her patterns, beliefs, and attitudes about tradition, ways of life, and resiliency factors. in indigenous http://nces.ed.gov/pubs2008/nativetrends/ind_6_1.asp http://nces.ed.gov/pubs2008/nativetrends/ind_6_1.asp www.companyofscientists.com/index.php/chd e3 cancer health disparities research contexts, haring et al. (2016) used social learning theory in a workplace obesity prevention intervention in native workforces, where it was noted to be successful. previous work has also been accomplished using social learning and modeling with indigenous populations in clinical frameworks (lafromboise & & rowe, 1983). further, modeling and community togetherness towards a productive and meaningful goal is also the premise for community-based participatory research, or cbpr. the cbpr process in the context of this paper involves sharing of culture, identity, and social interaction towards the social growth and interconnectedness of individual, family, and community involvement (hicks et al., 2012). perspectives and process concepts shared include the experiences of an indigenous cohort of scholars who attended an indigenous-based writing retreat in the aboriginal landscapes of the seneca nation of indians (niagara falls, ny). the second set of concepts shared includes perspectives from indigenous writing retreat attendees who participated in a writing retreat in the aboriginal landscape of the mohawk indian nation (fonda, ny). both areas are part of the haudenosaunee, also known as the iroquois, a confederacy of federally recognized native nations. there were originally five nations, later six (when the tuscarora were included), which form the haudenosaunee also known as the iroquois confederacy. the mohawks are the easternmost, living in upstate new york’s mohawk valley region, and the senecas reside in the western new york region (snow, gehring, & starna, 1996). a methods section is not included as this is a perspective piece based on points of view collected in an evaluative context for feedback. this included responses from multiple cohort retreat attendees (n=22) in combination with multiple scholars’ (n=6) reflections. scholars were indigenous writers from across the u.s., while others participants were mainly tribal members from the haudenosaunee. participants included three faculty fellow cohorts, for a total of 10 scholars, who had a proven dedication to improving the quality of life of indigenous peoples (seven were tribal members). participants, as fellows and scholars, were part of the mayo clinic’s spirit of eagles program, hampton faculty fellowship (kaur, dignan, burhasstipanov, baukol, & claus, 2006). the spirit of eagles is a nationally funded native american/alaska native-focused community networks program center consisting of research initiatives in research projects, community outreach, and training (retrieved from http://www.nativeamericanprograms.org/indexspirit.html on october 7, 2016). this unique fellowship was named in honor of the first indigenous medical oncologist, james hampton, m.d. these fellows were qualified health disparity researchers, dispersed across the country in varied academic and clinical practices, with experience in community-based participatory research and cancer prevention and control. twenty-two others were participants in multiple cohorts of indigenous writing retreats held in mohawk country. setting. (mayo clinic, hampton faculty fellows) the mayo clinic, spirit of eagles, hampton faculty fellows and staff members attended a social evening with indigenous community members in the aboriginal areas of the haudenosaunee. the http://www.nativeamericanprograms.org/index-spirit.html http://www.nativeamericanprograms.org/index-spirit.html www.companyofscientists.com/index.php/chd e4 cancer health disparities research spirit of eagles, housed within the mayo clinic in rochester, mn, supported the travel of the hampton faculty fellows and staff members. the participants were also welcomed by the oldest comprehensive cancer center in the u.s., roswell park comprehensive cancer center, which hosted the fellows for a campus visit (www.roswellpark.org, retrieved on october 7, 2016). the retreat was hosted in various venues, which included a hotel with writing space and small conference rooms, an indigenous urban center (http://www.nacswny.org/ retrieved on october 7, 2016) and a cancer institute with an academic setting. (kanatsiohareke) the setting for the mohawk retreat at kanatsiohareke (ga na jo ha lay gay) was a small rural community in the homelands of the mohawk nation along the northern shore of the mohawk river in the mohawk valley of upper new york state. the community provides workshops on traditional teachings, mohawk language and culture, spiritual understanding, and local historical sightseeing. food preservation, basket-making, drum-making, leather-work, and other such traditional artisan workshops, and information sessions are also held regularly by indigenous presenters who are experts in their fields. as an educational component to kanatsiohareke’s programming, along with the traditional talks, a language camp and cultural celebrations, the community began hosting a week-long writing retreat for indigenous authors in december 2009. this became the first of four successful retreats hosted by kanatsiohareke. each season, the agenda changed based on program evaluation suggestions from previous years. a typical week may include breakfast, a discussion of the days’ writing plans, writing time/quiet time, 1:1 writing coach time, if requested; lunch, more 1:1 writing coach times, meeting with a spiritual liaison or academic counselor, if requested; writing/quiet time, and meeting to discuss the day’s accomplishments via a round table, dinner, and either a cultural activity or a field trip in the region. description of the intervention. the intervention goals of the writing retreats were to provide: 1. a quiet, cultural environment to work on writing requirements; 2. a space for indigenous scholars to meet and exchange information on their research and writings; 3. time for the attendees to speak with academic and spiritual advisors (spiritual advisors were available at the kanatsiohareke retreat only); and 4. the opportunity for attendees to gain answers to questions and words of encouragement regarding their research, writing and personal goals. both events were planned to give writers in various areas and from an array of academic institutions an opportunity to gather together to share their research and ideas. participants at kanatsiohareke were able to spend time with traditional advisors, who shared cultural teachings and provided insight on working in indigenous communities and with indigenous people. in subsequent retreats, an opportunity was given to meet one-on-one with both an indigenous ph.d. advisor and a traditional spiritual advisor. the academic advisor was available to lend information on his/her experiences going through academic writing tasks and to offer tips on successful completion of the required work for institutions of higher learning. the traditional advisor at kanatsiohareke was available to share cultural teachings with the writers and provide a sense of purpose and cultural connection in their research and writing. individual advice was also available on maintaining personal health and wellness in what could be a http://www.roswellpark.org/ www.companyofscientists.com/index.php/chd e5 cancer health disparities research stressful time in completing their required work. for the indigenous scholars and writers who were brought together for a week, the vision gained from that experience of living and working in the ancestral homelands of the haudenosaunee provided greater inspiration and meaning to their work and thoughts. outlooks perspectives from both of the indigenous-based writing retreats were encouraging. a majority of on-site mentors at both retreats were indigenous and held professional graduate degrees (i.e., ph.d.). they also had a strong foundation in indigenous community knowledge, culture, history, and tradition. during the time frame discussed in this paper, 28 writers attended retreats either through the mayo clinic’s hampton faculty fellowship (n=6) or over a three-year period at kanatsiohareke’s indigenous writing retreats (n=22). the goals of the retreats were to develop, continue, or revise with new knowledge peerreviewed articles, book chapters, grant applications, poetry, or non-fiction and fiction pieces. protected writing times. overall findings indicated that writing retreats in the indigenous landscape continued and grew, not only in these two venues, but among other indigenous nations, urban centers, and academic institutions. the results indicated that writing retreats were beneficial for those needing the time for uninterrupted writing. this corresponded with previous findings showing that writing retreat participants found the location away from their normal work place with no distractions a successful component of the writing retreat. that uninterrupted time was something many experienced for the first time (cable, boyer, colbert, & boyer, 2013). providing for productive work. the writing retreats evolved as a space for indigenous scholars, proposal writers, report writers, and authors. the retreats further developed as direct results of input and planning of ideas, concerns, and feedback. both events provided an environment in which writing tasks were tackled and completed, academic suggestions and spiritual support were gained from noted indigenous advisors, and networking with indigenous peers became a lasting benefit. core values of haudenosaunee communities. the hampton faculty fellows shared views, perceptions, and experiential reactions from invited guests to observe a haudenosaunee social gathering. the observations of these fellows were unique because it gave them an opportunity to see tribal cultures from a different perspective in a community different from their own. it provided an additional opportunity to see public health in action through the eyes of these observers (outsiders), which resulted in the creation of a set of perceived core values from haudenosaunee communities that shaped public health. we defined “community” as the interactions, activities, and relational experience among the people at the social ceremony, who shared a core value of culture. we distinguished community not as the specific people present, but as the core values of culture being expressed by those present at the social gathering. culture in indigenous perspectives goes back to the beginning of time; for example, many indigenous cultures, including the haudenosaunee, pray for seven generations in the past and seven generations in the future for www.companyofscientists.com/index.php/chd e6 cancer health disparities research health and wellbeing. indigenous peoples are always mindful of the seventh generations because every action and decision that is made will affect the seventh generation ahead. this mindset of looking for ways to benefit future generations coincides not only with academia but also with health research (haring et al., 2016). the opening “thanksgiving address” was given at the beginning of the community event that the hampton faculty fellows attended at native american community services in buffalo, ny. the following were core values that emerged from participants who had experiences among the haudenosaunee communities that translated into cultural wellbeing, which, in turn, influenced good writing health and promotion. 1. throughout the evening social event, the attendees observed kinship and friendships strengthen with a common goal of community gathering; an oasis away from “home,” reserves or indian country. this included a display of love from mothers, grandmothers, or a member of the community to babies, who were lovingly carried throughout the social dances. the babies heard and felt the water drum, horn-rattles, and the stick dance throughout the evening. this aspect of the social event deepened relationships and formed life-time friendships among everyone from babies to elders. 2. a hampton faculty fellow served as a cultural broker and organized the event with local leaders. the definition of the process of cultural-brokering is a person or group of people who provide a means to network, connect, meet, and interact with communities and cultures. traditionally speaking, indigenous peoples are group-oriented, with a sense of cooperation (johnson et al., 2010). this happens in a majority of indigenous communities across indian country. finally, with only three days’ notice, the event was disseminated online to the indigenous urban population and neighboring tribes, i.e., email messages, facebook, and listserv. the community gathering had nearly 100 intertribal people present at the evening social event. 3. if there was a feeling of being displaced from moving/visiting from “home,” reserves or indian country, that feeling dissipated during the social event. instead, a proud display of inter-tribal togetherness emerged. the indigenous culture is in place in all settings within the haudenosaunee -urban or reservation based. it is not in the past but in the present moment of happiness. before each social dance, introductions were given, explaining the dance and its meaning. 4. throughout the evening, wisdom-holders (keepers) openly taught young men, women and children. they embraced their cherished moments of mentorship and responsibilities by carrying forward openings, songs, and cultural practices. for instance, youths (3 or 4 years of age) joined the singers in the center and picked up a drumstick and began singing. a mother grabbed her young son’s hand to invite him to dance with her; he unwillingly went. however, moments later, his little sneakers stepped up and down to the beat as a huge smile on his face beamed from ear to ear. 5. we observed that dancing and aerobic exercise reduced pain in older members. the community dancers’ physical tension was released through dancing and they became more flexible with each foot pounding the www.companyofscientists.com/index.php/chd e7 cancer health disparities research floor up and down with increased natural rhythm. elders were also helped by younger members of the audience to move about the event. those who did not dance visited, joked and laughed, with their knees and feet moving up and down to the rhythm of the songs. these learned songs come from generations past up to the present day. 6. the meal at the gathering focused on traditional haudenosaunee food ways; heirloom varieties of corn, beans, and squash continue to be grown and harvested by members of the community. heirloom varieties of corn have been passed down in the community since time immemorial. encounters with the haudenosaunee and other tribes in the northeast date back to the 1600s, when there was interest in the ways in which the indigenous peoples ground corn and the changes that were made as they were introduced to non-indigenous people and their tools (beauchamp, 1898). by using traditional foods in ceremonies, a direct connection is made to ancestral consciousness, i.e., the traditional foods being consumed are directly descended from the plants historically used by the community. the nutritional content of the traditional corn is different from almost any contemporary sweet corns. there are different varieties of traditional corn, which should not be mistaken for the sweet yellow corn that is usually eaten, especially during the summer months. there is white corn, red corn (similar to white corn; different in color), flint corn, and black corn (harrington, 1908). some traditional corns contain anthocyanins, which reduce inflammation, cholesterol, and blood pressure, and lower the risk of obesity, diabetes and heart disease (robinson, 2013). 7. the hampton faculty fellows observed the modeling of generational behavior of social acceptance. the youth at the event followed and watched the ways their elders’ interacted with each other, including leadership roles, communication-styles, and dancing. the traditional modeling of accepted social behaviors, as observed in one event by the hampton faculty fellows, was a life-long learning experience for the youth. 8. an example of inclusion and respect by all members of the community was an enormous hand-embroidered blanket made by the community elders. the blanket was breathtaking, with different squares embellished with figures of a man and woman in matching regalia, representing the balance of masculine and feminine pairing. it was laid out on a frame in the middle of the floor for all to see and admire. one of the elders spoke about the various projects to raise funds for the indigenous urban center. for example, the blanket was being raffled, with the proceeds going to the community as a donation from the elders. 9. the tribal language being spoken was an important aspect of each event that the hampton faculty fellows visited. before the dances, a welcome and instructions were given in the tribal language, as well as the acknowledgement of meals served as sustenance for community people. the openings and closings for each event were given to thank the creator for providing nutritious traditional meals and to gain strength. 10. for indigenous societies, traditional tribal songs are sung and revered. it is no different for the haudenosaunee. the haudenosaunee www.companyofscientists.com/index.php/chd e8 cancer health disparities research songs were foreign to the hampton faculty fellows from other tribal affiliations such as the dine’, the turtle mountain band of chippewa indians, and chippewa/anishinaabe. during an open forum and in side conversations with elders, the place, importance and meaning of these traditional songs were shared. 11. the principles of peace, strength, and what is known as the good mind represent the core values of haudenosaunee culture. in mohawk, the principles of skennen (peace), kariwiio (good word) and kasastensera (strength) serve as a foundation and guiding force. in mohawk and other haudenosaunee tribal philosophies, the people should strive for peace as individuals, communities and nations. peace, in essence, is more than just the absence of conflict or war, but is based on social development and healthy foundations. it also includes the ability to enact principles such as education. further, it is a means of spiritual consciousness in which societies can frame their skills and resiliencies towards productive reason. in summary, when communities work towards peace, a good mind is developed. this occurs when people put their minds together with good intentions. when these values are followed, strength is developed that moves the community forward in healthy, productive and resilient ways (retrieved on october 21, 2015 from http://www.ipcb.org/ resources/archived/akw_protocol.html). discussion an adjustment in timing and hosting procedures was considered at one of the writing retreats. at kanatsiohareke, each registrant was provided with separate accommodations, writing space, and meals. the community house made arrangements to have a cook prepare breakfast, lunch and supper daily for the participants so they could concentrate on only having to do their writing. costs for the event, which mainly included cooking services, food expense, honoraria for advisors, accommodations, utilities, maintenance, and local travel, were shared, with donations or small grants received for the event and a minimal registration fee charged to each participant. in the beginning, december was thought to be a good time of the year at kanatsiohareke to invite indigenous writers to work on getting some tasks completed during an otherwise hectic month. the four indigenous ph.d. students who registered for the first writing retreat were from different institutions. unfortunately, due to stormy weather at the time, one of the registrants was unable to make it to the session. the feedback from this event, however, entailed strong recommendations to host the event again but perhaps during warmer, less hazardous weather. the next writing retreat was therefore planned as an august event. the 10 registrants for this retreat had varied backgrounds as graduate students, writers preparing articles and reports, and others doing some personal journaling. there was an expressed appreciation for the community’s quiet peaceful environment and the healthy meals that were provided. it was suggested, however, that the event be held earlier than august as most participants needed the time in mid-august to prepare for a return to their studies or teaching positions. there was also a concern expressed through the evaluations that participation in the event be open only to those who were indigenous people in order to maintain a more focused http://www.ipcb.org/resources/archived/akw_protocol.html http://www.ipcb.org/resources/archived/akw_protocol.html http://www.ipcb.org/resources/archived/akw_protocol.html. www.companyofscientists.com/index.php/chd e9 cancer health disparities research atmosphere of peer exchange and support for their writing goals. another suggestion was to have the group meet daily to discuss their day’s accomplishments and share any concerns with their writing. with these recommendations in mind, the planning of the subsequent writing retreats saw a time-change for the event from august to july, and registration geared towards indigenous writers and scholars. the july event went forward with nine participants and a repeat of the retreat format, with daily provisions of meals, time to speak personally with both the ph.d. and traditional advisors, writing time, and social networking time. the attending indigenous ph.d. and traditional advisors were changed, but a gender balance continued for the meeting comfort of the participants. time was slotted into this july daily schedule for a sharing circle in the late afternoon before dinner. the evenings remained a time for socializing, traditional talks and games, and storytelling. feedback from this july group was positive and again participants were very thankful for the opportunity, time and space provided at kanatsiohareke to accomplish writing tasks for their academic requirements, job tasks, and personal goals. a suggestion that came from the evaluations was to add to the schedule an opportunity for those who want to take a break to tour local historical sights while they are in the mohawk homelands. conclusion this article provides an overview of observations from the hampton faculty fellows’ experiences in the haudenosaunee region as well as the accomplishments of the kanatsiohareke community nestled in the aboriginal landscape of mohawk country. the hampton fellows’ experience as well as that of the indigenous writers at kanatsiohareke has affirmed the heterogeneity of indigenous nations in the u.s. and canada. both academic and community projects provided a positive experience for the hampton faculty fellows and other indigenous writers. the next steps include sharing and disseminating the foundational pieces of creating and building success stories of indigenous-based writing retreats with more indigenous nations, academic institutions, and authors from various disciplines. indigenous writing retreats can prove beneficial to indigenous graduate students and writers if organized in other parts of the country, where the opportunity for uninterrupted writing could take place. the continued support of indigenous scholars and writers will in turn provide benefits in the long-run to many indigenous communities at large and perhaps other minority communities. the writing retreat as an event and over the course of time has proven to be a welcomed success not only for indigenous scholars, but also for an increasing number of indigenous professionals and writers from various programs and communities. writing retreats not only have the ability to shape writing projects but they also provide a means to place these movements into public health action across indigenous nations for the betterment of the country’s first inhabitants. acknowledgements perspectives shared in this publication were supported by the national institutes of health, national cancer institute (nci) under award number u54 ca153605. the paper development also used shared resources supported by roswell park comprehensive cancer center’s cancer www.companyofscientists.com/index.php/chd e10 cancer health disparities research center support grant from the nci (p30ca016056). the content is solely the responsibility of the authors and does not necessarily represent the official views of the national institutes of health. we also send much gratitude to sakokwenionkwas (tom porter) and the kanatsiohareke mohawk community, 4934 state hwy #5 fonda, ny 12068, (518) 673-4197, www.mohawkcommunity.com, native american community services, inc., marcy averill from the mayo clinic, and paula jones from roswell park comprehensive cancer center for editorial assistance. conflict of interest the authors declare that no competing or conflict of interests exists. the funders had no role in writing of the manuscript or 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(1996). in mohawk country: early narratives about native people. syracuse, ny: syracuse university press. http://www.mohawkcommunity.com/ http://dx.doi.org/10.4300/jgme-d-12-00159.1 www.companyofscientists.com/index.php/chd e1 cancer health disparities research looking at cancer health disparities without the colored lenses mohammad aslam khan1, girijesh kumar patel1, sanjeev kumar srivastava1,2, james elliot carter3, jennifer young pierce4, rodney paul rocconi4, seema singh1,5, ajay pratap singh1,5* 1department of oncologic sciences, mitchell cancer institute, university of south alabama, mobile, al 36604, usa; 2division of cell biology and genetics, tatva biosciences, coastal innovation hub, 600 clinic drive, mobile, al, 36688, usa; 3department of pathology, college of medicine, university of south alabama, mobile, al 36617, usa; 4division of gynecologic oncology, mitchell cancer institute, university of south alabama, mobile, al, 36604, usa; 5department of biochemistry and molecular biology, college of medicine, university of south alabama, mobile, al 36688, usa *corresponding author-mail: asingh@health.southalabama.edu abstract cancer health disparities (chds), defined as the adverse differences in cancer incidence and mortality, are prevalent in certain racial and ethnic groups. underlying causes of chds are multi-factorial and debatable. while low socioeconomic status, geographical location, lifestyle and behavioral factors are mostly believed to contribute to chds, regardless of ethnic and racial background, significant data now also exist to support a genetic basis of such disparities as well. clearly, chds could best be understood by studying the interplay of multiple (genetic and non-genetic) factors and then translating the resulting knowledge into effective approaches for reducing the existing disparity gaps. this review article highlights these aspects in brief and calls the people of different expertise to work together to make an impact and tackle the challenges associated with chds. keywords: cancer, health disparities, socioeconomic status, genetics, epigenetics, ancestry citation: khan m.a, et al (2019) looking at cancer health disparities without the colored lenses. cancer health disparities 3:e1-e9. doi:10.9777/chd.2019.1004. www.companyofscientists.com/index.php/chd e2 cancer health disparities research introduction cancer is the second most leading cause of deaths in the unites states (us). american cancer society estimates that 1,735,350 new cancer cases will be reported and 609,640 lives will be taken by this devastating disease in 2018 (siegel et al., 2018). as a result, besides being cause of pain and despair to the affected individuals and their families, cancer also remains a huge economic burden to the society. national cancer institute (nci) reported that the total expenditures for the cancer care in the us was about $125 billion in 2010, and it could reach up to $156 billion by 2020 (https://www.cancer.gov/aboutcancer/understanding/statistics). moreover, federal agencies spend significant amount of money on cancer research to develop a better understanding of tumor biology at the molecular level and to find novel ways for its prevention and therapy. several private foundations also provide funding support at the local and national levels for ground-breaking cancer research. consequently, we have witnessed some decline in cancer-associated mortality since early 1990s for several tumor types; however, not every section of the society has benefitted equally (desantis et al., 2016; deshmukh et al., 2017). cancer health disparities (chds) are the most evident among certain racial and ethnic minorities living in america. national cancer act of 1971 founded surveillance, epidemiology, and end results (seer) database within the national cancer institute (nci) to track the progress in cancer care outcomes and to better analyze chds. nci-seer collects and maintains race and ethnicity information for all cancer types, which is helpful in analyzing the incidence, mortality and survival in different racial and ethnic groups such as african-american/black, european-american/white, asian/pacific islander, american indian/alaska natives, and hispanic/latino (polite et al., 2017)). the seer data suggest that the people of some racial minorities are disproportionately affected by cancer in terms of incidence, mortality and co-morbidities associated with cancer. considering these evidence, nci and other funding agencies are investing in chds research to tackle them at various levels. underlying causes of cancer health disparities chds are multi-factorial. it is believed that various complex and interrelated factors are involved in disparate cancer incidence and clinical outcomes. these include differences in socioeconomic status (ses), geographical location, genetic predisposition, race, ethnicity, gender/sex identity, language barrier, food habits, cultural acuities, and access to health care system (polite et al., 2017; raghavan, 2007; winkleby et al., 1992). socioeconomic factors: there is no doubt that ses determinants influence cancer risk globally and there is evidence to suggest that cancer mortality rates are declining at relatively slow rates in low ses individual/families as compared to those with higher ses (ward et al., 2004). residential segregation is an important ses factor associated with health disparities, and it is more prevalent among african americans in the us as compared to other minorities (o'keefe et al., 2015). for example, lung cancer mortality rate is very high in african american patients living in segregated neighborhoods (hayanga et al., 2013). the residential segregation limits the access to better healthcare, recreational facilities and clean environment, which may all serve as risk factors for cancer development and/or enhanced mortality (moore et al., 2008; o'keefe et al., 2015; williams, 1999). several racial and ethnic minorities in the us live close to the industrial areas www.companyofscientists.com/index.php/chd e3 cancer health disparities research or work in the agriculture fields wherein they expose themselves to pollutants, insecticides and pesticides, which potentially put them at a greater risk for developing cancer. study suggests that hispanics have high cumulative cancer risks (ccrs) due to their high exposure to hazardous air pollutants (haps) such as chloroform and benzene as compared to white people (hun et al., 2009). the linkage of ses with chds is not limited to the people living in the united states. in fact, australian women living in the remote or rural areas were also reported to have high rates of breast cancer death as compared to the residents of metropolitan cities (yu et al., 2015). similarly there is evidence for the high rates of advanced stage breast cancer in australian and pakistani women living in deprived regions (aziz et al., 2008; baade et al., 2011). low ses groups, maori and pacific island of new zealand, are also reported to have greater cancer incidence and mortality as compared to european populations (jeffreys et al., 2005). geographical factors: cancer incidence and mortality rates vary among geographical locations. for example, the incidence of leukemia is greater in australia and new zealand, but reported least in western africa (miranda-filho et al., 2018). similarly, mortality related to cervical cancer is three times higher in the caribbean and latin america as compared to north america (melan et al., 2017). however, incidence and mortality related to this malignancy is less in many developed countries. even within the united states, we see disparate incidence in cancer types and their clinical outcomes depending upon the geographical locations, which could be related to their exposure to certain pollutants and environmental conditions (mahal et al., 2014; miller et al., 2014; zonderman et al., 2014). ground water near superfund sites is highly contaminated in florida and people living near those geographical locations have higher chances of developing cancer (kirpich and leary, 2017). similarly, the incidence of lung, brain and bladder cancer is higher in areas with increased content of copper, arsenic and cadmium present in soil, respectively (lopez-abente et al., 2018). people living in louisiana and mississippi have high cadmium exposure and study have shown the correlation between high cadmium exposure and increased risk of pancreatic cancer (luckett et al., 2012). drinking water is significantly contaminated with arsenic in new hampshire and wisconsin regions and retrospective studies suggested the link between arsenic exposure and skin cancer (mayer and goldman, 2016). life style and other behavioral factors: it is observed that the highest incidence of gastric cancer is in the eastern asian and south american countries. helicobacter pylori infection is shown to put people at six fold higher risk of developing gastric cancer (giesecke, 1993). an earlier study suggested a close association of diet and h. pylori infection in gastric cancer. consumption of high salt and fermented foods is also associated with h. pylori infection (rocco and nardone, 2007). this suggests that life style factors and food habits could be responsible for existing disparities in gastric cancer (luo et al., 2017). high rates of hepatitis b and c infection and aflatoxin exposure through diet lead to higher incidence of hepatocellular cancer in the region of sub-sahara africa and china. hepatitis b and c virus infection are associated with chronic liver disease, and these viral infections are more prevalent in many low income countries due to lack of knowledge about the route of transmission, awareness and some tribal rituals (coppola et al., 2015). in the us, hepatitis, which is more common in latino and asian immigrants, is an established risk factor for hepatocellular cancer development (jemal et al., 2010). prostate, breast and pancreatic malignancies are linked with obesity and www.companyofscientists.com/index.php/chd e4 cancer health disparities research are more common in north america, australia/new zealand, and europe as compared to the developing countries. in fact, looking at the yearly trends, we notice that the incidence rates of breast and prostate cancer have started to increase in people of asia and africa continents, which could be due to changes in their life style, diet and reproductive behaviorassociated factors in addition to increases in the reporting and awareness (wallace et al., 2011). gender and sexual orientation: high numbers of non-sex specific cancer cases and cancer-associated deaths have been reported in males as compared to females (dorak and karpuzoglu, 2012; najari et al., 2013). certain types of malignancies like brain cancer (meningioma), thyroid cancer and bladder cancer are more common in women as compared to men and this could be due to the differences in sex hormones and prevalence of autoimmune disorders and gallbladder stone-induced chronic inflammation among them (dorak and karpuzoglu, 2012). in the us, sexual and gender minorities (sgm) have greater chance of developing cancer as compared to heterosexual people. a recent study suggests that people from sexual minorities avoid social gatherings, living in isolated places and more likely to be poor than heterosexual (mccabe et al., 2018). approximately 30% of sgm do not take advantage of preventative healthcare services due to the lack of insurance or undercoverage for related mental health, gender affirmation surgery, hormone therapy, and coverage to partners (quinn et al., 2015). in fact, a majority of sgm members do not disclose their sexual orientation due to the fear of discrimination and social stigma (brown and mcelroy, 2018). collectively, all these factors contribute to the increasing cancer incidence in sgm relative to heterosexuals. moreover in the us, many healthrelated surveillance registries do not have sexual orientation and gender identity (sogi) questions, which may lead to ignorance of many health comorbidities including cancer in sgm people (brown and mcelroy, 2018; obedin-maliver, 2017). genetics and epigenetic factors: gene mutations, deletion, amplification, and polymorphism in key growth homeostasis genes are considered the underlying causes of cancer etiology, progression and poor clinical outcomes. although socioeconomic, life style and other factors were long believed to be the major determinants of chds, emerging data now also clearly suggest that there could be a genetic and/or epigenetic basis as well (deshmukh et al., 2017). high frequencies of triple negative breast cancer and intra-tumor genetic heterogeneity are tied with aggressive variant of disease in african american women (keenan et al., 2015). deregulation of immune system due to polymorphisms in il-6 and ifn-γ gene has also been reported in african american women (park and kang, 2013). increased serum levels of proinflammatory cytokines, il-6 and resistin, have also been associated with breast cancer disparity (deshmukh et al., 2015). in another study, difference in the haplotype, pten/10q, is associated with disparate incidence and outcome of endometrial cancer in african american and caucasian american women (sutton et al., 2015). prostate cancer burden is quite high in african american people and several mutations and polymorphism in genes associated with androgen biosynthesis, metabolism and androgen receptor signaling has been reported in this group (bhardwaj et al., 2017). another study identified locus 8q24 as a risk factor for prostate cancer in african american men (freedman et al., 2006; wallace et al., 2011). mutations and amplification of phosphatidylinositol 3-kinase catalytic subunit alpha (pi3kca) gene has been reported in cervical cancer. pi3kca mutations and amplification rate found to be higher in american www.companyofscientists.com/index.php/chd e5 cancer health disparities research indian population (femi, 2018). higher rate of alterations in mitochondrial genes of african lineage is also linked with cancer predisposition and disparities (choudhury and singh, 2017). apart from genetic factors, epigenetic determinants are also suggested to be involved in chds. high hypermethylated cpg islands are associated with cell signaling, survival, cellular communication and cell death, in normal breast tissues of african american women as compared to their caucasian counterparts. promoters of many genes tied with epithelial-to-mesenchymal transition (emt) and cell cycle are found to be hypermethylated in african american breast cancer patients (ahmad et al., 2017). differential methylation pattern of cd44 gene may also be involved in the prostate cancer pathogenesis in african american cancer patients (woodson et al., 2003). considering these data, it has become imperative that we pay attention how we categories patients into different racial groups. currently, people living in the united states are categorized into different racial and ethnic groups primarily based on their selfreporting. this could be problematic considering the fact that inter-racial marriages are common and more so in modern times leading to the genetic admixtures rather than defined racial/ethnic identities. indeed, genetic analyses have suggested that some of the self-reported african americans have up to 99% of european ancestry(mersha and abebe, 2015). in the us, hispanics are highly diverse population and study suggest that self-reported hispanic individual could be more close to being of african, european, or native american lineage due to population admixtures (lee et al., 2010). to overcome these artifacts, we should rely on genetic ancestry profiling by using advanced molecular techniques such as single nucleotide polymorphisms (snps) and short tandem repeat (str) typing. in addition, haploid markers like y-snps and mitochondrial dna can also be used for determination of paternal and maternal lineage (egeland et al., 2004; phillips et al., 2007). some of our recent studies took advantage of modern genomic technologies to classify patients based on their racial genetic admixtures and noticed that categorization of patients based on their racial genetic admixtures provided more accurate determination of clinical outcomes (rocconi et al., 2016; ross et al., 2017). emerging outlook years of money and manpower investment in cancer research has resulted in effective screening approaches and therapies for several cancers leading to considerable improvements in patient’s survival. although not all sections of the society have benefitted equally, we have succeeded in recognizing such health inequalities and have developed an improved understanding of underlying causes. we have learnt that differences in ses, life style, and geographical location impact cancer incidence and mortality rates regardless of race and ethnic identities. moreover, gender-based inequalities are also common that could in part be associated with life style factors, but may also have a biological basis as well. in addition, many new findings have also suggested certain races and ethnic groups experience greater incidence and mortality of cancer even when ses and other factors are accounted for. in support of such observations, several genetic and epigenetic differences in people belonging to these minority groups have also been reported. therefore, while the skin color and ethnicity may not be the primary determinant of chds, there is strong evidence to suggest a genetic basis as well. in fact, the emerging notion now is that it is the interplay of multiple (genetic and non www.companyofscientists.com/index.php/chd e6 cancer health disparities research genetic) factors that underlies the prevalent chds (figure 1). therefore, finding these connections at the molecular levels and translating the resulting knowledge into effective approaches for prevention and clinical management are of utmost importance to reduce existing disparity gaps. in addition, currently, the race and ethnicity classification is based on self-reporting, which could be socio-political or cultural rather than being based on genetics and biology of the individual (rebbeck and sankar, 2005; wallace et al., 2011). therefore, it is important to include genetic screening in categorizing race and ethnicity of the participant groups to avoid any artifacts. it is also the need of the hour that people of different expertise (public health professional, physical scientists, biologists, social scientist, epidemiologists, and community members) work together to make an impact. more research funding opportunities emphasizing minority health disparities, commitment of research centers and hospitals and improvisation of research policies will also be helpful in addressing the challenges associated with chds. figure 1: schematic diagram showing cross-talk between biological and non-biological factors involved in cancer health disparities (chds). acknowledgements www.companyofscientists.com/index.php/chd e7 cancer health disparities research the authors acknowledge the funding support from nih/nci ca17577204 (to aps) and ca204801 (to ss) and usamci. conflict of interest aps and ss are co-founders and serve on executive management team of tatva biosciences, llc, which is involved in the development of tools and models for cancer health disparity research. sks is the director of cell biology and genetics at tatva biosciences llc. authors’ contributions conception and design: mak, gkp, sks, ss and aps. writing, review, and revision of the manuscript: mak, gkp, sks, jec, jyp, rpr ss and aps. references ahmad, a., azim, s., zubair, h., khan, m. a., singh, s., carter, j. e., rocconi, r. p., and singh, a. p. 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(2014). the influence of health disparities on targeting cancer prevention efforts. am j prev med 46, s87-97. www.companyofscientists.com/index.php/chd e1 cancer health disparities research commercial tobacco exposure in first nations, inuit and métis in ontario: results from population-based health surveys and implications for cancer control caroline cawley*1, maegan v. mazereeuw1, sehar jamal1, amanda j. sheppard1,2, loraine d. marrett1,2 1aboriginal cancer control unit, cancer care ontario, toronto, canada 2dalla lana school of public health, university of toronto, toronto, canada *corresponding author email: caroline.cawley@cancercare.on.ca abstract the lack of comprehensive health data is a significant barrier to better understanding and reducing the risk of chronic diseases among first nations, inuit and métis people in ontario. this study estimates commercial tobacco exposure (cigarette smoking and second-hand smoke) in first nations (onand off-reserve), inuit and métis in comparison to non-aboriginal ontarians using three health surveys. we measured age-standardized prevalence using the first nations regional health survey phase 2 (for first nations on-reserve), canadian community health survey (for first nations off-reserve, métis and non-aboriginal ontarians) and the aboriginal peoples survey (for inuit). a higher proportion of first nation men, women and adolescents onand off-reserve smoked compared to their non-aboriginal counterparts. métis adults and adolescents were more likely to smoke than non-aboriginal adults and adolescents. métis adolescents were more likely to be regularly exposed to second-hand smoke than non-aboriginal adolescents, both at home and in public places. inuit adults had a higher prevalence of current smoking and a higher prevalence of regular second-hand smoke exposure at home. the high prevalence of cigarette smoking and second-hand smoke exposure suggests that first nations, inuit and métis people may experience a greater future burden of cancer and other chronic diseases related to smoking. differences in survey questions and methodology, and the lack of ethnic identifiers in most canadian health databases limit our understanding of cancer burden and other health outcomes in these populations. knowledge-sharing and relationship building between first nations, inuit and métis organizations, researchers and data custodians are essential to ensure appropriate data governance, meet health needs and further cancer control activities, including prevention. keywords: commercial tobacco exposure; population health survey; cancer control; ontario tobacco exposure and cancer citation: cawley c, mazereeuw mv, jamal s, sheppard aj, marrett ld (2018) commercial tobacco exposure in first nations, inuit and métis in ontario: results from population-based health surveys and implications for cancer control. cancer health disparities 2:e1-e12. doi:10.9777/chd.2018.10002 www.companyofscientists.com/index.php/chd e2 cancer health disparities research introduction first nations, inuit and métis are the three indigenous peoples of canada.(government of canada, 1982) there are more indigenous people living in ontario than any other province or territory in the country, numbering 374,395 people, or about 3 percent of the provincial population (statistics canada, 2017). first nations, inuit and métis are not a cultural group, but rather distinct, peoples whose existing aboriginal and treaty rights were recognized and affirmed by the constitution (government of canada, 1982). the arrival of europeans and resulting policies of assimilation, such as the residential school system and the current indian act (applying specifically to first nations), continue to extensively impact first nations, inuit and métis peoples’ ways of life and all aspects of their health. first nations represent the largest of the three groups named in canada’s constitution act of 1982. there are approximately 236,680 first nations in ontario, of whom 94,312 live on-reserve or on crown lands (indigenous and northern affairs canada, 2014. http://www.aadncaandc.gc.ca/eng/1429798605785/1429798785836# tbc1303). the genesis of the métis culture and nation dates back to the 1600s, when european settlers first came into contact with local indigenous communities. early unions between these predominantly male fur trading european settlers and local first nations women led to the emergence of a new and highly distinctive aboriginal people with a unique identity. ontario has the largest métis population in canada, with 120,585 people, or 20.5 percent of all métis (statistics canada, 2017). the word inuit means “the people” in the most commonly used inuit language of inuktitut (indigenous and northern affairs canada). inuit are culturally similar indigenous peoples who have lived throughout the arctic for thousands of years (public history inc., 2008). inuit in ontario constitute a small but fast-growing population. about 65,025 people in canada (3,860 in ontario) identified as being inuit. over one-quarter (27 percent) of self-identifying inuit in canada live in southern canada, outside of inuit nunangat (the inuit homeland made up of four regions stretching across much of the canadian arctic) (statistics canada, 2017). table 1. first nations, métis and inuit populations in ontario (2016 census). first nations métis inuit population total 236,680 120,585 3,860 male 112,835 (48%) 59,015 (49%) 1,830 (47%) female 123,845 (52%) 61,570 (51%) 2,025 (53%) age 0-14 61,590 (26%) 23,775 (20%) 1,165 (30%) 15-24 41,410 (18%) 19,250 (16%) 695 (18%) 25-34 32,800 (14%) 16,490 (14%) 600 (16%) 35-44 29,365 (12%) 15,765 (13%) 410 (11%) 45-54 31,375 (13%) 18,030 (15%) 495 (13%) 55-64 23,825 (10%) 15,905 (13%) 310 (8%) 65+ 16,320 (7%) 11,365 (9%) 180 (5%) source: statistics canada (2017). 2016 census of population, statistics canada catalogue no. 98-400-x2016155. www.companyofscientists.com/index.php/chd e3 cancer health disparities research studying the prevalence of behavioural risk factors for cancer using routine, population-based health surveys where respondents are asked about their indigenous (referred to as ‘aboriginal’ by statistics canada) identity offers a timely approach to determining how and where prevention resources can be most effectively directed to reduce the future burden of disease. using commercial tobacco products (in particular, smoking cigarettes) is known to account for more cases of cancer than any other known risk factor western populations (u.s. department of health and human services, 2004). in ontario, about 15 percent of all new cancer cases (and 71 percent of lung cancer cases specifically) are attributable to cigarette smoking (cancer care ontario, 2014). to many first nations and métis peoples, tobacco is a plant that has cultural, ceremonial and/or spiritual significance. for example, it is commonly held in the left hand during prayer or ceremony, and is often given to elders and traditional knowledge keepers as a sign of respect (chiefs of ontario and cancer care ontario, 2016). tobacco holds no traditional significance to inuit, and was first introduced in arctic communities by european traders. the use of commercial tobacco (e.g., smoking cigarettes or cigars, chewing tobacco or snuff) has no connection to the historical or traditional uses of tobacco among first nations and métis (tobacco has no place here). in ontario, tobacco policy is legislated by the provincial government. the smoke free ontario act regulates where cigarettes cannot be smoked (e.g., schools, hospitals, restaurants) or sold, and enforces a minimum age of 19 for such purchases (government of ontario, 2017). under federal legislation, first nations people living on reserves (land held by the crown for the “use and benefit of [first nations] (government of canada, 1982)) are exempt from provincial laws, and create and enforce their own tobacco policies within their jurisdictions. individual first nations councils can pass by-laws to regulate smoking in their communities. the objectives of this study were to (a) develop indicators of commercial tobacco exposure as a risk factor for cancer for first nations (living on and off-reserve), inuit and métis people in ontario using data available from three population-based health surveys; and (b) compare the prevalence estimates for first nations, inuit and métis with those of the non-aboriginal population in ontario. materials and methods data sources the canadian community health survey (cchs) is a population-based survey of the canadian population aged 12 years and over living in all provinces and territories, excluding individuals living on first nations reserves and crown lands, institutional residents, full-time members of the canadian forces and residents of some remote regions (statistics canada, 2007-2013). respondents are asked whether they are an aboriginal person, and if so whether they are first nations, inuit or métis. non-aboriginal ontarians were defined as respondents to the cchs who did not self-identify as aboriginal or who identified as aboriginal but were born outside of canada, the u.s., germany or greenland (in survey years prior to 2011).1 the regional health survey (rhs) is the only first nations-governed national health survey that collects health-related information about first nations people living on-reserve aged 12 years and over (first nations information governance centre, 2013). the rhs phase 2 was a single survey completed between the spring of 2008 and the fall of 2010 in 24 of the 133 first nations communities (reserves) in ontario. the rhs includes an adult survey for respondents aged 18 1 as of 2011, the cchs restricted the question about aboriginal identity to those born in canada, the united states, germany or greenland. to be consistent, we classified respondents in 2007 to 2010 as nonaboriginal if they identified as aboriginal and reported being born outside one of these four countries. www.companyofscientists.com/index.php/chd e4 cancer health disparities research and older and a youth survey for those aged 12 to 17. data for inuit living in ontario were obtained from the 2012 edition of the aboriginal peoples survey (aps). the aps, administered by statistics canada, is a national survey of first nations (off-reserve), métis and inuit aged six years and over and its sample is drawn from individuals who reported aboriginal identity on the 2011 national household survey (statistics canada, 2016). the aps includes fewer health-related variables than the cchs, but the cchs has poorer coverage of the inuit, particularly in southern canada. even after combining multiple survey cycles, the number of inuit respondents captured by the cchs was too small to report estimates with certainty. first nations data for first nations people living on reserve were obtained from the ontario portion of phase 2 (2008/10) of the rhs. on-reserve first nations people were defined as respondents to the rhs who were on the band/membership list of one of the 24 communities selected for participation in the rhs phase 2 (chiefs of ontario, 2012). data for first nations people living off-reserve and nonaboriginal ontarians were obtained from the ontario portion of the cchs administered by statistics canada. seven annual waves of the cchs (2007–2013) were combined due to the consistency of the aboriginal identity questions used during this time period. off-reserve first nations people were defined as respondents to the cchs who self-identified as either first nations only or as both first nations and inuit and were born in canada, the united states, germany or greenland.2 2 as of 2011, the cchs restricted the question about aboriginal identity to those born in canada, the united states, germany or greenland. to be consistent, we classified respondents in 2007 to 2010 as nonaboriginal if they identified as aboriginal and reported being born outside one of these four countries. the prevalence of current smoking in first nations adults living onand off-reserve, and nonaboriginal adults in ontario, was defined as the proportion of respondents aged 20 years and older who reported smoking cigarettes daily or occasionally. the cchs and rhs had equivalent questions and response options on the subject of cigarette smoking. the prevalence of second-hand smoke exposure in first nations adults and adolescents and non-aboriginal adults and adolescents was defined as the proportion of nonsmokers who reported being exposed to secondhand smoke in their home, in a vehicle or in a public place every day or almost every day. the prevalence of second-hand smoke exposure among first nations people living on-reserve could not be estimated, as relevant questions were not included in the rhs. métis data for métis people living in ontario and nonaboriginal ontarians were obtained from the ontario portion of the cchs cycles 2007–2014. métis people were defined as respondents to the cchs who were born in canada, the u.s., germany or greenland, and self-identified as métis only or as métis in combination with any other aboriginal identity (i.e., first nation or inuit). the prevalence of current smoking in métis adults and non-aboriginal adults was defined as the proportion of adults aged 20 years and older who report smoking cigarettes daily or occasionally. the prevalence of second-hand smoke exposure in métis adults and adolescents and nonaboriginal adults and adolescents was defined as the proportion of non-smokers who reported being exposed to second-hand smoke in their home, in a vehicle or in a public place every day or almost every day. inuit inuit living in ontario were defined as respondents of the aps who identified as inuit and reported residing in ontario at the time of the 2011 national www.companyofscientists.com/index.php/chd e5 cancer health disparities research household survey. due to small numbers of inuit respondents to the aps in ontario, inuit living in southern canada more broadly (outside of the traditional inuit homeland of inuit nunangat (inuit tapiriit kanatami, 2008)) were used as a proxy for inuit living in ontario for some indicators. the aps includes a variable that indicates whether a respondent lives in one of the four constituent regions of inuit nunangat (nunatsiavut in labrador, nunavik in northern quebec, the territory of nunavut, or inuvialuit in the northwest territories) or outside of inuit nunangat. a study of cancer risk factors among inuit demonstrated that prevalence estimates for inuit in ontario are largely similar to those of inuit living outside nunangat, across indicators of cancer risk (tungasuvvingat inuit and cancer care ontario, 2017). the prevalence of current smoking in inuit adults, and non-aboriginal adults in ontario, was defined as the proportion of respondents aged 20 years and older who reported smoking cigarettes daily or occasionally. the cchs and aps had equivalent questions and response options on the subject of smoking. second-hand smoke exposure could not be reported for inuit living in ontario due to small sample size. analysis sampling weights assigned by statistics canada (for the cchs and aps) or the first nations information governance centre (for the rhs) were used for all estimates. first nations and métis estimates (and non-aboriginal estimates for comparison) were age-standardized using the 2006 ontario aboriginal identity population. inuit estimates (and non-aboriginal estimates for comparison) were age-standardized using the inuit identity population in canada outside inuit nunangat (the traditional inuit homeland in northern canada) in the 2006 census. we used bootstrapping techniques, with the appropriate multiplicative factor (fay adjustment) in the case of inuit analyses, to calculate the coefficient of variation (cv) and 95% confidence intervals (cis). estimates with a cv ranging from 16% to 33% were flagged to be interpreted with caution (statistics canada). two percentages were determined to be statistically significant if the 95 percent confidence intervals of the two estimates did not overlap. where possible, results were reported by age group, sex and educational attainment. respondents ages 12 to 19 were considered to be adolescents, except for in first nations analyses, as the rhs youth survey was limited to respondents ages 12 to 17. highest reported level of attained education was classified into three categories: less than secondary school graduation, secondary school graduation or some post-secondary school, and post-secondary graduation. only respondents aged 25 years and older were included in education analyses. results first nations the rhs included 1500 first nations adults and 600 first nations adolescents living on-reserve, while the cchs (2007 to 2013) included 2119 first nations adults and 376 adolescents living offreserve, and 123 105 non-aboriginal adults and 11 636 adolescents in ontario. first nations adults living on-reserve (50 percent of men and 49 percent of women) and off-reserve (44 percent of men and 41 percent of women) had a significantly higher prevalence of current smoking than nonaboriginal adults (26 percent of men and 18 percent of women). first nations adolescents (both sexes combined) living on-reserve (30 percent) and off-reserve (14 percent) were also significantly more likely to smoke cigarettes compared to nonaboriginal adolescents (4 percent). the prevalence of smoking significantly declined from 2007 to 2013 for off-reserve first nations and for nonaboriginal adults. the proportion of off-reserve first nations adults who reported smoking decreased from 51 percent in 2007 to 39 percent www.companyofscientists.com/index.php/chd e6 cancer health disparities research in 2013 (figure 1). no time trend data were available for on-reserve first nations adults, as the rhs phase 2 was a one-time survey in the time period of interest. figure 1. percentage of first nations and non-aboriginal adults (age 20+) who were current smokers, by year, 2007– 2013, ontario. first nations adults (both onand off-reserve) with less than secondary education were significantly more likely to smoke than those with a postsecondary degree. the prevalence of cigarette smoking was significantly higher among first nations adults living onand off-reserve for all levels of education. non-smoking first nations adults living off-reserve (18 percent) were more likely to be exposed to second-hand smoke in their home or vehicle than non-smoking non-aboriginal adults (8 percent). similar percentages of non-smoking first nations and non-aboriginal adults were regularly exposed to second-hand smoke in public. métis the cchs (2007 to 2014) included 1592 métis adults and 285 métis adolescents. there were also 135 817 non-aboriginal adults and 17 383 adolescents surveyed in ontario. the prevalence of current smoking was significantly higher for métis adults (36 percent) and adolescents (16 percent) than it was for non-aboriginal adults (21 percent) and adolescents (7 percent). the proportion of métis adults who reported smoking decreased significantly over time (figure 2), from 44 percent in 2007 to 32 percent in 2014. figure 2. percentage of métis and non-aboriginal adults (age 20+) who were current smokers, by year, 2007–2014, ontario. the prevalence of smoking was significantly higher for métis adults with less than secondary education (57 percent), compared to those with a postsecondary degree (29 percent). non-smoking métis adults (15 percent) were significantly more likely to be exposed to secondhand smoke in private vehicles or at home than non-smoking non-aboriginal adults (8 percent). second-hand smoke exposure at home or in vehicles was also significantly higher for métis adolescents (37 percent) than for non-aboriginal adolescents (17 percent) and métis adults (15 percent). métis adolescents (30 percent) were significantly more likely to be exposed to secondhand smoke in public places than métis adults (16 percent). inuit the prevalence of current smoking was higher in inuit adults living in ontario (34 percent) than in non-aboriginal adults (23 percent), although not significantly. there is also high variability in the estimate for inuit adults due to small sample sizes. inuit living outside the traditional territories of inuit nunangat (i.e., living in southern canada) were significantly more likely to smoke cigarettes, compared to non-aboriginal adults. a significantly higher proportion of inuit women living outside inuit nunangat (41 percent) than non-aboriginal ontario women (18 percent) smoked; among men, www.companyofscientists.com/index.php/chd e7 cancer health disparities research 33 percent of inuit living outside inuit nunangat smoked, compared to 27 percent of non-aboriginal men in ontario (figure 3). figure 3. percentage of inuit adults in canada and non-aboriginal adults in ontario (age 20+) who were current smokers, by sex, 2012. inuit living outside inuit nunangat who had completed less than secondary education (60 percent) were more likely to smoke than those who had completed a post-secondary degree (21 percent). the proportion of non-smoking inuit living outside inuit nunangat regularly exposed to second-hand smoke in the home (19 percent) was significantly higher than the proportion of non-aboriginal non-smoking ontarians exposed to second-hand smoke in the home (7 percent). www.companyofscientists.com/index.php/chd e8 cancer health disparities research table 2. age-standardized prevalence (%) of commercial tobacco exposure in first nations, métis, and inuit populations and corresponding 95% confidence intervals. first nations and comparison population (2007-2013) métis and comparison population (2007-2014) inuit and comparison population (2012) first nations on-reserve in ontario (rhs) first nations off-reserve in ontario (cchs) non-aboriginal in ontario (cchs) métis in ontario (cchs) non-aboriginal in ontario (cchs) inuit outside nunangat (aps) non-aboriginal in ontario (cchs) current smoking by age (years) men (20+) 50% (45, 55) 44% (39, 49) 26% (25, 26) 41% (35, 46) 25% (25, 26) 33%* (21, 44) 27% (24, 29) women (20+) 49% (45, 54) 41% (36, 46) 18% (17, 18) 33% (28, 38) 17% (17, 18) 41% (31, 50) 18% (16, 21) adolescents (12-17) 30% (25, 36) 14%* (9, 19) 4% (4, 5) teens (12-19) 16%* (10,21) 7% (7, 8) current smoking by education (both sexes combined, adults 25+) less than secondary 58% (51, 64) 60% (53, 67) 34% (33, 36) 57% (47, 67) 38% (36, 40) 60%* (44, 76) 43% (36, 51) secondary or some post-secondary 47% (41, 53) 41% (34, 47) 27% (26, 28) 40% (31, 48) 29% (28, 30) 50%* (31, 69) 29% (25, 32) post-secondary 41% (35, 46) 30% (25, 34) 16% (15, 16) 29% (25, 34) 17% (16, 17) 22%* (13, 31) 16% (15, 17) second-hand smoke by location (both sexes combined, adults 20+) home only 19% (14, 25) 7% (6, 8) home and vehicle 18% (15, 21) 8% (8, 9) 15% (10, 20) 8% (8, 9) public places 14% (11, 17) 12% (12, 13) 16% (12, 20) 13% (12, 13) www.companyofscientists.com/index.php/chd e9 cancer health disparities research discussion implications first nations, inuit and métis people in ontario generally had higher rates of exposure to commercial tobacco than non-aborigi¬nal ontarians. the high prevalence of cigarette smoking and second-hand smoke exposure suggests that first nations, inuit and métis people may expe¬rience a greater future burden of cancer and other chronic diseases related to smoking. in addition to lung cancer, smoking ciga¬rettes is an established cause of many other types of cancer including mouth and throat, stomach, colorectal, pancreas, liver, cervix, ovary, kidney and bladder, and leu¬kemia (gandini et al., 2008). smoking also increases the risk of many other serious health conditions, including cardiovascular disease (e.g., heart attack) and chronic respiratory diseases (e.g., copd) (u.s. department of health and human services, 2004). of particular concern among the findings of this study is the proportion of first nations, inuit and métis adolescents who reported smoking cigarettes. lung cancer risk is closely linked to duration of smoking (peto, 1986). therefore, initiating cigarette use as an adolescent can increase the total number of years a person spends smoking and their risk of developing cancer. studies of first nations youth show very early smoking initiation (age 12 and younger) and easy access to cigarettes (elton-marshall et al., 2011; lemstra et al., 2011). although few studies of cancer incidence in indigenous populations have been conducted in ontario (and in canada), recent research has demonstrated increasing rates of smoking-related cancers in the first nations population of the province. among registered first nations people (individuals who have status under canada’s indian act) in ontario, the incidence of numerous cancers associated with tobacco exposure (including lung, colorectal and kidney cancers) is significantly higher than in the rest of the population (chiefs of ontario et al., 2017). data on cancer patterns in métis populations are even more limited. in manitoba, the métis population was found to have higher rates of lung cancer compared to all other manitobans. métis women also had higher lung cancer mortality rates than non-aboriginal women in canada (tjepkema et al., 2009). there are no data available on cancer rates among inuit living outside the traditional homeland, but studies of inuit nunangat and inuit in the circumpolar region indicate lung cancer rates that are the highest in the world (carrière et al., 2012; circumpolar inuit cancer review working group et al., 2008). data challenges the lack of good-quality and comprehensive health data is a significant barrier to better understanding and reducing the risk of chronic diseases, including cancer, among first nations, inuit and métis people in ontario. a lack of ethnic identifiers in health administrative databases in canada limits our understanding of the burden of cancer and health outcomes in these populations. in ontario, the few studies that have estimated cancer incidence, mortality or survival in indigenous populations have involved complex and costly data linkages between the ontario cancer registry and registers of qualifying first nations and métis people (marrett and chaudhry, 2003; withrow et al., 2012. http://www.metisnation.org/media/229177/mno%2 0cancer%20clinical%20significance%20report%20( 29-mar-2012).pdf). these studies are limited in their generalizability, small population sizes (especially for inuit) and relatively dated results; all of which convolute their ability to inform cancer control programming. differences in survey questions and methodology limit our ability to assess certain indicators, for instance, second-hand smoke exposure and smoking time trends for first nations people living on-reserve. in addition, small sample sizes mean that some risk factor prevalence estimates for inuit living in ontario could not be reported (e.g., www.companyofscientists.com/index.php/chd e10 cancer health disparities research second-hand smoke exposure), and we could not stratify by the same sociodemographic factors across first nations, inuit and métis populations. the need to use three different surveys (cchs, rhs and aps), and three different time periods of observation is indicative of the challenges faced in this type of research. no one survey could be used to assess the prevalence of tobacco exposure across all three groups in ontario. access to data also varies by survey. the rhs is not publicly available, in keeping with the first nations principles of ocap™, or ownership, control, access and possession. partnerships and knowledge-sharing between first nations, inuit and métis groups, researchers and data custodians are essential to ensuring appropriate data use and governance. given that the cchs, rhs and aps collect information through self-report, there may be a risk of social desirability bias, where survey respondents tend to under-report behaviours that are socially undesirable (i.e. smoking). it is unlikely that there would be a major difference in this effect across first nations, inuit, métis and nonaboriginal populations, and the effect on the relative estimates of prevalence for any given risk factor would be minimal. what is being done in ontario? the path to prevention report, published by cancer care ontario in 2015, summarizes the many organizations that are involved in chronic disease prevention activities—including tobacco control activities—specific to first nations, inuit and métis populations in ontario. the report presents four main recommendations to reduce or eliminate smoking and commercial tobacco use: develop a coordinated plan to prevent commercial tobacco use among first nations, inuit and métis children and youth; establish commercial tobacco cessation programs and services in first nations, inuit and métis communities; support the development of resources to address secondand third-hand smoke (residue from tobacco smoke on indoor surfaces) and support communityinitiated and managed tobacco control measures, while respecting first nations’ rights. these recommendations were developed based on the knowledge and experience shared by first nations, inuit and métis communities, organizations and individuals in a series of focus groups and interviews. building productive relationships is a strategic priority of the aboriginal cancer strategy iii. the aboriginal cancer control unit works closely with first nations, inuit, métis and other organizations to better address their cancer issues and needs by formalizing relationships through protocols or memoranda of understanding. this relationship building is key to building to kind of respect, trust and partnerships essential to further cancer control activities, including prevention. acknowledgements the authors thank michelle rand for her assistance in reviewing the path to prevention content. we also thank the aboriginal cancer control unit and aboriginal tobacco program of cancer care ontario for their support. conflict of interest statement the author has declared that no competing or conflict of interests exist. the funders had no role in study design, writing of the manuscript and decision to publish. authors’ contributions cc and sj performed the data analysis. lm, as and mm conceptualized and implemented the study. cc drafted the article, all authors critically reviewed it for important intellectual content. all authors gave final approval of the version to be published. references cancer care ontario (2014). cancer risk factors in ontario: tobacco (toronto, ontario). www.companyofscientists.com/index.php/chd e11 cancer health disparities research carrière, g.m., tjepkema, m., pennock, j., and goedhuis, n. (2012). cancer patterns in inuit nunangat: 1998–2007. int j circumpolar health 71, 18581. chiefs of ontario (2012). first nations regional health survey (rhs) phase 2 (2008/10) ontario region final report: ontario region report on the adult youth and children living in first nations communities (toronto). chiefs of ontario, and cancer care ontario (2016). cancer in first nations in ontario: risk factors and screening (toronto, on). chiefs of ontario, cancer care ontario, and institute for clinical evaluative sciences (2017). cancer in first nations people in ontario: incidence, mortality, survival and prevalence (toronto, on). circumpolar inuit cancer review working group, kelly, j., lanier, a., santos, m., healey, s., louchini, r., friborg, j., young, k., and ng, c. (2008). cancer among the circumpolar inuit, 1989-2003. ii. patterns and trends. int j circumpolar health 67, 408-420. elton-marshall, t., leatherdale, s.t., and burkhalter, r. (2011). tobacco, alcohol and illicit drug use among aboriginal youth living off-reserve: results from the youth smoking survey. cmaj : canadian medical association journal 183, e480-e486. first nations information governance centre (2013). about rhs (ottawa: fnigc). gandini, s., botteri, e., iodice, s., boniol, m., lowenfels, a.b., maisonneuve, p., and boyle, p. (2008). tobacco smoking and cancer: a meta-analysis. int j cancer 122, 155-164. government of canada (1982). the constitution act, 1982, c. 11 (u.k.), part ii: rights of the aboriginal peoples of canada (section 35) (ottawa). government of ontario (2017). smoke free ontario act. in so 1994, c 10. indigenous and northern affairs canada. inuit (ottawa: government of canada). indigenous and northern affairs canada (2014. http://www.aadncaandc.gc.ca/eng/1429798605785/1429798785836#tbc130 3). registered indian population by sex and residence 2014 – statistics and measurement directorate (ottawa: government of canada). inuit tapiriit kanatami (2008). inuit in canada: a statistical profile (ottawa, on). lemstra, m., rogers, m., thompson, a., moraros, j., and tempier, r. (2011). prevalence and risk indicators of smoking among on-reserve first nations youth. paediatrics & child health 16, e71-77. marrett, l.d., and chaudhry, m. (2003). cancer incidence and mortality in ontario first nations, 1968-1991 (canada). cancer causes and control 14, 259-268. peto, r. (1986). influence of dose and duration of smoking on lung cancer rates. iarc sci publ, 23-33. public history inc. (2008). canada's relationship with inuit: a history of policy and program development (ottawa: minister of public works and government services canada). statistics canada. canadian community health survey (cchs) annual component user guide 2012 and 2011-2012 microdata files (ottawa: statistics canada). statistics canada (2007-2013). canadian community health survey annual component user guides [2007-2013 microdata files] (toronto, canada). statistics canada (2016). 2011 national household survey (ottawa: statistics canada catalogue no. 99-011x2011035). statistics canada (2017). 2016 census of population, statistics canada catalogue no. 98-400-x2016155. tjepkema, m., wilkins, r., senécal, s., guimond, é., and penney, c. (2009). mortality of métis and registered indian adults in canada: an 11-year follow-up study. health reports 20, 31-51. tobacco has no place here. (2016. https://nuquits.gov.nu.ca/tobacco-101) tobacco was never part of inuit culture (iqaluit: government of nunavut). tungasuvvingat inuit, and cancer care ontario (2017). cancer risk factors and screening among inuit in ontario and other canadian regions (toronto, ontario). u.s. department of health and human services (2004). the health consequences of smoking: a report of the surgeon general (atlanta: u.s. department of health and human services, centres for disedase control and prevention, national centre for chronic disease prevention and health promotion, office on smoking and health). withrow, d., kewayosh, a., and marrett, l. (2012. http://www.metisnation.org/media/229177/mno%20canc er%20clinical%20significance%20report%20(29-mar2012).pdf). cancer in the métis nation of ontario: clinical significance report (métis nation of ontario). https://nuquits.gov.nu.ca/tobacco-101 www.companyofscientists.com/index.php/chd e1 cancer health disparities research breast cancer disparities among american indian women marilyn a. roubidoux, md, department of radiology, university of michigan health systems, tc 2910, box 5326, 1500 e. medical center drive, ann arbor, mi 48109-5326, corresponding author email: roubidou@umich.edu abstract health disparities in breast cancer among american indian women include historically higher stage at diagnosis, younger age at diagnosis, higher ratios of rates of mortality vs incidence, geographic variability of incidence and mortality rates, more difficult access to breast imaging and cancer treatment, and racial misclassification in medical records resulting in underestimation of breast cancer data. this population is understudied as well as underserved and more research is needed to reveal specific causes and interventions for these breast cancer disparities. proactive efforts may include improving access to regular screening, diagnosis and treatment, identifying high risk women for intervention, and continuing community based research and educational programs. after a cancer diagnosis, patient navigators and prompt access to up to date breast cancer therapy treatment may improve outcomes. keywords: : health disparities, american indians, breast cancer, screening mammography, breast cancer mortality citation: roubidoux ma (2018) breast cancer disparities among american indian women. cancer health disparities 2:e1-e9. doi:10.9777/chd.2018.10003 www.companyofscientists.com/index.php/chd e2 cancer health disparities research the relative paucity of information about breast cancer in american indian (ai) women compared to larger population racial groups makes assessment of this healthcare disparity among ai women more difficult. breast cancer risk and outcomes information about this underserved population is limited or incomplete (emerson et al., 2017; martin et al., 2016). studies of racial differences in breast cancer often do not include information about the ai population (ahmed at, 2017). furthermore, information regarding breast cancer screening, incidence, and mortality rates in american indian and alaska native women is commonly merged into a single group. however, looking at data from this merged single data group masks wide and unique variations in subgroups and regions. since american indian subgroups are heterogeneous by tribe, geographic location, and urban vs. rural residence, merging data into one mean value can obscure differences and disparities. as a result, evidence based breast cancer control in this population is more challenging. to address inequities in breast cancer screening, prevention, treatment and survivorship, accurate, timely, and specific data is needed. community based participatory research among these women is a key method to obtain useful insight about breast cancer detection and treatment challenges, and from which to guide the design of interventions needed to address the inequities (burhansstipanov l, 2010; burhansstipanov et al., 2017). racial or ethnic minority patients are underrepresented in cancer registries due to racial misclassification occurring from missing or incorrect entries in medical records, and misclassification of american indian patients is common. this misclassification results in underestimation of the breast cancer burden in ai women (haozous ea, 2014; johnson et al., 2009; roen et al., 2014; white et al., 2014b). accuracy in medical records may be improved by matching records from different sources, i.e., linking cancer registries to tribal and indian health service records. data linkage changes breast cancer incidence rates substantially(roen et al., 2014). recently, linkages between indian health service patient files and the national death index have improved accuracy in american indian breast cancer mortality and incidence data (espey dk, 2014; roen et al., 2014; white et al., 2014b). in addition to problems of misclassification, 71% of american indians reside in urban areas with medical care outside of the indian health service (emerson et al., 2017). therefore indian health service records represent only part of the entire population and data among urban american indians is only recently emerging(jacobs-wingo jl, 2016). in the united states there are medically underserved populations which have higher cancer burdens in incidence, mortality and/or outcomes. the national breast cancer incidence rate had a historic decrease 1998-2007, dropping 1.7% per year, with about 3% per year decrease between 1999-2004; in contrast, the overall incidence rates in american indians and alaska natives were level during that time period (krieger n, 2010). for american indian women the overall incidence of breast cancer historically has been lower than that of the us population, but dramatic and persistent geographic differences in incidence rates among subgroups have been reported over many years (white et al., 2014b). data from 19992009 demonstrated an overall incidence of breast cancer of 100/100,000, compared to 131/100,000 for white women (white et al., 2014b). however, the mean value masks the regional variability in www.companyofscientists.com/index.php/chd e3 cancer health disparities research this population. the highest incidence rate was 141.3 in alaska native women, followed by 136.1/100,000 among women in the southern plains tribes; the lowest incidence was in ai women in the southwest at 59.6 (white et al., 2014b). this regional variability of breast cancer incidence is unusual, as it is not found among other ethnicities or races (wingo et al., 2008) and persists even when improving the accuracy of records by adjusting for racial misclassification (white et al., 2014b). although the average breast cancer mortality rate in american indian and alaska native women (22.2/100,000) has been lower than white women (24.1/100,000) (white et al., 2014a), it is not as low as would be expected when comparing incidence rates. similar to the incidence rates, the mortality rates vary regionally, with higher death rates from breast cancer among american indian women compared to white women in the northern plains, alaska, and the southern plains (white et al., 2014b). since the ratios of mortality to incidence were reported higher for the years 1990 to 2009 among american indian women than among white women, american women had a comparatively higher risk of death from breast cancer (white et al., 2014b). breast cancer mortality rates nationally decreased 39% after screening mammography became commonly used, beginning in 1989to 2015. this improvement is attributed to a combination of better and earlier detection with screening mammography and improved therapies, with 5080% of the mortality rate decline due to screening mammography (desantis et al., 2017; vervoort mm, 2004). the mortality rate decline occurred for white women and african american women but was comparatively unchanged among ai/an in the years up to 2009 (white et al., 2014b). in more recent years, death rates for ai/an women were reported to have decreased although, the decline in death rates among ai/an women began in 2005, more than a decade later than other racial and ethnic groups (desantis et al., 2017). additionally that same recent data indicated that ai/an women continue to have a lower proportion of localized stage and a higher proportion of regional stage disease than white women (desantis et al., 2017). survival from breast cancer was poorer among urban american indian women who were northern california kaiser permanente enrollees compared to non-hispanic white women, with mortality rates from breast cancer that were 47% higher (emerson et al., 2017). survival from breast cancer in this study was lower even when controlling for income and comorbid conditions (emerson et al., 2017). although not proven, it was presumed in this study that these california ai women had approximately equal access to cancer care services, suggesting that the survival differences were not due to differences in cancer screening or treatment. further studies like these are needed to study factors that influence breast cancer mortality in american indian women, including cancer stage and histology, screening, treatment, and socialbehavioral-cultural factors. for example, differences in breast cancer by hormone receptor and her2 status have been reported for american indian/alaska native women who were found to have had a 3.9 fold higher risk of stage iv triple negative breast cancer, an aggressive subtype (chen and li, 2015). breast cancer incidence varies by age, among all races and ethnicities, with many more cancers occurring in older women than younger women. the older the woman, the more likely she will be diagnosed with breast cancer, and although more www.companyofscientists.com/index.php/chd e4 cancer health disparities research attention has been given to breast cancer among young women, women ages 60 years or older are at the highest risk for breast cancer. it has been reported that more american indian woman are diagnosed with breast cancer at a younger age, mean age of 53.5 years, compared to nonhispanic white (nhw) women, who are diagnosed at a mean of 63.4 years (wingo et al., 2008). although the overall average breast cancer incidence rate is lower compared to nhw, the incidence rate among american indian women less than 50 years of age (2007) is not lower than the national incidence rate for this age group (national cancer institute, 2010). prior studies reported that 30% of ai/an women with breast cancer are diagnosed before they reach 50 years of age, a substantially higher proportion than for nhw women, of whom only 19% are diagnosed before age 50 years (wingo et al., 2008). similar findings were reported in a michigan study, with a mean age of breast cancer diagnosis for ai women younger than that of white women, and a greater percentage diagnosed under 50 years compared to white women (roen et al., 2014). younger age of breast cancer diagnosis confers a higher mortality because the tumors are larger and higher grade cancers than occur in younger women. thus, if screening in american indian women does not occur until age 50 years, a substantial proportion of women with breast cancer will miss a chance for early detection (arleo et al., 2017). annual screening mammography increases the rate of early detection of localized disease and improves patient health. screening mammography detects breast cancer several years before the cancer is palpable (rosenberg et al., 2006), increases patient survival (kopans, 2007) and allows women the option of breast preservation treatments such as lumpectomy and radiation therapy. screening mammography could improve the health disparity among american indians by detecting breast cancer at an earlier stage (desantis et al., 2017). the minimal ‘risks’ of mammography, including false positive biopsies and anxiety from the need for additional views, are minor, far outweighed by a diagnosis of a later stage of breast cancer. mammography is the lowest cost, most widely available, standardized, and evidence-based method to detect breast cancer. there is a strong consensus that mammography screening for women 50 to 69 years of age reduces breast cancer mortality. unfortunately, screening women 40 to 49 years of age has been controversial (arleo et al., 2017). however, since 40% of the years of life that are lost by women due to breast cancer are among women 40 to 49 years of age (arleo et al., 2017; kopans, 2007; kopans, 2010; wingo et al., 2008) screening mammography beginning at age 40 years is recommended by the american cancer society, and is a definite recommendation by the national comprehensive cancer network (nccn), the american college of obstetrician and gynecologists, and the american college of radiology (arleo et al., 2017). results from clinical trials suggest that the mortality rate from breast cancer can be reduced by 30% when recommendations for screening are followed (arleo et al., 2017; de gelder r1, 2015; kopans, 2007; kopans, 2010). since the vast majority of women who get breast cancer have no family history of the disease (neal ch et al., 2018), it is not appropriate to limit mammogram screening to high risk women in the 40 to 49 years age group. targeted screening for specific subgroups of young women at higher risk is indicated, including genetic testing and supplementary screening at an www.companyofscientists.com/index.php/chd e5 cancer health disparities research early age with breast mri examinations (expert panel on breast et al., 2017; samphao et al., 2009). in addition to screening high risk women in this younger age group, elderly women can also benefit from screening mammography, preventing breast cancer morbidity and death 5-10 years later (arleo et al., 2017). racial minorities are less likely than white women to receive adequate mammogram screening, and of all racial minorities, american indians have historically had the least breast cancer mammogram screening (peek and han, 2004; roen et al., 2013; smith-bindman r, 2006). historically, use of screening mammography can vary by region, such that the average national screening rates for american indian women can obscure regional disparities (peek and han, 2004; schumacher et al., 2008). data regarding the prevalence of any method of screening (mammography, clinical breast exam, or breast self-examination) in minority populations is scarce. self-reported mammography use from the behavioral risk factor surveillance system (brfss) has typically shown less use of mammography among ai/an than other racial groups (centers for disease control and prevention, 2010). in the northern plains, an area of elevated breast cancer prevalence among ai women, only 51% of women reported “ever” having had breast cancer screening (pandhi et al., 2010). the percentage of ai women in the southwest reporting “never” was 30.1% (schumacher et al., 2008). self-reported estimates of adherence to screening mammography are not accurate and are commonly higher than medical records (peek and han, 2004) , and self-reported mammography use among minority and low income women is over estimated because of under sampling. using medical records to assess mammogram screening, the indian health service gpra report of 2009 indicated that only 45% (40-55% by region) of ai women had screening mammograms (service, 2010). in a study with screening mammogram data obtained directly from mobile mammography records, the majority (60.14 %) of women in the northern plains who presented to the mobile mammogram unit reported not having had a screening mammogram in the previous 2 years, which is lower screening adherence than found nationally, and screening rates were lowest among women ages 41-49 years (roen et al., 2013). the recommendations for the interval between screening mammograms vary from one to two years. in computer models, more frequent mammogram screening dramatically reduces the mortality rate of breast cancer (arleo et al., 2017; michaelson et al., 1999). the likelihood of metastatic disease is decreased by 51% when mammography is performed annually (michaelson et al., 1999). increasing the compliance with annual screening mammography is the most evidencebased intervention to decrease the mortality rate of american indian women since adherence to recommended screening intervals may reduce breast cancer mortality rates (de gelder r1, 2015; smith-bindman et al., 2006). historically, adherence to screening intervals has substantial variation by race/ethnicity, age, insurance status, and family history (strzelczyk and dignan, 2002). there is minimal data about adherence to screening mammography among ai/an women. wampler et al. found that american indian women in colorado were less likely than non-hispanic white women to adhere to recommendations for screening mammography, both annually and biennially, with the chief predictor being economic status (wampler et al., 2006). among northern plains ai women presenting to a mobile www.companyofscientists.com/index.php/chd e6 cancer health disparities research mammography unit, adherence to screening mammography guidelines (defined as a prior mammogram within the past two years) occurred in 39.86 % of the ai women, lower than adherence to screening reported in the same time period where 74.34 % of white women complied with screening mammography guidelines in a national mammography database (roen et al., 2013). disparities in screening mammography are improving among medically underserved populations but still persist among racial/ethnic minorities and low income women (peek and han, 2004). while regular compliance with screening mammography is important for early detection, many factors affect compliance such as local availability of mammographic facilities, physician recommendations, financial issues (insurance, low cost programs), and patient attitudes. the earth study found that predictors for mammography compliance included higher educational status, higher income, older age, positive family history, and urban location (schumacher et al., 2008). pandhi found that the strongest predictor for compliance with cancer screening in the northern plains was the provider recommendation (pandhi et al., 2010). in 1990 the national breast and cervical cancer early detection program (nbccedp) was initiated to improve the access of medically underserved women to screening mammography and subsequent diagnostic procedures. this program provides support to women in all 50 states and to 12 tribal programs among 6 states. published data from the nbccedp indicate that while first round screening in ai/an women yields fewer cancers than screenings in white women, subsequent round screening detections and positive predictive values are similar to that of other racial/ethnic groups (eheman et al., 2006). this indicates that mammography is equally effective and accurate in ai/an and nhw women. it is estimated that approximately 49% of eligible ai/an women in nbccdp programs have been screened, which is a higher rate than any other racial/ethnic group and demonstrates the importance of this cdc program to native women (tangka et al., 2006). difficult access to breast screening and diagnosis may contribute to the disparity in american indian women in breast cancer mortality to incidence ratios. a recent study of geographic access to breast imaging services reported marked differences among population subgroups (onega et al., 2014). travel time to mammography and ultrasound for 85% of us women was less than 20 minutes, with black and asian women having the shortest median travel times. travel times greater than 30 minutes for mammography and ultrasound were found for 39.6% of native american women compared to only 12.6% of white women and 6% of black women. access to mr imaging is even worse. long travel times (>30 min) for breast mri were found in 85% of american indian women, as compared to only 46.5% of white women and 26.1% of black women. these disparities in american indian women persisted despite rural or urban locations. the authors concluded that american indian women are disadvantaged in geographic access to breast imaging as measured by travel times. potential interventions could be designed to reduce these transportation inequities, improve racial disparity in early breast cancer diagnosis and mortality from this malignancy (desantis et al., 2017; onega et al., 2014) rural women in general have lower screening mammography rates than urban women, a finding seen in the earth study (schumacher et al., 2008). a contributing factor is the lack of convenient mammography facilities. www.companyofscientists.com/index.php/chd e7 cancer health disparities research one countermeasure taken to improve mammography access in this region, was a mobile screening mammography unit taken to 18 rural and urban clinics in this rural ihs area in 20062017 (roen et al., 2013; roubidoux et al., 2006). in addition to mobile mammography, telemedicine is another way to encourage screening and to assess breast cancer risk among women who live in remote areas, for whom regular screening is more challenging. through telemedicine, alaska native and american indian women may meet with providers or patient navigators to discuss their breast cancer risk and to learn life style modifications to which can reduce breast cancer risk. using telemedicine, high risk women in remote areas can be identified and targeted for screening, and for preventive therapy with risk reducing strategies and medications. a previous pilot study showed that telemedicine risk counseling, enabled by technology and a patient navigator, is feasible and has high patient satisfaction. (pruthi et al., 2013) to effectively advise american indian patients about breast cancer screening, individual risk needs to be determined because screening recommendations are based upon assessing a patient’s risk for breast cancer (expert panel on breast et al., 2017). when a woman’s risk is determined to be average, screening mammography and/or digital breast tomosynthesis is recommended beginning at age 40 years. thereafter, annual repeat mammogram screening confers the greatest years of life saved from detecting a breast cancer.(arleo et al., 2017) when a woman has dense breasts, breast ultrasound may be an adjunct to mammography for incremental cancer detection, although ultrasound may result in increased false positive results. for women at very high risk due to prior mantle irradiation between the ages of 10 to 30 years, mammography is recommended starting 8 years after radiation therapy but not before age 25 years. in these patients, screening with breast mri should also be done. for women with a genetic risk, such as women with brca gene mutations, or a 20% lifetime risk of breast cancer, annual screening mammography is recommended beginning 10 years earlier than the affected relative’s age of onset, but not before age 30. additionally, breast mri is recommended for this group of women because mri has greater sensitivity than screening mammography. (expert panel on breast et al., 2017) in order to determine patient risk, providers and patient navigators may use one of a few available breast cancer risk prediction models. commonly used models are the international breast intervention study (ibis), or tyrer-cuzick, model and the gail model. (millstine et al., 2014) the tyrer-cuzick model is based on data from the international breast intervention study (ibis) from the united kingdom. this model can be employed to determine whether a woman is a candidate for annual screening mri in conjunction with annual mammograms. the need for screening mri should be based on 2007 american cancer society guidelines, which indicate that a lifetime risk of greater than 20 percent merits supplemental mri screening. the gail model, which uses age, race, menarche, age at first live birth, history of cancer in first degree relatives, history of breast biopsy, and history of atypical ductal hyperplasia to predict 5-year and lifetime risks is used only in women age 35 years or older and cannot be applied to those with a history of breast cancer, lobular carcinoma in situ, or ductal carcinoma in situ. however, it is well suited to determine www.companyofscientists.com/index.php/chd e8 cancer health disparities research whether chemoprevention is indicated for breast cancer risk reduction. when a woman is identified to be at high risk, chemoprevention may also be prescribed, using tamoxifen, raloxifene, or exemestane, each of which has been shown to lower lifetime risk of breast cancer.(burns et al., 2016; millstine et al., 2014; visvanathan et al., 2013) historically, racial/ethnic minorities and low income women have been less likely to receive physician recommendations for mammography, and this variability in physician recommendations must be addressed (peek and han, 2004). native american women are strongly influenced by their relationship with their provider, their experiences and their degree of trust in the health care system (canales and geller, 2004). however, lack of consistency in provider from one year to the next, and frequent moves between urban and reservation domiciles undermines a good provider relationship (burhansstipanov l, 2010). lay health advisers in the communities can also be effective in improving compliance of native american women to screening mammography, especially since barriers to participation can be complex (burhansstipanov l, 2010). although breast cancer is the most common malignancy among american indian women, it is second to lung cancer as a cause of death. this is because survival of women with breast cancer is much higher than survival of women with lung cancer. therefore, breast cancer is less likely to threaten the life of a smoker than are smoking related diseases such as chronic obstructive pulmonary disease and cardiovascular disease. as screening mammography becomes better established in native american communities, mammogram screenings become opportunities for teachable moments to encourage other healthy behaviors such as smoking cessation and colorectal cancer screening (carlos and fendrick, 2004). aside from risk reducing chemoprevention medications, american indian women may decrease their risk of breast cancer with exercise, minimizing alcohol intake, and practicing breast feeding for durations as long as feasible. other actions that may decrease the risk of breast cancer include increasing the intake of omega 3 fatty acids (fish oil), citrus fruits, and vegetables of the cabbage family. further positive steps include reducing dietary omega 6 fatty acid (vegetable oils) by substituting extra virgin olive oil, reducing the intake of red meat, high fat and hormone containing dairy products, and by using vitamin d supplements. (ronco et al., 2010) they may decrease their risk of death from breast cancer by engaging in annual screening mammography and for supplemental screening with magnetic resonance imaging when genetic risk is evident. finally, guideline concordant breast cancer care and treatment needs to be more universally received by this population. (javid sh, 2014) disparities in breast cancer among american indian women may be addressed through a variety of activities. first, the heterogeneity of american indian populations must be recognized and health information examined by local group rather than being lumped into one large group. furthermore, the accuracy of the information must be improved by reducing racial misclassification. in addition to analyzing data among geographic subgroups, differences between rural and urban women must be recognized. access to breast cancer screening and treatment must be improved for all native american women, and continuing community needs assessments and educational www.companyofscientists.com/index.php/chd e9 cancer health disparities research interventions and needed for this understudied population. acknowledgements the author is thankful to judith s. kaur for inviting this article. conflict of interest the authors declare that no competing or conflict of interests exists. the funders had no role in study design, writing of the manuscript, or decision to publish. authors’ contributions mar designed and conceived the study and wrote the manuscript. references ahmed at, w.b., brinjikji w, farah wh, henrichsen tl, murad mh, knudsen jm (2017). racial disparities in screening mammography in the united states: a systematic review and meta-analysis. j am coll radiol 14, 157-165. arleo, e.k., hendrick, r.e., helvie, m.a., and sickles, e.a. 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(2008). breast cancer incidence among american indian and alaska native women: us, 19992004. cancer 113, 1191-1202. www.companyofscientists.com/index.php/chd e1 cancer health disparities research notch as an immunologic basis of cancer disparities portia laliah thomas1,2,3 and anil shanker1,3,4,5,*1 1department of biochemistry, cancer biology, neuroscience and pharmacology, school of medicine, meharry medical college, nashville, tn, usa 2department of microbiology, immunology and physiology, school of medicine, meharry medical college, nashville, tn, usa 3school of graduate studies and research, meharry medical college, nashville, tn, usa 4host–tumor interactions research program, vanderbilt-ingram comprehensive cancer center, vanderbilt university school of medicine, nashville, tn, usa 5vanderbilt institute for infection, immunology and inflammation, vanderbilt university school of medicine, nashville, tn, usa *corresponding author: email: ashanker@mmc.edu abstract inter-individual differences due to racial/ethnic backgrounds may alter host immunity responsible for the cancer immunosurveillance and elimination, leading to disparate cancer incidence and relapse. one basis of disparity in tumor incidence, progression or therapeutic outcomes could lie in the components of notch intercellular communication system, which provide instructive signals for a variety of pathways regulating cell commitment and differentiation including context-dependent lymphocyte polarization in tumor microenvironment. notch signaling in hematopoietic cells is perturbed by tumor growth for its advantage, and there are indications that differences in notch components could underlie poor cancer prognosis in certain populations. here, we discuss the oncogenic and immunologic aspects of notch, which should inform on cancer health disparities and therapeutic outcomes. keywords: cancer immunity, health disparity, notch, lymphocytes, immunosurveillance, immunotherapy citation: thomas pl, shanker a (2019) notch as an immunologic basis of cancer disparities. cancer health disparities 3: e1-e-10. doi:10.9777/chd.2019.1006. www.companyofscientists.com/index.php/chd e2 cancer health disparities research introduction immunologic basis of racial disparities racial disparities in cancer are well documented in various solid cancers. this disparity is particularly evident in breast cancer, where paradoxically, the mortality rates in african-american compared to white american/caucasian women are considerably higher despite lower lifetime incidence rates of breast cancer (fregene and newman, 2005; howlader et al., 2018). although many differences in breast cancer incidence/outcome can be explained by socioeconomic disadvantages, recent studies have broadened our understanding of the correlation of genetic mutations and ancestry with race/ethnic-associated disparities. it is crucial to note that genetics not only affects cancer susceptibility but the immune response to cancer as well. it has long been recognized that lymphocytes, specifically natural killer (nk) cells and t cells, differ significantly in their ability to mediate effector responses depending on the genetic constitution of an individual. the major histocompatibility and the leukocyte receptor complexes are the two most polymorphic regions of the immune genome. individuals with increasingly diverse repertoires of mhc class-i molecules have a greater potential for their nk cells to be more responsive. this is evident from the differential susceptibility of some individuals to hiv infection and their wide range of asymptomatic phase (kulkarni et al., 2009; martin et al., 2018; ramsuran et al., 2018). the underlying mechanism of the differences in lymphocyte effector responses against tumor in disparate populations could involve differential expression of inhibitory and activating receptors on lymphocytes. one of these receptors belongs to the notch family, which offers a major juxtacrine signaling system that allows cellular crosstalk to program almost every cell type in the body. notch signaling is highly conserved evolutionarily as it is important for cell-to-cell communication for tissue patterning during embryonic development. mammals express four notch receptors (notch 1-4), which can bind to five canonical transmembrane ligands from two paralogous gene families– delta-like (dll1, dll3, dll4) and jagged (jag1 and jag2) (andersson et al., 2011; radtke et al., 2010; yuan et al., 2010). the delta ligands transactivate notch amongst neighboring cells and cis-inhibit notch in its own cells following receptor engagement (crabtree et al., 2016; sprinzak et al., 2010; yaron and sprinzak, 2012). the receptor-ligand interaction between juxtaposing cells initiates a cascade of events involving transendocytosis, proteolytic cleavages, ubiquitination and deubiquitination transforming the cell surface receptor into a nuclear factor acting on the transcription of several target genes. briefly, a conformational change in the ligated receptor exposes the s2 cleavage site (12–13 amino acids external to the transmembrane domain) for proteolysis by metalloproteases of the disintegrin-and-metalloproteinase (adam) family. the notch extracellular domain is shed and endocytosed by the ligand-expressing cell (radtke et al., 2010). after shedding, the transmembrane domain is cleaved at the s3 site by secretase freeing the notch intracellular domain (nicd). the nicd subsequently traffics to the nucleus, heterodimerizing with dna binding transcription factor cbf1/suppressor of hairless/lag-1 (csl). the c promoter-binding factor (cbf1) in humans is also known as recombination signal binding protein for immunoglobulin  j region (rbpj-) or -binding factor 2 (kbf2) in mice, as suppressor of hairless [su(h)] in drosophila and longevity-assurance gene-1 (lag-1) in caenorhabditis elegans. the csl-bound nicd recruits various coactivators, including mastermind proteins (maml13), inducing transcriptional expression of notch downstream target genes hairy enhancer of split www.companyofscientists.com/index.php/chd e3 cancer health disparities research (hes1) and hairy related (hey1 or hrt). notch signaling can also crosstalk with other signaling pathways such as nf-b and tgf- widening the notch downstream target genes involved in effector t cells (kuijk et al., 2013; radtke et al., 2010; yuan et al., 2010). promiscuous receptor-ligand binding makes notch signaling highly doseand context-dependent (previs et al., 2015). notch can contribute to tumorigenesis if partnered with another onco-signaling, or can improve antitumor lymphocyte function if presented with the right repertoire of notch receptor-ligands in the tumor microenvironment (biktasova et al., 2015; huang et al., 2011; lobry et al., 2011). there are indications that differences in notch components could underlie poor disease prognosis in certain populations. based on data from the chronic obstructive pulmonary disease (copd) clinical trial nct00774176, the expression of mastermind-like protein 1 (maml1), which affects notch-dependent angiogenesis in lung, was found to be associated with copd exacerbation in african americans (busch et al., 2016). as per the cancer genome atlas (tcga) data, a novel notch protein, notch 2 nterminal like protein (notch2nl/n2n), was found to be increased in breast cancer tissue of africanamericans relative to caucasians. correspondingly, disparities in notch signaling can impact cancer development and therapy as discussed below. notch in cancer development although notch signaling plays a crucial role in embryonic development, tissue homeostasis, cell proliferation, apoptosis, hematopoiesis, as well as differentiation and function of various immune cells including lymphocytes, dysregulation of notch signaling leads to several diseases, including cancer (radtke et al., 2010; yuan et al., 2010). for instance, crosstalk between tgf-β and notch is essential for epithelial-mesenchymal transition (emt) as notch signaling is needed to sustain the expression of tgfβ-induced notch target gene hey1, which acts as a transcriptional repressor (klinakis et al., 2011). deregulation of the notch pathway can occur by various mechanisms including overexpression, mutational activation or inactivation, posttranslational modifications and epigenetic regulation (ntziachristos et al., 2014). notch signaling in breast cancer progression notch signaling drives many human hematologic and solid malignancies including breast cancer, medulloblastoma, colorectal cancer, lung cancer and melanoma (ntziachristos et al., 2014). notch signaling plays a central role in breast cancer development and progression by promoting tumor growth, invasiveness and metastasis (previs et al., 2015). increased expression of notch1 and notch3 receptors have been associated with triplenegative breast cancer (tnbc). notch4 overexpression has been correlated with hormonereceptor positive breast cancer. on the contrary, notch2 has been associated with better survival (parr et al., 2004). in addition, notch1 has lowered expression in her-2 positive breast cancers (touplikioti, 2012). studies also indicated that high notch1 and jag1 in breast cancer patients correlated with poorer overall survival (reedijk et al., 2005). recently, notch1, notch3 and jag1 were shown to be at the nexus of a vicious cycle of macrophage infiltration into basal-like breast cancers by regulating the expression of proinflammatory cytokines, il-1β and ccl2, thus increasing cancer invasiveness (shen et al., 2017). notch signaling in lung cancer progression notch signaling plays an integral role in lung cancer initiation and progression. in non-small cell lung www.companyofscientists.com/index.php/chd e4 cancer health disparities research cancer (nsclc), notch signaling crosstalks with various transcription factors to enhance emt during cancer development. blockade of notch signaling inhibits progression and migration of nsclc by reversing emt (xu et al., 2018; yuan et al., 2014). in a wide variety of lung cancer patients (squamous cell carcinoma, adenocarcinoma, transitional cell carcinoma and large cell carcinoma) expression levels of delta-like notch ligands dll1 and their target gene hes1 were significantly altered in hematopoietic compartment by tumor-derived factors. these changes in notch components were reproduced in various murine cancer models including lung cancer. the decreased expression of notch components resulted in tumor-induced immunosuppression in t cell function that correlated with poor prognosis (biktasova et al., 2015; huang et al., 2011; thounaojam et al., 2015). notch basis of cancer disparities expression of notch in breast cancer is subtypedependent although the role of notch in cancer initiation and progression is known, its contribution to cancer disparities has not been explored. the plausible effect of notch on cancer disparities, however, can be seen in breast cancer where more aggressive subtypes known to disproportionately affect minority populations have differential notch signaling than less aggressive types (hormone-receptor positive). overexpression of notch target gene hes1, secretase protein presenilin-1 (psen1), and lunaticfringe (lfng) – a β3n-acetylglucosaminyl-tranferase, which regulates ligand-mediated activation of the notch pathway – were found to be favorable for disease-free survival in luminal type a breast cancer. overexpression of these same notch genes, however, was unfavorable for disease-free survival in tnbc as analyzed in the tcga breast cancer cohort (orzechowska et al., 2017). in a study using next generation sequencing to identify notch mutations in solid tumors, only tnbcs showed notch1 and notch2 rearrangements which led to constitutive receptor activation (stoeck et al., 2014). these studies provide evidence of distinct notch signaling profiles in various breast cancer subtypes, which also have known racial disparities of incidence and outcome. findings suggest that the differential expression of notch components can affect breast cancer progression and elucidate response to treatment. expression of notch2n in breast cancer is racedependent a novel notch protein, notch 2 n-terminal-like protein (notch2nl/n2n), has been found to be highly upregulated in breast, colorectal, and prostate cancer as reported in the cancer genome atlas (tcga). notably, african-americans show an increase in n2n expression in breast cancer relative to caucasians (p = 0.0037), per tcga database (fig. 1). figure 1. expression of notch 2 n-terminal like (n2n) rna as a predictor of breast cancer disparities. genomic data available in the cancer genome atlas (tcga) were used to analyze n2n gene expression of breast cancer tissues from african americans (n = 41) in comparison with caucasians (n = 423). *unpaired two-tailed t-test with welch’s correction. www.companyofscientists.com/index.php/chd e5 cancer health disparities research in vitro, n2n has been shown to repress the transcriptional activities of notch 2 and notch 1 intracellular domains, which are important for antitumor lymphocyte effector function and memory (biktasova et al., 2015; huang et al., 2011; thounaojam et al., 2015). thus, n2n could be a possible predictive candidate for cancer disparities and poor prognosis amongst the african-american population. n2n has also been shown to be targeted by neutrophil elastase and implicated in hereditary neutropenia (duan et al., 2004). role of notch in cancer immunity notch signaling in t lymphocytes it is well established that tumor-induced immune suppression by multiple mechanisms is a major impediment to the success of cancer therapy. an intact functional immune system is required for the induction of sustained tumor regression upon inactivation of the tumor-driving oncogenes (rakhra et al., 2010). the generation of effector cd8+ t cells is imperative for antitumor immunity (kuijk et al., 2013; thounaojam et al., 2015; uzhachenko and shanker, 2016). the notch signaling pathway plays an important role in the regulation of differentiation and function of lymphocytes, while being extremely pleiotropic with an interrelated network of receptorligand interactions. most gain-of-function studies indicate that delta-like ligands promote cd4+ t cell commitment to th1 (amsen et al., 2009; amsen et al., 2004). although controversy exists, the bias is that jag ligands associate with th2-promoting notch function (amsen et al., 2009; krawczyk et al., 2008). notch has also been reported to associate with the regulation of il17 and rort gene promoters to influence th17 differentiation (keerthivasan et al., 2011). in addition to promoting th1, th2 and th17 differentiation, some notch ligands, on the contrary, play an immunosuppressive function. expression of jag ligands by antigen-presenting cells or hematopoietic progenitors favored generation of suppressive t cells in vitro and regulatory t cells (treg) in vivo (kared et al., 2006; vigouroux et al., 2003; yvon et al., 2003). in addition, expression of delta-like notch ligands in hematopoietic compartment is significantly altered by tumorderived factors resulting in tumor-induced immunosuppression (biktasova et al., 2015; huang et al., 2011; thounaojam et al., 2015). systemic blockade of jag1/2 or dll1 overexpression overcame tumorinduced t cell tolerance suggesting the involvement of these ligands in anti-tumor t cell function (huang et al., 2011; palaga et al., 2003; sierra et al., 2017). evidence supports that notch signaling promotes differentiation of naïve cd8+ t cells into cytotoxic and memory t lymphocytes by upregulating the transcription factor eomesodermin responsible for regulating expression of effector molecules ifn, granzymes, and perforins (biktasova et al., 2015; palaga et al., 2003; radtke et al., 2010; sauma et al., 2012; thounaojam et al., 2015; tsukumo and yasutomo, 2004). conditional transgenic expression of notch 1 intracellular domain in cd8+ t cells induces maturation towards a central memory phenotype (sierra et al., 2014). in murine cd8+ t cells, notch signaling controls activated cd8+ t cell fate towards terminal effector cell versus memory precursor cell fates (backer et al., 2014). studies also noted that notch1/2 signaling was associated with increased il-2 synthesis and upregulated expression of il-2 receptor  chain, cd25 on t cells and inhibition of notch signaling resulted in decreased proliferation of cd4+ and cd8+ t lymphocytes (adler et al., 2003; thounaojam et al., 2015). in addition, treatment of tumor-bearing mice with cancer therapeutic drug bortezomib, a proteasome inhibitor, enhanced expression of notch signaling components in lymphoid tissues resulting in cd8+ t www.companyofscientists.com/index.php/chd e6 cancer health disparities research cell expression of effector molecules, perforin and granzyme b as well as ifn-secretion (thounaojam et al., 2015). furthermore, there appears to be a consensus in the published data to suggest that notch 1 and notch 2 are key players in the induction of cytolytic and memory t cell function (auderset et al., 2012; biktasova et al., 2015; huang et al., 2011; laky et al., 2015; sierra et al., 2014; sugimoto et al., 2010; thounaojam et al., 2015). recently, it was shown that notch 1 activation could occur in peripheral t cells in a ligand-independent manner through chemical adjustments in the endosome within a few hours post-tcr stimulation (steinbuck et al., 2018). alternatively, notch 1/2 may fine-tune the sensitivity, magnitude and quality of the t cell response by promoting metabolic reprogramming besides specifying lineage choice or controlling expression of regulators following the initial steps of antigen encounter by t cells (laky et al., 2015). also, it is known that a transient pulse of a high level of notch 1/2 cognate delta-like ligand is capable of inducing hes1 expression for a duration that is sufficient to induce a binary cell fate switch. for example, transient dll-notch signaling has been shown to be sufficient to induce t cell (lefort et al., 2006) or nk cell differentiation (carotta et al., 2006). notch signaling in nk cells human studies indicate that notch 1 signaling is crucial for nk cell maturation and effector function as well, with an increase in notch 1 signaling leading to an enhanced inhibitory killer immunoglobulin-like receptor (kir) expression on nk cells. augmented notch 1 signaling also induces increased cytolytic effector capacity and cytokine secretion of human peripheral nk cells, enhancing their antitumor functions (felices et al., 2014). furthermore, an increase in notch signaling by mir-181 increases production of ifn- in primary nk cells (cichocki et al., 2011). in murine studies, dendritic cell overexpression of notch ligand jag2, which signals through notch 2, directly enhances nk cytotoxicity, ifn-production, and proliferation (kijima et al., 2008). from these studies, it is evident that notch signaling apparatus is critical not only for t cell effector and memory functions but also for nk cell function. overcoming tumor interference with lymphopoietic notch given the critical roles of notch in providing instructive signals for t cell and nk cell differentiation and function, it is logical to consider that tumors will interfere with notch signaling in lymphocytes to promote and sustain tumor growth. indeed, tumors downregulate or perturb notch signaling in lymphocytes to escape immune surveillance. moreover, tumors tend to alter the expression of notch ligands as a prominent mechanism of immunosuppression in conjunction with elevated circulating levels of vascular endothelial growth factor (vegf) (huang et al., 2011; novitskiy et al., 2010). in particular, tumors specifically downregulate expression of delta-like ligands dll1 and dll4 in the tumor microenvironment to escape from t cellmediated immunity (biktasova et al., 2015; huang et al., 2011; thounaojam et al., 2015). restoring the cognate notch receptor signaling by enhancing the availability of dll1 by endogenous overexpression or pharmacological administration of clustered multivalent dll1 leads to improved tumor rejection (biktasova et al., 2015; huang et al., 2011). furthermore, tumor-bearing mice following treatment with the proteasome inhibitor bortezomib, showed increased cd8+ t lymphocyte ifn- secretion and perforin and granzyme b expression by enhanced notch-nf-b signaling crosstalk (thounaojam et al., 2015; uzhachenko and shanker, www.companyofscientists.com/index.php/chd e7 cancer health disparities research 2016). thus, for effective treatments and addressal of disparities in cancers, immunotherapeutic strategies would need to overcome tumor-induced notchbased immunosuppression. concluding remarks and future perspectives although much remains to be learned about key aspects of notch basis of cancer disparities, available evidence is clear to suggest that notch signaling is crucial for antitumor lymphocyte effector and memory functions. notch signaling is perturbed in hematopoietic cells by tumor growth for its advantage, and there are indications that differences in notch components could underlie poor cancer prognosis in certain racial/ethnic populations. due to the heterogeneity of notch signaling in tumors and the potential for notch to be oncoand tumorigenic on one hand and lymphostimulatory on the other, racial disparities in cancer may be addressed through systematic elucidation of following profiles. (1) characterizing the notch profiles of various cancer subtypes and tumor-infiltrating immune cells in various racial/ethnic populations should serve to provide a useful resource for understanding notchbased tumor-immune interactions in the tumor microenvironment. (2) understanding the interindividual host factors that influence naturally occurring lymphocyte responses will also be an important prerequisite to understand the host immune responsiveness and design a successful immunotherapeutic modality. in contrast to our understanding of the naturally occurring immune responses to many infectious agents, our knowledge of the immunogenetic factors that influence immune responsiveness to tumor-associated antigens is vastly incomplete. (3) an improved understanding of the immunogenetic mechanisms underlying t cell and nk cell immunity in disparate racial/ethnic populations will be helpful in designing efficient personalized immune strategies against cancer. this knowledge would also be instrumental in the proper evaluation of lymphocyte-based immunotherapy trials as some people could be naturally high responders to adoptive cell immunotherapy, while others could be low responders. this possibility, unless taken into account, could confound the evaluation of immunotherapy trials. (4) based on the outcomes of these studies, it will, then, be important to develop an immunogenetic signature of notch signaling components, their receptors, ligands and downstream targets, in various racial/ethnic populations and establish their association with antitumor immune response patterns impacting cancer etiology. the studies could also shed light on the prognostic aspects of notch in predicting possible cancer health disparities and the outcome of immunotherapy. findings of these prospective studies would be critical to devise strategies to reverse notch dysfunction in lymphocytes for effective tumor eradication and durable remission in cancer patients of varied ethnic backgrounds. acknowledgements the authors are thankful to the editorial board of cancer health disparities for inviting this article. they are also thankful to gladys simiyu, phd and siddharth pratap, phd for help with the tcga data sets. funding as is supported by funds from the following national institutes of health (nih) grants u54 ca163069-6963, u54 md007593, sc1 ca182843, and r01 ca175370. plt is an md phd candidate supported by grant s21md000104. www.companyofscientists.com/index.php/chd e8 cancer health disparities research conflict of interest the authors declare that no competing or conflict of interests exist. the funders had no role in study design, writing of the manuscript, or decision to publish. authors’ contributions conception and design: as literature review and manuscript writing: plt, as references adler, s.h., chiffoleau, e., xu, l., dalton, n.m., burg, j.m., wells, a.d., wolfe, m.s., turka, l.a., and pear, w.s. 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(2003). overexpression of the notch ligand, jagged-1, induces alloantigen-specific human regulatory t cells. blood 102, 3815-3821. www.companyofscientists.com/index.php/chd e1 cancer health disparities research colorectal adenoma detection rate in northeast texas – outcome from community service project using the fecal immunochemical test and colonoscopy gabriela orsak1, harrison ndetan1, carlton allen2, karan p. singh1, paul mcgaha3 1 university of texas health science center at tyler, department of epidemiology and biostatistics, tyler, tx, usa 2 university of texas health science center at tyler, center for rural and community health, tyler, tx, usa 3 university of texas health science center at tyler, department of community health, tyler, tx, usa *corresponding author email: gabriela.orsak@uthct.edu abstract colorectal cancer (crc) is the fourth most frequently diagnosed cancer in the united states. crc incidence rates in northeast texas, a primarily rural region of the state, far exceed state and national averages. the current study sought to determine the proportion of polyps found in a sample of 5,391 individuals living in northeast texas using either colonoscopy or fecal immunochemical testing. in addition, the role of insurance to crc screening was also investigated. an adenomatous polyp was detected in 44.7% participants in the colonoscopy group and in 2.6% of participants undergoing fit testing. additionally, participants in the colonoscopy group who were unor under-insured were 30% more likely to have an adenomatous polyp detected. while a larger proportion of participants had an adenomatous polyp detected in the colonoscopy group, many including the unor under-insured are not able to afford, at which point fit testing may be a better option. keywords: colorectal cancer; adenoma; rural; colonoscopy; fecal immunochemical test citation: orsak g et al (2019) colorectal adenoma detection rate in northeast texas – outcome from community service project using the fecal immunochemical test and colonoscopy, research reports 3: e1-e10. doi:10.9777/chd.2019.1009. www.companyofscientists.com/index.php/chd e2 cancer health disparities research introduction northeast texas is a primarily rural, medically underserved, region of texas with many health disparities (nehme et al., 2016). a recent report published on the health status of this region found that if northeast texas was its own state, it would be ranked 45th in all-cause mortality (nehme et al., 2016). access to primary or specialty care in this underserved region is limited due to a lack of providers. in addition other barriers to care exist, such as distance to specialty care, high rates of poverty, and an older population (nehme et al., 2016). around 21% of northeast texas adults report not visiting a doctor in the past 12 months due to cost. one such condition that disproportionately affects this area, primarily affects older adults and requires regular screening for prevention is colorectal cancer (crc). crc is the fourth most frequently diagnosed cancer in the united states (u.s. cancer statistic working group, 2016) with an age-adjusted incidence rate of 38.27 per 100,000 (national cancer institute, 2017a). while these rates are similar to those observed in the state of texas (38.1; texas cancer registry, 2018b), rates of crc in the primarily rural region of northeast texas (regions 4 and 5) far exceed the state rate and national averages (age adjusted incidence in region 4 = 43.3, region 5 = 43.6; texas cancer registry, 2018b) this follows a similar trend of crc mortality, where rates in northeast texas (15.8 – 16.9; texas cancer registry, 2018a) far exceed the state (14.4; texas cancer registry, 2018a) and national (14.1; national cancer institute, 2017b) averages. as in most cancers, crc morbidity and mortality can be reduced or even prevented if crc is diagnosed early. crc typically develops from adenomatous polyps (american cancer society, 2017). these polyps are precancerous polyps that can develop into crc. therefore, the detection and subsequent removal of adenomatous polyps prevents crc (american cancer society, 2018). this has been achieved through preventive screenings with the use of the fecal immunochemical test (fit) and colonoscopy. however, with a high poverty rate, difficulty accessing specialty care (distance to provider and lack of provider), and an older population in northeast texas, receiving preventive care for crc can be challenging. colonoscopy is invariably considered the gold standard for crc screening (friedrich et al., 2015; lieberman et al., 2012). colonoscopy is able to identify and remove polyps that can be divided into the following types: 1) hyperplastic (polyps with no malignant potential), 2) adenomatous (polyps with malignant potential), and 3) malignancies (lieberman et al., 2012). detection and removal of adenomatous polyps can prevent these polyps from progressing into malignancies and hence reduce or prevent mortality (lieberman et al., 2012). however, colonoscopy is an invasive procedure, with many barriers that tend to prevent many individuals from completing the procedure. for example, the need for sedation, arranging transportation to and from the hospital, missing work, etc. which are typical experiences with the procedure. fit testing, on the other hand, has attracted a lot of interest and seemed to be better accepted (segnan et al., 2007) by the general public. this procedure is less invasive and less time consuming than colonoscopy but is not complete crc screening method on its own (quintero et al., 2012). with fit, participants send a stool sample to www.companyofscientists.com/index.php/chd e3 cancer health disparities research a laboratory from the convenience of their home. the test identifies the stool sample as either normal or abnormal. if the test comes back abnormal, participants are urged to undergo a colonoscopy in order to detect and remove potential polyps. thus, this test enables only participants with abnormal fit test results to have undergoing the less desired colonoscopy. the current goal set by the u.s. department of health and human services in the healthy people 2020 is to achieve a 70.5% crc screening rate. however, even with the availability of both screening methods, crc screening rates remain suboptimal in the general public (62.4%; u.s. department of health and human services, 2018) and in rural communities (58.2%; u.s. department of health and human services), with rates being even lower in northeast texas (44.63%; hall, 2018). they are even much lower among the uninsured (25.1%). the high crc prevalence and yet low screening rates in the northeast texas region is a growing concern. while the reason for this remains elusive, a few factors typical of a rural setting, may potentially be incriminated. having other health burdens coupled with low health literacy, preventive care is hardly a priority. the region is vast in size and consists of rural counties with few small metropolitan statistical areas. poor access to safe and affordable transportation presents an extra challenge to residents who must often travel long distances to a healthcare facility. due to fewer available providers compared to urban settings, waiting periods to get an appointment is generally longer (texas medical board, 2017). the region is predominantly inhabited by low-to moderate income individuals and families living below the federal poverty line, (the henry j. kaiser family foundation, 2014) making it difficult for them to afford health insurance. crc detection rates for rural residents are not well established. in addition, with the emergence of fit testing, detection rates for rural residents have not been established. particularly, the role of insurance to crc screening in this setting has never been investigated. as a consequence, the current study sought to: 1. investigate crc adenoma detection rates in primarily rural northeast texas by fit test and colonoscopy. 2. examine the impact of not having health insurance on adenoma detection rates. materials and methods the study was part of a community outreach program for crc screening in 19 counties of northeast texas organized by the northeast texas center for rural and community health (netcrch) at the university of texas health science center at tyler (uthsct). the project was funded by the cancer prevention research institute of texas (cprit) and was deemed exempt by the uthsct institutional review board (irb). study participants were recruited either by referrals from uthsct clinics (general population) or through community outreach events organized by netcrch which targeted unor under-insured individuals. with the exception of some small metropolitan statistical areas, the catchment area consisted of rural communities with little or no access to public transportation. data was collected between 2014 and 2017. it includes all colonoscopies and fit tests performed at uthsct. a resident of northeast texas was considered eligible to participate in the study if the resident www.companyofscientists.com/index.php/chd e4 cancer health disparities research was 44 to 76 years of age, spoke english or spanish, and was currently undergoing a colonoscopy and/or fit test. individuals previously diagnosed with crc were considered ineligible. figure 1 describes the flow of participants through the study. the final study sample consisted of 5,391 participants. if participants were seen at the uthsct clinics and met all inclusion/exclusion criteria, they were recommended/referred for colonoscopy and/or fit test regardless of payer source. participants were offered colonoscopy and/or fit test based on their preference and/or provider recommendation. if participants were deemed unor underinsured and unable to pay for services, screenings were provided free-ofcharge, as a part of the cprit grant, otherwise they had to pay for their screening. participants recruited through clinics or outreach events that were a part of the cprit grant were provided an additional gift card of $20 for transportation upon completion of a colonoscopy. participants who elected to take the fit test were scheduled for colonoscopy if they had an abnormal fit result (and subsequently received the same $20 gift card for transportation upon completion of colonoscopy). figure 1. consort diagram outcome and other variables of interest the key outcome variables of interest for this study were the results of the fit test and colonoscopy. fit test participants who completed a fit test received a normal or abnormal result. if an abnormal result was received, participants were scheduled for a follow-up colonoscopy. for analytical purpose, the results of the fit test were categorized as: 1) normal, 2) hyperplastic polyp only, 3) adenomatous polyp, 4) malignancy and 5) abnormal fit test result, but no follow-up result with colonoscopy. colonoscopy colonoscopy outcomes were divided into four categories: 1) normal, 2) hyperplastic polyp only, 3) adenomatous polyp, and 4) malignancy. www.companyofscientists.com/index.php/chd e5 cancer health disparities research demographic and medical information demographic (gender, race/ethnicity) and medical information (insurance status, family history of cancer) were gathered through patient record and electronic medical record. insurance status, gender, previous screening, and family history of colon cancer were coded as dichotomous, race/ethnicity was coded as non-hispanic white, non-hispanic black, hispanic, and asian. meanwhile age was retained as continuous. statistical analysis data was analyzed using statistical package for social science (spss) version 23.(ibm corporation, 2015) descriptive statistics are reported for demographic and medical variables, including prevalence rates of neoplasms (table 1). table 1. demographic and other distributions of study participant who originally opted for fit and colonoscopy for colorectal cancer screening (outcome of a northeast texas community service project). variable overall n (%) fit test** n (%) colonoscopy n (%) p-value* overall 5,391 2,108 (39.1) 3,283 (60.9) <0.001 age mean (sd) 59.0 (6.6) 57.5 (5.6) 60.0 (6.9) <0.001 gender male 1,978 (36.7) 665 (31.5) 1,313 (40.0) <0.001 female 3,413 (63.3) 1,443 (68.5) 1,970 (60.0) race/ethnicity <0.001 non-hispanic white 3,057 (56.7) 1,081 (51.3) 1,976 (60.2) non-hispanic black 1,119 (20.8) 332 (15.7) 787 (24.0) asian 40 (0.7) 16 (0.8) 24 (0.7) hispanic 1,170 (21.7) 676 (32.1) 494 (15.0) missing 5 (0.1) 3 (0.1) 2 (0.1) insurance status <0.001 unor underinsured 3,033 (56.3) 1,962 (93.1) 1,071 (32.6) insured 2,358 (43.7) 146 (6.9) 2,212 (67.4) previous screening <0.001 no 2,429 (45.1) 1,218 (57.8) 1,211 (36.9) yes 1,667 (30.9) 439 (20.8) 1,228 (37.4) did not provide an answer/missing 1,295 (24.0) 451 (21.4) 844 (25.8) family history of colon screenings < .001 no 4,210 (78.1) 1,546 (73.3) 2,664 (81.1) yes 463 (8.6) 97 (4.6) 366 (11.2) did not provide an answer/missing 718 (13.3) 465 (22.1) 253 (7.7) details of test results normal 1,913 (90.7) 1,472 (45.2) hyperplastic polyp 11 (0.5) 285 (8.8) adenomatous polyp 53 (2.6) 1,467 (45.0) malignancy 2 (0.1) 33 (1.0) www.companyofscientists.com/index.php/chd e6 cancer health disparities research abnormal fit test result, but no follow-up with colonoscopy 129 (6.1) missing ɨ 26 (0.9) *p-value for age was based on analysis of variance, and for the rest were based on the pearson’s chi-square test. **fit: fecal immunochemical test. of the 247 who tested abnormal, 129 failed to follow-up with colonoscopy and 118 underwent colonoscopy followup (resulting in 52 normal and 66 abnormal results) with details as specified in the table. ɨ final result for colonoscopy not available due to poor bowel prep demographic and other differences in the distribution of the results of the fit test and colonoscopy were assessed using the pearson’s chi-square test or a binomial test of proportion. the multinomial logistic regression model that controlled for gender, age, race/ethnicity, previous screening, and family history of colon cancer was applied to generate odds ratio (or) and 95% confidence interval (ci) that assesses the likelihood that individuals who received any of the abnormal screening results (fit and colonoscopy) were un-/under-insured compared to those who were insured. results descriptive statistics the general characteristics of the study sample is depicted in table 1. of the 5,391 participants, 3,057 (56.7%) were non-hispanic white, 1,119 (20.8%), non-hispanic black, 1,170 (21.7%) hispanic, 40 (0.7%) asian, and 5 (0.1%) were of unknown race/ethnicity. the mean age was 59 ± 6.6 years. they were predominantly females (n = 3,413, 63.3%), with a slight majority being unor under insured (n = 3,033, 56.3%). a family history of colon cancer was identified in 463 (8.6%) individuals. originally, a majority of the study participants elected to undergo a colonoscopy screening (3,283, 60.9%) compared to fit test (2,108, 39.1%), a statistically significant difference (p < 0.001). there was also statistically significant differences in the demographics of these individuals. the fit group was generally younger (p < .001), with fewer males (p <0.001) and being unor underinsured (p < 0.001), compared to the colonoscopy group. finally, a larger proportion of colonoscopy results (1,785, 54.2%) were found to be abnormal than fit test results (195, 9.3%) as compared to having a normal result, a statistically significant difference (p <0.001). fit test results of the 2,108 who underwent fit testing originally, 247 (11.7%) had abnormal results. of those deemed abnormal, subsequent colonoscopies identified both normal and abnormal outcomes. of the 247 with abnormal fit results, 129 (52.2%) receiving an abnormal result, but failed to undergo a colonoscopy for further diagnosis. the remaining 118 (47.8%) who opted for a follow-up colonoscopy screening reported the following results: 53 (44.9%) normal, 11 (9.3%) hyperplastic polyp, 54 (45.8%) adenomatous polyp, and 2 (1.6%) malignancies (table 1). finally, likelihood ratio tests revealed a non-significant effect of insurance status on fit test result (p = 0.419). colonoscopy results results of colonoscopy revealed, 1,472 (44.8%) had a normal results, 285 (8.6%) had a hyperplastic polyp, 1,467 (44.7%) had an adenomatous polyp, and 33 (1%) had a malignancy (table 1). likelihood ratio tests revealed a significant difference in colonoscopy outcome among the insured and un-/underinsured, p = 0.047. there was a statistically www.companyofscientists.com/index.php/chd e7 cancer health disparities research significant 30% increased odds of having an adenomatous polyp among the un-/under-insured as compared to the insured [or = 1.30, 95% ci: 1.05, 1.61]. no significant differences were found for those with a hyperplastic polyp or a malignancy. results are displayed in table 2. table 2. odds ratios and 95% confidence intervals of multinomial logistic regression results examining effect of insurance status on colonoscopy group. colonoscopy group results variable hyperplasia adenoma malignancy gender 0.95 [0.70, 1.29] 0.72 [0.60, 0.86]* 1.28 [.48, 3.37] age 0.99 [0.96, 1.01] 1.04 [1.02, 1.05]* 1.04 [.97, 1.13] family history of colon cancer 1.14 [0.75, 1.73] 1.03 [0.79, 1.34] 1.03 [.29, 3.61] previous screening 1.43 [1.03, 2.05]* 0.91 [0.73, 1.13] 0.93 [.31, 2.78] non-hispanic black 0.78 [0.54, 1.11] 0.85 [0.69, 1.05] 0.47 [.13, 1.63] asian 0.38 [0.05, 2.97] 0.45 [0.17, 1.23] hispanic 0.53 [0.33, 0.85]* 0.61 [0.47, 0.80]* 0.26 [.05, 1.23] insurance status 0.98 [0.69, 1.39] 1.30 [1.05, 1.61]* 0.60 [.20, 1.76] note. race/ethnicity was compared to non-hispanic white; results of colonoscopy group are compared to normal results; insurance status coded as 0 for insured and 1 for uninsured; family history of cancer coded as 0 for no and 1 for yes; previous screening coded as 0 for no and 1 for yes; results with no odds ratio and 95% confidence interval entered were not able to be calculated due to low sample sizes; * p <0 .05 discussion tests that can identify adenomatous (precancerous) polyps before they become cancerous are crucial to reduce health disparities among rural residents. the current study found a very high adenoma detection rate. while results differ from study to study, different studies report prevalence rates as low as 1.3% (gupta et al., 2013), or as high as 58%, (øines et al., 2017) although most rates vary between 25 to 50% (bretthauer et al., 2016; giacosa et al., 2004; hilsden et al., 2016; ijspeert et al., 2015; øines et al., 2017; quintero et al., 2012),depending on country where study was conducted or other factors. however, studies focus on adenoma detection rates identified via colonoscopy in primarily urban settings and research among underserved rural populations is sparse. further, studies are limited on fit test adenoma detection rates due to its nascence, especially among underserved rural populations. the high prevalence rates detected add to the current literature on rural populations and are important to note, especially when compared to a recent randomized control trial conducted in a different part of the state. specifically, a similar study conducted in southern texas found adenoma detection rates that ranged between .8% for fit test and 1.3% for colonoscopy (gupta et al., 2013). while the study did not examine differences among insurance rates and was conducted in a primarily urban setting, the adenoma detection rates for the current study were much higher, with rates ranging from 2.6% for fit test and 44.7% for colonoscopy. these results shine to light: 1) the large disparity in adenoma detection rates when using a fit test as compared to a colonoscopy and 2) the large adenoma detection rate in this primarily rural setting. while the adenoma detection rate was lower for fit testing when compared to colonoscopy, a previous study found that the fit test results are www.companyofscientists.com/index.php/chd e8 cancer health disparities research not as high as colonoscopy (quintero et al., 2012). however, the discrepancy between adenoma detection rate between fit and colonoscopy varied only by a small amount (.9% for fit vs. 1.9% for colonoscopy), (quintero et al., 2012) while the current study found a much larger variation. other potential explanations may be that for example the fit test group consisted of participants who were younger and more likely to be female, both factors that contribute to adenoma detection (corley et al., 2013). nevertheless, the fit test provides many practical benefits that warrant its use, especially among low income populations. first, the fit test is less burdensome on participants and allows for not having to take off of work or figuring out transportation. second, it is a far less costly procedure (corley et al., 2013) that can therefore be disseminated to a larger public health population. however, it is suggested that a fit test need be completed every year (corley et al., 2013). this might prove to be burdensome for many, as compared to a colonoscopy which needs to be completed every few years (depending upon physician recommendation for follow-up). due to this burden the un-/under-insured may not complete fit testing as often as recommended after their initial fit test, with the potential of future adenomas or malignancies being undetected until it is too late. proportions of adenomas detected were higher for colonoscopies, with almost half of all participants having an adenomatous polyp detected. the removal of these polyps will help to hopefully reduce the rate of colorectal cancer among this population, although such outcomes could not be surmised by the current study. being un-/under-insured played a very important role in colonoscopy, but not fit test results. the un-/under-insured were more likely to have an adenomatous polyp detected for colonoscopy. while insurance status did not have an effect on fit test results, a large proportion of participants with abnormal results failed to follow-up for subsequent colonoscopy. an abnormal fit test result without follow-up colonoscopy to further diagnose and/or remove potential polyps deems the fit test impractical. it is especially important to note since all fit tests and colonoscopies were provided free-of-charge to the un-/under-insured and a transportation gift card was provided for the un-/under-insured who underwent a colonoscopy, therefore reducing the additional barrier of cost to this population. however, we were not able to reduce the barrier of having to take time off of work to undergo a colonoscopy. implications and limitations the current research has implications for public health policy and/or initiatives in rural, underserved regions. both fit test and colonoscopy proved to have many benefits, as well as disadvantages. while colonoscopies allow participants to undergo just one procedure and allow for removal of polyp at the time of the visit, they are costly and may not be able to be implemented on a larger scale for the un-/underinsured. on the other hand, fit tests are not cost prohibitive and are able to reach a larger population, especially among the un-/under insured. it is important that if public health programs elect to disseminate a fit test program that emphasis be placed on the importance of retesting the same individuals every year, to insure a higher efficacy of the test. this warrants a costeffectiveness or return-on-investment analysis to www.companyofscientists.com/index.php/chd e9 cancer health disparities research assess the efficacy of a fit test outreach program as compared to a colonoscopy outreach program in order to see true implications for public health policy and/or initiatives. the current study was not able to examine differences among those with an abnormal fit test result due to low number of participants receiving a positive fit test result. however, future research will analyze these differences as well as assess the duration of time to follow-up. the current study was also not able to assess whether the removal of adenomatous polyps resulted in decreased crc detection. however, this is outside of the scope of the study as follow-up with this patient population will warrant years of future research. finally, unlike the gupta et al.(gupta et al., 2013) study, the current study gave participants the option to choose between colonoscopy and fit test, which could have resulted in biased results when comparing abnormal rates for fit as compared to colonoscopy. however, adenoma detection rates were still high for both fit and colonoscopy when compared to previously mentioned studies and warrant attention (gupta et al., 2013; quintero et al., 2012). acknowledgements this study was funded by the cancer prevention & research institute of texas (pp140018) and the 1115 medicaid waiver. conflict of interest the authors declare that no competing or conflict of interests exists. the funders had no role in study design, writing of the manuscript, or decision to publish. authors’ contributions carlton allen and paul mcgaha contributed to the acquisition of data and the conduct of the project. karan singh, harrison ndetan, and gabriela orsak contributed to the statistical analysis of the project and generated the initial draft of the article. references american cancer society (2017). colorectal cancer risk factors. https://www.cancer.org/cancer/colon-rectalcancer/causes-risks-prevention/risk-factors.html american cancer society (2018). can colorectal polyps and cancer be found early? . https://www.cancer.org/cancer/ colon-rectal-cancer/detection-diagnosisstaging/detection.html bretthauer, m., kaminski, m.f., løberg, m., and et al. (2016). population-based colonoscopy screening for colorectal cancer: a randomized clinical trial. jama internal medicine 176, 894-902. corley, d.a., jensen, c.d., marks, a.r., zhao, w.k., de boer, j., levin, t.r., doubeni, c., fireman, b.h., and quesenberry, c.p. (2013). variation of adenoma prevalence by age, sex, race, and colon location in a large population: implications for screening and quality programs. clinical gastroenterology and hepatology 11, 172-180. friedrich, k., grüter, l., gotthardt, d., eisenbach, c., stremmel, w., scholl, s., rex, d.k., and sieg, a. (2015). reduced mortality in colorectal cancer patients diagnosed by screening colonoscopy. gi endoscopy 2015, 133-137. giacosa, a., frascio, f., and munizzi, f. (2004). epidemiology of colorectal polyps. techniques in coloproctology 8, s243-s247. gupta, s., halm, e.a., rockey, d.c., hammons, m., koch, m., carter, e., valdez, l., tong, l., ahn, c., and kashner, m. 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(2007). comparing attendance and detection rate of colonoscopy with sigmoidoscopy and fit for colorectal cancer screening. gastroenterology 132, 23042312. texas cancer registry (2018a). age-adjusted cancer mortality rates in texas colon & rectum, 2011-2015 by public health region. texas cancer registry (2018b). age-adjusted invasive cancer incidence rates in texas colon & rectum, 2011-2015 by public health region. https://www.cancer-rates.info/tx/ texas medical board (2017). physicians by county then specialty. http://www.tmb.state.tx.us/dl/8bb44990-aef074d3-defa-c3afe3f33ea8 the henry j. kaiser family foundation (2014). the affordable care act and insurance coverage in rural areas. u.s. cancer statistic working group (2016). united states cancer statistics: 1999–2013 incidence and mortality web-based report (atlanta: u.s. department of health and human services, centers for disease control and prevention, national cancer institute). www.cdc.gov/uscs u.s. department of health and human services. healthy people 2020 (washington dc: u.s. department of health and human services, office of disease prevention and health promotion). https://www.healthypeople.gov/2020/ topics-objectives/topic/cancer/objectives u.s. department of health and human services (2018). c-16 increase the proportion of adults who receive a colorectal cancer screening based on the most recent guidelines. https://www.healthypeople.gov/2020/datasearch/search-the-data#objid=4054;topic-area=3513 www.companyofscientists.com/index.php/chd e1 cancer health disparities research community-clinical linkage intervention to improve colorectal cancer screening among underserved korean americans grace x. ma1,2 minsun lee1 maayan beeber,3 rina das,4 ziding feng,5 min qi wang,6 yin tan,1 lin zhu,1 khursheed navder,3 theresa i. shireman,7 philip siu,8 joanne rhee,1 minhhuyen t. nguyen9 1 center for asian health, lewis katz school of medicine, temple university, philadelphia, pa. 2 department of clinical sciences, lewis katz school of medicine, temple university, philadelphia, pa. 3 hunter college, city university of new york, new york city, new york 4 division of scientific programs, integrative biological and behavioral sciences, national institute of minority, health and health disparities, national institutes of health. 5 the university of texas md anderson cancer center, houston, tx. 6 department of behavioral and community health, school of public health (sph), university of maryland, college park, md 7 department of health services, policy and practice, school of public health, brown university, providence, ri. 8 greater philadelphia health action, chinatown medical services, philadelphia, pa 9 department of medicine, section of gastroenterology, fox chase cancer center, philadelphia, pa. corresponding author email: grace.ma@temple.edu abstract korean americans report the lowest and declined rates of colorectal cancer (crc) screening, compared to general population in the united states. the present study aimed to evaluate the efficacy of a community-based multifaceted intervention designed to improve crc screening among korean americans. a cluster-randomized trial involving 30 korean church-based community organizations (n = 925) was conducted. fifteen churches were assigned to intervention (n=470) and the other 15 to control (n = 455) groups. main components of the intervention included interactive group education, patient navigation, physician engagement, and provision of fecal immunochemical test (fit) kit. crc screening rates were assessed at a 12-month follow-up. participants in the intervention group were significantly more likely to receive crc screening (69.3%) as compared with those in the control group (16%). the intervention was particularly effective in promoting fit among the more disadvantaged individuals in the korean american community. regression analysis revealed that controlling for the intervention effect, male gender, high school education, annual income of $20,000–40,000 were significantly associated with increased screening by fit, whereas english inefficiency was significantly and lack of health insurance was marginally significantly associated with decreased screening by colonoscopy/sigmoidoscopy. culturally and linguistically appropriate multifaceted intervention combining fit provision with community-clinical linkage has a potential to be a cost-effective and practical approach to effectively targeting hard-to-reach disadvantaged minority populations and enhance crc screening to reduce cancer disparities. keywords: colorectal cancer (crc) screening, korean american, intervention, fit, communitybased participatory research citation: ma gx et al (2019). community-clinical linkage intervention to improve colorectal cancer screening among underserved korean americans. cancer health disparities 3:e1-e15. doi:10.9777/chd.2019.1001. www.companyofscientists.com/index.php/chd e2 cancer health disparities research introduction colorectal cancer (crc) is the second most common cancer among korean americans, after lung cancer for korean men and breast cancer for korean women (miller et al., 2008). in the united states, crc incidence rates have decreased over the past decade, with the change of rates by more than 4% per year in both men and women (american cancer society, 2017). however, unlike the general trend, the crc incidence rates among korean americans have increased with the annual percent change (apc) of 3.6% between 1988 and 2007 (giddings et al., 2012; lee et al., 2007). despite the high burden from crc among korean americans, crc screening rates in this population are significantly lower than the national average (maxwell and crespi, 2009; maxwell et al., 2010; hwang, 2013; oh and jacobsen, 2014). currently, several screening tests can be used to find polyps or colorectal cancer. the fecal immunochemical test (fit) uses antibodies to detect blood in the stool, which is an early sign of cancer. colonoscopy and sigmoidoscopy both use a thin flexible lighted tube with a camera at the end to check for polyps or cancer inside the rectum and the colon. the difference between the two procedures is that a flexible sigmoidoscopy examines the left lower third of the colon with a short tube, while colonoscopy examines the entire colon with a longer tube (center for disease control and prevention, 2017). the prevalence of crc screening in accordance with guidelines among the general us population 50 years of age and older and overall asian americans in 2015 was 62.6% vs 49.4% (american cancer society, 2014). however, a systematic review of thirteen studies on crc screening among korean americans published until may 2013 (oh and jacobsen, 2014) indicated that only one in four korean americans aged 50 and older reported having ever had fit and approximately 40% reported having ever had a sigmoidoscopy or colonoscopy in different studies. in addition, screening rates decreased for both colonoscopy and fit in korean americans, while the rates increased or were stable in the us general population (maxwell and crespi, 2009). the factors contributing to the low rates of and declining trend in screening among korean americans are complex. inadequate knowledge about screening, screening methods, and its benefits, as well as low perceived risks of crc have been identified as major factors related to low rates of screening among koreans (juon et al., 2003; ma et al., 2009; maxwell et al., 2010). these studies suggest that korean americans may be less familiar with utilizing health care system to detect health problems before the onset of symptoms than other groups, emphasizing the need for education of the benefit of screening before symptoms develop. in addition, the decline of crc screening rates of this population has been associated with limited access to health system due to lack of insurance, language inefficiency, and lack of transportation (jo et al., 2008; lee and im, 2013; lee and lee, 2013). with the high crc burden combined with low rates of screening uptake due to multilevel barriers, korean americans, particularly, disadvantaged groups with limited english proficiency and low income are an important target group for implementation of innovative and culturally tailored programs to enhance crc screening. collaboration among multisector stakeholders, the community members and leaders, clinical providers and researchers, has great potential to enhance cancer screening for this population. community-based organizations (cbos) who work directly with the target population serve as a venue for promotion of knowledge and awareness of crc screening and reduction of barriers to screening (israel et al., 2005). engaging cbos and clinical providers (primary care practices, pcps) can deliver screening test more effectively by reaching the underserved and hard-to-reach individuals who rarely visit doctors for preventive care. therefore, implementation of crc screening in this www.companyofscientists.com/index.php/chd e3 cancer health disparities research underserved population requires establishing strategic partnerships between community and clinical settings and sharing their infrastructure and capacity to enhance engagement of potential patients and pcps in crc screening, and follow-up care (ockene et al., 2007; krist et al., 2013; persson, 2016). however, there is clear paucity of culturally and linguistically appropriate crc community clinical linkage intervention (ccl), designed to improve crc screening among korean americans. to our knowledge, no study has investigated the impact of the ccl intervention for crc screening in korean americans, except for the one we conducted in a small scale quasi-experimental design (ma et al., 2009). in our previous study, we reported that a culturally and linguistically tailored church-based intervention combined with patient navigation assistance and physician engagement (including screening reminder, scheduling appointment, transportation assistance to clinic sites, navigation for screening, follow up care and medical record verification) was effective in increasing crc screening rate. building on our preliminary data (ma et al., 2009), the present study was designed to evaluate the impact of a large-scale cluster group randomized trial on crc screening. regarding crc screening methods or modalities, colonoscopy is most commonly recommended in the united states. colonoscopy has a high sensitivity for polyps and cancer, but is invasive, cumbersome, expensive, and thus, has limited availability in many underserved minority populations (lieberman et al., 2000; inadomi et al., 2012; elmunzer et al., 2015). although fit has less sensitivity for polyps and cancer than colonoscopy, it has advantage of being non-invasive, easy-to-do at home, inexpensive, and more readily available as a first step of detecting abnormality. indeed, when offered or recommended, individuals, particularly from underserved communities, were more likely to complete fit than colonoscopy, suggesting that fit based outreach was more effective than colonoscopy-based outreach in increasing screening rates among underserved populations (inadomi et al., 2012; gupta et al., 2013; singal et al., 2016). according to these studies, a programmatic method with less invasiveness and more availability with minimal resources and infrastructure such as fit appears to be a promising intervention modality for improvement of crc screening among underserved populations. this article evaluated the primary outcome, efficacy of a culturally and linguistically appropriate communityclinical linkage intervention that included provision of fit, group education, patient navigation, and physician engagement on crc screening. methods participants korean americans (n = 925) enrolled in this study were members of korean churches (n = 30) in philadelphia and new jersey regions that serve a predominately underserved immigrant population. more than 78% of koreans in the us are affiliated with churches (chang, 2003; ma et al., 2009; min, 2002) and the churches serve as one of the community-based organizations facilitating discussion of and participation in various cultural, social and personal activities. thus, korean church is one of the important venues to deliver culturally appropriate intervention to provide health education and promote crc screening among korean americans. participants were eligible to participate in this study if they: (1) were selfidentified korean americans; (2) were 50 years and older; (3) did not have a colorectal polyp, crc cancer, or a family history of crc (first degree relative); and (4) non-adherent to crc screening guidelines (never had any crc screening or were overdue for screening). based on the crc screening guidelines recommended by the acs, “overdue” was defined by no fit in the past year www.companyofscientists.com/index.php/chd e4 cancer health disparities research or no sigmoidoscopy in the past five years, no double-contrast barium enema in the past five years, or no colonoscopy within the past ten years. procedures the study was designed as a collaborative partnership among an academic institution, korean churches, community-based organizations (cbos), and healthcare providers/organizations. a framework for community-clinical linkages was used to guide the current study and collaboratively established crc screening program and referral systems that connect individuals with abnormal screening results to clinical care. as part of collaboration, korean churches provided facilities and resources to promote awareness and knowledge about crc screening through provision of education sessions and fit kits. academic researchers coordinated each stage of study by linking community and clinical settings and provided navigation services as needed. participants who performed fit testing were asked to mail the samples in a provided envelope to their providers. participants do not have regular physicians or health insurance, were encouraged to mail the samples to the partnering clinicians or health centers of our network. participants with an abnormal fit result were notified with a letter written by a clinician and referred to diagnostic colonoscopy. the cah research team at temple university has an established network of participating clinical partners who provide a range of health services either at reduced cost to patients who are uninsured or underinsured. thus, those who had no primary care physician or medical insurance were sent to the collaborating clinical partners for the diagnostic test. this study was approved by the temple university institutional review board. study design the study utilized a two-arm cluster randomized design with churches as the unit of randomization (fig 1). based on organization profile information provided by collaborating church leaders, we paired the 30 churches by size and geographic location. then, each cbo of the 15 pairs was randomly assigned to the intervention or control group. we conducted baseline evaluation, postintervention assessment, and a 12-month followup on screening outcome. baseline and postintervention assessments were administered in person while the 12-month follow-up assessments were conducted by telephone interviews and primary outcome of screening was verified through medical record. intervention and control conditions the intervention was designed to improve crc screening among participants who are nonadherent to crc screening guidelines by addressing multilevel barriers. main intervention components included interactive group education, navigation services and engagement of health care providers for referrals, and linkage to care. the interactive group education was aimed to increase participant overall understanding of crc, screening methods, and utilization of available resources such as home test kit and navigation services, with the ultimate goal of increasing screening rates. bilingual health educators facilitated discussion on crc susceptibility and severity among korean americans and the u.s. general population, benefits of crc screening, and crc screening options and their associated clinical procedures, as well as the pros and cons of each option. to increase their motivation for crc screening and awareness of the different methods, fit home kit was offered to the participants with instructions in korean. although it is provided to all participants in intervention group, they were encouraged to choose any screening methods convenient for them. clinical partners provided clinical support and ensured successful screening assessment and follow-ups by offering more flexible hours of clinic operation with bilingual medical staff on site. patient navigation assistance was also offered based on participants’ needs. the range of assistance included scheduling www.companyofscientists.com/index.php/chd e5 cancer health disparities research appointments with clinical partners for sigmoidoscopy/ colonoscopy for screening and diagnosis after a fit positive result, assisting paper work and communication with a physician, and arranging transportation. figure 1. study design flow chart. in the control condition, participants (n = 455) received a group education session in a similar format with that of the intervention group delivered by trained korean community health educators. different from the intervention group, the education focused on general health education and primary prevention issues, including routine health examinations and screening for various diseases such as cancer. korean version of standard printed materials and guidelines related to the education contents were also provided, including crc screening guidelines. measures this study assessment was designed to evaluate the multilevel intervention including individual participants’ level, cbo organization level and clinical linkage to care level, as a result of www.companyofscientists.com/index.php/chd e6 cancer health disparities research education, patient navigation, and physician engagement for linkage to care. at participants’ level, we assessed participants’ satisfaction on each component of intervention, screening behaviors and knowledge improvement. in addition, as a process outcome, we assessed the adherence of main stakeholders (cbos, patient navigators and clinical providers) to basic cbpr principles of collaboration in various stages of the project implementation. since the main purpose of this article was to report the efficacy of the intervention on participants’ screening behaviors, we only reported crc screening as primary outcome measures and relevant results. participant characteristics. demographic information such as age gender, education, marital status, household income, employment was collected at baseline. acculturation related information such as years living in the us and the english ability was also collected. in addition, information on health insurance and regular physician status was collected to learn the levels of health care access of the participants. barriers to screening. barriers to crc screening were evaluated by asking them the question: “if you have never had any of the screening such as stool blood test, sigmoidoscopy or colonoscopy, what are the major reasons?” the choices include ‘do not know what it is’, ‘do not know where to get it’, ‘do not have time’, and ‘feel healthy and do not think needing a test.’ screening behavior. the primary outcome was crc screening status (completion of either fit kit, sigmoidoscopy, or colonoscopy) at the 12-month follow-up. bilingual interviewers contacted participants at 12-month follow-up and assessed screening behavior using self-report (“over the past 12 months, have you had a test for colorectal cancer?”; yes/no, and “if you had, what is the test?”; stool blood test using fit kit/colonoscopy/sigmoidoscopy). participants who reported receiving fit were verified with the list of those who returned the stool sample and received the test results from the collaborating clinical laboratory. participants who reported receiving colonoscopy or sigmoidoscopy were asked to provide a medical release consent to allow project staff to contact their health care providers to validate self-reported testing. participants who received positive fit results and were referred to diagnostic colonoscopy were also followed-up. data analysis participant characteristics were described using frequencies and percentages within each of the treatment groups (intervention versus control). the chi-square test was used to assess whether the distributions differed between the treatment groups. the chi-square test was also used to compare the proportion of participants in the intervention and control groups who completed crc screening within 12 months of the intervention. the proportion of participants who completed screening was compared by different crc screening methods and by recruitment sites. to investigate whether the intervention was particularly effective in disadvantaged individuals, the comparison of screening rates between intervention and control groups was conducted only among the disadvantaged group (i.e., high school or less education, income of <$40,000, no insurance etc.). finally, logistic regression analyses were conducted to explore the factors associated with fit and colonoscopy/sigmoidoscopy. in the models, the covariance matrix was adjusted to account for clustering of individuals at the church level. all analyses were performed in sas version 9.3 assuming a type 1 error of 0.05. results www.companyofscientists.com/index.php/chd e7 cancer health disparities research participant characteristics overall, there were slightly more women (59.2%) than men enrolled in the study. majority of participants were married (80.4%) and did not speak english well (74.1 %). roughly half were college or higher level educated (50.4), insured (49.7%), and had a regular physician (55.5%). more than half were employed (56.8%) and earned less than $40,000 (66.1%). table 1 describes and compares sociodemographic characteristics for the intervention and control groups. more participants in the control group than in the intervention group earned greater than $40,000 in annual income (28.1% vs. 21.2%; p = 0.050), and had health insurance (55.5% vs. 46%; p = 0.005). the distribution of other demographic, acculturation, and health access variables were not significantly different between groups. barriers of screening were generally similar in distribution between the intervention and control groups, with the exception of three variables. participants in the intervention group were more likely than those in the control group to endorse ‘not being able to afford it’ (28.4% vs. 22.9%; p = 0.012), and ‘feeling healthy’ (22.9% vs. 14.3%; p =0.001) as the reason of not having had screening. however, less participants (16.0%) of the intervention group reported ‘not knowing what screening is’ compared to those in the control group (21.6%; p = 0.035) (table 1). screening rates by methods and sites as shown in table 2-1, crc screening behaviors were significantly different between intervention and control groups. in the intervention group, a total of 277 out of 400 participants (69.3%) were screened for crc at 12 months, compared to 61 out of 382 (16.0%) in the control group (χ2 (1) = 226.04, p<0.001). in the intervention group, the majority (66.8%) screened by fit, and minority screened by colonoscopy (2.0%) and sigmoidoscopy (0.3%). in contrast, in the control group a minority (1.8%) screened by fit, and the majority screened by colonoscopy (11.5%) and sigmoidoscopy (5.8%). as shown in table 2-2, out of the 15 paired church sites in the study, the majority (n = 12) had screening rates significantly higher by intervention group than by control group: the screening rates in the intervention group ranged from 60.0% to 93.8%, while corresponding control group screening rates ranged from 0% to 38.9%. however, at 3 church pairs (5th, 8th, and 14th), screening rates were not significantly different between the two treatment groups, with substantially low level of screening rates (33.3% 45.8%) compared to other sites in the intervention group. compared to the intervention participants from the other church sites, those from the 5th, 8th, and 14th church pairs were more likely to have college or higher education (73.8% vs. 51.2%; p = 0.005), be employed (73.8 % vs. 55.7%; p = 0.01), have greater than $40,000 annual income (49.1% vs. 15.9%; p < 0.001), and have health insurance coverage (56.5% vs. 42.9%; p = 0.048). screening rates among disadvantaged individuals difference in crc screening rates between intervention and control groups were heightened when examined among disadvantaged individuals only (table 3). specifically, among the participants who had an education of high school level or below, annual household income of less than $40,000, were unemployed, could not speak english, and had no health insurance or access to a regular physician, the average rates of screening were consistently over 70% in the intervention group. however, the screening rates in the control group among the disadvantaged individuals were generally lower than the overall screening rates in the control group except for the unemployed participants. the difference in screening rates between the two groups were even higher among those who faced barriers to screening such as not knowing what crc screening is (69.4% vs. 7.8%), www.companyofscientists.com/index.php/chd e8 cancer health disparities research not knowing where to get it (81% vs. 10%), not being able to afford it (70.6% vs. 6.3%), having a language difficulty (80% vs. 11.1%) and feeling healthy (71.4% v. 9.3). table 1. characteristics of intervention and control group participants: crc screening program (n=925). variable intervention group (n=470) no. (%) control group (n=455) no. (%) p1 age (mean years) 62.28±9.94 62.93±9.27 0.361 gender 0.158 male 197 (42.5) 171 (37.8) female 267 (57.5) 281 (62.2) marital status 0.404 married 378 (81.5) 351 (79.2) not married 86 (18.5) 92 (20.8) education 0.104 below high school 55 (12.1) 71 (16.2) high school graduate 150 (32.9) 153 (34.9) some college or higher 251 (55.0) 215 (49.0) annual household income 0.050 less than $20,000 157 (36.9) 139 (36.2) $20,000 $40,000 178 (41.9) 137 (35.7) greater than $40,000 90 (21.2) 108 (28.1) employment 0.736 employed 257 (56.2) 251 (57.4) unemployed/retired/homemaker 200 (43.8) 186 (42.6) year living in us <0.001 less than 10 yrs 90 (12.2) 104 (15.5) between 10 and 20 yrs 145 (19.7) 178 (26.6) more than 20 years 501 (68.1) 388 (57.9) ability to speak english 0.296 not at all 43 (9.3) 54 (12.1) not well 299 (64.7) 289 (64.8) well/very well 120 (26.0) 103 (23.1) health insurance status 0.005 no 248 (53.9) 199 (44.5) yes 212 (46.1) 248 (55.5) regular physician status 0.411 no 191 (42.7) 171 (40.0) yes 256 (57.3) 257 (60.0) barriers to screening do not know what it is 0.035 unchecked 393 (84.0) 356 (78.4) www.companyofscientists.com/index.php/chd e9 cancer health disparities research checked 75 (16.0) 98 (21.6) do not know where to get it 1.000 unchecked 442 (94.4) 429 (94.5) checked 26 (5.6) 25 (5.5) cannot afford 0.012 unchecked 335 (71.6) 358 (78.9) checked 133 (28.4) 96 (21.1) do not have time 0.339 unchecked 413 (88.2) 410 (90.3) checked 55 (11.8) 44 (9.7) transportation difficulty 0.579 unchecked 460 (98.3) 449 (98.9) checked 8 (1.7) 5 (1.1) language difficulty 0.698 unchecked 453 (96.8) 442 (97.4) checked 15 (3.2) 12 (2.6) afraid of pain 0.243 unchecked 439 (93.8) 434 (95.6) checked 29 (6.2) 20 (4.4) feel healthy 0.001 unchecked 361 (77.1) 389 (85.7) checked 107 (22.9) 65 (14.3) 1 p-values based on rao-scott chi-square test excluding missing values. rao-scott chi-square test used to account for design effects of clustering at the site level. table 2-1. crc screening rates at 12 months follow-up by screening methods outcome intervention group (n=400) no. (%) control group (n=382) no. (%) p screened for crc 277 (69.3) 61 (16.0) < 0.001 type of screening fit 267(66.8) 7 (1.8) < 0.001 colonoscopy 8 (2.0) 44 (11.5) < 0.001 sigmoidoscopy 1 (0.3) 22 (5.8) < 0.001 p-values based on chi-square test of fisher’s exact test excluding missing values. www.companyofscientists.com/index.php/chd e10 cancer health disparities research table 2-2. crc screening rates at 12 months follow-up by community sites intervention (n=400) control (n=382) p pair n test rate (%) n test rate (%) 1 33/41 80.5 2/20 10.0 <0.001 2 22/36 61.1 3/17 17.6 0.004 3 30/37 81.1 7/35 20.0 <0.001 4 16/31 51.6 0/21 0.00 <0.001 5 5/15 33.3 10/47 21.3 0.489 6 15/16 93.8 4/30 13.3 <0.001 7 13/20 65.0 1/31 3.2 <0.001 8 11/24 45.8 10/37 27.0 0.171 9 21/28 75.0 0/20 0.0 <0.001 10 30/34 88.2 7/18 38.9 0.001 11 18/21 85.7 4/17 23.5 <0.001 12 18/22 81.8 4/36 11.1 <0.001 13 22/31 71.0 3/14 21.4 0.003 14 11/24 45.8 6/18 33.3 0.530 15 12/20 60.0 0/21 0.0 <0.001 p-values based on chi-square test of fisher’s exact test excluding missing values. table 3. crc screening results 12 months follow-up only among disadvantaged individuals variable intervention n (%) control n (%) p-value high school or below (n=365) 132/175 (75.4) 29/190 (15.3) <0.001 income < $40,000 (n=516) 211/287 (73.5) 37/229 (16.2) <0.001 unemployed (n=310) 117/161 (72.7) 31/149 (20.8) <0.001 englishnot well/not at all (n=580) 207/292 (70.9) 39/288 (13.5) <0.001 no health insurance (n=390) 154/215 (71.6) 14/175 (8.0) <0.001 no regular physician (n=310) 114/162 (70.4) 12/148 (8.1) <0.001 barriers to screening do not know what it is (n=139) 43/62 (69.4) 6/77 (7.8) <0.001 do not know where to get it (n=41) 17/21 (81.0) 2/20 (10.0) <0.001 cannot afford (n=199) 84/119 (70.6) 5/80 (6.3) <0.001 do not have time (n=89) 29/49 (59.2) 2/40 (5.0) <0.001 language difficulty (n=24) 12/15 (80.0) 1/9 (11.1) =0.001 afraid of pain (n=44) 17/25 (68.0) 3/19 (15.8) =0.001 feel healthy (n=144) 64/90 (71.1) 5/54 (9.3) <0.001 www.companyofscientists.com/index.php/chd e11 cancer health disparities research table 4. factors associated with fit and colono/sigmoidoscopy at 12 month follow-up (n=782) variable fit or (95% ci) colono/sigmoidoscopy or (95% ci) intervention group intervention 151.39 (56.97, 402.26)*** 0.10 (0.04, 0.24)*** control (ref) 1.00 1.00 age 1.03 (0.99, 1.07) 0.99 (0.95, 1.04) years in us 1.05 (0.71, 1.55) 0.84 (0.52, 1.36) gender male 2.02 (1.17, 3.49)* 1.06 (0.52, 2.15) female (ref) 1.00 1.00 marital status married 0.99 (0.48, 2.04) 0.64 (0.29, 1.41) not married 1.00 1.00 education below high school 1.50 (0.55, 4.04) 1.80 (0.61, 5.33) high school graduate 2.69 (1.44, 5.03)* 0.92 (0.41, 2.06) some college or higher (ref) 1.00 1.00 annual household income less than $20,000 1.80 (0.78, 4.18) 1.11 (0.38, 3.18) $20,000 $40,000 2.01 (1.02, 3.95)* 1.59 (0.63, 4.00) greater than $40,000 (ref) 1.00 1.00 employment employed 0.934 (0.454, 1.92) 0.61 (0.27, 1.38) unemployed/retired (ref) 1.00 1.00 ability to speak english not at all 0.587 (0.16, 2.11) 0.66 (0.16, 2.65) not well 0.838 (0.45, 1.56) 0.45 (0.20, 0.99)* well/very well (ref) 1.00 1.00 health insurance status no 2.54 (1.20, 5.37)* 0.34 (0.10, 1.18)ɨ yes (ref) 1.00 1.00 regular physician status no 0.80 (0.40, 1.59) 0.80 (0.24, 2.71) yes (ref) 1.00 1.00 analysis accounts for clustering at the church level ɨp-value < 0.1, *p-value < 0.05, **p-value <0.01, ***p-value <0.001 factors associated with fit and colonoscopy as shown in table 4, controlling for intervention effect, several predictors were significantly associated with screening by fit. males were twice as likely to have screened by fit (or = 2.02, 95% ci 1.17–3.49, p = 0.012). individuals who have high school education (or = 2.69, 95% ci 1.44–5.03) www.companyofscientists.com/index.php/chd e12 cancer health disparities research and those who had an annual income of $20,000– $40,000 (or = 2.01, 95% ci 1.02–3.95, p=0.046) were more likely to be screened by fit than those with college or higher education and those with greater than $40,000 income. compared to individuals with health insurance, those without health insurance were 2.5 times as likely to screen by fit (or = 2.54, 95% ci 1.20–5.37, p=0.017). on the other hand, english inefficiency was significantly (or = 0.45, 95% ci 0.20–0.99, p=0.031) and having no health insurance was marginally significantly (or = 0.34, 95% ci 0.10– 1.18, p=0.081) associated with decreased odds of screening by colonoscopy/ sigmoidoscopy. regarding the barriers, controlling for the demographic covariates, ‘fear of pain’ was associated with decreased odds of screening by fit (or = 0.29, 95% ci 0.09–0.98, p=0.050), while ‘not feeling healthy’ was associated with increased screening by colonoscopy / sigmoidoscopy (or = 3.47, 95% ci 1.13–10.67, p=0.031). screening results and follow-up care twenty eight out of 267 (10.2%) who completed fit in the intervention group were screened positive. all the 28 participants with abnormal fit results completed diagnostic colonoscopy with patient navigation assistance and physician engagement in referral and facilitation the linkages to follow up care. discussion this study is the first large-scale cluster randomized, multifaceted community-clinical linkage intervention trial to improve crc screening among underserved and less acculturated korean americans. we found that the intervention consisting of culturally appropriate education, provision of fit, navigation services, and physician engagement was significantly effective in increasing crc screening, particularly among the hard-to-reach korean americans with limited english proficiency. compared to the previous study that 90% of whom had public or private insurance (tu et al., 2006), it is noteworthy that the present study achieved high screening rate among 50% participants were uninsured. the finding of the present study demonstrates the efficacy of a multilevel intervention through community-clinical linkage in this population. korean americans have reported to have the lowest crc screening rates as us general populations with a significant increase in crc screening (maxwell and crespi, 2009; maxwell et al., 2010; hwang, 2013; oh and jacobsen, 2014). as the contributing factors to the crc screening disparities in korean americans, large proportion of them are foreign-born, lack of health insurance, and have a lower household income, in addition to limited awareness and knowledge about crc screening guidelines. indeed, majority of the participants in our study who either never had crc screening or were overdue for screening were with low income, unemployment, english inefficiency, and no health insurance. substantial number of those who have never had crc screening also endorsed ‘cannot afford’, ‘not knowing what it is’, and ‘feeling healthy’ as the main barriers to screening. the successful implementation and outcome of our intervention suggest that enhancing knowledge and access to crc screening through community-clinical linkage is the effective way to improve crc screening, particularly among the hard-to-reach underserved korean american population who experience multiple barriers to screening. community participation played a crucial role in raising awareness, facilitating motivation about cancer screening, and reducing logistical www.companyofscientists.com/index.php/chd e13 cancer health disparities research challenges among this population when clinical settings have the limitation that they can provide services only to individuals who visit the clinical settings. offering education and low-cost fit kits through community settings made it possible to reach the underserved korean americans and engage them in screening behaviors. on the other hand, physician engagement compensated the limited ability of community settings in delivery of clinical care and warranted quality services for the participants in need. this community-clinical linkage intervention seemed to be an essential component in enhancing screening behavior for hard-to-reach populations with multiple barriers to screening. the finding that the intervention was particularly effective in promoting fit is also consistent with the previous studies suggesting that when offered, fit is accepted better than colonoscopy among the underserved populations (inadomi et al., 2012; singal et al., 2016). we did not design our study to compare fit versus colonoscopy, but instead incorporated low-cost fit kit provision into a multifaceted intervention that included education sessions addressing all types of crc screening and navigation assistance to colonoscopy/sigmoidoscopy appointments, allowing the participants to select the methods of crc screening. despite the different options, the majority of the participants in the intervention group selected fit, confirming the previous studies. moreover, we found that the difference in screening rates between intervention and control groups were greater among those who were less educated, having less income, unemployed, unable to speak english, with no health insurance or a regular physician, suggesting that our intervention is more beneficial among the disadvantaged individuals. in contrary, relatively better-off participants did not seem to be as receptive to the resources offered by intervention. for instance, the three paired church sites with the lowest screening rates after intervention were attended by the participants with generally higher education, higher income, and greater health care access compared to their counterparts at the other paired church sites where the screening rates were higher. these findings highlight a promising potential of a multifaceted intervention combining fit provision with cbpr approach for enhancing screening behavior among the most socially and economically disadvantaged members in racial minority communities. furthermore, we found that certain demographic characteristics and barriers to screening were associated with different modalities of crc screening. multivariate analysis revealed that different modalities of crc screening seemed to appeal to different subgroups of participants. controlling for intervention effect, fit screening behavior was associated with high school educated, lower income, males, and those without health insurance. in contrast, colonoscopy/sigmoidoscopy screening behavior was associated with participants who have health insurance and better english proficiency. among the barriers, ‘being afraid of pain’ was associated with increased fit whereas, ‘not feeling healthy’ was associated with increased colonoscopy. these results indicate that the less invasive, low-cost, and more convenient fit screening test are preferred by disadvantaged groups facing generally more barriers to screening. the more invasive but more sensitive and specific colonoscopy/sigmoidoscopy screening modality seems to be preferred among individuals who typically have health care access and have health concerns. future work is needed to gain a deeper understanding of the factors that predetermine preference of crc screening modality among racial minorities. there are several limitations to this study. first, the present study had a short follow-up period which www.companyofscientists.com/index.php/chd e14 cancer health disparities research only studied one-time screening behavior at 12month follow up. since fit screening warrants annual testing to be effective in crc prevention (singal et al., 2017), full understanding about screening behavior compliance requires a longer follow-up study to examine sustained adherence over time. in a previous long term comparative outreach study, the rates of screening decreased as low as 28% when participants were followed up for 3 years (singal et al., 2017) compared to 1-time screening rate of 58.8% (min, 2002). the authors of the study attributed the lower adherence rates in the fit outreach group to the suboptimal completion of colonoscopy after a positive fit result, in addition to the failures of completing subsequent yearly fit screens after initial negative test results. however, given that 100% of those who had positive fit test results in the intervention group underwent diagnostic colonoscopy with navigation assistance in our study, compared to 49.3% in the outreach study for 1-time screening (min, 2002), our study shed the light on the potential impact of the intervention incorporating cbpr approach and navigation service to fit provision on drawing long-term effect with improved sustained adherence to fit. second, despite the randomization procedures, the two groups differed on several demographic variables, including household income, health insurance status, and barriers to screening. however, participants in the control group were more likely to have higher income and health insurance, which are the factors that generally facilitate access to care. significantly lower screening rates in the control group even with this advantage confirm the true robustness of the intervention used in the present study. despite the limitations, our findings support the feasibility and efficacy of a culturally and linguistically appropriate multifaceted communityclinical linkage intervention among the most underserved members in a high-risk racial minority population. the study offers strong evidence that such an intervention approach can be a practical intervention method to effectively target hard-toreach disadvantaged individuals who are otherwise vulnerable to crc screening disparities. future studies will look to investigate deeper into preference of crc screening modality among korean americans and evaluate screening behavior over a longer follow-up period, as well as explore effective strategies to scale up the evidence-based community-clinical linkage intervention for broad dissemination and implementation. acknowledgements this research was supported by center to reduce cancer health disparities, national cancer institute, national institutes of health (nih) (grant u54 ca153513 to pi: grace x. ma, phd, community cancer health disparities center. the authors wish to thank the asian community health coalition and its member community-based organizations for their collaboration and contributions. the contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the funding agency, nih. conflict of interest statement the author has declared that no competing or conflict of interests exist. the funders had no role in study design, writing of the manuscript and decision to publish. authors’ contributions please add. references american cancer society (2014). colorectal cancer facts & figures 2017-2019 (atlanta, ga). american cancer society (2017). colorectal cancer facts & figures | facts about colon cancer. center for disease control and prevention (2017). colorectal cancer screening tests. 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(2006). promoting culturally appropriate colorectal cancer screening through a health educator. cancer 107, 959–966. www.companyofscientists.com/index.php/chd e1 cancer health disparities research comparative study of hpv and cervical cancer knowledge and beliefs between mexican immigrant women in the us and peruvian women john s. luque1*; jonathan maupin2; daron g. ferris3,4 1 institute of public health, florida a&m university, tallahassee, fl, usa 2 jmaupin@asu.edu school of human evolution and social change, arizona state university, tempe, az, usa 3 dferris@augusta.edu department of obstetrics and gynecology, augusta university, augusta, ga, usa 4 cervicusco, cusco, peru *corresponding author email: john.luque@famu.edu abstract cervical cancer remains one of the major cancers affecting women from developing countries, especially those from socioeconomically disadvantaged backgrounds. in the us, hispanic immigrant women experience restricted access to health care and higher incidence rates of cervical cancer compared to the non-hispanic white population. knowledge of cervical cancer risk factors and symptoms is associated with greater interest in participating in regular cervical cancer screening. to explore knowledge and beliefs about cervical cancer, survey questionnaires were administered to mexican immigrant women in southeast georgia, us and to mestizo women primarily quechua language dominant speakers in cusco, peru. as part of these survey studies, there was a list of 32 items asking participants to agree or disagree with whether certain symptoms or risk factors could cause cervical cancer and a pile sort of 15 of the most salient items. cultural consensus analysis was used to calculate overall agreement with a cultural model of cervical cancer risk factor knowledge in each sample independently. for the georgia sample, there was marginal consensus, but for the peru sample, there was no consensus. analysis of cultural competence values and residual agreement show significant differences across education in the georgia study, with a positive correlation between education and cultural competence (r=0.50, p=0.001), but not in the peru study. likewise, the results of the pile sort data exhibited consensus for the georgia sample for the cervical cancer risk factors, but not for the peru sample. the lack of consensus among the peru sample on either task suggests little widespread knowledge on risk factors of cervical cancer. additional analyses related to factors associated with screening behaviors from the cultural cancer screening scale indicated more pronounced fatalistic beliefs and catastrophic disease expectations about cervical cancer among the peruvian women compared to the mexican immigrant women. keywords: cervical cancer screening, human papillomavirus, hispanics, peru citation: luque js et al (2019) comparative study of hpv and cervical cancer knowledge and beliefs between mexican immigrant women in the us and peruvian women. cancer health disparities 3: e1-16. doi:10.9777/chd.2019.1007. www.companyofscientists.com/index.php/chd e2 cancer health disparities research introduction cervical cancer is a disease that is preventable through public health interventions. early detection of cervical cancer is critical to reduce mortality from the disease. the primary prevention strategy is the administration of the human papilloma virus (hpv) vaccine for adolescents and young adults between 9 and 26 years old. the secondary prevention strategy is cervical cancer screening (the papanicolaou test with or without and hpv dna testing or primary hpv dna testing alone) combined with treatment for any detected pre-cancerous lesions to prevent progression to cervical cancer. since the primary risk factor for cervical cancer is hpv infection, vaccination has had significant impacts in reducing cervical cancer incidence in countries such as australia where adoption has been widespread through its schoolbased vaccination programs (smith and canfell, 2017). other risk factors which may be either independent risk factors for cervical cancer or cofactors modifying the risk in women infected with hpv include immunosuppression (e.g., caused by hiv infection or immunosuppressive drugs), exposure to certain sexually transmitted diseases, long-term use of oral contraceptives, high parity, obesity, eating a diet low in fruits and vegetables, and smoking (bosch and de sanjose, 2007). despite major advances in cervical cancer prevention worldwide, most cervical cancer deaths continue to occur in developing countries with poor public health infrastructure for organized screening programs. in 2012, there were an estimated 265,700 deaths from cervical cancer, making it the third leading cause of cancer death in developing countries (torre et al., 2015). in latin america and the caribbean, there were an estimated 28,600 cervical cancer deaths (torre et al., 2015). cervical cancer incidence rates remain high in many developing countries in latin america, disproportionately affecting women who are socioeconomically disadvantaged (lopez et al., 2017). recent studies have suggested that in some countries, hpv dna testing might be a more effective frontline strategy where screening with conventional cytology programs is either unavailable or unreliable (catarino et al., 2015). therefore, there have been concerted public health efforts to bolster support for cervical cancer prevention in some countries. for example, in peru, researchers described the use of selfsampling kits to expand the reach of screening programs into rural areas and the challenges with implementing national cancer control plans (aguilar et al., 2016). another project demonstrated that hpv self-sampling testing was a superior method compared to testing by visual inspection by acetic acid (via) for reaching rural populations (levinson et al., 2013). concurrent with these medical technology advancements connecting hpv dna screening and cervical cancer prevention, there is a growing body of research to understand barriers and facilitators to cervical cancer screening and hpv vaccination in special populations experiencing the greatest burden of disease (aharon et al., 2017; ginsburg et al., 2017; mann et al., 2015; thompson et al., 2014; vasilevska et al., 2012). cervical cancer, while a relatively rare diagnosis in the us, is a disease which persists in poor and marginalized communities such as the colonias along the us/mexico border, parts of appalachia, and other areas of the us characterized by high rates of poverty, low socioeconomic status, and distrust of medical facilities (scarinci et al., 2010; smith et al., 2013). while individual behaviors toward screening and vaccination are associated with adherence to medical recommendations, there are also systematic processes which create conditions wherein some population groups are better positioned to access preventive health care. in the us, what is often termed “cancer disparities” in the academic literature has been explained as a byproduct of structural vulnerability, or a situation resulting from a market-based health system which contributes to health disparities by increasing financial barriers for poor and www.companyofscientists.com/index.php/chd e3 cancer health disparities research disenfranchised populations to access preventive health care (quesada et al., 2011). disproportionate access to health care may in some cases result in a late-stage cervical cancer diagnosis in patients suffering from a preventable cancer. for hispanic immigrants in the us, an additional factor besides socioeconomic status affecting health care access is immigration status. fear related to seeking or receiving care and difficulties in actually obtaining care linked to immigration status was reported in a study almost 20 years ago during the time of california’s controversial proposition 187, which prohibited undocumented immigrants from accessing non-emergency health care, among other public services (berk et al., 2000). since that time, undocumented immigrants in the us have been subject to increasingly antiimmigration policies which have negatively affected their ability to access health insurance programs and health care more generally (martinez et al., 2015). undocumented immigrants were further excluded from health care coverage under the provisions of the affordable care act (alcalá et al., 2017). they often rely on safety net programs which accept patients without insurance and must use referrals, sometimes on a case-bycase basis, to provide the array of health care services that some patients require to manage their health conditions (castañeda, 2017). moreover, because of language barriers and lack of familiarity with us health care systems and billing structures, hispanic immigrants might also experience difficulties in securing a regular health care provider, finding a trusted provider, accessing relevant health education on varied topics from prenatal care to diabetes management, and understanding payment options for different types of medical procedures or office visits (rhodes et al., 2015). medical anthropologists studying cancer prevention seek to understand how people’s cultural backgrounds might influence their knowledge, attitudes, and beliefs around behaviors that moderate cancer risk (mcmullin, 2016). research which examines whether cervical cancer risk factors, and specifically awareness of hpv infection risk, are understood and how such understandings may reflect a cultural model of risk around the disease is the focus of this comparative research study. this comparative study seeks to understand how models of risk are culturally constructed and vary in different us and latin american contexts. methods participant recruitment for the georgia study in 2013, a female, native spanish speaker research coordinator administered a spanish-language survey to mexican immigrant women living in rural, southeast georgia. to participate in the survey, study inclusion criteria included women who were either actively participating in crop agriculture or had recently participated in this type of work and were between 21 and 65 years of age to align with us cervical cancer screening age guidelines (committee on practice bulletins—gynecology, 2016). to capture a range of acculturation experiences, equal numbers of participants had lived in the us more than 10 years or for 10 years or less. thirty-nine participants were recruited from area farms and a poultry processing plant. for the peru study in 2014, a female, nursemidwife research coordinator administered a spanish-language survey to peruvian women who were patients of cervicusco. cervicusco is a nonprofit clinic in cusco, peru which provides cervical cancer screening to over 10,000 women every year. they have a clinic in the city of cusco but also conduct regular mobile cervical cancer screening outreach to serve patients living in remote mountain villages. survey participants had either received a pap test during mobile outreach clinic services (n=20) or had received a pap test in the cervicusco clinic (n=10). participants were between 30 and 49 years old in alignment with cervical cancer screening guidelines in peru (hpv www.companyofscientists.com/index.php/chd e4 cancer health disparities research information centre, 2016). participants received either a $10 gift card in georgia or a useful gift item in peru for their research participation. participants in both studies completed a written informed consent process before the survey was administered. the protocols for these research studies were approved by the institutional review boards of georgia southern university, augusta university, and the peru ministry of health. measures each of the research studies consisted of administering a survey questionnaire. the survey began with open ended questions about health care resources in the community and knowledge about cancer and cervical cancer. these questions were followed by a section on clinical history of pap tests and results, other health history questions, and knowledge of hpv and the hpv vaccine. questions about knowledge and beliefs about hpv/cervical cancer were drawn from the health information national trends survey (national cancer institute, 2016). next, participants were presented with 32 items and asked to agree or disagree with whether each item was a possible cause or risk factor for cervical cancer. these items included both biomedically accepted factors (e.g., hpv, multiple sex partners) and other factors which may be more ethnomedically defined (e.g., abortion, vaginal trauma, stress). participants were also asked to sort 15 index cards of the most salient items using a constrained pile sort of no more than four piles. in addition, participants were asked to agree or disagree with seven belief statements related to cervical cancer such as, “i am very likely to get cervical cancer sometime in my lifetime.” these items and statements were drawn from previous structured research questions about cervical cancer cultural models with hispanic participants (chavez et al., 1995; luque et al., 2010). participants also completed the 20-item cultural cancer screening scale (ccss), which has demonstrated good internal consistency (α=0.84) with us hispanics and identifies cultural factors related to screening behavior (betancourt et al., 2010). the ccss is comprised of the following five constructs: sociocultural deterrents; cancer screening fatalism; symptomatic deterrents; catastrophic disease expectations; and negative beliefs about health professionals. the research coordinators administering the survey also collected sociodemographic data including age, marital status, education, employment status, language preference, housing characteristics, and health insurance coverage. participants also responded to questions about having a regular provider, whether they visited the doctor in the last year, and smoking status. data analysis descriptive statistics for sociodemographic data, correlation analysis of cultural competence values, and bivariate analysis for between sample analysis of ccss measures were generated using spss statistics v. 24 (spss, inc. chicago, illinois). for the quantitative data from the structured questions on risk factor/symptom items, ucinet 6.0 (analytic technologies, lexington, kentucky) was used to calculate cultural consensus for the overall sample, and each group individually. for the pile sort data, each pile sort was analyzed using visual anthropac 1.0 pilesorts (analytic technologies, lexington, kentucky) to calculate consensus among respondents. nonmetric multidimensional scaling (mds) was used to visualize the results of the pile sort analysis and average linkage clustering set to five clusters. results sociodemographic and health characteristics despite the wider range of participant ages in the georgia sample, the average age in both samples was 40 years. the average number of years of schooling in the georgia sample was 8 years, and in the peru sample it was 6.5 years. places of origin for the mexican immigrant women included campeche, cardenas, guanajuato, guerrero, jalisco, hidalgo, michoacan, queretaro, www.companyofscientists.com/index.php/chd e5 cancer health disparities research tamaulipas, veracruz, oaxaca, and san luis potosi. the two provinces with the highest percentage of participants were guanajuato (36%) and tamaulipas (21%). the peruvian women were multiethnic women from the greater cusco region, and two-thirds were quechua dominant speakers, with the other third either monolingual spanish speakers or bilingual quechua/spanish speakers. because the participants in peru were largely covered under the government health insurance program, and most mexican immigrants in georgia did not have access to either government or employer provided health insurance, there were major differences in responses to the health insurance question. however, there were similar answers to the question about having a regular provider, with only a third reporting having one in each sample, yet a smaller percentage of the mexican immigrant women had received a pap test in the last three years compared to the peruvian women (87% vs. 50%), probably since the peru sample was clinic-based. despite more recent contact with health care, a smaller percentage of the peruvian women had heard of hpv (20% vs. 56%) or the hpv vaccine (17% vs. 41%). similarly, in the peru sample there was less knowledge about some facts about hpv, for example that hpv could cause cervical cancer or lead to abnormal pap test results. in the peru sample, there was even less awareness of the purpose of the hpv vaccine. other participant sociodemographic characteristics are detailed in table 1, and hpv knowledge questions are listed in table 2. table 1. sociodemographic characteristics. characteristics georgia, us (n=39) % cusco, peru (n=30) % age group (years) 20-29 28 0 30-39 23 50 40-49 26 50 50-64 23 0 marital status single/other 26 13 married/living with a partner 74 87 education < 11 years 62 67 12 years or hs 33 23 some college, tech, or higher 5 10 employed yes 87 67 no 13 33 language(s) spoken at home english 3 0 spanish 74 27 www.companyofscientists.com/index.php/chd e6 cancer health disparities research quechua 0 63 spanish & quechua 0 10 spanish & english 23 0 housing rent 51 70 own 49 20 other 0 10 health insurance coverage yes 3 80 no 97 20 have a regular provider yes 38 30 no 62 70 visited doctor in last year yes 39 100 no 61 0 current smoker yes 3 0 no 97 100 current chronic health condition yes 24 0 no 73 63 don’t know 3 37 table 2. cervical cancer screening and knowledge of hpv/hpv vaccine. characteristics georgia, us (n=39) % cusco, peru (n=30) % when was your last pap test? 1 year or less 41 80 > 1 year < 3 years 9 7 > 3 years < 5 years 19 3 >5 years 6 0 never 22 3 don’t know 3 7 have you heard of hpv? www.companyofscientists.com/index.php/chd e7 cancer health disparities research yes 56 20 no 44 67 don’t know 0 13 do you think hpv causes abnormal pap tests? yes 49 17 no 23 20 don’t know 28 63 do you think hpv causes cervical cancer? yes 46 20 no 15 10 don’t know 39 70 do you think hpv is a sexually transmitted disease? yes 51 27 no 18 3 don’t know 31 70 have you heard of the hpv vaccine? yes 41 17 no 59 83 do you think the hpv vaccine is an effective way to prevent hpv infection? yes 87 7 no 8 13 don’t know 5 80 thoughts and understanding of cervical cancer, hpv and the hpv vaccine participants were asked a series of open-ended questions about cervical cancer, hpv and the hpv vaccine. in the georgia study, while more than two-thirds of the women had heard about cervical cancer and that it was a serious illness, they admitted they did not know that much about the disease. for example, a participant explained, “it is cancer of the vagina, i’m not that sure.” another participant answered, “it is in the uterus, i know very little.” there were also some accurate explanations such as, “i’ve heard that you have to do the pap after you have relations … you get them in private parts of a woman.” there was some awareness of the vaccine to prevent it also, for example, one participant said, “for this reason, www.companyofscientists.com/index.php/chd e8 cancer health disparities research we get checked. they are trying to prevent it with thirteen-year-olds who get three shots.” when asked what they had heard about hpv, slightly more than half of the participants did not offer response. some misconceptions included the belief that one could contract cervical cancer in lavatories or from using tampons. those who responded to questions about hpv tended to have more information, for example participants responded with answers such as, “the vaccine helps to avoid the high risk of getting the virus,” and “that it is important to give to young people before they are sexually active.” participants were generally positive about the hpv vaccine and responded that sources of motivation to receive the vaccine included to be protected, for family reasons, to avoid a hysterectomy, to prevent cancer, and to prevent the illness so you would be able to have sexual relations with other people and then be immune from further infection. reasons for not getting vaccinated included physical factors such as being pregnant, side effects, allergies, or becoming sterile. other reasons for not getting vaccinated listed were costs, ignorance, fear, embarrassment and religious beliefs. in the peru study, when asked about preventing cervical cancer, women responded that personal hygiene, cleaning with herbs, receiving pap tests, having only one partner or few partners were all important. women also spoke about living in peace and having a good relationship with partners. participants were asked if they had any concerns about the pap test. one participant responded, “i got my tubes tied, and i am afraid that will cause cancer.” another echoed this concern about tubal ligation and was afraid that it could cause an infection or cancer. another woman was concerned about her symptoms by expressing, “i have vaginal leakage and am afraid.” regarding the hpv vaccine, motivating factors to receive the vaccine included receiving educational information and campaigns where the vaccine would be available. reasons for not getting vaccinated were lack of financial resources, negative beliefs about the effectiveness of vaccines, and fear of side effects, such as childhood deformities, or pain at the injection site. cultural consensus results for risk factors and symptoms participants were asked to agree or disagree with a list of possible risk factors/symptoms that could cause cervical cancer. there was consensus amongst all participants (0.4, sd = 0.03), and for the georgia sample independently there was marginal consensus with an average cultural competence value of 0.49 (sd = 0.28), an eigenratio of 5.93, and 5% negative competency values. for the peru sample, there was a lack of consensus, with an average cultural competence value of 0.30 (sd = 0.24), an eigenratio of 1.83, and 10% negative competency scores. the convention for consensus, or a shared cultural model, is to produce an eigenratio of 3.0 or greater. one individual from the georgia sample and two individuals from the peru sample were removed from the analysis because there was no variability in their responses since they agreed with all risk factors/symptoms (table 3). after dividing the two separate samples by education (primary or some secondary, secondary and higher), there was a significant difference in the cultural competence values for the georgia sample (t=-2.15, p=0.04), and the higher education sample (0.60, sd = 0.27) exhibited significantly higher competence in the model of knowledge of cervical cancer causes than the lower education sample (0.41, sd = 0.26) (figure 1). analysis of residual agreement also showed that higher educated individuals in georgia are a distinct sub-group, meaning they have higher within than between-group agreement, while lower educated individuals are not a distinct sub-group (f=4.515, p<0.05). www.companyofscientists.com/index.php/chd e9 cancer health disparities research table 3. cultural consensus analysis. measure agree/ disagree cusco, peru (n=28) agree/ disagree georgia, us (n=38) pile sort risk factors cusco, peru (n=30) pile sort risk factors georgia, us (n=39) eigenratio a 1.8 5.9 2.6 7.1 average competence 0.30 (±0.24) 0.49 (±0.28) 0.30 (±0.19) 0.61 (±0.10) aeigenvalue ratios of 3.0 or greater and lack of negative competence values indicate a good fit to the consensus model. a competence value of 0.50 indicates an average level of cultural competence. notes. for the agree/disagree questions, two participants from the peru dataset and one participant from the georgia dataset were removed because of 100% endorsement of all items. figure 1. mean cultural competence by education category, georgia, us the average percentage agreement with the items was 70% in the georgia sample and 60% in the peru sample (table 4). when only considering the biomedically defined risk factors, the average percentage agreement was 74% in the georgia sample and 76% in the peru sample. both samples reported high agreement with hpv as a risk factor for cervical cancer (>80%). the peru sample www.companyofscientists.com/index.php/chd e10 cancer health disparities research endorsed the following possible cervical cancer risk factors significantly higher (>20% difference) than the georgia sample: drinking alcohol, smoking, high blood pressure, stress, urinating frequently, fate, worry, pelvic rash, and weight loss. however, the georgia sample had higher endorsement (>20% difference) of poor feminine hygiene and use of birth control pills as risk factors. table 4. endorsement of cervical cancer risk factors/symptoms. risk factor/symptom georgia, us (n=39) % cusco, peru (n=30) % multiple sex partners* 95 97 poor feminine hygiene 92 73 spouse with multiple sex partners* 90 87 not getting regular check-ups* 90 93 gonorrhea* 87 73 syphilis* 87 77 human papilloma virus (hpv)* 85 83 abnormal vaginal bleeding* 82 87 sex before age 16 years* 79 80 abortion 77 87 vaginal trauma 74 77 hiv infection* 74 87 yeast infection 74 87 birth control pills* 72 53 chlamydia* 72 87 sex during menstrual period 69 77 family history 67 77 many pregnancies 64 80 smoking* 56 83 drink alcohol 51 93 bloody stools 51 63 diet* 49 53 pelvic rash 49 80 chemicals in food 46 67 urinating frequently 38 67 fate 31 57 stress 28 67 weight loss 23 60 www.companyofscientists.com/index.php/chd e11 cancer health disparities research high cholesterol 23 43 high blood pressure 18 50 worry 16 57 low income* 13 30 average endorsement 70 60 average endorsement of biomedical risk factors* 74 76 *risk factors/symptoms generally accepted by medical profession. notes. columns represent % who agreed that the risk factor or symptom was a cause of cervical cancer similar to the agree/disagree task, there was consensus for the pile sort data in the georgia sample and no negative competency values (table 3). the mds plot had a stress value of 0.13. the mds plot produced five clusters from the constrained pile sort. the first cluster included family history and destiny, or unmodifiable factors. the second cluster included items about sex and infection—hpv, hiv, multiple sex partners, sex under 16 years old, and lack of a regular pap test. the third cluster grouped risk factors around reproductive factors—birth control pills, abortion, and multiple pregnancies. the fourth cluster grouped not using condoms and poor feminine hygiene. the fifth cluster included environmental and behavioral risk factors—smoking, poor diet, and chemicals in food. the mds plot for the peru sample had high stress value of 0.20, and the pile sort data did not produce consensus. cervical cancer belief statements study participants responded to seven statements about cervical cancer and were asked to agree or disagree with each statement (table 5). there was very high agreement in both samples with two statements: 1) that cervical cancer was curable if found early; and 2) that even if treatment were painful, the participant would endure it if it meant living longer. the greatest disagreement was about not wanting to know about a cervical cancer diagnosis, with 63% of peruvian women not wanting to know compared to only 13% of mexican immigrant women. similarly, only half of peruvian women believed that there was something they could do to prevent cervical cancer compared to 18% of mexican immigrant women. table 5. endorsement of cervical cancer beliefs. statement of cervical cancer beliefs georgia, us (n=39) % cusco, peru (n=30) % i would be afraid to tell my husband or partner if i had cervical cancer 18 37 i need a pap smear only when i experience vaginal bleeding other than menstruation (or when i experience other symptoms) 28 53 i am very likely to get cervical cancer sometime in my lifetime 62 40 if cervical cancer is found early, it can be cured 95 87 i would undergo cervical cancer treatment that is unpleasant or painful if it would improve my chances of living longer 97 100 i would rather not know if i had cervical cancer 13 63 there is not much i can do to prevent cervical cancer 18 50 www.companyofscientists.com/index.php/chd e12 cancer health disparities research notes. columns represent % who agreed with the statement. cultural cancer screening scale the cultural cancer screening scale (ccss) assesses items relevant to cancer screening (table 6). in the georgia sample, the internal consistency of the ccss (20 items) was 0.91, indicating excellent reliability. on the 5-point scale (ranging from 1 = never to 5 = always), the mean values for the subscales were at or below the midpoint on the scale: (1) catastrophic disease expectations (2.1, sd = 1.5); (2) cancer screening fatalism (2.1, sd = 1.6); (3) sociocultural deterrents (2.5, sd = 0.9); (4) symptomatic deterrents (2.4, sd = 2.4); and (5) negative beliefs about health professionals (1.8, sd = 0.9). table 6. responses from the cultural cancer screening scale a . characteristics georgia, us mean ±sd cusco, peru mean ±sd p-values catastrophic disease expectations 2.1 ±1.5 4.0 ±0.9 <0.001 cervical cancer is the worst thing that can happen to a woman cervical cancer is a deadly disease cancer screening fatalism 2.2 ±1.6 3.3 ±0.6 <0.001 it is not important to screen regularly for cervical cancer because everyone will eventually die of something anyway it is not necessary to screen for cervical cancer regularly because it is in god’s hands anyway screening regularly is not very important because if you are meant to get cancer you will get it no matter what you do sociocultural deterrents 2.5 ±0.9 3.2 ±0.7 0.002 having problems making an appointment not knowing where i can get a screening exam not being able to get time off work not having transportation to get to my appointment not receiving a reminder call or text for the screening exam having to take care of my child(ren) of family not having health insurance or the money to pay for the exam symptomatic deterrents 2.4 ±1.6 3.3 ±0.8 0.001 feeling healthy having several normal screening results not feeling anything abnormal www.companyofscientists.com/index.php/chd e13 cancer health disparities research negative beliefs about health professionals 1.8 ±0.9 2.5 ±0.5 <0.001 the health care professionals are not compassionate towards their patients health professionals are always in a hurry and do not have time for their patients i don’t not feel comfortable with health professionals doing the screening examination some health professionals inappropriately touch their patients during the screening examination health professionals performing screening examinations are not trustworthy notes. values in bold represent summary scale scores for this validated measure. aresponse categories for the items in this scale are: 1 = “never”; 2 = “i don’t think so”; 3 = “neutral”; 4 = “very sure”; 5 = “always” in the peru sample, the internal consistency of the ccss was 0.72, indicating acceptable reliability. the mean values for the subscales were significantly higher than the georgia sample for each construct based on the independent samples t-test: (1) catastrophic disease expectations (4.0, sd = 0.9); (2) cancer screening fatalism (3.3, sd = 0.6); (3) sociocultural deterrents (3.2, sd = 0.7); (4) symptomatic deterrents (3.3, sd = 0.8); and (5) negative beliefs about health professionals (2.5, sd = 0.5). for the peruvian women, the values were above the midpoint value for four of the five subscales. the largest difference in average scores was for catastrophic disease expectations, indicating peruvian women were more likely to endorse the belief that a diagnosis of cervical cancer was equivalent to a death sentence. discussion to our knowledge, this is only the second study comparing knowledge about cervical cancer using the same survey instrument between hispanic women in the us and multiethnic women in south america. these results suggest that overall, women in cusco held beliefs about cervical cancer that are more fatalistic than mexican immigrant women in georgia. the higher incidence and mortality from cervical cancer in peru might be associated with more fatalistic beliefs about cervical cancer and by extension, cancer. this difference in fatalism scores could also be partially attributed to the mexican immigrant women having a higher regard for the quality of health services in the us, compared to the peruvian women’s perception of their chances of surviving a diagnosis of cancer in peru. negative perceptions toward the quality and accessibility of government health care facilities for the prevention and control of cervical cancer were reported in the results of other survey projects with women in this area of cusco (ferris et al., 2015a; luque et al., 2016). the presence of consensus among the georgia sample, and lack of consensus among the peruvian participants, also suggests differences in the social distribution of knowledge regarding cervical cancer. for while there appears to be a general cultural model among hispanics in georgia, with some variation according to education, there is no consensus among the peru sample either in the agree/disagree or the pile sort task. similar to shiu et al.’s (2010) results among a sample of older women in hong kong, the lack of consensus on questions regarding cervical cancer indicates little public or general knowledge on the www.companyofscientists.com/index.php/chd e14 cancer health disparities research topic. the explanation given in that study was that there was substantial disagreement about the most highly ranked cervical cancer factors (shiu et al., 2010). responses may be based more on personal knowledge or opinion. our study results are not dissimilar to a previous survey study which compared responses to cervical cancer knowledge questions between women in the cusco area with women in augusta, georgia—both englishand spanish-speaking (han et al., 2012). in this prior comparative study, lower levels of knowledge about cervical cancer were similarly identified among peruvian women compared to hispanic women in the us. for example, when asked if hpv could cause an abnormal pap test, 69% of us hispanic women answered correctly, compared to 40% of peruvian quechua speakers, 27% of peruvian spanish speakers, and 39% of bilingual peruvians. moreover, in the same study when asked if they were embarrassed to receive a pap test, 38% of us hispanic women answered affirmatively, compared to 39% of peruvian quechua speakers, 50% of peruvian spanish speakers, and 39% of bilingual peruvians. in that study the reference group for comparison was non-spanish-speaking women, and the survey found significant differences on cervical cancer knowledge questions—higher knowledge among non-spanish-speaking women— and on belief questions such as fear and embarrassment of getting a pap test—less fear and embarrassment among non-spanish-speaking women. in our study, in both samples it is possible that there was confusion about the difference between hiv and hpv, suggested by the grouping of these risk factors in the pile sort exercise and the low knowledge levels in response to the hpv and hpv vaccine survey questions. hiv was endorsed by a higher percentage of peru participants than hpv, but in the georgia sample, hiv was endorsed by a lower percentage of participants as a risk factor for cervical cancer. nevertheless, both samples endorsed hpv as a risk factor for cervical cancer similarly (above 80%). importantly, related to hpv vaccination behaviors, previous research in multiple sites in peru reported that even though 59-71% of low-income 25-65 year old women had low awareness of hpv, the hpv vaccine, and cervical cancer, over 90% would agree to be vaccinated and 58% would be willing to pay some amount for the vaccine (lee et al., 2010). our results about the barriers to screening affecting peruvian women based on the cultural cancer screening scale for the catastrophic disease expectations and the responses to the belief statements, for example about the questionable benefits of receiving cervical cancer screening, are similar to another study based on focus group discussions with women in four peruvian cities which reported that many women cited fear, embarrassment, and lack of knowledge as being barriers for not getting a pap test (pazsoldan et al., 2010). in our work to educate gynecologic patients, we have previously developed animated videos to educate patients in their native languages in peru and georgia about cervical cancer prevention and treatment procedures to increase understanding of hpv and hpv vaccination awareness (ferris et al., 2015b; luque et al., 2017). limitations of this study include a small number of questions used in the agree/disagree survey. the 32 questions may not be enough to accurately measure patterns of agreement and variation, particularly with small sample sizes. the limited number of questions also prevents analysis of consensus in any sub-domain (e.g., causes, symptoms, or treatments), which would help in identifying whether the lack of consensus is rooted in specific areas or on the topic in general. however, the lack of consensus among peruvian participants in the pile sort task, which is not as dependent upon the number of items, may suggest that there is limited agreement on risk factors for cervical cancer overall. however, the pile sort data is limited in terms of the number of www.companyofscientists.com/index.php/chd e15 cancer health disparities research items participants can negotiate in terms of producing piles. combining pile sort data with rank data for the same items can produce better understanding of how some clusters of cervical cancer risk factors may be perceived as more serious than others. for example, it was previously reported in a prior analysis of the georgia survey data that the sex-related risk factors were ranked higher compared to the genetic and environmental risk factors (luque et al., 2014). conclusion the comparison of survey studies highlights the potential of exploring knowledge in this domain as well as revealing the limitations in using this type of methodology for a disease which may be poorly understood and the diagnosis perceived as catastrophic. cervical cancer is highly curable when detected in its early stages, and the goal of the peru clinic cervicusco is to bring screening and more timely treatment to women who have unfortunately experienced the burden of the disease in their communities (ferris et al., 2009). future studies are planned in peru to explore the psychological stress produced by screening and diagnosis of cervical cancer to benefit patients in negotiating their treatment and reduce stigma around the disease. ethical approval research for this article was approved by the research ethics committees of georgia southern university, augusta university, and the peru ministry of health. acknowledgements in peru, we acknowledge the collaboration of the cervicusco staff, especially ms. wendy guevara condorhuaman, and the peruvian ministry of health in lima. in georgia, we acknowledge mrs. claudia reyes-garcia for data collection, southeast georgia communities project and their team of promotoras, especially mrs. andrea hinojosa, the vidalia onion farms, and claxton poultry. funding this paper was supported by funding from the national cancer institute (r21ca163159, r03ca173105). content presented is solely the responsibility of the authors and does not necessarily represent the official views of the national cancer institute. conflict of interest the authors declare that no competing or conflict of interests exist. the funders had no role in study design, writing of the manuscript, or decision to publish. authors’ contributions conception and design: jl data analysis: jl, jm literature review and manuscript writing: jl, jm, df references aguilar, a., pinto, j.a., araujo, j., fajardo, w., bravo, l., pinillos, l., and vallejos, c. 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(2012). relative risk of cervical cancer in indigenous women in australia, canada, new zealand, and the united states: a systematic review and meta-analysis. j public health policy 33, 148-164. www.eopenaccess.com/index.php/chd e1 cancer health disparities review health disparity of prostate cancer: molecular insights into the role of exosomes hamdy ea ali1, shaimaa a. gad1, gagan deep2, hamed i. ali1, zakaria y. abd elmageed1* 1department of pharmaceutical sciences, rangel college of pharmacy, texas a&m health sciences center, texas 2department of cancer biology, wake forest school of medicine, winston-salem, north carolina, usa. *corresponding author: zakaria y. abd elmageed; e-mail: elmageed@tamhsc.edu abstract prostate cancer (pca) is the second leading cause of morbidity among older men in the states. the morbidity and mortality rates of pca are twice as prevalent in african american (aa) than in caucasian american (ca) men. owing to the involvement of multiple factors contribute to such disparities, it remains unclear whether the high incidence and mortality rates of pca among aa men are associated with genetic and epigenetic factors. the molecular mechanisms underlying these biological factors have yet to be fully elucidated. exosomes are cell-derived extracellular bodies secreted by normal and tumor cells therefore promoting cell-cell communications. exosomes are vesicular bodies that transfer different biological materials such as micrornas, mrnas, lipids, dna and proteins to recipient cells. our goal here is to illustrate the role of exosomes contributing to different biological activities, especially aggressive behavior of cancer cells and poor clinical outcomes of pca in aa patients. there is a need to discover new biomarkers used in diagnosis and prognosis of pca. it follows that a special focus on cancer disparities among aa men. this review indicates that more studies are needed to build on these recent findings for future understanding of the role of pca-associated exosomes in promoting pca aggressiveness in aa and other cancer disparities. elucidating exosomal interactions in cancer and other chronic diseases should help to eliminate morbidity and mortality disparities among us minorities. keywords: prostate cancer, health disparity, exosomes, micrornas citation: ali hea. et al. (2017). health disparity of prostate cancer: molecular insights into the role of exosomes. cancer health disparities;1:e1-e13. doi: 10.9777/chd.2017.10002 www.eopenaccess.com/index.php/chd e2 cancer health disparities review the incidence of prostate cancer remains high, biomarkers and molecular targets are an unmet need. although the efforts in the field of biomedical research are advancing, more integrated research procedures and new strategies are still needed to promote early discovery, and hence reduce the burden while increasing the overall survival of cancer patients. prostate cancer (pca) is the second leading cause of death among older men in the united states (jemal et al., 2008). after diagnosis, systemic therapies have been used as an option for managing the disease; however, chemotherapy is the ultimate solution, especially in castration-resistant pca (crpc) patients (paller and antonarakis, 2011). although pca is a multifactorial disease, androgens and their receptors (ar) represent the main driving forces for promoting pca at all stages: initiation, progression and metastasis. therefore, inhibition of ar and its downstream signaling pathways is the mainstream of current therapeutic targeting approaches. ar variant 7 (arv7) is one of the most common ar variants that has a current clinical applications. arv7 sequence contains the first three exons of the full length of ar sequence; exons 4-8 are replaced with a “cryptic exon” and, therefore, arv7 lacks a ligand-binding domain. a recent emerging role of arv7 in advanced pca has been documented in pca cells (hu et al., 2009), animal models (guo et al., 2009; watson et al., 2010) and crpc patients (del re et al., 2017; djusberg et al., 2017). the challenge in advanced stages of pca is to develop new therapeutic agents and suppress androgen activity at its ar (wild form or its variants) and/or androgen metabolizing enzymes. the most common diagnostic tools for pca are serum prostatic specific antigen (psa), systematic prostate biopsies under ultrasound guidance and pathological staging with grading according to the gleason score system (heidenreich et al., 2014; mottet et al., 2017). although psa is still the gold standard utilized for detection of pca, it is also elevated in men who have benign prostate hypertrophy, urinary tract infection, prostatitis, and after prostate surgeries and biopsies. hence, the escalated level of psa is not specific to pca; this might lead to overdiagnosis followed by overtreatment accompanied with adding extra-cost on patients with low-risk of pca (lee et al., 2013). other biomarkers have been developed to stratify patients according to their tumor stage, response to treatment, crpc status, and metastasis. current biomarkers, such as prostate cancer antigen 3 (pca3), αmethylacyl coenzyme a racemase (amacr), tmprss2 (transmembrane serine protease isoform 2)-erg (ets transcription factor) gene fusion, and pten (phosphatase and tensin homolog) gene deletion, are clinically evaluated and some of them awaiting approvals. accordingly, tremendous efforts have been directed towards the discovery of second-generation pca biomarkers that can predict poor prognosis of the disease and can assist oncologists for proposing better treatment options for their patients. owing to tumor heterogeneity, none of the current biomarkers is ideal to account for the wide variety of human samples, state of the disease and other clinical outcomes. as such, it is essential to develop new strategies for early detection and prognostication of pca that may serve as surrogate endpoints for better evaluation of disease progression and effective treatment regimens thereby increasing patients’ survival. www.eopenaccess.com/index.php/chd e3 cancer health disparities review molecular mechanisms underlying health disparities of pca have not been well determined. the mortality rate of pca in african americans (aa) is about twice that of caucasian americans (ca) or any other minorities (hsing et al., 2000). considering cancer disparity as a multifactorial event, it remains unclear whether the high incidence of mortality rate of pca among aa men is promulgated principally by genetic, lifestyle, or socioeconomic-related factors. the molecular mechanisms underlying these discrepancies have yet to be fully elucidated. levels of ame, growth factors, non-coding rna and other genetic factors are higher in aa men than in other races (hatcher et al., 2009; khani et al., 2014). interestingly, the hormonal level of estrogen but not testosterone significantly differs between aa and ca men (rohrmann et al., 2007). our recent study substantiated higher circulating estrogen and selective expression of its receptor (erβ) in pca tissues of aa compared to ca men (abd elmageed et al., 2013). presumably, another factor associated with disease aggressiveness in aa men is the overexpression of spink1 (serine peptidase inhibitor kazal type-1) in tissues of aa men (khani et al., 2014). other genetic and epigenetic factors may involve in health disparities of pca. for example, chaudhary et al. (2016) reported that aa pca cells exhibited reduced endogenous reactive oxygen species, mitochondrial membrane potential and less expression of heat shock proteins compared to ca pca cells (chaudhary et al., 2016). intriguingly, the mitochondrial genome may contribute to the inherited racial disparities via the crosstalk between the mitochondria and the nucleus, which may overactivate signaling pathways in aa patients (choudhury and singh, 2017). also, immunohistochemical studies on formalin-fixed paraffin-embedded tissues collected from 169 aa patients have demonstrated that, although pten and erg expression are less frequent in aa patients, nonetheless, pten loss associated with poor prognosis of aa compared ca patients (davenport, 2004). in a more recent study, the gene locus of rgs12 (regulator of g protein signaling 12) on chromosome 4p16.3 was not detected in aa men suggesting the tumor suppressive role of this gene in regulating cancer progression (wang et al., 2017). in contrast, using three standard models of risk prediction in pca, genotype and epigenetic data collected from 59,089 men of aa and ca origin exhibited insignificant difference between the two ethnicities suggesting high similarities in their genetics hallmarks (gusev et al., 2016). micrornas (mirs) are small non-coding regulatory rnas that regulate gene expression at the post-transcriptional level. a growing body of evidence suggests that mirs are involved in the progression of many cancer types including pca. profiling of mirs has identified a specific set of mirs that can be utilized in pca diagnosis and prognosis. the effect of mirs as epigenetic factors contributes disproportionately to pca that has been recently studied. a group of scientists applied genomic-wide profiling for micrornas (mirs)mrna in 60 primary pca compared to 16 normal counterparts; they found that mir106b-25 cluster/mcm7 and mir-32/c9orf5 are highly expressed in pca compared to controls (ambs et al., 2008). using integrative genomic approach, 10 specific mirs were identified along with their target genes, which were differentially expressed in to aa compared to ca men with pca (wang et al., 2015). in this regard, egfr was the more likely signaling pathway used in cancer cells of aa origin. the https://www.ncbi.nlm.nih.gov/pubmed/?term=chaudhary%20ak%5bauthor%5d&cauthor=true&cauthor_uid=27115471 www.eopenaccess.com/index.php/chd e4 cancer health disparities review same study also suggests that regulation of mir-mrna crosstalk is the key step to control the oncogenic activities of mir-133a-mcl1, mir-513c-stat1, mir-96-foxo3a, mir-145itpr2 and mir-34a-ppp2r2a in aa pca tumor cells. mir-24 was reported to have a possible regulatory role in pca progression based on the race. in this study, aa pca cells mda-pca2b treated with 5-aza-2'-deoxycytidine differentially restored mir-24 compared to ca pca cells du-145. reconstitution of mir-24 in pca cells reduced cells growth, induced cell death and decreased ar, etv1, igf1 and igfb5 in aa cells (hashimoto et al., 2017). the role of exosomes in pca progression and metastasis exosomes are cell-derived extracellular bodies (30-120 nm in size) secreted by normal and tumor cells to promote cell-cell communications. exosomes acting as a delivery devices or shuttles for various biological molecules (micrornas, mrnas, lipids, dna and proteins) to recipient cells (mathivanan et al., 2012). exosomes are detected in most of body fluids including blood, ascetic fluids, lymphatic fluids, urine, saliva, tears and milk. the molecular content of exosomes is dependent on their cell of origin. therefore, the identification of tissueor disease-specific exosomal proteins, mirnas and mrnas will enable the use of these vesicles as a source of new noninvasive biomarkers and serve as indicators in the diagnosis, prognosis and surveillance of a variety of diseases including cancer. the crosstalk between exosomes released from cancer cells as well as stromal cells in and around tumor niche, presumably along with other key players, is a critical factor for promoting metastasis. carrying a message of exosomes from cells of origin ‘donor’ and delivering it to the recipient/effector cells, depends on three main basic biological steps: biogenesis, release and internalization. during each step, there is a tight control of the quantity, biological contents and specificity of exosomes delivery to their target cells. the process of exosomal biogenesis and release is securely regulated by several factors inside the donor cells comprising endosomal sorting complex required for transport (escrt-o, -i, ii, iii) machinery, syndecan-syntenin-alix, rab proteins, small integral membrane protein of the lysosome/late endosome (simple), phospholipase d, and sphingomyelinase (reviewed in (hessvik and llorente, 2017)). a growing body of research in exosomes suggests that their release by cancer and cancer-associated cells is a key-step for promoting pca cell survival, growth, angiogenesis and suppression of immune system (ge et al., 2012). interestingly, collecting exosomes from highly metastatic melanoma cells promoted melanoma metastasis from the pre-metastatic site through reprogramming of bone marrow stem cells and silencing of rab27a decreased exosomal production and reduced melanoma metastasis (peinado et al., 2012). our group demonstrated that exosomes are associated with pca progression by transferring known and uncharacterized set(s) of mirs into recipient stem cells altering network of genes to transform non-malignant into pca-like cells (abd elmageed et al., 2014). the tumor microenvironment contains a variety of cells such as fibroblasts, cancerassociated fibroblasts (cafs), endothelial cells, white cells, epithelial cells, and mesenchymal www.eopenaccess.com/index.php/chd e5 cancer health disparities review stem cells as well as soluble growth factors, cytokines, chemokines, and exosomes (ono et al., 2014). the different biological activities in which exosomes contribute to cell survival, cell proliferation, angiogenesis, immunomodulation and metastasis are depicted in figure 1. here, the role of exosomal cargoes in transferring different biologically active materials to exert specific biological effects on different cells in tumor niche (summarized in table 1) are described. by activating tgf-β/smad3 signaling pathway, pca-associated-exosomes can reprogram fibroblasts into cafs, which is a critical step needed for cancer progression (webber et al., 2015). in the same vein, pca-associated exosomes altered the adipogenic differentiation of mesenchymal stem cells towards cafs, which gain proangiogenic activities by secreting vegf-a, hgf and metalloproteinases (chowdhury et al., 2015). co-culturing of pancreatic cancer cells with primary pancreatic fibroblasts isolated from wild type c57 mice induced the transformation of fibroblasts to cafs through exosomal mir-155-tp53inp1 axis (pang et al., 2015). exosomes derived from cafs have proven to transfer mirs to alter the tumor niche and promoting cell proliferation, invasion, epithelial-to-mesenchymal transition to develop chemoresistance in pca cells (au yeung et al., 2016; li et al., 2016a). other research groups have reported that exosomes derived from different pca cells and tramp mouse model are enriched with igf-1r, src, fak, cd9 and g-protein-coupled receptor kinases (grk5 & 6) to support tumor progression and migration (derita et al., 2017; soekmadji et al., 2016). exosomes released from pca cells can directly or indireclty through circulation transfer their cargo contents (proteins, mrna, micrornas and lipids) into tumor microevironment (tme). tme contains fibroblasts, lymphocytes, macrophage, dentretic cells, extracellular matrix, and growth factors. this will change the signaling pathways in cancer and cancerassociated cells to promote cell proliferation, survival, angiogenesis, metastasis and drug resisiatnce. these molecular events suggest that exosomes could be a determining factor contributing to health disparities among african american men. the role of exosomes in evasion of immune response in cancer disease is a growing area of research. exosomes carry immunosuppressive molecules, tumorassociated antigens, costimulatory molecules, major histocompatibility complex (mhc), and intraluminal cytokines (whiteside, 2013, 2016). pca-associated exosomes were found to express ligands of nkg2d (natural-killer group 2, member d) and selectively suppress the expression of nkg2d on the surface of nk and cd8+ t cellscase leading to diminish the cytotoxic actions of these receptors (lundholm et al., 2014). in a group of crpc patients, the same investigators found a remarkable decrease of nkg2d expression on the surface of nk and cd8+ t cells regarding matched controls. cancer-associated exosomes upregulate the suppressor activity of treg and myeloid-derived suppressor to evade the immune response towards cancer cells (xiang et al., 2009); this could occur by transferring of fasl, tgf-β, galectin-9 and hsp72 by exosomes into recipient cells (naito et al., 2017). www.eopenaccess.com/index.php/chd e6 cancer health disparities review exosomes as non-invasive biomarkers in pca in 2009, a group of researchers was able to detect the mrna fusion gene tmrss2: erg and pca-3 in the exosomes isolated from the urine of pca patients. these findings suggest that circulating exosomes can act as a potential non-invasive biomarker by carrying in their cargoes of enriched mrna compared to their donor cells (nilsson et al., 2009). in american cohort, other scientists validated the accuracy of using tmprss2: erg in urinary exosomes versus 21 pca tissue specimens (motamedinia et al., 2016). the detected tmprss2: erg in urinary exosomes had 81% sensitivity, 80% specificity and 81% overall accuracy of the fused genes in exosomes collected from urine versus pca tissues. this was followed by investigating the differential expression of tmprss2: erg in large number of urine samples collected from 39 men with prostate biopsy negative, prostate biopsy 47 biopsy positive, 37 men had radical prostatectomy, and 84 healthy men (44 agematched 40 young men). data from roc analyses showed that tmprss2: erg, erg, pca3, birc5, and tmprss2 genes were able to segregate subjects with prostate biopsy positive from negative ones. figure 1. schematic representation showing suggested biological activities of exosomes in cell survival, cell proliferation, angiogenesis, immunomodulation and metastasis www.eopenaccess.com/index.php/chd e7 cancer health disparities review table 1. list of exosomes-associate cargoes transferred into recipient cells and used as biomarkers or have a biological impact exosomes cargo content effect/role reference tgf-β protein transform fibroblast into cancer associated fibroblast (webber et al., 2015) c-src, igf-ir, fak protein pca progression (del re et al., 2017) cd9 protein pca progression (soekmadji et al., 2016) cd33, cd34, cd117, tgfβ1 protein decreased cytotoxic activity of nk towards cancer cells (whiteside, 2013) fasl, pd-l1 protein apoptosis of activated cd8+ cells (andreola et al., 2002; kim et al., 2005) ligands for nkg2d protein has immunosuppressive effect (lundholm et al., 2014) hsp72 protein has immunosuppressive effect (chalmin et al., 2010) galectin-9 protein apoptosis of t-lymphocytes (klibi et al., 2009) cd44 protein transform monocytes into tumorassociated macrophage-like phenotypes (baj-krzyworzeka et al., 2007) dna methyltransferase 1 (dnmt1) protein cisplatin resistance in ovarian cancer cells (cao et al., 2017) ar/arv7 protein prostate cancer (read et al., 2017) mir-155 microrna transform fibroblast into cancer associated fibroblast by targeting tp53inp1 (pang et al., 2015) mir-17-3p, mir-21, mir106a, mir-146, mir-155, mir-191, mir-192, mir203, mir-205, mir-210, mir-12 and mir-214 microrna tumor signature of lung adenocarcinoma (rabinowits et al., 2009) mir-21 microrna tumor progression in esophageal squamous cell carcinoma (tanaka et al., 2013) mir-551b, mir-96, mir-183, mir-182, mir-153, mir625, mir-141, mir-193b, mir-200c, mir-193a-3p, mir-205, mir-708, mir-365 and mir-34 tumor signature in pc-3 prostate cancer cell (hessvik et al., 2012) mir-200c and mir-214 microrna tumor stage of ovarian cancer (taylor and gercel www.eopenaccess.com/index.php/chd e8 cancer health disparities review taylor, 2008) mirmir-1290 and mir375 microrna prostate cancer prognosis (huang et al., 2015) mir-16, mir-92a, mir103, mir-107, mir-97, mir-34b, mir-328, mir-485-3p, mir486-5p, mir-92b, mir-5743p, mir-636, mir-640, mir766 and mir-885-5p microrna prostate cancer (stage 3&4) (lodes et al., 2009) pca3 long noncoding rna prostate cancer (donovan et al., 2015) in plasma, exosomes were isolated from 67 patients (39 pca, 8 with recurrence and 20 bph) in addition to 16 healthy controls. in these exosomes, the expression of survivin was higher in pca patients compared to bph and health controls (khan et al., 2012). the acidic ph of tumor microenvironment increases the secretion of psaand cd81-expressing exosomes in pca cells and as well as in peripheral blood of pca patients corresponding to bph and healthy controls (logozzi et al., 2017). proteomic analysis has shown that about 64 proteins were detected pc-3-associated exosomes and claudin 3 was the top expressed protein. cldn3 level was assessed in plasma collected from 69 pca in addition to bph and control subjects. the expression of cldn3 was specific to pca patients versus other control groups (worst et al., 2017). interestingly, in vitro and preclinical studies aimed to investigate whether: 1) pcaassociated exosomes express egfr (epidermal growth factor receptor) on their surface and 2) if it has any role in the aggressiveness of cancer cells. the study evidenced that the expression of egfr in exosomes isolated from the conditioned media of pca cell lines as well as lncap xenograft serum and patient blood (kharmate et al., 2016). nuclear translocation of egfr in other cells was governed by pcaassociated exosomes in an independent fashion of nuclear localization signal. in parallel, ar and its variant arv7 have shown to be transferred through exosomes into the nucleus of ar-naïve pca cells (read et al., 2017). it has been reported that exosomal gamma-glutamyltransferase activity is higher in the serum of pca versus bph patients. (kawakami et al., 2017). rna sequencing data demonstrated that mir1290, mir-1246, and mir-375 were top-listed mirs in exosomes isolated from the plasma procured from 21 crcp patients. after their validation in 100 crpc specimens, exosomesassociated mir-1290 and mir-375 had a positive correlation with overall survival of pca patients (huang et al., 2015). the level of mir141 and mir-375 was assessed in exosomes collected from serum and data have shown that it was higher in 78 pca compared to 28 normal control subjects. there was a positive correlation between mir-141 and mir-375 with metastatic pca (bryant et al., 2012). other mirs are dysregulated in pca and can segregate in early versus late stages as well as www.eopenaccess.com/index.php/chd e9 cancer health disparities review in localized versus metastatic status (gallo et al., 2012; li et al., 2016b; lodes et al., 2009). exosomes-based pathway in drug resistance of prostate cancer the development of crpc is a current major concern in pca management. several mechanisms are proposed to understand how crpc develops including: ar-independent tumor growth, conversion of estrogen to testosterone, activation of androgen metabolizing enzymes, intracrine activation of ar, and exosomes-based pathways. the multifactorial steps in developing resistance in pca patients suggests the urgent need for adopting a new treatment strategy of targeting multiple signaling pathways contributing to crpc and improving other methods of disease management. treatment of crpc patients with taxanes may lead to the development of resistance. the transfer of exosomal cargoes into different recipient cells could be one of crpc mechanisms especially exosomes have shown to carry ar, arv7, growth factors, mrnas and mirnas. using a digital droplet pcr (ddpcr), a recent study suggested that plasma-derived exosomal mrna of arv7 is associated with resistance to hormonal therapy in patients with crpc (del re et al., 2017). along similar lines, exosomes were isolated from the blood of docetaxelresistant crpc patients and was shown that their cargo contains mdr-1, mdr3 and pabp4 proteins (endzelins et al., 2016). kawakami et al., performed proteomic analysis on exosomes isolated from taxaneresistant pc-3 cells and, interestingly, integrin β4 and vinculin were upregulated (kawakami et al., 2015). these findings present exosomal integrin β4, vinculin and mdr1 (kato et al., 2015) as new biomarkers in patients of taxaneresistance. in a recent study, pmet and mir130b were identified in exosomes isolated from sera of primary and metastatic pca (cannistraci et al., 2017). both factors can significantly differentiate crpc from early stages and can be used as non-invasive marker for active surveillance and therapy monitoring of crpc patients. li et al. investigated the potential networks of exosomes-associated mirnas derived from chemoresistant pca cells with their known target genes (li et al., 2016a). they identified 29 dysregulated mirnas, in exosome isolated from paclitaxel-resistance pca cells. the link between mirnas and their target genes suggests that mir-3176, mir-141-3p, mir5004-5p, mir-16-5p, mir-3915, mir-488-3p, mir-23c, mir-3673 and mir-3654 are potential targets to ar and pten while mir32-5, mir-141-3p, mir-606, mir-381 and mir429 are targets to tcf4. in another study conducted on neuorblastoma cells, exosomesassociated mir-21 and mir-155 mediate the crosstalk between neuroblastoma cells and monocytes in cisplatin resistance cells, possibly, through mir-21/tlr8-nf-кb and mir155/terf1 signaling pathways (challagundla et al., 2015). concluding remarks the role of exosomes is emerging as an interesting component in cancer biology but their contribution to cancer disparities and drug resistance remains unclear. increasing evidence points towards eminent role of exosomal cargoes in transferring cellular messages between cancer cells and their tumor niche. the presence of exosomal protein receptors on the surface of pcahttps://www.ncbi.nlm.nih.gov/pubmed/?term=kawakami%20k%5bauthor%5d&cauthor=true&cauthor_uid=25997717 www.eopenaccess.com/index.php/chd e10 cancer health disparities review associated exosomes may explain, in part, the reasons of pca disparities among aa men regarding ca men and other minorities. this review justifies the need for more studies to build on these recent findings for future understanding of the role of pca-associated exosomes in promoting health disproportionate in pca and other cancer disparities. adopting such exosomal findings in cancer and other chronic diseases might help to eliminate morbidity and mortality disparities among different minorities. future studies need to address these questions to fasciltate the development of new generations of therapeutic agents to target tumor exosomes. in parallel, exosomes standardization for their detection and evaluation as well as understanding their biogenesis, release and uptake are of paramount importance. with a growing accessibility to these biological information, new specific and less toxic drugs will be discovered. acknowledgements the authors would like to thank dr. david potter, ph.d., farvo, for helpful discussions and carefully reading the manuscript. the present study was supported by grant from the nih/nci r21ca194750 (z.y.a). conflict of interest statement the authors declare that there is no conflict of interest to report it. the funders had no role in study design, writing of the manuscript and decision to publish. authors’ contributions conception and design of the study: zya; data collection and preparation: heaa and sag; writing the manuscript: heaa, hia, sag, gd and zya; reviewing the final version of the manuscript: ga, hia and zya. references abd elmageed, z.y., moroz, k., srivastav, s.k., fang, z., crawford, b.e., moparty, k., thomas, r., and abdelmageed, a.b. 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(2009). induction of myeloid-derived suppressor cells by tumor exosomes. int j cancer 124, 2621-2633. www.companyofscientists.com/index.php/chd e1 cancer health disparities research patterns of cancer related health disparities in arizona ken batai*, francine c. gachupin1, antonio l. estrada2, david o. garcia3, jorge gomez4, rick a. kittles5 *division of urology, department of surgery, university of arizona, university of arizona cancer center, 1515 n. campbell ave., p.o. box 245024, tucson, az 85724. 1department of family and community medicine, university of arizona, p.o. box 245052, tucson, az 85724. 2department of mexican american studies, university of arizona, cesar e. chavez building, 1110 e. james e. rogers way, p.o. box 210023, tucson, az 85721. 3department of health promotion sciences, university of arizona, mel and enid zuckerman college of public health, 3950 s. country club, suite 330, tucson, az 85714. 4department of community, environment, and policy, 1295 n. martin ave., po box: 210202, tucson, az 85724. 5division of health equities, department of population sciences, city of hope comprehensive cancer center, 1500 e. duarte rd, duarte, ca 91010-3000 *corresponding author email: kbatai@email.arizona.edu. abstract cancer incidence rates vary regionally among american indians (ais) and latinos. the goal of this was to identify areas of research necessary to reduce cancer health disparities in ais and latinos, the two major racial/ethnic minority groups in arizona. in an effort to better understand cancer health disparities, cancer incidence rates in ais and latinos in arizona were compared to non-hispanic whites (nhws). age-adjusted incidence rates (per 100,000) were obtained from the arizona cancer registry and the north american association of central cancer registries. spearman’s rank test was used to examine correlation between county-level cancer incidence rates and socio-demographic factors. ais and latinos had lower incidence rates of screening for detectable cancers than nhws. among older men (age ≥65), however, ais and latinos had similar prostate cancer incidence rates to nhws. some of less common cancers, such as kidney, stomach, liver, and gallbladder, were more frequently diagnosed in ais and latinos than nhws. ais and latinos were more likely to be diagnosed with advanced cancer stage, except for cervical cancer. correlations between prostate and breast cancer incidence rates and percent urban residents as well as correlations between incidence rates of these two cancer types and population size were significantly positive. poverty levels were inversely correlated with colorectal and lung cancer incidence rates. our review of cancer incidence rates suggests that socio-demographic factors, such as population size (rural/urban) and poverty levels, have influenced cancer detection and incidence rates in arizona. keywords: cancer disparity, health disparity, american indians, latinos, cancer incidence citation: batai et al (2019) patterns of cancer related health disparities in arizona. cancer health disparities 2:e1-e20. doi:10.9777/chd.2019.1008. www.companyofscientists.com/index.php/chd e2 cancer health disparities research introduction nationally, cancer is the second leading cause of death after heart disease (kochanek et al., 2016), but in arizona, cancer was the leading cause of death in 2015 among latinos and non-hispanic whites (nhws). cancer is the second leading cause of death among american indians (ais) and african americans (aas) (bureau of public health statistics). cancer incidence and mortality varies across racial/ethnic groups and geographic regions in the u.s. (jemal et al., 2017; mokdad et al., 2017). cancer incidence and mortality also varies among ais by indian health service regions and among latino subgroups (e.g., mexican americans, puerto ricans, and cubans) has been reported (borrell and crawford, 2009; pinheiro et al., 2009; pinheiro et al., 2011; white et al., 2011; white et al., 2014). in the southwest region of the united states (u.s.), cancer incidence and mortality rates, especially rates for lung, prostate, breast and colorectal cancer, are lower in ais than nhws (white et al., 2014). among latinos, mexican americans have lower cancer incidence rates that other latino subgroups or nhws (pinheiro et al., 2009), but they also have lower survival rates for common cancers than nhws (pinheiro et al., 2011; white et al., 2011). furthermore, ais and latinos are more likely to be diagnosed with advanced stage cancer than nhws (clegg et al., 2002; hoffman et al., 2014; hoffman et al., 2001; iqbal et al., 2015). lower cancer survival rates may be attributed to delayed diagnosis among these medically underserved populations. however, the reasons for the variations in incidence rates are not fully understood. arizona is uniquely situated to investigate cancer health disparities focusing on ais and latinos. arizona has the third largest population of ais in the u.s. (norris et al., 2012). there are 21 federally recognized ai tribes in arizona and approximately 353,000 ais live in arizona (about 5.5% of total arizona population) (norris et al., 2012). the largest tribe is navajo, and their reservation is located in northern arizona, new mexico, utah, and colorado. tohono o’odham is the second largest tribe in arizona and their reservation is east of tucson and northern mexico. several apache tribes have their reservation on the central-eastern part of arizona. however, many ais live in urban areas, such as phoenix and tucson, rather than remote rural areas. ais living in urban areas and on reservations have varying degrees of issues related to access to health care, such as social structural, physical (transportation and physical distance), supportive, and cultural barriers (call et al., 2006; itty et al., 2014). arizona is also one of four u.s.-mexico border states, along with california, texas, and new mexico. latinos constitute the largest racial/ethnic minority group in arizona, which accounts for approximately 30% (1.8 million) of the arizona residents (ennis et al., 2011). mexican americans are the largest latino subgroup in arizona (1,657,668). many latinos live in urban areas and southern arizona. over 30% of residents in southern arizona counties along the border are latinos, and over 50% of residents in two rural counties, santa cruz and yuma, that border with mexico are latinos. like ais, latinos face multiple barriers related to health care access, and undocumented immigrants faces even more barriers to health care, such as lack of documentations to receive health insurance (ortega et al., 2015). the goal of this paper was to identify areas of research necessary to reduce cancer health www.companyofscientists.com/index.php/chd e3 cancer health disparities research disparities. in an effort to further understand cancer health disparities, cancer incidence rates among ais and latinos in arizona were compared to nhws and aas with a focus on common types of cancer (breast, prostate, lung, and colorectal) and cancers that disproportionately affect ais and latinos (kidney, liver, stomach, cervical, myeloma, gallbladder, and uterine cancer). this paper focuses on ais and latinos, the two major racial/ethnic minority groups in arizona. other racial/ethnic minority groups including aas, asian americans, and native hawaiian and other pacific islanders account for less than 5% of arizona population (approximately 4.5%, 3.5%, and 0.5% respectively). methods incidence rates the cancer incidence data was retrieved in november and december 2016 from the arizona cancer registry (acr) and north american association of central cancer registries (naaccr). to compare cancer incidence rates among racial/ethnic groups and among arizona counties, age-adjusted incidence rates (per 100,000 using the 2000 u.s. standard population) between 2004 and 2013 for each racial/ethnic group and county in arizona were obtained from the acr. age-adjusted incidence rates between 1995 and 2003 were also obtained from the acr to examine cancer incidence trends for each racial/ethnic group. the data on cancer incidence in asian americans and pacific islanders were analyzed but not used due to both the small number of cancer cases and the small statewide population size. from the naaccr, cancer incidence rates with 95% confidence interval (ci) stratified based on age group (age <65 vs. age ≥65) and stage at diagnosis data (number of cases) between 2009 and 2013 were also obtained to reflect recent screening recommendations. cancer incidence rates and 95% ci for each stage was retrieved from the naaccr in march 2018. socio-demographic factors to compare the cancer incidence rate and sociodemographic factors, county-level percent urban residents, population size, poverty rates, median income, and high school graduation rates were obtained. first, percent urban population for 15 arizona counties were obtained from 2010 census. second, population size based on 2010 census data was obtained from arizona state employment and population statistics. the data on poverty rates (all ages) and median income in 2014 was obtained from the u.s. census bureau small area income and poverty estimates (saipe). the 2015 five-year high school graduation rates were also obtained from the arizona department of education. arizona behavioral risk factor surveillance system (brfss) data between 2010 and 2014 was reviewed and a proportion (%) and 95% ci of individuals who have barriers to health care (e.g., poverty, lack of health insurance, and not having usual source of health care) and who have had breast, colorectal, prostate, and cervical cancer screening were obtained. statistical methods incidence rate ratios (irrs) between ais and nhws and between latinos and nhws were calculated stratified by medicare eligible age (<65 and ≥65) to examine if irrs were significantly different for the younger and older age groups. irrs were calculated by dividing the reported incidence rate in ais or latinos by the incidence rate in nhws. we used 95% ci to evaluate statistical difference in incidence rates. spearman’s correlation was used to assess the correlation of cancer incidence rates with arizona county population sizes, poverty www.companyofscientists.com/index.php/chd e4 cancer health disparities research rates, median incomes, and high school graduation rates. from number of cases for each diagnostic stage obtained from naaccr, chisquare test was used to test if diagnosis with localized or distant cancers were more frequent in ais and latinos. the two-tail test was used for spearman’s correlation and chi-square test. results cancer incidence rate and stage we first examined differences in cancer incidence among racial/ethnic groups in the ten-year period between 2004 and 2013 (figure 1). ais and latinos had significantly lower incidence rates than nhw and aas for common screen detectable cancer (breast, prostate, and colorectal cancer) and lung cancer. in latinos and nhws, breast cancer incidence was higher than prostate cancer incidence. on the other hand, in ais and aas, prostate cancer incidence rate was higher than breast cancer incidence. prostate cancer in aa men had the highest incidence rate. some of less common types of cancer were more frequent in ais, latinos, and aas than nhws. ais had a significantly higher incidence of kidney cancer, uterine cancer, liver cancer, stomach cancer, gallbladder cancer, and myeloma than nhws. latinos had significantly higher incidence of kidney cancer, cervical cancer, liver cancer, stomach cancer, and gallbladder cancer. ais had a higher cervical cancer incidence rate than nhws and aas, but it was not statistically significant. ais had slightly higher prostate cancer incidence rate than latinos (statistically not significant), but breast cancer, lung cancer, and male colorectal cancer incidence rates for ais were significantly lower than for latinos. when stratified by gender, males had higher incidence of cancer than females. kidney cancer incidence was very high in ai men (1.9 fold higher in ais than in nhws), and was the second most commonly diagnosed cancer among them. figure 1. age-adjusted cancer incidence rates (per 100,000) between 2004 and 2013 in arizona * indicates statistically significant different incidence rate compared to nhw. irrs between ais and nhws and between latinos and nhws were examined stratified by age of diagnosis (<65 compared to ≥65) for four common cancers (breast, prostate, lung, and colorectal) and cervical cancer (table 1). the irrs were different between the younger age group and the older age group for prostate cancer (ai/nhw and latino/nhw), lung cancer (latino/nhw among men), colorectal cancer (ai/nhw among women), and cervical cancer (latina/nhw). ais had significantly lower prostate cancer incidence rate in the younger group, but www.companyofscientists.com/index.php/chd e5 cancer health disparities research ais and nhws had similar incidence rates in the older group. the gap in the prostate cancer incidence rates between latinos and nhws also decreased in the older age group (irr of 0.67 in the younger group compared to 0.91 in the order group). the difference in lung cancer incidence rate between latino and nhw men also decreased from irr of 0.46 in the younger group to 0.69 in the older group. on the other hand, ai women had a similar colorectal cancer incidence rate as did nhw women in the younger age group (irr 1.05), but significantly lower incidence rate in the older age group (irr 0.65). irr for cervical cancer between latina and nhw was moderately high (irr 1.32), but even bigger incidence rate difference was observed in the older age group (irr 2.01). between 1995 and 2013, overall incidence rate of all cancer types combined declined for nhw, latino, and aa men, reflecting the decline in incidence rate of three major cancer types in men (prostate, lung and colorectal) (figure 2, supplementary figure 1). the prostate and lung cancer incidence followed national trends and declined for nhw, latino, and aa men. colorectal cancer incidence also declined for nhw men, but not for other racial/ethnic groups. overall cancer incidence did not change for nhw, latina, and aa women. colorectal cancer incidence declined for nhw women, but it did not change for latinas or aa women. incidence of two other major caner types (breast and lung) did not change for nhw, latina, and aa women. overall cancer incidence slightly increased for ais during this period. colorectal cancer incidence increased for ai women. breast cancer incidence rate did not change. among ai men, incidence rate for prostate, colorectal, and lung cancer did not change. over time, as the prostate and colorectal cancer incidence rates in nhw and aa men and the colorectal cancer rate in nhw women declined, the differences in prostate and colorectal cancer incidence rates among racial/ethnic groups narrowed. incidence rates of two less common types of cancer, kidney and liver cancer, increased in all the racial/ethnic groups. incidence rates for each stage of diagnosis were reviewed for five cancer types, breast, prostate, lung, colorectal, and cervical cancer (supplementary table 1). we also examined the proportion of individuals diagnosed in each stage (supplementary figure 2). the incidence rates for each stage generally reflect the overall incidence rates for these cancer types exhibiting overall lower incidence rates for ais and latinos compared to nhw while a higher proportion of ais and latinos were diagnosed with advanced stage cancer, except for cervical cancer. one exception is incidence rate for distant prostate cancer. ais and latinos had lower overall prostate cancer incidence rate than nhws, but they had higher incidence rate for distant (metastatic) prostate cancer than nhws. distant prostate cancer was more common among ais and latinos (17% and 8% respectively) than nhws (5%). incidence rate of distant breast cancer was lower in ai women compared to nhw women, but a significantly higher proportion of ai women had distant breast cancer (8% in ais compared to 5% in nhw). latina women had similar incidence rates for distant breast and colorectal cancer to nhw women, but a proportion of latina women with distant breast and colorectal cancer was higher than that of nhw. latinos and ais have lower incidence rates of distant lung cancer. however, a higher proportion of latino men and ai women had distant lung cancer compared to nhw men and women. www.companyofscientists.com/index.php/chd e6 cancer health disparities research table 1. comparison of cancer incidence among ais, latinos, and nhws in two age groups (age-adjusted incidence rate per 100,000 between 2009-2013 based on 2000 us standard population). age <65 age ≥65 incidence rate irr incidence rate irr cancer type gender ai latino nhw ai/nhw latino/nhw ai latino nhw ai/nhw latino/nhw breast female 39.3 (34.8-44.2) 57.0 (54.559.7) 77.4 (75.679.3) 0.51* 0.74* 157.2 (128.4191.0) 292.7 (273.3313.3) 405.4 (396.7414.2) 0.39* 0.72* prostate male 16.4 (13.5-19.9) 25.2 (23.527.1) 37.5 (36.438.6) 0.44* 0.67* 434.0 (374.9500.5) 375.0 (349.7402.0) 412.2 (402.8421.8) 1.05 0.91* lung and bronchus male 5.2 (3.67.3) 8.0 (7.1-9.1) 17.3 (16.618.1) 0.30* 0.46* 127.0 (95.7166.5) 257.7 (235.9281.3) 372.2 (363.1381.5) 0.34* 0.69* female 6.8 (5.09.1) 6.8 (6.07.8) 15.1 (14.415.8) 0.45* 0.45* 103.9 (80.3132.5) 159.8 (145.2175.5) 298.7 (291.2306.4) 0.35* 0.53* colorectal male 16.9 (13.920.4) 17.9 (16.419.4) 16.6 (15.817.4) 1.02 1.08 125.7 (95.5163.9) 217.6 (197.6239.3) 191.4 (184.8198.1) 0.66* 1.14 female 13.5 (10.916.5) 12.7 (11.514.0) 12.8 (12.013.5) 1.05 0.99 98.5 (75.4126.7) 141.1 (127.3155.9) 152.6 (147.3158.1) 0.65* 0.92 cervix uteri female 5.4 (3.97.5) 7.8 (6.98.8) 5.9 (5.36.4) 0.92 1.32* 12.0 (5.124.4) 14.9 (10.820.2) 7.4 (6.3-8.7) 1.62 2.01* numbers in parentheses indicate 95% confidence interval. ai/nhw – incidence rate in ai / incidence rate in nhw latino/nhw – incidence rate in latino / incidence rate in nhw * significant difference in incidence rate based 95% confidence interval www.companyofscientists.com/index.php/chd e7 cancer health disparities research figure 2. trends in overall cancer incidence in arizona between 1995 and 2013 impacts of socio-demographic factors we compared cancer incidence rate between 2004 and 2013 with percent urban residents, population size, median income, and high school graduation rate in arizona counties for four common cancers and cervical cancer. counties with high percent of urban residents and large population size had significantly higher breast and prostate cancer incidence rate (supplementary table 2). strong positive correlations between prostate cancer incidence rate and population size were observed (spearman’s correlation rho=0.775, p=0.001). the correlation was significant, even when nhws and latinos were analyzed separately. poverty levels were inversely correlated with prostate, colorectal, and lung cancer incidence rate among men (p<0.05). the strongest correlation was observed for nhw men and colorectal cancer (spearman’s correlation rho=0.747, p=0.001). colorectal cancer incidence rates among men also increased with median income among men (p<0.05). cervical cancer incidence rate was significantly inversely correlated with population size for nhw women. however, overall there were a small number of cases and three small counties had less than ten cases within each county as well as a large incidence rate with a very large 95% ci. five-year high school graduate rates were not correlated with incidence rates of any cancer types. arizona brfss the arizona 2014 brfss results show that ais and latinos have more barriers to health care than nhws. compared to nhws, a higher proportion of ais and latinos reported living below poverty line and not having health insurance (supplementary table 3). more latinos also reported not being able to afford health care than nhws (23.1% vs. 12.6%). a significantly smaller proportion of ais and latinos had usual source of health care (having primary care providers as a main source of health care) than nhws and have had a preventative check-up in the past year. aas were more likely than nhws to report living below poverty level, but they were more likely to have a preventive check-up. while ai and latina women had higher breast and cervical cancer screening rates than nhws, ais and latinos had lower colon and prostate cancer screening rate than nhws. it also should be noted that some risk factors of cancer are more prevalent in ais and latinos than nhws. for example, obesity is more prevalent in www.companyofscientists.com/index.php/chd e8 cancer health disparities research ais and latinos than nhws (44.9% in ais, 33.8% in latinos, and 26.4% in nhws). smoking rates, on the other hand, were lower in ais (12.0%) and latinos (14.0%) than in nhws (17.5%). discussion cancer incidence rates were reviewed as a first step to understand cancer health disparities among ais and latinos in arizona. our review of cancer incidence rates suggests that many sociodemographic factors may have influenced the cancer detection and reported cancer incidence rates in ais and latinos. cancer incidence trend as well as observed differences between incidence rate of each stage at diagnosis and a proportion of patients diagnosed in each stage are reflective of differences in cancer screening participation in ais, latinos, nhws, and aas. decline in prostate and colorectal incidence rates in nhw and aa men generally reflect changes in screening participations. decline in prostate cancer screening due to a recent recommendation against prostate specific antigen (psa) screening reduced prostate cancer diagnosis, while high colon cancer screening uptake increased removal of precancerous polyps reducing colorectal cancer incidence. on the other hand, continuously low screening participation in ais may have resulted in persistently low screening detectable cancer incidence rates. colon cancer screening rate among latinos is also low, and colorectal incidence rate did not change over time. although ais and latinos have lower cancer incidence rates, when they are diagnosed, a higher proportion of them was diagnosed with advanced stage cancer as reported in other studies (clegg et al., 2002; siegel et al., 2015). population size (urban vs. rural) and poverty levels within given counties, physician and screening facility availability, and health care coverage are interconnected factors that influence cancer screening, detection, stage at diagnosis, cancer care, and ultimately mortality (faruque et al., 2015; odisho et al., 2010; stimpson et al., 2012; tatalovich et al., 2015; tian et al.). issues related to health care access in ais and latinos in the younger age group (age <60) may have caused less frequent psa testing and lower detection of prostate cancer among younger ai and latino men compared to the older ai and latino men in medicare eligible age group (≥65). in the arizona 2010 brfss, a smaller proportion of ai and latino men reported ever having had a psa test than nhws men. limited availability of urologists and primary care physicians in rural counties may also have reduced prostate cancer detections, especially in early stage. high incidence rates of distant prostate cancer in ais and latinos further support low screening rate influencing the prostate cancer diagnosis patterns. the reason for lower colorectal cancer incidence in ais in the older age compared to younger is not known, but educational level and ability to speak english may have influenced their knowledge on colon cancer screening, screening participation and detection among the older ai women (sanderson et al., 2011). colorectal cancer incidence and screening rates among ais and latinos in arizona may also reflect issues related to health care access. increasing colorectal cancer screening rate in nhws reduced colorectal cancer incidence rate in nhws. ais and latinos have lower colorectal cancer screening rates than nhws, and their incidence rate did not change over time. higher percentage of latinas were diagnosed with distant colorectal cancer than www.companyofscientists.com/index.php/chd e9 cancer health disparities research nhw women. low cancer, especially colorectal cancer, incidence rates were observed in arizona counties with high poverty rates. high poverty rates are usually found in rural counties where large ai reservations are located or a high proportion of residents are latinos. low density of high quality health care facilities in rural areas with high poverty rates may have reduced cancer screening and detection. however, we did not observe significant correlation between poverty levels and colorectal cancer incidence rate in latinos. women’s health programs that provided service to low-income uninsured and underinsured women have been successful (lantz and mullen, 2015), and ai and latino women in arizona have similar or higher breast and cervical cancer screening rate when compared with nhws women. however, higher proportion of ais and latinas were diagnosed with distant breast cancer than nhws. ai and latina women living rural areas of arizona are less likely to receive breast and cervical cancer screening than in ai and latina women living urban areas (nuño et al., 2012). it is likely that ais and latinas tended to be diagnosed with more advance stage cancer due to lower screening rates in these rural areas with high poverty levels. cancer incidence rate in ais and latinos are generally lower than nhws, but incidence rate of less common types of cancer was higher in ais and latinos. kidney and liver cancer incidence rates were particularly high in ais and latinos compared to nhws and increasing. kidney and liver cancer as well as other less common types of cancer, such as stomach and uterine cancer, that are disproportionately affecting ais and latinos, are linked to obesity (lauby-secretan et al., 2016), and obesity is more prevalent in ais and latinos in arizona. although there is an effort to provide service to medically underserved women (lantz and mullen, 2015), ai and latino men may have heavier burden of cancer than ai and latina women. cancer incidence rates in men are generally higher than women. in the general population, lung and breast cancer have a higher mortality rate than other types of cancers, but in arizona ais, prostate cancer mortality rate is higher than the mortality rate for other types of cancers (arizona cancer registry, 2013). despite the high cancer burden, ai and latino men have low health care utilization (livingstone et al., 2008; rhoades, 2003). one of limitations of this study is that this was an ecological study and cancer incidence trends and correlations with socio-demographic factors were investigated, and this study did not investigate how individual level socio-demographic, behavioral factors, and cultural values affected cancer screening behavior and detection. the independent effects of these correlated factors will be explored in our future studies. after reviewing cancer incidence rates among ais and latinos in arizona, we identified several issues that need to be addressed through research. first, it is necessary to develop programs to increase cancer screening among ais and latinos. ais and latinos are less likely to participate in colon and prostate cancer screening, and they are more likely to be diagnosed with advanced cancer. because of potential harms including high rate of false positive, overdiagnosis and overtreatment, and treatment complication, ai and latino men should be encouraged to discuss the benefit and risk of prostate cancer screening with their health care provider (u. s. preventive services task force, 2018). second, it is necessary to find effective ways www.companyofscientists.com/index.php/chd e10 cancer health disparities research to reduce barriers to health care, especially in rural areas. ais and latinos have more barriers to health care and are less likely to receive medical care. racial/ethnic minority individuals living in rural areas may have additional barriers to health care. third, some of risk factors for cancer, such as obesity and diabetes, are more prevalent in ais and latinos and need to be reduced. culturally tailored intervention and education programs need to be developed to increase cancer screening and reduce cancer risk factors. fourth, ai and latino men are less likely to receive health care. programs targeting to ai and latino men, especially low-income uninsured and underinsured men, need to be developed to improve their health care utilization and cancer screening. conclusion differences in incidence rates among racial/ethnic groups reflect differences in socio-demographic factors (poverty, population density, and age), health care access, screening participation, and/or lifestyle. ais and latinos in arizona have multiple barriers to health care and barriers to health care influence their cancer screening participation, detection, care, and ultimately mortality. acknowledgements we would like to acknowledge the individual affected by cancer represented in our data. we are grateful for the editorial assistance from alicia allen, phd, amit algotar, md, carol howe, md, jerome koleski, md, and jessie pettit, md. this research was funded by the arizona area health education centers program career development award, the arizona cancer center health disparities program, institutional research grant number irg-16-124-37-irg from the american cancer society, and the partnership for native american cancer prevention (nacp), funded under parallel grants, u54ca143924 (university of arizona cancer center) and u54ca143925 (northern arizona university). online source arizona cancer registry database query system http://healthdata.az.gov/query/module_selection/a zcr/azcrselection.html north american association of central cancer registries fast stats https://faststats.naaccr.org/ conflict of interest the authors declare that no competing or conflict of interests exists. the funders had no role in study design, writing of the manuscript, or decision to publish. authors’ contributions kb, fcg, ale, and rak conceptualized the study. kb performed analysis. all the authors contributed to interpretation of analysis results, writing, and editing. references arizona cancer registry (2013). cancer in arizona: cancer incidence and mortality 2008-2009 (phoenix, az: arizona department of health services). borrell, l.n., and crawford, n.d. 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(2014). colorectal cancer incidence and mortality disparities in new mexico. j cancer epidemiol 2014, 8. hoffman, r.m., gilliland, f.d., eley, j.w., harlan, l.c., stephenson, r.a., stanford, j.l., albertson, p.c., hamilton, a.s., hunt, w.c., and potosky, a.l. (2001). racial and ethnic differences in advanced-stage prostate cancer: the prostate cancer outcomes study. j natl cancer inst 93, 388-395. iqbal, j., ginsburg, o., rochon, p.a., sun, p., and narod, s.a. (2015). differences in breast cancer stage at diagnosis and cancer-specific survival by race and ethnicity in the united states. jama 313, 165-173. itty, t.l., hodge, f.s., and martinez, f. (2014). shared and unshared barriers to cancer symptom management among urban and rural american indians. j rural health 30, 206-213. jemal, a., ward, e.m., johnson, c.j., cronin, k.a., ma, j., ryerson, a.b., mariotto, a., lake, a.j., wilson, r., sherman, r.l., et al. 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(2017). trends and patterns of disparities in cancer mortality among us counties, 1980-2014. jama 317, 388406. norris, t., vines, p., and hoeffel, e. (2012). the american indian and alaska native population: 2010. in 2010 census briefs (united states census bureau). nuño, t., gerald, j.k., harris, r., martinez, m.e., estrada, a., and garcía, f. (2012). comparison of breast and cervical cancer screening utilization among rural and urban hispanic and american indian women in the southwestern united states. cancer causes control 23, 1333-1341. odisho, a.y., cooperberg, m.r., fradet, v., ahmad, a.e., and carroll, p.r. (2010). urologist density and county-level urologic cancer mortality. j clin oncol 28, 2499-2504. ortega, a.n., rodriguez, h.p., and bustamante, a.v. (2015). policy dilemmas in latino health care and implementation of the affordable care act. annu rev public health 36, 525-544. pinheiro, p.s., sherman, r.l., trapido, e.j., fleming, l.e., huang, y., gomez-marin, o., and lee, d. (2009). cancer incidence in first generation u.s. hispanics: cubans, mexicans, puerto ricans, and new latinos. cancer epidemiol biomarkers prev 18, 2162-2169. pinheiro, p.s., williams, m., miller, e.a., easterday, s., moonie, s., and trapido, e.j. (2011). cancer survival among latinos and the hispanic paradox. cancer causes control 22, 553-561. rhoades, e.r. (2003). the health status of american indian and alaska native males. am j public health 93, 774-778. sanderson, p.r., weinstein, n., teufel-shone, n., and martínez, m.e. (2011). assessing colorectal cancer screening knowledge at tribal fairs. prev chronic dis 8, a16. siegel, r.l., fedewa, s.a., miller, k.d., goding-sauer, a., pinheiro, p.s., martinez-tyson, d., and jemal, a. (2015). cancer statistics for hispanics/latinos, 2015. ca cancer j clin 65, 457-480. stimpson, j.p., pagán, j.a., and chen, l.-w. (2012). reducing racial and ethnic disparities in colorectal cancer screening is likely to require more than access to care. health aff 31, 2747-2754. tatalovich, z., zhu, l., rolin, a., lewis, d.r., harlan, l.c., and winn, d.m. (2015). geographic disparities in late stage breast cancer incidence: results from eight states in the united states. int j health geogr 14, 31. tian, n., goovaerts, p., zhan, f.b., chow, t.e., and wilson, j.g. (2012). identifying risk factors for disparities in breast cancer mortality among african-american and hispanic women. womens health issues 22, e267-e276. u. s. preventive services task force (2018). screening for prostate cancer: us preventive services task force recommendation statement. jama 319, 1901-1913. white, a., coker, a.l., du, x.l., eggleston, k.s., and williams, m. (2011). racial/ethnic disparities in survival among men diagnosed with prostate cancer in texas. cancer 117, 1080-1088. white, m.c., espey, d.k., swan, j., wiggins, c.l., eheman, c., and kaur, j.s. (2014). disparities in cancer mortality and incidence among american indians and alaska natives in the united states. am j public health 104, s377-s387. www.companyofscientists.com/index.php/chd e12 cancer health disparities research supplementary materials supplementary figure 1. trends in cancer incidence in arizona between 1995 and 2013 (age-adjusted incidence rate per 100,000) 0 20 40 60 80 100 120 140 160 19 9 5 19 9 7 19 9 9 2 0 0 1 2 0 0 3 2 0 0 5 2 0 0 7 2 0 0 9 2 0 11 2 0 13 breast 0 50 100 150 200 250 19 9 5 19 9 7 19 9 9 2 0 0 1 2 0 0 3 2 0 0 5 2 0 0 7 2 0 0 9 2 0 11 2 0 13 prostate 0 20 40 60 80 100 120 140 160 lung male 0 10 20 30 40 50 60 70 80 19 9 5 19 9 7 19 9 9 2 0 0 1 2 0 0 3 2 0 0 5 2 0 0 7 2 0 0 9 2 0 11 2 0 13 lung female www.companyofscientists.com/index.php/chd e13 cancer health disparities research 0 20 40 60 80 100 19 9 5 19 9 7 19 9 9 2 0 0 1 2 0 0 3 2 0 0 5 2 0 0 7 2 0 0 9 2 0 11 2 0 13 colonectal male 0 10 20 30 40 50 60 70 19 9 5 19 9 7 19 9 9 2 0 0 1 2 0 0 3 2 0 0 5 2 0 0 7 2 0 0 9 2 0 11 2 0 13 colorectal female 0 5 10 15 20 25 30 35 19 9 5 19 9 7 19 9 9 2 0 0 1 2 0 0 3 2 0 0 5 2 0 0 7 2 0 0 9 2 0 11 2 0 13 kidney 0 5 10 15 20 25 19 9 5 19 9 7 19 9 9 2 0 0 1 2 0 0 3 2 0 0 5 2 0 0 7 2 0 0 9 2 0 11 2 0 13 liver 0 10 20 30 40 19 9 5 19 9 7 19 9 9 2 0 0 1 2 0 0 3 2 0 0 5 2 0 0 7 2 0 0 9 2 0 11 2 0 13 uterine 0 5 10 15 20 19 9 5 19 9 7 19 9 9 2 0 0 1 2 0 0 3 2 0 0 5 2 0 0 7 2 0 0 9 2 0 11 2 0 13 stomach www.companyofscientists.com/index.php/chd e14 cancer health disparities research 0 5 10 15 20 25 30 19 9 5 19 9 7 19 9 9 2 0 0 1 2 0 0 3 2 0 0 5 2 0 0 7 2 0 0 9 2 0 11 2 0 13 ovarian 0 5 10 15 20 19 9 5 19 9 7 19 9 9 2 0 0 1 2 0 0 3 2 0 0 5 2 0 0 7 2 0 0 9 2 0 11 2 0 13 cervical 0 2 4 6 8 10 12 14 19 9 5 19 9 7 19 9 9 2 0 0 1 2 0 0 3 2 0 0 5 2 0 0 7 2 0 0 9 2 0 11 2 0 13 gallbladder www.companyofscientists.com/index.php/chd e15 cancer health disparities research supplementary figure 2. comparison of stage at diagnosis between 2009 and 2013 (percentage). * indicates statistically significant difference compared to nhw with p<0.05. 55* 36 8* 59* 35 6* 67 29 5 0 10 20 30 40 50 60 70 localized regional distant breast female 75 8 17* 78 14 8* 80 15 5 0 20 40 60 80 100 localized regional distant prostate 21 16 64 15 22 62* 21 25 54 0 10 20 30 40 50 60 70 localized regional distant lung male 23 16 61* 25 25 50 27 25 48 0 10 20 30 40 50 60 70 localized regional distant lung female www.companyofscientists.com/index.php/chd e16 cancer health disparities research supplementary table 1. comparison of stage at diagnosis between 2010 and 2014: incidence rate (ir) and 95% ci. * indicates significantly higher incidence rate compared to nhw localized regional distant ir 95% ci ir 95% ci ir 95% ci breast female nhw 73.8 72.3-75.3 33.3 32.2-34.4 5.6 5.2-6.0 latina 50.4 47.9-53.0 26.4 24.7-28.3 4.9 4.2-5.8 ai 29.7 25.8-34.2 18.8 15.8-22.4 3.2 2.0-4.9 44 33 22 42 35 23 45 35 20 0 10 20 30 40 50 localized regional distant colorectal male 41 41 18 38 38 24* 45 35 20 0 10 20 30 40 50 localized regional distant colorectal female 61 39 51 38 11 50 35 15 0 10 20 30 40 50 60 70 localized regional distant cervical www.companyofscientists.com/index.php/chd e17 cancer health disparities research prostate male nhw 54.8 53.5-56.0 10.6 10.0-11.1 4.2 3.8-4.52 latino 39.7 37.2-42.4 7.8 6.8-9.0 5.5 4.51-6.7 ai 34.7 29.5-40.7 3.5 2.1-5.8 11.3* 8.1-15.5 lung male nhw 10.4 9.9-11.0 12.1 11.5-12.7 25.8 25.0-26.7 latino 4.7 3.8-5.9 6.6 5.4-7.9 18.5 16.6-20.6 ai 4.2 2.4-6.9 3.2 1.7-5.8 10.9 8.0-14.8 female nhw 11.2 10.6-11.7 10.2 9.7-10.7 20.0 19.3-20.8 latina 5.4 4.6-6.4 5.3 4.4-6.3 10.7 9.6-12.1 ai 2.9 1.7-4.7 3.2 1.9-5.0 10.0 7.6-12.9 colorectal male nhw 14.6 14.0-15.3 12.1 11.5-12.7 6.9 6.5-7.4 latino 14.9 13.3-16.6 14.1 12.5-15.8 8.1 7.0-9.4 ai 11.1 8.4-14.7 9.9 7.4-13.2 6.1 4.1-8.9 female nhw 11.8 11.2-12.4 9.4 8.8-9.8 5.5 5.1-5.9 latina 9.4 8.3-10.6 10.2 9.0-11.5 5.4 4.6-6.4 ai 7.6 5.6-10.0 9.1 6.8-11.8 3.1 1.9-4.9 cervical female nhw 2.9 2.5-3.3 1.6 1.3-1.9 0.7 0.5-0.9 latina 3.4 2.8-4.0 2.7 2.2-3.3 1.0 0.7-1.4 ai 2.2 1.3-3.6 1.9 1.0-3.3 www.companyofscientists.com/index.php/chd e18 cancer health disparities research supplementary table 2. correlation between cancer incidence rate and socio-demographic factors. percent urban population population size in 2010 poverty level median income high school graduation rate percent urban population population size in 2010 gender rho p rho p rho p rho p rho p prostate male all 0.475 0.07 0.775 0.001 -0.375 0.17 -0.004 0.99 -0.175 0.53 nhw 0.627 0.01 0.670 0.006 -0.524 0.045 0.265 0.34 0.057 0.84 latino 0.604 0.02 0.593 0.02 -0.479 0.07 0.361 0.19 0.243 0.38 breast female all 0.639 0.01 0.689 0.004 -0.533 0.04 0.314 0.25 -0.150 0.59 nhw 0.689 0.004 0.471 0.08 -0.223 0.42 0.132 0.64 0.311 0.26 latino 0.518 0.048 0.425 0.11 -0.177 0.53 0.396 0.14 -0.161 0.57 lung both all 0.004 0.99 -0.007 0.98 -0.572 0.03 0.264 0.34 -0.246 0.38 nhw 0.011 0.97 -0.157 0.58 -0.306 0.27 0.143 0.61 0.004 0.99 latino -0.089 0.75 -0.229 0.41 -0.048 0.86 0.236 0.40 0.132 0.64 male all -0.018 0.95 0.089 0.75 -0.552 0.03 0.229 0.41 -0.129 0.65 nhw 0.111 0.69 0.061 0.83 -0.259 0.35 0.057 0.84 0.093 0.74 latino 0.032 0.91 -0.334 0.22 -0.268 0.33 0.329 0.23 0.011 0.97 female all 0.282 0.31 0.375 0.17 -0.272 0.33 0.004 0.99 -0.336 0.22 nhw 0.104 0.71 0.000 1.00 -0.429 0.11 0.193 0.49 -0.157 0.58 latina -0.020 0.95 -0.029 0.92 0.378 0.18 -0.156 0.59 0.209 0.47 colorectal both all 0.257 0.36 0.071 0.80 -0.697 0.004 0.343 0.21 -0.039 0.89 nhw 0.236 0.40 0.039 0.89 -0.602 0.02 0.314 0.25 -0.043 0.88 latino -0.068 0.81 -0.171 0.54 -0.088 0.76 0.143 0.61 -0.193 0.49 www.companyofscientists.com/index.php/chd e19 cancer health disparities research male all 0.354 0.20 0.218 0.44 -0.731 0.002 0.518 0.048 -0.032 0.91 nhw 0.336 0.22 0.271 0.33 -0.747 0.001 0.525 0.04 -0.125 0.66 latino -0.229 0.41 -0.096 0.73 0.011 0.97 0.057 0.84 0.093 0.74 female all 0.225 0.42 0.064 0.82 -0.379 0.16 0.057 0.84 -0.254 0.36 nhw 0.182 0.52 0.057 0.84 -0.172 0.54 -0.043 0.88 -0.229 0.41 latina 0.021 0.94 -0.221 0.43 -0.200 0.47 0.282 0.31 -0.107 0.70 cervix female all -0.239 0.39 -0.282 0.31 -0.082 0.77 -0.004 0.99 -0.139 0.62 nhw -0.615 0.03 -0.769 0.002 0.272 0.37 0.154 0.62 0.038 0.90 latina -0.216 0.46 0.051 0.86 -0.123 0.67 -0.286 0.32 -0.095 0.75 statistically significant correlations are shown with bold. supplementary table 3. barriers to health care, cancer screening rate, and cancer risk factors (arizona behavioral risk factor surveillance system data) ai latino/latina aa nhw % 95% ci % 95% ci % 95% ci % 95% ci barriers to health care living below 133% federal poverty line 11.1 6.4-15.8 13.8 12.0-15.6 9.9 6.0-13.7 2.8 2.3-3.2 not having health insurance coverage 16.0 10.4-21.6 27.6 24.4-30.8 14.7 9.1-20.4 8.9 7.7-10.0 could not afford health care 14.0 8.9-19.1 23.1 20.1-26.1 16.1 10.7-21.5 12.6 11.5-13.7 usual source of health care 54.1 46.8-61.5 58.9 55.4-62.3 75.7 68.7-82.6 79.7 77.7-80.4 preventive care utilization had preventive check up in the last year 64.0 56.5-71.4 58.0 54.6-61.5 76.9 70.1-83.7 66.1 64.7-67.6 cancer screening www.companyofscientists.com/index.php/chd e20 cancer health disparities research ever had a fecal occult blood test 27.5 17.4-37.6 21.4 17.4-25.4 41.4 33.0-49.7 40.1 38.7-41.5 ever had a colonoscopy or sigmoidoscopy 34.6 24.9-44.3 54.6 49.4-59.8 70.6 62.3-78.9 71.5 70.1-72.9 had a mammogram in the past year 62.4 49.9-75.0 57.6 52.1-63.2 62.1 51.6-72.6 55.9 54.0-57.9 had a pap smear within the last 3 years 84.5 77.5-91.5 81.7 77.9-85.6 83.9 77.2-90.7 69.5 67.9-71.1 ever had a psa testa 19.2 53.8 77.2 80.5 cancer risk factors current smoker 12.0 7.8-16.2 14.0 11.5-16.5 16.2 10.9-21.6 17.5 16.3-18.8 obesity (bmi>30) 44.9 37.4-52.5 33.8 30.5-37.1 36.8 29.6-44.0 26.4 25.1-27.7 diabetes 14.8 10.2-19.3 10.4 7.7-13.8 10.7 7.7-13.8 9.9 9.2-10.6 high blood pressure 30.4 20.5-40.4 22.0 17.9-26.0 40.1 29.5-50.8 33.1 31.2-34.9 2014 arizona behavioral risk factor surveillance system report (http://azdhs.gov/preparedness/public-health-statistics/behavioral-risk-factorsurveillance/index.php#reports) a prostate specific antigen (psa) screening test data is from 2010 arizona behavioral risk factor surveillance system report, and 95% ci was not reported. http://azdhs.gov/preparedness/public-health-statistics/behavioral-risk-factor-surveillance/index.php#reports http://azdhs.gov/preparedness/public-health-statistics/behavioral-risk-factor-surveillance/index.php#reports www.companyofscientists.com/index.php/chd e1 cancer health disparities research absolute and relative black-white disparities in cancer incidence and survival in the united states, 2009-2014 tomi akinyemiju department of epidemiology, college of public health, university of kentucky, lexington, ky 40508 corresponding author email: tomiakin@uky.edu abstract progress has been made in reducing the overall burden of cancer among us adults. however, racial differences persist across multiple cancer types. this report shows absolute and relative inequalities in cancer incidence and survival among blacks and whites in the us. data from the surveillance epidemiology and ends results database between 2009-2014 were used to generate age-adjusted estimates of absolute and relative black-white differences in incidence and survival rates. in 2010-2014, the overall cancer incidence rate ratio (irr) comparing blacks to whites was 1.03 (95% ci: 1.03-1.04), while the incidence rate difference (ird) was 19.3 per 100,000 (95% ci: 17.5-21.1). during this period, the largest relative racial disparities in incidence were observed for kaposi sarcoma (black vs. white irr: 3.20, 95% ci: 2.80-3.40) and melanoma of the skin (black vs. white irr: 0.04, 95% ci: 0.03-0.04), and in absolute terms it was prostate cancer (black-white ird per 100,000: 40, 95% ci: 39.3-40.9) and skin cancer (black-white ird per 100,000: -35.1, 95% ci: -34.9, -35.1). in 2009-2014, the overall 5-year relative survival rate ratio (srr) comparing blacks to whites was 0.92 (95% ci: 0.92-0.92), corresponding to a survival rate of 64.3% (95% ci: 64.0-64.6) among blacks and 69.8 (95% ci: 69.7-69.9) among whites. during this period, the cancer sites with the largest relative racial difference in survival were mesothelioma (black vs. white srr: 1.82, 95% ci: 1.38-2.20) and oral cavity and pharynx (black vs. white srr: 0.54, 95% ci: 0.38-0.69). these findings indicate that racial disparities in cancer incidence and survival persist on the relative and absolute scale in the us. further studies are needed to understand and address differential distribution of cancer-related risk factors, and improve access to high-quality and timely cancer treatment to enhance survival across racial groups. keywords: cancer incidence; cancer survival; seer; racial disparities citation: akinyemiju t (2019) absolute and relative black-white disparities in cancer incidence and survival in the united states, 2000-2014. cancer health disparities 3:e1-e9. doi:10.9777/chd.2019.1011. mailto:tomiakin@uky.edu www.companyofscientists.com/index.php/chd e2 cancer health disparities research introduction cancer health disparities are defined by the national cancer institute (nci) as adverse differences in cancer incidence, prevalence and mortality that exist among population subgroups in the united states1. nearly 1.7 million new cancer cases and 596,000 cancer deaths occurred in the us in 20162. these numbers reflect a 23% reduction in cancer deaths since the 1990s, attributable to the success of public health efforts focused on reducing smoking, and improving access to early detection and frontline treatment strategies2. however, these positive trends mask significant racial disparities in cancer incidence and mortality in the us1-3, a trend that emerged in the 1970s and has become more pronounced in recent years4. the issue of cancer health disparities is highlighted in the nci annual plan, which outlines a focus on improving understanding of the multifactorial causes of cancer health disparities5. disparities in cancer constitute a unique public health problem because the gap between population subgroups with the best and worse cancer outcomes represents theoretically avoidable diagnoses and deaths. identifying the complex genetic, social (socio-economic status and access to healthcare), as well as behavioral factors associated with cancer risk and survival are critical to reducing the disproportional burden of cancer in all racial groups. continuous assessment of the prevalence and magnitude of cancer disparities will provide valuable information to guide the allocation of effort and resources for specific cancer types, risk factors and racial groups to better understand and ultimately eliminate existing disparities. using data from the population-based surveillance epidemiology and ends results (seer), black and white absolute and relative disparities in cancer incidence and survival by cancer site in the us in 2009-2014 are presented. methods data from the national cancer institute seer database (november 2016) submission was utilized for this analysis6. seer is a population-based database that covers approximately 30% of the us population, and includes detailed clinical information on all incident cancer cases diagnosed in the following states/regions: atlanta, georgia; connecticut; detroit, michigan; hawaii; iowa; new mexico; san-francisco-oakland, california; seattle, washington; utah; los angeles, california; san jose-monterey, california; rural georgia; greater california; kentucky; louisiana; greater georgia; and new jersey. age-adjusted incidence (20102014) and 5-year relative survival (2009-2014) rates for each first primary cancer site by race (black and whites) among individuals ages 20 years and older were obtained from seer*stat. incidence and survival rates and 95% confidence intervals were calculated in seer*stat, ageadjusted to the 2000 us standard million population for each time period evaluated. absolute measures of inequality in both incidence and survival were calculated as the difference of black-to-white incidence and survival rates, while relative measures of inequality were calculated as the ratio of black-to-white incidence and survival rates. this approach of reporting both absolute and relative racial differences in measures of health outcomes has been recommended by the national cancer institute for evaluating the burden and progress towards eliminating health disparities7. results between 2010 and 2014, the overall irr comparing blacks to whites was 1.03 (1.03-1.04), corresponding to an age-adjusted incidence rate www.companyofscientists.com/index.php/chd e3 cancer health disparities research of 610.6 per 100,000 among blacks and 591.3 per 100,000 among whites. kaposi sarcoma (irr: 3.20, 95% ci: 2.80-3.40) and melanoma of the skin (irr: 0.04, 95% ci: 0.03-0.04) were sites with the largest relative incidence disparity (fig 1). blacks had higher irr compared with whites in 39 out of 101 cancer sites, while whites had higher irr than blacks in 43 out of 101 cancer sites. in absolute terms, the overall incidence rate difference between blacks and whites was 19.3 per 100,000 (17.5-21.1), with prostate (40.1, 95% ci: 39.3-40.9) and skin cancer (-35.1, 95% ci: -34.9, -35.1) having the largest absolute incidence rate difference (fig 2). between 2009 and 2014, the overall srr comparing blacks to whites was 0.92 (95% ci: 0.92-0.92), ranging from 0.54 (95% ci: 0.38-0.69) for other oral cavity and pharynx to 1.82 (95% ci: 1.38-2.20) for mesothelioma (fig 3). blacks had lower relative 5-year survival compared with whites in 76 out of 99 cancer sites, while whites had lower relative 5-year survival compared with blacks in 20 out of 99 cancer sites. in absolute terms, there was a 5.5% (95% ci: -5.7, -5.3) lower survival among blacks compared with whites overall, ranging from -26.1% (95% ci: -31.9, -19.3) for other oral cavity to 8.7% (95% ci: 5.6-11.1) for other endocrine including thymus (fig 4). in 20102014, the cancer sites with at least a 2-fold greater incidence among blacks compared with whites were kaposi sarcoma, myeloma and uterus, and those with greater incidence among whites compared with blacks (> 5-fold) were melanoma of the skin, skin cancer, lip cancer, eye and orbit, testis and ureter. www.companyofscientists.com/index.php/chd e4 cancer health disparities research figure 1: black vs. white incidence rate ratios and 95% ci, seer 2010-2014 www.companyofscientists.com/index.php/chd e5 cancer health disparities research figure 2: black vs. white incidence rate difference and 95% ci, seer 2010-2014 www.companyofscientists.com/index.php/chd e6 cancer health disparities research figure 3: black vs. white survival rate ratios and 95% ci, seer 2009-2014 www.companyofscientists.com/index.php/chd e7 cancer health disparities research figure 4: black vs. white survival rate difference and 95% ci, seer 2009-2014 www.companyofscientists.com/index.php/chd e8 cancer health disparities research discussion cancer remains a leading cause of morbidity and mortality among us adults, and while progress has been made on the ‘war against cancer’, significant gaps remain in incidence and mortality by race. this persistent disparity in the us often constitutes a public health failure, signifying inequitable access to primary (risk reduction), secondary (screening and early detection) and tertiary (timely, highquality treatment) prevention strategies, or may reflect underlying differences in etiology of specific cancers e.g. higher risk of skin cancer observed among whites compared with blacks. while the fundamental causes of cancer disparities are multifactorial and complex, they include aspects of genetic, epigenetic, molecular, behavioral and social factors. racial differences in cancer outcomes may operate through differential access to cancer prevention strategies, prevalence of mediating risk factors such as sun exposure, obesity and diabetes, and/or distribution of chronic inflammation, metabolic and/or immunerelated biological changes that play a key role in tumorigenesis and prognosis. critically, the interplay between race, social and biological factors in predicting cancer risk and outcomes remains poorly understood. targeted strategies to reduce incidence of specific cancers are critical, which requires better understanding of racial differences in risk and prognostic factors e.g. hiv and hpv infection linked with kaposi sarcoma and oral/cervical cancers, and exposures to environmental carcinogens linked with mesothelioma. research studies characterizing how multiple risk factors interact to differentially impact cancer outcomes by race, and identifying effective and targeted prevention and treatment strategies remain scarce and inadequate for the magnitude of the problem. precision therapies and genomics targeting specific pathways in cancer are heralded as the next frontier in cancer care; however, population-based approaches to reduce racial differences in cancer risk and survival, and inclusion of racially diverse populations in precision medicine trials, are critical to ensure equitable access to these benefits. author affiliations department of epidemiology, university of kentucky college of public health; markey cancer center author contribution dr. akinyemiju had full access to the data in the study and takes responsibility for the integrity of the data and accuracy of the data analysis funding/support dr. akinyemiju was supported by grant k01tw010271 from the national institutes of health role of the funder/sponsor the national institute of health had no role in the design and conduct of the study. the content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies. acknowledgement the author thanks arnisha atkinson and nimish valvi for their help in preparing the data tables, and dr. stella aslibekyan for comments on an earlier draft. conflict of interest the authors declare that no competing or conflict of interests exist. the funders had no role in study design, writing of the manuscript, or decision to publish. www.companyofscientists.com/index.php/chd e9 cancer health disparities research references 1. national cancer institute. cancer health disparities. 2008; https://www.cancer.gov/about-nci/organization/crchd/ cancer-health-disparities-fact-sheet q1. accessed january 31, 2017. 2. siegel rl, miller kd, jemal a. cancer statistics, 2017. ca cancer j clin. 2017;67(1):7-30. 3. mokdad ah, dwyer-lindgren l, fitzmaurice c, et al. trends and patterns of disparities in cancer mortality among us counties, 1980-2014. jama. 2017;317(4):388406. 4. henschke uk, leffall ld, jr., mason ch, reinhold aw, schneider rl, white je. alarming increase of the cancer mortality in the u.s. black population (1950-1967). cancer. 1973;31(4):763-768. 5. institute nc. annual plan and budget proposal for fiscal year 2017. 2016. 6. surveillance e, and end results (seer) program seer*stat database: incidence seer 18 regs research data + hurricane katrina impacted louisiana cases, nov 2014 sub (2000-2012) <katrina/rita population adjustment> linked to county attributes total u.s., 1969-2013 counties, national cancer institute, dccps, surveillance research program, surveillance systems branch, released april 2015, based on the november 2014 submission. 2014. 7. harper sal, john. methods for measuring cancer disparities: using data relevant to healthy people 2010 cancer-related objectives. center for social epidemiology and population health: university of michigan;2005. www.companyofscientists.com/index.php/chd e1 cancer health disparities research breast cancer incidence and mortality by molecular subtype: statewide age and racial/ethnic disparities in new jersey aishwarya kulkarni1,2,3, antoinette m. stroup, 1,2,3, lisa e. paddock, 1,2,3, stephanie m. hill, 2,3, jesse j. plascak,1,2, adana a.m. llanos1,2 1 department of epidemiology, rutgers school of public health, piscataway, nj, usa; 2 rutgers cancer institute of new jersey, new brunswick, nj, usa; 3 new jersey state cancer registry, state of new jersey, department of health, trenton, nj, usa *corresponding author email: adana.llanos@rutgers.edu abstract the objective of this study was to assess breast cancer incidence and mortality rates by molecular subtype for cases diagnosed in new jersey. data on all primary, histologically confirmed, invasive breast cancers diagnosed among women between january 1, 2008 and december 31, 2013 were retrieved from the new jersey state cancer registry. age-adjusted incidence rates were calculated for each subtype, by age and race/ethnicity. logistic regression models, cox proportional hazards models, and kaplan meier curves were used to describe the relative risks for breast cancer incidence, mortality, and survival, respectively. in this population-based sample of 32,770 breast cancer cases, non-hispanic blacks (nhbs) had the highest triple-negative breast cancer (tnbc) incidence rate (17.8 per 100,000, 95% ci 16.5-19.2) compared to other races/ethnicities. nhbs had also higher odds of tnbc (or 2.1, 95% ci 1.95-2.36) and higher hazards of death when diagnosed with tnbc (hr 1.28, 95% ci 1.05-1.56), luminal a (hr 1.64, 95% ci 1.41-1.91), or luminal b (hr 1.54, 95% ci 1.10-2.15) than non-hispanic whites (nhws). younger women (20-39 years) had higher odds of tnbc (or 1.77, 95% ci 1.54-2.02) and luminal b (or 1.56, 95% ci 1.35-1.80) compared to women 50-64 years; minority women had higher odds of non-luminal her2expressing and lower odds of luminal a than nhws. tnbc was associated with the poorest survival rates. these findings highlight a need for enhanced screening to promote earlier diagnosis and improve breast cancer outcomes, particularly in minorities and younger women, which will be essential for achieving health equity. keywords: breast cancer; surveillance; incidence; mortality; molecular subtype; diverse population; disparities citation: kulkarni a et al (2019) breast cancer incidence and mortality by molecular subtype: statewide age and racial/ethnic disparities in new jersey, cancer health disparities 3:e1e17,doi:10.9777/chd.2019.1012. www.companyofscientists.com/index.php/chd e2 cancer health disparities research introduction in the united states (us), breast cancer is the most commonly diagnosed cancer and the leading cause of cancer-related deaths among women of all age and racial/ethnic groups (acs, 2017). in 2017, approximately 252,710 new cases of invasive breast cancer were diagnosed and 40,610 breast cancer deaths occurred among us women (acs, 2017). breast cancer was the most common cancer diagnosed among new jersey women from 20102014 (njscr, 2017). in 2014, new jersey ranked 9th in the us for breast cancer incidence, with a rate higher than the us average (134.3 per 100,000 vs. 123.9 per 100,000), and elevated age-adjusted rates among whites (137.8 per 100,000), blacks (120.8 per 100,000), and hispanics (105.7 per 100,000), in contrast to us average rates for these groups (124.8, 122.4, and 91.8 per 100,000, respectively) (cdc, 2017). the estimated breast cancer mortality rate was also slightly higher for new jersey than the us average (21.5 per 100,000 vs. 20.5 per 100,000), with higher rates among whites and blacks (20.9 and 30.6 per 100,000, respectively) when compared to us average rates for these groups (20.0 and 28.1 per 100,000, respectively) (cdc, 2017). based on global gene expression patterns (bastien et al., 2012; network, 2012; perou et al., 2000; sorlie et al., 2001; sweeney et al., 2014) and/or clinical approximation of immunohistochemistry (ihc) expression patterns of the estrogen receptor (er), progesterone receptor (pr) and human epidermal growth factor receptor 2 (her2) (bhargava et al., 2009; morrison et al., 2012; tamimi et al., 2008), at least four breast cancer subtypes have been identified, including luminal a (er+/pr+/her2-), luminal b (er+/pr+/her2+), her2-enriched (luminal, er+/pr+; non-luminal, er-/pr-) and triple-negative breast cancer (tnbc, er-/pr-/her2-), with differing distributions, risk factors, tumor behaviors and clinical outcomes (carey et al., 2006; clarke et al., 2012; howlader et al., 2014; kroenke et al., 2014; sineshaw et al., 2014; sweeney et al., 2014; yang et al., 2011). although gene expression profiles are the gold standard, data show that ihc expression patterns are concordant with gene expression profiles and have substantial clinical utility in subtype classification (bastien et al., 2012; carey et al., 2006). as a result, state and regional cancer registries began collecting her2 data in 2010 (thornton m). distributions of breast cancer subtypes among racially and ethnically diverse populations such as those residing in new jersey, are important data for understanding cancer disparities and ultimately achieving health equity, particularly in terms of disseminating optimal treatment (albain et al., 2009; chlebowski et al., 2005; dignam, 2001) within the state. we expanded on prior surveillance research by retrospectively collecting and validating two additional years of her2 data (2008-2009) for invasive breast cancers diagnosed in new jersey. our objective was to assess age and racial/ethnic disparities in incidence and mortality by molecular subtype. we calculated age-adjusted incidence and mortality rates for each molecular subtype by age at diagnosis and race/ethnicity; and, compared new jersey incidence and mortality rates to those of the general us population for diagnosis years 2010 to 2013 (years for which er, pr, and her2 data were collected nationally). finally, we estimated relative risks for breast cancer diagnosis and death by breast cancer subtype. www.companyofscientists.com/index.php/chd e3 cancer health disparities research materials and methods study population and data collection data for all primary, histologically confirmed, invasive breast cancers diagnosed among women of all races/ethnicities in new jersey from january 1, 2008 through december 31, 2013 were retrieved from existing records at new jersey state cancer registry (njscr), which is a high-quality, population-based cancer incidence registry established in october 1978 serving the population of new jersey (currently about 8.9 million residents (mccaig et al., 2002)). women <20 years of age at breast cancer diagnosis, diagnosed with noninvasive breast cancer, and non-residents of new jersey diagnosed at an in-state medical facility were excluded from this study as the focus for the current analysis was adult women (age ≥20 years) diagnosed with invasive breast cancer and who reside in the state of new jersey. because cancer registries did not routinely collect her2 data for incident breast cancer diagnoses until january 1, 2010, her2 data for diagnosis years 2008 and 2009 were retrospectively collected and coded from pathology records for this study. her2 data for 2010 through 2013 were reviewed and validated from existing njscr records. if there was insufficient information to code her2 status in existing records, data were obtained by contacting hospital cancer registrars and using in-house pathology reports. electronic pathology reports were also reviewed to glean additional data. all coding was conducted within the njscr database (seer*dms). classification of er/pr/her2 status an array of standard variables corresponding to collaborative stage site-specific factors (ssfs) for breast cancer was used. er status (ssf 1) and pr status (ssf 2), corresponding to the er and pr assays, respectively, were coded as positive/elevated, negative/normal, borderline, or unknown (unknown includes test not done, borderline/undetermined, test ordered but results not entered in chart, or unknown for either er or pr status). a series of eight (8) additional variables were used to code her2 status (ssf 8 – ssf 15), and ssf 16 was used to define breast cancer subtype (summary of er/pr/her2 status). for her2 ihc screening, scores 0 and 1+ were coded as negative; score 2+ was coded as borderline; and score 3+ was coded as positive. fluorescence in situ hybridization (fish) was performed on ihc borderline cases. without positive fish information, tumors scored 2+ by ihc were coded as her2 negative. fish results were classified as a range of values: 0-120 was considered negative; 120-180 was considered borderline; and values >180 were considered positive. these results were used to derive the her2 summary result (ssf 15). the combination of er, pr and her2 (ssf 16) was used to classify breast cancer subtype. the final subtype classifications used were luminal a (er+ and/or pr+/her2-), luminal b (er+ and/or pr+/her2+), non-luminal her2-expressing (er/pr-/her2+), tnbc (er-/pr-/her2-), and unknown. although included in descriptive analysis (table 1), cases with unknown breast cancer subtype were excluded from subsequent analyses. we reviewed ssfs 1, 2, and 8 through 16 and identified 1942 cases that were ineligible (due to unknown/borderline er, pr, or her2). we also identified 1442 unresolved cases requiring hospital follow-back (due to unknown or not applicable codes for er, pr, and/or her2) and for which we were unable to code ssf 16 (due to insufficient er, www.companyofscientists.com/index.php/chd e4 cancer health disparities research pr, and her2 information). the final analytical sample included 32,770 women (figure 1). figure 1. flow diagram describing the selection of the analytic cohort. statistical analysis sociodemographic and tumor characteristics were described using frequencies and proportions, and chi-square tests were used to compare the distributions of each variable. custom incidence files for new jersey data from 2008 to 2013 were imported into seer*prep v2.5.3 (nci, 2017a) to create a seer*stat database for this study. seer*stat v8.3.2 (nci, 2017b) was used to calculate the age-adjusted incidence rates for each breast cancer subtype. the population denominators used to generate rates were based on detailed county population estimates by age, sex and race/ethnicity available in the seer*stat database (nci, 2017b). the 2000 us standard population was used for age-specific weights for direct ageadjustment. subtype-specific incidence rates were generated by age group (20-39, 40-49, 50-64, ≥65), and race/ethnicity (non-hispanic white [nhw], non-hispanic black [nhb], asian pacific islander [api, non-hispanic], hispanic, other/unknown). rates were estimated per 100,000 population, and the tiwari et al. (tiwari et al., 2006) modification for 95% confidence intervals (ci) was used to quantify the associations between breast cancer subtype and age and race/ethnicity. we estimated odds ratios (ors) for breast cancer risk by molecular subtype in new jersey from 2008 to 2013, overall and by age at diagnosis and race/ethnicity, using multivariable logistic regression models. cox proportional hazards regression analysis was performed to estimate breast cancer-specific mortality hazard ratios (hrs). tests for the assumption of proportional hazards were conducted by visual inspection of schoenfeld residuals and no violations were found. the last date of follow-up for cases was december 31, 2014. models were adjusted for age at diagnosis, race/ethnicity, and tumor stage. the www.companyofscientists.com/index.php/chd e5 cancer health disparities research ors, hrs and corresponding 95% confidence intervals (cis) were generated using sas v9.4 (sas institute, cary, nc). all statistical analyses were two-sided and p <0.05 was considered statistically significant. results among 32,770 invasive breast cancer cases diagnosed in new jersey women from 2008 to 2013, 13.1% (n = 4,315) were of unknown subtype. for nearly all cases with unknown subtype (95%), the test result was borderline or uninterpretable; the test was not performed or it was unknown if the test was performed; or, the result was not documented and, therefore, not reported to njscr. chi-square analyses revealed that women with unknown subtype were older (≥65), minority race/ethnicity (nhb, api, hispanic), diagnosed as distant or unknown stage and deceased at last follow-up. additionally, 13%, 20% and 3.6% had er-, pr-, and her2breast cancer, respectively. the distribution of sociodemographic and tumor characteristics is shown in table 1. larger proportions of cases were diagnosed among women age 50-64 years (37.1%), ≥65 years (38.0%), and nhws (73.0%). almost one-third (32.8%) of breast cancers were diagnosed in the upper outer quadrant, most were histologically classified as ductal carcinoma (73.1%), diagnosed at localized (61.4%) or regional stage (29.9%), and were moderately (40.7%) or poorly differentiated (34.0%). luminal a was the most common subtype (63.3%), followed by tnbc (10.2%), luminal b (8.9%) and non-luminal her2-expressing (4.2%). table 1. selected sociodemographic and breast cancer clinicopathologic characteristics among incident breast cancer cases diagnosed in new jersey, 2008-2013, n = 32,770. characteristics n (%) sociodemographic characteristics age at diagnosis (years) 20-39 1,773 (5.4) 40-49 6,344 (19.3) 50-64 12,179 (37.1) ≥65 12,474 (38.0) race/ethnicity white, non-hispanic 23,930 (73.0) black, non-hispanic 3,829 (11.7) asian/pacific islander, non-hispanic 1,826 (5.6) hispanic (any race) 2,831 (8.6) other/unknown 354 (1.1) breast cancer clinicopathologic characteristics primary site of breast cancer nipple (areolar) 152 (0.5) central (sub-areolar) 1,509 (4.6) upper inner quadrant 3,513 (10.7) lower inner quadrant 1,767 (5.4) upper outer quadrant 10,760 (32.8) lower outer quadrant 2,286 (7.0) www.companyofscientists.com/index.php/chd e6 cancer health disparities research axillary tail 158 (0.5) overlapping lesion 6,532 (19.9) breast, nos 6,093 (18.6) cancer sequence number one primary cancer diagnosed 29,373 (89.6) first of two or more primaries diagnosed 3,397 (10.3) histology adenocarcinoma 613 (1.9) ductal carcinoma 23,948 (73.1) lobular carcinoma 3,074 (9.4) ductal and lobular carcinoma 1,942 (5.9) mixed a 1,086 (3.3) other/unknown b 2,107 (6.4) tumor stage c localized 20,117 (61.4) regional 9,810 (29.9) distant 2,039 (6.2) unknown 804 (2.5) tumor grade well differentiated 4,883 (14.9) moderately differentiated 13,364 (40.7) poorly differentiated 11,140 (34.0) missing/unknown 3,383 (10.3) er status (ssf 1) positive 25,750 (78.6) negative 5,656 (17.3) borderline 27 (0.1) other/unknown 1,337 (4.1) pr status (ssf 2) positive 22,518 (68.7) negative 8,768 (26.8) borderline 102 (0.3) other/unknown 1,382 (4.2) her2 ihc lab value (ssf 8) 0 4,318 (13.1) 1+ 5,750 (17.5) 2+ 2,760 (8.4) 3 2,019 (6.2) unknown 17,923 (54.4) her2 ihc interpretation (ssf 9) positive 2,484 (7.7) negative 11,875 (36.5) borderline 2,414 (7.4) www.companyofscientists.com/index.php/chd e7 cancer health disparities research other/unknown 15,997 (48.4) her2 fish lab value (ssf 10) 1.00-9.79 11,889 (36.3) 9.80-9.87 127 (0.4) other/unknown 20,754 (63.3) her2 fish interpretation (ssf 11) positive 2,185 (6.7) negative 12,153 (37.3) borderline 410 (1.3) other/unknown 18,022 (54.7) her2 cish lab value (ssf 12) 1.00-9.79 32 (0.1) 9.80-9.87 15 (0.1) other/unknown 32,723 (99.8) her2 cish interpretation (ssf 13) positive 30 (0.1) negative 164 (0.5) borderline 10 (0.1) other/unknown 32,566 (99.4) her2 result of other or unknown test (ssf 14) positive 768 (2.4) negative 5,351 (16.5) borderline 166 (0.5) other/unknown 26,485 (80.6) her2 summary result (ssf 15) positive 4,373 (13.5) negative 24,268 (74.0) borderline 630 (1.9) other/unknown 3,499 (10.0) breast cancer subtype (ssf 16) luminal a (er+ and/or pr+/her2-) 20,775 (63.3) luminal b (er+ and/or pr+/her+) 2,938 (8.9) non-luminal her2-expressing (er-/pr-/her2+) 1,396 (4.2) triple-negative (er-/pr-/her2-) 3,346 (10.2) unknown 4,315 (13.1) vital status d dead 5,734 (17.5) alive 27,036 (82.5) note: percentages may not sum to 100 due to rounding. p values were generated using chi-square test. abbreviations: cs ssf, collaborative stage site-specific factor; er, estrogen receptor; cish, chromogenic in situ hybridization; fish, fluorescence in situ hybridization; her2, human epidermal growth factor 2; ihc, immunohistochemistry; nos, not otherwise specified; pr, progesterone receptor a mixed histology includes breast cancers classified as: duct and cribriform carcinoma, duct and mucinous carcinoma, duct and tubular carcinoma, or duct and colloid carcinoma. www.companyofscientists.com/index.php/chd e8 cancer health disparities research b other & unknown histology includes breast cancers classified as: neoplasm, tumor cells, carcinoma nos, pleomorphic carcinoma, spindle cell carcinoma nos, pseudosarcomatous carcinoma, small cell carcinoma nos, papillary carcinoma, squamous cell carcinoma nos, squamous cell carcinoma keratinizing nos, basaloid carcinoma, adenocarcinoma, adenocarcinoma nos, scirrhous adenocarcinoma, adenoid cystic carcinoma, cribriform carcinoma nos, tubular adenocarcinoma, solid carcinoma nos, neuroendocrine carcinoma, adenocarcinoma with mixed subtypes, papillary adenocarcinoma nos, clear cell adenocarcinoma nos, glycogen-rich carcinoma, mixed cell adenocarcinoma, apocrine adenocarcinoma, papillary serous cystadenocarcinoma, mucinous cystadenocarcinoma nos, mucin producing adenocarcinoma, signet ring cell carcinoma, comedenocarcinoma nos, secretory carcinoma of breast, intraductal papillary adenocarcinoma with invasion, intracystic carcinoma nos, medullary carcinoma nos, atypical medullary carcinoma, infiltrating ductular carcinoma, infiltrating lobular mixed with other types of carcinoma, inflammatory carcinoma, paget’s disease (mammary), paget’s disease with intraductal carcinoma of breast, adenosquamous carcinoma, adenocarcinoma with spindle cell metaplasia, adenocarcinoma with neuroendocrine differentiation, metaplastic carcinoma nos, sarcoma nos, giant cell sarcoma, epithelioid sarcoma, malignant fibrous histiocytoma, liposarcoma nos, myxoid liposarcoma, leiomyomatosis nos, spindle cell rhabdomyosarcoma, stromal sarcoma nos, carcinosarcoma nos, malignant myoepithelioma, phyllodes tumor, hemangiosarcoma, or osteosarcoma nos. c seer summary stage. d vital status as of december 31, 2014. age-adjusted breast cancer incidence rates by subtype and age at diagnosis, race/ethnicity, and tumor stage are shown in table 2. as expected, incidence rates for the luminal a subtype were highest among women ≥65 years (203.3, 95% ci 198.9-207.8), compared to the other subtypes. among luminal b breast cancer cases, incidence was lowest among women 20-39 years (4.1, 95% ci 3.7-4.7) and highest among those 50-64 years (21.8, 95% ci 20.6-23.1). a similar pattern was observed for the non-luminal her2-expressing subtype, with the lowest incidence among women 20-39 years (1.9, 95% ci 1.6-2.3) and highest among those 50-64 years (11.3, 95% ci 10.4-12.2). among tnbc cases, incidence rates increased with age (20-39 years: 4.8, 95% ci 4.3-5.3; 40-49 years: 17.1, 95% ci 15.9-18.5; 50-64 years: 23.0, 95% ci 21.8-24.3; and ≥65 years: 26.0, 95% ci 24.5-27.7). www.companyofscientists.com/index.php/chd e9 cancer health disparities research table 2. age-adjusted breast cancer incidence rates (per 100,000) in new jersey, by subtype and by age at diagnosis, race/ethnicity, and tumor stage, 2008-2013. breast cancer subtype age group 20-39 years 40-49 years 50-64 years ≥65 years count incidence rate (95% ci) count incidence rate (95% ci) count incidence rate (95% ci) count incidence rate (95% ci) luminal a a 869 13.5 (12.7-14.5) 3,884 92.3 (89.4-95.3) 7,624 139.6 (136.4-142.7) 8,398 203.3 (198.9207.8) luminal b b 270 4.1 (3.7-4.7) 676 16.2 (15.0-17.5) 1,179 21.8 (20.6-23.1) 813 19.8 (18.5-21.3) non-luminal her2expressing c 121 1.9 (1.6-2.3) 287 6.8 (6.1-7.7) 611 11.3 (10.4-12.2) 377 9.2 (8.2-10.1) triple-negative d 310 4.8 (4.3-5.3) 711 17.1 (15.9-18.5) 1,250 23.0 (21.8-24.3) 1,075 26.0 (24.5-27.7) new jersey population 6,712,391 4,104,990 5,408,652 4,226,407 breast cancer subtype race/ ethnicity 20-39 years 40-49 years 50-64 years ≥65 years count incidence rate (95% ci) count incidence rate (95% ci) count incidence rate (95% ci) count incidence rate (95% ci) luminal a a 15,873 72.2 (71.0-73.3) 1,996 51.7 (49.5-54.1) 1,049 44.3 (41.5-47.1) 1,724 45.3 (43.1-47.5) luminal b b 2,070 10.1 (9.7-10.6) 342 8.7 (7.8-9.7) 203 8.0 (6.9-9.2) 305 7.6 (6.8-8.6) non-luminal her2expressing c 913 4.4 (4.1-4.7) 213 5.4 (4.7-6.2) 108 4.5 (3.6-5.4) 154 3.8 (3.2-4.5) triple-negative d 2,151 10.4 (9.9-10.9) 693 17.8 (16.5-19.2) 162 6.6 (5.6-7.7) 333 8.3 (7.4-9.3) new jersey population 16,228,596 3,745,444 2,438,511 4,714,148 note: risk estimates and 95% confidence intervals (ci) were generated using logistic regression; adjusted for age, race/ethnicity and stage at diagnosis. counts by age group and race/ethnicity and subtype do not add up to 32,770 (which is the total number of breast cancer cases included in table 1) due to missing data on race/ethnicity and/or breast cancer subtype among some cases. a luminal a (er+ and/or pr+/her2-); b luminal b (er+ and/or pr+/her2+); c non-luminal her2-expressing (er-/pr-/her2+); d triple negative (er/pr-/her2-) www.companyofscientists.com/index.php/chd e10 cancer health disparities research breast cancer incidence and mortality risks by subtype and by age at diagnosis and race/ethnicity are shown in table 3. among all races/ethnicities, luminal a incidence rates were highest, ranging from 51.7 (95% ci 49.5-54.1) among nhbs to 72.2 (95% ci 71.0-73.3) per 100,000 among nhws. incidence rates of tnbc among nhbs were nearly twice as high as those among other racial/ethnic groups, (17.8, 95% ci 16.5-19.2). incidence rates of the non-luminal her2-expressing subtype were also higher among nhbs (5.4, 95% ci 4.7-6.2). nhbs (or 2.15, 95% ci 1.95-2.36), hispanics (or 1.19, 95% ci 1.05-1.35), and younger women (2039 years: or 1.77, 95% ci 1.54-2.02 and 40-49 years: or 1.10, 95% ci 1.00-1.20) had higher odds of tnbc compared to nhws and women aged 50-64 years, respectively. younger women also had higher odds of luminal b breast cancer (or 1.56, 95% ci 1.35-1.80). women ≥65 years, however, had higher odds of the luminal a subtype (or 1.22, 95% ci 1.16-1.29) and lower odds of all other subtypes. all minority women had higher odds of developing non-luminal her2expressing breast cancer compared to nhw women (nhb: or 1.31, 95% ci 1.12-1.53; api: or 1.55, 95% ci 1.27-1.90; hispanic: or 1.20, 95% ci 1.00-1.44). apis had an increased risk of the luminal b subtype (or 1.24, 95% ci 1.06-1.44) compared to nhws. when compared to women 50-64 years, those ≥65 years had higher risk of breast cancer death regardless of subtype, but the risk of death was more than double among those with the nonluminal her2-expressing subtype (hr 2.21; 95% ci 1.62-3.01). women 40-49 years had lower risk of breast cancer death when diagnosed with luminal a and luminal b subtypes. nhbs had increased risk of breast cancer death for all subtypes except nonluminal her2-expressing subtype compared to nhw , with hrs ranging from 1.28 (95% 1.05-1.56) for tnbc to 1.64 (95% 1.41-1.91) for luminal a. table 3. multivariable logistic regression and cox proportional hazards regression models for breast cancer incidence and mortality risk, among incident breast cancer cases diagnosed in new jersey, by molecular subtype and by age at diagnosis and race/ethnicity, 2008-2013. luminal a a luminal b b non-luminal her2expressing c triple-negative d incidence or (95% ci) or (95% ci) or (95% ci) or (95% ci) age at diagnosis (years) 20-39 0.62 (0.56-0.68) 1.56 (1.35-1.80) 1.22 (0.10-1.50) 1.77 (1.54-2.02) 40-49 0.95 (0.89-1.02) 1.10 (1.00-1.21) 0.87 (0.76-1.01) 1.10 (1.00-1.20) 50-64 1.00 (ref) 1.00 (ref) 1.00 (ref) 1.00 (ref) ≥65 1.22 (1.16-1.29) 0.67 (0.61-0.73) 0.61 (0.54-0.69) 0.84 (0.77-0.92) race/ethnicity nhw 1.00 (ref) 1.00 (ref) 1.00 (ref) 1.00 (ref) nhb 0.59 (0.55-0.63) 0.93 (0.82-1.05) 1.31 (1.12-1.53) 2.15 (1.95-2.36) api 0.78 (0.71-0.86) 1.24 (1.06-1.44) 1.55 (1.27-1.90) 0.94 (0.80-1.11) hispanic 0.76 (0.70-0.82) 1.05 (0.92-1.19) 1.20 (1.00-1.44) 1.19 (1.05-1.35) mortality hr (95% ci) hr (95% ci) hr (95% ci) hr (95% ci) www.companyofscientists.com/index.php/chd e11 cancer health disparities research age at diagnosis (years) 20-39 0.96 (0.74-1.25) 0.81 (0.50-1.30) 1.10 (0.66-1.84) 0.99 (0.74-1.34) 40-49 0.80 (0.68-0.95) 0.65 (0.43-0.97) 0.75 (0.49-1.17) 1.03 (0.82-1.30) 50-64 1.00 (ref) 1.00 (ref) 1.00 (ref) 1.00 (ref) ≥65 1.51 (1.33-1.71) 1.69 (1.28-2.24) 2.21 (1.62-3.01) 1.25 (1.03-1.53) race/ethnicity nhw 1.00 (ref) 1.00 (ref) 1.00 (ref) 1.00 (ref) nhb 1.64 (1.41-1.91) 1.54 (1.10-2.15) 1.34 (0.95-1.91) 1.28 (1.05-1.56) api 1.00 (0.76-1.31) 0.59 (0.28-1.25) 0.99 (0.56-1.74) 1.00 (0.69-1.46) hispanic 0.94 (0.75-1.17) 1.06 (0.68-1.64) 0.81 (0.47-1.39) 1.14 (0.86-1.52) note: risk estimates and 95% confidence intervals (ci) were generated using logistic regression for incidence and cox proportional hazards regression for breast cancer specific mortality; adjusted for age, race/ethnicity and stage at diagnosis. bolded values represent statistical significance. a luminal a (er+ and/or pr+/her2-); b luminal b (er+ and/or pr+/her2+); c non-luminal her2-expressing (er-/pr-/her2+); d triple negative (er-/pr-/her2-) as shown in the kaplan-meier survival curves (adjusted for age, race/ethnicity, and tumor stage), women diagnosed with tnbcs had the poorest breast cancer-specific survival, followed by those diagnosed with the non-luminal her2-expressing subtype (p <0.0001; figure 2). analysis stratified by race/ethnicity (figure 3) suggested that this was likely driven by tnbc diagnosed among nhbs (p <0.001) and apis (p <0.05). figure 2. breast cancer survival by subtype, new jersey, 2008-2013 www.companyofscientists.com/index.php/chd e12 cancer health disparities research figure 3. breast cancer survival by breast cancer subtype, stratified by race/ethnicity, a) non-hispanic whites; b) non-hispanic blacks; c) asians/pacific islanders; and d) hispanics (any race), in new jersey, 2008-2013. note: models were adjusted for age at diagnosis and stage at diagnosis. discussion in this study, which is the largest population-based sample of breast cancer in new jersey to date (n = 32,770), we demonstrated the feasibility of retrospectively coding her2 data not previously recorded in njscr files for cases diagnosed in 2008 and 2009. analyses of these data showed that nhb women had the highest age-adjusted incidence rates of tnbcs (17.8 per 100,000) compared to all other racial/ethnic groups, which ranged from 6.6 (api) to 10.4 (nhw). nhbs also had a 28% higher risk of breast cancer death than their nhw counterparts, which is consistent with the literature (clarke et al., 2012; desantis et al., 2016; howlader et al., 2014; noone et al., 2016; parise et al., 2009). in terms of incidence, young women (20-39 years) had higher risks of tnbc and luminal b breast cancers compared to women 50-64 years, and hispanic women had higher risks of non-luminal her2-expressing and tnbc subtypes than nhws. our findings also showed tnbcs were associated with the poorest survival. incidence of the non-luminal her2-expressing subtype was highest among nhbs compared to www.companyofscientists.com/index.php/chd e13 cancer health disparities research other racial/ethnic groups, while rates were lowest among hispanics and similar between nhws and apis. the latter finding is in contrast to several studies, which have shown the highest rates for this subtype to be among apis compared to nhws (clarke et al., 2012; howlader et al., 2014; parise et al., 2009; sineshaw et al., 2014). we suspect that our findings are suggestive of differences in tumor biology and/or etiologic mechanisms of tnbcs and non-luminal her2expressing breast cancers associated with racial/ethnic exposures, which are also related to poorer outcomes, as reported herein and elsewhere (akinyemiju et al., 2015; carey et al., 2006; leone et al., 2015; li et al., 2017; llanos et al., 2015; sorlie et al., 2001; warner et al., 2015). additionally, it is quite possible that our finding of similar rates of the non-luminal her2-expressing subtype among apis and nhws could be reflective of differences in subgroups of apis that reside in new jersey (as compared to populations in other states), that may be underrepresented in prior breast cancer epidemiology studies. this warrants further analysis. many studies have focused on the tnbc subtype due to its aggressive nature and limited treatment options, but it should be noted that non-luminal her2expressing tumors are also associated with relatively poor survival, have similar penetrance among minority women, and exhibit features that are indicative of a more aggressive phenotype than the luminal a subtype. poorer survival among tnbc and non-luminal her2-expressing breast cancer cases may also relate to lack of timely and optimal/guideline-concordant treatment, particularly among racial/ethnic minorities and underserved populations (bustami et al., 2014; chen and li, 2015; daly and olopade, 2015; freedman et al., 2013; george et al., 2015; hassett et al., 2016; reeder-hayes et al., 2014; sheppard et al., 2015). a recent study suggested differences in response to treatment by race/ethnicity even when subtype was the same (rauscher et al., 2017), warranting further analysis. population-based studies with the ability to explore etiologic, risk factor, and prognostic differences by subtype are critically needed to better understand disparities and achieve health equity for breast cancer outcomes. as we consider the burden of breast cancer in new jersey, another important finding was that approximately 30% and 6% of breast cancers were diagnosed at regional stage and distant stage, respectively. given the high risk of mortality associated with later stage diagnosis reported here and elsewhere (markossian and hines, 2012; tian et al., 2012; tian et al., 2011), it is important to address this issue at the population level. in fact, data suggests a high-degree of spatial variation in late-stage breast cancer incidence in new jersey (roche et al., 2016). future research to evaluate the geographic distribution of molecular subtypes is needed given the observed disparities in breast cancer incidence and mortality in new jersey. there were some limitations of this study that should be considered. first, our use of hormone receptor expression by ihc rather than gene expression for classifying breast cancer subtypes was a limitation, although one could argue that gene expression has its limitations as well. studies have shown good concordance between ihc and gene expression for classifying the major subtypes (bastien et al., 2012; carey et al., 2006), supporting utility of ihc, and its use in the seer program. another limitation was that >10% of the cases had unknown breast cancer subtype, due to incomplete reporting of hormone receptor data or www.companyofscientists.com/index.php/chd e14 cancer health disparities research inconsistencies in reporting, particularly for her2, as a result of variations in reporting sources (e.g., physician’s private offices vs. larger hospitals/medical facilities). additionally, we were unable to account for known (and suspected) breast cancer risk factors (e.g. age at menarche, age at menopause, menopausal status, family history of breast cancer, parity, bmi) (althuis et al., 2004; ambrosone et al., 2015; bethea et al., 2016; hwang et al., 2005; krieger, 2008; rosenberg et al., 2016), which could have strengthened our analysis. nonetheless, the distribution of breast cancer subtypes reported herein were consistent with other studies (bastien et al., 2012; howlader et al., 2014; morrison et al., 2012; network, 2012; perou et al., 2000; sorlie et al., 2001; sweeney et al., 2014). bias that may have resulted from missing data is also a concern, particularly for missing or misclassified race/ethnicity. however, this is minimal due to the stringent data quality standards promulgated by the north american association of central cancer registries (naaccr). prior studies have assessed the use of standard registry data and have demonstrated sufficient reliability of race and ethnicity variables (clegg et al., 2007; knowlton et al., 2014; patel et al., 2005). the exclusion of 13% of new jersey breast cancer cases due to unknown er/pr/her2 status is another source of bias. as our analysis revealed, women with unknown subtype were older (≥65), minority race/ethnicity, diagnosed at distant stage or have unknown stage, and deceased at the time of last follow-up. the exclusion of these women would have likely biased our results toward the null, thereby underestimating incidence rates, risks of nonluminal her2-expression and tnbc subtypes, and risks of breast cancer death. there were also important strengths of this study, including a large, population-based sample of racially and ethnically diverse women with data on er, pr and her2 status. in fact, this is the largest dataset currently available with breast cancer subtypes in new jersey. findings reported herein highlight a need for enhanced screening among some subgroups of women to promote earlier diagnosis, and improve breast cancer outcomes. understanding the mechanisms leading to the development of each breast cancer subtype is essential and will play a major role in improving prognosis and addressing breast cancer outcomes disparities; and, may contribute to improved treatment options that will hopefully reduce the observed breast cancer mortality and survival differences by molecular subtype. acknowledgements we sincerely thank jie li, mph, gerald harris, phd, annette werts, rudmilla chowdhury, ctr, and adrian botchway, ctr at the new jersey state cancer registry for their contributions to this work. this study was supported by the national cancer institute (cancer center support grant number p30 ca072720) through a new investigator award and k01 ca193527 awarded to a.a.m. llanos. cancer epidemiology services, including the new jersey state cancer registry, receives financial support from the: surveillance, epidemiology, and end results program of the national cancer institute, national institutes of health, under contract hhsn 261201300021i and control no. n01-pc-2013-00021; national program of cancer registries, centers for disease control and prevention, under cooperative agreement 5u58/ dp003931; the state of new jersey and rutgers cancer institute of new jersey. www.companyofscientists.com/index.php/chd e15 cancer health disparities research conflict of interest the authors have no conflicts of interest to declare. authors’ contributions conceptualization: ak ams aaml. development of methodology: ak ams lep aaml. acquisition of data: ak smh. analysis and interpretation of data: ak ams lep jjp aaml. writing, review, and/or revision of the manuscript: ak ams lep smh jjp aaml. administrative, technical, or material support: ams aaml. references acs (2017). american cancer society. breast cancer facts & figures 2017-2018 (atlanta, ga: american cancer society, inc.). akinyemiju, t., moore, j.x., and altekruse, s.f. 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(2011). associations of breast cancer risk factors with tumor subtypes: a pooled analysis from the breast cancer association consortium studies. journal of the national cancer institute 103, 250-263. www.companyofscientists.com/index.php/chd e1 cancer health disparities research a southwestern tribal perspective on traditional and commercial tobacco priscilla r sanderson1*, erelda gene2, rebecca scranton3, angela a a willeto4; lori joshweseoma5; lisa j hardy6 health sciences department of the college of health and human services at northern arizona university1; northeastern state university oklahoma, college of optometry2; arizona department of health services3; sociology and social work department in the college of social and behavioral sciences at northern arizona university4; hopi tribe, hopi health department5; anthropology department in the college of social and behavioral sciences at northern arizona university6 *corresponding author e-mail: priscilla.sanderson@nau.edu abstract american indian or alaska natives have the highest rates of current cigarette (36.5%) and smokeless tobacco use (5.3%), and tobacco product (40.1%) and the second highest rate of current cigar use (6.1%) compared to all other racial-ethnic groups in the u.s. rates of american indian or alaska native tobacco use vary by gender. few studies examine perceptions of tobacco use among tribal members residing on and off the reservation. this study fills a gap in the literature by reporting the perceptions of 34 enrolled members of a southwestern tribe who reside on and off a tribal land using a communitybased participatory research (cbpr) design through a collaboration between a university and a tribal health program. researchers conducted seven focus groups; four on the southwest reservation and three within an urban community. the discussions were audio-recorded, transcribed, and analyzed using a multi-investigator consensus model. the use of tobacco (commercial or traditional) in southwest tribes is essential to cultural practices. results depicted different views on cultural meaning and health impacts of commercial and traditional tobacco. findings suggest the importance of local research to understand dimensions of tobacco use before moving forward with tobacco cessation programming. keywords: american indians, commercial tobacco, traditional tobacco, community-based participatory research, focus groups citation: sanderson p et al (2018) a southwestern tribal perspective on traditional and commercial tobacco. cancer health disparities 2:e1-e10. doi:10.9777/chd.2018.10004 www.companyofscientists.com/index.php/chd e2 cancer health disparities research introduction american indian or alaska natives (ai/an) have the highest rates of cigarette (36.5%) and smokeless tobacco use (5.3%) compared to all other racial-ethnic group (substance abuse and mental services administration, 2014), current tobacco product (40.1%) and the second highest rate of current cigar use (6.1%). high rates of tobacco use factor in various health problems evident among american indians or alaska natives, such as heart disease and cancer (heron, 2016). yet, american indian and alaska natives’ tobacco use rates vary across regions. northern plains and alaska areas demonstrate the highest rates of smoking [40.2% and 40.0%, respectively], while the southwest reveals the lowest rates [21.1%] (steele, cardinez, robertson, tom-orme, & shaw, 2008). studies show different use patterns among men and women. historical analyses indicate differentiation in use rates by gender began in the 1930s (kunitz, 2016). northern plains tribes demonstrate high rates of smoking among both men (49%) and women (51%) (nez-henderson et al., 2005). whereas, in a southwest tribe, men (19%) have higher rates of smoking than women (10%); furthermore southwest women have the highest prevalence of never smoking (75%) (nezhenderson et al., 2005). however, rates of tobacco use also differ by age. a longitudinal study on indigenous adolescents found that girls aged 10 to 13 years (20%) smoked more frequently than boys aged 10 to 13 years (14%) (yu & whitbeck, 2016). literature review american indians have used traditional tobacco epochs prior to the introduction of commercial tobacco (struthers & hodge, 2004; redwood et al., 2010; nadeau, blake, poupart, rhodes, & forster, 2012; henderson & henderson, 2015). use of traditional tobacco varies by ceremony and tribe. many people of different tribal affiliations share a common belief that traditional sacred tobacco is non-addictive (struthers & hodge 2004; henderson & henderson, 2015; arndt et al., 2013). unlike commercial tobacco practice, traditional smoke is not inhaled, but held in one’s mouth then released skyward towards the atmosphere where the smoke from the tobacco carries thoughts and prayers to deities (struthers & hodge, 2004; nadeau et al., 2012). traditional smoke is used to cleanse, heal those who are ill, protect those who feel they need to be shielded from harm, or to teach lessons (struthers & hodge, 2004; nadeau et al., 2012; arndt et al., 2013). while commercial tobacco is typically used recreationally and traditional tobacco is expended for spiritual purposes, that distinction is becoming blurred as some tribes struggle to access traditional tobacco and use commercial tobacco due to availability (struthers & hodge, 2004; nez-henderson et al., 2005; unger, soto, & baezconde-garbanati, 2006; forster et al., 2007; margalit et al., 2013). some tribes evidence both men and women’s use of tobacco while in other tribes, tobacco use is restricted to men in ceremonial environments. beliefs and use practices on tobacco on and off tribal lands also vary. however, studies comparing on/off reservation or rural/urban are few in number, even more so when examining tribes’ perceptions of ceremonial and commercial tobacco use (unger, soto, & baezconde-garbanati 2006). american indian people (combining southwestern and northern plains regions) that reside 75% or more of their lives on reservations had lower rates of current smoking (men=46%, women=48%) than those who reside less than www.companyofscientists.com/index.php/chd e3 cancer health disparities research 75% of their lives on the reservation (men=56%, women=61%) (nez-henderson et al., 2005). urban american indian men in california demonstrated higher rates of smoking (57%) than their rural male counterparts (43%) (hodge, fredericks, & kipnis, 1996). enhancing the nuances of tobacco use among different people based on place, age, and gender is important to effectively target programs for locally and culturally appropriate smoking cessation. these findings add to the literature indicating distinct perceptions and uses of commercial and traditional tobacco. the uses for the different types of tobacco are important to explore for the sake of better understanding the health impacts of tobacco within american indian communities. this study addresses the following: what are perceptions toward commercial and traditional tobacco use among members of a southwestern tribe, particularly in light of this region's’ comparatively low rates of cigarette use? do tribal members make distinctions of tobacco use as recreational or ceremonial; will theme differences emerge among men and women; or will residing on the reservation or in an urban locale lead to different themes on tobacco use among members of the same southwestern tribe? materials and methods the team obtained permission from the tribe and the university institutional review board before beginning research. project goals naturally developed through community based participatory research (cbpr) (israel, schulz, parker, & becker, 1998; buchwald, beals, & manson, 2000; wallerstein & duran, 2006; wallerstein & duran, 2010; verney et al., 2016), in that the original idea for the research came from community members knowledgeable about tribal health. the research team included members of a tribal health organization, university professor, and undergraduate students of public health and applied indigenous studies. the research team developed focus group questions, recruited participants, and held four focus groups on a reservation (n=20) and three in a bordertown, a city adjacent to the reservation (n=12). inclusion criteria included being 18 years or older and an enrolled member of the tribe. participants had to reside on either the reservation or urban location for six continuous months. at the focus group sessions, participants signed an informed consent, received a $25.00 stipend and resource materials. participants completed a survey beforehand to collect demographic information, current smoking status, and smoking cessation status. data analysis qualitative analysis of participant responses included a multi-investigator consensus method as described in two studies (teufel-shone, siyuja, watajomigie, & irwin, 2006; sanderson, teufelshone, baldwin, sandoval, & robinson, 2010). audio-recorded discussions were transcribed verbatim and analyzed by researchers through coding and memoing (miles & huberman, 1984; groenewald, 2004) using atlas.ti. descriptive statistics were used to analyze the demographic information. results participant demographics table1 shows the participant demographics. five (14.7%) of the participants reported currently smoking tobacco. www.companyofscientists.com/index.php/chd e4 cancer health disparities research table 1. demographics by focus group location. characteristic reservation n=22 (65%) urban n=12 (35%) total n=34 (100%) gender women men 12 (55%) 10 (45%) 5 (42%) 7 (58%) 17 (50%) 17 (50%) education less than high school high school grad/ged some college or higher college 4 years or more 1 (5%) 8 (36%) 12 (55%) 1 (5%) 0 (0%) 2 (17%) 6 (50%) 4 (33%) 1 (3%) 10 (29%) 18 (53%) 5 (15%) current smokers? yes no 2 (9%) 20 (91%) 3 (25%) 9 (75%) 5 (15%) 29 (85%) age mean (range, sd) 38 (21-69, 14)* 28 (20-44, 9) 35 (20-69, 14) *one participant refused to provide their age. traditional tobacco traditional tobacco is sacred, and preparation requires traveling long distances and using an involved process. in response to the question about what participants thought about smoking traditional tobacco, tribal members (irrespective of gender or residential location) believe traditional tobacco is sacred and serves important spiritual functions in their culture and society. one participant reflected: “…traditional tobacco is the most important thing in all [removed tribal name for privacy] ceremonies where, smoking is a part of everything, and the smoking of the [ceremonial place], it’s it own ceremony, how they smoke, how they acknowledge each other in that circle and how it’s passed, how it’s held, so it’s vital i think, to keep that as tobacco.” (reservation woman). furthermore tobacco plays an active role in carrying prayers. one participant stated, “…i feel the use of traditional tobacco in the ceremony has more significance in the ceremony…because usually when traditional tobacco is being used, that’s when you know that the prayers are actively happening at that time,” (reservation woman). other participants also reflected on these beliefs throughout the focus groups in the discussions of the meaning and value of traditional tobacco use. women who lived off of tribal lands said that traditional tobacco use was culturally important: “i think it’s necessary for us...like, a lot of them smoke just the regular cigarettes and everything, but i think it would be just most men, they just do it... around the ceremonies sometimes and other than that, they don’t smoke at all, so some people just do it specifically for the ceremonies and our tradition.” participant women also discussed the difference between recreational and ceremonial use of tobacco: “but i think that people who use the traditional tobacco during the traditional ceremonies have a purpose, and aren’t just using it to have something to smoke.” this difference between ceremonial and traditional uses of tobacco remained clear in all focus groups with www.companyofscientists.com/index.php/chd e5 cancer health disparities research general statements regarding the differences in use patterns and meaning/value of the tobacco. participating men living on reservation also reflected on the importance of traditional tobacco use in how traditional tobacco use is intertwined within the cultural landscape. “…i think using traditional tobaccoit’s very sacred, a building block that’s part of our [tribal name] society as they find this where-where we need to.” this participant discusses tobacco as a “building block” underscoring the foundational importance of this part of life and ritual among people within this tribal context. another participant raised the importance of understanding the traditional substance and use of tobacco and set this apart from non-traditional use: “…the understanding of traditional tobacco, you really have to be, true to understand what it’s used for and how it’s used. so, my understanding is really highly respected toward traditional tobacco.” men living off-reservation showed consensus on the traditional use of tobacco: “what we call it, is, the purpose behind it carries our prayers and so it’s used in multiple ceremonies.” and beyond the use of the tobacco, one participant also discussed the purpose of tobacco as an active entity: “the use of the traditional tobacco is a way of communicating your prayers to what [tribal name] we [tribal name] believe is the rain clouds.” men, though, expressed difficulties obtaining traditional tobacco in their local areas when they were in a rush to get to a ceremony while commercial tobacco was more accessible in local stores. women stated strong opposition to commercial tobacco use, though all participants discussed traditional tobacco as a vehicle for prayer interwoven within the foundation of tribal identity. commercial tobacco with regard to the use of commercial tobacco, participants had other ways of understanding and discussing the substance and its purpose. men and women stated that there were negative risks associated with commercial tobacco that could lead to death. some participants focused on the impact of commercial tobacco on the respiratory system, “...obviously you can develop problems with your lungs, problems breathing people who do a lot of smoking obviously have asthma and all these other breathing difficulties that don’t make for much of a quality of life” (urban woman). another participant echoed these thoughts, by noting the difference between smokers and nonsmokers, “their health is a little bit different than someone who doesn’t smoke at all. and you can see the difference, i mean they’re coughing, hacking, and like can barely breath. they just sound awful.” (urban woman). and beyond that: “…it affected my lungs, my mind, and even my muscles... i took weight classes and i wasn’t lifting as much as i used to and i just had a motivational shut to my body where it wasn’t working as much as it was, used to cut down my motivation.” another man stated that: “…all of these health issues that come up, of course it starts slowly and it eventually starts eating away at the body, eventually leads to death.” another risk of commercial tobacco use that participants discussed was oral health: “oral health…that starts to become a factor and you look at the addiction that’s not natural that starts to consume and control your life, to a point that you wake up first thing in the morning and that’s what you’re reaching for.” each of these quotes demonstrates negative associations with commercial tobacco that are both immediate and long-term. www.companyofscientists.com/index.php/chd e6 cancer health disparities research generational role data collection included participants spanning five generations from age 20 to 69. findings about generational perceptions and use of tobacco included older people reflecting on youth practices and young people discussing their own ideas on tobacco. in general, participants felt that education on tobacco use was present in schools, however it is the main responsibility of elderly and older male relatives. some stated that education is insufficient in light of the need to reduce risks to young people. one of the women living on reservation pointed out how local schools are addressing the manner: “since that time i think some of the other local schools have picked up that type of education, but now it’s usually only during certain times of the year like during drug week or what-whatever national smoking week or whatever it is. but at least they’re starting to get it into the curriculum at school. i think that’s one of the first steps of teaching, i mean, ‘cause i think every one of us has said that we weren’t really aware.” another woman supported previous statement in that education is the key: “i think ...in order to try to stop them from doing that, we need to do a lot of education and the dangers of smoking, what it can lead to, especially addiction to tobacco and how it affects your life if you continue to smoke.” other participants discussed education within families that could be transmitted across generations. one man stated: “i think the majority of education that we can do as adults, as parents, as uncles, as nephews, as grandparents is at home and also with the males is in the [ceremonial place]. and: “there’s not that much education about tobacco use, and what the consequences are about it, the teaching just don’t stop in school, it continues into the community, into the family.” participants discussed reasons why young people use commercial tobacco including ‘modeling the behavior of adults’. in the urban focus group, one participant stated: “kids are exposed to [commercial tobacco] at a young age, watching their elders smoke or family members smoke, it’s definitely present, but if it’s being reflected in the culture or the environment then, it shows up in the kids” (urban man). other participants in the urban focus groups discussed this further by stating that “…the kids and teenagers just do what the adults are doing, what they see, so if the adults didn’t do it, or the elders, or like…well the elders in the [ceremony place], they do it for a purpose, but not all kids and teenagers see it that way.” with regard to traditional tobacco use, participants had different perspectives on the behavior of young people. participants said that youth did not know how to respect traditional tobacco. one woman stated, “i see them just doing it, just for that purpose…and the older men allowing that … if they’re taught right, they know how to respect that and to do it and use it only during the ceremonial purposes” (urban woman). adults, and in particular uncles, were viewed as having a responsibility to teach youth about how to use tobacco with the right purpose, “maybe [young people] would [listen] to their their uncles if their uncles would step up and get mad at them and tell them when’s the right time and when not to, but sometimes the uncles are the only guys that, cheer or laugh at then. when they cough they laugh like it’s okay” (urban male). young men living in urban areas state that other young people used tobacco for the nicotine high and to fit in with their peers. one man stated. www.companyofscientists.com/index.php/chd e7 cancer health disparities research “...the men know how to use [tobacco], what the purpose of it. but then it’s the younger children, kids, teens, who just smoke it just to feel the nicotine high and impress other people or try to fit in so they’re not left out.” men and women had differing responses regarding the use of commercial tobacco in ceremony. women stated a strong preference for men to use only traditional tobacco in ceremony. in the urban group, one woman stated: “i would think tobacco is more important that the men should stick to the traditional tobacco instead of commercial.” another woman added that traditional tobacco use over commercial use would reduce direct health risks and help to educate young people about the meaning of traditional tobacco: “i think if they did use the traditional tobacco [all] the time, it would be less people just smoking the commercial tobacco and that the younger generation would understand more of how to use and not just go down there [traditional ceremonial place] just to smoke cigarettes.” some men differed on this perception, however, stating: “you pray then your prayers go to the spirits no matter what kind of tobacco you use.” participants also noted resistance by the youth to listen to their elders, “...now-a-days teenagers, kids, they don’t listen to the elders, to the older folks, they sometimes even get mad at them or argue with them back. they get high-headed, they think they know everything, the elders are just trying to look out for the health. the kids really [do not] have respect as much as they used to…” (urban man). the reflection of older and young people on their observations of youth tobacco use is illustrative of the ways in which elders perceive of differences, value, respect, and ritual associated with traditional versus commercial tobacco. discussion findings demonstrate important differences in perceptions regarding the use of commercial and traditional tobacco. emergent themes included gender and generational roles in understanding the use of commercial and traditional tobacco. the common thread among participants was the knowledge that traditional tobacco is a vital part of culture and commercial tobacco is unhealthy and harmful to the body. women stated more clearly that commercial tobacco should never be used in ceremony because of health risks and potential impact on younger generations. men stated immense health risks associated with commercial tobacco but were less strongly opposed to commercial tobacco in ceremony. upon entering a ceremonial place, men are welcomed and invited to sit and smoke. participants stated that smoke is used to send prayers in ceremonies, which aligns with other studies reporting the customary practice where smoke from the tobacco carries thoughts and prayers to deities (struthers & hodge, 2004; nadeau et al., 2012). most participants, regardless of gender, saw no negative side effects from using traditional tobacco, which is consistent with other studies (struthers & hodge, 2004; unger et al., 2006; arndt et al., 2013; henderson & henderson, 2015). other studies cite challenges in securing traditional tobacco have lead members of other tribes to use commercial tobacco in proxy of traditional tobacco due to its ready availability (struthers & hodge, 2004; nez-henderson et al., 2005; unger et al., 2006; forster et al., 2007; margalit et al., 2013). participants confirmed the importance of tobacco in traditional ceremonial milieu. the men shared personal experiences with smoking traditional and www.companyofscientists.com/index.php/chd e8 cancer health disparities research sometimes commercial tobacco during ceremonies. while women do not have direct experience with traditional tobacco, they have observed the negative impact on men’s health with the transition from traditional to commercial tobacco use in ceremonies. these underlying cultural differences in tobacco use by gender could partially explain why several studies have observed higher rates of tobacco use among southwest american indian men, when compared to southwest american indian women (nezhenderson et al., 2005; redwood et al., 2010). women were strongly opposed to commercial tobacco due to concern for their children’s health. the men did not come to a consensus on youth smoking in general. most of the men stated that kids have access to commercial tobacco, but they did not voice direct opinions either for or against youth smoking. in addition, it was mentioned that there is leniency among some of the tribal members toward commercial tobacco and youth smoking. they seem to value beliefs about ceremonial purpose of tobacco as more important than what substance is being smoked. this theme was particularly prominent among urban men who had a lower mean age relative to the reservation men. other studies have found higher rates of commercial tobacco use among young american indian southwest men (nez-henderson et al., 2005; redwood et al., 2010; kunitz, 2016), which may explain complacency toward commercial tobacco. men and women were hopeful that the younger generation would learn culturally-specific purposes behind the use of traditional tobacco. recommendations this study provides an example of a promising cbpr practice between a tribal health program initiated collaboration with university partners. understanding the nuances of traditional tobacco in a cultural context is imperative for effective smoking cessation program planning with tribal communities. the authors were able to work with the tribe to identify policy change strategies that were implemented to reduce the youth’s exposure to commercial tobacco used in ceremonies. once community-engaged research and practice lays the foundation for tobacco cessation programs, the authors suggest obtaining financial support to the tribal tobacco prevention programs where possible. additional resources could support community-engaged efforts to advertise the dangers of commercial tobacco through the use of billboards and other visual means. other suggested policies include prohibiting youth from smoking commercial cigarettes at traditional ceremonies, pow-wow, or tribal gatherings. most importantly, tobacco cessation programs must be implemented in an engaged way with a clear understanding of local uses and perceptions of tobacco for ceremonial and individual uses. without that understanding, programs may not be successful in communicating with and to the people who may be positively impacted by a reduction in the use of commercial tobacco on tribal lands. acknowledgements the authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: research reported in this publication was supported by the national institute of health (nih), national cancer institute (grant number: 5u54ca143925, the partnership for native american cancer prevention) and national institute on minority health and health disparities of the national institutes of health under award number www.companyofscientists.com/index.php/chd e9 cancer health disparities research p20md006872 to co-pi: priscilla r. sanderson, ph.d., crc and nicolette i. teufel-shone. the content is solely the responsibility of the authors and does not necessarily represent the official views of the national institutes of health.” the authors would like to thank both the funders and participants who made this research project. this work would not have been possible without the support of kwaayesnom onsae, jalen redhair, b.s., eldon kalemsa, joyce hamilton, and kassondra yaiva who contributed to the research. the authors recognize the partnership support of the university of arizona team: sylvia brown, ph.d, mph, robin harris, ph.d., and neil weinstein, ph.d. conflict of interest statement the co-authors have declared that no competing or conflict of interests exist. the funders had no role in study design, writing of the manuscript and decision to publish. author’s contributions priscilla r. sanderson was the co-leader of the pilot research project, supervised and mentored the undergraduate research students while the research was conducted, focus group facilitator, led the multi-investigator analysis meetings, and draft paper editing and review. erelda gene and rebecca scranton assisted with focus group discussions, assisted with the multiinvestigator analysis meetings, transcribed and coded with atlas, t.i., conducted the literature review, wrote the draft paper, and draft paper editing and review. angela a a willeto conducted the literature review, wrote the literature review section, and draft paper editing and review. lori joshweseoma presented and received tribal council approval, assisted with focus group discussions and facilitator, and assisted with the multi-investigator analysis meetings lisa j hardy draft paper editing and review. references arndt, l. n., caskey, m., fossum, j., schmitt, n., davis, a. r., smith, s. s., kenote, b. strickland, r., & waukau, j. 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(2016). culturally sensitive assessments as a strength-based approach to wellness in native communities: a community-based participatory research project. american indian alaska native mental health research, 23(3), 271-92. wallerstein, n.b., duran, b. (2006). using community-based participatory research to address health disparities. health promotion practice, 7(3), 312-323. wallerstein, n., duran, b. (2010). community-based participatory research contributions to intervention research: the intersection of science and practice to improve health equity. american journal of public health, 100(s1), s40-s46 yu, m. & whitbeck, l. b. (2016). a prospective, longitudinal study of cigarettes smoking status among north american indigenous adolescents. addictive behaviors, 58, 35-41. https://doi.org/10.1016/j.addbeh.2016.02.007 http://doi.org/10.1007/s10900-012-9648-7 http://doi.org/10.1016/j.amepre.2012.08.003 http://doi.org/10.2105/ajph.2004.050096 http://doi.org/10.1093/ntr/ntq087 http://dx.doi.org/10.1007/s13187-009-0036-7 http://doi.org/10.1002/cncr.23727 http://dx.doi.org/10.1177%2f0898010104266735 http://www.samhsa.gov/data/sites/default/files/nsduhresultspdfwhtml2013/web/nsduhresults2013.pdf http://www.samhsa.gov/data/sites/default/files/nsduhresultspdfwhtml2013/web/nsduhresults2013.pdf http://dx.doi.org/10.2105/ajph.2004.054254 http://doi.org/10.1016/j.jadohealth.2005.02.002 http://doi.org/10.1016/j.addbeh.2016.02.007 www.companyofscientists.com/index.php/chd e1 cancer health disparities research potentially preventable cancers diagnosed among alaska native people sarah h nash1*, diana g redwood1 1alaska native epidemiology center, community health services, alaska native tribal health consortium, anchorage, ak *corresponding author e-mail: shnash@anthc.org abstract cancer is the leading cause of death among alaska native (an) people, and the third leading cause of years of potential life lost. an tribal health leaders and researchers want to understand the cancer burden attributable to modifiable risk factors among an people to inform the design of cancer prevention strategies. to address this question, we estimated the population attributable risk (par) associated with modifiable cancer risk factors including obesity, smoking, physical inactivity, and alcohol use among an people. par varied by cancer site and risk factor, and was highest for lung cancer and smoking, with an estimated 78.8% of cancers among males, and 69.8% among females attributable to this risk factor. a smaller, but still substantial proportion of cancers were associated with obesity (up to 37% for endometrial cancer among females), physical inactivity (up to 18% for endometrial cancer among females), and alcohol use (up to 34% for breast cancers among heavy drinking females). overall, we estimated that approximately 1500 cancers could be prevented over a 10-year period if these four risk factors were eliminated among an people. this study demonstrates the importance of smoking as a primary prevention target to reduce the burden of cancer and other chronic diseases among an people. however, it also indicates that obesity, physical activity, and alcohol use may account for a varying, but substantial proportion of cancers in this population. given the high burden of cancer among an people, a comprehensive approach to primary prevention is warranted.. keywords: native american, population attributable risk, cancer prevention citation: nash sh and redwood dg (2017).potentially preventable cancers diagnosed among alaska native people. cancer health disparities 2:e1-e15. doi:10.9777/chd.2018.10001 www.companyofscientists.com/index.php/chd e2 cancer health disparities research introduction cancer is the leading cause of death among alaska native (an) people, and the third leading cause of years of potential life lost (alaska native epidemiology center, 2017; blake, 2016; carmack, 2015). in contrast to u.s. whites (usw), for whom cancer incidence and mortality rates have been significantly declining over the past 20+ years (ryerson et al., 2016), rates remained fairly constant among alaska native people, resulting in a significant health disparity (blake, 2016; carmack, 2015). furthermore, disparities in incidence of several cancer sites exist between an people and usw, including lung, colorectal, and nasopharyngeal cancers, which are 1.5, 2.3, and 17.3 times higher among an people than usw, respectively (carmack, 2015; kelly jj et al., 2014). for these reasons, cancer is a leading concern among alaska tribal health leaders and researchers, and the alaska native tribal health consortium’s (anthc) cancer program has developed a comprehensive cancer control plan (cccp) specifically for the alaska tribal health system (aths) (2006). reducing the burden of cancer among an people may be achieved through a focus on cancer prevention. it has been estimated that upwards of 50% of cancer deaths globally may be preventable (colditz et al., 2006; colditz and wei, 2012), and a growing number of cancers are known to have risk factors that are potentially modifiable (stein and colditz, 2004). these include some of the leading cancer sites among alaska native people: female breast, lung, colorectal, and prostate cancers (carmack, 2015). leading modifiable risk factors for cancer include tobacco use, alcohol use, diet, infectious diseases, obesity, and physical inactivity (siegel et al., 2017; stein and colditz, 2004). little is known about the burden of potentially preventable cancers among an people. yet, an people do not meet national recommendations for many modifiable cancer risk factors, including tobacco use, overweight and obesity, and fruit and vegetable consumption (lanier et al., 2012). there is a critical need to better understand modifiable risk factors for cancer among an people, and the burden of potentially preventable cancers. the potential contribution of modifiable risk factors to cancer burden can be assessed using population attributable risk (par). this study analyzed the par associated with modifiable risk factors for cancer among an people, including obesity, smoking, physical inactivity, and alcohol use. materials and methods study population american indian and alaska native people (ai/an) represent a diverse group indigenous to north america. the alaska department of labor estimated that in 2014, 143,367 ai/an people (alone or in combination) resided in alaska, accounting for 19% of the total alaska population (alaska department of labor and workforce development, 2015). there are 229 federally recognized tribes in alaska (american congress of american indians, 2017; williams, 2009). the alaska tribal health system (aths) is made up of over 14 regional tribal health organizations, which provide health care services, including health promotion and disease prevention programs, to all ai/an beneficiaries living in alaska. the alaska native tribal health consortium (anthc), a consortium of regional tribal health organizations, provides statewide health services, and co-manages alaska’s only tertiary tribal healthcare facility, the alaska native medical center (anmc) located in anchorage. cancer sites we estimated par for all cancer sites known to be associated with smoking, obesity, physical inactivity, or alcohol use. smoking-related cancers were those determined by the 2014 surgeon general’s report to be causally linked to smoking, and included acute myeloid leukemia (aml), as well as cancers of the bladder, colon and rectum, esophagus, kidney, larynx, liver, lung, oral cavity, www.companyofscientists.com/index.php/chd e3 cancer health disparities research pancreas, stomach, and uterine cervix (alberg et al., 2014). obesity-related cancers were those determined by the world cancer research fund/american institute for cancer research to be associated with obesity (wiseman, 2008), including cancers of the esophagus, stomach, colon and rectum, liver, gallbladder, pancreas, postmenopausal breast, kidney, advanced prostate, thyroid, and endometrium. physical inactivity-related cancers were those determined by a recent systematic review and meta-analysis to be convincingly or probably associated with physical activity or inactivity (friedenreich et al., 2010), and included cancers of the colon, lung, prostate, breast, endometrium, and ovaries. finally, alcohol-related cancers were those determined by a recent systematic review and meta-analysis to be statistically significantly associated with moderate, or heavy drinking (bagnardi et al., 2015), including cancers of the colon and rectum, esophagus (squamous cell carcinoma (icd-o histologies 8070-8076) only), gallbladder, larynx, liver, lung, oral cavity, stomach, prostate, and breast. data sources and definitions prevalence of cancer risk factors among alaska native people was estimated using data from the alaska behavioral risk factor surveillance survey (brfss), collected by the alaska department of health and social services, division of public health, and the centers for disease control and prevention. data reported are for the 5-year period 2011-2015, unless otherwise noted. individuals were defined as current smokers if they reported having smoked more than 100 cigarettes in their lifetime, and also reported current smoking. obesity was defined according to world health organization (who) guidelines as having a body mass index (bmi) ≥ 30 kg/m2. physical inactivity was defined as not meeting the cdcrecommended 150 minute/week of aerobic activity (centers for disease control and prevention, 2008). information on physical activity was available from the 2011, 2013, and 2015 brfss surveys only. alcohol intake (g ethanol/day) was estimated as (average number of drinks/day*g ethanol/drink). we estimated that each drink contained 12.5 g ethanol (bagnardi et al., 2015). we categorized moderate and heavy drinking as 12.5 ≤ 50 g/d (4 drinks/d) and >50 g/d (4 drinks/d), respectively, as per a recent review and meta-analysis (bagnardi et al., 2015). cancer case counts were from the national cancer institute surveillance, epidemiology, and end results (seer) program’s alaska native tumor registry (antr). the antr is a population-based registry that records cancer information on ai/an people who meet eligibility requirements for indian health service benefits, who have been diagnosed with cancer in the state of alaska, and who are alaskan residents at the time of cancer diagnosis. as part of the antr’s standard surveillance process for collecting seer data, cases were identified through a variety of sources, including: tumor registry and pathology files of anmc and other native and non-native healthcare facilities throughout the state; linkage to the alaska state cancer registry and the washington state cancer registry; and death certificates (<1% cases). for this study we used data on the number of cancers diagnosed between january 1, 2006 and december 31, 2015. classification of cancer site of origin, histologic cell type, behavior and grade coding followed the international classification of diseases for oncology (icd-o) third edition (2013). we included only invasive malignancies (icd-o behavior code 3); benign and in situ tumors were not included in case counts (icd-o behavior codes 0 and 2, respectively), nor were tumors of uncertain or unknown behavior (icd-o behavior code 1). menopausal status was not available through the registry; therefore, age at diagnosis (< 50y, ≥50 y) was used as a proxy to define post-menopausal breast cancer. advanced prostate cancer was defined by having an ajcc stage group (7th edition; ref) of iii or iv, or a derived summary stage 2000 of “distant.” www.companyofscientists.com/index.php/chd e4 cancer health disparities research table 1. relative risk of cancer associated with each cancer site, and modifiable risk factor, used herein to estimate population attributable risk.a-d cancer site smoking obesity physical inactivity moderate alcohol use heavy alcohol use male female male female male female male female male female acute myeloid leukemia 1.09 1.09 -------- bladder 3.14 3.14 -------- colorectal 1.19 1.28 ----1.21 1.07 1.53 1.24 colon --1.45 1.12 1.32 1.32 ---- rectum --1.25 1.05 ------ esophagus 2.52 2.28 1.12 1.06 ------ esophageal scc ------2.23 2.23 4.95 4.95 gallbladder --1.54 1.75 ----2.64 2.64 kidney and renal pelvis 1.59 1.35 1.59 1.91 ------ larynx 6.98 6.98 ----1.44 1.44 2.65 2.65 liver 1.85 1.49 1.99 1.43 ----2.07 2.7 lung 9.87 7.58 --1.43 1.43 ---- oral cavity 3.43 3.43 ----1.83 1.83 5.13 5.13 pancreas 1.63 1.73 1.45 1.28 ------ stomach 1.74 1.45 1.11 1 ------ thyroid --1.14 1.26 ------ male only prostate ----1.25 ----- advanced prostate --1.15 ------- female only breast -----1.33 -1.23 -1.61 postmenopausal breast ---1.16 ------ endometrium ---2.54 -1.43 ---- ovarian -----1.23 ---- www.companyofscientists.com/index.php/chd e5 cancer health disparities research uterine cervix -1.83 -------- a relative risk estimates for smoking taken from: gandini et al int j cancer 2008: 122;155-164. botteri et al jama 2008:300;2765-2778. b relative risk estimates for obesity taken from cheragi et al plos one 2012:7;e51446. xue et al eur j cancer prev 2016: 26, 94-105. jenabi et al pub health 2015:129;872-880. c relative risk estimates for physical inactivity modified from friedenreich et al eur j cancer 2010:46;2593-2604. d relative risk estimates for alcohol use (moderate and heavy) taken from bagnardi et al br j cancer 2015:112;580-593 table 2. prevalence of modifiable risk factors for cancer among alaska native people, alaska behavioral risk factor surveillance system, 2011-2015. obesity smoking physical inactivity current drinking current drinking (yes) moderate (1-4 drinks/day) heavy (>4 drinks/day) average drinks/ day total 34.8 (33.0, 36.6) 37.7 (35.9, 39.5) 50.9 (47.4, 54.3) 42.4 (40.2, 44.7) 8.9 (7.7, 10.3) 10.4 (9.1, 11.8) 0.41 (0.36, 0.46) sex male 31.6 (29.2, 34.0) 40.2 (37.6, 42.9) 49.8 (44.9, 54.8) 44.8 (41.5, 48.2) 12.0 (9.9, 14.4) 11.6 (9.8, 13.8) 0.56 (0.47, 0.66) female 38.4 (35.7, 41.1) 35.1 (32.6, 37.7) 51.9 (47.0, 56.7) 40.0 (36.9, 43.1) 5.8 (4.6, 7.3) 9.1 (7.4, 11.1) 0.25 (0.21, 0.29) age (yr) 18-34 26.3 (23.4, 29.4) 42.2 (38.9, 45.5) 44.8 (38.8, 5.9) 45.3 (41.3, 49.5) 10.2 (7.9, 13.1) 11.1 (8.7, 14.0) 0.42 (0.33, 0.5) 35-49 42.4 (38.8, 46.0) 40.9 (37.4, 44.5) 53.5 (46.9, 60.1) 48.4 (44.1, 52.8) 10.7 (8.4, 13.4) 9.3 (7.2, 11.9) 0.54 (0.43, 0.66) 50-64 39.3 (36.0, 42.7) 35.9 (32.7, 39.2) 54.0 (47.8, 60.1) 37.6 (33.8, 41.5) 8.1 (6.0, 10.8) 8.6 (6.8, 10.8) 0.35 (0.27, 0.44) 65+ 38.4 (33.7, 43.4) 17.0 (13.9, 20.6) 58.5 (47.8, 68.4) 30.4 (23.9, 37.9) 3.7 (2.5, 5.5) 12.0 (8.4, 16.8) 0.2 (0.14, 0.25) www.companyofscientists.com/index.php/chd e6 cancer health disparities research table 3. population attributable risk (par) percent and estimated preventable cases (epc) of cancers classified as associated with tobacco, obesity, and physical inactivity. tobacco obesity physical inactivity male female male female male female par epc par epc par epc par epc par epc par epc acute myeloid leukemia 3.6 0.7 3.1 0.4 -------- bladder 47.3 16.1 42.9 7.7 -------- colorectal 7.3 25.2 8.9 30.9 -------- colon ----12.6 42.9 4.4 15.1 13.6 29.8 14.1 35.9 rectum ----6.9 8.5 1.8 1.7 ---- esophagus 38.9 16 31 6.8 3.5 1.4 2.2 0.5 ---- gallbladder ----13.9 0.4 22.2 1.8 ---- kidney and renal pelvis 19.8 22.0 10.9 10.0 15.0 16.7 25.7 23.4 ---- larynx 71.5 17.9 67.7 3.4 -------- liver 26.3 15.3 14.7 4.0 22.9 12.8 14 3.5 ---- lung 78.8 280.7 69.8 201.7 ----17.5 62.6 18.1 52.6 oral cavity 50.5 44.5 46 26.7 -------- pancreas 20.9 11.1 20.3 10.8 11.9 6.3 9.6 5.1 ---- stomach 23.7 24.9 13.6 9.8 3.2 3.4 ------ thyroid ----4.0 1.1 9.0 7.8 ---- male only prostate --------11.1 22.7 -- advanced prostate ----4.3 1.6 ------ female only breast ----------14.7 94.0 postmenopausal breast ------5.7 26.9 ---- endometrium ------36.9 29.9 --18.1 14.6 www.companyofscientists.com/index.php/chd e7 cancer health disparities research ovarian ----------10.9 5.5 uterine cervix --22.6 13.3 -------- total 474.4 325.5 95.1 115.7 115.1 202.6 a epc for a 10-year period, calculated using the number of cancers diagnosed among an people for the 10-year period from 2006-2015. table 4. population attributable risk (par) percent and estimated preventable cases (epc) of cancers classified as associated with moderate and heavy alcohol use. moderate drinking heavy drinking males females males females cancer site par epc par epc par epc par epc colorectal 2.5 8.4 0.4 1.4 5.8 19.8 2.1 7.4 esophageal scc 12.9 3.5 6.7 0.5 31.4 8.5 26.4 2.1 gallbladder ----16.0 1.3 13 1.8 larynx 5.0 1.3 2.5 0.1 16.1 4 13.1 0.7 liver ----11.0 6.2 8.9 2.2 lung ----1.7 6.1 1.3 3.9 oral cavity 9.1 8 4.6 2.7 32.4 28.5 27.3 15.8 stomach ----2.4 2.5 1.9 1.4 female only breast --1.3 8.4 --5.3 33.5 total 21.2 13.1 76.9 68.8 a epc for a 10-year period, calculated using the number of cancers diagnosed among an people for the 10-year period from 2006-2015. www.companyofscientists.com/index.php/chd e8 cancer health disparities research statistical methods prevalence estimates of cancer risk factors are given with 95% confidence intervals (ci), to account for the brfss sampling strategy and weighting. differences in prevalence of cancer risk factors by sex and age categories (18-34, 35-49, 50-64, and 65+ years) were assumed to be statistically significant where 95% ci did not overlap. population attributable risk was estimated using levin’s formula: par = [ppop x (rr-1)]/[ppop x (rr-1) +1] where ppop is the prevalence of the risk factor among alaska native people and rr is the relative risk of cancer associated with each risk factor (levin, 1953). rr estimates specific to alaska native people were unavailable; therefore we used sexspecific estimates (where available), generated from meta analyses conducted among other us/european populations (bagnardi et al., 2015; botteri et al., 2008; cheraghi et al., 2012; friedenreich et al., 2010; gandini et al., 2008; jenabi and poorolajal, 2015; xue et al., 2017). relative risk estimates used for calculations are given in table 1. the estimated preventable cancers (epc) for each risk factor was estimated by multiplying the par for that risk factor/cancer by the number of cancers at that site diagnosed among an people over the most recent 10-year period: 2006-2015. a longer duration (i.e., 10-year period vs 5-year period examined for risk factor prevalence) was chosen to reduce the impact of case number fluctuations on our estimates of epc, given small an population numbers and case counts. institutional review board review and approval were not required for the current study because both brfss and seer program data are publically available, and all patient data were deidentified. appropriate tribal review and approval was obtained for publication of this study. results prevalence of modifiable cancer risk factors among alaska native people self-reported brfss prevalence of obesity, current smoking, physical inactivity, and current drinking (light/heavy/moderate) among an people is given in table 2. over a third of an people reported being obese; prevalence of obesity was higher among females (38.4%) than males (31.6%). obesity prevalence was lowest in those aged 1834 years, but was similar between all other age categories. overall, smoking prevalence was almost 38%; current smoking was slightly higher among males (40.2%) than females (35.1%). smoking prevalence was similar among those aged 18-34, 35-49, and 50-64; however, it was substantially lower among those aged 65 years and older. overall, prevalence of physical inactivity was high, with over half (50.9%) of an people reporting they did not meet the guidelines; this proportion was similar in strata of sex and age. finally, over one third (42.4%) of an people reported consuming at least one alcoholic drink/ month; a far smaller proportion reported moderate (8.9%) and heavy (10.45) drinking, respectively. the proportion of moderate and heavy drinkers was slightly higher among males, relative to females; yet there was no consistent pattern evident within strata of age. potentially preventable cancers among alaska native people par and epc for obesity-, smoking-, and physical inactivity-related cancers are given in table 3. the number and proportion of potentially preventable cancers varied by risk factor and cancer site. the highest par was observed for smoking: over 70% of lung cancers (78.8% among males, 69.8% among females), and a similar proportion of www.companyofscientists.com/index.php/chd e9 cancer health disparities research laryngeal cancers (71.5% male, 67.7% female) could be potentially preventable with elimination of this risk factor. overall, we estimated that approximately 800 cancers could be prevented in alaska over a 10-year period if smoking were eliminated among an people. obesity and physical inactivity represented a smaller, but still substantial, number of potentially preventable cancers (table 3). again, par varied by cancer site, but was highest for obesity and liver cancer (22.9% among males, 14.0% among females), and physical inactivity and lung cancer (17.5% among males, 18.1% among females). both obesity and physical inactivity showed a particularly strong prevention potential for female cancers: par for endometrial cancer was 36.9% for obesity, and 18.1% for physical inactivity. similarly, par associated with physical inactivity was 14.7% for breast cancer, and 10.9% for ovarian cancer. we estimated that approximately 210 cancers could be prevented among alaska native people by eliminating obesity and 317 by eliminating physical inactivity over a 10-year period. finally, we examined the prevention potential associated with both moderate and heavy drinking for alcohol-related cancers; these data are given in table 4. overall, both par and epc were higher for heavy drinking than for moderate drinking; total epc over a 10-year period for these risk factors was 146 and 34, respectively. as with the other risk factors that we examined, par varied by site. for heavy drinking, the highest par was observed for female breast cancer (33.5%), esophageal squamous cell carcinoma (31.4% males, 26.4% females), and cancers of the oral cavity (32.4% males, 27.3% females). in addition, a smaller, but still substantial proportion of cancers of the gallbladder, larynx and liver could also be prevented with the elimination of heavy drinking among an people. similar to heavy drinking, the highest par for moderate drinking was observed for esophageal squamous cell carcinoma (12.9% males, 6.7% females), and cancers of the oral cavity (9.1% males, 4.6% females). we estimated that eliminating moderate and heavy drinking may prevent up to 34 and 146 cancers among alaska native people, respectively, over a 10-year period. discussion the burden of cancer among an people is high (carmack, 2015; kelly jj et al., 2014). yet, our results suggest that a potentially substantial proportion of these cancers may be prevented if exposure to four key modifiable risk factors: smoking, obesity, physical inactivity, and alcohol use, could be eliminated in this population. par was highest for several smoking-related cancer sites; the high prevalence of smoking among an people and importance of tobacco cessation and prevention efforts has been previously recognized (patten et al., 2007; patten et al., 2008; renner et al., 2004; smith et al., 2010; state of alaska tobacco prevention and control program, 2015; wolsko et al., 2009). however, these results also suggest the importance of recognizing and addressing other modifiable risk factors in a comprehensive approach to the primary prevention of cancer. such an approach is also likely to have additional benefit to an people, as obesity, physical inactivity and alcohol use have been linked to other outcomes of concern, including diabetes, heart disease, chronic liver disease, and unintentional injury (murphy et al., 1997; murphy et al., 1995). while we recognize that reducing or eliminating exposure to these risk factors will provide a challenge to the alaska tribal health system, this study provides data to help prioritize primary prevention efforts for the greatest reduction in an cancer burden. these data reinforce the alaska tribal health system’s focus on tobacco use prevention and smoking cessation, and emphasize the importance of encouraging other healthy behaviors as well, including being physically active, maintaining a healthy weight, and low consumption of alcohol. these data suggest that the greatest cancer prevention potential for the an population is to reduce smoking. of particular note, between 43% www.companyofscientists.com/index.php/chd e10 cancer health disparities research and 79% of cancers of the lung, larynx, oral cavity, and bladder could be prevented with elimination of this risk factor. this is at the high end of the range of values observed across other, non-native populations (whiteman and wilson, 2016), likely due to the high prevalence of smoking among an people (lanier et al., 2012; redwood et al., 2010). in this study, prevalence of smoking was twice as high as has been reported for u.s. (2012) or alaska whites (alaska department of health and social services, 2016), and several rural alaska boroughs (counties) with a high proportion of alaska native residents have among the highest smoking prevalence in the nation (e.g., 42% in the northern region, 2014 (dwyer-lindgren et al., 2014)). furthermore in 2014, 15% of an people reported using smokeless tobacco (alaska department of health and social services, 2016), which has been linked to oral cancer, esophageal cancer, and pancreatic cancer, as well as heart and gum disease (boffetta et al., 2008; organization and cancer, 2007). our estimates of par did not include smokeless tobacco use; including this would likely inflate the estimates of par given here. importantly, the high prevalence of smoking is likely a key contributor to several cancer disparities among an people. for example, incidence of and mortality from lung cancer is 1.5 times higher among an people, relative to u.s. whites (carmack, 2015). several stateand triballymanaged tobacco use prevention programs exist to encourage and support an people who wish to quit smoking, including the alaska quitline and anthc’s tobacco prevention and control program, which provides tobacco cessation services to an people statewide, as well as training for community tobacco treatment specialists. in addition to smoking, these data demonstrate that obesity and physical inactivity may also be associated with a substantial proportion of cancer among an people (e.g., up to 37% for obesity and endometrial cancer); however, these results must be considered in context of what we know about obesity and physical activity among an people. for example, the associations of obesity with chronic disease risk factors has been shown to be modified by intake of n-3 polyunsaturated fatty acids (lemas et al., 2013; makhoul et al., 2011; vaughan et al., 2015), which are high in many an traditional foods (bersamin et al., 2008; bersamin et al., 2006; bersamin et al., 2007). thus, it is possible that an traditional subsistence activities, including consumption of an traditional foods, may alleviate some of the cancer risk associated with obesity. furthermore, an people may experience physical activity differently than recommended by national guidelines, which could also modify the par estimates presented herein. studies have shown that while few an people may reach guideline amounts of moderate and vigorous physical activity, a potentially larger proportion may engage in lower intensity traditional activities such as harvesting wild berries and greens, and fishing for potentially longer periods of time (redwood et al., 2009). an increasing body of literature supports the importance of increasing physical activity levels and avoiding sedentary behaviors (arem et al., 2014; arem et al., 2015; howard et al., 2015; matthews et al., 2012; matthews et al., 2015; moore et al., 2016), perhaps to include the an (yup’ik) concept of “keeping busy” (hopkins et al., 2007), as a key component of disease risk reduction. several anthc programs support healthy behaviors around food and physical activity among alaska native people. recently, anthc partnered with the state of alaska’s play every day childhood obesity prevention campaign to create culturally-appropriate public service announcements for an youth (alaska department of health and social (services, 2017). in addition, anthc activities such as “store outside your door” which promotes knowledge and use of an traditional wild foods from around the state, and “alaskan plants as foods and medicine” promote healthy eating and traditional food consumption for all an people. while these activities are not explicitly geared towards cancer prevention, our www.companyofscientists.com/index.php/chd e11 cancer health disparities research results suggest that reducing obesity and increasing physical activity may be beneficial in reducing cancer risk among an people, and support the continued investment in, and evaluation of, such programs. alcohol use is also an important consideration for cancer prevention among an people. these data demonstrate a lower prevalence of occasional drinking among an people than has been reported for u.s. whites (henley et al., 2014). patterns of alcohol use may differ among an people because of the cultural and political landscape around its consumption. many rural an communities are “dry” or “damp,” meaning that they do not permit the consumption or sale of alcohol, respectively. we observed a high rate of abstinence among an people, with over 65% of an people reporting they do not currently drink (table 2). yet, our data also show that a substantial proportion of potentially preventable cancers may be related to alcohol use (e.g., up to 33.5% of breast cancers, among heavy drinking females). in addition to the substantial cancer prevention potential presented herein, elimination of excess alcohol use could have immediate implications for reducing other leading causes of an mortality, including unintentional injury and suicide (blake, 2016). while alcohol use is recognized as a cancercausing agent (baan et al., 2007), strategies and activities to reduce its use are not always included in tribal and state comprehensive cancer control plans (henley et al., 2014), including the alaska tribal health system comprehensive cancer control plan (2011-2017) (2006). future iterations of the plan should include strategies that address the cancer prevention potential associated with reduced exposure to this risk factor at a population level. finally, these data can be compared to recent reports on par from across the u.s. a recent analysis by islami and colleagues (islami et al., 2017) estimated that up to 42% of incident cancers in the u.s. could be attributed to major modifiable cancer risk factors. as in the present study, smoking was a leading cause of both preventable cancers and cancer deaths: the authors estimated that approximately 80% of lung cancer cases were attributable to cigarette smoking. this is remarkably similar to our findings, given that prevalence of smoking and tobacco use is known to be substantially higher among alaska native people (e.g. 35-40% in the present study, versus approximately 15% nationwide (jamal, 2016)). nevertheless, differences can be observed: for example, approximately 20% of colon and rectal cancer cases (combined) among males may be attributed to obesity among an men, compared to only 4.8% of colorectal cancer cases among u.s. males nationwide (islami et al., 2017). yet, despite differences in the methodology and cancer sites examined in the two studies, both estimate that a substantial proportion of cancers could be attributable to obesity, physical inactivity, and alcohol use. similar findings have been reported for other populations globally (arnold et al., 2015; arriaga et al., 2017a; parkin et al., 2011; whiteman and wilson, 2016). this growing body of research emphasizes need for dissemination and implementation of known cancer preventive measures. our study further supports the need to understand population attributable risk associated with modifiable cancer risk factors in minority populations across the u.s., in order to be able to provide appropriate, population-specific prevention programs. this is the first study to examine the burden of potentially preventable cancers among an people using the population attributable risk metric, and provides a new way of looking at potential causes of cancer among this underserved population. furthermore, these data may provide a novel and effective way of communicating risk to an tribal health leaders and community members; future research should address the acceptability and accessibility of this metric for cancer risk communication among an people. yet this study also has several limitations that should be acknowledged. first, we were unable to use an www.companyofscientists.com/index.php/chd e12 cancer health disparities research specific relative risk estimates in our calculations; associations of risk factors with cancer outcomes may differ among an people from the predominantly u.s./european populations on which the risk estimate meta-analyses used in this study were based. it is also assumed that risk factors for cancer among an people mirror those observed in other populations; however, further research is necessary to explore whether there are an specific risk or protective factors that might be the focus of successful primary prevention programs, and the strength of these associations. for example, the importance of helicobacter pylori in the etiology of stomach cancer (keck et al., 2014) and colorectal cancer (lee et al., 2016; qing et al., 2016; sonnenberg and genta, 2013; zumkeller et al., 2006), or hbv/hcv in the etiology of liver cancer among an people (connelly et al., 2016) has been previously demonstrated. furthermore, we acknowledge that our use of levin’s formula may have resulted in overestimation of the par, as this method does not account for effect modification, confounding, or competing risks (arriaga et al., 2017b; flegal, 2014; flegal et al., 2004; flegal et al., 2007). in particular, obesity and physical inactivity are likely to be highly interlinked. in addition, we note that par was calculated using brfss prevalence data from 2011-2015, and epc using antr case count data from 2006-2015. thus, our calculations do not account for any potential lag between exposure to the risk factors examined, and incidence of cancer. changes in both risk factor prevalence, and cancer case counts, over time, would result in changes to the results presented herein. finally, we note that brfss data are selfreported, and may not represent “true” risk factor exposure among the an population. importantly, potentially sensitive exposures such as alcohol may be underreported. despite these limitations, these data provide a novel view of cancer among alaska native people, and provide data that may be useful to tribal health leaders and public health practitioners alike. this study examined the population attributable risk for several leading modifiable risk factors for cancer among an people. while smoking was the primary leading modifiable risk factor, a smaller, but still substantial proportion of cancers may be linked to other risk factors including obesity, physical inactivity and alcohol use. our results demonstrate the need for a comprehensive approach to primary cancer prevention among an people. eliminating tobacco use, increasing healthy diet and physical activity, and moderating alcohol use would help substantially decrease the cancer burden and resultant health disparities experienced by an people. by enhancing evidence-based prevention efforts in these areas, cancer morbidity and mortality would be reduced. acknowledgements dr. nash and the alaska native tumor registry are supported by the nci’s surveillance, epidemiology and end results program, nci contract number hhsn26120130010i, task order hhsn26100005. dr. redwood is supported by the centers for disease control and prevention, building public health infrastructure for alaska native people component a, grant # 1 nu58dp006379-01-00. conflict of interest statement the author has declared that no competing or conflict of interests exists. the funders had no role in study design, writing of the manuscript and decision to publish. authors’ contributions shn: conceptualization, formal analysis, methodology, project administration, writing original draft, writing review and editing. dgr: writingreview and editing. references agaku, i., brian king, b., dube, s.r.(2012). current cigarette smoking among adults united states, 2011. mmwr morbidity and mortality weekly report 61, 889-894. alaska department of health and social services, division of public health (2016). alaska tobacco facts: 2016 update www.companyofscientists.com/index.php/chd e13 cancer health disparities research (anchorage, ak). < http://dhss.alaska.gov/dph/chronic/documents/tobacco /pdf/2016_aktobaccofacts.pdf> alaska department of health and social services, division of public health (2017). state of alaska play every day < http://dhss.alaska.gov/dph/playeveryday/pages/default.a spx> alaska department of labor and workforce development, research and analysis section. 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(2006). helicobacter pylori infection and colorectal cancer risk: a meta-analysis. helicobacter 11, 75-80. www.companyofscientists.com/index.php/chd e1 cancer health disparities research quality of evidence on prostate cancer in nigeria omolara aminat fatiregun*1,2, frank chinegwundoh1,3, proffessor nicholas d james1,4, odunayo ikuerowo1,5, olufunmilade omisanjo1,5, abimbola abolarinwa1,5, anthonia chima sowunmi1,6, funlayo buraimoh1,7, folakemi odedina1, 8 1 prostate cancer transatlantic consortium,2 oncology unit, department of radiology, lagos state university college of medicine, ikeja, lagos, nigeria 3 department of urology, barts health, national health service trust, london 4 university hospitals birmingham nhs foundation trust, the medical school, university of birmingham, birmingham, uk 5 department of surgery, lagos state university college of medicine/ lagos state university teaching hospital, ikeja, lagos, nigeria 6 department of radiotherapy & oncology, lagos university teaching hospital/ university of lagos, lagos, nigeria. 7department of biochemistry, lagos state university college of medicine. 8 department of pharmacotherapy and translational research and department of radiation oncology, university of florida, lake nona campus, fl, 32832, usa *corresponding author email: omolarafatiregun@gmail.com. prostate cancer is the 2nd commonest malignancy in men worldwide. it is, however, the commonest in nigeria. while several disparities have been documented between caucasian men and men of african descent, there is limited research on prostate cancer in nigeria. evidence based medicine is a key tool in making clinical decisions and developing screening and treatment guidelines. this review was undertaken to assess the levels of evidence on prostate cancer research in nigeria. a systematic review of all research published on prostate cancer from january 1975 to may 2018 in nigeria was conducted. we reviewed all articles found on various databases by searching for “prostate cancer in nigeria”. we classified them based on their study designs into different levels of evidence as well as year of publication. meta-analyses were not considered in the review. a total of 171 articles were eligible for this review. most publications were at the 4th (66%) and 5th levels of evidence (17%) respectively. no clinical trials on prostate cancer in nigeria was seen or registered on clinicaltrials.gov, hence no studies at level 1 (a, b or c) of evidence published in nigeria. the commonest type of study design was cross-sectional studies accounting for 56% of all publications. prostate cancer research is currently at low levels of evidence in nigeria. it is pertinent to explore and increase funding channels for cancer related research. keywords: prostate,cancer, nigeria. citation: fatiregun et al (2019) quality of evidence on prostate cancer in nigeria. cancer health disparities. 4: e1-e9. doi:10.9777/chd.2019.1005 www.companyofscientists.com/index.php/chd e2 cancer health disparities research introduction in 2012, an estimated 14.1 million new cases of cancer were diagnosed worldwide. prostate cancer was the second most prevalent malignancy in men after lung cancer worldwide. it is the fifth most common cause of cancer deaths (ferlay et al., 2015). in nigeria, it is the commonest malignancy in men and its incidence continues to rise (elima et al., 2012; adeloye et al., 2016). globally, several disparities have been documented between caucasian men and men of african descent. these include an increased risk of developing prostate cancer in black men, younger age of incidence in black men, and genetic differences. these factors might have an impact on survival outcomes (odedina et al., 2009; brawley, 2012). prostate cancer management in african men is quite challenging as most patients present with metastatic disease (shenoy et al. 2016). evidence-based medicine is a crucial tool in making clinical decisions and developing guidelines for management. (burns, rohrich, and chung, 2011) most screening and treatment guidelines used in different parts of the world for managing prostate cancer are formulated from evidence-based results obtained from mostly clinical trials and metanalyses on studies conducted in those countries. the national institute for health and care excellence (nice) guidelines for treatment is predominantly based on research carried out in the united kingdom (uk). a similar situation pertains regarding the national comprehensive cancer network (nccn) guidelines in the united states of america (usa). evidence based medicine is a concept developed in the early 80s, then further described and modified by sackett in 1989 (sackett et al., 1996). it groups different studies based on their levels of evidence from one to five. randomized controlled trials (rct) and metanalyses are placed at the highest level of evidence, whilst, case series, case studies and expert opinions are at the lowest level. rcts are structured to be unbiased; subjects are allocated randomly to two or more treatment groups whilst case series or expert opinion are associated with bias and based on writer’s experience or opinions and there is often no control of confounding factors. the centre for evidence-based medicine in oxford developed an adaptable tool to assess the levels of evidence in 2011 (table 1). the tool is a hierarchical system of classifying based on evidence and designed for use by researchers. table 1: the centre for evidence-based medicine in oxford published the levels of evidence in 2009, and modified in 2011(ocebm levels of evidence working group et al. 2011) www.companyofscientists.com/index.php/chd e3 cancer health disparities research in nigeria, prostate cancer prevention, screening, and clinical treatment modalities should be based on evidence-based research done or validated in nigerian patients, in the expectation that this would lead to improved treatment outcomes and therefore survival. however, there are no publications exploring the levels of evidence in prostate cancer research in nigeria. this review was done to explore levels of evidence on prostate cancer in nigeria. methods we followed the preferred reporting for systematic reviews and meta-analyses (prisma) statement for the conduct of our systematic review (except that we did not consider metanalyses). figure 1: illustrating the prisma selection criteria study selection an electronic literature search of all research published on prostate cancer from january 1975 to www.companyofscientists.com/index.php/chd e4 cancer health disparities research may 2018 in nigeria was conducted. we reviewed all articles found on pubmed, web of science, embase, and google scholar search engines by searching “prostate cancer in nigeria”. using the prisma and national institute of health (nih) guidelines, we reviewed and classified the articles based on their study designs into different levels of evidence. we included all studies on prostate cancer in nigeria with either the full article or abstract having adequate information on the methodology of the study and excluded those with insufficient details. information extracted from studies include the year of publications, study design, and level of evidence. studies selected were grouped into five levels of evidence according to the oxford centre for evidencebased medicine classification (ocebm levels of evidence working group et al. 2011). metaanalyses were not considered in the review due to varying study designs and difficulty in pooling them together. evidence synthesis during our search we identified 302 publications, 106 duplicates were removed and 25 were excluded based on inadequate information on the methodology of the study. a total of 171 articles were eligible for this review. most studies published were cross sectional studies (56%), followed by cohort studies (15%), laboratory studies(13% ), case reports (7%), expert opinion (3%), systematic reviews (2%) and meta-analysis (1%). there were no clinical trials on prostate cancer in nigeria seen or registered on clinicaltrials.gov or other clinical trials registries (figure 2). figure 2: types of study designs on prostate cancer in nigeria based on levels of evidence, most studies (66%), were at level 4a of evidence (figure 3). these include case reports, case series, and cross-sectional studies. seventeen percent of studies were at the level 5a evidence levels, including laboratory studies and expert opinion. nine percent of the studies were at level 2b of evidence, which included cohort studies, 5% at level 3b of evidence including casecontrol 1 3 0 0 25 8 95 12 5 22 meta-analysis systematic reviews randomised clinical trials non randomised clinical trials cohort studies case-control studies cross-sectional studies case reports/ case series background information/expert opinion animal research/lab studies types of study designs www.companyofscientists.com/index.php/chd e5 cancer health disparities research studies, whilst levels 2c and 2a constituted 2% and 1% respectively. there were no studies at level 1 (a, b or c) of evidence (systematic reviews with homogeneity of randomised clinical trials, individual randomised clinical trials and all or none studies). figure 3: levels of evidence on prostate cancer research in nigeria most studies were published in 2017 (29 publications were identified that year), followed by 2012, 18 publications, 2013, 2014 and 2015 had 11, 12 & 13 publications respectively (figure 4). 0 20 40 60 80 100 120 1a 1b 1c 2a 2b 2c 3a 3b 4a 5a levels of evidence on prostate cancer www.companyofscientists.com/index.php/chd e6 cancer health disparities research figure 4: showing number of publications per year discussion this study demonstrates the paucity of high level evidence research in prostate cancer in nigeria. it showed that the commonest study design in prostate cancer research conducted in nigeria is the cross-sectional study. although, this design can rapidly generate data on some health-related events, it may however be plagued with different types of bias (sedgwick 2014). cross sectional studies can be used to generate a hypothesis and establish an association but not causation. most researchers in nigeria adopt this methodology because cross sectional studies are relatively cheap and easy to conduct, especially in a low-resource environment where the financial and personnel costs are lower than that required for higher level and more informative studies. there are very limited funding avenues available for research in nigeria. studies at higher levels of evidence, like clinical trials, are more rigorous, require higher levels of expertise and are capital intensive. however the benefits of this type of study remain numerous, including their ability to establish causation, assess impact of an intervention and develop treatment guidelines to improve treatment outcomes and survival. (christensen et al. 2007) 0 5 10 15 20 25 30 35 1975 1977 1979 1981 1983 1985 1987 1989 1991 1993 1995 1997 1999 2001 2003 2005 2007 2009 2011 2013 2015 2018 year of publication www.companyofscientists.com/index.php/chd e7 cancer health disparities research in nigeria, there are limited efforts to foster high level biomedical research. these efforts are often led by established consortia focused on specific research goals. for example, the prostate cancer transatlantic consortium (captc), established in 2005, has supported prostate cancer research in nigeria since 2006 (https://epi.grants.cancer.gov/ captc/) . captc is a national cancer institute (nci) epidemiology and genomics research program (egrp) supported consortium. captc has over 150 members who are prostate scientists, clinicians, and consumer advocates from countries connected by the transatlantic slave trade, including north america, europe, the caribbean, and africa countries. captc investigators collaborate on projects based on the following scientific aims: 1. explore and quantify the magnitude of prostate cancer morbidity and mortality variance among black men of african ancestry; 2. explore genetic, environmental and behavioral etiology of this variance; and 3. develop community-sensitive initiatives to control prostate cancer globally. the official scientific conference for the captc is the biennial science of global prostate cancer conference for black men, which was held in jacksonville (usa) in 2010, nassau (bahamas) in 2012, montego bay (jamaica) in 2014, orlando (usa) in 2016, and will be held in ilorin (nigeria) in 2018. other active consortia in nigeria are the african colorectal cancer group (argo), the men of african descent and carcinoma of the prostate (madcap), and breast cancer consortium. the commonest level of evidence of prostate cancer in this review is level 4, which includes: the case reports, case series, and cross-sectional studies. these levels of evidence are relatively low and are less likely to be adopted in developing treatment guidelines. most international treatment guidelines are developed based on level 1 evidence, clinical trials. they analyse results from these clinical trials conducted on prostate cancer patients in their countries and then adapt them in the development of treatment guidelines. an example is the stampede trial in the uk (james et al. 2015) which has led to changes in the standard of care of prostate cancer patients in the uk another is the chattered trial (sweeney et al. 2015), a similar clinical trial as the stampede, which was conducted in the usa. clinical trials have always sharpened the paradigms of treatment internationally. the study showed a steep increase in publications on prostate cancer in nigeria from the year 2000 to date. despite this increase the proportion remains very low when compared to prostate cancer studies in other countries. the highest number of publications was published in 2017, when a total of 29 articles were published on prostate cancer. when compared with other parts of the world, the usa and uk uniquely had over 300 publications on prostate cancer on pubmed search engine in 2017. a major reason for low levels of prostate cancer research in nigeria is the low funding available for cancer research from public and private agencies/organizations. a major funding channel for research in nigeria is the tertiary education trust fund (tetfund) established under the tetfund act (tertiary education trust fund) in 2011. tetfund gets the funding by imposing a 2% education tax on all registered companies in nigeria. the fund is disbursed to tertiary educational institutions at federal and state levels as research grants in all fields (tetfund 2014). www.companyofscientists.com/index.php/chd e8 cancer health disparities research however, the rising trend of cancers in nigeria necessitates an increase in cancer research funding as exemplified by developed countries. developed countries have several funding channels for research. these include government funding and, non-governmental organisations and charities. in the united states, the 2017 budget allocated $33.1 billion (0.8%), out of the $4.2 trillion to the national institute of health to accelerate groundbreaking research on cancer, precision medicine and others (sargent et al. 2017). in the uk, the total investment is £26.3 billion between 2016/17 to 2020/21 with an average of £5 billion pounds yearly as allocations for the science and research in the budget (hm government 2016). it is therefore not surprising that prostate cancer survival has improved in both united states and uk. to make significant leap in fighting prostate cancer in nigeria, there needs to be focus on funding prostate cancer research. while it will greatly help to have governmental funding, corporate and philanthropic giving will also be very important. in september 2005, the foundation for carcinoma of the prostate transatlantic research was established to accelerate prostate cancer research in nigeria. this foundation is a step in the right way to raise the profile of prostate cancer research in nigeria. conclusion prostate cancer research is currently at low levels of evidence in nigeria. as stated by prof. folakemi odedina, “actionable research is key to defeating prostate cancer” (nigerian guardian, july 8, 2017). prostate cancer researchers should make efforts to conduct and publish more studies especially at higher levels of proof like rcts and metanalysis/systematic reviews of rct as well as develop treatment guidelines for patients based on these higher levels of evidence. it is also pertinent that the nigerian government increases its efforts in providing the support needed on funding cancer-related research. the nigerian government should also develop and implement policies related to increasing cancer research funding through governmental grants. finally, there needs to be increase in corporate funding and philanthropic funding for prostate cancer research. acknowledgements we acknowledge ms. kimberly meza for her editorial review conflict of interest the authors declare that no competing or conflict of interests exists. the funders had no role in study design, writing of the manuscript, or decision to publish. authors’ contributions o.a.f, a.c.s & f.b did the manuscript writing and design. o.i, o.o, a.a did the data extraction and literature search. f.c, n.d, f.o supervised the project. references adeloye, davies, rotimi adedeji david, adewale victor aderemi, alexander iseolorunkanmi, ayo oyedokun, emeka e.j. iweala, nicholas omoregbe, and charles k. ayo. 2016. ‘an estimate of the incidence of prostate cancer in africa: a systematic review and meta-analysis’. plos one 11 (4). https://doi.org/10.1371/journal.pone. 0153496. brawley, otis w. 2012. ‘trends in prostate cancer in the united states’. journal of the national cancer institute monographs, no. 45: 152–56. https://doi.org/10.1093/ 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vijayakumar. 2016. ‘do african-american men need separate prostate cancer screening guidelines?’ bmc urology 16 (1). https://doi.org/10.1186/s12894-0160137-7. sweeney, christopher j., yu-hui chen, michael carducci, glenn liu, david f. jarrard, mario eisenberger, yu-ning wong, et al. 2015. ‘chemohormonal therapy in metastatic hormone-sensitive prostate cancer’. new england journal of medicine 373 (8): 737–46. https://doi.org/10.1056/nejmoa1503747. tetfund. 2014. ‘guideline for accessing tetfund national research fund tertiary education trust fund ( tetfund ) publication’, 1–53. www.companyofscientists.com/index.php/chd e1 cancer health disparities research mammography utilization trends at a safety-net center bridget a. oppong1,2,3, chiranjeev dash1,3, kepher h. makambi4, xiaoyang ma4, holly s. greenwald5, lucile adams-campbell*,1,3 1. georgetown university lombardi comprehensive cancer center, washington d.c. 20057, usa 2. department of surgery, reston hospital center, reston, va (current mailing address), 20190, usa 3. capital breast care center, georgetown lombardi comprehensive cancer center, washington d.c., 20003, usa 4. department of biostatistics, georgetown lombardi comprehensive cancer center, washington d.c., 20003, usa 5. uc san diego, dept. of internal medicine, san diego, ca, 92093, usa *corresponding author email: lla9@georgetown.edu abstract among uninsured and resource-poor populations, community safety net clinics are important providers of breast cancer screening services however there is little data on screening utilization patterns. using data from a safety net screening center in washington dc, we assessed trends in mammography utilization by selected sociodemographic factors. prospectively collected demographic data were abstracted from the electronic medical records of the capital breast care center (cbcc) during 2010 – 2015. time trends of mammography utilization over the 6 years were calculated and statistical significance of the differences between trends by the selected sociodemographic factors were analyzed using the cochran-armitage test. 8448 black/ african-american and hispanic women were screened at cbcc with 106 diagnoses of breast cancer. the proportion of women <50 years of age declined over the 6year study period, decreased from 42% in 2010 to 35% in 2015 (p-value <0.0001). trends in the racial/ethnic composition of the women screened shifted, with african-american women decreasing, while the proportion of latina patients increased from 42% in 2010 to 51% in 2015 (p-value <0.0001). our data suggest a declining trend in screening among women less than 50 years of age, which may reflect a change in referring providers following guideline concordant screening recommendations. future studies are warranted to monitor and evaluate the changing effects of population and demographics and screening guidelines. keywords: mammography screening, safety-net, blacks, latinas, trends citation: oppong ba et al (2019) mammography utilization trends at a safety-net center. cancer health disparities 2:e1-e9 doi:10.9777/chd.2019.1010. www.companyofscientists.com/index.php/chd e2 cancer health disparities research introduction secondary prevention in the form of mammographic screening is recognized as an important strategy for reducing mortality from breast cancer (us preventative service task force, january 2016). mammography has been shown to reduce breast cancer mortality in women aged 50-69 years by as much as 30% (loberg et al., 2015; mandelblatt et al., 2016; myers et al., 2015; oeffinger et al., 2015). although controversial, younger women, ages 4049, have also been shown to benefit from mammography with reduced breast cancer mortality (moss et al., 2006; nelson et al., 2009). a healthy people 2010 goal set by the u.s. departments of health and human services was at least 70% of women 40 and over to have received a mammogram within the last two years while the 2020 goal seeks to increase this rate by a further 10% (plescia and white, 2013; sabatino et al., 2015). although such goals have been established, many reports suggest that black women undergo mammography less often, than white counterparts (brooks et al., 2013; komenaka et al., 2010; mishra et al., 2012; swan et al., 2003). a recent systematic review and meta-analysis of racial disparities in screening mammography shows that disparities in utilization of screening mammography are still evident in black and hispanic populations in the u.s.(ahmed et al., 2017). factors associated with decreased screening rates include lowsocioeconomic status, non-caucasian ethnicity, low education level, and recent immigration status (brooks et al., 2013; komenaka et al., 2010; mishra et al., 2012; swan et al., 2003). the diversity in prevalence and time trends of mammography screening with regards to socioeconomic status, education, reproductive history, within these minority groups have not been well described. access to mammography for low-resource communities is being addressed by communitybased initiatives, including mobile mammogram vehicles and screening facilities participating in the national breast and cervical cancer early detection program (nbccedp)(stanley et al., 2013). to meet this need in our nation’s capital, which has some of the most disparate breast cancer outcomes in the country (centers for disease control and prevention (cdc), 2012; desantis et al., 2011), the georgetown lombardi comprehensive cancer center established the breast care center (cbcc) in 2004. cbcc serves as a critical safety net breast cancer screening facility for minority and medically under-insured women hailing from dc, maryland and virginia. cbcc traditionally serves a population that is majority black and hispanic, and on the younger spectrum of the recommended screening age (oppong et al., 2016; wallington et al., 2016). utilizing data from cbcc, we evaluated mammography screening patterns and time trends by sociodemographic characteristics in a population of primarily black and hispanic women who received breast cancer screening between 2010 and 2015. materials and methods the study population is derived from cbcc, which serves as a safety net for under and un-insured, and medically underserved women residing in dc, maryland and virginia. the data were abstracted from january 2010 to december 2015 with approval from the institutional review board at georgetown university. women presenting to the cbcc within screening age (40 or older) proceed to mammography. www.companyofscientists.com/index.php/chd e3 cancer health disparities research women who require additional workup are assigned a patient navigator, who facilitates the diagnostic evaluation with further imaging or biopsies. all women presenting for screening have their information prospectively collected and entered into the electronic medical record system (emr). the results of the screening test are entered into the emr. variables collected include demographic data (including, race, ethnicity, highest education attainment level and ward of residence), insurance status, family history of breast cancer, and menopausal status. the imaging results were recorded with standard breast imaging reporting and data system (birads) category values (markossian et al., 2012). out of a total of 20,959 screening and diagnostic exams, data on women undergoing screening mammograms were abstracted from january 2010 to december 2015 with approval from the institutional review board at georgetown university. women who present to cbcc but did not receive a screening mammogram (i.e. they had an abnormal physical exam and required a diagnostic mammogram) were not included in the study. electronic medical record data abstraction (emr) we abstracted the density description recorded at the first screening mammogram for each woman. statistical methods patient characteristics were presented as frequencies and corresponding proportions for variables including age (<50 years, >50 years), race (black/african american, hispanic), insurance (commercial, bccp/medicaid program/medicare), residence state (dc, md/va), education (did not complete hs, completed hs and above), family history of breast cancer (no/yes), menopausal status (no/yes). cochran-armitage test was used to examine the significance of trends in the proportions of screening across years (between 2010 and 2015) by categories of several characteristics including age, race, insurance, residence state, education, and family history of breast cancer. all tests were two-sided and significance was assessed at 0.05 level. results a total of 8,448 women underwent mammographic screening at cbcc from january 2010 to december 2015. the characteristics of the population are shown in table 1. there were significant trends for age, race, and residence. the trend in screening mammography increased for older (58% to 65%) compared to younger women who decreased from 42% in 2010 to 35% in 2015 (p-value <0.0001). there was also a trend in the racial/ethnic composition of women screened with the proportion of latinas increasing and african americans decreasing (p-value <0.0001). the number of d.c. residents also decreased as more patients traveled from maryland and virginia to obtain breast cancer screening (p-value <0.0001). there was no significant change in the uninsured population, with 13-19% annually having private commercial insurance. this shows an unchanging reliance on the national breast and cervical cancer early detection program (nbccedp) for the remainder of women screened who have medicaid and medicare. furthermore, over the 6year period there were no differences in those screened having a family history of breast cancer and reported menopausal status. about 45% of the patients seen each year over this period were new patients who did not have a previously reported mammogram at cbcc. there was no significant trend in the proportion of new patients seen between 2010-2015. www.companyofscientists.com/index.php/chd e4 cancer health disparities research table 1. characteristics of women presenting for screening mammography at cbcc, 2010-2015. 2010 2011 2012 2013 2014 2015 p* total patients 1429 1584 1596 1364 1056 960 age (years) <50 578(42) 663(43) 641(41) 525(40) 362(36) 306(35) <0.0001 >=50 814(58) 895(57) 915(59) 800(60) 650(64) 580(65) race black/african american 770(58) 765(54) 731(51) 595(48) 488(52) 424(49) <0.0001 hispanic 548(42) 646(46) 713(49) 640(52) 456(48) 441(51) insurance commercial 203(16) 216(17) 175(13) 185(15) 152(16) 162(19) 0.23 bccp/medicaid program/medicare 1058(84) 1080(83) 1178(87) 1064(85) 804(84) 681(81) residence state dc 746(54) 768(49) 667(43) 516(39) 450(45) 392(44) <0.0001 md/va 643(46) 788(51) 889(57) 809(61) 561(55) 494(56) education did not finish hs 385(30) 447(31) 456(31) 371(29) 296(31) 266(31) 0.52 complete hs and above 919(70) 985(69) 1003(69) 894(71) 645(69) 579(69) family history of breast cancer no 1167(84) 1272(84) 1314(85) 1135(84) 865(84) 794(83) 0.64 yes 225(16) 234(16) 234(15) 220(16) 163(16) 159(17) menopausal status no 642(46) 722(47) 767(49) 677(50) 487(47) 443(46) 0.47 yes 767(54) 816(53) 793(51) 683(50) 548(53) 512(54) *p value from cochran-armitage test the trends in proportion of women with benign screening mammography, bi-rads 1 findings are presented in table 2. although the proportion of women with normal findings decreased from 2010 to 2015, trends were not statistically different by age, race/ethnicity, state of residence, insurance status, family history or menopausal status. table 2. trends in proportions of women with normal (bi-rads 1) screening mammography findings at cbcc. 2010 2011 2012 2013 2014 2015 total patients 848 (0.59) 904 (0.57) 931 (0.58) 843 (0.62) 530 (0.50) 478 (0.50) age <50 years 0.67 [0.63,0.71] 0.64 [0.6,0.67] 0.66 [0.62,0.69] 0.68[0.64,0.72 ] 0.58 [0.53,0.63] 0.57[0.52,0.63 ] >=50 years 0.54 0.52 0.53 0.58 0.46[0.42,0.5] 0.43 www.companyofscientists.com/index.php/chd e5 cancer health disparities research [0.51,0.58] [0.49,0.56] [0.5,0.56] [0.54,0.61] [0.39,0.47] race black/african american 0.56 [0.53,0.6] 0.55 [0.52,0.59] 0.57 [0.54,0.61] 0.60 [0.56,0.64] 0.47 [0.42,0.51] 0.48 [0.43,0.52] hispanic 0.63 [0.59,0.67] 0.58 [0.54,0.62] 0.58 [0.54,0.62] 0.62 [0.59,0.66] 0.53[0.48,0.57 ] 0.50 [0.45,0.55] insurance commercial 0.67 [0.61,0.74] 0.59[0.52,0.65 ] 0.66 [0.59,0.73] 0.63 [0.56,0.7] 0.50 [0.42,0.58] 0.49 [0.41,0.56] bccp/medicaid program/medicare 0.57 [0.54,0.6] 0.57 [0.54,0.6] 0.57 [0.54,0.59] 0.62 [0.59,0.65] 0.51 [0.47,0.54] 0.48 [0.44,0.51] residence state dc 0.58 [0.54,0.62] 0.54[0.51,0.58 ] 0.58[0.54,0.6 2] 0.62 [0.58,0.66] 0.45 [0.41,0.5] 0.46[0.41,0.51] md/va 0.61[0.58,0. 65] 0.60[0.56,0.63 ] 0.58 [0.55,0.61] 0.62 [0.58,0.65] 0.54 [0.5,0.58] 0.50 [0.46,0.55] education did not finish hs 0.59 [0.54,0.64] 0.56 [0.51,0.6] 0.56 [0.51,0.6] 0.59 [0.54,0.64] 0.49 [0.44,0.55] 0.45[0.39,0.51 ] complete hs and above 0.60[0.57,0. 63] 0.57[0.54,0.6] 0.59[0.56,0.62 ] 0.63[0.6,0.66] 0.50[0.46,0.5 4] 0.51 [0.47,0.55] family history of breast cancer no 0.60[0.57,0. 62] 0.58[0.55,0.6] 0.58 [0.55,0.6] 0.62 [0.59,0.65] 0.50 [0.47,0.53] 0.51 [0.47,0.54] yes 0.59 [0.52,0.65] 0.55 [0.48,0.61] 0.59 [0.52,0.65] 0.59[0.53,0.66 ] 0.49 [0.41,0.57] 0.46 [0.38,0.54] menopausal status no 0.64[0.61,0. 68] 0.64[0.6,0.67] 0.63[0.6,0.67] 0.66 [0.62,0.69] 0.56 [0.51,0.6] 0.55 [0.5,0.59] yes 0.55 [0.51,0.58] 0.51 [0.48,0.54] 0.53 [0.49,0.56] 0.58 [0.54,0.62] 0.45 [0.41,0.49] 0.45 [0.41,0.49] of the 106 cancers diagnosed over 6 years, there were no statistically significant trends in age, race/ethnicity, insurance status, or family history of breast cancer (table 3). although a higher proportion of the cancer cases were in black women over 50, there was no statistically significant time trend by age at diagnosis. the number of cancer cases diagnosed in women residing in maryland and virginia increased from 2010-2015, while those in dc residences declined (p-value 0.04) www.companyofscientists.com/index.php/chd e6 cancer health disparities research table 3. trends analysis of cancer patients diagnosed 2010-2015. year of screening p* 2010 2011 2012 2013 2014 2015 total patients 19 16 10 22 20 19 age <50 years 8 (42) 6 (38) 3 (30) 8 (36) 8 (40) 7 (37) 0.86 >=50 years 11 (58) 10 (63) 7 (70) 14 (64) 12 (60) 12 (63) race black/african american 13 (76) 11 (73) 6 (67) 7 (44) 11 (65) 10 (63) 0.24 hispanic 4 (24) 4 (27) 3 (33) 9 (56) 6 (35) 6 (38) insurance commercial 5 (29) 1 (8) 1 (10) 5 (23) 3 (16) 6 (32) 0.68 bccp/medicaid program/medicare 12 (71) 11 (92) 9 (90) 17 (77) 16 (84) 13 (68) residence state dc 11 (58) 8 (50) 4 (40) 9 (41) 6 (30) 6 (32) 0.043 md/va 8 (42) 8 (50) 6 (60) 13 (59) 14 (70) 13 (68) family history of breast cancer no 15 (83) 10 (63) 9 (90) 17 (81) 17 (85) 14 (78) 0.69 yes 3 (17) 6 (38) 1 (10) 4 (19) 3 (15) 4 (22) *p value from cochran-armitage test discussion main finding of this study our results showed a significant trend in the decline in the screening of women less than 50 years of age over the study period. this may represent a change in the screening guidelines followed by the local referring physicians and partnering community organizations, especially with the varied recommendations from the us preventative task force and other organizations such as the american cancer society (us preventative service task force, january 2016; loberg et al., 2015; oeffinger et al., 2015). during the study period, cbcc followed the screening recommendations consistent with the american cancer society and the national breast and cervical cancer early detection program (nbccedp) offering annual mammography starting at age 40. another demographic shift is an increase in hispanic patients from 42% to 51% from 2010 to 2015, a trend that is statistically significant. a related observation is the increase in maryland and virginia residents among the women screened. in the washington metropolitan area, the largest immigrant groups are from latin america (u.s. census bureau, dec. 12, 2012), with many living outside dc proper. over the past three years, cbcc outreach efforts have increased in the latino community with the hiring of spanish speaking health educators and patient navigators. www.companyofscientists.com/index.php/chd e7 cancer health disparities research extending our community reach is likely contributing to our observations. in this climate of healthcare change, it is interesting that we did not see any trends representing changes in the proportion of women having commercial insurance coverage. the affordable care act (aca)(meyer et al., 2017; silva et al., 2017) was implemented in 2014 and this study does not show a decline in the uninsured population. most of the cbcc population remains covered by medicare, medicaid and the nbccedp in conjunction with other state and local screening programs. funding from these programs are integral in providing screening for the under and uninsured. as we collect more data under the aca, shifts in the coverage landscape will undoubtedly impact the uninsured women. what is already known results from our study underscore the importance of community based clinics in increasing cancer screening uptake among underserved communities. to provide access to mammography for lowresource populations, community-based initiatives utilize mobile mammogram vehicles and screening facilities that participate in the national breast and cervical cancer early detection program (nbccedp) (stanley et al., 2013). in order to do this effectively, the community that is served has to be evaluated on a continuing basis to ensure adequate outreach. as minority communities evolve and demographics shift, such program evaluations can direct resource allocation and outreach targets. limitations at the cbcc our database instituted in 2010 has enabled data analyses for program evaluation. this established emr, however does have limited variables which in turn limits our analyses of trends to only the available collected factors [age, race, insurance, residence state, education, and family history of breast cancer]. to enhance our data, variables including, ethnicity or country of origin, having a primary care physician, primary spoken language, access to transportation or how a woman arrived at the facility would be desirable. furthermore, the demographic data is based on patient report with accuracy unable to be confirmed. an example is, omitted or misrepresented information from some undocumented patients who may be uncomfortable giving some specific details such as place of residence. we also present the completed data over a 6-year period and for a trends analysis a longer period of time would make our observation more robust and increase accuracy. what this study adds the data reported here exemplify demographic changes in a dynamic screening population and the ongoing evaluation and assessments needed to identify such changes. in addition, our data also underscores the importance of changes in community outreach and support services within the organization to effectively provide cancer screening and prevention services to a changing population. over the past few years there has been an increase in hispanic women and maryland and virginia residents seeking cbcc’s services in our catchment area. monitoring these trends has guided our increased outreach efforts in the latina community and in communities in maryland and virginia which are part of the georgetown lombardi cancer center’s catchment area. the enhanced outreach in the latina community has been facilitated by increased access to spanish language education materials and interpretation services; and new partnerships with community-based organizations that provide an array of services for hispanic women. this ensures breast cancer screening services are www.companyofscientists.com/index.php/chd e8 cancer health disparities research available to those in need and that the outreach is done in a culturally sensitive manner. our data suggest a declining trend in screening among women less than 50 years of age, which may reflect a change in referring providers following guideline concordant screening recommendations. now that there are recent changes in mammography screening guidelines, we expect these trends to change in coming years. future studies are warranted to monitor and evaluate the changing effects of population and demographics and screening guidelines. acknowledgements avon foundation for women grant #05-2017-008. conflict of interest the authors declare that no competing or conflict of interests exists. the funders had no role in study design, writing of the manuscript, or decision to publish. authors’ contributions bao, cd, hsg and lac conceived of the presented idea. cd, khm and xm developed the theory and performed the computations. cd and khm verified the analytical 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(2003). progress in cancer screening practices in the united states: results from the 2000 national health interview survey. cancer 97, 1528-1540. u.s. census bureau (dec. 12, 2012). u.s. census bureau projections show a slower growing, older, more diverse nation a half century from now. us preventative service task force (january 2016). final update summary: breast cancer: screening. wallington, s., oppong, b., dash, c., coleman, t., greenwald, h., torres, t., iddirisu, m., and adams-campbell, l.l. (2016). a community-based outreach navigator approach to establishing partnerships for a safety net mammography screening center. j. cancer educ. www.companyofscientists.com/index.php/chd e1 cancer health disparities research overcoming barriers in conducting a transatlantic prostate cancer familial study in africa: best practice from the captc cohort study iya e. bassey*1,2, theophilus i. ugbem1,2, uwem o. akpan1,2, stanley o. anyanwu1,2, enakirerhi e. glen 1,2, rebecca m. gali 1,3 , catherine a. oladoyinbo 1, 4, abidemi omonisi1,5, getachew dagne 1,6, ernest t. kaninjing1,8, nissa a. askins 1,7, motolani e. ogunsanya1,9 , mohammed faruk1, 10, ademola a. idowu1, 11, 1captc investigators, folakemi t. odedina 1,7 1 prostate cancer transatlantic consortium 2 university of calabar calabar, nigeria; 3 university of maiduguri, maiduguri, nigeria; 4 federal university of agriculture, abeokuta, nigeria; 5 ekiti state university, nigeria; 6 university of south florida, florida, usa; 7 university of florida, florida, usa; 8georgia & state university, milledgeville, usa; 9 university of oklahoma health sciences center, oklahoma, usa; 10 ahmadu bello university, zaria, nigeria; 11 ekiti state university teaching hospital, ado-ekiti, nigeria *corresponding author: iya eze bassey, email: iyantui@yahoo.com abstract conducting prostate cancer research, especially prospective data collection in africa, has numerous challenges. some of the difficulties stem from socio-cultural factors that consider sensitive topics about men’s health as taboo. our primary aim was to determine how to overcome barriers in conducting a transatlantic prostate cancer familial study in african males. key research personnel of the captc transatlantic prostate cancer familial project were surveyed about their experiences in implementing the study. a mixed-method approach was used for the study analysis and data interpretation. the quantitative data from the survey was analyzed using spss version 18 while the qualitative data was analysed based on the principles of grounded theory for emerging themes. a total of 15 key study personnel responded to the survey. about 73% of the respondents reported that the participants requested a home or office visit rather than visit a data collection center. eighty percent (80%) of the respondents reported that the participants had no preference for interviewer gender. the majority (80%) of the interviewers agreed that answers to questions about participants’ sexuality were most challenging to obtain, but with an in-depth explanation of the importance of the study and assurance of privacy, the answers were obtained. the best practice for engaging the community for research include community mobilization through sensitization visits and one-on-one talks, use of community ‘gatekeepers’, introduction by relatives, assurance of privacy of health data obtained, the use of incentives and a promise to give feedback on the results of the study both on a personal and community level. keywords: prostate cancer, community-engagement research, black men, nigerian men. citation: bassey, et al. (2019) overcoming barriers in conducting a transatlantic prostate cancer familial study in africa: best practice from the captc cohort study. cancer health disparities 4: e1-9. doi:10.9777/chd.2019.1001 mailto:iyantui@yahoo.com www.companyofscientists.com/index.php/chd e2 cancer health disparities research introduction in a typical african society, discussion of men's sexual health is not a common practice as most men feel very uncomfortable sharing sexual experiences with researchers. this may be attributed to the need to maintain social status, family respect, spiritual integrity and other cultural factors that men consider sensitive topics about men’s health as taboo (olapade-olaopa et al., 2014). this, therefore, poses a significant challenge to conducting research on african men’s sexual and prostate health. prostate cancer research in africa is growing and has become multifaceted because it has become the number one cancer in men with increasing incidence and morbidity in black men of african ancestry (akinremi et al., 2011). patients often present at a late stage with complications and an earlier age compared to several other ethnic groups (akinremi et al., 2014). there are several unknowns about prostate cancer risk factors that are specific to black africans. although some similarities have been documented between native african and united states (us) african-american men, there are also significant differences (odedina et al., 2006). still, there is a dearth of research data in africa on prostate cancer (okuku et al., 2016). so it has, therefore, become imperative that comprehensive research on prevention, early diagnosis, identification of behavioral risk and predisposing factors to prostate cancer as well as health-seeking behaviors of the african men be carried out. the captc transatlantic prostate cancer familial cohort project in 2017, the prostate cancer transatlantic consortium (captc), a us national cancer institute (nci)-supported consortium, implemented the transatlantic prostate cancer familial cohort project. this ongoing project focuses on studying 2,000 west african men. the primary objective of the project is to explore the contributions of behavioral, environmental, and genetic factors in the etiology of prostate cancer among men of west african origin. the study design for the captc west africa familial cohort study was a cross-sectional prospective study design. study participants were black men of nigerian or cameroonian origin who lived in nigeria, cameroon, or the us. the inclusion criteria for the study were: men of west african origin regardless of a history of prostate cancer; between 35 and 70 years old; and men who provided consent to complete the study survey and provided saliva samples. using flyers, the participants were recruited in different parts of the selected countries at some settings which included clinics, and wide-ranging community settings such as town hall meetings, eateries, churches, mosques, as well as health events. before data collection, ethical clearance was obtained for each study site in nigeria, cameroon and the us. the coordinating center for the study was the university of florida in usa. participating institutions are ahmadu bello university, university of calabar, covenant university, ekiti state university, federal university of agriculture abeokuta, lagos state university teaching hospital, university of maiduguri, national hospital abuja, ace medicare clinics limited, university of ilorin, and lagos university teaching hospital in nigeria. the participating institution in cameroon was the university hospital center yaounde in cameroun. written informed consent was obtained from all the eligible participants before www.companyofscientists.com/index.php/chd e3 cancer health disparities research they were allowed to participate in the study. the participants completed the survey instrument by self-administration or were assisted by a research assistant using the study instrument. english, french or west africa pidgin english were the languages used to administer the survey. all participants were given an incentive of either a tshirt or a monetary incentive tailored to the study sites. implementing this study at multiples sites, especially in west africa, required overcoming several challenges. the specific aim of this study was to explore these challenges and determine best practices on how to overcome barriers in conducting a transatlantic prostate cancer familial study in west africa. methodology this project focused on developing best practices for conducting field research for prostate cancer in africa. thus, the study participants were the data collectors of the transatlantic prostate cancer familial cohort project, including principal investigators, investigators, research coordinators and research assistants in nigeria and cameroon. a structured survey was developed by investigators to collect data from participants. the survey is provided in appendix i. the items in the survey include: questions on sensitization visits and the methods used; the subjects preference for going to the data collection center for interviews or requesting for a personal visit; the average time it took to fill one questionnaire; participants preferences as pertained to interviewer gender; what questions the participants felt most uncomfortable answering; peculiar challenges the interviewers had while collecting data, how they overcame them, suggestions for best practices; interviewers suggestions for the best way to engage your community for research; and the best ways to appropriately disseminate results back to participants. the survey was administered on qualtrics software. the link to the survey was sent to participants by email. the study data were analyzed using spss version 18. descriptive analyses were used to summarize quantitative data. for the qualitative data, emerging themes were identified from the responses of participants. results a total of 15 key personnel participated in the study. they were from ahmadu bello university, university of calabar, covenant university, ekiti state university, federal university of agriculture abeokuta, university of maiduguri and university of ilorin. responses of data collectors to survey questions about 73% percent of the data collectors had to carry out pre-data collection sensitization visits. seventy-three percent of the interviewers also reported that participants requested a home or office visit rather than visit a data collection center. the questionnaire required an average of two hours of personal interview. however, the respondents declared that participant incentives were well worth it. about 80% of the participants had no preference for interviewer gender. results showed that 80% of the interviewers agreed that answers to questions about participants’ sexuality were most difficult to obtain, but with an in-depth explanation of the importance of the study and assurance of privacy, the answers were obtained. about 46% of the participants requested that their www.companyofscientists.com/index.php/chd e4 cancer health disparities research results be typed and given to them personally, 21% requested results be sent as to them as text messages, while 26% requested general results of the study be made available to them in the form of booklets, flyers and orally in town hall meetings. the results are summarized in table 1. table 2 shows the challenges faced while collecting data and successful approaches used by the data collectors to overcome them. complaints about the bulkiness of the questionnaire. this was the most frequent challenge reported by the data collectors (n = 6). below are typical responses made by the respondents: “the clients complained of the time taken to respond to the questionnaires.” “there was difficulty in filling the questionnaire because of the volume.” this challenge was overcome by initial education about and an in-depth explanation of the importance of the study. also, the use of incentives and assurance that the results will be communicated back to them both on a personal and community level also helped to overcome this challenge. time taken to fill questionnaires this was another challenge reported by the data collectors (n = 4). this is exemplified by the statements below: “the clients complained of the time taken to respond to the questionnaires.” “finding a time that works best for the participant given that it took about 2.5 hours on average to complete the survey”. some of the measures taken to tackle this challenge included making the data collector’s schedule more flexible to allow for the convenience of the participants and sometimes the session had to be divided into 2 timeframes. complaints about the personal nature of questions in the questionnaire. the personal nature of questions in the questionnaire posed a challenge to some data collectors (n = 2) as exemplified by these statements: “they also felt the questions were a bit too personal.” “the clients complained and said some of the questions are irrelevant.” assurance of privacy of their health information as well as an emphasis on the importance of the study were some of the ways used to tackle this problem. lack of knowledge of ancestral medical history one of the respondents complain about the participants “lack of knowledge of ancestral medical history” as a setback, which resulted in longer time being spent. suggestions for presentation of results obtained from the study several of the respondents had different suggestions which included giving personal feedback either as typed reports or text messages delivered to them personally and confidentially by the data collectors as exemplified by these comments. www.companyofscientists.com/index.php/chd e5 cancer health disparities research “the result should be disseminated back personally to the participants in the presence of a health professional.” “phone numbers of the respondents through each respondent data collector.” “ideally, the results should be typed and formally presented and reviewed with the clients by a medical expert, who can interpret the findings.” however, some also suggested that public feedback be given as booklets, flyers or oral communications through the community gatekeeper or town hall meetings as supported by these sample statements “go back to those communities where you collected data, work with the community leader or gatekeeper who helped you gain access to participants and schedule a forum in which you can disseminate the outcome. another alternative is to provide publication of the study to the community at large”. table 1. responses of data collectors to survey questions. variable response n (%) p-value did you carry out sensitization visits? yes 11(73.3) no 4(26.6) 0.012 participants choice of venue for data collection data collection center 4(26.6) home or office visit 11(73.3) 0.012 length of time for filling the questionnaire ≤2hrs 12(80) >2hrs 3(20) 0.001 did participants have a preference or request for male interviewers? yes 3(20) no 12(80) 0.001 what questions did the participants find most difficult to answer in the questionnaire? questions bordering on sexuality and history of sexually transmitted diseases 14(93.3) no response 1(6.7) 0.0001 what are your suggestions for presentation of results obtained from the study? typed and personally delivered to be sent as text messages results of the study should be available as booklets, flyers etc. 7 (46.7) 3 (20) 4 (26) table 2. challenges faced while collecting data and successful approaches used by the data collectors to overcome them. challenges (n) successful approaches to overcome them complaints about the bulkiness of the questionnaire (6) initial education about and an in-depth explanation of the importance of the study use of incentives. assurance that the results will be communicated back to them both on a personal and community level. time taken to fill questionnaires (4) the flexibility of the data collector’s schedule to allow for the convenience of the participants sometimes the session had to be divided into 2 timeframes www.companyofscientists.com/index.php/chd e6 cancer health disparities research complaints about the personal nature of questions in the questionnaire (2) assurance of privacy of their health information. lack of knowledge of ancestral medical history (1) exercising patience while waiting for them to remember or confirm with other relatives discussion to overcome the initial resistance to recruitment and educate the participants about the benefits of the study, pre-data collection sensitization visits are necessary. this involves various approaches including one-on-one visits, rallies, group talks, distribution of flyers, and use of community ‘gatekeepers’ as well as referrals by close relatives trusted by the participants. neglecting to do this may result in apathy by prospective participants towards the study. this approach was found very useful by woods et al. in their study. they noted that 53.1% of the participants in their study were recruited in community settings, whereas 46.9% were recruited in healthcare settings. they also reported that one-onone recruitment resulted in an immediate 100% increase in client contact and enrollment (wood et al., 2004). a study by enaworu and khutan (2016) also stressed the importance of involvement of family members and friends as a contributing factor to them seeking medical advice; as informal support systems may be a critical part in the decision-making process of men (jones et al. 2010). it is therefore important for researchers to understand the type of support networks that may influence african men’s decision to participate in this type of research. that most participants requested a home or office visit rather than visit a data collection center may have been due to the participants need for privacy or a need to avoid being labeled and probably stigmatized for identifying with a study involving the prostate. this finding is in concordance with findings by barber et al., who studied the differences between black and white men regarding participation in prostate cancer screening and found out that black men were twice as likely to choose a private appointment over mass screening. they also observed that black men tended to participate in preventive activities when they received personal attention (barber et al., 1998). the longer duration for a personal interview (about twice the time envisaged) actually constituted a major barrier during the study, and this may have been due to the time taken to explain the questions in the booklet as well as convincing the participants about the need to answer questions they felt were too personal. it was also observed that some of the participants had difficulties remembering ancestral medical history. therefore, for future studies with similar aims to succeed, the data collectors might consider being more flexible about the place and time of data collection and personal interviews. the use of participant incentives may also encourage participation as participants in the study declared that incentives, though not the primary motivating factor, were worth the time taken for the personal interview. woods et al., (2004) observed that changing to a more flexible schedule and the use of incentives resulted in a dramatic increase in subsequent enrollment. this was because it showed the participants that the researchers valued their input and time. contrary to what has been reported in several health-related studies (hinchliff et al. 2004; witty et al., 2014; hajizadeh et al., 2015; knight et al., 2017), most of the participants had no preference for www.companyofscientists.com/index.php/chd e7 cancer health disparities research interviewer gender. this may suggest progressiveness in how men view the role of female personnel in healthcare issues relating to men’s sexual health. the findings in our study are in concordance with those of another study in botswana by letshwenyo-maruatona, (2017) who reported that gender is of minor importance compared with other characteristics such as competence and confidentiality. the difficulty in obtaining answers to questions about participants’ sexuality and sexual health is a confirmation that discussions of african men’s sexuality or sexual history are not common. this may be attributed to the need to maintain social status, family respect, spiritual integrity, and cultural factors that consider sensitive topics about men’s health as taboo (olapade-olaopa et al., 2014). from the observations made in the study by the data collectors, it would seem that getting the results back to the participants personally would be a more effective tool in recruitment rather than giving general feedback. conclusion the transatlantic prostate cancer familial project study survey questionnaire is a very workable tool that has a high acceptance rate among participants. the best practice for engaging the community for research include community mobilization through sensitization visits and one-on-one talks, use of community ‘gatekeepers’, introduction by relatives, assurance of privacy of health data obtained, the use of incentives, and a promise to give feedback on the results of the study both on a personal and community level. acknowledgments funding support for this project was provided by the prostate cancer transatlantic consortium (captc). conflict of interest the authors declare that no competing or conflict of interests exist. the funders had no role in study design, writing of the manuscript, or decision to publish. authors’ contributions dr. folakemi t. odedina provided content and reviewed the final manuscript. iya e. bassey, abidemi omonisi, theophilus i. ugbem, uwem o. akpan, stanley o. anyanwu, enakirerhi e. glen, catherine a. oladoyinbo, ernest t. kaninjing mohammed faruk, ademola a. idowu wrote the initial draft. getachew dagne and nissa a. askins did the statistical data analysis. ernest t. kaninjing and rebecca m. gali reviewed the initial draft. motolani e. ogunsanya and iya e, bassey reviewed the initial draft and final manuscript. captc investigators provided the data used in the study references akinremi, t. o., ogo, c. n., & olutunde, a. o. (2011). review of prostate cancer research in nigeria. infectious agents and cancer, 6(suppl 2), s8. akinremi, t. o., adeniyi, a., olutunde, a., oduniyi, a. & ogo, c. n. (2014). need for and relevance of prostate cancer screening in nigeria. ecancer, 8,457. barber, k. r., shaw, r., folts, m., et al. (1998). differences between african american and caucasian men participating in a community-based prostate cancer screening program. journal of community health, 23, 441– 451. enaworu, o. u., & khutan, r. (2016). factors influencing nigerian men’s decision to undergo prostate specific antigen testing. african health sciences, 16(2), 524–532. hajizadeh, m., javadnoori, m. & javadifar n. (2015). educational needs of adult men regarding sexual and www.companyofscientists.com/index.php/chd e8 cancer health disparities research reproductive health in ahvaz, iran. journal of midwifery and reproductive health, 3(3): 385-393. hinchliff, s., gott, m. & galena, e. (2004). gps' perceptions of the gender-related barriers to discussing sexual health in consultations: a qualitative study. the european journal of general practice, 10:2, 56-60. ikuerowo, s. o., omisanjo, o. a., bioku, m. j., ajala, m. o., mordi, v. p. n., & esho, j. o. (2013). prevalence and characteristics of prostate cancer among participants of a community-based screening in nigeria using serum prostate specific antigen and digital rectal examination. the pan african medical journal, 15, 129. jones, r. a., steeves, r., & williams, i. (2010). family and friend interactions among african-american men deciding whether or not to have a prostate cancer screening. urologic nursing, 30(3), 189–166. knight, r., chabot, c., & shoveller, j. (2017). qualitative research with young men about sexual health. faculty research and publications. o. retrieved july 26, 2018, from https://open.library.ubc.ca/circle/collections/52383/ items/1.0363418 latreille s., collyer, a., & temple-smith, m. (2014). finding a segue into sex: young men’s views on discussing sexual health with a gp. australian family physican, 43(4), 217221. letshwenyo-maruatona, s. (2017). who do botswana men prefer: male or female health providers? american journal of men’s health, 11(6), 1642–1652. odedina, f. t., ogunbiyi, j. o., & ukoli, f. a. m. (2006). roots of prostate cancer in african-american men. journal of the national medical association, 98(4), 539–543. okuku, f., orem, j., holoya, g., de boer, c., thompson, c. l., & cooney, m. m. (2016). prostate cancer burden at the uganda cancer institute. journal of global oncology, 2(4), 181–185. olapade-olaopa e. o., owoaje, e. t., kola, l., ladipo, m. m., adebusoye, l. & adedeji, t. g. (2014). knowledge and perception of nigerian men 40 years and above regarding prostate cancer. journal of the west african college of surgeons, 4(1): 1-16. witty, k., branney, p., bullen, k., white, a., evans, j., & eardley, i. (2014). engaging men with penile cancer in qualitative research: reflections from an interview-based study. nurse researcher, 21(3), 13-19. woods, v. d., montgomery, s. b., herring, r. p. (2004). recruiting black/african american men for research on prostate cancer prevention. cancer, 100(5):1017-25. www.companyofscientists.com/index.php/chd e9 cancer health disparities research supplementary data appendix i questionnaire for overcoming barriers in conducting a transatlantic prostate cancer familial study in africa: best practice from the captc cohort study: to be answered by all data collectors and principal investigators 1. did you go on sensitization visits? yes or no a. what places did you go to on sensitization visits b. did you i. hold group talks ii. do a one-on-one sensitization iii. a combination of both? c. what factor(s) influenced the places visited for sensitization and recruitment of clients d. from your own point of view which of the recruitment method gave highest turnout 2. did the subjects prefer to come to the collection centre or did you have to go to their offices, homes or places of worship? 3. how many people did you invite to your study a. how many refused outright to participate b. how many declined to participate after looking at the questionnaire i. what were their reasons for declining a. lost interest b. questions are too personal c. questionnaire is time cosuming d. other reasons c. how many have you fully recruited 4. what is the average time it took to fill one questionnaire? 5. did they have any gender preferences for interviewers? • they preferred male interviewers • they preferred female interviewers • they had no gender preferences 6. what questions did they feel most uncomfortable answering? or what questions did they decline to answer most? 7. what peculiar challenges did you have while collecting data a. how did you overcome those challenges? 8. what are your suggestions for best practices? 9. what are your suggestions for the best way to engage your community for research? 10. what do you think is/are the best ways to appropriately disseminate results back to participants www.companyofscientists.com/index.php/chd e1 cancer health disparities research risk factors for prostate cancer in west african men: the familial cohort study catherine a. oladoyinbo 1,7*, oluwafunke o. akinbule1,7, opeyemi o. bolajoko 1,7, justice moses k. aheto2,7, getachew dagne 3,7 , faruk mohamed 4,7, iya eze bassey5,7, folakemi t. odedina6,7, ruth agaba 7, nissa askins 6,7, olubanke o. ogunlana8,7, motolani e. ogunsanya 9,7, aishat m. suleiman 4,7, stanley o. anyanwu 5,7, rebecca m. gali 10,7, ernest kaninjing 11,7, blaise nkegoum 12,7, abidemi omonisi13,7, anthonia c. sowunmi 14,7, paul jibrin 15,7, emeka e. iweala8,7, omolara a. fatiregun16,7 and ademola a. popoola17,7 authors’ affiliations: 1federal university of agriculture, abeokuta, ogun state, nigeria 2department of biostatistics, university of ghana, accra 3university of south florida, usa 4ahmadu bello university, zaria, nigeria 5duniversity of calabar, calabar, nigeria 6university of florida, lake nona campus, fl, usa 7prostate cancer transatlantic consortium (captc) 8covenant university, ota, nigeria 9university of oklahoma health sciences center, oklahoma city, ok 73117, usa 10university of maiduguri, maiduguri, nigeria 11georgia college & state university, usa 12university hospital center, yaounde, cameroon 13ekiti state university, nigeria 14lagos university teaching hospital 15national hospital, abuja, nigeria 16lagos state university colege medicine, nigeria 17university of ilorin teaching hospital, ilorin, nigeria *corresponding author: oladoyinbo catherine a, email:oladoyinboca@funaab.edu.ng mailto:oladoyinboca@funaab.edu.ng www.companyofscientists.com/index.php/chd e2 cancer health disparities research abstract prostate cancer (cap) has been identified as the most common cancer among men globally with higher prevalence, incidence and mortality rates in black men. this study aims to assess the risk factors for cap among west african men residing in nigeria, cameroon and the united states. a validated prostate cancer transatlantic consortium (captc) familial cohort study questionnaire was used to collect data on the respondents’ characteristics, alcohol consumption pattern, smoking pattern, knowledge of cap, physical activity level and cancer status. anthropometric measurements were taken using standard procedures. data was summarised using descriptive statistics and penalized maximum likelihood logistic regression analysis via firth method to determine the association between cap status and independent variables. the results show that 2.21% of the respondents reported to have been diagnosed with cap. the median age of the respondents was 47 years with 62.21% having poor knowledge of cap, and 17.11% with central obesity. more than half (62.07%) of the respondents currently drink alcohol, 24.4% are current smokers and 51.5% engage in low physical activity. number of daughters (or=1.2435, 95%ci: 1.0045, 1.5393), consistent alcohol drinkers in years (or=1.0484, 95%ci: 1.0151, 1.0829) and glasses of drink on a typical occasion (or=1.2145, 95%ci: 1.0560, 1.3968) were associated with cap status. in the multiple logistic regression, only number of daughters (or=1.2531, 95%ci: 1.0055, 1.5617) was associated with cap status. in conclusion, poor knowledge of cap was observed among the respondents. alcohol consumption, increased number of glasses of alcohol consumed on typical occasion and increasing number of daughters were associated with cap status and increased risk of the disease. keywords: prostate cancer, west africa, obesity, daughters, alcohol consumption citation: oladoyinbo et al (2019) risk factors for prostate cancer in west african men: the familial cohort study. 4: e1-e11. doi:10.9777/chd.2019.1007 www.companyofscientists.com/index.php/chd e3 cancer health disparities research introduction prostate cancer is the most frequently diagnosed cancer in men. it occurs as a result of genetic mutations or changes of the gene’s blueprint of the prostate cell causing the normal prostate cells to divide too quickly or die too slowly (odedina et al, 2016). black africans have 70% higher risk of developing prostate cancer (cap) when compared to non-hispanic whites and 137% higher death rates (american cancer society, 2016). findings have shown that african americans living in the us have 1.6 times risk of developing cap when compared to caucasian men (al olama et al, 2014; american cancer society, 2016). prostate cancer has been reported to be the second leading cause of cancer death in men, both in developed and developing countries, with an estimate of 180,890 new cases and 26,120 cancer death in the united states in 2016 (american cancer society, 2016). the burden of cap is projected to rise, with over 75 million prevalent cases, 27 million incident cases and 17 million cancer deaths globally by 2030 (parkin et al, 2003; ferlay et al, 2010). the higher incidence and prevalence of cap in black african and african american compared to other races in the world has increased rate of morbidity and mortality among these populations (odedina et al, 2006; delongchamps et al, 2007; odedina et al, 2009; akinremi et al, 2010; rebbeck et al, 2013). the known risk factors for developing cap include: increasing age, african ancestry, family history and certain inherited genetic conditions. other modifiable risk factors include tobacco use, alcohol consumption, increased body weight, central obesity, poor nutrition, physical inactivity, poor knowledge levels and certain infectious agents. these factors also play major roles in the development of cap (ihme: 2013; jacobs et al, 2015; world cancer research fund, 2015). findings have linked genetic susceptibility of cap to african heritage and familial disease (iarc, 2014; american cancer society, 2016). also, there are strong evidences that increased body mass index and central obesity increases the risk of cap incidence and mortality (maclnnis et al, 2003; gong et al, 2006; pischon et al, 2008; martin et al, 2009; stocks et al, 2010; batty et al, 2011; dehal et al, 2011; discacciati et al, 2011; shafique et al, 2012). alcohol consumption and smoking have also been implicated with the risk of developing cap (sawada et al, 2014) and reduced smoking have been associated with a decline in cap mortality rates (jones et al, 2016). studies on risk factors for cap in west african countries are scarce. since nigeria is an ancestral home of many black men living in the diaspora, studies involving black men from nigeria and other west african countries may provide information on some of the risk factors predisposing black men to cap. this study therefore aims to assess the risk factors for cap in west african black men. methodology this study was a cross-sectional study of west african black men residing in nigeria, cameroon and the united states. data were collected from ten (10) captc sites across the six (6) geopolitical zones in nigeria, one site from cameroon and one site from the usa. respondents within the age range of 35 to 75 years, who were willing to participate in the www.companyofscientists.com/index.php/chd e4 cancer health disparities research study and duly signed the informed consent were recruited. a validated captc familial project study questionnaire was used to collect data on the respondents’ characteristics, alcohol consumption and smoking patterns, knowledge of cap (causes, prevention, screening test, signs and symptoms), physical activity level and selfreported cancer status. anthropometric measurements (height, weight and waist circumference) were taken using the appropriate equipment. body mass index and central obesity were calculated from the anthropometric measurements. knowledge of cap was assessed from twenty (20) questions. every correct answer was scored as 1 and incorrect answers were scored as 0. individual total knowledge score was derived by summing all the scores. the individual score was divided by the maximum score (20) and multiplied by 100 to convert it to percentage. the percentage values were then categorized into poor (0 – 40%), moderate (41 – 69%) and adequate (≥70%) knowledge. data were summarised using frequencies and percentages for categorical variables while median and interquartile range (upper quartile – lower quartile) were used to summarise the continuous variables. we applied penalized maximum likelihood logistic regression analysis via firth method to determine the association between cap status and independent variables. in the regression analysis, only 470 out of the 498 respondents were included due to missing observations in some risk factors considered in the model. in addition, several important risk factors could not be included in the model due to missing data which could lead to removal of respondents who reported to have been diagnosed of cap. not removing such risk factors could have led to a reduced data pool, especially for those with a positive diagnosis of cap. to reduce bias in maximum likelihood estimates due to small number of cancer cases in the data, we applied penalized maximum likelihood logistic regression analysis via firth method (firth, 1993; heinze and schemper, 2002) to examine risk factors for cancer status among the respondents. firth method is also used to address the problem of separation in logistic regression (heinze and schemper, 2002). results characteristics of the respondents a total of 498 men participated in the study out of which 11 (2.21%) respondents reported to have been diagnosed with cap. among those who reported to have been diagnosed of cap, 10 (90.91%) reside in nigeria and only 1 (9.09%) resides in cameroon. the median age of participants is 47 years with an interquartile range (iqr) of 15 years. the median age at first drink of alcohol was 20 years with an interquartile range of 7 years. the median number of years respondents consistently drank alcohol was 20 years (iqr = 23) and the glasses of drink consumed on a typical occasion among respondents was 3 (iqr = 2). a total of 443 respondents (92.48%) of the respondent were married while 408 (85.18%) of the respondents reside in nigeria (table 1). www.companyofscientists.com/index.php/chd e5 cancer health disparities research table 1: respondents’ characteristics. characteristics median (lq-uq) age (n = 478) 47 (40-55) number of brothers (n = 479) 3 (2-5) number of sisters (n = 460) 3 (2-5) number of daughters (n = 474) 2 (1-3) number of sons (n = 478) 2 (1-3) age at first drink of alcohol in years (n = 480) 20 (17-24) consistent alcohol drinkers in years (n = 480) 15 (5-28) glasses of drink on typical occasion (n = 480) 3 (2-4) self-reported cancer status(n=498) yes n=11 2.21% no n=487 97.79% marital status (n= 479) married n = 443 92.48% not married n = 36 7.52% country (479) cameroon n=27 5.64% nigeria n=408 85.18% usa n=44 9.18% lq: lower quartile. uq: upper quartile. n: number of observations consistent alcohol drinkers: drank alcohol at least once a week for at least 6 months in years figure 1 histogram showing the age distribution of respondents. www.companyofscientists.com/index.php/chd e6 cancer health disparities research modifiable risk factors for prostate cancer among respondents table 2 shows the description of the modifiable risk factors for prostate cancer among the respondents. more than half (62.21%) of the respondents had poor knowledge, 27.81% had moderate knowledge and 9.98% had good knowledge of cap. a quarter of the respondents were overweight, 20.9% were obese and 17.1% had central obesity. about 20.4% of the respondents smoke and 79.6% have never smoked. among the smokers, 24.44% are current smokers while 75.56% had smoked at one time or the other in their lifetime. about 55.65% respondents drink alcohol while 44.35% never drank. among the alcohol drinkers, 62.07% currently drink alcohol while 37.93% had drank alcohol at one time or the other in their lifetime. about half (51.59%) of the respondents engage in low physical activity. table 2: modifiable risk factors for prostate cancer among respondents. modifiable risk factors frequency percentage knowledge of cap (n=471) poor moderate adequate 293 131 47 62.21 27.81 9.98 body mass index (n=345) underweight normal weight overweight obesity 69 112 92 72 20.0 32.46 26.67 20.87 central obesity (n=480) yes no 82 398 17.08 82.92 physical activity (n=471) low moderate high 243 77 151 51.59 16.35 32.06 smoking status (n=442) smokers non-smokers 90 352 20.36 79.64 smokers (n=99) current smokers smoked in a lifetime 22 68 24.44 75.56 breathe in smoke in the past seven days (n= 480) none one day two or more days don’t know / refused to answer 306 18 26 130 63.75 3.75 5.42 27.08 number of days/week tobacco smoke was inhaled (n=480) none one day 332 5 69.17 1.04 www.companyofscientists.com/index.php/chd e7 cancer health disparities research two or more days don’t know / refused to answer 13 130 2.71 27.08 alcohol drinking status (n=469) drinkers non-drinkers 261 208 55.65 44.35 alcohol drinkers (n=261) current drinkers drank in a lifetime 162 99 62.07 37.93 capprostate cancer smoking in this context is defined as tobacco smoking factors associated with prostate cancer status and risk presented in table 3 are the results from the penalized maximum likelihood logistic regression analysis. in the univariate logistic model, the variables, number of daughters (or=1.2435, 95%ci: 1.0045, 1.5393), consistent alcohol drinkers in years (or=1.0484, 95%ci: 1.0151, 1.0829) and glasses of drink on a typical occasion (or=1.2145, 95%ci: 1.0560, 1.3968) were associated with cap status. increase in number of daughters, consistent alcohol drinkers in years, and glasses of drink on a typical occasion were associated with increased risk of cap in men. age, marital status, number of brothers and sisters, number of sons, age at first drink were not associated with cap status. in the multiple logistic regression, only number of daughters (or=1.2531, 95%ci: 1.0055, 1.5617) was associated with cap status. likelihood of developing cap increases with increasing number of daughters. table 3: factors associated with prostate cancer status among men (n=470). univariate logistic model multiple logistic model characteristics uor 95% ci aor 95% ci socio-demographic factors age 0.9987 (0.9412, 1.0597) 0.9997 (0.9401, 1.063) marital status married ref not married 1.7364 (0.3034, 9.9395) number of brothers 1.1126 (0.9258, 1.337) number of sisters 1.0755 (0.8692, 1.3308) number of daughters 1.2435* (1.0045, 1.5393) 1.2531* (1.0055, 1.5617) number of sons 1.1888 (0.9486, 1.4898) drinking habits age at first drink 0.9815 (0.9283, 1.0377) consistent alcohol drinkers (years) 1.0484** (1.0151, 1.0829) 1.0394 (0.9983, 1.0823) glasses of drink on typical occasion 1.2145** (1.056, 1.3968) 1.0715 (0.8841, 1.2986) www.companyofscientists.com/index.php/chd e8 cancer health disparities research uor: unadjusted odds ratio. aor: adjusted odds ratio. ci: confidence interval. *: p<0.05, ref: reference category discussion this study assessed the risk factors for prostate cancer in west african men in the captc familial cohort study. previous findings revealed a high prevalence of cap in black african men (odedina et al, 2006; delongchamps et al, 2007; odedina et al, 2009; akinremi et al, 2010; rebbeck et al, 2013). in this study, the number of respondents who reported to have been diagnosed with cap out of the 498 was 2.21%, relatively lower. other respondents who reported not to have been diagnosed with cap may not have undergone any cap screening test. studies have revealed poor screening behaviour among west african men, particularly nigerian men (agbuguiet al, 2013; ogundele and ikuerowo, 2015). this might have contributed to the under-reporting of cap cases. poor screening behaviour of respondents towards cap may lead to high prevalence of advanced stage of cap which is prevalent in cap management in nigeria and hence reduce the rate of surviving the disease. most of the respondents had poor knowledge on cap and only one-tenth had adequate knowledge. few studies conducted in some nigerian states revealed a low level of awareness and knowledge of cap risk factors and symptoms (ukoli et al, 2003; oladimeji et al, 2010; ajape et al, 2010; ogundele and ikuerowo, 2015). adequate knowledge on cap may promote early detection, prevent cap progression into the advanced stage as well as the rate of morbidity and mortality associated with cap (ogunbiyi, 2011; akinremi et al, 2014). poor knowledge among respondents in this study may put them at risk of developing cap or having an advanced stage of cap. the prevalence of overweight, obesity and central obesity was high among the respondents. overweight and obesity have been reported to be associated with increased risk of cap (stocks et al, 2010; batty et al, 2011; dehal et al, 2011; discacciati et al, 2011;; basset et al, 2012; shafique et al, 2012). obesity has been reported to influence the levels of some hormones and growth factors including insulin and leptin and thereby stimulates the growth of cancer cells (platz et al, 2005). obesity, particularly central obesity has been reported to increase the risk of advanced cap (maclnnis et al, 2003; gong et al, 2006; pischon et al, 2008; martin et al, 2009). this is due to its lowering effect on serum testosterone levels. testosterone plays an important role in determining the differentiation status of the prostate epithelium. therefore, low levels of testosterone may increase the growth of a less differentiated, destructive cap phenotype (de pergola and silvestris, 2013). this study revealed that about one in five of the respondents smoke and more than half consume alcohol. studies have revealed that smoking, number of packs smoked, years of smoking and alcohol consumption increase the risk of developing cap, as well as advanced cap and death from cap (huncharek et al, 2010; rolison et al, 2012; ; sawada et al, 2014; nunzio et al, 2015). also, a study conducted in the us revealed that smokers are less likely to undergo cap screening and less likely to screen frequently (rolison et al, 2012). this study showed that increasing number of daughters was associated with increased odds of developing cap. an earlier study carried out www.companyofscientists.com/index.php/chd e9 cancer health disparities research among the jerusalem perinatal cohort study by harlap et al., (2007), found that israeli men who developed cap have an impaired ability to reproduce male children. the y-chromosome has been implicated in the onset of prostate cancer in men (krausz et al., 2004) and has been suggested to harbour cap risk (harlap et al., 2007). however, another study in the us reported that men who were unable to give birth to male children had a lower risk of cap (spatz, et al., 2004; eisenberg et al., 2011) submitting that prostate carcinogenesis may be linked to the x chromosomes. given these mixed findings, more studies are needed to clearly understand the role of fatherhood and cap status. also, consistent alcohol consumption was found to increase the risk of cap. previous studies have established that consistency in alcohol consumption is associated with cap( rota et al., 2012; fowke et al., 2014; demoury et al., 2016). this might be due to the metabolism of alcohol which releases acetaldehyde which has been suggested to be carcinogenic because it interferes with dna replication (seitz and becker, 2007; lachenmeier et al., 2012; zhao et al., 2016). the current study also shows that cap risk increases with the number of glasses of alcoholic drink consumed. earlier studies have consistently shown that a higher volume of alcohol intake on a typical occasion is indeed associated with increased risk of cap (fowke et al., 2014; demoury et al., 2016; zhao et al., 2016). in conclusion, poor knowledge of the causes, screening test, signs and symptoms of cap was observed among the respondents. alcohol consumption, increased number of glasses of alcohol consumed on typical occasion and an increasing number of daughters were found to be associated with cap status and increased risk of the disease. acknowledgements funding support for this project was provided by the prostate cancer transatlantic consortium (captc) conflict of interest the authors declare that no competing or conflict of interests exist. the funders had no role in study design, writing of the manuscript, or decision to publish. authors’ contributions all authors contributed to the study. from data collection, data entry and analysis, manuscript writing and editing. references agbugui jo, obarisiagbon eo, nwajei co, osaigbovo eo, okolo jc, akinyele ao (2013).awareness and knowledge of prostatecancer among men in benin city, nigeria. journal of biomedical science vol 12 (2): 42-47 ajape, a., ibrahim, k., fakeye, j., abiola, o. 2010. an overview of cancer of the prostate diagnosis 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(2010). int j cancer; 127: 1660-8. ukoli, f., osime, u., akereyeni, f., okunzuwa, o., kittles, r., adams-campbell, l. 2003. prevalence of elevated serum prostate-specific antigen in rural nigeria. int j urol, 10(6), 315-22. world cancer research fund international (2015). cancer preventability estimates for food, nutrition, body fatness, and physical activity. http://www.wcrf.org/int/cancerfacts-figures/preventability-estimates/cancerpreventability-estimates-diet-nutrition (accessed september 29, 2015) zhao, j., stockwell, t., roemer, a., chikritzhs, t. 2016. is alcohol consumption a risk factor for prostate cancer? a systematic review and meta-analysis. bmc cancer, 16(1), 845. http://doi.org/10.1155/2013/560857 www.companyofscientists.com/index.php/chd e1 cancer health disparities research five year record on cancer incidence from a diagnostic centre in mizoram, northeast india mary vanlalhruaii tonsing1, souvik ghatak1, freda lalrohlui1, nachimuthu senthil kumar1 and john zohmingthanga2* 1department of biotechnology, mizoram university, aizawl -796004, mizoram, india 2office of the medical superintendent, civil hospital, aizawl -796001, mizoram, india *corresponding author email: johnzo05@yahoo.co.in, nskmzu@gmail.com. abstract cancer has become leading cause of death in northeast indian population. the main reason being poor knowledge of prevention and diagnosis combined with modern lifestyle of the mizo population. all cancers have been reported in mizo population including the cancers of stomach, cervix, lungs, breast, oesophagus, rectum, prostate, liver, bladder, oral etc. the cause of such high incidence rates of these cancers may be inherited or genetic and environmental factors such as life style and food habits, especially high consumption of tobacco and alcohol. a peculiar habit of tobacco smoke-infused water (tuibur) is also in practice in this population. in view of these facts, the present article describes the status of various types of cancers in mizo population. besides, attempts have been made to describe the main causes of cancer in this population with their frequency and grading. in this study, increasing number of cancer patients in different age group was observed from 2011 – 2015. the highest incidence of cancer was observed in the patients with age group 50 60, followed by age groups above 60 years. in age group 20-30 years, the breast and cervix cancers were more prevalent from 2011 – 2015. in middle age group (30-40 and 40-50 years), the cervix, stomach and oesophagus cancers were more prevalent. the common type of cancer in female includes cervical cancer, followed by breast cancer which is shown to be increasing with age of the patients and also increasing each year within this 5 year period from 2011 – 2015. in 2014 and 2015, adenocarcinoma (ac) and squamous cell carcinoma (scc) are both commonly seen. this study will help in understanding the etiology of cancer and also in developing preventive measures in future. keywords: cancer prevalence, life style habits, adenocarcinoma, squamous cell carcinoma, mizo population, northeast india citation: tonsing mv et al (2019) five year record on cancer incidence from a diagnostic centre in mizoram, northeast india. cancer health disparities 3:e1-e15. doi:10.9777/chd.2019.1003. mailto:johnzo05@yahoo.co.in www.companyofscientists.com/index.php/chd e2 cancer health disparities research introduction cancer is a major public health problem in india. cancer is the second and third most common cause of death in the developed and developing countries, respectively [bener et al.,2008]. a large network of population based cancer registries in india, provides valuable data for cancer. population-based survival comparisons for cancer between nine asian countries showed that india has the lowest 5-year survival for most cancer sites; 5-year survival for breast cancer was 52% and for colorectal cancer was 28%, compared with 82% and 44% in china. breast cancer (145000 cases per year), tobacco-related head and neck cancers (141000), cervical cancer (123000), lung cancer (70000), large bowel cancer (64000), and stomach cancer (63000) account for more than half of the burden, implying that prevention, along with early detection and treatment, are important interventions for cancer control [bener et al.,2008]. about 70% cancer cases have been diagnosed, with little survival of the patients, over the last decades. the poor prospects of cancer survival indicates inadequate health care financing, and also because cancer diagnosis and treatment are becoming increasingly unaffordable for healthcare systems in india as well as in many lowincome and middle-income countries since it has centred on expensive diagnostic and staging investigations such as imaging, and on specialised treatments and costly drugs. most frequently observed cancers in indian population are lungs, breast, colon, rectum, stomach and liver [ncrp, 2010; rao, 1998; murthy et al., 2004]. it is important to study the status of cancers in india so that advance measures may be taken to control this havoc in near future. in view of these facts, attempts have been made to study the status of cancers in india including its causes, preventive measures, effect on indian economy and comparison with global scenario. data sources and methods study area the study area mizoram is flanked by bangladesh on the west and myanmar on the east and south. the total area is 21,081 sq. km. it mainly consists of 8 districts, namely aizawl, lunglei, champhai, lawngtlai, mamit, kolasib, serchhip and saiha. the total population of the state is 10,97,206 with about 5,55,339 males and 5,41,867 females as per the 2011 census. patients from other districts also visit the capital city, aizawl for diagnosis and treatment. data collection genesis laboratory, aizawl acts as the major diagnostic facility of cancer. ethical approval was obtained from the institutional ethics committee. the study subjects included 1,477 cancer patients diagnosed/registered in genesis laboratory, aizawl between 2011 – 2015. this data included different types of cancer and the type of cells being affected both in males and females, within different age groups and its staging on the basis of clinical symptoms and histopathology at the genesis laboratory, aizawl, mizoram. the patients coming from all the different districts of mizoram were included in this analysis. statistical analysis the frequencies of the collected data were represented according to their age group, type of cancer, staging and sex ratio. the association in each group was estimated using odds ratios (ors) and 95% confidence intervals (cis). the association of various cancers and stages of the patients was tested for hardy–weinberg equilibrium by a chisquare test with one degree of freedom (df). www.companyofscientists.com/index.php/chd e3 cancer health disparities research table 1. list of various cancers year wise, stratified by age group. age group cancer type no (%) male female ors (95% ci) p value 2011 20-30 breast a liver b colon b 3 (60) 1 (20) 1 (20) 0 0 0 3 1 1 2.00 (0.42 9.33) 0.20 (0.03 – 1.29) 0.20 (0.03 – 1.29) 0.0497 31-40 breast ab uterus b cervix a endometrium b colon b stomach b 6(24) 1(4) 10(40) 2(8) 1(4) 1(4) 0 0 0 0 0 1 6 1 10 2 1 1 0.31 (0.12 – 0.76) 0.92 (0.42 – 1.98) 0.13 (0.04 – 0.42) 0.08 (0.02 – 0.33) 0.04 (0.007 0.24) 0.04 (0.007– 0.24) 0.0159 41-50 cervix a tongue c stomach a oesophagus ab pyriform fossa bc breast abc nasopharynx bc liver abc lung abc 13(22.4) 1(1.72) 13(22.4) 11(18.96) 3(5.17) 4(6.89) 3(5.17) 4(6.89) 5(8.62) 0 1 6 10 3 0 1 3 3 13 0 7 1 0 4 2 1 2 0.08 (0.03 – 0.18) 0.26 (0.15 – 0.45) 0.12 (0.06 – 0.25) 0.01 (0.002– 0.06) 0.17 (0.09 – 0.32) 0.03 (0.01 – 0.11) 0.03 (0.01 – 0.11) 0.01 (0.002– 0.06) 0.01 (0.002– 0.06) 0.0001 51-60 oesophagus c pharynx ab breast abc uterus a cervix c lung c stomach c nasopharynx c tonsil c endometrium c liver c pyriform fossa c 1(2.56) 13(33.33) 7(17.94) 14(35.89) 1(2.56) 3(7.69) 3(7.69) 1(2.56) 1(2.56) 1(2.56) 1(2.56) 1(2.56) 0 2 7 13 1 2 2 1 1 1 0 0 1 11 0 1 0 1 1 0 0 0 1 1 0.04 (0.01 – 0.12) 0.20 (0.11 – 0.37) 0.10 (0.04 – 0.21) 0.22 (0.12 – 0.40) 0.01 (0.002– 0.07) 0.04 (0.01 – 0.12) 0.04 (0.01 – 0.12) 0.01 (0.002– 0.07) 0.01 (0.01 – 0.07) 0.01 (0.01 – 0.07) 0.01 (0.01 – 0.07) 0.01 (0.01 – 0.07) 0.0016 > 60 stomach a oesophagus ab nasopharynx ab tonsil b breast ab cervix ab pyriform fossa b tongue b urinary bladder b epiglottis b lung b liver a 26(29.88) 3(3.44) 3(3.44) 1(1.14) 3(3.44) 3(3.44) 1(1.14) 1(1.14) 1(1.14) 1(1.14) 26(29.88) 18(20.68) 14 3 3 1 0 0 1 1 1 1 14 11 12 0 0 0 3 3 0 0 0 0 12 7 0.10 (0.03 – 0.30) 0.03 (0.005– 0.18) 0.73 (0.37 – 1.45) 0.10 (0.03 – 0.30) 0.06 (0.01 – 0.24) 0.03 (0.005– 0.18) 0.10 (0.03 – 0.30) 0.03 (0.005– 0.18) 0.03 (0.005– 0.18) 0.03 (0.005– 0.18) 0.03 (0.005– 0.18) 0.03 (0.005– 0.18) 0.0715 2012 20-30 breast a stomach a colon a cervix a nasopharynx a 1(12.5) 2(25) 1(12.5) 3(37.5) 1(12.5) 0 0 0 0 0 1 2 1 3 1 0.05 (0.01 – 0.34) 0.12 (0.03 – 0.48) 0.05 (0.01 – 0.34) 0.05 (0.01 – 0.34) 1.25 (0.50 – 3.07) 0.0119 31-40 liver ab 6(19.35) 2 4 0.09 (0.03 – 0.29) 0.0012 www.companyofscientists.com/index.php/chd e4 cancer health disparities research cervix a breast abc tongue c stomach bc oesophagus a uterus c tonsil c thyroid c pyriform fossa c pharynx c 7(22.58) 3(9.6) 1(3.22) 2(6.45) 7(22.58) 1(3.22) 1(3.22) 1(3.22) 1(3.22) 1(3.22) 0 0 1 1 6 0 1 0 1 1 7 3 0 1 1 1 0 1 0 0 0.13 (0.04 – 0.36) 0.25 (0.11 – 0.58) 0.03 (0.005– 0.17) 0.03 (0.005– 0.17) 0.06 (0.01 – 0.23) 0.03 (0.005– 0.17) 0.06 (0.01 – 0.23) 0.03 (0.005– 0.17) 0.41 (0.20 – 0.85) 0.03 (0.005– 0.17) 41-50 liver a lung abcd oesophagus ab stomach abc nasopharynx bcd cervix abcd vocal cord d tonsil d larynx d uterus d pyriform fossa d breast d mouth d colon cd 10(17.24) 5(8.62) 9(15.51) 8(13.79) 3(5.17) 7(12.06) 1(1.72) 1(1.72) 1(1.72) 1(1.72) 1(1.72) 7(12.06) 1(1.72) 2(3.44) 5 5 8 8 2 0 1 1 1 0 1 0 1 2 5 0 1 0 1 7 0 0 0 1 0 7 0 0 0.18 (0.09 – 0.36) 0.18 (0.09 – 0.36) 0.20 (0.10 – 0.40) 0.01 (0.003– 0.10) 0.03 (0.009– 0.13) 0.05 (0.01 – 0.16) 0.03 (0.009– 0.13) 0.01 (0.003– 0.10) 0.01 (0.003– 0.10) 0.01 (0.003– 0.10) 0.09 (0.03 – 0.22) 0.11 (0.05 – 0.26) 0.03 (0.009– 0.13) 0.03 (0.009– 0.13) 0.0001 51-60 lung bc liver c stomach a tongue c pyriform fossa c caecum c oesophagus ab nasopharynx c thyroid c pharynx c tonsil c cervix c uterus c colon c breast bc epiglottis c 9(9.57) 4(4.25) 29(30.85) 2(2.12) 4(4.25) 2(2.12) 20(21.27) 1(1.06) 1(1.06) 2(2.12) 3(3.19) 3(3.19) 1(1.06) 1(1.06) 7(7.44) 3(3.19) 5 2 17 2 4 2 18 0 0 2 2 0 1 0 1 3 4 2 12 0 0 0 2 1 1 0 1 3 0 1 6 0 0.10 (0.05 – 0.21) 0.47 (0.30 – 0.74) 0.35 (0.21 – 0.57) 0.05 (0.01 – 0.13) 0.02 (0.006– 0.09) 0.02 (0.006– 0.09) 0.01 (0.002– 0.06) 0.01 (0.002– 0.06) 0.02 (0.006– 0.09) 0.07 (0.03 – 0.17) 0.03 (0.01 – 0.11) 0.01 (0.002– 0.06) 0.02 (0.006– 0.09) 0.01 (0.002– 0.06) 0.01 (0.002– 0.06) 0.01 (0.002– 0.06) 0.0001 >60 lung a liver b nasopharynx b stomach b cervix b epiglottis b oesophagus b breast b pyriform fossa b 37(33.33) 10(9.00) 4(3.60) 36(32.43) 5(4.50) 2(1.80) 10(9.00) 3(2.70) 2(1.80) 15 5 3 23 0 1 10 0 2 22 5 1 13 5 1 0 3 0 0.04 (0.01 – 0.15) 1.08 (0.62 – 1.87) 0.25 (0.12 – 0.49) 0.06 (0.02 – 0.19) 0.04 (0.01 – 0.15) 0.02 (0.003– 0.11) 0.08 (0.03 – 0.23) 0.02 (0.003– 0.11) 0.02 (0.003– 0.11) 0.0779 2013 20-30 stomach a breast a tongue a 3(50) 1(16.67) 2(33.33) 0 0 2 3 1 0 0.20 (0.03 – 1.29) 1.00 (0.23 – 4.33) 0.50 (0.10 – 2.33) 0.1889 www.companyofscientists.com/index.php/chd e5 cancer health disparities research 31-40 cervix ab nasopharynx c oesophagus abc tongue bc stomach bc breast a larynx c tonsil c uterus bc 12(21.42) 1(1.78) 8(14.28) 4(7.14) 5(8.92) 14(25.00) 1(1.78) 1(1.78) 4(7.14) 0 0 7 3 3 0 1 0 0 12 1 1 1 2 14 0 1 4 0.38 (0.21 – 0.71) 0.85 (0.49 – 1.47) 0.11 (0.45 – 0.27) 0.02 (0.003– 0.11) 0.02 (0.003– 0.11) 0.02 (0.003_ 0.11) 0.04 (0.01 – 0.15) 0.04 (0.01 – 0.15) 0.02 (0.003– 0.11) 0.0002 41-50 lung b liver b cervix ab stomach ab caecum b uterus b breast ab oesophagus a pharynx b bladder b 4(4.30) 5(5.37) 17(18.27) 14(15.05) 1(1.07) 2(2.15) 12(12.90) 27(29.03 1(1.07) 1(1.07) 0 2 0 10 0 0 0 23 1 0 4 3 17 4 1 2 12 4 0 1 0.31 (0.17 – 0.57) 0.61 (0.36 – 1.03) 0.20 (0.10 – 0.40) 0.01 (0.003– 0.10) 0.01 (0.003– 0.10) 0.05 (0.01 – 0.16) 0.01 (0.003– 0.10) 0.01 (0.003– 0.10) 0.07 (0.02 – 0.19) 0.01 (0.003– 0.10) 0.0001 51-60 lung b liver b stomach a epiglottis b oesophagus a tongue b cervix b skin b gall bladder b tonsil b pharynx b breast b pyriform fossa b tongue b colon b nasopharynx b bladder b 13(9.55) 10(7.35) 37(27.20) 2(1.47) 35(25.73) 1(0.73) 14(10.29) 1(0.73) 1(0.73) 1(0.73) 2(1.47) 6(4.41) 6(4.41) 1(0.73) 4(2.94) 2(1.47) 1(0.73) 7 5 17 2 30 1 0 1 0 1 2 0 6 1 2 2 1 6 5 20 0 5 0 14 0 1 0 0 6 0 0 2 0 0 0.06 (0.02 – 0.14) 0.25 (0.15 – 0.42) 0.54 (0.35 – 0.83) 0.06 (0.02 – 0.14) 0.04 (0.01 – 0.12) 0.02 (0.006– 0.08) 0.02 (0.006– 0.08) 0.02 (0.006– 0.08) 0.02 (0.006– 0.08) 0.01 (0.002– 0.06) 0.01 (0.002– 0.06) 0.07 (0.03 – 0.16) 0.01 (0.002– 0.06) 0.01 (0.002– 0.06) 0.01 (0.002– 0.06) 0.01 (0.002– 0.06) 0.02 (0.006– 0.08) 0.0033 >60 lung ab liver b stomach a pyriform fossa b nasopharynx b tongue b colon b bladder b cervix b breast b oesophagus b 40(25.64) 8(5.12) 64(41.02) 1(0.64) 2(1.28) 3(1.92) 5(3.20) 7(4.48) 1(0.64) 4(2.56) 19(12.17) 23 5 49 1 1 1 3 2 0 1 9 17 3 15 0 1 2 2 5 1 3 10 0.08 (0.01 – 0.49) 0.18 (0.04 – 0.73) 0.18 (0.04 – 0.73) 0.08 (0.01 – 0.49) 0.08 (0.01 – 0.49) 0.08 (0.01 – 0.49) 0.08 (0.01 – 0.49) 0.08 (0.01 – 0.49) 0.08 (0.01 – 0.49) 0.08 (0.01 – 0.49) 0.08 (0.01 – 0.49) 0.2237 2014 20-30 oesophagus ab cervix a breast ab colon b 2(22.22) 4(44.44) 2(22.22) 1(11.11) 2 0 0 0 0 4 2 1 0.22 (0.05 – 0.91) 1.20 (0.38 – 3.70) 0.10 (0.01 – 0.60) 0.10 (0.01 – 0.60) 0.0265 31-40 liver b 1(2.85) 1 0 0.20 (0.08 – 0.48) 0.0037 www.companyofscientists.com/index.php/chd e6 cancer health disparities research breast ab colon ab oesophagus b cervix a stomach ab pyriform fossa ab nasopharynx b 7(20.00) 3(8.57) 1(2.85) 12(34.28) 9(25.71) 2(5.71) 1(2.85) 1 2 1 0 3 1 1 6 1 0 12 6 1 0 0.75 (0.38 – 1.44) 0.25 (0.11 – 0.55) 0.06 (0.01 – 0.22) 0.02 (0.005– 0.17) 0.02 (0.005– 0.17) 0.06 (0.01 – 0.22) 0.02 (0.005– 0.17) 41-50 liver bc cervix a oesophagus ab mouth c epiglottis c breast abc stomach ab colon bc larynx c pyriform fossa bc uterus bc penis c 7(8.33) 22(26.19) 16(19.04) 1(1.19) 1(1.19) 10(11.90) 16(19.04) 3(3.57) 1(1.19) 3(3.57) 2(2.38) 1(1.19) 6 0 15 0 0 0 13 2 1 3 0 1 1 22 1 1 1 10 3 1 0 0 2 0 0.13 (0.06 – 0.25) 0.48 (0.30 – 0.75) 0.16 (0.08 – 0.29) 0.07 (0.03 – 0.16) 0.22 (0.13 – 0.39) 0.03 (0.01 – 0.10) 0.03 (0.01 – 0.10) 0.04 (0.01 – 0.12) 0.01 (0.002– 0.06) 0.01 (0.002– 0.06) 0.01 (0.002– 0.06) 0.01 (0.002– 0.06) <0.0001 51-60 lung c liver c ovary c cervix bc oesophagus ab stomach a epiglottis c nasopharynx c pyriform fossa c uterus c gall bladder c breast c 3(2.80) 8(7.47) 4(3.73) 10(9.34) 30(28.03) 31(28.97) 1(0.93) 1(0.93) 5(4.67) 2(1.86) 2(1.86) 5(4.67) 2 5 1 0 26 24 1 0 5 0 2 0 1 3 3 10 4 7 0 1 0 2 0 5 0.06 (0.02 – 0.14) 0.16 (0.08 – 0.29) 0.36 (0.22 – 0.58) 0.62 (0.40 – 0.95) 0.03 (0.01 – 0.10) 0.01 (0.002– 0.06) 0.01 (0.002– 0.06) 0.02 (0.006– 0.08) 0.03 (0.01 – 0.10) 0.01 (0.002– 0.06) 0.01 (0.002– 0.06) 0.01 (0.002– 0.06) <0.0001 >60 lung ab liver bc stomach a vocal cord c nasopharynx c pyriform fossa c colon c oesophagus bc cervix c breast c epiglottis c anus c vaginal wall c 33(25.00) 10(7.57) 45(34.09) 1(0.75) 2(1.51) 1(0.75) 6(4.54) 13(9.84) 8(6.06) 4(3.03) 2(1.51) 2(1.51) 2(1.51) 12 7 29 1 2 1 6 12 0 0 2 0 1 21 3 16 0 0 0 0 1 8 4 0 2 1 0.03 (0.01 – 0.10) 0.10 (0.05 – 0.19) 0.85 (0.58 – 1.25) 0.01 (0.005– 0.07) 0.15 (0.08 – 0.26) 0.10 (0.05 – 0.19) 0.07 (0.03 – 0.14) 0.03 (0.01 – 0.10) 0.009(0.001-0.05) 0.009(0.001-0.05) 0.01 (0.005– 0.07) 0.009(0.001-0.05) 0.009(0.001-0.05) 0.0008 2015 20-30 cervix a thyroid b stomach b breast b ovary b 5(45.45) 2(18.18) 1(9.09) 2(18.18) 1(9.09) 0 0 1 0 0 5 2 0 2 1 0.14 (0.03 – 0.56) 1.00(0.38 – 2.57) 0.14 (0.03 – 0.56) 0.14 (0.03 – 0.56) 0.14 (0.03 – 0.56) 0.1132 31-40 liver ab breast ab thyroid b 4(16.00) 4(16.00) 2(8.00) 4 0 1 0 4 1 0.34 (0.17 – 0.67) 1.15 (0.63 – 2.07) 0.07 (0.02 – 0.22) <0.0001 www.companyofscientists.com/index.php/chd e7 cancer health disparities research pyriform fossa b bladder b uterus b cervix a stomach b caecum b 1(4.00) 1(4.00) 1(4.00) 9(36.00) 2(8.00) 1(4.00) 1 1 0 0 1 1 0 0 1 9 1 1 0.13 (0.05 – 0.32) 0.04 (0.01 – 0.18) 0.02 (0.004– 0.13) 0.02 (0.004– 0.13) 0.02 (0.004– 0.13) 0.04 (0.01 – 0.18) 41-50 liver ab lung b oesophagus a stomach ab breast ab cervix b endometrium b urinary bladder b mouth b epiglottis b uterus b 7(12.28) 3(5.26) 14(24.56) 8(14.03) 14(24.56) 4(7.01) 3(5.26) 1(1.75) 1(1.75) 1(1.75) 1(1.75) 4 2 14 5 0 0 0 1 1 1 0 3 1 0 3 14 4 3 0 0 0 1 0.21 (0.13 – 0.34) 0.38 (0.25 – 0.57) 0.33 (0.22 – 0.50) 0.12 (0.06 – 0.21) 0.02 (0.008– 0.07) 0.008 (0.001-0.04) 0.04 (0.01 – 0.10) 0.008 (0.001-0.04) 0.04 (0.01 – 0.10) 0.008 (0.001-0.04) 0.01 (0.004 – 0.06 <0.0001 51-60 liver ab lung abc stomach a breast bc thyroid bc oesophagus a pyriform fossa bc gall bladder c endometrium bc bladder bc tongue c cervix bc pharynx c epiglottis c 11(13.92) 9(11.39) 15(18.98) 5(6.32) 2(2.53) 16(20.25) 4(5.06) 1(1.26) 3(3.79) 2(2.53) 1(1.26) 4(5.06) 1(1.26) 1(1.26) 4 4 8 0 1 16 4 0 0 2 1 0 1 0 7 5 7 5 1 0 0 1 3 0 0 4 0 1 0.06 (0.03 – 0.14) 0.18 (0.10 – 0.30) 0.30 (0.20 – 0.47) 0.11 (0.06 – 0.20) 0.009(0.001-0.05) 0.02 (0.009– 0.08) 0.22 (0.13 – 0.35) 0.05 (0.02 – 0.12) 0.07 (0.03 – 0.15) 0.01 (0.005– 0.06) 0.05 (0.02 – 0.12) 0.009(0.001-0.05) 0.009(0.001-0.05) 0.009(0.001-0.05) <0.0001 >60 liver bc lung a epiglottis c stomach ab oesophagus bc caecum c breast c larynx c pharynx c bladder c colon c pyriform fossa c cervix c ureter c gall bladder c 11(11.70) 28(29.78) 1(1.06) 25(26.59) 11(11.70) 1(1.06) 2(2.12) 1(1.06) 1(1.06) 1(1.06) 4(4.25) 2(2.12) 3(3.19) 1(1.06) 2(2.12) 8 15 1 15 8 0 0 1 1 1 3 2 0 1 1 3 13 0 10 3 1 2 0 0 0 1 0 3 0 1 0.03 (0.01 – 0.10) 0.64 (0.43 – 0.95) 0.10 (0.05 – 0.19) 0.17 (0.10 – 0.29) 0.15 (0.08 – 0.26) 0.01 (0.005– 0.07) 0.02 (0.009– 0.08) 0.01 (0.005– 0.07) 0.009(0.001–0.05) 0.01 (0.005– 0.07) 0.009(0.001-0.05) 0.009(0.001-0.05) 0.009(0.001-0.05) 0.01 (0.005– 0.07) 0.03 (0.01 – 0.10) 0.2267 or – odds ratio ci – confidence interval a, b, c, ab, bc – level of significance using duncan’s anova test results a total of 1,477 patients with malignancy reported to genesis laboratory (aizawl) from 2011 – 2015. the highest incidence of cancer was observed in the patients with age group 50 60 (423), followed by age groups above 60 (399). this shows an increase in the disease with increase in age. there was a statistical significance observed between the www.companyofscientists.com/index.php/chd e8 cancer health disparities research age group and different types of cancers. in 2011, 2012 and 2014, the age group 20-30, 30-40, 40 – 50 and 50 to 60 are shown to be significant, whereas in 2013 and 2014 the age group 30-40, 40-50 and 50-60 shows significance (table 1). remarkably, only in 2014 the age group more than 60 years of age was significant with different cancer types. in age group 20-30, breast and cervix cancer were more prevalent, throughout all the years. in middle age group (30-40 and 40-50) cervix, stomach and oesophagus cancer were more prevalent, throughout all the years. in older age group (41 to 60 and >60), stomach cancer was the leading cancer followed by oesophagus cancer in throughout all the years. cancer is dominant in females (778) than in males (710). the common type of cancer in female includes cervical cancer, followed by breast cancer which is shown to be increasing with age of the patients and also increasing each year within this 5 year period from 2011 – 2015 (figure 1). in males, stomach cancer is the most prevalent type of cancer followed by oesophagus cancer. both the type of cancers are found commonly in the patients with age 40 yrs and above. figure 1. various cancer frequency based on age group for the years 2011 (a), 2012 (b), 2013 (c), 2014 (d), 2015 (e). www.companyofscientists.com/index.php/chd e9 cancer health disparities research different types of cells were involved with the different types of cancers. in 2011, squamous cell carcinoma (scc) was the most common pathological variety of cancer in males, followed by adenocarcinoma (ac). in 2013, moderately differentiated squamous cell carcinoma (mdscc) had the highest percentage of occurrence. in 2014 and 2015 ac and scc are both commonly seen. in the year 2011 the adenocarcinoma stomach and squamous cell carcinoma oesophagus showed prevalence in older age group, but in middle age group the squamous cell carcinoma cervix was the leading cancer group (figure 2). adenocarcinoma stomach and squamous cell carcinoma oesophagus were the ladder of all the cancer types for the year of 2012. in 2013 the older age group had significant growth than other age group, because the adenocarcinoma stomach and moderately differentiated squamous cell carcinoma in oesophagus were the leading cancer. the same prevalence was also observed for the year of 2014 and 2015. but for 2015 other types of cancers prevalence was also observed. www.companyofscientists.com/index.php/chd e10 cancer health disparities research figure 2. frequency of cancer prevalence and status in mizo population for the years 2011 (a), 2012 (b), 2013 (c), 2014 (d), 2015 (e). www.companyofscientists.com/index.php/chd e11 cancer health disparities research ac – adenocarcinoma; idc – invasive duct carcinoma; scc – squamous cell carcinoma; mdac – moderately differentiated adenocarcinoma; mdscc – moderately differentiated squamous cell carcinoma; pdac – poorly differentiated adenocarcinoma; wdscc – well differentiated squamous cell carcinoma; nkscc – non – keratinising squamous cell carcinoma. discussion our studies reveal that cancer is diagnosed more in women than in men. it also shows an increase in occurrence of cancer with increase in age. women are showing high rate of cancer because of the alarming increase in cervical and breast cancer for the last five years. cervical cancer is caused by human papillomavirus infection. human papillomavirus promotes uncontrolled cell division and accumulation of genetic damage. other cancers attributed to human papillomavirus infection include those of vagina (70%), penis (50%), vulva (43%), and oropharynx (26%) (table 1)[hariri et al.,2011]. breast cancer occurrence is highest after 35 years of age. the possible risk factor for occurrence of breast cancer was contributed by stress in the form of higher education and occupation, late menopause, history of induced abortion, first-degree family history of the disease and body mass index [thapa et al.,2016]. the most common type in males is stomach cancer, followed by oesophageal. tobacco smoking and use of smokeless tobacco, chewing tobacco and tuibur coupled with unhealthy food items such as smoked meat and vegetables and fermented soyabean and pork etc. may attribute to the high incidence of cancer in mizoram [ghatak et al.,2016]. the food habits of mizoram are known to contribute to various different types of cancers. smoke-drying and preservation leads to formation of n-nitroso compounds. nitrite reacts with amines and amides found in meats and other proteins to form n-nitroso compounds, which are animal carcinogens and possible human carcinogens. furthermore, although salt is not a carcinogen, it is thought to increase the risk of gastric cancer through direct damage to the gastric mucosa, which results in gastritis, increased dna synthesis, and cell proliferation. this indirectly contributes to the development of chronic atrophic gastritis, leading to the development of stomach cancer. because of the presence of both salt and nitrite in processed fish and meats, its role in the development of stomach cancer cannot be ignored, as was found by phukan et al. [phukan et al.,2006]. frequent consumption of sa-um was found to be associated with the risk of developing stomach cancer. this is a food material uniquely consumed in mizoram. dietary intakes of total or saturated fat have been shown to be associated with stomach cancer. boiled pork fat, in addition to being a rich source of saturated fat, may form carcinogenic compounds during long storage, as in other stored meats. use of soda was shown to be a risk factor. indigenous people of the northeastern region of india use soda (alkali) or other alkaline preparations frequently as food additives. the consumption of tobacco is the leading cause of cancers in india. the regular use of tobacco via smoking, chewing, snuffing etc. in mizoram, which is responsible for 65 to 85% cancer incidences in men and women, respectively. the various cancers produced by the use of tobacco are of oral cavity, pharynx, esophagus, larynx, lungs and urinary bladder. smoking is the most notorious factor for the causation of lung cancer [hammond et al.,1966]. approximately, 87 and 85% males and females have been found to have lung cancer due to tobacco smoking in the form of local zozial (a thin south asian cigarette type structure filled with tobacco flake and wrapped in a white paper, tied with a string at one end) [behera et al.,2004] and cigarette in india [jayant et al.,1991]. the severe carcinogenic nature of asian local made cigarette has been proved by the studies of jussawalla and jain [jussawalla et al.,1979] and [pakhale et al.,1990]they observed that the unrefined form of tobacco used in bidis (who, 1999) and the www.companyofscientists.com/index.php/chd e12 cancer health disparities research frequency with which a bidi needs to be puffed per minute may be responsible for its relatively higher carcinogenic effects as compared to cigarettes [bano et al.,2009]. bidi smoking at two puffs per minute produces about equal amounts of carcinogens (steam volatile phenols, hydrogen cyanide and benzopyrene) as produced by one puff per minute of unfiltered cigarette [pakhale et al.,1990 ] hookah (a special cigar used in mizoram using raw tobacco) smoking causes lung cancer; as reported by nafae et al. [nafae et al.,1973] in mizoram, north-eastern india high incidences of stomach cancer are attributed to the consumption of smoked meat and chewing of tobacco. high incidences of stomach cancer in mizoram are the result of the excessive use of tuibur (water filterate of tobacco). similarly, the consumption of areca nut, pan masala, opium and bhang (leaves and flower powder of female cannabis plant) has been recognized as the major cause of mouth cancer in mizoram. the daily consumption of the number betel leaves by an individual is about 15-25 in various districts of mizoram, which continuously acts as an irritant to the buccal mucosa [mehrotra et al.,2003]. one of the most important factors responsible for the oropharyngeal malignancy in mizoram is the chewing of raw betel nut [wahi et al.,1965]. among various risk factors for the occurrence of oesophageal cancer in mizoram, betel quid chewing carries a relative risk of 1.5 to 3.5%. the salted cooked vegetables made by adding sodium bicarbonate has shown to possess a high methylation activity and may lead to the endogenous formation of nitrosamine [malkan et al.,1997] and that can lead to stomach cancer. alcohol consumption has been considered as one of the major causes of colorectal cancer as per a recent monograph of who [baan et al.,2007]. annually, about 9.4% new colorectal cancer cases are attributed to the consumption of alcohol, globally [parkin et al.,2006]. an increased risk of 10% was observed with consumption of more than two drinks per day, which suggests a causative role of alcohol consumption in colorectal cancer [toriola et al.,2008]. recently, a study revealed that an increased risk of colorectal cancer was limited to consumption of more than 30.0 g of alcohol per day [longnecker et al.,1990]. relationship between alcohol consumption and high risk of oesophageal cancer was first known in 1910 [tuyns et al.,1979]. however, chronic alcohol consumption has been found to be a risk factor for the cancers of the upper respiratory and digestive tracts, including oral cavity, hypopharynx, larynx and oesophagus as well as liver, pancreas, mouth and breast cancers [tuyns,1979;maier,1994;seitz et al.,2004]. a 10.0 g/day intake of alcohol by a woman increases its relative risk of breast cancer by 7.1% [doll et al.,1981]. the mechanism of carcinogenesis due to alcohol consumption is not exactly known, however, it is thought that ethanol being a cocarcinogen might play a crucial role in the carcinogenesis [poschl et al.,2004]. the metabolic products of ethanol are acetaldehyde and free radicals. the free radicals are responsible for alcohol assisted carcinogenesis through their binding to dna and proteins, which destroy foliate leading to secondary hyper proliferation [anand et al.,2008]. non–tobacco risk factor includes infections, dietary factors, alcohol use, physical activities and body composition. other risk factors include exposure to asbestos, air pollution (indoor and outdoor), occupational exposures and exposure to radiation. consumption of alcohol is shown to be associated with cancers of the mouth, pharynx, larynx, oesophagus, colo-rectum (men) and breast (pre and postmenopausal). aflatoxins causes liver cancer. arsenic in drinking water and betacarotene supplements are known to contribute to lung cancer. colo-rectum is known to be caused by excess consumption of red and processed meat in our diet. associations between infections and cancer: hpv(human papilloma virus) infection and cervical cancer, epstein barr virus(ebv) and burkitt lymphoma as well as non-hodgkin and hodgkin lymphoma, hepatitis-c virus and hepatocellular www.companyofscientists.com/index.php/chd e13 cancer health disparities research carcinoma, kaposi sarcoma herpes virus (kshv) and kaposi sarcoma [harford et al.,2012]. acknowledgements the authors thank bioinformatics infrastructure (bt/bi/12/060/2012 (nerbif-mua), and dbt delcon facility at mizoram university sponsored by the department of biotechnology (dbt), new delhi, govt. of india. the authors thank mary k zothanpari for her help during data collection. conflict of interest the authors declare that no competing or conflict of interests exists. the funders had no role in study design, writing of the manuscript, or decision to publish. authors’ contributions jz and nsk conceptualized the study; 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cancer center, philadelphia, pa 19111 3claremont graduate university, school of global health *corresponding author: email: kashing@coh.org abstract women were recruited from two socioeconomically and ethnically similar regions to participate in the intervention. regions were assigned to one of two conditions: print only or print plus media-based social marketing. baseline and follow-up data were collected and analyzed using univariate and bivariate statistical approaches. there was a statistically significant relationship between intervention condition and reporting a pap test at follow up (p = .013). compared to women in the print only condition, women in the print plus media-based social marketing condition reported significantly increased pap testing. across both conditions, intention to receive pap testing was high. in the print only condition, 37 out of 40 (92.5%) participants reported intention to receive pap screening within two years, while 47 out of 57 (82.5%) participants in the print and media condition reported intention to have a test within two years. hpvv knowledge increased among all participants with no differences across intervention condition. the print only group reported no change in pap test completion at follow up. however, the enhanced trial condition showed a 25% increase in pap testing from baseline to follow-up. therefore, in both intervention conditions, hpv knowledge and hpvv acceptability significantly increased from baseline to follow-up among all participants. this study suggests a multicomponent media-based social marketing strategy may be useful in promoting pap testing and knowledge about hpvv among black women. keywords: kindly add. citation: ashing k et al (2021) testing a multicomponent intervention to increase pap uptake and hpv vaccination knowledge and acceptability among black women. cancer health disparities 5: e1-e10 doi:10.9777/chd.2020.1006 www.companyofscientists.com/index.php/chd e2 cancer health disparities research introduction black women in the united states suffer the greatest cervical cancer disparity. blacks have the highest cervical cancer incidence – 41% higher than white women – and are twice as likely to die from the disease than their white counterparts (desantis et al., 2016). although pap test and human papillomavirus vaccination (hpvv) offer the potential to prevent and even eradicate cervical cancer, black women continue to be disproportionately burdened. therefore, the reduction and elimination of persistent and troubling hpv-related cancer disparity among black women ought to be prioritized. the current guidelines for cervical cancer screening recommend women begin pap testing at age 21 and continue screening every three years until age 29. from age 30-65, women can continue screening every three years or at five year intervals if their pap test also includes an hpv test and there is no past positive screening result. the guideline for hpvv is the two vaccine series administered 6 to 12 months apart for individuals starting the series before age 15, and the three vaccine series for teens and young adults 15 to 26 years old. the second dose of the three vaccine series is administered 1-2 months after initiation and the third dose at 6 months (centers for disease control and prevention, 2016). despite the recommendations, pap-testing and hpvv uptake among blacks fall short of healthy people 2020 goals of 93% and 85%, respectively. blacks’ hpv vaccination coverage is 37.4%,which is lower than the national coverage of 44.8%, and their pap testing rate is 74% (arnett et al., 2016). low hpv vaccine uptake and underutilization of pap screening in this population may be partly a function of lack of knowledge (ashing et al., 2017; blackman et al., 2013; galbraith et al., 2016), absence of medical homes, and nonrecommendation by providers of these cancer prevention and control strategies (centers for disease control and prevention, 2016; galbraith et al., 2016). blacks’ knowledge of hpv and pap testing lags behind non-hispanic whites (ashing et al., 2017), and blacks are less likely to have a medical home or utilize primary care (arnett et al., 2016). many of the barriers to uptake in this population will need broader social and policy level interventions, but issues such as acceptability and lack of knowledge can be successfully addressed at the community and individual level. for example, an educational intervention among african american college students reported a statistically significant increase in participants’ knowledge post-intervention and high participant affirmation of intention to get regular pap smears (94%) and the hpv vaccine (87%) (staples et al., 2018). other strategies that have proved efficacious in increasing pap test uptake and knowledge and acceptability of hpvv among minorities include access-enhancing programs, community interventions, approaches directed at individuals, culturally and ethnically tailored materials, and mass media campaigns (chan et al., 2015; han et al., 2011). mass media have been used extensively in social marketing campaigns for various types of health behavior change ( hall et al., 2015; wakefield et al., 2010). this form of intervention offers a costeffective way to reach large, dispersed populations and is particularly useful in realizing episodic or one-time behaviors. in the context of cervical cancer prevention, the evidence suggests combining mass media and social marketing with other types of tailored interventions such as reminder letters results in increases in pap screening (wakefield et al., 2010). in one intervention, researchers used social marketing www.companyofscientists.com/index.php/chd e3 cancer health disparities research that combined radio public service announcements, doctor's recommendation, posters, and brochures targeting parents and providers to increase hpvv among preteen boys (cates et al., 2014). social marketing is a program planning and implementation process that applies commercial marketing concepts and techniques to promote voluntary attitude and behavior change (nowak et al., 2015). while these strategies have proven efficacious, only a few interventions have attempted to increase hpvv acceptability (galbraith et al., 2016), and even fewer simultaneously attempt to increase pap uptake and hpvv knowledge and acceptability among african american women. within the black culture, women, including grandmothers, play a central role in health decision-making (kennedy et al., 2007). therefore, targeting women of all ages for the intervention seems an efficient approach to increase pap testing among women and concurrently influence hpvv acceptability and uptake within families. the purpose of this study was to assess the efficacy of a multicomponent trial intervention to increase pap testing and hpvv knowledge and acceptability among african american women in two california counties. methods this behavioral trial was conducted in collaboration with community partners to enhance cultural and community relevance. we readily gained community buy-in because of the documented elevated cervical cancer prevalence and mortality in california. our community partners formed an active advisory council made up of health leaders from community-based health organizations. the advisory council guided the overall trial including the recruitment and intervention protocol. they also advised on best platforms for the intervention, hosted health fairs, and posted fliers at their community sites. the intervention strategies were informed by an effective pap testing media campaign conducted by the los angeles county office of women’s health (stone-francisco et al., 2003). thus, our intervention integrated a community engaged approach and a social marketing intervention to increase pap testing and hpvv knowledge and acceptability. setting the study was conducted across sub-urban cities within the san gabriel valley area of los angeles county, which served as the mailed intervention region; and sub-urban cities in riverside county, which served as the enhanced intervention region. the targeted regions, each of which was treated as a cluster, have similar demographics including ethnicity (40% latino, 5% black); median age (36.4); median household income ($65,744); high school graduation rate (about 70%); and number of foreign born residents (about 35%). these regions are approximately 55 miles apart. the distance reduces the likelihood of intervention contamination. participants inclusion criteria and justification. african american women 18 years or older living in these two socioeconomically and ethnically similar regions were invited to participate in the study. women were excluded if they had any type of cancer diagnosis history because the medical characteristics (e.g. disease progression, prognosis) and perceptions (e.g. health care seeking behaviors) are significantly different for these women. additionally, women with other major medical conditions (e.g. stroke and degenerative illness) who are likely to present with distinct medical and quality of life issues were excluded. www.companyofscientists.com/index.php/chd e4 cancer health disparities research procedures participant recruitment and enrollment. we used a multi-method recruitment approach that combined passive strategies – posting fliers at community centers and health clinics – and active strategies – distributing invitation fliers via community health networks, and direct participant invitation at various community cultural and health events. study advertisements included contact details for the research team. recruitment, enrollment and participation followed all institutional review board (irb) and other regulatory procedures. all participants signed an informed consent form to participate in the study. we send pre-intervention study packets to all women who expressed an interest in participating. the packets contained a letter of invitation that described the study; an informed consent form; the questionnaire; and a self addressed, stamped envelope. three weeks after initial mailing, a research assistant (ra) made a follow-up telephone call if no response was received. when a call was received from a potential participant and/or when the ra called, the ra described the study, reviewed the consent form, and answered any questions regarding the study. the preferred method of survey completion was mail; however, potential participants who were slow to respond were given the choice of completing the survey by mail or by telephone. the telephonic means of data collection allowed for the inclusion of women with low literacy. additionally, participants recruited at community events were given the choice to return the completed survey the same day or to return the survey via mail. recruitment and enrollment were conducted over a threemonth period. study participants were provided with a $20 gift card. trial intervention conditions. this trial was informed by the social marketing approaches and materials from the cdc; nih; and a successful social marketing cca prevention initiative launched by the los angeles county department of public health, office of women’s health (the multiethnic cervical cancer prevention and education initiative). the county’s multiethnic initiative resulted in 17,747 cca screenings, 10% of which were abnormal. our social marketing strategy used traditional media outlets (e.g., local tv and radio, ethnic newspapers, and circulars) and direct mailing to deliver the intervention. the study was titled “end stigma, end fear, and end cervical cancer”. each study region was assigned to one of two intervention conditions: 1) the enhanced intervention using traditional media plus direct mailing of printed materials with pap test and hpvv resources and 2) direct mailing of printed materials with pap test and hpvv resources, only. women in the enhanced intervention region were exposed to public service announcements (psas) on public access tv and radio, and printed information posted in community circulars and newspapers distributed in the targeted region. psas, developed by the study team in collaboration with community partners, were aired each day at 11a.m. and 8p.m. for three months. this schedule was intended to increase exposure while reducing cost. the intervention content included information about pap testing, hpv and hpvv, and health clinics and facilities that offered free or low-cost pap testing and hpvv. at three months post intervention (6 months post baseline), we mailed post-intervention packets that contained a “thank you” letter, the questionnaire, and a self-addressed, stamped envelope to all enrolled participants. two follow-up phone calls were made to encourage participants to return the questionnaires. www.companyofscientists.com/index.php/chd e5 cancer health disparities research measure participants were assessed at two time points: baseline and post-intervention. participants completed a self-report assessment comprised of standardized measures (e.g., mos social support), items drawn from related studies, and new items generated from the lead author’s previous research with multiethnic samples (ashing et al., 2017; blackman et al., 2013; lim and ashing-giwa, 2011; ragin et al., 2017). the questionnaire included items that queried medical history, pap test completion, hpv knowledge, hpv vaccine attitude, stigma, life stress, health care utilization, quality of health care, sexual practices, and demographic variables. one item queried pap test intention and completion (when do you plan to have your next pap test?); three items queried pap test knowledge (e.g. can pap test find abnormal cervical cancer cells early?); three items queried hpv knowledge (e.g. do you think you can get hpv through sexual contact? can hpv cause certain cancers?); and three items queried hpv vaccine acceptability (e.g. would you/have you ever recommended that a relative or friend get the hpv vaccine?). the questionnaire took about 3545 minutes to be completed. outcome measures primary outcome measures in the analysis were knowledge and beliefs about pap testing and hpv vaccine, intention to receive pap test, pap test completion, and hpvv acceptability. pap test knowledge was examined using three questions that examined participants’ knowledge about the benefit of regular pap tests, where to get more information about pap testing, and where to refer someone to receive the pap test. pap test acceptability items asked about their perceptions of the cost and safety of pap test, and willingness to recommend pap testing to a friend. pap test completion was assessed by asking participants if they intend to receive a pap test within the next year. hpv vaccine knowledge was examined using two questions that examined participants’ knowledge of ever hearing of hpv vaccine to prevent cervical cancer and knowledge that you can get hpv through sexual contact. hpv vaccine acceptability was measured from participants’ responses to three items that asked participants if they would recommend hpv vaccine to a relative or friend, if the vaccine cost too much, and if they believed the hpv vaccine is safe. the items for knowledge and acceptability were summed to obtain a composite score measuring knowledge and acceptability of hpv vaccine and pap test. data analysis data analysis was conducted using spss version 24. an alpha level of .05 was chosen for all statistical tests. to check for differences between experimental conditions at baseline, t-tests were used for scales and chi-square tests or fishers exact tests were performed for categorical data as needed. chi-square test was used to examine if there was a relationship between plan to receive the pap test within two years between intervention groups. analysis was conducted separately for those who had reported having had a pap test and those who did not report a pap test at baseline. repeated measure anova was used to examine changes in hpv vaccine knowledge and acceptability between intervention groups from pretest to posttest. results the study sample consisted of 141 participants aged 18 years and above, with a mean age of 46.13 (sd= 14.09). overall, 35.8% of participants were between 40-54 years old; 49.3% had some college/associate degree education; 61% reported having private insurance; 44% had over $45k yearly income; 27% lived with a partner and children; and 42% were partnered. our analysis showed a significant difference in educational www.companyofscientists.com/index.php/chd e6 cancer health disparities research status between intervention conditions (χ2 (2) =9.77, p =.008). those in the enhanced intervention condition were more likely to report having a college degree or more (49.1%) compared to the direct mailing only condition (24.1%). there were no significant differences mean age (t = -0.61, p =.541), marital status (χ2 (1) =0.002, p = .963), income (χ2 (2) =0.09, p = .954) or having private insurance (χ2 (1) =3.39, p = .066). for the enhanced intervention delivery, we used of multiple channels – radio, tv, newspapers, and circulars. eight-seven percent of the enhanced intervention trial participant indicated that they were exposed to at least two of the intervention condition. pap test knowledge and completion there was no overall significant increase in knowledge from baseline to follow up (p=.956); and no significant difference between groups in pap knowledge at follow up (p=.632). fisher’s exact test was used to examine the relationship between trial conditions and pap testing completion at follow up among 44 african american women who did not report having had a pap test. there was a significant relationship between intervention group and reporting a pap test at follow up, (p = .013). none of the participants in the print only group reported a pap test at follow up. however, the enhanced trial condition showed a 25% increase in pap testing from baseline to follow-up with 4 out of 16) participants in the enhanced intervention reported having had a pap test at follow up. intent to receive pap test in the future chi-square tests and fisher’s exact tests were used to compare demographic, knowledge and beliefs for those who reported an intention to test within two years and those who did not. there were no significant difference between both groups at p<.05 level. for those who did not report a pap test at baseline, there was a non-significant trend when comparing the relationship between intervention group condition and intention to have a pap test within two years (χ2 (1) =2.45, p =.107). in the print only condition, 9 out of 28 (32%) participants reported an intention to receive pap screening within two years, while 9 out of 16 (56%) of participants in the enhanced intervention condition reported an intention to have a test within two years. among those who had reported a pap test at baseline, there was a significant relationship between intervention trial group and intention to have a pap test within two years (χ2 (1) =19.83, p <.001). in the print only group, 28 out of 56 (50%) participants reported an intention to receive pap screening within two years, while 38 out of 41 (92.6%) of participants in the print and media group reported an intention to have a test within two years. hpv vaccine knowledge a mixed-design repeated-measure anova revealed no significant effect of the enhanced intervention group (f(1, 95)=1.57, p=.213 ) or timeby-group interaction (f(1, 95)=0.18, p=.674) on hpv knowledge. however, there was a significant effect of time on hpv knowledge, f(1, 95) = 5.79, p = .018, η2 = .06. this indicates both intervention conditions showed increases on hpv knowledge. therefore, in both intervention conditions, hpv knowledge significantly increased from baseline to follow-up among all participants. www.companyofscientists.com/index.php/chd e7 cancer health disparities research figure 1. results of mixed-design repeated-measure anova showing change in hpv knowledge between groups hpv vaccine acceptability there was no significant effect of enhanced intervention condition on hpv acceptability f(1, 95) = 0.51, p < .478. similarly, no time-by-intervention interaction was found (p = .497, η2 = 0.005). however, there was a statistically significant effect of time on hpv acceptability, f (1, 95) = 53.37, p < .001, η2 = 0.36. both intervention conditions improved on hpv acceptability. follow-up univariate analyses using paired t-test confirmed significant increases in acceptability between the pretest and posttest for both the direct mailing condition (t = -4.64, p <.001), and the enhanced intervention condition (t = -5.95, p <.001). therefore, in both trial conditions, hpv acceptability significantly increased from baseline to follow-up. figure 2. results of paired t-test showing increase in hpv acceptability from baseline to follow-up. www.companyofscientists.com/index.php/chd e8 cancer health disparities research table 1. mean and standard deviations for hpv knowledge and acceptability. print only print and media baseline follow up baseline follow up hpv knowledge 1.18 (0.12) 1.40 (0.11) 1.37 (0.10) 1.53 (0.09) hpv acceptability 1.05 (0.18) 1.85 (0.17) 1.11 (0.15) 1.07 (0.14) discussion hpvv vaccination and early detection through pap screening are critical to cervical cancer prevention and control, but only 39% of african american women receive an early cervical cancer diagnosis compared to 48% of non-hispanic whites (ashing et al., 2017). african american women also have a poorer prognosis and higher mortality than their white counterparts. in addition, despite this greater hpv related cancer burden, african americans have unacceptably low hpvv. there is an urgent need to reduce cervical cancer disparities among african americans by implementing and disseminating interventions that increase knowledge and timely uptake of hpv vaccination and pap testing. the results of this study suggest a multicomponent approach has the potential to increase pap testing in this population. at follow up, more participants in enhanced intervention reported having a pap test than participants assigned to the direct mailing condition. adding the enhanced mediabased social marketing component, therefore, increased the effectiveness of the intervention in boosting pap test uptake. this finding adds to the growing evidence in support of interventions that use multiple strategies versus a single-focus approach (han et al., 2011). is also suggests there is utility in fusing media, community-based approaches, and social marketing strategies in interventions to increase pap testing among african american women. in african american populations, mass media and in particular black media have been identified as an effective health promotion communication tool (hall et al., 2015). the centers for disease control (cdc), for example, used radio advertisements and small media to enhance the reach and impact of the agency’s african american women and mass media (aamm) campaign (hall et al., 2015). evaluation of the aamm showed the program reached target audience and resulted in increased awareness of breast cancer screening services. based on the preliminary results of our study, it is worth exploring further how adding a social marketing component can make media interventions even more appealing to african american women and reduce barriers to pap uptake. the added benefit of the enhanced intervention was not realized for hpvv outcomes. specifically, regarding hpvv knowledge and acceptability, adding the social marketing component did not result in statistically significant differences across trial conditions. comparison of baseline and follow up results shows, overall, the trial was effective in significantly increasing african american/black women’s knowledge and acceptability of hpvv. therefore, among african americans in our sample, targeted, media-based social marketing www.companyofscientists.com/index.php/chd e9 cancer health disparities research did not provide added value in reducing hpvv hesitance and improving hpvv. this finding is a little surprising. considering the success of social marketing in health promotion (stead et al., 2007), we anticipated the enhanced intervention would show greater efficacy in increasing hpvv knowledge and acceptability. as this study focused on hpvv acceptability relevant to adolescent vaccination, it is plausible that cultural factors relevant to sexual beliefs and practices may be potent barriers. therefore, research to increase hpvv among blacks may need to closely attend to and address cultural and health system factors. limitations and conclusion the findings reported here should be interpreted within the limitations of this study. first, the study relied on self-report. however, the responses and scores on the outcome measures seem reasonable and realistic. it would be useful for future studies to also include objective measures, such as medical chart reviews for pap testing and hpvv, as complements for subjective assessments. for the enhanced intervention delivery, we used multiple channels – radio, tv, newspapers, and circulars. eight-seven percent of the enhanced intervention trial participant indicated that they were exposed to at least two of the intervention condition. however, we did not measure frequency and duration of exposure. also, our media channels were limited to local outlets, only. this may have limited the impact compared to using larger outlets with broader foothold in african american/black markets. however, utilizing larger media outlets would have disseminate the enhanced intervention to women in regions assigned to the direct mailing condition. despite the limitations, this study makes an important contribution to the small but growing research on intervention strategies to increase pap and hpvv. overall, this study suggests a multicomponent, media-based social marketing strategy that is informed by the community may be useful in promoting pap testing and providing information about hpvv. both the direct mail of the printed resources and the enhanced approach showed the potential to significantly boost knowledge and acceptability of hpvv among african american women. in summary, studies targeting women for both hpvv and pap testing improvements are critical since women are often the health decision-makers for themselves and adolescents within families. there is need for greater understanding of multilevel (including health systems and providers) and multi-channel best practices targeting behavior change to increase pap testing and hpvv. further, since the vaccine is now approved for individuals 9-45 years old, giving an opportunity for hpvrelated cancer prevention among youth to middleadulthood, future studies will need to develop and disseminate effective strategies for targeting african americans/blacks and other groups to vaccinate their adolescents and themselves. acknowledgement this research received funding from the city of hope excellence award, and did not receive any support from funding agencies in the public or commercial sectors. the authors wish to thank the participants for the study for sharing their experiences. we thank dr lenna dawkins-moulton for her assistance in formatting this manuscript for submission. conflicts of interest the authors declare that they have no conflict of interest. www.companyofscientists.com/index.php/chd e10 cancer health disparities research authors' contributions kimlin ashing led the overall study and writing. camille ragin and ndifreke etim contributed to the conceptualization and writing. dr etim contributed to the data analyses. references arnett, m. j., thorpe, r. j., gaskin, d. j., bowie, j. v., and laveist, t. a. 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(2010). use of mass media campaigns to change health behaviour. lancet 376, 1261-1271. introduction methods setting participants procedures measure outcome measures data analysis results pap test knowledge and completion intent to receive pap test in the future hpv vaccine knowledge hpv vaccine acceptability discussion limitations and conclusion acknowledgement conflicts of interest authors' contributions www.companyofscientists.com/index.php/chd e1 cancer health disparities research mortality disparities: a comparison with the haudenosaunee in new york state rodney c. haring1, melissa a. jim2, deborah erwin3, judith kaur4, whitney ann e. henry5, marissa l. haring6, dean s. seneca7 1 office of community outreach and engagement , department of cancer prevention and control, roswell park comprehensive cancer center, buffalo, ny 2 division of cancer prevention and control, national center for chronic disease prevention and health promotion, centers for disease control and prevention, albuquerque, nm 3 office of community outreach and engagement, department of cancer prevention and control, roswell park comprensive cancer center, buffalo, ny 4 mayo clinic, jacksonville, fl 5 office of community outreach and engagement, department of cancer prevention and control, roswell park comprehensive cancer center, buffalo, ny 6 student research experience program in cancer science, department of educational affairs, roswell park comprehensive cancer center, buffalo, ny 7 partnership support unit, office for state, tribal, local and territorial support, centers for disease control and prevention, atlanta, ga *corresponding author email: rodney.haring@roswellpark.org abstract: identifying health status and disparities for indigenous populations is the first logical step toward better health. we compare the mortality profile of the american indian and alaska native (ai/an) population with that of non-hispanic whites in the haudenosaunee nations in new york state, the indian health service (ihs) east region (nashville area) and the united states. data from the linkage of ihs registration records with decedents from the national death index (1990-2009) were used to identify ai/an deaths misclassified as non-ai/an. analyses were limited to persons of non-hispanic origin. we analyzed trends for 1990-2009 and compared ai/an and white persons in the haudenosaunee nations in new york state, ihs east region and the united states. all-cause death rates over the past two decades for haudenosaunee men declined at a greater percentage per year than for ai/an men in the east region and united states. this decrease was not observed for haudenosaunee women with all-cause death rates appearing to be stable over the past two decades. haudenosaunee all-cause death rates were 16% greater than that for whites in the haudenosaunee nations. the most prominent disparities between haudenosaunee and whites are concentrated in the 25-44 year age group (risk ratio=1.85). chronic liver disease, diabetes, unintentional injury, and kidney disease death rates were higher in haudenosaunee than in whites in the haudenosaunee nations. the haudenosaunee cancer death rate (180.8 per 100,000) was higher than that reported for ai/an in the east (161.5 per 100,000).haudenosaunee experienced higher rates for the majority of the leading causes of death than east ai/an. these results highlight the importance of haudenosaunee-specific data to target prevention efforts to address health disparities and inequalities in health. keywords: cancer, diabetes, health disparities, obesity, native american, american indian, haudenosaunee, iroquois, new york, minority health. citation: haring rc et al (2018) mortality disparities: a comparison with the haudenosaunee in new york state. cancer health disparities 2:e1-e20, doi:10.9777/chd.2018.10009 mailto:rodney.haring@roswellpark.org www.companyofscientists.com/index.php/chd e2 cancer health disparities research background health disparities are health differences that are closely linked with social, economic, or environmentally disadvantaged communities or populations (u.s. department of health and human services, 2008). health disparities adversely affect groups of people who have systematically experienced greater obstacles to health based on characteristics historically linked to discrimination or exclusion. health disparities are measured by tracking rates of illness, death, chronic conditions, and behaviors related to sociodemographic features such as race and ethnicity (u.s. department of health and human services, 2008) –as well as income and education. american indians and alaska natives (ai/ans)— native americans—experience excesses of a number of diseases that may be linked to environmental obstacles, health behaviors, or lifestyles attributed to the possible epigenetic factors of trauma or stress (brown et al., 2010; shonkoff, boyce, & mcewen, 2009; cobb, espey, & king, 2014; warne, 2006). the most common causes of death for ai/an populations are heart disease, cancer, unintentional injuries, diabetes, stroke, chronic liver disease and cirrhosis, chronic lower respiratory disease, suicide, influenza, pneumonia, and kidney diseases. health disparities in indian country (natural resources conservation science, n.d.) vary regionally and correspond to similar trends in mortality rates (espey et al., 2014a; white et al., 2014; li et al., 2014; murphy et al., 2014; indian health services, 2016). obesity is likely a contributing factor to many of these diseases with ai/an men and women having a higher prevalence of obesity than their white counterparts (cobb et al., 2014; moore, chadid, singer, kreger, & denis, 2014; haring et al. 2016). cancer health disparities kilbourne and colleagues define health disparities for public health as the “observed clinically and statistically significant differences in health outcomes or health care use between socially distinct vulnerable and less vulnerable populations that are not explained by the effects of selection bias,” (kilbourne, switzer, hyman, crowley-matoka, & fine, 2006). the national cancer institute (nci) has further defined cancer-related health disparities as “adverse differences in new and existing cancer incidence (new cases), morbidity (cancer related health complications), cancer mortalities (death), cancer survivorship and burden of cancer or related health conditions that exist among specific population groups in the united states” (nci, n.d.). cancer is the second leading cause of death in new york state (nys). in 2009, the age-adjusted cancer incidence rate for all cancers was 484.2 cases per 100,000 new yorkers, which is the ninth highest in the united states (u.s.). the nys ageadjusted mortality rate for all cancer sites is 164.3 per 100,000 population, which is almost 6% lower than the u.s. rate (173.8); the state’s overall cancer mortality rate decreased by an average of 2% each year across all ages and races between 2005 2009. notably for this report, only cancers of the uterus and liver/bile duct had increases in annual mortality rates when looking at 5-year rate changes (nys cancer consortium, 2012). incidence and mortality rates in nys by race/ethnicity are reported highest among black men (nys cancer consortium, 2012); however, incidence and mortality rates for ai/an populations in nys are not available for comparison from the state cancer profiles on cancer control p.l.a.n.e.t. (https://ccplanet. www.companyofscientists.com/index.php/chd e3 cancer health disparities research cancer.gov/) or the latest nys comprehensive cancer control plan, possibly due to the challenges of reporting smaller case counts from identifiable areas and possible data-reporting errors. however, the 2012-2017 nys comprehensive cancer control plan text states that ai/an populations were one of several populations identified by new york’s medicaid redesign team health disparities workgroup “that may experience greater health disparities,” (nys cancer consortium, 2012). this team further states that “ai/an groups face greater socioeconomic barriers than many other racial/ethnic groups” and “…should receive priority consideration when intervention strategies are being developed and implemented” (nys cancer consortium, 2012). haudenosaunee & indian health service east region to address race misclassification in death records and cancer surveillance data, efforts have been made to better characterize and track the health status of ai/an populations (espey et al., 2014b; espey et al., 2008). mortality data provide essential information for measuring the health of a population. ai/an mortality data are often presented for 12 indian health service (ihs) areas (indian health service, n.d.) and six ihs regions (northern plains, alaska, southern plains, southwest, pacific coast, and east) (espey et al., 2014b; espey et al., 2008; espey et al., 2007). our interest lies in the ihs east region, which contains the same states as those in the ihs nashville area. this catchment includes a mixture of tribes with varying degrees of “first contact” with europeans; varying levels of nation-to-nation relationships with the united states; differences in culture, customs, and language; and vast geographic distances between states from the northeast to the southeast. previous studies have worked with individual northeast native nations to look at tribal data on matrilineal enrolled members only (mahoney, va, stevens, kahn, & michalek, 2009). others have used nation-specific health center data for review (schulz, lalicata, carnes, & rith-najarian, 1997) or obtained data from school systems for community health information (botash, kavey, emm, & jones, 1992). specific tribal data are useful for each nation individually and helpful when looking at enrolled citizens, non-enrolled membership populations, or school-aged children. there is also a need to look at population health from both enrolled and non-enrolled tribal members to paint an inclusive picture of global tribal wellness and its relation to disparities. therefore, the ihs east region lacks an aggregated picture of health disparities from the largest confederacy of tribes in nys, whose bloodlines are distinctly related through clan systems, language, and traditional practices. the haudenosaunee have land throughout a majority of nys (figure 1). the haudenosaunee confederacy tribes include the mohawk, oneida, onondaga, tuscarora, cayuga, and seneca. the mohawk are known as the “keepers of the eastern door” and are responsible for protecting and defending the eastern boundaries of haudenosaunee territory (smithsonian nmai, n.d.). the onondaga are the “keepers of the central fire” since the onondaga nation is considered the capital of the confederacy (smithsonian nmai, n.d.). the seneca are the “keepers of the western door” and are responsible for protecting and defending the western boundaries of haudenosaunee territory (smithsonian nmai, n.d.). www.companyofscientists.com/index.php/chd e4 cancer health disparities research figure 1. haudenosaunee – iroquois confederacy in this article, we provide an overview of leading causes of death and all-cause mortality trends for ai/ans and whites in the haudenosaunee nations, the east region, and the united states. we utilize national mortality data that have been linked to the ihs patient registration data to improve race/ethnicity classification. results will provide guiding information that can help shape solutions for health care needs for the haudenosaunee in nys. methods detailed methods for generating the analytic mortality files are described elsewhere (espey et al., 2014b). an abbreviated description follows. data sources population estimates. we used county-level population estimates produced by the u.s. census bureau as denominators in the rate calculations. to manage multiple race/ethnicity data collected since 2000, we used the national center for health statistics (nchs)/census bureau method of bridging race/ethnicity categories into singlerace/ethnicity (ingram et al., 2003). the nci made further refinements regarding race/ethnicity, county geographic codes, and adjustments for population shifts because of hurricanes katrina and rita in 2005, and provided public access to these estimates at the surveillance, epidemiology, and end results (seer) website (nci seer, n.d.). during preliminary analyses, we discovered that the updated bridged intercensal populations estimates significantly overestimated ai/an persons of hispanic origin (edwards et al., 2013). therefore, to avoid underestimating mortality in ai/an populations, we limited analyses to non www.companyofscientists.com/index.php/chd e5 cancer health disparities research hispanic ai/an persons. non-hispanic white was chosen as the most homogeneous referent group. for conciseness, the term “non-hispanic” is henceforth omitted when discussing both groups. death records. each state compiles death certificate data and sends them to the nchs, where they are edited for consistency. the nchs makes this information available to researchers as part of the national vital statistics system (nvss), and includes underlying and multiple cause of death fields, state of residence, age, sex, race, and ethnicity (national center for health statistics, n.d.). nchs and the census bureau use the same bridging algorithm to assign a single race to decedents with multiple races reported on the death certificate (national center for health statistics, 2004). the ihs patient registration database was linked to the national death index (ndi) to identify ihs decedents who had received health care in ihs or tribal facilities and were misclassified as non-ai/an (espey et al., 2014b). following this linkage, ihs records for persons identified as deceased were then linked to 1990 to 2009 annual nvss mortality files as an additional indicator of ai/an ancestry. these files were combined with corresponding annual bridged race intercensal population estimates to create an analytic file, the ai/an mortality database (amd), in seer*stat software version 8.0.4 (surveillance research program, n.d.). race for ai/an deaths is assigned as reported elsewhere (espey et al., 2014b). in short, the amd combines race classification by nchs on the basis of the death certificate and information derived from data linkages between the ihs patient registration database and the national death index. for the years 1990-1998, the underlying cause of death was coded according to the international classification of diseases, ninth revision (icd-9) (world health organization, 1980). for 1999-2009, the international classification of diseases, 10th revision (icd-10) was used (world health organization, 1999). trend analyses spanning icd9 and icd-10 reporting years took into account comparability of cause of death recodes between the two revisions (anderson, minino, hoyert, & rosenberg, 2001). to present the leading cause of death in rank order, as established by death counts, we used the method developed by nchs based on the recode for 113 selected causes of death (anderson et al., 2001; heron, 2012). geographic coverage. the analyses in this article are restricted to ihs contract health service delivery area (chsda) counties, which follow county boundaries and are established by ihs for each federally recognized tribe. the chsda consists of counties that include all or part of a reservation, and any county or counties that have a common boundary with the reservation (indian health service, 2016). linkage studies have indicated less misclassification of race/ethnicity for ai/an persons in these counties (jim et al., 2014). the analyses were completed for ai/an and white persons in the haudenosaunee nations, east region, and the united states. the haudenosaunee nations are situated in nine nys counties: allegany, cattaraugus, chautauqua, erie, franklin, genesee, madison, niagara, and onondaga. only counties that touched one of the haudenosaunee nations were included in the analyses (figure 1). the east region consists of alabama, arkansas, connecticut, delaware, florida, georgia, kentucky, louisiana, maine, maryland, massachusetts, mississippi, missouri, www.companyofscientists.com/index.php/chd e6 cancer health disparities research new hampshire, new jersey, new york, north carolina, ohio, pennsylvania, rhode island, south carolina, tennessee, vermont, virginia, west virginia, and washington, d.c. identical or similar regional analyses have been used for other healthrelated publications focusing on ai/an populations (espey et al., 2014a; denny & taylor, 1999; espey, paisano, & cobb, 2005; wiggins et al., 2008). statistical methods. all rates, expressed per 100,000 population, were directly age-adjusted, using seer*stat software (surveillance research program, n.d.), to the 2000 u.s. standard population and using 11 age groups (<1 year, 1-4 years, 5-14 years, 15-24 years, 25-34 years, 35-44 years, 45-54 years, 55-64 years, 65-74 years, 7584 years, and ≥ 85 years) in accordance with a 1998 department of health and human services recommendation (anderson, 1998a; anderson, 1998b). readers should avoid comparison of these data with published death rates adjusted using a different standard population. using the age-adjusted, all-cause death rates, standardized rate ratios (rrs) were calculated for ai/an using white rates for comparison. ninetyfive percent confidence intervals (ci) for ageadjusted rates and standardized rrs were calculated based on methods described by tiwari, clegg, & zou (2006) using seer*stat and were rounded to two decimal places. we conducted trend analyses and comparability tests for age-standardized death rates using joinpoint software, version 4.0.3 (joinpoint regression program, 2017). we calculated annual percent change (apc) for each of the trend segments and average annual percent change (aapc) for 1990-2009 to quantify the average trend over this period. we conducted tests to assess pairwise differences between ai/ans and whites to determine whether the trends lines were parallel or coincident (kim, fay, feuer, & midthune, 2000), then we tested the average annual percentage change for the two groups to determine whether they were statistically different. statistical significance was set at p<.05. results all-cause death rates and leading causes of death for the haudenosaunee nations, east, and united states comparing ai/an with white persons in chsda counties are presented in table 1. in subsequent results as well as in the discussion, “death rates” refers to analyses restricted to chsda counties only and for conciseness, the term “haudenosaunee” will be used when discussing “haudenosaunee nations ai/an”. comparisons of all-cause death rates in haudenosaunee with those of whites in the haudenosaunee nations (rr=1.16) were greater than those in the east (rr=1.03) but not as high as those in the u.s. (rr=1.41). table 1 also ranks the leading causes of death for ai/an compared to white persons by sex for the haudenosaunee nations, east, and united states for 1990-2009. the ten leading causes of death among the haudenosaunee, in order, were heart disease, cancer, unintentional injury, diabetes, stroke, chronic liver disease, chronic lower respiratory disease, influenza and pneumonia, kidney disease, and septicemia. rates for haudenosaunee were significantly higher than whites for all causes (rr=1.16), heart disease (rr=1.12), unintentional injury (rr=2.08), diabetes (rr=3.46), chronic liver disease (rr=4.06), kidney disease (rr=3.31), and septicemia (rr=1.85); and significantly lower for cancer (rr=0.89). rates for www.companyofscientists.com/index.php/chd e7 cancer health disparities research stroke, chronic lower respiratory disease, suicide, and influenza and pneumonia were similar for haudenosaunee and whites in the haudenosaunee nations. table 1. death rates for all causes for american indians and alaska natives compared with whites, males and females, all ages: chsda counties, united states, 1990-2009. haudenosaunee nations east united states ai/an white ai/an:white ai/an white ai/an:white ai/an white ai/an:white cause of deatha rank count rate rank count rate rate ratio rank count rate rank count rate rate ratio rank count rate rank count rate rate ratio males and females all causes ... 2,419 975.9 ... 376,422 844.6 1.16* ... 9,833 847.1 ... 2,787,191 824.1 1.03* ... 184,633 1,158.4 ... 8,298,817 823.7 1.41* heart disease 1 688 306.2 1 124,096 272.6 1.12* 1 2,396 232.4 1 851,677 246.3 0.94* 1 36,199 265.0 1 2,401,219 234.6 1.13* cancer 2 442 180.8 2 89,832 203.6 0.89* 2 1,827 161.5 2 666,908 197.6 0.82* 2 30,837 205.5 2 1,961,477 193.3 1.06* unintentional injury 3 182 53.5 6 10,196 25.7 2.08* 3 939 55.2 5 103,959 35.2 1.57* 3 24,299 102.9 5 349,035 38.3 2.69* diabetes mellitus 4 151 61.1 7 7,865 17.6 3.46* 4 684 59.4 7 60,945 17.9 3.31* 4 10,549 71.0 8 194,187 19.1 3.71* stroke 5 109 48.7 3 24,581 53.4 0.91 5 504 51.9 3 176,518 50.6 1.03 6 7,816 61.5 3 557,403 54.3 1.13* chronic liver disease 6 105 34.5 11 3,529 8.5 4.06* 6 402 26.9 12 29,969 9.4 2.86* 5 8,547 42.0 11 93,030 9.6 4.39* chronic lower respiratory disease 7 104 46.2 4 19,761 43.3 1.07 7 313 30.1 4 144,806 41.8 0.72* 7 6,348 47.9 4 483,387 47.0 1.02 influenza and pneumonia 8 55 27.2 5 12,132 26.4 1.03 8 230 25.5 6 84,987 24.3 1.05 9 5,455 42.3 6 253,216 24.7 1.71* kidney disease 9 51 21.8 8 5,384 11.8 3.31* 12 138 7.3 22 8,736 3.2 2.29* 10 3,540 13.1 21 28,058 3.3 4.01* septicemia 10 50 20.9 9 5,256 11.7 1.85* 9 199 18.2 9 40,278 11.6 1.57* 11 3,137 22.6 10 99,171 9.7 2.34* suicide 11 30 8.1 12 3,156 8.5 0.95 11 158 8.7 11 33,398 11.7 0.75* 8 5,582 20.9 9 128,794 14.3 1.46* males all causes ... 1,251 1,184.1 ... 178,253 1,040.7 1.14* ... 5,215 995.9 ... 1,357,842 1,012.6 0.98 ... 101,696 1,390.9 ... 4,140,089 997.3 1.39* heart disease 1 360 395.0 1 59,191 348.5 1.13* 1 1,279 283.0 1 417,231 313.8 0.90* 1 20,488 337.1 1 1,215,776 296.0 1.14* cancer 2 200 199.2 2 45,076 251.6 0.79* 2 932 196.2 2 343,655 245.4 0.80* 3 15,503 242.1 2 1,025,335 236.3 1.02* unintentional injury 3 124 81.9 5 6,183 36.3 2.26* 3 628 76.2 5 65,649 49.5 1.54* 2 16,673 146.7 4 222,193 53.0 2.77* diabetes mellitus 4 74 69.1 7 3,700 21.0 3.29* 4 316 59.5 7 29,582 21.5 2.77* 5 4,830 71.3 8 94,905 22.3 3.20* chronic liver disease 5 64 44.3 11 2,180 11.8 3.77* 5 235 33.6 10 19,146 13.2 2.54* 4 4,836 50.3 10 59,327 13.0 3.86* stroke 6 48 50.6 4 9,094 55.0 0.92 6 222 53.4 4 66,913 51.6 1.03 7 3,350 61.8 5 216,472 54.6 1.13* chronic lower respiratory disease 7 47 51.9 3 9,441 54.9 0.95 7 145 34.2 3 69,171 51.2 0.67* 8 3,182 58.8 3 238,332 57.1 1.03 influenza and pneumonia 8 27 38.2 6 5,353 33.6 1.14 9 113 33.0 6 37,341 29.8 1.11 9 2,794 52.6 6 113,846 29.7 1.77* suicide 9 27 15.5 8 2,671 15.3 1.01 8 123 14.0 8 26,340 19.3 0.72* 6 4,452 34.6 7 102,346 23.7 1.46* www.companyofscientists.com/index.php/chd e8 cancer health disparities research kidney disease 10 24 26.7 9 2,500 15.3 1.74* 11 91 19.6 9 19,719 15.4 1.28 11 1,370 23.7 11 49,475 12.5 1.89* assault (homicide) 11 20 10.9 23 399 2.3 4.68* 10 110 12.0 19 5,902 4.4 2.73* 10 2,663 20.1 20 18,832 4.4 4.56* females all causes ... 1,168 827.9 ... 198,169 708.5 1.17* ... 4,618 730.9 ... 1,429,349 683.9 1.07* ... 82,937 970.8 ... 4,158,728 688.3 1.41* heart disease 1 328 248.5 1 64,905 218.9 1.14* 1 1,117 194.6 1 434,446 196.0 0.99 1 15,711 209.2 1 1,185,443 186.7 1.12* cancer 2 242 169.3 2 44,756 174.4 0.97 2 895 139.5 2 323,253 166.5 0.84* 2 15,334 180.2 2 936,142 164.1 1.10* diabetes mellitus 3 77 54.8 6 4,165 15.3 3.58* 3 368 58.4 8 31,363 15.3 3.81* 4 5,719 70.2 8 99,282 16.7 4.20* stroke 4 61 46.2 3 15,487 51.7 0.89 5 282 50.0 3 109,605 49.1 1.02 5 4,466 60.8 3 340,931 53.3 1.14* unintentional injury 5 58 31.7 7 4,013 16.9 1.87* 4 311 36.2 7 38,310 22.4 1.62* 3 7,626 63.4 7 126,842 24.8 2.56* chronic lower respiratory disease 6 57 42.5 4 10,320 37.0 1.15 6 168 27.8 4 75,635 36.2 0.77* 7 3,166 40.9 4 245,055 40.7 1.01 chronic liver disease 7 41 25.5 12 1,349 5.7 4.47* 7 167 21.3 12 10,823 6.1 3.49* 6 3,711 34.7 13 33,703 6.5 5.37* septicemia 8 33 23.8 9 2,890 10.3 2.30* 10 99 15.6 10 20,222 9.5 1.64* 10 1,396 16.7 10 41,899 6.9 2.41* influenza and pneumonia 9 28 21.6 5 6,779 22.3 0.97 8 117 21.2 5 47,646 21.0 1.01 8 2,661 35.5 6 139,370 21.6 1.65* kidney disease 10 27 19.2 10 2,884 9.9 1.94* 9 108 17.5 9 20,559 9.5 1.85* 9 1,767 22.2 9 49,696 8.0 2.79* note: ai/an indicates: american indian/alaska native; chsda: contract health service delivery area. all analyses were limited to decedents of non-hispanic origin. ai/an race is reported from death certificates or through linkage with the ihs patient registration database. rates are per 100,000 people and were age-adjusted to the 2000 us standard population (11 age groups; census p25-1130). rate ratios were calculated in seer*stat (version 8.3.2) before rounding of rates and may not equal rrs calculated from rates presented in the table. states and years data excluded because hispanic origin was not collected on the death certificate: la: 1990; nh: 1990-1992; ok: 1990-1996. east region is defined as: al†, ar, ct†, de, fl†, ga, ky, la†, me†, md, ma†, ms†, mo, nh, nj, ny†, nc†, oh, pa†, ri†, sc†, tn, vt, va, wv, dc. percentage regional coverage of ai/an persons in chsda counties to ai/an persons in all counties: east = 18.4%; total us = 64.2%. source: ai/an mortality supplement database (1990-2009). † identifies states with ≥ 1 county designated as chsda. *p<0.05 www.companyofscientists.com/index.php/chd e9 cancer health disparities research in men, all cause death rates in the haudenosaunee nations (1,184.1 per 100,000) were higher than those in the east (995.9) but not as high as those in the u.s. (1,390.9). the leading cause of death was heart disease for both ai/an and white men, with rates that ranged from 283.0 in east ai/an to 395.0 for haudenosaunee. the next ten leading causes of death for haudenosaunee men were cancer, unintentional injury, diabetes, chronic liver disease, stroke, chronic lower respiratory disease, influenza and pneumonia, suicide, kidney disease, and homicide. rates for haudenosaunee males were significantly higher than whites for all causes (rr=1.14), heart disease (rr=1.13), unintentional injury (rr=2.26), diabetes mellitus (rr=3.29), chronic liver disease (rr=3.77), kidney disease (rr=1.74) and homicide (rr=4.68); and significantly lower for cancer (rr=0.79). rates for suicide, stroke, chronic lower respiratory disease, and influenza and pneumonia were similar for haudenosaunee and whites in the haudenosaunee nations. in women, all cause death rates in the haudenosaunee nations (827.9 per 100,000) were greater than those in the east (730.9) but not as high as those in the united states (970.8). for ai/an and white populations, all-cause death rates were substantially lower for women than for men in the haudenosaunee nations, east, and united states. the two leading causes of death for both ai/an and white women were heart disease and cancer with heart disease death rates that ranged from 186.7 for u.s. whites to 248.5 for haudenosaunee and cancer death rates that ranged from 139.5 for east ai/an to 180.2 for u.s. ai/an. the remaining leading causes of death for haudenosaunee women are diabetes mellitus, stroke, unintentional injury, chronic lower respiratory disease, chronic liver disease, septicemia, influenza and pneumonia, and kidney disease. rates for haudenosaunee women were significantly higher than whites for all causes (rr=1.17), heart disease (rr=1.14), unintentional injury (rr=1.87), diabetes mellitus (rr=3.58), chronic liver disease (rr=4.47), kidney disease (rr=1.94), and septicemia (rr=2.30). rates for cancer, stroke, chronic lower respiratory disease, and influenza and pneumonia were similar for haudenosaunee and whites in the haudenosaunee nations. cancer death rates and leading cancer causes of death for the haudenosaunee nations, east, and u.s. comparing ai/an with white persons by sex for 1990-2009 are presented in table 2. the six leading causes of cancer death among the haudenosaunee were lung and bronchus (lung), colon and rectum (colorectal), liver and intrahepatic bile duct (liver), pancreas, kidney and renal pelvis (kidney), and stomach cancer. the haudenosaunee all malignant cancers death rates was 180.8, which was higher than the east ai/an death rates (161.5) but not as high as those for u.s. ai/an (205.5). rates for haudenosaunee were significantly higher than whites for liver cancer (rr=2.58) and significantly lower for all malignant cancers (rr=0.89). the rates for lung, colorectal, pancreas, stomach and kidney cancer were similar for haudenosaunee and whites in the haudenosaunee nations. comparisons of liver cancer mortality in ai/an with white populations were greatest in the haudenosaunee nations (rr=2.58) than those in the east region (rr=1.57) and the united states (rr=2.40). very large differences in liver cancer mortality were observed with higher rates among haudenosaunee men (rr=2.69) and haudenosaunee women (rr=2.84 – data not shown) when compared to whites. www.companyofscientists.com/index.php/chd e10 cancer health disparities research table 2. death rates for cancer causes for american indians and alaska natives compared with whites, males and females, all ages: chsda counties, united states, 1990-2009. haudenosaunee nations east united states ai/an white ai/an:white ai/an white ai/an:white ai/an white ai/an:white cause of deatha rank count rate rank count rate rate ratio rank count rate rank count rate rate ratio rank count rate rank count rate rate ratio males and females all malignant cancers ... 442 180.8 ... 89,837 203.6 0.89* ... 1,827 161.5 ... 666,932 197.6 0.82* ... 30,838 205.5 ... 1,961,554 193.3 1.06* lung and bronchus 1 135 54.0 1 25,949 58.8 0.92 1 497 43.2 1 194,011 57.3 0.75* 1 7,906 53.1 1 563,590 55.2 0.96* colon and rectum 2 49 21.4 2 9,554 21.3 1.01 2 189 17.5 2 67,629 19.8 0.89 2 3,137 21.5 2 193,141 18.9 1.14* liver and intrahepatic bile duct 3 21 9.1 11 1,558 3.5 2.58* 4 79 6.6 9 14,036 4.2 1.57* 4 1,463 9.7 9 40,715 4.0 2.40* pancreas 4 19 8.1 3 5,044 11.3 0.71 3 90 8.3 3 37,287 11.0 0.76* 3 1,479 10.0 3 107,762 10.6 0.95* kidney and renal pelvis 5 15 6.0 9 1,837 4.2 1.44 6 59 5.1 10 13,800 4.1 1.24 6 1,215 7.8 8 41,953 4.1 1.88* stomach 6 13 5.3 8 1,906 4.3 1.24 5 59 5.0 8 14,393 4.2 1.19 5 1,237 8.2 10 37,171 3.7 2.23* males all malignant cancers ... 200 199.2 ... 45,081 251.6 0.79* ... 932 196.2 ... 343,674 245.4 0.80* ... 15,503 242.1 ... 1,025,385 236.4 1.02* lung and bronchus 1 59 52.6 1 14,513 78.9 0.67* 1 287 57.9 1 110,650 76.9 0.75* 1 4,354 67.6 1 320,431 71.8 0.94* colon and rectum 2 21 21.6 3 4,623 26.1 0.83 2 86 17.9 3 33,390 24.1 0.74* 2 1,586 24.7 3 97,516 22.7 1.09* prostate 3 21 28.5 2 4,690 28.2 1.01 3 86 27.5 2 35,587 27.3 1.01 3 1,319 27.7 2 114,978 28.7 0.97 liver and intrahepatic bile duct 4 12 13.9 11 937 5.2 2.69* 4 51 9.3 8 8,966 6.3 1.47* 4 878 12.7 10 25,830 5.8 2.19* females all malignant cancers ... 242 169.3 ... 44,756 174.4 0.97 ... 895 139.5 ... 323,258 166.5 0.84* ... 15,335 180.2 ... 936,169 164.1 1.10* lung and bronchus 1 76 53.4 1 11,436 45.2 1.18 1 210 32.8 1 83,361 43.4 0.76* 1 3,552 42.4 1 243,159 42.8 0.99 colon and rectum 2 28 20.6 3 4,931 18.1 1.14 3 103 17.0 3 34,239 16.8 1.02 3 1,551 19.1 3 95,625 16.1 1.19* breast 3 27 17.9 2 7,255 29.5 0.61* 2 124 17.6 2 50,154 26.9 0.65* 2 1,970 21.6 2 146,357 26.5 0.82* pancreas 4 12 8.8 4 2,658 10.0 0.88 4 54 9.3 4 19,256 9.6 0.98 4 771 9.4 4 54,284 9.3 1.02 note: ai/an: american indian/alaska native; chsda: contract health service delivery area. all analyses were limited to decedents of non-hispanic origin. ai/an race is reported from death certificates or through linkage with the ihs patient registration database. rates are per 100,000 people and were age-adjusted to the 2000 us standard population (11 age groups; census p25-1130). rate ratios were calculated in seer*stat (version 8.3.2) before rounding of rates and may not equal rrs calculated from rates presented in the table. states and years data excluded because hispanic origin was not collected on the death certificate: la: 1990; nh: 1990-1992; ok: 1990-1996. east region is defined as: al†, ar, ct†, de, fl†, ga, ky, la†, me†, md, ma†, ms†, mo, nh, nj, ny†, nc†, oh, pa†, ri†, sc†, tn, vt, va, wv, dc. percentage regional coverage of ai/an persons in chsda counties to ai/an persons in all counties: east = 18.4%; total us = 64.2%. source: ai/an mortality supplement database (1990-2009). † identifies states with ≥ 1 county designated as chsda. *p<0.05 www.companyofscientists.com/index.php/chd e11 cancer health disparities research in men, the all malignant cancers death rates range from 196.2 for east ai/an to 251.6 for haudenosaunee nations whites. for all ai/an males, the leading cancer causes of death are lung, colorectal, prostate, and liver. with the exception of lung cancer, haudenosaunee men have higher cancer death rates for the leading cancer causes of death than the east ai/an men. rates for haudenosaunee males were significantly higher than whites for liver cancer (rr=2.69); and significantly lower for all malignant cancers (rr=0.79) and lung cancer (rr=0.67). rates for colorectal and prostate cancer were similar for haudenosaunee and whites in the haudenosaunee nations. in women, the all malignant cancers death rates range from 139.5 for east ai/an to 180.2 u.s. ai/an. haudenosaunee cancer mortality rates in women were 169.3 compared to 139.5 for the east ai/an. the haudenosaunee reflected rates that were lower than those of whites, but this new data showed all malignant cancer death rates for haudenosaunee women to be higher than those reported for the east ai/an. for females in the haudenosaunee nations, the leading cancer causes of death were lung, colorectal, breast, and pancreatic cancer. with the exception of pancreatic cancer, haudenosaunee women had higher cancer death rates for the leading cancer causes of death than the east ai/an women. rates for haudenosaunee females were significantly lower than whites for breast cancer (rr=0.61). rates for all malignant cancers, lung, colorectal and pancreatic cancer were similar for haudenosaunee and whites in the haudenosaunee nations. death rates for all causes by age for ai/an compared to whites for 1990-2009 are shown in table 3. when examined by age, disparities in allcause mortality were most evident in younger age groups, particularly ages 25 to 44 years. this pattern was apparent for the haudenosaunee nations, east, and united states. it was particularly prominent in the united states, where all-cause death rates in this age group for ai/an were 2.6 times higher than that for whites, and the haudenosaunee nations, where all-cause death rates for haudenosaunee were 1.9 times higher than that for whites. the disparities in all-cause mortality were higher in the haudenosaunee nations than in the east and were statistically significantly different for all age groups. table 3. death rates for all causes by age for american indians and alaska natives compared with whites, males and females: chsda counties, united states, 1990-2009. ai/an white ai/an:white region age group count rate count rate rate ratio 95% ci haudenosaunee nations 0-24 years 148 89.7 6,330 56.5 1.59* 1.34-1.87 25-44 years 247 225.3 12,065 121.6 1.85* 1.63-2.10 45-64 years 711 964.2 53,480 602.2 1.60* 1.48-1.72 65-84 years 1,047 4273.9 191,781 3770.6 1.13* 1.06-1.21 85+ years 266 12190.7 112,766 15251.0 0.80* 0.71-0.90 www.companyofscientists.com/index.php/chd e12 cancer health disparities research east 0-24 years 737 95.1 51,632 61.9 1.54* 1.43-1.65 25-44 years 1,239 228.9 116,623 148.7 1.54* 1.45-1.63 45-64 years 2,959 790.2 426,452 613.3 1.29* 1.24-1.34 65-84 years 3,813 3617.8 1,358,821 3528.4 1.03 0.99-1.06 85+ years 1,085 10875.0 833,663 14863.3 0.73* 0.69-0.78 us 0-24 years 18,394 144.2 177,184 65.1 2.22* 2.18-2.25 25-44 years 28,658 386.3 367,061 149.4 2.59* 2.55-2.62 45-64 years 50,735 1063.7 1,319,759 606.0 1.76* 1.74-1.77 65-84 years 64,931 4638.5 4,019,450 3511.5 1.32* 1.31-1.33 85+ years 21,915 15583.2 2,415,363 14974.6 1.04* 1.03-1.05 note: ai/an: american indian/alaska native; chsda: contract health service delivery area. all analyses were limited to decedents of non-hispanic origin. ai/an race is reported from death certificates or through linkage with the ihs patient registration database. rates are per 100,000 people and were ageadjusted to the 2000 us standard population (11 age groups; census p25-1130). rate ratios were calculated in seer*stat (version 8.3.2) before rounding of rates and may not equal rrs calculated from rates presented in the table. states and years data excluded because hispanic origin was not collected on the death certificate: la: 1990; nh: 1990-1992; ok: 1990-1996. east region is defined as: al†, ar, ct†, de, fl†, ga, ky, la†, me†, md, ma†, ms†, mo, nh, nj, ny†, nc†, oh, pa†, ri†, sc†, tn, vt, va, wv, dc. percentage regional coverage of ai/an persons in chsda counties to ai/an persons in all counties: east = 18.4%; total us = 64.2%. source: ai/an mortality supplement database (1990-2009). † identifies states with ≥ 1 county designated as chsda. *p<0.05 figure 2 summarizes trends in all-cause mortality in chsda counties from 1990-2009 for haudenosaunee, east ai/an, u.s. ai/an, and u.s. whites by sex. all-cause death rates for haudenosaunee males declined 2.2% per year, whereas for east ai/an males death rates declined 1.6% per year. nationally, all-cause death rates remained stable for ai/an males, whereas for white males, death rates declined 1.3% per year. haudenosaunee females and east ai/an females remained stable. nationally, all-cause death rates for ai/an females significantly increased 0.5% per year, whereas white female death rates were stable. www.companyofscientists.com/index.php/chd e13 cancer health disparities research note. ai/an = american indian/alaska native; chsda: contract health service delivery area. analyses are limited to persons of non-hispanic origin. ai/an race is reported from death certificates or through linkage with the ihs patient registration database. * α = 0.05. figure 2. annual age-adjusted all-cause death rates and joinpoint trend lines for males and females: chsda counties, us, 1990-2009 0 200 400 600 800 1000 1200 1400 1600 1800 2000 r a te p e r 1 0 0 ,0 0 0 year males haudenosaunee rate haudenosaunee trend east ai/an rate east ai/an trend us ai/an rate us ai/an trend us nhw rate us nhw trend annual percent change average annual percent change haudenosaunee (-2.2*) haudenosaunee (-2.2*) east ai/an (-1.6*) east ai/an (-1.6*) us ai/an (-0.2) us ai/an (-0.2) us nhw (1990-2002: -1.0*; 2002-2009: -1.8*) us nhw (-1.3*) 0 200 400 600 800 1000 1200 r a te p e r 1 0 0 ,0 0 0 year females haudenosaunee rate haudenosaunee trend east ai/an rate east ai/an trend us ai/an rate us ai/an trend us nhw rate us nhw trend annual percent change average annual percent change haudenosaunee (0.1) haudenosaunee (0.1) east ai/an (1990-2004: 1.4*; 2004-2009: -5.4*) east ai/an (-0.4) us ai/an (1990-2003: 1.1*; 2003-2009: -0.7) us ai/an (0.5*) us nhw (1990-2002: 0.1; 2002-2009: -1.5*) us nhw (-0.5) www.companyofscientists.com/index.php/chd e14 cancer health disparities research discussion haudenosaunee all-cause death rates were substantially greater than those for east ai/an but not as great as those for u.s. ai/an. the most prominent disparities for all-cause death rates of haudenosaunee are concentrated in the younger age groups. the significant decrease in all-cause death rates over the past two decades for haudenosaunee males is declining at a greater percentage per year than east ai/an, u.s. ai/an and u.s. whites. unfortunately, this decrease was not observed for haudenosaunee females with allcause death rates appearing to be stable over the past two decades. lastly, the leading specific cause of death and age at death disparities indicates potential areas of intervention that can improve mortality among the haudenosaunee. health disparities among the haudenosaunee of nys, the six leading causes of death compared to whites for both males and females combined between 1990 and 2009 were heart disease, cancer, unintentional injury, diabetes, stroke, and liver disease. statistically significant differences were found between haudenosaunee and whites for deaths related to unintentional injury, diabetes, and chronic liver disease (see table 1). although cancer was the second leading cause of death for both haudenosaunee and whites, the haudenosaunee had a lower cancer death rate than whites. cancer deaths related to all malignant cancers were higher among the haudenosaunee than the ihs east region as a whole. after ihs linkage, death rates for haudenosaunee men and women were higher than the ihs east region. however, these numbers were lower than all ai/ans combined and whites which also coincided with previous findings (mahoney et al., 2009; mahoney, michalek, cummings, hanley, & snyder, 1989). the top two leading cancers that caused death among the haudenosaunee were lung and colorectal, with death rates nearly equivalent to those of whites. these new results were comparable to previous studies listing lung cancer and colon cancer as the leading causes of mortality for tribally enrolled men of one tribe of the haudenosaunee, followed by lung, cervix, and breast cancer for enrolled women of the same nation (mahoney et al., 1989). this analysis shares new concerns which were difficult to assess in a previous study of one haudenosaunee nation based on a limited number of cases (mahoney et al., 2009). first, liver disease and liver cancer is of significant concern in these new findings. chronic liver disease was classified as the fifth leading cause of death in ai/ans, with alcoholic liver disease, hepatitis c virus (hcv) infection and non-alcoholic fatty liver disease as the most common contributors (suryaprasad et al., 2014). nonalcoholic fatty liver disease or nash, sometimes referred to as diabetes hepatitis, is an increasingly recognized condition that may progress to endstage liver disease and cancer (batman & scheuer, 1985; nagore & scheuer, 1988; picardi & d’avola, 2006). obesity, type 2 diabetes, and hyperlipidemia are also coexisting conditions frequently associated with this disease (suryaprasad et al., 2014; than & newsome, 2015; aleksandrova, stelmach-mardas, & schlesinger, 2016). further, there are data that suggest that steatosis with other liver disease, such as the hcv www.companyofscientists.com/index.php/chd e15 cancer health disparities research infection, could increase the risk of liver disease (angulo, 2002). diabetes type 2 diabetes is often related to obesity and both often co-occur with other conditions and chronic diseases (bril & cusi, 2017; rice et al., 2016; vigneri, p., frasca, sciacca, pandini, & vigneri, r., 2009). these include fatty liver disease and certain types of cancer. both chronic liver disease and liver cancer were concerns for both males and females of the haudenosaunee compared to whites. regionally, diabetes mortality for the haudenosaunee nearly mirrored that found in the east region and among other ai/an populations in nys (data not shown) (cho et al., 2014). however, mirroring nationwide findings, haudenosaunee men and women die nearly 3.5 times more than whites from diabetes. in regards to sex, diabetes rates in haudenosaunee men were higher than those reported for east ai/an, and closely mirrored rates for us ai/an men. mortality associated with diabetes for haudenosaunee women was slightly lower than previous statistics shown for all ai/an women in the east. these findings are similar to recent national data that indicated that ageadjusted diabetes prevalence rates among ai/an persons were at least twice those of whites or the total u.s. population and ranked as the fourth leading cause of death for ai/an persons (cho et al., 2014). limitations these results have several limitations. first, although linkage with the ihs patient registration database improves the classification of race for many ai/an decedents, the issue is not completely resolved. ai/an who are not members of federally recognized tribes are not eligible for ihs services and are therefore not represented in the ihs patient registration database. additionally, some eligible decedents may have never used ihs services and were therefore not included in the ihs patient registration database. second, the findings from chsda counties do not represent all ai/an populations in the us or the east region, which includes only 18.2% of the total ai/an population (espey et al., 2014b). furthermore, the analyses based on chsda designation exclude many ai/an decedents in urban areas that are not part of a chsda county. ai/an residents of urban areas differ from other ai/an persons in poverty level, health care access, and other factors that may influence mortality trends (jacobs-wingo et al., 2016; urban indian health institute, 2008). third, federally recognized tribes vary substantially in the proportion of native ancestry required for tribal membership and therefore for eligibility for ihs services. whether or how this discrepancy in tribal membership requirements may influence some of our findings is unclear, although our findings are consistent with prior reports. fourth, to capture enrolled and non-enrolled haudenosaunee, analyses were restricted to the nine counties that comprise most of the haudenosaunee nations. the nine county restriction may have excluded haudenosaunee that that do not live in these counties and included ai/ans that belong to other tribes. finally, although the exclusion of hispanic ai/an persons from the analyses reduces the overall us ai/an deaths by less than 5%, it may disproportionately exclude some tribal members. for instance, tribal members in states along the us-mexico border and possibly elsewhere who have hispanic www.companyofscientists.com/index.php/chd e16 cancer health disparities research surnames and may be coded as hispanic on the death certificate. future research more research is needed to investigate what is causing the high mortality of liver disease and associated cancers affecting the haudenosaunee. the relationship between mortality and obesity has been further supported in previous research from a member tribe of the haudenosaunee. the research showed that, during a 30-year study period, 8.3 percent of years of potential life loss were due to digestive disorders that may be related to obesity and dietary practices (mahoney et al. 1989). further, in another tribe of the haudenosaunee, six cardiovascular disease risk factors were evaluated. of 95 school children, 55 represented 39 interrelated families. seventy-two percent of the family histories included diabetes mellitus and 42% of the children’s physical examinations revealed obesity (weight/height greater than 90th percentile) (botash et al., 1992). future investigation is needed to discover if variables causing liver disease differ among the haudenosaunee. these include specific variances between fatty liver disease, hcv, and the role of both alcoholic and non-alcoholic cirrhosis. potential co-occurring conditions of concern related to liver disease and liver cancer are common among the haudenosaunee and may be additive or synergistic in the development of disease. hepatitis c infection rates should be evaluated. otherwise, the stereotype of assuming the problems are all related to alcoholism might delay a more complete understanding of the health risks within this population. the impact of historical trauma, inducing adverse childhood experiences, among ai/ans is just now being evaluated for its relationship to cancer (brown et al., 2010; shonkoff et al., 2009). this is an initial paper and comparisons to ethnically and racially diverse populations that may be facing similar social determinants of health in the same geographic regions should be explored. recent updated cancer incidence and mortality evaluations have clearly identified the importance of regional differences across ai/an populations (espey et al., 2014a; plescia, henley, pate, underwood, & rhodes, 2014). disparities in cancer and other diseases are due to inequalities in socioeconomic status, sexual orientation, gender, disability status, geographic location, discriminatory practices, or some combination of factors (brennan ramirez, baker, & metzler, 2008; krieger, emmons, & williams, 2009). further, future studies could also include the review of other haudenosaunee populations outside of nys (i.e., haudenosaunee located in canada, wisconsin, and oklahoma). for the haudenosaunee and other ai/an populations, chronic diseases, such as diabetes, heart disease and cancer, are now the norm (cobb et al., 2014; acton et al., 2002; burrows, geiss, engelgau, & acton, 2000; go et al., 2013). there was a time when infectious diseases were the major health focus. cancer was previously reported for whites and blacks only in the seer cancer statistics review. now we know that all segments of the population, large and small, should have data that will guide resources and appropriate interventions in reducing cancer (wallerstein & duran, 2010). the definitions of population data are also very important, as shown here, so that the limitations can be understood and data of higher quality can be collected going forward. understanding factors affecting small www.companyofscientists.com/index.php/chd e17 cancer health disparities research population groups is crucial to overcoming disparities and will likely require new research designs with community-based participatory research as the guiding principle (srinivasan et al., 2015). the community should be heard and their feedback incorporated into the way in which questions are asked and data used to develop culturally appropriate interventions (cochran et al., 2008). overall, these new findings provide a crucial framework for tribal health centers, ai/an urban centers, and those who work with the haudenosaunee in nys. these new data identify health disparity rates higher for the haudenosaunee than previously published or in comparison to aggregate data for all native nations in the ihs east region. there should be a realization of cultural and traditional views of the haudenosaunee and understanding of what is important to future generations, including the integration or enhancement of interventions and prevention programs. such programs could also include the philosophies and traditional viewpoints of the people of the confederacy wrapped in a framework of resiliency and courage. lastly, it is also important to be cognizant of historical factors related to environmental shifts, and generational stress, and how these may contribute to current health disparities (brown et al., 2010; shonkoff et al., 2009; warne, 2005; anda, butchart, felitti, & brown, 2010; felitti et al., 1998; mehta et al., 2013). acknowledgements the study used shared resources supported by roswell park comprehensive cancer center support grant from the nci (p30ca016056). the authors also wish to thank the kanatsiohareke mohawk community’s indigenous writing retreat, paula jones, and dr. brenda battleson-white (copy editors). disclaimer the findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the centers for disease control and prevention. conflict of interest the authors declare that no competing or conflict of interests exists. the funders had no role in study design, writing of the manuscript, or decision to publish. authors’ contributions dr. rodney haring, dean seneca, and melissa jim worked collaboratively on conceptualization, project aims, goals, methods, and results. melissa jim was the primary statistician and epidemiological reviewer. dr. deborah erwin focused on health disparities overview and manuscript structuring and dr. judith kaur assisted with discussion items. whitney ann henry and marissa haring provided literature review support and assistance with manuscript writing and review. references acton, k. j., ríos burrows, n., moore, k., querec, l., geiss, l. s., & engelgau, m. m. 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(2008). cancer among american indians and alaska natives in the united states, 1999–2004. cancer: interdisciplinary international journal of the american cancer society, 113(s5), 1142-1152. http://nmai.si.edu/sites/1/files/pdf/education/haudenosauneeguide.pdf http://nmai.si.edu/sites/1/files/pdf/education/haudenosauneeguide.pdf http://www.uihi.org/wp-content/uploads/2009/01/health_health-influencing_behaviors_among_urban_indiansupdate-121020081.pdf http://www.uihi.org/wp-content/uploads/2009/01/health_health-influencing_behaviors_among_urban_indiansupdate-121020081.pdf http://www.uihi.org/wp-content/uploads/2009/01/health_health-influencing_behaviors_among_urban_indiansupdate-121020081.pdf www.companyofscientists.com/index.php/chd e1 cancer health disparities research hpv vaccination strategies in immigrant dense communities kimlin ashinga, mayra serranoa, marisela garciaa, katty nerioa, alejandro fernandeza, margaret martinezb , rita singhalc, andrette ward b, aneesah robinsonb , karen tinsley b, camille ragind marcella nunez-smithe, rebecca perkinsf, gerard antoineg a. center of community alliance for research and education, department of population sciences, city of hope national medical center, duarte, ca, united states. b. chapcare, 455 w. montana street, pasadena, ca 91103, united states c. los angeles county department of public health, office of women’s health, 3400 aerojet avenue, third floor, el monte, ca 91731 d. fox chase cancer center, 333 cottman avenue, philadelphia, pa 19111-2497 e. yale school of medicine, p.obox 208088, ie-61 shm, new haven, ct 06520-8088 f. boston university school of medicine, 72 east concord st. boston, ma 02118 g. caribbean medical providers practicing abroad, kailua, hawaii, 96734 *corresponding author: kimlin ashing, email: kashing@coh.org abstract we aimed to identify practices and barriers affecting hpv vaccination (hpvv) within immigrant dense communities. interviews were conducted with multisectoral stakeholders including safety-net clinic personnel, parents, and members of the hpvv community advisory council. the results underscored poignant issues relevant to immigrant communities at local and national levels: 1) immigrant inclusive, public health and health system interventions to increase awareness of health facilities safe zone for immigrant children tied to hpvv campaigns. 2) clear and strong provider hpvv recommendation approaches that are culturally and linguistically responsive. 3) provider must be aware of his/her own biases and attend to the cultural beliefs and practices of parents for a more genuine and effective facilitation of vaccination. providers, in particular, emphasized examining the provider cultural continuance relevant to hpvv clinical encounter and provider-patient relationship, as well as ongoing provider education and communication for increased hpvv among immigrant providers. at the national and local levels, we must ensure health facility safe-zone for immigrant children to obtain low/no cost healthcare including hpvv to attain the healthy people 2020 goals of 85% hpvv. keywords: adolescent hpv vaccination, immigrant health, hpv-related cancer prevention citation: ashing k et al (2019) hpv vaccination strategies in immigrant dense communities. cancer health disparities. 4: e1-8. doi:10.9777/chd.2019.1013 www.companyofscientists.com/index.php/chd e2 cancer health disparities research introduction oncogenic human papillomavirus (hpv) is responsible for several cancers including cancers of the genitalia and oral cavity. every year approximately 27,000 individuals are affected by cancers caused by hpv(8). low income, ethnic minority and immigrant communities suffer unequal burden and death due to hpv-related cancers (aragones et al., 2013; bruno et al., 2014; kobetz et al., 2012). today we have the hpv vaccine (hpvv) that is one of only two cancer prevention vaccines. therefore, it is not surprising that increasing hpv vaccination (hpvv), among eligible population aged 9-26 years, is singled out as “one of the most profound opportunities for cancer prevention” in the report “accelerating hpv vaccine uptake: a report to the president of the united states.”(2014) improving hpvv rates among all youths is highly desirable. unfortunately, uptake and coverage remain unacceptably low. therefore, increasing hpvv in youths who are members of communities with elevated risk and burden of hpv infection, and hpv-related illnesses and cancers is especially critical and urgent. (aragones et al., 2013; bruno et al., 2014; jeudin et al., 2013; joseph et al., 2014; kobetz et al., 2012). immigrant hpv vulnerability and missed opportunity for cancer prevention: immigrant populations, in particular latin american and caribbean immigrants, have the highest hpv-related cancer burden and death in the u.s.(jeudin et al., 2013; joseph et al., 2014). among immigrant women, hpv-related cervical cancer incidence is 2 times, and mortality 3 times greater than the general u.s. population. further, the mortality rate for whites at 2.8 reflects a 17% decline compared black and latina immigrants with a mortality rate of 6.5 that is equivalent to a 22% increase (kobetz et al., 2012; senkomago et al., 2017; villa, 2012). in general, mortality from cervical cancer is declining nationally (smith et al., 2018) and even in the caribbean (cancer, 2012; warner et al., 2018), but cervical cancer mortality shows increases for immigrant women (schleicher, 2007; seeff and mckenna, 2003). immigrants’ hpv-related cancer burden is an unacceptable yet preventable u.s. health disparity. immigrant communities must be targeted for hpv vaccination (hpvv) to prevent cancer and reduce mortality disparities. however, immigrant communities face unique healthcare barriers and challenges. immigrants tend to concentrate in ethnic enclaves and immigrant dense neighborhoods with low provider hpvv recommendation and delivery (aragones et al., 2013; bruno et al., 2014). additionally, immigrants while suffering disproportionate disease burden, have low hpvv acceptability, and uptake (ashing et al., 2017; blackman et al., 2013; cofie et al., 2018; goss et al., 2013; jemal et al., 2013; joseph et al., 2014), leaving immigrants at persistent, elevated risk for oncogenic hpv infections and hpv-related cancers. hpvv can prevent cervical, genital and oral cancers (siegel et al., 2015). the u.s. advises hpvv improvement by changing clinic and provider practice (senkomago et al., 2017) (kessels et al., 2012; krantz et al., 2018; perkins et al., 2012). providers who are predominant in hpv-vulnerable immigrant communities ought to be identified. health organizations, and the fields of public health and behavioral medicine acknowledges the importance of multisectoral engagement including patient/community involvement to inform both population as well as local community responsive healthcare structure and practice (alcaraz et al., 2017; martin et al., 2016). immigrant community members and parents are valuable sources of data, yet they www.companyofscientists.com/index.php/chd e3 cancer health disparities research are often not included in developing health care practice. this informative study aims to engage multisectoral stakeholders including clinic personnel, providers, public health professionals, advocates and parents to identify practices and barriers affecting hpvv within an immigrant dense community. approach and methods a discovery science informative research design was employed using qualitative methods. therefore, we conducted informative, qualitative research employing a semi-structured interview. this format allowed us to exam targeted domains with open discussions to capture the relevant narrative of the issue(s) of interest.(jamshed, 2014) specifically for this study, in-depth interviews were conducted with diverse stakeholder participants. the city of hope irb was submitted and reviewed, and the study was approved as exempt status. participants as community clinics provide much of the hpvv to adolescents in particular low-income and immigrant families; for example, over 55% of hpvv in la county adolescents occur at community clinics (los angeles county department of public health and office of health assessment and epidemiology, 2011). thus, clinic personnel were interviewed including administrators (e.g., 1 medical director and 1 ceo), 5 providers (pediatricians (n=2), physician assistant, nurse, behavioral health specialist); support teams (e.g., scheduler, administrative analyst). additionally, we interviewed14 persons representing regional hpvv community advisory boards – public health professionals and community advocates within county and regional hpvv focused coalitions. these interviews were conducted via phone or faceto-face in their offices by the lead author. in addition, semi-structured interviews and openended questions were conducted with 8 clinic parent/patients who were immigrants (5 vaccine initiators and 3 non-initiators). immigrant participants were identified via community organization partners. we had a high response rate of 80% as 8 of the 10 invited participated. clinic participants were latina (3 mexicans; 3 central americans; and 2 afro-caribbeans, english language proficient). the latinas were mostly spanish language preferred; thus, there interviews were conducted in spanish. the patient interviews were conducted by well-trained bilingual staff at community centers. all interviews lasted about 45 minutes and copious notes were taken. the notes were then organized into a thematic matrix. results clinic-level the clinic-level formative interviews underscored community clinic administrative and provider buy-in as well as technological capacity to implement and evaluate multilevel hpvv improvements. most community clinics, especially those designed as federally qualifies health centers (fqhc) under the affordable care act, have in-place electronic medical records (emr) systems in place that can be effectively utilized. coordinated utilization of clinic’s emr system for hpvv improvements was identified by the clinical administrators and providers. they highlighted that, emr systems can be used to better track hpvv dosage and completion, identify patients who are hpvv naivee, and identity patients who are schedule for well visits and other adolescent vaccine – so that providers can be prompted, both via the emr and on the schedule to recommend the hpvv. clinic administrators and support staff endorsed addressing system-level factors such as improving clinic vaccination scheduling and diversity inclusive www.companyofscientists.com/index.php/chd e4 cancer health disparities research visual and printed displays that is careful not to label or stigmatize any particular ethnic or immigrant group. it was recommended that the clinic provide more flexible immunization and hpvv appointments, including vaccine only appointments; as well as displaying the benefits of all adolescent immunization. further, these prominent visual and printed displays must be culturally and linguistically responsive. community advisory board (cab) the hpvv community advisory board (cab) formative interviews focused on healthcare system factors that emphasized the community clinic model of healthcare for the community, especially youth and children. the cab emphasized that healthcare facilities must be safe zones for immigrant families and children. the cab recommended creating a vaccine friendly clinic culture by: 1) displaying prominent, culturally and linguistically informed poster and printed resources highlighting the benefits of adolescent vaccine including hpv vaccine; 2) having vaccine only appointments and giving provider recommendation and reminders so that following the initial dose that subsequent vaccine completion appointments are made prior to patients leaving the clinic; and 3) attending to broader social determinants including community and neighborhood characteristics and socioeconomic status including education, age, gender, job status and immigrant experience. additionally, the cab highlighted parental constraints (including concerns about safety and cost, as well as time needed for the two or three hpvv within 612months for hpvv completion –depending on age at initiation). the cab also presented parental values that inhibit parents from vaccination due to country of origin cultural stigma associated with hpvv due to the hpv-infection link with sexually transmitted diseases (std), sexual promiscuity that is particularly prominent among immigrant populations especially from the latin american region(joseph et al., 2014; villa, 2012). provider-level the formative narrative from the providers also revealed concerns about parents’ hesitance due to: 1) parental stigma associated with hpv as a std and hence, the hpv vaccine is condoning early sexual initiation; 2) parental cultural gender attitude that influence practices allowing for positive increases in vaccination among boys but hesitance for vaccination among their girls. this is evident by data showing greater progress in male hpvv (control and prevention, 2013); 3) parental mistrust of the health system that may be especially present in a cross cultural provider-patient relationship. the providers also identified provider-driven factors that can improve hpvv; they advised their provider colleagues to de-emphasize provider fragility -“do not take the vaccine rejection personally and permanently”. these providers emphasized provider responsibility such that each new visit is an opportunity to reintroduce vaccination…“doctors are influential” and “persistence pays”. these providers acknowledged that providers ought to consider their/provider cultural issues… “as providers may themselves be immigrants with cultural beliefs and practices that may influence their [provider] hpvv recommendation and facilitation. these providers believe that these hpvv focused trainings will enhance their patient education and communication during physical examination visit. together with using every visit as an opportunity to educate and vaccinate, this patient-centered, provider-directed approach for building trust and parental adherence were noted. www.companyofscientists.com/index.php/chd e5 cancer health disparities research the three professional groups including clinic administrators, cab and providers all agreed that there are social determinant factors that critically influence hpvv uptake among immigrants. these social determinants include immigration histories of both providers and patients e.g., country of origin. these stakeholders identified social status as another social determinant. the interviewees, affirmed that many recent immigrants in particular those who are lower income, educational attainment and job status experience both health care cost (i.e., hpvv cost) as well as health care access (e.g., hpvv initiation and completion) concerns. they also asserted that health care access is further hampered by a related social determinant– place and stability of residence. these interviewees identified that immigrants who are poor suffer housing instability. they contended that housing instability and insecurity exacerbate health care access challenges and make having a place to call ones medical home extremely difficult. patient-level overall, immigrant parents advised that parents are not sufficiently aware of the hpvv and where to get the vaccine. our immigrant parents voiced that they are, in general, very concerned about where to safely access healthcare (health facility safe-zone for healthcare delivery) and the cost of health care. thus, the parents recommended: 1) ensure healthcare safe zone for all immigrant children; and 2) create welcoming health centers by prominent culturally and linguistically responsive displays e.g., pictures within the clinics. these parents also recommended posting clinic specific ads within local ethnic newspapers and on local advocacy organizations’ websites -that reflect the immigrant communities. the parents advised that these ads should inform them where to get the vaccine, lists the benefits of the vaccine, and state that the vaccines are covered regardless of all youth regardless of immigration status. among the parents, they agreed that stigma is a consideration that may be a more serious concern especially among the elite classes of immigrants. only two parents reported stigma as a primary barrier. all parents underscored the centrality of the provider role as they reported that most immigrants and immigrant communities are served by immigrant providers. moreover, they acknowledged that in many immigrant communities medical providers are held in great esteem and prominence in their countries of origin(esposito and castaneda, 2017). however, provider-parent communication challenges were revealed. immigrant parents had specific advice for providers regarding improving hpvv: 1) give hpvv recommendation that is strong, matter-of-fact and states the greater protection benefit for younger girls and boys and that “ it [hpvv] is best medicine for 11-12 year olds”. in fact, 4 of the 5 who vaccinated, revealed that they had some concerns i.e., safety-but the provider recommendation prevailed; this was revealed and supported in the provider input. 2) remove the words “new vaccine” from their recommendation (as commonly done by providers). these parents articulated that “new” means “innovation” to providers, but “new” means “experimental” within the community. experimental for our parents connotes that they and their children are being used without full disclosure for medical experiments. they confirmed that the provider recommendation of the “new vaccine” feeds into parents’ safety and efficacy concerns. 3) schedule subsequent vaccine dose appointments at the time of vaccine initiation so the parent has the appointments before leaving the clinic. parents preferred this pre-scheduling that served as an education about the vaccines as well as it give them sufficient time to plan for this brief medical visit. saturday clinics were highly favored. www.companyofscientists.com/index.php/chd e6 cancer health disparities research the parents also indicated that, personal time constraints and being able to vaccinate up to age 18 may contribute to low vaccine uptake especially at the younger ages—parent believed that they can wait till the teen is older. discussion immigrant communities are at elevated risk for hpvrelated cancers. hence, immigrant communities ought to be prioritized for hpvv improvements. our results underscored poignant issues relevant to immigrant communities that may be relevant no only at our local level but at the national level as well. our findings suggest that: 1) immigrant inclusive, public health and health system interventions to increase awareness of health facilities safe zone for immigrant children tied to hpvv health literacy campaigns including where to obtain low/no cost hpvv are urgently needed. 2) clear and strong provider hpvv recommendation approaches that are culturally and linguistically responsive. 3) provider must be aware of his/her own biases and attend to the cultural beliefs and practices of parents for a more genuine and effective facilitation of vaccination. the parents and providers agreed on the centrality of the providerparent relationship and appropriate communication. the caring, trustworthy, persistent providers trump parental hesitation and results in acceptance and vaccination. the provider responsibility finding, suggests that providers’ cultural persistence and continuance - that is the adherence to cultural beliefs and values, in particular beliefs and values about sexuality and gender roles -may influence providers’ own hpvv acceptability and practice. hence, these providers emphasized examining the provider cultural continuance relevant to hpvv clinical encounter and provider-patient relationship, as well as ongoing training to increase hpvv. populations with particularly low hpvv rates and those with high hpv infection and hpv-related cancer burden must be prioritized for providerdriven and parent focused vaccination improvement projects. this formative research underscored the importance of focusing on hpvv within immigrant dense communities. our findings suggest that there are distinct facilitators and barriers to hpvv improvements among immigrant groups. this discovery science with key stakeholders also suggested that social determinants including immigration histories of providers and patients as well as social status -type and place of residence, income, education and job status of patients - influence immigrant providers’ clinical encounter and hpvv care delivery. this paper presents the voices of immigrant parents and broad based community advocates along with clinic administration and providers to inform clinic practice aimed at appropriate and sustainable hpvv improvement practices particularly targeting immigrant populations. therefore, systemic factors including assuring health facility safe zone for immigrant children ought to be considered in order to achieve the nations’ health agenda of protecting all our children against hpv-related cancers. over all, responding to systemic, provider and parent issues are central to informing our efforts to improve the clinical encounter promoting hpvv among all populations -especially among immigrant and hpv vulnerable communities towards attaining the healthy people 2020 goal of 85% hpvv. www.companyofscientists.com/index.php/chd e7 cancer health disparities research acknowledgements the authors wish to thank the los angeles county hpv vaccine coalition and chapcare community health clinics conflict of interest the authors declare that they have no conflict of interest. funding this research did not receive any specific grant from funding agencies in the public, commercial, or notfor-profit sectors. authors’ contributions kimlin ashing led the overall study and writing. mayra serrano, marisela garcia, katty nerio, alejandro fernandez contributed to the data collection and writing. margaret martinez , rita singhal, andrette ward, aneesah robinson, karen tinsley, camille ragin, marcella nunez-smith, rebecca perkins, gerard antoine contributed to the conceptualization and writing references report: accelerating hpv vaccine uptake – urgency for 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(2018). cancer screening in the united states, 2018: a review of current american cancer society guidelines and current issues in cancer screening. ca: a cancer journal for clinicians 68, 297-316. villa, l.l. (2012). cervical cancer in latin america and the caribbean: the problem and the way to solutions. cancer epidemiology and prevention biomarkers 21, 1409-1413. warner, w.a., lee, t.y., badal, k., williams, t.m., bajracharya, s., sundaram, v., bascombe, n.a., maharaj, r., lamontgreene, m., and roach, a. (2018). cancer incidence and mortality rates and trends in trinidad and tobago. bmc cancer 18, 712. www.companyofscientists.com/index.php/chd e1 cancer health disparities research colorectal cancer education and screening program for the unor under insured in a primarily rural setting in northeast texas: design and methods gabriela orsak1, carlton m. allen2, anastasia miller3, karan p. singh1, paul mcgaha2 1the university of texas health science center at tyler, department of epidemiology and biostatistics, tyler, tx, usa, 2the university of texas health science center at tyler, department of community health, tyler, tx, usa, 3the university of texas health science center at tyler, department of healthcare policy, economics and management, tyler, tx, usa *corresponding author: gabriela orsak, email: gabriela.orsak@uthct.edu, abstract although early detection and screening for colorectal cancer (crc) saves lives, screening rates remain suboptimal, especially for minorities, underserved populations, older adults (>60), men, un/under insured, and those living in rural settings. the goal of the colorectal cancer education and screening program is to target the unor underinsured in a 19-county primarily rural target area to provide: 1) education concerning crc and crc screening to 12,000 individuals, and 2) crc screenings (colonoscopy and/or fecal immunochemical test [fit]) to 5,1613 unor underinsured individuals. the education outreach team targets local health fairs, clinics, churches, etc. to educate individuals on crc and the importance of screening. the program aims to then have those individuals electively undergo a colonoscopy and/or a fit test. the number of those educated and screened is recorded. the results related to colonoscopy, fit, and follow-up are collected. primary outcomes include number of individuals educated, number of fit test/colonoscopies performed and results of screening procedures. this education and screening outreach program is designed to reach primarily rural and underserved populations eligible for colorectal screening. results of efficacy of program will advance knowledge on how to conduct colorectal cancer outreach programs in rural settings. keywords: colorectal cancer; rural colorectal cancer outreach program; colonoscopy; fit testing; uninsured; underinsured citation: orsak g, et al (2019) colorectal cancer education and screening program for the unor under insured in a primarily rural setting in northeast texas: design and methods. cancer health disparities 4: e1-e11. doi:10.9777/chd.2019.1010 www.companyofscientists.com/index.php/chd e2 cancer health disparities research 1. introduction and rationale 1.1 burden of colorectal cancer and the importance of early screenings colorectal cancer (crc) prevention is an important public health issue. crc is the fourth most common cancer and the fourth most common cause of malignancy-related death in the united states (u.s. cancer statistic working group, 2018). mortality can be significantly reduced through regular crc screenings (friedrich et al., 2015). crc lends itself well to public health initiatives as it is a slowly progressive disease that can be cured if treated early. specifically, the detection and removal of precancerous polyps can prevent colorectal cancer with recent reports reporting subsequent reduced mortality by 67% (doubeni et al., 2018; lieberman et al., 2012). crc survival is dependent upon early detection, thus, highlighting the importance of early screenings (levin et al., 2008). although screenings save lives, screening rates remain suboptimal, especially for minorities, underserved populations, older adults (>60), men, un/under insured, and those living in rural settings (alteri et al., 2014; salas et al., 2014). 1.2 crc screening methods two common methods for crc screening are colonoscopy and the fecal immunochemical test (fit). colonoscopy is considered the gold standard for crc screening due to its ability to screen and consequently remove precancerous polyps (friedrich et al., 2015). however, there are significant barriers to patients undergoing a colonoscopy such as education, a significant financial and temporal commitment, as well as fear or avoidance of the invasive procedure. for example, patients often are not aware they need the procedure, need to take time off work, prep in advance, arrange transportation (it is not recommended to drive afterward), and personally finance the procedure. finally, there is an additional burden of the fear or avoidance of the procedure. while colonoscopy is considered the gold standard in the medical profession, fit seems to be better accepted (segnan et al., 2007). fit offers an alternative to the financial, temporal, and personal barriers of a colonoscopy. fit is an inexpensive crc screening option that allows patients to send in a stool sample to a laboratory, collected at their own convenience. this eliminates the need for prep, transportation, fear and avoidance of an invasive procedure, time off work, and financial burden for many patients with a normal result. while this can be especially advantageous to the unor under-insured, it is not a complete crc screening method on its own (quintero et al., 2012). fit test results yield either a normal or abnormal result. after an abnormal test result, patients are urged to undergo a colonoscopy. 1.3 crc in northeast texas northeast texas is a 35-county area that is home to over 1.5 million individuals (nehme et al., 2016). it consists of primarily rural communities, with few small metropolitan statistical areas. crc incidence and mortality is higher in this rural setting (cancer prevention & research institute of texas, 2010). specifically, the age-adjusted incidence (43.3-43.6 in northeast texas vs. 38.1 in texas and 38.27 in the united states) and crc mortality (15.8-16.9 in northeast texas vs. 14.4 in texas and 14.1 in the united states) far exceed state and national levels (national cancer institute, 2017; texas cancer registry, 2018a, b). 1.4 rationale for targeting improving crc screening rates in northeast texas the u.s. department of health and human services’ current goal is to achieve a 70.5% crc screening rate (u.s. department of health and human services, www.companyofscientists.com/index.php/chd e3 cancer health disparities research 2018). however, even with the availability of both screening methods, crc screening rates remain suboptimal in the general public (62.4%; (u.s. department of health and human services, 2018) and in rural communities (58.2%(u.s. department of health and human services), with rates being increasingly suboptimal in northeast texas (44.63%(hall, 2018). they are even lower among the uninsured (25.1%). the high crc prevalence and lower screening rates in the northeast texas region represent a growing concern. the high incidence and mortality rates of crc may be due to factors such as non-adherence to cancer screening recommendations, diagnosis of cancer at a later stage, and higher cancer mortality, which are more likely among rural residents (cole et al., 2012; fan et al., 2012; hines et al., 2014). with evidence demonstrating the slow progression of the disease and proven efficacy of crc screening to reduce cancer mortality(doubeni et al., 2018; friedrich et al., 2015), it is imperative that public health programs develop programs that target populations with historically low rates of screening, such as the un/under insured, older populations, minorities, underserved populations, and those living in rural settings. the current program aims to target these individuals. 1.5 challenges of a colorectal cancer education and screening program in a primarily rural setting for the unor under-insured living in a rural or mostly rural community offers unique challenges to implementing a colorectal education and screening program targeting the un or underinsured. challenges to screening such a lack of education concerning the importance of screening and the different screening options are common. dissemination of educational information is also onerous as residents are widespread and various events (e.g. health fairs) do not attract the same number of participants as in urban settings. transportation problems often prove burdensome in the region. specifically, residents often must travel long distances to seek care and the number of specialists in the area is often limited. this problem intensifies for older adults or for those who are un or underinsured. public transportation is mostly lacking in the area, limiting ones’ ability to return home following the procedure, as driving is restricted for safety reasons. therefore, seeking preventive services such as colonoscopies and/or fit may not be a priority for individuals in these communities. 1.6 the university of texas health science center at tyler (uthsct) crc education and screening program for the unor underinsured the goal of the uthsct crc education and screening program is to target the unor under insured in a 19-county primarily rural target area concerning crc education and screening over a 5year period (years 1 and 2 targeted 7 counties with expansion into 19 counties for years 3-5). specifically, the program aims to provide: 1) education concerning crc and crc screening to 12,000 individuals, and 2) crc screenings (colonoscopy and/or fit) to 5,161 unor underinsured individuals. 2. methods 2.1 overview process flow of the program is detailed in figures 13. figure 1 details the initial participant process. figure 2 details participant process when electing fit testing, while figure 3 details participant process when undergoing colonoscopy. this is an education and screening program targeting the unor underinsured. the education outreach team targets local health fairs, clinics, churches, etc. to educate individuals on crc and the importance of screening. the program aims to then have those individuals www.companyofscientists.com/index.php/chd e4 cancer health disparities research electively undergo a colonoscopy and/or a fit test. the number of those educated and screened is recorded. the results related to colonoscopy, fit, and follow-up are collected. figure 1. initial participant process www.companyofscientists.com/index.php/chd e5 cancer health disparities research figure 2. participant fit process www.companyofscientists.com/index.php/chd e6 cancer health disparities research figure 3. participant colonoscopy process 2.2 the program team the members of the team consist of a program director, co-program director, program manager, an outreach education coordinator, program specialist, nurse navigator, and 3 health education coordinators. the program manager, outreach education coordinator, program specialist, nurse navigator, and health education coordinators have gone through the texas chw certification training. they maintain their certification by completing chw continuing education requirements. in addition, they are trained in motivational interviewing. 2.3 recruitment setting, eligibility, and enrollment recruitment had both a community based and a clinical focus. our strategy involved reaching out to individuals to make them aware of the need to undergo crc screening, educating them about their screening options, performing the screening methodology of choice (fit or colonoscopy), providing access to treatment for crc, and providing follow-up. individuals are recruited from clinics at uthsct, health fairs, charity clinics, local health departments and districts, and federally qualified health centers (fqhcs). the primarily rural www.companyofscientists.com/index.php/chd e7 cancer health disparities research 19county region, known as northeast texas, has an area of about 14,762 (national association of counties, 2017) square miles with a total population of 2,167,769 (united states census bureau, 2017) in 2017. eligibility for colonoscopy/fit are determined after education outreach and/or physician recommendation. to determine eligibility, us preventive services task force (uspstf) guidelines, which recommend screening all races/ethnicities between the ages of 50 and 75, were followed. individuals are eligible to participate if they are between 50 and 75 years of age, speak english or spanish, are unor under insured, do not have a medical reason for not undergoing the procedure(s) (e.g. taking blood thinners), and have not been previously diagnosed with crc. individuals also couldn’t have had a colonoscopy in the last ten years, a sigmoidoscopy in the last five years, or a stool test in the last year before becoming eligible for the cancer prevention and research institute of texas (cprit) screening program. 2.4 crc education our community-based approach reaches out through social media and community events. social media is used through facebook, twitter and youtube. educational sessions at various community venues and health fairs throughout east texas stressed the need for routine screenings and recruited individuals from these events. community health workers (chws), in conjunction with the program manager and other support staff, coordinated these community educational activities, with the support of many church and minority business groups to spread awareness of the screening program and provided venues for community education. an educational tool that was used in the community outreach program was a giant inflatable colon. this colon model includes various stages of crc progression (from normal through polyps to invasive cancer). this among other tools served as an educational and interactive exhibit during outreach activities by chw’s to educate communities. promotion is also being accomplished through partnerships and outreach with various community organizations including churches, workplaces, and barber/beauty shops. individuals attending these meetings are asked to listen to a brief presentation about crc screening, review a tailored decision-aid, complete a short intake form to determine eligibility, and sign a commitment specifying which screening option they plan to choose if eligible. the intake form includes demographics, screening status, health insurance, screening method preference, reminder preferences, barriers to participation, and intention to undergo screening. the intake form responses are entered and maintained in an electronic community outreach registry. our clinical based approach involved us enlisted the help of multiple clinical partners to optimize recruitment. our partners include an academic medical center, a charity clinics, local health departments and districts, and fqhcs. we work with providers in primary care at uthsct and at other healthcare facilities to refer their patients for crc screening. the focus of our recruitment is on the unand under-insured. we worked with the american cancer society (acs) to align cancer control opportunities and solutions with the needs and challenges of our health center, emphasizing sustained capacity building to result in improved public health outcomes. specifically, the acs assisted us by providing strategic planning guidance, provider and chw education to optimize client and provider interventions. the acs has www.companyofscientists.com/index.php/chd e8 cancer health disparities research trained cprit and clinical staff. the partnership with acs has increased our ability to educate providers and staff to optimize participant education and crc screening. the acs also provided linkages to community resources and other health systems to support sustained continuity of care. 2.5 crc screening once all inclusion/exclusion criteria have been met, participants are offered colonoscopy and/or fit test based on their preference and/or provider recommendation. our nurse navigator will identify eligible individuals from a weekly report. the navigator will facilitate the coordination of the participant through the system for colonoscopy. once it was determined that participants who were deemed unor underinsured were unable to pay for services, screenings were provided free-ofcharge. in addition, participants undergoing a colonoscopy received a $20 gift card for transportation upon completion of a colonoscopy. if a participant did not undergo proper bowel prep and the colonoscopy is unsuccessful, an alternative date is scheduled. participants who elected to have a fit were scheduled for a colonoscopy if they had an abnormal fit result (and subsequently received the same $20 gift card upon completion of services). the team works diligently to contact participants in regard to mailing fit to the appropriate addresses, recontact individuals with their results and to schedule colonoscopy appointments with those who elect colonoscopy or receive an abnormal fit test. if no additional procedures are immediately warranted, after the procedure, the patient is sent a letter detailing their results and when they should follow-up. they are also spoken to about attaining a primary care physician, if they do not already have one. if something additional is required, the patient is called and asked to return to the clinic. during that visit, the nurse navigator is present for support and clarification of treatment plan and decision making when diagnosis is given. for participants that require surgery first, the navigator will assist, if necessary, in treatment plan decisions (post-op radiation, post-op radiation and chemotherapy, or post-op chemotherapy). the navigator will continue to follow the participant through the continuum of care. if individuals who were educated at local events are found to have adequate insurance, they are referred to colonoscopy/fit services, but are not financially compensated for their procedures. for individuals who were uninsured and required cancer treatment, chws and a nurse navigator assisted in finding alternative methods of funding for future procedures if needed. these alternative methods, included but were not limited to, the affordable care act/marketplace insurance, medicaid, the county indigent health care program, or hospital insurance. for surveillance, the navigator will hand-off patients to the oncology team but will ensure follow-up of crc screening is scheduled. for alternative pathways, nurse navigator will hand-off participant to medical/radiation oncology nurse and receive updates periodically. the nurse navigator will still ensure follow-up of crc screening is scheduled. due to the difficulty of tracking those individuals, data is only available for the unor underinsured. 2.6 challenges concerning no-show rates. noncompliance to completion of a crc procedure is very common, especially with colonoscopy. our program isn’t unique to the many barriers faced by individuals including coordinating transportation, fear the test is painful, embarrassment, and/or fear of abnormal findings (chen et al., 2008). our program uses chws to call individuals using motivational interviewing for participants that cancelled or noshowed to their appointments. our gi clinic also www.companyofscientists.com/index.php/chd e9 cancer health disparities research attempts to reach out to individuals via phone calls as well. if unable to reach via phone, a letter is sent to their listed address inviting them to call to reschedule their appointment. we also work with community partners and update the clinics on the status of individuals that were referred to us by them. this was done so if an individual were to return to their primary care clinic before contacting us, the linic would be able to get in contacts with the individual again. 2.7 data collection data collection is conducted at uthsct and outreach events. data is comprised of self-reported questionnaire items and medical records. reports are collected on a quarterly basis. 2.7.1 education outreach data the data collected at outreach events includes: name, phone number, address, date of birth, race, ethnicity, gender, insurance status, if individuals are a health professional, if they have had a colorectal screening in the past, and if they would like to receive more information. this data was collected at outreach events by project staff. sign-in sheets were then scanned into password-protected folders and the data was transferred into an excel sheet. 2.7.2 demographic data demographic data is collected from medical chart data and through survey questionnaires. data collected include, age, race, ethnicity, zip code, family history of crc, previous crc screenings, and insurance status. 2.7.3 colonoscopy data data concerning colonoscopy procedures is collected from medical chart data. the data includes the date of colonoscopy, bowel prep (adequate/insufficient), result of colonoscopy, whether additional colonoscopies were warranted by the treating physicians. 2.7.4 fit data data concerning fit is collected from medical chart data. the data includes the date of fit test, test result, duration of time to colonoscopy following abnormal fit result. 3.1 discussion 3.1 need for intervention to increase crc education and screening rates crc screening to prevent cancer is only effective if individuals elect to undergo screening services (friedrich et al., 2015). despite the efficacy of screening services such as colonoscopy and fit, screening rates remain suboptimal (alteri et al., 2014; levin et al., 2008; salas et al., 2014). therefore, interventions targeting improvement in education and screening regarding crc are crucial. public health programs can initiate such programs and target populations with low screening rates. this will help to reduce the incidence of crc and crc mortality. the un/underinsured can particularly benefit from such programs, as they would not regularly undergo this preventive screening, as it would be an added medical cost. in addition, the un/under insured are particularly vulnerable as they would most likely not be able to afford treatment if crc would develop, highlighting the important of public health programs adopting similar initiatives to increase education and subsequent crc screening in populations with low screening rates. an additional barrier to many potential programs may include the rurality of the proposed region for intervention. whereas, the education and screening of thousands of adults may be achieved with more ease in urban areas, teams working in rural settings face unique challenges to motivate individuals to undergo www.companyofscientists.com/index.php/chd e10 cancer health disparities research screening. the primary barrier to care that is unique to rural areas is distance. interventions programs must persuade individuals about the important of crc screening and follow-up despite the additional burden of transportation and distance. 3.2 potential limitations and methodological considerations the current program has several limitations. first, while some individuals will elect to undergo colonoscopy first, others will undergo colonoscopy after a positive fit test. however, both groups will have many individuals who fail to arrive for their scheduled colonoscopy due to transportation issues and despite receiving a $20 gift card for travel. unfortunately, to the current program does not provide transportation services to individuals. second, as mentioned earlier, many individuals choosing to undergo fit testing will not follow-up with colonoscopy after an abnormal fit test result. this will hinder assessing the efficacy of fit test in detecting polyps. similarly, those with a negative fit will not undergo a colonoscopy. third, the degree of education retained by individuals will not be able to be assessed due to the lack of time provided in health fairs. only the number educated can be assessed. 3.3 conclusion and implications in conclusion, the crc education and screening program aims to increase education and crc screenings in a primarily rural population in northeast texas with low crc screening rates and high crc incidence and mortality. results from this program have the potential to advance knowledge on effective ways to increase crc screenings among underserved populations. due to the nascency of fit testing, evaluation of programs utilizing both fit and colonoscopy are limited. the current program will provide insight into the advantages and disadvantages to each method in a primarily rural setting. finally, it may also provide a method to those who were educated but did not undergo screening at the time, to undergo screening in the future, or for those who underwent screening to continue with screening methods outside of the program. acknowledgements this study was funded by the cancer prevention & research institute of texas (pp140018) and the 1115 medicaid waiver. conflict of interest the authors declare that no competing or conflict of interests exist. the funders had no role in study design, writing of the manuscript, or decision to publish. authors’ contributions carlton allen and paul mcgaha contributed to the acquisition of data and the conduct of the project. gabriela orsak, anastasia miller and karan singh contributed to the statistical analysis of the project and generated the initial draft of the article. references alteri, r., kramer, j., and simpson, s. (2014). colorectal cancer facts and figures 2014-2016. atlanta: american cancer society, 1-30. cancer prevention & research institute of texas (2010). colorectal cancer in texas: a closer look. chen, l.a., santos, s., jandorf, l., christie, j., castillo, a., winkel, g., and itzkowitz, s. (2008). a program to enhance completion of screening colonoscopy among urban minorities. clinical gastroenterology and hepatology 6, 443-450. cole, a.m., jackson, j.e., and doescher, m. (2012). urban–rural disparities in colorectal cancer screening: cross‐sectional analysis of 1998–2005 data from the centers for disease control's behavioral risk factor surveillance study. cancer medicine 1, 350-356. doubeni, c.a., corley, d.a., quinn, v.p., jensen, c.d., zauber, a.g., goodman, m., johnson, j.r., mehta, s.j., becerra, t.a., zhao, w.k., et al. (2018). effectiveness of screening colonoscopy in reducing the risk of death from right and www.companyofscientists.com/index.php/chd e11 cancer health disparities research left colon cancer: a large community-based study. gut 67, 291-298. fan, l., mohile, s., zhang, n., fiscella, k., and noyes, k. (2012). self‐reported cancer screening among elderly medicare beneficiaries: a rural‐urban comparison. the journal of rural health 28, 312-319. friedrich, k., grüter, l., gotthardt, d., eisenbach, c., stremmel, w., scholl, s., rex, d.k., and sieg, a. (2015). reduced mortality in colorectal cancer patients diagnosed by screening colonoscopy. gi endoscopy 2015, 133-137. hall, j. (2018). colorectal cancer sceening data, g. orsak, ed. hines, r., markossian, t., johnson, a., dong, f., and bayakly, r. (2014). geographic residency status and census tract socioeconomic status as determinants of colorectal cancer outcomes. american journal of public health 104, e63-e71. levin, b., lieberman, d.a., mcfarland, b., smith, r.a., brooks, d., andrews, k.s., dash, c., giardiello, f.m., glick, s., levin, t.r., et al. (2008). screening and surveillance for the early detection of colorectal cancer and adenomatous polyps, 2008: a joint guideline from the american cancer society, the us multi-society task force on colorectal cancer, and the american college of radiology. ca cancer j clin 58, 130-160. lieberman, d.a., rex, d.k., winawer, s.j., giardiello, f.m., johnson, d.a., and levin, t.r. (2012). guidelines for colonoscopy surveillance after screening and polypectomy: a consensus update by the us multisociety task force on colorectal cancer. gastroenterology 143, 844-857. national association of counties (2017). texas. national cancer institute (2017). seer cancer statistic review (csr) 1974-2014. nehme, e., elerian, n., morrow, j., mandell, d., puga, e., patel, d., and lakey, d. (2016). the health status of northeast texas 2016 (austin, tx: ut health northeast/university of texas system office of population health). quintero, e., castells, a., bujanda, l., cubiella, j., salas, d., lanas, á., andreu, m., carballo, f., morillas, j.d., and hernández, c. (2012). colonoscopy versus fecal immunochemical testing in colorectal-cancer screening. new england journal of medicine 366, 697-706. salas, d., vanaclocha, m., ibáñez, j., molina-barceló, a., hernández, v., cubiella, j., zubizarreta, r., andreu, m., hernández, c., and pérez-riquelme, f. 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(2007). comparing attendance and detection rate of colonoscopy with sigmoidoscopy and fit for colorectal cancer screening. gastroenterology 132, 23042312. texas cancer registry (2018a). age-adjusted cancer mortality rates in texas colon & rectum, 2011-2015 by public health region. texas cancer registry (2018b). age-adjusted invasive cancer incidence rates in texas colon & rectum, 2011-2015 by public health region. u.s. cancer statistic working group (2018). u.s. cancer statistics data visualizations tool, based on november 2017 submission data (1999-2015) (u.s. department of health and human services, centers for disease control and prevention and national cancer institute,). u.s. department of health and human services. healthy people 2020 (washington dc: u.s. department of health and human services, office of disease prevention and health promotion). u.s. department of health and human services (2018). c-16 increase the proportion of adults who receive a colorectal cancer screening based on the most recent guidelines. united states census bureau (2017). american fact finder. www.companyofscientists.com/index.php/chd e1 cancer health disparities commentry improving first nations cancer journeys: current policy perspectives and approaches in british columbia, canada nadine r. caron2,3, kevin linn1; john j. spinelli2,3, harmony johnson1*; 1. first nations health authority, vancouver, bc, canada 2. bc cancer, vancouver, bc, canada 3. university of british columbia, vancouver, bc, canada *corresponding author email: harmony.johnson@fnha.ca abstract processes of reconciliation in canada have created a new climate for discussions about systemic racism and a lack of cultural safety and humility as a root cause of health outcome disparities for first nations people. in british columbia, efforts to improve first nations cancer outcomes and experiences are now formalized through an indigenous cancer strategy that incorporates bc first nations perspectives on health and wellness. in partnership with the unique first nations health governance structure in the province, health system and community partners are leveraging the current climate for change to improve first nations cancer journeys, and are leading the way to improving culturally safe health services for all british columbians. keywords: first nations, indigenous, aboriginal, cancer, disparities, cultural safety, cultural humility citation: caron n et al (2018) improving first nations cancer journeys: current policy perspectives and approaches in british columbia, canada. cancer health disparities 2:e1-e8. doi:10.9777/chd.2018.10012 www.companyofscientists.com/index.php/chd e2 cancer health disparities commentry first nations in british columbia (bc), canada have enjoyed a rich history of health and wellness since time immemorial. this health and wellness was intentionally disrupted through processes of colonialism implemented by governments and other institutions, including policies of forcible displacement of people from family and community, culture and ceremony, language and land. the resulting loss and subsequent trauma from these policies continue to negatively impact many first nations people in their interaction with western institutions, including the healthcare system. colonialism continues to manifest itself in structural barriers for first nations people in achieving equitable access to health and wellness resources and services, including those that relate to cancer control. canada is a country in the midst of facing this history of colonialism and its continuing impact on the health and wellness of indigenous people. in 2015, the truth and reconciliation commission (trc) of canada documented the history of canadian federal government policy that resulted in aboriginal children being taken from their families and placed in indian residential schools. in the trc’s report, it was concluded that indian residential schools amounted to cultural genocide. as part of the reconciliation process, ninety four ‘calls to action’ were presented by the trc to redress the harms inflicted through various policies of colonialism, including calls related specifically to health and health service delivery (trc, 2015). in this era of truth and reconciliation in canada, there is increasing acknowledgement of the ongoing systemic racism and bias against first nations people that is unacceptable. in this context, it is recognized that first nations people have a right to access health and cancer care services that are free of discrimination and that address unique community and individual needs. however, health services in bc, including cancer care, were never designed with an understanding of first nations’ definitions of health and wellness, nor of colonialism and its impact on first nations people. a transparent recognition of the need for cultural safety as part of quality improvement in health services is required, and there is now a unique and unprecedented system-wide movement underway to achieve this in bc. the first nations perspective on health and wellness in figure 1 presents a visual depiction of bc first nations’ philosophy and definition of health and well-being, which recognizes the health and wellness of individuals as consisting and being an outcome of many interrelated internal and external factors (first nations health authority [fnha], nd-a). this perspective was developed based on guidance provided by bc first nations and founded in traditional teachings. the centre circle represents individual human beings, recognizing that wellness starts with individuals. the second circle illustrates the importance of mental, emotional, spiritual and physical facets of a healthy, well and balanced life. the third circle represents the overarching values that support wellness, including: respect, wisdom, responsibility, and relationships. the fourth circle depicts the people that surround us and the places from which we come: nations, family, community and land. and the fifth circle depicts the social, cultural, economic and environmental determinants of our health and well-being. recognizing all components of the circle and the interconnectedness of the physical, emotional, spiritual and mental dimensions and determinants of first nations health and wellbeing is a starting point towards improving quality and addressing disparities in cancer care www.companyofscientists.com/index.php/chd e3 cancer health disparities commentry between first nations and non-first nations people in the province. figure 1. first nations perspective on health and wellness this perspective is a visual depiction of first nations peoples’ collective philosophy that the mind, heart, body and spirit are all connected and are supported by internal and external factors including culture, relationships, and responsibility, and are shaped by family, community, the land and broader environmental, social and economic factors (fnha, nd-a). a recent study of incidence and survival rates between first nations and non-first nations people living in bc between 1993 and 2010 highlighted disparities in cancer incidence and outcomes (mcgahan et al., 2017). data from this study, the first of its kind, demonstrated that first nations people in bc were more likely to be diagnosed with colorectal (men and women) and cervical cancers while enduring the same incidence rates of breast cancer, which was the most commonly diagnosed cancer in first nations and non-first nations women, as indicated in table 1. colorectal cancer was the second most commonly diagnosed cancer in first nations men and women, and cervical cancer was the fourth most common among first nations women. study findings also showed lower survival rates in 10 out of the 12 cancer sites examined in first nations men and 10 out of 15 cancer sites examined in first nations women, including lower survival rates for colorectal (men and women), breast and cervical cancers as indicated in table 2. lower cancer survival rates can be caused by a combination of differences in access to or utilization of primary www.companyofscientists.com/index.php/chd e4 cancer health disparities commentry care, screening programs (and subsequent impact on stage of cancers at time of diagnosis), and/or high quality, timely, appropriate and effective cancer treatment, to name a few. while this study was a key step in understanding the quality of cancer care from an equity perspective, it needs to be acknowledged that first nations health goals and targets should not be solely defined by comparisons with the health status of non-first nations people. table 1: incidence counts, age-standardized incidence rates and standardized rate ratios (srrs) by disease site for each sex, in first nations (fn) and non-fn populations 1993-2010. incidence age-standardized incidence rate (95% ci) srr (95% ci) fn non-fn fn non-fn females breast 767 45,478 224.0 ( 207 241) 240.0 ( 238 243) 0.93 (0.87 1.01) cervical 134 2,810 33.1 (27.0 39.3) 17.2 (16.6 17.9) 1.92 (1.49 2.48) colorectal 292 18,226 92.9 (81.5 104) 76.4 (75.1 77.6) 1.22 (1.06 1.39) males colorectal 366 21,834 154 ( 137 171) 111 ( 109 113) 1.39 (1.22 1.58) note: adapted by permission from mcgahan et al: springer international publishing. cancer causes & control. cancer in first nations people living in british columbia, canada: an analysis of incidence and survival from 1993 to 2010. copyright springer international publishing ag 2017 table 2: observed 1-year and 5-year cause-specific survival and age-adjusted cause-specific hazard ratio (95% ci) by disease site in first nations (fn) and non-fn populations, 1993-2010. fn incidence 1-year age-standardized causespecific survival 5-year age-standardized causespecific survival agestandardized hr (95% ci) fn non-fn fn non-fn females breast 767 0.97 (0.95-0.98) 0.96 (0.96-0.97) 0.83 (0.80-0.86) 0.85 (0.850.86) 1.14 (0.96-1.35) cervical 134 0.89 (0.82-0.93) 0.89 (0.88-0.90) 0.73 (0.64-0.80) 0.73 (0.710.75) 1.19 (0.84-1.67) colorectal 292 0.82 (0.77-0.86) 0.78 (0.78-0.79) 0.57 (0.50-0.63) 0.57 (0.560.57) 1.16 (0.97-1.39) males colorectal 366 0.78 (0.73-0.82) 0.81 (0.81-0.82) 0.51 (0.45-0.57) 0.57 (0.560.57) 1.30 (1.12-1.52) note: adapted by permission from mcgahan et al: springer international publishing. cancer causes & control. cancer in first nations people living in british columbia, canada: an analysis of incidence and survival from 1993 to 2010. copyright springer international publishing ag 2017 understanding bc’s cancer care system is important when interpreting these statistics. cancer care services in bc were designed and are delivered by a diverse matrix of health system partners. for example, there are six regional bc cancer centres in the province that provide all radiation therapy treatments, over 50% of chemotherapy treatments, specialized imaging www.companyofscientists.com/index.php/chd e5 cancer health disparities commentry services (such as pet scans and breast mri), and a range of patient assessments, follow-up and supportive cancer care services. other important cancer care services, such as surgery, diagnostics and palliative care, as well as some local delivery of chemotherapy treatments, are planned and provided by regional health authorities. for the province’s population-based colon, breast and cervical cancer screening programs, a partnership framework is followed with bc cancer overseeing the provincial approach, primary care providers identifying eligible patients for screening, and regional health authorities and community (private) imaging clinics and laboratories delivering the screening tests. as with many health services in bc, participation in these screening programs requires access to a primary care provider. this is concerning, as in addition to the cancer outcome disparities noted earlier, it has also been found that first nations people are less likely than nonfirst nations people to be attached to a primary care physician (fnha, nd-b). bc also has a publicly funded vaccination program against the human papilloma virus (hpv), which includes free vaccinations for all boys and girls as part of a school-age child vaccination schedule. considering this complexity in service delivery, full engagement and coordination amongst bc cancer, regional health authority, and primary care partners is needed to improve the quality of cancer care services in the province. for first nations people, families and communities, there is an additional level of complexity and planning required for health service delivery, as the federal government has a constitutional responsibility for first nations in canada while the provinces are constitutionally responsible for health services (health canada, 2014). this mix of federal and provincial responsibility for first nations has created a lack of jurisdictional clarity that results in barriers for first nations people in accessing healthcare (indigenous services canada, 2018; lavoie, j. g., 2013). there are concerns that these barriers to accessing healthcare also extend to receiving vital cancer care services in the province. since 2006, a significant shift has been underway in bc to resolve these jurisdictional barriers and recognize the need to meaningfully involve first nations in decision-making when it comes to health service planning. a unique first nations health governance structure in bc, which includes the first nations health authority (fnha), has been established. fnha is the first populationbased health authority in the province and amongst the largest first nations public service organizations in canada (gallagher, mendez, & kehoe, 2015). it works to drive quality improvement in service delivery for first nations and all british columbians by promoting partnerships, collaborations, and innovation with provincial and regional health authorities. fnha is responsible for the design and delivery of first nations health programs and services that were formerly handled by the federal government in bc, and is involved in decision-making within the larger provincial health system related to prioritization, planning, service coordination, and accountability monitoring. as a result, and in the context of reconciliation, addressing disparities in first nations care and outcomes is now being built into key processes of health service planning and quality improvement efforts in the province. one of the quality improvement priorities being championed by fnha and health system partners has been a system-wide movement on embedding cultural safety and humility within health services. fnha’s policy statement on cultural safety and humility provides a vision for www.companyofscientists.com/index.php/chd e6 cancer health disparities commentry this work (fnha, nd-e). in reflection of this vision, cultural safety is an outcome based on respectful engagement that recognizes and strives to address power imbalances inherent in the healthcare system. it results in an environment free of racism and discrimination, where people feel safe when receiving care. cultural humility is a process of self-reflection for healthcare providers to understand personal and systemic biases, and to develop and maintain respectful processes and relationships based on mutual trust. when healthcare professionals engage with first nations people from a place of cultural humility, they are helping to create a safer healthcare environment where individuals and families experience respect. this puts power in the hands of clients to define what culturally safe care looks and feels like, and requires training of healthcare providers to be lifelong learners and self-interrogators to understand how their culture and society impacts their practice. by improving cultural safety in health services, first nations people will be more likely to access care when needed; increased access and utilization of healthcare services will inevitably result in improved health outcomes. to operationalize cultural safety and humility as a health system priority, key provincial and regional health partners have signed declarations of commitment to advance cultural safety and humility and are undertaking associated action planning and implementation work. health system partners include all bc regional and provincial health authorities (fnha, nd-c) and all twentythree bc health regulators (provincial regulatory colleges of health professions; fnha, nd-d). work is also underway with universities and education providers in the province to support the education needs of students studying in the health and social sciences; thereby supporting improvements in cultural safety on many fronts and for the long term. as per the trc’s ‘calls to action’ #23 and #24, cultural safety and humility has now become necessary and expected (trc, 2015). these essential concepts are no longer considered progressive or optional. in a country as diverse as canada, this is seen as progress not just for indigenous people, but for all canadians. the issue of cultural safety and humility is now also firmly embedded in provincial cancer care quality improvement efforts through a first-of-its-kind indigenous cancer strategy released in 2017 (fnha, métis nation british columbia, bc association of aboriginal friendship centres, and bc cancer, nd). embodying a culturally safe philosophy throughout its development, the strategy took a “best of both worlds” approach, blending western models of strategy development with a deep commitment to indigenous decisionmaking and community engagement. in the context of reconciliation, the strategy posits that the disparities in cancer outcomes are at least partially attributable to processes of colonialism, intergenerational trauma and a lack of cultural safety in the healthcare system, particularly as it relates to primary care and tertiary cancer treatment services. therefore, the indigenous cancer strategy aims to improve indigenous cancer journeys by implementing actions that promote cultural safety and humility along all steps of the cancer journey, from prevention through to survivorship and end-of-life. examples include:  completing relevant data linkages to identify first nations hpv vaccination rates, cancer screening (colon, cervical and breast cancer) program participation rates, and updating first nations cancer incidence (including stage at diagnosis) and survival rates to evaluate the www.companyofscientists.com/index.php/chd e7 cancer health disparities commentry performance of the cancer control system for first nations people in order to direct solutions for improvement specific to such findings.  promoting client and community awareness and engagement in cancer prevention (environment, commercial tobacco, physical activity, healthy eating and hpv vaccination) and screening programs (colon, cervical and breast cancer);  supporting health system partners to improve quality of service across the cancer care spectrum through applying a lens of cultural safety and humility to their values and attitudes, structures and policies, system performance frameworks, and staff training and development; and,  connecting first nations people, families and communities impacted by cancer to build an empowered first nations cancer survivorship network to provide peer-support and further identify and guide first nations cancer quality improvement priorities. the development and now implementation of an indigenous cancer strategy in bc is an essential approach to strategically improving first nations cancer journeys in the province. the processes of reconciliation in canada have created a new climate for discussions about systemic racism, and highlighted the lack of cultural safety as a root cause of health outcome disparities for first nations and the need for greater first nations decision-making. in bc, one of these processes of reconciliation is the establishment of a first nations health governance structure that works in partnership with federal and provincial governments in the design and delivery of health services accessed by first nations people. through this process, efforts have been initiated to support quality improvement in health services through cultural safety and humility. these broad priorities and processes are being focused specifically to improve cancer care and associated outcomes for first nations people. through the development of an indigenous cancer strategy, fnha and health system partners are now leveraging the current climate for change and reconciliation to improve cancer outcomes and experiences for first nations people, families and communities, and are leading the way of improving culturally safe health services for all british columbians. acknowledgements the authors would like to acknowledge the contribution of the late preston guno who was instrumental in the development of the bc indigenous cancer strategy. conflict of interest the authors declare that no competing or conflict of interests exist. the funders had no role in study design, writing of the manuscript, or decision to publish. authors’ contributions all authors contributed equally to this manuscript. references first nations health authority. 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http://www.trc.ca/websites/trcinstitution/file/2015/findings/calls_to_action_english2.pdf http://www.trc.ca/websites/trcinstitution/file/2015/findings/calls_to_action_english2.pdf www.companyofscientists.com/index.php/chd e1 cancer health disparities research modifiable risk factors implicated in prostate cancer mortality and morbidity among nigerian and cameroonian men ernest t. kaninjing*1,2, getachew dagne1,3, sunday e. atawodi1,4, adewumi alabi1,5, olubanke o. ogunlana1,6, patrick t. adegun1,7, haruna nggada1,8, ifeoma okoye1,9, abidemi e. omonisi1,7, mohammed faruk1,4, iya eze bassey1,10, faoziyat a. sulaiman1,11, nissa askins1,12, blaise nkegoum1,13, ademola a. popoola1,11, anthonia c. sowumni1,14, catherine oladoyinbo1,15, omolara a. fatiregun1,5, paul jibrin1,16, emeka e. iweala1,6, wole kukoyi1,17, kayode adeniji1,11,18, ayo salako1,19, iheanyi okpala1,9 uche okoro1,14, okezie mbadiwe1,19 hassan m. dogo1,8, mtaku gali1,8, & folakemi t. odedina1,12. *1prostate cancer transatlantic consortium; 2georgia college & state university, usa; 3university of south florida, usa; 4ahmadu-bello university, zaria, nigeria; 5lagos state university teaching hospital, nigeria; 6covenant university, ota, nigeria; 7ekiti state university, nigeria; 8university of maiduguri, nigeria; 9university of nigeria college of medicine, enugu, nigeria; 10university of calabar, nigeria; 11university of ilorin, nigeria; 12university of florida, usa; 13university hospital center, yaounde, cameroon; 14lagos university teaching hospital, nigeria; 15federal university of agriculture, abeokuta, nigeria; 16national hospital, abuja, nigeria; 17ace medicare clinics limited, ota, nigeria; 18hebron international diagnostic & molecular pathology center, ilorin, nigeria; 19obafemi awolowo university, ife, nigeria. *corresponding author: ernie.kaninjing@gcsu.edu abstract prostate cancer is a significant public health problem affecting men globally. in 2018, it was the second most commonly diagnosed cancer among men world-wide and disproportionately impact men of african ancestry. some of the modifiable risk factors for prostate cancer include knowledge and attitudes about the disease, the belief system of individuals and their diet. moreover, physical activity, alcohol and tobacco consumption have also been suggested as behavioral factors that contribute to prostate cancer disparities. this study compares modifiable risk factors implicated in prostate cancer among men living in africa and african immigrants living in the united states to identifying behavioral factors that can be targeted for intervention. a cross-sectional study design was employed among black men in nigeria, cameroon and african immigrants in united states using the global prostate cancer measure for black men. findings indicate that nigerian and cameroonian men residing in the united states expressed a more positive attitude towards screening than their counterparts in africa. knowledge levels about prostate cancer was higher among african immigrants in the united states compared to those living in africa. additionally, fatalism, attitude and knowledge of prostate cancer signs and symptoms were statistically significant in the prediction of prostate cancer screening. cancer control and prevention efforts in nigerian and cameroon should focus on educating men about the signs and symptoms of this disease to increase knowledge levels and ensure awareness of screening methods. prostate cancer survivors should be part of health promotion campaigns to reduce fatalistic beliefs. keywords: risk factors, prostate cancer, health disparity, african ancestry, behavioral factors, citation: kaninjing et al (2019) modifiable risk factors implicated in prostate cancer mortality and morbidity among nigerian and cameroonian men. cancer health disparities 4: e1-e13. doi:10.9777/chd.2019.1002 www.companyofscientists.com/index.php/chd e2 cancer health disparities research introduction prostate cancer (cap) is a significant public health problem affecting men globally. according to the international agency for research in cancer, it was the second most commonly diagnosed cancer among men worldwide in 2018 (bray, 2018) and disproportionately impact men of african ancestry (american cancer society, 2018). it accounted for 359,000 associated deaths globally in 2018, with an increasing number of fatalities reported in subsaharan africa (bray et al 2018). established risk factors for this disease include older age; family history; and african ancestry (centers for disease control and prevention, 2018). while these factors are non-modifiable, there are other contributing factors to cap disparities that are modifiable. they include knowledge and attitudes about the disease, beliefs, and lifestyle factors, such as diet, physical inactivity, alcohol and tobacco consumption. these behavioral factors exacerbate disparities in cap outcomes among black men. current literature indicates that low knowledge and awareness about the disease, socio-economic status, lack of access to quality care, diagnostic centers and treatment play significant roles in late stage presentation and mortality (akpuaka et al., 2013; baade, youlden, & krnjacki, 2009; cobran et al., 2014; mcfall, hamm, & volk, 2006). in the united states (us), cap is the most common cancer diagnosed among men and the second ranked cause of cancer mortality, with about 1 man in 7 likely to be impacted by this disease during their life time (acs, 2018). it is estimated that in 2018 about 164,690 men were diagnosed with this disease in the us with about 29,430 deaths (acs, 2018). ethnic/racial and geographic disparities characterize the burden of cap among sub populations and regions within the us. for example, in 2015, black men in america experienced the highest incidence rate (158 per 100,000 persons) compared to all races (99 per 100,000 persons). similarly, death rates for the same year showed black men were more likely to die of cap than any other racial or ethnic group in america (cdc, 2018). according to the united states cancer statistics working group (u.s. cancer statistics working group, 2017), between 1999 and 2012, the northeast region had the highest incidence of 115.4 per 100,000 people followed by the midwest with 105.3 per 100,000 people and the south with 104.3 per 100,000 people. in terms of death rates, the midwest and south regions had the highest at 19.8 per 100,000 people followed by the west region at 19.5 per 100,000 and the northeast at 18.8 per 100,000 people (u.s. cancer statistics working group, 2017). reasons for these unequal distribution in health outcomes are complex and include social determinants of health such as lack of access to medical care, low socio-economic status, and the structural determinants and conditions of daily life (marmot, friel, bell, houweling, & taylor, 2008; schroeder, 2007). significant challenges exist in quantifying the burden of cap in sub-saharan africa (ssa) (adeloye et al., 2016). few countries in this region have established population-based cancer registries, and existing registries lack adequate resources (morhason-bello et al., 2013; odedina et al., 2009). the african organization for research and training in cancer (aortic) estimates that while 80% of the united states population is covered by cancer registries, only about 1% of african population are presently covered (morhason-bello et al., 2013). data from the international agency for research on cancer (globocan 2012) show that in 2012, the most www.companyofscientists.com/index.php/chd e3 cancer health disparities research common cancer among men in ssa was prostate which accounted for 16.4% of new cancer cases (parkin, bray, ferlay, & jemal, 2014). in ssa, the risk of developing cap before age 75 was estimated at 3.4% in 2012 affecting almost 1 in 30 men (parkin et al., 2014). published data reveals wide geographic variations in reported incidence and mortality from cap in africa. in 2012, cap death rates were higher in southern africa (agestandardized rate 24.4 per 100,000 population per year), middle africa (age-standardized rate of 24.2 per 100,000 population per year), and western africa (age-standardized rate of 21.2 per 100,000 population per year) compared to north africa (age-standardized rate of 7.0 per 100,000) which is 7 times lower than the rates of the other three regions (ferlay et al., 2015). these figures may not reflect the actual burden of this disease in africa as several studies have noted underreporting of cancer cases (angwafo, 1998; chu et al., 2011; jemal, 2012; klassen & platz, 2006; morhason-bello et al., 2013; odedina et al., 2009) due to lack of population-based cancer registries. moreover, the population of africa between 2010 and 2030 is projected to increase by 60% overall (from 1.03 billion to 1.65 billion) and by 90% for individuals 60 years and older (from 55 million to 103 million), the age at which cancer frequently occurs (united nations department of economic and social affairs population division, 2017). among men in nigeria, cap is the most common malignancy with an incidence rate of 30 per 100.000 cases and mortality rate of 26 per 100,000 cases (ferlay et al., 2013). a hospital-based study showed incidence of 127/100,000 cases with a national population risk of 2% (osegbe, 1997). this was compared to the low incidence in previous years owing to gross underestimation of the disease. alabi and colleagues (alabi, sowunmi, alabi a.s., & fatiregun, 2016) reported an incidence of 12.1% in lagos nigeria, which was comparable to other studies from kano, zaria, benin, and maiduguri with incidence of 16.5%, 9.2%, 7.13% and 6.15% of all male cancers respectively (akinremi, ogo, & olutunde, 2011). these results are contrary to previous perception on the rarity of the disease in africa. in cameroon, cap is the leading cause of death from cancer among men (orock, ndom, & doh, 2012). in 2012, the population-based age standardized incidence for cap among men was 23.0 per 100,000 persons and mortality rate was 18.6 per 100,000 persons (ferlay et al., 2015). this number might not reflect the true burden of the disease as there is no active national surveillance system, and some cancer deaths are neither reported nor recorded (angwafo et al., 2003; doh, 2006). behavioral factors have been shown to offer the single greatest opportunity to bring about reduction in cancer incidence, improvement in health outcomes and reduction in the global burden of cancers (klein et al., 2014; schroeder, 2007; stein & colditz, 2004). a study by mokdad and colleagues (mokdad, marks, stroup, & gerberding, 2004; stein & colditz, 2004) showed that behavioral factors account for nearly 40% of all deaths in the united states. behavioral factors provide an opportunity to understand the etiology of cancer and effectively address potential areas for cancer control and prevention intervention. this study aimed to identify the behavioral factors associated with cap among men with common ancestral background, living in three countries: united states, nigeria, and cameroon. we examined the similarities and differences in modifiable risk factors such as diet, health literacy, www.companyofscientists.com/index.php/chd e4 cancer health disparities research physical activity, cigarette smoking, attitudes, fatalism and knowledge about the signs and symptoms of this disease. results of this study indicate that nigerian and cameroonian men residing in the united states expressed a more positive attitude towards screening than their counterparts in africa. knowledge levels about prostate cancer was higher among african immigrants in the united states compared to those living in africa. additionally, fatalism, attitude and knowledge of prostate cancer signs and symptoms were statistically significant in the prediction of prostate cancer screening. one public health application of this result entail tailored interventions in nigeria and cameroon that seek to improve attitudes and knowledge about this disease and address fatalistic beliefs. methods study design and sites this was a cross-sectional study design implemented by the prostate cancer transatlantic consortium (captc) investigators in three countries (united states, nigeria and cameroon). the study sites included: federal university of agriculture abeokuta, covenant university otta, lagos state university teaching hospital, lagos university teaching hospital, ace medicare clinic lagos, ekiti state teaching hospital, obafemi awolowo university teaching hospital complex ile-ife, university of ilorin, national hospital abuja, university of maiduguri, ahmadu bello university zaria, and the university of calabar. in cameroon, the university hospital center of the university of yaounde 1 participated, and in the united states, the university of florida. participants participation in this study was limited to nigerian and cameroonian men between the age of 35 and 70 years residing in nigeria, cameroon, or the united states regardless of any cancer diagnosis. the inclusion criteria were men with a first-degree male relative living in one of the three countries. exclusion criteria were men below age 35 or older than 70 years. study variables and measures the global prostate cancer measure for black men developed by captc and the african caribbean cancer consortium (ac3) investigators was used for data collection. this multi-item standardized instrument has been validated for use in other studies conducted in black men (odedina et al., in press; blackman et al., 2018; cobran et al., 2014; kaninjing et al., 2017; kumar et al., 2009; odedina et al., 2011a; ogunsanya et al., 2016a). the study variables and measures are presented next: demographic variables included participants’ age, educational level, religion, marital status, and employment. age was categorized into four strata (35-44); (45-54); (55-64); and 65 plus. marital status was categorized into single or married. religion was stratified into three categories: christian, muslim, and other. employment status was divided into three groups: employed, not employed, and refused to provide information. education included four levels: less than high school, high school, university and refused to provide information. outcome variables for this study was having had a prostate specific antigen test (psa) and or digital rectal examination (dre). both were measured by asking participants “how long has it been since you had your last psa test?” and “how long has it been since you had your last dre exam?” www.companyofscientists.com/index.php/chd e5 cancer health disparities research response options were: a) within the past year; b) within the past 2 years; c) within the past 3 years; d) within the past 5 years; e) 5 or more years ago; and f) never. both variables were dichotomized into 1 (if participant had received a psa test options a-e) or 0 (if participant had not received a psa testoption f). independent variables were smoking status, fatalism, attitude, health literacy, knowledge, meat diet, poultry diet, fish diet, physical activity, and alcohol consumption. with regards to smoking status, participants were asked “what are your smoking habits?” with the following response options: a) i smoke daily; b) i smoke daily but i have cut down; c) i smoke every once in a while; d) i used to smoke, but quit less than 6 months ago; e) i used to smoke, but quit more than 6 months ago; f) i have never smoked; g) i used to smoke, quit time unknown; h) don’t know/not sure g) refused. this variable was categorized as current smoker if response was either a, b, or c.; past smoker if response was either d, or e; and never if response was f or g. participants were also asked, “have you smoked at least 100 cigarettes in your entire life?”. the equivalent of 100 cigarettes is 5 packs. participant choices were a) yes, b) no, c) don’t know/not sure and d) refused. four items were used to measure cancer fatalism among study participants with response captured on a likert-type scale (strongly agree; agree; neutral; disagree; strongly disagree). the items were: a) i believe if someone has prostate cancer, it is already too late to do something about it; b) getting prostate cancer means the end of the world; c) if someone is told “you have prostate cancer”, there is nothing to be hopeful for; and d) the first thing that comes to my mind when i hear “prostate cancer” is death. the score range for this variable was 4 – 20. higher scores indicate higher fatalism or the sense that things are beyond the control of the individual. three items measured participant’s attitude towards screening for prostate cancer with responses in a scale (very favorable; favorable; neutral; unfavorable; very unfavorable). the items include: a) weighing the advantages and disadvantages of prostate cancer screening to make a decision about screening for prostate cancer; b) getting tested for prostate cancer with digital rectal examination (dre) every year; and c) getting tested for prostate cancer using my blood sample for serum prostate specific antigen (psa) test every year. the score range for this variable was 3 – 15. higher scores indicate positive attitude. health literacy was measured by four items with responses in a likert-type scale (always; often; sometimes; rarely; never). the items were: a) i have someone help me read health materials; b) i am confident filling out health forms by myself; c) i have problems understanding written information about prostate cancer; and d) when someone discusses prostate cancer with me, i have problems understanding the information. the score range for this variable was 4 – 20. lower scores indicating low literacy levels. twenty items assessed participants’ knowledge of prostate cancer signs and symptoms. responses were “true”; “false”; and “don’t know”, with “don’t know” and blank responses coded as wrong response. participants were asked about their diet, particularly consumption of meat, poultry, fish, animal organs and animal fats. participants had the option to report their frequency of consumption of these items per week, or per www.companyofscientists.com/index.php/chd e6 cancer health disparities research month. physical activity was measured by a single item with a “yes” or “no” response to the following question: “are you involved in vigorous-intensity activity that causes large increases in your breathing or heart rate (for example carrying or lifting heaving loads, digging or construction work) for at least 10 minutes continuously?”. the internal consistency of sampling instrument was established at 0.88 cronbach’s alpha for cancer fatalism, 0.84 for attitude and 0.47 for health literacy. recruitment and data collection after institutional review board approval from each participating institution, data collection commenced in may 2017 and is still ongoing. the data reported in this paper is the data collected between may 2017 and july 2017. the global prostate cancer measure for black men was administered by trained investigators, research staff and student assistants. prior to administration of study survey, informed consent was obtained from each participant. recruitment took place in community settings at all participating sites. in addition, there were recruitment at clinics in nigeria and cameroon. the first 500 participants who participated in the study were included for this report. participants in the united states were provided a $25.00 gift card for completing questionnaire while those in nigeria and cameroon received either a t-shirt or a small monetary incentive. data management and statistical methods the research electronic data capture (redcap) was used for data entry and management. the data was exported to sas software for data analyses. descriptive statistics was used to summarize the study variables. we then computed proportions for quantitative measures and compared qualitative measures using t and chisquare tests. logistic regression was used to assess the effects of demographic and independent variables on outcome variables. results a total of 500 participants completed questionnaire for this study, with 428 (85.6%) participants from nigeria, 34 (6.8%) from cameroon and 38 (7.6% african immigrants from the us with first-degree male relatives living in either cameroon or nigeria. majority of the participants had achieved university level education, were married, identified as christians, and were employed. table 1 shows the demographic variables for study participants. table 1. demographic characteristics of study participants (n=500). countries variables cameroon n=34 (6.8%) nigeria n=428 (85.6%) united states n=38 (7.6%) age 35-44 8 (23.53) 189 (44.25) 19 (50.00) 45-54 12 (35.29) 133 (31.15) 15 (39.47) 55-64 9 (26.47) 68 (15.93) 4 (10.53) 65+ 5 (14.71) 37 (08.67) 0 (00.00) education < high school 8 (23.53) 79 (18.77) 0 (00.00) high school 10 (29.41) 97 (23.04) 1 (02.63) university 14 (41.17) 243 (57.72) 37 (97.37) www.companyofscientists.com/index.php/chd e7 cancer health disparities research refused 2 (05.88) 2 (00.48) 0 (00.00) marital status single 4 (11.76) 28 (6.55) 5 (13.89) married 30 (88.24) 399 (93.44) 31 (86.11) religion christian 31 (96.88) 288 (68.74) 35 (94.59) muslim 0 (00.00) 128 (30.55) 1 (02.70) other 1 (03.13) 3 (00.72) 1 (02.70) employment status employed 23 (67.65) 372 (88.15) 32 (86.44) not employed 11 (23.53) 50 (11.86) 5 (12.95) refused 3 (08.82) 0 (00.00) 1 (00.61) table 2 provides a comparison of the study variables across the three study sites. the variables that were statistically significant (p<.05) across the three study populations were cancer fatalism, attitude, knowledge, diet of poultry, intensive physical activity, psa test and dre. nigerian and cameroonian men residing in the us had a lower mean score for cancer fatalism (6.6666) compared to participants in cameroon (8.9642) and those from nigeria (8.7839). this means that participants in the us felt they had the power to influence their behavior and health outcome, as opposed to participants from the other sites who considered the events around their health as inevitable and controlled by fate. regarding attitude and knowledge, nigerian and cameroonian men residing in the us expressed more positive attitude (13.2500) compared to those from nigeria (11.2052) and from cameroon (11.5357). knowledge level about cap was higher among nigerian and cameroon men residing in the us than those in cameroon and nigeria. concerning diet, participants from cameroon and nigeria consumed less poultry than those living in the us. higher physical activity was reported among participants from nigeria (2.1392) followed by participants from the us (2.0833) and those from cameroon reported the lowest physical activity (1.0000). reported psa test was more common among participants from cameroon (0.8928) followed by participants from the us (0.6666) and least common among participants from nigeria (0.2919). history of dre was more commonly reported by participants from the us (0.7500) followed by participants from cameroon (0.6071) and least reported among participants from nigeria (0.2267). table 2. descriptive statistics of behavioral factors across study sites. variable cameroon (n=30) nigeria (n=355) us (n=36) pvalue smoking status (%) current smoker past smoker never 3.57% 25.00% 71.43% 4.94% 16.36% 78.70% 2.94% 17.65% 79.41% 0.8123 fatalism 8.96 8.78 6.66 0.0048 attitude 11.53 11.20 13.25 <.0001 health literacy 12.78 13.38 14.66 0.1500 www.companyofscientists.com/index.php/chd e8 cancer health disparities research knowledge 6.75 6.79 9.66 0.0002 diet (meat) 1.74 1.65 1.53 0.6258 diet (poultry) 1.33 1.42 2.08 0.0009 diet (fish) 2.45 2.11 1.68 0.0621 diet (organ) 1.08 1.32 0.94 0.1353 diet (fats) 2.09 2.13 2.05 0.2832 physical activity 1.00 2.13 2.08 <.0001 alcohol consumption 2.43 1.67 1.91 0.2709 psa (1=yes; 0=no) 0.89 0.29 0.66 0.0001 dre (1=yes; 0=no) 0.60 0.22 0.75 0.0006 regarding dre, participants from nigeria had an 81% lower odds of getting a dre compared to participants in the us, whereas no difference was found between participants in cameroon and those in the us (table 3). when examining the effect of diet, individuals consuming meat on average had a 52% lower odds of having a dre relative to those who did not consume meat (or = 0.48; 95% ci: 0.29 – 0.80); furthermore, the odds of having a dre was 2.15 times higher for study participants who consumed fish (or= 2.15; 95% ci:1.46 – 3.16), compared to those who did not. in terms of psa, a meat-based diet was found to be a significant predictor whereby meat-consuming participants, with an or of 0.56 (95% ci 0.37 – 0.85) had a 44% lower odds of having a psa test compared to those who did not consume meat. conversely, participants who reported a fish-based diet or of 1.77 (95% ci: 1.28 – 2.44) on average had a 77% higher odds of getting a psa test than participants whose diet did not contain fish. these findings indicate that participants who were more likely to exhibit cap preventative behavior were also more likely to participate in cap screening. for all other variables no difference was found in the odds of having a dre. attitude in this analysis was found to be a significant predictor of cap screening, with an or of 1.21 (95% ci: 1.05 – 1.39) meaning that for each unit increase in the score for attitude, the odds of having a psa on average increased by 21% (table 3). all other remaining variables assessed for an association with the psa were not found to be significant. table 3. odds ratio estimates of the association between behavioral factors and having a dre or a psa. psa dre s2q1: cameroon vs us 2.17 (0.52 9.02) 0.68 (0.14 3.28) s2q1: nigeria vs us 0.57 (9.02 1.51) 0.19 (0.06 0.58) fatalism 1.02 (0.94 1.12) 1.02 (0.92 1.14) attitude 1.21 (1.05 1.39) 1.06 (0.90 1.24) health literacy 1.01 (0.92 1.10) 1.03 (0.93 1.15) knowledge 1.04 (0.97 1.11) 1.02 (0.94 1.11) diet (meat) 0.56 (0.37 0.85) 0.48 (0.29 0.80) diet (poultry) 1.30 (0.90 1.88) 1.08 (0.72 1.62) diet (fish) 1.77 (1.28 2.44) 2.15 (1.46 3.16) diet (organ) 0.99 (0.75 -1.29) 1.10 (0.80 1.51) www.companyofscientists.com/index.php/chd e9 cancer health disparities research diet (fats) 0.80 (0.57 1.11) 0.83 (0.56 1.23) physical activity 1.11 (0.82 1.49) 1.03 (0.71 1.48) alcohol duration 1.14 (0.96 1.36) 1.14 (0.92 1.41) smoking status: current smoker vs past smoker 1.38 (0.31 6.19) 0.67 (0.104.66) smoking status: never vs past smoker 0.78 (0.35 1.73) 0.67 (0.26 1.71) discussion since human behavior is a significant contributor to the etiology and management of cancer outcomes (klein et al., 2014; mokdad et al., 2004), effective cancer prevention and control efforts can benefit from behavioral intervention strategies. this study uniquely focuses on exploring modifiable behavioral factors for cap among nigerian and cameroonian men residing in nigeria, cameroon and the united states. the important findings with implications for health promotion and cap awareness among this population are summarized next. cancer fatalism and prostate cancer detection while participants in the us felt they had the power to influence their behavior and health outcome, participants from nigeria and cameroon considered the events around their health as inevitable and dependent on fate. this perception has been described as cancer fatalisma belief that death is inevitable following a diagnosis of cancer, and it is a major barrier to cancer detection and control (west, 1993). other studies from nigeria and cameroon have reported strong perception of fatalism about this disease as conversations about cancer in these countries are often shrouded in fear and strongly held superstitious beliefs (aderounmu et al., 2006; kaninjing et al., 2018; ojewola et al., 2017). similarly, a 2011 study among ethnically diverse black men in florida (odedina et al., 2011) noted that us-born black men and caribbean-born us citizens reported less cancer fatalism compared to african-born black men. another study among men in a rural kenyan community reported relatively high fatalistic beliefs of prostate cancer screening (mutua, pertet, & otieno, 2017). this feeling of powerlessness or the fear of “getting to know” one’s status is detrimental to early detection of cap and management of the disease. therefore, cancer prevention and control efforts should focus on educating men in nigeria and cameroon on measures and behaviors that are within their reach in maintaining their health. education about signs and symptoms for this disease, screening and diagnostic tests and treatment options can increase perception of control over one’s overall health. in addition, it is important to involve cap survivors in education and awareness campaigns. if men in nigeria and cameroon are exposed to men who have survived the disease and living a productive life as survivors, this may diminish cancer fatalism. attitude and knowledge participants from the us expressed a more positive attitude towards screening for cap compared to those from nigeria and cameroon. additionally, knowledge levels about cap was higher among participants from the us than those from cameroon and nigeria. the knowledge gap among participants from these two sites on risk factors, signs, symptoms, and treatment options for cap may be linked to their literacy levels. while 97% of us-based participants in this study had university education, only about 57% of the participants from nigeria and 41% of participants from cameroon had university education. this is consistent with the findings of damiani et al (2015) who reported an increased level www.companyofscientists.com/index.php/chd e10 cancer health disparities research of cancer screening in women with highest level of education. among participants in the florida study (odedina et al., 2011), low cap fatalism was associated with increase in education level. therefore, lower level of education has the potential to negatively affect uptake of screening advice and early cancer detection (damiani et al., 2015). however, this finding is contrary to results from a study by magnus (2004) that found no significant difference in knowledge and nativity in participants who screened for cap (magnus, 2004). this may be due to the fact that participants in the magnus study were all americans with higher literacy level. other studies have shown that poor knowledge and attitudes regarding prostate cancer screening exist even among health care providers (bourne, 2010; mcnaughton-collins & barry, 2011). effective cancer control efforts should include sensitization among physicians as they are a trusted source for cancer prevention and control information (morrison bf, aiken wd, mayhew r, gordon y, 2017; walshchilders, et al., 2018). therefore, the negative attitude and lower knowledge levels exhibited by study participants from nigerian and cameroon indicate barriers that should be addressed to improve early cancer detection among men in these countries. health care providers as well cap survivors/advocates are a good source for such education. another important finding from this study was that a fish-based diet was a significant predictor of screening with psa test and or dre. one explanation of this finding could be that participants who consumed a fish-based diet were more health conscious and pro-active in their health seeking behaviors compared to those who favored a meatbased diet. while the role of diet in the etiology of prostate carcinogenesis is still unsettled, some studies have noted the preventive role of diet, particularly vegetables, fruits, and nuts, to different classes of natural compounds, including polyphenols. in this study, higher levels of physical activity was reported among participants from nigeria followed by participants from the us while participants from cameroon reported lower physical activity. according to the 2008 physical activity guidelines for americans (cdc, 2014) adults need a minimum of 2.5 hours (150 minutes) of moderate-intensity aerobic activity each week. globally, physical inactivity is prevalent with 51% of people in the us (cdc, 2014) and 31% of people worldwide not attaining recommended physical activity levels (hallal et al., 2012). a study by moore and colleagues, found higher levels of physical activity were associated with an increased risk of prostate cancer (hr=1.05, ci:1.03–1.08). although there is no conclusive evidence showing physical activity as a protective factor for prostate cancer, higher levels of physical activity has been associated with lower risk of 13 cancers including colon, breast and endometrial cancers but higher risk of malignant melanoma (moore et al., 2016). the world cancer research fund has estimated that 27–39% of the main cancers can be prevented by improving diet, physical activity and body composition (world cancer research fund & american institute for cancer research, 2007). this study identified some important differences in modifiable cap risk factors among nigerian and cameroonian men residing in africa and their counterparts living in the us. it is evident that men living in nigeria and cameroon will benefit significantly from behavioral interventions on cap prevention and early detection. based on this study, the modifiable behavioral factors that can be targeted with tailored messages for cap control and www.companyofscientists.com/index.php/chd e11 cancer health disparities research prevention in nigeria and cameroon include attitudes, cancer fatalism, knowledge about cap, and physical activity. health care providers and cap survivors should be integral in any behavioral intervention to address fatalistic beliefs and increase awareness about this disease. acknowledgements we acknowledge the support of the research assistants who assisted with data collection at various sites, notably ms. ruth agaba, mrs. sarah adewumi, mrs. nike obafemi, and ms. christiale feuatsap. funding support funding for this study was made available by a grant from the carnegie corporation in new york, moffitt cancer center support grant federal award no: 3p30ca075292-19s2, and the prostate cancer transatlantic consortium (captc). conflict of interest the authors declare that no competing or conflict of interests exist. the funders had no role in study design, writing of the manuscript, or decision to publish. authors’ contributions design; kaninjing, odedina, dagne. introduction; faruk, sulaiman, ogunlana, atawodi, alabi. methods; askins, nggada, kaninjing. results; dagne, kaninjing, odedina, adegun. discussion; okoye, bassey, nkegoum, popoola, omonisi, sowumni. data collection; sowumni, oladoyinbo, fatiregun, jibrin, iweala, kukoyi, adeniji, salako, okpala, 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(2007). food, nutrition, physical activity, and the prevention of cancer: a global perspective. cancer research. https://doi.org/978-0-9722522-2-5 www.companyofscientists.com/index.php/chd e1 cancer health disparities research epidemiology of prostate cancer in nigeria: observations at lagos state university teaching hospital ⃰emiogun festus edobor, williams oluwaseun olatunde, obafunwa john oladapo department of pathology and forensic medicine, lagos state university teaching hospital, 1 – 5 oba akinjobi way, ikeja, lagos, nigeria. *corresponding author: e-mail: edos2infinity@yahoo.com abstract prostate cancer is a leading cause of morbidity and mortality among men, especially of african descent. over the years, there has been relative paucity of research work on the subject of prostate cancer in sub-saharan africa. the objective of the study is to examine records of prostate cancers diagnosed at mayo height laboratory, lagos state university teaching hospital, lagos, nigeria between january 2015 and june 2018, with a view to studying the epidemiological variables and pattern seen. histopathological slides were retrieved and reviewed; relevant data were extracted from the laboratory information systems, laboratory requisition forms and the hospital records where necessary. the data were statistically analyzed. a total of 333 cases of prostate cancer were diagnosed during the study period, representing 46.4% of all prostate specimens received. the median age of the patients at diagnosis was 70 years, with the lowest recorded age being 50 years, while the highest age was 90 years. individuals in the 7th decade of life (61-70 years) were the most commonly affected. overwhelming number of cases (97.3%) were diagnosed based on trucut biopsy specimens, compared to open prostatectomy specimen. majority of the cancers were histologically adenocarcinomas (97.3%) and majority of the tumours were of high grade (gleason grade 5) representing 37.5%. prostate cancer is an obvious scourge in nigeria. it is commonly seen in the 7th decade of life. majority of the patients had high grade adenocarcinoma. keywords: prostatic carcinoma, histopathology, epidemiology, lagos, nigeria. citation: emiogun fe, williams oo, obafunwa jo (2019) epidemiology of prostate cancer in nigeria: observations at lagos state university teaching hospital. cancer health disparities 4: e1-e-9. doi:10.9777/chd.2019.1003 www.companyofscientists.com/index.php/chd e2 cancer health disparities research introduction prostate cancer is rated the second most common cancer and sixth leading cause of cancer deaths among men globally, making it an important cause of morbidity and mortality (ferlay et al., 2012). prostate cancer is the most frequent cancer in men in the united states. african american ancestry, family history, and increased age are the primary risk factors for prostate cancer (haas et al., 2008). prostate cancer is the most common urological malignancy affecting black africans (magoha, 2007 and baade et al., 2009) the incidence of prostate cancer has tripled during the past decade, chiefly because of increased diagnosis with the widespread use of serum prostate-specific antigen (psa) testing, digital rectal examination (dre), transrectal ultrasound and needle biopsy of the prostate (oluwole, et al., 2015 and amin et al., 2005). cancer of the prostate is currently the most frequent malignancy of the adult nigerian male with increasing incidence annually. studies on prostate cancer from the ibadan cancer registry showed that the relative ratio frequency for prostate cancer when compared to other male cancers increased from 4.45% to 10.5% over the last three decades (okolo et al., 2008 and ogunbiyi et al., 1999). most cases of prostate cancer occur after the age of 50 years and there is an exponential increase in incidence which peaks in the 70s. worldwide, about three-quarters of all cases occur in men aged 65 or more (who, 2004). various histologic studies on prostate specimens taken in different centres across nigeria have shown prostate cancer incidences ranging from 22.4% to 37.4% (mohammed et al., 2003, okeke et al., 2017 and obiorah et al., 2011). the incidence of prostate cancer has also been shown to vary across various african countries to include gambia 2.5 per 100,000, south africa 30.8 per 100,000 and uganda 35.5 per 100,000 (bah et al., 2001, baab et al., 2014 and parkin et al., 2010). the low incidence areas globally include the asiapacific region and north africa with 3 per 100,000 and 10.6 per 100,000 respectively (baade et al., 2013). the most common histologic type of prostate cancer type is adenocarcinoma with other histologic types being quite rare (haaa et al., 2008). the gleason score system is the most widespread grading tool for prostate cancer. it is the system recommended by the 1993 who consensus conference on prostate cancer diagnosis due to its high reproducibility across different institutions (murphy et al., 1994). it is one of the most reliable predictors of prostate cancer progression and survival (seyed et al., 2004). the system is based on glandular architecture which is used to define five histological patterns or grades with decreasing differentiation (gleason, 1966). this study aims to examine the pattern of prostate cancer seen among men of nigerian descent. the finding in this study will enrich the understanding of the characteristics of prostate cancer among african men which in turn will guide further effort at curbing the scourge. materials and methods laboratory reports on all cases of prostate samples (core biopsies and prostatectomy submissions) were retrieved from the laboratory www.companyofscientists.com/index.php/chd e3 cancer health disparities research information system at mayo heights laboratory of the lagos state university teaching hospital. the laboratory receives and process samples from the teaching hospital where the department is located. samples are also received from across the general hospitals within lagos state, and many of the private hospitals. the formalin-fixed paraffin embedded samples of tissues of prostatic origin, and associated histological slides were retrieved from storage and reviewed independently by the authors to reach a consensus as to the diagnosis. relevant clinical data were also retrieved from the requisition forms. data were then specifically extracted for the malignant cases. prostate cancer grading was done using the gleason score system. the data compiled were analysed and also where indicated, subjected to statistical analysis, utilizing spss statistical package software version 19. results a total of 717 prostate specimens were received in mayo heights laboratory, lagos state university teaching hospital, over a 42-month period between january 2015 and june 2018. of this number, 333 were prostate cancers, representing 46.4% (table 1). the lowest age at diagnosis was 50 years, while 90 years was the highest age recorded at diagnosis (figure 1). the mean age was 69 ± 8.0 years while the median age was 70 (24 cases). the most frequent age group was 61 – 70 years (141, 42.3%), followed by 71 – 80 years (112, 33.6%) while 26 (7.8%) was recorded for patients above 80 years. table 1. annual distribution. year number percentage 2015 63 19.0 2016 114 34.2 2017 122 36.6 2018 (6 months) 34 10.2 total 333 100 figure 1. age at diagnosis. 0.0% 5.0% 10.0% 15.0% 20.0% 25.0% 30.0% 35.0% 40.0% 45.0% 50 – 60 61 – 70 71 – 80 above 80 not stated 43 (12.9%) 141 (42.3%) 112 (33.6%) 26 (7.8%) 11 (3.4%) pe rc en t age at diagnosis www.companyofscientists.com/index.php/chd e4 cancer health disparities research majority of the patients were yorubas (247, 74.2%) followed by ibos (77, 23.1%) while only 9 (2.7%) were from other ethnic groups (table 2). table 2. ethnic distribution. ethnic group number of cases percentage yoruba 247 74.2 ibo 77 23.1 others 9 2.7 total 333 100 prostate cancer diagnosis was made on 316 (94.9%) trucut biopsy specimens, while 17 (5.1%) were prostatectomy specimens (figure 2). figure 2. showing type of tissue for diagnosis. majority (324, 97.3%) were diagnosed as adenocarcinoma; papillary carcinoma accounted for 7 (2.1%) of the cases, while clear cell carcinoma and mucinous carcinoma represented 0.3% each (table 3). table 3. histological types. type number percentage adenocarcinoma 324 97.3 papillary carcinoma 7 2.1 clear cell carcinoma 1 0.3 mucinous carcinoma 1 0.3 adenocarcinomas were categorized according to the gleason patterns observed. figures 3-7 typifies gleason patterns 1 to 5 as seen in this series. most of the prostate cancers diagnosed at our centre were gleason grade 5 (high grade, figs. 6 and 7) which accounted for 125 (37.5%) of all the tumours, while grade 3 (fig. 4 and 5) was the least with 34 (10.2%). low grade tumour (grade 1) was observed in 37 (11.1%) of the cases (figures 3 and 4). figure 3. photomicrograph (x 100, h&e) showing closely packed glands with little intervening stroma prostatic adenocarcinoma gleason pattern 1. figure 4. photomicrograph (x40 h&e) showing infiltrating small-sized distinct neoplastic glands with appreciable amount of intervening stroma. prostatic adenocarcinoma gleason pattern 2. 94.9% 5.1% biopsy prostatectomy www.companyofscientists.com/index.php/chd e5 cancer health disparities research figure 5. photomicrograph (x40 h&e) showing infiltrating, irregular small-sized neoplastic glands. prostatic adenocarcinoma, gleason pattern 3. figure 6. photomicrograph (x40 h&e) showing fused neoplastic glands forming a cribriform pattern. prostatic adenocarcinoma gleason pattern 4. figure 7. photomicrograph (x100 h&e) showing sheet of neoplastic cells. prostatic adenocarcinoma gleason pattern 5. grade 1 tumour was most commonly observed in the 50-60 years age group (11, 28.2%), while grade 5 was most frequently seen in the 71-80 years group this study showed that the commonest number of prostate biopsy cores sent to our laboratory by surgeons is 10 (11.2%). in some cases, as few as 2 cores (2, 3.0%) and as many as 32 cores (1, 0.3%) were received (table 5). table 4. association between grades and age (p = 0.380). age group in years (%) gleason grade 50 – 60 61 – 70 71 – 80 above 80 grade 1 11 (28.2%) 14 (10.6%) 11 (11.7%) 1 (4.5%) grade 2 4 (10.3%) 20 (15.2%) 10 (10.6%) 2 (9.1%) grade 3 4 (10.3%) 16 (12.1%) 10 (10.6%) 3 (13.6%) grade 4 5 (12.8%) 28 (21.2%) 19 (20.2%) 6 (27.3%) grade 5 15 (38.5%) 54 (40.9%) 44 (46.8%) 10 (45.5%) total 39 (100.0%) 132 (100.0%) 94 (100.0%) 22 (100.0%) table 5. frequency of the number of cores. number of cores frequency percent 1-5 30 17.2 6-10 129 74.1 11-15 106 60.9 www.companyofscientists.com/index.php/chd e6 cancer health disparities research 16-20 16 9.2 above 20 5 2.9 not stated 47 27.0 total 174 100.0 discussion this study revealed that prostate cancer accounted for 46.4% of all newly diagnosed prostate pathologies at our centre. this is higher than a range of 22.4% to 37.4% reported from studies from other parts of nigeria (mohammed et al., 2003, okeke et al., 2017 and obiorah et al., 2011). the higher incidence reported in our study may be due to the considerably higher sample size in our study as compared to the works done in kano, port harcourt and a previous study in lagos (okeke et al., 2017, obiorah et al., 2011 and bah et al., 2001). the higher sample size at our centre may also be partly due to the fact that the lagos state government has in the recent years embarked on free prostate cancer screening exercise for some elderly citizens which resulted in a high turn-out of subjects, some of whom were diagnosed with prostate cancer. besides, lagos is nigeria’s commercial capital and the most populous city in the country. the median age of men diagnosed with prostate cancer in our series is 70 years, with the lowest age being 50 years, while the highest was 90 years. this finding is consistent with a who report which states that majority of cases of cancer of the prostate occur after the age of 50 years and its incidence peaks in the 70s (who, 2004). the who report further stated that worldwide, about three-quarters of all cases occur in men aged 65 or more. studies from other parts of africa show that the incidence of prostate cancer rises from the age of 50 years (bah et al., 2001 and babb et al., 2014). oluwole et al in zaria, nigeria, reported that prostate cancer was seen in two subjects aged 30 and 32 years, with a peak age of diagnosis being the sixth decade and a mean of 64.5 years. majority of the subjects in this study are of the yoruba ethnic extraction, representing 74.2%. the reason for this observation is that the study was done in lagos, which is located in the south-west of nigeria, home to the yoruba ethnic group. the remarkable proportion of non-yoruba men in this study, representing 25.8%, gives credence to the fact that lagos is a cosmopolitan city, where people of all ethnic nationalities, including foreign nationals in nigeria live and work. most of the cancer diagnoses in this study were made on trucut prostate biopsy specimens (94.9%) as against prostatectomy specimens which represent only 5.1%. this is similar to the report in a study done in port harcourt, nigeria by (obiorah et al., 2011) which also shows a much higher proportion of cancer diagnosis on trucut biopsy specimens (82.8%) compared to prostatectomy specimen (17.2%). on the other hand, a study in zaria (oluwole et al., 2015) revealed a much lower proportion of cancer diagnosis in trucut biopsies (57%) as compared to open prostatectomy (43%). cases of carcinoma in prostatectomy specimen tend to be an incidental finding, as most prostatectomies are done on the grounds of an impression of benign prostate disease. this observation draws attention to the need for thorough histological examination of www.companyofscientists.com/index.php/chd e7 cancer health disparities research prostatectomy specimens considering the possibility of finding a focus of cancer. an important highlight of the present study is the fact that majority of the prostate cancer were adenocarcinoma (97.8%). this is similar to the observation of authors of similar studies both locally and around the world (haas et al., 2008, oluwole et al., 2015, obiorah et al., 2011, odedina et al., gueye et al 2003, elen et al., 1991 and anunobi et al., 2011). our study shows that grade 5 prostate cancer is the most commonly diagnosed at our centre (37.5%). this is followed by grade 3 disease, seen in 10.2% of cases. this is in contrast to the finding in ibadan, nigeria where it was observed that the commonest gleason grade was 3 (okolo et al., 2008). on the other hand, the study in port harcourt, south-south nigeria, (obiorah et al., 2011) shows that the majority of the cases in that series were of gleason score of 8 (grade 4) which is similar to findings in zaria (oluwole et al., 2015) and another study in lagos (anunobi et al., 2011). however, a study in the united states shows that the commonest gleason grade is 3 with an overall decline in scores from 8-10 to less than 6 in recent years (gueye et al., 2003). a plausible explanation for the higher proportion of high grade cancers diagnosed at our centre is that most of the patients present late to the hospital and already have advanced disease at diagnosis. the decline noted in the us study is as a result of improved early detection and diagnosis of prostate cancer in that country (harget et al., 2016). grade 1 tumour was most commonly observed in the 50-60 years age group (11, 28.2%). conversely, high grade tumour (grade 5) was most frequently seen in the 71-80 years group. it is pertinent to note that grade is not statistically dependent on age at diagnosis (p>0.05). our study shows that the most frequent number of prostate biopsy cores sent to our laboratory is 10 (11.2%), with some surgeons rarely sending as few as 2 cores and as many as 32. or observation is consistent with the finding in an asian study which revealed that 6 to 12 cores of prostate biopsy provide similar efficacy as more biopsy cores (tanaka et al., 2015). these authors also opined that the number of cores to be taken should be determined by the prostate volume. they further suggested that increasing the number of cores increases the rate of cancer detection; however, the optimal number of prostate cores to obtain is still an open question. conclusion this study shows that most of the prostate cancer diagnoses made in the mayo height laboratory, lagos state university teaching hospital were on trucut biopsy specimen. prostate cancer is more commonly seen in men in the 7th decade of life (61-70 years) with a median age of 70 years. majority of these patients already have high grade adenocarcinoma at diagnosis. this observation calls for the need for early detection so as to reduce mortality from the disease. public awareness on prostate cancer will enable men to recognize early symptoms and seek medical help before the disease advances. the need for routine screening for early detection is also very crucial. this study also shows that surgeons frequently sent between 6 to 10 prostate biopsy cores to our centre. this number is shown to be adequate for diagnosis. the observation that carcinoma was diagnosed in some prostatectomy specimen which were believed to be benign, draws attention to the www.companyofscientists.com/index.php/chd e8 cancer health disparities research need for pathologists to thoroughly examine prostatectomy tissues as foci of cancer may present. acknowledgements the authors want to acknowledge the assistance rendered by the management of mayo heights laboratory in extracting relevant data from the laboratory information system. conflict of interest the authors confirm that there is no conflict of interest and no funding was received for this work. authors’ contributions emiogun ef, was responsible for study conceptualization, design and literature search. williams oo, performed literature search and data collation. obafunwa jo was involved in study conceptualization, data analysis and editing of final draft. references anunobi cc, akinde or, elesha so, daramola ao, tijani kh, ojewola rw. (2011). prostate diseases in lagos, nigeria: a histologic study with tpsa correlation. niger postgrad med j 18, 98-104. amin mb, boccon-gibod l, egevad l, epstein ji, humphrey pa, mikuz g, newling d, nilsson s, sakr w, srigley jr, wheeler tm, montirono r. (2005). prognostic and predictive factors and reporting of prostate carcinoma in prostate needle biopsy specimens. scand j urol nephrol suppl 216, 20–33 babb c, urban m, kielkowski d, kellett p. prostate cancer in south africa: pathology based national cancer registry data (1986–2006) and mortality rates (1997–2009). prostate cancer. 2014 419801. http://doi.org/10.1155/2014/419801. baade pd, youlden dr, krnjacki lj. (2009). international epidemiology of prostate cancer: geographical distribution and secular trends. mol nutr food res 53, 171–84. baade pd, youlden dr, cramb sm, dunn j, gardiner ra. 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(2008). the worldwide epidemiology of prostate cancer: perspectives from autopsy studies. can j urol. 15, 3866–3871. herget ka, patel dp, hanson ha, sweeney c, lowrance wt. (2016). recent decline in prostate cancer incidence in the united states, by age, stage, and gleason score. cancer med 5, 136-141. magoha ga. (2007). overview of prostate cancer in indigenous black africans and blacks of african ancestry in diaspora 1935-2007. east afr med j 8, 3-11. mohammed az, alhassan su, edino st, chicha o. (2003) histopathological review of prostatic diseases in kano, nigeria. niger post grad med j 10, 1-5. murphy gp, busch c, abrahamsson pa, epstein ji, mcneal je, miller gj. (1994). histopathology of localized prostate cancer. consensus conference on diagnosis and prognostic parameters in localized prostate cancer. stockholm, sweden, may 12-13, 1993. scand j urol nephrol suppl 162, 7-42. odedina ft, akinremi to, chinegwundoh f, roberts r, yu d, reams r, freedman ml, rivers b, green bl, kumar n. (2009). prostate cancer disparities in black men of african descent: a comparative literature review of prostate cancer burden among black men in the united states, carribean, united kingdom, and west africa. infect agent cancer 4 (suppl.): s2. ogunbiyi jo, shittu ob. (1999). increased incidence of prostate cancer in nigerians. j natl med assoc 91, 159164. okolo ca, akinosun om, shittu ob, olapade-olaopa eo, okeke li, akang ee, ogunbiyi jo. (2008). correlation of serum psa and gleason score in nigerian men with prostate cancer afr j urol 14, 15-22. oluwole op, rafindadi ah, shehu ms, samaila moa. (2015). a ten-year study of prostate cancer specimens at ahmadu www.companyofscientists.com/index.php/chd e9 cancer health disparities research bello university teaching hospital (a.b.u.t.h), zaria, nigeria. afr j urol 21, 5-18. seyed mk, shahrokh fs, yair l, hossein s, john dm, arthur is, claus gr, kenneth sk. (2004). predictive value of primary gleason pattern 4 in patients with gleason score 7 tumours treated with radical prostatectomy. bju 94, 426. tanaka n, shimada k, fujimoto k. (2015). the optimal number of initial prostate biopsy cores in daily practice: a prospective study using the nara urological research and treatment group normogram. bmc res notes 8, 689. tumours of the prostate. in: eble j.n., sauter g., epstein j.i., sesterhenn i.a. (eds.) (2004): world health organization classification of tumours. pathology and genetics of tumours of the urinary system and male genital organs. iarc press: lyon. p. 158-214. www.companyofscientists.com/index.php/chd e1 cancer health disparities research exploring the employment challenges and concerns of minority women cancer survivors dinorah martinez tysona, silvia sommarivaa*, aria walsh-felza, peggie sherryb, joanne c. sandbergc a college of public health, university of south florida, 13201 bruce b. downs blvd, mdc56, tampa, fl 33612-3805. b faces of courage 501(c)(3). cross creek bldv #519, tampa, fl 33647-2595. c department of family and community medicine, wake forest school of medicine, medical center boulevard, winston-salem, nc 27157. *corresponding author: silvia sommariva, sommarivas@health.usf.edu (929) 264-8128 abstract employment plays an essential role in cancer survivorship. the study emerged from needs identified by community partners who voiced concerns about employment-related issues encountered by cancer survivors. thus, the purpose of this exploratory study is to understand the experiences of minority women cancer survivors after cancer. we explore how type of occupation shapes the employment status of minority women cancer survivors after treatment. a community-based purposive sample of diverse cancer survivors (n=57) who reported working shortly before being diagnosed with cancer were administered a semi-structured questionnaire. close-ended responses were analyzed using descriptive statistics. open-ended responses were analyzed using applied thematic analysis techniques as well a crisp set qualitative comparative analysis (qca). work-related concerns were similar across occupation types, while disparities were observed in reported job loss rates after diagnosis and employment rates after treatment. women’s concerns related to productivity losses at work due to treatment side effects, disease management issues, fear of job loss, and economic concerns. the qca pathway that appeared to best explain the outcome of working after treatment completion included the following components: working during treatment, having employer-based health insurance and being eligible for medical leave (perception of). this study provides relevant insights on the work experience and concerns of minority women cancer survivors, a population segment that has been frequently underrepresented in the literature on survivors’ work outcomes after cancer diagnosis and treatment. keywords: cancer disparities, minorities, employment, work citation: tyson dm et al (2019) exploring the employment challenges and concerns of minority women cancer survivors. cancer health disparities.e1-13. doi:10.9777/chd.2019.1014. www.companyofscientists.com/index.php/chd e2 cancer health disparities research introduction progress in cancer research and treatment has led to an increased number of survivors and a consequential need to address disease management and quality of life after diagnosis (hoffman, 2005). previous studies on survivorship have shown that achieving a sense of normalcy includes resuming activities carried out before diagnosis such as maintaining/obtaining employment (kennedy, haslam, munir, & pryce, 2007; spelten, sprangers, & verbeek, 2002), which also has a positive influence on wellbeing (clarke et al., 2015). employment plays an essential role in cancer survivorship because of the benefits it provides including income, better psychosocial health, and possibly employer-based health insurance (amir, neary, & luke, 2008; main, nowels, cavender, etschmaier, & steiner, 2005; nachreiner et al., 2007). multiple factors affect the likelihood that women employed at time of diagnosis will work after cancer treatment, including federal, state, and employer policies; work environment; short and long-term and late effects of cancer treatment; and individual factors (mehnert, 2011). direct physical impacts of disease, such as pain and fatigue, as well as treatment side effects may impair the survivors’ ability to work (amir, neary, & luke, 2008; jagsi et al., 2014). coworkers support and general positive workplace climate can also influence the likelihood of return to work or continuance of employment during and after cancer treatment (bradley & wilk, 2014; islam et al., 2014; pryce, munir, & haslam., 2007). characteristics of the work environment, such as type of occupation, level of physical demands, and work schedule flexibility, also influence job-related outcome (bouknight, bradley, & luo, 2006; islam et al., 2014; spelten, sprangers, & verbeek, 2002). thus, understanding how work after cancer diagnosis can differ across employment conditions is crucial. while literature exists on the work-related outcomes among women cancer survivors in general (mehnert, de boer, & feuerstein, 2013), research that examines the work outcomes (employment status) for racial and ethnic minority women is limited (blinder et al.. 2012; bouknight, bradley, & luo, 2006; bradley, neumark, luo, & schenk, 2007; bradley, & wilk, 2014; mujahid et al., 2011; mujahid et al., 2010). although the evidence is not uniform (bradley & wilk, 2014), studies generally indicate that minority survivors experience greater financial problems attributable to a cancer diagnosis and its treatment than european american women (jagsi et al., 2014). moreover, minority women may experience racial and ethnic discrimination that further disadvantage them in the workplace. still, our overall understanding of minority survivors’ work experiences following diagnosis remains inadequate. the purpose of this study is to understand the experiences of minority women cancer survivors in relation to work and the factors contributing to their employment status after treatment (regardless of type of employment). the study emerged from needs identified by community partners who voiced concerns about employment-related issues encountered by the cancer survivors they worked with. the analysis explores how type of occupation and employment benefits (medical leave, insurance) contribute to shaping the employment status of women cancer survivors after diagnosis and treatment. materials and methods sample and recruitment recruitment was aided by previously established and long-standing partnerships with community www.companyofscientists.com/index.php/chd e3 cancer health disparities research based organizations that serve cancer survivors. a purposive sample of cancer survivors was recruited at two cancer survivorship workshops in west central florida. the events were purposefully selected as survivors who attend them are from culturally and ethnically diverse backgrounds. participation in the study was voluntary. each participant was presented with detailed study information verbally consented. inclusion criteria were: being a woman who had ever been diagnosed with cancer and being 18 years old or older. data collection based on the literature on work and cancer survivorship presented above, input from cancer survivor advocates and the authors’ work with minority cancer survivors, we developed a semistructured questionnaire comprised of 7 openended and 21 close-ended items. the questionnaire was pilot-tested with two cancer survivors. information captured included time of cancer diagnosis, type of cancer and treatment, work status before diagnosis, job loss after cancer diagnosis, work status during and after cancer treatment, current work status, type of job and duties, as well as general socio-demographic data such as age, education, and income. these variables have been identified as key in influencing survivors’ employment status after treatment in previous literature. the questionnaire utilized a skip pattern. participants who reported they were working three months prior to their cancer diagnosis were directed to open-ended questions about main duties at their jobs. these participants were asked open-ended questions about workrelated concerns or challenges they experienced after diagnosis. they were also directed to structured questions about their perceived eligibility to take a medical leave (yes/no); coverage by employer-based health insurance (yes/no); and job loss after diagnosis (yes/no). participants were also asked about what type of work-related information would be helpful and whether they considered programs to support working women survivors beneficial. all participants were asked to self-rate their health using the 2002 who world health survey scale of self-rated health (subramanian, huijts, & avendano, 2010). facilitated by the standard occupational classification system (bureau of labor statistics, 2010), participants’ occupations were placed into one of three categories: (1) management or professional; (2) services, sales and office support; and (3) construction, production and transportation. due to the limited number of survivors whose occupations were construction, production and transportation, the latter two categories were combined for analysis, and will be referred to as “service, office support, and production.” the questionnaire was designed to be self-administered. however, a few participants requested assistance and the items were read to them. the questionnaire was available in both english and spanish. the institutional review board at the [university name masked for blind review] approved this study. data analysis all questions and responses were entered into excel. close-ended responses were analyzed descriptively, with frequencies and proportions reported for each question. qualitative responses to open-ended questions were systematically and iteratively coded by two bilingual research team members using applied thematic analysis techniques (bernard, wutich, & ryan, 2016). a codebook was developed in microsoft excel that included a priori and emergent codes. the team held debriefing meetings to review and discuss the www.companyofscientists.com/index.php/chd e4 cancer health disparities research emerging themes and adjust the codebook. illustrative quotes considered the relevance to the research questions were also identified. qualitative data were further analyzed using crisp set qualitative comparative analysis (qca) to understand if certain combinations of coded factors/conditions are part of the outcome set “work after treatment completion” (work =1, nonwork =0). crisp set qca is an analytic induction method, used to build up causal explanations of phenomena by analyzing a small number of cases (bernard & ryan, 2009). the qca method was formalized by ragin (ragin, 1987) using a boolean algebra approach to identify contribution of the presence or absence of certain factors to an outcome of interest. a crisp set, or conventional set, is dichotomous and can be compared to a binary variable with value 1 when the factor is present and 0 when it is absent (e.g., if a condition represented by a code is present or absent). using the software fs/qca1, the following factors were tested in the analysis to identify which ones/ which combinations contribute to work status after having received primary treatment for cancer: medical leave eligibility (participants’ perception of), availability of medical insurance through the employer (insurance status), work status while receiving primary treatment for cancer, work status after having received primary treatment, and type of occupation. the qca applies the rules of logical inference to identify which combinations among all the possible combinations of variables found in the data contribute to the outcome of interest. results the following paragraphs detail our findings. first, we present participant demographics followed by 1 ragin, c., and davey, s. 2014. fs/qca [computer programme], version [2.5/3.0]. irvine, ca: university of california. the description of work related patterns and outcomes by occupation for cancer survivors that were working before diagnosis (n=57). this is followed by participants’ work-related concerns and qca results. participant demographics the researchers were able to successfully recruit 75 minority women, in a short period of time (two days). of the 75 women cancer survivors for which data were collected, 57 reported they were working shortly before being diagnosed with cancer. the findings reported in the following paragraphs consider the results on work during and after treatment completion, current work status, and work-related challenges for the participants who stated that they were working shortly before being diagnosed with cancer (n=57). this is a predominantly minority sample, with hispanic participants making up the largest group, followed by black or african american survivors. thirty-seven percent (n=21) of participants’ occupation were classified as management or professional, while 63% (n=36) of participants’ jobs were classified as non-managerial/ nonprofessional and primarily worked in the service, sales, office support or production. overall participants were moderately to highly educated, with the majority of participants having attended college. eighty percent of participants in management or professional occupations had at least a college degree, compared to 26% of the participants who are in service, office support, or production occupations. median income was between $24,000 and $47,999. over 30% reported having had some financial difficulties in the recent past. median income for participants in management or professional occupations was the same as participants in service, office support or www.companyofscientists.com/index.php/chd e5 cancer health disparities research production occupations. seventy-one percent of the participants’ report having a household income of less than $47,000 per year, even though a large proportion (68%) have attended college. ninety-six percent of participants believed that having programs that support working women diagnosed with cancer would be beneficial. table 1. socio-demographic, economic and health indicators among women employed before cancer diagnosis (n=57). managerial service/sales/ production total n n=21 (%) n=36 (%) 57 age at interview 18-39 1 (5) 2 (8) 3 40-54 9 (43) 14 (39) 24 55-64 6 (29) 11 (31) 16 65 or older 5 (24) 8 (22) 13 missing 1 (0) 1 education less than high school diploma 0 (0) 5 (14) 5 high school diploma or ged 0 (0) 11 (31) 11 some college, no degree 4 (20) 10 (29) 14 associate/junior college degree 0 (0) 6 (17) 6 bachelor’s degree 9 (45) 3 (9) 12 graduate or professional degree 7 (35) 0 (0) 7 missing 1 (0) 1 (0) 2 ethnicity* race hispanic 8 (43) 25 (74) 33 white non latino 1 (0) 1 (0) 2 black or african american 12 (57) 9 (26) 21 missing 1 (0) 1 household income less than $24,000 4 (19) 17 (49) 21 $24,000-$47,000 8 (38) 11 (31) 19 $48-$71,999 4 (19) 2 (6) 6 $72,000 or more 4 (19) 3 (9) 7 unsure 1 (5) 2 (6) 3 missing 1 (0) 1 adequate financial resources in the last 30 days yes 17 (70) 21 (60) 38 self-reported health very good 5 (24) 10 (29) 15 good 6 (29) 14 (40) 20 moderate 9 43) 10 (29) 19 bad 1 (5) 1 (3) 2 missing 1 (0) 1 cancer breast 17 (81) 30 (83) 47 other 4 (19) 6 (17) 10 diagnosed > 10 years ago 4 (19) 13 (36) 17 www.companyofscientists.com/index.php/chd e6 cancer health disparities research 610 years ago 7 (33) 10 (28) 17 ≤ 5 years ago 10 (48) 13 (36) 23 cancer treatment** surgery 19 (90) 28 (78) 45 chemotherapy 17 (81) 27 (75) 44 radiation 16 (76) 17 (47) 33 support programs for women cancer survivors programs to support women would be beneficial 21 (100) 34 (97) 55 *participants can be of any race; therefore, percentages do not add up to 100% **participants may have had more than treatment; therefore, percentages do not add up to 100% work patterns, environment and factors affecting work outcomes of the 57 participants who were employed before diagnosis, twenty-one participants (37%) were employed in management or professional occupations. of these 21 participants, two (10%) reported losing their job at diagnosis; 12 (57%) continued to work during treatment, including 10 (83% of the 12) at the same job; and seven (33%) stopped working during treatment. one person who stopped working while receiving treatment was older than 55 years at the time. two of the seven participants (29%) who had to stop working during treatment were able to return to work following treatment completion with their previous employer. five of the seven (71%) who had stopped working during treatment did not work post-treatment completion. see table 2. of the 36 women employed in service, office support or production occupations, twenty-three (64%) reported keeping their job at diagnosis, while 13 (36%) lost their job as a result. during treatment 12 out of 23 (52%) kept working, all 12 at the same job as before diagnosis, while 11 out of 23 (48%) stopped working during treatment. ten of these 11 (91%) returned to work after treatment was completed, 8 at the same job as before and two in a different job. job loss rates are higher for women who worked in service, office support, or production occupations than for women who worked in management and professional occupations (36% and 10% respectively). however, return rates were higher among women who had held service, office support, and production occupations compared to women who had held management or professional occupations (91% and 29% respectively). in the long run, employment rates were higher for women in management and professional occupations, compared to the remaining participants (52% and 39% respectively). both groups of respondents reported similar rates of disability or difficulties in performing work tasks. table 2. comparison of work outcomes by occupation type. management/ professional service, office support, production working at time of diagnosis n=21 (%) n=36 (%) eligible to take medical leave at diagnosis 17 (81) 24 (67) health insurance through employer at time of diagnosis 18 (86) 23 (64) loss job after diagnosis 2 (10) 13 (36) working at treatment start n=19 (%) n=23 (%) www.companyofscientists.com/index.php/chd e7 cancer health disparities research continued to work during treatment 12 (63) 12 (52) stopped working during treatment n=7 (%) n=11 (%) returned to work post treatment 2 (29) 10 (91) work related concerns analysis of the qualitative open-ended questions of the questionnaire shows that most frequently reported work-related concerns experienced after receiving the news of diagnosis were related to productivity losses at work due to treatment side effects or pain attributable to the disease (20/57), followed by disease management issues (12/57), fear of job loss (9/57) and economic concerns (8/57) (see table 3). twelve participants explicitly reported not being concerned about their employment. table 3. illustrative example of concerns reported by survivors employed prior to diagnosis. emergent themes theme/concern illustrative quotes work productivity loss fatigue and other treatment side effects “i would not be able to continue to work in the same capacity due to fatigue and effects of treatment” (participant e52) “i was worrying about having the strength to work” (participant s19) pain “holding babies, not sure if i could hold” (participant e27) fear of job loss resulting from absence from work “not be able to continue to work during treatment. is my attendance record going to affect my future at my place of employment” (participant s38) resulting from poor productivity “not able to do my job for pain and tiredness” (participant e31) “will they fire me for so many missing days” (participant s77) concern on how to manage disease and work duties concern regarding benefits (sick days etc.) “would i have enough sick leave in case the treatment was extensive” (participant s18) due to lack of flexibility of the employer “my manager gave me a hard time about time off for treatment” (participant e5) “stress of the job – boss that was a bully” (participant e4) general economic concern ability to pay medical bills, sustain the family economically “how was i going to cover medical bills and additional cost related to cancer treatment” (participant s73) no work-related concerns focus on health “i was not so worried about the job because i was more worried about the diagnosis which was devastating at the time” (participant s15) “my only worry was completing the recovery process” (participant s11) qca results the qca pathway that appeared to best explain the outcome of working after treatment completion included the following components: working during treatment, having employer-based health insurance and being eligible for medical www.companyofscientists.com/index.php/chd e8 cancer health disparities research leave (perception of). type of occupation (management or professional versus service, office support, or production) does not appear to influence the outcome of work after treatment completion. considering the intermediate pathway resulting from the qca, the solution terms involving presence of working during treatment, health insurance and medical leave eligibility explain 49% of participant work status following treatment completion. consistency for all the pathways were above 0.85, the typically accepted threshold (thygeson et al., 2012). table 4. qca results: configuration leading to work after treatment outcome. consistency raw coverage unique coverage being eligible for medical leave at diagnosis and being insured through work at diagnosis and working during treatment 0.947368 0.486486 0.486486 discussion the purpose of this exploratory study is to explore the factors that influence employment status among minority women cancer survivors following diagnosis and treatment. our findings delineate how work environment, type of occupation and job-related concerns contribute to shape the work experience of women cancer survivors. workrelated concerns appear to be similar across different occupation types. initial examination of the data suggests that cancer survivors in service, office support, and production occupations are more likely than survivors working management and professional occupations to lose their jobs following diagnosis. furthermore, the qca analysis suggests that working after treatment completion was not explained by type of occupation per se, but rather by a combination of working during treatment, having health insurance and being eligible for medical leave. these findings, in conjunction with other research, suggest that work-based resources are associated with posttreatment employment. blinder and colleagues (blinder, eberle, patil, gany, & bradley, 2017) for example, report that when adjusted for ethnicity, breast cancer survivors who held nonmanagement or professional jobs have decreased odds of having a job, either at which they are currently working or from which they are on leave, four months following treatment completion, than management and professional workers. they also note that survivors who have employer-sponsored health insurance, or whose workplaces have at least 50 employees have increased odds of having a job four months after treatment completion (blinder, eberle, patil, gany, & bradley, 2017). this suggests that type of occupation may be associated both with access to job retention and access to health insurance. among private sector employees, large establishment size is associated with the increased likelihood that employees will be offered health insurance and medical leave. due to historical circumstances, health insurance is a benefit provided by many employers in the u.s. (blumenthal, 2006). employees who work in the public sector have access to employer-provided health insurance. for example, among full-time state, and local public sector employees, 99% have access to health insurance (bureau of labor statistics, 2016). within the private sector, access to employer-based coverage varies by size of establishment. in 2012, for example, 57% and 94% of establishments in the private sector with fewer than 50 workers and at least 500 workers, respectively, offered health benefits to at least www.companyofscientists.com/index.php/chd e9 cancer health disparities research some employees (wiatrowski, 2013). the employer shared responsibility provision of the affordable care act (aca), implemented in 2015, penalizes employers with more than 50 full-time employees who decline to offer coverage that meets minimum value and affordability standards (kaiser family foundation, 2015). the aca does not, however, require employers to provide health insurance. many of our participants underwent cancer diagnosis and treatment prior to implementation of the aca. access to employer-provided health care is spread unevenly across occupations. substantially more private sector management and professional workers have access to employer-based health insurance than those in other major occupational categories. sixty percent of private sector workers in management and professional occupations have access to employer-based healthcare. in comparison, only 22% of private sectors workers in service occupations, and 38% workers in sales and office and administrative support occupations, have access to employer-based healthcare (bureau of labor statistics, 2016). cancer patients who obtain their health insurance through their employer may be particularly motivated to retain their jobs to maintain relatively affordable health insurance (nekhlyudov et al., 2016). as bradley and colleagues noted, women who depend on employer-based insurance are less likely to reduce their labor after a cancer diagnosis (bradley, neumark, & barkowski, 2013). being eligible for medical leave is also associated with employer size. the family and medical leave act (fmla) (29 u.s.c. 2601 et seq.) applies to private establishments with more than 50 employees within a 75-mile radius as well as public agencies. covered employers are required to provide up to 12 weeks of unpaid leave a year to eligible employees for qualified medical reasons and to maintain health insurance coverage. eligible employees are those whose job tenure is at least 12 months or who worked at least 1,250 hours during the previous year (hewitt, greenfield, & stovall, 2005; us department of labor). survivors whose employers provide 12 weeks of medical leave may experience substantial challenges given that cancer treatment and its sideand late-effects frequently extend beyond this period. cancer survivors would also benefit from paid leave. again, size of employer matters. workers employed by small employers are less likely than those working for larger employers to have access to paid sick leave (hill, 2013). access to paid leave would increase the incentive for cancer patients to retain their jobs during treatment. work concerns were similar across participants in management and professional occupations, and participants in service, office support or production occupations, with reduced work productivity and management of the disease being the two main areas of concern. these concerns and issues are well documented among cancer survivors (nekhlyudov et al., 2016; sandberg, strom, & arcury, 2014). our findings are consistent with nekhlyudov’s (nekhlyudov et al., 2016) who suggests cancer survivors felt that cancer interfered with physical or mental tasks or productivity at work. the qca analysis shows that ability to keep working while receiving primary treatment is one important factor in explaining whether cancer survivors were working after treatment completion. studies have indicated that being able to maintain employment while receiving treatment is affected by workplace environment, such as the ability of employers to accommodate survivors’ needs: such www.companyofscientists.com/index.php/chd e10 cancer health disparities research accommodations have been shown to substantially increase job retention (bouknight, bradley, & luo, 2006; moskowitz, todd, chen, & feuerstein, 2014; torp, nielsen, gudbergsson, & dahl, 2012). it is therefore not surprising that ninety-six percent (n=55) of participants who were working at the time of diagnosis highlighted the need for programs to assist working women diagnosed with cancer. encouraging programs that support survivors to continue to work during treatment could be important to improve work outcomes for women in this population. while studies have shown that recruitment of minorities can be challenging (ejiogu et al., 2011; ford et al., 2008; tosti, 2015), we were able to successfully recruit minority cancer survivors in a relatively short time. selecting research questions that directly affect the community under study can be key to recruiting and retaining minority participants (ejiogu et al., 2011; fouad et al., 2000), to this end, collaboration with community partners who are informed of issues that are relevant to a specific minority population, as done in this study, can be an effective strategy for successful inclusion of these groups. the study team’s flexibility with respect to location and time during which the interviews were conducted (over the weekend at survivorship events) was also conducive to recruitment of participants who work hourly jobs and with little freedom to change their work schedule to be interviewed. the specific focus on minority women adds to a literature in which european american women are typically disproportionally represented (bouknight, bradley, & luo, 2006; bradley, neumark, luo, & schenk, 2007; bradley & wilk, 2014; mujahid et al., 2011; mujahid et al., 2010). inclusion of minority segments of the population was made possible due to a recruitment strategy that involved community-based organizations, which proved to be successful. while we recognize the challenges of purposive sampling (hennink, 2011), this strategy is commonly used in exploratory studies such as the present one (bernard & ryan, 2009). while it certainly deems caution with respect to the generalizability of study results, the heterogeneous nature of the sample in terms of occupational categories allowed us to explore a broad range of occupational experiences that could inform future studies. certain limitations should be taken into account when considering the study’s results. while the majority of participants are minorities, the sample was too small to conduct more sophisticated statistical analysis. severity and stage of disease progression are not captured in the data, even though disease burden is found to be relevant in explaining employment outcomes (tevaarwerk et al., 2016), nor are physical and mental job demands included in the analysis. our analysis has some limitations as an fs/qca. the pathways resulting from qca analysis only partially explain work outcomes. further research with a larger sample is needed to uncover additional factors not captured in this preliminary study. while crisp set calibration was appropriate for the focus of this analysis, it required a certain degree of simplification with respect to participants’ experiences: for instance, we record if the participant had health insurance (yes/no) but we do no measure to what extent health insurance covered their medical needs during cancer treatment. moreover, the data collected did not allow us to stratify and compare participants based on the type (e.g. private/public, part-time/fulltime) and size of the employer, which affects access to benefits and therefore can influence www.companyofscientists.com/index.php/chd e11 cancer health disparities research employment status during and after treatment. our data did not distinguish between participants who stopped working during treatment while continuing to hold their job (e.g., being on a medical leave) from those who lost their job during treatment. additionally, our data did not capture whether the participant willingly stopped working or was fired as a result of circumstances related to the cancer diagnosis. this preliminary work fills a knowledge gap about survivorship experiences of women in underserved populations (tisnado et al., 2017), by exploring employment pathways after cancer treatment in a predominantly minority sample that includes survivors who held different types of jobs. work outcomes after cancer and associated risk factors are not fully understood (tevaarwerk et al., 2016). yet, the employment aspect of cancer survivorship is salient as work outcomes have substantial implications for cancer survivor’s short and longterm economic, physical and psychosocial wellbeing (hewitt, greenfield, & stovall, 2005; nowrouzi, lightfoot, cote, & watson, 2009). future research could explore the role of federal, state, and employer policies and procedures and driving organizational characteristics, such as employer size and being a public or private sector employer, in cancer survivors’ employment outcomes. these issues should be explored in light of the increase in the number of jobs that do not provide stable, full time employment, with good wages and benefits (kalleberg, 2011), the impact of the affordable care act on cancer survivors’ coverage (davidoff, 2015), potential consequences of the repeal of the law (goldstein, 2017), and resources potentially available to cancer survivors under the americans with disability act, which covers employers with fewer than 15 employees (us equal employment opportunity commission). this study provides relevant insights on the work experience and concerns of minority women cancer survivors, a population segment that has been frequently underrepresented in the literature on survivors’ work outcomes after cancer diagnosis and treatment. our findings highlight the need for the development of programs that assist minority cancer survivors during their workrelated transitions and the importance of tailoring such interventions to different work environments. future studies should integrate survivors’ perspectives with employers’ views on the impact of cancer on work (grunfeld, low, & cooper, 2010), which would be crucial for the development of effective programs to assist working women cancer survivors. we also need to examine in detail how work experiences following a cancer diagnosis may vary by race and ethnicity as well as how culture (beliefs, norms and values) and discrimination may influence women’s workrelated decisions and work outcomes after cancer diagnosis and treatment. acknowledgements the authors would like to thank the study participants whose involvement made this study possible. we would also like to acknowledge the ongoing support from luna inc., hispanic health initiatives, creando conciencia por reina, faces of courage, dr. cathy meade, the florida prevention research center and the tampa bay community cancer network. we would also like to thank linda bomboka for her editorial assistanceconflict of interest the authors declare that they have no conflict of interest authors’ contributions each author contributed substantially to the final manuscript. all authors contributed to the design of the study. dmt, awf, and ps collected the data. www.companyofscientists.com/index.php/chd e12 cancer health disparities research dmt, ss and jcs worked on data analysis. dmt, ss and jcs wrote the draft paper. all authors contributed to outlining the main study implications. . references amir, z., neary, d., and luke, k. 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(2013). employment-based health benefits in small and large private establishments. beyond the numbers: pay & benefits, u.s. bureau of labor statistics, 2(8). www.companyofscientists.com/index.php/chd e1 cancer health disparities commentar architecture of the chicago cancer health equity collaborative – a partnership delivering transformative cancer health equity research, education and community engagement catherine a. o’brian,1 marian fitzgibbon,2,3 christina ciecierski,4 lidia filus,5 joseph feinglass,6 robert a. winn,3,7 and melissa a. simon1,8,* 1department of obstetrics and gynecology, northwestern university feinberg school of medicine, chicago, il, 2department of pediatrics, university of illinois at chicago, chicago, il,3university of illinois cancer center, university of illinois at chicago, chicago, il, 4department of economics, northeastern illinois university, chicago, il,5department of mathematics, northeastern illinois university, chicago, il, 6division of general internal medicine and geriatrics, northwestern university feinberg school of medicine, chicago, il, 7university of illinois hospital and health sciences system mile square health centers, university of illinois at chicago, chicago, il, 8robert h. lurie comprehensive cancer center at northwestern university, chicago, il *corresponding author: melissa a simon m-simon2@northwestern.edu abstract: reducing cancer health inequities requires transformation of longstanding structures, including ways of ‘doing business’ and other deeply rooted traditions that perpetuate social injustice. we posit that moving the needle toward cancer health equity requires the building of large-scale partnerships with the infrastructure and reach to reshape the architecture defining how education, training, and research are conducted. it is with this vision that the chicago cancer health equity collaborative (chicagochec) was conceived in response to a call for proposals by the national cancer institute (nci) in 2015 that sought applications for a partnership across a nci designated comprehensive cancer center and up to two institutions serving underserved health disparity populations and underrepresented students. chicagochec was conceived as a tri-institutional partnership comprised of the robert h. lurie comprehensive cancer center of northwestern university, a nci-designated comprehensive cancer center which serves a diverse nine county catchment area, northeastern illinois university, a minority-serving institution known for its connection to minority students, and the university of illinois cancer center at the university of illinois at chicago (uic), a minority-serving institution and leader in community-focused cancer care and disparities research. established in 2016, chicagochec is comprised of four functionally distinct cores that together serve the mission of advancing cancer health equity through meaningful scientific discovery, education, training, and community engagement. the successful functioning of of chicagochec is evident from the fruits borne by the partnership in research, education, and community engagement toward the goal of eradicating cancer health inequities. keywords: cancer health equity; cancer health disparities; citation: o’brian ca et al (2019) architecture of the chicago cancer health equity collaborative – a partnership delivering transformative cancer health equity research, education and community engagement. 4: e1-5. doi:10.9777/chd.2019.1015 www.companyofscientists.com/index.php/chd e2 cancer health disparities commentar reducing cancer health inequities requires transformation of longstanding structures, including ways of ‘doing business’ and other deeply rooted traditions that perpetuate social injustice. we posit that moving the needle toward cancer health equity cannot be done in isolation but rather requires the building of large-scale partnerships with the infrastructure and reach to reshape the architecture defining how education, training, and research are conducted. key to success is the forging of authentic partnerships, rather than mere top-down relationships, between scientists and educators at academic institutions, representatives of community organizations, and other stakeholders. it is with this vision that the chicago cancer health equity collaborative (chicagochec) was conceived in response to a call for proposals by the national institutes of health (nih)/ national cancer institute (nci) in 2015 (national_cancer_institute, 2015). the funding announcement, par-15-103, sought applications for a partnership across a nci designated comprehensive cancer center (cc) and up to two institutions serving underserved health disparity populations and underrepresented students (isups). it was envisioned in the program announcement that the partnership would be mutually beneficial to the cc and the isups, bringing increased diversity among the students, faculty and investigators conducting cancer research as well as increased emphasis on cancer health equity, with a focus on inclusion at the cc and provision of the isups with an elevated national profile and access to the expertise and cutting edge technology at the cc. we immediately recognized the importance of forging such a partnership that could fortify cancer health equity research, education, and community engagement in the chicago area. chicago is one of the most segregated cities in the us with numerous pockets of impoverished and resource poor areas (us_census_bureau, 2018), and it is rife with cancer health inequities. the majority of residents in chicago are underrepresented minorities – approximately a third are african american and a third are hispanic (us_census_bureau, 2018). compared to whites, racial/ethnic minorities in chicago experience health disparities in major cancers (e.g,, breast, cervical, prostate, lung, and colorectal cancer), despite the presence of five major medical centers in the metropolitan area; observed cancer health disparities include increased rates of cancer incidence and mortality, and later stage of diagnosis (center_to_reduce_cancer_health_ disparities, 2004; chicago_departmentof_public_health, 2017; formigoni et al., 2017; garner and shen, 2018; pallok et al., 2019). chicagochec was conceived in response to the par-15-103 funding announcement as a triinstitutional partnership comprised of the robert h. lurie comprehensive cancer center of northwestern university (nu), a nci-designated comprehensive cancer center which serves a diverse nine county catchment area, northeastern illinois university (neiu), a minority-serving institution known for its connection to minority students, and the university of illinois cancer center (uicc) at the university of illinois at chicago (uic), a minority-serving institution (msi) and leader in community-focused cancer care and disparities research. established in 2016, the organizational structure of chicagochec is comprised of 4 functionally distinct cores that together serve the mission of advancing cancer health equity through meaningful scientific www.companyofscientists.com/index.php/chd e3 cancer health disparities commentar discovery, education, training, and community engagement. in brief, the research education core functions to build a pipeline of summer student fellows focused on reducing and eliminating cancer health disparities; the community engagement core serves to enhance community engagement, cancer education, and survivorship support, and helps to build the research capacity of our community partners; the planning and evaluation core initiates and monitors new and ongoing projects, monitors the progress of our early stage investigators (esis), and evaluates chicagochec’s progress toward realizing the goals of its mission; and the administrative core provides the overall leadership, administrative management, and program coordination of chicagochec. in the governance model operative in chicagochec, guidance is provided to the cores by the nci and three distinct steering bodies. the program steering committee (psc) is the external evaluating board for chicagochec partnership activities and accomplishments toward realizing the goals of its mission; the internal advisory committee (iac) is an internal evaluating board that is structured to ensure that the goals and objectives of the chicagochec partnership are met; and the community steering committee (csc) is a body with representation from more than 30 community organizations serving vulnerable populations in the chicago area that functions to ensure that community engagement activities are done in true partnership with those engaged. the successful functioning of the governance model and organizational structure of chicagochec is evident from the fruits borne by the partnership in research, education, and community engagement toward the goal of eradicating cancer health inequities. the vibrant collaborative relationships forged amongst nu, neiu, and uic by chicagochec have increased the cancer research capacity at the isups and reinforced the commitment of the cc at nu to the mission of eradicating cancer health disparities. innovations in community engaged research advanced by chicagochec are exemplified by the recruitment of african american men as citizen scientists to validate a biomarker for prostate cancer (watson et al., 2019), adaption of a smoking cessation program to increase participation by lgbtq smokers (matthews et al., 2019), and development of an mhealth tool for persons with disabilities and cancer (magasi et al., 2019). innovations in education and training include the chicagochec research fellows program which contrasts with traditional healthcare career stem pipeline programs insofar as, rather than being paired individually with one mentor, the research fellows advance through the summer as one cohort with exposure to a wide array of transdisciplinary researchers. strengths of this model include exposure of fellows to a variety of healthcare career options, facilitation and support of the beginning of mentor-mentee relationships, and social and professional network development between fellows and program lecturers and leaders (taylor et al., 2019). following this broader summer experience, the fellows have a subsequent opportunity to have a dry or wet lab immersion experience where they are paired with an individual mentor. finally, community engagement is at the heart of the cancer health equity mission of chicagochec, and the community engagement core purposefully fosters group dynamics that break with tradition with the goal of leveling the playing field amongst www.companyofscientists.com/index.php/chd e4 cancer health disparities commentar academic institutions, researchers, community residents and leaders, health care providers, and community organizations so that all voices are heard and counted (giachello et al., 2019). in summary, we applaud the wisdom of initiatives such as nci’s comprehensive partnerships to advance cancer health equity (cpache) that seek to break with traditional models by supporting large scale partnerships with the scale that allows the establishment of new architectural elements designed to drive the eradication of health inequities. we are gratified that we have been afforded the opportunity to realize this vision in a metropolitan area with steep cancer health inequities through the establishment and continued development of chicagochec, a thriving partnership model wherein representatives of academic institutions, researchers, community residents and leaders, health care providers, and community organizations give voice to their concerns and priorities and collectively engage in research and education initiatives squarely aimed at reducing health disparities. acknowledgements we thank the members and community partners of chicagochec for their important contributions to the partnership. funding this work was supported by the national cancer institute (u54ca202995, u54ca202997, u54ca203000). conflict of interest there are no conflicts of interest to report. melissa simon is a member of the united states preventive services task force (uspstf). this article does not necessarily represent the views and policies of the uspstf. authors’ contributions .all authors are affiliated with chicagochec, and each substantially contributed to the writing and editing of the manuscript. references center_to_reduce_cancer_health_disparities (2004). economic costs of cancer health disparities. https://nciphub.org/resources/434/download/nciecono miccosts.pdf accessed on june 20, 2019. chicago_department-of_public_health (2017). chicago health atlas. https://www.chicagohealthatlas.org/ accessed on june 20, 2019. formigoni, l., koch, l., garner, k., and bostwick, j. 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(2019). wecanconnect: development of a community informed mhealth tool for people with disabilities and cancer. prog community health partnersh, in press. matthews, a., breen, e., veluz-wilkins, a., ciecierski, c., simon, m.a., burrell, d.l., and hitsman, b. (2019). adaptation of a proactive smoking cessation intervention to increase tobacco quitline use by lgbt smokers. prog community health partnersh, in press national_cancer_institute (2015). comprehensive partnerships to advance cancer health equity (cpache) (u54). https://grants.nih.gov/grants/guide/pa-files/par-15103.html. accessed on may 13, 2019. pallok, k., de maio, f., and ansell, d.a. (2019). structural racism a 60-year-old black woman with breast https://nciphub.org/resources/434/download/ncieconomiccosts.pdf https://nciphub.org/resources/434/download/ncieconomiccosts.pdf https://www.chicagohealthatlas.org/ http://www.dph.illinois.gov/sites/default/files/publications/cancer-illinois-2017-102417.pdf http://www.dph.illinois.gov/sites/default/files/publications/cancer-illinois-2017-102417.pdf http://www.dph.illinois.gov/sites/default/files/publications/ers18-04-county-cancer-statistics-review-2011-2015-091018.pdf http://www.dph.illinois.gov/sites/default/files/publications/ers18-04-county-cancer-statistics-review-2011-2015-091018.pdf http://www.dph.illinois.gov/sites/default/files/publications/ers18-04-county-cancer-statistics-review-2011-2015-091018.pdf https://grants.nih.gov/grants/guide/pa-files/par-15-103.html https://grants.nih.gov/grants/guide/pa-files/par-15-103.html www.companyofscientists.com/index.php/chd e5 cancer health disparities commentar cancer. n engl j med 380, 1489-1493 https://www.ncbi. nlm.nih.gov/pubmed/30995369 taylor, s., iacobelli, f., luedke, t., matthews, a., monge, m., cooper, j., moreira, j., grippo, p., girotti, j., molina, y., et al. (2019). improving healthcare career pipeline programs for underrepresented students: program design that makes a difference. prog community health partnersh, in press. us_census_bureau (2018). 2013-2017 american community survey five-year estimates. https://www.census.gov/ newsroom/press-releases/2018/2013-2017-acs5year.html. accessed on may 13,2019. watson, k.s., henderson, v., murray, m., murphy, a.b., ben levi, j., mcdowell, t., holloway-beth, a., gogana, p., dixon, m.a., moore, l., et al. (2019). engaging african american men as citizen scientists to validate a prostate cancer biomarker: work-in-progress. prog community health partnersh, in press. https://www.ncbi.nlm.nih.gov/pubmed/30995369 https://www.ncbi.nlm.nih.gov/pubmed/30995369 https://www.census.gov/newsroom/press-releases/2018/2013-2017-acs-5year.html https://www.census.gov/newsroom/press-releases/2018/2013-2017-acs-5year.html https://www.census.gov/newsroom/press-releases/2018/2013-2017-acs-5year.html www.companyofscientists.com/index.php/chd e1 cancer health disparities commentry introduction to special issue on cancer health disparities in native americans i am very pleased to serve as the guest editor for this special edition of cancer health disparities focussing on american indian and alaska native (aian) populations. the majority of these articles were presented initially as part of our spirit of eagles community networks program at our national conference held at niagara falls, new york in september 2017. this conference was cosponsored by the mayo clinic comprehensive cancer center and roswell park cancer institute. over 300 community members, providers, survivors, researchers and policy makers from across the country attended as well as colleagues from canada, australia and new zealand! we want to recognize the important work being done in aian communities covering all aspects of disparities including social, cultural, behavioral, environmental and other determinants contributing to differences in cancer incidence, prevalence, death, survivorship and the burden of cancer. the range of topics in this edition range from prevention and screening to end of life care—the full continuum of cancer care! special thanks to the haudenosaunee of new york state, our local hosts, and the national cancer institute for the efforts needed to bring our efforts to fruition! judith salmon kaur citation: kaur j.s (2018) introduction to special issue on cancer health disparities in native americans. cancer health disparities 2:e1. doi:10.9777/chd.2018.10011 www.companyofscientists.com/index.php/chd e1 cancer health disparities research quality of evidence on prostate cancer in nigeria omolara aminat fatiregun*1,2, frank chinegwundoh1,3, proffessor nicholas d james1,4, odunayo ikuerowo1,5, olufunmilade omisanjo1,5, abimbola abolarinwa1,5, anthonia chima sowunmi1,6, funlayo buraimoh1,7, folakemi odedina1, 8 1 prostate cancer transatlantic consortium,2 oncology unit, department of radiology, lagos state university college of medicine, ikeja, lagos, nigeria 3 department of urology, barts health, national health service trust, london 4 university hospitals birmingham nhs foundation trust, the medical school, university of birmingham, birmingham, uk 5 department of surgery, lagos state university college of medicine/ lagos state university teaching hospital, ikeja, lagos, nigeria 6 department of radiotherapy & oncology, lagos university teaching hospital/ university of lagos, lagos, nigeria. 7department of biochemistry, lagos state university college of medicine. 8 department of pharmacotherapy and translational research and department of radiation oncology, university of florida, lake nona campus, fl, 32832, usa *corresponding author email: omolarafatiregun@gmail.com. prostate cancer is the 2nd commonest malignancy in men worldwide. it is, however, the commonest in nigeria. while several disparities have been documented between caucasian men and men of african descent, there is limited research on prostate cancer in nigeria. evidence based medicine is a key tool in making clinical decisions and developing screening and treatment guidelines. this review was undertaken to assess the levels of evidence on prostate cancer research in nigeria. a systematic review of all research published on prostate cancer from january 1975 to may 2018 in nigeria was conducted. we reviewed all articles found on various databases by searching for “prostate cancer in nigeria”. we classified them based on their study designs into different levels of evidence as well as year of publication. meta-analyses were not considered in the review. a total of 171 articles were eligible for this review. most publications were at the 4th (66%) and 5th levels of evidence (17%) respectively. no clinical trials on prostate cancer in nigeria was seen or registered on clinicaltrials.gov, hence no studies at level 1 (a, b or c) of evidence published in nigeria. the commonest type of study design was cross-sectional studies accounting for 56% of all publications. prostate cancer research is currently at low levels of evidence in nigeria. it is pertinent to explore and increase funding channels for cancer related research. keywords: prostate,cancer, nigeria. citation: fatiregun et al (2019) quality of evidence on prostate cancer in nigeria. cancer health disparities. 4: e1-e9. doi:10.9777/chd.2019.1005 www.companyofscientists.com/index.php/chd e2 cancer health disparities research introduction in 2012, an estimated 14.1 million new cases of cancer were diagnosed worldwide. prostate cancer was the second most prevalent malignancy in men after lung cancer worldwide. it is the fifth most common cause of cancer deaths (ferlay et al., 2015). in nigeria, it is the commonest malignancy in men and its incidence continues to rise (elima et al., 2012; adeloye et al., 2016). globally, several disparities have been documented between caucasian men and men of african descent. these include an increased risk of developing prostate cancer in black men, younger age of incidence in black men, and genetic differences. these factors might have an impact on survival outcomes (odedina et al., 2009; brawley, 2012). prostate cancer management in african men is quite challenging as most patients present with metastatic disease (shenoy et al. 2016). evidence-based medicine is a crucial tool in making clinical decisions and developing guidelines for management. (burns, rohrich, and chung, 2011) most screening and treatment guidelines used in different parts of the world for managing prostate cancer are formulated from evidence-based results obtained from mostly clinical trials and metanalyses on studies conducted in those countries. the national institute for health and care excellence (nice) guidelines for treatment is predominantly based on research carried out in the united kingdom (uk). a similar situation pertains regarding the national comprehensive cancer network (nccn) guidelines in the united states of america (usa). evidence based medicine is a concept developed in the early 80s, then further described and modified by sackett in 1989 (sackett et al., 1996). it groups different studies based on their levels of evidence from one to five. randomized controlled trials (rct) and metanalyses are placed at the highest level of evidence, whilst, case series, case studies and expert opinions are at the lowest level. rcts are structured to be unbiased; subjects are allocated randomly to two or more treatment groups whilst case series or expert opinion are associated with bias and based on writer’s experience or opinions and there is often no control of confounding factors. the centre for evidence-based medicine in oxford developed an adaptable tool to assess the levels of evidence in 2011 (table 1). the tool is a hierarchical system of classifying based on evidence and designed for use by researchers. table 1: the centre for evidence-based medicine in oxford published the levels of evidence in 2009, and modified in 2011(ocebm levels of evidence working group et al. 2011) www.companyofscientists.com/index.php/chd e3 cancer health disparities research in nigeria, prostate cancer prevention, screening, and clinical treatment modalities should be based on evidence-based research done or validated in nigerian patients, in the expectation that this would lead to improved treatment outcomes and therefore survival. however, there are no publications exploring the levels of evidence in prostate cancer research in nigeria. this review was done to explore levels of evidence on prostate cancer in nigeria. methods we followed the preferred reporting for systematic reviews and meta-analyses (prisma) statement for the conduct of our systematic review (except that we did not consider metanalyses). figure 1: illustrating the prisma selection criteria study selection an electronic literature search of all research published on prostate cancer from january 1975 to www.companyofscientists.com/index.php/chd e4 cancer health disparities research may 2018 in nigeria was conducted. we reviewed all articles found on pubmed, web of science, embase, and google scholar search engines by searching “prostate cancer in nigeria”. using the prisma and national institute of health (nih) guidelines, we reviewed and classified the articles based on their study designs into different levels of evidence. we included all studies on prostate cancer in nigeria with either the full article or abstract having adequate information on the methodology of the study and excluded those with insufficient details. information extracted from studies include the year of publications, study design, and level of evidence. studies selected were grouped into five levels of evidence according to the oxford centre for evidencebased medicine classification (ocebm levels of evidence working group et al. 2011). metaanalyses were not considered in the review due to varying study designs and difficulty in pooling them together. evidence synthesis during our search we identified 302 publications, 106 duplicates were removed and 25 were excluded based on inadequate information on the methodology of the study. a total of 171 articles were eligible for this review. most studies published were cross sectional studies (56%), followed by cohort studies (15%), laboratory studies(13% ), case reports (7%), expert opinion (3%), systematic reviews (2%) and meta-analysis (1%). there were no clinical trials on prostate cancer in nigeria seen or registered on clinicaltrials.gov or other clinical trials registries (figure 2). figure 2: types of study designs on prostate cancer in nigeria based on levels of evidence, most studies (66%), were at level 4a of evidence (figure 3). these include case reports, case series, and cross-sectional studies. seventeen percent of studies were at the level 5a evidence levels, including laboratory studies and expert opinion. nine percent of the studies were at level 2b of evidence, which included cohort studies, 5% at level 3b of evidence including casecontrol 1 3 0 0 25 8 95 12 5 22 meta-analysis systematic reviews randomised clinical trials non randomised clinical trials cohort studies case-control studies cross-sectional studies case reports/ case series background information/expert opinion animal research/lab studies types of study designs www.companyofscientists.com/index.php/chd e5 cancer health disparities research studies, whilst levels 2c and 2a constituted 2% and 1% respectively. there were no studies at level 1 (a, b or c) of evidence (systematic reviews with homogeneity of randomised clinical trials, individual randomised clinical trials and all or none studies). figure 3: levels of evidence on prostate cancer research in nigeria most studies were published in 2017 (29 publications were identified that year), followed by 2012, 18 publications, 2013, 2014 and 2015 had 11, 12 & 13 publications respectively (figure 4). 0 20 40 60 80 100 120 1a 1b 1c 2a 2b 2c 3a 3b 4a 5a levels of evidence on prostate cancer www.companyofscientists.com/index.php/chd e6 cancer health disparities research figure 4: showing number of publications per year discussion this study demonstrates the paucity of high level evidence research in prostate cancer in nigeria. it showed that the commonest study design in prostate cancer research conducted in nigeria is the cross-sectional study. although, this design can rapidly generate data on some health-related events, it may however be plagued with different types of bias (sedgwick 2014). cross sectional studies can be used to generate a hypothesis and establish an association but not causation. most researchers in nigeria adopt this methodology because cross sectional studies are relatively cheap and easy to conduct, especially in a low-resource environment where the financial and personnel costs are lower than that required for higher level and more informative studies. there are very limited funding avenues available for research in nigeria. studies at higher levels of evidence, like clinical trials, are more rigorous, require higher levels of expertise and are capital intensive. however the benefits of this type of study remain numerous, including their ability to establish causation, assess impact of an intervention and develop treatment guidelines to improve treatment outcomes and survival. (christensen et al. 2007) 0 5 10 15 20 25 30 35 1975 1977 1979 1981 1983 1985 1987 1989 1991 1993 1995 1997 1999 2001 2003 2005 2007 2009 2011 2013 2015 2018 year of publication www.companyofscientists.com/index.php/chd e7 cancer health disparities research in nigeria, there are limited efforts to foster high level biomedical research. these efforts are often led by established consortia focused on specific research goals. for example, the prostate cancer transatlantic consortium (captc), established in 2005, has supported prostate cancer research in nigeria since 2006 (https://epi.grants.cancer.gov/ captc/) . captc is a national cancer institute (nci) epidemiology and genomics research program (egrp) supported consortium. captc has over 150 members who are prostate scientists, clinicians, and consumer advocates from countries connected by the transatlantic slave trade, including north america, europe, the caribbean, and africa countries. captc investigators collaborate on projects based on the following scientific aims: 1. explore and quantify the magnitude of prostate cancer morbidity and mortality variance among black men of african ancestry; 2. explore genetic, environmental and behavioral etiology of this variance; and 3. develop community-sensitive initiatives to control prostate cancer globally. the official scientific conference for the captc is the biennial science of global prostate cancer conference for black men, which was held in jacksonville (usa) in 2010, nassau (bahamas) in 2012, montego bay (jamaica) in 2014, orlando (usa) in 2016, and will be held in ilorin (nigeria) in 2018. other active consortia in nigeria are the african colorectal cancer group (argo), the men of african descent and carcinoma of the prostate (madcap), and breast cancer consortium. the commonest level of evidence of prostate cancer in this review is level 4, which includes: the case reports, case series, and cross-sectional studies. these levels of evidence are relatively low and are less likely to be adopted in developing treatment guidelines. most international treatment guidelines are developed based on level 1 evidence, clinical trials. they analyse results from these clinical trials conducted on prostate cancer patients in their countries and then adapt them in the development of treatment guidelines. an example is the stampede trial in the uk (james et al. 2015) which has led to changes in the standard of care of prostate cancer patients in the uk another is the chattered trial (sweeney et al. 2015), a similar clinical trial as the stampede, which was conducted in the usa. clinical trials have always sharpened the paradigms of treatment internationally. the study showed a steep increase in publications on prostate cancer in nigeria from the year 2000 to date. despite this increase the proportion remains very low when compared to prostate cancer studies in other countries. the highest number of publications was published in 2017, when a total of 29 articles were published on prostate cancer. when compared with other parts of the world, the usa and uk uniquely had over 300 publications on prostate cancer on pubmed search engine in 2017. a major reason for low levels of prostate cancer research in nigeria is the low funding available for cancer research from public and private agencies/organizations. a major funding channel for research in nigeria is the tertiary education trust fund (tetfund) established under the tetfund act (tertiary education trust fund) in 2011. tetfund gets the funding by imposing a 2% education tax on all registered companies in nigeria. the fund is disbursed to tertiary educational institutions at federal and state levels as research grants in all fields (tetfund 2014). www.companyofscientists.com/index.php/chd e8 cancer health disparities research however, the rising trend of cancers in nigeria necessitates an increase in cancer research funding as exemplified by developed countries. developed countries have several funding channels for research. these include government funding and, non-governmental organisations and charities. in the united states, the 2017 budget allocated $33.1 billion (0.8%), out of the $4.2 trillion to the national institute of health to accelerate groundbreaking research on cancer, precision medicine and others (sargent et al. 2017). in the uk, the total investment is £26.3 billion between 2016/17 to 2020/21 with an average of £5 billion pounds yearly as allocations for the science and research in the budget (hm government 2016). it is therefore not surprising that prostate cancer survival has improved in both united states and uk. to make significant leap in fighting prostate cancer in nigeria, there needs to be focus on funding prostate cancer research. while it will greatly help to have governmental funding, corporate and philanthropic giving will also be very important. in september 2005, the foundation for carcinoma of the prostate transatlantic research was established to accelerate prostate cancer research in nigeria. this foundation is a step in the right way to raise the profile of prostate cancer research in nigeria. conclusion prostate cancer research is currently at low levels of evidence in nigeria. as stated by prof. folakemi odedina, “actionable research is key to defeating prostate cancer” (nigerian guardian, july 8, 2017). prostate cancer researchers should make efforts to conduct and publish more studies especially at higher levels of proof like rcts and metanalysis/systematic reviews of rct as well as develop treatment guidelines for patients based on these higher levels of evidence. it is also pertinent that the nigerian government increases its efforts in providing the support needed on funding cancer-related research. the nigerian government should also develop and implement policies related to increasing cancer research funding through governmental grants. finally, there needs to be increase in corporate funding and 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vijayakumar. 2016. ‘do african-american men need separate prostate cancer screening guidelines?’ bmc urology 16 (1). https://doi.org/10.1186/s12894-0160137-7. sweeney, christopher j., yu-hui chen, michael carducci, glenn liu, david f. jarrard, mario eisenberger, yu-ning wong, et al. 2015. ‘chemohormonal therapy in metastatic hormone-sensitive prostate cancer’. new england journal of medicine 373 (8): 737–46. https://doi.org/10.1056/nejmoa1503747. tetfund. 2014. ‘guideline for accessing tetfund national research fund tertiary education trust fund ( tetfund ) publication’, 1–53. www.companyofscientists.com/index.php/chd e1 cancer health disparities research cortisol and health-related quality of life as prognostic indicators for prostate cancer risk in west african black men in nigeria, cameroon and the usa: the captc cohort study mohammed faruk*1,2, folakemi t. odedina1,3,4, sani ibrahim1,5, abdulmumini hassan rafindadi1,2, ahmed adamu1,6, danladi amodu ameh1,5, sirajo mohammed aminu1,7, abdullahi adamu1,8, ahmad bello1,6, ernie kaninjing1,9, john idoko1,10, aishatu maude suleiman1,7, solomon o. rotimi1,11, , getachew a. dagne1,12, nissa askins1,3,4, clayton c yates1,13, emeka j. iweala1,11, yawale iliyasu1,2, iya eze bassey1,14, r. renee reams1,15, abdullahi mohammad1,2, mohammed sani shehu1,2, abdullahi jubril randawa,1,16 hussaini yusuf maitama1,6, dauda m. maigatari1,6, abdulkadir lawal rafinadadi1,17, ahmad bello kumo1,18, haruna a nggada1,19 rebecca gali1,20, hassan m. dogo1,21, ademola popoola,1,22 serah adewumi1,22, ruth agaba1,11, kimberly meza1,3,4, nkegoum blaise1,23, paul jibrin1,24, rakiya saidu,1,25,26 haruna mohammad muktar1,7, ahmad mai1,6, titilola akinremi1,27, sunday ene-ojo atawodi1,5, saad aliyu ahmed1,2, aliyu muhammad1,5, kasimu umar adoke1,2, ahmad tijjani lawal1,6, jamilu ya’u,1,28 ahmed muhammed1,6, muhammad sa’idu tanko1,29 omolara fatiregun1,30, aliyu a babadoko1,7 shehu akuyam1,31, yusuf rasheed1,31, mubarak labaran liman1,32, abidemi e omonisi1,33, anthonia sowunmi1,34, jigo dangude yaro1,2, catherine adebukola oladoyinbo1,35, faoziyat adenike sulaiman,1,22 ogo chidiebere ndukwe,1,27 abdussamad abdulrahaman,1,36 olubanke o. ogunlana,1,11, ayo a salako1,37, frank chinegwundoh1,38, wole kukoyi,1,39 esther isaiah1,39 adenike onibokum 1,40, ibrahim suleiman1,41, motolani e ogunsanya1,42, fredrick ugwumba1,43 , okezie mbadiwe1,43 , kayode adeniji,1,22, akinwumi oluwole komolafe1,44, suleiman alege kuranga,1,22 iheanyi okpala1,45 1 prostate cancer transatlantic consortium (captc); 2 department of pathology, college of health sciences, faculty of basic clinical sciences, ahmadu bello university, zaria 810001, nigeria; 3department of pharmacotherapy and translational research, college of pharmacy, university of florida, orlando, florida 32827, usa; 4minority cancer research and training (micart) center, university of florida, orlando, florida, usa; 5department of biochemistry, faculty of life sciences, ahmadu bello university, zaria nigeria; 6department of surgery, college of health sciences, faculty of clinical sciences, ahmadu bello university, zaria nigeria; 7department of haematology and blood transfusion, college of health sciences, faculty of basic clinical sciences, ahmadu bello university, zaria, nigeria; 8department of radiology and radiotherapy, college of health sciences, faculty of clinical sciences, ahmadu bello university, zaria, nigeria, 9school of health and human performance, georgia college and state university, milledgeville, georgia 31061 usa 10department of pathology, ahmadu bello university teaching hospital shika zaria, nigeria; 11department of biochemistry, covenant university, ota, ogun state, nigeria; 12department of epidemiology and biostatistics, college of public health, university of south florida, tampa, florida usa; 13department of biology and center for cancer research, tuskegee university, tuskegee alabama 36088, usa; 14department of medical laboratory science, faculty of allied medical health sciences, college of www.companyofscientists.com/index.php/chd e2 cancer health disparities research medical sciences, university of calabar, calabar, nigeria.1,15college of pharmacy and pharmaceutical sciences, florida a&m university, tallahassee, florida usa; 16department of obstetrics and gynaecology, college of health sciences, faculty of basic clinical sciences, ahmadu bello university, zaria, nigeria; 17department of ophthalmology, college of health sciences, faculty of basic clinical sciences, ahmadu bello university, zaria, nigeria; 18department of medicine, college of health sciences, faculty of basic clinical sciences, ahmadu bello university, zaria, nigeria; 19department of pathology, college of medical sciences, university of maiduguri, maiduguri, nigeria; 20department of medical laboratory science, college of medical sciences, university of maiduguri, maiduguri, nigeria; 21department of surgery, college of medical sciences, university of maiduguri, maiduguri, nigeria; 22faculty of basic clinical sciences, college of health sciences, university of ilorin, ilorin, nigeria; 23university hospital center, yaounde, cameroon; 24department of pathology, national hospital, abuja, nigeria; 25department of obstetrics and gynaecology, faculty of medicine, university of ilorin, ilorin, nigeria; 26department of obstetrics and gynaecology, university of cape town, south africa; 27federal medical center, abeokuta, nigeria; 28department of pharmacology and therapeutics, faculty of pharmaceutical sciences, ahmadu bello university, zaria nigeria; 29veterinary teaching hospital, ahmadu bello university zaria, nigeria 30department of radiotherapy and oncology, lagos state university teaching hospital, lagos, nigeria; 31department of chemical pathology, college of health sciences, faculty of basic clinical sciences, ahmadu bello university, zaria, nigeria; 32department of science laboratory technology, nuhu bamalli polytechnic, zaria, nigeria; 33department of anatomic pathology, faculty of basic clinical sciences, ekiti state university, ado-ekiti, nigeria; 34department of radiotherapy, lagos university teaching hospital, lagos, nigeria; 35department of nutrition and dietetics federal university of agriculture, abeokuta, nigeria; 36department of pharmaceutics and pharmaceutical microbiology, faculty of pharmaceutical sciences, ahmadu bello university, zaria nigeria; 37department of surgery, obafemi awolowo university, ile-ife, nigeria; 38barts health nhs trust/ school of health sciences, city university london, uk; 39ace medicare clinics limited ota, nigeria; 40department of nursing sciences, university of ibadan, ibadan nigeria; 41department of physiology, ahmadu bello university, zaria, nigeria; 42college of pharmacy, health science center, university of oklahoma health science center, oklahoma city, ok 73117, usa; 43department of surgery, university of nigeria, nsuka, nigeria; 44department of pathology, obafemi awolowo university, ile-ife, nigeria; 45institute of human genomics and infectious diseases, university of nigeria, nsukka, nigeria *corresponding author: mohammed faruk, e-mail: fmohammed@abu.edu.ng mailto:fmohammed@abu.edu.ng www.companyofscientists.com/index.php/chd e3 cancer health disparities research abstract poor understanding of the clinicopathological features of prostate cancer (cap) in black men (bm) is one of the major challenges implicated in the management and prevention of the disease. the development of cap involves an accumulation of multiple oncogenic events with associated increase in prostate specific antigen (psa) and stress related hormones such as cortisol. this research aims to examine the role of cortisol and health-related quality of life (hrqol) in cap development. data was collected as part of a large captc familial cap cohort study. the hrqol indicators were measured and salivary cortisol levels evaluated by enzyme immunoassay. cap tissue expression patterns of cortisol and annexin v were also studied by immunohistochemistry. the hrqol indicators showed a significant difference between participants with and without physical activity (p = 0.025), stress (p = 0.008) and self-care (p = 0.005). there was significant increase in salivary cortisol levels in the cap patients compared to cap-free participants (p = 0.003). the salivary cortisol level for the cap patients ranged from 1.029 µg/dl to 0.037 µg/dl while the range for the cap-free participants was from 0.139 µg/dl to 0.026 µg/dl. in addition, we found increased expression of the cortisol protein in cap patients with gleason score 8 compared to those with lower scores and the cap tissues showed overexpression of annexin v protein. salivary and tissue cortisol levels with an accompanying annexin v expression may serve as important biomarkers for cap diagnosis and prognosis in west african black men. keywords: prostate cancer, african black men, nigerian men, cameroonian men, cortisol, health related quality of life citation: faruk et al (2019) cortisol and health-related quality of life as prognostic indicators for prostate cancer risk in west african black men in nigeria, cameroon and the usa: the captc cohort study. cancer health disparities 4: e1-17. doi:10.9777/chd.2019.1009. www.companyofscientists.com/index.php/chd e4 cancer health disparities research introduction prostate cancer (cap) is a significant public health challenge that has disproportionately overburdened black men of african ancestry with increased prevalence, poor prognosis and heavy mortality rates (odedina et al., 2009 (a); bray et al., 2013). a number of studies have documented significant cap burden among nigerian and cameroonian black men in west africa and the diaspora (odedina et al., 2009 (b); kumar et al., 2009; akinremi et al., 2011; odedina et al., 2011(a); odedina et al., 2011 (b); enow orock et al., 2012; ferlay et al., 2015; kaninjing et al., 2017; odedina et al., 2017). in african americans, the incidence and mortality rates of cap are disproportionately higher than in caucasians, and the prognosis worse, due largely to genetic factors (odedina et al., 2009 (b); american cancer society, 2013). personal factors (such as lack of awareness), provider factors (such as shortage of human resources) and healthcare systems factors (such as limited access to appropriate treatment) contribute to the late cap presentation with metastatic disease as the first presenting features at diagnosis in black men of african ancestry (farré and kibera, 2018). it is pertinent to note that available diagnostic and prognostic tools for cap which includes prostate specific antigen (psa) lack specificity and sensitivity. this makes it difficult to distinguish between aggressive and nonaggressive state of the disease for proper stratification, further evaluation and therapeutic intervention (farran et al., 2018). to explore the distinct biological and environmental etiology of cap, the prostate cancer transatlantic consortium (captc https://epi.grants.cancer.gov/captc/), a us national institutes of health (nih)/ national cancer institute (nci) – epidemiology and genomics research program (egrp) approved consortium, utilizes multilevel, collaborative, transdisciplinary, translational, and global team science research approach to study black men globally. specifically, captc investigators address the complexity of cap taking into consideration the ethnic heterogeneity and geographical classifications of black men with african ancestry. this approach is pertinent to understanding the etiology of african-associated cap risk and utilizing the diverse west african population will be of immense benefit. the initial state of cap and its progression involves an accumulation of multiple oncogenic events resulting in gene amplification, which is associated with increased levels of androgens and prostatespecific antigen (psa). the psa has been reported to be higher in black men compared to caucasians, however, this has been associated with complications and controversies (visakorpi et al., 1995; moul et al.., 1996; us preventive services task force recommendation statement, 2018). the complications with increase in psa level are aggravated by several abnormal mutations that make cap cells more aggressive via the stress and cortisol axis mechanisms and an increase in the amino acid content within the cancer microenvironment (gaddipati et al., 1994; zhao et al., 2000; wang et al., 2013; tee, 2013; huang et al., 2018). in addition, amino acids via anabolic pathways generate nucleotide and membrane biomolecule precursors for aggressive cap cells (andrew et al., 2013). perhaps, this explains why leucine may serve as a source of fuel for aggressive prostate cancer cells. however, it has not been unequivocally demonstrated that leucine is secreted mostly by cortisol overexpression. the cortisol, an important glucocorticoid hormone, is synthesized in the body by adrenal https://epi.grants.cancer.gov/captc/ www.companyofscientists.com/index.php/chd e5 cancer health disparities research cortex via adrenocorticotropin stimulation. therefore, cortisol fluctuation as a result of stress has been linked to allostatic load-associated diseases including immune suppression (kirschbaum and hellhammer, 1999). only about 5% of cortisol is unbound and freely circulate to the tissues including salivary gland for biological activity, whereas the remaining 95% is bound to several components of the blood including corticosteroid-binding globulin (ekins, 1990; walker et al., 1978). thus, saliva provides a simple and non-invasive means of assessing unbound cortisol level because blood cortisol levels may be affected by the corticosteroid-binding globulin activity (walker et al., 1978). health-related quality of life (hrqol) has also been reported to be associated with psa status in men with cap (gidron et al., 2011). since a deficiency in cortisol secretion results to quiescent immune system and overexpression of cortisol contribute to suppression of immune responses and possible tumorigenesis (munck and narayfejes-toth, 1995; coussens and werb, 2002), our study focused on the expression pattern of cortisol in cap tissue cells, taking into considerations the gleason score by immunohistochemistry. the ability of cortisol to regulate immunological and inflammatory processes prompted us to explore the expression pattern of annexin v, an intracellular protein with affinity to phosphatidylserine, which is expressed on the surface of physiologically stressed cells and functions in inhibition of cancer angiogenesis (blankenberg, 2009). in line with our long-term goal of addressing the burden of cap in west african men, the primary objective of this study was to examine the role of cortisol and hrqol in the development of cap among nigerian and cameroonian men living in nigeria, cameroon and united states. findings from this study show significant differences in hrqol, salivary cortisol level and tissue cortisol expression pattern in the cap patients compared to cap-free participants. these findings may have a significant impact on cap risk and prognosis, and may contribute to the understanding of the genetic, environmental and behavioral etiological factors associated with the disease in black men. methods study participants and recruitment the participants recruited for this pilot study were nigerian and cameroonian black men within the age bracket of 35 to 70 years and residing in nigeria, the republic of cameroon and the united states of america (us) participants were recruited as part of the large-scale captc study focused on studying a familial cohort of west african men in multiple countries. the captc study (which is ongoing) is using the heterogeneity of the study participants, including geographical locations, to explore the genetic, environmental and behavioral etiological factors associated with cap. the study inclusion criteria were: (1) west african men regardless of the history of cap diagnosis; (2) men between the age of 35 and 70 years; and (3) men who consented to complete the study survey. participants were recruited from multiple settings using a flyer, including at clinics and diverse community settings such as social organizations, churches, mosques, health events and also business facilities. study variables and measures the study variables were: (1) health-related quality of life indicators including exercise, stress, ability to self-care and perceived emotional health status,-; www.companyofscientists.com/index.php/chd e6 cancer health disparities research (2) personal history of cap,-; and (3) demographic information, including age, religion, ethnicity, education, income, employment, country of residence, and previous history of cancer. these variables were assessed using the standardized global prostate cancer measure for black men that was developed by captc and the african caribbean cancer consortium (ac3). data collection ethical approval was obtained at each study site prior to data collection. the ethics approval include implementing informed consent process for each participant. following informed consent approval by participants, the key study personnel in charge of data collection administered the survey and collected saliva drool using a saliva kit. the salivary samples were collected from 8am to 12 noon. participants were provided a monetary incentive or a t-shirt for the time taken to participate in the study. statistical considerations and data analyses the study data entry and management was conducted using the research electronic data capture (redcap) software. subsequently, data were exported into the pc-sas analytical software for data analysis. frequency analysis of the variables was conducted to confirm responses are appropriately entered and errors corrected. the internal consistency of the study scales was calculated to establish the reliability of the scales. the study variables were evaluated using descriptive statistics of means procedure for continuous variables and frequency analyses for categorical variables. microsoft excel (microsoft office professional plus 2013; microsoft corp., redmond, wa, usa) was used to produce the charts. subsequently t-test statistical analysis was used to determine the differences in cortisol levels and expression using the spss software, version 20.0 (ibm corp., armonk, ny, usa). a p -value of <0.05 was considered statistically significant. salivary cortisol analysis by enzyme-linked immunosorbent assay the salivary cortisol was quantified using an enzyme-linked immunosorbent assay (elisa) kit (salimetric inc, college park, pa) as per manufacturer’s procedure. all elisa experiments were performed in duplicate analysis. tissue cortisol analysis by immunohistochemistry immunohistochemistry (ihc) was performed on 5μm cap formalin fixed paraffin embedded (ffpe) tissue and non-malignant prostatic ffpe tissues for cortisol and annexin v protein expression using anti-cortisol (abin3208586) and anti-annexin v (bin4964891) antibodies (antibodies-online aachen, germany). briefly, the slides containing tissue sections were baked for 1 hour, then deparaffinized with 100% xylene at room temperature for 1 minute, and hydrated in a graded alcohol stages consisting of 30-second dips each in 100% and 95% ethyl alcohol diluted in water (total volume is 5 ml) at room temperature, and finally hydrated in water. sections were incubated in 3% hydrogen peroxidase in water at room temperature for 10 minutes to block endogenous peroxidase activity. the slides were then washed, blocked and incubated at room temperature for 30 minutes. the slides were incubated with the anti-cortisol antibody and in 5 µg/ml dilutions and with hrp-linked secondary antibody in blocking buffer. the same protocol was used for anti-annexin v (bin4964891) antibody staining using 2.5 µg/ml. the nuclei of the cells were counterstained with haematoxylin (blue). the expression level was categorized as low and high based on a combined score of intensity www.companyofscientists.com/index.php/chd e7 cancer health disparities research and distribution. the expression was categorised base on intensity of the stain (0 = absent; 1 = weak; 2 = moderate; 3 = strong) and distribution (per cent of tumour positive). results a total of 500 black men of west african descent participated in the study. of the 500 black men, 85% are resident in nigeria, 8% in the usa and 7% in the republic of cameroon. demographic characteristics of the participants are displayed in table 1. the results revealed that 8% (40) of the participants had previous diagnosis of prostate cancer whereas 1% (4) had previously been diagnosed with other malignancies such as colorectal, liver, nasopharyngeal cancers and sarcoma. about 82% (401) of the participants were non-smokers and 85% (427) were employed. table 1. demographic characteristic for the captc cohort study. characteristics frequency percent demographic characteristics, n = 500 country of resident nigeria 428 85.60 cameroon 34 6.80 usa 38 7.60 age range of participants recruited 35-44 216 43.20 45-54 160 32.00 55-64 82 16.40 65 and above 42 8.40 personal history of cancer prostate cancer 40 8.00 colorectal cancer 2 0.40 liver cancer 1 0.20 nasopharyngeal 1 0.20 sarcoma 1 0.20 do not know 455 91.00 marital status married or living as married 460 92.00 never married or divorced/ widowed 37 7.40 non-disclosed 3 0.60 smoking status at present 20 4.00 in the past 72 14.40 never 329 68.80 non-disclosed 79 15.80 education 8 to 11th grade 87 17.4 high school 108 21.6 university 294 58.8 non-disclosed 11 2.20 employment status employed 427 85.40 not employed 63 12.60 non-disclosed 10 2.00 household income less than $25,000 419 83.80 $25,000 to $49,999 10 2.00 $50,000 to $74,999 9 1.80 $75,000 and above 15 3.00 non-disclosed 47 9.40 participant’s health-related quality of life five relevant factors associated with hrqol indicators were examined in this study: exercise, stress, ability to self-care, health status perception and the need for specialized equipment towards personal daily life support. results show significant differences (p = 0.0353) in participants physical activity levels within the last month, with 57% of participants reporting up to 30 days active exercise, 19% reporting 0 to 9 days of no exercise, 3% reporting 10 to 19 days of no exercise, and 4% reporting 20 to 30 days of no exercise within the last month (see figure 1). there was also significance difference (p = 0.0080) across stress levels of participants within the last month. sixtyfour per cent (64%) of participants reported absence of emotional stress for 30 days within the last month, 13% reported presence of stress for 0 www.companyofscientists.com/index.php/chd e8 cancer health disparities research to 9 days, 3% reported presence of stress for 10 to 19 days and 3% reported presence of stress for 20 to 30 days (figure 1). there were significant differences (p = 0.0051) in participants’ report on self-care within the last month. sixty-three (63%) indicated that they had not been able to carry out self-care for 30 days, 16% indicated that they had not been able to carry out self-care for 0 to 9 days, 2% had not been able to carry out self-care for 10 to 19 days and 3% had not been able to carry out self-care 20 to 30 days. in general, most of the participants reported good healthcare status. eighty-four per cent of the participants indicated that they were in good health while 14% reported poor or fair health within the last month. furthermore, 94% of the participants reported that they had no need for specialized equipment to carryout daily personal activities while 4% reported that they needed special equipment for daily life activities within the last month. table 2 compares hrqol indicators between participants with history of cap and cap-free participants. the hrqol indicators show no significant difference in exercise (p = 0.1441), stress (p = 0.1789), ability to self-care (p = 0.1434), health status perception (p = 0.3066), and need for specialized equipment (p = 0.3784) between patients with history of cap and cap-free participants. figure 1. summary of health related quality of life of participants recruited. www.companyofscientists.com/index.php/chd e9 cancer health disparities research figure 2. response of perceived health status of the participants. table 2. comparison of health-related quality of life for participants with history of prostate cancer and prostate cancer-free participants. variable s participants with cap history n=40 (%) participant without cap history n=460 (%) p-value exercise 30 days active exercise 19 (47.5) 289 (64.3) 0.1441 no exercise 0-9 days 13 (32.5) 101 (21.9) no exercise 10-19 2 (5.0) 14 (3.0) no exercise 20-30 days 3 (7.5) 13 (2.8) no response 3 (7.5) 43 (7.9) stress no stress 30 days 22 (55.0) 316 (70.1) 0.1789 stress 0-9 days 8 (20.0) 61 (13.3) stress 10-19 days 2 (5.0) 14 (3.1) stress 20-30 days 3 (7.5) 13 (2.8) no response 5 (12.5) 56 (10.7) ability to self-care self-care 30 days 25 (62.5) 290 (63.0) 0.1434 no self-care 0-9 6 (15.0) 74 (16.1) no self-care 10-19 3 (7.5) 7 (1.5) no self-care 20-30 2 (5.0) 13 (2.8) no response 4 (10.0) 76 (16.5) 0 10 20 30 40 50 60 70 80 90 100 good – excellent health poor – fair health unclassified do not need special equipment need special equipment unclassified re sp on se o f t he s ub je ct s ( % ) perceived health status scale of the subjects recruited www.companyofscientists.com/index.php/chd e10 cancer health disparities research health status perception good to excellent 20 (50) 390 (84.8) 0.3066 poor to fair 17 (42.5) 63 (13.7) no response 3 (7.5) 7 (1.5)10 need for specialized equipment do not need 24 (60) 436 (94.8) 0.3784 need 13 (32.5) 11 (2.4) no response 3 (7.5) 13 (2.8) salivary cortisol levels of cap patients and capfree participants results from the salivary cortisol analysis by elisa show significant increase in expression (p =0.003) of salivary cortisol levels (0.18±0.03) in the prostate cancer patients (n=10) compared to the values (0.08±0.01) from the cap-free participant (n=40) (figure 3a). the maximum value of the salivary cortisol level among the cap patients was 1.029 and the minimum value was 0.037. the maximum and minimum values of the salivary cortisol in cap-free participants were 0.139 and 0.026 respectively (figure 3b). figure 3a. salivary cortisol levels of few of the participants recruited. figure 3b. salivary cortisol levels from a portion of cap patients and cap-free participant recruited. one of the cap participants in position 8 above showed abnormal increase in cortisol even after repeating the analysis for accuracy. 0 0.2 0.4 0.6 0.8 1 1.2 1 2 3 4 5 6 7 8 9 10 prostate cancer patients control subjects sa liv ar y co rt iso l l ev el s ( µg /d l) cap patients and cap-free participants www.companyofscientists.com/index.php/chd e11 cancer health disparities research tissue cortisol and annexin v expression in cap patients and cap-free participants result show overexpression of cortisol protein in the cap cases with gleason score of 8 compared to those with lower gleason scores. the cap-free tissues show negative expression of the cortisol protein (figure a). figure 4b contains h&e stained sections of cap showing cap cells and 3 different sections stained for ihc with the anti-cortisol antibody signifying strong expression of the cortisol protein. the sections are cap cases with gleason score of 8 . also shown in the ihc result is moderate expression of cortisol protein in the cap cells with lower gleason score of 6 and below (figure 4c). all but one of the cap cases stained with anti-annexin v antibody show increased expression of annexin v protein (figure 4d). www.companyofscientists.com/index.php/chd e12 cancer health disparities research figure 4a. left: benign or non-malignant prostate tissue stained with haematoxylin and eosin (h&e), and right: anti-cortisol antibody stain for showing no cortisol expression in the prostate. figure 4b: cortisol expression pattern in cap cells with gleason score 8. the top left photograph is an h&e stained section of cap tissue showing malignant cells. the other photographs show sections of cap cells with gleason score 8 stained by immunocytochemistry with anti-cortisol antibody; there is strong expression of cortisol. fig 4c: expression pattern of cortisol in cap cells with gleason score 6 and below. the ihc result show moderate expression of the cortisol in the cells. figure 4d. expression pattern of annexin v protein in cap cells. the stain shows all but one of the cap sections stained with anti-annexin v antibody to have increase expression of the protein. www.companyofscientists.com/index.php/chd e13 cancer health disparities research figure 4e. show h score depicting pattern of cortisol expression in normal prostatic lesion and cap cells. the score show 2-fold increase in cortisol expression in the cap sections. discussion the results from this captc pilot study of 500 west african balck men within the age bracket of 35 and 70 years show variation in hrqol indicators such as exercise, stress, and ability to self-care, health status perception and the need for specialized equipment in carrying out daily life activities. the most interesting finding was, indicators associated to hrqol themes appeared to have the existence of about 3% of the respondents reporting their inability to carry out daily exercise, self-care and hence consistent stress for 20 to 30 days within period of one month. the percentage of the hrqol indicators increased slightly to about 19% for the participants when increasing the number of days for physical activity by 10 days. poor health-related quality of life parameters which interfere with physical, functional, social and emotional states of an individual have been associated to worsen disease prognosis especially in african american men with cap (blankenberg 2009; desantis et al., 2012). previous studies have showed that western lifestyle, reduced physical activity and high fat diet intake are related to cap risk (freedland and aronson, 2009; fradet et al., 2009). stress and psychosocial factors are also associated with the onset and prognosis of malignant tumours. a recent meta-analysis of 165 studies reports that psychosocial factors are predictive of cancer prognosis, independent of initial tumor stage and other confounders (chida et al., 2008). of the 500 study participants, 40 were patients diagnosed with cap, thus contributing to the percentage of the participants with poor health-related quality of life in this research. results that compare hrqol indicators between participants with history of cap and cap-free participants show no significant differences between the two groups. the lack of differences in the hrqol indicators between the groups may be associated to the small number of cap participants (n=40) as compared to cap-free participants (n=460) recruited in this study. however, since the study recruitment is on-going, further effort will lay emphasis on recruiting sufficient cap patients. the salivary cortisol level analysis of 40 participants without cap and 10 patients with cap e www.companyofscientists.com/index.php/chd e14 cancer health disparities research showed a significant increase in the mean average cortisol level from 0.08±0.01 to 0.18±0.03 respectively. however, one of the patients with cap showed a four-fold increase in salivary cortisol level compared to the highest level in the non-cap participants even after repeating the analysis to rule out possible errors. previous studies have shown that cortisol levels are associated with circadian disruption and poor health status which in turn contribute to immune dysfunction and cap risk (touitou 1983; coussens and werb, 2002; desantis et al., 2012; tai et al., 2016). findings from this study further showed about 14% of the respondents to have poor health status, while 4% needed specialized equipment to be able to perform regular daily activities, probably for reasons, not unrelated to stress. additionally, the expression patterns of cortisol protein at tissue level were assessed by immunohistochemistry to further explore the role of the protien in cap pathogenesis. the results obtained show an increase in the expression of the cortisol in cap cells, which was directly associated with increase in gleason score and hence the disease aggressiveness. the luminal cells of the glandular epithelium in cap secrete various hormones including androgens (feldman and feldman, 2001) and perhaps cortisol for a role in cellular proliferation and apoptosis. previous report shows that stress increases cytokines level especially interleukin 6 on the hypothalamicpituitary-adrenal axis (zhou et al., 1993) which may result to fluctuation in the body cortisol level. the t877a androgen receptor mutation in the cap microenvironment increases the binding affinity of the androgen receptor to cortisol and its metabolite, cortisone, creating a cortisol responsive cap cells leading to androgen independent growth and higher tumour grade (zhao et al., 2000). interestingly, the abnormal mutations of the androgen receptor molecule results in the ability of cortisol to bind to the androgen molecule thereby functioning as a “pseudo-androgen”, promoting the increase in secretion of psa and making cap cells more aggressive (gaddipati et al., 1994; zhao et al., 2000). these factors explain the potential source and role of cortisol in cap. cap cells with metastatic features including metastatic castrationresistant phenotypes have been reported to be highly dependent on amino acid uptake through the l-amino acid transporters (lats) for cellular growth and proliferation, as well as malignant transformation (wang et al., 2013). the lats are part of atf4 genes that function in the exchange of branch chain amino acids for intracellular amino acids (tee, 2013). amino acids via anabolic pathways have been reported to generate nucleotide and membrane biomolecule precursors for aggressive cap cells (tee, 2013). perhaps this explains why leucine may serve as a source of fuel for aggressive prostate cancer cells. the study also shows increased tissue expression of annexin v protein in the cap cells. annexin v have been reported to regulate immunological and inflammatory processes and commonly expressed on the surface of stressed cells for inhibition of malignant tumour angiogenesis (desantis et al., 2012). previous findings have shown that abnormal increase in stress contributes to increase in cortisol, inflammation and immune dysfunction via activation of the hypothalamic-pituitary-adrenal axis (blankenberg, 2009). these underlining mechanisms have been proposed to play significant role in prostate cancer pathology and poor prognosis (touitou et al., 1983; gidron et al., 2011; coussens and werb 2002; desantis et al., www.companyofscientists.com/index.php/chd e15 cancer health disparities research 2012; tai et al., 2016). the limitation of our pilot study includes the small sample size of participants with cap compared to cap-free participants. additional research parameters which include but not limited to inflammatory markers are necessary to increase our understanding of the role of cortisol in the development and prognosis of cap in black african men. further in-depth studies that take into consideration all the necessary parameters are required. conclusion in conclusion, this study to a large extent has demonstrated associations of salivary cortisol level, tissue cortisol expression activity and hrqol of life in west african black men in nigeria, cameroon and the usa with or without cap. the study show that salivary and tissue cortisol levels with an accompanying annexin v expression may serve as important biomarkers for prostate cancer diagnosis and prognosis in west african black men. the findings further suggest the possibility that tissue and salivary cortisol in combination with indicators of hrqol may mediate prostate cancer risk in west african balck men. acknowledgements we acknowledge the support of mrs. nike obafemi who assisted with data collection and our participants who took the time to participate in this study. in addition, ms. kimberly meza is acknowledged for providing editorial review for the manuscript. funding support funding support for this project was provided by the prostate cancer transatlantic consortium (captc). conflict of interest the authors declare that no competing or conflict of interests exist. the funders had no role in study design, writing of the manuscript, or decision to publish. authors’ contributions conception and design: mf, fto, sa, aa, sma, abdullahi adamu, ab, ji, ams, ek, ccy, rrr, development of methodology: mf, fto, rrr, cy, fc, so acquisition of data: mf, na, sa,ams, ra, km analysis and interpretation of data: mf, gad, na writing, review, and/or revision of the manuscript: mf, fto, si, ahr, aa, daa, sma, abdullahi adamu, ab, ek, ji, ams, sor, gad, na, ccy, eji, yi, ieb, rrr, am, mss, ajr, hym, dmm, alr, abk, han, rg, hmd, ap, sa, ra, km, nb, pj, rs, hmm, ahmad mai, ta, sea, saa, aliyu muhammad, kua, atl, jy, ahmad muhammad, mst, ot , aab, shehu akuya yr, mll, aeo, as, jdy, cao, fas, ocn, aa, ooo, aas, fc, wk, ei, ao, is, meo, fu, om, ka, aok, sak, io. administrative, technical, or material support: na, sa, ra, km study supervision: mf references akinremi, t.o., ogo, c.n., and olutunde, a.o. 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(1993). exposure to physical and psychological stressors elevates plasma interleukin 6: relationship to the activation of hypotha-lamic-pituitary-adrenal axis. endocrinology 133, 2523-30. www.companyofscientists.com/index.php/chd e1 cancer health disparities research cervical cancer outcome by type of health care facilities: national cancer database, 2004-2015 hyounkyoung g. park1,4, zhixin e. wang1,4, chenguang wang2, warner k. huh3,4, sejong bae1,4 1division of preventive medicine, department of medicine, school of medicine, university of alabama at birmingham, birmingham, al 2division of biostatistics and bioinformatics, sidney kimmel comprehensive cancer center, the johns hopkins university, baltimore, md 3division of gynecology oncology, department of obstetrics and gynecology, school of medicine, university of alabama at birmingham, birmingham, al 4o’neal comprehensive cancer center, university of alabama at birmingham, birmingham, al abstract the national cancer database from 2004 to 2015 was analyzed to identify cervical cancer outcomes associated with demographic and clinical characteristics measured by types of facility. chi-square tests were used to compare proportions and logistic regression to determine factors associated with cervical cancer outcomes. women treated at academic/research programs (arps) were younger at diagnosis, more likely black, less educated and more in stage 2, lived further away from treatment facilities, had less comorbidities and better 5year survival, and were more likely to be alive at 30 and 90 days after surgery compared to other programs. women treated at community cancer programs were more likely 75 and older at diagnosis, more likely to receive radiation treatment and more in stage 4, more living in rural areas and less than 10 miles from the facility, and had more comorbidities, and lower 5year survival compared to other programs. women treated at comprehensive community cancer programs were more likely white and educated, had more private insurance, and underwent surgery. women treated at integrated network cancer programs were more likely to live in urban, south region, and in stage 1b2, had more surgery and one comorbidity, and died fewer than 30 days after surgery. the type of facility and treatment had varied effects on mortality and 5-year survival. considering the different cervical cancer outcomes from different health care facilities, further research is needed to identify what factors influence women to choose a health care facility for their treatment and how this choice can affect different health outcomes. keywords: cervical cancer, type of facility, mortality, survival citation: park hg et al (2019) cervical cancer outcome by type of health care facilities: national cancer database, 2004-2015; cancer health disparities. 4: e1-e-13. doi:10.9777/chd.2019.1011 www.companyofscientists.com/index.php/chd e2 cancer health disparities research introduction cervical cancer is the most common type of gynecological cancer but one of the most preventable and treatable cancers (fedewa et al., 2012; ferlay et al., 2015). in the united states, cervical cancer incidence and mortality rates continue to decline since regular cervical cancer screening tests and vaccination were introduced (akinlotan et al., 2017; cdc, 2018; scarinci et al., 2010.). several studies have investigated risk factors associated with higher cervical cancer incidence and mortality. for example, being black (arvizo and mahdi, 2017; beavis et al., 2017; furlow, 2018; powell et al., 2018 ; scarinci et al., 2010. ; singh and jemal, 2017; weragoda et al., 2016 ; yoo et al., 2017), getting older (fedewa et al., 2012; furlow, 2018; yosta and hoekstra, 2018), living in the south (yoo et al., 2017), less income (singh and jemal, 2017), less education (singh and jemal, 2017), having comorbidity (diaz et al., 2018), stages of cancer (acharya and grigsby, 2016; landy et al., 2016), insurance (acharya and grigsby, 2016; churilla et al., 2016 ; davis et al., 2018; fedewa et al., 2012) and distance (barrington et al., 2016) have been reported as risk factors responsible for the incidence and mortality of cervical cancer. identifying risk factors for cervical cancer is critical for developing proper prevention and treatment approaches connecting to risk factors, thus reducing racial disparities on the outcomes of cervical cancer, such as higher incidence and mortality rates, as well as lower five-year survival and overall survival among black women (american cancer society, 2018). there were significant differences in the characteristics between white and black women with cervical cancer in the ncdb data. for example, black women were diagnosed with laterstage disease with more comorbidities than white women, which resulted in increased morbidity and mortality in black women. in addition, most black women had treatment in academic/research programs that were close to their residence and higher mortality rates among white women were identified in community cancer programs and comprehensive community cancer programs. considering significant racial disparities in healthcare outcomes, it is essential to understand the impact of the type of health care facility on health outcomes among cervical cancer patients. several studies have been conducted on the relationship between outcomes in cervical cancer patients based on distance from hospitals (barrington et al., 2016; gunderson et al., 2013; powell et al., 2018; spees et al., 2018) and the impact of facility volume on quality treatment and survival (ross et al., 2010; showalter et al., 2016). in their study on racial disparities in outcomes after surgical procedures, haider and associates (2013) reported systemic factors such as access to care, hospital volume, and hospital patient population have been shown to contribute to disparities (haider et al., 2013). study results report that high volume hospitals have more favorable outcomes than low volume hospitals. connecting to the choice of hospitals for treatment, it is also important to understand possible factors affecting the patient’s choice of treatment options resulting in the subsequent oncologic outcome and causing significant disparities in survival among minority patients (luo et al., 2015). for example, black patients and living in rural areas were associated with the choice of surgery to treat other cancers, resulting in less www.companyofscientists.com/index.php/chd e3 cancer health disparities research surgery compared to white patients (cykert et al., 2010; steenland et al., 2011). the purpose of this study was to investigate the impact of different health care facilities on types of treatments and cervical cancer outcomes using the national cancer database (ncdb) data. the research question was “how would different types of health care facilities influence the outcomes of patients with cervical cancer and their types of treatment?” materials and methods to assess cervical cancer outcomes by different facility types, cervical cancer data were drawn from the national cancer database (ncdb) for the years 2004 to 2015. ncdb is jointly sponsored by the american college of surgeons and the american cancer society, and it is the largest clinical cancer registry in the world (steenland et al., 2011). it covers more than 70% of newly diagnosed cancer cases in the united states (lin et al., 2014). each facility reporting cases to the ncdb is assigned to a category classification, i.e., the facility type, by the commission on cancer accreditation program. the ncdb classified all facilities into four types: academic cancer programs, community cancer programs, comprehensive community cancer programs, and integrated network cancer programs (source: http://ncdbpuf.facs.org/content /participant-use-file-facility-type). academic comprehensive cancer program or academic/research programs (arps) participate in postgraduate medical education in at least four program areas, including internal medicine and general surgery. the facility accessions more than 500 newly diagnosed cancer cases each year, and offers the full range of diagnostic and treatment services either on-site or by referral. community cancer programs (ccps) accession more than 100 but fewer than 500 newly diagnosed cancer cases each year and provides a full range of diagnostic and treatment services, but referral for a portion of diagnosis or treatment may occur. comprehensive community cancer programs (cccps) accession 500 or more newly diagnosed cancer cases each year and provide a full range of diagnostic and treatment services either on-site or by referral. integrated network cancer programs (incps) own, operate, lease, or are part of a joint venture with multiple facilities providing integrated cancer care and offer comprehensive services. we used this classification to analyze demographic characteristics, disease status, treatment and cervical cancer outcomes by the type of facility. for our data analysis, women younger than 40 years old were excluded from this study in addition to women other than white and black (hispanic origin was not distinguished). age was categorized into 5 groups: 40-49, 50-59, 60-69, 70-79, and 80+. regional information was deduced from the location of the reporting facility (suppressed for cases aged 0-39). there are 6 categories for insurance in ncdb: uninsured, private insurance/managed care, medicaid, medicare, other government, and unknown. we further separated the medicare group into younger medicare (< 65 years old) and older medicare (≥ 65 years old) because of the difference in eligibility for these two groups. cervical cancer stages were identified based on the t, n, and m elements as defined by the american joint committee on cancer (ajcc). to analyze the association between disease status and facility types, “tnm clin stage group” that identifies the anatomic extent of disease based on http://ncdbpuf.facs.org/content/participant-use-file-facility-type http://ncdbpuf.facs.org/content/participant-use-file-facility-type www.companyofscientists.com/index.php/chd e4 cancer health disparities research the t, n, and m elements known prior to the start of any therapy was re-categorized into 5 groups:1a-1b1 (tnm clin stage group=1,1a,1a1, 1a2,1b,1b1), 1b2 (tnm clin stage group=1b2), 2 (tnm clin stage group=2,2a,2a1,2a2,2b), 3 (tnm clin stage group=3,3a,3b), and 4 (tnm clin stage group=4,4a,4b). comorbidity was measured by charlson score, which is a weighted score derived from the sum of the scores for each of the comorbid conditions listed in the charlson comorbidity score mapping table. household income was categorized as quartiles based on equally proportioned income ranges among all us zip codes. education was estimated by matching the zip code of the patient recorded at the time of diagnosis against files derived from the 2012 american community survey data, spanning years 2008-2012. this item provides a measure of the number of adults in the patient's zip code who did not graduate from high school, and is categorized as equally proportioned quartiles among all us zip codes. residence, which represents the area-based measure of rurality and urban influence, was estimated by matching the state and county fips code of the patient recorded at the time of diagnosis against 2013 files published by the united states department of agriculture economic research service. metro counties and urban counties (as defined in the 2014 ncdb participant use data file (puf) data dictionary) were combined together as “urban”, and compared with rural counties. sas version 9.4, a software package for statistical analysis, was used to compute descriptive statistics. chi-square tests were used to compare the differences in demographic characteristics, disease status (cervical cancer stage at diagnosis), treatment, and cervical cancer outcomes among programs. multivariable analysis was performed using stepwise modeling for variables associated with the outcomes of cervical cancer including vital status and 5 year survival. odds ratio with 95% confidence intervals were calculated. results table 1 presents the association between demographic information and facility types. about forty-four percent of women used arps, followed by cccps (37.4%), incps (11.4%), and ccps (6.8%). arps had more black women and younger women aged 40-59 years at diagnosis compared to ccps and cccps, had less income and education (more women from the area who did not graduate from high school) compared to cccps and incps, more income compared to ccps, more living far from hospitals, more uninsured, more lived in midwest and northeast compared to all other programs. ccps had more women aged 75 and older when diagnosed compared to arps and incps, income with $38,000-47,999, education with 13-20.9% who did not graduate from high school, more living in rural areas and less than 10 miles away from the facility compared to all other programs. cccps had more white women compared to arps and incps, more women aged 65-74 years when diagnosed compared to arps, more education with less than 7% and with 7-12.9% who did not graduate from high school compared to arps and ccps, more living in 21-50 miles away from the facility compared to all other programs, more private and other government insurance program www.companyofscientists.com/index.php/chd e5 cancer health disparities research compared to arps and ccps, and more living in west region compared to all other programs. incps had more income with $48,000-$62,999 compared to arps and ccps, and more living in urban, 11-20 miles from the facility and in south region compared to all other programs. table 1. the demographic information by facility types (ncdb, 2004-2015). type of facility demo facility type total n (%) arps ccps cccps incps facility 35719(44.43) 5447(6.78) 30050(37.38) 9169(11.41) 80385 race* white 28096(78.66) 4670(85.74) 25911(86.23) 7328(79.92) 66005 black 7623(21.34) 777(14.26) 4139(13.77) 1841(20.08) 14380 age*† 40-44 6489(18.17) 914(16.78) 5088(16.93) 1636(17.84) 14127 45-49 6466(18.10) 883(16.21) 4937(16.43) 1567(17.09) 13853 50-54 5690(15.93) 818(15.02) 4416(14.70) 1406(15.33) 12330 55-59 4970(13.91) 699(12.83) 4016(13.36) 1262(13.76) 10947 60-64 3956(11.08) 609(11.18) 3257(10.84) 1026(11.19) 8848 65-69 2912(8.15) 472(8.67) 2779(9.25) 782(8.53) 6945 70-74 2026(5.67) 354(6.50) 1987(6.61) 551(6.01) 4918 75+ 3210(8.99) 698(12.81) 3570(11.88) 939(10.24) 8417 income* <$38,000 9807(27.46) 1452(26.66) 6756(22.48) 2172(23.69) 20187 $38,000-47,999 8356(23.39) 1669(30.64) 7961(26.49) 2245(24.48) 20231 $48,000-62,999 8450(23.66) 1322(24.27) 7841(26.09) 2444(26.66) 20057 >=$63,000 8733(24.45) 942(17.29) 7095(23.61) 2183(23.81) 18953 unknown 373(1.04) 62(1.14) 397(1.32) 125(1.36) 957 education*†† <7% 5646(15.81) 606(11.13) 5236(17.42) 1561(17.02) 13049 7-12.9% 9094(25.46) 1530(28.09) 9099(30.28) 2752(30.01) 22475 13-20.9% 9928(27.79) 1709(31.38) 8763(29.16) 2761(30.11) 23161 >=21% 10694(29.94) 1542(28.31) 6574(21.88) 1971(21.50) 20781 missing 357(1.00) 60(1.10) 378(1.26) 124(1.35) 919 residence* urban 34135(95.57) 5125(94.09) 28463(94.72) 8819(96.18) 76542 rural 489(1.37) 195(3.58) 656(2.18) 61(0.67) 1401 missing 1095(3.07) 127(2.33) 931(3.10) 289(3.15) 2442 distance* <=10 15743(45.65) 3301(62.80) 14379(49.80) 4757(53.80) 38180 11-20 5578(16.18) 981(18.66) 5250(18.18) 1702(19.25) 13511 21-50 6742(19.55) 742(14.12) 5758(19.94) 1585(17.93) 14827 >50 6421(18.62) 232(4.41) 3486(12.07) 798(9.03) 10937 insurance* uninsured 3829(10.78) 424(7.83) 2113(7.06) 800(8.77) 7166 medicaid 7373(20.76) 1273(23.50) 4320(14.44) 1601(17.55) 14567 younger medicare 1579(4.45) 312(5.76) 1343(4.49) 368(4.03) 3602 older medicare 6039(17.00) 1265(23.35) 6815(22.79) 1863(20.42) 15982 private 14866(41.85) 1979(36.53) 14443(48.29) 4262(46.71) 35550 other 301(0.85) 41(0.76) 371(1.24) 109(1.19) 822 www.companyofscientists.com/index.php/chd e6 cancer health disparities research government missing 1536(4.32) 123(2.27) 504(1.69) 121(1.33) 2284 region* midwest 9076(25.41) 1777(32.62) 6209(20.66) 1867(20.36) 18929 northeast 9083(25.43) 900(16.52) 4534(15.09) 873(9.52) 15390 south 12833(35.93) 1928(35.40) 13429(44.69) 5421(59.12) 33611 west 4727(13.23) 842(15.46) 5878(19.56) 1008(10.99) 12455 * p<.0001 † all women whose age were less than 40 years were missing in this facility analysis (26,927, 25.1%). †† education was measured using the number of adults in the patient's zip code who did not graduate from high school and is categorized as equally proportioned quartiles among all us zip codes. tnm clin stage group presented that arps had more women in stage 2, ccps in stage 4, and incps in stage 1b2 compared to all other programs. arps had more women with no comorbidity while incps had more women with 1 comorbidity compared to all other programs (table 2). table 2. disease status by facility types (ncdb, 2004-2015). type of facility disease status facility type total n (%) arps ccps cccps incps tnm clin stage group* 1a-1b1 9357(32.92) 1293(30.71) 7702(33.67) 2324(33.71) 20676 1b2 1516(5.33) 176(4.18) 1186(5.18) 405(5.87) 3283 2 5806(20.42) 784(18.62) 4270(18.67) 1313(19.04) 12173 3 6885(24.22) 989(23.49) 5456(23.85) 1692(24.54) 15022 4 4862(17.10) 968(22.99) 4262(18.63) 1161(16.84) 11253 comorbidity* 0 29874(84.61) 4507(83.66) 24861(83.59) 7434(82.19) 66676 1 4521(12.81) 722(13.40) 4031(13.55) 1361(15.05) 10635 2 911(2.58) 158(2.93) 849(2.85) 250(2.76) 2168 * p<.0001 the association between treatment types and race by the types of facility was analyzed. black women had more surgery, radiation, and chemotherapy in arps compared to all other programs, while white women had more surgery and chemo in cccps compared to arps and incps and more radiation in ccps compared to arps and incps. women who did not have surgery were about five times as likely to die of cervical cancer (odds ratio 4.90, 95%ci: 4.74-5.06), while women who did not have radiation or chemotherapy were less likely to die of cervical cancer (odds ratio 0.84, 95%ci: 0.81-0.87; odd ratio 0.86, 95%ci:0.82-0.89) (data not shown). incps had more women with surgery compared to all other programs. table 3. treatment status by race and facility types (ncdb, 2004-2015). www.companyofscientists.com/index.php/chd e7 cancer health disparities research type of facility treatment facility type total n (%) arps ccps cccps incps surgery* yes 16432(46.10) 2293(42.40) 14818(49.51) 4682(51.22) white 13597(82.75) 2013(87.79) 13126(88.58) 3910(83.51) 32646 black 2835(17.25) 280(12.21) 1692(11.42) 772(16.49) 5579 no 19210(53.90) 3115(57.60) 15113(50.49) 4459(48.78) 41897 chemo* yes 22110(62.43) 3328(62.03) 18034(60.73) 5641(62.13) 49113 white 17165(77.63) 2836(85.22) 15487(85.88) 4479(79.40) 39967 black 4945(22.37) 492(14.78) 2547(14.12) 1162(20.60) 9146 no 13308(37.57) 2037(37.97) 11663(39.27) 3439(37.87) 30447 radiation* yes 22470(63.31) 3425(63.50) 18547(62.26) 5612(61.51) 50054 white 17409(77.48) 2940(85.84) 15832(85.36) 4453(79.35) 40634 black 5061(22.52) 485(14.16) 2715(14.64) 1159(20.65) 9420 no 13024(36.69) 1969(36.50) 11242(37.74) 3511(38.49) 29746 * p<.0001 five outcomes were analyzed to identify their association with facility types. arps had more women alive at 30 and 90 days after surgery compared to ccps, while incps had more cases died less than 30 days after surgery compared to arps and cccps. ccps had more cases that died fewer than 90 days after surgery, more cases with no surgery or alive cases that had fewer than 30 and 90 days of follow up and more deceased cases compared to all other programs. cccps had more cases with no surgery or alive cases that had fewer than 30 days of follow up compared to all other programs. regarding the outcome of readmission within 30 days of surgical discharge, overall 94.6% was either no surgical procedure of the primary site was performed, or patient was not readmitted. incps had more cases with unplanned readmission within 30 days of discharge compared to all other programs. arps presented more five-year survival compared to ccps and less comorbidity compared to incps, while ccps had less five year survival compared to all other programs. regarding the outcome of vital status (mortality), arps had more cases who were alive compared to ccps and cccps, while ccps had more cases who were deceased compared to all other programs (table 4). table 4. survival outcomes by facility types (ncdb, 2004-2015). type of facility outcomes facility type total n (%) arps ccps cccps incps 30 day mortality* alive at 30 days after surgery died < 30 days after surgery no surgery, or alive cases have < 30 days of follow up 14681(98.38) 1988(96.18) 13102(97.81) 4127(98.10) 33898 56(0.38) 11(0.53) 56(0.42) 25(0.59) 148 186(1.25) 68(3.29) 237(1.77) 55(1.31) 546 90 day mortality* alive at 90 days after surgery died < 90 days after surgery no surgery, or alive cases have < 90 days of follow up 14461(96.90) 1949(94.29) 12902(96.32) 4052(96.32) 33364 168(1.13) 34(1.64) 173(1.29) 62(1.47) 437 294(1.97) 84(4.06) 320(2.39) 93(2.21) 791 www.companyofscientists.com/index.php/chd e8 cancer health disparities research readmission within 30 days of surgical discharge* no surgical procedure unplanned readmission planned readmission planned and unplanned readmission unknown 33713(94.38) 5111(93.83) 28519(94.91) 8675(94.61) 76018 690(1.93) 87(1.60) 454(1.51) 190(2.07) 1421 417(1.17) 66(1.21) 278(0.93) 102 (1.11) 863 33(0.09) 2(0.04) 23 (0.08) 5(0.05) 63 866(2.42) 181(3.32) 776(2.58) 197(2.15) 2020 5 year survival* yes no 10895(33.27) 1471(29.53) 8918(32.49) 2684(32.28) 23968 21855(66.73) 3511(70.47) 18531(67.51) 5630(67.72) 49527 vital status (mortality) * dead alive 12456(38.03) 2225(44.63) 11480(41.82) 3219(38.72) 29380 20299(61.97) 2760(55.37) 15971(58.18) 5095(61.28) 44125 * p<.0001 table 5 presents the result of multivariate logistic regression on vital status (mortality) and 5-year survival in cervical cancer. there were slight differences in predicting vital status and 5-year survival. black women, insurances other than private insurance, less income, more education, more comorbidity, more advanced stages, older women, treatment in ccps and cccps, and not having surgery and chemo were more likely to die of cervical cancer compared to the reference groups. black women, insurances other than private insurance, more education, more comorbidity, more advanced stages, living far from facilities, older women, treatment in cccps and incps, and not having surgery and radiation were less likely to survive for five years compared to the reference groups. although distance in predicting vital status and income in predicting 5-year mortality were not significant from stepwise, we added them to the model to adjust confounding effects. table 5. predictors of the outcomes of cervical cancer (ncdb, 2004-2015). vital status (mortality) 5 year survival adjusted odds ratio 95% confidence interval adjusted odds ratio 95% confidence interval race white black 1.00 1.10 1.04-1.16 1.00 0.94 0.89-0.99 region south midwest 1.00 1.03 0.98-1.09 1.00 1.03 0.97-1.08 northeast 0.94 0.88-1.00 1.01 0.95-1.07 west 0.94 0.89-1.01 1.10 1.04-1.17 insurance private uninsured 1.00 1.03 0.96-1.11 1.00 0.80 0.74-0.86 medicaid 1.24 1.17-1.31 0.75 0.71-0.79 younger medicare 1.49 1.35-1.64 0.70 0.63-0.78 older medicare 1.54 1.40-1.70 0.84 0.75-0.93 other government 0.85 0.69-1.05 0.85 0.70-1.03 missing 1.05 0.94-1.19 0.92 0.82-1.03 www.companyofscientists.com/index.php/chd e9 cancer health disparities research income <$38,000 $38,000-47,999 1.00 0.90 0.84-0.95 1.00 1.03 0.97-1.09 $48,000-62,999 0.86 0.80-0.92 1.03 0.96-1.10 >=$63,000 0.78 0.72-0.84 1.05 0.96-1.13 unknown 1.02 0.40-2.58 1.03 0.41-2.62 education† >=21% <7% 1.00 1.12 1.03-1.23 1.00 0.94 0.86-1.02 7-12.9% 1.16 1.08-1.24 0.93 0.87-0.99 13-20.9% 1.13 1.07-1.20 0.98 0.92-1.03 missing 2.60 1.01-6.68 0.30 0.11-0.78 comorbidity 0 1 1.00 1.37 1.29-1.45 1.00 0.79 0.74-0.84 2 1.98 1.75-2.24 0.60 0.52-0.69 stage 1a-1b1 1b2 1.00 1.34 1.21-1.49 1.00 0.64 0.59-0.71 2 1.84 1.72-1.97 0.76 0.71-0.81 3 3.62 3.38-3.87 0.42 0.39-0.45 4 11.52 10.68-12.43 0.12 0.10-0.13 distance(miles) <=10 11-20 1.00 0.99 0.94-1.05 1.00 0.94 0.89-0.99 21-50 1.00 0.95-1.06 0.91 0.86-0.96 >50 1.05 0.98-1.11 0.82 0.77-0.87 age 40-44 45-49 1.00 1.20 1.12-1.29 1.00 0.99 0.93-1.06 50-54 1.27 1.18-1.36 0.95 0.89-1.02 55-59 1.38 1.28-1.49 0.88 0.82-0.95 60-64 1.52 1.41-1.65 0.85 0.79-0.92 65-69 1.51 1.36-1.69 0.84 0.75-0.94 70-74 1.91 1.69-2.15 0.71 0.63-0.81 75+ 3.53 3.15-3.96 0.46 0.40-0.51 facility academic/research program community cancer program 1.00 1.16 1.07-1.27 1.00 0.93 0.86-1.02 comprehensive community cancer program 1.19 1.14-1.25 0.94 0.90-0.99 integrated network cancer program 1.04 0.97-1.11 0.87 0.81-0.93 surgery yes no 1.00 1.90 1.80-2.01 1.00 0.77 0.73-0.82 radiation yes 1.00 1.00 www.companyofscientists.com/index.php/chd e10 cancer health disparities research no 0.90 0.85-0.96 0.70 0.66-0.75 chemo yes no 1.00 1.16 1.09-1.22 1.00 1.09 1.03-1.15 † education was measured using the number of adults in the patient's zip code who did not graduate from high school and is categorized as equally proportioned quartiles among all us zip codes. discussion to prevent and treat cervical cancer effectively, it is critical to understand risk factors and how they impact the disease. while assessing the differences in risk factors and outcomes of cervical cancer between races in our previous study, we found there were differences in using health care facilities between black and white women. therefore, we further analyzed the ncdb data to identify differences in demographics, disease status, treatment status and health outcomes by facility type. arps had more black women, women younger at diagnosis with less education, more living far from treatment facilities, more in stage 2, less comorbidity and more 5-year survival, and more cases alive at 30 and 90 days after surgery compared to other programs. ccps had more women aged 75 and older at diagnosis, living in rural areas and fewer than 10 miles from hospitals, more stage 4 and comorbidity, less 5 year survival, and more radiation compared to other programs. cccps had more white women, more education and more private insurance, and more surgery. incps had more women living in urban and south region, more stage 1b2 and more surgery, more 1 comorbidity, and more women who died less than 30 days after surgery. previous studies reported having treatment at high-volume hospitals was associated with lower mortality rates and better survival (haider et al., 2013; lin et al., 2014). however, when assessing the impact of the type and volume of facility on health care outcome, it is critical to consider patients’ disease status. arps that would be classified as high volume centers presented better outcomes in being alive at 30 and 90 days after surgery, 5-year survival and, vital status, compared to ccps that would be classified as low volume centers. however, it was noted that ccps had more women diagnosed at stage 4 while arps had more women diagnosed at stage 2, so the result should be interpreted carefully. it is also interesting that younger age groups had more treatment in arps while older age groups had more treatment in ccps and cccps. that may explain the possible association with a better survival outcome in cervical cancer in arps, which is consistent with prior works (fedewa et al., 2012; furlow, 2018; yosta and hoekstra, 2018). from multivariate analysis results, under-insured women were more likely to die of cervical cancer and, uninsured and under-insured women were less likely to survive for five years compared to privately insured women. it is interesting that the uninsured women were not more likely to die of cervical cancer compared to private patients. although women without health insurance are less likely to receive cervical cancer treatment and survive (acharya and grigsby, 2016; fedewa et al., 2012), our analysis shows over 53% of uninsured patients were treated in arps and had better health outcomes in 30 day and 90 day mortality www.companyofscientists.com/index.php/chd e11 cancer health disparities research and vital status, which proves promising in developing cervical cancer centers that may improve healthcare access and provide a high quality of care to those with underor no insurance. however, when the population was stratified by race within arps, black women had more deaths less than 30 days and 90 days after surgery (respectively p<.05) and had more deaths (vital status: p<.0001) compared to white women. further analyses showed black women in arps were older, less income, more living in urban area and close to treatment facilities, more uninsured and underinsured, more advanced stages (stage 3 & 4), more comorbidities, less surgery, and more chemo and radiation therapy compared to white women (data not shown). considering the proportion of black women (21%) and still overall better outcomes for women with cervical cancer in arps, it addresses clear cervical cancer outcome disparities between black and white women (arvizo and mahdi, 2017; dalton & farley, 2017; fleming and et al., 2014). therefore, it is needed to assess the effectiveness of cervical cancer treatment/programs according to the facility type, especially, to explore how to manage patients without insurance and with less income and how to reduce outcome disparities by targeting barriers identified. as another interesting result, we found there was an interaction between education and income (data not shown) that women from higher education areas had less survival, which is contradicting to previous study results (franceschi et al., 2009; singh and jemal, 2017). this might be associated with the fact that education was measured using the number of adults in the patient's zip code who did not graduate from high school, not based on an individual’s educational attainment. therefore, further study is necessary to investigate how the level of education and income are related to cervical cancer risk and mortality. our study has some limitations especially in assessing the outcomes of cervical cancer in each facility. we compared the association between cervical cancer outcomes and facility type based on responses from a large national sample of cancer patients, so our results should not be interpreted as actual evaluation of cervical cancer treatment in each facility classified by ncdb. also, considering a disproportionate number of women treated at each facility, for example, 44.4% patients at arps compared with about 6.8% at ccps, the generalizability of this study may be limited. more importantly, a significant number of patients had missing data on facility at each stage of their diagnosis (e.g., 34.99% did not have facility information in stage 1a-1b1). as another limitation, our analysis was limited by the variables collected in the ncdb. for example, there was no data to assess factors contributing to choosing a facility and treatment, so the reason for racial differences in using different facilities could not be explored. considering a complex situation that patients with cervical cancer may confront, it is imperative to understand what factors contribute to choosing their treatment option including health care facility. for example, possible reasons resulting from limited access to high-volume/quality hospitals, such as geographic location and underor no insurance among minorities leading to outcome disparities, should be considered and reflected when developing cervical cancer centers and www.companyofscientists.com/index.php/chd e12 cancer health disparities research programs (beavis et al., 2017; haider et al., 2013; singh and jemal, 2017). our study results include some contradicting outcomes, which may encourage further research on understanding treatment choices and outcomes better. this will help identify critical factors that make cancer care programs successful and effective. acknowledgements this article was partially supported by the national cancer institute (p30ca013148, p50ca098252, 2u54ca118948). the contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the funding agency, nih. conflict of interest the authors declare that there are no conflicts of interest or financial disclosures. authors’ contributions conceptualization: hp sb cw formal analysis: hp zw sb methodology: hp sb supervision: sb wh writing ± original draft: hp sb writing ± review & editing: hp zw cw wh sb references acharya, s and grigsby, p.w., access to health care and disparities in cervical cancer diagnosis, treatment, and survival. international journal of radiation oncology, 2016. 96(2): p. e290. 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gynecol oncol, 2018 12(18): p. 31407-0. steenland, k., goodman, m., liff, j., diiorio, c., butler, s., roberts, p., smith, j.l., ekwueme, d. and hall, i.j., the effect of race and rural residence on prostate cancer treatment choice among men in georgia. urology, 2011 77(3): p. 581-7. weragoda, j., azuero, a., badiga, s., bell, w.c., matthews, r., and piyathilake, c., an examination of racial differences in 5-year survival of cervical cancer among african american and white american women in the southeastern us from 1985 to 2010. cancer med, 2016 5(8): p. 2126-35. yoo, w., et al., recent trends in racial and regional disparities in cervical cancer incidence and mortality in united states. plos one, 2017. 12(2): p. e0172548. yosta and hoekstra, a., cervical cancer in women over 65: an analysis of screening. gynecol oncol rep, 2018. 25: p. 48–51. www.companyofscientists.com/index.php/chd e1 cancer health disparities commentary speech: synergistic partnership for enhancing equity in cancer health olorunseun o. ogunwobi1,2 and grace x. ma3,4 1department of biological sciences, hunter college of the city university of new york, new york, ny. 2hunter college center for cancer health disparities research (cchdr), new york, ny 3center for asian health, and 4department of clinical sciences, lewis katz school of medicine, temple university, philadelphia, pa. *correspondence to email: oo158@hunter.cuny.edu or grace.ma@temple.edu abstract minority populations disproportionately bear the burden of cancers in the united states of america. the synergistic partnership for enhancing equity in cancer health (speech) was established to focus on research, workforce development and community-based activities relevant to cancer health disparities in the philadelphia-new jersey-new york city (pnn) corridor. speech's overarching goal is to impact cancer health disparities through research and training, and by improving community health, cancer awareness, and access to good quality healthcare. keywords: cancer; health disparities; minorities; translational research; collaboration; multidisciplinary research; team science citation: ogunwobi et al (2019) speech: synergistic partnership for enhancing equity in cancer health. cancer health disparities. 4: e1.e5. doi:10.9777/chd.2019.1012 mailto:oo158@hunter.cuny.edu mailto:grace.ma@temple.edu www.companyofscientists.com/index.php/chd e2 cancer health disparities commentary according to the unites states (us) census bureau, in 2018 approximately 39% of the entire us population identified themselves as members of a minority group (us census bureau, 2018). these groups include african americans (13.4%), hispanics (18.1%), asian americans (5.8%), american indian (1.3%) and pacific islanders (0.2%) (us census bureau, 2018). presently, the us is much more ethnically diverse than it has been before (caplan et al., 2016; us census bureau, 2011). racial and ethnic diversity is increasing rapidly along with population increase (kolb et al., 2006). asian americans are the fastest growing group in the united states (narayan et al., 2010; colby and ortman, 2017). according to the united states census bureau, the asian american population is projected to increase by 143% to 49 million, accounting for 11.7% of the us population by 2060 (colby and ortman, 2017). the hispanic population is the largest ethnic minority group in the us; it is projected to increase by 114.8% to 119 million, accounting for 28.6% of the us population (colby and ortman, 2017). in addition, african americans, or non-hispanic blacks, are the second largest minority group in the us, and would increase to 74 million, making up 14.3% of the total us population by 2060 (colby and ortman, 2017). the center for disease control and prevention (cdc) predicts that by 2050, the minority population would increase to nearly 50% of the entire u.s population (agency for healthcare research and quality, 2011; centers for disease control and prevention, 2004). in concert with the increasing diversity of the us population is the concomitant rise of health challenges that are most prevalent amongst minority groups. one major concern that remains an unfortunate reality is the disproportionate burden of disabilities, diseases and premature deaths experienced by racial and ethnic groups (agency for healthcare research and quality, 2011), whereby approximately 80% of combined deaths are associated with diabetes, heart disease, stroke, cancer, liver cirrhosis and homicide/accidents (caplan et al., 2016). in the 2011 cdc health disparities and inequalities report, health disparities was defined as, “differences in health outcomes and their determinants between segments of the population, as defined by social, demographic, environmental, and geographic attributes” (centers for disease control and prevention, 2011). these “differences,” as they are called, were demonstrated to have a relationship to disease in the 1967 landmark whitehall study in britain (o’keefe et al., 2015). similarly in the us, it was reported that disease incidence, mortality and survival rates were strongly associated with socioeconomic status, as well as race/ethnicity (o’keefe et al., 2015). in addition to socioeconomic factors, leading health indicators that continue to contribute to health disparities in minorities include social environment, lifestyle behaviors and access to clinical preventative services (centers for disease control and prevention, 2004). whereas only 9% of whites in the us live below the poverty line, 21% of african americans live below the poverty line (american cancer society, 2019). this difference likely correlates with african americans being less likely to be diagnosed early enough to receive adequate clinical care, and are being more likely to die from a disease than whites (american cancer society, 2019). racial and ethnic disparities definitely exist for cancer. although reports suggest that cancerrelated deaths in the overall us population are declining, cancer remains a significant public health burden among ethnic minority populations. underserved african, asian-pacific, and hispanic www.companyofscientists.com/index.php/chd e3 cancer health disparities commentary americans have higher incidence of certain cancers, and higher rates of overall mortality due to distinct risk factors and cancer screening barriers. specifically, cancer is the leading cause of death among hispanics (20.7%) and asians/pacific islanders (27.1%). it is the second leading cause of death for african americans (25.1%) and american indians/alaskan natives (18.6%) (centers for disease control and prevention, 2010). cancer mortality and morbidity rates remain significantly higher among african american men and women, while overall survival rates are much shorter when compared to their white counterparts (caplan et al., 2016; o’ keefe et al., 2015; american cancer society, 2019). in fact, overall, african americans experience a higher cancer death rate than that of all other ethnic groups, excluding american indian/alaska-natives (caplan et al., 2016; o’ keefe et al., 2015). asian americans experience the highest incidence and mortality rates of both liver and stomach cancers, in correlation with incidence and prevalence of hepatitis b virus infection (national institute on minority health and health disparities, 2016). several initiatives and public awareness campaigns, such as the executive order on increasing participation of asian americans and pacific islanders in federal programs, and the healthy people 2020 initiative, were launched as an attempt to address this problem (kolb et al., 2006; centers for disease control and prevention, 2004; us department of health and human services, 2000). however, addressing health disparities, including cancer health disparities, will require more than just an improving access to resources for minority groups. to address the problem of cancer health disparities in the philadelphia-new jersey-new york city (pnn) corridor, we have established the synergistic partnership for enhancing equity in cancer health (speech). speech is a collaborative effort between hunter college of the city university of new york and temple university/fox chase cancer center. speech’s overarching goal is to better understand and reduce cancer health disparities in underserved and minority populations in the pnn area. one objective of speech is to serve underrepresented groups by launching initiatives to expand knowledge, and implement evidence-based practices in african american, asian american and hispanic american communities in the pnn region. the partnership, which is spear-headed by dr. grace ma of temple university, and dr. olorunseun ogunwobi of hunter college, aims to focus on three core areas: (1) innovative and rigorous multidisciplinary cancer research including basic, translational and clinical cancer research; (2) building a diverse cancer research workforce through training and mentorship of undergraduate students, graduate students, postdoctoral fellows, and junior faculty; and (3) community outreach through communitybased initiatives that promote cancer screening, early detection, prevention, and access to highquality cancer care. the activities of speech are organized through five integrated cores: administrative core, planning and evaluation core, community outreach core, bioinformatics and biostatistics core, and research education core. speech is initially focused on tackling liver cancer, lung cancer, and colorectal cancer. however, we have already started developing new projects focused on cancers in other organ sites. speech will impact cancer health disparities by improving community health and cancer awareness, while implementing strategies to improve better healthcare access. additionally, speech will build a more diverse research and medical community, such that the cultural and scientific strengths of a www.companyofscientists.com/index.php/chd e4 cancer health disparities commentary more diverse cancer research workforce significantly contribute to solutions addressing cancer health disparities. acknowledgements fayola levine assisted in compiling information used in writing this article. olorunseun ogunwobi and grace ma are supported by the tufccc/hc regional comprehensive cancer health disparity partnership, award number u54 ca221704(5) (contact pis: grace x. ma, phd; olorunseun o. ogunwobi, md, phd) from the national cancer institute. the content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the national cancer institute or the national institutes of health. conflict of interest the authors declare that no competing or conflict of interests exists. the funders had no role in study design, writing of the manuscript, or decision to publish. authors’ contributions ooo and gxm jointly conceived of this article. ooo wrote the first draft of the article. both authors revised, and approved final version of the article. references 1. u.s. census bureau. 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(2016). the center for asian health engages communities in research to reduce asian american health disparities. nimhd. https://www.nimhd.nih.gov/ news-events/features/training-workforce-dev/centerasian-health.html. accessed march 20, 2019. 14. us department of health and human services, office of disease prevention and health promotion, us department of health and human services, office of www.companyofscientists.com/index.php/chd e5 cancer health disparities commentary disease prevention and health promotion. (2000). healthy people 2020. https://www.healthypeople.gov/. accessed march 20, 2019. www.companyofscientists.com/index.php/chd e1 cancer health disparities research microrna 204 mediated negative regulation of the igf2r promotes breast cancer progression and is a potential mechanism driving breast cancer disparity lourdes m nogueira1,4, clare e burton1, laurel black1, jasmine d fox6, kristi l helke1, elizabeth garrettmayer3-5, dennis k watson1,4,5, david p turner1,4,5 and victoria j findlay1,4,5* department of 1pathology & laboratory medicine, 2biochemistry & molecular biology, 3public health sciences; 4college of medicine, 5hollings cancer center, medical university of south carolina, charleston, sc, usa. 6south carolina state university, orangeburg, sc, usa. *corresponding author’s email: findlay@musc.edu abstract in the us, african american women have a significantly higher rate of mortality due to breast cancer compared to caucasian american women. molecular differences in tumor biology exist between racial groups; however, their contribution to cancer disparity is not well understood. our studies have identified a race-specific, mechanistic link between microrna-204 and the igf2r. the igf2r is a tumor suppressor gene in several cancers including breast cancer and igf2r levels are found at significantly lower levels in african american women with breast cancer when compared to their caucasian counterparts. we observed elevated levels of mir-204 in serum of african american women with breast cancer when compared to caucasian american women and identified igf2r as a direct target of mir204. we show mechanistically that mir-204 mediated inhibition of igf2r leads to activation of the igf1r signaling pathway resulting in increased proliferation, migration and invasion, processes that are required for tumor progression. we developed a unique doxycycline-inducible mir-204 transgenic mouse model to define in vivo the oncogenic potential of mir-204 and the mechanism and functional consequences of igf2r loss. we observed a significant increase in tumor growth and increased metastasis in these animals when compared to non-transgenic controls. this is the first characterization of mir-204 in an in vivo model. these data support a mechanism whereby mir-204 promotes tumor aggression through the igf2-mediated hyperactivation of the igf1r signaling pathway in response to direct negative regulation of the tumor suppressor igf2r and that this could be a potential mechanism promoting breast cancer disparity. keywords: oncogenes, igf2, breast neoplasms, transgenic mice, igf1r citation: nogueira lm et al (2019) microrna 204 mediated negative regulation of the igf2r promotes breast cancer progression and is a potential mechanism driving breast cancer disparity. cancer health disparities 3:e1-e19. doi:10.9777/chd.2019.1016. www.companyofscientists.com/index.php/chd e2 cancer health disparities research introduction breast cancer (bc) is a worldwide health issue as it represents the leading cause of cancer and remains the second leading cause of cancerrelated mortality in women. in the us, african american (aa) women have a significantly higher rate of bc mortality compared to caucasian american (ca) women. recent studies have highlighted the need for understanding the molecular basis of cancer disparities as these contribute to the observed differences in mortality that we observe in hormonally driven cancers (albain et al., 2009). the insulin-like growth factor 2 receptor (igf2r) is a transmembrane receptor that binds insulin-like growth factor (igf-2), resulting in its degradation via internalization and transport to lysosomes (oka et al., 1985). removal of igf-2 from the extracellular environment precludes activation of the insulin-like growth factor 1 receptor (igf1r); thus the igf2r is believed to reduce the mitogenic effects of igf-2. igf2r is also involved in the activation of transforming growth factor beta (tgf-β) (dennis and rifkin, 1991) and may be a high affinity binding receptor for retinoic acid, an agent known to have diverse biological effects in both embryogenesis and oncogenesis (kang et al., 1997). thus, important homeostatic controls regulating cell proliferation and apoptosis would be lost with the inactivation of igf2r, suggesting that this receptor normally functions to inhibit tumor formation. indeed, loss of heterozygosity (loh) at the igf2r locus has been reported in breast carcinomas, and somatic missense mutations of the remaining allele have altered ligand binding (hu et al., 2006; iwamoto et al., 2006; tsujiuchi et al., 2004). the igf2r has been proposed to be a tumor suppressor gene given its antagonist role on cellular growth and evidence of loh and loss-of-function mutations in several cancers including breast cancer (chappell et al., 1997; chen et al., 2002; hankins et al., 1996; oates et al., 1998). more recently, studies have shown that reduced igf2r expression correlates with poor patient prognosis in bc patients (yu et al., 1996) and that decreased igf2r expression may contribute to bc disparity (kalla singh et al., 2010). this study shows that circulating igf2 levels, a potent mitogen that signals through the igf1r, are higher in breast tissue from aa women when compared to ca women. they further went on to show that igf2r levels were significantly lower in aa breast tumor samples, important as igf2r acts as a non-signaling sink for igf2 thereby preventing its pro-survival signaling function. importantly, igf2 can also signal through the a isoform of the insulin receptor (ir-a) in many tumor types including breast cancer resulting in tumor promoting effects (frasca et al., 1999; ulanet et al., 2010). micrornas (mirnas) are small non-coding rnas that are generally involved in the negative regulation of mrna through seed sequences present within the 3’utr of protein coding genes. they have been studied in mammalian species for almost two decades and have been shown to be involved in most all cellular processes. each mirna has multiple targets and each 3’utr can be targeted by multiple mirnas. understanding the regulation of these small molecules is complex; however, great strides have been made in a relatively short amount of time. it should be noted that controversy surrounds the role of mir-204 in breast cancer , with some authors reporting mir-204 as a tumor suppressor (imam et al., 2012; li et al., 2014) and others, www.companyofscientists.com/index.php/chd e3 cancer health disparities research including our group, reporting it as an oncogenic mirna or “oncomir” (findlay et al., 2008). micrornas, by their nature, have been shown to play many different roles in different cellular contexts including both tumor suppressive and oncogenic roles. classic examples of other mirnas that have been shown to have context dependent tumor suppressive and oncogenic effects in breast cancer include mir-205 and mir-27 (vimalraj et al., 2013). a recent review details the dual nature of mir-204 in cancer (li et al., 2016). this study describes a mechanistic link between mir-204 and a novel direct target igf2r. we developed a unique inducible mir-204 transgenic mouse model to examine for the first time, in an intact system, the oncogenic potential of mir-204 and we show data to support a role for mir-204 mediated activation of the igf1r signaling pathway and propose that this could be a potential biological mechanism driving aggressive tumor growth. materials and methods cell culture and reagents all cell lines were cultured and maintained at 37°c with 5% co2. mda-mb-231 and hek293 cells were grown in dmem media supplemented with 10% fetal bovine serum (fbs) and 100 u of penicillin/streptomycin (p/s). bt549 cells were grown in rpmi media supplemented with 10% fbs and 100 u of p/s. mcf10a and mcf12a cells were grown in dmem:f12 (50:50) media supplemented with 2mm l-glutamine, 5% horse serum, 10µg/ml insulin, 20ng/ml epidermal growth factor (egf), 500ng/ml hydrocortisone, and 10µg/ml cholera toxin. the mcf10a with (control) and without igf1r stably overexpressed were a kind gift of adrian lee (university of pittsburgh, pa). all other lines were obtained from atcc. ethical approval for our work with human breast cancer cell lines was not required for our in vitro studies. all tissue culture reagents were purchased from invitrogen (carlsbad, ca). shigf1r vectors were obtained from the hollings cancer center genomics/shrna shared technology resource. the igf2r construct was a kind gift of lukas mach (university of natural resources and life sciences, vienna (boku)). transgenic mice animal care and procedures were approved by the institutional animal care and use committee at the medical university of south carolina, approval # arc-2995. to generate the tet-regulatable mir-204 transgenic mice, the 0.5-kb region surrounding mir-204 was amplified by pcr from the human genome using the following primers: teto 204f 5’-gcgcatcgatttggacccaga actattag-3’ and teto 204r 5’-gcgca ctagtggacagggtgatggagagg-3’ and cloned into the pteto splice vector (a kind gift of dr. tracy vargo-gogola, indiana university school of medicine). the clones were screened for mir204 induction and minimal leaky expression by transfection into the mcf7 teto cell line (a kind gift of dr. tracy vargo-gogola, indiana university school of medicine). the resultant vector was confirmed by sequencing and was subsequently microinjected into the pronuclei of fertilized fvb/n oocytes by the medical university of south carolina transgenic mouse core, yielding 6 potential founder lines. mice were maintained on an inbred fvb/n background. bigenic mice were obtained by breeding teto-204 mice to mtb (mmtv-rtta) mice (a kind gift of dr. lewis chodosh, perelman school of medicine, university of pennsylvania), which contain the reverse tet www.companyofscientists.com/index.php/chd e4 cancer health disparities research transactivator under the control of the mmtv promoter (gunther et al., 2002). the teto204/mtb bigenic mice were bred to mmtv-neu transgenic mice (002376; jackson laboratories, bar harbor, maine) to obtain trigenic teto204/mtb/mmtv-neu and control mice. all mice were maintained on an fvb/n background. for genotyping, pcr amplification of the mtb and 204 transgenes was performed on genomic dna prepared from tail cuts using the following oligonucleotide pairs: for teto-204, 5’cacgaaattgcttctggtggc-3’ and 5’tcgaagatgttggggtgttgg-3’; reaction conditions were 98°c for 3 minutes followed by 40 cycles of 98°c for 30 seconds, 62°c for 30 sec., 72°c for 1 min., followed by a 10 min. extension at 72°c; for mtb 5’tccaagggcatcggtaaaca-3’ and 5’gcatcaagtcgctaaagaag-3’; reaction conditions were 98°c for 3 min. followed by 30 cycles of 98°c for 30 sec., 58°c for 30 sec, 72°c for 30 sec., followed by a 10 min. extension at 72°c. neu mice were genotyped following protocols supplied by jackson laboratories. to induce transgene expression, mice were fed doxycycline-containing chow (2g/kg ad libitum) for the duration of the study. immunohistochemistry ihc was performed as described (guo et al., 2013). the ki67 antibody was used at a 1:200 dilution. quantitative real time pcr total rna from cell lines was extracted using the rneasyplus mini kit (qiagen; valencia, ca). qpcr was performed on a roche light cycler 480 as previously described (guo et al., 2013). primer sequences and upl probe numbers are listed in table 1. for microrna analysis rna was extracted from cell lines using the rneasyplus mini kit from qiagen (valencia, ca). 10ng total rna was reverse transcribed using mir-204 specific primers using the applied biosystems reverse transcription kit as per the manufacturer's instructions. real time pcr was performed with 1µl of reverse transcribed cdna using the taqman assay from applied biosystems as per the manufacturer's instructions on the roche lightcycler 480 (nutley, nj). triplicate reactions were run for each sample. the relative expression of each gene was quantified on the basis of ct value measured against an internal standard curve for each specific set of primers using the software (2nd derivative max) provided by the instrument manufacturer (roche, nutley, nj). table 1. primers (forward (f) and reverse (r)) and probes used in the study. primer name primer sequence (5’ – 3’) amplicon length (nt) probe # igf2r (f) gagcgatacctctcaagtcaaag (r) gtgaggtctccatccgaatatc 75 4 igf1r (f) ttcagcgctgctgatgtg (r) aagttcccggctcatggt 75 7 puma (f) ctgcctcaccttcatcagg (r) gcagagcacaggattcacag 61 79 noxa (f) ggagatgcctgggaagaag (r) cctgagttgagtagcacactcg 94 67 gapdh (f) agccacatcgctcagacac (r) gcccaatacgaccaaatcc 66 60 www.companyofscientists.com/index.php/chd e5 cancer health disparities research transfection of cell lines the cloning of mir-204 into psuppressor-neo vector is already described (findlay et al., 2008). for the generation of clonal stable mcf12a cells overexpressing mir-204 (204-1; 204-2), psuppressor-neo vector (imgenex; san diego, ca) expressing mir-204 was transfected into mcf12a cells and stable cells were selected in medium containing g418. mcf10a cells were transiently transfected with the psuppressor-neo vector. for inhibition studies, cells were transiently transfected with antisenseoligoribonucleotides (aso) specific for mir-204 (aso-204) or scrambled controls (scr). cells were transfected with x-tremegenetm sirna transfection reagent (roche, nutley, nj). luciferase assays the igf2r 3′utr luciferase reporter vector (pmirtarget) was purchased from origene (rockville, md). the sequence complementary to the seed of mir-204 was deleted with the primers igf2rmutf 5’-gcttctataacagaaactttcaaga gtttttgtgatgggggagaggg-3’ and igf2rmutr 5’-ccctctcccccatcacaaaaac tcttgaaagtttctgttatagaagc-3’ using a quikchange site-directed mutagenesis kit (stratagene; la jolla, ca). mutated sequences were validated by sequencing at mwg operon (huntsville, al). mcf12a cells were plated at 50,000 cells per well in a 24-well plate. the pmirtarget reporter constructs (0.5μg, firefly luciferase) were co-transfected with prl–tk (0.05μg, renilla luciferase) using xtremegene hp reagent as per the manufacturer’s instructions (roche). luciferase activity was measured after 48h using the dual luciferase reporter assay system (promega, madison, wi). firefly luciferase activity was normalized to renilla luciferase activity for each transfected well. western blot analysis cell lysate preparation and western blot analysis using enhanced chemiluminescence were performed as described previously (findlay et al., 2008). experimental antibodies include igf2r (santa cruz biotechnology, dallas, tx), igf1r, irs-1, p-akt, akt, p-erk and erk, p-igf1r, p-irs1 (cell signaling technology, danvers, ma) and p-ir and ir (abcam, cambridge, ma). gapdh (santa cruz biotechnology) was used as a loading control. transwell migration and invasion assay assays were performed as previously described (guo et al., 2013). images were taken at a 40x objective for analysis. statistical analysis sample size for mouse experiments n ≥ 9. for statistical testing, two-sided paired (in vitro assays) and two-sample (in vivo assays) student's t-tests were performed using excel (in vitro assays) and graphpad prism (in vivo assays). p-values are reported for each individual experiment. error bars represent standard deviations (sd) of three independent experiments unless indicated otherwise. time to event outcomes were assessed using kaplan-meier curves and distributions compared between groups using the peto-peto test which is less sensitive to late differences than the traditional log rank test. for hypothesis testing, the alpha level was set at 0.05. results mir-204 modulates migration and invasion in nontransformed and invasive breast cancer cell lines. our group has shown previously that overexpression of mir-204 was able to increase migration and invasion in the non-invasive breast cancer cell line mcf7 (findlay et al., 2008). however, in order to explore this function further, www.companyofscientists.com/index.php/chd e6 cancer health disparities research we wanted to assess the role of mir-204 as an oncomir in both non-transformed breast cells as well as invasive breast cancer cells. a breast cell line screen demonstrated that non-transformed mcf10a and mcf12a cells had the lowest expression levels of mir-204 and the invasive breast cancer cell lines mda-mb-231 and bt549 had the highest expression levels of mir-204 (supplemental figure 1b). therefore, we examined migration and invasion in non-transformed mcf10a and mcf12a breast cell lines in which mir-204 had been overexpressed either transiently (mcf10a) or stably (mcf12a) (supplemental figure 1d & e). we observed that mir-204 expression was able to significantly increase both migration and invasion of non-transformed breast cells (mcf10a & mcf12a) when overexpressed (figure 1a & b). we also examined migration and invasion in the invasive breast cancer cell lines mda-mb231 & bt549, in which mir-204 was inhibited (supplemental figure 1f & g). we observed that migration and invasion was inhibited in two invasive breast cancer cell lines in which mir-204 had been suppressed (figure 1c & d). these data lend further support to the proposed oncogenic role of mir-204 in breast cancer. we also observed that mir-204 increases proliferation in the non-invasive mcf10a (figure 1e) and mcf12a (figure 1f) cells, similar to that observed in mcf7 cells (findlay et al., 2008). figure 1: mir-204 regulates migration and invasion. transwell migration (a & c), invasion (b & d) and proliferation (e & f) assays of various breast cell lines with either overexpression (a, b, e & f) or inhibition (c & d; aso-204) of mir-204 compared to scrambled (scr) control. mcf10a, mda-mb-231 and bt549 www.companyofscientists.com/index.php/chd e7 cancer health disparities research cells were transiently transfected. mcf12a cells were stably transfected. aso-204 – antisenseoligoribonucleotides (mir-204 inhibitors). mir-204 is racially disparate and elevated in breast cancer to further explore potential targets of mir-204 that may mediate its role as an oncomir in breast cancer, we performed a bioinformatical search of potential targets in publically available databases (targetscan and mirbase) and identified igf2r as a predicted target, which has been semi-validated for mir-204 in human trabecular meshwork (htm) cells (li et al., 2011). igf2r is proposed as a tumor suppressor and studies have shown that reduced igf2r expression correlates with poor patient prognosis in bc patients. therefore, we wanted to explore its role as a direct target of mir-204 in breast cancer. to examine whether igf2r expression is repressed by mir-204 through the predicted elements, a luciferase reporter construct containing the 3′ utr of igf2r was transfected into breast cancer cells. cells were co-transfected with either mir-204 or an empty vector (ev) control. the overexpression of mir-204 led to a ~30% decrease in luciferase activity when compared to ev control (figure 2a). to show that the predicted mir-204 seed sequence within the igf2r 3’utr was functional we mutated the seed sequence of mir-204 in the luciferase reporter construct. co-transfection of cells with the mutated luciferase reporter construct (mut 3’utr) and mir-204 did not result in a decrease in luciferase activity (figure 2a) suggesting that mir204 directly binds to the predicted site within the 3’utr of igf2r to negatively regulate its expression. with respect to cancer disparities, a study showed significantly higher levels of igf2r in ca compared to aa tumor samples, suggesting that decreased igf2r expression may contribute to bc disparity (kalla singh et al., 2010). therefore, we wanted to examine whether mir-204 levels differed by aa ancestry in bc patients by performing quantitative pcr (qpcr) for mir-204 on serum samples. we first found that mir-204 levels were elevated in high grade when compared to low grade in both aa and ca women (figure 2b). however, it was observed that mir-204 levels were significantly elevated in aa compared to ca women in the low grade cohort of bc patients, but not observed in the high grade cohort. we also performed data mining in oncomine for breast cancer using trpm3 as a surrogate marker for mir-204, as (1) mir-204 is encoded in the sixth intron of trpm3, (2) the expression of both genes is driven by the same promoter, and (3) the expression of both genes is positively correlated both in vitro (courboulin et al., 2011; ying et al., 2013) and in vivo (ding et al., 2015). we found that in this dataset that could be examined by race, trpm3 levels were higher in aa women when compared to ca women with breast cancer. of interest, this dataset showed strikingly decreased levels of trpm3 in women of asian descent (figure 2c). igf2r is a direct target of mir-204 in breast cancer cells and tissue to validate igf2r as a mir-204 target in breast cancer cell lines, mir-204 was overexpressed in mcf10a and mcf12a cells by either transient or stable transfection. in each case the increased expression of mir-204 inhibited endogenous igf2r expression (figure 2d). mrna levels of igf2r were assessed by qpcr and analysis indicated that the levels of igf2r mrna did not decrease, which is what we would expect if mir www.companyofscientists.com/index.php/chd e8 cancer health disparities research 204 was regulating igf2r by transcriptional degradation. in some cases, we observed an increase in igf2r mrna transcript levels, suggesting that mir-204 regulates igf2r through translational repression (figure 2e). mda-mb-231 and bt549 cells, two invasive breast cancer cell lines, were used as a model to inhibit mir-204 expression. transfection of antisense oligoribonucleotides (aso) targeted against mir204 (aso 204) in mda-mb-231 and bt549 cells resulted in an increase in igf2r protein (figure 2f) and mrna levels (figure 2g). figure 2: mir-204 directly targets igf2r and is racially disparate in breast cancer. (a) upper panel: schematic representation of the binding site and complementary seed sequence (upper case bold letters) of mir-204 within the 3’utr of igf2r. lower panel: luciferase activity of breast cells transiently cotransfected with igf2r 3’utr (wt 3’utr) or mutated igf2r 3’utr (mut 3’utr) and mir-204 (204) or ev and renilla as a control. (b) qpcr analysis of mir-204 expression in serum samples from (n=19) african american (aa) and (n=17) caucasian american (ca) women with either low grade (lg) or high grade (hg) breast cancer. (c) trpm3 mrna levels in breast cancer patients of asian, aa and ca race/ethnicity (bittner data set, oncomine; (rhodes et al., 2004)). western blot (d & f) and qpcr (e & g) analysis of igf2r in breast cells either transiently transfected with mir-204 expression vector (mcf10a), or antisense oligonucleotides to mir-204 (aso 204; mda-mb-231 & bt549) or stably transfected with mir-204 (204-1, 204-2) or scrambled (scr) control (mcf12a). *p < 0.05 to examine whether mir-204 regulates igf2r in vivo, we generated a tet-regulatable mir-204 transgenic (mir-204 tg) mouse (see methods). six founder lines were generated and assessed for www.companyofscientists.com/index.php/chd e9 cancer health disparities research germline transmission of the transgene and leaky expression of mir-204 in the absence of dox. we also assessed inducible expression of mir-204 by breeding the mir-204 tg founder mice to mouse mammary tumor virus (mmtv)-rtta (mtb) mice that express the reverse tet transactivator (rtta) in the mammary epithelium under the control of the mouse mmtv long terminal repeat (figure 3a) (gunther et al., 2002). bigenic mice were fed mouse chow containing the tet analog doxycycline (dox) ad libitum to induce transgene expression. the mice were sacrificed, and the mammary glands were extracted and either fresh frozen for rna extraction or fixed and embedded for immunohistochemical analysis. qpcr analysis on rna from the dox-fed mice (for 7 days) showed that we achieved a 15 30 fold increase in expression of mir-204 in the mir-204 tg mice when compared to the control non transgenic (non tg) mice (figure 3b). we also examined the mammary tissue for igf2r expression and observed a significant decrease in igf2r protein levels in the mir-204 tg mice when compared to non tg control mice (figure 3c), suggesting that mir-204 negatively regulates igf2r in vivo. interestingly, we observed no significant decrease in igf2r mrna levels when mir-204 was overexpressed in vivo (figure 3d), suggesting that mir-204 regulates igf2r by translational repression, similar to that observed in vitro. mir-204 transgene expression in the mammary epithelium of mmtv-neu mice increases tumor growth and metastasis to examine the effects of mir-204 overexpression on mammary tumor growth, mir-204 tg mice were bred to the mmtv-neu mice (see methods). this model was chosen since we have observed a significant increase in the expression levels of mir204 in tumors derived from these mice when compared to mammary tissue from normal ‘nontumor’ mice (supplemental figure 1c). mice were fed dox chow from 3 weeks of age to induce transgene expression in the trigenic mice and to control for any effects of dox on mammary tumorigenesis and progression in the bigenic control groups. mice were palpated weekly at 5 months of age to detect tumors, and the age of onset and location of the tumor were recorded. we found that mir-204 overexpression did not affect tumor latency (supplemental figure 2a). the median time to tumor onset for non tg mice was 37.5 weeks (95% ci: 35,47) and for mir-204 tg mice was 39.0 weeks (95% ci: 35,inf) as determined by kaplan-meier analysis (p=0.55). however, once tumors formed (tumor onset), time to sacrifice was shorter in the mir-204 tg mice (2.0 weeks (95%ci: 2, inf)) than in the non tg mice (5.5 weeks (95% ci: 4, inf)) (p=0.02) (figure 3e). there was no statistical difference in either multiplicity or tumor location between the groups (supplemental figure 2b). histological examination of the tumors revealed differences between the non tg and mir-204 tg mice (figure 3f). tumors from mir-204 tg mice displayed cells arranged in nests and packets with increased numbers of pseudo-rosettes surrounding blood vessels. these tumors also displayed more abundant vasculature, and peripherally, the cells appeared more spindloid in shape with looser arrangement of cells centrally. altogether, these changes in the mir-204 tg derived tumors are consistent with neuroendocrine differentiation. the tumors from the non tg derived mice are arranged in solid sheets. few mitoses are present, and most cells are monomorphic with no evidence of differentiation. a few apoptotic cells were observed scattered throughout the tumors. no major differences were www.companyofscientists.com/index.php/chd e10 cancer health disparities research observed in mir-204 expression between the non tg and 204 tg tumors as expected at the endpoint of analysis, as we have previously described that this model increases expression of mir-204 during tumorigenesis. as the tumors displayed a more aggressive phenotype once formed, we assessed proliferation by immunostaining with ki67 (figure 3f). although we observed a trend towards an increase in the mir-204 tg tumors, quantitative analysis showed that the observed increase did not reach statistical significance (p=0.17) when compared to the non tg controls (figure 3g). to determine whether mir-204 overexpression altered tumor metastasis, the number of micrometastatic lesions was analyzed in serial sections of lungs from tumor bearing mice. we observed an increase in the total number of lung micrometastases in the mir-204 tg (27.1 ± 2.0 sd) mice when compared to the non tg (51.9 ± 5.7 sd) control mice (p<0.001) (figure 3h). figure 3: mir-204 drives aggressive tumor growth in vivo. (a) a schematic of the two constructs used to generate bigenic tet-regulatable mir-204 transgenic mice (adapted from (vargo-gogola et al., 2006)). (b) qpcr analysis of mir-204 transgene expression in mammary glands from control and dox-induced (for 7 days; 6 week old) mice. (c) immunohistochemistry of igf2r in non-transgenic (non tg) and mir-204 bigenic (mir-204 tg) mice fed dox for 4 days. (d) qpcr analysis of igf2r levels in rna extracted from glands illustrated in panel c. (e) time to sacrifice from time of onset in non tg (black lines) and mir-204 tg (red lines) mice. (f) representative images of h&e and ki67 ihc. quantitation of (g) ki67 and (h) lung metastases in non tg (black circles) and mir-204 tg (black squares) mice. bars represent the mean ± sem. exogenous igf2r expression inhibits mir-204mediated cell migration and invasion mirnas have multiple targets, and therefore, the effects observed after mir-204 expression may be the result of the decreased igf2r protein, as well as non igf2r-related mir-204 effects. one way to evaluate these possibilities is to examine the phenotypes in cells in which a non-targeted igf2r is expressed. to test this possibility, the open reading frame (orf) of igf2r was transiently transfected into mcf10a cells stably infected with mir-204 (supplemental figure 3). as we have previously observed, the protein levels of igf2r were reduced in the mir-204 expressing cells. in contrast, a smaller www.companyofscientists.com/index.php/chd e11 cancer health disparities research reduction of igf2r was observed in the cells expressing the non-targetable (orf) form of igf2r (figure 4a). when we assessed migration and invasion in the igf2r overexpressing cells, we did not observe an increase in either migration (figure 4b) or invasion (figure 4c) when mir-204 was coexpressed suggesting that mir-204 does increase migration and invasion through the negative regulation of igf2r. igf2 stimulates the igf1r signaling pathway when igf2r is inhibited by mir-204 igf2 preferentially binds to the igf2r; however, it is also known to act as an autocrine and paracrine regulator of igf1r, leading to downstream activation of the pi3k and mapk/erk signaling pathways and cell proliferation/survival (flanigan et al., 2013; leroith and roberts, 2003). therefore, to determine whether igf2 stimulates the igf1r signaling pathway preferentially in the presence of mir-204 (or in the absence of igf2r), we treated mcf10a cells expressing mir-204 with igf2 and performed western blot analysis to assess the igf1r signaling pathway (supplemental figure 4ac). we observed a decrease in igf2r protein expression when control cells were treated with igf2; however, no further decrease in igf2r expression was observed in the mir-204 expressing cells treated with igf2 (figure 4d). importantly, we observed more robust activation of the igf1r signaling pathway upon igf2 treatment when mir-204 was overexpressed as illustrated by increased phosphorylation of irs-1, an intracellular signaling adaptor protein and the main substrate of the igf1r (dearth et al., 2007), and akt (figure 4e). we did not observe increased activation of the erk pathway in 204-expressing cells in response to stimulation with igf2. figure 4: mir-204 drives igf2 mediated activation of the igf1r signaling pathway. western blot (a) and transwell migration (b) and invasion (c) assays of mir-204 stably infected mcf10a cells transiently www.companyofscientists.com/index.php/chd e12 cancer health disparities research transfected with igf2r or empty vector (ev). western blot analysis (d & e) of the igf1r signaling pathway and qpcr analysis of puma and noxa (f) in mcf12a cells stably infected with mir-204 or scr control and treated with (+) or without (-) 50 nm igf2 for 5 minutes. puma (p53 upregulated modulator of apoptosis) and noxa (phorbol-12-myristate-13-acetateinduced protein 1) are proteins that play a key role in apoptotic signaling and have been shown to be negatively regulated by igf1r/irs-1/akt signaling pathway in response to certain stimuli to increase cell survival and proliferation (bean et al., 2013; you et al., 2006). we performed qpcr to assess puma and noxa levels in response to igf2 stimulation in mir-204 expressing cells. in contrast to cells with an intact igf2r ‘sink’ for igf2, we observe a significant decrease in puma and noxa transcripts when stimulated with igf2 in mir-204 expressing cells (figure 4f). mir-204 mediates migration through activation of the igf1r signaling pathway to determine whether mir-204 mediates its functional effects through activation of the igf1r we transiently transfected igf1r expressing, or control, mcf10a cells (kim et al., 2007) with mir204 (supplemental figure 4d & e). we observed activation of akt in the igf1r expressing cells alone, but no additional increase when mir-204 was co-expressed (figure 5a). as expected, both mir-204 and igf1r expression alone increased migration; however, no additional increase in migration was observed when they were coexpressed (figure 5b), suggesting that igf1r and mir-204 function through the same signaling pathway to increase migration. to assess whether igf1r is required for mir-204 mediated increase in migration, we inhibited igf1r expression in mcf12a cells with and without mir-204 expression with two short hairpins specific to igf1r (figure 5c). as expected, we observed a significant decrease in migration when igf1r was inhibited in the mcf12a control cells. however, when mir-204 was expressed in the presence of the igf1r inhibitor, no increase in migration was observed suggesting that igf1r is required for mir-204 mediated migration in breast cells (figure 5d). www.companyofscientists.com/index.php/chd e13 cancer health disparities research figure 5: mir-204 mediates migration through activation of the igf1r signaling pathway. western blot (a) and transwell migration (b) assays of igf1r stably infected mcf10a cells transiently transfected with mir204 or scr control. western blot (c) and transwell migration (d) assays of mcf12a cells stably infected with mir-204 or scr control and transiently transfected with short hairpin constructs to igf1r (sh #1 & sh #2). igf1r in panel c is shown for both a short (upper panel) and long (lower panel) exposure time. discussion mir-204, the mirna of interest in this proposal, is located on chromosome 9q21, a region that is reported to be amplified in cancer (bussemakers et al., 1999). there are multiple studies that have investigated the role of mir-204 in solid cancers, including melanoma, glioma, nsclc, bladder cancer, gastric cancer, head and neck cancer, and endometrial cancer. these studies have all reported reduced levels of mir-204 in these solid cancers (chung et al., 2012; lam et al., 2011; schultz et al., 2008; xia et al., 2014). however, with respect to hormonally driven cancers, e.g., prostate and breast, the story appears to be more complex. our group and others have shown that mir-204 levels are significantly elevated in breast cancer samples compared to normal controls (findlay et al., 2008; mattie et al., 2006). published studies also suggest its role as a tumor suppressor in breast cancer (li et al., 2014). more recently, two studies were published by independent groups that support the role of mir204 acting as an oncogene, or “oncomir”, in cancer (lee et al., 2016; todorova et al., 2016). the first was a study aimed at solving the controversy surrounding the seemingly opposing effects of mir-204 in breast cancer (lee et al., 2016). they performed genome wide pathway analysis and showed definitively that many of the mir-204 target genes are tumor suppressors. it is this characteristic that drives the breast cells towards being oncogenic. however, they agree and support the idea that context is important, and the potential dual activity requires further investigation. the second paper, recently published, investigated specifically the proposed dual role of mir-204 in cancer (todorova et al., 2016). this study showed that the genomic instability incurred rearrangement could turn tumor suppressor mirnas into pro-oncogenic ones, using metastatic prostate cancer as a model system. both studies clearly demonstrate a dual role for mir-204 depending on context. furthermore, a study in prostate cancer showed a dual role for mir-204 depending additionally on the subtype of prostate cancer in which it was expressed (ding et al., 2015). in brief, the authors show that in the context of androgen receptor positive (ar+) prostate adenocarcinoma, mir-204 functions as a tumor suppressor. however, in the context of androgen receptor negative (ar-) neuroendocrine prostate cancer, mir-204 functions as an oncogene. the dual regulatory role of mir-204 in cancer was recently reviewed and highlighted the fact that the cell type in which mir-204 is being expressed, as well as the makeup of that cell, are critical to the function of mir204 within that cell (li et al., 2016). more studies are required to determine whether the role of mir-204 in breast cancer is also dependent upon ar expression, an understudied receptor in the breast cancer field. of interest, a study was recently published showing a positive correlation between ar expression and pdef in breast cancer (cao et al., 2018). this is important in the www.companyofscientists.com/index.php/chd e14 cancer health disparities research discussion of mir-204 as (i) pdef was one of the first identified targets for mir-204 in breast cancer (findlay et al., 2008); and (ii) we observed a neuroendocrine pathology in mammary tumors derived from our 204 tg animals and neuroendocrine prostate tumors are known to be ar negative (tsai et al., 2017). our studies support the working hypothesis that mir-204 mediated inhibition of igf2r frees igf2 to bind the igf1r leading to hyperactivation of this pathway, resulting in increased proliferation, migration and invasion, processes required for tumor progression (figure 6). the generation and utility of an in vivo model for mir-204 is a more physiologically representative model than cells grown in culture. our development of a unique inducible transgenic mouse model has allowed us to investigate the oncogenic potential of mir-204 and furthermore, has provided compelling data to help resolve the controversy surrounding the role of mir-204 in a cellular context. histologically, the tumors that developed in the mir-204 transgenic mice were distinct from the control non-transgenic mice. we observed increased vasculature and a more spindle-like appearance, indicative of neuroendocrine differentiation. this has potential interest based on the observation mentioned above that mir-204 is specifically expressed and functions as on oncomir in neuroendocrine prostate cancer. future studies aimed at investigating the potential role of mir-204 in driving neuroendocrine differentiation in tumors may have implications for both prostate and breast cancers. figure 6: schematic model of our proposed mechanism for mir-204 mediated tumor progression. in normal (low mir-204) cells, igf2 preferentially binds to the igf2r where it gets internalized and degraded by the lysosomes. therefore, igf1r signaling is kept to a minimum. however, in cancer (high mir-204) cells, we propose that mir-204 mediated inhibition of igf2r frees igf2 to bind the igf1r leading to hyperactivation of this pathway resulting in increased proliferation, migration and invasion, processes required for tumor progression. www.companyofscientists.com/index.php/chd e15 cancer health disparities research reduced igf2r expression correlates with poor patient prognosis in bc patients (chappell et al., 1997; hankins et al., 1996), and a recent study showed significantly higher levels of igf2r in caucasian americans (ca) compared to african american (aa) tumor samples, suggesting that decreased igf2r expression may contribute to bc disparity (kalla singh et al., 2010). we observed elevated mir-204 levels in aa compared to ca women; specifically in the low-grade samples. interestingly, loss of igf2r is an early transformational event in breast cancer, occurring in the initiation rather than the progression stage of carcinogenesis. therefore, we postulate that overexpression of mir-204 may be an early initiating event in aa women, leading to the loss of igf2r and more aggressive disease (figure 6). acknowledgements we thank dr. tracy vargo-gogola (indiana university school of medicine) for the ptetosplice vector and the mcf7 tet on cell line, dr. lukas mach (university of natural resources and life sciences, vienna (boku)) for the igf2r construct, dr. adrian lee (university of pittsburgh) for the mcf10a/igf1r cell lines, dr. lewis chodosh (university of pennsylvania) for the mtb mice and drs. jeffrey rosen, suzanne fuqua, kent osbourne (baylor college of medicine) and dr. steve rosenzweig (musc) for their scientific expertise and guidance throughout the study. conflict of interest the authors declare that no competing or conflict of interests exist. the funders had no role in study design, writing of the manuscript, or decision to publish. authors’ contributions lmn and jdf performed the luciferase and western blot assays. lmn and lb performed the qpcr assays. lmn and dpt performed the functional and rescue experiments. lmn and ceb performed the in vivo experiments. klh performed the histological analysis of the tumors. egm analyzed and performed statistical analysis on the in vivo data. vjf conceived of the study and participated in its design and coordination, and with dpt and dkw drafted the manuscript. all authors read and approved the final manuscript. funding this work was supported in part by the transgenic mouse core facility, the genomics/shrna shared resource, hollings cancer center, medical university of south carolina (p30 ca138313) and by the department of defense inter-institutional training award w81xwh-10-bcrp-iita. references albain, k.s., unger, j.m., crowley, j.j., coltman, c.a., jr., and hershman, d.l. 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(1996). associations between insulin-like growth factors and their binding proteins and other prognostic indicators in breast cancer. br j cancer 74, 1242-1247. www.companyofscientists.com/index.php/chd e18 cancer health disparities research supplementary data: supplemental figure 1: western blot of igf2r (a) and qpcr analysis of mir-204 expression levels in various human breast cell lines (b) and normal and breast cancer mouse tissue (c). qpcr analysis of mir-204 expression levels in cell lines after either mir-204 overexpression in mcf10a(d) and mcf12a(e) cells or mir-204 inhibition in mda-mb-231 (f) and bt549(g) cells. *p < 0.05 supplemental figure 2: time to tumor onset (a) and tumor multiplicity (b) in non tg (black lines) and mir204 tg (red lines) mice. www.companyofscientists.com/index.php/chd e19 cancer health disparities research supplemental figure 3: qpcr analysis of (a) igf2r and (b) mir-204 expression levels in mcf10a cells transiently transfected with igf2r or empty vector (ev) control. supplemental figure 4: qpcr analysis of (a) mir-204, (b) igf2r and (c) igf1r expression levels in mcf12a cells stably transfected with mir-204 and either untreated or treated with 50nm igf2 for 5 minutes. qpcr analysis of (d) igf1r and (e) mir-204 expression levels in mcf10a cells stably expressing igf1r or control cells and then transiently transfected with mir-204 or scr control. www.companyofscientists.com/index.php/chd e1 cancer health disparities commentary what do we want? increased hispanic accrual on cancer clinical trials! when do we want it? now! brian o. warnecke1 , anand b. karnad1 , ian m. thompson, jr2 1mays cancer center, ut health md anderson, san antonio, tx 78229 and 2christus santa rosa hospital medical center, texas urology group, san antonio, tx 78229 *corresponding author: brian warnecke, warneckeb@uthscsa.edu abstract the hispanic population is one of the fastest growing racial/ethnic group in the united states. cancer is leading cause of death in this demographic group and have up to 50% higher cancer mortality rates compared to the non-hispanic white population in the united states. hispanics face numerous cancer health disparities, including poverty, obesity, and access to health care and insurance. in our previous study, we noted a poor hispanic accrual rate of 3.9% in all phase ii and iii cancer clinical trials published in the united states in 2012 and argued for better representation. to assess if a change was made seven years later, we reexamined the clinical trials published in the united states in 2019. we found 48 cancer clinical trials meeting our inclusion criteria. only 23 (48%) reported information regarding minority accrual. of these, 8 (17% of all) reported hispanic accrual. altogether, of the 2559 patients reported in the 8 clinical trials, 104 (4.1%) were of hispanic ethnicity, which nearly matches the 3.9% that we reported in 2014. in this manuscript, we highlight the disproportionately low rates of hispanic accrual in cancer clinical trials and propose processes that will increase representation. keywords: hispanic, clinical trials, health disparities, socioeconomic status citation: warnecke bo et al (2021). what do we want? increased hispanic accrual on cancer clinical trials! when do we want it? now! cancer health disparities. doi:10.9777/chd.2021.1001 www.companyofscientists.com/index.php/chd e2 cancer health disparities commentary hispanics constitute the fastest growing demographic group in the united states and represented 18.5% of the us population in 2019 (census bureau quickfacts, 2020). by 2050, the number of hispanics in the u.s. is expected to triple from 46.7 million to 132.8 million and will represent about 30% of the us population (haile et al., 2012). although hispanics have lower rates of the four most common cancers (breast, colorectal, lung, and prostate cancer) than their non-hispanic white counterparts, this ethnic group has higher rates of cervical, gallbladder, liver, and gastric cancers. in addition to higher prevalence of these cancers, they have up to 50% higher cancer mortality rates compared to the non-hispanic white population. cancer is the leading cause of death among hispanic/latinos (haile et al., 2012). hispanics face significant cancer health disparities due to several factors. poverty, access to care, and obesity play major roles in hispanic cancer predisposition and higher cancer-mortality rates. hispanics are the least likely to have health insurance of any racial or ethnic group; among those 18-64 years of age, 25% of hispanics were uninsured during 2016-2017 compared to 9% of non-hispanic whites (hales, 2018). in 2015-2016, 80% of hispanic adult females and 83% of hispanic adult males were overweight or obese, compared to 65% and 74% of their non-hispanic white counterparts. obesity likely plays a significant role in cancer risk in this population (hales, 2018). we have previously highlighted the poor hispanic accrual rate of 3.9% in cancer clinical trials published in 2012 and raised an alarm urging actions to increase hispanic accrual (parra et al., 2014). at that time, we examined hispanic accrual to phase ii or phase iii cancer clinical trials in the us published in 2012. we identified 159 clinical trials, only 33 of which presented data regarding patient ethnicity. only 13 of those 33 studies stated rates of hispanic accrual, a mere 8.18% of all phase ii or iii cancer clinical trials in the us. the problem was clear as was the solution: an increased focus on hispanic accrual, universal reporting on how representative the trials are of the u.s. population, and the need for improvement. seven years later, we have reexamined our national response. we examined all phase ii and phase iii cancer clinical trials published in 2019 by clinical investigators in the us. we identified studies published in one of the following journals: the new england journal of medicine, journal of clinical oncology, journal of the national cancer institute, lancet, and blood. we collected data related to reports of patient ethnicity, patient accrual, and hispanic enrollment. we found 48 cancer clinical trials that met these inclusion criteria. of these, only 23 (48%) reported information regarding minority accrual; of this group of 23 reports, 8 (17% of all) reported hispanic accrual. ultimately, of the 2559 patients reported in the 8 clinical trials, 104 (4.1%) were of hispanic ethnicity, almost exactly the same fraction (3.9%) that we reported in 2014. although these data demonstrate an increase in the number of clinical trials reporting minority and hispanic accrual, the proportion of hispanics participating in clinical trials remains minimal. this plateau in low rates of hispanic accrual to cancer clinical trials is disconcerting and demands action. while the need for broad population representation in clinical trials seems self-evident, we should stress the rationale: with significant differences in risk factors, access-to-care, cultural and other variables related to cancer outcomes in the racial and ethnic groups in the u.s., we must be sure that conclusions we reach regarding cancer management can be generalized for all americans. we do recognize that the challenges to cancer clinical trial accrual are www.companyofscientists.com/index.php/chd e3 cancer health disparities commentary complex and will require multi-level systemic changes. however, amidst these challenges is an opportunity: as cancer is highly related to age, the absolute number of cancer cases among hispanics in 2020 is disproportionately lower than their current population. however, while 8.4% of the 65+ u.s. population in 2018 was hispanic, this group will constitute 21% of the 65+ population in 2060. (frey, 2018). every effort to enhance the accrual of hispanic elderly with cancer will translate into better quality of evidence for treatment decisions in this group. we thus have a unique opportunity to, as bobby orr quipped, ‘skate to where the puck will be’ now and establish how to best provide cancer care for hispanics rather than react years from now without data. we propose three simple steps to catalyze this process. first, minority recruitment plans for cancer clinical trials must include specific plans for hispanic accrual. second, journals should require data related to hispanic accrual in demographic tables (classically, ‘table 1’). finally, an annual ‘national report card’ should provide hispanic accrual for all trials registered at clinicaltrials.gov. indeed, these are steps that can be applied to enhance clinical trial accrual in all underrepresented minority groups. we are confident that these simple steps will place a bright light on the issue and will ensure that, over time, we will enhance cancer care of this important group of our fellow citizens. acknowledgement this publication was supported by the nih/nci cancer center support grant (ca054174) at the university of texas health, san antonio, tx. conflicts of interest there are no conflicts of interest for any authors. authors' contributions bw, ak, and it conceptualized the study. bw collected the primary data. bw, ak, and it conceived analysis and interpretation of the data. bw, ak, and it wrote and edited final abstract. references census bureau quickfacts. 2020. u.s. census bureau quickfacts: united states. [online] available at: <https://www.census.gov/quickfacts/fact/table/us/rhi72 5219> [accessed 9 august 2020]. frey, wh. “the us will become ‘minority white’ in 2045, census projects.” brookings institution. 2018. https://www.brookings.edu/blog/theavenue/2018/03/14/the-us-will-become-minority-whitein-2045-census-projects/. cited 9/16/2020 haile rw, john em, levine aj, cortessis vk, unger jb, gonzales m, et al. a review of cancer in u.s. hispanic populations. cancer prev res (phila). 2012 feb;5(2):150-63. hales cm. national health and nutrition examination survey data, 2015-2016. obesity in ages ≥20 years. [online] national center for health statistics. available at: <https://www.cancer.org/content/dam/cancerorg/research/cancer-facts-and-statistics/cancer-factsand-figures-for-hispanics-and-latinos/cancer-facts-andfigures-for-hispanics-and-latinos-2018-2020.pdf> [accessed 1 august 2020]. parra a, karnad, ab, thompson im. hispanic accrual on randomized cancer clinical trials: a call to arms. j clin oncol 2014; 37:1871-1873. acknowledgement conflicts of interest authors' contributions www.companyofscientists.com/index.php/chd e1 cancer health disparities research prostate cancer risk-reduction behaviors among us black males less than 40 years old motolani e. ogunsanya*,1,7, folakemi t. odedina2,7, ernest kaninjing3,7, sunday e. atawodi4,7, titilola akinremi5,7, anthonia sowunmi6,7 1college of pharmacy, university of oklahoma health sciences center, oklahoma city, ok 73117, usa 2department of pharmacotherapy and translational research and department of radiation oncology, university of florida, lake nona campus, fl, 32832, usa 3college of health sciences, school of health and human performance, georgia college, ga 31061, usa 4department of biochemistry, ahmadu bello university, zaria, nigeria 5department of pathology, federal medical center, abeokuta, nigeria 6department of radiotherapy, lagos university teaching hospital, nigeria 7prostate cancer transatlantic consortium (captc) *corresponding author: motolani-ogunsanya@ouhsc.edu abstract prostate cancer (cap) is the leading cause of cancer deaths among black men and modifications in lifestyle represent an important means of primary cap prevention in young black men. thus, this study aimed to explore the cognitive-behavioral and demographic factors related to prostate cancer riskreduction behaviors (capb) among young black men in texas, united states and to examine relationships between these factors. this was a cross-sectional study of 267 black men aged 18 to 40 years. a survey collected information on demographics, exercise, knowledge of cap and screening, cues to action, and current engagement in capb. participants were young black males of different ethnicities and education levels recruited from local universities, churches, organization, and fraternities. descriptive statistics (means, standard deviations, and frequencies) were calculated for all variables, and multiple regression was employed to determine the significant (p<0.05) predictors of capb. participants had low knowledge levels (mean=5.25±3.81; range 0-14), engaged in moderate levels, duration, and intensity of exercise (mean=6.44±3.147; range 0-10), mostly reported negative cues to action (79.4%), and engaged in low levels of capb (mean=13.7±5.62; range 0-40). knowledge, academic classification, major field of study, and regular source of care were significant predictors of cap risk-reduction behaviors, and the overall model accounted for 39% (p<0.01) of the behaviors. the significant, modifiable factors (such as knowledge levels and regular source of care) should be considered in the development of strategies aimed at increasing younger black men’s engagement in capb. keywords: prostate cancer, young black men, risk-reduction, health behaviors citation: ogunsanya et al. (2019) prostate cancer risk-reduction behaviors among us black males less than 40 years old. cancer health disparities 4: e1-e14. doi:10.9777/chd.2019.1004 mailto:motolani-ogunsanya@ouhsc.edu www.companyofscientists.com/index.php/chd e2 cancer health disparities research introduction black men have the highest incidence of prostate cancer (cap) in the us (siegel et al., 2014). the cap disparities observed in black men are alarming when compared to men from other ethnicities on survival rates (li et al., 2012), morbidity (powell et al., 2010), or mortality (odedina et al., 2009). compared to caucasian men, black men have a cap incidence rate more than 60% higher and a mortality rate almost three times greater (odedina et al., 2009). despite the controversies associated with cap screening (lin et al., 2011; mcnaughton-collins and barry, 2011; moyer, 2012), it still remains the only method of detecting the disease early. while the survival rate for cap when diagnosed and treated early can be as high as 100%, black men still have worse cap prognosis when compared to other men (sanchez et al., 2007). a review of the literature indicates that, despite attempts to increase awareness of and access to cap screening, there have been delays among black men in utilizing primary health care services (cheatham et al., 2008). black men often forgo preventive services, choosing instead to delay treatment or avoid health care altogether (cheatham et al., 2008). further, several studies conducted in black men have demonstrated low knowledge levels regarding cap, especially its risk factors like positive family history and ethnicity (lee et al., 2012; ogunsanya et al., 2017). this knowledge gap is especially important because two of the major risk factors associated with cap are race (black race) and ethnicity (scher et al., 2015; tourville and nguyen, 2013). while there have been mixed findings on the relationship between lifestyle choices and cap, increased intake of dietary fat have been found to play an independent role in the development of cap (odedina et al., 2011a; tourville and nguyen, 2013). cumulative exposure to androgens and high-fat diets, for example, have been reported to increase cap risk (wu and modlin, 2012). this pattern of exposure has been established across case-control studies, ecologic studies, animal models, and studies involving immigrants (mauermann et al., 2011; simopoulos, 2010; wigle et al., 2008). conversely, studies have demonstrated the potential anticancer and antioxidant effects of lycopene or tomato products, especially against cap (giovannucci et al., 2002). however, these studies also reported a lower consumption of tomato-based products among black men compared to other ethnic groups, which translated to lower serum lycopene levels and a higher risk of cap. physical activity has also been associated with reduced risk of cap, especially beginning from the mid-teens (liu et al., 2011). other lifestyle modifications such as smoking cessation, weight control, and the use of chemopreventive agents can decrease cap risk (cuzick et al., 2014). however, other studies have reported no additive benefits of these primary modes of cancer prevention (lippman et al., 2009; whittemore et al., 1995). modifications in lifestyle are the most likely means of primary prevention of cap. there are mixed or inconclusive findings from research concerning the relationship between lifestyle modification and cap, but given the known relationship between diet, exercise, smoking, and other modifiable factors related to other common cancers, lifestyle modification can be an important prevention consideration (verma et al., 2014). diet remains the only known risk factor that may be modified to www.companyofscientists.com/index.php/chd e3 cancer health disparities research reduce a man’s chance of developing cap, thus an important element in primary prevention. some research studies indicate that meat cooked at high temperatures contain considerable levels of mutagens that can lead to an elevated level of cap risk (daniel et al., 2011; mandair et al., 2014). a diet low in fat and high in vegetable intake may have some preventive effects (kolonel et al., 2000), however many men do not meet the recommended dietary guidelines and therefore appear to be at increased risk of developing cap (dixon et al., 2007). millon-underwood and sanders (millonunderwood and sanders, 1990) examined the factors responsible for health promotion behaviors in black men (n=177). this study was specifically focused on modifiable behaviors that reduced cancer risk, or that can detect cancer early. findings from the study showed that beliefs related to cancer risk, decreasing carcinogen exposures, and beliefs related to the influence of health care providers significantly contributed to explaining 72% of the variance in healthpromoting behaviors. further, the black men in the study did not consider themselves very healthconscious with just over half of the sample (56%) having reported paying attention to their bodies while only 42% stated that they were involved in one form of physical activity or the other. twentythree percent of the men in the survey reported that their diet consisted of an adequate amount of vitamins, minerals, fiber, and dietary fat. some chemoprevention agents such as 5-α-reductase inhibitors, nsaids, selenium, allium vegetables, soy/isoflavones, green tea polyphenols, vitamins d and e, and statins, have been considered for reduction of cap and may reduce cap mortality (colli and amling, 2009). while there is no conclusive evidence for the chemopreventive benefit of nutrients or vitamins, it remains a significant part of cap prevention and early detection. in order to limit the focus of this study to behaviors conformable to interventions on cancerrelated outcomes in black males, this study was based on the following assumptions: (1) starting the conversation about preventive health behaviors in the early adult years can increase the likelihood of risk-reduction behaviors and early detection of cap in later years; (2) informed decision-making regarding cap screening among high-risk men (black ethnicity and familial history) will reduce mortality and morbidity rates; (3) and that when adequately informed about the potential risks of this disease, younger men can be proactive in reducing some of the modifiable risks associated with cap. thus, the primary objective of this study was to explore the cognitive-behavioral and demographic factors related to capb among young black men and to examine the relationships between these factors. methods research design and participants this was a cross-sectional survey design study using questionnaires. young black males (aged between 18 and 40 years), who identified as black and understood written and spoken english were included in the study. non-black males, nonenglish speaker, and those aged under 18 or over 40 years were excluded from the study. participants were recruited from churches, local organizations, and colleges and universities surrounding the university of texas at austin in texas. www.companyofscientists.com/index.php/chd e4 cancer health disparities research measures a 39-item instrument was administered to participants. the questionnaire contained a 10item scale measuring current engagement in cap risk-reduction behaviors and 29 items measuring: age (1 item), cues to action (1 item), knowledge (14 items), exercise (3 items), and demographic/personal factors (10 items). study variables dependent variable current engagement in risk reduction behaviors was measured using the 10-item prostate cancer prevention behavior (capb) scale from the personal integrative model of prostate cancer disparity (pipcad) developed by odedina et al.(odedina et al., 2011b) the items in the pipcad scale assessed participants’ engagement in lifestyle activities to reduce cap risk factors, including lowfat diet consisting mainly of fruits and vegetables, and the use of supplements within the last week. items were measured on a 5-point scale ranging from never (0) to 2 or more times a day (4), with higher scores indicating higher levels of engagement in capb. scores ranged from 0 to 40. participants were asked to indicate: 1) how often they consumed fruits, vegetables, meat products, dairy products, and butter/oil within the last week, and 2) if they have taken the following supplements selenium, lycopene, vitamin a and other retinoids, vitamin d and soy within the last week. the pipcad has been used in other studies (cobran et al., 2014; morrison et al., 2017) and reported to have high internal consistency. independent variables age age was calculated by subtracting the year of birth reported by participants from the year of study (2014). cues to action using a yes (1)/no or don’t know (0) response scale, a single item was used to measure participants’ cues to action. the measure asked about cap histories from person(s) close to the participants. those who responded to ‘no’ or ‘don’t know’ were coded as ‘0,’ while those who responded ‘yes’ to knowing someone with cap were coded as ‘1.’ knowledge knowledge was assessed using a 14-item scale with six domains (limitations, side effects from treatment, symptoms, risk factors, screening age guidelines, and screening controversy). the knowledge scale comprised of twelve items from the knowledge about prostate cancer screening questionnaire by weinrich et al. (weinrich et al., 2004) and two items assessing dietary knowledge and screening controversy by odedina et al. (odedina et al., 2011b). exercise participants’ exercise level, frequency, and duration were measured using three items derived from the personal integrative model of prostate cancer disparity (pipcad model) by odedina et al. (odedina et al., 2011b). the three items were summed up to create a composite score for exercise with higher scores indicating higher exercise time, intensity, and level. composite scores ranged from 0 to 10. demographic/personal factors ten items assessed demographic/personal factors. they include: 1) academic classification (less than www.companyofscientists.com/index.php/chd e5 cancer health disparities research high school or high school graduate or ged, college freshman, college sophomore, college junior, college senior, graduate student, or postgraduate); 2) income (<$30,000 or ≥$30,001); 3) ethnicity (african american of american origin [born and grew up in america], african, african american of african origin [born in africa but now american citizen], african american of caribbean origin [born in one of the caribbean islands but now american citizen], or caribbean); 4) family history of cap (yes, no); 5) health insurance status (private insurance [e.g., bluecross/ blue shield, humana], no insurance/self-pay, public insurance [e.g., medicaid] or not sure); 6) major/field of study (professional and applied sciences (e.g., architecture, business, communication, education, engineering and law), humanities (e.g., fine arts, liberal arts and public affairs) and natural/healthcare sciences (e.g., natural sciences, nursing, pharmacy, social work and medicine)); 7) marital status (single, not in a relationship; single, in a relationship; and married/partner/ living together); 8) perception of health status (fair, good, excellent); 9) regular source of care (none, less than 1 year, 1–5 years, 6–10 years, more than 10 years); and 10) residency (rural, urban, suburban). prior to administering the study questionnaire, it was pretested among 15 black men to ensure content validity and readability of all questions and response categories. recruitment of participants and data collection the institutional review board (irb) at the university of texas at austin approved the study. following irb approval, participants were recruited from colleges and universities located around the university of texas at austin, as well as local organizations, community liaisons, and churches. a $20 visa gift card was provided to participants as compensation for the time spent in completing the survey. data was collected from local universities, churches, organization, and fraternities between february 2014 to april 2014, in austin texas using a mixed mode of survey distribution (paper-pencil and web-based using qualtrics). data analyses all study variables were summarized using descriptive statistics (frequencies, means, and standard deviations). the reliability of the multiitem scales, capb, and knowledge, were evaluated via cronbach’s alpha. to develop a more parsimonious model, demographic/personal factors that were not related to the dependent variable were excluded from the multivariate analyses. multiple regression models were constructed to examine statistically significant predictors of capb. the significance levels were set at 0.05 and data analyses were conducted using statistical package spss 24 (international business machine corp., armonk, new york). results a total of 267 black men participated in the study, with an average age of 26±7 years (range, 18-40). of the 267 participants, 171 (64%) were africanamerican of american origin, 50 (18.9%) reported their academic classification as college freshmen. more than 70% (n=212) reported negative cues to action and majority (n=233; 87.6%) reported a negative family history of cap. more than half (n=138; 52.5%) of the participants perceived their health to be good and more than 30% (n=90) had private insurance. most participants (n=134; 51.0%) resided in urban areas and 41.9% (n=112) reported having no regular source of care. the exercise scale had a mean of 6.44±3.14 out of a possible www.companyofscientists.com/index.php/chd e6 cancer health disparities research score of 0-10 (higher scores indicate a higher level, duration, and intensity of exercise). mean knowledge levels were low among respondents with a score of 5.25 ± 3.81 (possible range of 0 to 14). descriptive characteristics of all other demographic variables are reported in table 1. to build the parsimonious model, bivariate comparisons of cap risk-reduction behavior scores were made with the independent variables. academic classification, cues to action, family history of cap, major field of study, and regular source of care were the only significant predictors of cap risk-reduction behavior and were included in the final multivariate model. the results are summarized in table 1. table 1. mean prostate cancer risk reduction behavior scores by study variables (n=267)a. demographics na (%) mean ± sd of intention scores t or f p academic classification 2.81 0.019* less than high school/ged/high school graduate 22 (8.3) 15.00 ± 5.54 freshman (college) 50 (18.9) 13.36 ± 6.03 sophomore (college) 35 (13.3) 12.69 ± 5.44 junior (college) 47 (17.8) 12.80 ± 5.56 senior (college) 48 (18.2) 12.93 ± 5.54 graduate student 30 (11.4) 15.83 ± 5.76 postgraduate (e.g., ms, jd, md, phd) 32 (12.1) 14.97 ± 5.04 cues to actionb 3.94 0.033* no 212 (79.4) 10.50 ± 5.43 yes 55 (20.6) 14.39 ± 6.23 ethnicity 1.28 0.283 african-american of american origin 171 (64.0) 13.80 ± 6.02 african 45 (16.9) 12.95 ± 4.88 african-american of african origin 28 (10.5) 15.18 ± 4.55 african-american of caribbean origin/caribbean 23 (8.6) 12.45 ± 4.81 family history of prostate cancer 8.18 0.005** no 233 (87.6) 13.64 ± 5.39 yes 33 (12.4) 14.21 ± 7.10 health insurance 1.07 0.364 private insurance (e.g., bluecross/blue shield) 90 (34.7) 13.78 ± 5.86 public insurance (e.g., chip, medicaid) 48 (18.5) 14.87 ± 5.22 not sure 41 (15.8) 12.73 ± 5.73 no insurance/self-pay 80 (30.9) 13.73 ± 5.65 income 0.70 0.404 ≤$30,000 126 (47.9) 13.04 ± 5.35 ≥ $30,001 137 (52.1) 14.06 ± 5.69 major/field of study 3.73 0.025* professional & applied sciences 153 (58.1) 13.00 ± 5.29 natural & healthcare sciences 65 (24.3) 15.29 ± 5.81 www.companyofscientists.com/index.php/chd e7 cancer health disparities research humanities 47 (17.6) 13.83 ± 6.08 marital status 1.19 0.305 single, not in a relationship 121 (46.2) 13.76 ± 5.62 single, in a relationship 88 (33.6) 13.15 ± 5.60 married/ partner/living together 53 (20.2) 14.69 ± 5.78 perception of health status 1.22 0.297 fair 44 (16.7) 14.73 ± 6.27 good 138 (52.5) 13.28 ± 5.19 excellent 81 (30.8) 14.00 ± 5.82 regular source of care 3.83 0.026* none 112 (41.9) 12.99 ± 5.17 less than 1 year 55 (20.6) 14.94 ± 5.64 1 – 5 years 60 (22.5) 13.13 ± 5.75 more than 6 years 40 (15.0) 14.78 ± 6.29 residency 0.84 0.433 urban 134 (51.0) 13.73 ± 5.51 suburban 110 (41.2) 13.51 ± 5.67 rural 19 (7.1) 15.32 ± 5.93 atotal does not equal 267 due to missing responses bcues to action was collapsed into two categories: “0” represents those who answered “no” to having someone close to them who has ever had prostate cancer and “1” represents those who answered “yes” to having someone close to them who has ever had prostate cancer *indicates significance at p < 0.05 **indicates significance at p < 0.01 prostate cancer risk-reduction behavior (capb) the capb scale showed acceptable reliability as measured via internal consistency (cronbach’s α=0.68). the capb scale had a mean of 13.70 ± 5.62 (range of 0-40). many of the participants ate fruits (n=111; 41.6%), vegetables (n=94; 35.5%), dairy products (n=83; 31.4%), and butter/oil 1-3 times a week (n=83; 31.4%). more than one-third (n=97; 36.5%) of participants consumed meat products two or more times a day. finally, the majority of the participants did not use chemoprevention products such as selenium, lycopene, vitamins a, and d, retinoid, and soy within the last week [see table 2]. www.companyofscientists.com/index.php/chd e8 cancer health disparities research table 2. frequency distribution of participants’ risk reduction behaviors (n=267) q. think about your eating habits within the last week. counting breakfast, lunch, dinner, snacks and eating out, please state how often you ate the stated food or took the stated nutrients: frequency distribution of response choices n (%) na mean sd never (0) 1 – 3 times a week (1) 4 – 6 times a week (2) once a day (3) 2 or more times a day (4) 1. fruit (fresh, canned or juice but not sodas). 267 1.88 1.10 12 (4.5) 111 (41.6) 71 (26.6) 43 (16.1) 30 (11.2) 2. vegetables (such as greens, vegetable soup, stew, green salad, string beans, peas, corn, broccoli). 265 2.02 1.08 8 (3.0) 94 (35.5) 82 (30.9) 47 (17.7) 34 (12.8) 3. meat products (such as beef, goat, chicken, pork, steaks, roasts, ribs, hamburgers, ground beef, hotdog, sausage).d 266 1.27 1.16 7 (2.6) 33 (12.4) 82 (30.8) 47 (17.7) 97 (36.5) 4. dairy products (such as milk, cheese, eggs). 264 1.86 1.10 7 (2.6) 83 (31.4) 75 (28.4) 63 (23.9) 36 (13.6) 5. butter or oil on food or in cooking. 267 1.91 1.09 10 (3.7) 83 (31.4) 81 (30.3) 60 (22.5) 33 (12.4) 6. selenium to prevent prostate cancer. 266 0.63 0.99 173 (65.0) 40 (15.0) 33 (12.4) 18 (6.8) 2 (0.8) 7. lycopene to prevent prostate cancer. 267 0.60 1.02 183 (68.5) 34 (12.7) 26 (9.7) 21 (7.9) 3 (1.1) 8. vitamin a and other retinoid to prevent prostate cancer. 267 1.15 1.22 113 (42.3) 60 (22.5) 46 (17.2) 38 (14.2) 10 (3.7) 9. vitamin d to prevent prostate cancer. 266 1.53 1.23 72 (27.1) 60 (22.6) 71 (26.7) 47 (17.7) 16 (6.0) 10. soy to prevent prostate cancer. 267 0.78 1.09 154 (57.7) 50 (18.7) 36 (13.5) 21 (7.9) 6 (2.2) score total 266 13.7b 5.62 cronbach’s alphac 0.68c atotals do not equal 267 due to missing responses bthe composite score for the overall scale calculation based on 267 responses, possible scale range 0 to +40 ccronbach’s alpha based on 10 items www.companyofscientists.com/index.php/chd e9 cancer health disparities research predictors of prostate cancer risk-reduction behavior (capb) knowledge and age were positively correlated with capb; the correlation matrix is reported in table 3. table 3. correlations (r), descriptive statistics, and reliability statistics for prostate cancer risk-reduction behavior scores, and other predictor variables (n=267) prostate cancer risk-reduction behavior scores, and other predictor variables age exercise knowledge mean (sd) actual range cronbach’s α 1. prostate cancer risk reduction behavior 0.13* -0.02 0.17** 13.70 (5.62) 1 to +30 0.68 2. age -0.14* 0.18** 26.44 (6.67) 18 to 40 3. exercise -0.05 6.44 (3.14) 0 to +10 0.85 4. knowledge 5.25 (3.81) 0 to +13 0.84 * p < .05 level (2-tailed); ** p < .01 level (2-tailed) the capb regression model was statistically significantly different from zero, f=4.12, df = 18, 250; p < 0.01. approximately 39% of the variation in capb (r2 = 0.39) was accounted for by the predictor variables, with knowledge, academic classification, major/field of study, and regular source of care being significant factors. the results of the multiple regression are presented in table 4. in summary, the model accounted for a large variance in engagement in capb. table 4. multiple regression analysis of prostate cancer risk-reduction behaviors (n=250). variable standardized coefficients 95.0% confidence intervala beta lower bound upper bound p-values intercept 11.31 20.80 <0.01** independent variables age -0.31 -0.05 -0.17 0.08 cues to actionb 0.07 -1.12 2.92 0.39 exercise 0.03 -0.17 0.29 0.61 knowledge 0.26 0.18 0.40 <0.05** covariates academic classificationc freshman (college) -0.13 -4.81 1.05 0.21 sophomore (college) -0.28 -5.94 -0.40 0.027* junior (college) -0.15 -5.10 0.72 0.14 senior (college) -0.22 -5.71 -0.28 0.018* graduate student 0.05 -2.21 4.05 0.56 postgraduate (e.g., ms, md, phd) -0.02 -3.71 2.97 0.83 family history of prostate cancerd -0.05 -3.36 1.71 0.52 major/field of studye professional & applied sciences -0.20 -4.15 -0.54 <0.05** humanities -0.12 -3.96 0.58 0.14 www.companyofscientists.com/index.php/chd e10 cancer health disparities research regular source of care less than 1 year 0.11 -0.35 3.62 0.11 1 – 5 years -0.05 -2.48 1.25 0.52 more than 6 years 0.16 -0.30 3.84 0.03* f statistic =4.12; df=18, 250; model p-value< 0.01; r2=0.39; adjusted r2=0.34 aci = confidence interval of unstandardized coefficients breference category: no creference category: less than high school/ged/high school graduate dreference category: no ereference category: natural & healthcare sciences *indicates significance at p < 0.05 **indicates significance at p < 0.01 discussion the summary score on the dependent variable, capb, was low with an average score of 13.7 (possible score of 40). this finding could be because the majority of the participants sampled were not taking vitamins/supplements to prevent cap, which is not unexpected given the age range of the participants. also, young black men in this study consumed more quantities of food associated with risk of cap (e.g., meat, butter) and fewer quantities of foods that can decrease risk (fruits, vitamin a, vitamin d). the low consumption of cap risk-reducing foods such as vegetables has been well documented in blacks, with black young adults consuming a higher intake of saturated fat and cholesterol (zamora et al., 2010) than their white counterparts. the capb scale was found to be reliable in assessing the variables of interest, which is consistent with studies done by cobran et al. and odedina et al. (cobran et al., 2014; odedina et al., 2011a). knowledge was positively and statistically significant (p<0.01) with engagement in capb, which shows that as knowledge scores increase, the level of engagement in capb for young black males increases. this relationship indicates that when younger black males have a better understanding of domains pertinent to cap and screening, such as limitations, side effects from treatments, symptoms, risk factors, screening age guidelines, and screening controversy, they are more likely to engage in behaviors that reduce their risk of cap. therefore, efforts made at improving engagement in capb in this special population could begin with assessing knowledge levels. the association found in the current study between knowledge and capb is similar to other study findings conducted in older black males (odedina et al., 2011b). the study by horwood et al. (horwood et al., 2014) had similar findings but reported that men were confused by conflicting messages in the media about dietary practices to promote overall health and preferred tailored dietary advice from their clinicians. while the current study did not assess source of information as a measure of cues to action, this could be a focal area of interest for future studies. other studies have also shown the importance of increasing knowledge levels to aid adoptions of healthier cancer risk-reduction behaviors (jepson et al., 2010; kyle et al., 2013). compared to those in the less than high school category, engagement in risk-reduction behavior www.companyofscientists.com/index.php/chd e11 cancer health disparities research reduced with increasing educational levels (in the college sophomore and college senior groups). while studies have not yet shown a direct relationship between educational levels and engagement in capbs, other findings have suggested that highly educated people tend to be more proactive about their health than those with low education levels (arora and mchorney, 2000). more studies are needed to clearly understand the role of education on preventive behaviors, especially among college students. participants in professional and applied sciences programs had lower levels of engagement in preventive behaviors compared to those in the natural/healthcare sciences. an explanation for this is that those in the natural/healthcare sciences may be more proactive about engaging in capb because of their scholastic knowledge of healthy behaviors. however, it is likely that several interrelating factors such as income/finance, personal beliefs, and information seeking status may also be responsible for this finding (ross et al., 2011). as a result, educational efforts can be designed to meet the knowledge needs of students from non-natural/healthcare science field to fill this gap. having a prolonged and constant source of care, which could be a proxy of sustained patientprovider communication, was a positive and significant predictor of engagement in capb. this can also mean that young black men who have steady interactions with their healthcare providers might be receiving pertinent information which could inform their decisions to engage in riskreduction behaviors. as a result, interventions aimed at improving engagement in capb could explore patient-provider communication and its impact on informed decision-making as it relates to future cap screening practices. it is also more paramount given that patient-provider interaction plays a huge role in engaging in more relevant proactive behaviors, such as cap screening (berglund et al., 2005; hoffman et al., 2010). age, cues to action, exercise, and family history of cap were not significantly associated with capb in the overall regression model. however, a positive relationship has been demonstrated between cues to action and capb in a study conducted in older black men (odedina et al., 2011b). thus, the insignificant relationship observed in the current study could be due to participants in this study being younger. several study limitations could have affected the interpretation and generalizability of the study results. the methodology utilized convenience sampling which limits the generalizability of study findings. self-report surveys are also prone to selection and response bias. since respondents self-reported their behaviors, it is possible that some of these were overor underreported. recall bias is also a limitation as some questions required participants to recall activities conducted within the previous week. also, the research design was cross-sectional in nature. thus study findings may not reflect causative relationships among variables of interest. finally, other relevant variables of correlational interest, such as tobacco and alcohol use, were not assessed in the current study. future studies could assess the impact of these variables. future studies can also examine the impact of environmental factors, such as promotional campaigns, as potential cues in engaging in capb. conclusion few intervention-based studies have explored cognitive-behavioral factors in younger black men www.companyofscientists.com/index.php/chd e12 cancer health disparities research with the goal of raising awareness about capb. the current study highlights the importance of raising awareness in the younger population who may be at risk of cap. thus, interventional efforts aimed at targeting this at-risk group should focus on improving knowledge gaps. in this population, modifiable health behaviors can be targeted to help reduce the overall future incidence of cap. the gains from an early start of behavior modification can help reduce the overall clinical, economic, and humanistic burden of cap. a prospective cohort design in future studies tracking cognitive-behavior change among black men (<40 years old) relative to cap modifiable factors would illuminate which behaviors are easily amenable to change and what factors influence that change. acknowledgments we acknowledge and thank all of our study participants. conflict of interest the authors declare that no competing or conflict of interests exists. authors’ contributions motolani ogunsanya conducted the statistical analysis of the project and provided content and generated the initial draft of the article.motolani ogunsanya and folakemi odedina contributed to the acquisition of data. folakemi odedina, ernest kaninjing, sunday atawodi, titilola akinremi, and anthonia sowumni provided content and reviewed the final manuscript references ibm corp. released 2016. ibm spss statistics for windows, version 24.0. armonk, ny: ibm corp. . national cancer institute. cancer trends progress report – costs of cancer care 2020. arora, n.k., and mchorney, c.a. 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(2010). diet quality and weight gain among black and white young adults: the coronary artery risk development in young adults (cardia) study (1985–2005)–. 92, 784-793. www.companyofscientists.com/index.php/chd e1 cancer health disparities research perceived behavioral control regarding prostate cancer screening among black men in west africa and the united states motolani e. ogunsanya1,18*, iya eze bassey2,18, mohammed faruk3,18, catherine oladoyinbo4,18, haruna nggada5,18, abidemi omonisi6,18, nissa askins7,18, blaise nkegoum8,18, ademola a. popoola9,18, iheanyi okpala10,18, omolara fatiregun11,18, paul jibrin12,18, emeka e. iweala13,18, wole kukoyi14,18, kayode adeniji15,18, ayo salako16,18, anthonia sowunmii17,18, folakemi t. odedina7,18 authors’ affiliations: *1college of pharmacy, university of oklahoma health sciences center, oklahoma city, ok 73117, usa 2department of medical laboratory science, college of medical sciences, university of calabar, calabar, cross river state, nigeria 3department of pathology, college of health sciences, faculty of basic clinical sciences, ahmadu bello university, zaria, nigeria 4department of nutrition and dietetics, federal university of agriculture, abeokuta, ogun state, nigeria 5department of pathology, university of maiduguri, nigeria 6department of anatomic pathology, ekiti state university, nigeria 7department of pharmacotherapy and translational research and department of radiation oncology, university of florida, lake nona campus, fl, 32832, usa 8department of anatomy and pathology, university of yaoundé teaching hospital, cameroon 9department of surgery, university of ilorin teaching hospital, ilorin, nigeria 10college of medicine, university of nigeria, enugu, nigeria 11department of radiology, oncology unit, lagos state university teaching hospital, ikeja, nigeria 12department of pathology, national hospital, abuja, nigeria 13department of biochemistry, covenant university, ota, nigeria 14ace medicare clinics limited, ota, ogun state, nigeria 15department of pathology, faculty of basic medical sciences, university of ilorin teaching hospital, ilorin, nigeria16urology unit, obafemi awolowo university, ife, nigeria 17department of radiotherapy and oncology, lagos university teaching hospital, idi-araba, nigeria 18prostate cancer transatlantic consortium (captc) corresponding author: motolani ogunsanya, email: motolani-ogunsanya@ouhsc.edu www.companyofscientists.com/index.php/chd e2 cancer health disparities research abstract to examine how perceived behavioral control (pbc) is affected by sociodemographic and behavioral factors, employing a socio-ecologic approach, and identify the relative importance of these factors. this was a cross-sectional, correlational study of 500 black men from the prostate cancer transatlantic consortium (captc) familial project. a survey using standardized captc and other measures collected information on intrapersonal (e.g., age, knowledge), interpersonal (e.g., cues to action, social support), and institutional factors (e.g., informed decision) that are predictive of pbc. black male participants, aged between 35-70 years, were recruited from the us, nigeria, and cameroon. descriptive statistics (mean, sd, and frequency) were calculated for all variables, and multiple regression was employed to determine significant (p<0.05) predictors of pbc. data were analyzed using spss v24. participants had an average age of 48±10 years, a low level of knowledge (mean=10.31±3.66; range 0-20), encountered very low cues to action (mean=1.60±2.13; range 0-13), had usual levels of social support (2.41±1.24), and were mostly (96.4%) not counseled on the advantages and disadvantages of prostate cancer screening. attitude, knowledge, informed decision, and prostate cancer information seeking behavior were significant predictors, and the overall model accounted for 49% (p < 0.01) of the variation in pbc. using a socio-ecologic approach, multi-level factors were integrated to facilitate a fuller understanding of the several factors impacting pbc in black men. the four significant factors (attitude, knowledge, informed decision, and prostate cancer information seeking behavior knowledge) could be considered when developing culturally-sensitive interventions aimed at engaging at-risk black men regarding prostate cancer prevention and early detection practices. keywords: prostate cancer, young black men, theoretical model, prevention, screening, health disparity citation: ogunsanya et al (2019) perceived behavioral control regarding prostate cancer screening among black men in west africa and the united states. cancer health disparities. 4: e1-17. doi:10.9777/chd.2019.1006 www.companyofscientists.com/index.php/chd e3 cancer health disparities research introduction prostate cancer has become the leading cancer in males of black ancestry (2016). black men are more likely to have a diagnosis of prostate cancer at an early age, a higher grade and stage prostate cancer present with complications and therefore have higher rates of morbidity and mortality compared to other races and ethnicities (shenoy et al., 2016). this disparity in morbidity and mortality has been attributed to some factors including biological differences in different ethnic groups as well as limited access to preventive care (odedina et al., 2009). positive family history has also been found to be a significant risk factor for prostate cancer (sanchez et al., 2007). globally, jamaican men of african descent, as well as african-american men, are known to have the highest incidence of prostate cancer (odedina et al., 2009; rebbeck et al., 2013). compared to caucasian men, the risk of developing prostate cancer in black men based purely on ethnicity is estimated to be 40 to 80% higher (eeles et al., 2014). survival rates comparing black men with caucasian men show a clear disparity (white et al., 2011). the risk of developing prostate cancer is higher in families with a history of the disease than in the general population (tourville and nguyen, 2013). inherited susceptibility appears to play an additional independent role in the development of prostate cancer. men diagnosed with prostate cancer are almost twice as likely to have a male blood relative (brother or father especially) who has been diagnosed with prostate cancer (ibrayev et al., 2013; murthy et al., 2011) in addition, prostate cancer risk increases with an increasing number of affected family members, such that men with two or three first degree relatives affected have a fiveand eleven-fold increased risk of developing prostate cancer, respectively (scher et al., 2015). a major factor responsible for this disparity in morbidity and mortality is that black men are less likely to get preventive care, such as prostate cancer screening when needed. several studies reveal that even after adjusting for socioeconomic status, comorbidities, and access to care, black men are less likely to undergo prostate cancer screening (consedine et al., 2006; lehto et al., 2010; winterich et al., 2009b). other factors that have been associated with lower prostate cancer screening include lack of prostate cancer knowledge, lower perceived risk and susceptibility to prostate cancer, and poor physician recommendation (drake et al., 2010; gonzalez et al., 2008; ogunsanya et al., 2016c). perceived behavioral control (pbc) has been defined as one’s perception of their ability to perform a given behavior (ajzen, 1985). pbc also refers to the degree of ease or difficulty of performing the behavior of interest, and is determined by the power of both situational and internal factors that might enable or hinder the individual from enacting the behavior (ajzen, 1991; ajzen and fischbein, 2005). pbc has been shown to be an important precursor of engaging in cancer preventative behaviors, such as breast cancer screening (baron-epel, 2009; steele and porche, 2005; tolma et al., 2014). it is important to assess an individual’s perceived control over resources and skills necessary for engaging in the future behavior. in addition, pbc is also assumed to be dependent on past experiences as well as perceived barriers and obstacles to prostate cancer screening (odedina et al., 2011b). in addition, men who perceive themselves to be in control of their health are more likely to engage in cancer www.companyofscientists.com/index.php/chd e4 cancer health disparities research reduction behaviors such as prostate cancer screening (niederdeppe and levy, 2007). to reduce the prostate cancer disparity gaps in morbidity and mortality in black men and increase screening practices in at-risk men, culturallysensitive interventions are needed. the likelihood of the success of such intervention will rely on examining behavioral change theories that identify motivations to partake in recommended health behaviors (fishbein and ajzen, 1975; hennessy et al., 2014b; riley et al., 2011). central to behavior change theories lies the assumptions that health interventions influence behavior through a series of influence, such as knowledge levels, beliefs, attitudes, pbc, which then impacts behavior (bellcross et al., 2011; busse and miranda, 2018; hennessy et al., 2014a; trivers et al., 2011). moreover, cues to action can also serve as a driver in modifying health behaviors. cues to action can also be derived from intrinsic or extrinsic factors. intrinsically, a positive family history of prostate cancer has been reported to serve as an influential source of prostate cancer information among family members (nivens et al., 2001; ogunsanya et al., 2016a). outside of the family, health care providers remain the most trusted source of health information (hesse et al., 2010; ogunsanya et al., 2016c). however, studies have reported lower rates of physician-patient discussion regarding prostate cancer in black men (mitchell, 2011; winterich et al., 2009a). regardless of the level with which prostate cancer communication occurs, other factors such as age, education, attitudes, education levels, may further impact pbc over prostate cancer and screening. a handful of studies have been conducted in black men to assess their beliefs regarding prostate cancer screening (odedina et al., 2011b; ogunsanya et al., 2016b; oliver, 2007). however, since these studies were conducted in us black men only, it would be interesting also to explore these beliefs in native african populations and ethnically-diverse black men who may be genetically similar but differ in lifestyle, behavior, cultural beliefs, and values. in addition, this is the first study, to our knowledge, examining the impact of pbc and its correlates over prostate cancer screening. also, the effects of pbc on a target behavior have been reported to be the most impactful in modifying behaviors (madden et al., 1992). therefore, the goal of the present research is to examine how pbc is affected by sociodemographic and behavioral factors, employing a socio-ecologic approach in black men from west africa and the united states. this proposal seeks to frame intrapersonal and contextual (interpersonal and institutional) that might influence black men’s pbc regarding prostate cancer and screening, and identify the relative importance of those factors. furthermore, a comprehensive understanding of the determinants of this primary outcome could inform the development of culturally appropriate interventions that might improve prostate cancer screening participation in men at the highest risk. methods this was a cross-sectional, correlational study designed to recruit 500 black men from the prostate cancer transatlantic consortium (captc) familial project over one year. data was extracted using standardized captc and other validated measures that collected information on intrapersonal (e.g., age, knowledge), interpersonal (e.g., cues to action, social support), and www.companyofscientists.com/index.php/chd e5 cancer health disparities research institutional factors (e.g., informed decisionmaking) which are predictive of perceived behavioral control (pbc). the study inclusion criteria were: (i) black men in nigeria, cameroon and the us, regardless of history of prostate cancer diagnosis, between the age of 35 and 70 recruited at clinics, health forums and in the community; (ii) men who consented to completing the study survey; and (iv) men willing to provide consent to access their medical records for clinical annotations (for those recruited at clinics). study variables dependent variable perceived behavioral control (pbc) in accordance with ajzen (ajzen, 1985), three items with a 5-point response scale (very difficult to very easy) assessed the ease or difficulty of specific prostate cancer prevention and early detection activities. the items were: 1) making a decision about prostate cancer screening is; 2) having a digital rectal examination (dre) every year is; and 3) giving a blood sample for serum prostatespecific antigen (psa) test every year is. total pbc scores ranged from 3 to 15, with a higher score indicating a higher level of ease. independent variables intrapersonal participants were asked what year they were born and this response was subtracted from the current year (2018) to calculate the age of respondents. attitude, derived from the theory of reasoned behavior (fishbein and ajzen, 1975), was measured accordingly by assessing beliefs toward prostate cancer using three items on a 5-point response scale ranging from very unfavorable to very favorable. the three items were: 1) weighing the advantages and disadvantages of prostate cancer screening to make a decision about screening for prostate cancer; 2) getting tested for prostate cancer with the digital rectal examination (dre) every year; and 3) getting tested for prostate cancer using my blood sample for serum prostate specific antigen (psa) test every year. scores ranged from 3 to 15 and higher scores indicated a positive attitude toward prostate cancer screening. education was assessed by asking the highest grade or year of school completed (primary school, secondary high school, high school, technical college, university (degree), or postgraduate). twenty items assessed knowledge about prostate cancer and prostate cancer screening using a “true,” “false,” and “don’t know” scale (odedina et al., 2011c). domains included: limitations, diet, symptoms, screening age guidelines, risk factors. responses were scored according to whether or not the participants responded correctly to each question, and the total number of correct responses was calculated (range from zero to 20) with higher scores indicating higher knowledge levels. participants were classified as either married, divorced, widowed, separated, never married, or a member of an unmarried couple, to determine marital status. participants were asked to rate their perceived susceptibility of prostate cancer using a 4-item questionnaire. the response scale ranged from strongly disagree to agree on a scale of 1 to 5, with higher scores indicating higher perceived susceptibility. this measure was developed from the perceived susceptibility concept from the health belief model (hochbaum, 1958; rosenstock, 1974a, b) and modified appropriately for use in the current study population. the four items were: 1) my chances of getting prostate cancer are great; www.companyofscientists.com/index.php/chd e6 cancer health disparities research 2) there is a good possibility that i will get prostate cancer; 3) i am not at risk for prostate cancer; and 4) there is no chance that i will get prostate cancer. perception of health was assessed using a single item on how participants perceived their health with response choices including poor, fair, good, very good, excellent, and don’t know/not sure. interpersonal cues to action regarding prostate cancer screening was measured using a 13-item questionnaire with yes/no responses and higher scores indicating a higher number of cues encountered within the last year. this measure was modified from the cues to action concept from the health belief model (hochbaum, 1958; rosenstock, 1974a,b). participants were asked about their type of employment to assess current employment status. annual household income from all sources was collected and categorized into low, medium, and high using specific cutoffs for the currencies provided. personal history of any cancer was assessed based on yes/no responses to a single question asking participants if they have had any type of cancer. prostate cancer family history was measured based on yes/no responses to a question asking whether their birth fathers have had cancer. social support was assessed by asking participants how often they get the social and emotional support they need using a single rating scale. institutional two items assessed informed decision-making (yes/no) by asking participants if their doctor had ever talked to them about the advantages and disadvantages of prostate cancer screening (rimer et al., 2004). prostate cancer information seeking was measured using four items with composite scores ranging from 4 to 20 and responses ranging from strongly disagree to strongly agree (odedina et al., 2011c). higher scores on this item indicated higher levels of engagement in seeking information regarding prostate cancer. provider satisfaction was measured with a 6-item question with yes/no responses which determined the level of trust participants have in their providers. this measure was derived from the trust of health care providers scale (blackman et al., 2018). higher scores on this measure indicated higher levels of trust in health care providers. regular source of care was measured using a single item to determine if participants had only one, more than one, or no person they thought of as their personal doctor or health care provider. it is important to note that the multi-item measures used in this study have been validated for use in other studies conducted in black men (blackman et al., 2018; cobran et al., 2014; kaninjing et al., 2017; kumar et al., 2009; odedina et al., 2011a; ogunsanya et al., 2016a). table 1. contains a description of the scales and construct used in the study. www.companyofscientists.com/index.php/chd e7 cancer health disparities research table 1. scales and constructs of measurement. dependent variable domain variable description of item item(s) sources dependent variable perceived behavioral control three items with a 5-point response scale measured the ease or difficulty of prostate cancer prevention and early detection activities. scores ranged from 3 to 15, with a higher score indicating a higher level of ease (very difficult, difficult, neutral, easy, very easy). 3 ajzen (ajzen, 1985) independent variables intrapersonal age what is your date of birth (mm/dd/yyyy)? 1 attitude toward prostate cancer screening three-item questionnaire with scores ranging from 3 to 15 and higher scores indicating positive attitude towards prostate cancer screening. scores ranged from 3 to 15 and higher scores indicating positive attitude towards prostate cancer screening (very unfavorable, unfavorable, neutral, favorable, very favorable). 3 fishbein and ajzen (fishbein and ajzen, 1975) education what is the highest grade or year of school you completed? (primary school, secondary high school, high school, technical college, university (degree), or post-graduate). 1 knowledge of prostate cancer and screening the 20 items on the knowledge scale assessed knowledge about prostate cancer and prostate cancer screening using a “true,” “false,” and “don’t know” scale. domains included: limitations, diet, symptoms, screening age guidelines, risk factors. responses were scored according to whether or not the participants responded correctly to each question, and the total number of correct responses was calculated ranging from zero to 20, with higher scores indicating higher knowledge levels. 20 odedina et al. (odedina et al., 2011c) marital status are you…? (married, divorced, widowed, separated, never married, or a member of an unmarried couple) 1 perceived risk of prostate cancer four items with scores ranging from 4 to 20, using a 5-point bipolar semantic differential scales ranging from 1 – 5 with a set of anchors (strongly disagree, disagree, neutral, agree, strongly agree). 4 hochbaum (hochbaum, 1958), rosenstock (rosenstock, 1974a, b) perception of health would you say that in general your health is…? (poor, fair, good, very good, excellent, don’t know/not sure) 1 www.companyofscientists.com/index.php/chd e8 cancer health disparities research interpersonal cues to action a 13-item measure with yes/no responses on cues regarding prostate cancer screening. higher scores indicated higher number of cues encountered within the last year (yes, no). 13 hochbaum (hochbaum, 1958), rosenstock (rosenstock, 1974a, b) employment status what is your current employment status? 1 household income what is your annual household income from all sources? 1 personal history of any cancer have you ever been told that you had any type of cancer? (yes, no) 2 prostate cancer family history has your birth father ever had cancer? (yes, no) 2 social support how often do you get the social and emotional support you need? (always, usually, sometimes, rarely, never). 1 institutional informed decision-making before you were tested for prostate cancer, did a doctor ever talk with you about the advantages of prostate cancer screening? (yes, no) before you were tested for prostate cancer, did a doctor ever talk with you about the disadvantages of prostate cancer screening? (yes, no) 2 rimer et al. (rimer et al., 2004) prostate cancer information seeking behavior four items with scores ranging from 4 to 20, using a 5-point bipolar semantic differential scales ranging from 1 – 5 with a set of anchors (strongly disagree, disagree, neutral, agree, strongly agree). 4 odedina et al. (odedina et al., 2011c) provider satisfaction six items focused on the individual’s perception of trust with their health care provider. a composite score was created from the items with higher scores indicating higher provider satisfaction (yes, no) 6 blackman et al. (blackman et al., 2018) regular source of care do you have one person you think of as your personal doctor or health care provider? (yes – only one, more than one or no). 1 www.companyofscientists.com/index.php/chd e9 cancer health disparities research study participants and recruitment this was a multi-institution study which included 16 universities/ medical health institutions in nigeria, cameroon, and the us. the institutional lead pi for each study site obtained local ethics committee/institution research board permission to conduct the studies. informed consents were obtained by research assistants. one copy from each participant was retained by the research assistant and a second copy provided to the participant. data were collected from participants who met the selection criteria and provided informed consent to participate in the study. the sample size estimated to power this study adequately was 290 respondents. the study model with all of the variables of interests is shown in figure 1. data analysis each continuous/interval variable was examined for its distribution, range, mode, median, mean, and standard deviation. normality tests, skewness, and kurtosis were carried out on continuous and interval-level variables. all interval-level data (dependent variable only) were screened to ensure that the normality assumptions were met before applying statistical tests. independent samples ttests (for explanatory variables with two levels) and anova (for explanatory variables with more than two levels) were conducted on study variables. for dichotomous and nominal-level variables, frequencies were assessed to determine if the requirements for cell sizes are met. finally, the data was screened for missing values and outliers. we tested the socio-ecological model using multiple regression analyses. in the interest of parsimony, the variables included in the final model were assessed regarding their statistical intrapersonal age attitude toward prostate cancer and screening education knowledge of prostate cancer and screening marital status perceived risk of prostate cancer perception of health interpersonal cues to action employment status household income personal history of any cancer prostate cancer family history social support institutional informed decisionmaking prostate cancer information seeking behavior provider satisfaction regular source of care www.companyofscientists.com/index.php/chd e10 cancer health disparities research significance (p<0.05). this approach allowed the final model to include combined intrapersonal, interpersonal, and institutional variables. to create meaningful and interpretable categories, variables with multiple levels of categories were collapsed. education was recoded into high school or less, college/university, and postgraduate. marital status was recoded into two categories: in a relationship (married/member of unmarried couple) and not in a relationship (divorced, widowed, separated, and never married). employment status was recoded into: currently employed (employed for wages, self-employed) and not currently employed (out of work, housewife, student, retired, unable to work, disability). probability values with p<0.05 were considered significant. reliability was assessed using an index of internal consistency (e.g., cronbach’s alpha). all analyses were coded and analyzed using spss version 24. results sample characteristics a total of 500 black men with an average age of 48±10 years (range 35 to 75 years) were recruited into the study. participant demographics and characteristics are included in table 2. the final model included the following significant variables from the bivariate analyses: attitude, education, knowledge, marital status, cues to action, informed decision, and information-seeking behavior. perceived behavioral control (pbc) the internal consistency, as measured by the cronbach’s alpha α, was 0.77, which indicates acceptable reliability. the composite pbc score was 10.51±2.54 out of a possible score range of 3 to 15 (higher scores indicating greater ease of pbc), which means that participants neither had ease or difficulty in engaging in specific prostate cancer prevention and early detection activities. pbc correlated positively with attitude (r=0.271, p<0.05), knowledge (r=0.115, p<0.011), cues to action (r=0.140, p<0.002), and prostate cancer information seeking behavior (r=0.251, p<0.001). those with a postgraduate degree (10.75±2.46) and college degree (10.68±2.51) had significantly higher pbc scores than those with high school or less degree (10.07±2.59). participants in a relationship had significantly higher pbc scores than those not in a relationship (10.52±2.54 vs. 8.13±2.61, respectively). finally, those who were informed about the advantages and disadvantages of prostate cancer screening (12.47±2.83) had significantly higher scores than those who were uninformed (10.44±2.50). the results are contained in table 2. table 2. participant demographic and characteristics (n=500). characteristics na (%) mean±sd of pbc scores bivariate significance (t, f,r)b p dependent variable perceived behavioral control 10.51±2.54 independent variables intrapersonal age 48±10 r=0.073 0.111 attitude towards prostate cancer screening 10.56±3.69 r=0.271 <0.001** www.companyofscientists.com/index.php/chd e11 cancer health disparities research education f= 3.255 0.039* high school or less 150 (30.0) 10.07±2.59 college/university 216 (43.2) 10.68±2.51 postgraduate 123 (24.6) 10.75±2.46 knowledge of prostate cancer and screening 10.31±3.66 r=0.115 0.011* marital status t=2.678 0.021* in a relationship (married/member of unmarried couple) 463 (92.6) 10.52±2.54 not in a relationship (divorced, widowed, separated, and never married) 34 (6.8) 8.13±2.61 perceived risk of prostate cancer 10.27±2.89 r=0.027 0.566 perception of health 4.43±8.72 r=-0.038 0.406 interpersonal cues to action 1.60±2.13 r=0.140 0.002** employment status currently employed (employed for wages, self-employed) 427 (85.4) 10.45±2.52 f=1.404 0.237 currently unemployed (not currently employed (out of work, housewife, student, retired, unable to work, disability) 71 (14.2) 10.85±2.70 household income low 117(23.4) 10.39±2.46 f=1.234 0.292 middle 90 (18.0) 10.36±2.61 high 178 (35.6) 10.80±2.59 personal history of any cancer yes 17 (3.4) 11.18±3.63 t=-1.096 0.274 no 481 (96.2) 10.49±2.50 prostate cancer family history yes 10 (2.0) 10.11±1.54 t=0.363 0.717 no 418 (83.6) 10.41±2.47 social support 2.41±1.24 r=-0.080 0.086 institutional informed decision-making yes 18 (3.6) 12.47±2.83 t=3.268 0.001** no 482 (96.4) 10.44±2.50 prostate cancer information seeking behavior 14.73±3.19 r=0.251 p<0.001** provider satisfaction 4.05±1.35 0.064 0.164 regular source of care no 260 (52.0) 10.45±2.55 0.476 0.753 yes, only one 142 (28.4) 10.79±2.50 more than one 78 (15.6) 10.39±2.57 atotal does not equal 500 because of missing responses. bt represent t-test statistics, f from the analysis of variance (anova) test and r from pearson’s correlation *p < .05 (two-tailed). **p < .01 level (two-tailed) www.companyofscientists.com/index.php/chd e12 cancer health disparities research model testing participants had a neutral attitude towards prostate cancer screening based on their score 10.56±3.69 (possible range of 5 to 15). the total knowledge score was low 10.31±3.66 (possible range of 0 to 20). cues to action were also very low 1.60±2.13 (possible range of 0 to 13). responses regarding prostate cancer seeking information were neutral: 14.73±3.19 out of a possible range of 4 to 20. majority of the respondents were those with a college/university degree (n=216, 43.2%). more than 90 percent of the respondents reported being in a relationship (n=463, 92.6%). similarly, majority of the participant (n=483, 96.3%) were not informed of the advantages and disadvantages of prostate cancer screening. the pbc regression model was significantly different from zero, f=9.32, df=8,463; p<0.001. the final model accounted for 49% of the variation in pbc (r2=0.49). the results are shown in table 3. table 3. multiple regression analysis of overall perceived behavioral control (n=500). variables unstandardized coefficients standardized coefficients 95.0% confidence intervala b std. error beta lower bound upper bound p-values intercept 6.60 0.79 5.04 8.16 <0.001** independent variables intrapersonal factors attitude 0.15 0.04 0.21 0.00 0.08 <0.001** educationb college/university 0.10 0.16 0.03 -0.21 0.41 0.523 postgraduate 0.30 0.27 0.21 -0.23 0.84 0.269 knowledge 0.92 0.57 0.27 0.49 1.33 0.017* marital statusc -0.34 0.49 -0.36 -1.31 0.62 0.482 interpersonal factors cues to actions 0.04 0.06 0.03 -0.07 0.15 0.493 institutional factors informed decision making 2.24 0.74 0.18 0.78 3.70 0.003* prostate cancer information seeking behavior 0.13 0.05 0.17 0.03 0.22 0.008* f statistic =9.32; df=8, 463; model p-value <0.001; r2=0.49; adjusted r2=0.41 discussion this was a study of a heterogeneous mix of black men from the nigeria, cameroon, and the us. the objectives of this study were to examine the pbc of black men in west africa and the us and to determine its correlates. this study has several findings. first, perceived control over engaging in prostate cancer screening were neither easy nor difficult. second, these beliefs are stronger in individuals with positive attitudes, when controlling for other factors. third, a higher knowledge level are associated with higher level of pbc. fourth, www.companyofscientists.com/index.php/chd e13 cancer health disparities research when participants are given the balanced information regarding the advantages and disadvantages of prostate cancer screening, their perceived control over engaging in the behavior is higher. fifth, individuals who are more proactive in seeking information regarding prostate cancer and screening have higher levels of pbc. though there is a lack of consensus among medical professional groups about its usefulness, prostate cancer screening remains the most common method for early detection of disease in men without symptoms (carter et al., 2013; ogunsanya et al., 2016b). the overall pbc score was neutral meaning that participants neither had ease or difficulty in engaging in specific prostate cancer prevention and early detection activities. the neutral overall pbc score could be because black men are less likely to seek care and participate in preventative health-related activities, such as prostate cancer screening (blocker et al., 2006; griffith et al., 2011; pedersen et al., 2012). furthermore, on examining the individual items that made up the pbc scale, participants responded having a higher degree of ease in engaging in making decisions regarding prostate cancer screening and engaging in psa screening. however, the question regarding dre had the lowest score, indicating a degree of difficulty in engaging in that behavior. as a result, the composite pbc score was neutral. the finding regarding unfavorable beliefs toward dre have been reported in studies where black men in general show greater resistance to dres and found it embarrassing and a threat to their masculinity (ogunsanya et al., 2016b; sanchez et al., 2007; winterich et al., 2009b). others explanations for the neutral pbc scores include the costs of the tests, poor access to healthcare facilities, low level of education, lack of awareness about prostate cancer screening, fear of loss of masculinity, physicians’ attitudes, fewer options of treatment, and religious and cultural beliefs/attitudes (ogunsanya et al., 2016b; winterich et al., 2009a). these factors may result in men presenting with late stages of prostate cancer with complications when they are diagnosed (adeloye et al., 2016; akinremi et al., 2011), consequently resulting in increased morbidity and mortality (olapade-olaopa et al., 2014). however, unlike previous studies which have mostly been conducted in us black and caucasian males, the current study is the first to focus on a heterogeneous sample of black males from the us and west africa. health education programs aimed at increasing levels of control an individual has over engaging in behaviors such as prostate cancer screening can target improving attitude. while attitude is yet to be explored as a determinant of pbc, it has been reported to be a strong predictor of engaging in prostate cancer preventative behaviors (mitchell, 2011; ogunsanya et al., 2016a). it was observed in this study that higher knowledge levels are associated with higher pbcs. sometimes education may be reflection of other socioeconomic factors such as income or health literacy (winterich et al., 2009a). a higher income may increase access to health care services. this may be the reason for higher pbcs observed in men with higher levels of education. so future interventions should also focus on men with low education as well as ensure the information in media campaign is understandable to audiences with low literacy levels. black men’s knowledge and perceptions of prostate cancer screening have been studied www.companyofscientists.com/index.php/chd e14 cancer health disparities research extensively (morrison et al., 2017; ogunsanya et al., 2017; owens et al., 2015). the current study shows that when men know the essential domains of prostate cancer and screening, such as diet, limitations, risk factors, and screening age guidelines, they were more likely to have higher levels of perceived control over engaging in prostate cancer screening. black men who were told of the advantages and disadvantages of prostate cancer screening were more likely to have a higher perception of control over screening. these findings highlight the importance of healthcare providers incorporating informed decision-making practices in messages aimed at increasing levels of prostate cancer screening engagement. the pivotal role providers play is well documented in the extant literature (ogunsanya et al., 2016c; pucheril et al., 2015). this observation is in line with the findings from another study which reported that majority of black men acted on their doctor's instruction to undergo prostate cancer screening after they had complained to their doctor about their symptoms (enaworu and khutan, 2016). finally, being proactive about one’s health and actively seeking information regarding prostate cancer prevention and early detection was positively associated with higher levels of pbc. several limitations of this study must be considered. the study design was cross-sectional, which only provides a one-time snapshot. given this was a self-reported survey, recall bias could also be a limitation as responses given by participants may have been inaccurate. cameroon is a francophone country, therefore including only english-speaking participants, who may not be bilingual, reduces the generalization of our study findings. regardless of these limitations, this study fills a critical gap in assessing pbc in a group of heterogeneous black men from nigeria, cameroon, and the us, and it provides insights for future studies. conclusion using a socio-ecologic approach, multi-level factors were integrated to facilitate a fuller understanding of the several factors impacting pbc in black men. the four significant factors (attitude, knowledge, informed decision-making, and prostate cancer information seeking behavior), which are all modifiable, could be considered when developing culturally-sensitive interventions aimed at engaging at-risk black men regarding prostate cancer prevention and early detection practices. while attitude and knowledge have been reported as positive correlates in engaging in prostate cancer screening in black males, the unique contribution of this study are the roles informed decision-making and prostate cancer information seeking behavior play as well, especially in ethnically-diverse black males. acknowledgements we acknowledge the support of all the men who participated in this study. we also acknowledge the support of the research assistants who assisted with data collection at various sites, notably ms. ruth agaba, mrs. sarah adewumi, and mrs. nike obafemi. funding support for this project was provided by the prostate cancer transatlantic consortium (captc). conflict of interest the authors declare that no competing or conflict of interests exist. the funders had no role in study design, writing of the manuscript, or decision to publish. authors’ contributions www.companyofscientists.com/index.php/chd e15 cancer health disparities research motolani ogunsanya conducted the statistical analysis of the project.motolani ogunsanya, iya bassey, mohammed faruk and catherine oladoyinbo provided content and generated the initial draft of the article.haruna nggada, abidemi omonisi, nissa askins, blaise nkegoum, ademola popoola, iheanyi okpala, omolara fatiregun, paul jibrin, emeka iweala, wole kukoyi, kayode adeniji, ayo salako, and anthonia sowumni contributed to the acquisition of data and the conduct 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(2009b). masculinity and the body: how african american and white men experience cancer screening exams involving the rectum. american journal of men's health 3, 300-309. www.companyofscientists.com/index.php/chd e1 cancer health disparities research is men’s health a priority for tribal health directors? results from a survey study katherine e. nowakowski1 eric bothwell2 mose herne3 leo nolan3 joel pacyna4 wesley petersen5 jon tilburt6 1stritch school of medicine, loyola university chicago | 2160 south 1st avenue maywood, il 60153, 2men’s health network | p.o. box 75972, washington, d.c. 20013, 3indian health service | 801 thompson avenue, rockville, maryland, 20852. 4biomedical ethics program, mayo clinic | 200 first street sw, rochester, mn 55905, 5office of health disparities research, mayo clinic | 200 first street sw, rochester, mn 55905 6division of general internal medicine, mayo clinic health care policy and research, mayo clinic, 200 first street sw, rochester, mn 55905 *corresponding author’s email: tilburt.jon@mayo.edu abstract programs and initiatives addressing american indian and alaska native (ai/an) health disparities have recently shifted to better understanding, identifying and promoting successful programs designed to improve the health of ai/an men. we sought to describe the priorities of front-line leadership of indian health service, tribal, and urban (itu) health programs, especially in relation to men’s health. we also sought to ascertain how potential future partners in men’s health research perceive the priorities established by the indian health care improvement act (ihcia). we surveyed directors of indian health service, tribally operated facilities/programs, and urban indian clinics (i/t/u’s) on the relative importance of a range of health topics and issues and whether gender-based strategies were crucial to implementation. i/t/u directors identified diabetes (68%), alcohol and substance abuse (61%), mental/behavioral health (56%), obesity (53%) and addiction (40%) as the highest priority issues affecting both men and women. only seven directors (6%) selected “men’s health” as a stand-alone priority. however, 80% said gender-tailored implementation was at least somewhat important for three or more of the priorities they selected. while neither men’s nor women’s health was identified as a standalone concern, health directors identified gender tailoring as a useful strategy for addressing many health issues. keywords: united states indian health service; men’s health; health priorities; health services citation: nowakowski ke et al (2018) is men’s health a priority for tribal health directors? results from a survey study. cancer health disparities 2:e1-e7. doi:10.9777/chd.2018.10003. www.companyofscientists.com/index.php/chd e2 cancer health disparities research introduction health disparities for american indian and alaska native (ai/an) people are significant and farreaching. ai/an people have higher mortality rates than the u.s. all-race population across a number of categories, including chronic liver disease, diabetes, unintentional injuries, suicide, and assault (homicide) (indian health service, 2015). health disparities for many ai/an populations have been widely reported in the literature (cho et al., 2014; herne et al., 2014; veazie et al., 2014; white et al., 2014). programs and initiatives addressing ai/an health disparities have focused to a large extent on women and children’s health, but attention has expanded recently to better understand, identify and promote the health of ai/an men. the indian health care improvement act (ihcia) was permanently reauthorized as part of the patient protection and affordable care act in 2010. the ihcia authorized the establishment of an “office of indian men’s health” in the indian health service (ihs) to “coordinate and promote the health status of indian men in the united states”(heisler, 2011) without further appropriations. while the ihcia was established with the best of intentions, we also noted that it lacked empirical grounding in the opinions of front-line, itu health leadership. in order to address this gap in data, we partnered with the men's health coalition to determine the extent to which men’s health as a free-standing health issue was prioritized among ihs, tribal, and urban (i/t/u) health program leadership. also, by gauging itu leaders’ perceived bandwidth for research in general, we sought to ascertain how potential future partners in men's health research perceive the ihcia priorities. ihs service units, tribally-operated health programs and urban indian health programs (itus) lack a number of resources, including funds, providers and equipment. programs tailored to the unique health needs of men, while potentially useful and effective, require time, personnel and money, which ai/an communities may or may not feel capable of supporting. we surveyed i/t/u health directors on the relative importance of a wide range of health issues and topics, one of which was men’s health. we also asked how important gender-tailoring was for each health issue they ranked. additional information concerning funding and other resources to support current programs was also collected. methods we sent a self-administered survey instrument to a national list of i/t/u health directors from all 12 ihs regions (see figure 1) in the summer of 2014. the survey was a short 28-item questionnaire, and all items were developed by the research team. respondents were asked to choose five health issues of greatest priority for their constituencies, estimate their capacity for research involvement, and gauge the importance of gender-tailored health programs in addressing health priorities identified. survey recipients were presented with a list of 22 health issues derived from one of three sources: documented major health challenges, current prevention and treatment programs, or ai/an health policy statements. respondents were asked to pick one of the 22 listed health issues. they also could select “other” and specify the health issue in a free-text field. following the issue selection, we asked participants to indicate the importance (very important, somewhat important, not important) of a gender-tailored program for addressing the selected health issue. the survey www.companyofscientists.com/index.php/chd e3 cancer health disparities research contained five successive iterations of this twoquestion set, and respondents were asked to use these question iterations as a way of indicating their “top five” health concerns of greatest priority for their constituencies (i.e. first iteration = first priority, second iteration = second priority, etc.). only rank order priority was captured in this way (the survey was not designed to assess the relative “distances” between identified priorities). our objective to ascertain the relative priority of men’s health was not disclosed in the survey materials. figure 1. comparison of ihs regions by count of sites invited to the survey (color gradient) and rates of response to the survey (percentages) in addition to the health priority items, respondents were queried about their past experiences about working with researchers (positive vs. negative experience), their capacity to take on new research projects and their interest in doing so, and their level of confidence that interventions developed from research in their constituencies would producing meaningful and lasting results. anyone with a functioning email address was first sent an electronic survey, and those who did not respond were subsequently sent a paper survey (group 1). the remaining group of participants received two waves of a paper survey. the electronic survey was deployed using redcap (harris et al., 2009). at the time of the first paper mailing, all participants (electronic respondents and all paper recipients in both groups) were mailed a copy of the book the land has memory. due to a typographical error for one item in the paper survey, trained phone survey staff also called paper survey respondents individually to www.companyofscientists.com/index.php/chd e4 cancer health disparities research clarify their survey responses for one item. instances of failure to reach participants and clarify their answers for these questions were reported as missing data for that item. the mayo clinic institutional review board determined that the survey was exempt. results out of the 566 native american entities recognized by the federal government (bureau of indian affairs, 2015), we were able to acquire contact information for 440 i/t/u directors. email addresses were available for 372 (85%) of these contacts. mailing addresses were available for all contacts; however, ten were undeliverable. the overall response rate was 114/430 (26.5%) (see figure 2). over 82% of respondents said funding deficiencies were a major challenge to their ability to implement programs and 31.7% of respondents currently had programs related to men’s health. figure 2. survey response rate i/t/u directors most often identified diabetes (67.5%), alcohol and substance abuse (60.5%), mental/behavioral health (56.1%), obesity (52.6%) and addiction (40.4%) as being among the top five health issues (table 1). in contrast, only seven directors (6.1%) selected men’s health as a priority. i/t/u directors indicated that gender-tailoring would be important for some of their top health priorities. aside from women’s health and men’s health, sexual abuse and domestic abuse showed the strongest support for gender tailoring. however gender-tailoring was also considered very important for issues such as cancer screening (80%), suicide (60%) and mental/behavioral health (51.9%) (table 1). most also said gender-tailoring was at least somewhat important for addiction (94.9%), alcohol and substance abuse (92.9%), www.companyofscientists.com/index.php/chd e5 cancer health disparities research tobacco (87.5%) and obesity (84.3%). overall, 80.2% of respondents said gender-tailoring was at least somewhat important for three or more of their priority health issues. there was no significant difference regarding importance of gender-tailoring between respondents with and without active men’s health programs (fisher’s exact p >.14). table 1. importance of gender tailoring for each health priority in the top 5 among 114 health directors. gender tailoring is important, n (row %) issue n (%) very somewhat not missing diabetes 77 (67.5) 22 (33.3) 31 (47.0) 13 (19.7) 11 alcohol and substance abuse 69 (60.5) 25 (44.6) 27 (48.2) 4 (7.1) 13 mental health/behavioral health 64 (56.1) 28 (51.9) 22 (40.7) 4 (7.4) 10 obesity 60 (52.6) 25 (49.0) 18 (35.3) 8 (15.7) 9 addiction and its consequences 46 (40.4) 16 (41.0) 21 (53.9) 2 (5.1) 7 cancer screening 32 (28.1) 20 (80.0) 4 (16.0) 1 (4.0) 7 tobacco 26 (22.8) 6 (25.0) 15 (62.5) 3 (12.5) 2 facilities improvements 25 (21.9) 1 (6.3) 5 (31.3) 10 (62.5) 9 suicide 21 (18.4) 12 (60.0) 6 (30.0) 2 (10.0) 1 other 18 (15.8) 6 (42.9) 7 (50.0) 1 (7.1) 4 domestic violence 17 (14.9) 13 (92.9) 1 (7.1) 0 (0) 3 adapting to health care reform 16 (14.0) 3 (18.8) 7 (43.8) 6 (37.5) 0 access to basic dental services 14 (12.3) 0 (0) 6 (54.5) 5 (45.5) 3 social assistance issues 14 (12.3) 3 (27.3) 6 (54.5) 2 (18.2) 3 strengthening health work force (eg, chrs) 14 (12.3) 3 (21.4) 6 (42.9) 5 (35.7) 0 women's health 11 (9.7) 8 (100) 0 (0) 0 (0) 3 health it 10 (8.8) 1 (12.5) 3 (37.5) 4 (50.0) 2 home health 9 (7.9) 3 (33.3) 6 (66.7) 0 (0) 0 men's health 7 (6.1) 5 (83.3) 0 (0) 1 (16.7) 1 sexual abuse 3 (2.6) 2 (100) 0 (0) 0 (0) 1 communicable diseases 1 (0.9) 0 (0) 0 (0) 1 (100) 0 public safety 0 (0.0) 0 (0) 0 (0) 0 (0) 0 giving our people access to clinical trials 0 (0.0) 0 (0) 0 (0) 0 (0) 0 discussion our results suggest that i/t/u directors do not commonly view the establishment of genderspecific programs as a health priority per se. rather, their health priorities reflect large, well-known, community-wide topics: diabetes, alcohol and substance abuse, mental/behavioral health, obesity and addiction. however, when asked whether gender-tailoring was important for these health priorities, frequently they agreed. ai/an communities have a number of pressing health issues that cross the gender divide. despite credible regularly monitored data that document that ai/an male mortality from suicide, diabetes, and alcohol can exceed ai/an females two to five fold in some age cohorts (cho et al., 2014; herne et al., 2014; veazie et al., 2014; white et al., 2014), the sheer magnitude of the health challenges encountered by ai/an community health leaders may overshadow consideration of gender-based priorities and gender-tailored health services. www.companyofscientists.com/index.php/chd e6 cancer health disparities research a growing body of literature examines sex differences in biological processes and disease, giving rise to clinical attention to gender as it relates to health promotion and disparities. in the ai/an community, a few studies have explored such gender differences (bella et al., 2006; blackett et al., 2005; blackett et al., 2012; brave heart et al., 2012; manzo et al., 2014; rink et al., 2012; spillane et al., 2012). these gender-sensitive studies identify plausible opportunities for discrete medical interventions that may improve health outcomes for specific conditions in ai/an men. for i/t/u directors, focusing prevention and treatment efforts in a way that addresses gender disparities may offer promise in reducing the overall disparities experienced in ai/an communities. gender tailoring could improve the effectiveness of care, could better reach a full range of community members, and could facilitate infrastructure to increase access to care. development and implementation of ai/an men’s health initiatives should be considered in the context of other pressing health priorities. efforts to utilize genderspecific strategies to promote health would need to leverage already existing resources and would need to conform to the priorities of the communities involved. gender tailoring of high priority health issues may be a strategy to achieve those overarching health priorities. more research is necessary to define and realize the potential impact of these strategies. due to limited resources, we were not able to collect data on patient perspectives about health priorities. future research could explore whether patients have perspectives about health priorities that resemble the perspectives of i/t/u directors, including whether gender tailoring of those programs would be important. some research— mainly qualitative focus groups—has been done in ai/an patients, but most of the available literature reports on disease-specific studies (e.g. diabetes programs (shaw et al., 2013), etc.) and does not interact with global perspectives from ai/an patients regarding how they might prioritize the services available to them. a significant limitation of this study is the response rate. a 26% response rate among i/t/u directors is modest; it by no means represents all i/t/u directors. also, this survey merely measured the perceived importance of men’s health as a freestanding health issue and gender-tailored approaches to health. it did not ask respondents to make resource-sensitive value judgments of various health programs with or without gender-tailoring. ai/an communities experience stark health disparities and a number of pressing health issues. men’s health programs may be helpful tools for addressing these realities if they focus on genderspecific approaches to improving health outcomes for community-specific priorities. acknowledgements this study was funded in part by the mayo clinic office of health disparities research. conflict of interest the authors declare that no competing or conflict of interests exists. the funders had no role in study design, writing of the manuscript, or decision to publish. authors’ contributions jt, eb, mh, and ln contributed to the design of the study; kn, jp, and jt analyzed the data; kn wrote the initial draft of the manuscript; and kn, jp, jt, eb, mh, ln and wp provided critical feedback and revisions. www.companyofscientists.com/index.php/chd e7 cancer health disparities research references bella, j.n., palmieri, v., roman, m.j., paranicas, m.f., welty, t.k., lee, e.t., fabsitz, r.r., howard, b.v., and devereux, r.b. (2006). gender differences in left ventricular systolic function in american indians (from the strong heart study)†. the american journal of cardiology 98, 834-837. blackett, p.r., blevins, k.s., stoddart, m., wang, w., quintana, e., alaupovic, p., and lee, e.t. (2005). body mass index and high-density lipoproteins in cherokee indian children and adolescents. pediatr res 58, 472-477. blackett, p.r., khan, s., wang, w., alaupovic, p., and lee, e.t. (2012). sex differences in hdl apoc-iii in american indian youth. biology of sex differences 3, 18-18. brave heart, m.y.h., elkins, j., tafoya, g., bird, d., and salvador, m. (2012). wicasa was'aka: restoring the traditional strength of american indian boys and men. american journal of public health 102, s177-s183. bureau of indian affairs (2015). federal register, department of the interior, ed., pp. 1942-1948. cho, p., geiss, l.s., burrows, n.r., roberts, d.l., bullock, a.k., and toedt, m.e. (2014). diabetes-related mortality among american indians and alaska natives, 1990-2009. am j public health 104 suppl 3, s496-503. harris, p.a., taylor, r., thielke, r., payne, j., gonzalez, n., and conde, j.g. (2009). research electronic data capture (redcap)--a metadata-driven methodology and workflow process for providing translational research informatics support. j biomed inform 42, 377-381. heisler, e.j. (2011). the indian health care improvement act reauthorization and extension as enacted by the aca: detailed summary and timeline, c.r. service, ed. herne, m.a., bartholomew, m.l., and weahkee, r.l. (2014). suicide mortality among american indians and alaska natives, 1999-2009. am j public health 104 suppl 3, s336-342. indian health service (2015). indian health disparities. manzo, k., tiesman, h., stewart, j., hobbs, g.r., and knox, s.s. 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(2014). trends and disparities in heart disease mortality among american indians/alaska natives, 19902009. am j public health 104 suppl 3, s359-367. white, m.c., espey, d.k., swan, j., wiggins, c.l., eheman, c., and kaur, j.s. (2014). disparities in cancer mortality and incidence among american indians and alaska natives in the united states. am j public health 104 suppl 3, s377387. www.companyofscientists.com/index.php/chd e1 cancer health disparities research hysterectomy-corrected cervical cancer incidence reveal larger racial disparities in texas 2012-2014 isela de la cerda1; miryoung lee1; kathleen m. schmeler2; joseph b. mccormick1; susan p fisher-hoch1 1 department of epidemiology, human genetics, & environmental sciences, university of texas health science center at houston, school of public health, brownsville, texas, usa, 2 department of gynecologic oncology and reproductive medicine, division of surgery, university of texas md anderson cancer center, houston, texas, usa. *corresponding author email: isela.delacerda@uth.tmc.edu abstract the purpose of this study was to determine the race specific age-standardized and age-specific annual texas cervical cancer incidence after correcting for hysterectomy prevalence. a registry-based crosssectional study design using texas state level data for the years 2012-2014 was used to evaluate cervical cancer incidence after applying a correction for hysterectomy and examined racial disparities by age and race. we merged into a single database annual ageand race-stratified hysterectomy prevalence, cervical cancer incident case counts, population at-risk denominators and us census 2000 population weights using the behavioral risk factor surveillance system (brfss) and texas cancer registry (tcr), and used these data to estimate hysterectomy-corrected, age-standardized and age-specific cervical cancer incidence. significant differences in hysterectomy prevalence by race were seen. for women aged 35-44 years, hysterectomy rates were highest in non-hispanic whites. among non-hispanic blacks and hispanics, the prevalence of hysterectomy peaked between the ages of 55 and 64 years, but thereafter continued to increase dramatically with age but only in non-hispanic whites. the largest adjustment between corrected and uncorrected cervical cancer rates (17.1%) was in non-hispanic white women followed by hispanics (4.1%) and non-hispanic blacks (3.6%). failing to correct reported cervical cancer rates underestimates the true burden of disease. hysterectomy prevalence in texas also suggest disparities in access to care based on race. these findings provide further evidence-based information to develop more effective region and ethnic specific cervical cancer prevention programs using unbiased estimates of disease burden. keywords: disparities, racial, cervical, cancer citation: de la cerda i et al (2021) hysterectomy-corrected cervical cancer incidence reveal larger racial disparities in texas 2012-2014. cancer health disparities 5:e1-e7. doi:10.9777/chd.2020.1003 www.companyofscientists.com/index.php/chd e2 cancer health disparities research introduction the centers for disease control and prevention (cdc) united states (us) cancer statistics data visualization tool shows that for the years 20112015, the incidence of cervical cancer was the highest for hispanic females between the age of 40-45 residing in southern states [1]. though ostensibly valid, this conclusion is subject to underlying bias. women who have undergone surgical removal of the cervix and uterus (hysterectomy) are no longer at risk for developing cancers in these organs and should therefore be excluded from the denominator when estimating incidence [2]. yet current reports of cervical cancer incidence in the us use uncorrected rates, potentially masking cervical cancer disparities [3]. similar studies in some states and in other countries show underestimation of cervical cancer burden among whites and blacks using this correction but were unable to evaluate the effect in hispanics due to insufficient sample sizes [4]. a study using massachusetts state level data reported that age standardized, corrected cervical cancer incidence among hispanics resulted in a 28.3% increase from uncorrected rates compared to a 17.1% increase in non-hispanic whites [5,6]. furthermore, geographic setting in the us, regardless of race, points to women in southern regions having both higher cervical cancer incidence and mortality rates than their counterparts in other us regions [7]. thus, texas state-level data provides the opportunity to evaluate the effect of correction on cervical cancer incidence among a large hispanic population in a southern region of the us. the purpose of this paper is to determine the age-standardized and age-specific annual hysterectomy correctedcervical cancer incidence using texas state level data for the years 2012-2014 and evaluate disparities by age and race. materials and methods a registry-based cross-sectional design using the texas cancer registry (tcr) cervical cancer incidence data and the behavioral risk factor surveillance system (brfss) data was used to arrive at age-specific and age-standardized hysterectomy corrected cervical cancer incidence. at the time of data access, the only complete and valid years with both cervical cancer incidence and hysterectomy prevalence data limited our analysis to only 2012-2014. the tcr institutional review board deemed this study exempt from review since it did not involve human subjects and only used publicly available de-identified information. data sources and linkage cervical cancer incidence state cancer registries are passive surveillance systems to which all state health care facilities that diagnose or treat cancer patients must report their cases to. for this study we obtained a limited-use cancer incidence dataset from the texas cancer registry (tcr). using the proprietary software seer*stat version 8.3.5 to open the limited-use dataset, we extracted the crude and adjusted cervical cancer incidence, counts, population at risk, and us 2000 standard population ageand racestratified for the years 2012-2014 [8]. only women 18 years or older with primary icd-o-3 site codes c53.0 cervix uteri excluding 9050-9055, 9140, 9590-9992 (morphological codes related to lymphoma and leukemias) were included in this analysis. the samples obtained for all three years had their own sample sizes and weights. www.companyofscientists.com/index.php/chd e3 cancer health disparities research hysterectomy prevalence the behavioral risk factor surveillance system (brfss) established in 1984, is an annual population-based health-related telephone survey performed in all 50 states [9]. each state randomly samples their area and collects information regarding health-related risk behaviors, chronic health conditions and use of preventive services in non-institutionalized adults. in 1988 the question “have you ever had a hysterectomy?” was added and administered for the texas survey of every even numbered year [9]. after obtaining access to the sas datasets for the texas brfss surveys for the years 2012 and 2014, we extracted surveyweighted, stratum-equivalent ageand racestratified hysterectomy prevalence for each year using sas 9.4. hysterectomy prevalence estimates for the year 2013 were calculated using the weighted average of the flanking years. data merge the annual ageand race-stratified hysterectomy prevalence (hx) from brfss, cervical cancer incident case counts (n), population at risk denominator (p) and us census 2000 population weights from tcr were merged into an excel worksheet. the hysterectomy corrected population at risk denominator (𝑝𝑝𝑐𝑐) was calculated in excel using the following formula: 𝑝𝑝𝑐𝑐 = 𝑝𝑝 ∗ (1− ℎ𝑥𝑥) statistical analysis hysterectomy prevalence estimates were obtained using stata 15 and graphs and trends created using r studio. age-standardized and age-specific corrected and uncorrected incidence, 95% confidence intervals (95%ci), rate ratios and pvalues were produced using proc stdrate command in sas 9.4. direct standardization using the us census 2000 population weights for both corrected and uncorrected estimates. tiwari, cleg and zou methodology for efficient interval estimation for cancer rates used in seer*stat was used to produce our estimates using sas [10]. results hysterectomy prevalence for 2014, 7,933 women answered the survey’s hysterectomy question, 28.1% were hispanic, 63.7% non-hispanic white, and 8.2% were nonhispanic black. overall the prevalence of hysterectomy for women ≥18 years of age was 22.74 per 100,00 (95% ci, 21.2%-23.3%). figure 1 shows the age-specific estimates of hysterectomy prevalence by three races (nh white; nh black; and hispanic). hysterectomy prevalence increased with age for all races but diverged markedly beginning at the 4554 year age category and older. in women over age 65, the hysterectomy prevalence rates were significantly higher among non-hispanic white women, compared with non-hispanic black (p = 0.021) and hispanics (p = 0.035). figure 1. line plot of texan women hysterectomy prevalence per 100 by age group and race in 2012-2014. there is a marked difference in women with hysterectomies depending on their race and www.companyofscientists.com/index.php/chd e4 cancer health disparities research age. nh white women have higher hysterectomy prevalence than hispanic and nh black women and is most distinctly observed in age groups older than 35. (nh: non-hispanic) age-specific and age-standardized cervical cancer incidence for the year 2012, 12,509,180 women consisted of 39.6% hispanic, 47.6% non-hispanic whites and 12.8% non-hispanic blacks similar to 2013. for the 12,890,550 women in 2014, 40.2% were hispanic, 46.8% non-hispanic white and 13.0% non-hispanic black. age-specific cervical cancer (cc) incidence was highest for hispanics for most excluding 18-24 and 65+ age categories, followed by non-hispanic blacks and then non-hispanic whites, even after correction for hysterectomy. table 1 shows that correction for hysterectomy increased cc incidence in all three categories. the most noteworthy change after correction was in nonhispanic white women 65+ with a 46% increase in cc incidence. table 1. uncorrected and corrected age-specific cervical cancer incidence and percentage increase (rate per 100,000) non-hispanic white non-hispanic black hispanic uncorrected rate corrected rate % increase uncorrected rate corrected rate % increase uncorrected rate corrected rate % increase 18-24 1.1 1.1 0 0.8 0.8 0 0.6 0.6 0 25-34 9.4 9.5 1 6.1 6.1 0 10.5 10.6 1 35-44 14.6 15.2 4 10.4 10.6 2 15.4 15.9 3.2 45-54 10.2 11.4 10.5 14.5 15.0 3.4 16.6 17.4 4.8 55-64 9.4 11.2 19 16.5 17.3 4.8 16.6 17.8 7.2 65+ 6.3 9.2 46 20.8 21.8 4.8 14.5 15.4 6.2 age-standardized cervical cancer incidence increased in all races after correction for hysterectomy and was highest among hispanics overall, both before and after correction. table 2 shows the agestandardized cervical cancer incidence and 95% confidence intervals by race before and after the correction. table 2. age-standardized cervical cancer incidence, uncorrected and corrected for the prevalence of hysterectomy for nh white, nh black, and hispanic 2012-2014 (rate per 100,000) uncorrected corrected nh white nh black hispanic nh white nh black hispanic rate 95% ci rate 95% ci rate 95% ci rate 95% ci rate 95% ci rate 95% ci 2012 8.7 [7.9,9.6] 12.1 [10.8,15.0] 11.8 [10.6,13.0] 9.7 [8.8,10.7] 13.3 [11.1,15.5] 12.3 [11.0,13.6] 2013 8.5 [7.6,9.3] 9.9 [8.1,11.7] 12.4 [11.2,13.6] 9.4 [8.5,10.3] 10.2 [8.4,12.0] 12.9 [11.6,14.2] 2014 8.7 [7.9,9.6] 10.3 [8.5,12.2] 12.3 [11.1,13.5] 9.9 [8.9,10.8] 10.7 [8.8,12.6] 12.8 [11.6,14.0] overall 8.2 [8.2,9.2] 11.0 [9.9,12.1] 12.2 [11.5,12.9] 9.6 [9.1,10.2] 11.4 [10.2,12.5] 12.7 [11.9,13.4] www.companyofscientists.com/index.php/chd e5 cancer health disparities research corrected rate ratio comparing rates between overall hispanics and nh whites (reference group) was 1.31 (p <0.0001) and uncorrected was 1.40 (p <0.0001). the difference between nh whites and hispanic incidence decreased after correction but remained significant. for nh blacks the rate ratio increased after correction (1.27; p<0.0001) compared with the uncorrected rate ratio (1.17; p=0.0049). figure 2 shows the percent increase between corrected and uncorrected agestandardized cervical cancer incidence in each race. nh white rates increased the most overall with a 17.1% increase compared to 4.1% in hispanics and 3.6% in nh blacks. figure 2. bar chart of percent increase between corrected and uncorrected cervical cancer rates for each race. although nh white had the biggest changes among the corrected and uncorrected rates hispanics remained having the highest agespecific and age-standardized cervical cancer rates. discussion integration of national surveillance databases provide the means for correcting reported biased gynecological cancer rates. our study revealed greater cervical cancer incidence and marked racial disparity than currently reported in texas. hysterectomy correction on the texas demographic uncovered that although correction increases incidence across all races, nh whites and hispanic women have a higher burden of cervical cancer and discrepancies in hysterectomy prevalence. hysterectomy prevalence trends in texas differ among nh white, nh black and hispanic women with a higher prevalence among nh whites, among whom there is high frequency in older age groups. the difference in hysterectomy prevalence also reveals racial disparities in access to care, primarily surgery which may be elective. cervical cancer incidence after correction increased for all races but had the highest impact on nh white women with an increase of 17.1% compared to 4.1% and 3.6% for hispanics and nh blacks respectively. correction of age-specific cervical cancer rates also retained the same significant differences but showed a marked increase in nh white women 65 years and older. cervical cancer screening and prevention has ameliorated its incidence and mortality through outreach programs. these initiatives reach out to all women considered at risk for developing cervical cancer. these women are then referred to clinics or programs that provide low-cost or free screening but fail to consider if these women have had a hysterectomy. implementing this question in routine screening and outreach efforts can decrease the amount of unnecessary pap smears and vaccines administered as well as allowing clinics and programs to correct the gynecological cancer rates reported by them. hysterectomy surveillance data collection in the us is ongoing but generally under-utilized and undervalued [11]. the american congress of obstetricians and gynecologists (acog) reports hysterectomy as the second most frequently performed surgical procedure among us. women of reproductive age second only to cesarean section [12]. this report www.companyofscientists.com/index.php/chd e6 cancer health disparities research used national hospital discharge data to arrive at hysterectomy prevalence of 33 per 100,000 in 2008 and to demonstrate a steady decrease since 1980 (55.6 per 100,000). another source of hysterectomy surveillance is brfss. this annual population-based surveillance system collects hysterectomy status for women over the age of 18, every even numbered year. this provides a source for continuous hysterectomy prevalence monitoring by races and states every other year that could be integrated with national or state level cancer registries to produce corrected cervical and uterine cancer rates. while adjustment of hysterectomy prevalence from brfss is a good approach to correct the biased rate, there are limitations in using brfss hysterectomy prevalence. one is that there is no specificity to the type of hysterectomy, age at surgery or reason for why the hysterectomy was performed, since it is self-reported without any surgical or medical details. the racial differences reveal bias probably due to access to care, however, this procedure may be elective and reflect social pressure as well as medical indications. the type of hysterectomy will determine whether a woman should be removed from the denominator for estimation of cervical cancer rate, as not all hysterectomies include the removal of the cervix (supracervical hysterectomy). the strength in our method of cervical cancer hysterectomy corrected rates is contingent on the databases used. tcr and brfss, are samples representative of the texas population, and provide a direct comparison. as opposed to another indirect method used for these types of analysis where they use national hospital discharge data for national hysterectomy prevalence estimates and use the same prevalence to correct rates for all states [13]. our results concur with findings of similar studies that revealed current cervical cancer incidence rates are an underestimation of disease burden especially among nh whites. the social determinant of access to health services is seen in effect in hysterectomy corrected cervical rates. unequal access to healthcare by these races in texas, in this case access to a physician trained to perform hysterectomies could cause the marked differences between hysterectomy prevalence’s by race. accurate, unbiased, assessment of both cervical cancer rates and racial disparities require the correction we report here. efforts between national surveillance systems, outreach programs, and health care providers can improve screening programs by targeting women who truly are at risk as well as providing for more accurate depictions of geographical disparities of access to health care for women. acknowledgements this project received no financial support. we would like to thank cassie fox, brfss epidemiologist who guided us through the process to retrieve the texas hysterectomy prevalence data. as well as dr. paige millergianturco for guiding us through the process to access the texas cancer registiry incidence data. the cancer data was provided by the texas cancer registry, cancer epidemiology and surveillance branch, texas department of state health services, 1100 west 49th street, austin, tx 78756, https://www.dshs.texas.gov/tcr/. conflict of interest the authors declare that no competing or conflict of interests exist. the funders had no role in study design, writing of the manuscript, or decision to publish. www.companyofscientists.com/index.php/chd e7 cancer health disparities research authors’ contributions conceptualization: isela de la cerda and susan p. fisher-hoch. development of methodology: isela de la cerda and miryoung lee. acquisition of data: isela de la cerda. analysis and interpretation of data: isela de la cerda and miryoung lee. writing, review, and/or revision of the manuscript: isela de la cerda, miryoung lee, susan p fisher-hoch, kathleen schmeler, joseph b. mccormick. administrative, technical, or material support: miryoung lee, kathleen schmeler, susan p. fisher-hoch, joseph b. mccormick. references group., u.s.c.s.s. (2018). u.s. cancer statistics data visualizations tool, based on november 2017 submission data (1999-2015): u.s. department of health and human services, centers for disease control and prevention and national cancer institute. hammer, a., rositch, a.f., kahlert, j., gravitt, p.e., blaaker, j., & sogaard, m. (2015). global epidemiology of hysterectomy: possible impact on gynecological cancer rates. am j obstet gynecol, 213(1), 23-29. doi: 10.1012/j.ajog.2015.02.019 beavis, a.l., gravitt, p.e., & rositch, a.f. (2017). hysterectomycorrected cervical cancer mortality rates reveal a larger racial disparity in the unites states. cancer, 123(6), 10441050. doi: 10.1002/cncr.30507 luoto, r., raitanen, j., pukkala, e., & anttila, a. (2004). effect of hysterectomy on incidence trends of endometrial and cervical cancer in finland 1953-2010. br j cancer, 90(9), 1756-1759. doi:10.1038/sj.bjc.6601763 stang, a. (2013). impact of hysterectomy on the age-specific incidence of cervical and uterine cancer in germany and other countries. eur j public health, 23(5), 879-883. doi:10.1093/eurpub/cks080 stang, a., hawk, h., knowlton, r., gershman, s. t., & kuss, o. (2014). hysterectomy-corrected incidence rates of cervical and uterine cancers in massachusetts, 1995 to 2010. ann epidemiol, 24(11), 849-854. doi:10.1016/j.annepidem.2014.07.018 yoo, w., kim, s., huh, w. k., dilley, s., coughlin, s. s., partridge, e. e., . . . bae, s. (2017). recent trends in racial and regional disparities in cervical cancer incidence and mortality in united states. plos one, 12(2), e0172548. doi:10.1371/journal.pone.0172548 registry, t. c. seer*stat database, limited_use 1995-2014 incidence, texas statewide, texas department of state health services, created january 2017, based on npcrcss submission, cut-off 11/14/16. brfss. behavioral risk factor surveillance system (brfss) historicalquestions.https://chronicdata.cdc.gov/behavior al-risk-factors/behavioral-risk-factor-surveillancesystem-brfss-h/iuq5-y9ct tiwari, r. c., clegg, l. x., & zou, z. (2006). efficient interval estimation for age-adjusted cancer rates. stat methods med res, 15(6), 547-569. doi:10.1177/0962280206070621 lepine, l. a., hillis, s. d., marchbanks, p. a., koonin, l. m., morrow, b., kieke, b. a., & wilcox, l. s. (1997). hysterectomy surveillance--united states, 1980-1993. mmwr cdc surveill summ, 46(4), 1-15. women’s health stats and facts: the american congress of obstetricians and gynecologists 2011 (2011). retrievedfromhttp://www.acog.org/media/newsroom/m ediakit.pdf merrill, r. m., lyon, j. l., & wiggins, c. (2001). comparison of two methods based on cross-sectional data for correcting corpus uterine cancer incidence and probabilities. bmc cancer, 1, 13. https://chronicdata.cdc.gov/behavioral-risk-factors/behavioral-risk-factor-surveillance-system-brfss-h/iuq5-y9ct https://chronicdata.cdc.gov/behavioral-risk-factors/behavioral-risk-factor-surveillance-system-brfss-h/iuq5-y9ct https://chronicdata.cdc.gov/behavioral-risk-factors/behavioral-risk-factor-surveillance-system-brfss-h/iuq5-y9ct www.companyofscientists.com/index.php/chd e1 cancer health disparities research nacp: partnership for native american cancer prevention francine c. gachupin, jani c. ingram, kelly a. laurila, maria c. lluria-prevatt, nicolette i. teufel-shone, margaret m. briehl* department of family & community medicine, university of arizona, department of chemistry & biochemistry, northern arizona university, department of anthropology, northern arizona university university of arizona cancer center, department of health sciences, northern arizona university department of pathology, university of arizona abstract cancer trends over a two-decade period show a greater reduction in cancer mortality rates for nonhispanic whites than for native americans. the partnership for native american cancer prevention (nacp) was established to address cancer health disparities that impact native americans. the partners are northern arizona university, the university of arizona cancer center, arizona’s tribal communities and the national cancer institute. the activities include outreach, research and cancer education. overall, nacp seeks to expand capacity for culturally-sensitive and community-relevant research on cancer, and to continue developing respectful collaborations that will empower sovereign native american communities to define, implement, and achieve their goals for cancer health equity. keywords: cancer, health disparities, american indian, native american, collaboration, research, education, outreach citation: gachupin fc et al (2021) nacp: partnership for native american cancer prevention. cancer health disparities 5:e1-e6. doi:10.9777/chd.2020.1002 www.companyofscientists.com/index.php/chd e2 cancer health disparities research cancer trends over a two-decade period show a greater reduction in cancer mortality rates for non-hispanic whites compared with native americans (melkonian et al., 2019; white et al., 2014). high rates of mortality and morbidity are attributed to delays and obstacles in seeking and receiving cancer care. limited funds allocated to native american health care; lower socioeconomic status; and cultural, social, and geographic barriers to cancer care impede patients’ ability to participate in screening, diagnosis, and treatment (bastani et al., 2004; warren-mears et al., 2013). low levels of health care literacy, mistrust in the health care delivery system, and dissatisfaction and cultural discordance with providers are further challenges specific to native americans (coughlin et al., 1999; guadagnolo et al., 2011; kanekar and petereit, 2009). despite improvements in cancer screening techniques and developments in cancer treatment, tribal communities do not benefit equally from these advances. furthermore, relatively few of the advancements in cancer research address the vulnerabilities and strengths in these communities. the state of arizona is well-positioned to address cancer health challenges faced by native americans. the state is home to 22 federally recognized sovereign tribal nations, including the largest land-based one in the united states (us) – the navajo nation. arizona cancer registry data shows that breast cancer is the most frequently diagnosed type of cancer among native american women and is responsible for the highest number of deaths compared to other cancers (timothy flood, personal communication). this is notable in that non-hispanic white women’s death rates from breast cancer have decreased with effective screening, detection, and treatment options. for native american men in arizona, prostate cancer has the highest incidence and mortality rates. when comparing native americans in arizona to other non-hispanic whites, the native americans suffer disproportionately from prostate, kidney, stomach, ovarian, and cervical cancers. the low representation of native americans in the biomedical workforce exasperates progress towards addressing cancer disparities in this population. while there has been some progress in the numbers of native americans receiving baccalaureate and graduate degrees (babco, 2015), their representation is much lower than for other minorities. the problem is particularly acute for science and engineering fields. a national survey of doctorate degrees awarded by us universities reports that of the almost 9,000 degrees conferred in the biological and biomedical sciences in 2016, only 11 (0.12%) were awarded to native americans (national science foundation 2016). the low number of doctorate degrees awarded to native americans results in a small number pursuing careers as independent scientists. data from more than 9,400 national institutes of health k-award applications showed that only three native americans per year applied for this career development funding (haak, 2011). this is more than ten times lower than expected based on the size of the native american population in the us. the representation of native americans among principal investigators on national institutes of health awards drops even further compared to career development awards (ginther et al., 2011). collaborative research with native american communities to address cancer disparities poses unique challenges as compared to work with other underserved populations. a major challenge is to overcome the history of distrust that developed as www.companyofscientists.com/index.php/chd e3 cancer health disparities research the result of broken treaties, establishment of reservations, forced boarding of schoolchildren, and other patterns of mistreatment (brave heart and debruyn, 1998). in contemporary times, academic researchers have contributed to this distrust through misguided research approaches that were disrespectful to native american tribes (burhansstipanov et al., 2001; dalton, 2004; garrison, 2013). some tribal nations have imposed a moratorium on genetic research. the partnership for native american cancer prevention (nacp) began in 2002 as a collaboration between two state universities and tribal communities. it developed from one navajo leader’s concern about the significant cancer burden among his people. this leader’s discussions with a university of arizona biochemistry faculty member blossomed into the initial vision for a partnership to tackle the challenge of cancer health disparities for native americans. the partnership brought together arizona’s only national cancer institutedesignated comprehensive cancer center, the university of arizona cancer center (uacc), with the native american-serving university in the northern part of the state, north arizona university (nau). nacp is part of the national cancer institute’s comprehensive partnerships to advance cancer health equity (cpache) program. the cpache goals are: 1) to increase the participation of underrepresented minority-serving institutions in cancer research and research training, and 2) to increase the involvement and effectiveness of comprehensive cancer centers in developing effective outreach, research, and education programs that encourage diversity among competitive researchers and reduce cancer health disparities. the cpache program’s goals shape the vision of nacp’s collaborative outreach, research, and education activities. additionally, the concerns of native american communities play a critical role in informing the direction of nacp. the rate of change in the cancer burden among arizona’s native american populations will depend, in part, on nacp’s success in engaging these communities and navigating centuries of mistrust, and on these communities determining if research outcomes are beneficial, nonthreatening, and useful. nacp’s progress towards building successful, trusting academic/community relationships has resulted in significant outcomes. in the face of historical divides, partnership leaders have worked to develop relationships with the sovereign nations and gain trust that nacp research would provide greater benefits than harm. since its launch in 2002, nacp has expanded nau’s research capabilities and capacities, contributing to more than a three-fold increase in its annual national institutes of health-funded research. nacp has initiated or fostered the career development of eleven native american early stage and mid-level investigators. the partnership has recruited and attracted more than thirty-eight investigators at uacc to address native american cancer health disparities. the outreach core has worked to increase community engagement skills and the competency of nacp students and investigators by providing training on culturally respectful research approaches with tribes and culturally relevant, evidence-based cancer education to tribal communities. across both institutions, >275 native american undergraduate and graduate students have participated in nacp’s cancer research education activities, with a focused on mentored research experiences. overall, the www.companyofscientists.com/index.php/chd e4 cancer health disparities research partnership has engaged fourteen of arizona’s twenty-two sovereign nations through cancer outreach, research, or education. nacp’s current research projects focus on cancers of the stomach, breast and cervix. data from the navajo department of health (2014) show ageadjusted incidence rates for stomach (gastric) cancer that are three to four times as high as the non-hispanic white population in arizona, making this cancer second only to colorectal cancer incidence. one nacp research project is investigating risk factors that contribute to this cancer disparity, including infection of the stomach with helicobacter pylori. relative to other ethnicities, native american women have a 3070% higher risk of dying from breast cancer (maskarinec et al., 2011; wampler et al., 2005); they are more likely to be diagnosed with late-stage disease. the incidence of triple-negative breast cancer is higher for native american than for nhw women at 14.6% of all breast cancers versus 11.6%, respectively (plasilova et al., 2016). a second nacp research project is investigating signaling pathways that may allow triple-negative breast cancers to avoid detection by the immune system and support aggressive metastatic expansion. the mortality rate from cervical cancer for native american women is higher than for non-hispanic white women (2.4 versus 1.8 per 100,000). infection with specific types of human papilloma virus is the primary cause of cervical cancer (bosch et al., 2002). an nacp team of researchers is investigating the role of differences in the vaginal microbiome, the microbes that naturally live in the vagina and are important to both health and disease, in persistence of hpv during chronic infection in native american women. in addition to the research project teams, nacp has administrative, planning and evaluation, research education and outreach core teams. a new shared resource core for the current funding cycle is called, guiding u54 investigators to develop sustainability (guides). the focus for this resource is to provide native american trainees and early stage investigators with assistance on publications and grant applications that will facilitate their career development and transition to research independence. all of the partnership activities are guided by nci program directors and three oversight bodies: a community advisory committee, internal advisory committee and program steering committee. since the inception of nacp in 2002, a major shift in direction for the partnership has been from basic bench research to community engaged research. this has been possible through a consistent focus on building relationships with native american community members that increase their trust in the benefits of nacp’s cancer research efforts. nacp’s overall goal remains steadfast – to move the state of arizona closer to cancer health equity for tribal communities. the partnership’s approach is to expand capacity for culturally-sensitive and community-relevant research on cancer and continue to develop respectful collaborations that will empower sovereign native american communities to define, implement, and achieve their goals for cancer health equity. acknowledgements cancer is a critical disease that affects hundreds of native americans and families. nacp acknowledges the struggles and challenges of native american cancer survivors and caregivers and the need for timely outreach, research and education that is culturally appropriate. we also acknowledge the www.companyofscientists.com/index.php/chd e5 cancer health disparities research efforts and contributions of the nacp researchers: drs. robin harris, priscilla sanderson, ken batai, julie armin, heather williamson, julie baldwin, hendrick dirk de heer, anna schwartz, jennifer bea, fernando monroy, juanita merchant, gregory caporaso, naomi lee, melissa m. herbst-kralovetz, narendiran rajasekaran and william montfort; and, nacp leaders and support: drs. andrew kraft, jason wilder, ron heimark, and ms. maria jackson and debora aguirre. funding the work reported in this publication was supported by the national cancer institute of the national institutes of health under the awards for the partnership of native american cancer prevention u54ca143924 (uacc) and u54ca143925 (nau). conflict of interest the authors declare that no competing or conflict of interests exists. the funders had no role in study design, writing of the manuscript, or decision to publish. authors’ contributions fcg, jci, nit-s and mmb jointly conceived of this article. fcg wrote the first draft. kl and ml-p double-checked the accuracy of the article’s content. all authors revised and approved the final version of the article. references babco, e. l. the status of native americans in science and engineering. from: national academy of engineering, workshop on engineering studies at the tribal colleges report, https://www.nae.edu/19582/reports/25466.aspx bastani, r., yabroff, k.r., myers, r.e., and glenn, b. 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(2019). disparities in cancer incidence and trends among american indians and alaska natives in the united states, 2010-2015. cancer epidemiol biomarkers prev 28, 16041611. national science foundation. 2016 survey on earned doctorates from u.s. universities. available from: https://www.nsf.gov/statistics/2018/nsf18304/static/report /nsf18304-report.pdf www.companyofscientists.com/index.php/chd e6 cancer health disparities research navajo department of health nec. cancer among the navajo, 2005-2013. window rock; 2014. plasilova, m.l., hayse, b., killelea, b.k., horowitz, n.r., chagpar, a.b., and lannin, d.r. (2016). features of triplenegative breast cancer: analysis of 38,813 cases from the national cancer database. medicine (baltimore) 95, e4614. wampler, n.s., lash, t.l., silliman, r.a., and heeren, t.c. (2005). breast cancer survival of american indian/alaska native women, 1973-1996. soz praventivmed 50, 230237. warren-mears, v., dankovchik, j., patil, m., and fu, r. (2013). impact of patient navigation on cancer diagnostic resolution among northwest tribal communities. j cancer educ 28, 109-118. white, m.c., espey, d.k., swan, j., wiggins, c.l., eheman, c., and kaur, j.s. (2014). disparities in cancer mortality and incidence among american indians and alaska natives in the united states. am j public health 104 suppl 3, s377387. www.companyofscientists.com/index.php/chd e1 cancer health disparities research prevalence of the ugt1a1*28 promoter polymorphism and breast cancer risk among african american women in memphis, tn alana smith1, cheryl d. cropp2,3, gregory vidal4,5, elizabeth pritchard5, jennifer cordero1, claire simpson1, and athena starlard-davenport1* *1department of genetics, genomics and informatics, university of tennessee health science center, memphis, tn 38163, usa, 2integrated cancer genomics division, translational genomics research institute (tgen), phoenix, az, 85004, usa, 3department of pharmaceutical, social and administrative sciences, mcwhorter school of pharmacy, samford university, birmingham, al, 35229, usa, 4division of hematology/oncology, department of medicine, university of tennessee health science center, memphis, tn 38163, 5the university of tennessee west cancer center; memphis, tn 38163 *corresponding author’s e-mail: astarlar@uthsc.edu abstract inherited variations in udp-glucuronosyltransferase 1a1 (ugt1a1) are associated with an increased breast cancer risk in women of african ancestry. the ugt1a1*28 promoter polymorphism is characterized by the presence of 7 ta repeats in the tata box sequence and results in reduced ugt1a1 gene expression and enzymatic activity. in this study, we investigated associations between the ugt1a1*28 polymorphism and breast cancer risk among african american (aa) women in memphis, tennessee, a city with increased breast cancer mortality rates among aa women. saliva was collected from 352 aa women, including breast cancer cases (n=82) and controls (n=270) between june 2016 to june 2017. dna was isolated and sequenced for the ugt1a1*28 polymorphism. the odds ratio for cases with the low ugt1a1 activity alleles (ta)7/8 repeat genotypes versus 5/5, 5/6, and 6/6 genotypes was 1.46 [95% ci, 0.65-3.31; p = 0.36] in premenopausal women and 1.10 (95% ci, 0.52-2.38; p = 0.79) in postmenopausal women. further analysis of tcga rna-seq data showed that ugt1a1 mrna was significantly lower among estrogen receptor (er)-negative breast cancers from aa as compared to non-hispanic white women with er-negative breast cancer. larger epidemiological studies are needed to determine the functional consequence of the ugt1a1*28 polymorphism on breast cancer risk in aa women. keywords: ugt1a1, ugt1a1*28, breast cancer disparities, african american, memphis, tn citation: smith a et al (2019) prevalence of the ugt1a1*28 promoter polymorphism and breast cancer risk among african american women in memphis, tn. cancer health disparities 3:e1-e12. doi:10.9777/chd.2019.1015. www.companyofscientists.com/index.php/chd e2 cancer health disparities research introduction breast cancer is a leading cause of cancer death among african american (aa) women (desantis et al., 2017). african american (aa) women under the age of 45 are most likely to develop breast cancer, and aa women of all ages are most likely to die from breast cancer (desantis et al., 2017). recent data showed that aa women in memphis, tennessee suffer disproportionately from higher breast cancer mortality rates compared to nonhispanic white women (hunt et al., 2014; vidal et al., 2017; whitman et al., 2012). epidemiological evidence highlights the influence of estrogen exposures with breast cancer development in women of african ancestry (ambrosone et al., 2015; corsini et al., 2017). established breast cancer risk factors, e.g. increased body mass index (bmi), obesity, and postmenopausal status (dietze et al., 2018; gerard and brown, 2018), are thought to increase breast cancer risk in women through modulation of estrogens. in support of these findings, aa women tend to have higher bmi and obesity rates compared to non-hispanic white women (tan et al., 2017). these factors, along with genetic variation in key genes involved in estrogen conjugation and metabolism, may contribute to increased breast cancer risk among aa women. a major pathway involved in estrogen conjugation and detoxification from circulation is through the process of glucuronidation, catalyzed by udpglucuronosyltransferases (ugts) (bock et al., 1987; starlard-davenport et al., 2007). human ugt1a1 is a major ugt enzyme involved in estrogen conjugation (lepine et al., 2004). variation in the number of thymine-adenine (ta) repeats in the tata-box of the ugt1a1 promoter (rs8175347) significantly alters ugt1a1 expression and catalytic activity towards estrogens and other compounds (boyd et al., 2006; iyer et al., 1999). the number of ta repeats vary from 5 to 8, with 6 ta repeats representing the most common (wild-type) number of repeats (beutler et al., 1998). individuals with more than 6 ta repeats (i.e., 7 ta repeats; ugt1a1*28) have markedly reduced enzymatic activity, resulting in increased estrogen and bilirubin levels, and increased risk for diseases, including breast cancer development (adegoke et al., 2004; guillemette et al., 2001; huo et al., 2008). studies have shown that the frequency of the low activity ugt1a1*28 promoter polymorphism varies significantly between ethnic groups, with prevalence being highest among populations of african descent (beutler et al., 1998; guillemette et al., 2000; huo et al., 2008). considering recent reports of higher breast cancer mortality rates among aa women in memphis, tn as compared to 49 of the largest us cities (hunt et al., 2014; vidal et al., 2017), the present study was conducted to determine the possible association between the ugt1a1 ta repeat polymorphism and breast cancer risk in a sample of aa women in memphis, tn. we further explored the relationship between ugt1a1 expression and breast cancer risk in aa and non-hispanic white women using rna sequencing data from the cancer genome atlas (tcga). materials and methods study population a total of 352 aa women participants, comprising 82 breast cancer cases and 270 healthy women controls age 18 and older were included in this pilot study. breast cancer patients treated at the west cancer center (wcc) in memphis, tn were recruited. normal healthy controls and cancer survivors were also recruited at local community outreach events in memphis, tn between june www.companyofscientists.com/index.php/chd e3 cancer health disparities research 2016 and june 2017. all recruited breast cancer patients in this study were either being treated for breast cancer or had a prior diagnosis of breast cancer. the control group included healthy volunteers without a prior diagnosis of breast cancer and who were recruited at community outreach events. all recruited participants completed a 3-page health questionnaire that included information on participants’ reproductive history, diet and lifestyle factors, and family history of cancer. race was classified according to selfreport. a 2 ml saliva sample was also collected using oragene® og-500 dna self-collection kit (ottawa, ontario, canada) at the same time the participants completed the health questionnaire. ethics written informed consent was obtained from each study participant and the study protocol (protocol # 16-04551-xp and 16-04502-xp) was approved by the institutional review board of the university of tennessee health science center, memphis, tn and was carried out in accordance with the guidelines of the declaration of helsinki. ugt1a1 promoter genotyping analysis. dna was isolated from saliva using dna genotek’s prep-it l2p dna isolation kit (ottawa, ontario, canada). dna was purified using a zymoresearch dna clean and concentrator kit (irvine, california). the ugt1a1*28 polymorphism was identified from dna that was pcr amplified as previously described (massacesi et al., 2006). briefly, polymerase chain reactions (pcr) were conducted in a total volume of 50 μl containing 100 ng of genomic dna, 25 pmoles of the ugt1a1 primer (ugt1a1 forward: 5’-gat ttg agt atg aaa ttc cag cca g-3’ and ugt1a1 reverse: 5′-cca gtg gct gcc atc cac t-3′) (massacesi et al., 2006) and the following reagents (promega, madison, wi): 0.1 mm each of dctp, dgtp, datp and dttp; 2.5 mm of mgcl2; 50 mm of potassium chloride; 10 mm of tris (ph 9.0); 0.1 % triton-x; and 2.5 u of taq polymerase. after 35 cycles of amplification (denaturation at 94 °c for 30 sec, annealing at 60 °c for 1 min, and extension at 72 °c for 1 min), the amplification products were electrophoresed in 3% agarose gel and visualized after staining with ethidium bromide. genotypes of the a(ta)6-8taa polymorphism were determined by bidirectional sequencing with forward or reverse primers. pcr products were purified using the qiagen dna purification kit (valencia, ca). dna sequencing of the ugt1a1 product (351 bp) containing the polymorphic ta repeats was performed using the sanger method employing applied biosystems big dye v3.1 reaction mix at 1/10x strength combined with an appropriate amount of pcr product and 5 pmol of the relevant primer. all sequencing data was generated in the molecular resource center (mrc) of excellence at the university of tennessee health science center, memphis, tn. all pcr protocols and template/primer ratios were those suggested by the manufacturer. the thermofisher (applied biosystems) bdxterminator system was used to remove salts, primers and unincorporated nucleotides from the labeling reaction. labelled samples were analyzed with an applied biosystems 3130xl genetic analyzer using sequencing analysis v5.2.0 software employing the kb.bcp program using the kb_3130_pop7_bdtv3 mobility file. all electropherograms were visually examined in the mrc to ensure the highest data quality. sample quality was determined prior to dntp incorporation by assaying the a260, a280 and a230 values using a nanodrop spectrophotometer: the preferred a260/a280 and www.companyofscientists.com/index.php/chd e4 cancer health disparities research a260/a230 ratios were 1.7 or better. ugt1a1 genotypes were assigned based on the number of ta repeats for each allele (i.e., 6/6, 6/7, 7/7, or 7/8). the percentage of samples with successful calls was ≥98%. rna sequencing analysis. rna sequencing analysis was done with cufflinks (trapnell et al., 2013). this algorithm reports changes at the transcript and gene level as fragment reads per kilobase of exon per million reads mapped (fpkm) values. breast carcinoma rna-seq data, made available by nationwide’s children, was queried through the national cancer institute gcd data portal using the following criteria: female, 18-90 years old at age of diagnosis, alive or dead, african american or european american, and not hispanic. the raw fpkm values from this rna-seq data were used for the analysis. no differential gene expression analysis, cuffdiff, was performed and thus no log2 (fold change) values were obtained. the raw fpkm values from cufflinks were converted to log scale for graphing purposes. statistical analysis demographic characteristics and selected risk factors for breast cancer were compared between cases and controls using t-tests for continuous variables and chi-square tests for categorical data. data were expressed as the mean ± standard deviation. ors and 95% cis for breast cancer were calculated from unconditional logistic regression models and used to estimate relative risk. to estimate the allele frequencies, data were analyzed using χ2 analysis and two-tailed fisher’s exact test. the observed genotype frequencies of ugt1a1 were compared with the expected frequencies, according to the hardy-weinberg equation. a pvalue of <0.05 was considered statistically significant. all statistical analyses were performed using graphpad prism, version 7 software (la jolla, ca). results participant characteristics this study was conducted on a total of 352 aa women participants, consisting of 82 breast cancer cases and 270 healthy women volunteers (table 1). the mean ± sd age of the breast cancer cases and the comparison group was 54.5 ± 13.8 and 48.2 ± 13.8 years, respectively. the minimum and maximum age among breast cancer cases was 20 and 88 years. the minimum and maximum age among healthy volunteers was 18 and 79 years. as can be seen from table 1, the group of breast cancer patients was matched to the control group on age (p > 0.05). there was no significant difference between cases and controls for body mass index (bmi), smoking status, alcohol consumption, family history of cancer or menopausal status. the majority of participants, both cases and controls, in the cohort had a bmi greater than 30, did not smoke, had a family history of breast cancer, or were postmenopausal. specifically, more than 90% of cases and 89% of controls reported that they do not smoke. however, more than 73% of breast cancer cases reported that they do not consume alcoholic beverages while greater than 52% of healthy volunteers reported that they do consume alcohol. overall, no differences were found between the groups regarding the characteristics shown in table 1. table 1. characteristics of study participants. www.companyofscientists.com/index.php/chd e5 cancer health disparities research characteristic cases (n = 82) a controls (n = 270) p-value age in years, mean  sd 54.5  13.8 48.2  13.8 0.170 minimum 20.0 18.0 25% percentile 44.0 38.0 median 52.5 50.0 75% percentile 64.3 58.0 maximum 88.0 79.0 body mass index (bmi), n (%) 0.920 optimal, bmi 18.5 – 25 17 (20.7) 47 (17.4) overweight, bmi 25-30 21 (25.6) 75 (27.8) obese, bmi > 30 43 (52.4) 146 (54.1) missing 1 2 smoking status, n (%) 0.886 yes 3 (3.66) 23 (8.52) no 79 (96.3) 241 (89.3) missing 0 6 alcohol consumption, n (%) 0.965 yes 22 (26.8) 141 (52.2) no 60 (73.2) 121 (44.8) missing 0 8 family history of cancer, n (%) 0.958 yes 52 (63.4) 141 (52.2) no 29 (35.4) 122 (45.2) missing 1 5 menopause status, n (%) >0.999 pre-menopausal 36 (43.9) 132 (48.9) post-menopausal 46 (56.1) 138 (51.1) distribution of ugt1a1 allele and genotype frequencies in our study population results of genotyping analysis for the ugt1a1 promoter tata box variants among breast cancer cases and controls in our study population are presented in table 2. the number of (ta) repeats in the ugt1a1 promoter tata box included 5ta, 6ta, 7ta and 8ta. the normal or wild-type allele is characterized by 6 ta repeats, while 5ta, 7ta, and 8ta repeats are variants. the polymorphism with the highest allele frequency among breast cancer cases was 7ta (ugt1a1*28) at 43%. however, among controls the normal or wild-type allele, consisting of 6ta, was most common at 47%. the allele frequency of the ugt1a1*36 (5ta) and ugt1a1*37 (8ta) was least common among both breast cancer cases and controls. table 2 also shows the ugt1a1 (ta) genotype frequencies. the 7/7 homozygous genotype of the ugt1a1 gene (ugt1a1*28) was identified in 17.8 % of breast cancer cases and 17.1% of controls. the 6/7 heterozygous genotype was the most prevalent in both breast cancer cases (35.6%) and controls (34.1%). there was no departure from hardy-weinberg equilibrium and no significant www.companyofscientists.com/index.php/chd e6 cancer health disparities research association in allele and genotype frequencies between cases and controls (χ2 test, p>0.05). the frequency distribution of the ugt1a1 promoter variants in our population and the dna sequence lengths of the promoter variants are shown in supplementary figure 1. table 2. ugt1a1 promoter allele and genotype frequencies of study population. allele a cases b controls b p-value 5 0.07 0.10 0.33 6 0.42 0.47 7 0.43 0.40 8 0.08 0.03 genotype c cases, n (%) d controls, n (%) d 5/5 4 (5.48) 7 (2.78) 0.63 5/6 2 (2.74) 17 (6.75) 6/6 17 (23.3) 68 (27.0) 6/7 26 (35.6) 86 (34.1) 7/7 13 (17.8) 43 (17.1) 7/8 7 (15.1) 31 (12.3) 8/8 0 (0) 0 (0) adapted from guillemette et al, 2000 (guillemette et al., 2001) a 2 test comparing distribution in cases versus controls for trend: p = 0.33 b number of alleles/number of chromosomes (unweighted) c 2 test comparing distribution in cases versus controls for trend: p = 0.63 d number of participants with genotype/total participants (unweighted) association between ugt1a1 genotypes and obesity and menopausal status we further determined the effect of ugt1a1 genotypes on menopausal status and obesity status using odds ratios (ors) (table 3). participants were divided into two categories based on ugt1a1 promoter activity. participants with high ugt1a1 (ta) activity alleles carried 5/5, 5/6, and 6/6 ta repeats and those considered to have low activity alleles had the presence of 6/7, 7/7 or 7/8 ta repeats. all comparisons were achieved with the reference group including 5 or 6 allele-containing genotypes (5/5, 5/6, and 6/6). on stratification by menopausal status, association between ugt1a1 high-risk genotypes and risk of breast cancer showed an or of 1.46 in premenopausal women (95% ci, 0.65-3.31; p = 0.361) and an or of 1.10 in postmenopausal women (95% ci, 0.52-2.38; p = 0.793). although not significant, overweight and obese status among women with the low activity 7/8 ta repeat alleles had a 92% increased risk of breast cancer compared to wild-type (5ta) and high activity (6ta) alleles. www.companyofscientists.com/index.php/chd e7 cancer health disparities research table 3. ugt1a1 genotypes and risk of breast cancer by menopause and obesity status. genotypes cases, n (%) controls, n (%) or (95% ci) p-value premenopausal women 5/5, 5/6, 6/6 10 (27.8) 45 (36.0) 1.46 (0.65-3.31) 0.361 6/7, 7/7, 7/8 26 (72.2) 80 (64.0) postmenopausal women 5/5, 5/6, 6/6 13 (35.1) 48 (37.5) 1.10 (0.52-2.38) 0.793 6/7, 7/7, 7/8 24 (64.9) 80 (62.5) optimal weight 5/5, 5/6, 6/6 6 (40.0) 14 (34.1) 0.78 (0.23-2.63) 0.686 6/7, 7/7, 7/8 27 (65.9) overweight/obese 5/5, 5/6, 6/6 12 (24.0) 75 (37.7) 1.92 (0.94-3.89) 0.073 6/7, 7/7, 7/8 38 (76.0) 124 (62.3) investigation of ugt1a1 mrna expression in breast tumor tissues from aa and non-hispanic white women in the tcga we previously showed that ugt1a1 mrna levels was significantly lower in breast tumors as compared to normal breast tissues from aa and non-hispanic white women (starlard-davenport et al., 2012). we demonstrated that low ugt1a1 mrna expression in breast tumors correlated with ugt1a1*28 low activity alleles. guillemette et al also showed that the ugt1a1*28 was associated with estrogen receptor (er)-breast cancers in premenopausal aa women (guillemette et al., 2000). therefore, we explored the cancer genome atlas (tcga), a comprehensive database that catalogues genomic alterations responsible for cancer from 500 patients, to determine whether ugt1a1 rna expression was altered in a group of human breast cancer samples from aa (n = 94) and non-hispanic white (n = 244) women by estrogen receptor (er) status. tcga rnasequencing data and the log2 (average raw fpkm) value was plotted per ugt1a1 gene for aa tumor and non-hispanic white tumor samples by er status (figure 1). we observed that ugt1a1 mrna expression was lower in breast tumors from aa as compared to non-hispanic white women although not significant (figure 1). we further showed that ugt1a1 gene expression was significantly higher in er negative breast tumors from non-hispanic white women as compared to aa women with er negative and er positive breast tumors. figure 1. ugt1a1 rna expression from tcga database. the log2(average raw fpkm) value is plotted per ugt1a1 gene expression for aa tumor and non-hispanic white tumor samples by estrogen receptor (er) status. the average raw fpkm values for ugt1a1 were zero or close to zero. discussion www.companyofscientists.com/index.php/chd e8 cancer health disparities research in the present study, we investigated the associations between the ugt1a1*28 ta repeat polymorphism located in the promoter region of ugt1a1 among aa breast cancer cases and healthy aa women volunteers. our study is the first to investigate the association between the ugt1a1*28 polymorphism and breast cancer risk among women in memphis, tn, a city with one of the highest breast cancer mortality disparity rates among aa women compared to non-hispanic white women in the us. the human ugt1a1 gene is a member of the ugt1a subfamily of enzymes that are encoded by the ugt1a gene locus on chromosome 2q37.1. the ugt1a isoforms share 4 common exons from exon 2 to exon 5 and have a unique exon 1 and individual promoter pairs (tukey and strassburg, 2000). ugt1a1 is the most abundant member of the ugt1a family in human liver and is also the major isoform responsible for the metabolism and clearance of many endogenous and exogenous compounds, including β-estradiol and its metabolites (lepine et al., 2004). it is well known that prolonged exposure to β-estradiol is a major risk factor for breast cancer development in women. elevated levels of circulating estrogens are associated with increased breast cancer risk in postmenopausal women. the carcinogenic potential of estrogens is not only mediated by estrogen receptor signaling but also mediated by increased cellular oxidative metabolism of estrogens to genotoxic estrogen metabolites (cavalieri et al., 1997). several studies have investigated the impact of inherited genetic variations in ugt1a1 on the incidence risk of various cancers including breast cancer (adegoke et al., 2004; guillemette et al., 2000; huo et al., 2008; shatalova et al., 2006). the scientific premise for the association of ugt1a1 genetic variants and breast cancer risk stems from the hypothesis that reduced ugt1a1 estrogen conjugating activity results in decreased cellular oxidative estrogen metabolism and increased estrogen bioavailability in circulation. the most studied ugt1a1 polymorphism is ugt1a1*28 (rs8175347) polymorphism is characterized by an extra ta repeat (ta-7) in the tata box region in the ugt1a1 promoter resulting in decreased gene transcription and glucuronidation activity (beutler et al., 1998). ugt1a1*28 has been previously linked to increased risk of breast cancer. for instance, a study by guillemette et al showed for the first time that 200 premenopausal aa women with er negative breast cancer have a higher prevalence of low ugt1a1 activity allele-containing genotypes than 200 female controls of african ancestry (guillemette et al., 2000). although a limitation of our genetic study was the small population sample size and lack of information regarding hormone receptor breast tumor status among breast cancer patients, we still observed the low activity ugt1a1*28 polymorphism among premenopausal aa women with breast cancer but not in postmenopausal aa breast cancer patients, which is in agreement with findings previously reported (guillemette et al., 2000). additionally, in our study, the gene frequency of all ugt1a1 alleles in african american women was similar to those reported previously by guillemette et al (guillemette et al., 2000). a similar study was conducted on women in the shanghai breast cancer study, a populationbased case-control study that found similar results (adegoke et al., 2004). in that study, adegoke et al also found that women under the age of 40 who carried the ugt1a1*28 risk allele had an increased risk of breast cancer with an or = 1.7; 95% ci = 1.0-2.7) but not among women 40 years old and www.companyofscientists.com/index.php/chd e9 cancer health disparities research over (or = 0.8; 0.7-1.1) (adegoke et al., 2004). likewise, similar findings have been found in russian women (shatalova et al., 2006). by contrast, huo et al genotyped dna for the ugt1a1*28 polymorphism among 512 nigerian breast cancer cases and 226 community controls and found that premenopausal indigenous nigerian african women with the low-activity ugt1a1 ta repeat alleles were protected against breast cancer (huo et al., 2008). these findings show that the frequency of the ugt1a1*28 polymorphism varies between populations by race and ethnicity. in our previous published study, we showed that the ugt1a1*28 promoter polymorphism was associated with decreased ugt1a1 gene expression in aa and non-hispanic white women with breast cancer (starlard-davenport et al., 2012). in that study, we observed a significant decrease in ugt1a1 mrna expression levels among breast tissues isolated from aa and nonhispanic white women with breast cancer (n = 17) and normal healthy controls (n = 30) (p = 0.02). based on these findings and those of guillemette et al (guillemette et al., 2000) who found an association between the ugt1a1*28 polymorphism and er negative breast cancer risk in aa women, we interrogated existing tcga rna sequencing datasets to determine whether ugt1a1 gene expression was differentially expressed among aa and non-hispanic white breast cancer patients by er status. in our analysis, we were unable to compare ugt1a1 mrna expression between aa breast cancer cases and aa healthy controls since there was only one healthy control available for comparison. thus, it was impossible to conduct statistical analysis of ugt1a1 mrna between normal and breast cancer aa patients in the tcga. however, further analysis of ugt1a1 mrna expression in the tcga database between aa breast cancers and non-hispanic white breast cancer cases showed that ugt1a1 expression was downregulated in breast cancers and was lower among aa breast cancers compared to nonhispanic white breast cancer cases, especially among er negative breast tumors from aa women. in conclusion, this genetic study supports previous findings highlighting the association between the ugt1a1*28 polymorphism and premenopausal breast cancer risk among aa women. this study also highlights the importance of investigating genetic studies in an underserved minority aa population such as memphis, tn where the breast cancer mortality rates is significantly higher among aa women compared to non-hispanic white women. larger epidemiological studies are required to replicate these findings in other populations of african ancestry and to delineate the exact biological mechanisms underlying the effects of the ugt1a1*28 promoter polymorphism in aa women. acknowledgements the authors wish to thank all participants in this study and volunteers who assisted in consenting and collecting biospecimens. special thanks to mrs. gwendolyn brown with the carin and sharin breast cancer support group and dr. osborne burks at southwest tennessee community college. the authors wish to acknowledge support from the university of tennessee health science center (uthsc) molecular resource center and the west cancer center. funding sources this work was supported by generous funds from the uthsc center for integrative genetics (citg) and methodist mission to as-d). www.companyofscientists.com/index.php/chd e10 cancer health disparities research conflict of interest the authors declare that no competing or conflict of interests exists. the funders had no role in study design, writing of the manuscript, or decision to publish. authors’ contributions conceptualization: as-d, formal analysis: as-d, cdc, cs. methodology: as, jc, gv, ep. supervision: as-d. writing ± original draft: as-d, as, cdc, gv. writing ± review & editing: as-d, as, cdc, gv, cs references adegoke, o.j., shu, x.o., gao, y.t., cai, q., breyer, j., smith, j., and zheng, w. 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(2012). the racial disparity in breast cancer mortality in the 25 largest cities in the united states. cancer epidemiology 36, e147-151. www.companyofscientists.com/index.php/chd e12 cancer health disparities research supplemental figure 1 www.companyofscientists.com/index.php/chd e1 cancer health disparities research enhancing african american participation in biospecimens: a case in point for pancreatic cancer linda behar-horenstein1,5,*, rueben c. warren2, v. wendy setiawan3,5, corey perkins,4 and thomas d. schmittgen4,5 1colleges of education and 4pharmacy, university of florida, gainesville, fl, usa, 2tuskegee university, tuskegee, al, usa and 3college of medicine, university of southern california, los angeles, ca, usa, 5florida-california cancer research, education and engagement (care2), health equity center. *corresponding author: linda behar-horenstein, lsbhoren@ufl.edu. abstract diseases of the pancreas (i.e. chronic pancreatitis, diabetes, and pancreatic cancer) disproportionally affect the african american community. challenges associated with engaging the african american community in biospecimen research are longstanding. we surveyed a number of pancreas-related biobanks, and data repositories for african american representation. while some of the biobanks and databases surveyed contain biospecimens and data from african american donors at levels that reflect minority representation among the general population, others do not. a number of factors have historically contributed to reduced participation of the african americans community in biospecimen donation including medical mistrust, lack of transparency, fear, and a poor knowledge and understanding about the use of biospecimens for research. suggestions for increasing african american participation in organ and biospecimen donation include educational interventions, particularly in community groups, and providing printed and online recruitment materials to patients, patient advocates, and care partners. increasing awareness of the many benefits of biospecimen donation among african americans will positively affect health disparities research into pancreatic cancer and other diseases. keywords: pancreatic cancer, health disparities, biospecimen citation: linda behar-horenstein et al (2021) enhancing african american participation in biospecimens: a case in point for pancreatic cancer. cancer health disparities 5:e1-e8. doi:10.9777/chd.2020.1005 www.companyofscientists.com/index.php/chd e2 cancer health disparities research introduction many facets of biomedical research require the collection, dissemination, and cellular, molecular, and genetic analysis of human biological specimens. for genetic and associated biological studies of racial disparity, it is essential to collect and analyze biological specimens from donors at levels that reflect minority representation among the general population. ensuring adequate representation is imperative as a matter of social justice, economics, and science (regnante et al., 2020). such biospecimens include normal and diseased tissues, blood, and other bodily fluids. while the most recent census data set the african american population at 13.2% (colby and ortman, 2015), biological specimen collection and associated data generated from those specimens may not reflect the representation of african americans in the usa. in an analysis of studies involving genomic sequencing, african americans are underrepresented for most cancers in the cancer genome atlas (tcga) program and male african americans are especially underrepresented compared to their female counterparts (kim and sarkar, 2019). these data underscore the need for appropriate samples. genome-wide association studies (gwas) of cancer have identified a large number of cancer risk loci, however, less than 1% were first discovered in african americans compared to 80% in european ancestry populations mainly because the small percentage of african ancestry samples included in the discovery phase of these studies (84% european; 4% african) (park et al., 2018). in this report, we surveyed a number of pancreasrelated biobanks, and data repositories for african american representation. we discuss how well those frequencies reflect minority representation among the general and specifically african american populations. we explore the challenges associated with procuring african american biospecimens and how a lack of donation impacts research outcomes designed to reduce the burden of diseases of the pancreas for this population. we conclude this paper with suggestions designed to increase african american participation in organ and biospecimen donation. representation of african american biospecimens for diseases of the pancreas diseases of the pancreas (i.e. chronic pancreatitis, diabetes, and pancreatic cancer) disproportionally affect the african american community. the incidences (per 100,000) of chronic pancreatitis, and pancreatic cancer in african americans are 11.3 and 11.7, respectively, compared to 5.1 and 7.5, respectively for non-hispanic whites (2019; yang et al., 2008). the percentage of diagnosed diabetes in the usa for african americans and non-hispanic whites are 13.3 and 9.4, respectively (2020). health disparity research on diseases of the pancreas are impacted by the minority representation of tissues, tumors and other biospecimens related to pancreatic diseases. the cancer genome alas (tcga) database contains only 3.6% of african american pancreatic cancers compared to 90% for non-hispanic whites (table 1). the largest repository of cancer cell lines in the world, the american type culture collection (atcc), offers no pancreatic cancer cell lines derived from african americans (table 1). data from the three centers (mid-western, eastern, and mid-atlantic) of the nci-supported cooperative human tissue network (chtn) report only 8.3% african american representation compared to 88.9% for non-hispanic whites (table 1). we are aware of ongoing gwas of pancreatic cancer that has considerable higher african american representation. these include samples from the multiethnic cohort study and the southern community cohort study (park et al., 2018; signorello et al., 2010; signorello et al., 2005) www.companyofscientists.com/index.php/chd e3 cancer health disparities research whereby most pancreatic cancer cases are african american (230 cases/5,235 controls), followed by japanese american (181 cases/3,285 controls), non-hispanic white (132 cases/570 controls), latino (105 cases/ 2,935 controls), and native hawaiian (43 cases/1,753 controls). table 1. racial representation of biobanks from diseases of the pancreas. biobank tissue type(s) inclusive years % african american % white % other total in biobank reference the cancer genome atlas pancreas cancer, normal pancreas 2006-2018 3.3 88 8.7 150 (cancer genome atlas research network. electronic address and cancer genome atlas research, 2017) american type culture collection pancreas cancer cell lines n/a 0 66 33 12 https://www.atcc.org/ prodo labs pancreas 2011-2016 11.5 54.9 33.6 226 (scharp et al., 2019) npod1 pancreas 2007-2020 18.3 68.1 13.6 492 gwas2 pancreas cancer 1993-2014 33.3 19.1 47.6 691 (park et al., 2018; signorello et al., 2010; signorello et al., 2005) chtn3 pancreas cancer 2015-2020 8.3 88.9 2.8 36 allegheny hospital pancreas 2013-2017 19.1 61.8 19.1 283 university of miami pancreas 2013-2017 19.5 54.9 25.6 195 1network for pancreatic organ donors with diabetes 2genome wide association studies 3coorporative human tissue network health disparities research on pancreas transdifferentiation we are presently engaged in a prospective study on how race affects the ability of normal human pancreas to transdifferentiate from an acinar to ductal phenotype; considered to be an early precursor to the development of pancreatic cancer (storz, 2017). in our study, normal pancreatic acinar cells are procured from pancreatic islet transplantation centers (table 1); pancreata are from individuals who have consented to organ donation. our study has been ongoing for 3 years, and to date we have collected 17, 7 and 14 pancreas specimens from non-hispanic white, african american, and hispanic donors, respectively. while the overall percentage of specimens from african americans in our study (18.4%), as well as the overall procurement from www.companyofscientists.com/index.php/chd e4 cancer health disparities research these transplantation centers (allegheny hospital 19.1% and university of miami 19.5%, table 1), parallels the percentage of african americans in the usa population (colby and ortman, 2015), the slow pace of procuring african american biospecimens has impacted our work’s progress and conclusions from the study. in a 2011 study, bratton, et al., reviewed the impact of race on organ donation over the years 1999-2008. they report that african american organ donation increased over these years to levels that reflect minority representation in the usa (bratton et al., 2011). historical/cultural issues a significant body of literature explores medical distrust of the research community by african americans (hughes et al., 2017). warren, et al., reported the barriers to participation among african americans in clinical trials. thirty-five interviews were conducted among national african american leaders from historically black health professions schools, black health professional associations, faith leadership centers, and civic organizations (warren rc, 2019). trustworthiness and trust were the top factors that determined research participation from the african american community; especially for the less understood clinical trials (kennedy et al., 2007). building trustworthiness in the research community forms the foundation for trust between african americans and researchers. however, trust is unlikely when the research community is not trustworthy or when the researchers demonstrate no evidence of their trustworthiness (smirnoff et al., 2018). in each instance, trustworthiness is a precondition for sustained trust. the historical evidence of bioethics and public health ethics violations, specifically related to african americans (crawley, 2001) is a challenge to sustaining trust. african americans have had regretful experiences related to seeking information about biospecimens. for example, in 2018, descendent family members of the men who were in the u.s. public health service syphilis study at tuskegee (syphilis study) formally requested the whereabouts of any syphilis study biospecimen from the centers for disease and prevention and the national institutes of health (r.c. warren, personal communication). the request came after a paper, published by the milbank quarterly, indicated that the biospecimen from the syphilis study existed (spector-bagdady and lombardo, 2018). through the freedom of information act, the information should have been obtainable. while both agencies responded, the information was not provided. the nih “all of us project”, to collect genetic and biospecimen material from the african american population will not be successful unless the trustworthiness between the black population and the research community is established and sustained. underrepresentation of african americans in biospecimens previous studies regarding african american underrepresentation in biospecimens suggest that there are several influential factors including mistrust of the medical community, a lack of transparency regarding how biospecimens will be used, and a lack of knowledge regarding the importance of participation. using a standardized phone survey with detroit area african americans 55 years or older, hagiwara, et al., (hagiwara et al., 2014) reported that african americans were rarely asked to participate in biobanking programs. study participants reportedly were not as concerned with research exploitation or mistrust of medical researchers. when they were concerned, these concerns or mistrust did not translate into an actual unwillingness to participate in biobanking programs. hagiwara, et al., found that www.companyofscientists.com/index.php/chd e5 cancer health disparities research transparency in medical research and biobanking programs was a more important predictor of african americans’ willingness to donate biospecimens for medical research (hagiwara et al., 2014). in a mixed methods study of african americans in southeast and southwest washington, dc, dash, et al., (dash et al., 2014) also reported that “mistrust of the medical community” was not the most commonly reported barrier. a lack of transparency in and knowledge of how biospecimens would be used were cited most often. these findings highlight the importance of education on biospecimens to increase minority participation in biospecimen research (dash et al., 2014). patel, et al., (patel et al., 2018) assessed the impact of an educational intervention using video and brochures on biospecimen knowledge and attitudes using preand post-tests. both average knowledge and attitude scores for biospecimen donation increased (p < 0.0001) for video and brochure conditions post-intervention. those who received the educational video showed a significantly greater increase in knowledge pre-topost compared to those who did not receive the educational brochure. there were significant interactions between both interventions for attitudes toward biospecimen donation. the results demonstrated the feasibility and efficacy of a university african american community partnership in developing educational tools for biospecimen donation (patel et al., 2018; rollins et al., 2018). rollins, et al., assessed the effectiveness of a community-engaged educational approach designed to increase clinical research participation among racial minorities (rollins et al., 2018). preand post-tests assessed changes in participants’ (n =60) knowledge, perceptions, and willingness to participate in clinical studies and biorepositories following a session about clinical research and biorepository participation. statistically significant changes in knowledge about joining a clinical study and registry or biorepository were observed. there was no statistically significant change in willingness to participate in clinical research or biorepositories. despite beliefs that participation would improve health, early detection, and care access, barriers included fear, lack of knowledge, historical mistrust of research, and time constraints. barrett, et al., reported that fear, mistrust and inflexible research protocols were barriers to african american recruitment (barrett et al., 2017). participants suggested that greater recruitment could be achieved by enhancing cross-cultural skillsets via training opportunities for recruiters, increasing greater community engagement among researchers, and improving engagement between clinic staff and research teams. knowledge, attitudes, and beliefs about biobanking and experiences with the donation of biospecimens among diverse participants were explored by dang, et al., (dang et al., 2014). overall, there was a poor knowledge and understanding about the use of biospecimens for research. racial and ethnic groups differed in the number of factors that were obstacles for participation. for african americans in this study, the issue was continuing medical mistrust. overall participants expressed interest and willingness to participate in biobanking for altruistic purposes, particularly to benefit future generations. however, interest was predicated on an expectation that requests be accompanied by an explication of study sponsorship and ownership, distribution, and use of biospecimens in a format that aligned with participants’ backgrounds and experiences. while www.companyofscientists.com/index.php/chd e6 cancer health disparities research the findings regarding medical mistrust may appear contradictory, it can be argued that a lack of transparency is related to trustworthiness. increasing procurement concerted and deliberate actions must be undertaken to ensure the representativeness of african americas in pancreatic cancer research. continuing to ignore or failure to respond to this issue renders it no less of a concern. potential strategies to include educational campaigns, testimonials, statistical messages, and community involvement (reinhard am, 2020). evidence points to partial success of educational interventions. culturally appropriate messaging in small community groups led to improved attitudes and beliefs among african americans. the intervention was not effective in changing their beliefs about the negative consequences of organ and tissue donation and transplantation or increasing actual registration behaviors (jacob arriola et al., 2019). nonetheless, creating an awareness of this issue, engaging the communities of interest in the conversation, explaining the dearth of tissue donation and its’ impact on developing treatment for african americans might be an important step. we concur with the recommendations of regnante, et al., (regnante et al., 2020): (1) launch community-based campaigns designed to raise awareness of cancer clinical trials research and support recruitment efforts, and (2) provide linguistically accessible printed and online recruitment materials to patients, patient advocates and care partners that are written in plain language and in the languages of desired participant population. they also propose providing transportation, meal vouchers, and childcare support to ease barriers and support patient participation. we believe that considering both the message as well as the messenger are likely to be important to enhance trustworthiness and to increasing biospecimen collection among african americans. to address the issues of trust and trustworthiness, we recommend building collaborative partnerships that engage the communities in which biospecimens are sought. first, it is important to engage trusted constituent gatekeeper groups, such as african american health professionals, and faith and civic leaders to ensure that the factors influencing african american underrepresentation in biospecimens are fully elucidated. subsequent interactions should be convened by these groups with interested majority researchers to forge an understanding of the historical precedents whereby researchers seek strategic guidance from the constituent gatekeeper groups. secondly, we recommend the development of a model curriculum that aims to heighten and increase participation among the trusted constituent gatekeeper groups. following the implementation of a collaboratively developed curriculum, we propose measuring the pre-post testing of the related interventions. conclusions and prospectus minority representation in biobanks or databases at levels that reflect their incidence in the general population is essential to biomedical research. historically, african americans have been less willing to participate in biospecimen and organ donation programs (dash et al., 2014; hagiwara et al., 2014; patel et al., 2018). reasons for the lack of participation include distrust in medical research, fear, lack of transparency, and misunderstanding of the use and perhaps benefits of biospecimen donation (barrett et al., 2017; dang et al., 2014; rollins et al., 2018; warren rc, 2019). the intent of this article was to survey a number of biobanks and repositories that supplied tissues and associated data used by pancreas and pancreatic cancer researchers. we conclude that several www.companyofscientists.com/index.php/chd e7 cancer health disparities research biobanks contained african american tissues at levels that were significantly less than the african american population (table 1) while others correspond to the most current census data that estimates the african american population in the usa at 13.2% (colby and ortman, 2015). although the percentage of african american biospecimen participation may reflect the census data in many of these biobanks, the low number of pancreatic biospecimens available to researchers negatively affects the pace of disparity research, in particular prospective studies. for these reasons, grass root efforts to educate the african american community on the many benefits of biospecimen donation and its impact on biomedical research will have a positive influence on research into diseases of the pancreas. acknowledgement we thank ada golowiejko and aubrey coulas for their assistance with collecting the procurement data. this publication was made possible by funding from the national cancer institute of the national institutes of health under the partnership of the u54ca233444 (uf) and u54ca233465 (usc). its contents are solely the responsibility of the authors and do not necessarily represent the official views of the nih or nci. the final peer-reviewed manuscript is subject to the nih public access policy. cp is supported by a mcknight graduate student fellowship. conflicts of interest/competing interests (include appropriate disclosures) the authors declare no conflict of interest. authors' contributions this manuscript was conceived by l.b.h.; r.c.w, t.d.s., and v.w.s., contributed to the manuscript concept, t.d.s., v.w.s., and c.p. contributed to data synthesis. l.b.h. led the writing. all authors contributed to writing and editing the manuscript. references (2019). cancer facts and figures for african americans. american cancer society, atlanta. 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(2008). epidemiology of alcohol-related liver and pancreatic disease in the united states. archives of internal medicine 168, 649-656. introduction representation of african american biospecimens for diseases of the pancreas health disparities research on pancreas transdifferentiation historical/cultural issues underrepresentation of african americans in biospecimens increasing procurement conclusions and prospectus acknowledgement conflicts of interest/competing interests (include appropriate disclosures) authors' contributions www.companyofscientists.com/index.php/chd e1 cancer health disparities research notch signaling pathway: an emerging therapeutic target for african-american triple negative breast cancer patients nikita wright1&, shristi bhattarai1&, bikram sahoo1, mishal imaan syed1, padmashree rida1, ritu aneja1,2* 1department of biology, georgia state university, atlanta, ga 30303 2international consortium for advancing research on triple negative breast cancer, georgia state university, atlanta, ga 30303 &co-first authors *corresponding author email: raneja@gsu.edu abstract the most fatal form of breast cancer, triple negative breast cancer (tnbc), continues to challenge clinicians worldwide with its lack of reliable prognostic biomarkers and pharmacologically actionable treatment targets. in the us, this aggressive disease disproportionately afflicts african-american women at a rate 2-3 times higher than european-american (ea) women, thereby contributing to the observed higher mortality rates of aa bc patients. in order to address the unmet clinical need for new and effective treatments for aa tnbcs, we describe herein a potentially actionable pathway that appears to be in overdrive in tnbcs of aa patients compared to ea tnbcs: the notch signaling pathway. notch signaling is implicated in multiple aspects of carcinogenesis and tumor progression including the regulation of proliferation, apoptosis, the biology of cancer stem cells, tumor angiogenesis and epithelial-to-mesenchymal transition. our gene expression analyses have uncovered significant upregulation of notch signaling as well as gene ontologies reflecting dysregulation of key processes regulated by notch signaling among aa compared to ea tnbc patients. furthermore, we present evidence suggesting that upregulated notch signaling may predict poor prognosis in tnbc. our findings thus suggest differences in notch signaling among racially-distinct tnbc patients that may contribute to the more aggressive clinical behavior of tnbc in aas. these observations also suggest that notch signaling may be an attractive therapeutic target for high-risk aa tnbc patients. keywords: triple negative breast cancer, racial disparity, notch signaling pathway, africanamerican citation: wright n et al (2019) notch signaling pathway: an emerging therapeutic target for africanamerican triple negative breast cancer patients. cancer health disparities 3:e1-e22. doi:10.9777/chd.2019.1013. www.companyofscientists.com/index.php/chd e2 cancer health disparities research the tip of the iceberg: racial disparities in triple negative breast cancer triple negative breast cancer (tnbc) is a significant public health concern in the us as it afflicts about one-fifth of the ~2.8 million women in the country with breast cancer (bc) (criscitiello et al., 2012; howlader n, 2014). worldwide, the disease accounts for approximately 20% of bc cases. tnbc is the most clinically challenging subtype of bc as it lacks expression of the pharmacologically-targetable estrogen receptor (er), progesterone receptor (pr) and human epidermal growth factor receptor 2 (her2) (bianchini et al., 2016b; lehmann et al., 2011; shah et al., 2012). furthermore, the disease is characterized by high rates of recurrence and metastases, especially within the first five years post diagnosis (bianchini et al., 2016a; kassam et al., 2009; lehmann et al., 2011; shah et al., 2012). tnbcs exhibit high interpatient heterogeneity and many classification schemes have emerged that categorize tnbcs into transcriptomically-distinct molecular subtypes and with unique dna copy number variations (burstein et al., 2015; lehmann et al., 2016). tnbcs also exhibit intratumoral heterogeneity which, together with the lack of clinically facile methods of determining molecular subtypes, thwarts the development of novel targeted treatments. thus, despite advances in treatments for other bc subtypes, chemotherapy remains the cornerstone of treatment for tnbc. tnbc disproportionately afflicts african-american (raab et al.) women, especially younger premenopausal aas (brewster et al., 2014; danforth, 2013; jiagge et al., 2018; keenan et al., 2015; newman and kaljee, 2017; wu et al., 2017). after adjusting for potentially confounding factors, including tumor stage and grade (which tend to be higher in aa women) and age at diagnosis and socioeconomic status (which tend to be lower in aa women), aa women exhibit ~2 times the likelihood of presenting with tnbc (dietze et al., 2015), which partially explains their worse outcomes relative to ea patients. the predisposition towards developing tnbc appears to be deeply rooted in biogeographic ancestry. for example, ~50% of nigerian (agboola et al., 2012) and malian (ly et al., 2012) and ~80% of ghanaian (stark et al., 2010a; stark et al., 2010b) women with bc have triple-negative breast tumors, in contrast with ~15% of ea (carey et al., 2006; stark et al., 2010a) or white british women (agboola et al., 2012; bowen et al., 2008). stark et al. found that 83% of african women presented with tnbc compared to only 41.9% of aas and 15.4% of eas (stark et al., 2010b). although controversial, racial disparities in disease course and outcomes have been reported within the tnbc subtype. accumulating evidence suggest that aas present with more unfavorable clinicopathological characteristics such as larger tumor size, higher proliferation, more extensive lymph node involvement, as well as present at a younger age than eas among tnbc patients (dietze et al., 2015; lund et al., 2009; sullivan et al., 2014). furthermore, aas have been reported to harbor more aggressive tnbc subtypes such as basal-like 1 and mesenchymal stem-like as well as greater intratumoral heterogeneity than eas (keenan et al., 2015; lindner et al., 2013). as a result, aas have been reported to experience shorter overall survival (os) and progression-free survival (pfs) than eas among tnbc patients (dietze et al., 2015; lund et al., 2009; sullivan et al., 2014). newman and colleagues observed 30% higher mortality rate among aa compared to ea tnbc patients (newman et al., 2006). these recent findings have www.companyofscientists.com/index.php/chd e3 cancer health disparities research sparked investigations into distinctions in inherent tumor biology between aa and ea tnbcs to elucidate the molecular underpinnings driving the racially disparate burden in tnbc. currently, there are no reliable methods to identify aa tnbc patients at high risk of poor outcomes, which would indicate the need to offer more aggressive treatment. identification of biomarkers that can risk-stratify aa tnbc patients and predict responsiveness to targeted and cytotoxic agents could improve prognosis of this high-risk patient population. top notch distinctions: shedding light on the notch signaling pathway in triple negative breast cancer the notch signaling pathway has recently emerged as a novel therapeutic target of interest in tnbc. the pathway is present in most multicellular organisms and is highly conserved. it is essential for cell proliferation, differentiation and development and plays keys roles in cell fate determination (ranganathan et al., 2011). there are four different notch receptors (notch1, notch2, notch3 and notch4) expressed in mammals (dontu et al., 2004). the notch receptor is a hetero-oligomer transmembrane receptor protein composed of an extracellular protein domain, a single transmembrane pass and a small intracellular region. notch receptors on the cell surface engage with notch ligandsdelta-like (dll1, dll3, dll4) and jagged (jag1, jag2) to initiate the signaling cascade (bray et al., 2008; brou et al., 2000; fiuza and arias, 2007). after the interaction of a notch ligand with its receptor, a metalloprotease protein from the adam-family (adam10) cleaves the notch receptor outside the membrane (van tetering et al., 2009); the extracellular portion of the notch receptor attached to its ligand is thus released and gets endocytosed by ligand-expressing cells. the remaining part of the notch receptor inside the inner leaflet of the cell membrane undergoes a cleavage by an enzyme called gamma-secretase, releasing the intracellular domain of the notch protein (borggrefe and liefke, 2012). the notch intracellular domain then forms a trimeric core transactivation complex with the sequence-specific dna binding protein, csl (cbf-1/su(h)/lag-1), and the transcriptional co-activator, mastermind, to activate transcription of target genes (nam et al., 2006; wilson and kovall, 2006). transcriptional targets include transcription factors (nf‐κb2 and c‐ myc), cell‐cycle regulators (cyclin d1 and p21), growth factor receptors and regulators of angiogenesis and apoptosis. dysregulated notch signaling is associated with various malignancies. expression of notch receptors and ligand protein have been reported to be upregulated in breast tumors compared to normal breast tissues (mittal et al., 2009; rizzo et al., 2008; zardawi et al., 2010). parr et al. observed an aberrant level of notch-1 and notch-2 expression in breast tumor tissue via immunohistochemistry and quantitative rt-pcr. the study demonstrated that high expression level of notch ligands and/or receptors correlated significantly with poor clinical outcomes (parr et al., 2004). moreover, several studies suggest that increased expression of notch is associated with oncogene expression, maintaining stemness of bc stem cells and deregulated cell cycle progression (harrison et al., 2010; ronchini and capobianco, 2001; sharma et al., 2006; weng et al., 2006). notch signaling plays a critical role in tnbc. dickson et al. were the first to uncover an association of notch expression with tnbc. the study revealed a significant correlation of overexpression of jag-1 and notch-1 with poor www.companyofscientists.com/index.php/chd e4 cancer health disparities research prognosis among tnbc patients (dickson et al., 2007). furthermore, notch-1 and notch-4 receptors have been discovered to be overexpressed in tnbc vascular endothelial cells (speiser et al., 2012). recent studies also uncovered a jagged1-notch1-cyclind1 axis playing a key role in maintaining proliferation of tnbc, as opposed to other types of bc (cohen et al., 2010). notch3 signaling controls survival of hypoxic tnbc cells and notch4 is involved in self-renewal of bc stem cells. (harrison et al., 2010; sansone et al., 2007) evidence reinforcing the notion that dysregulation of notch signaling is pathogenetically relevant in tnbc came from a study wherein chromosomal rearrangements producing constitutively active versions of notch1 or notch2 were detected almost exclusively in tnbc cell lines and tumors (robinson et al., 2011). when the notch signaling pathway gets activated, the notch intracellular domain (icd), generated by the enzyme gamma-secretase, translocates from the cytoplasm to the nucleus where it binds to the csl complex to initiate the transcription of downstream targets (shih ie and wang, 2007). the nuclear localization of notch has been reported to occur more frequently in tnbc compared to hormone receptor-positive tumors (touplikioti, 2012). moreover, speiser et al. discovered more positive nuclear and cytoplasmic staining of notch-1 and notch-4 in tnbc samples and more positive membrane staining of these proteins in hormone receptor-positive breast tumor specimens (speiser et al., 2012). many studies on notch signaling have postulated that its cellular localization can be a morphological illustration of its function (bray et al., 2008). as previously described, upon interaction of the transmembrane notch receptor with its ligand, the receptor is proteolytically cleaved and the nicd is released into the nucleus. inside the nucleus, nicd modulates transcription of target genes via interaction with csl (schroeter et al., 1998; weijzen et al., 2002). thus, the subcellular localization of the notch protein reflects the functional activity of the receptor. membrane localization of the notch protein represents a mature receptor that has not yet been activated; cytoplasmic localization of the protein represents a newly synthesized receptor which is on its way to plasma membrane; and nuclear localization of notch protein reflects the activated state of the receptor (speiser et al., 2012). however, the correlation between the amount of notch staining and notch pathway activity, especially if the staining is distributed to the nucleus or cytoplasm, remains unknown. furthermore, in a study by yao et al., there was significantly more membranous staining in the er-positive compared to the ernegative bc cases (yao et al., 2011). this finding suggests that estrogen increases notch-1 protein levels and causes it to accumulate at the cell membrane [which represents a mature but nonactivated form of notch-1], but not in the nucleus (rizzo et al., 2008). thus, nuclear localized notch-1 and notch-4 may serve as potential therapeutic targets for tnbc patients. moreover, rizzo et al. observed sensitivity of tnbc cells to notch inhibitors. the authors demonstrated arrest of tnbc cells in g2 phase of cell cycle upon knockdown of notch-1 and notch-4 with sirna or pharmacological inhibition of gamma-secretase (gsi) (rizzo et al., 2008). gsi inhibitors are currently in clinical trials to reduce notch signaling in patients with recurrent tnbc (olsauskas-kuprys et al., 2013). a recent clinical trial demonstrated that the administration of a gsi inhibitor in combination with docetaxel elicited anti-tumor activity in patients with locally advanced/metastatic www.companyofscientists.com/index.php/chd e5 cancer health disparities research tnbc (locatelli and curigliano, 2017). thus, notch signaling, which is highly upregulated in tnbc, may be a potential therapeutic target for tnbc patients, who lack good targeted therapy options. uncharted territory: investigating disparities in the notch signaling pathway among racially-distinct triple negative breast cancer patients the emergence of notch signaling as a therapeutic target of interest in tnbc has spurred interest in this pathway as a potential suspect in the racially disparate burden in tnbc. however, literature evidence supporting this speculation remains sparse. a genome-wide association study conducted by adriano and colleagues revealed that a snp in the notch4 locus was significantly associated with aa but not ea sarcoidosis patients and this finding remained consistent in multivariate models (adrianto et al., 2012). sarcoidosis disproportionately afflicts aas suggesting that this genetic variant may play a role in the disease’s disparate burden (cozier et al., 2011; james and sherlock, 1994). furthermore, stewart et al. discovered that the notch 2 n-terminal-like (notch2nl) gene was significantly upregulated among aa compared to ea bc patients in the tcga dataset (stewart et al., 2013). however, ethnic differences in notch signaling and its role in the higher incidence of and poorer outcomes from tnbc remain understudied. we recently queried tcga breast dataset for aa and ea tnbc patients and exploited bioinformatics tools to determine differentiallyexpressed genes, biological pathways, and gene ontologies between the racially-distinct tnbc patients. according to our deseq2 or differential gene expression analyses, we observed significant upregulation of genes encoding key components of the notch signaling network such as notchregulated ankyrin repeat protein (nrarp), notch2nl, delta/notch-like egfr repeat containing (dner), jagged 1 (jag1), jagged 2 (jag2), hess family belch transcription factor 4 (hes4), and matrix metalloproteinase-9 (mmp9) among aa compared to ea tnbc samples (p<0.05) (table 1). we employed the gage and pathview packages to identify differentiallyexpressed biological pathways or experimentallyderived differential expression sets (table 2) and gene ontologies (table 3) between rna sequenced aa and ea tnbc samples. interestingly, we discovered that the notch signaling pathway expression set was more upregulated in aa compared to ea tnbc samples (p=0.054). we also observed significant downregulation of key processes that are normally repressed by notch signaling such as focal adhesion, extracellular matrix (ecm)-receptor interaction, and adherents junction expression sets as well as cell junction assembly, cell-cell junction organization, cell-cell adhesion, epithelial cell development, negative regulation of endothelial cell proliferation, double-strand break repair, and regulation of dna repair gene ontologies (p<0.05). furthermore, we observed significant upregulation of gene ontologies reflecting t cell antitumoral immunity (which is enhanced by notch signaling) such as t cell differentiation, t cell activation, adaptive immune response, and interferon-gamma production (p<0.05). moreover, kaplan-meier survival analyses revealed that overexpression of dner predicted significantly poorer relapse-free survival (rfs) in tnbcs (hr=2.4; p=0.0012); jag2 expression also www.companyofscientists.com/index.php/chd e6 cancer health disparities research table 1. genes significantly upregulated among aa compared to ea tnbc patients in the tcga dataset. gene symbol entrez name base mean log2foldchange p value ensg00000198435 nrarp 441478 notch-regulated ankyrin repeat protein 516.3894051 5.051550368 4.38e-07 ensg00000167244 igf2 3481 insulin like growth factor 2 2619.306453 -1.233367377 1.02e-05 ensg00000157764 braf 673 b-raf proto-oncogene, serine/threonine kinase 214.9862772 -0.502496583 2.33e-05 ensg00000165105 rasef 158158 ras and ef-hand domain containing 162.6660192 -0.958748689 7.76e-05 ensg00000184916 jag2 3714 jagged 2 836.7242091 3.853121028 0.0001166 ensg00000188290 hes4 57801 hes family bhlh transcription factor 4 137.2454011 3.84511881 0.0001205 ensg00000171408 pde7b 27115 phosphodiesterase 7b 70.86301288 -0.806853305 0.0001551 ensg00000073921 picalm 8301 phosphatidylinositol binding clathrin assembly protein 4146.086807 -0.328030427 0.0001577 ensg00000264343 notch2nl 388677 notch 2 n-terminal like 1130.083257 3.692675235 0.0002219 ensg00000185737 nrg3 10718 neuregulin 3 18.2400562 -1.093851375 0.0002292 ensg00000046889 prex2 80243 phosphatidylinositol-3,4,5-trisphosphate dependent rac exchange factor 2 35.37360263 -0.965093716 0.0003995 ensg00000151689 inpp1 3628 inositol polyphosphate-1-phosphatase 257.8331804 -0.464334443 0.0007263 ensg00000151151 ipmk 253430 inositol polyphosphate multikinase 66.09782388 -0.677173589 0.0007599 ensg00000101384 jag1 182 jagged 1 2029.134072 3.352573762 0.0008006 ensg00000169435 rassf6 166824 ras association domain family member 6 87.45601131 -0.732054428 0.0010291 ensg00000041353 rab27b 5874 rab27b, member ras oncogene family 67.49077359 -0.735088474 0.0011336 ensg00000175985 plekhd1 400224 pleckstrin homology and coiled-coil domain containing d1 3.551807893 -0.997599044 0.0012151 ensg00000169220 rgs14 10636 regulator of g-protein signaling 14 356.4357972 0.493690701 0.0013154 ensg00000154678 pde1c 5137 phosphodiesterase 1c 63.21150224 -0.857678049 0.0014838 ensg00000151491 eps8 2059 epidermal growth factor receptor pathway substrate 8 895.8248723 -0.525349111 0.0016848 ensg00000064932 sbno2 22904 strawberry notch homolog 2 1823.609706 3.135072772 0.0017181 ensg00000011405 pik3c2a 5286 phosphatidylinositol-4-phosphate 3-kinase catalytic subunit type 2 alpha 1239.790208 -0.396160165 0.0017905 ensg00000109452 inpp4b 8821 inositol polyphosphate-4-phosphatase type ii b 152.8627179 -0.735904178 0.0018282 ensg00000178568 erbb4 2066 erb-b2 receptor tyrosine kinase 4 74.66419079 -0.896585238 0.0024244 ensg00000187957 dner 92737 delta/notch like egf repeat containing 173.0818588 2.870907184 0.004093 ensg00000078142 pik3c3 5289 phosphatidylinositol 3-kinase catalytic subunit type 3 551.5572258 -0.281487717 0.0055186 www.companyofscientists.com/index.php/chd e7 cancer health disparities research ensg00000085832 eps15 2060 epidermal growth factor receptor pathway substrate 15 1725.645419 -0.21533493 0.0055454 ensg00000137825 itpka 3706 inositol-trisphosphate 3-kinase a 11.85034496 -0.688848495 0.0061921 ensg00000137142 igfbpl1 347252 insulin like growth factor binding protein like 1 12.11877278 -0.790048534 0.0062746 ensg00000073536 nle1 54475 notchless homolog 1 347.5008396 2.711514433 0.0066977 ensg00000163964 pigx 54965 phosphatidylinositol glycan anchor biosynthesis class x 740.0513792 -0.330509569 0.0084688 ensg00000097033 sh3glb1 51100 sh3 domain containing grb2 like endophilin b1 2960.384131 -0.219544393 0.0084951 ensg00000169752 nrg4 145957 neuregulin 4 7.692847298 -0.718554497 0.0086447 ensg00000161896 ip6k3 117283 inositol hexakisphosphate kinase 3 11.780405 -0.794971219 0.0092705 ensg00000162434 jak1 3716 janus kinase 1 3697.004587 -0.265820839 0.0099595 ensg00000197563 pign 23556 phosphatidylinositol glycan anchor biosynthesis class n 628.3454755 -0.361073745 0.0100388 ensg00000146648 erbb1 1956 epidermal growth factor receptor 788.1655218 -0.514822969 0.0106547 ensg00000186479 rgs7bp 401190 regulator of g-protein signaling 7 binding protein 9.793117489 -0.738439155 0.0107012 ensg00000197081 igf2r 3482 insulin like growth factor 2 receptor 3893.882883 -0.353086769 0.0109115 ensg00000100985 mmp9 4318 matrix metallopeptidase 9 2820.554471 0.550370107 0.0117042 ensg00000106780 megf9 1955 multiple egf like domains 9 788.1489691 -0.382312117 0.0121799 ensg00000182836 plcxd3 345557 phosphatidylinositol specific phospholipase c x domain containing 3 16.82951336 -0.73024397 0.0140536 ensg00000122126 ocrl 4952 ocrl, inositol polyphosphate-5-phosphatase 1231.48057 -0.285100271 0.0151527 ensg00000184588 pde4b 5142 phosphodiesterase 4b 1333.079513 -0.509410864 0.0163107 ensg00000114302 prkar2a 5576 protein kinase camp-dependent type ii regulatory subunit alpha 311.0446898 -0.458155081 0.0166052 ensg00000116711 pla2g4a 5321 phospholipase a2 group iva 336.2022255 -0.582605068 0.0171755 ensg00000171105 insr 3643 insulin receptor 1909.416792 -0.295867756 0.0173053 ensg00000164318 egflam 133584 egf like, fibronectin type iii and laminin g domains 229.0134131 -0.469580197 0.0176762 ensg00000132554 rgs22 26166 regulator of g-protein signaling 22 4.574242623 -0.636004928 0.0192316 ensg00000184613 nell2 4753 neural egfl like 2 196.5001129 -0.572676436 0.0232947 ensg00000142892 pigk 10026 phosphatidylinositol glycan anchor biosynthesis class k 781.7799581 -0.208806421 0.0234037 ensg00000141639 mapk4 5596 mitogen-activated protein kinase 4 208.7727368 -0.569541107 0.0325864 ensg00000107643 mapk8 5599 mitogen-activated protein kinase 8 324.7787941 -0.300393202 0.033222 ensg00000100078 pla2g3 50487 phospholipase a2 group iii 6.341731975 -0.631494614 0.0378273 ensg00000198759 egfl6 25975 egf like domain multiple 6 182.8515839 -0.479870257 0.0381221 www.companyofscientists.com/index.php/chd e8 cancer health disparities research ensg00000107175 creb3 10488 camp responsive element binding protein 3 1217.85437 -0.203621813 0.0407954 ensg00000145725 ppip5k2 23262 diphosphoinositol pentakisphosphate kinase 2 756.5355326 -0.222844677 0.0425919 ensg00000154217 pitpnc1 26207 phosphatidylinositol transfer protein, cytoplasmic 1 348.007567 -0.291090967 0.0466811 ensg00000158786 pla2g2f 64600 phospholipase a2 group iif 1.839617956 -0.585514584 0.0480319 ensg00000166997 cnpy4 245812 canopy fgf signaling regulator 4 378.1533882 -0.251460656 0.0527973 ensg00000109339 mapk10 5602 mitogen-activated protein kinase 10 137.1476556 -0.515298729 0.0555319 ensg00000138698 rap1gds1 5910 rap1 gtpase-gdp dissociation stimulator 1 1021.906809 -0.195978894 0.0566303 ensg00000138798 egf 1950 epidermal growth factor 142.104671 -0.531883076 0.0619204 ensg00000070193 fgf10 2255 fibroblast growth factor 10 3.462625673 -0.562797728 0.0638813 ensg00000113070 hbegf 1839 heparin binding egf like growth factor 277.4721214 -0.313566424 0.0768535 ensg00000065361 erbb3 2065 erb-b2 receptor tyrosine kinase 3 3949.329412 -0.056599349 0.7418933 table 2. biological pathways significantly upregulated and downregulated among aa compared to ea tnbc patients in tcga dataset. upregulated kegg pathways p-value hsa03010 ribosome 0.005533158 hsa04672 intestinal immune network for iga production 0.006164042 hsa04640 hematopoietic cell lineage 0.028001619 hsa04330 notch signaling pathway 0.053768917 downregulated kegg pathways hsa00600 sphingolipid metabolism 0.01816452 hsa00512 mucin type o-glycan biosynthesis 0.02316771 hsa04510 focal adhesion 0.02628723 hsa00982 drug metabolism cytochrome p450 0.02880007 hsa04520 adherens junction 0.03365944 hsa00500 starch and sucrose metabolism 0.03901639 hsa00983 drug metabolism other enzymes 0.04328416 hsa04512 ecm-receptor interaction 0.04359347 www.companyofscientists.com/index.php/chd e9 cancer health disparities research table 3. gene ontologies significantly upregulated and downregulated among aa compared to ea tnbc patients in tcga dataset. upregulated p value go:0048534 hematopoietic or lymphoid organ development 0.000429373 go:0002521 leukocyte differentiation 0.000467453 go:0030097 hemopoiesis 0.000595111 go:0002252 immune effector process 0.000606896 go:0030098 lymphocyte differentiation 0.000668007 go:0002520 immune system development 0.000752091 go:0001816 cytokine production 0.001262715 go:0001817 regulation of cytokine production 0.001304632 go:0019080 viral genome expression 0.002009214 go:0019083 viral transcription 0.002009214 go:0060337 type i interferon-mediated signaling pathway 0.002260808 go:0071357 cellular response to type i interferon 0.002260808 go:0001818 negative regulation of cytokine production 0.002341488 go:0034340 response to type i interferon 0.002360857 go:0045087 innate immune response 0.002660009 go:0050776 regulation of immune response 0.003381564 go:0006415 translational termination 0.003994976 go:0019058 viral infectious cycle 0.004289754 go:0045321 leukocyte activation 0.005368308 go:0046649 lymphocyte activation 0.006021313 go:0002443 leukocyte mediated immunity 0.006737807 go:0043241 protein complex disassembly 0.006915896 go:0045619 regulation of lymphocyte differentiation 0.00711599 go:0043624 cellular protein complex disassembly 0.009113965 go:0032609 interferon-gamma production 0.009394054 www.companyofscientists.com/index.php/chd e10 cancer health disparities research go:0030217 t cell differentiation 0.009403061 go:0071356 cellular response to tumor necrosis factor 0.009678773 go:0009615 response to virus 0.009744867 go:0051250 negative regulation of lymphocyte activation 0.009818976 go:0050778 positive regulation of immune response 0.009903295 go:2000106 regulation of leukocyte apoptotic process 0.010825095 go:0071887 leukocyte apoptotic process 0.011246013 go:0042089 cytokine biosynthetic process 0.011366604 go:0002695 negative regulation of leukocyte activation 0.011891576 go:0002684 positive regulation of immune system process 0.012690724 go:0050866 negative regulation of cell activation 0.012821361 go:0034113 heterotypic cell-cell adhesion 0.012850245 go:0006414 translational elongation 0.013939004 go:0002253 activation of immune response 0.014337616 go:0051607 defense response to virus 0.01448594 go:0034341 response to interferon-gamma 0.014747388 go:0032984 macromolecular complex disassembly 0.01485217 go:0032649 regulation of interferon-gamma production 0.015069142 go:0051707 response to other organism 0.017081494 go:0002263 cell activation involved in immune response 0.017140132 go:0002366 leukocyte activation involved in immune response 0.017140132 go:0045580 regulation of t cell differentiation 0.017360252 go:0000184 nuclear-transcribed mrna catabolic process, nonsense-mediated decay 0.017466425 go:0071346 cellular response to interferon-gamma 0.017582795 go:0021903 rostrocaudal neural tube patterning 0.01828075 go:0071706 tumor necrosis factor superfamily cytokine production 0.018894657 go:0008544 epidermis development 0.019826968 www.companyofscientists.com/index.php/chd e11 cancer health disparities research go:0050701 interleukin-1 secretion 0.01990773 go:0032088 negative regulation of nf-kappab transcription factor activity 0.020009424 go:0032640 tumor necrosis factor production 0.02003891 go:0032680 regulation of tumor necrosis factor production 0.02003891 go:0002460 adaptive immune response based on somatic recombination of immune receptors built from immunoglobulin superfamily domains 0.020144927 go:0042113 b cell activation 0.020274634 go:0035587 purinergic receptor signaling pathway 0.021137639 go:0042035 regulation of cytokine biosynthetic process 0.021288775 go:0034470 ncrna processing 0.021369145 go:0002444 myeloid leukocyte mediated immunity 0.021915664 go:0009607 response to biotic stimulus 0.02334661 go:0051249 regulation of lymphocyte activation 0.02428066 go:0042107 cytokine metabolic process 0.025345542 go:0030917 midbrain-hindbrain boundary development 0.025352336 go:0060333 interferon-gamma-mediated signaling pathway 0.025576575 go:0006941 striated muscle contraction 0.026309493 go:0003009 skeletal muscle contraction 0.026410898 go:0006959 humoral immune response 0.027278157 go:0071345 cellular response to cytokine stimulus 0.027348302 go:0032715 negative regulation of interleukin-6 production 0.028648897 go:0031348 negative regulation of defense response 0.028778621 go:0002703 regulation of leukocyte mediated immunity 0.028922763 go:0043299 leukocyte degranulation 0.029801087 go:0043173 nucleotide salvage 0.029893126 go:0006613 cotranslational protein targeting to membrane 0.030068796 go:0006614 srp-dependent cotranslational protein targeting to membrane 0.030068796 www.companyofscientists.com/index.php/chd e12 cancer health disparities research go:0071219 cellular response to molecule of bacterial origin 0.030789397 go:0002250 adaptive immune response 0.030841904 go:0097028 dendritic cell differentiation 0.031317678 go:0002697 regulation of immune effector process 0.031523821 go:0071222 cellular response to lipopolysaccharide 0.031667044 go:0007606 sensory perception of chemical stimulus 0.032245552 go:0050865 regulation of cell activation 0.032311054 go:0051930 regulation of sensory perception of pain 0.034463637 go:0051931 regulation of sensory perception 0.034463637 go:0045047 protein targeting to er 0.034644877 go:0072599 establishment of protein localization to endoplasmic reticulum 0.034644877 go:0043433 negative regulation of sequence-specific dna binding transcription factor activity 0.034934546 go:0002764 immune response-regulating signaling pathway 0.035070643 go:0050848 regulation of calcium-mediated signaling 0.035464555 go:0051216 cartilage development 0.035996334 go:0070586 cell-cell adhesion involved in gastrulation 0.036025281 go:0010470 regulation of gastrulation 0.03613861 go:0006402 mrna catabolic process 0.036140008 go:0042074 cell migration involved in gastrulation 0.036712677 go:0002757 immune response-activating signal transduction 0.036719431 go:0050704 regulation of interleukin-1 secretion 0.037451445 go:0070972 protein localization to endoplasmic reticulum 0.037618557 go:0000956 nuclear-transcribed mrna catabolic process 0.037782421 go:0002694 regulation of leukocyte activation 0.03779717 go:0061383 trabecula morphogenesis 0.038343425 go:0032612 interleukin-1 production 0.038674489 go:0035809 regulation of urine volume 0.038920075 www.companyofscientists.com/index.php/chd e13 cancer health disparities research go:0002449 lymphocyte mediated immunity 0.039034069 go:0002683 negative regulation of immune system process 0.039201076 go:0030183 b cell differentiation 0.039462908 go:0001783 b cell apoptotic process 0.040421151 go:0042249 establishment of planar polarity of embryonic epithelium 0.040903568 go:0006400 trna modification 0.040910207 go:0070228 regulation of lymphocyte apoptotic process 0.04166174 go:0006399 trna metabolic process 0.041688021 go:0032729 positive regulation of interferon-gamma production 0.041968537 go:0050909 sensory perception of taste 0.042391791 go:0033209 tumor necrosis factor-mediated signaling pathway 0.043478576 go:0031334 positive regulation of protein complex assembly 0.044230876 go:0050868 negative regulation of t cell activation 0.044579293 go:0042110 t cell activation 0.045651071 go:0071347 cellular response to interleukin-1 0.045684339 go:0003416 endochondral bone growth 0.046119963 go:0060026 convergent extension 0.046776142 go:0023021 termination of signal transduction 0.046852554 go:0038032 termination of g-protein coupled receptor signaling pathway 0.047117236 go:0010657 muscle cell apoptotic process 0.047468866 go:0006401 rna catabolic process 0.047552326 go:0042254 ribosome biogenesis 0.047629412 go:0022904 respiratory electron transport chain 0.048240328 go:0043094 cellular metabolic compound salvage 0.048452721 go:0006612 protein targeting to membrane 0.048517893 go:0042401 cellular biogenic amine biosynthetic process 0.048738698 go:0051495 positive regulation of cytoskeleton organization 0.048955127 www.companyofscientists.com/index.php/chd e14 cancer health disparities research go:0002285 lymphocyte activation involved in immune response 0.049073929 go:0050864 regulation of b cell activation 0.049545191 downregulated go:0043687 post-translational protein modification 0.000493768 go:0007156 homophilic cell adhesion 0.000891909 go:0070085 glycosylation 0.001919505 go:0006486 protein glycosylation 0.002075176 go:0043413 macromolecule glycosylation 0.002075176 go:0006665 sphingolipid metabolic process 0.002745447 go:0007270 neuron-neuron synaptic transmission 0.002807343 go:0051966 regulation of synaptic transmission, glutamatergic 0.003328871 go:0006687 glycosphingolipid metabolic process 0.003952335 go:0009101 glycoprotein biosynthetic process 0.004520639 go:0035249 synaptic transmission, glutamatergic 0.004653915 go:0007158 neuron cell-cell adhesion 0.004656323 go:0006643 membrane lipid metabolic process 0.005041899 go:0018196 peptidyl-asparagine modification 0.005612873 go:0018279 protein n-linked glycosylation via asparagine 0.005612873 go:0006487 protein n-linked glycosylation 0.005970635 go:0031645 negative regulation of neurological system process 0.006532083 go:0051968 positive regulation of synaptic transmission, glutamatergic 0.006542085 go:0009100 glycoprotein metabolic process 0.007071823 go:0016266 o-glycan processing 0.00822715 go:0007595 lactation 0.008438853 go:0007610 behavior 0.009407186 go:0007420 brain development 0.009694387 go:0050808 synapse organization 0.010243263 www.companyofscientists.com/index.php/chd e15 cancer health disparities research go:0036148 phosphatidylglycerol acyl-chain remodeling 0.010257756 go:0042391 regulation of membrane potential 0.010342608 go:0006805 xenobiotic metabolic process 0.010598743 go:0071466 cellular response to xenobiotic stimulus 0.011270151 go:0030879 mammary gland development 0.011361444 go:0001508 regulation of action potential 0.011440865 go:0051970 negative regulation of transmission of nerve impulse 0.011501433 go:0048667 cell morphogenesis involved in neuron differentiation 0.012566558 go:0051932 synaptic transmission, gabaergic 0.012763237 go:0044723 single-organism carbohydrate metabolic process 0.012821492 go:0006664 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www.companyofscientists.com/index.php/chd e18 cancer health disparities research predicted significantly worse rfs in tnbcs (hr=1.75; p=0.027); nrarp expression was associated with a trend towards poorer rfs in tnbcs (hr=1.53; p=0.17); and notch2nl expression was associated with poorer rfs in tnbc (hr=1.001; p=0.01). the prognostic value of notch2nl expression level was upheld after adjusting for age, stage and race (aa vs. ea); in fact, the expression of notch2nl was the only significant predictor of rfs in multivariable analyses (p=0.003). interestingly, dner ranked in the top 1% of genes most highly dysregulated in the basal-like immuno-suppressed (blis) tnbc molecular subtype. aas tend to harbor basal-like subtypes of tnbc and the blis molecular subtype is 1 of 2 basal-like tnbc molecular subtypes recently identified (burstein et al., 2015) that has the worst disease-free survival and bc-specific survival among the 4 prognostically-distinct tnbc molecular subtypes. our group’s findings collectively suggest that the notch signaling pathway may be upregulated among tnbc patients of african compared to european ancestry, and upregulated notch signaling may serve as a poor prognosis biomarker in tnbc. targeting notch signaling may therefore be a promising personalized therapeutic strategy for tnbc patients of african descent, including aas. taking it up a notch: establishing notch signaling as therapeutic target of interest for triple negative breast cancer patients of african descent tnbc remains the primary culprit for disproportionately lower survival rates of aa compared to ea bc patients. thus, identifying novel therapeutic targets and/or risk-predictive biomarkers for tnbc patients of african ancestry will be critical to alleviating the racially disparate burden in bc. emerging evidence suggest that inherent differences exist in tumor biology between aa and ea tnbc patients. getz et al. discovered that dysregulated genes in the wnt/catenin pathway were significantly more enriched among tnbc patient samples of african compared to european ancestry, which may rationalize the aggressive tnbc phenotypes observed among patients of african descent (dietze et al., 2015). however, more work is warranted to examine inherent tumor biological differences between racially-distinct tnbc patients. our group sought to investigate differences in tumor biology between aa and ea tnbc patients through analyzing the publicly-available gene expression dataset, tcga. interestingly, notch signaling emerged as a pathway significantly upregulated among aa compared to ea tnbc patients. we observed upregulation of the notch signaling pathway among aa compared to ea tnbc samples as well as significant upregulation of genes encoding key notch signaling proteins in this pathway such as nrarp, dner, jag1, jag2, hes4, and mmp9. nrarp is a downstream effector in the notch pathway and its overexpression has been associated with breast carcinogenesis and bc cell proliferation (imaoka et al., 2014). jag1 and jag2 encode two major ligands in the canonical notch signaling pathway (wang et al., 2010). the hes family of transcription factors represent a major family of downstream target genes in the notch signaling pathway (acar et al., 2016). mmp9 is implicated in the breakdown of the extracellular matrix to facilitate invasion and metastasis in tnbc (mehner et al., 2014). furthermore, we observed significant downregulation of biological pathways and gene www.companyofscientists.com/index.php/chd e19 cancer health disparities research ontologies reflecting loss of cell-cell contacts, focal adhesion, and ecm-receptor interaction as well as reduced epithelial cell development, reduced endothelial cell proliferation, and dna damage response among aa compared to ea patients. notch signaling regulates proliferation, apoptosis, angiogenesis, hypoxia, emt, and metastasis (acar et al., 2016). thus, significant downregulation of these processes among aa compared to ea samples may reflect increased proliferation, angiogenesis, metastasis, and reduced cell death among aa patients. we also observed significant upregulation of gene ontologies reflecting t cellmediated immune response, which is upregulated by notch signaling (uzhachenko and shanker, 2016). hence, we have uncovered notch signaling as a key biological pathway that may contribute to the racially disparate burden in tnbc and serve as a potential therapeutic target for aa patients. our findings thus encourage a closer look at this biological pathway as a potential racial disparity biomarker and therapeutic target for tnbc. however, validation of our results in additional gene expression datasets as well as at the protein expression level among patient samples of known tnbc molecular subtypes will be critical to achieving this aim. furthermore, investigating the effects of manipulating notch signaling among racially-distinct tnbc patient-derived cell lines or in vivo will be pertinent to effectively targeting this pathway in patients of african ancestry. notch signaling inhibitors such as gsi and aspartyl protease inhibitors are currently under clinical development and in clinical trials as investigational targeted therapies for tnbc patients (jamdade et al., 2015). gsi inhibitors are associated with side effects including fatigue, myelosuppression, fever, rash, chills, anorexia, and hypophosphatemia. improving the toxicity profile and efficacies of gsis, and development of more effective inhibitors of notch signaling could be crucial for improving outcomes among aa tnbc patients. acknowledgements we have no individuals to acknowledge. conflict of interest the authors declare that no competing or conflict of interests exists. the funders had no role in study design, writing of the manuscript, or decision to publish. authors’ contributions nikita wright was involved in the data collection and drafting of the article. shristi bhattarai was involved in the drafting and editing of the article. bikram sahoo and mishal imaan syed were involved in data collection/analysis. dr. padmashree rida was involved in conceptualization and editing of the article. dr. ritu aneja was involved in conceptualization, editing, and oversight of the study. references acar, a., simoes, b.m., clarke, r.b., and brennan, k. 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(2010). high notch1 protein expression is an early event in breast cancer development and is associated with the her-2 molecular subtype. histopathology 56, 286-296. www.companyofscientists.com/index.php/chd e1 cancer health disparities research adaptation of a community health advisor intervention to increase colorectal cancer screening among african americans in the southern united states matthew a. vargas1, olayemi o. matthew1, deloria r. jackson1, tifini austin1, rima tawk1, kristin wallace2,3, clement k. gwede4,5, john s. luque*1 1 college of pharmacy & pharmaceutical sciences, institute of public health, florida a&m university, 1515 martin luther king, jr. blvd., tallahassee, fl 32307, usa 2 department of public health sciences, college of medicine, medical university of south carolina, 68 president street, charleston, sc 29425, usa 3 hollings cancer center, medical university of south carolina, 86 jonathan lucas street, charleston, sc 29425, usa 4 division of population sciences, department of health outcomes and behavior, moffitt cancer center, 12902 magnolia dr., fow-edu, tampa, fl 33612, usa 5 morsani college of medicine, university of south florida, 12902 magnolia dr., fow-edu, tampa, fl 33612, usa *corresponding author and email: john s. luque; john.luque@famu.edu. abstract community health advisor (cha) interventions increase colorectal cancer (crc) screening rates. african americans experience crc disparities in incidence and mortality rates compared to whites in the us. focus groups and learner verification were used to adapt national cancer institute crc screening educational materials for delivery by a cha to african american community health center patients. such academic-community collaboration improves adoption of evidence-based interventions. this short article describes the adaptation of an evidence-based cancer education intervention for implementation in an african american community. keywords: colorectal cancer; colorectal cancer screening; health disparities; african americans. citation: vargas ma et al (2021) adaptation of a community health advisor intervention to increase colorectal cancer screening among african americans in the southern united states. cancer health disparities 5:e1-e10. doi:10.9777/chd.2021.1002. www.companyofscientists.com/index.php/chd e2 cancer health disparities research introduction evidence-based public health involves merging science-based interventions and programs with community-identified needs and capacity aiming for the goal of improving population health (kohatsu et al., 2004). patient navigation for colorectal cancer (crc) is an evidence-based approach to improve patient outcomes in the areas of cancer screening, diagnostic procedures, and follow-up for cancer treatment (leach et al., 2021). a recent systematic review reported that colorectal, breast, and cervical cancer screening rates were higher in patients who received patient navigation services, which can be very impactful for african americans who experience cancer health disparities (nelson et al., 2020). african americans have lower crc screening rates than whites, and consequently, there have been numerous intervention studies to increase screening rates for african americans through patient navigation, technological innovations, and improvements to appointment scheduling or reminder systems (boutsicaris et al., 2021; davis et al., 2017; miller et al., 2020). as one of the four major cancer sites, crc mortality rates have been declining since 1980, but in recent years these declines have slowed (siegel et al., 2021). african americans experience crc disparities in mortality rates which can be attributed to persistent income inequalities and its effects on access to healthcare and lower screening adherence, which may result in late-stage diagnosis and lower survival rates (desantis et al., 2019). according to the latest available data, the mortality rate for african americans is 36% higher than whites (18.5 per 100,000 population compared to 13.6 per 100,000 population for whites), with more pronounced disparities for men compared to women (siegel et al., 2021). crc incidence rates are also higher among african americans compared to whites, and in terms of geographic variation, incidence rates in the us south are higher compared to other regions of the us, which is another factor to consider especially with the rise in early-onset colorectal cancer (siegel et al., 2019). this short article summarizes the adaptation and refinement of a community health advisor (cha) intervention which employs evidence-based patient navigation approaches and includes educational materials from the national cancer institute (nci) screen to save (s2s) colorectal cancer outreach and screening initiative (national cancer institute, 2021). educational materials development s2s is a national initiative which aims to enhance crc outreach and screening. according to the nci, the aim is to increase crc screening rates among men and women ages 50 and older from racially and ethnically diverse communities and in rural areas (national cancer institute, 2021). in alignment with the nci’s goal of increasing crc screening rates, the test up now education program (tune-up) created and adapted materials which consisted of an educational brochure and a narrated presentation video based on the s2s materials to deliver a culturally tailored intervention to african americans living in low-income communities. the intervention is delivered by the cha to african americans in north florida who are patients of community health centers and are not up to date with crc screening. this research project is part of a research centers in minority institutions grant from the national institute on minority health and health disparities which is focused on addressing cancer health disparities in leon county and gadsden county, florida. gadsden county is the only county in florida with a majority african american population. the utilization of a cha and the adaptation of s2s is an evidence-based approach for promoting crc screening. the s2s initiative has been shown to be effective based on the published findings from the national outreach initiative which leverages ncidesignated cancer centers. the program evaluation reported 3,183 pre/post surveys were obtained from www.companyofscientists.com/index.php/chd e3 cancer health disparities research participants, ages 50 to 74, during 347 educational events (whitaker et al., 2020). results demonstrated an increase in colorectal cancer-related knowledge and revealed a positive association between attending educational events and intention to receive subsequent crc screening. in addition, 82% of participants who received a crc screening three months after attending the events successfully obtained their screening results (whitaker et al., 2020). the results of the s2s initiative suggest the effectiveness of the community-based approach to achieve positive outcomes in terms of crc screening adherence in diverse populations. focus group learner verification the tune-up study began with formative research with african american community participants using focus group methodology. the objective of the focus groups was to explore knowledge, attitudes, and beliefs about crc and crc screening as well as to obtain learner verification of the educational brochure. this was an important step to ensure that the educational materials were comprehensible to the intended audience and provided easily digestible information on crc screening. in this article, we describe the sections of the educational brochure and the adaptation of the presentation, but the complete findings from the focus group results have been published elsewhere (luque et al., 2021). the brochure was designed as a tri-fold brochure. for the initial version, the brochure cover had a header of the study name, stock photos of a group of friends walking for exercise and an older couple with the tune-up title and university logo and underneath, the text “what black men and women need to know about colorectal cancer screening.” the back cover contained tune-up contact details, information on covering the cost of crc screening and where to get more information from the american cancer society and the nci. the inside flap covered information on the types of available screening tests with an emphasis on stool-based tests and a picture of the test kit. most importantly for our study, under the description of the fecal immunochemical test (fit) were bullet points describing that the fit is used to check stool for blood, the stool sample is placed in a small vial, and is then returned to the doctor or laboratory for testing. in addition, it was described that the fit is done every year, and in the case of a positive fit, the patient is referred to colonoscopy. the inside panel 1 showed a picture of the human colon with polyps and a bulleted list of modifiable and nonmodifiable risk factors for crc. the inside panel 2 showed a picture of the anatomy of the colon and a definition of crc. the inside panel 3 described what happens after a crc screening, details on the colonoscopy procedure and answered some questions about crc screening with a short testimonial on how to overcome the fear of completing the test. based on the feedback we received from focus group meetings 1 and 2, changes were made to the brochure and the second version was created. specifically, the color was changed to make it more attractive, texts were made bold for ease of reading, a picture of a famous person who had died from crc was added, detailed formatting was done and the picture of the anatomical figure depicting the colon was edited by darkening the skin tone so it did not appear to be a white person based on feedback from the focus groups. this version of the brochure was used for focus groups 3, 4, and 5. focus group feedback was further used to make changes to the brochure for a final version. a professional design of the entire brochure was done, and the color scheme changed, using two major colors – blue signifying crc and green signifying our university’s school colors. on the inside of the brochure, a picture of a newer test kit replaced the older kit picture, and a photo of a well-known black couple in the community was inserted. this final www.companyofscientists.com/index.php/chd e4 cancer health disparities research version was used for focus group meetings 6 and 7 with no further suggested changes (figure 1). community health advisor chas also known as community health workers, peer health educators, promotoras, lay health advocates and other similar titles are trusted public health workers who possess intimate knowledge about the communities they serve and facilitate access to health and social services with improved quality and cultural competency. chas may be paid employees within a health care system or volunteer patient advocates, and for increasing cancer screening, their work is costeffective (attipoe-dorcoo et al., 2021). improved adherence to recommended health practices is a recognized benefit of cha services and several reviews of cha crc screening interventions have shown a positive effect on receipt of screening (naylor et al., 2012; rawl et al., 2012). in the context of our current behavioral clinical trial, a cha was trained by the research team to deliver a 6-week intervention consisting of an initial face-to-face or virtual crc educational presentation, two weeks of phone-call follow-up, and three weeks of text message follow-up. the intervention’s one-on-one education, small media, follow-up reminders, and reduction of structural barriers to screening aligns with clientoriented recommendations of the community guide to preventive services (guide to community preventive services, 2021). we hypothesize that the cha intervention described here and utilized in the behavioral clinical trial will demonstrate positive crc screening outcomes compared to a “usual care” approach among a population of african americans not up to date with current screening recommendations. we prioritized designing a cha screening intervention for effectiveness in promoting crc screening among african americans who suffer disproportionately from crc (figure 2). therefore, we sought to identify and recruit a cha from our local african american community. we engaged african american community leaders for assistance promoting the figure 1. cha intervention development s2s resources draft brochure, video & text messages focus group feedback research team refinement finalization of materials delivery of cha intervention intervention materials www.companyofscientists.com/index.php/chd e5 cancer health disparities research cha job opportunity. the candidate selected through this outreach had been a member of the community for many years, had provided community education around other health topics, was comfortable discussing crc with african american women and men, and expressed desire to work in service to the community. to prepare the cha to deliver the crc educational intervention, we developed and delivered the didactic and interactive training described below. cha training the cha training consisted of three didactic and two interactive sessions focused on colorectal cancer education, the role of the cha, intervention components, and practice interactions using role playing. the training was delivered by three study investigators (jl, cg, kw) and the project coordinator (mv). the cancer module provided an overview of cancer and crc and covered crc incidence, risk factors, common symptoms, lifestyle changes, prevention, and screening recommendations and options (i.e., stool-based tests, colonoscopy, sigmoidoscopy and ct colonography). didactic materials were drawn from reliable sources such as the nci, the cdc, and the american society of clinical oncologists (asco). the didactic powerpoint modules included hyperlinks to all information sources and were supplemented with graphics (e.g., anatomical images) and youtube video tutorials. delivery of the didactic modules was recorded as a training product for future reference. the training also discussed the importance of intervention fidelity and skills for maintaining fidelity of the cha educational intervention using a conversation script and presenting different possible scenarios. additionally, an introduction to motivational interviewing was provided, and the cha trained on using basic principles of motivational interviewing to help them achieve success with participants who present with barriers to screening and need support or counseling (luckmann et al., 2013). in the final training session, the cha completed practice sessions to simulate cha-client interaction situations, using talking points, followed by feedback from the project coordinator, who assessed fidelity using checklists. nci, cdc, asco resources didactic & interactive modules research team refinement cha didactic trainings cha interactive trainings cha training www.companyofscientists.com/index.php/chd e6 cancer health disparities research refining the cha intervention the cha educational presentation to intervention arm participants includes the use of nci crc resources and materials, including the approximately 11-minute s2s powerpoint presentation video that was adapted and created. using pictures, charts and figures, the video begins with an initial description of crc, its incidence, risk factors and prevention, with a highlight on health disparities, comparing crc incidence and mortality rates between the black and white u.s. population. screening recommendations and options are further explained, with a focus on colonoscopy and the stool-based test. the final part of the video transitions to provide information on the tune-up study including eligibility criteria, study procedures, and details on participant incentives. the cha meets with participants at their preferred location to provide the intervention. after using a tablet to show the s2s video to the study participant and allowing for questions/discussion, the cha shows the participant a second video which explains how to complete a stool-based crc screening test (fit kit) at home. this 5-minute crc screening patient tutorial video was obtained by the study team through agreement with the manufacturer. following presentation of the second video, the cha again engages the participant to allow for questions or discussion. at the conclusion of the face-to-face meeting, the cha informs the participant that the cha will check in with them by phone a week later to ask if they were successful in completing and mailing in their fit kit. intervention arm participants receive this 30-minute face-toface meeting followed by two cha phone calls in one-week intervals over a period of three weeks beginning within one month following baseline survey completion. using fidelity checklists for weeks 1-3, the cha records qualitative data from the intervention session and subsequent phone calls. the duration of educational intervention sessions depends on the participants’ inquiries and typically last 25-35 minutes. follow-up phone calls for weeks 2 and 3 are generally short in duration. to maintain intervention fidelity, the cha follows a conversation guide/standard script and completes checklists for the face-to-face meeting and phone calls. the cha takes notes of each interaction to document call length, tone, and deviations from the script. participants are already knowledgeable regarding fit screenings at weeks 2-3 and therefore the fidelity checklists for weeks 2-3 document receipt or non-receipt, completion, and mailing in of fit screenings, and to address any concerns that the participant raises following the intervention. the cha implements motivational interviewing to address any questions or concerns the participant may have about the educational presentation. participants receive an additional text message reminder once a week for an additional three-week period. the personalized text messages have positive tones and include short messages about the importance of crc screening (weaver et al., 2015). the three text messages selected were the most preferred by focus group participants during the learner verification phase. the initial text message that is sent in week 4 of the intervention states, “screening for colon cancer saves lives.” the text message sent in week 5 states, “seven out of ten people diagnosed with colorectal cancer often have no obvious signs and symptoms, regular screening is the key to early detection.” the final text message sent in week 6 states, “don’t let fear of diagnosis stop you from getting tested, early detection is key to prevent colon cancer. get tested today.” acceptability of the cha intervention is assessed by two items included in the 3-month phone survey with intervention arm participants. one question asks participants to rank on a likert scale their satisfaction with support www.companyofscientists.com/index.php/chd e7 cancer health disparities research received from the cha, and the second item asks if they would recommend working with a cha to others who have not been screened. conclusion academic-community partnerships provide a mechanism to test intervention strategies to increase crc screening and address cancer health disparities (meade et al., 2011). by seeking community input on the adaptation of the s2s evidence-based crc screening education resources as part of a cha intervention, the resulting intervention is received well in the community. in addition, the engagement of the community health centers and other community partners to advertise the study (churches, small businesses) is being used to leverage participation of african american patients in the community. the findings from these academic-community research partnerships will generate knowledge about how to adapt evidence-based community health educator programs in both community and clinical settings. acknowledgement we acknowledge support of the u54 rcmi center office – ms. leola hubert-randolph and ms. gloria o. james–academic support services, florida a&m university college of pharmacy and pharmaceutical sciences, institute of public health and u54 rcmi principal investigator, dr. karam f. soliman. we acknowledge study team members dr. cynthia m. harris, dr. askal ali, and dr. gebre kiros. we also acknowledge the assistance of dr. alexandria washington with help facilitating in-person focus groups. this article was supported by funding from the national institute on minority health and health disparities of the national institutes of health under award number u54 md007582. the content is solely the responsibility of the authors and does not necessarily represent the official views of the national institutes of health. conflict of 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(2020). screen to save: results from nci's colorectal cancer outreach and screening initiative to promote awareness and knowledge of colorectal cancer in racial/ethnic and rural populations. cancer epidemiol. biomarkers prev. 29, 910-917. www.companyofscientists.com/index.php/chd e9 cancer health disparities research supplemental figure 1. tune-up brochure www.companyofscientists.com/index.php/chd e10 cancer health disparities research introduction educational materials development focus group learner verification cha training refining the cha intervention conclusion acknowledgement conflict of interest authors’ contributions supplemental figure 1. tune-up brochure www.companyofscientists.com/index.php/chd e1 cancer health disparities research racial disparities in the genetic landscape of lung cancer shashi anand1,2, kunwar somesh vikramdeo1,2, seema singh1,2,3, ajay pratap singh1,2,3, santanu dasgupta1,2,3* 1department of pathology, college of medicine, university of south alabama, mobile, al 36617 2cancer biology program, mitchell cancer institute, university of south alabama, mobile, al 36604 3department of biochemistry and molecular biology, university of south alabama, mobile, al 36688. *corresponding author: santanu dasgupta, phone: 251-445-9805, fax: 251-460-6994, email: dasgupta@southalabama.edu. abstract lung cancer has the highest cancer-related mortality worldwide and in the united states. although reduced tobacco consumption and advancement in therapies have led to a modest decline in lung cancer death rates over the past two decades; the overall survival rate is still disappointing. moreover, raceassociated disparities are also observed, especially in the clinical outcomes. socioeconomic factors are considered major contributors in cancer health disparities, however, the differences in the genetic landscape of lung cancer among different racial groups have also been reported. in this review, we shed light on the genetic heterogeneity of lung cancer and race-associated differences in genetic alterations to build a framework for future studies to understand the biological basis of lung cancer disparities. keywords: lung cancer, smoking, racial disparity, gene mutation, mitochondria. citation: anand s et al (2022) racial disparities in the genetic landscape of lung cancer. cancer health disparities 6:e1-9. doi:10.9777/chd.2021.1006 www.companyofscientists.com/index.php/chd e2 cancer health disparities research introduction lung cancer (lc) is a lethal disease that took 1.8 million lives globally in 2020 [1]. this year, it is expected to kill nearly 131,880 people in the united states alone, with around 235,760 new diagnoses [1]. although with advances in therapy, the lc mortality rate has been on a mild decline over the past two decades, the overall 5-year survival rate of lc patients is still at 21.7% [1,2]. another upsetting fact is that in the united states, lc disproportionately affects people of african descend (aa, african american) compared to those of european origin (ca, caucasian american). the incidence of lc is 1.15 times higher among the aa men compared to the ca men (85.4/100,000-aa vs. 74.3/100,000-ca), whereas it is 0.86 times lower among the aa women compared to the ca women (49.2/100,000-aa vs. 57.4/100,000-ca) [3]. similarly, the lc mortality is 1.18 times higher among the aa men than the ca men (63.9/100,000-aa vs. 54.1/100,000-ca) and 0.88 times lower among the aa women than ca women (33.9/100,000-aa vs. 37.9/100,000-ca). moreover, aa lc patients are 16% less likely to have an early diagnosis and are diagnosed at advanced stages [3]. the 5-year overall survival rate among the aa is also lower (16%) than that of the ca group (19%) [3], underscoring the need to define the factors underlying these racial health disparities. potential contributing factors associated with lung cancer disparity cigarette smoking plays a significant role in lung tumorigenesis [4–7]. although the overall cigarette smoking prevalence is similar in both aa and ca populations (15%-aa vs. 16% ca), it appears to be higher among ca women compared to the aa women (15% vs. 12%) [2]. notably, the metabolic capability of cigarette smoke-derived carcinogens may also vary in different racial populations giving rise to an increased risk of lc. for example, the clearance of cigarette smoke-derived nicotine in the body is regulated by the cyp2a6 gene, which converts nicotine to cotinine [8]. different genetic variants of cyp2a6 could potentially be associated with increased risk of lc in aa, as a higher level of cotinine was detected in the blood of aa lc patients compared to ca lc patients. however, a clear link associating the metabolism of nicotine and other tobacco carcinogens with lc disparity has not yet been established. the geographical location and socioeconomic status (ses) of the patients also seem to be important contributing factors in lc health disparities. people from various races living in heavily industrialized areas and areas with a high rate of air pollution may be associated with an increased risk of lc development [9]. in addition, body mass index, alcohol consumption, radon, and alternative or unidentified environmental exposures may also potentially contribute to lc health disparities [10]. on the other hand, the lc risk may increase in socioeconomically disadvantaged racial groups continuously exposed to low ses-derived stressors accompanied by a high prevalence of smoking and other unhealthy behavior. genetic heterogeneity in lung cancer and its association with racial health disparity through comprehensive next-generation deep sequencing, numerous genetic anomalies have been cataloged in lc. to date, a panel of twenty genes with the highest frequency of mutations have been identified in lc (figure 1). in addition, several different types of genetic mutations have been reported, including nonsense substitution, missense substitution, synonymous substitution, inframe insertion, frameshift insertion or deletion mutations (figure 2). among these genes, egfr and kras appear to be the most frequently mutated ones in lc. egfr gene mutations predominantly occur www.companyofscientists.com/index.php/chd e3 cancer health disparities research among non-smoker patients with adenocarcinoma histology, whereas kras mutations are common among smokers with squamous cell carcinoma histology [11]. in an earlier study by liedner et al., aa lc patients were found to harbor a significantly lower number of egfr mutations compared to their ca counterparts, thereby predicting a poorer therapeutic response from treatment with the tyrosine kinase inhibitors [12]. a subsequent study by harada et el. reported a novel egfr exon-20 mutation in aa subjects [13]. in addition, they also identified five egfr-activating mutations in eight aa cases who were either never or light smokes, whereas no egfr mutation was detected among the heavy smokers. interestingly, a couple of insertional egfr gene mutations encompassing exon 20 such as n771gy and a767-v769dup were identified exclusively in the aa lc patients . other than egfr, n375s-met gene mutation was detected in around 13% of east asian lc patients and 2.6% ca lc patients but not in the aa lc patients [14]. inactivation of stk11 gene, also known as lkb1, either due to deletion or insertions, have been reported to be more frequent in caucasian americans compared to african american and asian nslc patients [15,16]. a more recent study by lusk et al. sequenced 193 aa lc cases for determining the mutational landscape and identified a panel of 88 distinctly mutated genes in addition to the commonly found lc-associated driver mutations [17]. novel mutations in pabpc1, pms2, cdc27, oxct2, gstm1, rhpn2, zc3hc1 and mll3 genes were noted exclusively in the aa subjects. figure 1. the landscape of gene mutations in lung cancer. top 20 gene mutations identified in lung cancer patients. data assembled with permission from the cosmic database (https://cancer.sanger.ac.uk/cosmic). asterisks indicate the genes, the mutation spectrum of which have been examined in various racial population. www.companyofscientists.com/index.php/chd e4 cancer health disparities research figure 2. nature of somatic gene mutation observed in a large number of lung cancer sample pools as analyzed from the cosmic database (https://cancer.sanger.ac.uk/cosmic). in a recent meta-analysis involving a total of 11,867 aa, ca, hispanic/latina (his) and asian patients, costa et al. performed a comparative analysis of lc associated mutations in key genes, including egfr, alk, ros-1 and braf [18]. the most frequently occurring mutations in the aa subjects involved egfr (6%), braf (1%), and alk (1%). however, the incidence of egfr and braf mutations was lower in the aa subjects compared to the ca subjects. another study in 116 lc cases by hunt et al. reported a higher prevalence of kras mutations in the aa lc subjects compared to the ca lc subjects [19]. on the contrary, analyses of 121 lc cases by reinersman et al. reported a higher abundance of kras mutations among the ca lc subjects, compared to the aa lc subjects (26% vs. 17%). of note, this study also reported higher rate of egfr gene mutations in the aa lc compared to the ca lc subjects (19% vs. 13%) [20]. more information about genetic mutations between ca and aa lung cancer patients is provided in table 1. the tp53 gene is well regarded as the key regulator of genomic stability and the most frequently altered molecule in human cancers [21]. in a comprehensive analysis of 431 subjects, kytola et al. have reported a significantly higher frequency of p53 gene mutation in aa lc patients compared to the ca lc patients [22]. moreover, significantly higher level of amplification of a 5-gene signature, including mcl1, runx1t1, cdk8, cat6a, and rad21, was noted in the aa lc cases, compared to the ca lc subjects. in another study, mitchell et al. reported a higher frequency of mutations in ptprt and jak2 in aas than cas [23]. they detected ptprt and jak2 gene mutations in 24% (13/54) and 7.4% (4/54) aa lc cases, respectively, compared to 8% (30/381) and 2% (7/381) in cas, respectively. changes in copy number have also been examined in lc using high-resolution singlenucleotide polymorphism arrays to decipher molecular alterations accumulated during lung tumorigenesis. considerably higher frequency of copy number gain on 16p13.13 and 16p13.11 was www.companyofscientists.com/index.php/chd e5 cancer health disparities research noted among the east asian lc patients [14]. on the contrary, genomic loss in 19p13.3 and 19p13.11 regions was noted to be higher in ca lc patients. besides lung cancer, race-specific genetic heterogeneity is noted in other human malignanies as well. mutation frequency was found to be appreciably different in aa and ca colorectal cancer patients for kras (aa:23-44%; ca:15-45%) and braf (aa:4-6%; ca:7-14%). similarly, mutation frequency of braf was 75-80% in ca papillary thyroid carcinoma patients as compared to 48% in aa patients. in melanoma, mutation frequency of braf was 8% in aa relative to 21% in ca patients. such striking differences are also noted for p53 in breast cancer patients with 43% mutation rate in aa compared to 26.7% in ca women [24]. table 1. the spectrum of genetic mutations in caucasian and african american lung cancer patients. gene name variant frequency in patients reference caucasian african american egfr kras g2303a or s768n codons 12 and 13 of exon 12 (n1=102) 17% 21% (n=53) 2% 23% [12] egfr kras braf pik3ca (n=264) 5.68% 13.87% 3.03% 0.75% (n=245) 4.89% 12.87% 2.44% 0.81% [25] egfrkras exon 19 deletions and t2573g or l858r c.34g, c.35g and c.38g in codons 12 and 13 of kras (n=399) 13.7% 25% (n=67) 4.8% 30.6% [26] egfr exon 19 deletions (n=335) 2% (n=137) 7% [27] braf point mutations in exon 11 or exon 15 (n=108) 13.72% (n=51) 3.7% [28] egfr braf ros-1 alk activating mutations (n=9507) 12% 3% 1% 2% (n=3363) 6% 1% 0% 1% [18] egfr kras exon 19 deletions and exon 21 (l858r) mutation in codon 12 and 13 (n=476) 13% 26% (n=121) 19% 17% [20] kras g→t transversion in codon 12 (n=51) 20% (n=60) 37% [19] (n=381) (n=52) [23] www.companyofscientists.com/index.php/chd e6 cancer health disparities research tp53 stk11 rb1 kras egfr smad4 pik3ca 49% 13% 4% 29% 13% 4% 5% 65% 21% 13% 27% 1% 8% 8% 1number of patients. in addition to the nuclear genetic alterations, changes in the mitochondrial genome and dysregulation of various mitochondrial functions also play a pivotal role in human tumorigenesis [29– 32]. mitochondria are regarded as the powerhouse of the cells and generate cellular energy in the form of atp [33]. in humans, mitochondria are maternally inherited and harbor their own dna (mtdna). the human mtdna is a 16.5-kb doublestranded closed circular molecule having 37 genes, which encode for 12s and 16s rrnas, 22 trnas, and 13 respiratory complex proteins (i, iii, iv, and v) essential for the oxidative phosphorylation system (oxphos) function [33–36]. because of the high copy number, mtdna mutation detection is easier in cells compared to nuclear dna. only a handful number of studies have reported mtdna mutations in lc, including our laboratory [37,38]. the frequency of mtdna mutations and copy number is higher in asian patients than in ca patients and associated with egfr gene mutation [38]. another study also reported alterations in mtdna copy number in lung cancer [39], however, a comparative analysis of mtdna copy number in ca lc and aa lc patients, particularly linking smoking habits remain to be determined. moreover, the disparities in the alteration in the nuclear genes associated with oxphos function are also less well defined between aa lc and ca lc subjects. in an interesting recent study, which utilized tcga datasets, nuclear dna encoded mitochondrial oxphos pathway-associated genes were found to be upregulated in both lung adenocarcinoma and squamous cell carcinoma of aa patients compared to the subjects of european origin [40]. this study also identified a predominance of err1-pgc1α– mediated transcriptional program enrichment, a key regulator of mitochondrial biogenesis in the aa lc subjects compared to the european american subjects. in addition to energy generation, mitochondria are involved in various critical cellular functions, including apoptosis, inflammation, innate and adaptive immune system, t cell function, macrophage polarization, mitophagy, calcium, and damage-associated molecular pattern (damp) signaling [29]. as a reason, alterations in mitochondrial metabolism and functions are regarded as cancer hallmarks. however, the differential molecular alteration pattern of these critical pathways remains to be determined in lc patients with different racial backgrounds. conclusion and future perspective although genetic differences have been reported among racially disparate populations, they have not been mechanistically linked to the observed disproportionate outcomes. with the power of next-generation deep sequencing of thousands of tissue samples, critical molecular pathways associated with lung cancer pathogenesis have been identified, and based on that knowledge, several new lines of targeted therapeutics are in place, and many are currently under clinical trials. of note, these cataloged molecular changes can also be helpful to develop race-specific biomarkers for diagnosis, prognosis, and therapeutic guidance. www.companyofscientists.com/index.php/chd e7 cancer health disparities research however, the alteration pattern of the majority of these molecules remains largely unknown in racially disparate populations. moreover, there are some discrepancies in the outcome of the mutational frequency of crucial lung cancer-associated genes among various racial groups in some studies, which could be due to significant differences in sample size, methods used, and/or the specificity of the type of mutations analyzed. notably, an in-depth analysis of a panel of potential molecular targets other than egfr and kras, remains to be carried out in diverse racial populations. moreover, in addition to the mutational landscape, analysis of genome-wide polymorphisms and profiling of genes that are differentially amplified or lost during lung tumorigenesis in various racial groups will also help further our understanding of the genetic basis of lung cancer health disparity. on the other hand, despite increasing and emerging evidence of alterations in mitochondrial dna and nuclear genes targeting mitochondrial pathways in various human malignancies, their association with lung cancer health disparity has remained largely undefined. in the coming decades, with the advent and power of multi-omics technology, including single-cell genomics and proteogenomics, we hope to achieve appreciable success in characterizing the specific factors and molecular pathways contributing to the lung health disparity to ultimately reduce the disparity gaps. acknowledgements this work is supported by funding from nih/nci [r01ca231925 (ss), and mitchell cancer institute, university of south alabama (ap, ss and sd). conflict of interest the authors declare that they have no conflicts of interests. authors’ contribution study design and oversight: sd, data acquisition: sd, sa, ksv, aps, ss, writing and review: sd, sa, ksv, aps, ss. references 1 sung h, ferlay j, siegel rl, laversanne m, soerjomataram i, jemal a, et al. global cancer statistics 2020: globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries. ca cancer j clin. 2021 doi: 10.3322/caac.21660 2 american cancer society. american cancer society: cancer facts and figures 2021. atlanta, ga am cancer soc. 2021 3 desantis ce, miller kd, goding sauer a, jemal a, siegel rl. cancer statistics for african americans, 2019. ca cancer j clin. 2019 doi: 10.3322/caac.21555 4 tyagi a, sharma s, wu k, wu sy, 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10.1371/journal.pone.0006533 38 dasgupta s, soudry e, mukhopadhyay n, shao c, yee j, lam s, et al. mitochondrial dna mutations in respiratory complex-i in never-smoker lung cancer patients contribute to lung cancer progression and associated with egfr gene mutation. j cell physiol. 2012 doi: 10.1002/jcp.22980 39 choudhury ar, singh kk. mitochondrial determinants of cancer health disparities. semin cancer biol. 2017 doi: 10.1016/j.semcancer.2017.05.001 40 piyarathna dwb, balasubramanian a, arnold jm, lloyd sm, karanam b, castro p, et al. err1and pgc1αassociated mitochondrial alterations correlate with pancancer disparity in african americans. j clin invest. 2019 doi: 10.1172/jci127579 introduction potential contributing factors associated with lung cancer disparity genetic heterogeneity in lung cancer and its association with racial health disparity conclusion and future perspective acknowledgements conflict of interest authors’ contribution www.companyofscientists.com/index.php/chd e1 cancer health disparities research cancer health disparities drivers with bertopic modelling and pycaret evaluation mary adewunmi1,2; saksham kumar sharma3; nistha sharma4; n sudha sharma3; bayangmbe mounmo5 1university of utas, australia, 2nacetem, nigeria, 3maharaja surajmal institute of technology, india, 4pune institute of computer technology, india, 5kanda weather group, usa. *corresponding author: nistha sharma email: sharmanistha2000@gmail.com abstract the complex interplay of social, behavioral, lifestyle, environmental, health system, and natural health variables contribute to disparities in cancer treatment across racial and ethnic groups. consequently, it is necessary to identify the variables contributing to cancer health inequalities and develop strategies to achieve health equality. pubmed abstract on cancer health disparities was scraped with a bio.entrez python package. preprocessed data with regex and natural tool kit (nltk), topic modeling with bertopic embeddings, and c-tf-idf to construct dense clusters and analyze top topics linked with cancer health disparities. model evaluation with pycaret coherence score and web app deployment with streamlit. the results showed that topic 32, with the terms obese, female, male, school, survey, student, poet, and discrepancy, had the best coherence score of 0.3687. in contrast, topic 8, with terms prevalence, adult, income, high, usage, diabetes, education, elderly, change, and low received the lowest coherence score of 0.3255. the model classifies each subject word score based on the scores, the granular topic concerns, and trends related to cancer health disparities, investigates the connection between drivers of cancer health disparities, and evaluates the model with their coherence score values. keywords: cancer health disparity, bertopic, c-tf-idf, pycaret. citation: adewunm m et al (2022) cancer health disparities drivers with bertopic modelling and pycaret evaluation. cancer health disparities 6: e1-e12. doi:10.9777/chd.2022.1005 www.companyofscientists.com/index.php/chd e2 cancer health disparities research introduction cancer disparities occur across geographic regions, socioeconomic classes, and racial and ethnic groupings. for example, rural areas had higher lung, cervical, and colorectal cancer death rates than urban ones, owing to poverty, risky behavior, and lower vaccination and screening rates [1]. this is consistent with the growing divide in life expectancy between rural and urban areas (torre et al., 2015). low educational attainment is a marker of socioeconomic deprivation and correlates with increased all-cause mortality in the general population. fifty per cent (50%) of all premature deaths may be avoided if all sectors of the u.s. population experienced college graduates’ death rates. socioeconomic status is also a significant predictor of cancer death. around a quarter of cancer deaths may be avoided if all americans obtain a college education (withrow et al., 2021) [2]. furthermore, cancer survival improves with increasing socioeconomic position across all racial and ethnic groups in the united states [3]. nonetheless, socioeconomic disparities in cancer mortality have shifted dramatically over time [4]. until the 1980s, the socioeconomic position was positively connected with cancer mortality rates in the united states, indicating that the wealthy face a greater risk of cancer. however, this link has shifted in the opposite direction, with affluent americans now having a lower risk of dying from cancer, owing to advancements in disease prevention, early cancer detection, and cancer therapy that benefit people with private health insurance. socioeconomic disparities are the primary cause of excess mortality from lung, colorectal, cervical, stomach, and liver cancers among americans living in deprived areas [3]. while prostate cancer mortality did not differ significantly by socioeconomic class in the past, an inverse socioeconomic gradient presently exists [5] [6]. additionally, neighborhood socioeconomic hardship is associated with shorter telomere length, a marker of premature ageing, and deadly malignancy [7]. global disparities in cancer incidence and mortality rates are observed across the board for most cancer sites, indicating socioeconomic disparities and considerable differences in risk factor expo sure [8]. breast, colorectal, and prostate cancer rates differ significantly between highand lowincome countries, geographic regions, and race/ethnic groupings. as migration studies for breast and other cancers have demonstrated, differences in health care and modifiable risk factor exposure are significant drivers of these global disparities [9] [10]. lung cancer is the most important cause of cancer death globally but is significantly underrepresented in sub-saharan africa due to low smoking rates. prostate cancer is the most frequent cancer in men worldwide, but its prevalence varies considerably by geography, with low rates in east asia and high speeds in western countries. the incidence disparity has lessened as east asia’s habits have become more westernized [11]. notably, prostate cancer is the leading cause of cancer death among men in sub-saharan africa and the caribbean [12], leading to the theory that males of sub-saharan african ancestry. this may predispose to prostate cancer and a more aggressive illness due to ancestral genetic characteristics. cervical cancer is the leading cause of cancer death in women in sub-saharan africa and southeast asia, owing to human papillomavirus infections and late disease identification [13]. other cancers with a high incidence and fatality rate in eastern asia include stomach and oesophagal cancer (lin et al., 2021). helicobacter pylori infection and a diet high in salt are significant risk factors for stomach cancer [14]. this cancer is more prevalent on the korean peninsula due to regional dietary risk factors and chronic helicobacter pylori infections [15]. www.companyofscientists.com/index.php/chd e3 cancer health disparities research in contrast, malawi in eastern africa is mainly affected by oesophagal cancers [16], with the highest global disease rates due to unknown risk factors. finally, liver cancer is most prevalent in northern and western africa and southeast asia [17]. for example, it is the leading cause of cancer mortality in mongolia [18]. chronic hepatitis b and c virus infections and aflatoxin exposure are significant causes of disease in these regions. in contrast, heavy alcohol use and non-alcoholic fatty liver disease are tremendous contributors to the rising incidence of liver cancer in several high income countries [19]. the remaining sections summarise prior research on topic modelling for language, project workflow, modelling experiment, results, evaluation, discussion and conclusion. the objectives of this study are: • find out granular topics related to cancer health disparities with topic modelling. • narrow down the knowledge structure of the high topics word scores and the associated trends. • validate the discovered trends. figure 1. why do u.s. cancer health disparities exist (aacr cancer disparities progress report 2022) reviewed methods topic modelling with bertopic and pycaret this is an unsupervised machine learning method for discovering abstract subjects in substantial text collections. it aids in organizing, comprehending, and summarising vast quantities of textual material and locating hidden issues that differ across documents within a particular corpus. the objective of topic modelling is to group documents and words with similar meanings. it has several critical applications, including natural language processing (nlp) and information retrieval (i.r.). it uses unsupervised machine learning algorithms to identify themes inside document sets. the www.companyofscientists.com/index.php/chd e4 cancer health disparities research probabilistic latent semantic analysis (plsa) was initially suggested in 1999 [20], followed by the latent dirichlet allocation (lda) in 2003 [21], which has since become one of the most used topic modelling methodologies. in addition, the development of pre-trained language models (plms) has contributed to the subject modelling problem. for instance, bertopic [22] is a topic modelling technique that employs bert embeddings and a class-based tf-idf to create dense clusters. additionally, it uses the uniform manifold approximation and projection (umap) technique to reduce the dimensionality of the embeddings before clustering the documents [23]. initial studies with the bertopic approach yielded promising results; consequently, this work aims to conduct experiments with the bertopic technique utilizing various plms and compare their results to well established methods such as lda. pycaret [24] is an open-source python toolkit for low-code machine learning that streamlines machine learning operations. it is an end-to-end machine learning and model management application that exponentially accelerates the trial cycle and increases your productivity. compared to other open-source machine learning libraries, pycaret is an alternative low-code library that can replace hundreds of lines of code with only a few lines. this makes experiments significantly quicker and more productive. pycaret is a wrapper for several machine learning libraries and frameworks, including sci-kit-learn, xgboost, lightgbm, catboost, spacy, optuna, hyperopt, ray, and a few more. figure 2. project workflow methods this article analyzes pubmed abstracts using embedding clustering-based models with lda [21]. history’s typical conventional topic model produces subjects using document-topic and topic-word distributions. in this study, we examine the topic of modelling text corpora and other discrete data sets by extracting the causes of health disparities in cancer care. bertopic modelling bertopic model exploits bert+umap+hdbscan [22], a clustering-based method that uses hdbscan (mcinnes and healy, 2017) to cluster sentences bert embeddings. uniform manifold approximation www.companyofscientists.com/index.php/chd e5 cancer health disparities research projection (umap) [25] and a classbased term frequency inverse document frequency (c-tf-idf) to reduce embedding dimensions. this method identifies themes on cancer health inequalities and narrows down the knowledge structure of highscoring themes and related trends. the objective is to discover concise descriptions of the cancer health disparity collection that facilitate the efficient processing of large groups while preserving the essential statistical relationships beneficial for fundamental tasks such as classification, novelty detection, summarization, and similarity and relevance judgments. experiments datasets we scraped abstracts on colon cancer disparities from the pubmed database with entrez global query cross-database search system, using the keyword ‘cancer health disparity’ and preprocessed the data with natural language tool kit (nltk) us ing the regex method. evaluation metrics we assess the subject’s quality in terms of topic diversity and topic coherence: topic diversity (t.u.)(nan et al., 2019) quantifies the originality of words across all subjects. normalized pointwise mutual information (npmi) (newman et al., 2010) measures topic coherence internally using a sliding window to count word co-occurrence patterns. topic coherence (cv) (roder et al., 2015) is a variant of npmi that uses one-set segmentation to calculate word co-occurrences and cosine similarity as the similarity measure. figure 3. topic word scores visualizing the chosen keywords for a few themes in figure 2. the relative c-tf-idf scores across and within articles provides insight [26]. additionally, it is simple to compare subject representations to one another. we can view the top words for each topic and the topic word scores. so, in topic 0, the top term racial care and ethnic. related topics, for other words, can be analyzed. from the topic similarity scores, the top 10 words in the document are patients, surgical, surgery, pain, disparities, total, white, racial, care, and black. patients have a word score of 0.049; surgical has a word score of 0.039; surgery is 0.032; disparities are 0.025, the total has a word score of 0.025, white has a word score of 0.023, racial has a word score of 0.021, care has a www.companyofscientists.com/index.php/chd e6 cancer health disparities research word score of 0.021, and black has a word score of 0.0. these words have a similarity score of 0.48. frequent topics in figure 4, topic -1, disparities_health_care_ patients, are the commonly ignored outliers, but this topic seems relevant to the researched theme. figure 4. frequent topics generated figure 5. topics and the probability as observed from the hierarchical clustering of the data, the closely clustered racial health disparity is linked to the youth’s mental health. therefore, the impact of racial health disparities on the mental health of individuals is considerable. furthermore, the healthcare sector and cancer disparity are clustered, suggesting the need for more thorough research in this field. therefore, increasing awareness and research on cancer disparity will substantially affect the healthcare sector. figure 6. hierarchical clusters of topics most similar topics figure 7. most similar topics fig 7. shows the related topics to cancer health disparity and its similarity score. the highest is cancer with 0.0508, and the least is the incidence, with a similarity score of 0.5603. www.companyofscientists.com/index.php/chd e7 cancer health disparities research heatmap matrix build a heatmap of the similarity matrix for the subject. a heatmap depicting the similarity of topics generated based on the cosine similarity matrix between topic embeddings. for example, the similarity score among racial-patients-disparities, maternal-women-birth, patients-surgical-surgery, children-youthdental, cancer-patients-survival, covid-pandemic-survival, healthdisparities-research and sexual-heterosexualbisexual are very high amongst others as displayed in fig.8. figure 8. similarity matrix heatmap model evaluation with pycaret coherence probabilistic topic models like lda are popular text analysis techniques because they provide both a corpus’s predictive and latent topic representation. however, because of the unsupervised training process, there is a longtime expectation that the latent space identified by these models is typically relevant and valuable and that testing such assumptions is difficult. furthermore, there is no universally accepted list of themes against which all compared corpora. however, it is equally vital to determine whether a trained model is excellent terrible and compare different models/methods. various methods have been employed in many www.companyofscientists.com/index.php/chd e8 cancer health disparities research practical applications to determine if "the right thing" has been learned about the word corpus. the coherence score is the evaluation method used in the proposed research to evaluate topic models. topic coherence assesses the semantic similarity between highscoring terms in a topic’s score. these metrics aid in the distinction between semantically interpretable issues and statistical inference artefacts. according to fig. 9, topic 32 words have the highest coherence score, i.e., 0.3687, and topic 8 words have the lowest, i.e., 0.3255. from fig. 10 obesity, female, male, school, survey, student, post, disparity, gender, and increase in topic 32. figure 9. topic with the highest coherence value. figure 10. words in topic 32 in contrast, the coherence score drops sharply until topic 64, then rises until topic 100. then, from 100 to 300, the coherence score is nearly steady, with just a minor decline. after topic 300, the coherence score begins to rise again as displayed in fig 11 and 12. www.companyofscientists.com/index.php/chd e9 cancer health disparities research figure 11. topics with the lowest coherence value figure 12. words in topic 8 streamlit deployment streamlit is used to deploy data visualisations generated by topic modelling using pycaret and bertopic. in addition, it is an opensource python framework for building machine learning and data science web applications. streamlit enables the application development by simplifying the interactive coding cycle and displays results in a web application. figure 10 depicts the web interface of the streamlit web. www.companyofscientists.com/index.php/chd e10 cancer health disparities research figure 13. streamlit display of cancer disparity web app conclusion identifying granular topics contributing to cancer health disparities is necessary and developing measures for achieving health equity. first, textual data was extracted from pubmed abstracts, then preprocessed the data with natural language toolkit (nltk) libraries, topic modelling using the pycaret and bertopic libraries and evaluation with pycaret. both models produced outcomes which have been discussed in the previous sections. following a thorough examination, phrases such as racial, health, care, black, ethnic, white, population, socioeconomic status, sexual and others appeared in most papers on cancer disparities. interestingly, rare topics like obesity, dental, children, school and discrepancy emerge from the models. as a result, it is safe to assume that these racial and ethnic minority groups, countries’ economically disadvantaged classes, and, in general, those with less representation or resources become the targets of cancer disparities. the paper also includes figures from pycaret and bertopic, such as hierarchical clustering, similarity matrix, and topic word scores. these analyses can be valuable in developing additional ways for more standardized cancer treatment, reducing existing disparities among minorities. future recommendation to eliminate cancer disparities, government, private, non-profit institutions and individuals need to be actively involved in policies guiding cancer research, prevention, and treatment. also, other rare terms discussed in the conclusion need further research, even though it is a challenging goal. furthermore, a thorough examination of the various individuals affected by cancer and how they differ in their treatment compared to the more privileged and minority classes need to be carried out. most importantly, artificial intelligence can be used to detect these subjects and act as a catalyst in many cancer treatment processes starting from a cancer diagnosis. funding the paper was not funded. declaration of interest all authors of this manuscript are part-time members of a newly founded cancer research ai www.companyofscientists.com/index.php/chd e11 cancer health disparities research group(caresai). the authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. acknowledgement special thanks to omdena for creating a platform for us to connect and share similar interest on cancer research using ai pathways. authors’ contributions ma – conceived the idea of using bertopic for extracting topics on cancer health disparity as a use case, designed the workflow,scraped the abstract data form pubmed, part of implementation phase, manuscript writeups and overall editing. sks – evaluated the model using pycaret coherence score, deployed it on streamlit webapp, results interpretation on the manuscript. ns – part of implementation phase using bertopic for topic extraction of the use case and result interpretation on the manuscript nss part of implementation phase using bertopic for topic extraction of 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low-code machine learning library in python."pycaret version 2(2020) 25. mcinnes, leland, john healy, and james melville."umap:uniform manifod approximation and projection for dimension reduction." arxiv preprint arxiv:1802.03426(2018). 26. zeng z, hua b. uncovering topics of public cultural activities: evidence from china. data intelligence. 2017; p. 1–19. introduction reviewed methods topic modelling with bertopic and pycaret methods bertopic modelling experiments datasets evaluation metrics frequent topics heatmap matrix model evaluation with pycaret coherence streamlit deployment conclusion future recommendation funding declaration of interest acknowledgement authors’ contributions www.companyofscientists.com/index.php/chd e1 cancer health disparities commentary advancing health equity and biomedical researcher diversity: a new aim-ahead consortium anil shanker1,2,3,4,* 1 department of biochemistry, cancer biology, neuroscience and pharmacology, school of medicine, meharry medical college, nashville, tn, usa 2 host–tumor interactions research program, vanderbilt-ingram comprehensive cancer center, vanderbilt university school of medicine, nashville, tn, usa 3 vanderbilt institute for infection, immunology and inflammation, vanderbilt university school of medicine, nashville, tn, usa 4 vanderbilt memory and alzheimer’s center, vanderbilt university, nashville, tn *corresponding author: ashanker@mmc.edu abstract despite widespread knowledge regarding racial and ethnic health disparities, little has changed over the last decades. a creative, inclusive, and competitive biomedical research workforce is the foundation for turning discovery into health for all. to date, the expertise for advancing data-driven medicine based on artificial intelligence and machine learning (ai/ml) approaches has resided in majority-oriented institutions with little demonstrated experience in engaging minority-serving institutions or communities. lack of diversity of both data and researchers runs the risk of creating and perpetuating harmful biases in the analytical algorithms, practice, and outcomes, thus fostering continued health disparities and inequities. thus, the national institutes of health recently launched an artificial intelligence and machine learning consortium to advance health equity and researcher diversity (aim-ahead) program. this two-year planning, assessment and capacity building program will be led by the aim-ahead coordinating center comprised of a consortium of institutions and organizations that have a mission to serve minorities and underrepresented or underserved communities impacted by health disparities. this aim-ahead research and development program seeks to illuminate underlying issues in health systems and research endeavors that need to be addressed to improve health for diverse communities. keywords: equity, aim-ahead, health, diversity, researcher citation: shanker a (2022) advancing health equity and biomedical researcher diversity: a new aimahead consortium. cancer health disparities 7:e1-4. doi:10.9777/chd.2021.1003 www.companyofscientists.com/index.php/chd e2 cancer health disparities commentary despite widespread knowledge regarding racial and ethnic health disparities, little has changed over the last 40 years. similarly, consistent evidence documents the benefits of workforce diversity across multiple disciplines including science and healthcare. yet, african americans, hispanics, american indians/alaskan natives, and native hawaiians/pacific islanders, and other minorities, including rural populations and persons with disabilities, continue to receive higher degrees and academic appointments in science, technology, engineering and mathematics (i.e., stem) at rates substantially lower than their representation in the us population. recommendations from the advisory committee to the national institutes of health (nih) director working group on diversity in the biomedical research workforce emphasize evidence-based and theory-informed strategies to increase diversity in the biomedical and health professional workforce. a creative, inclusive, and competitive biomedical and behavioral research workforce is the foundation for turning discovery into health for all. importantly, the widespread adoption of electronic health records (ehr) has ushered in a new age of data-driven medicine, with the emergence of novel methods such as artificial intelligence, machine learning (ai/ml), and reinforcement learning. these new methods hold promise to provide new insights, derived from patient and other data, to improve health outcomes. to date, the expertise and leadership for advancing ai/ml approaches has resided in majority-oriented institutions, led by faculty with little demonstrated experience or interest in engaging minority-serving institutions, investigators, or communities. addressing this void requires transformative approaches that cannot be grounded in the same systems that have failed to generate solutions. therefore, a new artificial intelligence and machine learning consortium to advance health equity and researcher diversity (aim-ahead) program was launched by the nih on september 17, 2021. this program will establish mutually beneficial, coordinated, and trusted partnerships to enhance the participation and representation of researchers and communities currently underrepresented in the development of ai/ml models and improve the capabilities of this emerging technology, beginning with ehr and extending to other diverse data to address health disparities and inequities. the rapid increase in the volume of data generated through ehr and other biomedical research studies presents opportunities for developing new approaches for biomedical research and improving healthcare. many challenges hinder the use of ai/ml technologies, such as the cost, capability for widespread operational and research application, and access to appropriate infrastructure, resources, and training. additionally, lack of diversity of both data and researchers runs the risk of creating and perpetuating harmful biases in the analytical algorithms, practice, and outcomes, thus fostering continued health disparities and inequities. many underrepresented and underserved communities, often disproportionately affected by diseases and health conditions, present untapped potential to contribute expertise, data, and strategies to inform the field on the most urgent research questions. but they lack funding, infrastructure, and training to apply ai/ml approaches to pertinent research questions. the two-year planning, assessment and capacity building aim-ahead award of $100 million will provide the much needed impetus to the cause. the university of north texas health sciences center at fort worth (unthsc) will lead the aimahead coordinating center to execute this federal research and development program. the coordinating center is a consortium of institutions and organizations that have a mission to serve minorities and other under-represented or www.companyofscientists.com/index.php/chd e3 cancer health disparities commentary underserved communities impacted by health disparities. the coordinating center is comprised of four main cores. the leadership/administrative core will be led by jamboor k. vishwanatha, ph.d., and harlan p. jones, ph.d., at unthsc along with a team of principal investigators to lead regional hubs: bettina beech, dr.p.h., at university of houston, spero manson, ph.d., at university of colorado-anschutz medical center, keith norris, m.d., ph.d., at university of california, los angeles, anil shanker, ph.d., at meharry medical college, herman taylor, m.d., at morehouse school of medicine, and roland j. thorpe, jr., ph.d., at johns hopkins university. toufeeq ahmed, ph.d., at vanderbilt university medical center will lead the communication and dissemination hub. the leadership core will recruit consortium members and coordinate partnerships, stakeholder engagement, and outreach to enhance the diversity of researchers in ai/ml-related field, with emphasis on health disparities. the inclusion of historically black colleges and universities, and asian american, native american, pacific islander, and hispanic serving institutions in the leadership core highlight commitment to minority interests. the leadership core will also coordinate with three aim-ahead technical cores of training, research, and infrastructure in executing this program. the data science training core will be led by legand l. burge, ph.d., at howard university. the training core will implement training opportunities in data science and health equity research, large scale data analysis and management, cloud computing, and other areas to increase ai/ml expertise. the data and research core will be led by jon puro, m.p.a., at oregon community health information network. the research core will determine and address research priorities and needs in linking and preparing multiple sources and types of research data to form an inclusive basis for ai/ml use cases that will inform on strategies and approaches to ameliorate health disparity. this may include facilitating the extraction and transformation of data from ehr, image data, social determinants of health data, and more to develop ai/ml algorithms for application to health equity research. the infrastructure core will be led by alex j. carlisle, ph.d., at national alliance against disparities in patient health, with co-leads paul avillach, m.d., ph.d., at harvard medical school, and bradley a. malin, ph.d., at vanderbilt university medical center. the infrastructure core will enable a coordinated data and computing infrastructure that enhances the interoperability of large-scale data resources with data that are maintained and governed by individual institutions in an environment preserving privacy and autonomy. building a consortium of right partners and key stakeholders is paramount to planning, assessment and capacity building to advance health equity and researcher diversity. this transformative aimahead program seeks to illuminate underlying issues in health systems and research endeavors that need to be addressed to improve health for diverse communities. as an outcome of this program, it is hoped that healthcare will encompass the spectrum of health and disease from prevention, diagnoses, treatments, and implementation strategies for all. acknowledgements the author is thankful to the editorial board of cancer health disparities for inviting this article. funding this author is, in part, funded by the national institutes of health (nih) agreement no. 1ot2od032581-01. the views and conclusions contained in this commentary are those of the author and should not be interpreted as www.companyofscientists.com/index.php/chd e4 cancer health disparities commentary representing the official policies, either expressed or implied, of the nih. the author is also supported by funds from the nih grants u54 ca163069, and sc1 ca182843. conflict of interest statement the author declares that no competing or conflict of interests exist. the funders had no role in content design, writing of the manuscript, or decision to publish. authors’ contributions conception, design and writing: as acknowledgements funding conflict of interest statement authors’ contributions www.companyofscientists.com/index.php/chd e1 cancer health disparities research standardized global behavioral and epidemiological measures for prostate cancer studies in black men folakemi t. odedina,1§+* camille ragin,2§++ damali martin,3 richard p. moser, 3 joann s. oliver,4++ alicia c. mcdonald,5++ elise l. rice,3 jennifer nguyen,6+ frank chinegwundoh,7+ belinda morrison blidgen,8++ernest t. kaninjing,9+ mohamed jalloh,10 r. renee reams11+ 1department of pharmacotherapy and translational research, university of florida, orlando, florida, usa; 2cancer prevention and control program, fox chase cancer center, philadelphia, pa, 19111, usa; 3division of cancer control and population sciences, national cancer institute, rockville, md 20850; 4the university of alabama, capstone college of nursing, box 870358, tuscaloosa, al 35487, usa; 5department of public health sciences, pennsylvania state university college of medicine, hershey, pa 17033, usa; 6 college of pharmacy, mercer university 3001 mercer university drive, atlanta, ga 30341, usa; 7barts health nhs trust & harley street, london, uk; 8department of surgery, university of the west indies, mona, kingston 7, jamaica; 9 school of health and human performance, georgia college, campus box 112, milledgeville, ga 31061, usa; 10hopital general de grand yoff, dakar senegal; 11college of pharmacy and pharmaceutical sciences, florida a&m university, tallahassee, fl, usa; +member of prostate cancer transatlantic consortium (captc) ++member of african caribbean cancer consortium (ac3) § both dr. folakemi odedina and dr. camille ragin are first authors. *corresponding author: folakemi odedina. fodedina@cop.ufl.edu abstract: multicenter trans-national studies may be required to understand the complex causes of and solutions to prostate cancer disparities in black men. in 2014, two cancer epidemiology consortia supported by the us national cancer institute (nci), the prostate cancer transatlantic consortium (captc) and african-caribbean cancer consortium (ac3), formed a consortia alliance to address the disproportionate burden of prostate cancer in black men. as part of the alliance, this global study focused on developing standardized and culturally tailored data elements and measures for prostate cancer research in these populations. the study objective was achieved by a consensus working group using the nci–grid-enable measures (gem) platform. the consensus working group members were assigned to two special interest groups to focus on behavioral and epidemiology topics. based on crowd-sourcing methodology, the initial standardization decisions were made by each group using gem. this was followed using nominal group technique to build consensus. finally, a one-day consensus development conference was held to facilitate the input of the scientific community. the use of the gem platform, nominal group technique and a consensus development conference resulted in agreement among stakeholders for a recommended set of measures that included 25 behavioral scales and 24 epidemiological scales. the measures developed in this process will facilitate data harmonization and data sharing for multiethnic studies of black men globally and these measures can be used by other researchers in this area. keywords: prostate cancer; black men, behavioral measures, epidemiological measures, cancer disparity citation: odedina ft (2019) standardized global behavioral and epidemiological measures for prostate cancer studies in black men. 4: e1-e16. doi:10.9777/chd.2019.1014 mailto:fodedina@cop.ufl.edu www.companyofscientists.com/index.php/chd e2 cancer health disparities research introduction globally, prostate cancer is the second most frequently diagnosed cancer in men and the fifth leading cause of cancer deaths among men (ferlay et al., 2013). while little is known about prevention and risk reduction for prostate cancer, three risk factors have been long-established: age, family history and african descent (american cancer society, 2018). us black men have been reported to have the highest incidence, highest mortality and lowest 5-year relative survival rates compared to other us racial/ethnic groups (american cancer society, 2018). the growing literature supporting the unequal burden of prostate cancer among men of african descent in africa and the caribbean underscores the significance of this public health issue (akang, aligbe, & olisa, 1996; ben-shlomo et al., 2008; chinegwundoh et al., 2006; dawam, rafindadi, & kalayi, 2000; eke & sapira, 2002; ekwere & egbe, 2002; jackson et al.,1980; magoha, 1995; mohammed, alhassan, edino, & ochicha, 2003; nwana, mohammed, & anjorin, 2005; ogunbiyi & shittu, 1999; ogunbiyi, 2000; oranusi, 2004; osegbe, 1997; udeh, 1981; ukoli et al., 2003) the multifactorial risk factors of prostate cancer disparity in men of african descent and the need for a unique approach to better understand and address this disease has resulted in many researchers opting for a team-science approach that is multilevel, collaborative, transdisciplinary, translational, and global. facilitated by the united states (us) national cancer institute (nci) epidemiology & genomics research program (egrp), a number of cancer consortia have emerged to effectively address the environmental, lifestyle, and genetic risk factors underlying prostate (burgio et al., 2013). two independently led cancer consortia supported by the nci/egrp, the prostate cancer transatlantic consortium (captc; https://epi.grants.cancer.gov/captc), and african-caribbean cancer consortium (ac3; http://ac3online.org) collaborated in 2014 to effectively address prostate cancer disparity among black men. the captc was formed in 2005 to address the global disproportionate burden of prostate cancer among black men. captc members focus on studying blacks who are connected by the transatlantic slave trade, with the goal to explore and quantify the magnitude of prostate cancer morbidity and mortality variance. additional goals of captc includes the investigation of: genetic and environmental etiology of prostate cancer, using valid and reliable instruments and biomarkers; and the development of ethnically sensitive, targeted approaches that will contribute to the elimination of prostate cancer disparities. the ac3, formed in may 2006, investigates the viral, genetic, environmental, and lifestyle risk factors for cancer in populations of african descent populations in the us, africa and the caribbean. the primary aims of ac3 are to conduct multi-centered research studies within an international research network through collaboration, capacity building, and training. in addition, investigators in ac3 aim to translate the study findings to targeted interventions that will reduce the incidence and mortality of cancer in african descent populations. to accelerate the pace of implementing population-based interdisciplinary research aimed at eliminating the disproportionate burden of prostate cancer in black men globally, captc and ac3 agreed to a consortia collaboration in 2014. a primary challenge for this large–scale research collaboration is the differences in study measures https://epi.grants.cancer.gov/captc http://ac3online.org/ www.companyofscientists.com/index.php/chd e3 cancer health disparities research employed by consortia investigators. these differences created the additional challenge of pooling of existing data to generate findings that will move the science forward. thus, the primary goal of this study was to develop standardized global captc-ac3 behavioral and epidemiological (cabe) constructs and measures that are culturally tailored for studying prostate cancer in black men. materials and methods the study objective was achieved by a consensus working group comprising members of the captc and ac3 (table 1). in addition, an nci epidemiology and genomic research program (egrp) program director and two representatives from the nci’s behavioral research program (brp) provided their expertise on the consensus working groups. the consensus working groups achieved consensus using the nci grid-enabled measures (gem) platform, nominal group technique, and a consensus-development conference. for this study, consensus was defined as the extent to which members of the consensus working groups agree with each other on the appropriateness of the data collection tools and procedures. initial standardization decisions through gem. gem is a dynamic, web-based collaborative tool used to gain consensus on the use of common measures for prospective research (moser et al., 2011). this platform enables a variety of stakeholders to evaluate measures by providing qualitative and quantitative feedback through collaborative workspaces. gem is a publiclyavailable resource (see: https://www.gemmeasures.org/public/home.aspx). the ultimate goal is to achieve harmonized data that can be shared and analyzed. with the support of nci’s brp’s, captc-ac3 virtual workspaces were set up for the behavioral and epidemiological consortia measures to foster standardization of study constructs and measures. in april 2016, a series of web conferences was conducted to discuss and finalize the methodologies for the initial standardization through gem, the nominal group technique and consensus development meetings. web conferences were also used to train consensus working group members on the use of gem and the nominal group technique process. in addition, consensus working group members were assigned to two special interest groups (sigs), behavioral sig and epidemiology sig. the sigs were chaired by the captc and ac3 principal investigators (see table 1). table 1: behavioral and epidemiology consensus working group. behavioral special interest group (sig) epidemiology special interest group (sig) folakemi t. odedina, phd (moderator, captc) camille ragin, phd (moderator, ac3) joann oliver, phd (ac3) renee reams, phd (captc) elsie rice, phd (nci) damali martin, phd (nci) catherine oladoyinbo, phd –(captc) alicia mcdonald, phd (ac3) mohammed jalloh, md (madcap) following the web conferencing, gem was used for the initial standardization decisions based on crowd-sourcing methodology. first, the consortia principal investigators populated the gem https://www.gem-measures.org/public/home.aspx https://www.gem-measures.org/public/home.aspx www.companyofscientists.com/index.php/chd e4 cancer health disparities research consortia workspaces with their existing consortia study constructs and measures for prostate cancer behavioral and epidemiological constructs. subsequently, the consensus working group members worked in their respective sigs to rate and provide critical feedback that drove initial consensus for the cabe constructs and measures. consensus working group members met within their respective sigs to review all cabe constructs and measures uploaded by the consortia; discussed supporting literature for the measures; conducted literature reviews for additional measures when necessary; and provided recommendations for consortia cabe constructs and measures for prostate cancer. discussion boards in the gem workspace and videoconferences were utilized for discussions and notes. the initial standardization was completed on october 2016. nominal group technique nominal group technique involves the use of expert panels to build consensus. we adapted the nominal group technique methodology proposed by jones and hunter (1995) for the second phase of consensus for the consortia cabe constructs and measures. all members of the consensus working group met in person on nov 8, 2016 prior to the science of global prostate cancer disparities in black men conference, in orlando, florida, usa. prior to the meeting, consensus working group members provided pre-meeting rankings on the appropriateness of data elements for all the cabe constructs and measures on a ranking sheet using a scale ranging from 1 (inappropriate) to 9 (appropriate). the nominal group meeting was used to forge consensus for the constructs and measures. for the measures, the consensus working group strongly weighed the reliability and validity evidence of the measures as well as cultural relevance of the measures in african americans (us black men), caribbean black men, and african black men. the following steps were employed to reach consensus: 1. presentation of the median scores and ranges of pre-meeting data element ranking, which enabled consensus working group members to assess their initial rankings relative to that of others. with the 9-point scale: scores of 1-3 represented a region where consensus working group members felt that the data element/measurement scale was inappropriate for black men, 4-6 represented an equivocal region, and 7-9 represented appropriate data element/measurement scale. we concluded that there was strict agreement if all members’ ratings fall within one of these three regions. 2. group discussion of data elements/measurement scales, including discussion of supporting literature. 3. revision of data elements/measurement scales when necessary. 4. re-ranking by consensus working group members followed by data analyses to assess agreement. 5. summary of re-rankings to assess degree of consensus. the process ended with an acceptable degree of consensus by consensus working group members. the scorings were between 7 and 9, indicating strict agreement on the scoring. after the nominal group meeting, the final consortia cabe constructs and measures were assembled for presentation to the open scientific community. www.companyofscientists.com/index.php/chd e5 cancer health disparities research consensus development meeting the final phase of the consensus methodology was the consensus development meeting, which was held on november 11, 2016 during the science of global prostate cancer disparities in black men conference. the consensus development meeting was open to conference participants to facilitate the input of the prostate cancer scientific community. the cabe constructs and measures were presented by members of the consensus working group, followed by discussion, invited comments, and presentation of additional data from the public. finally, there was a vote to adopt the cabe constructs and measures for the study of prostate cancer in black men globally. results the goal of this project was to reach consensus for the cabe data elements and measures, which was achieved using the gem platform, nominal group technique and face-to-face meetings for consensus development. the cabe measures focus on both behavioral and epidemiological measures, including demographic and risk factors impacting prostate cancer. the nominal group members deliberated intensely on items included in the cabe measures and made a decision to be more comprehensive in its approach with the inclusion of items that may impact prostate cancer, including co-morbidities and polypharmacy. it is expected that investigators will choose cabe items that are relevant for their research. standardized global behavioral measures for prostate in black men the captc-ac3 consensus working group reached a consensus on and approved 25 behavioral constructs for the cabe measures (see table 2). of the 25 constructs, the measures for the following 15 constructs were based on existing generic instruments in the literature acculturation (klonoff & landrine, 2000; zane & mak, 2003), attitude toward screening (fishbein & ajzen, 1975), cancer fatalism (powe, 1995a, 1995b; powe & finnie, 2003), cues to action (hochbaum, 1958; rosenstock, 1974a, 1974b), health literacy (u.s. department of health and human services, office of disease prevention and health promotion (2010), national action plan to improve health literacy. washington, n.d.), perceived behavioral control (ajzen, 1985), perceived benefits (hochbaum, 1958; rosenstock, 1974a, 1974b), perceived health status (hochbaum, 1958; rosenstock, 1974a, 1974b)perceived severity (hochbaum, 1958; rosenstock, 1974a, 1974b), perceived susceptibility (hochbaum, 1958; rosenstock, 1974a, 1974b), subjective norm (fishbein & ajzen, 1975), shared decision making (rimer, briss, zeller, chan, & woolf, 2004), perceived barriers, (hochbaum, 1958; rosenstock, 1974a, 1974b), religiosity/spirituality (carver, scheier, & weintraub, 1989; thoresen, 1998), and temporal orientation (brown & segal, 1996; brown & segal, 1997; holman & silver, 1998). it is important to note that these measures had been tailored for prostate cancer research and culturally tailored for black men in prior captc (cobran et al., 2014; kaninjing et al., 2017; kumar, yu, akinremi, & odedina, 2009; morhason-bello et al., 2013; odedina et al., 2009; odedina, dagne, et al., 2011; odedina, scrivens, et al., 2011; ogunsanya, brown, odedina, barner, & adedipe, 2017) and ac3 studies (blackman, et al., 2017). three of the 25 measures were originally developed by captc prostate cancer information seeking behavior (odedina, scrivens., et al., 2011), prostate cancer screening behavior (odedina, scrivens, et al., https://www.gem-beta.org/public/constructdetail.aspx?cid=1497&cat=1 https://www.gem-beta.org/public/constructdetail.aspx?cid=1494&cat=1 https://www.gem-beta.org/public/constructdetail.aspx?cid=1524&cat=1 https://www.gem-beta.org/public/constructdetail.aspx?cid=1542&cat=1 https://www.gem-beta.org/public/constructdetail.aspx?cid=1527&cat=1 https://www.gem-beta.org/public/constructdetail.aspx?cid=1495&cat=1 https://www.gem-beta.org/public/constructdetail.aspx?cid=1495&cat=1 https://www.gem-beta.org/public/constructdetail.aspx?cid=1541&cat=1 https://www.gem-beta.org/public/constructdetail.aspx?cid=1547&cat=1 https://www.gem-beta.org/public/constructdetail.aspx?cid=1520&cat=1 https://www.gem-beta.org/public/constructdetail.aspx?cid=1519&cat=1 https://www.gem-beta.org/public/constructdetail.aspx?cid=1620&cat=1 https://www.gem-beta.org/public/constructdetail.aspx?cid=1496&cat=1 www.companyofscientists.com/index.php/chd e6 cancer health disparities research 2011), and screening controversy scale (odedina, segal, kimberlin, lee, 2011); two were originally developed by ac3 prostate medical procedures (blackman, et al., 2017; jackson et al., 2010) and trust of health care providers (blackman, et al., 2017); three were developed by both captc and ac3 knowledge (odedina, scrivens, et al., 2011), medical care access (blackman, et al., 2017) and prostate cancer health (odedina, dagne, et al., 2011); and two were new measures developed by the consensus working group behavioral sig (diversity of residence and patient-provider concordance). the two new measures were proposed by captc and ac3 investigators based on two ongoing qualitative prostate cancer studies, which found two unique themes of racial concordance and socio-demographically diverse residence from interview transcripts. table 2. captc-ac3-madcap standardized global behavioral measures for prostate in black men. constructs description of measures source acculturation cross-cultural psychology concept that “reflects the extent to which individuals (from a non-dominant culture) learn the values, behaviors, lifestyles, and language of the host (dominant) culture. adapted from acculturation construct by zane and mark (zane & mak, 2003) and further refined by the cwg. attitude toward screening positive or negative evaluations about prostate cancer screening. adapted from the theory of reasoned action model (fishbein & ajzen, 1975) and further refined by the cwg. cancer fatalism individual’s belief that death is bound to happen when diagnosed with cancer, is a major barrier to cancer detection and control adapted from the cancer fatalism construct by(powe & finnie, 2003) and further refined by the cwg. cues to action strategies to inform about and activate prostate cancer screening action. adapted from the (hochbaum; united states. public health service. division of special health, 1958; rosenstock, 1974a) and further refined by the cwg. diversity of residence participants’ perception of how diverse their residence is based on socio-demographic factors. developed by captc (odedina, dagne, et al., 2011; odedina, scrivens, et al., 2011) and ac3 cwg for behavioral measures. health literacy the degree to which individuals have the capacity to obtain, process, and understand basic health information and services needed to make appropriate health decisions. adapted from the national action plan to improve health (u.s. department of health and human services, office of disease prevention and health promotion. (2010). national action plan to improve health literacy. washington, n.d.) knowledge participants’ understanding of prostate cancer disease, prevention and detection. adapted from captc and ac3 measures (odedina et al., 2014) medical care access access to medical care and medical care services received adapted from captc and ac3 measures (blackman et al., 2017) https://www.gem-beta.org/public/constructdetail.aspx?cid=1497&cat=1 https://www.gem-beta.org/public/constructdetail.aspx?cid=1494&cat=1 https://www.gem-beta.org/public/constructdetail.aspx?cid=1494&cat=1 https://www.gem-beta.org/public/constructdetail.aspx?cid=1524&cat=1 https://www.gem-beta.org/public/constructdetail.aspx?cid=1524&cat=1 https://www.gem-beta.org/public/constructdetail.aspx?cid=1542&cat=1 https://www.gem-beta.org/public/constructdetail.aspx?cid=1498&cat=1 https://www.gem-beta.org/public/constructdetail.aspx?cid=1527&cat=1 https://www.gem-beta.org/public/constructdetail.aspx?cid=1540&cat=1 https://www.gem-beta.org/public/constructdetail.aspx?cid=1545&cat=1 www.companyofscientists.com/index.php/chd e7 cancer health disparities research patient-provider concordance participants’ perception of their similarity to their provider based on race, ethnicity, gender, and age. developed by captc and ac3 cwg for behavioral measures. perceived barriers belief about the potential negative aspects of a particular health action adapted from health belief model construct (hochbaum, 1958; rosenstock, 1974a) and further refined by the cwg. perceived behavioral control confidence of participants’ ability to screen for prostate cancer. adapted from theory of planned behavior (ajzen, 1985) and further refined by the cwg perceived benefits belief about the potential positive aspects of prostate cancer screening. adapted from health belief model construct (hochbaum, 1958; rosenstock, 1974b) and further refined by the cwg. perceived health status perception of overall health in terms of physical, emotional, psychological and social well being. physical well-being is defined as the absence of disease or infirmity. emotional well-being includes perceived life satisfaction, happiness, cheerfulness, peacefulness. psychological well-being includes selfacceptance, personal growth including openness to new experiences, optimism, hopefulness, purpose in life, control of one’s environment, spirituality, selfdirection, and positive relationships. social wellbeing includes social acceptance, beliefs in the potential of people and society as a whole, personal self-worth and usefulness to society, sense of community. adapted from physical, emotional, psychological and social well-being (cdc, 2013; keyes, 1998; ryff, 1989; ryff & keyes, 1995). perceived severity belief about the seriousness of prostate cancer, or leaving it untreated and its consequences. adapted from health belief model construct (hochbaum, 1958; rosenstock, 1974b) and further refined by the cwg. perceived susceptibility belief about getting prostate cancer. adapted from health belief model construct (hochbaum, 1958; rosenstock, 1974b) and further refined by the cwg. prostate cancer health perceived physical signs and symptoms of prostate cancer. adapted from captc (odedina et al., 2014) and ac3 measures (blackman et al., 2017) prostate cancer information seeking behavior proactive information seeking about prostate cancer. adapted from captc measure (odedina et al., 2014) prostate cancer screening participants self-report on prostate cancer screening activities within the last five years, including the prostate specific antigen (psa) and digital rectal examination (dre) diagnostic tests. adapted from captc measure (odedina et al., 2014) https://www.gem-beta.org/public/constructdetail.aspx?cid=1546&cat=1 https://www.gem-beta.org/public/constructdetail.aspx?cid=1546&cat=1 https://www.gem-beta.org/public/constructdetail.aspx?cid=1496&cat=1 https://www.gem-beta.org/public/constructdetail.aspx?cid=1495&cat=1 https://www.gem-beta.org/public/constructdetail.aspx?cid=1495&cat=1 https://www.gem-beta.org/public/constructdetail.aspx?cid=1541&cat=1 https://www.gem-beta.org/public/constructdetail.aspx?cid=1547&cat=1 https://www.gem-beta.org/public/constructdetail.aspx?cid=1547&cat=1 https://www.gem-beta.org/public/constructdetail.aspx?cid=1520&cat=1 https://www.gem-beta.org/public/constructdetail.aspx?cid=1519&cat=1 https://www.gem-beta.org/public/constructdetail.aspx?cid=1519&cat=1 https://www.gem-beta.org/public/constructdetail.aspx?cid=1492&cat=1 https://www.gem-beta.org/public/constructdetail.aspx?cid=1492&cat=1 https://www.gem-beta.org/public/constructdetail.aspx?cid=1537&cat=1 https://www.gem-beta.org/public/constructdetail.aspx?cid=1537&cat=1 https://www.gem-beta.org/public/constructdetail.aspx?cid=1537&cat=1 https://www.gem-beta.org/public/constructdetail.aspx?cid=1539&cat=1 https://www.gem-beta.org/public/constructdetail.aspx?cid=1539&cat=1 www.companyofscientists.com/index.php/chd e8 cancer health disparities research prostate cancer subjective norm perceived social pressure arising from one's perception adapted from theory of reasoned action (ajzen, 1991; fishbein & ajzen, 1975) and further refined by the cwg prostate medical procedures participant’s recollection of diagnostic and treatment procedures that he has done in the past. adapted from ac3 measure (blackman et al., 2017) religiosity/spirituality defined as organized system of beliefs, practices, rituals, and symbols (1). adapted from captc measure (odedina et al., 2014) screening controversy scale knowledge of controversies about prostate cancer prevention, screening, and treatment. adapted from captc measure (odedina, segal, kimberlin, & lee, 2011). shared decision making (screening) shared decision making involves the patient, provider and family being informed with the best available evidence about options, benefits, harms, preferences and values (rimer et. al., 2004) adapted from shared decision making measure (rimer, briss, zeller, chan, & woolf, 2004) measure. temporal orientation an individual’s perception of time as being in the past, present or future (1, 2). adapted from captc measure (f. odedina et al., 2014) trust of health care providers participants' expression of valuing their providers recommendations relative to their care, including screening and treatment decision-making. adapted from ac3 measure (blackman et al., 2017) the captc-ac3 behavioral measures are ideal for studies focused on identifying behavioral factors impacting prostate cancer across the continuum of care; intervention studies to improve prostate cancer prevention, screening, detection, treatment and survivorship in black men; migration and immigrant health studies; and comparative studies of prostate cancer among ethnically-diverse black men. behavioral measures are very important in identifying modifiable variables, which can be targeted to effectively reduce health disparities in minority and underserved populations. according to the institute of medicine, the potential sources of disparities in health care occur at individual (personal or provider), institutional or health systems levels (nelson, 2003). the modification of individual behaviors of black men with respect to prostate cancer risk reduction, informed decision making for prostate cancer screening, and adherence to prostate cancer treatment and survivorship strategies remains a key weapon to eliminate prostate cancer health disparity in this population. the captc-ac3 behavioral measures are thus important tools in identifying behavioral factors impacting prostate cancer prevention, screening, detection, treatment and survivorship in black men. in addition, these measures will provide a means of testing the fidelity of intervention programs targeting black men’s behavior. uniquely, these measures will provide an opportunity to compare behavioral factors among ethnically-diverse black men globally. the captcac3 instrument is provided in the appendix. standardized global epidemiological measures for prostate in black men the captc-ac3 consensus working group reached a consensus on and approved 24 epidemiological data elements for the cabe https://www.gem-beta.org/public/constructdetail.aspx?cid=1620&cat=1 https://www.gem-beta.org/public/constructdetail.aspx?cid=1620&cat=1 https://www.gem-beta.org/public/constructdetail.aspx?cid=1493&cat=1 https://www.gem-beta.org/public/constructdetail.aspx?cid=1493&cat=1 https://www.gem-beta.org/public/constructdetail.aspx?cid=1543&cat=1 https://www.gem-beta.org/public/constructdetail.aspx?cid=1526&cat=1 https://www.gem-beta.org/public/constructdetail.aspx?cid=1526&cat=1 https://www.gem-beta.org/public/constructdetail.aspx?cid=1491&cat=1 https://www.gem-beta.org/public/constructdetail.aspx?cid=1491&cat=1 https://www.gem-beta.org/public/constructdetail.aspx?cid=1523&cat=1 https://www.gem-beta.org/public/constructdetail.aspx?cid=1544&cat=1 https://www.gem-beta.org/public/constructdetail.aspx?cid=1544&cat=1 www.companyofscientists.com/index.php/chd e9 cancer health disparities research measures (table 3). for each construct, the measures were either adapted or new measures. adapted measures were from existing instruments of behavioral risk factors surveillance system (brfss), national health and nutrition examination survey (nhanes), the southern community cohort study (sccs), and ac3 and/or captc studies. baldness was adapted from the norwood hamilton scale (norwood, 1975). these measures were either generic measures that did not need to be culturally tailored (e.g. demographics, country of birth, smoking cessation, environmental tobacco exposure and anthropometrics) or were already culturally tailored for black men in africa, us and caribbean and had been included in prior ac3 and captc studies (e.g. languages and fluency, sun habits, personal history of cancer, environmental exposures and social environment). new measures were created from existing instruments of brfss and sccs and were further refined and culturally tailored in order to ensure that the data capture was specific and responsive to the cultural and lifestyle heterogeneity between black men born in africa, the caribbean and us. the reason for choosing the brfss and sccs for adaptation over other study instruments was because (a) the brfss and nhanes instruments are already national and standardized instruments established by the centers for disease control and prevention (cdc 2012a, cdc 2012b) and (b) the instrument from the sccs (signorello et al., 2005) is also standardized, was developed for the recruitment of adults from southeastern us, and among existing us cohorts the sccs has the largest representation of blacks. table 3: captc-ac3-madcap standardized global epidemiological measures for prostate in black men. constructs description of measures source demographics participants’ age, family status and religion. adapted from ac3 measure (blackman et al., 2017) race/ethnicity self-defined race as well as self, maternal and paternal ethnicity defined as country of origin and citizenship or immigrant status (for us participants), hispanic/latino. country-specific measures for ethnic groups in, ghana, kenya, liberia, nigeria, south africa, senegal and trinidad and tobago are also included. adapted from brfss (cdc 2012a) and sccs (signorello et al., 2005) measures and was further refined by the cwg. socioeconomic status (ses) subjective social status, community ladders (adler, adler, epel, castellazzo, & ickovics, 2000) (adler et al., 2000) as well as educational attainment, income, employment status and occupation, home ownership and household information including number and relationships with persons living in the household adapted from brfss (cdc 2012a) and sccs (signorello et al., 2005) measures and was further refined by the cwg. residency participant’s current country and duration of residence, it defines whether the participant lived in a rural community, as well as historical residence. documentation of geospatial coordinates based on participants address are also recommended. adapted from brfss (cdc 2012a) and sccs (signorello et al., 2005) measures and was further refined by the cwg. country of birth birth country and the number of years lived in that country for participants as well as for mother, father, maternal and paternal grandmother/grandfather. adapted from ac3 measure (blackman et al., 2017) www.companyofscientists.com/index.php/chd e10 cancer health disparities research languages and fluency participant’s native language and comfort level speaking their ethnic dialect compared to other languages; as well as measures of fluency and amount of time speaking the country’s official language at home, school, work, prayer and with friends for participants living in countries where the official language is their second language. adapted from ac3 (blackman et al., 2017) and captc (odedina et al., 2014) measures. nutrition dietary measures as well as a culturally tailored food frequency questionnaire these include participants’ dietary intake, food portions described as general plate portions of meat, starches and vegetables as well as a) current intake (past 30 days) frequency and b) average annual intake frequency of: heterocyclic amines based on food preparation methods, dietary fats, meat organs, grains, starchy foods and tubers, lycopene rich fruits, beans, glucosinolate-rich cruciferous vegetables, antioxidant-rich fruits and vegetables, sources of refined sugar such as sweets and sweeteners, non-alcoholic beverages. adapted from brfss measure (cdc, 2012a) and was further refined by the cwg. physical activity duration, frequency and intensity for the past year and frequency of strengthening exercises in the past month only. adapted from brfss measure (cdc, 2012a) and was further refined by the cwg. sun habits participants’ exposure and duration in the sun during the months of summer, on weekdays and weekends as well as sun protection habits on sunny days. skin pigmentation based on skin tone on the inside part of their upper arm (ho chien-ju, 2015) and latitude obtained from participants’ residence location are also included. adapted from ac3 (blackman et al., 2017) and captc (odedina, 2011) measures. smoking habits participants’ smoking status and history of tobacco use including smoking initiation age, type of tobacco used and frequency of use a measure of marijuana use adapted from brfss and nhanes (cdc 2012a, 2012b) measures and was further refined by the cwg. smoking cessation length of time since last cigarette was smoked adapted from brfss measure (cdc, 2012a) environmental tobacco exposure participants’ exposure to second hand cigarette smoke at home, workplace, indoor public place or vehicle and includes documentation of in-home or vehicle cigarette smoking policy adapted from brfss measure (cdc, 2012a) alcohol use participants’ history of alcohol use and includes age of first drink, duration of alcohol use and number of drinks on average as well as for specific alcohol products such as beer, wine, liquor and common alcoholic drinks consumed in caribbean and african settings. adapted from brfss (cdc 2012a) and sccs (signorello et al., 2005) measures and was further refined by the cwg. health care access type of health care coverage and method of payment for health care. adapted from sccs measure (signorello et al., 2005) and was further refined by the cwg. personal history of cancer participants’ history of any cancer and of recurrence (for men with a history of prostate cancer). adapted from ac3 measure (blackman et al., 2017) family history of participants’ family history of cancer, with responses adapted from sccs measure www.companyofscientists.com/index.php/chd e11 cancer health disparities research cancer indicating if sons, daughters, wife, birth parents, full/half siblings, uncles, cousins, maternal and paternal grandparents have been diagnosed with cancer. the specific type of cancer, smoking status and diagnosis before age 50 is also documented. (signorello et al., 2005) and was further refined by the cwg. medication use participants’ duration of use of anti-inflammatory and cholesterol-reducing medications in the past year as well as current use and duration of use of urinary retention medicines and other medications. adapted from sccs measure (signorello et al., 2005) and was further refined by the cwg. vitamin and supplement use participants’ past year duration of use of vitamins and supplements including commonly used supplements and herbs to promote prostate health adapted from sccs measure (signorello et al., 2005) and was further refined by the cwg. baldness norwood-hamilton scale of male pattern baldness at ages 30 and 45 years old adapted from norwood measure (norwood, 1975) anthropometrics participants’ self-reported weight loss or gain in the past five years, previous heaviest weight, as well as measurements of current weight, waist and hip/buttocks reported in inches in triplicate with notations taken with or without clothing and thickness of clothing current and previous body shape is measured with a rating scale from stunkard visual figures for five decades of life from 20 years old to 50 years old (cheung et al., 2011; stunkard, sorensen, & schlusinger f, 1983) adapted from ac3 measure (blackman et al., 2017). personal history of chronic conditions and risk factors participants’ history of prostatic diseases and other chronic conditions and age at diagnosis adapted from sccs measure (signorello et al., 2005) and was further refined by the cwg. family history of chronic conditions and risk factors participants’ family history of prostatic diseases and age at diagnosis for father and full/half-brother as well as family history of other chronic conditions and age at diagnosis for birth father, birth mother, full/half-sister and full/half-brother. adapted from sccs measure (signorello et al., 2005) and was further refined by the cwg.. environmental exposures participants’ history and age worked as an agricultural/groundsman, pesticide worker or exposure to chemical fertilizers or pesticides used on the farm these measures were adapted from ac3 measure (blackman et al., 2017). social environment participants’ perception of personal social environment such as neighborhood interactions, physical environment and personal safety. adapted from ac3 measure (blackman et al., 2017). captc-ac3 epidemiological measures will support research questions that require comparative analysis between us-born, africa-born and caribbean-born men whether within the us or between geographic populations in the caribbean and africa. furthermore, the captc-ac3 epidemiological measures can also be easily adapted and implemented in research studies that also involve black women since these constructs are not gender-specific. the captc-ac3 instrument is provided in the appendix. discussion www.companyofscientists.com/index.php/chd e12 cancer health disparities research the cabe measures are currently being used as standard data collection tools in multiple countries globally. the captc consortium adopted the measures in march 2017 for the west africa prostate cancer familial cohort study, which will recruit 2,000 west african men in united states, nigeria, cameroon and england. supported by the nci p20 award (p20ca192992), the geographic management of cancer health disparities (gmap) program award and the carnegie african diaspora fellowship program, this captc study has recruited over 1,000 participants administering the cabe measures in english language and pidgin english in the united states, nigeria, and cameroon. on average, it takes about 1 hour to complete all the measures. in addition to the behavioral, epidemiological and clinical data, the study includes biological data collection in form of saliva and formalin-fixed paraffin-embedded prostate tissue. captc is currently developing a methodology to integrate and harmonize the cabe data with existing captc database of over 5,000 participants. ac3 adopted the measures for use in an existing us-based multi-ethnic cohort of african descent (cancer prevention project of philadelphia – cap3). this cohort is funded by the american cancer society (rsg-14-033-01-cppb) and fox chase cancer center and includes 946 (female and male) participants. integration of the cabe measures for the current (n=326) and prospective male participants in this cohort is in progress. genomic data are currently being generated from dna collected from saliva and biomarker data are being generated from urine samples. expansion of this multi-ethnic cohort to two us sites and two caribbean sites is in development. one caribbean site in jamaica will begin in october 2019 and we will recruit 8,000 participants affected and unaffected by cancer (3,200 males and 4,800 females). the second caribbean site in the bahamas was established in september 2017 and the first round of enrollment includes 380 black men unaffected and affected with prostate cancer. approximately 600 males are anticipated to be enrolled annually. further expansion of this and other caribbean sites are planned through supported activities of an nci p20 award in planning for a regional center for cancer and cardiometabolic research in the caribbean (1p20ca210294-01). in addition to the cabe data, saliva and paraffin-embedded samples (from prostate cancer cases) will be collected for genomic and epigenetic studies. data sharing is essential for expedited translation of research results into knowledge that can be used to accelerate the pace of research. the nih has implemented policies that require investigators to share their data and resources, including the 2003 nih data sharing policy and the 2015 nih genomic data sharing policy (https://grants.nih.gov/grants/policy/data_sharing/ ). in addition, nci is moving towards methods that will enhance data sharing and encourage the broad sharing of data (beyond current scientific collaborations). the gem database is one such example, the publicly available cabe measures are easily downloaded and access in different formats to enhance data sharing (moser et al., 2011). the cabe measures provide global access to culturally appropriate data collection tools for the study of prostate cancer in black men. specifically, the use of standardized and common measures will facilitate data pooling and harmonization across several populations. the long-term impact of the cabe measures is catalyzed progress for prostate cancer disparity research through https://grants.nih.gov/grants/policy/data_sharing/ https://grants.nih.gov/grants/policy/data_sharing/ www.companyofscientists.com/index.php/chd e13 cancer health disparities research harmonized data. for example, the prostate cancer research community will be able to create big data from all the studies using the cabe measures. access to big data provides the ability to do analyses that cannot be done with single studies, including exploring the influence of genetic and lifestyle factors on prostate cancer, fostering the identification of genetic changes for cancer growth, accurate prediction of cancer health outcomes, guiding treatment decision making, and predicting behavioral risk factors for cancer. ultimately, the cabe measures will contribute to the goal of understanding and ultimately reducing the disproportionate effects of prostate cancer in black men. acknowledgements this work is supported in part by the national institutes of health/national cancer institute (p20ca192992, p30ca006927, p20ca210294, r13ca189451, r13ca210494, and r13ca192672-03) and the 2017 carnegie african diaspora fellowship program. the authors are grateful to the members of the african caribbean cancer consortium and the prostate cancer transatlantic consortium who provided support and feedback during this project. conflict of interest the authors declare that no competing or conflict of interests exist. the funders had no role in study design, writing of the manuscript, or decision to publish. authors’ contributions odedina conceptualized the project, participated in the review and development of behavioral measures, actively participated in the writing of the manuscript; ragin participated in the review and development of epidemiological measures and actively participated in the writing of the manuscript; martin participated in the review and development of epidemiological measures and actively participated in the writing of the manuscript; moser coordinated the gem platform consensus process and actively participated in the writing of the manuscript; oliver participated in the review and development of behavioral measures and actively participated in the writing of the manuscript; mcdonald participated in the review and development of epidemiological measures and actively participated in the writing of the manuscript; rise assisted with the gem platform consensus process and participated in the writing of the manuscript; nguyen participated in the review and organization of the behavioral measures and participated in the review of the manuscript; chinegwundoh actively participated in the writing of the manuscript; morrison-blidgen actively participated in the writing of the manuscript; kaninjing actively participated in the writing and editing of the manuscript.; jalloh participated in the review and development of epidemiological measures, and participated in the editing of the manuscript; reams participated in the review of measures on gem platform and review of the manuscript. references adler, n., adler, n. e., epel, e. s., castellazzo, g., & ickovics, j. r. 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(2003). major approaches to the measurement of acculturation among ethnic minority populations: a content analysis and an alternative empirical strategy. acculturation: advances in theory, measurement, and applied research, (2007), 39–60. https://doi.org/10.1037/10472-005 www.companyofscientists.com/index.php/chd e1 cancer health disparities research race is related with increased covid-19 infection in oncology patients john nakayama*a, gino cioffib,i, sharanya iyerc, ravi kumar kyasaramd, john shanahand, paolo caimie, kristin a. waiteb,i, thomas a. sellersf, jill s. barnholtz-sloanb,g,h,i a division of gynecologic oncology, department of obstetrics and gynecology university hospitals cleveland medical center. cleveland, ohio. usa b department of population and quantitative health sciences, case western reserve university school of medicine. cleveland, ohio. usa c case western reserve university school of medicine. cleveland, ohio. usa d cancer informatics, seidman cancer center. cleveland, ohio. usa e division of hematology, department of medicine, university hospitals seidman cancer center. cleveland, ohio. usa f tas consulting. tampa, florida. usa g case comprehensive cancer center. cleveland, ohio. usa h research and education division, university hospitals of cleveland. cleveland, ohio. usa i cleveland center for health outcomes research (cchor). cleveland, ohio. usa corresponding author: john nakayama. email: john.nakayama@ahn.org abstract we seek to assess racial disparities in oncology patients with covid19 compared to appropriately matched controls with and without covid19. all patients treated at the seidman cancer center with a diagnosis of covid19 and cancer were identified from the electronic medical record using icd9/icd10 codes for cancer diagnoses and database of all patients diagnosed with covid19. two control groups, cancer patients without covid19 and patients without cancer but with covid19, were generated and matched 3:1 on age at date of data extraction, age at cancer diagnosis, and sex to covid19 positive cancer cases. african americans (aa) and whites made up 8.6% vs. 76.9% of the baseline oncologic population without covid19, respectively. aa representation (41.0%) was significantly increased in cancer patients positive for covid19 compared to those negative for covid19 (p<0.001). in the comparison of patients with covid19 with or without cancer, the proportion of aa cases was greater in the nononcologic population (41.0% vs. 47.6%, p=0.014). aa are disproportionately affected with covid19 in oncologic and benign populations. despite similar rates of adverse outcomes to covid19 in cancer patients by race, we found a 32.4% increase in the aa proportion compared to those without covid19. these findings suggest covid19 prevention policies and future studies should account for racial differences in the oncology population. keywords: covid19, coronavirus 19, racial disparities, oncology, citation: nakayama j et al (2021) race is related with increased covid-19 infection in oncology patients. cancer health disparities 5:e1-e8.doi:10.9777/chd.2021.1004 mailto:john.nakayama@ahn.org www.companyofscientists.com/index.php/chd e2 cancer health disparities research introduction the novel coronavirus sars-cov-2 (covid19) pandemic led to radical shifts in oncology care. new reports indicate that cancer patients have increased morbidity and mortality from covid191–4. one study from new york, showed 40% of cancer patients with covid19 required hospital admission. older age (>65 years) and recent immunotherapy predicted admission and disease severity while chemotherapy or surgery did not5. these findings may not be generalizable given that the proportion of minority subjects was lower than other studies conducted in the same area3,6. in an attempt to overcome some of the limitations of prior studies,a case control study of chinese covid19 patients with and without cancer was performed. it showed oncology patients had a nearly significant increased risk of death (or: 2.17, p= 0.06) and significantly more icu admissions (or: 3.13, p<0.01) or at least one severe symptom (or: 1.99, p<0.01)7. cancer patients are often obliged to continue care. during the covid19 pandemic this can be dangerous for patients who lack the resources or ability to limit their exposure. while higher covid19 infection rates have been observed in minority communities through the lay press and editorials, a limited body of scientific literature is available3,8. a recent study using veteran’s affairs (va) data showed a higher prevalence of covid19 infection and hospitalization, but not mortality, in african americans (aa)9. this data may not be generalizable due to the unique va population. given these realities and the racially diverse population of the university hospitals seidman cancer center (uhscc), we investigated the dynamics of covid19 infection in oncology patients in order to: (1) determine the demographic differences between cancer patients infected with covid19 versus covid19 infected patients without a cancer history, (2) compare the outcomes of cancer patients infected with covid19 to patients without cancer who are infected with covid19, and (3) compare characteristics and outcomes of cancer patients infected with covid19 to cancer patients without covid19 diagnosis. materials and methods after receiving approval by uhscc institutional review board, a search from 3/16/2020 to 7/7/2020 was performed of all patients treated at the seidman cancer center. a cancer diagnosis was determined by searching the electronic medical record for a cancer icd9/10 code and then manually verifying the cancer diagnosis. covid19 positive patients were identified using a database maintained by the hospital of all patients diagnosed with covid19. adult (>18years old), covid19 positive oncology patients were identified (ca+/covid+). two control groups, cancer patients without covid19 (ca+/covid-) and patients without cancer but with covid19 (ca/covid+), were generated. the ca+/covid group was matched based upon age at date of data extraction, age at cancer diagnosis, and sex at 3:1, and the ca-/covid+ group was matched for age at data extraction at 3:1 (figure 1). the weighted elixhauser-comorbidity score was used to quantify the rate of comorbid medical conditions present in each group10,11. descriptive statistics were generated using r software (version 3.6.3) to assess demographic and treatment differences between cases and each control group. t-tests were performed to compare differences in mean and chi-square tests assess differences in proportion. a p < 0.05 was considered statistically significant. www.companyofscientists.com/index.php/chd e3 cancer health disparities research figure 1. flow diagram of included patients a total of 166 cases were identified (table 1). the median follow-up time was 53 days from covid19 diagnosis. distribution of cancer differed between the ca+/covid+ and ca+/covidgroups (p=0.026), with a notably higher proportion of oral cavity and pharynx cancers in the ca+/covid population (0.6% compared to 4.2%, p=0.045). cancer related treatment in ca+/covid+ patients was uncommon with 7.2% and 0.6% of patients receiving chemotherapy or radiation, respectively, within 30 days of their covid19 diagnosis. only 4 ca+/covid+ patients (2.4%) had a surgery in the year prior to their covid19 diagnosis. significant racial differences were identified between groups. the racial distribution of patients in the ca+/covidgroup was 8.6% aa vs. 76.9% white (table 1). a significantly higher proportion of aa, 41.0%, was noted in patients with cancer and covid19 (p<0.001). in the comparison of ca+/covid+ to ca-/covid+, the proportion of aa patients was greater in the non-oncologic population (41.0% vs. 47.6%, p=0.014). measures associated with covid19 severity were examined. a weighted elixhauser comorbidity score >5 was present in 91.6% of ca+/covid+ patients compared to 82.3% (p=0.003) of ca+/covidand 52.3% (p<0.001) of ca-/covid+ patients. over 1 in 5 (22.3%) of the ca+/covid+ patients were admitted to the icu. this was not significantly greater than the ca-/covid+ (16.3%, p= 0.101). there was no difference in ventilator use (p=0.999). the death rate from covid19 was 3.0% in the ca-/covid+ group versus 4.8% in the ca+/covidgroup, which was not statistically significant (p=0.391). the ca+/covid+ group was further stratified by race (table 2). there was no difference in types of cancer (p=0.394) and comorbidity score by race (p=.794). outcomes were equivalent between racial groups in terms of ventilator use (94.7% vs. 95.6%, p=0.999), icu admission (76.8% vs. 77.9%, p=0.999), and death (94.7% vs. 95.6%, p=0.999). www.companyofscientists.com/index.php/chd e4 cancer health disparities research table 1. descriptive statistics of patients diagnosed with primary cancer and covid19 with corresponding cancer and covid19 controls. patients with cancer and covid19 (cancer+/covid+) patients with cancer without covid19 (cancer+/covid-) p* patients with cancer without covid19 (cancer-/covid+) p* overall n 166 498 498 age at cancer diagnosis, mean (sd)[range] 63.5 (15.0) [19-91] 63.5 (15.0) [19-91] 0.99 -- age at covid diagnosis, mean (sd)[range] 68.2 (15.1) [26-97] --68.2 (15.1) [26-97] 0.86 gender, n (%) female 97 (58.4%) 291 (58.4%) 0.999 303 (60.8%) 0.647 male 69 (41.6%) 207 (41.6%) 195 (39.2%) race, n (%) white 95 (57.2%) 383 (76.9%) <0.001 218 (43.8%) 0.014 african american 68 (41.0%) 43 (8.6%) 237 (47.6%) other 2 (1.2%) 39 (7.8%) 20 (4.0%) unknown 1 (0.6%) 33 (6.6%) 23 (4.6%) ethnicity, n (%) hispanic 2 (1.2%) 5 (1.0%) 0.999 0 (0.0%) 0.137 non-hispanic 160 (96.4%) 453 (91.0%) 418 (83.9%) unknown 4 (2.4%) 40 (8.0%) 80 (16.1%) first cancer, n (%) bones and joints 3 (1.8%) 6 (1.2%) 0.026 -- brain and other nervous system 3 (1.8%) 19 (3.8%) - breast 31 (18.7%) 96 (19.3%) - digestive system 20 (12.0%) 92 (18.5%) - endocrine system 8 (4.8%) 11 (2.2%) - female genital system 11 (6.6%) 30 (6.0%) - leukemia 10 (6.0%) 18 (3.6%) - lymphoma 8 (4.8%) 18 (3.6%) - www.companyofscientists.com/index.php/chd e5 cancer health disparities research male genital system 22 (13.3%) 52 (10.4%) - oral cavity and pharynx 1 (0.6%) 21 (4.2%) - respiratory system 14 (8.4%) 39 (7.8%) - skin 5 (3.0%) 39 (7.8%) - urinary system 11 (6.6%) 20 (4.0%) - other/unspecified 19 (11.4%) 37 (7.4%) - weighted elixhauser comorbidity score, n (%) <0 3 (1.8%) 16 (3.2%) 0.003 122 (26.2%) <0.001 0 2 (1.2%) 48 (9.6%) 60 (12.9%) 1-4 9 (5.4%) 24 (4.8%) 40 (8.6%) >=5 152 (91.6%) 410 (82.3%) 243 (52.3%) ventilator use, n (%) no 158 (95.2%) --476 (95.6%) 0.999 yes 8 (4.8%) - 22 (4.4%) admitted to icu, n (%) no 129 (77.7%) --417 (83.7%) 0.101 yes 37 (22.3%) - 81 (16.3%) died within 30 days of covid diagnosis no 158 (95.2%) --483 (97.0%) 0.391 yes 8 (4.8%) - 15 (3.0%) *: p considered significant if <0.05, sd: standard deviation table 2. descriptive statistics of cases (cancer+/covid19+) stratified by race. study population (cancer+/covid19+) white black p* overall n 95 68 age at cancer diagnosis, mean (sd) 65.0 (13.7) 61.8 (15.5) 0.162 age at covid diagnosis, mean (sd) 69.4 (14.3) 66.8 (15.6) 0.276 gender, n (%) female 55 (57.9%) 40 (58.8%) 0.999 male 40 (42.1%) 28 (41.2%) ethnicity, n (%) www.companyofscientists.com/index.php/chd e6 cancer health disparities research hispanic 2 (2.2%) 0 (0.0%) 0.609 non-hispanic 89 (97.8%) 68 (100.0%) unknown 0 (0.0%) 4 (4.2%) first cancer, n (%) bones and joints 1 (1.1%) 2 (2.9%) 0.394 brain and other nervous system 2 (2.1%) 1 (1.5%) breast 13 (13.7%) 17 (25.0%) digestive system 13 (13.7%) 6 (8.8%) endocrine system 3 (3.2%) 4 (5.9%) female genital system 8 (8.4%) 3 (4.4%) leukemia 6 (6.3%) 4 (5.9%) lymphoma 5 (5.3%) 3 (4.4%) male genital system 11 (11.6%) 11 (16.2%) oral cavity and pharynx 1 (1.1%) 0 (0.0%) respiratory system 10 (10.5%) 9 (13.2%) skin 11 (11.6%) 3 (4.4%) urinary system 5 (5.3%) 0 (0.0%) other/unspecified 6 (6.3%) 5 (7.4%) weighted elixhauser comorbidity score, n (%) <0 2 (2.1%) 1 (1.5%) 0.794 0 1 (1.1%) 0 (0.0%) 1-4 4 (4.2%) 4 (5.9%) >=5 88 (92.6%) 63 (92.6%) ventilator use, n (%) no 90 (94.7%) 65 (95.6%) 0.999 yes 5 (5.3%) 3 (4.4%) admitted to icu, n (%) no 73 (76.8%) 53 (77.9%) 0.999 yes 22 (23.2%) 15 (22.1%) died within 30 days of covid diagnosis no 90 (94.7%) 65 (95.6%) 0.999 yes 5 (5.3%) 3 (4.4%) www.companyofscientists.com/index.php/chd e7 cancer health disparities research *: p considered significant if <0.05 discussion this study reflects the disproportionate effect of covid19 on aa with and without cancer. aa normally make up 8.6% of the oncology patients at uhscc as shown in the ca+/covidgroup. however, this increases over 4.5 times to 41.0% of oncology patients with covid19 infections. further studies evaluating socioeconomic factors that limit the ability to social distance or work remotely as well as other social determinants of health are needed to determine why this disparity exists. interestingly, the proportion of aa is even greater (47.6%) in non-oncologic patients (ca-/covid19+) than oncology patients (ca+/covid19+). to our knowledge, this has not been previously reported. cancer patients may be taking additional precautions that ameliorate identified factors predisposing this community to covid198,12. alternatively, the smaller proportion of aa among cancer patients could reflect impaired access to cancer care which would decrease the likelihood of covid19 testing; such an investigation was beyond the scope of this report. there was no difference in ventilator use, icu admission, or death in cancer patients with covid19 versus patients without cancer. this finding remained true when stratified by race. this absence of difference in covid19 related complications occurred despite cancer patients having a greater proportion of patients with elevated comorbidity scores and could be related to the low percentage of patients receiving active treatment, a known risk factor for worse outcomes 4,7,13–15. this study has several limitations. given its retrospective nature, it was not possible to control for rapidly evolving covid19 care, however, the limited time frame of interest minimizes the effects of cancer care specifics to mortality and morbidity. the study population was that of a large urban academic center and may not represent other patient groups. this study illustrates the disproportionate effect of covid19 on aa oncology patients. despite similar rates of adverse outcomes to covid19 amongst racial groups, the proportion of aa patients was significantly higher among cancer patients with covid19 when compared with controls without covid19. these findings suggest racial differences in covid19 rates in the oncology population should inform infection control efforts like vaccination programs as well as future study designs to protect vulnerable populations. acknowledgement none conflicts of interest the authors declare no conflict of interest. authors' contributions design: nakayama, cioffi, waite, sellers, barnholtzsloan, caimi, sellers data collection: nakayama, iyer, kyasaram, shanahan analysis: nakayama, cioffi, iyer, caimi, waite, sellers, barnholtz-sloan manuscript: nakayama, cioffi, iyer, caimi, waite, sellers, barnholtz-sloan references 1. liang w, guan w, chen r, et al. cancer patients in sarscov-2 infection: a nationwide analysis in china. lancet oncol. 2020;21(3):335-337. doi:10.1016/s14702045(20)30096-6 www.companyofscientists.com/index.php/chd e8 cancer health disparities research 2. trapani d, marra a, curigliano g. the experience on coronavirus disease 2019 and cancer from an oncology hub institution in milan, lombardy region. eur j cancer. 2020;132:199-206. doi:10.1016/j.ejca.2020.04.017 3. mehta v, goel s, kabarriti r, et al. case fatality rate of cancer patients with covid-19 in a new york hospital system. cancer discov. 2020;10(7):935-941. doi:10.1158/2159-8290.cd-20-0516 4. rugge m, zorzi m, guzzinati s. sars-cov-2 infection in the italian veneto region: adverse outcomes in patients with cancer. nat cancer. 2020;1(8):784-788. doi:10.1038/s43018-020-0104-9 5. robilotti e v., babady ne, mead pa, et al. determinants of covid-19 disease severity in patients with cancer. nat med. 2020;26(8):1218-1223. doi:10.1038/s41591-020-09790 6. kabarriti r, brodin np, maron mi, et al. association of race and ethnicity with comorbidities and survival among patients with covid-19 at an urban medical center in new york. jama netw open. 2020;3(9):e2019795. doi:10.1001/jamanetworkopen.2020.19795 7. dai m, liu d, liu m, et al. patients with cancer appear more vulnerable to sars-cov-2: a multicenter study during the covid-19 outbreak. cancer discov. 2020;10(6):783. doi:10.1158/2159-8290.cd-20-0422 8. balogun od, bea vj, phillips e. disparities in cancer outcomes due to covid-19 a tale of 2 cities. jama oncol. 2020;6(10):1531-1532. doi:10.1001/jamaoncol.2020.3327 9. fillmore nr, la j, szalat re, et al. prevalence and outcome of covid-19 infection in cancer patients: a national veterans affairs study. j natl cancer inst. 2020. doi:10.1093/jnci/djaa159 10. thompson nr, fan y, dalton je, et al. a new elixhauserbased comorbidity summary measure to predict inhospital mortality. med care. 2015;53(4):374-379. doi:10.1097/mlr.0000000000000326 11. moore bj, white s, washington r, coenen n, elixhauser a. identifying increased risk of readmission and inhospital mortality using hospital administrative data. med care. 2017;55(7):698-705. doi:10.1097/ mlr.0000000000000735 12. newman l, winn ra, carethers jm. similarities in risk for covid-19 and cancer disparities. clin cancer res. october 2020:clincanres.3421.2020. doi:10.1158/10780432.ccr-20-3421 13. nepogodiev d, bhangu a, glasbey jc, et al. mortality and pulmonary complications in patients undergoing surgery with perioperative sars-cov-2 infection: an international cohort study. lancet. 2020;396(10243):27-38. doi:10.1016/s0140-6736(20)31182-x 14. kapteijn ba, nieweg oe, liem i, et al. localizing the sentinel node in cutaneous melanoma: gamma probe detection versus blue dye. ann surg oncol. 1997;4(2):156160. 15. albiges l, foulon s, bayle a, et al. determinants of the outcomes of patients with cancer infected with sars-cov2: results from the gustave roussy cohort. nat cancer. september 2020:1-11. doi:10.1038/s43018-020-00120-5 introduction materials and methods results discussion acknowledgement conflicts of interest authors' contributions www.companyofscientists.com/index.php/chd e1 cancer health disparities research liver cancer incidence and mortality: disparities based on age, ethnicity, health and nutrition, molecular factors, and geography santosh kumar singh and rajesh singha* adepartment of microbiology, biochemistry and immunology, cancer health equity institute, morehouse school of medicine, atlanta, ga, usa, 30310 *corresponding author: rajesh singh, e-mail: rsingh@msm.edu abstract liver cancer (lca) is the fifth and eighth leading cause of cancer death for men and women, respectively. however, despite improvements in treatment strategies and options, it has limited therapeutic options. worldwide, the prevalence of lca varies widely. various factors are associated with the development of lca, and its incidence, morbidity, and mortality rates differ due to disparities that are multifactorial and complex, including genetic and geographic factors. the frequency of lca varies by race/ethnicity, age and sex and relates to viral infections, lifestyle, nutrition, obesity, and health. in addition, various molecular factors, including cytokines, hormones, apoptosis, and mutations, are involved in disparities in the progression and mortality of lca. here, we provide an overall perspective on lca by presenting available information on these associated factors and discussing their importance in its disproportionate incidences and clinical outcomes. keywords: liver cancer, health disparity, nutrition and health, morbidity citation: sk singh and r singh (2019) liver cancer incidence and mortality: disparities based on age, ethnicity, health and nutrition, molecular factors, and geography. cancer health disparities 4: e1-e10. doi:10.9777/chd.2019.1014 mailto:rsingh@msm.edu www.companyofscientists.com/index.php/chd e2 cancer health disparities research introduction in the united states, liver cancer (lca), including intrahepatic bile duct cancer, is the fifth and eighth leading cause of cancer for men and women, respectively (chen, 2018). for the united states, 42,030 cases are expected to be diagnosed in 2019, and 31,780 deaths are predicted (siegel et al., 2019). the death rates for lca are increasing at a faster pace than those for other cancers (islami et al., 2017; jemal et al., 2017). in the united states, the incidence of liver cancer is projected to rise continuously from the mid-1970s through 2030. a factor contributing to this increase is the hepatitis c virus (hcv) infections in those called “baby boomers,” who were born during 1945 to 1965 (geboy et al., 2016). a decline in overall cancer mortality rates in the united states was evident in the 1990’s, due to widespread cancer screening, improvements in treatments, and reductions in cancer risk factors such as tobacco smoking (jemal et al., 2017; o'keefe et al., 2015). however, the mortality rate for lca increased, with an unequal distribution throughout the population. additionally, hepatocellular carcinoma (hcc), reported more often in asia than in the united states, is the third leading cause of cancer mortality worldwide (altekruse et al., 2009). thus, hcc is one of the most fatal cancers, with only a 7% 5-year survival (ruggieri et al., 2010). moreover, in the united states, geographical and biological factors are associated with racial disparities. in the development of hcc, exposure to hepatitis b virus (hbv) and hcv infections, alcoholic liver disease, hemochromatosis, and non-alcoholic steatohepatitis are involved; there are also genetic and environmental contributions (ruggieri et al., 2010). furthermore, some racial groups are more affected, as shown by data on cancer incidence and mortality (deshmukh et al., 2017). in the united states, the mortality for african americans (aa) with hcc is worse than for any other racial group. in addition, in eastern and southern asia, middle and western africa, melanesia, and micronesia/polynesia, the incidence of hcc is higher for males than females (ferlay et al., 2010). according to the nih surveillance, epidemiology, and end results (seer) database, the annual incidence of hcc has tripled between 1975 and 2005 (altekruse et al., 2009). the statistical data of the national institutes of health (nih) and the centers for disease control and prevention (cdc) show a difference in the lca-based mortality rates by race/ethnicity. a schematic presentation of liver cancer disparity associated factors are shown in figure 1. in the present review, our focus was to estimate the worldwide burden of lca disparities based on race/ethnicity, health and nutrition, and molecular and geographical factors. figure 1. schematic presentation of liver cancer disparity associated factors factors associated with lca disparities of lca occurrence by sex and race/ethnicity the incidence of lca varies by race/ethnicity due to differences in the prevalence of risk factors and, to some extent, disparities in access to high-quality care. recently, an annual report on cancer www.companyofscientists.com/index.php/chd e3 cancer health disparities research incidences from 1975-2012 and/or 2014 (islami et al., 2017; ryerson et al., 2016), showed lower rates of overall cancer incidences among both men and women but increased rates of lca-related deaths for both sexes. from 2003 through 2012, the mortality rates were higher among men (ryerson et al., 2016). early 2000 estimates indicated that lca incidence was the fifth most common cancer in men and eighth for women worldwide, with male/female ratios regularly averaging between 2:1 and 4:1. (montalto et al., 2002). however, for countries with low incidences of lca, the age distribution for males and females was rare before the age of 50. among high-risk countries such as those in southeast asia and west and coastal africa, the occurrence of lca was evident before the age of 20; gender ratios were higher, and the male excess was greater for those less than 50 years of age. in addition, clinical observations and death statistics showed that lca due to hepatitis infections appeared to progress more in males than females and that cirrhosis was largely a disease of men and postmenopausal women (giannitrapani et al., 2006; ruggieri et al., 2010). in the united states, there were disparities in the rates and survival for various races/ethnicities and between states; the relative risk of death for all cancers combined was 33% higher for nonhispanic (nh) blacks and 51% higher for nh indian/alaska natives compared to nh whites (islami et al., 2017). however, there was a disparity in lca incidence in that it was higher among nh whites, nh blacks, and hispanic men and women born after 1938-1947; it was minimal for nh asian and pacific islanders (ryerson et al., 2016). among hispanics, the disparities in lca incidence and mortality were related to their nativity. the hcc incidence was twice as high for us-born hispanic men compared to the foreign-born hispanic men (setiawan et al., 2016). the risk factors of smoking status, hepatitis b/c infection, and diabetes accounted for hcc among us-born hispanics. an overview of the disparities of lca incidence according to race and ethnicity is presented in table 1. table 1. disparities of lca incidences according to race and ethnicity. region born ethnicity/ gender incidence (per 100,000) severity causes mortality (per 100,000) reference us born men (overall) 21-35 --- (altekruse et al., 2009) women (overall) 3.8-13.6 --- (altekruse et al., 2009) hispanic (men/women) 1.8-60.2/1.248 localized to advanced and unknown chronic hepatitis/fibrosis/ alcohol-related/other 63/42 (setiawan et al., 2016) asian (men/women) 35-83/5.937.9 localized to advanced hcv/hbv infection (altekruse et al., 2009) african (men/women) 37-40/6.913.6 localized to advanced hcv/hbv infection/other (altekruse et al., 2009) white 16.5-28/310.2 localized to advanced hcv/hbv infection/obesity/0ther (altekruse et al., 2009) www.companyofscientists.com/index.php/chd e4 cancer health disparities research non-us born men 75.9 ---- (njei et al., 2015) women 24.5 ---- (njei et al., 2015) hispanic (men/women) 0-44/0-50 localized to advance and unknown chronic hepatitis/fibrosis/alco hol related/other 35/19 (setiawan et al., 2016) asian 18.9-24 localized to advanced hcv/hbv infection (njei et al., 2015) african 10.9-12.5 localized to advanced hcv/hbv infection/other (njei et al., 2015) white 67 localized to advanced hcv/hbv infection/obesity/other (njei et al., 2015) geographical factors associated with disparities in lca hcc is the dominant histologic type of lca, accounting for approximately 80% of total cases globally (petrick et al., 2016). hcc poses a prominent disease burden throughout the world and particularly in africa and asia where hbv is the principal cause (bosch et al., 2005). in western countries, chronic alcohol abuse is the primary factor associated with hcc. high disease levels in northern thailand are due to chronic infections with the liver fluke, opisthorchis viverrini, which is ingested through infected raw fish (petrick et al., 2016; sripa et al., 2012). in countries undergoing socio-economic development, such as some in asia, hcc cases account for nearly 75% of all lcas, and china accounts for 56% of the world’s burden. the highest incidence of hcc occurs in mongolia; the lowest incidence is in nepal (baatarkhuu et al., 2017; shrestha, 2018). however, hcc incidence has been increasing in several other countries, but there have been declines in some asian countries (mcglynn and london, 2011; mcglynn et al., 2015; mcglynn et al., 2001; zhang et al., 2015). however, the rates of hcc remain highest in asian counties (petrick et al., 2016). although there was a decrease in hcc burden in these high-risk countries, there was a rise in india as well as in low-risk countries of africa, europe, the americans, and oceania; in thailand, france, and italy, there was a decline. the decreased incidence in highrisk countries was likely due to a lower prevalence of hbv infections. particularly in low-risk countries, a reduction in hcc burden will be seen when incidences of hcv, diabetes, and obesity are lowered. disparities of lca from the nutritional and health perspective “food insecurity” refers to a lack of access to sufficient, safe, and nutritious food that fulfils the dietary needs and food preferences for living a healthy life. there is evidence suggesting a relationship between specific dietary components and risk of cancers at various anatomic sites (schutte et al., 2016). the nutritional status of patients is related to their performance status and to their tolerance for cancer therapy (schutte et al., 2016). few studies are investigating the role of diet in hepatocarcinogenesis. risk factors for the occurrence of lca include chronic viral infections (hepatitis b and c), excess alcohol consumption, www.companyofscientists.com/index.php/chd e5 cancer health disparities research non-alcoholic fatty liver disease, dietary exposure to aflatoxin, obesity, smoking, and diabetes mellitus (el-serag and rudolph, 2007). however, a substantial portion of lca occurs in patients without exposure to these risk factors, suggesting a role of additional factors. observational studies indicate a protective role of a diet containing vegetables, fruits, and cereals (koumbi, 2017) in preventing cancer. although various studies have presented conflicting results, high intakes of red meat, fish, and dietary sugars are associated with a high risk for western europeans (fedirko et al., 2013). among japanese, italians, and europeans, high intakes of vegetables, fruits, cereals, eggs, milk, and yogurt are associated with a lower occurrence of lca (kurozawa et al., 2004; negri et al., 1991; talamini et al., 2006). these results are supported by findings of a study of chinese men and women, which showed that a vegetablebased diet is associated with reduced risk of lca (zhang et al., 2013). for japanese individuals, overweight or obesity moderately increases the risk of lca (tanaka et al., 2014). obesity among americans has reached an epidemic proportion (vastag, 2004), and 64% of the adult population is overweight or obese. there is a positive association between obesity and high death rates for liver and other cancers (calle et al., 2003). it was estimated that more than 90,000 cancer deaths per year could be avoided with the maintenance of normal weight, and obesity was a major risk factor for cancer (donaldson, 2004). among americans, obesity, nutrient-sparse foods such as concentrated sugars and refined flour products that contribute to reduced glucose metabolism, low fiber intake, consumption of red meat, and an imbalance of omega 3 and omega 6 fats contribute to excess risk of lca (donaldson, 2004). a study focused on the type of therapy and patients with diagnosed stages shows that for lca stage a patients, liver transplants, radiofrequency ablation (rfa), and embolization were utilized less often for hispanics, nh blacks, patients with medicaid, and patients in the highest income quartile. stage d patients were less likely to receive cancer therapy if they had medicaid insurance (harlan et al., 2015). additionally, 26.8% of patients diagnosed with stage b received surgery, followed by 12.4% of those with stage 0. for younger patients, those diagnosed and treated at earlier stages were more likely to receive surgery than nh black medicaid patients. furthermore, transplants were more frequent for stage 0 (36.5%) and stage a disease (48.1%) than for patients aged 50 or older, nh blacks, hispanic patients, and stage b-d medicaid patients (harlan et al., 2015). in addition to surgery and transplantation, rfa was more often used for stage 0 (3.7%) and stage a (3.9%); for stage b disease, tumor embolization was most often performed in combination with systemic chemotherapy (15.3%) (harlan et al., 2015). molecular perspectives related to disparities in lca morphologically, liver tumors are heterogeneous within the same tumor and for different tumors. some subtypes of lca have stem cell features; others have a phenotype intermediate between hepatocytes and cholangiocytes (sia et al., 2017). these observations have raised the possibility of disparities in the origin of lca. hepatic precursor cells might generate primary liver tumors as, during development, hepatocytes and cholangiocytes can arise from a common precursor cell. however, tumors developing from mature hepatocytes and cholangiocytes could be different. moreover, hepatocytes could be a source of lca as these cells can undergo mutations in their genes, dedifferentiate into www.companyofscientists.com/index.php/chd e6 cancer health disparities research precursor cells, and ultimately transform into lca cells with precursor cell markers (chen et al., 2012; sia et al., 2017; tanimizu et al., 2013). the liver is a sexually dimorphic organ. for males and females, there are differences in gene expression, mitochondrial function and enzyme activity, lipids composition of cell membranes, and immune responses (dhir et al., 2006). the differentiation of liver gender is maximum at puberty, with the elevation of testosterone in males associated with the tyrosine phosphorylation cascade of jak2/stat5, which is involved in the transcription of masculine genes that repress feminine genes. however, for females, secretion of growth hormone continues, but at a lower rate, with unphosphorylated stat5 associated with gene transcription. such differences could account for the disparity in the development of lca between the two sexes (dhir et al., 2006; waxman and holloway, 2009). molecular factors involved in the disparities of incidence and mortality of lca are shown in table 2. a separate study of hcc showed that inhabitants of asian and african countries were more likely to have chronic hbv infections, whereas those in japan and the united states were more likely to have hcv infections (el-serag and rudolph, 2007). in addition, about half of the cancers are activated due to tp53 mutations; in a clinical study of chinese patients, nearly half had a point mutation at codon 249 (aravalli et al., 2008). thus, understanding the molecular mechanism of hcc is a promising strategy for dealing with cancer disparities. table 2. molecular factors involved in disparities in incidence and mortality of lca. cellular and molecular factors/mechanisms dysregulation associated with reference cytokines il-6 overexpression hcv (rogers et al., 2007); (nakagawa et al., 2009); (wong et al., 2009) il-10 polymorphism in promoter hcv (paladino et al., 2006); (persico et al., 2006) interferon overexpression hcv (rogers et al., 2007) sex hormones androgen, estrogen, and progesterone differential expression regulation of transcriptional factors nfkb and c/ebpβ, immune response, and cell proliferation (naugler et al., 2007); (ohnishi et al., 1986) reactive oxygen species production depletion of antioxidant defences; changes in key organelles, including mitochondria (tien kuo and savaraj, 2006) mutations hypermethylation of genes lztr1, eef1a1, sf3b1, and smarca4, ccr5 32 delta (et.al., 2017) chemokines are the low molecular weight proteins that function in leukocyte trafficking and other biological activities. they belong to the g-protein coupled receptor family, bind to their cognate receptors, and determine the metastatic destination of tumor cells (singh et al., 2018). chemokines are involved in liver inflammation, which regulates activities of circulating immune cells, endothelial cells, and hepatocytes. moreover, they contribute to cell proliferation, pathogenesis, www.companyofscientists.com/index.php/chd e7 cancer health disparities research angiogenesis, and the inflammatory microenvironment of hccs (abdolmohammadi et al., 2016). therefore, we reviewed the role of chemokines and their receptors in the regulation of lca disparities. chemokine receptor 5 (ccr5) delta 32 alleles may predispose patients to chronic hbv infections. a total of 812 iranian individuals, grouped into hbv-infected and healthy controls, demonstrated that ccr5 delta 32 was more frequent in healthy controls than in hbv-infected individuals (abdolmohammadi et al., 2016). in addition, the ccr5 receptor is a coreceptor for the hiv gp120 protein (wilkin et al., 2010). a ccr5 delta 32 mutation is present in 10-15% of caucasians. those who have a copy of the gene encoding ccr5 delta 32 have a greater probability of recovery from hbv infection (thio et al., 2007). indians having ccr5 delta 32 heterozygosity are more susceptible to hbv-related liver disease (suneetha et al., 2006). this shows that, due to differences in genetic background, those with ccr5 delta 32 are resistant to hbv infection. the ccr5 delta 32 allele is not present in residents of southeast asian countries, and, in a study of ccr5 delta 32 polymorphism in china, no mutated allele was detected. conclusions in the future, the burden of lca in the united states and worldwide is expected to increase. despite improvements in lca treatments and survival rates, the overall prognosis for lca remains poor. wide disparities in lca rates by sex, age, gender, and ethnicity reflect differences in the major risk factors and inequalities in access to high-quality care. the increase in obesity in the general population, lack of healthy nutrition, inappropriate lifestyles, and limited understanding of the molecular aspects and origin of lca are impediments in preventing and treating these cancers. to curb the rising problem of lca and its disparities, interventions should include the application of existing knowledge in prevention, early detection, and treatment, maintaining healthy body weight, providing access to highquality diabetes care, preventing excessive alcohol drinking, and controlling tobacco consumption. acknowledgements this study was supported in part by the national institutes of health under award number sc1ca193758 and u54ca118638, and by the department of defence, award number w81xwh1810429. conflict of interest all authors declare no potential conflicts of interest. authors’ contributions sks was involved in data collection and drafting of the article. rs designed the concept, critically reviewed and editing of the final version of the manuscript. all authors read and approved the final manuscript. references abdolmohammadi, r., azar, s.s., khosravi, a., and shahbazi, m. 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(2015). international trends in primary liver cancer incidence from 1973 to 2007. bmc cancer 15, 94. www.companyofscientists.com/index.php/chd e1 cancer health disparities research characteristics of incident liver cancer cases in the district of columbia metropolitan area nandita krishnan1*, lorien c abroms1,2, kim robien2,3, daisy le1,2,4, y tony yang2,4,5, farshad aduli6 1 department of prevention and community health, milken institute school of public health, the george washington university, washington, d.c. 20052, usa 2 the george washington university cancer center, the george washington university, washington, d.c. 20052, usa 3 department of exercise and nutrition sciences, milken institute school of public health, the george washington university, washington, d.c. 20052, usa 4 department of policy, populations, and systems, the george washington university school of nursing, washington, d.c. 20052, usa 5 department of health policy and management, milken institute school of public health, the george washington university, washington, d.c. 20052, usa 6division of gastroenterology and hepatology, howard university hospital, washington, d.c. 20060, usa *corresponding author: nandita krishnan, nkrishnan@gwu.edu. abstract the district of columbia (d.c.) has the highest liver cancer incidence in the united states (u.s.), but the reasons for this are not fully known. we examined socio-demographic, clinical and behavioral characteristics of incident liver cancer cases in d.c., maryland (md) and virginia (va) to identify potential risk factors. we obtained data from d.c., md and va cancer registries for individuals diagnosed with hepatocellular carcinoma (hcc) or intrahepatic cholangiocarcinoma (icc) between 2013 and 2016. we estimated age-adjusted incidence rates and conducted descriptive analyses stratified by state/territory, sex, stage at diagnosis, and race/ethnicity. 5,928 incident hcc/icc cases occurred between 2013-2016. age-adjusted incidence rates (per 100,000) for hcc/icc were highest in d.c. (12.2, 95% ci=10.9, 13.5), for males (12.6, 95% ci=12.2, 12.9), and non-hispanic blacks (11.3, 95% ci=10.8, 11.8) and asian/pacific islanders (apis) (10.8, 95% ci=9.7, 11.9). racial disparities in hcc/icc incidence were widest in d.c. a substantial proportion of cases were missing data on country of birth and behavioral risk factors. mean age at diagnosis, marital status, country of birth, insurance status, and alcohol and tobacco use history varied across analytic sub-groups. non-hispanic blacks, apis and males experience a high burden of liver cancer in the d.c. metropolitan area. there are several socio-demographic disparities by state/territory, sex, and race/ethnicity. more data on country of birth, behavioral risk factors, and comorbidities are urgently needed to understand their contribution to the burden of liver cancer in the d.c. metropolitan area. keywords: hepatocellular carcinoma, intrahepatic cholangiocarcinoma, epidemiology, disparities. citation: krishnan n et al (2022) characteristics of incident liver cancer cases in the district of columbia metropolitan area. cancer health disparities. 6:e1-12. doi:10.9777/chd.2021.1005 www.companyofscientists.com/index.php/chd e2 cancer health disparities research introduction liver cancer incidence has been increasing in the united states (u.s.) (siegel et al., 2020). in 2020, it accounted for 30,160 deaths and was the fifth leading cause of cancer deaths for men and the seventh leading cause of cancer deaths for women (siegel et al., 2020). liver and intrahepatic bile duct cancers are projected to become the third leading cause of cancer deaths in the u.s. by 2040 (rahib et al., 2021). between 2014 and 2018, the district of columbia (d.c.) had the highest age-adjusted liver cancer incidence rate (per 100,000) in the u.s. (12.4 (overall), 19.5 (males), 6.6 (females)) (uscs, 2021). in contrast, the surrounding states of maryland (md) and virginia (va) had relatively lower incidence rates (md: 8.8 (overall), 13.5 (males), 4.8 (females); va: 7.5 (overall), 11.6 (males), 4.1 (females)) (uscs, 2021). while there are several hypotheses for the high incidence of liver cancer in d.c., little is definitively known about the populations experiencing the burden of liver cancer, as well as factors that could account for these differences in liver cancer incidence rates between d.c. and its neighboring states, and the clinical and behavioral risk factors driving liver cancer incidence in the d.c. metropolitan area. current data indicates that there are racial and ethnic disparities in liver cancer incidence in d.c. non-hispanic blacks (17.0/100,000, 95% ci=15.2, 18.9) have an age-adjusted incidence rate three times higher than non-hispanic whites (5.3/100,000, 95% ci=4.1, 6.8) (uscs, 2021). hepatitis b virus (hbv) and hepatitis c virus (hcv) are prominent clinical risk factors for hepatocellular carcinoma (hcc) and intrahepatic cholangiocarcinoma (icc) (de martel et al., 2015; massarweh & el-serag, 2017), the two most common types of liver cancer. hbv and hcv are endemic in several countries in africa and asia (world health organization, 2021a, 2021b). approximately 15% of the d.c. population is estimated to be foreign born (tatian et al., 2018; the metropolitan washington council of governments, 2017), and migration of individuals from hbv and hcv endemic countries to d.c. could be contributing to the high incidence of liver cancer. behavioral risk factors may also play a role. tobacco use and heavy alcohol use are recognized risk factors for hcc and icc (petrick et al., 2018), and there is also evidence that links obesity to a higher liver cancer risk (campbell et al., 2016). d.c. has one of the highest rates of binge drinking in the u.s. (centers for disease control and prevention, 2020). additionally, almost a quarter of adults in d.c. are obese, with a particularly high prevalence among non-hispanic blacks (38%) (centers for disease control and prevention, 2021). while state level liver cancer incidence data is publicly available from uscs, several gaps exist in the information provided by current data. one limitation is that uscs estimates aggregate hcc and icc. although these two types of liver cancers share several risk factors, they also have unique risk factors and etiologies (massarweh & el-serag, 2017). thus, there is a need to independently monitor hcc and icc trends to better inform prevention and control efforts. uscs enables comparisons of liver cancer incidence and mortality only across select socio-demographic characteristics, such as sex and race/ethnicity. more research that examines a wider range of factors is needed to characterize the liver cancer population in the d.c. area and identify prevailing risk factors to inform the development of targeted interventions. additionally, owing to the proximity of d.c. to md and va, and fluid population movement between d.c. and these neighboring states (maciag, 2018; rabinowitz, 2017), understanding the profile of liver cancer cases in md and va can provide a more comprehensive picture of risk factors for liver cancer in the d.c. www.companyofscientists.com/index.php/chd e3 cancer health disparities research metropolitan area. therefore, the objective of this study was to identify socio-demographic, clinical, and behavioral characteristics of incident liver cancer cases in d.c., md and va over a four-year period (2013-2016). additionally, we aimed to examine characteristics of incident liver cancer cases stratified by sex, stage at diagnosis, and race/ethnicity. methods data and sample data were requested and obtained from the dc, md, and va cancer registries. the inclusion criteria for this analysis were a diagnosis: (i) of hcc (icd10-cm code: c22.0) or icc (icd-10-cm code: c22.1), (ii) in d.c., md or va, (iii) between 2013 and 2016. a total of 5,928 incident hcc/icc cases were identified during this period and included in the analysis. measures for each incident hcc/icc case, the following variables were requested from the respective cancer registry: socio-demographic characteristics: age at diagnosis, sex, race, ethnicity, marital status, country of birth, and health insurance based on primary payer at diagnosis. clinical characteristics: primary cancer site, stage at diagnosis based on seer summary stage 2000, family history, and comorbid complications, obtained as icd-9-cm codes. behavioral risk factors: alcohol and tobacco use history analysis data cleaning included recoding and creating calculated variables. the following variables were collapsed and/or recoded as follows: combined race and ethnicity (non-hispanic white, nonhispanic black, hispanic, asian/pacific islander (api), and other); marital status (single (including unmarried and domestic partner), married (including common law), and separated, divorced or widowed); u.s. born (yes/no); health insurance (not insured, private insurance, medicaid, medicare, uniformed services (including tricare, military and va), and other); stage at diagnosis (localized, regional, and distant); family history of cancer (no history, history of liver cancer (including liver cancer only or liver and other cancer), and history of other cancer only (including type of cancer not specified)); alcohol history (never use, current use, and past use); tobacco history (never use, current use (including combustible only, smokeless only, and combination tobacco product use), and past use). as a different number of comorbidity fields were provided by each registry, this variable was not included in the analysis and instead summarized based on the primary comorbidity recorded. for all variables, unknown or missing was treated as an independent category, except for race/ethnicity and health insurance, where it was combined with “other”. age-adjusted incidence rates for 2013-2016 were calculated for all sites (hcc and icc) combined and by primary site (hcc or icc) across state/territory, sex, and race/ethnicity. additionally age-adjusted incidence rates were calculated by sex and race/ethnicity within each state/territory. incidence rates were age-adjusted to the 2000 u.s. standard population using 19 age groups, and confidence intervals (cis) for incidence rates were estimated using the method proposed by keyfitz (1966). rates were suppressed for sub-groups with 1-15 cases due to low reliability, and counts for variables by state/territory were suppressed for cells with <10 cases for confidentiality. descriptive analyses, stratified by state/territory, sex, stage at diagnosis, and race/ethnicity were www.companyofscientists.com/index.php/chd e4 cancer health disparities research conducted. tests for statistically significant differences between groups were conducted using chi-square tests for categorical variables and t-tests or anova for continuous variables. all analyses were conducted using stata version 14. a p-value of 0.05 was considered statistically significant. ethical approval this research was approved by the george washington cancer center protocol review and monitoring committee, and the institutional review boards of the george washington university, and the d.c., md and va departments of health results a summary of sample characteristics is provided in table 1. several variables had missing data. family history, alcohol history, and tobacco history data were not available for md and were missing for a large proportion of cases in d.c. and va (>34%). country of birth was missing for almost half the overall sample (48.5%), and for a majority of cases from va (70.8%). a sizable proportion of cases were also missing data for stage at diagnosis (31.1%). table 1. characteristics of incident liver cancer cases in d.c., maryland and virginia by state/territory and sex (2013-2016). variable state/territory sex total (n=5,928) d.c. (n=343) maryland (n=2,559) virginia (n=3,026) male (n=4,209) female (n=1,719) incidence rate/100,000 (95% ci)a (hcc and icc) 8.2 (8.0, 8.4) 12.2 (10.9, 13.5) 8.8 (8.5, 9.2) 7.6 (7.3, 7.8) 12.6 (12.2, 12.9) 4.5 (4.3 – 4.7) incidence rate/100,000 (95% ci)a (hcc only) 7.0 (6.8, 7.2) 10.7 (9.5, 11.9) 7.5 (7.2, 7.8) 6.4 (6.1, 6.6) 11.2 (10.8, 11.5) 3.4 (3.2 – 3.6) incidence rate/100,000 (95% ci)a (icc only) 1.2 (1.1, 1.3) 1.5 (1.0, 1.9) 1.3 (1.2, 1.4) 1.2 (1.1 – 1.3) 1.4 (1.2 – 1.5) 1.1 (1.0 – 1.2) socio-demographics age at diagnosis, mean (sd) 64.6 (11.7) 62.7 (11.8) 64.7 (11.8) 64.7 (11.7)* 63.8 (10.9) 66.7 (13.3)**b male, n (%) 4,209 (71.0) 245 (71.4) 1,809 (70.7) 2,155 (71.2) -- race/ethnicity, n (%) non-hispanic white non-hispanic black hispanic api other/unknown/missing 3,312 (55.9) 1,928 (32.5) 181 (3.1) 367 (6.2) 140 (2.4) 35 (10.2) 286 (83.4) 10 (2.9) <10 <10 1,359 (53.1) 932 (36.4) 89 (3.5) s s 1,918 (63.4)** 710 (23.5) 82 (2.7) 207 (6.8) 109 (3.6) 2,339 (55.6) 1,418 (33.7) 107 (2.5) 251 (6.0) 94 (2.2) 973 (56.6)** 510 (29.7) 74 (4.3) 116 (6.8) 46 (2.7) marital status, n (%) single married 1,275 (21.5) 2,462 (41.5) 160 (46.7) 85 (24.8) 579 (22.6) 1,030 (40.3) 536 (17.7)** 1,347 (44.5) 966 (23.0) 1,875 (44.6) 309 (18.0)** 587 (34.2) www.companyofscientists.com/index.php/chd e5 cancer health disparities research separated/divorced/ widowed unknown/missing 1,241 (20.9) 950 (16.0) 82 (23.9) 16 (4.7) 458 (17.9) 492 (19.2) 701 (23.2) 442 (14.6) 745 (17.7) 623 (14.8) 496 (28.9) 327 (19.0) u.s. born, n (%) no yes unknown/missing 353 (6.0) 2,699 (45.5) 2,876 (48.5) 38 (11.1) 182 (53.1) 123 (35.9) 146 (5.7) 1,801 (70.4) 612 (23.9) 169 (5.6)** 716 (23.7) 2,141 (70.8) 222 (5.3) 1,981 (47.1) 2,006 (47.7) 131 (7.6)** 718 (41.8) 870 (50.6) health insurance, n (%) not insured private insurance medicaid medicare uniformed services other/unknown/missing 258 (4.4) 1,420 (24.0) 529 (8.9) 2,377 (40.1) 235 (4.0) 1,109 (18.7) <10 66 (19.2) 91 (26.5) 104 (30.3) <10 70 (20.4) s 636 (24.9) 258 (10.1) 1,059 (41.4) s 483 (18.9) 192 (6.4)** 718 (23.7) 180 (6.0) 1,214 (40.1) 166 (5.5) 556 (18.4) 206 (4.9) 1,026 (24.4) 401 (9.5) 1,611 (38.3) 219 (5.2) 746 (17.7) 52 (3.0)** 394 (22.9) 128 (7.5) 766 (44.6) 16 (1.0) 363 (21.1) clinical hcc, n (%) 5,082 (85.7) 304 (88.6) 2,196 (85.8) 2,582 (85.3) 3,788 (90.0) 1,294 (75.3)** stage at diagnosis, n (%) localized regional distant unknown/missing 2,043 (34.5) 1,187 (20.0) 854 (14.4) 1,844 (31.1) 127 (37.0) 58 (16.9) 48 (14.0) 110 (32.1) 926 (36.2) 546 (21.3) 380 (14.9) 707 (27.6) 990 (32.7)** 583 (19.3) 426 (14.1) 1,027 (33.9) 1,495 (35.5) 880 (20.9) 592 (14.1) 1,242 (29.5) 548 (31.9)** 307 (17.9) 262 (15.2) 602 (35.0) family history, n (%) no history liver cancerc other cancer only/not specified unknown/missing (n=3,369) 864 (25.7) 65 (1.9) 845 (25.1) 1,595 (47.3) 78 (22.7) 0 (0.0) 69 (20.1) 196 (57.1) 786 (26.0)** 65 (2.2) 776 (25.6) 1,399 (46.2) 652 (27.2) 49 (2.0) 550 (22.9) 1,149 (47.9) 212 (21.9)** 16 (1.7) 295 (30.4) 446 (46.0) behavioral alcohol history, n (%) never use current use past use unknown/missing (n=3,369) 879 (26.1) 1,200 (35.6) 57 (1.7) 1,233 (36.6) 50 (14.6) s s 169 (49.3) 829 (27.4)** s <10 1,064 (35.2) 502 (20.9) 979 (40.8) 46 (1.9) 873 (36.4) 377 (38.9)** 221 (22.8) 11 (1.1) 360 (37.2) tobacco history, n (%) never user current user past user unknown/missing (n=3,369) 670 (19.9) 709 (21.0) 823 (24.4) 1,167 (34.6) 50 (14.6) 63 (18.4) 63 (18.4) 167 (48.7) 620 (20.5)** 646 (21.4) 760 (25.1) 1,000 (33.1) 349 (14.5) 581 (24.2) 637 (26.5) 833 (34.7) 321 (33.1)** 128 (13.2) 186 (19.2) 334 (34.5) notes. % = column totals; blank cells = data not available; <10 = case counts of 1-9 are suppressed for confidentiality; s = case counts are suppressed to prevent back calculation of counts in other cell(s); sd=standard deviation; *p<0.05, **p<0.0001 www.companyofscientists.com/index.php/chd e6 cancer health disparities research aincidence rate age-adjusted to the 2000 u.s. standard population; bone-way anova with post-hoc bonferroni adjustment indicated that mean age in dc was significantly different from md and va; cincludes liver cancer only or liver and other cancer the overall age-adjusted incidence rate of hcc/icc for d.c., md and va between 2013-2016 was 8.2/100,000 (95% ci=8.0, 8.4), with a higher incidence rate for hccs (7.0/100,000, 95% ci=6.8, 7.2) than for iccs (1.2/100,000, 95% ci=1.1, 1.3). the mean age at diagnosis was 64.6 years (standard deviation (sd)=11.7). the majority of cases were male (71%) and non-hispanic white (55.9%). almost half the sample was u.s. born (45.5%). a large proportion of cases were married at the time of diagnosis (41.5%), and a sizable proportion of cases had medicare insurance (40.1%). in terms of clinical characteristics, a majority of cases were hccs (85.7%) and commonly diagnosed at the localized stage (34.5%). the most commonly recorded primary comorbidities were hypertension (6.3%), hcv (4%), alcoholic liver cirrhosis (3.3%), and diabetes (3%). a larger proportion of individuals currently used alcohol (35.6%) compared to tobacco (21%). differences in characteristics between incident hcc/icc cases in d.c., md and va are also provided in table 1. of the 5,928 hcc/icc cases, 343 occurred in d.c., 2,559 occurred in md, and 3,026 occurred in va. the hcc/icc incidence rate was highest in d.c. (12.2/100,000, 95% ci=10.9, 13.5) and lowest in va (7.6/100,000, 95% ci=7.3, 7.8). similar trends in hcc and icc incidence rates were observed when evaluated separately, although differences in icc incidence rates across d.c., md, and va were not statistically significant. incidence rates in d.c., md and va did differ by sex and race/ethnicity. incidence rates were higher for males in all 3 states/territories, and incidence rates for males (18.9/100,000, 95% ci=16.5, 21.3) and females (6.6/100,000, 95% ci=5.3, 7.9) were highest in d.c. (figure 1). racial disparities were wider in d.c. compared to md and va (figure 2). sociodemographic characteristics of liver cancer cases in d.c. were also significantly different from md and va with regard to mean age of diagnosis, which was lower (62.7 years (d.c.) vs 64.7 years (md, va)). d.c. had a higher proportion of individuals who were single or unmarried (46.7% (d.c.) vs 22.6% (md), 17.7% (va)), non-u.s. born (11.1 (d.c.) vs 5.7% (md), 5.6% (va)), and covered by medicaid (26.5% (d.c.) vs 10.1% (md), 6% (va)). figure 1. age-adjusted incidence rate of liver cancer (2013-2016) in d.c., maryland and virginia by sex www.companyofscientists.com/index.php/chd e7 cancer health disparities research figure 2. age-adjusted incidence rate of liver cancer in d.c., maryland and virginia by race/ethnicity note. rates for hispanics and apis in d.c. were suppressed for reliability as the number of cases was below 15. sex-stratified analyses are also presented in table 1. the incidence rate for males (12.6/100,000, 95% ci=12.2, 12.9) was almost three times the rate for females (4.5/100,000, 95% ci=4.3, 4.7). this trend held for hccs, but the icc incidence rate was only marginally higher for males (1.4/100,000, 95% ci=1.2, 1.5) compared to females (1.1/100,000, 95% ci=1.0, 1.2). males differed from females with respect to younger age at diagnosis (63.8 years vs 66.7 years). males were more likely to be nonhispanic black compared to females (33.7% vs 29.7%), while females were more likely to be hispanic than males (4.3% vs 2.5%). a higher proportion of males were married (44.6% vs 34.2%), whereas a higher proportion of females were separated, divorced or widowed (28.9% vs 17.7%). iccs made up a larger share of liver cancers for females compared to males (24.7% vs 10%). females were more likely than males to have medicare insurance (44.6% vs 38.3%), and report never use of alcohol (38.9% vs 20.9%) and tobacco (33.1% vs 14.5%). characteristics of cases by stage at diagnosis are presented in table 2. a slightly higher proportion of uninsured individuals were diagnosed at the regional and distant (5.9%) stages vs localized stage (3.3%). iccs were more likely to be diagnosed at the distant stage (30.7%) than the localized (7.7%) and regional (15.7%) stages. table 2: characteristics of incident liver cancer cases in d.c., maryland and virginia (2013-2016) by stage at diagnosis variable total (n=4,084†) localized (n=2,043) regional (n=1,187) distant (n=854) socio-demographics age at diagnosis, mean (sd) 63.8 (11.4) 64.0 (10.7) 63.3 (11.7) 64.1 (12.5) race/ethnicity, n (%) non-hispanic white non-hispanic black hispanic api other/unknown/missing 2,301 (56.3) 1,296 (31.7) 133 (3.3) 267 (6.5) 87 (2.1) 1,122 (54.9) 671 (32.8) 71 (3.5) 131 (6.4) 48 (2.4) 683 (57.5) 356 (30.0) 30 (2.5) 96 (8.1) 22 (1.9) 496 (58.1)* 269 (31.5) 32 (3.8) 40 (4.7) 17 (2.0) marital status, n (%) single married separated/divorced/widowed 980 (24.0) 1,964 (48.1) 930 (22.8) 514 (25.2) 950 (46.5) 481 (23.5) 279 (23.5) 591 (49.8) 258 (21.7) 187 (21.9) 423 (49.5) 191(22.4) www.companyofscientists.com/index.php/chd e8 cancer health disparities research unknown/missing 210 (5.1) 98 (4.8) 59 (5.0) 53 (6.2) u.s. born, n (%) no yes unknown/missing 261 (6.4) 1,807 (44.3) 2,016 (49.4) 120 (5.9) 847 (41.5) 1,076 (52.7) 92 (7.8) 547 (46.1) 548 (46.2) 49 (5.7)** 413 (48.4) 392 (45.9) health insurance, n (%) not insured private insurance medicaid medicare uniformed services other/unknown/missing 187 (4.6) 1,126 (27.6) 415 (10.2) 1,840 (45.1) 200 (4.9) 316 (7.7) 67 (3.3) 506 (24.8) 197 (9.6) 970 (47.5) 133 (6.5) 170 (8.3) 70 (5.9) 379 (31.9) 129 (10.9) 493 (41.5) 44 (3.7) 72 (6.1) 50 (5.9)** 241 (28.2) 89 (10.4) 377 (44.2) 23 (2.7) 74 (8.7) clinical hcc, n (%) 3,478 (85.2) 1,885 (92.3) 1,001 (84.3) 592 (69.3)** family history, n (%) no history liver cancera other cancer/ not specified unknown/missing (n=2,232) 666 (29.8) 43 (1.9) 651 (29.2) 872 (39.1) 337 (30.2) 20 (1.8) 285 (25.5) 475 (42.5) 182 (28.4) 13 (2.0) 203 (31.7) 243 (37.9) 147 (31.0)* 10 (2.1) 163 (34.4) 154 (32.5) behavioral alcohol history, n (%) never use current use past use unknown/missing (n=2,232) 629 (28.2) 877 (39.3) 42 (1.9) 684 (30.7) 294 (26.3) 418 (37.4) 22 (2.0) 383 (34.3) 180 (28.1) 270 (42.1) 12 (1.9) 179 (27.9) 155 (32.7)* 189 (39.9) 8 (1.7) 122 (25.7) tobacco history, n (%) never user current user past user unknown/missing (n=2,232) 488 (21.9) 505 (22.6) 606 (27.2) 633 (28.4) 224 (20.1) 244 (21.8) 288 (25.8) 361 (32.3) 141 (22.0) 150 (23.4) 185 (28.9) 165 (25.7) 123 (26.0)* 111 (23.4) 133 (28.1) 107 (22.6) notes. †stage unknown or missing for n=1,844; % = column totals; sd=standard deviation; *p<0.05, **p<0.0001; a includes liver cancer only or liver and other cancer. analyses of characteristics stratified by race/ethnicity are presented in table 3. across d.c., md and va, incidence rates for hcc/icc and hccs only were highest among non-hispanic blacks (hcc/icc: 11.3/100,000, 95% ci=10.8, 11.8; hcc: 10.1/100,000, 95% ci=9.6, 10.6), followed by apis (hcc/icc: 10.8/100,000, 95% ci=9.7, 11.9; hcc: 9.4/100,000, 95% ci=8.3, 10.4). icc incidence rates were highest for apis (1.5/100,000, 95% ci=1.1, 1.9), although differences were not statistically significant. hispanics (62.1 years) and non-hispanic blacks (62.4 years) had the youngest average age at diagnosis. non-hispanic blacks were most likely to be single or unmarried (34.1%), while apis were most likely to be married (65.1%). hispanics were most likely to be uninsured (14.4%). non-hispanic blacks were least likely to report never use of alcohol (18.4%) or tobacco (15.4%), and hispanics www.companyofscientists.com/index.php/chd e9 cancer health disparities research (40.2%) and apis (40.7%) were more likely to report never use of alcohol. hispanics were also most likely to report never use of tobacco (41.3%). table 3: characteristics of incident liver cancer cases in d.c., maryland and virginia (2013-2016) by race/ethnicity. variable total (n=5,788†) nh white (n=3,312) nh black (n=1,928) hispanic (n=181) api (n=367) incidence rate/100,000 (95% ci)a (hcc and icc) 6.9 (6.6, 7.1) 11.3 (10.8, 11.8) 7.0 (6.0, 8.0) 10.8 (9.7, 11.9) incidence rate/100,000 (95% ci)a (hcc only) 5.6 (5.4, 5.9) 10.1 (9.6, 10.6) 5.8 (4.9, 6.7) 9.4 (8.3, 10.4) incidence rate/100,000 (95% ci)a (icc only) 1.2 (1.1, 1.3) 1.2 (1.0, 1.3) 1.2 (0.8, 1.6) 1.5 (1.1, 1.9) socio-demographics age at diagnosis, mean (sd) 64.6 (11.8) 65.9 (12.0) 62.4 (10.2) 62.1 (15.4) 65.6 (13.0)**b marital status, n (%) single married separated/divorced/widowed unknown/missing 1,247 (21.5) 2,401 (41.5) 1,219 (21.1) 921 (15.9) 522 (15.8) 1,535 (46.4) 738 (22.3) 517 (15.6) 657 (34.1) 551 (28.6) 402 (20.9) 318 (16.5) 41 (22.7) 76 (42.0) 34 (18.8) 30 (16.6) 27 (7.4)** 239 (65.1) 45 (12.3) 56 (15.3) health insurance, n (%) not insured private insurance medicaid medicare uniformed services other/unknown/missing 247 (4.3) 1,390 (24.0) 521 (9.0) 2,322 (40.1) 227 (3.9) 1,081 (18.7) 95 (2.9) 799 (24.1) 193 (5.8) 1,518 (45.8) 109 (3.3) 598 (18.1) 101 (5.2) 450 (23.3) 279 (14.5) 616 (32.0) 106 (5.5) 376 (19.5) 26 (14.4) 36 (19.9) 25 (13.8) 50 (27.6) 5 (2.8) 39 (21.6) 25 (6.8)** 105 (28.6) 24 (6.5) 138 (37.6) 7 (1.9) 68 (18.5) clinical hcc, n (%) 4,959 (85.7) 2,740 (82.7) 1,751 (90.8) 149 (82.3) 319 (86.9)** family history, n (%) no history liver cancerc other cancer/not specified unknown/missing (n=3,257) 841 (25.8) 63 (1.9) 827 (25.4) 1,526 (46.9) 491 (25.1) 38 (2.0) 561 (28.7) 863 (44.2) 251 (25.2) 17 (1.7) 224 (22.5) 504 (50.6) 30 (32.6) 1 (1.1) 14 (15.2) 47 (51.1) 69 (31.9)** 7 (3.2) 28 (13.0) 112 (51.9) behavioral alcohol history, n (%) never use current use past use unknown/missing (n=3,257) 846 (26.0) 1,177 (36.1) 56 (1.7) 1,178 (36.2) 538 (27.6) 756 (38.7) 6 (0.3) 653 (33.4) 183 (18.4) 361 (36.2) 48 (4.8) 404 (40.6) 37 (40.2) 19 (20.7) 2 (2.2) 34 (37.0) 88 (40.7)** 41 (19.0) 0 (0.0) 87 (40.3) tobacco history, n (%) (n=3,257) www.companyofscientists.com/index.php/chd e10 cancer health disparities research never user current user past user unknown/missing 650 (20.0) 694 (21.3) 796 (24.4) 1,117 (34.3) 393 (20.1) 421 (21.6) 524 (26.8) 615 (31.5) 153 (15.4) 250 (25.1) 210 (21.1) 383 (38.5) 38 (41.3) 4 (4.4) 16 (17.4) 34 (37.0) 66 (30.6)** 19 (8.8) 46 (21.3) 85 (39.4) notes. †race and ethnicity unknown or missing for n=140; % = column totals; nh=non-hispanic; sd=standard deviation; *p<0.05, **p<0.0001; aincidence rate age-adjusted to the 2000 u.s. standard population; bone-way anova with post-hoc bonferroni adjustment indicated that mean age was significantly different for nh white vs nh black, nh white vs hispanic, nh black vs api, and api vs hispanic; cincludes liver cancer only or liver and other cancer. discussion this analysis examined socio-demographic and clinical characteristics, and behavioral risk factors that could potentially explain the high liver cancer incidence in the d.c. metropolitan area. the overall incidence rate of liver cancer between 2013-2016 in the d.c. metropolitan area (8.2/100,000) was similar to the national incidence rate during a similar period (2014-2018) (8.6/100,000) (uscs, 2021). incidence rates by sex (males: 12.6/100,000, females: 4.5/100,000) also mirrored national rates (males 13.1/100,000, females 4.7/100,000) (uscs, 2021), but patterns in incidence rates by race/ethnicity somewhat differed from national patterns. like in the u.s., the incidence rate in the d.c. metropolitan area was also high among apis (10.8/100,000 (d.c. region) vs 12.3/100,000 (u.s.)). however, nonhispanic blacks had the highest incidence rate in the d.c. metropolitan area (11.3/100,000), in contrast to the overall u.s., where hispanics have the highest incidence rate (13.7/100,000) (uscs, 2021). stratified analyses revealed several other notable disparities by state/territory, sex, stage at diagnosis, and race/ethnicity. racial disparities were far more pronounced in d.c., relative to md and va. in d.c., the incidence rate for non-hispanic blacks was more than four times the rate for non-hispanic whites. these geographic, sex and racial disparities in liver cancer incidence are likely driven by disparities in hcv. a previous study found patterns of hcv prevalence that correspond to our findings on hcc/icc incidence by state/territory, sex, and race/ethnicity. d.c. had the highest hcv prevalence among males (3.1/100) and females (1.8/100) (bradley et al., 2020). furthermore, in d.c., the prevalence ratio of hcv for non-hispanic blacks to other racial and ethnic groups was 12.4, compared to a prevalence ratio of 2.2 for non-hispanic blacks nationally (all u.s. states and d.c) (bradley et al., 2020). in our sample, hcv was the second most common primary comorbidity, reported in 4% of cases. future studies could examine whether disparities in hcv incidence are in fact a key driver of racial disparities in liver cancer incidence. although a substantial proportion of cases were missing data on country of birth, and any findings pertaining to this variable should be interpreted with caution, it is noteworthy that d.c. had a higher proportion of foreign-born cases (11.1%) compared to md (5.7%) and va (5.6%). in immigrant populations, hbv is thought to be a key risk factor for liver cancer and studies conducted in the d.c. area have found a high prevalence of hbv in foreign-born individuals, particularly those born in asia (ha et al., 2019; juon et al., 2019). in addition to hepatitis exposures, dietary exposure to aflatoxin is another known hcc risk factor for people born outside of the u.s. (hamid et al., 2013; smith et al., 2017). however, lack of adequate data on comorbidities, country of birth, and dietary exposures did not allow us to examine the associations between these variables. more www.companyofscientists.com/index.php/chd e11 cancer health disparities research complete and systematic collection of these variables by state cancer registries and hospitalbased registries is needed. partnering with community-based organizations that serve immigrant populations in the d.c. metropolitan area could help to ascertain the burden of liver cancer in foreign-born individuals. additionally, this data could inform screening efforts for hbv and other known exposures, such as dietary aflatoxin. prospective studies that monitor foreign-born individuals for the development of liver cancer or its intermediate markers are needed to determine the contribution of these risk factors to liver cancer incidence in the d.c. metropolitan area. consistent with previous studies, we found that males with hcc/icc were diagnosed at a younger age, and were more likely to have a history of alcohol and tobacco use compared to females with hcc/icc (ladenheim et al., 2016; wu et al., 2018). we also found that hispanics made up a slightly higher proportion of cases among females compared to males. two analyses using national data found that the incidence of liver cancer has stabilized in hispanic men, but continues to increase in hispanic women (ryerson et al., 2016; salvatore et al., 2019). however, the reason for this finding is unclear and more research is needed to identify sex differences in risk factors across racial and ethnic groups. other racial disparities identified included a lower mean age at diagnosis for non-hispanic blacks and hispanics than other groups, which correspond with findings on racial and ethnic disparities in mortality (ryerson et al., 2016). however, a large retrospective cohort study found that, on average, hispanic patients had an older age at diagnosis compared to non-hispanic whites (pomenti et al., 2020). a few studies among hcc patients have found that compared to other racial and ethnic groups, hispanics are more likely to have modifiable metabolic risk factors, such as diabetes and hyperlipidemia, and less likely to have hcv or a history of tobacco use (pomenti et al., 2020; venepalli et al., 2017). although we were unable to examine racial and ethnic differences in the distribution of comorbidities, we found that hypertension and diabetes were among the most commonly reported primary comorbidities overall. we also found that hispanics were less likely to have a history of tobacco use. thus, it is likely that different risk factors are relevant for different racial and ethnic groups in the d.c. metropolitan region, which has implications for liver cancer prevention approaches. in light of the growing evidence for the association between metabolic (ren et al., 2019; welzel et al., 2011) and behavioral risk factors (petrick et al., 2018) and liver cancer risk, more data is urgently needed to identify their contribution to the increasing burden of liver cancer in the d.c. metropolitan area and inform tailored intervention approaches. disparities by stage at diagnosis included cancer site and insurance status. iccs tended to be diagnosed at a later stage, likely owing to a lack of clear symptoms (blechacz et al., 2011; zhang et al., 2016). consistent with previous research, we found that uninsured individuals more likely to be diagnosed at later stages (wang et al., 2018). lack of insurance may contribute to delays in seeking care and reduced utilization of preventative services, such as screening, which could lead to delayed detection of cancer. limitations this analysis had several limitations. lack of adequate data on several important variables, including country of birth, comorbidities, metabolic factors, and alcohol and tobacco use hindered our ability to examine differences in their distributions by state/territory, sex, stage of diagnosis, and race/ethnicity. as this analysis was cross-sectional www.companyofscientists.com/index.php/chd e12 cancer health disparities research and lacked a non-cancer comparison group, no causal conclusions can be made regarding the association between any risk factors and liver cancer incidence. strengths of this analysis included a large sample size. additionally, the inclusion of cases from md and va provided a broader snapshot of the burden of liver cancer in the d.c. metropolitan area and highlighted differences in the profile of liver cases between d.c. and neighboring states, which can inform intervention approaches. we also separately estimated incidence rates for hccs and iccs. although we did not identify major differences in icc incidence rates across socio-demographic groups, other studies have documented sex and racial/ethnic differences in icc incidence (mosadeghi et al., 2016), highlighting the need to independently monitor hcc and icc trends and risk factors. conclusions males, non-hispanic blacks and apis are priority populations for liver cancer control efforts in the d.c. metropolitan area. data on country of birth, comorbidities, and alcohol and tobacco use are urgently needed to inform tailored intervention approaches by state/territory, sex, and race/ethnicity. to address limitations in data availability from state cancer registries, hospitalbased case control or cohort studies could provide more robust evidence for the association between a wider range of well-established and emerging socio-demographic, clinical and behavioral risk factors and the increasing burden of liver cancer in the d.c. metropolitan area. acknowledgments cancer data was provided by: the district of columbia cancer registry, district of columbia department of health; the maryland cancer registry, center for cancer prevention and control, maryland department of health, with funding from the state of maryland and the maryland cigarette restitution fund; and the virginia cancer registry, virginia department of health, office of family health services (ofhs), division of chronic disease prevention and control authors’ contributions research design, data acquisition, data analysis and writing of the manuscript: krishnan, n. research design and critical revision: robien, k., abroms, l.c. critical revision: le, d., yang, y.t., aduli, f. all authors approved the final version of the manuscript. availability of data and materials data cannot be shared due to the terms of the data use agreements with the d.c, md and va cancer registries funding sources this research was supported by a grant from the gw cancer center and the dr. cyrus and myrtle katzen cancer research center at the george washington university (pi abroms) conflicts of interest all authors declared that there are no conflicts of interest references blechacz, b., komuta, m., roskams, t., & gores, g. j. 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[1] compared with the severe acute respiratory syndrome (sars) and middle east respiratory syndrome (mers) outbreaks, covid-19 has spread much faster due to increased globalization and adaptation of the virus to multiple environments. [2] its widespread incidence and rates of intensive care hospitalizations has strained the health care system, as well as the social and economic foundation of society. other recent pandemics, such as the 2009 h1n1 (swine flu) pandemic caused concern and led to uncertainty, however the scale of its spread and consequent societal disruption was less notable. early april of 2009 in mexico, h1n1 first appeared. within 3 months, it was reported in every country. by october 11, 2009, close to 400,000 laboratoryidentified h1n1 influenza cases and >4735 deaths had been reported to the world health organization. [3] in comparison, and as reported by the coronavirus resource center at johns hopkins university, there are more than 33 million reported covid-19 cases worldwide and over 1,103,791 deaths, in less than eight months.[4] in the united states alone, there are more than 7.19 million cases and over 205,000 deaths.[5] in addition to the apparent threats the covid-19 poses to all individuals, one report from italy suggested that this epidemic hide subtle menaces, like the “distraction effect,” that are particularly important for patients with cancer. the distraction effect for cancer patients may lead to diverting the attention exclusively to the covid-19 situation and overshadowing the everyday clinical practice may have substantial negative implications, especially for cancer patients. [6] considering not only the intersection of covid-19 and cancer, in the united states we must consider the added risk of overlooking the ongoing and systematic health inequities faced by racial and ethnic minorities. covid-19 in the united states although china and italy were differentially affected in the early stages of the pandemic, the united states now has more cases and more deaths than any other country. inconsistent messages emanating from the president’s office at the federal level and from multiple governors at the state level have fostered confusion and heightened the potential of greater risks not only to those who are immune compromised but also to others in the community. missteps such as a lack of a coordinated, systematic national approach, a failure to issue timely shelter-in-place orders, inadequate numbers of hospital icu beds in nyc while they awaited the arrival of naval hospital ships, and individual disbelief, claiming that the virus was a hoax, slowed the receipt of essential resources, and likely have resulted in avoidable infections. [7] compared to five other countries (i.e., china, south korea, italy, france, united kingdom) one cannot help but question if the u.s.’s lagging response and hesitancy to escalate the stringency of its public policies might have saved lives. in april, states like new york and california, large metropolitan areas that have had high transmission rates, stay at home orders were announced and put in effect at earlier dates. the need to shelter-in place, mandated by some state governors, was designed to stem the tide of www.companyofscientists.com/index.php/chd e3 cancer health disparities research community spread, with the hope that the need for emergency department and hospital admissions would flatten and result in slowed transmission in other less densely populated states that are predominately rural, like north dakota, such mandates were not implemented [8]. (figure 1). figure 1. states with orders to stay home as of april 20) racial and ethnic disparities related to covid-19 while the nation strives to address the economic and social impacts of the covid-19 pandemic, concerns related to the likelihood of overwhelming the healthcare system with crisis-related health care occurred in new york in the first phase of the virus, and are seemingly inevitable now as numbers surge currently in texas, arizona, and florida. economic impacts are being experienced as nearly 20% of the workforce faces unemployment, while hourly workers must grapple with basic survival and insufficiency due to lost wages and hunger, debt, and a need to care for children at home due to school and daycare closures. social losses, equally staggering, continue to emanate from a loss of daily connections and livelihoods as well as ceremonial occasions that mark predictable achievements. although many geographic regions have experienced differential impacts from covid-19, there are stark disparities for several populations that have received little attention. one of the most alarming disparity trends is the high incidence of infection and the elevated mortality rate among ethnic/racial minorities, particularly african and hispanic americans compared to non-hispanic whites. [9] reports of disparities in testing, access to care, and poor triage practices and decisions resulted in minority individuals being sent home because their symptoms were not severe. however, such cases extending beyond ethnic/racial minority populations appear to be more fatal in minority communities who already face significant barriers to adequate care. adding to this detriment, many ethnic/racial minorities have existing chronic conditions superimposed on covid-19 and this leads to progressive worsening of health and www.companyofscientists.com/index.php/chd e4 cancer health disparities research eventual death from the coronavirus. for example, african americans people are being infected and dying at higher rates in chicago, new orleans, philadelphia, detroit, louisiana, and milwaukee. [9, 10] in milwaukee, the life expectancy of african americans is 14 years shorter, on average, compared to whites. [11] by april 3, 2020, almost half of milwaukee county’s 945 cases were african american and 81% of the 27 deaths occurred in a county whose african american population constituted 26% of residents. while african americans make up 13% of the us population, they account for 23% of all deaths. as of may, the death rate for covid-19 in illinois was 34%, while they make up 15% of the population; michigan 41%, while they comprise 14% of the population; and kansas 33% while they make up 6% of the population. in chicago, where african americans represent ~30% of the population they represent 43.1 of covid-19 deaths and 29.8% of all cases [12, 13] in addition, north carolina and connecticut are seeing the same disproportionate cases of deaths. [10, 14, 15] moreover, collateral cases, such as that illustrated in the exemplars presented earlier, are not accounted for in the mortality rates. in april, the extent to which states report data by race/ethnicity varies: 2 states reported testing, 34 states reported confirmed cases, and 26 states reported deaths and collected information on race/ethnicity.[15] by august, 6 states reported testing, 49 states reported confirmed cases, and 46 states reported deaths and collected information on race/ethnicity,[15] yet not all states collect this data, thus, true epidemiological trends are limited. failure to capture complete demographic data (1) ignores the hidden inequities in healthcare and public health, (2) perpetuates disparities and structural racism by failing to fully investigate and understand the health of a population of people, and (3) subsumes that race is an unimportant factor in the prevention, mitigation, and mortality from covid-19. some of the trends driving the curve in african american communities may include culturally-specific responses to endemic racism such as the communal mistrust, a high prevalence of risk factors that contribute to death with covid-19 (diabetes mellitus, high blood pressure, asthma, and immunocompromised), and the fact that african americans are more likely to be essential workers with required physical presence. black american men may be concerned about wearing face masks due to the stigma of being viewed as a criminal. also, minority serving hospitals may not have the resources required for covid-19 patients while more affluent hospital may limit care to lowincome patients. well known among african americans and as reported by researchers is that healthcare workers tend to interact differently with african americans compared to other racial/ethnic groups. [16-20] the intersection of covid-19 with cancer has led to further inequities. research from two large healthcare systems in the midwest found that cancer patients undergoing active treatment saw their risk for death increase 15-fold with a covid19 diagnosis.[21] specifically, among covid-19 patients with a history of cancer, an increased risk for death was seen for those ages 60 to 69 years (or 6.3, 95% ci 1.1-35.3), 70 to 99 years (or 18.2, 95% ci 3.9-84.3), and those with a history of coagulopathy (or 3.0, 95% ci 1.2-7.6).[22] in this same study of 2,186 us adults with invasive cancer and laboratory-confirmed sars-cov-2 infection, african american patients were approximately half as likely to receive remdesivir as white patients. despite black patients consisting of less than 10% of the total study population, gadgeel noted that 39.4% of covid-19 diagnoses in the active cancer group were among african american patients, as www.companyofscientists.com/index.php/chd e5 cancer health disparities research were a third of diagnoses in the cancer survivor group. impacts of covid-19 across the spectrum of cancer treatment in the united states, african americans bear a disproportionate share of the cancer burden, having the highest death rate and the lowest survival rate of any racial or ethnic group for most cancers. [23] key variables associated with this disparity results from a combination of social factors that influence exposure to racism, food deserts, and access to and receipt of appropriate healthcare. [9, 24] covid-19 may further increase the burden in multiple ways across the cancer prevention and treatment spectrum. severely immunosuppressed patients generally have a higher risk of developing complications in covid infections. thus, it should be assumed that cancer patients are at increased risk of a more severe course of covid-19. [25] an early report from china indicated [20] a higher incidence of covid in patients diagnosed with cancer [20]. in another report from china, of 2007 cases from 575 hospitals of patients with cancer were observed to have a higher incidence of covid, higher risk of severe events (a composite endpoint defined as the percentage of patients being admitted to the intensive care unit requiring invasive ventilation, or death) compared with patients without cancer. [26] cancer survivors who have been treated with cardiotoxic chemotherapy may also be at higher risk for poor outcomes. [27] in addition to increased morbidity and mortality associated with covid-19, cancer patients and individuals at risk for cancer have been adversely affected by the covid-19 pandemic in several other ways. for patients in active treatment, one of the major risks is the inability to receive necessary medical services (both in terms of getting to hospital and provision of normal medical care once there) because of the outbreak. guidance for prioritizing the use of radiotherapy and systemic treatments during the covid-19 pandemic focuses on including diseases with an imminent risk of early mortality (such as acute leukemias) or substantial morbidities (such as spinal cord compression). [28] with a lack of ppe in combination with risk factors associated with covid-19, cancer patients’ treatment plans were altered earlier in the pandemic with chemotherapy and radiation treatment plans delayed or modified. this is the result of the risk factors associated with covid-19 as having cancer increases risk of contracting the virus, being hospitalized, being placed on a ventilator and death. [29] another contributing factor of covid19 risks is that cancer treatments suppress the immunity system of cancer patients. a delay in patient treatment minimizes potential immune suppressive treatments as well as risks of transmission at treatment sites. [30] long-standing protocols for administration of chemotherapy and radiotherapy for lower or middle risk patients are being implemented differently during the pandemic, with different regimens suggested and potential delays in treatment. the excerpt below highlights the risk to an individual whose death may have been hastened by the covid-19 triage. my sister-in-law died today. she survived breast cancer twice. the cancer wing was shutdown to make space for covid-19 patients. she was told that her treatments were going to be stopped. she died at home. she will not be included in the covid death count. it makes the numbers look lower than they actually are. in the past three weeks, 3 people within my circle of friends have died, and now family member too ». (a. lawson, personal communication. 16 april 2020). www.companyofscientists.com/index.php/chd e6 cancer health disparities research differential effects on racial and ethnic minorities with cancer-related pain within the african american community, it is a well-known that african americans who report symptoms of pain are not believed by the health care providers to the same extent as white patients. [16] similar patterns are noted in patients with cancer pain. for example, having cancer and/or receiving chemotherapy may benefit minority populations because their complaints of new health concerns are likely to be taken more seriously. in contrast, individuals with cancer may be more susceptible to covid-19 [31], and may experience pain symptoms in addition to cancerrelated pain and other non-malignant chronic pain. further, these pain symptoms may not be taken as seriously given the immediate priorities to contain and mitigate the covid infection. according to recently published pain guidelines, pain clinics should triage cancer-associated pain syndromes as an urgent priority. [32] two general consensus statements on pain management have been published to guide care for all patients with covid-19. [32, 33] the application of identified best practices must be applied consistently and equitably to ethnic/racial minorities. telemedicine, though a novel solution to healthcare access, may not translate in ways that are beneficial to minorities. some older racial/ethnic minorities or rural residents with cancer or their caregivers may lack access to the internet, have insufficient bandwidth, or lack smart devices, all of which are necessary for participating in telehealth visits or support groups. if we are to stem the tide of covid-19 while ensuring patients have adequate pain relief, we must explore the roles of intersectionality and justice moving forward. survivors many cancer survivors are concerned and wonder how their cancer status affects potential covid-19 risks as individuals with underlining health conditions appear to be at higher risk for major complications [1]. the immunosuppressive effects of cancer treatment increases the risks for cancer patients and survivors. in a study of a cohort of 1571 patients with covid-19, 8 of whom had a prior history of cancer, patients with a history of cancer had a higher incidence of severe events – defined as the percentage of patients admitted to an intensive care unit requiring invasive ventilation, or death – compared with other patients. [34] routine surveillance in patients considered to be at relatively low risk of recurrence, and those who are asymptomatic during the follow-up period were postponed during the early stages of the pandemic and rates of preventive appointments continue to lag. [35] this trend continues as the pandemic has progressed. data from march 15 to june 16, 2020 show that 285,000 (breast), 95,000 (colon), and 40,000 (cervical) exams were missed, which represent deficits of 63%, 64%, and 67% relative to the number of screenings in a prior year for the community at-large, it is unknown at this point how the delay in cancer screening examinations may affect future morbidity and mortality for individuals who have not yet received screening examinations in a timely manner. as quarantine restrictions are relaxed, planning for resuming screening to mitigate harms is an important aspect of cancer detection at early stages in at risk individuals. increasing likelihood for optimal outcomes for cancer patients and individuals at heightened risk of health disparities historically, many african american individuals distrust hospital-, universityand clinic practitioners due to historical racism. addressing racism will require a long-term commitment and a willingness to build partnerships. however, the onus rests with the medical community and the www.companyofscientists.com/index.php/chd e7 cancer health disparities research governmental structures of the united states to demonstrate trustworthiness. [36] building partnerships with local african american community organizations such as churches, initiating the delivery of forums, retreats, and other social events that are designed to enhance approachability and getting to know individuals on a more personal level are some of the venues that can be implemented to establish trustworthiness. we suggest convening gatekeeper-identified leadership groups, african american physicians, nurses, faith and civic leaders who are trusted by their communities and partnering with them to develop community-based print and media strategies that are responsive to their constituents. seeking their insight and advice as to best practices for interacting with racial/ethnic minorities and those who suffer disparities are likely to be instrumental in building healthcare systems which are responsive to their sociocultural preferences and healthcare needs. addressing health disparities in cancer treatment and outcomes so that treatment delays do not result in sentinel events must also be considered. kutikov, weinberg, edelman and colleagues recommend that physicians must be mindful of increased vulnerability to potential adverse outcomes that may emanate from covid-19 following oncological surgery, systemic chemotherapy, or radiation therapy. [37] they recommend that differentiating treatment options based on cancer types. for example, they suggest that solid tumors arising from pancreatic or lung cancer as well acute leukemia require immediate diagnosis and treatment. however, early-stage cancers such as prostate and breast among others may not. [36] while weighing comorbidities, they recommend weighing the risk of progression with cancer care delay alongside the probably of significant morbidity. telemedicine, an emerging approach to ensuring practitioner access, has the potential to mediate long wait times and ensure triaged care. perhaps, following this pandemic, it will become a viable alternative to in-office visits, where appropriate. overall increasing the likelihood of optimal outcomes could be addressed by enacting system level responses designed to foster practice and policy for cancer care equity, infection prevention and control, cancer pain management, and cancer palliative care (see table1) table 1. recommendations for practice and policy for cancer care domain recommendation cancer care equity • all cancer care centers should develop and implement a standard, system-wide plan for cancer care equity. • utilize multiple modalities, e.g., telehealth and traditional methods (phone and mail), to communicate and follow-up with patients. • cancer care centers are encouraged to develop a helpline and/or online portal that allow patients a safe space to ask questions. • ensure all patients have access to covid-19 testing at cancer care centers or at-home, and maintain accurate documentation of positive cases for future data science work. www.companyofscientists.com/index.php/chd e8 cancer health disparities research infection prevention and control • ensure all patients with cancer have access to necessary ppe. • develop an emergency response plan with patients and provide education on how to utilize plan. • convene gatekeeper-identified leadership groups within the african american community to provide factual information about covid-19 and infection control. cancer pain management • ensure patients have a self-management pain treatment plan in place, in case palliative radiation or other clinic-based pain-relieving procedures are inaccessible. • implement and/or adapt consensus-based covid-19 pain management guidelines for patients with cancer. as a society, we must prepare for the toll that this pandemic has exerted on patients, families, and caregivers alike for african americans, their families, and communities. the potential for traumatic impact among family members who lose loved ones without an opportunity to say goodbye, and among those who care for dying patients while family members say their goodbyes virtually, and express unremitting grief to those strangers who witnessed patients’ passages, must be recognized. mental health practitioners must become prepared to treat and care for those who exhibit a sudden onset of depression, anxiety, hypervigilance, or other behaviors that impede their functionality or ability to resume the habits of daily living. irrespective of the duration of symptomatology, the need for psychological care that is tailored to address acute and chronic mental health issues arising from the pandemic should be anticipated. conclusion despite efforts to reduce the unequal impacts being felt by minorities, generations of systemic disadvantage and inequality in healthcare and cancer care for communities of color have become amplified and made more urgent during the coronavirus crisis. understanding the risks, intersection, and additive effect of covid-19 in minority individuals with cancer is crucial. ethnic and racial disparities already pervasive in our health care system coupled with covid-19 and existing racial and ethnic disparities in cancer outcomes may lead to greater morbidity and mortality in existing at-risk groups. unequal access to and use of healthcare and unequal access to treatment in the healthcare environment are a few of the factors that contribute to health disparities specifically for african americans. it is imperative that the disparities gap does not widen as a result of the covid-19 pandemic. acknowledgement this publication was made possible by funding from the national cancer institute of the national institute of health under the partnership of the u54ca233444 (uf). its contents are solely the responsibility of the authors and do not necessarily represent the official views of the nih or nci. the final peer-reviewed manuscript is subject to the nih public access policy. conflicts of interest the authors declare no conflict of interest. authors' contributions this manuscript was conceived by l.b.h. and d.e. l. l.b.h. and d.e.l. led the writing. all authors contributed to writing and editing the manuscript. www.companyofscientists.com/index.php/chd e9 cancer health disparities research references 1. lagace-wiens, p.r., e. rubinstein, and a. gumel, influenza epidemiology--past, present, and future. crit care med, 2010. 38(4 suppl): p. e1-9. 2. vellingiri, b., et al., covid-19: a promising cure for the global panic. sci total environ, 2020. 725: p. 138277. 3. etkind, s.n., et al., the role and response of palliative care and hospice services in epidemics and pandemics: a rapid 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16 [cited 2020 april 15]; available from: https://www.asco.org/asco-coronavirusinformation/care-individuals-cancer-during-covid-19. 36. warren rc, s.m., alema-mensah e, obasaju c, hodge da. (2019). clinical trials participation among african americans and the ethics of trust: leadership perspectives. ethics, medicine and public health 10, 128 138. 37. kutikov a, weinberg ds, edelman mj, horwitz em, uzzo rg, fisher ri (2020). a war on two fronts: cancer care in the time of covid-19. ann intern med. 172(11):756758. https://www.uptodate.com/contents/coronavirus-disease-2019-covid-19-cancer-care-during-the-pandemic https://www.uptodate.com/contents/coronavirus-disease-2019-covid-19-cancer-care-during-the-pandemic https://www.uptodate.com/contents/coronavirus-disease-2019-covid-19-cancer-care-during-the-pandemic https://www.asco.org/asco-coronavirus-information/care-individuals-cancer-during-covid-19 https://www.asco.org/asco-coronavirus-information/care-individuals-cancer-during-covid-19 introduction covid-19 in the united states racial and ethnic disparities related to covid-19 impacts of covid-19 across the spectrum of cancer treatment differential effects on racial and ethnic minorities with cancer-related pain survivors increasing likelihood for optimal outcomes for cancer patients and individuals at heightened risk of health disparities conclusion acknowledgement conflicts of interest authors' contributions www.companyofscientists.com/index.php/chd e1 cancer health disparities research a genetic roadmap of gallbladder cancer disparities: a potential for development of targeted therapies madhuri r. kashyap1, claudia p. garcia1, ana laura leal1, balraj mittal2, mahendra k. singh1$ 1division of molecular oncology, department of surgery, university of miami miller school of medicine, sylvester comprehensive cancer center, miami, florida, usa. email: mahendra.singh@miami.edu 2emeritus professor, ambedkar university, lucknow, up, india. $corresponding author: mahendra.singh@med.miami.edu abstract gallbladder cancer (gbc) is an aggressive disease with a dismal prognosis and resistance to chemotherapy. due to difficulties in early diagnosis of gbc, about 90% of patients are detected at advanced stages with palliative care being the only viable option. while surgery remains the mainstay treatment for early gbc, most patients who undergo surgical resection suffer from the high rates of recurrence. unfortunately for many patients, surgical resection is not considered a possibility due to the stage at which they are diagnosed. adjuvant therapies in the form of radiation and/or embolization of the tumor have been probed for the disease with moderate success. while there have been multiple studies (both retrospective and pooled analysis) that suggest an added advantage of combining adjuvant therapy with surgical resection, data from prospective studies is limited. interestingly, gbc affects women, american indians, alaska natives, black people, and certain ethnic groups in peculiar geographic locations such as chile, india, china more than other groups elsewhere. these disparities in gender and ethnicities demonstrate the need for better understanding of underlying genetic events of gbc so that molecularly targeted therapies could be developed to provide hope for improving treatment response and better outcome. however, for gbc not much progress has been made mainly due to the lack of understanding of molecular pathogenesis of this disease. this article presents a review of literature focused on molecular and genetic alterations in gbc, and as to how effective targeted therapeutic strategies can be developed with demonstrated survival benefit. keywords: gallbladder cancer, gbc, gallstone, genetic polymorphism, mutation, targeted therapy, molecular pathogenesis, health disparity citation: kashyap mr et al (2020) a genetic roadmap of gallbladder cancer disparities: a potential for development of targeted therapies. cancer health disparities 4: e1-e24. doi:10.9777/chd.2019.1014 www.companyofscientists.com/index.php/chd e2 cancer health disparities research introduction early detection of gbc has been challenging despite advancements in medical imaging technologies such as contrast tomography (ct) and ultrasound scanning. the majority of the cases are detected incidentally during surgery for cholelithiasis and hence detected at very advanced stage of the disease. gbcs are the commonest biliary tract cancers worldwide. the main associated risk factors for the development of gbc include, obesity, chronic asymptomatic cholelithiasis, female gender, smoking, chronic infections of the gallbladder (especially salmonella), diabetes and certain medications such as methyldopa, ocps, and isoniazid. they are also known to be associated with gallbladder polyps, pancreaticobiliary duct abnormalities, congenital biliary cysts, and carcinogen exposure (lazcanoponce et al., 2001). gbc is indeed a cancer type with layers of disparities associated with it. the disease prevalence and incidence is extremely high in latin america and asia, and comparatively high in some european countries such as hungary and poland. gbc incidence in the united states, however, is low. chile accounts for the highest incidence and mortality rates of gbc in the world, with a higher death rate in women (15.6 per 100,000) compared to men (7.0 per 100,000) (andia et al., 2008). it is also the leading cause of death in these women, overtaking breast, lung and cervical cancers. the southern region of chile exhibits a higher incidence and mortality of the disease where there is a large population of the mapuche (amerindian) tribe, known to have the highest incidence of gbc. interestingly, this geographic area of chile has poor access to medical and surgical facilities attributable to extreme poverty in this part of the country (andia et al., 2008). worldwide, incidence of the disease has been shown to increase with age and is found to be two to six times higher in women than in men (singh et al., 2004a). interestingly, patients with gbc in india are usually younger ones as compared to their counterparts in the west who are typically in the 5th and 6th decade of their age at the time of presentation with this disease. it is important to note that in india, almost 80% patients with gbc do also have gallstones and its presence increases the vulnerability of the gb to mucosal injury. the incidence of gbc is out of proportion to the prevalence of gallstones in india. on the other hand, in the united states, it is one of the few cancers that has a low incidence in the african americans while the disease has the highest incidence rates in hispanics, alaskan native (an) and american indians (ai) and association of gallstones with gbc is not so much common as compared to india (henley et al., 2015). often, patients with gbc present with severe, persistent abdominal pain that can be diffuse or localized to the right upper quadrant. more often than not, however, the disease is “masked” thereby presenting with no clinical symptoms and as aforementioned, detected incidentally on surgery for gallstone disease. patients may also present with complaints of weight loss and anorexia a sign of late stage disease. on examination, they may present with jaundice, abdominal pain in the right upper quadrant with or without associated tenderness. a non-tender palpable mass in the same region (a tenderness is more indicative of gallstone disease), periumbilical lymphadenopathy, and palpable left supraclavicular lymph nodes are also found to be associated with advanced gbc. nausea, vomiting and abdominal bloating are some of the other vague accompanying symptoms. prior www.companyofscientists.com/index.php/chd e3 cancer health disparities research to the advent of radiographic techniques in diagnosing gbc, the preoperative rate for detecting the disease was 10-15%. use of abdominal ultrasound and cross sectional imaging with ct/mri, have become the mainstay diagnostic tools for detecting gbc. endoscopic ultrasound (eus) may also be employed in detecting pre-cancerous lesions. gallbladder polyps ≥2 cm in size, or a calcified rim of the gallbladder termed “porcelain gallbladder” are indications for surgical resection as these are pre-malignant conditions. however, it is important to note that porcelain gallbladder is no longer thought to be as strongly associated with gbc as previously reported, but this belief continues to be propagated as dogma in the medical literature and textbooks. several large studies from the united states (articles attached) have shown little to no association between porcelain gallbladder and gbc (stephen and berger, 2001; khan et al., 2011). however, it is important to note that the population in the united states is very different from that of the previous studies from other countries which likely included a large demographic of amerindians and reported a very high incident of gbc in patients with porcelain gallbladder. geographical variability in the incidence of gbc is often found to be associated with the prevalence of gallstone disease in the same population. however, the presence of gallstones alone does not appear to cause cancer in the gallbladder, as populations that have high incidence of gallstones do not necessarily have high incidence of gbc. chronic infection with salmonella typhi is another recognized risk factor for gbc (singh et al., 2004b). a research group from varanasi, india, in particular, has not only shown the association of chronic infection with gallbladder cancer but also has demonstrated underlying mechanism as to how infection of salmonella species can help promote transformation of normal gallbladder cells (sharma et al., 2007; scanu et a., 2015). additionally, socioeconomic status and genetic elements that impede access to early detection and surgical procedures such as cholecystectomy are thought to be contributory to poor outcome. in addition to varied geographical incidences, some other factors such as the differences in age, race and sex also contribute to the occurrence of the disease. figure 1 briefly describes some characteristic features of gbc. figure 1: gallbladder cancer: basic features, risk factors, and therapeutic options. • risk factor: gallstones, gallbladder polyps, chronic cholecystitis, chronic typhoid carrier state, obesity, diabetes • females are at more at risk than their male counterparts • typically presents as an incidental finding following cholecystectomy (localized stage) or with abdominal pain (advanced stage) • majority of them are adenocarcinoma • level 1 evidence for adjuvant chemotherapy: capecitabine • palliative 1st line chemotherapy: gemcitabine www.companyofscientists.com/index.php/chd e4 cancer health disparities research • no 2nd line palliative chemotherapy with a demonstrated survival benefit over active symptom control • median overall survival: ~12 months molecular pathogenesis late 70s and early 80s was an exciting time in biomedical research for cancer researchers who invested their efforts in establishing a link between cancer and heredity. the role of mutated genes in cancer biology was beginning to be discovered and explored in various types of cancers. mechanistic insight into discovering the molecular basis for the development of gbc in the western world started very early on and in full force. reports implicating the role of genetic/hereditary predisposition can be traced back to as early as the 80s (trajber et al., 1982; weiss et al., 1984). karyotyping techniques first were used by hecht and his colleagues in 1983 to demonstrate the presence of a high level of aneuploidy in the form of missing or extra chromosomes and/or chromosomal rearrangement in a tissue specimen obtained from a papago indian woman with gbc in the united states (hecht et al., 1983). this study reported the presence of double minute chromosomes as well as homogenously stained regions on chromosomes in those cancer cells. a decade later, another group explored the correlation between the dna content and the cytological and histological features in the tumor cells obtained from the patients with gbc (roa et al., 1993). these reports were the among the first ones to have used molecular techniques to decipher the molecular/genetic basis for gbc. the following year, a small but an important study conducted by japanese researchers, demonstrated mutations in the p53 gene in almost one-third of the patients with gbc. they used pcr-single strand conformation polymorphism (sscp) for the very first time to discover and establish their findings (takagi et al., 1994). the next several years brought about an increase in the number of published studies mostly from the japanese investigators. these studies involved discovering various mutations in k-ras (watanabe et al., 1994; hanada et al, 1996; matsubara et al., 1996; tomono et al., 1996; saetta et al., 1996; iwase et al., 1997., tanno et al., 1998) and p53 genes (hanada et al, 1996 ; ajiki et al., 1996; fujii et al., 1996; hanada et al., 1997; jonas et al., 1997; yokoyama et al., 1998) in a significant percentage of patients presenting with gbc. by late 1990s, many studies were able to detect the mutations and/or the altered expression of tumor suppressor genes and oncogenes in the patients with gbc. however, most of them lacked mechanistic explanations for their findings. in 1999, a study was published discussing the molecular mechanisms underlying tumorigenesis of gallbladder carcinomas, the first of its kind (wistuba et al., 1999). the researchers pointed out that while nearly all of the gallbladder carcinomas evolved from dysplasia and carcinoma in situ, role of pre-cancerous lesions such as gallbladder adenomas in the pathogenesis of gbc was still controversial. they further analyzed dna obtained from micro-dissected tissue samples of pyloric and intestinal-type gallbladder adenomas to compare the molecular abnormalities found in adenomas with the ones seen in carcinomas. tissue samples derived from carcinoma samples displayed tp53 mutations alongside mutations in both the kas well as n-ras genes. they also demonstrated loss of heterozygosity (loh) at chromosomal regions 5q22 apc-mcc region, 9p21-cdkn2a, tp53, rb, and dcc. these genetic aberrations have been known to be associated with and play important www.companyofscientists.com/index.php/chd e5 cancer health disparities research role in tumor initiation and progression in several other cancer types. since these mutations/molecular changes were not exhibited by adenoma samples, the researchers concluded that adenomatous changes were not similar to those seen in conditions of dysplasia, carcinoma in situ, and/or invasive carcinoma of the gallbladder. similarly, it was shown that in 25% of adenomas, there was a mutation in the k-ras oncogene at codons 12 and 61, suggesting strongly that these adenomas were not forerunners of invasive gbc (wistuba et al., 1999). later in 2001, a japanese study confirmed this hypothesis by analyzing betacatenin protein expression and mutation in the corresponding genes. beta catenin is a regulator of cell-cell adhesion and intranuclear transcription in gallbladder carcinogenesis. the authors also observed that the gallbladder adenomas, in comparison to carcinomas, showed a remarkably high expression of beta-catenin protein in both the cytoplasm as well as the nucleus (p < 0.05 and p < 0.001 respectively). 62.5% of adenomas, while a mere 4.8% of carcinomas demonstrated exon 3 mutations in the beta-catenin gene. it was further demonstrated that the adenoma to carcinoma sequence was a minor pathway in the pathogenesis of gbc using beta-catenin as a molecular marker) (yanagisawa et al., 2001). besides k-ras and p53, role of other cancer associated proteins were also explored in the pathogenesis of gbc. for example, two mucin proteins muc1 and muc2 expressions were examined both at mrna as well as at protein level in carcinoma (55 cases), dysplasia (20 cases) and non-dysplastic epithelia of the gallbladder, in a japanese study (yamato et al., 1999). based on their observation, the authors suggested that muc1 expression indicated histological dedifferentiation, increased proliferation and invasion. muc2 expression, on the other hand, showed a correlation to decreased proliferation with reflection of some differentiation into goblet cells. it was further suggested that expression of muc1 in a dysplastic gallbladder reflected the potential to developing into a malignancy (yamato et al., 1999). in the same year, another study from north korea revealed the role of molecular alterations in the carcinogenesis of gallbladder. they analyzed 32 carcinomatous cases and 11 dysplastic cases for loh and microsatellite instability (msi) using 17 microsatellite markers, on chromosomal 3p, 5q, 8p, 9p, 13q, 17p, and 18q sites (chang et al., 1999). loh on 5q indicated a premature transformation to carcinogenesis while presence of loh on chromosomal sites 3p and 9p showed an association to the advancement of gbc. late event of the disease was likely to be due to presence of loh on chromosomal sites of 13q and 18q. they observed that loh on 17p was present not only in dysplastic disease but also found to be higher in the different stages of tumor development. the authors further demonstrated that while accumulation of loh was associated with carcinogenesis of the gallbladder, role of mi was not of much significance (chang et al., 1999). a subsequent japanese study then aimed to investigate the various genetic changes associated with gallbladder carcinogenesis and thus implied that the presence of loh on chromosome 17p led to the progression of gbc at a fairly early stage, while presence of loh on 18q and 9p played a crucial role in further advancement of the disease (hidaka et al., 1999). another study from japan emphasizing on the etiologic context of pancreaticobiliary maljunction, a unique yet an important factor associated with gbc in japanese patients, hypothesized that hyperplastic epithelium played an important role in carcinogenesis. based www.companyofscientists.com/index.php/chd e6 cancer health disparities research on their findings, they believed that development of neoplasia in a gallbladder with this anatomic anomaly, advanced through the processes of hyperproliferation and genetic variations (obara et al., 1999). while most of the early research in japan was primarily focused on genetic alterations in gbc, a group of medical researchers in varanasi, a city in india located on the banks of river ganges where incidence of gbc is very high, started exploring association of various etiologic agents and their role in the pathogenesis of this cancer. they were first research group from india, which demonstrated the presence of salmonella typhi in gallbladder cancer tissues as compared to control subjects and established the etiopathogenic role of chronic typhoid carriage in gallbladder carcinogenesis (nath et al., 1997). another important study from this group in varanasi, india, demonstrated significantly higher level of heavy metals such as cadmium, chromium, and lead in the patients of gbc than in those with gall stones (shukla et al., 1998). role of these well-known chemical carcinogens was further corroborated by the presence of dangerously high concentrations of these metals in drinking water in this geographic location of india. interestingly, more than a decade later a comparative study using resected gallbladder samples obtained from india and japan confirmed that indian patients with gbc had significantly higher level of chromium, lead, arsenic and zinc compared to their japanese counterparts (chhabra et al., 2012). this finding indicates towards a need for more focused study to explore the role of heavy metals derived genetic aberrations and relevant signaling pathways so as to develop targeted therapeutics. by the end of 1990s, it was widely believed that abnormalities in tp53 (17p13) and p16(ink4)/cdkn2 (9p21-22) loci were regularly encountered and frequently associated with early pathogenesis of the neoplastic disease of the gallbladder. mutations in the k-ras genes appeared to be a rare neoplastic event, the exceptions of which included anomaly associated gbc. the sequence of dysplasia to carcinoma (cis) was believed to be a major route for the development of this disease in gallbladders with associated anomalies (wistuba et al., 1999). in a small but significant study that examined the role of genetic variation in tumorigenesis and as to how these variations were associated with the clinicopathological features of gbc using multiple markers to study msi and loh, authors observed that there was one genetic pathway dependent on the msi pathway and another on loh pathway in gbc [31]. interestingly, metastasis to the lymph nodes was not seen in patients with msipositive tumors. an inverse relationship was also found between the presence of loh and msi in gbc (yoshida et al., 2000). soon, a korean study demonstrated that development of dysplastic and/or subsequent malignant features in gbc was associated with the presence of multiple loh. malignant changes from dysplastic gallbladder was associated with alterations in k-ras, p53 and p16 genes, while role of msi is limited in the development of gbc (kim et al., 2001). however, a follow up report from chile which is another geographic area almost endemic for gbc, emphasized the role of msi in gbc (roa et al., 2005). this group observed msi in equal proportions in early as well as late stages of gbc. they also demonstrated that msi was seen in premalignant lesions and indicated that inactivation of hmlh1, hmsh2, and hmsh6, genes www.companyofscientists.com/index.php/chd e7 cancer health disparities research were responsible for mismatch repair, occurred early in gallbladder carcinogenesis. in the meantime, contradicting reports on the role of msi in gbc kept emerging from different parts of the world. a greek study in 2006 asserted the role of msi in gbc was minor (saetta et al., 2001). however, it is vital to make a note of the differences in the results which could be due to a varied selection of markers required to study msi. it is also imperative to note the role of different mechanisms due to varied etiologies in a diverse patient population, as a possibility. availability of newer and more effective molecular methods in the early years of the 21st century made it possible for gallbladder researchers to conduct more studies using sophisticated analyses to detect molecular alterations in gallbladder carcinogenesis. a japanese study using allelotyping analysis demonstrated that gbc associated with anomalous junction of pancreaticobiliary duct (ajpbd) exhibited a high frequency of loss of alleles along with the presence of two new regions, believed to harbor genes with putative tumor suppressor function (nakayama et al., 2001). in the same year, a group of investigators from johns hopkins medical institute in the usa developed their interest in studying this intriguing disease and used genome-wide allelotyping analysis, a sophisticated global analytical technique, to reveal multiple sites of allelic loss in gbc (wistuba et al., 2001). according to this study, frequent allele losses were seen in 21 chromosomal regions, thereby being suggestive of the inactivation of the supposed tumor suppressor genes in the pathogenesis of gbc. this study was the first of its kind, that too from west, where gbc is a rare disease, to provide a global estimate of the extent to which genetic changes were involved in gbc development and to have the potential to identify new tumor suppressor genes and thus identifying numerous new markers in translational research. another similar study followed up in the the same year from europe, also demonstrated that alterations in the p53 gene had a likely role in the new pathway of gallbladder carcinogenesis (saetta et al., 2001). one of the most significant studies reporting other aberrated molecular lesions (besides p53 and kras) in gbc resulted from a collaborative effort between chile and us based researchers. presence of a tumor suppressor gene at chromosomal location 3p14.2 containing the fragile histidine triad (fhit) was shown to be involved in the pathogenesis of this disease (wistuba et al., 2002). much later in 2009, another us based study, demonstrated that the loss of fhit and a fragile gene product wwox expression were part of an earlier events underlying pathogenesis of gbc (bloomston et al., 2009). the same year, a group based in india analyzed loh and msi in fhit gene (priya et al., 2009). this group of investigators from india also looked for the expression of the p53 gene in gbc, chronic cholecystitis (cc), xanthogranulomatous cholecystitis (xgc) and the normal gallbladder to establish the role of the fhit gene in the gallbladder cancer using microsatellite markers such as d3s1217, d3s1300, d3s1313, d3s1600, and d3s2757. this study reported 17.5% of msi and 27.5% of loh in the gbc cases from india. significant differences were also noted in loh between gbc and cc (p=0.002) and gbc and normal gb (p=0.02). their results suggested that cc acts as a pre-invasive lesion in the pathogenesis of gbc (priya et al., 2009. it is important to note that some researchers believe that xgc, an uncommon variant of cc, is a precursor lesion of gbc. this was the first report to www.companyofscientists.com/index.php/chd e8 cancer health disparities research study and compare genomic instability in gbc versus different variants of cc and normal gallbladder from any asian country. however, an earlier report in 2001 had studied xgc at molecular level and confirmed that while etiopathologic factors of xgc could have a correlation to cancer, xgc might not be an immediate cause of cancer (takada et al., 2002). in a study conducted in italy, expression of the p53 gene as well as microsatellite instability (msi) status were studied in tumor tissues obtained from 71 patients with gbc. examination of all neoplasms were conducted using ihc staining for hmsh2, hmlh1, p53 proteins and markers of gi differentiation along with a microsatellite analysis at mononucleotide locus bat-26. the authors showed that although msi was not a key factor in gbc development, alteration in the p53 gene played a critical role in a large percent of cases with the exclusion of mucinous and squamous gbc (sessa et al., 2003). concurrently, a small study at johns hopkins medical institute, found hypermethylated regions at various promoter sites of tumor suppressor genes that contributed to the formation of the tumor as well as its progression inside a gb that was chronically inflamed. since this study included a large cohort of specimens obtained from two different populations, chile and the united states, plain disparities in the patterns of methylation between the gallbladders obtained from these two countries led to the hypothesis that these differences indicated a varied and distinctive biology associated with this disease around the world (house et al., 2003). in a subsequent chilean study, mutations in mitochondrial dna (mtdna) was observed in gbc which suggested that mtdna be additionally investigated in patients from different geographical regions thus including it in a list of molecular biomarkers for early detection of gbc (tang et al., 2004). same year, investigators at johns hopkins demonstrated that gbc had a unique pattern of abnormal gene methylation in a study which encompassed the most inclusive methylation profiling. the finding of methylation in gallbladders with cc (and without cancer) in healthy individuals suggested that this was an important phenomenon in the early pathogenesis of gbc (takahashi et al., 2004). subsequently, a group from chile observed that the high frequency of methylation of promoter areas for cdkn2a (p16), fhit, apc, and cdh1 genes led to the inactivation of genes responsible for tumor suppression and control of cellular proliferation in the carcinogenesis mechanism (roa et al., 2006). another chilean study then confirmed by epigenetic inactivation that abnormal methylation in the promoter regions of tumor suppressor genes such as dutt1 (3p12), fhit (3p14.2), blu, rassf1a, sema3b and hmlh1 (3p21.3) on chromosome 3p was a frequent occurrence (riquelme et al., 2007). a small study from greece reported mutations in the b-raf gene for the first time, which is an important component of ras signaling pathway (ras/raf/mek/erk). they reported that almost one third of all patients with gbc also presented with mutations in the b-raf gene (saetta et al., 2004). it is imperative to note that the ras pathway is an organized, downstream pathway in which raf proteins are activated in a ras dependent manner. considering the fact that ras signaling pathway could be activated by mutations at various levels including b-raf, it was an important finding of reemphasizing the role of ras pathway in those gbc cases where no mutation was detected in the k-ras www.companyofscientists.com/index.php/chd e9 cancer health disparities research oncogene (saetta et al., 2004). same year, our group demonstrated that almost one third of all the patients with gbc has mutations in codon 12 of the k-ras oncogene (singh et al., 2004b). while this study was the first of its kind from india to use methods to detect changes at a molecular level in an oncogene, it also demonstrated that detection of such molecular aberration in an oncogene could be performed on a small number of tumor cells retrieved from fine-needle aspirates. additionally, together with cytological examination, this work showed a possibility to help making a definitive diagnosis in patients with other risk factors, at least in a sub-set of patients harboring k-ras mutations. besides, this work also suggested the role of chronic inflammation in the etiology of gallbladder carcinogenesis (singh et al., 2004b). in the dawn of 21st century, with growing realization of cancer being a much more complex disease, than it was thought to be earlier, cancer researchers working on gbc initiated pathwaymechanism oriented studies in various parts of the world. one such study conducted in japan cited factors such as homozygous deletions, promoter and loh hypermethylations and multiple loh to be the major mechanisms involved in inactivation of the p16 gene in gbc (tadokoro et al., 2007). another such study to understand geographical differences in genetic changes involved in gbc between japan and hungary, was conducted in a collaborative effort by collecting specimens obtained from patients living in these two countries. a considerable difference between the two populations was attributed to the presence of high msi seen in japanese patients as opposed to just one high msi patient in hungary. this further affirmed the notion that geographic variation could play a significant role in the process of gallbladder carcinogenesis at mechanistic level (nagahashi et al., 2008). investigators in the united states relying on serial analysis of gene expression (sage) created cdna libraries from the tumor tissues of stage matched gbc patients of native american, caucasian and hispanic/latino descent, along with the tissues from normal gallbladder. rt-qpcr analysis was performed on the microdissected epithelia extracted from both gbc as well as their corresponding non-neoplastic mucosae. to further understand the complexity of the disease, immunohistochemistry on the gbcs was done in a complex tissue microarray format. the hallmark of this study was using sage to make an impartial assessment of the transcriptome in gbc, and identifying a new positive prognostic marker expression of connective tissue growth factor (ctgf). gbc and non-neoplastic mucosae from the gallbladder have sage libraries which are available publicly at the cancer genome anatomy project that would help facilitate the research needed for this deadly cancer (alvarez et al., 2008). in another small attempt to identify metastasis-associated proteins in gbc, a chinese study demonstrated that overexpression of chloride intracellular channel 1 (clic1) encouraged cell motility and inundation of gbc-sd18l (cell line with a low potential for metastasis) in vitro. it was interesting to note that inhibition of clic1 expression by rnai significantly decreased the cell motility as well as the invasiveness of gbc-sd18h (a cell line with a high potential for metastasis). this study thus demonstrated that clic1 could play a crucial role in gbc metastasis, and was hence identified to be a regulator of metastasis in gbc (wang et al., 2009). an overview of some such key studies reporting mutational spectrum in gbc is provided in table 1. in another such www.companyofscientists.com/index.php/chd e10 cancer health disparities research interesting study from india, investigators identified e-cadherin (cdh1) genomic instability and demonstrated a correlation between their findings with cdh1 protein expression in conditions of gbc and other non-neoplastic conditions of cc, xgc, as well as with normal gb, to define its role in gbc carcinogenesis. more importantly this study provided solid evidence as to how cc acts as precursor lesion to gbc (priya et al., 2010). table 1. important mutations during various stages of gallbladder cancer development. gene and reference adenoma (%) dysplasia (%) carcinoma (%) k-ras hanada et al., 1999 watanabe et al., 1999 kim et al., 2001 wistua et al., 1999 singh et al., 2004 li et al., 2014 17 0 0 25 15 0 38 19 20 38 8 beta-catenin yanagisawa et al., 2001 rashid et al., 2001 chang et al., 2002 kumari et al., 2014 63 57 58 0 5 9 0 4 egfr/erbb2/erbb3 nakazawa et al., 2005 leone et al., 2006 pignochino et al., 2010 li et al., 2014 16 15 10 37 p161nk4a kim et al., 2001 ueki et al., 2004 0 0 31 62 tp53 wistua et al., 1999 kim et al., 2001 li et al., 2014 kumari et al., 2014 noguchietal., 2017 0 0 0 36 47 18 64 abovementioned studies to identify genetic alterations in the gbc were based on conventional sequencing methods such as sanger sequencing, which had its own limitations. in the recent past, altered genetic pathways involved in human cancer are being studied using next-generation sequencing (ngs) technologies which has really helped in understanding the disease mechanism. ngs has numerous advantages when compared to the conventional sequencing methods in that it is a highly throughput method. it permits a large number of parallel sequencing simultaneously in multiple genomic regions of many samples to identify any associated mutations in the same run sequence. another crucial benefit to using ngs is the reduction in the turnaround analysis time www.companyofscientists.com/index.php/chd e11 cancer health disparities research during routine tumor sequencing, which ultimately will lead to short clinical reporting time. in addition, the amount of rna/dna required for analysis is very low in comparison to traditional methods. genomic aberrations such as single/multiple nucleotide variants, copy number variations (cnvs), fusion transcripts, and small and large insertions and deletions can be detected simultaneously with high sensitivity and rate of accuracy. the highlight of ngs is the high rate of sensitivity and quantitative evaluation of the mutated allele that is significantly better than sanger sequencing (2-10% vs 15-25%). a group of investigators from china were the first to take advantage of the newly available ngs technique to identify new mutations in gbc (li et al., 2014). here, they studied 57 pairs of tumornormal tissues and subjected them to a combination of exome as well as ultra deep targeted sequencing of cancerrelated genes [54]. they found that there was an increase in c>t/g>a transition in gbc. this identification of somatic mutation framework of gbc was done in a systematic manner, discovering gbc driver genes in the c>t/g>a transition along with studying a pathway centered around erbb signaling. they also pointed out that genetic mutations in the erbb pathway was a poor prognostic indicator of the disease. this study also went on to suggest that patients exhibiting genetic mutations in the erbb pathway could potentially benefit from therapies already available or in the process of development (li et al., 2014). in a similar kind of study using ngs techniques, a japanese group analyzed 29 tissues obtained from japanese patients with gbc, using an integration of wholeexome and transcriptome sequencing techniques to uncover molecular variations and thus, prospective therapeutic targets (nakamura et al., 2015). it was suggested in this study that apobecmediated somatic mutational signature, associated with apobec3b expression and a higher number of mutations, selectively contributed to gbc initiation and progression. the japanese authors also reaffirmed the findings in the previous study (nakamura et al., 2015) and suggested that activation of the egfr family of genes (egfr, erbb2, erbb3) was seen frequently in gbc and could be clinical important as they could be used as potential targets. a recent study by one of the authors (bm) of this article, determined the presence of 184 non synonymous somatic mutations and 60 rare germline mutations in smad family member 4 (smad4), lysine methyltransferase 2c (kmt2c) and tp53 genes using ultra deep sequencing across 409 cancer related genes in gbc patients of northern india (yadav et al., 2017). of note, somatic mutations of high significance within 9 novel genes in gbc were identified. the results in study hinted at the presence and significance of rare, inherited germline mutations in the genes of the dna-repair pathway in addition to acquired somatic mutations in the carcinogenesis of gbc. a high throughput sequencing based analysis of the mutation profile in gbc was carried out for the very first time by an indian group from the northern part of the country. this study was different in the sense that they restricted the study to regions of common genetic aberrations so as to take advantage of targeting sequencing approaches and covering rare mutations high confidence. cancer initiating as well as progressing events were tagged with biological pathways associated with 409 cancer genes which were analyzed in the study (yadav et al., 2017). the somatic mutation spectrum in this study was found to be dominated by substitution of the c>t/g>a www.companyofscientists.com/index.php/chd e12 cancer health disparities research transition, consistent with other gbc sequencing studies (li et al., 2014; nakamura et al., 2015). this study from india (yadav et al., 2017) holds promises for its possible role in future precision medicine practice in gbc, as it suggests that both the somatic mutation profile as well as the information regarding various germline mutations could be beneficial for understanding the disease pathology as well as for developing novel therapeutic strategies. genetic polymorphism and risk of gbc it is believed that majority of the cancers are derived from single somatic cells along with the cells derived by the rapid division of those parent cells. these new cells acquire various genetic or epigenetic changes within them that lead to altered genetic and thus to phenotypic variants. however, with the advent of the human genome project in early 2000s and published evidences started supporting the theory that common genetic variations play important role in determining the range of individual susceptibility to neoplastic diseases within a particular population. it was thought that they may result, among others, from the differences in the metabolism of environmental carcinogens and mechanisms of dna repair and the kind and rate of metabolism is genetically determined by polymorphic enzyme coding genes participating in the process of xenobiotic transformation. a large number of enzymes involved in the reaction of oxidation or conjugation of exo-endogenous xenobioties have shown genetic polymorphism. gene variability may alter the expression or enzymatic activity of coded enzymes. first such study in gbc was conducted in japan in which authors investigated the correlation between the genetic polymorphisms in cytochrome p4501a1 (cyp1a1) gene and the risk of development of gbc. the frequency and relationship between the cyp1a1 genetic polymorphisms and the development of gbc was closely examined in order to determine the differences in susceptibility to developing the disease. they demonstrated that females with genotypes c and/or ile/val in cyp1a1 gene were potentially more susceptible to developing gbc (tsuchiya et al., 2002). next was our own study that was performed on a large cohort of 153 patients with gbc from north india (singh et al., 2004a). we reported that the frequency of the xallele of apolipoprotein b (apob) was significantly increased in gbc patients irrespective of the presence or absence of gallstones (gs). the odds ratio was found to be 2.3 and 1.7 respectively. apolipoprotein b (apob) is a gene that is widely known to be associated with alteration in serum lipid levels and susceptibility to gallstone (gs) disease. by the abovementioned findings, we suggested that a polymorphism in the apob-xbai gene results in increased susceptibility to gbc in a favorable environment (singh et al., 2004a). with time many other similar studies started appearing looking for polymorphic variants associated with risk of developing gbc in endemic areas. in 2006, a chinese study investigated the potential risk associated with polymorphisms in the cytochrome p450 17alpha-hydroxylases-c-(17,20)lyase (cyp17) enzyme (involved in synthesis of sex hormones) in gbc. it was found that cyp17 mspa1 polymorphism was associated with an exaggerated increase in gbc development and was also contributory to the development of biliary stones among the overweight and diabetic individuals. this finding led to the study of an intertwining relationship between the genetic and hormonal risk factors associated with gallbladder disease www.companyofscientists.com/index.php/chd e13 cancer health disparities research (hou et al., 2006). same year, a study conducted by one of the authors (bm) in india reported an association between glutathione s-transferase (gst) polymorphic variants (gstt1, gstm1, gstp1, and gstm3) with risk of gallbladder cancer (pandey et al., 2006). these gsts are a family of detoxifying enzymes and are thus intricately involved in the metabolism of many known and potential carcinogens. various allelic variants of these polymorphic gsts show deformed enzymatic activity and thus are reckoned to increase cancer risk and susceptibility. this was first study to show a correlation between val allele of gstp1 and an increased risk of gbc in the indian population (pandey et al., 2006). following year, same group including one of authors of this article [bm] went on to show that a polymorphic variant of n-acetyl transferase2 (nat2) which is also known as slow acetylator phenotype, influenced the susceptibility of gbc (pandey et al., 2007). that same year a study from china demonstrated that ser326cys polymorphism in human oxoguanine glycosylase 1 (hogg1), a gene involved in the excision repair mechanism for damaged dna, has an association with gbc (jiao et al., 2007). another casecontrol study was undertaken in japan in order to examine and determine the relationship between the various genetic polymorphisms of genetic polymorphisms of cytochrome p450 1a1 (cyp1a1), glutathione s-transferase class mu (gstm1), and tumor protein p53 (tp53) genes, and gbc risk, observed that the val allele of cyp1a1 ile462val and the pro allele of tp53 arg72pro polymorphisms aided in a heightened incidence of gbc among japanese women and men, respectively (tsuchiya et al., 2007). another collaborative study demonstrated that val allele of cytochrome p4501a1 (cyp1a1) gene contributes to the development of gbc in women of two different populations of japan and hungary (kimura et al., 2008). last decade has seen a growing body of data to demonstrate an association between various polymorphic variants of many cancers associated genes with risk of gbc. majority of these studies came from researchers including one of the authors of this article (bm) from north india. some of the important ones are those that report a strong link between genetic variants of signaling molecules such as tumor necrosis factor alpha (tnfa) and interleukin 6 (il6) (vishnoi et al., 2007), a-204c of cholesterol 7alpha-hydroxylase (cyp7a1) (srivastava et al., 2008a), cholecystokinin receptor a gene polymorphism (srivastava et al., 2008b), interleukin-1 gene polymorphism (vishnoi et al., 2008), single nucleotide polymorphism in abcg8 transporter gene (srivastava et al., 2009), toll-like receptor gene polymorphisms (srivastava et al., 2010a), and caspase-8 gene polymorphisms-genes that regulate apoptosis in cancer cells (srivastava et al., 2010b). in another significant study on larger sample size obtained from northern india from the same group led by one of us (bm), strong association of a haplotype of tumor suppressor gene dcc, grs2229080ars4078288-crs7504990-ars714 was reported to confer high risk of gbc in northern indian population (rai et al., 2013a). in a follow up genome wide association study (gwas) using same patients’ cohort, this group also identified that some polymorphic variants of phospholipase c epsilon 1 (plce1) gene which is known to play a critical role in both formation and progression of esophageal and gastric cancers and psca gene which plays an important role in inhibition of cell proliferation and/or inhibition of cell death. this study showed that these polymorphic variants confer susceptibility to gbc through gallstone www.companyofscientists.com/index.php/chd e14 cancer health disparities research mediated inflammatory pathway and in a gender specific manner respectively (sharma et al., 2013; rai et al., 2013b). one of the authors (bm) of this article, recently published a gwas study which to our knowledge is the largest study worldwide as it comprised of 523 gbc patients and 274 controls all from northern india (yadav et al., 2018). this study reaffirms the fact that the link between genetic polymorphism and disease risk may be very specific with regards to directional effect and histology/ethnicity by demonstrating that genetic variants on tert-clptm1l and 8q24.21 loci affect gbc prognosis and predisposition. in order to describe the inter-relationship between genetic variants and gbc susceptibility in populations at risk, the study stressed on the need to perform complete gene sequencing of the 5p15.33 and 8q24.21 loci. however, it is important to note that in spite of huge amount of efforts involved in these studies to study genetic risk factors, it is still unclear that which genetic pathways are actually important in order to make a person susceptible living in a geographically prone area for gbc such as north india. all these genes demonstrated above which have been shown to be associated with gbc as risk factor belong to different signaling pathways, which further complicates the issue of making a coherent picture of all these genetic susceptibility factors. many more studies have been published in recent past from different parts of the world showing one or other type of polymorphic variants of different genes involves in metabolism, signal transduction, drugmetabolizing enzymes related pathways, however, most of them are actually adding more complexity to the existing mechanistic insights about gbc. interestingly, genetic aberrations in genes associated with inflammation which is an important aspect of gallbladder carcinogenesis has not been much explored in these gwas studies. foxm1, nf-kb, stat3, wnt/βcatenin, hif-1α, nrf2, androgen and estrogen receptors are some examples of the tumor suppressive as well as oncogenic transcription factors, the interaction between which, results in chronic inflammation of the gallbladder. the chronic inflammation may be either due to stones or a long standing infection of the organ. studies conducted in various clinical models, pre-clinical samples as well as cell lines, show that numerous products obtained from natural resources namely, polyphenols, alter the expression and activity of many transcription factors in various tumor models (agrawal et al., 2015). additional information regarding alterations in the aforementioned genes and their regulator pathways could help design a new and improved form of therapy combining these natural products along with the standard currently approved chemotherapeutic regimen. the combined therapy has been considered promising and the hope is to be able to not only treat the inflammation and cancer but also prevent the two conditions. targeted therapy in gbc while there were a multitude of studies by mid 2000s that demonstrated that overexpression of tyrosine kinase growth factor receptors such as erbb-2, epidermal growth factor receptor (egfr), and met could potentially lead to the formation of solid tumors, there were a group of investigators in japan who studied biliary tract carcinomas. the investigators, with the intention of assessing novel chemotherapies, focused on these receptors in gbc and demonstrated overexpression of the www.companyofscientists.com/index.php/chd e15 cancer health disparities research tyrosine kinase receptor proteins by ihc in tumor tissues obtained from 89 gbc patients. another technique, fluorescence in situ hybridization was used for gene amplification in tumor tissues that stained positive. there was an overexpression of the erbb-2 and the egfr genes in 15.7 and 8.1% of gbc cases with gbc gene amplification of 79%. this study suggested the new adjuvant chemotherapies could be used in gbc in which erbb-2 and egfr are overexpressed (nakazawa et al., 2005). later, an italian study observed that in a subgroup of patients with gbc, somatic mutations of the egfr gene in the tyrosine kinase domain exhibited cell signals maintaining proliferation and survival. further these investigators suggested a small molecule inhibitor of egfr for treatment (leone et al., 2006). that same year, a chinese study reported that p53 vascular endothelial growth factor (vegf), a marker for angiogenesis) pathway potentially played a role in regulating tumor angiogenesis in gbc (tian et al., 2006). this study suggested that analyzing the expressions of the p53 as well as the vegf genes could be useful in predicting the tumor vascularity in gbc and targeting advanced tumors with anti-vegf inhibitors could be a good therapeutic strategy. in order to better understand the underlying mechanisms of tumor development and progression and to improve the prognosis of gbc patients, an austrian study observed an increased expression in the her2/neu gene which clinically and statistically correlated with advanced disease (puhalla et al., 2007). in various cancer types, it has been shown that p110alpha catalytic subunit of phosphatidylinositol 3-kinase (pi3k), encoded by the pik3ca gene harbor somatic mutations. exons 9 and 20 which encode the helical and kinase domains of the p110alpha are the major hotspots for clusters of genetic mutations. another group based in switzerland also reported that somatic mutations in the pik3ca gene resulted in recurrent activations of the pi3k/akt pathway in a very small sub-set of carcinomas of the gallbladder (riener et al., 2008). having realized the limitations in treatment options other than surgical resection (which was an unfavorable prognostic marker), a group of surgeons in japan identified cellular targets that were gbc specific and which could potentially be used as a therapeutic approach for the disease. they identified a cell cycle-related gene, topoisomerase iialpha (topo iialpha) as one of the highly upregulated gene in gbc tissue which they further confirmed as a potential chemotherapeutic target, because those cells strongly positive for topo iialpha had shown increased sensitivity against etoposide, as well as doxorubicin and idarubicin (washiro et al., 2008). in the subsequent year, another japanese group demonstrated genomic instability due to amplification in myc oncogene which resulted in specific amplification of egfr and/or erbb2 in gbc (ooi et al., 2009). another in-vitro study used a combination of a histone deacetylase inhibitor (saha) with repression of ezh2 by sirna treatment which revealed an increased sensitivity of the gbc cells to saha as opposed to the normal cells. this was then considered to be indicative of the efficacy of the new anticancer agent (yamaguchi et al., 2010). in a significant study to evaluate the response rate by response evaluation criteria in solid tumors (recist) of targeted therapy in biliary cancers which included gbc, eligible patients (10 patients with gbc) were treated with bevacizumab (a vegf inhibitor) and erlotinib (egfr inhibitor) in combination with chemotherapy. using a www.companyofscientists.com/index.php/chd e16 cancer health disparities research combination chemotherapy of bevacizumab with erlotinib resulted in clinical activity with infrequent grade 3 and 4 adverse effects in advanced gbc cases. preliminary molecular analysis showed that presence of a mutation in the k-ras oncogene altered the efficacy of erlotinib. though a small study in sample size (only 10 cases of gbc), results clearly warrant a larger study in future on a bigger cohort of gbc patients to investigate the efficacious performance of bevacizumab and erlotinib when used together, as an alternative treatment option for patients with advanced gbc (lubner et al., 2010). in an independent but encouraging small case report, the idea of using egfr-tyrosine kinase inhibitor (tki) in combination with conventional chemotherapy was tested to treat gallbladder cancer in the us based hospital (mody et al., 2010). in this case report, a patient with stage iv gbc was shown to have complete and prolonged response, a not so common observation in gbc, to oral egfr-tki plus chemotherapy regimen. of note, this study mentions that this rare response to the treatment for this patient with gbc was due to an absence of a mutation in the egfr gene. this discovery should again reiterate the need for clinical trials using egfr-tkis to treat gbc. this study also suggest that future clinical trials should not always consider the mutation status of the egfr gene as inclusion criteria (mody et al., 2010). in an italian study, investigators analyzed mutations, amplifications and over-expression of egfr, her2, and their molecular transducers in biliary tract cancers so that they could explore possibilities of combining standard therapies with or without molecular targeting (pignochino et al., 2010). they reported that egfr was expressed in ~38% of patients with gbc. activated forms of cancer relevant signaling proteins such as p-mapk and p-akt were also highly expressed in little less than 46% of gbc, hinting at an activation of the egfr pathway. with the aid of genomic amplification, about 10% of gbcs showed an overexpression of her2 gene. they went on to conduct a preclinical in-vitro study using tgbc1tkb, a gbc cell line (deleted on pten and negative for her2 expression) for testing the efficacy of the drugs either alone or in combination with gemcitabine, targeting the aforementioned molecules. this study also demonstrated that the her2 and egfr pathways could pose to be potential therapeutic targets for biliary tract cancers (btcs). the combination of gemcitabine with gefitinib and lapatinib (both of which are reversible selective inhibitors of the tyrosine kinase domain of egfr and drugs known to target her2 and egfr pathways) appeared to have encouraging results and thus warrants for further clinical studies for testing the expression levels and mutations in these signaling molecules in future clinical studies (pignochino et al., 2010). while developing strategies to target gbc molecularly, it is important to understand the subtle changes at the molecular/genetic level between gbc and other related cancers. although they are histologically similar, they are anatomically different in terms of the origin of the tumor. for example, cholangiocarcinomas arises from within the liver parenchyma, peri-hilar regions, or the distal biliary tree, and these tumors are collectively known as btcs. although these tumors share an anatomic origin in the biliary system, they have very different disease patterns, molecular profiles and also respond differently to various therapies. historically, gbc has a tendency to initially be sensitive to chemotherapy but the survival rate is much shorter when compared to cholangiocarcinoma (eckel et al., 2007). www.companyofscientists.com/index.php/chd e17 cancer health disparities research traditionally, treatment of btcs with cytotoxic chemotherapy have not taken into account the anatomic origin of tumor or its molecular profile. however, in light of emerging molecular techniques, such as cost effective sequencing platforms, it will be worthwhile to have a detailed molecular genetic profiling of patients with gbc before considering a regimen of targeted therapy for gbc. increasingly, molecular tests to detect changes at genetic level are being applied regularly (in developed countries where advance health facilities are available to common people) to aid in the forming of therapeutic decisions in cancer treatment. routine testing such as genetic amplification of her2/neu, and/or genetic mutations involving egfr and kras are done in clinics so as to determine treatment benefit with targeted specific anti-cancer therapies (mcdermott et al., 2009). patients in which molecular genetic profiling has been conducted that indicate a potential benefit with egfr inhibitors and other molecularly targeted drugs, braf inhibitors are also being tested at the earliest phases of the disease (brower t, 2010). discovering patterns of genetic changes within gbc is very critical in order to not only gain insight into the disease biology but also to bring out about improvised treatment options, especially in light of emerging and established studies showing that tumor genetics determine drug sensitivity. in another study carried out at massachusetts general hospital in the us, almost 13% of patients with gbc were identified with activating mutations in pik3ca (deshpande et al., 2011). activating mutations in the pik3ca pathways has dual advantages in it being helpful for cancer diagnosis as well as discovering new targets for therapies such as pi3 kinase inhibitors. most recently, in a large whole-exome and targeted gene sequencing based study, a chinese chohort of gbc patients, several recurrent mutations in erbb pathway were identified (li et al., 2014). in this study, it was observed that genes like tp53, k-ras, and erbb3 had a significant frequency of non-silent mutations of 47.1%, 7.8%, and 11.8% respectively with a false discovery rate (fdr) of <0.0.5. furthermore, it was also discovered that the erbb signaling pathway including egfr, erbb2, erbb3 and erbb4 along with their downstream genes, affected 36.8% of gbc samples, making it the most extensively mutated pathway. mutations in the erbb pathway genes were also found to be associated with a dismal prognosis in gbc patients, thus suggesting that targeted therapies, that are presently in development or already in use in clinics, could be of major benefit (li et al., 2014). role of erbb pathway in gbc was further confirmed in few other independent studies from different cohorts of patients. in one of such study, retrospectively conducted in the patients with gbc in the united states, her2/neu blockade was found to be a promising treatment strategy to treat gbc patients who have gene amplification (javle et al., 2015). in another significant study conducted in japan, in a large cohort of biliary tract cancers, egfr family genes such as erbb2 and erbb3 were found to be activated while pten and tsc1 genes were found to be inactivated, in gbc. frequent genetic variations in the tp53 and rb cell cycle modules were also reported in gbc (nakamura et al., 2015). an interesting study from india using integrated genomic and proteomic analysis provides a compelling evidence that erbb2 is an important therapeutic target under neo-adjuvant or adjuvant settings for treatment of patients with gbc. in addition, this study also shows that presence of k www.companyofscientists.com/index.php/chd e18 cancer health disparities research ras mutations may preclude patients with gbc to respond to anti-egfr treatment, similar as to how a clinical algorithm is often used to opt for antiegfr treatment in patients with colorectal cancer (iyer et al. 2018). most recently, in a collaborative study between investigators from india and the us, pim1 kinase has been demonstrated to promote cell proliferation of gallbladder cancer cells via inhibition of pras40 (subbannayya et al., 2019). it is important to note that several small molecule inhibitors of pim1 kinase have been developed, some of which are currently being tested for their efficacy in clinical trials for several types of cancers. currently, some of the authors of this article (cpg, all and mks) are investigating the role of mycaurora kinase signaling in the gallbladder cancer and as to how this signaling axis can be therapeutically targeted (unpublished work). conclusion recent studies employ large cohorts of gbc to emphasize the differences between the various gbc subtypes at a basic genetic/molecular level. functional studies and clinical trials only including patients with specific subtypes of gbc, and stratifying them based on their genetic drivers, were the next steps to accomplishing these goals. for instance, use of inhibitors of the egfr were to be examined only in the patients with gbc carrying mutations/genetic amplifications of the egfr gene. constructing a precise approach to genomic medicine for the treatment of this disease uses a combination of biological studies, drug research and development, technological advancements in genomics as well as research that determines health outcomes. based on the genomic information as summarized in table 2, several clinical trials are currently underway to examine the efficacy of targeted therapies in patients. this, in the long run, is going to help build a staircase to developing a targeted therapy for gbc. based on the outcome of these studies, we should be able to offer effective therapies based on their genomic profiles to the patients with deadly gbc in the future. table 2: ongoing clinical trials using targeted therapies in gallbladder cancer. drug(s) target in combination with phase clinical trials identifier cetuximab, gefitinib trastuzumab, lapatinib, everolimus sorafenib crizotinib egfr, her2, her2, egfr mtor raf kinase, vegfr-2/pdgfr-beta alk and ros1 gemcitabine, oxaliplatin (gem ox) ii nct02836847 sorafenib raf kinase, vegfr 2/pdgfr-beta gemcitabine and cisplatin p ii nct00919061 guadecitabine durvalumab dna methyltransferase programmed cell death-1 ligand 1 i nct03257761 www.companyofscientists.com/index.php/chd e19 cancer health disparities research sorafenib raf kinase, vegfr 2/pdgfr-beta gemcitabine, oxaliplatin (gemox) ii nct00955721 regorafenib receptor tyrosine kinase, vegfr2 ii nct02053376 pazopanib receptor tyrosine kinases including vegfr-1, vegfr 2, vegfr-3, pdgfr-α and –β, fgfr -1 and -3 gemcitabine ii nct01855724 ramucirumab vegfr2 ii nct02520141 lapatinib her2, egfr ii nct00107536 durvalumab, tremelimumab programmed cell death-1 ligand 1 ctla-4 gemcitabine, cisplatin ii nct03473574 pembrolizumab programmed cell death protein 1 gemcitabine, cisplatin ii nct03260712 in patients with advanced stages of unresectable gbc, treatment options are limited because of no so well defined molecular targets. complete surgical resection remains the only curative modality to treat patients with gbc, offering benefit only for patients with localized disease. as evident from the past studies on gbc, most research efforts have focused on identifying genetic mutations, which did not provide much insight into signaling molecules that could be targeted therapeutically. gbc still continues to have a poor prognosis worldwide. it is widely accepted that cancer is primarily a signaling disease. therefore, one strategy to identify functional therapeutic targets in gbc is to get deeper insights into major signaling mechanisms underlying initiation and progression of gallbladder cancer, which will have potential to be used in clinical decision-making as well as conducive to the design of personalized cancer treatments. given the ethnic, geographic, and gender disparities associated with gallbladder cancer, lack of funding and resources to initiate prospective studies using cutting edge omics studies to decipher signaling events underlying gallbladder cancer is a major impediment. in recent years, with identification of few molecular targets in gbc such as erbb2, erbb3, and myc amplifications, it is becoming apparent that development of effective therapies will be benefitted by focusing on personalized therapy such as by identification and targeting of genetic mutations specific to an individual patient. investigation of epidermal growth factor receptors (egfr) such as cetuximab and erlotinib in a clinical trial for gbc patients’ cohorts will in turn help decide whether or not such targeted therapeutics can be recommended as standard-of-care. acknowledgements authors acknowledge support by sylvester comprehensive cancer center startup funds (to mks) as well as departmental support by nih grants r01 ca124723 and r01 ca170946. special thanks to anthony ferrantella, a gastrointestinal surgeon at university of miami miller school of medicine, for reading the manuscript and correcting it where ever needed. conflict of interest the authors declare no conflict of interest. www.companyofscientists.com/index.php/chd e20 cancer health disparities research authors’ contributions this invited review article was conceptualized and designed by bm and mks. review of literature and other data was collected by cpg, all, and mks. article was written, reviewed, and edited by mrk and mks. references agrawal, m. 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(2000). microsatellite instability in gallbladder carcinoma: two independent genetic pathways of gallbladder carcinogenesis. j gastroenterol. 35, 768-74. www.companyofscientists.com/index.php/chd e1 cancer health disparities the capci network: a cancer prostate consortium of india for conducting nextgeneration genomic sequencing studies devendra sharma1+, saloni someshwar2+, bhumandeep kour3+, nidhi shukla2+, barkha khilwani4+, maneesh vijay5, ayam gupta2, as ansari4, sugunakar vuree3,20, ashok kumar6, saurabh singh7, amrit ravi7, praveen mathur8, ashwani kumar mishra9, gopalakrishna ramaswamy10, renuka suravajhala13, nripesh sadasukhi5, jayaraman valadi12,20, krishna mohan medicherla2, geetha kumar13, bipin nair13, rupert ecker14, 17, bhawana bissa11, tc sadasukhi5*, nandita mishra13, rune mathiesen15, keshav k singh16, nirmal kumar lohiya4, jyotsna batra17, obul reddy bandapalli18,19* and prashanth suravajhala13,20* +equal contributing authors 1 urology and renal transplant department of renal sciences, rukmani birla hospital, jaipur, rajasthan 2 department of biotechnology and bioinformatics, birla institute of scientific research, jaipur, rajasthan 3 department of biotechnology, lovely professional university, jalandhar, punjab 4 department of zoology, university of rajasthan, jaipur, rajasthan 5 mahatma gandhi university of medical sciences and technology, jaipur, rajasthan 6center for systems biology and bioinformatics, panjab university, chandigarh 7 brainpan.co, gurugram, haryana 8 department of pediatrics, sms hospital jaipur, rajasthan 9 dna xperts private limited, noida, up 10theracues innovations private limited, bangalore, karnataka 11 department of biochemistry, central university of rajasthan, bandar sindri, ajmer, rajasthan 12school of computing and data sciences,, flame university, pune, maharashtra 13 amrita school of biotechnology, amrita vishwa vidyapeetham, kollam, kerala 14tissuegnostics, vienna, austria 15 inova4health, nova medical school (nms), faculdade de ciências médicas (fcm), universidade nova de lisboa, 1150-082 lisbon, portugal 16 department of genetics, heersink uab school of medicine, birmingham, usa 17translational research institute, queensland university of technology, woolloongabba qld, australia translational research institute, 37 kent street, woolloongabba, qld 4102, australia 18 division of molecular genetic epidemiology, german cancer research center (dkfz), heidelberg, germany 19 division of applied biology, csir-iict, hyderabad, india 20 bioclues.org, india *corresponding authors:prash@bioclues.org, drsadasukhi@rediffmail.com and bandapalli@gmail.com www.companyofscientists.com/index.php/chd e2 cancer health disparities abstract the cancer prostate consortium of india (capci) was established in september 2020 by a group of researchers and clinicians interested in identifying inherited and somatic risk factors that are related to the onset of prostate cancer (pca). the consortium aims to improve the patient care and treatment in india by exploring and expanding the utility of genomic repositories associated with pca. these aims are achieved by advancing discovery in genome science particular to indian phenotypes, translating scientific discoveries into improved standards of care. one of the vital goals of the consortium is to combine the data from the western, european and other ancestries, and identify common and exclusive risk profiles associated with pca in indian scenarios. these findings would additionally allow us to validate them in experimental settings to explore the molecular mechanisms underlying pathogenesis of pca besides understanding new personalized therapeutic regimens. keywords: genomics, consortium, prostate cancer, genetic variants, collaborative convergence. citation: sharma d et al (2023) the capci network: a cancer prostate consortium of india for conducting next-generation genomic sequencing studies. cancer health disparities 7: e1-13. doi:10.9777/chd.2023.1001 www.companyofscientists.com/index.php/chd e3 cancer health disparities introduction the cancer prostate consortium of india (capci) network is a bioclues.org and brainpan.co supported consortium of six institutions. the network was formed to explore the utility of genomic repositories associated with prostate cancer (pca) for advancing discovery in genome science particular to indian phenotypes, further translating scientific discoveries to improved standards of care. we strive to carry out this mission by ensuring efficient sample collection, research and development besides educating the stakeholders to address the issues related to social stigma associated with pca. organization the institutional sites, viz. amrita school of biotechnology, amrita university, kollam, birla institute of scientific research (bisr), jaipur, rukmani birla hospitals (rbh), jaipur, mahatma gandhi university of medical sciences and technology (mgumst), jaipur, university of rajasthan (uor), jaipur, indian institute of chemical technology (iict), hyderabad, sawai man singh (sms) hospital, jaipur and queensland university of technology (qut), brisbane, australia form academic partners while dna xperts, noida., theracues, bengaluru and tissuegnostics, austria form industrial partners, supported by the scientists of these network groups in the areas of genomics, next generation sequencing, clinical research, big data and machine learning. bioclues.org serves as a hub for bringing together the steering committee composed of principal investigators responsible for accomplishing goals for the development of these scientific panels. the consortium page can be found at www.bioclues.org/capci. current progress and future activities the consortium efforts began in early 2020 with seed funding obtained from brainpan.co in 2018. as the collaborators converged, there was a need to bring equivocal thoughts, action and debate on the emerging areas of pca research. the consortium sub-network got their first publication in 2020 in pca genomics from their pilot analysis of sequencing (gupta et al., 2020). from the first few meetings that were setup, the network peers discussed the need for bringing india specific phenotypes for which samples would steadfastly be used for sequencing, genotyping that are largely focused in the areas of indolent tumors, benign prostatic hyperplasia (bph), malignant and radical prostatectomy. we agreed to come up and emerge as a consortium of cross-network initiatives through a community consultation. we further discussed expanding the network of all regions and states in india by maintaining the diversity of pca phenotypes (figure1). currently, over 30 scientists and clinicians are a part of this cohesive group as we convene four times a year. over the last few years, diminutive knowledge about the etiology of pca has largely been known. the patient risk group is clearly articulated largely for elderly men, albeit consequently majority of therapies and aetiological disquisitions have centered on male sex hormones (patel & klein, 2009). after an initial positive response to these treatments, pca eventually progresses to a more resistant and androgen independent form, which is usually untreatable and lethal within 2 years of recurrence on average. india has largely seen a steep increase in incidence of pca and palliative care during the past two decades (vlachostergios et al., 2017). the population based cancer registry for 2020 shows ca. 48,000 casualties and as many http://www.bioclues.org/capci www.companyofscientists.com/index.php/chd e4 cancer health disparities as a million cases pan-india (global cancer observatory, n.d.).. given the paradigm shifts in incidence and casualties, multi-centric collaborative efforts are required to bring about a change in patient detection, treatment, and care, and this is where we believe the capci add values. indian context of human genome project the human genome project (hgp) is one of the significant projects in biological sciences and clinical medicine with a major impact on clinical medicine in understanding the molecular and biochemical interactions of every individual (emmert-streib et al., 2017). in particular, it has given us an impetus to understand the diversity as reflected by the various polymorphisms occurring in genes of our genome. the chance of acquiring a polymorphism is one in 1000/base pairs in the genome, single nucleotide polymorphisms (snps) being the most common. on an average, 4 to 8 snps can be located in any gene whether it is in the exonic region or in the exon-intron boundary. these snps are now used to target and track the gene of interest through whole genome studies. this has led us to understand how altered gene expression and its altered regulation play a role in disease manifestation. such a molecular level of understanding makes it possible for us in present times to design potential therapies for different ailments and their classifications (lele, 2003). hence, after the hgp, for the first time ever, there are a whole lot of repositories on genetic variation of diseases, pan-cancer genomes etc. and all the diseases. while this has led to growth in computational biology, managing huge amounts of genomic data across the world has set a big data challenge (gibbs, 2020). on the other hand, it has brought changes in indian research from the last decade, as growth of the biotechnology industry for designing personalized medicine is more intended (nogrady, 2018). india harbors not only cultural diversity but also genetic diversity as a result of a heterogeneous population. the indian population structure is basically reflected by set marriage patterns and consanguinity practices.. as a result, the burden of rare or even extremely rare disorders is increasing in india. genomics based approaches are capable of speeding up the diagnosis and management of such rare conditions. for such technologies, the genomics for understanding rare diseases: india alliance network (guardian) consortium was formed to provide genomics solutions in india (sivasubbu and scaria, 2019). in 2020 department of biotechnology (dbt) has launched a project ‘genome india project’ (gip) for creating indian reference genome. such an initiative shows india’s growth in gene therapies and is a step towards raising next generation medicine (bajaj. 2020). under an ‘indigen’ program, whole genome studies were carried out and publicly available population databases called ‘indigenomes’ were created which are not only at the population level but also at the individual level. this database has already helped both researchers and clinicians identify causal genetic factors for any condition. as an all-inclusive resource for a total of about 18 million genetic variants of indian population specifically, it includes single allelic genetic variants from genomes of geographically distinct populations, allele frequency, allele count, allele number, number of heterozygous and homozygous were also calculated (jain et al., 2021). however, given this paucity of data on pca, there are no reported variants specific to indian www.companyofscientists.com/index.php/chd e5 cancer health disparities phenotype until we explored through our pilot study. given the number of sporadic and hereditary pca cases that might be associated, we therefore believe capci could bring a pivotal change in exploring these understudied avenues. international consortia on pca the national institute of health (nih) funded postgwas initiatives with the establishment of elucidating loci involved in prostate cancer susceptibility (ellipse) (dbgap, https://www.ncbi.nlm.nih.gov/projects/gap/cgibin/study.cgi?study_id=phs001081.v1.p1). as part of this, the clinical ellipse consortium (cec) was formed to develop risk models, analyze risk profiles and investigate clinical applications. other consortia include the prostate cancer association group to investigate cancer associated alterations in the genome (practical) which is a section of the collaborative oncological gene environment study (cogs) along with other three cancer genetics consortium of breast, ovarian and brca1/2 mutation carriers (szulkin et al., 2015). to provide specific prevention and screening approaches for those men who are at higher risk, snps were shown more promising to use for genetic risk profiling (martens et al., 2016).the consortia efforts resulted in making the prostatespecific antigen (psa) testing as not the only essential or sensitive test regimen avoiding the apparent conflicting results from two of the largest screening trials, the european randomized study of screening for prostate cancer (erspc ) and prostate, lung, colorectal, and ovarian (plco) cancer screening trial have elicited a strong debate among the experts. the national cancer institute (nci) mouse models of human cancers consortium (mmhcc) has also assembled a group of pathologists from both human and veterinary departments to inspect and discuss the present animal models for their recommendations in pathological analysis (ittmann et al., 2013). on the other hand, the international consortium of prostate cancer genetics (icpcg) brought together the genome wide linkage data taken from 11 different international prostate cancer research (prca) groups (camp et al., 2007; schaid & chang, 2005). the prostate cancer consortium in europe (peace) assisted europeans in gaining faster access to the most recent treatment options and data generation in the fight against pca (fizazi et al., 2015). chinese prostate cancer consortium-risk calculator (cpcc-rc) (chen et al., 2014), was designed in 2016 based on gleason grade cancer (7 or above) in chinese or other asian countries who are exposed to the same genetic and environmental background. furthermore, to address the pca burden in black men, a consortium named “the prostate cancer transatlantic consortium (captc)” was formed in 2005 (https://epi.grants.cancer.gov/captc/). this is an open consortium, which has a group of pca scientists, clinicians, legal personnel and survivors from all across europe, north america, the caribbean islands, and west africa. the main aim of captc is to explore differences in morbidity and mortality among black men and further study reliable biomarkers in addition to developing sensitive diagnostics approaches to remove the global disparity associated with pca in black men (oladoyinbo et al., 2020). capci organization, goals and objectives the main goal of capci is to promote collaboration between clinicians and academic researchers which will also help in knowledge exchange between these two groups. the capci is www.companyofscientists.com/index.php/chd e6 cancer health disparities dedicated to developing programs that will lead to better approaches for prevention, diagnosis, and management of cancer, besides contributing to the broader agenda of pca control in the country (figure1). although early linkage analyses and candidate gene approaches are used to identify variants, this coordination would be of great importance when we discuss adequate sample sizes, investigate the genetic–clinical interactions. even though authentic statistics of associated risk and combined relationship of these snps could be established on a large-scale case-control evaluation, as previously described (kote-jarai et al., 2008), these cases have important implications for public health as well as individualized pca management strategies. having said this, broader scientific collaborations are needed for better organization of data quality and to protect confidentiality of participants as well. india has seen varied phenotypes of diabetes as a lifestyle disease. it is surprising that though india receives splendid sunshine and is one of the largest milk producers, the vitamin d deficiency is immense and what is more concerning is that these are susceptible to urogenital cancers/pca. furthermore, the diet based mutations associated with pca risk from our pilot study (gupta et al. 2020) further augments the hypothesis that there are a growing number of genetic contributions not just associated with disparities but also from epigenetics, environment and socio-economic status which motivates us to assess the objectives based on the varied phenotypes. 1. to establish pca as a public health priority and a leading healthcare disparity in the indian context. 2. to aid in research and development, education, data storage, curation, and public awareness in the direction of saving lives and improving patient outcomes 3. to collect data for inherent storage, entry and downstream data curation patient longitudinal follow-ups the most important things to consider for disease classification studies are a proper sample size and statistical evaluation. any influence of age on the study population and specific demographics should be taken into account. use of archival samples can be challenging because of potential dna/rna damage (gaffney et al, 2018; jackson et al., 2012). regular check-ups of subjects in the case of longitudinal cohort studies may increase a candidate's health when information is fed back to them. screening for pca for those with normal psa (<4ng/ml) must be done in conjunction with (a) annual digital rectal examination (dre) beginning at the age of 50 (b) psa screening with 4k (kallikrein tests) and discussed with a health care provider as a yearly test amidst ages of 5569. (c) procuring a positive family history, screening intended to be divulged amongst a healthcare benefactor, starting at age 40 (catalona and loeb, 2010). if psa/dre results are alarming, they can be supported by prostate ultrasound and biopsy (schroder et al, 2001). active surveillance (as) of notably low risk pca is recommended, in which psa is screened every 6 months, dre performed every 12 months, and repeat biopsy approximately every 12 months (nieboer et al, 2018). on the other hand, approximately 30% of men are found to have higher grade pca at repeat biopsy. post recovery from pca is also statutory as multifarious therapy has side effects such as hormone therapy (castration therapy) resulting in low testosterone, hot flashes, osteoporosis, loss of muscle mass, weight gain, erectile dysfunction, www.companyofscientists.com/index.php/chd e7 cancer health disparities decrease mental sharpness, depression, fatigue and increased cholesterol levels. monitoring psa and dre after definitive therapy is compulsory, if the risk of recurrence is high (loeb et al. 2007). the dre could be performed early, regardless of whether the psa is undetectable as patients treated with radiation therapy have a truncated, but measurable psa. prevalence of some psychological morbidity (distress, anxiety and depression) is also reported in pca patients who can both directly or indirectly influence the patient's outcomes (quality of life). earlier mental status in these patients was given less attention; however nowadays it has been critically included as a part of high quality cancer care during longitudinal follow ups (kershaw et al., 2008) (punnen et al., 2013). figure 1: a pictorial representation of capci inception, current developments and future goals overcoming sample conundrum for isolation of biomolecules for next generation sequencing over the years, several genome wide association studies (gwas) have yielded substantial pca risk alleles/snps in various populations. by and large, the african american (aa) population is largely affected followed by european american (ea) when compared to other sub-population across the world. however, a very limited number of next-generation sequencing (ngs) strategies have been done to ascertain the risk of pca. we at capci foresee that it is inevitable to sequence as many samples to identify risk alleles associated with the genetic contribution of pca. this is also due to the supporting evidence that the gwas has probably not identified the snps associated with pca risk, accounting for the lack of psa in the www.companyofscientists.com/index.php/chd e8 cancer health disparities african population which leads us to study this in developing countries including india. the ngs would allow us to identify a number of variants in tumor samples in a clinical setting. whole genome sequencing (wgs) or whole exome sequencing (wes) could serve as a diagnostic determinant in identifying new mutations. this is ably supported and followed by sanger sequencing which validates the analyzed regions to accomplish sufficient depth of coverage or to create data of superior quality and further checks for downstream validation (li et al., 2020). in addition, the capci aims to establish a new collaborative site for the collection of tissues for research that would be essential for pca screening. from our prior experience in handling the samples, we hope to document sustainable goals for isolation should be performed. in biomedical research, to ensure effortless identification of specimens, correct labeling and barcoding of each specimen of tissue is paramount. unlabeled and/or mislabeled (e.g., illegible handwriting) specimens might present a great clinical risk, which can be prevented by using a proper and defined method of labeling. holistically, barcodes can be an efficient way of labeling. developing and implementing a barcode system will allow links to construct high-throughput analysis of tissue microarrays (tmas). tmas are basically tissue “archives” developed by the recurring transfer of small tissue cores, from paraffin embedded ‘donor’ blocks into a single tma ‘recipient’ block. the tmas represent a unique approach of simultaneous analysis of up to 1000 different tissue samples at the dna, rna or protein level by immunohistochemistry (ihc), in situ hybridization (ish), or immunofluorescence (if). tmas could be obtained from tissue repositories which provide a section of tmas to investigators and preserve precious raw material (archived tissue samples). we have recently tweaked a protocol for the extraction of biomolecules from formalin-fixed, paraffin embedded (ffpe) tissue blocks that would be used for downstream sequencing analysis (shukla et al. 2021) cell lines in pca research cancer cell lines are developed as a significant model system for research based studies into the molecular mechanisms underlying the various aspects of pca. in vitro studies with cancer cell lines can be used to identify novel gene candidates and investigate different molecular mechanisms. pca resulting from different cell sources in the prostate lead to the development of a large number of pca cell lines. pca cell lines can be of two types i.e. androgen independent and androgen dependent. a database of the great number of pca cell lines has been provided by british columbia cancer agency (bcca) and another detailed and comprehensive compendium of pca cell lines is available from sobel and sadar (russell & kingsley, 2003). the availability of different prostate cancer cell lines that mimic human disease progression is a challenging task. prostate cell lines developed from patients have been instrumental in advancing research in understanding mechanistic details of cancer progression. there are two types of pca, hormone-sensitive and hormone-resistant. hormone-sensitive pca responds well to androgen deprivation therapy (adt), but most patients relapse with aggressive hormone-resistant pca after an initial therapeutic response. the mechanism of hormone resistance isn’t well understood and therefore appropriate prostate cell line models would assist in delineation of associated pathways. the most common prostate www.companyofscientists.com/index.php/chd e9 cancer health disparities cell lines include (i) non-cancerous prostate epithelial cell lines including rwpe-1, bph-1, prns-1-1, rc77n/e, hprepc etc; (ii) hormone sensitive prostate cancer cell lines including lncap, lapc-4, lapc-9, vcap, mda-pca 2a/2b, lucap 23.1, rc-77t/e etc; (iii) hormone resistant prostate cancer cell lines including pc-3, du-145, c4-2/c4-2b, 22rv1, arcap etc (saranyutanon et al., 2020). the major disadvantage of existing cell lines is that they are either derived from normal tissue or malignant tissue and are established by gene transduction using human telomerase reverse transcriptase (htert) (murofushi et., 2006). therefore, apart from using established cell lines, an effort will be made to establish patient-derived pca cell lines of epithelial and mesenchymal origin. the acquisition of these cell lines would enable a thorough study of the mechanisms underlying hormone resistance in prostate cancer (namekawa et al., 2019). the culture of human cell lines requires appropriate biosafety labs (bsl). bio safety cabinet is a set of biocontainment facilities to grow and propagate biological agents. the cell lines that do not contain human or animal pathogens are designated bsl-1. bsl-1 is selected for agents that present minimal potential hazard to personnel and the environment. however, primary cell lines, cell lines transformed by human oncogenic viruses, fresh or frozen tissue explants are required to be handled using bsl-2 facility. bsl-2 is designated for all the agents associated with human diseases that pose a moderate health hazard. the national centre for cell sciences (nccs), pune has been at the center of providing such cell lines for multifarious fields of cell biology, conspicuously those addressing imperative human health affairs such as cancer, integrating modern and conventional disciplines including cell biology, cellular signaling, stem cell biology, immunology, genomics, proteomics and systems biology. (national centre for cell science, n.d.) need for pca biobank a biobank is a biorepository that stores human biological samples and provides access for scientific research. while research on these samples is non-therapeutic, it is not directly applicable to the donor/patient. classification is based on either (a) specific disease or condition along with possible control data collection specifically designed for non-therapeutic research or existing collections with samples that were used for diagnosis, or (b) population or cohort studies wherein phenotypic (lifestyle/medical/ environmental) data associated with genetic data, would be used as a resource for different types of research. the convenience in the latter is that it provides a better understanding of the prevalence of gene variations and relation between phenotype and genotypes. participating in research may pose a limited physical and emotional risk... confidentiality may be an issue due to concerns that third parties (insurers, employers, schools, and the government) may gain access to data, the risk of personal or group stigma, and the sensitivity of medical and genetic data. a stigmatization for ‘fair institutions’ and societal access, privacy protection could be done by security, anonymization or coding of identifiable samples which would also be beneficial for biological materials that are traceable. informed consent could include allowing people to assess the risk for themselves, honoring their participation, and stressing the divide between research and medical care. many patients or donors are reluctant in some complex consent procedures. nevertheless, it could be useful if www.companyofscientists.com/index.php/chd e10 cancer health disparities disease/condition is treatable and volunteers have a right to this kind of information. to overcome this, commercial companies should share a part of the profit with people who need it the most (benefit sharing). for example, collections of blood spot cards could be used to study prevalence of cancer susceptibility genes. research progress should be communicated with the participants in a detailed and transparent manner either via personal interaction or website/newsletter. there should be a policy for providing information related to preventable diseases and those details need to be included in informed consent forms. it would have the right to entreat citizens to partake in akin research. on the other hand, pca biobanks could allure the general public to scrub in genetic research on the kernel of solidarity provided the aim of such research is to aid diagnosis and treatment of pca conditions. we aim to develop this as an extended program with industry partners wherein a biobank containing biospecimens, coupled with both clinico-pathological and epidemiological data would be used for collaboration of urologists, scientists, pathologists and research personnel. blood, urine and prostate tissue could be obtained, systematically processed in a timely fashion and banked on site using standard operating procedures. although a few biobanks in india such as sapinebio have offshoot, there needs to be strict informed consents and anonymised patient specimens with affiliated clinical data implemented road ahead the capci is aimed to bridge the gap between cancer geneticists and clinicians/urologists associated with pca diagnosis. screening genomic parameters for pca will discover functional aspects which in turn will help in understanding pathogenesis and chemo preventive therapeutic measures. as we strive for ample statistical data that could be helpful in explaining genetic-clinical and genetic-epidemiological data, a reliable risk predicting model could ease the screening and treatment regimen (goh et al., 2012). on the other hand, standard operating procedures (sops) are not properly framed and with very limited progress in this field in india, efforts to distinguish between indolent and aggressive tumors could be on the anvil. this can be possible largely due to reproducibility of data pertaining to tumor heterogeneity observed in the same patient between primary and metastatic lesions. one can address the heterogeneity problems through spatial transcriptomics approach, especially using tma/ffpe sections (brady et al., nature communication, 2021).the capci’s establishment of sops would aid in developing a better method of data evaluation obtained from different centers with focus on sample collection and storage along with improving dna, rna and protein extraction methodologies. a need for establishment of biobanks to achieve a decent amount of source material for future studies would provide an impetus and this is only possible by bringing collaborative convergence to the fore, as we say “ome” ( many ~ together). declarations acknowledgments the authors would like to acknowledge all the patients and their family, members of support staff of the hospital for possible assistance in many ways. authors’ contributions ps ideated and conceptualized framework for capci. ss and bdk wrote the first draft with ds, www.companyofscientists.com/index.php/chd e11 cancer health disparities ns and ps. other authors chipped in with lateral sections. availability http://www.bioclues.org/capci competing interests the industrial partners as a part of this consortium including the academic authors do not have any conflicts of interests. bioclues.org is a not-for-profit organization which propounded the capci. ethics approval not applicable funding none references 1. bajaj, a. 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(2017). emerging variants of castration-resistant prostate cancer. current oncology reports. https://doi.org/10.1007/s11912017-0593-6 https://doi.org/10.1002/pros.20198 https://doi.org/10.1002/pros.20198 https://doi.org/10.1186/s40246-019-0215-5 https://doi.org/10.1002/pros.23037 https://doi.org/10.1002/pros.23037 introduction organization current progress and future activities indian context of human genome project international consortia on pca capci organization, goals and objectives patient longitudinal follow-ups figure 1: a pictorial representation of capci inception, current developments and future goals overcoming sample conundrum for isolation of biomolecules for next generation sequencing cell lines in pca research need for pca biobank road ahead declarations acknowledgments authors’ contributions availability competing interests ethics approval funding www.companyofscientists.com/index.php/chd e1 cancer health disparities research interventions addressing breast cancer mammography screening barriers in non-hispanic black women: an integrative review debra a. neblett1*, wanda m. williams school of nursing, university of north carolina greensboro, greensboro, nc, usa *corresponding author: debra a. neblett, email: daneblet@uncg.edu abstract breast cancer disparity in non-hispanic black women is a major concern due to higher breast cancer death rates in this population. this integrative review explores interventions aimed at addressing barriers to screening mammography in this population. a literature search was conducted of full-text, peerreviewed articles published over ten years between 2013-2023 using the cumulated index of nursing and allied health and pubmed. of the 396 articles identified, nine met the inclusion criteria. the studies identified used various strategies to implement screening interventions in non-hispanic black women that were culturally tailored and considered social determinants of health, barriers to breast cancer screening, community engagement, and patient navigation. these findings suggest that focused interventions should consider the challenges to non-hispanic black women to schedule and complete mammogram screenings. future research is recommended to conduct interventional studies with non-hispanic black women specifically tailored to meet their needs to promote engagement in the recommended mammography screening guidelines. keywords: breast cancer screening, mammography, interventions, black or african american, or non-hispanic black women. citation: neblett d et al (2023). interventions addressing breast cancer mammography screening barriers in non-hispanic black women: an integrative review. cancer health disparities 7:e1-e11. doi:10.9777/chd.2023.1005 mailto:daneblet@uncg.edu www.companyofscientists.com/index.php/chd e2 cancer health disparities research introduction in the united states breast cancer disparity in nonhispanic black women is evident with little improvement noted in reducing the gap between non-hispanic black women and white women. the incidence of breast cancer is higher in white women. still, black women have a higher chance of developing breast cancer before age 40 and are more likely to die from breast cancer (american association of cancer research steering committee, 2022; the american cancer society medical and editorial content team, 2023). breast cancer mortality rates among non-hispanic black women are 29.2 deaths per 100,000 persons compared with 20.6 deaths per 100,000 persons among white women (the american cancer society medical and editorial content team, 2023). non-hispanic black women are more likely to be diagnosed with late-stage breast cancer (giaquinto et al., 2022 & mcdowell, 2022). mammography screening is effective for early detection, which has led to decreased mortality and improved survival. in 2019, 70.8% of black women 40 and over reported having a mammogram within the past two years (national center for health statistics (us), 2023). along with this gradual improvement over the last several years, barriers to mammograms still exist. a recent qualitative study among non-hispanic black women identified the following barriers to mammogram screening in non-hispanic black women: fear of pain associated with the procedure, inability to make time (not a priority), socioeconomic status, employment constraints, lack of childcare, and lack of transportation (williams & fu, 2023). some system barriers were identified as lack of or inadequate insurance, misconceptions about the mammogram procedure, poor communication from the medical provider, mammograms at under-resourced facilities, and a lag in routine screening mammograms and followup of abnormal results (giaquinto et al., 2022 & williams & fu, 2023). a study by guo et al. (2019) also supported most of these barriers identified above as the reason for inconsistent mammogram screening in non-hispanic black women. therefore, this integrative review examines the current literature regarding breast cancer screening interventions to address barriers to mammography utilization in on-hispanic black women. methods a literature search was conducted of full-text, peerreviewed articles published over ten years between 2013-2023 using cinahl and pubmed. search terms were breast cancer, breast neoplasm, mammogram, mammography, interventions or strategies or best practices, faith-based, mobile, and navigation. the following inclusion criteria were used to identify studies in this integrative review: women who identified as non-hispanic black or african american, greater than 18 years of age, intervention studies (randomized and nonrandomized) with reported mammogram outcomes conducted in the united states. gray literature was not included in this review. the authors independently identified all the articles selected using the inclusion criteria. clarification of articles selected for inclusion was resolved through discussion and consensus of both authors. search results the database searches resulted in 396 articles, and after duplicates were removed, 168 articles remained, which were further reduced to 9 articles based on the inclusion criteria. the integrative review process was guided by the preferred reporting items for systematic reviews and metaanalyses (prisma) diagram and is presented in figure 1. figure 1. flow diagram for inclusion and exclusion of studies. www.companyofscientists.com/index.php/chd e3 cancer health disparities research results table 1 provides an overview of the studies included in this integrative review. they are listed in chronological order of publication date with the author(s), study design and timeframe, study objective, sample, and outcomes. six of the nine studies were conducted in the southeast (gathiruamwangi et al., 2016; hatcher et al., 2016; khaliq et al., 2017; mayfield-johnson et al., 2016; mosavel & genderson, 2016; richman et al., 2020), three studies in the midwest (allgood et al., 2018; drake et al., 2015; gathirua-mwangi et al., 2016), and one in the northeast (hendren et al., 2014). three studies were randomized-control trials, two were pilot studies, and four were non-randomized intervention studies. the average ages of the women in the studies ranged from 4069 years old. in five out of nine studies, 46-81% of the women were uninsured. studies reported various locations for mammogram completion, such as hospitals, reports assessed for eligibility (n =10) records identified through cinahl (n = 262, and pubmed (n = 134) total (n = 396) records screened (n = 168) reports sought for retrieval (n = 11) studies included in the review (n = 9) reports excluded: (n =1) study did not meet the inclusion criteria records removed before screening: duplicate records removed (n = 228) records excluded (n =157) studies did not meet the inclusion criteria reports not retrieved (n =1) only abstract available identification of studies via databases id en tif ica tio n sc re en in g in clu de d www.companyofscientists.com/index.php/chd e4 cancer health disparities research imaging centers, healthcare provider offices, and community clinics. in three of the nine studies, mammogram completion was self-reported, limiting access for future comparisons or follow-up of abnormal findings. a study found that women who received a recommendation from their medical provider were more likely to obtain a mammogram (gathirua-mwangi et al., 2016). about 66% of the studies in the review used multiple intervention strategies to engage participants in deciding to obtain a screening mammogram. table 1. overview of studies for this integrative review. year, author study description and study timeframe objective sample outcome 2014 hendren et al. randomized control trial april to september 2010 to assess an intervention to increase cancer screening (*breast and colon) among patients in a safety-net primary care practice. n =366 control group (usual care) n =185 intervention group n =181 *breast cancer screening (intervention and control group numbers were not reported separately) n = 126 women age range 40-60+ 41% african american breast and colon cancer intervention and control group results were reported separately. mammography completion: overall, the sample was 29.7% in the intervention group and 16.7% in the control group. african american was 27.7% in the intervention group and 10.5% in the control group. 2015 drake et al. non-randomized intervention study 2009-2011 to implement patient navigation in a high-need area to identify women due or overdue for a mammogram and increase mammography utilization in this population. n = 792 women age range 40-69 89.3 % african american mammography completion in the women (n = 710) who received navigation was 87.2% (n = 655) of the women who were navigated and includes 55 women who had repeat mammograms in year 2 of the study. 2016 gathiruamwangi et al. randomized control trial 2007-2009 to compare the effects of two interventions with usual care on mammography adherence among a subsample of african american women. n = 244 usual care (n = 72) mean age 50.6 dvd (n = 87) mean age 51.3 telephone (n = 85) mean age 51.7 mammography completion: usual care – 35.2% dvd – 41% telephone – 42.2% 2016 hatcher et al. randomized control trial 2010-2013 to test the efficacy of a pilot intervention to increase mammography n = 96 mean age 51.9 (age range 40-83) of the retained participants (n = 62) who received one of the interventions, one www.companyofscientists.com/index.php/chd e5 cancer health disparities research utilization among african american women recruited from those waiting in the ed. control group (n = 33) brochure only (n = 30) motivation interview (n = 33) quarter (27%) reported having a mammogram during the study or in the preceding three months. 2016 mayfieldjohnson et al. non-randomized intervention study/ one year to increase the relatively low screening rate for african american women in the mississippi delta through partnerships with community-based organizations, state health departments, and academia. n = 554 women age range 40 >65 94.72% african american mammography completion: n = 554 screening mammogram – 90.43% diagnostic mammogram – 9.57% 2016 mosavel et al. pilot study not included to report on findings from a community-based study that assessed the feasibility of upward communication by adolescent females to influence their female family members to obtain recommended breast and cervical cancer screenings or to consult with their doctor regarding their need for a colonoscopy. african american women and adolescent females 48 dyads (n = 96) completed baseline interviews and 36 dyads completed the exit interviews mean age 52 for women mean age 15 for adolescent females control group n = 14 intervention group n = 22 mammography completion – self-reported: control group – 2 of the seven (29%) reported receiving a mammogram. intervention group 5 (42%) reported making appointments, and 5 obtained a mammogram. 2017 khaliq et al. prospective intervention pilot study october 2012 – march 2013 to evaluate whether an intervention that includes breast cancer screening education during a hospital stay and scheduling an outpatient mammography appointment before hospital discharge would improve adherence to mammography screening. n = 30 women mean age 57.8 57% african american (n = 17) mammography completion: 10 women (2 were african american), and five needed additional imaging and follow-up. 2018, allgood et al. non-randomized intervention study september 2011may 2015 to assess the effectiveness of the mammogram party in increasing mammography n = 3,003 women < 40 (11%) > 40 (88%) 49% african american mammography completion in mammogram parties (65.8%) was comparable to standard one-on-one www.companyofscientists.com/index.php/chd e6 cancer health disparities research uptake, particularly among under-served populations. navigation (63.7%) but is less labor-intensive than one-on-one navigation. 2020 richman et al. non-randomized intervention study 2015-2017 to outline program outcomes in relation to the educational component of the program across a two-year period. n = 735 women mean age 48 23% african american all women were educated on breast cancer; 365 women were navigated and assessed for breast health needs; 299 were either recommended for a clinical breast exam or mammogram. 193 women (65%) were recommended for a mammogram. 139 women (72%) received mammograms (data was not separated by race). 2016 mosavel et al. pilot study not included to report on findings from a community-based study that assessed the feasibility of upward communication by adolescent females to influence their female family members to obtain recommended breast and cervical cancer screenings or to consult with their doctor regarding their need for a colonoscopy. african american women and adolescent females 48 dyads (n = 96) completed baseline interviews and 36 dyads completed the exit interviews mean age 52 for women mean age 15 for adolescent females control group n = 14 intervention group n = 22 mammography completion – self-reported: control group – 2 of the seven (29%) reported receiving a mammogram. intervention group 5 (42%) reported making appointments, and 5 obtained a mammogram. 2017 khaliq et al. prospective intervention pilot study october 2012 – march 2013 to evaluate whether an intervention that includes breast cancer screening education during a hospital stay and scheduling an outpatient mammography appointment before hospital discharge would improve adherence to mammography screening. n = 30 women mean age 57.8 57% african american (n = 17) mammography completion: 10 women (2 were african american), and five needed additional imaging and follow-up. www.companyofscientists.com/index.php/chd e7 cancer health disparities research 2018, allgood et al. non-randomized intervention study september 2011may 2015 to assess the effectiveness of the mammogram party in increasing mammography uptake, particularly among under-served populations. n = 3,003 women < 40 (11%) > 40 (88%) 49% african american mammography completion in mammogram parties (65.8%) was comparable to standard one-on-one navigation (63.7%) but is less labor-intensive than one-on-one navigation. 2020 richman et al. non-randomized intervention study 2015-2017 to outline program outcomes in relation to the educational component of the program across a two-year period. n = 735 women mean age 48 23% african american all women were educated on breast cancer; 365 women were navigated and assessed for breast health needs; 299 were either recommended for a clinical breast exam or mammogram. 193 women (65%) were recommended for a mammogram. 139 women (72%) received mammograms (data was not separated by race). highlighted components of interventional studies early detection of breast cancer reduces breast cancer mortality, and screening mammography is essential in addressing the health disparities experienced by non-hispanic black women who experience poorer health outcomes. black women are 40 percent more likely to die from breast cancer and be diagnosed with aggressive cancers at younger ages (national center for health statistics, 2023). due to this finding, the 2023 u.s. preventive services taskforce now recommends that black women start screening at age 40. however, this change may not be enough to improve health inequities, but it is a crucial first step. additionally, healthcare providers are vital in supporting patients through conversations about routine mammography screening and timely follow-up and treatment when indicated (u.s. preventive services taskforce, 2023). implementing interventions focused on the specific needs of non-hispanic black women is essential to address the barriers impacting breast cancer screening practices among this population. the specific interventions identified by this integrative review are summarized in table 2. the interventions can be grouped or labeled under five areas: culturally tailored, social determinants of health, barriers to breast cancer screening, community engagement, and patient navigation. some of the most successful programs focused on lay and community health workers and the importance of a patient navigator. www.companyofscientists.com/index.php/chd e8 cancer health disparities research table 2. highlighted components of interventional studies. culturally tailored interventions social determinants of health barriers to breast cancer screening addressed engaging community patient navigation hatcher et al., 2016 hendren et al., 2013 access to care drake et al., 2015 resources to assist with the cost of mammogram hatcher et al., 2016 lay health workers drake et al., 2015 mayfield-johnson et al., 2016 richman et al., 2020 hatcher et al., 2016 access to care khaliq et al., 2017 gift card (incentive) to offset transportation costs to mammogram allgood et al., 2018 transportation provided mayfield-johnson et al., 2016 community health workers richman et al., 2020 lay breast health educators hatcher et al., 2016 khaliq et al., 2017 richman et al., 2020 transportation provided allgood et al., 2018 culturally tailored interventions were found to be important to improve mammogram screening for non-hispanic black women. for example, a brochure developed from focus groups with black women in the emergency department (ed) was used to increase mammography in black women who presented to the ed for non-urgent complaints (hatcher et al., 2016). mayfield-johnson et al. (2016) described the use of multiple culturally targeted strategies in the use of media, community-based education, healthcare assistance, and use of community health workers. another study used the pitt county breast wellness initiative-education (pcbwi-e), using latina and black community members to educate the participants (richman et al., 2020). understanding how other associated barriers, such as social determinants of health, affect nonhispanic black women’s access to care is critical. interventions in two studies provided community resources for the uninsured or underinsured, where participants were provided free or reduced-cost screening services or assistance with co-pays through various payment sources (drake et al., 2015; hatcher et al., 2016; hendren et al., 2014). transportation to imaging centers is reported as a common barrier to mammography screening (miller et al., 2019). four of the nine studies addressed this barrier by offering gift cards for transportation or providing transportation either to or from the imaging center or both (allgood et al., 2018; drake et al., 2015; khaliq et al., 2017; richman et al., 2020). the breast cancer and cervical early detection program provides mammograms for uninsured women. hendren and colleagues (2014) provided information about this program to the participants as part of the study’s intervention, but no outcomes were reported on where mammograms were obtained. breast and cervical cancer control program was one of three mammogram sites in a study evaluating a community-based breast cancer www.companyofscientists.com/index.php/chd e9 cancer health disparities research prevention that allowed for tracking mammogram completion. however, locations for screening were not reported individually (richman et al., 2020). a third factor was using multiple intervention strategies, which can reduce barriers to cancer screening. one randomized controlled trial mailed letters and used automated telephone calls in the intervention group versus the usual care in the control group to remind african american women about obtaining a mammogram. there was a higher completion rate in the intervention group in this study (hendren et al., 2014). other interventions included breast health education by community health workers, mammogram scheduling, and follow-up and treatment services if indicated (mayfield-johnson et al., 2016). richman and colleagues (2020) incorporated various interventions that were culturally tailored, addressed barriers to breast cancer screening, and engaged the community. a fourth factor was the importance of support and education within the community. three studies engaged community members through lay health workers, community health workers, and lay breast health educators (hatcher et al., 2016; mayfieldjohnson et al., 2016; richman et al., 2020). community health workers were recruited from the community where the research would occur. they served as gatekeepers due to their familiarity with the needs and health issues of the community. lastly, patient navigation was identified in four studies (allgood et al., 2018; drake et al., 2015; hatcher et al., 2016; khaliq et al., 2017). the patient navigator’s tasks varied. some of the duties included educating women about breast health and breast cancer, identifying women who need mammograms, scheduling mammograms, assessing for any barriers to adherence, assisting with resources to address these barriers, supporting women regarding the results, and following up on abnormal mammography results (allgood et al., 2018; drake et al., 2015; hatcher et al., 2016; khaliq et al., 2017; richman et al., 2020). one study compared navigation using a mammogram party versus one-on-one navigation and found comparable completion rates. however, mammogram parties can foster a sense of community among the women and provide support within the party members through the shared experience of having a mammogram on the same day. more mammograms can be completed in mammogram parties versus one-on-one navigation. this same study reported a range of total navigation contacts of 10.9 in women invited to a mammogram party and 15.0 in women not invited to a party (allgood et al., 2018). patient navigation was first used to address barriers in cancer care in 1990 and continues to have support as an effective strategy to promote early detection and treatment (stringer-reasor et al., 2021). discussion mammography screening is an effective tool for early detection of breast cancer and a means to improve the health outcome of non-hispanic black women. breast cancer disparity gaps that are still prevalent today must be addressed to reduce this population's higher breast cancer death rate. healthcare providers must recognize and be willing to improve how they relate and communicate with non-hispanic black women, which could foster better adherence to mammogram screening. a free cme toolkit, “talking to patients about breast cancer screening,” on the american college of radiology website is available for healthcare providers. the toolkit includes clinical decision aids, education handouts about breast cancer, infographics, and clinical education videos (american college of radiology, n.d.). in addition, a study by fung et al. (2021) supports that more www.companyofscientists.com/index.php/chd e10 cancer health disparities research culturally and linguistically targeted education is needed to increase mammogram screening among non-hispanic black women. the healthcare community should consider challenges to breast cancer screening for nonhispanic black women, such as childcare, and incorporate effective measures to address this issue. taking time off from work is a significant concern. offering screening schedules in the evening or on weekends so women would not have to lose income from taking time off from work could improve non-hispanic black women’s adherence to screening. consideration of these interventions is needed to reduce the higher breast cancer death rates in non-hispanic black women. other issues to address breast cancer screening disparities are advocating for affordable health insurance, supporting safety-net facilities that provide breast cancer screening, and partnering with leaders in healthcare systems for mammography and patient navigation services (stringer-reasor et al., 2021). there are limitations to consider in this integrative review. barriers to early detection of breast cancer are multifaceted. this review focused on interventions addressing barriers to mammography screening in non-hispanic black women, which did not allow for comparison. the studies' socioeconomic and insurance status varied, with many uninsured participants. the long-term effects of the interventions are not known. breast cancer diagnosis, treatment, and survivorship were not included. despite these limitations, the review highlighted strategies to address barriers to mammography screening in non-hispanic black women. the findings from this review emphasize the significance of accepting, understanding and addressing the cultural differences and the multilevel barriers (social determinants of health) that contribute to a non-hispanic black woman not being able to or not obtaining a mammogram as recommended. in addition, the 2023 u.s. preventive services taskforce now recommends that black women start screening at age 40. future studies should consider incorporating measures to track mammogram completion versus self-reporting. more longitudinal interventional studies tailored to non-hispanic black women are needed to support their engagement in mammogram screening guidelines for early detection of breast cancer. acknowledgments the authors thank dr. debra wallace for her editorial support. author contributions conception and plan for integrative review: dn and ww. initial manuscript writing, review, and revisions: dn and ww. conflict of interest the authors declare that they have no conflicts of interest with the contents of this article. funding there was no funding support for this integrative review. references allgood, k.l., hunt, b., kanoon, j.m., and simon, m.a. 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(2023). understanding breast cancer disparities affecting black women: obtaining diverse perspectives through focus groups comprised of patients, providers, and others. j. community health. 10.1007/s10900-023-01227-3. https://www.acr.org/clinical-resources/breast-imaging-resources/mammography-cme-toolkit https://www.acr.org/clinical-resources/breast-imaging-resources/mammography-cme-toolkit introduction methods search results results highlighted components of interventional studies discussion acknowledgments author contributions conflict of interest funding www.companyofscientists.com/index.php/chd e1 cancer health disparities research racial differences in prostate tumor microenvironment: implications for disparate clinical outcomes and potential opportunities sandeep goswami 1,2 chandrani sarkar 1, 2,3, seema singh 1, 2,3 ajay pratap singh 1,2,3 debanjan chakroborty 1,2,3 1 department of pathology, university of south alabama, mobile, alabama, usa. 2 cancer biology program, mitchell cancer institute, university of south alabama, mobile, alabama, usa. 3 department of biochemistry and molecular biology, university of south alabama, mobile, alabama, usa. *corresponding author: debanjan chakroborty, email: dchakroborty@southalabama.edu, abstract disparities in cancer incidence and outcome are common among the racial and ethnical minorities in the united states and are of significant social and clinical concern. prostate cancer is the most commonly diagnosed non-cutaneous malignancy in american men and exhibits substantial racial disparities with african american men bearing the highest burden in terms of incidence and mortality. a multitude of factors, including socioeconomic, behavioral, and access to healthcare, have been implicated as the underlying causes of such disparities. more recent data also suggest that there are inherent molecular and biological differences in prostate tumors of patients having distinct racial backgrounds. tumor microenvironment has tremendous impact on the course of cancer progression and clinical outcome and may also contribute to the racial disparities observed in prostate cancer. therefore, a better understanding of critical differences in the tumor microenvironment components may provide newer directions to study the biological causes of prostate cancer health disparities and may identify novel therapeutic targets. this review discusses the findings related to the tumor microenvironment differences between african american and caucasian american prostate cancer patients and makes suggestion regarding their potential significance in prostate cancer disparities. keywords: prostate cancer, racial disparity, tumor microenvironment citation: goswami s et al (2022) racial differences in prostate tumor microenvironment: implications for disparate clinical outcomes and potential opportunities. cancer health disparities. 6: e1-e14. doi:10.9777/chd.2022.1003 www.companyofscientists.com/index.php/chd e2 cancer health disparities research 1.0. introduction prostate cancer (pca) is the most commonly diagnosed non-cutaneous malignancy and the second leading cause of cancer-related death in american men [1, 2]. among all the cancers, pca not only shows extreme variations in its potential to cause morbidity and death in men but also displays great variations in geographic and racial distribution [1, 2, 3, 4]. in the united states, despite significant improvements in cancer diagnosis and treatment strategies, african american (aa) men suffer disproportionately from pca with over 80% higher incidence rates than men of european american (ca, caucasian american) origin [5, 6, 7, 8]. aa men are also more likely to be diagnosed at a younger age and present with more advanced and aggressive disease stages [8-12] compared to men with ca ancestry. accordingly, for aa men, the lifetime risk of developing pca is 1 in 6, while that for ca men is 1 in 8. aa men are also greater than twice as likely to succumb to the disease compared with ca men as the pca specific mortality in aa men is 1 in 23 whereas it is 1 in 42 in ca men [1, 2, 7]. in order to overcome the disparity that affects aa population negatively and to develop personalized therapeutic approaches, we need to identify and understand the factors that drive pca tumor progression and metastasis in aa men. over the years, a number of such interconnected factors including socioeconomic status, lifestyle and dietary issues, problems with accessing healthcare have been identified as probable causes of this epidemiological disparity in pca incidence and mortality [1, 2, 8]. interestingly, several newer lines of evidence have also demonstrated genetic and biological variations among patients of different racial backgrounds. the androgen hormonal axis, the androgen receptor (ar), and its signaling pathway play critical roles in pca progression [13].several aspects of the ar pathway have also been implicated in pca associated racial differences [14-16]. however, in addition to androgens and ar signaling, the crosstalk between epithelial cells and cellular components of the tumor microenvironment (tme), such as mesenchymal stem cells, endothelial cells, fibroblasts/myofibroblasts, and immune cells also plays an integral role in pca progression and metastasis [2,17]. the immune cells as well as the endothelial cells forming the blood vessels in the pca tme, secrete growth factors and cytokines to induce pca cell proliferation and spread [2, 17]. increasing evidences now indicate that the tme components may also be a significant contributor to the racial disparity observed in pca incidence, aggressiveness and clinical outcomes between aa and ca populations [2, 18-20]. therefore, we have reviewed the pertinent data to discuss the potential contribution of the tme to the observed racial disparity associated with pca (table 1). www.companyofscientists.com/index.php/chd e3 cancer health disparities research table 1. role of stromal cells in aa and ca pca. cell type role in pca differences in aa and ca pca references fibroblasts • secrete chemokines, cytokines, growth factors (brain derived neurotrophic factor and chemokines like ccl5, cxcl5, sdf1-alpha and soluble factors such as vegf, bfgf, hgf) • promote tumor growth and metastasis • pro-inflammatory cytokines and growth factors [brain-derived neurotrophic factor (bdnf), vegf, and fibroblast growth factor 7 (fgf7)] are significantly elevated in aa pca • higher expressions of myofibroblast activating markers [αsma, vimentin, and fap1] and mesenchymal stem cell marker, cd90, in cancer associated fibroblasts (cafs) of aa pca 2,19 immune cells • inflammation promotes initiation and progression • increased lymphocytic infiltration in aa pca tissues • pro-inflammatory cytokines (interferon-alpha (ifnα), ifnγ, tumor necrosis factor-alpha (tnfα), and interleukin 4 and interleukin 13) are upregulated in pca of aa men • increased nk cell activity in aa pca 2, 28, 34-36 endothelial cells • form neovesels to support tumor growth and metastatic progression • increased vegf secretion in aa pca • higher mvd in aa pca tissues 2,19, 44, 50 2.0. prostate cancer microenvironment prostate, a tubule-alveolar gland is primarily composed of prostatic epithelial cells surrounded by the stromal components [17, 21]. the gland has three distinct zones; peripheral, central, transition, and a mixed zone called the anterior fibro-muscular zone or stromal zone [17, 21, 22]. it is mainly composed of four major epithelial cell typesbasal cells, neuroendocrine cells, epithelial stem/progenitor cells, and secretory luminal cells [17, 22]. the stroma consists primarily of fibroblasts, myofibroblasts, endothelial cells, immune cells, nerve cells and smooth muscle cells [17, 22]. the development and progression of pca is a complex process and the disease is extremely heterogeneous from molecular, cellular and clinical standpoints [23]. in most cases, pca originates in prostatic epithelial cells. therefore, studies on pca development and progression have mainly focused on these cells [22, 23]. however, epithelial cells are not sole players contributing to pca tumorigenesis; the stromal cells in the tme also play critical roles in pca development and progression [2, 17, 24]. the crosstalk between the stroma and the epithelium is a major driver of pca pathogenesis and disease progression [24, 25]. the interaction between the epithelial or cancer cells and the non-epithelial or stromal cells in pca is mediated by a variety of paracrine factors secreted both by cancer cells as well as by the stromal cells [2, 25] (figure 1). several studies have emphasized the contribution of altered/reactive stromal microenvironment characterized by increase in the numbers of myofibroblasts and fibroblasts and significant decrease in the numbers of smooth muscle cells in tumorigenesis and progression of pca [17, 25]. www.companyofscientists.com/index.php/chd e4 cancer health disparities research figure 1: interaction between pca cells and the stroma (created by biorender) regarding the disproportionate burdens of pca between aa and ca populations, while most studies have focused on genetic differences within different prostate tumor subtypes, emphasizing mostly on pca cells, a handful of studies have also indicated how differences in pca tme can affect tumor progression among men with different racial and ethnic backgrounds [18, 19]. altered gene expression profiles of fibroblasts, immune cells and angiogenic components was noted between the tme of aa and ca men with pca [18-20, 26-27]. in a study involving pca samples from patients of aa and ca backgrounds, a total of 677 genes associated with 103 pathways were identified to be differentially expressed in the pca tme [20]. furthermore, pathway analysis and disease association studies have revealed a significant difference in tumor inflammatory response and cytokine secretion between aa and ca patient samples [18, 20, 21, 28, 29].the differences in tme of aa and ca pca patients may account for the differences observed in tumor growth, progression and therapeutic response. in the following sections, we will therefore discuss the racial differences observed in three important cellular components of the tme in pca: cancer associated fibroblasts (cafs), immune cells and endothelial cells. 2.1. fibroblasts the stromal fibroblasts play a major role in normal prostate development as well as in pca progression [2, 17, 25]. cancer associated fibroblasts (cafs) form a major component of tme and they actively communicate with pca cells both via direct contact www.companyofscientists.com/index.php/chd e5 cancer health disparities research and via soluble mediators such as chemokines, cytokines, growth factors secreted by both of the cell types [2, 17, 25, 30, 31]. this bidirectional communication between pca cells and cafs is crucial for tumor progression and metastasis. cafs secrete growth factors like brain derived neurotrophic factor and chemokines like ccl5, cxcl5, sdf1-alpha and soluble factors such as vegf, bfgf, hgf that promote pca growth and progression [2, 19]. studies have shown cafs can differentially impact pca progression in aa and ca patients. in a study where prostate fibroblasts from pca specimens of aa and ca patients with similar clinicopathologic characteristics were isolated, it was noted that pro-inflammatory cytokines and growth factors [brain-derived neurotrophic factor (bdnf), vegf, and fibroblast growth factor 7 (fgf7)] were significantly elevated in caf isolated from aa pca samples compared to ca pca [19]. in addition, myofibroblast activating markers [αsma, vimentin, and fap1] and mesenchymal stem cell marker, cd90, showed significantly higher expressions in aa cafs compared with ca cafs [19]. with increased myofibroblastic components and presence of a population of mesenchymal-like cells (cd90+) it was inferred that aa-derived cells would show increased response to growth factors compared with ca-derived cells [19]. on the other hand, the expression of caveolin1 (cav1) that is a membrane-associated protein , whose expression in cancer cells increases with progression but loss in pca stroma correlates with reduced relapse-free survival [19, 32, 33], was found to be lower in aa cafs compared with ca cafs. upon exposure of pca cells to conditioned media from fibroblasts isolated from aa and ca pca patients, it was seen that there was increased proliferation and migration in vitro when pca cells were exposed to conditioned media from aa prostate fibroblasts compared to ca prostate fibroblasts [19]. furthermore, this study demonstrated that regardless of the racial background of pca cells, growth and/or proliferation of pca cells was significantly increased when conditioned media from aa patients’ fibroblasts was used (19). in addition, the study also reported an increased collagen deposition and myofibroblasts forming the ‘reactive stroma’ and elevated expression of fibroblast specific marker, tenascin-c, in the extracellular matrix (ecm) of aa pca patients [19]. high expression of tenascin-c in cafs is associated with poor prognosis in pca [34].taken together; these data suggest that cafs in aa pca patients produce significantly higher levels of growth factors that enhance the tumorigenicity of pca cells compared with cafs in ca pca patients. 2.2. immune cells although pca is considered as a poorly immunogenic tumor, chronic inflammation has been consistently shown to be associated with the development and progression of the disease [35]. immune cells form the cellular arm of inflammatory responses and presence of inflammatory cells in pca tme is well documented.only a few studies however have explored the immunological differences observed in the tme of aa and ca pca.[36]. very recently, it was reported that there is over-representation of immunogenic tme in aa pca patients, with significantly higher inflammatory cytokines and lymphocytic infiltrates which increases the potential for better response to immunotherapy in these patients [37] . studies have reported a significant difference in both the numbers and types of inflammatory cells and inflammatory responses between aa and ca pca populations. differences were noted between aa and ca pca patients in expression of chronic inflammatory cytokines, such as interferon-alpha (ifnα), ifnγ, tumor necrosis factor-alpha (tnfα), interleukin (il) il-1β, il 4, il 6, il 8 and il 13. these pro-inflammatory cytokines show significant www.companyofscientists.com/index.php/chd e6 cancer health disparities research upregulation in pca of aa men [20, 38]. il-6 promotes migration of cells and helps to evade apoptosis through stat and pi3k pathways and is considered immunosuppressive as it helps to recruit myeloid derived suppressor cells (mdsc) to the tme [37, 39]. il-8 activates neutrophil and plays a role in cell proliferation and invasion. higher levels of il-8 expression in pca was associated with higher tumor grade but this association was comparable in aa and ca pca [37, 40]. a recent study that was conducted using grade, stage matched aa and ca pca, has reported an increased lymphocytic infiltration in aa pca tissues compared to pca tissues of ca origin [28]. upon further analysis of the lymphocytic population, the study reported a higher presence of plasma cells in tme of aa pca that correlated with ifnγ expression and increased inflammation observed in these tissues [28]. high expression of igg was also noted in these aa pca samples, which suggested more antibody secretion by these cells [28]. in addition, increased activity of nk cells, which primarily drives antibody dependent cellular toxicity, have been reported in aa pca tissues compared to tissues from ca patient [28]. a different study also reported that aa pca had higher expression of cd4+ and cd8+ t-cell markers in tme [38]. in contrast, there is also a report that indicated no difference in t-cell infiltration between aa and ca pca but increased regulatory t-cells in aa pca that correlated with disease recurrence [41]. poor disease prognosis associated with lymphocytic tme infiltrates may be due to their association with more aggressive tumors, or as the infiltrating t-cells were dysfunctional, or as were immunosuppressive regulatory t-cells [37, 42]. macrophages comprise a major portion of the immune cells in the tme. m1 type or classically activated macrophages which are anti-tumorigenic and m2 type or alternatively activated macrophages which are pro-tumorigenic have been shown to be present in the pca tme. in the tme, the tumor-associated macrophages (tams) are converted from a m1-type to the m2-type phenotype that secrete numerous growth factors, which influence diverse processes during pca progression.the density and type of tams present in pca thus provide prognostic information [2, 43]. aa pca patients show increased tam numbers compared to ca pca patients as both cd68+ (m1), and cd163+ (m2) cells were significantly higher in aa pca tissues [2]. a study investigating the role of inflammation and immune genes in aa pca characterized 124 tme and immune response genes in aa pca patients [44]. it was reported that 22% of total aam patients showed adverse pathology features, high genomic risk (53%) and higher expressions of immuneresponse genes some of which along with their functions have been included in table 2. table 2: immune response genes elevated in aa pca patients compared to ca pca patients. gene name expression in aa pca patients role in cancer references cluster of differentiation 2 (cd2) immunomodulatory in the tme; associated with delayed disease progression; enhances tumor immunogenicity and may improve response to immunotherapy. 44, 45 www.companyofscientists.com/index.php/chd e7 cancer health disparities research cluster of differentiation 3 (cd3) activates cytotoxic t cells (cd8+ naive t cells) and t helper cells (cd4+ naive t cells). 44, 46 cluster of differentiation 4 (cd4) immunosuppressive; may help in identifying patient subset that would benefit from immunotherapy. 44, 47, 48 cluster of differentiation 45 (cd45) regulates lymphocyte survival, cytokine responses, and tcr signaling; altered cd45 could result in severe combined immunodeficiency. 44, 49 cluster of differentiation 96 (cd96) inhibits function of cd8+ t cells; regulates nk cell effector function and cellular metastasis. 44, 50 c-c motif chemokine ligand 5 (ccl5) promotes angiogenesis and metastasis; increases drug resistance; promotes self-renewal of pca cells. 44, 51 c-x-c motif chemokine ligand 9 (cxcl9) inhibits cytokine secretion from t cells; promotes pca progression. 44, 52 c-x-c motif chemokine ligand 10 (cxcl10) increase infiltration of pre-adipocytes and tams in pca tme; promotes migration and invasion of pca cells. 44, 53 c-x-c motif chemokine ligand 11 (cxcl11) promotes pca cell migration and invasion. 44, 54 signal transducer and activator of transcription 1 (stat1) tumor suppressor in early pca stages; promotes drug resistance. 44, 55 indoleamine 2,3dioxygenase 1(ido1) mediates immunosuppression; associated with significantly worse clinical outcomes. 44,56 matrix metallopeptidase 9 (mmp9) promotes angiogenesis. 18, 57 autocrine motility factor receptor (amfr) mediates amf-mediated cell migration and metastasis. 18, 58 taken together, the tme in pca exhibits an immunosuppressive microenvironment and manifests a unique immune repertoire in aa population characterized by increased inflammatory mediators and significant enrichment of proinflammatory immune pathways creating a tumor supportive environment that negatively associates with disease outcomes. however, a study also indicates that there is no significant association between inflammatory infiltrate and inflammation and the difference in pca incidence and outcomes in different racial groups [59, 60].therefore, more studies are needed to draw a conclusion regarding www.companyofscientists.com/index.php/chd e8 cancer health disparities research contribution of immune microenvironment to pca associated racial disparity. 2.3. endothelial cells in addition to the fibroblasts and immune cells, endothelial cells form a major cellular component of the tme. endothelial cells form new blood vessels from existing vasculature by a process termed angiogenesis to meet the nutrient and oxygen requirements of the rapidly dividing cancer cells. additionally, these cells by forming neovessels provide routes for dissemination of cancer cells to other parts of the body [61-67]. in order to propagate and form new blood vessels the endothelial cells in tme respond to growth factors secreted by cancer cells and cells in tme including endothelial cells themselves , such as vascular endothelial growth factor (vegf) and fibroblast growth factor (fgf). pca, like other solid tumors depends on angiogenesis and overexpression of proangiogenic factors like vegf and fgf have been shown to be associated with poor pca prognosis [65, 68-71]. vegf is the most prominent cytokine regulating the process of angiogenesis [65, 70, 72, 73 ]. in pca, the expressions of vegf and/or its receptor vegfr-2 are directly correlated to tumor gleason grade, metastatic potential, and progression-free survival (pfs). in aa pca tme increased vegf secretion by fibroblasts may impact tumor angiogenesis [71]. microvessel density (mvd) a surrogate marker assessing angiogenic response in tissues has been shown be higher in pca tissues collected from aa patients compared to patients with ca background. [2, 19]. these differences in expression of angiogenic factors and angiogenic response observed between pca of aa and ca men could differentially influence pca growth, metastasis and clinical outcomes in these two populations. 3.0. clinical implications of the racially different tumor microenvironment composition in prostate cancer tme in pca patients with different racial backgrounds show prominent genetic variability which influences their ability to synthesize, secrete and, respond to growth factors which results in differential growth, progression and therapeutic responses [2, 17, 19, 20, 24]. with the differences observed in tme, it is more likely that aa pca patients may respond differently to different therapeutic strategies. recent evidence indicates that even though immunotherapy has not been very successful in pca, aa patients might benefit from it due to the differences in the immune landscape. in the proceed (nct01306890) trial for receiving immunotherapy with sipuleucel-t for metastatic castration resistant prostate cancer (mcrpc), aa pca patients showed a higher survival advantage than ca pca patients [74]. in the psamatched set, median overall survival (os) for aa patients was 35.3 and that for ca patients was 25.8 months and in the all patient set, os of aa patients was 35.2 monthsas compared to 29.9 months for ca patients. mcrpc aa patients with lower baseline psa showed even longer os of over 4.5 years compared to 2.8 years for ca patients. the better response to immunotherapy shown by aa pca patients proves the differences in immune response in aa and ca pca patients [35]. aa pca patients have been predicted to have higher response score to dna damage and alkylating agent-based chemotherapy whereas ca pca has a higher response score to microtubule-based chemotherapy [44]. other studies have reported that the regular use of aspirin can significantly reduce both the risk of developing metastatic pca and disease recurrence in aam [75, 76] by targeting the pro-inflammatory cyclooxygenase/ thromboxane a2 pathway [77]. evidence also suggests reduced mortality due to pca in aam www.companyofscientists.com/index.php/chd e9 cancer health disparities research using aspirin [78].furthermore, tme facilitates therapeutic resistance by modification of stromal components to promote invasion, angiogenesis, and metastases. patient response to therapy depends strongly on activation of tumor stroma. the presence of myofibroblasts, that show higher expressions in aa patients than ca patients, predicts biochemical recurrence in pca patients [79]. cafs were also shown to induce chemoresistance through induction of emt [80]. interaction of tams and cancer stem cells (cscs) can result in resistance to adt therapy. cscs help in tam remodeling and tams promote the stemlike properties of cscs and drug resistance by acting through the il-6/stat3 signaling pathway [81]. 4.0. conclusion and future perspective the tme is a key contributor to pca progression and determinant of clinical outcomes. the stromal cells and the extracellular milieu of the tme regulate the plasticity of the phenotypic traits of pca cells. the interaction between pca cells and surrounding tme components (immune, vascular, and stromal) are therefore being studied extensively to understand its broader role in pathobiology and disease outcomes [2, 17, 19, 20, 24] using traditional in vitro and in vivo experiments and recently by fluorescence-activated cell sorting or laser microdissection with rna sequencing and spatial transcriptomics [82, 83, 84]. the recent technique of multiplex immunofluorescence (mif) with tyramide signal amplification helps to gather maximum information from a single tissue section with accurate classification of the tme cell population [85]. use of single-cell rna transcriptome sequencing (scrna-seq) can indicate the cell heterogeneity and help to analyze cellular interactions [82]. the use of these techniques will further help to identify the role of the modulated genes in individual tme components of aa and ca pca. data related to the role of tme in race-associated cancer health disparity has only recently begun to emerge in prostate and other cancers. further studies involving larger datasets from diverse patient populations would provide more strengths to tme differences and their association with clinical outcomes and clinicopathologic progression of cancer. similarly, more efforts should also be made to determine the exact contribution of tme to differential pca progression using appropriate experimental models and delineate the underlying molecular mechanisms. unlike the cancer cells, cells of the tme are genetically stable, which make them attractive targets for cancer management (prevention and treatment) and to reduce the risk of acquiring therapy resistance leading to treatment failure and recurrence. a better understanding of the role of the tme will also help in the development of race-specific biomarkers and therapeutic targets leading to personalized approaches for risk prediction, diagnosis, monitoring, and management of pca. acknowledgments authors are supported by funding from nih/nci (r01ca231925 to ss) and usa health mitchell cancer institute, university of south alabama. conflicts of interest the authors declare that they have no conflicts of interest with the contents of this article. authors’ contributions conception and design: dc. initial manuscript writing: sg, cs, and dc. review and revision of the manuscript: sg, cs, ss, aps and dc. www.companyofscientists.com/index.php/chd e10 cancer health disparities research references 1. siegel, r.l., miller, k.d., fuchs, h.e., and jemal, a. 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(2021). multiplex immunofluorescence tyramide signal amplification for immune cell profiling of paraffin-embedded tumor tissues. frontiers in molecular biosciences, 8, 667067. https://doi.org/10.3389/fmolb.2021.667067 https://doi.org/10.1158/1055-9965.epi-19-0792 https://doi.org/10.3390/ijms23063042 https://doi.org/10.1186/s12885-021-08529-6 https://doi.org/10.1186/s12885-021-08529-6 https://doi.org/10.18632/oncotarget.17893 https://doi.org/10.3389/fmolb.2021.667067 1.0. introduction 2.0. prostate cancer microenvironment 2.1. fibroblasts 2.2. immune cells 2.3. endothelial cells 3.0. clinical implications of the racially different tumor microenvironment composition in prostate cancer 4.0. conclusion and future perspective acknowledgments conflicts of interest authors’ contributions www.companyofscientists.com/index.php/chd e1 cancer health disparities research spatial analysis of clinical trial accrual within an nci comprehensive cancer center catchment area by race and ethnicity daniel holguin stanford university, 1206 whitton ave, san jose, ca 95116 *corresponding author: daniel holguin, dholguin@stanford.edu abstract accrual into cancer clinical trials is concerningly low, approximately 5% of all u.s. adult cancer patients enroll into a trial, and racial/ethnic disparities in clinical trial accrual between white and minority patients, (i.e., native american, latino, asian, and black) are well documented 1-5. this paper uses geographic information system (gis) spatial analysis to identify racial and ethnic disparities in clinical trial accrual within the stanford cancer institute (sci) comprehensive cancer centers (ccc) catchment area between 2012-2020 and compares drive times to the sci by ethnicity overall and within each county it serves. 215 studies in the adult gastrointestinal oncology clinic trials department were reviewed to collect patient data on race and ethnicity, zip code at registration, and the type of trial they enrolled in. arcgis was used to plot ethnicity and zip code, and to calculate drive times to the clinical trial site in palo alto within the 10county catchment area. 848 patients were available for analysis. the ethnicities of our trial patients were 61% white (n=514), 25% asian/pacific islander (n=210), 13% latino (n=107), 2% black (n=14), and <1% native american (n=3). most patients enrolled into non-interventional studies (54.83%), followed by treatment trials (33.13%) and non-therapeutic trials (12%). latino patients had the longest drive on average (mean maximum drive time of 67 minutes) and minority patients faced longer drive times than white patients in 8/10 counties in the catchment area. this analysis showed racial disparities in clinical trial accrual at the sci ccc as well as disparities in drive times to the clinical trial site. counties closest to the sci had minority patient accrual approximately equal to that of the general population and higher accrual in general compared to counties further away, suggesting the need for additional clinical trial sites within the catchment area. keywords: cancer clinical trial accrual, health disparity, race/ethnicity, nci, comprehensive cancer center, catchment area, spatial analysis, drive time, san francisco citation: holguin d (2022) spatial analysis of clinical trial accrual within an nci comprehensive cancer center catchment area by race and ethnicity. cancer health disparities 6:e1-10.doi:10.9777/chd.2022.1002 mailto:dholguin@stanford.edu www.companyofscientists.com/index.php/chd e2 cancer health disparities research www.companyofscientists.com/index.php/chd e3 cancer health disparities research introduction accrual into cancer clinical trials is concerningly low, approximately 5% of all u.s. adult cancer patients enroll into a trial and approximately 40% of national cancer institute (nci) trials fail to attain their minimum accrual goals(hamel et al., 2016). since the 1970’s, studies have documented racial and ethnic disparities in clinical trial accrual between white and minority patients, (i.e., native american, latino, asian, and black)(duma et al., 2018; loree et al., 2019; nazha et al., 2019; siegel et al., 2020) despite other studies reporting that minorities are just as interested in engaging in cancer clinical trials as whites(katz et al., 2007), especially when controlling for previous knowledge of trials(durant et al., 2011). in addition to disparities in accrual, there are also significant ethnic disparities in incidence and mortality rates of various cancers(axtell and myers, 1978; cancer prevention institute of california and greater bay area cancer registry, 2018; zahnd et al., 2021). increasing clinical trial accrual overall and achieving health equity among different ethnicities as outlined by the american society of clinical oncology (asco)(patel et al., 2020; winkfield et al., 2021) will undoubtedly require an increase of minority enrollment in clinical trials. racial segregation is one mechanism of systemic racism theory(feagin, 2006) that has propagated various health disparities in the u.s., yet no studies have addressed its’ role on cancer clinical trial accrual(kanarek et al., 2010). segregation creates health disparities by excluding minority patients from communal resources limited to wealthy (mostly white) neighborhoods – including housing, schools, and hospitals(coleman, 1992; cornely, 1956; firebaugh and acciai, 2016; jha et al., 2011; national academies of sciences, engineering, and medicine et al., 2017; rothstein, 2017) – and forcing them to live in areas with increased environmental and social risk factors linked to worse health outcomes, such as pollution, food desserts, lack of mental health resources, and crime, in order to maintain access to jobs in those areas(alexander, 2012; cheng et al., 2020; chhatre and jayadevappa, 2018; hilmers et al., 2012; krieger et al., 2020; mcguire and miranda, 2008; mcguire et al., 2006; nardone et al., 2020; new york law school racial justice project., 2012; williams and mohammed, 2013). racial segregation reflects the root cause of other factors associated with barriers to cancer clinical trials for minority patients(hamel et al., 2016) by means of the disinvestment in their communities and the devaluation of their lives. though most nci comprehensive cancer centers (ccc) are in metropolitan areas where much of the patient population is white,(onega et al., 2017) the association between ethnically segregated areas and proximity to treatment centers is confounded by covariates such as inadequate community engagement and attitudes towards clinical trials, as well as the availability of trials in hospitals that serve patients with similar socioeconomic factors such as low-income and public health insurance(mccaskillstevens et al., 2005; sutton et al., 2019; wenzel et al., 2015). for example, the sidney kimmel ccc in baltimore performed a spatial analysis of their catchment area and found that even though minorities constituted a majority of the ethnic demographic in that area, white patients that lived outside of baltimore city in wealthy suburbs made up a majority of their clinical trial patients(kanarek et al., 2010). on a national level, research suggests that the effects of segregation on clinical trial accrual may be more significant in other ccc catchment areas. two decade after the national institute of health’s (nih) revitalization act of 1993(institute of medicine, 1994), which mandated the enrollment of women and minority race patients in nih-funded research, approximately 2% of trials www.companyofscientists.com/index.php/chd e4 cancer health disparities research have enrolled enough minority patients to meet the goals outlined by the act(chen et al., 2014). racial segregation in the stanford cancer institute (sci) catchment area (i.e., the san francisco bay area) began with the state-sanctioned genocide of native american tribes from the 17th to 19th centuries – the native american population in the bay area today is <1%(madley, 2016). in the 20th century, discriminatory real estate practices only approved home loans for racial and ethnic minorities in less desirable neighborhoods within big cities like the mission district in san francisco, or adjacent to wealthy suburbs, like palo alto and east palo alto(rothstein, 2017). the only clinical trial sites for bay area patients are in wealthy neighborhoods in the peninsula, at ucsf and stanford (i.e., west bay). this paper analyzes gastrointestinal cancer clinical trial patient accrual at the stanford cancer institute (sci) between 20122020 by ethnicity and trial type and compares drive times to the sci between patients of different ethnicities. it hypothesizes that the location of the sci contributes to racial disparities in clinical trial accrual within its’ catchment area (as designated by the nci) by requiring minority patients in historically segregated communities to travel to the clinical trial site to receive treatment on trial. methods this cohort is derived of adult gastrointestinal (gi) oncology patients (i.e., colorectal, pancreatic, hepatic, bile duct, gastric, and esophageal) that enrolled in a clinical trial at the sci between 2012 to 2020. data was made available through internal review and verified through oncore (forte research systems, madison, wi). 215 studies were reviewed for demographic data – i.e., self-reported race, ethnicity, and zip code at time of enrollment (u.s. patients only) – and study type – therapeutic, non-therapeutic, and non-interventional (i.e., observational). only patients with self-reported race and ethnicity were included in the final analysis. under california state law, health insurers are required to cover routine or standard of care costs for all clinical trial patients, so the type of insurance a patient had (private, public, or uninsured) was not considered a relevant factor in deciding to enroll. geographic analysis was limited to the sci catchment area as designated by the nci. the 10 counties served by the sci are alameda, contra costa, merced, monterrey, san benito, san joaquin, san mateo, santa clara, santa cruz, and stanislaus counties. san francisco and the counties north of the golden gate bridge are served by the ucsf cancer center and are not addressed in this analysis. though patients from all over the world come to the sci for cancer clinical trials, these patients were not appropriate for this analysis. arcgis pro by esri® was used to plot patients within our catchment area and generate descriptive statistics. patients were plotted using their zip code at the time of enrollment. the ethnicity field of the patient was layer was joined to the sci catchment area polygon using the spatial join tool. the summarize within tool was then used to generate the proportion of patient ethnicities by county. the location of the sci in palo alto was geocoded to derive drive times to the clinical trial site. drive times to the sci were calculated by ethnicity overall and by county using the network analysis service area tool. polygons with a radius of x minimum and maximum drive time to the sci were used to compare drive times among patients by ethnicity. the minimum and maximum cutoff times chosen for this calculation are 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 110, 120, 140, 160, and 180 minutes, based on expected drive times to the sci without traffic. https://www.advarra.com/about-advarra/ https://www.advarra.com/about-advarra/ www.companyofscientists.com/index.php/chd e5 cancer health disparities research results 848 patients were available for analysis. overall, 61% of patients were white, 25% asian and pacific islander (aapi), 13% latino, 2% black, and <1% native american (table 1). most patients enrolled into non-interventional studies (54.83%), followed by treatment trials (33.13%) and non-therapeutic trials (12%). white patients were the most represented in each trial type. table 1. gi clinical trial patients by ethnicity and trial type. ethnicities total therapeutic trials non-therapeutic non-interventional white 514 176 64 274 black 14 3 1 10 aapi 210 66 26 118 latino 107 36 10 61 native american 3 0 1 2 total 848 281 102 465 the approximate location of trial patients within the sci’s catchment area are plotted in figure 1. the breakdown of trial patient ethnicity by county within the catchment area was 44% white, 41% asian, 11% latino, and 4% black in alameda. 62% white, 19% latino, 16% asian, and 3% black in contra costa. 63% white, 31% latinos, and 6% asian in merced. 49% latino and white, and 3% asian in monterrey. 67% white and 33% latino in san benito. 73% white, 14% black, 9% asian, and 5% latino in san joaquin. 65% white, 23% asian, 11% latino, and 1% native in san mateo. 49% white, 40% asian, 9% latino, 2% black, and <1% native in santa clara. 89% white, 8% latino, and 3% asian in santa cruz. and 77% white, 23% latino in stanislaus (table 2). figure 1. www.companyofscientists.com/index.php/chd e6 cancer health disparities research table 2. comparison of trial patients’ ethnicity, and drive time to the cancer center by county. ethnicities alameda contra costa merced monterrey san benito san joaquin san mateo santa clara santa cruz stanislaus white 33 23 10 17 6 16 51 121 34 10 black 3 1 0 0 0 3 0 4 0 0 aapi 31 6 1 1 0 2 18 99 1 0 latino 8 7 5 17 3 1 9 21 3 3 native american 0 0 0 0 0 0 1 1 0 0 total 75 37 16 35 9 22 79 246 38 13 average minimum/maximum drive times to the sci (minutes) white 41/47 68/78 125/144 89/100 70/80 96/107 16/21 26/31 55/65 117/134 black 43/52 90/100 0/0 0/0 0/0 93/103 0/0 20/25 0/0 0/0 aapi 35/40 60/70 140/160 80/90 0/0 90/100 17/22 26/31 70/80 0/0 latino 31/36 76/67 134/152 85/95 70/80 100/110 26/31 26/31 63/73 110/123 native american 0/0 0/0 0/0 0/0 0/0 0/0 25/30 30/35 0/0 0/0 overall, latino patients had the longest drive on average (mean max drive time of 67 minutes), while the means for black, white, asian, and native patients were 60, 53, 36, and 33 minutes, respectively. in alameda and contra costa counties, black patients faced the longest commutes to the sci of all ethnicities, 52 and 100 minutes, respectively (table 2). aapi patients had the longest commutes in merced and santa cruz counties (160min. and 80min). latino patients had the longest commutes in san joaquin and san mateo counties. white patients had the longest commutes in monterrey and stanislaus counties. one patient identifying as native american in santa clara county had the longest commute of all ethnicities. discussion this report demonstrated racial disparities in clinical trial accrual at the sci ccc using a cohort of adult gastrointestinal cancer patients. spatial analysis showed that the counties closest to the sci had the highest accrual (santa clara and san mateo) and there was an inverse relationship between distance the sci and patient accrual overall. in santa clara and san mateo counties, the racial and ethnic demographics of trial patients was approximately equal to the racial and ethnic makeup of the general population. for example, approximately 2% of trial patients from santa clara county were black compared to 3% in the general population, but the proportion of black patients from alameda county was much less than expected, approximately 4% compared to 11% in general(u.s census bureau quickfacts, 2020). drive time analysis suggested that accrual could be increased if trials were offered at satellite sites in counties further away, and minority accrual would reflect the demographics of the counties in general, as is the case for santa clara county. www.companyofscientists.com/index.php/chd e7 cancer health disparities research limitations to this study include a lack of demographic information on the cohort, studies have shown that variables such as sex (male/female, non-binary), cancer type, stage at diagnosis, socioeconomic status, type of insurance, and the patients’ referring hospital, are also associated with low minority patient accrual in clinical trials(awidi and al hadidi, 2021; krieger et al., 2020). these missing variables are partially due to deficiencies in the data collection processes at the sci as well as the migration of data between the electronic medical record system and research databases. demographic and sociological variables tend to be overlooked in cancer clinical trials research, one study found that 7.8% of trials leading to fda oncology drug approvals between 2008-2018 reported the main race and ethnicity categories used in the united states(loree et al., 2019). limitations of the spatial analysis are the use of patient zip codes rather than exact addresses’, and the exclusion of patients outside the sci catchment area. excluding non-catchment area patients from the analysis was justified to determine where a future clinical trial site would make the most impact on minority patient accrual. the calculated drive times assumed no traffic though this is rarely the case, and it also does not take into consideration the fact that east bay patients face tolls that patients from most other counties in the catchment area do not. though this report lacked the quantitative analysis to conclude that historical segregation played a role in minority patient trial enrollment patterns within the sci catchment area, it did show ethnic disparities in accrual and drive times to trials within different counties. in the past decade the nci mandated all ccc’s applying for p30 support grants to address racial disparities in their catchment area and increase community outreach and engagement (coe), leading to two approaches to increase minority patient enrollment. one approach is to invest resources into transportation programs that reduce out-of-pocket costs for low-income patients in underserved areas. for example, massachusetts general hospital (mgh) and the lazarex cancer foundation started a patient navigation and slidingscale reimbursement program in 2013 which funds all transportation and lodging costs for clinical trial patients, but saw no increase in minority patient enrollment in the first two years(nipp et al., 2016). similarly, the sci implemented a shuttle program to palo alto for clinical trial patients in east bay, though this paper suggests these efforts were also met with limited results. the other approach, used by the nci’s community oncology research program (ncorp) and several cccs, has been to invest in new clinical trial sites within underserved minority and rural communities through partnerships with local healthcare providers. in 2014, ncorp tested whether community-based hospitals with little to no clinical research experience could develop and sustain clinical trial programs with guidance from a local, larger ccc(wong et al., 2014). 3 of 6 hospitals received 10 years of funding through nih u56 and u54 grants, increased their yearly patient accrual by ~60% to nci cooperative group trials, required approximately a year into their implementation phase to fully open their programs, and all were able to recruit principal investigators to help sustain their new programs. though the trials offered to patients were limited in comparison to their mentor site, the study showed that investing resources in underserved communities is feasible and translates to a significant increase in clinical trial accrual. regardless of the approach used, studies show that coe and staff cultural sensitivity training is pivotal to making underserved communities aware of clinical trial resources in their area and overcoming explicit and “implicit” racial biases that perpetuate feelings of mistrust by minority patients and create barriers to enrollment. for example, the georgetown ccc increased enrollment of black www.companyofscientists.com/index.php/chd e8 cancer health disparities research patients to non-therapeutic clinical trials by 62% at two community sites in underserved areas by implementing staff cultural competence training at those sites(wallington et al., 2016). in “systemic racism and u.s. healthcare,”(feagin and bennefield, 2014) feagin and bennefield demonstrate that the degree to which a healthcare provider identifies with these biases positively correlates with preferential treatment of white patients and poor treatment of minority patients. one study among a group of healthcare professionals showed that people of color are seen as “less promising” candidates for trials, and in some cases, not considered for studies they may be eligible for(niranjan et al., 2020). though some studies report that black and other minority race patients are just as willing to enroll in clinical trials as whites when access and awareness are equivalent,(durant et al., 2011, 2014) other patients are still skeptical due to past crimes against uninformed patients (e.g., the tuskegee syphilis study(katz et al., 2007)). to overcome this barrier, the abramson cancer center formed partnerships with faith-based organizations and community health centers and achieved black patient accrual representative of the percentage of black cancer patients among all cancer cases in the catchment area over 5 years(guerra et al., 2021). cccs looking to increase minority patient accrual to clinical trials should begin by taking an honest look at accrual statistics within their catchment area and invest resources in the underserved areas that often lack clinical trials nearby, or are simply unaware of them. acknowledgement i would like to acknowledge dr. george a. fisher, susan segar, and the stanford gi oncology research team for their support and encouragement of this project. i would also like to acknowledge madeline comer for directing me towards relavent literature. conflicts of interest the authors declare no conflict of interest. authors' contributions the data review, literature search, manuscript development, and data analysis were done 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(2014). national cancer institute’s cancer disparities research partnership program: experience and lessons learned. front. oncol. 0. zahnd, w.e., gomez, s.l., steck, s.e., brown, m.j., ganai, s., zhang, j., adams, s.a., berger, f.g., and eberth, j.m. (2021). rural-urban and racial/ethnic trends and disparities in early-onset and average-onset colorectal cancer. cancer 127, 239–248. u.s. census bureau quickfacts: santa clara county, california; alameda county, california; san francisco county, california. institute of medicine (us) committee on ethical and legal issues relating to the inclusion of women in clinical, mastroianni, a.c., faden, r., and federman, d. (1994). nih revitalization act of 1993 public law 103-43 (national academies press (us)). introduction methods results discussion acknowledgement conflicts of interest authors' contributions www.companyofscientists.com/index.php/chd e1 cancer health disparities research lack of disparities studies related to pharmacogenomics satyajit patra1, shivani modi2,. 1american international medical university, saint lucia. 2keck graduate institute, claremont, ca 91711 *corresponding author: satyajit patra, satyajitpatra@gmail.com abstract based on personal polymorphism and algorithmic interpretation, pharmacogenomics interventions in healthcare are chosen, directing pharmacotherapies in patients. as a part of precision medicine, pharmacogenomics offers a unique chance to set the bar for treating patients as particular individuals with specific needs. like with any intervention, the benefitthe to-risk ratio needs to be considered. information gaps and people’s lack of knowledge of pharmacogenomics will always be problems, as will their unfamiliarity with the subject. as there are more genes, there are more potential diseases and environmental factors that could mask the impact of genes. as a result, multigene models in vast populations must always be considered for research. there aren’t many studies that look at how pharmacogenomics affects health disparities. additional research is needed to assess health differences between ethnic groups and nations and within a single country. keywords: disparities; efficacy; equity; genetics; pharmacogenomics. citation: patra s et al (2023) lack of disparities studies related to pharmacogenomics. cancer health disparities 7:e1-3. doi:10.9777/chd.2023.1002 introduction pharmacogenomics is known to investigate the influence of genetic factors on the human body’s response to drugs. pharmacogenomic technology redirects drug development towards improving the security and effectiveness of patient care. specifically formulated drugs that address a variety of medical diseases, such as asthma, cancer, alzheimer’s disease, and cardiovascular disease, are made using pharmacogenomics. it is an authentic example of precision medicine at work. however, considering the lack of genome-wide arrays in most clinical pharmacogenetic labs limits the ability to infer the patient’s genetic history. racial variations in humans and their genetic origins may have resulted from the extensive movement and interaction of human populations. despite significant advances in the capacity of genetic technologies and enhancing disease management, using genomic data to alleviate health disparities in marginalized people still requires a lot of research and development. the ongoing gwas(genome-wide association study) analyses highlight the growing problem of genetic variation and the danger of leaving out population-specific snps, which are essential for ensuring that precision medicine is accessible to all people. even though these pharmacogenomic www.companyofscientists.com/index.php/chd e2 cancer health disparities research relevant markers have improved our understanding of the underlying mechanisms underlying drug treatments, they are common in patients of one ancestry. they do not always replicate in other populations due to differences in allelic frequency, linkage disequilibrium (ld), and confounding environmental factors. this additional source of variation may affect how strongly snps are connected with the intended characteristic because ancestry varies in admixed groups. for example, mexican americans are among those of mexican descent who live in the us. there may be significant differences in ancestry among mexican americans based on their ancestral origins and geographic locations within central america, depending on their ancestors’ migration from european countries to mexico, their ancestors’ indigenous origins in mexico, or a combination of the aforementioned geographical areas (martin et al., 2017; zhang et al., 2019). numerous populations, more importantly from a diverse group, must be included in genomic studies to evaluate the accuracy and broader applicability of findings that can help us comprehend the genetic variation in complex traits. cost-effectiveness has caused a lack of clinical practice, which may have hindered research on the effects of pharmacogenomics on healthcare inequities (davies, 2006; plumpton et al., 2016). adverse drug responses (adrs) brought on by genetic variations in the population are a common and severe public health hazard since they can potentially exacerbate patient conditions and increase the cost burden on healthcare systems. for example, amlodipine accumulates within cells in the abcb1 gene. polymorphisms impact amlodipine’s pharmacokinetics in this transporter and gender differences affect how this gene is expressed. the authors of the study claim that men with abcb1 gene variants require higher amlodipine concentrations than women. there is no correlation between the frequency of variance and its effect on the efficiency of amlodipine because there are so few studies on the predicted gene’s function (johnson et al., 2019). the challenges with access, availability, ability to pay privately, and comprehension of medical information are also the primary hurdle for uniform application in various populations. when introducing ground-breaking technologies in healthcare services, many factors could impair resilience over the long run and affect long-term effectiveness. the availability of funds and allocation among these criteria are essential because they can establish priorities and direct the course of technological advancement, aspects that impact a particular technology’s long-term viability and success and, consequently, its resilience. for instance, if funding for pharmaceutical research and development is inadequate, it may be harder to discover novel therapies that can better address public health needs. in less affluent areas compared to more educated and rich ones, new treatments or tests may also be embraced more slowly and in lower numbers. one of the many reasons behind the failure to include diverse populations in genomic studies is that a person’s level of personal risk awareness, scheduling difficulties brought on by time constraints, sociodemographic traits, and psychosocial issues can all make receiving medical care more difficult. as a result, it is vital to support proactive measures to reduce and eliminate inequities brought on by these factors (olivier and williams-jones, 2011). to guarantee that the potential advantages of research are fully realized, deliberate choices should be taken to permit participation across sociodemographic categories throughout the development process. there is ambiguity regarding what the difference between disparity and race means to health and www.companyofscientists.com/index.php/chd e3 cancer health disparities research disease when it comes to an understanding of how race has been defined to eliminate health inequities. the institute of medicine’s report on health disparities emphasizes that race significantly impacts health status and that many of these variances are environmental and associated with racial identity in the united states. there is currently a lack of knowledge regarding the significance of nativity, length of stay with other immigrants, and acculturation factors in illness risk. it is acknowledged that migration and acculturation impact migrant communities’ risk in disparity in the west. combining it with dietary and lifestyle modifications brought on by immigration. the fda should require companies and researchers that relate racial variations in drug response to conduct additional research that clarifies the underlying causes. research data used to make racialized conclusions should at the very least be made publicly available to let other researchers investigate further the theoretical foundations of findings of difference among groups. the need for coordinated efforts to ensure that underprivileged and poor individuals in the future would also have access to medical developments is widely acknowledged. in subsequent pharmacogenomics studies, equity assessments should be employed to fill the information gap. to make the distribution of advantages in the future as nearly equal as possible, a system of compensations (in the form of healthcare services) is in place for pharmacogenomic orphans. the list of limits may expand if further ethical issues caused by pharmacogenomics are taken into account; until now, only one has been addressed. acknowledgment none conflicts of interest the authors declare no competing interests. authors’ contributions sp and sm contributed equally to draft, review and revise the paper. references davies, s.m. (2006). pharmacogenetics, pharmacogenomics and personalized medicine: are we there yet? hematology american society of hematology education program, 111-117. johnson, r., dludla, p., mabhida, s., benjeddou, m., louw, j., and february, f. (2019). pharmacogenomics of amlodipine and hydrochlorothiazide therapy and the quest for improved control of hypertension: a mini review. heart failure reviews 24, 343-357. martin, a., downing, j., maden, m., fleeman, n., alfirevic, a., haycox, a., and pirmohamed, m. (2017). an assessment of the impact of pharmacogenomics on health disparities: a systematic literature review. pharmacogenomics 18, 1541-1550. olivier, c., and williams-jones, b. (2011). pharmacogenomic technologies: a necessary "luxury" for better global public health? globalization and health 7, 30. plumpton, c.o., roberts, d., pirmohamed, m., and hughes, d.a. (2016). a systematic review of economic evaluations of pharmacogenetic testing for prevention of adverse drug reactions. pharmacoeconomics 34, 771-793. zhang, h., de, t., zhong, y., and perera, m.a. (2019). the advantages and challenges of diversity in pharmacogenomics: can minority populations bring us closer to implementation? clinical pharmacology and therapeutics 106, 338-349. introduction acknowledgment conflicts of interest authors’ contributions www.companyofscientists.com/index.php/chd e1 cancer health disparities research racial disparities in expression of gdf15 and nfκb in prostate cancer and benign prostatic epithelium kenneth a iczkowski1, oleksandr kravtsov1, sudha sadasivan2, watchareepohn palangmonthip1,3, yalei chen2, m scott lucia4, james r lambert4, kathleen c torkko4, benjamin a rybicki2 1department of pathology, medical college of wisconsin, pathology, milwaukee, wi, united states, 2department of public health sciences, henry ford health system, detroit, mi, united states, 3department of pathology, faculty of medicine, chiang mai university, chiang mai, thailand, and 4university of colorado, aurora, co, united states *corresponding author: kenneth a. iczkowski, e-mail: kaiczkowski@mcw.edu abstract: prostate cancer (pc) outcomes are more adverse for african-american (aa) than white/european american (ea) men. growth differentiation factor 15 (gdf15, pdf, nag-1) is a stressinduced anti-inflammatory cytokine with immunosuppressive and tumor growth-promoting functions. gdf15 inversely regulates nfκb, a transcription factor enabling pro-inflammatory gene expression and becomes constitutively activated in androgen-independent pc. tissue microarrays (tmas), prepared from prostatectomy tissue at three institutions, comprised 688 cases (364 ea and 324 aa). each case included ≥3 tumor punches plus ≥3 non-neoplastic punches. tmas were stained separately for gdf15 and nfκb and evaluated by two pathologists, using the 0-3+ scale. pc, compared to benign epithelium, had elevated median gdf15 expression (1.93 vs. 0.99) and also, nfκb (1.18 vs. 0.96, both p<0.0001). only in aa men did pc show gradewise or stagewise altered expression of these markers. in aa men, gdf15 expression fell as stage rose in pc (p=0.007) and also in benign epithelium (p =0.003). in ea men, gdf15 expression in benign epithelium fell as stage (p=0.01) and grade (p=0.01) rose. nfκb expression was higher in aa than ea men only in high-grade pc (p =0.01). nfκb expression rose with increasing tumor grade only in aa men (p =0.027) and in the benign prostate component only in ea men (p=0.007). benign and tumor nfκb expression did not vary with stage. pc showed significant alterations in gdf15 and nfκb expression in accord with cancer aggressiveness in aa men only: stagewise decrease in gdf15, and gradewide increase in nfκb. findings suggest a racial disparity in cell growth, immune response, stress response, or other functions relevant to prostate carcinogenesis. keywords: racial disparity, prostate cancer, gdf15, nfκb. citation: iczkowski1 et al (2021) racial disparities in expression of gdf15 and nfκb in prostate cancer and benign prostatic epithelium. cancer health disparities. 5:e1-e22. doi:10.9777/chd.2020.1010 mailto:kaiczkowski@mcw.edu www.companyofscientists.com/index.php/chd e2 cancer health disparities research introduction african-american (aa) men generally have worse prostate cancer (pc) outcomes than white/european american (ea) men or other races. the role of chronic inflammation in development of prostate cancer is well documented (puhr et al., 2016). lymphocytic infiltration is normal in the prostate (bostwick et al., 2003), but whether there are racial differences in the level of prostatic inflammation is unclear. immune response-associated gene expression differs between aa and ea prostate cancers (wallace et al., 2008); and some studies have found chronic inflammation to be more frequent in aa men (eastham et al., 1998) while others have noted no difference (bostwick et al., 2003; vidal et al., 2016) although the studies reporting no difference did not distinguish types of inflammatory cells and digital quantification was not used. observed differences were not accounted for by race-related differences in patients' age, serum testosterone level, or prostate volume (eastham et al., 1998). although many studies have shown that interaction of inflammatory cytokines with inflammatory pathways greatly influence prostate cancer risk, the role of some cytokines such as growth differentiation factor 15 (gdf15) in prostate cancer is ambiguous (vaňhara et al., 2012). gdf15, also called prostate-derived factor or pdf, nag-1, or mic-1, is a stress-induced anti-inflammatory cytokine possessing immunomodulatory functions. it is known to interact with nuclear factor of kappa b (nfκb) which regulates genes involved in cellular proliferation, apoptosis, migration and angiogenesis (bennett et al., 2018). gdf15 is known to have both pro-tumorigenic and tumorsuppressing functions. gdf15 is a divergent member of the tgf-β and bone morphogenic protein family. it directly induces p53, and its high expression is associated with progression of several cancers, including pc (iczkowski and pantazis, 2003). gdf15 was found to be upregulated in situ and in primary cultures of cancerassociated fibroblasts from prostate cancer. ectopic expression of gdf15 in fibroblasts produced prominent paracrine effects on pc cell migration, invasion, and tumor growth (bruzzese et al., 2014) and the same effects were noted in cervical cancer (li et al., 2018). consistent with an anti-inflammatory role, inflammatory lesions in the prostate correlated with decreased prostatic gdf15 expression (lambert et al., 2015). moreover, an inverse correlation was demonstrated between gdf15 and cd3+, cd4+, cd8+, cd68+, and inos (no synthase)+ leukocytes (bennett et al., 2018); and gdf15 exerts immunosuppressive effects (zhang et al., 2018). nuclear factor kappa-light-chain-enhancer of activated b cells, nfκb is a transcription factor (also called p65(rela)) that regulates pro-inflammatory gene expression and is constitutively activated in androgen-independent prostate cancer, increasing anti-apoptotic bcl-2 and angiogenesis (jin et al., 2008). gdf15 expression was shown to correlate inversely with inflammatory lesions in the prostate and acts through the pi3k pathway to suppress nfκb activity (lambert et al., 2015); cervical cancer demonstrated this same inverse relationship (li et al., 2018). expression of the nfκb target, interleukin 8 (il-8), was downregulated by gdf15 in pc3 cells (lambert et al., 2015). whether these pro-tumorigenic factors show a racial disparity in pc is uncertain. in this study we examined immunoexpression of gdf15 and nfκb in tissue from african-american and white cancerous and benign prostate. www.companyofscientists.com/index.php/chd e3 cancer health disparities research materials and methods retrospective study in prostatectomy tissue tissue microarrays (tmas), prepared at three different institutions, comprised prostatectomy tissue from 697 cases. each tma contained at least 3 individual 0.6 mm punches of the dominant tumor nodule plus at least 3 punches of non-neoplastic epithelium. sources were medical college of wisconsin (57 cases), prostate cancer biorepository network (pcbn, via johns hopkins) (153 cases), pcbn high-grade racial disparity (120 cases), and henry ford hospital (up to 12 evaluable cores each of tumor and benign, 367 cases). each study set contained an approximate 1:1 match of aa to white cases, based on grade and stage, for a total of 364 ea and 324 aa men. gleason score according to current consensus (epstein et al., 2016) and tumor pathologic stage (pt) were available for all groups; for analysis, grade was expressed according to the 5tier international society of urological pathology (isup) grade group system (epstein et al., 2016). patient ages were available only for the henry ford and medical college of wisconsin cases. the results from two hopkins study sets were combined in all analyses going forward. separate slides were stained with polyclonal antibody to gdf15 or monoclonal antibody to nfκb. slides were dried 30 min at 60°c, then deparaffinized down to deionized water. antigen retrieval was performed on a pt link (dako) by preheating target retrieval solution to 65°c and heating for 20 min at 97°c in ph=6 (dako). slides were washed with buffer for 5 minutes. all ihc staining was performed on the dako autostainer plus (agilent) using the dako envision™ flex high ph detection kit (catalog k8010) with 3 drop zones at 100 µl each and dako protein block (agilent). antibodies used were goat polyclonal antibody to gdf15 (1:150, 20 min incubation, catalog af957, r&d systems, minneapolis) or rabbit monoclonal antibody to nfκb (1:2000, 10 min incubation, clone d14e12, cell signaling technologies, beverly, ma). background was stained with hematoxylin dako flex. slides were rinsed with deionized water and oven dried 15 min. evaluation of immunostaining tma cores of tumor and benign prostatic tissue for each case were evaluated by two pathologists. (digital evaluation of the tmas was not feasible because the frequent admixture of tumor glands and benign glands in many spots required assessment by pathologists. moreover, occasional spots that were sampled as benign were actually cancer and vice versa, and again pathologists’ interpretations were needed to visually dissect out the admixture and evaluate the tumor or benign epithelium separately.) immunoreactivity (figures 1-2) was scored on a scale of 0 (negative) to 3+ (strong and diffuse), including half-steps (0.5). disagreements ≥1 were resolved by consensus. figure 1. example of strong gdf reactivity in cancer. non-neoplastic glands at lower left are negative. 10x objective. www.companyofscientists.com/index.php/chd e4 cancer health disparities research figure 2. example of strong nfκb reactivity in cancer. non-neoplastic glands at lower left are negative. 10x objective. statistical analysis to adjust for potential batch effects from tmas from 3 sites, we first digitally measured the expression of both markers in the benign tissue spots corresponding to gleason grade group 2 tumors from all sites using the qupath software (bankhead et al., 2017). in qupath, the stained color for a marker (brown) is separated from counter stain (blue) using stain vectors autoestimated by the software. percentage of positive expression area (ppea) is determined as the ratio of the number of positive brown stained pixels (brown optical density (od) > 0.2) over total number of tissue pixels (overall od > 0.05). the average expression intensity (aei) is calculated as the mean brown od of positively stained pixels. the log transformed product of ppea and aei, log(ppea*aei), is used as the marker expression level of a subject. under the assumption that the marker expression in benign regions of gleason grade group 2 tumors should be the same across the 3 study sites, the batch correction factor for a study site with respect to the reference henry ford study site was defined as the ratio of median marker expression level for the benign prostate spots evaluated for the study site over median marker expression level of benign prostate spots of the henry ford study site. subsequently, all pathologist-assessed data for each study site were adjusted by dividing original measures over the batch correction factor (the reference henry ford site had a batch correction factor of 1). mean age difference between races was tested by wilcoxon signed rank test. comparisons of expression in pc vs. benign prostate were done by wilcoxon signed rank test. the non-parametric mann-whitney test was used for testing expression differences between two races. kruskal-wallis test was applied for testing expression differences across tumor stages (pt2, pt3a, or pt3b) and gleason grade groups (isup groups 1-5). correlation of the two markers with each other (in benign or tumor) was examined by pearson and spearman correlation tests. statistical significance was set at p< 0.05. results the racial distribution of cases did not differ by grade (p=0.9) or pt stage (2, 3a, or 3b) (p=0.9). the mean age of aa men was 60.7; this was less than for ea men at 62.2 (p=0.03). gdf15 reactivity was cytoplasmic, while nfκb reactivity was both cytoplasmic and nuclear, as expected (domingodomenech et al., 2005). between mean reactivities of the tmas from 3 study sites—in both cancer and benign spots, some batch effect was noted in both normal and www.companyofscientists.com/index.php/chd e5 cancer health disparities research tumor regions. this was attributed to differences in tissue processing across institutions, different lots of antibodies used, and other technical procedures. therefore, the above-described normalization was applied to all benign and tumor results. the degrees of deviation in expression before and after batch correction are shown in normal and tumor spots of prostate tissue from men from all sites for gdf15 expression and nfκb expression (supplementary figure 1). representative marker reactivity is shown (figure 3). median gdf15 (1.93 vs. 0.19, p<0.0001) and nfκb (1.18 vs. 0.96, p<0.0001) expression was elevated in pc compared to benign prostate (table 1). median gdf15 expression for ea men was 2.06 in tumor versus 0.87 in benign (p<0.0001); comparable values for aa men were 2.06 vs. 0.83 (p<0.0001). median nfκb expression for ea men was 1.04 in tumor versus 0.88 in benign (p<0.0001); comparable values for aa men were 1.04 vs. 0.96 (p<0.0001). tumor-tumor and benign-benign comparisons of expression levels for both proteins by race were not significant except that nfκb was borderline-higher in the prostate benign epithelium of aa men (p=0.06). (nfκb expression in prostate benign epithelium was also significantly higher in aa than ea men when we separately analyzed the pcbn highgrade tma set (p=0.01) but not in the other cases; namely 41.4% of aa men had reactivity >1 in benign glands but 30.2% of ea did (p=0.03); for further analysis, however, both pcbn cohorts were combined.) figure 3. representative tma spots illustrating trends in aa patients. (a) gdf15 in stage 2 tumor, (b) gdf15 in stage 3b tumor, (c) nfκb in low grade (group 1) tumor with a few stronger-staining benign glands at bottom, (d) nfκb in high grade (group 5) tumor. gradewise gdf15 in tumor showed changes of indeterminate direction (p=0.010), while nfκb expression was increased in gleason grade groups 3, 4, and 5 in tumor (p=0.009) and benign (p=0.003) (table 2). by pathologic stage (table 3), gdf15 expression markedly decreased in tumor (p=0.001) and benign epithelium (p<0.001) with increasing stage. nfκb expression rose in tumor (p=0.02) with increasing stage. results for each site-specific sampling generally followed similar trends as the combined sample (supplementary tables 1-5). racial disparities of gdf15 and nfκb expression emerged, according to tumor grade and stage, in both tumor and non-neoplastic prostate. the only expression trend by grade in tumor was for increasing nfκb expression with grade in aa (p=0.03) (table 4). gdf15 significantly increased with grade only in ea men (p=0.01). by stage (table 5), www.companyofscientists.com/index.php/chd e6 cancer health disparities research gdf15 significantly decreased in aa men in prostate tumor (p=0.007), compared to a non-significant trend in the same direction observed in ea men (p=0.07); thus the significant decrease in the overall study group was driven by aa men. gdf15 expression in benign epithelium decreased in ea men with increasing stage (p=0.01), as well as in aa men (p=0.003). nfκb showed no race-specific trends according to stage in either tumor or benign epithelium. finally, the two markers did not correlate with each other in normal (supplementary figure 1a1c) or tumor samples (supplementary figure 1d-1f), either overall or in ea or aa cohorts, shown as scatter plots. trends are summarized (table 6). discussion the current study shows a newly-described, significant stagewise decline in gdf15 expression in prostate tumors of african-american (aa) men not observed in european american (ea) men, and a grade-proportional rise of nfκb expression in aa tumors. also, nfκb expression was higher in benign epithelium of aa men than ea men in the pcbn high-grade disparity cohort. although aa men have shown higher gleason scores in other series (p = 0.037) (powell et al., 2013) the lack of significant differences between our aa and ea men groups rules out differing average grades as a cause of the differences observed. since gdf15 is considered to repress nfκb, this may explain the increase in nfκb expression in tumor (although the latter was gradewise, not stagewise) that was noted in aa men but not ea, a finding possibly related to androgen independence (jin et al., 2008). these findings suggest racially differing effects of these molecules on biologic functions including immune response. gdf15 is widely associated with inflammation, regulating apoptosis, cell repair, growth, and tumorigenesis. gdf15 expression is normally relatively high in the prostate, and gdf15 immunoreactivity in human prostatectomy specimens had shown an inverse relationship to inflammatory cells (bruzzese et al., 2014). the lowering of gdf15 expression in aa tumor progression may be consistent with the known effect of vitamin d to upregulate gdf15 (lambert et al., 2015). that is, higher prevalence of vitamin d deficiency in aa men (hollis et al., 2013) could explain our finding that aa men have lower tumor gdf15 expression as the stage progresses. stated differently, whereas white men do not show a lowering of gdf15 expression as tumor spreads outside the prostate, such a reduction occurs in aa men. whether this highly significant (p=0.003) lowering of gdf15 expression in benign epithelium in aa men predicts future cancer detection will require a prospective trial, based on repeated biopsies. notably, increased circulating gdf15 was significantly correlated with aa race, smoking, and hypertension (powell et al., 2013), suggesting that some gdf15 originates from extraprostatic sources. this finding supports a role for gdf15 in tumor development; for example, increased gdf15 targets p53 and acts through the pi3k/akt and mapk/erk signaling pathways, with upregulation of cyclins d1 and e1, to promote proliferation in cervical carcinogenesis (li et al., 2018). recent evidence supports the concept that the greater modulation of gdf15 in aa men is related to higher risk of pc progression. a racial disparity was found in the link between psa velocity and eventual pc diagnosis such that nsaid use was associated with increased pc risk only in aa men but not ea men (wallace et al., 2008; kryvenko et al., 2019). since nsaid use induces gdf15 expression (wang et al., 2013), this aligns with astronger role of immunerelated genes in tumor development in aa men than www.companyofscientists.com/index.php/chd e7 cancer health disparities research in ea men (wallace et al., 2008), and may relate to the current study where a greater stagewise modulation of gdf15 was found in aa men than in ea men (table 5). nfκb is the most important transcription factor for oxidative susceptibility in the body. after activation, nfκb can activate and regulate the expression of many inflammatory factors, which makes it the key promoter of the inflammatory response. infection or hypoxia activates nfκb, which is inactive in cells, and activates inflammatory genes, induces the upregulation of cytokines, adhesion molecules, and vasoactive regulators and increases the concentration of further downstream cytokines such as tumor necrosis factor-α (tnf-α), interleukin-6 (il6), interleukin-8 (il-8) and others (moresco et al., 2011). our finding of more pronounced rises in nfκb in cancer glands in aa tumor development may correlate with the more frequent prostatic inflammation reported by some (eastham et al., 1998) (but not all) studies in aa men (bostwick et al., 2003). previous studies suggested nfκb to have a reciprocal interaction with gdf15 (lambert et al., 2015; zhang et al., 2018). thus, a firefly luciferase construct was used to show that expression of the nfκb target, interleukin 8 (il-8), was downregulated by gdf15 in pc3 cells (lambert et al., 2015). gdf15 also inactivates nfκb signaling in dendritic cells, enabling induction of immune tolerance after heart transplantation (zhang et al., 2018). on this basis, upregulation of nfκb with tumor stage might be expected, but this was noted in the tumor only in aa men (with stagewise upregulation in benign glands in ea men). this could be explained by lower gdf15 in progression of aa men’s tumors, allowing a greater rise in nfκb expression in response to tumor. the altered nfκb in aa men could correlate with inflammatory response to the cancer tissue, but the non-neoplastic cells also have a greater rise in ea men which may cause localization of inflammatory cells to the tumor. in cancer, nfκb becomes constitutively activated in a high proportion of androgen-independent prostate cancers (jin et al., 2008; nadiminty et al., 2008). apparently, the ability of nfκb to promote transcription of the prominent anti-apoptotic protein bcl-2 and cyclin d1, cyclooxygenase-2, matrix metalloproteinase 9, nitric oxide synthase-2 (nos-2), and vascular endothelial growth factor aids the survival of cells that would otherwise die owing to loss of androgen activity (shukla et al., 2004). we observed a gradewise increase of tumor expression of nfκb in aa men but not ea men, a finding possibly related to greater attainment of androgen independence in aa men. signaling linked to nfκb and inflammatory cytokine factors was preferentially upregulated in pc from aa race (powell et al., 2013). in the face of lower nfκb expression by the tumor, this suggests a greater sensitivity of the post-nfκb cascade in aa men. aside from these two molecules, other signaling pathways involved in the immune response have also been noted to show a racial disparity in prostate cancer. a germline variant called interferon lambda 4 was twice as common in prostate tumors of aa men than white men (42-67% versus 18-33%); this relied on pro-tumorigenic jak-stat signaling, and was associated with decreased survival (tang et al., 2018). it is uncertain whether our results are consistent with the current understanding of the prostatic inflammatory environment. the normal prostate contains lymphocytes, of which >90% are t cells; and those in the epithelium are predominantly cytotoxic/suppressor (cd8+) (bostwick et al., 2003; eastham et al., 1998). studying just tumor-infiltrating t-cell density with three immunohistochemical www.companyofscientists.com/index.php/chd e8 cancer health disparities research markers and image analysis, kaur et al. found no association with ea or aa racial ancestry (kaur et al., 2018) although increased t-cell density was associated with erg positivity and pten loss in both races. the reduce study, a 4-year, multicenter, placebo-controlled study in which a negative prostate biopsy was criterion for enrollment, involved 7,982 men: 7,271 white and 180 aa men. no differences were noted in chronic inflammation, but aa men were less likely (or = 0.65, 95%ci: 0.41-1.03, p= 0.07) and asian men (or = 1.74, 95%ci: 1.142.65, p= 0.001) more likely, to have acute inflammation (vidal et al., 2016). inflammation in biopsies was associated with decreased cancer risk in other case-control studies (kryvenko et al., 2012; ylihemminki et al., 2013). our topographic/spatial study of atrophy had found only a weak association of inflammation with cancer provided the inflammation was accompanied by atrophy (iczkowski et al., 2014). acute inflammation has also been linked with lower future pc risk (allott et al., 2018; moreira et al, 2014). inflammation was not significantly predictive of pc in another study (khani et al., 2014). high bmi was a greater risk factor for pc in aa men than in white men (barrington et al., 2015), and adiposity causes generalized inflammation. one limitation of the study was its exclusion of stromal changes. there is increased reactive stroma associated with chronic inflammation in prostate cancer of aa men, and fibroblasts isolated from aa prostate cancer tissues showed increased growth response to androgens, fibroblast growth factor 2, and platelet-derived growth factor. conditioned media from aaderived fibroblasts enhanced the proliferation, motility, and in vivo tumorigenicity of prostate cancer cells more than european-americanderived fibroblasts did, and they had elevated markers of myofibroblast activation such as expression of sma, vimentin, and tenascin-c. also, proinflammatory paracrine mediators bdnf, c hi3l1, dppiv, fgf7, ili8bp, il6, and vegf were comparatively enriched in aa-derived fibroblasts (gillard et al., 2018). it is possible that the high, and rather constant level of gdf15 we observed in the benign and cancer epithelia is counteracting these stromal proinflammatory mediators. a second limitation is not knowing the anatomic sites within the prostate from which tma cancer cores were derived. dominant tumor nodules in aa men are larger and more often in the anterior peripheral zone, making them less amenable to rectal palpation than posterior tumors, and this location correlates with an adverse outcome (sundi et al., 2014). a third limitation was that serum psa measurements were not available for comparison to marker expression; this would have given further insight into their roles in tumor development, although inflammation had been shown to be unrelated to the racial disparity in serum psa (zhang et al., 2000). in summary, we report that tumor immunoreactivity showed significant alterations with progression in aa men only: a stagewise decrease in gdf15 expression, and a gradewide increase in nfκb expression. these findings have ramifications for tumor development and androgen independence, and further work is needed to determine whether the racial disparities observed in non-neoplastic prostate are influenced by the presence of tumor or independent of it. acknowledgements this work is supported by nih grant 5r01es01112614 [bar] and department of defense pcbn, award no. w81xwh-10-2-0056 and w81xwh-10-2-0046 (tissue microarrays). conflict of interest www.companyofscientists.com/index.php/chd e9 cancer health disparities research dr. iczkowski has no consultancies, stock ownership, equity interest, patent-licensing agreements, research support, or honoraria from companies whose product figures prominently in this manuscript. authors’ contributions study design: kai, msl, bar. immunostain protocol and science background: jrl. data acquisition: kai, ok, ss, wp, bar. statistical analysis: yc, kct. references 1. allott eh, markt sc, howard le, vidal ac, moreira dm, castro-santamaria r, andriole gl, mucci la, and freedland sj (2018). geographic differences in baseline prostate inflammation and relationship with subsequent prostate cancer risk: results from the multinational reduce trial. cancer epidemiol biomarkers prev 27, 783789. 2. bankhead p, loughrey mb, fernández ja, dombrowski y, mcart dg, dunne pd, mcquiad s, gray rt, murray lj, coleman hg, james ja, salto-tellez m, and hamilton pw (2017). qupath: open source software for digital pathology image analysis. sci rep 7, 16878. 3. barrington we, schenk jm, etzioni r, arnold kb, neuhouser ml, thompson im jr, lucia ms, and kristal ar (2015). difference in association of obesity with prostate cancer risk between us african american and non-hispanic white men in the selenium and vitamin e cancer prevention trial (select). jama oncol 1, 342-349. 4. bennett j, capece d, begalli f, verzella d, d’andrea d, tornatore l, and franzoso g (2018). nf-κb in the crosshairs: rethinking an old riddle. int j biochem cell biol 95, 108-112. 5. bostwick dg, de la roza g, dundore p, corica fa, and iczkowski ka (2003). intraepithelial and stromal lymphocytes in the normal human prostate. prostate 55, 187-193. 6. bruzzese f, hägglöf c, leone a, sjöberg e, roca ms, kiflemariam s, sjöblom t, hammarsten p, egevad l, bergh a, ostman a, budilon a, and augsten m (2014). local and systemic protumorigenic effects of cancerassociated fibroblast-derived gdf15. cancer res 74, 3408-3417. 7. domingo-domenech j, mellado b, ferrer b, truan d, codony-servat j, sauleda s, alcover j, campo e, gascon p, rovira a, ross js, fernández pl, albanell j. 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liu y, chen r, zhao d, mcalister v, mele t, liu k, and zheng x (2018). gdf15 regulates malat-1 circular rna and inactivates nf-κb signaling leading to immune tolerogenic dcs for preventing alloimmune rejection in heart transplantation. front immunol 9, 2407. www.companyofscientists.com/index.php/chd e11 cancer health disparities research table 1. expression of gdf15 (top) and nfκb (bottom) according to race in benign and tumor, tissue microarray. african-american, median (range) european american, median (range) overall population, median tumor benign p tumor benign p tumor benign p gdf15 2.06 (0, 3) 0.83 (0, 3) <0.0001 2.06 (0, 3) 0.87 (0, 3) <0.0001 1.93 0.99 <0.0001 p (aa-ea) 0.96 0.08 nfκb 1.04 (0, 3) 0.96 (0, 3) <0.0001 1.04 (0, 3) 0.88 (0, 2.83) <0.0001 1.18 0.96 <0.0001 p (aa-ea) 0.82 0.06 aa= african-american; ea = european-american white table 2. expression of gdf15 and nfκb according to gleason grade group. grade group gdf15. tumor, median (range) p n= gdf15. benign, median (range) p n= 1 2.06 (0, 3) 0.010 221 0.83 (0, 3) 0.9475 250 2 2.06 (0, 3) 198 0.83 (0, 3) 210 3 2.06 (0, 3) 87 0.93 (0, 3) 94 4 2.42 (0.4 ,3) 52 0.95 (0, 3) 59 5 1.70 (0, 3) 70 0.83 (0, 3) 72 grade group nfκb. tumor, median (range) p n= nfκb. benign, median (range) p n= 1 1.00 (0, 3) 0.009 221 0.88(0, 2.7) 0.003 248 2 0.97 (0, 3) 195 0.85 (0, 2.5) 210 3 1.17 (0, 3) 87 1.08 (0, 2.3) 94 4 1.50 (0, 2.9) 57 1.06 (0, 3) 59 5 1.06 (0, 3) 72 0.96 (0, 2.8) 71 n= number of informative cases table 3. expression of gdf15 and nfκb according to pathologic stage. pathologic stage gdf15. tumor, median (range) p n= gdf15. benign, median (range) p n= 2 2.20 (0, 3) 0.001 462 1.43 (0.188, 2.56) <0.001 514 3a 1.91 (0, 3) 106 1.82 (0.5, 2.81) 109 3b 1.65 (0, 3) 56 1.16 (0.25, 2.56) 58 4 1.33 (0.6, 2.8) 4 1.16 (0.625, 1.69) 4 pathologic stage nfκb. tumor, median (range) p n= nfκb. benign, median (range) p n= 2 1.04 (0, 3) 0.02 466 0.9 (0, 3) 0.10 511 3a 0.97 (0, 3) 105 0.9 (0, 2.5) 109 3b 1.20 (0, 3) 57 1.08 (0, 2.1) 58 4 0.54 (0, 0.7) 4 0.86 (0.7, 1.2) 4 n= number of informative cases www.companyofscientists.com/index.php/chd e12 cancer health disparities research table 4. racial disparity of expression of gdf15 and nfκb according to gleason grade group. african-american european american grade group gdf15. tumor, median (range) p n= gdf15. benign, median (range) p n= gdf15. tumor, median (range) p n= gdf15. benign, median (range) p n= 1 2.15 (0, 3) 0.08 107 0.83 (0, 3) 0.80 118 2.06 (0, 3) 0.19 114 0.97 (0, 2.9) 0.01 132 2 2.06 (0.4, 3) 93 0.83 (0, 3) 97 2.00 (0, 3) 105 0.83 (0, 3) 113 3 2.17 (0.2, 3) 42 0.83 (0, 3) 44 2.01 (0, 3) 45 1.1 (0, 3) 50 4 2.71 (0.4, 3) 22 0.88 (0, 3) 27 2.34 (0.5, 3) 30 1.15 (0, 3) 32 5 1.63 (0, 3) 36 0.96 (0 ,3) 37 2.03 (0.3, 3) 34 0.69 (0, 2.5) 35 grade group nfκb. tumor, median (range) p n= nfκb. benign, median (range) p n= nfκb. tumor, median (range) p n= nfκb. benign, median (range) p n= 1 0.96 (0 ,3) 0.03 107 0.96 (0, 2.7) 0.37 117 1.04(0, 3) 0.23 114 0.82 (0, 2.5) 0.007 131 2 1.04 (0 ,3) 89 0.91 (0, 2.3) 97 0.87 (0, 3) 106 0.75 (0, 2.5) 113 3 1.15 (0, 3) 42 1.08 (0, 2.3) 44 1.25 (0, 3) 45 1.04 (0, 2.1) 50 4 1.50 (0, 2.9) 25 1.00 (0, 3) 27 1.46 (0, 2.9) 32 1.07 (0, 2.1) 32 5 1.12 (0, 3) 37 0.96 (0, 1. 8) 36 1.04 (0.2, 3) 35 0.96 (0, 2.8) 35 n= number of informative cases table 5. racial disparity of expression of gdf15 and nfκb according to pathologic stage. african-american european american stage gdf15. tumor, median (range) p n= gdf15. benign, median (range) p n= gdf15. tumor, median (range) p n= gdf15. benign, median (range) p n= 2 2.20 (0, 3) 0.007 221 0.83 (0, 3) 0.003 242 2.08 (0, 3) 0.07 241 1.00 (0, 3) 0.01 272 3a 1.61 (0.4, 3) 49 0.42 (0, 2) 50 2.06 (0, 3) 57 0.80 (0, 3) 59 www.companyofscientists.com/index.php/chd e13 cancer health disparities research 3b 1.63 (0, 3) 28 1.10 (0, 2.5) 29 1.65 (0.3, 3) 28 0.75 (0, 2.5) 29 4 2.01 (0, 2.8) 2 1.38 (0.8, 1.9) 2 1.02 (0.6, 1.4) 2 0.92 (0.2, 1.7) 2 stage nfκb. tumor, median (range) p n= nfκb. benign, median (range) p n= nfκb. tumor, median (range) p n= nfκb. benign, median (range) p n= 2 1.04 (0, 3) 0.21 222 0.96 (0, 3) 0.96 240 1.08 (0, 3) 0.15 244 0.86 (0, 2.8) 0.18 271 3a 1.06 (0, 3) 48 0.96 (0, 1.9) 48 0.89 (0, 3) 57 0.88 (0, 2.5) 59 3b 1.23 (0, 2.8) 28 0.96 (0, 1.8) 28 1.12 (0.2, 3) 29 1.12 (0.1, 2.1) 29 4 0.54 (0.4, 0.7) 2 0.93 (0.7, 1.2) 2 0.36 (0, 0.7) 2 0.86 (0.8, 1.0) 2 n= number of informative cases note: with only 2 cases for stage 4, values are probably not representative. table 6. summary of inflammatory markers in prostate. marker by increasing stagek by increasing gradek gdf15 in ea men decreases in benign (p=0.01), not in tumor decreases in benign only (p=0.01) gdf15 in aa men decreases in tumor (p=0.007) as well as benign (p=0.003) no change in benign or tumor nfκb in ea men no change in benign or tumor increases in benign (p=0.007) but not tumor (p=0.23) nfκb in aa men no change in benign or tumor increases in tumor (p=0.027) but not benign (p=0.37) aa= african-american; kkruskal-wallis; wwilcoxon test; ea= european american www.companyofscientists.com/index.php/chd e14 cancer health disparities research supplementary figure 1. normalization of gdf15 and nfκb expression in normal and tumor regions of prostate of men with gleason grade group 2 prostate cancer from the three study sites. box plots showing digitally assessed gdf15 (a,b) and nfκb (c,d) expression in normal prostate before (a,c) and after (b,d) normalization. additional box plots show effect of normalization on pathologically assessed gdf15 (e-h) and nfκb (i-l) expression in normal (e,f & i,j) and malignant (g,h & k,l) prostate before (e,g,i,k) and after (f,h,j,l) normalization. ford=henry ford, hopkins=johns hopkins, mcw=medical college of wisconsin. www.companyofscientists.com/index.php/chd e15 cancer health disparities research supplementary figure 2. correlation of gdf15 and nfκb expression in normal and tumor regions of prostate in european/white american (ea) and african american (aa) men with prostate cancer. scatter plots and associated correlation coefficients are shown for all normal samples (a), normal prostate regions in ea (b), normal prostate regions in aa (c), all tumor samples (d), tumor regions in ea (e), tumor regions in aa (f). supplemental table 1. expression of gdf15 (top) and nfκb (bottom) according to race in benign and tumor, tissue microarray stratified by study site. henry ford african-american, median (range) white american, median (range) overall population, median (range) tumor benign p tumor benign p tumor benign p gdf15 2.83 (0, 3) 1.14 (0, 3) <0.0001 2.75 (0, 3) 1.18 (0, 3) <0.0001 2.75 (0, 3) 1.17 (0, 3) <0.0001 p (aa-w) 0.251 0.931 nfκb 1.50 (0, 3) 1.15 (0, 3) <0.0001 1.42 (0, 3) 0.90 (0, 2.83) <0.0001 1.45 (0, 3) 1.00 (0, 3) <0.0001 p (aa-w) 0.992 0.039 www.companyofscientists.com/index.php/chd e16 cancer health disparities research johns hopkins african-american, median (range) white american, median (range) overall population, median tumor benign p tumor benign p tumor benign p gdf15 2.50 (0.5, 3) 0.83 (0, 3) <0.0001 2.00 (0, 3) 1.00 (0, 3) <0.0001 2.00 (0, 3) 1.00 (0, 2.6) <0.0001 p (aa-w) <0.0001 0.148 nfκb 1.25 (0.2, 2.94) 0.60 (0, 2.52) <0.0001 1.56 (0.38, 3) 0.67 (0, 2.5) <0.0001 1.47 (0, 3) 0.67 (0, 2.5) <0.0001 p (aa-w) <0.0001 0.73 medical college of wisconsin (mcw) african-american, median (range) white american, median (range) overall population, median tumor benign p tumor benign p tumor benign p gdf15 2.00 (0.67, 3) 0.88 (0, 2.33) <0.0001 1.00 (0, 3) 0.67 (0, 2.5) 0.082 1.58 (0, 3) 0.77 (0, 2.5) <0.0001 p (aa-w) 0.007 0.454 nfκb 2.00 (0.75, 3) 1.83 (0.17, 3) 0.161 2.00 (0, 3) 1.67 (0.5, 3) 0.943 2.00 (0, 3) 1.75 (0.17, 3) 0.297 p (aa-w) 0.283 0.384 aa= african-american; w= white supplemental table 2. expression of gdf15 and nfκb according to gleason grade group stratified by study site. henry ford grade group gdf15. tumor, median (range) p n= gdf15. benign, median (range) p n= 1 2.81 (0, 3) 0.668 103 1.17 (0, 3) 0.268 132 2 2.75 (0, 3) 101 1.17 (0, 3) 113 3 2.83 (0.167, 3) 32 1.30 (0.056, 3) 39 4 2.75 (0.5 ,3) 43 1.11 (0, 3) 50 5 2.50 (0.75, 3) 20 0.92 (0, 3) 33 grade group nfκb. tumor, median (range) p n= nfκb. benign, median (range) p n= 1 1.25 (0, 3) 0.128 106 0.95 (0, 2.67) 0.544 130 2 1.25 (0, 3) 101 0.90 (0, 2.5) 113 3 1.47 (0, 3) 32 1.19 (0, 2.33) 39 4 1.71 (0, 2.92) 48 1.25 (0, 3) 50 5 1.83 (0.167, 3) 22 1.23 (0, 2.82) 21 johns hopkins grade group gdf15. tumor, median (range) p n= gdf15. benign, median (range) p n= 1 2 (0,3) 0.458 112 1 (0,2.56) 0.040 112 www.companyofscientists.com/index.php/chd e17 cancer health disparities research 2 2.12 (0,3) 80 0.91 (0,2.56) 81 3 2.41 (0.5,3) 26 1.47 (0,2.56) 26 4 2.44 (2.06,2.83) 9 1.4 (0.67,2.56) 9 5 2.12 (0.5,3) 45 1.44 (0.25,2.6) 45 grade group nfκb. tumor, median (range) p n= nfκb. benign, median (range) p n= 1 1.35 (0,3) 0.001 110 0.40 (0,2.38) <0.00 01 112 2 1.44 (0,2.88) 80 0.42 (0,2.12) 81 3 1.5 (0.25,2.69) 26 0.86 (0.1,2.5) 26 4 1.62 (0.69,2.94) 9 1.06 (0.58,1.69) 9 5 2 (0.25,2.81) 45 1.31 (0.38,2.52) 45 medical college of wisconsin (mcw) grade group gdf15. tumor, median (range) p n= gdf15. benign, median (range) p n= 1 1.25 (0.5,2) 0.085 6 0.75 (0,1) 0.573 6 2 1.5 (0.5,3) 16 0.5 (0,2.5) 16 3 2.33 (0,3) 29 1 (0,2.5) 29 4 -- 0 -- 0 5 1.67 (0.5,2.17) 5 0.5 (0,2.33) 5 grade group nfκb. tumor, median (range) p n= nfκb. benign, median (range) p n= 1 1.5 (0.75,3) 0.049 5 1.5 (0.8,1.8) 0.000 3 6 2 1.5 (1,2.83) 16 1.4 (0.17,2) 16 3 2.08 (0,3) 29 2 (0.5,3) 29 4 -- 0 -- 0 5 2.5 (2.25,2.62) 5 2 (1.4,2.83) 5 n= number of informative case supplemental table 3. expression of gdf15 and nfκb according to pathologic stage stratified by study site. henry ford pathologic stage gdf15. tumor, median (range) p n= gdf15. benign, median (range) p n= 2 2.83 (0,3) .015 243 1.25 (0,3) 0.01 295 3a 2.71 (0.167,3) 34 0.88 (0,3) 37 3b 2.2 (0.75,3) 20 1.19 (0.25,2.5) 22 4 2.1 (1.42,2.79) 2 1.06 (0.19,1.94) 2 pathologic stage nfκb. tumor, median (range) p n= nfκb. benign, median (range) p n= 2 1.42 (0,3) 0.203 253 1.00 (0,3) 0.589 292 3a 1.42 (0,3) 33 0.88 (0,2.5) 37 3b 1.62 (0,3) 21 1.25 (0,2.08) 22 4 0.18 (0,0.36) 2 0.71 (0.67,0.75) 2 www.companyofscientists.com/index.php/chd e18 cancer health disparities research johns hopkins pathologic stage gdf15. tumor, median (range) p n= gdf15. benign, median (range) p n= 2 2.25 (0,3) 0.081 183 1 (0,2.56) 0.900 183 3a 2 (0.5,3) 57 1 (0,2.6) 58 3b 2 (0.5,3) 30 1.04 (0.25,2.5) 30 4 1.41 (1.31,1.5) 2 1.16 (0.63,1.69) 2 pathologic stage nfκb. tumor, median (range) p n= nfκb. benign, median (range) p n= 2 1.38 (0,3) 0.005 181 0.58 (0,2.5) <0.00 01 183 3a 1.38 (0,2.88) 57 0.5 (0,1.98) 58 3b 2.25 (0.25,2.81) 30 1.11 (0.42,2.52) 30 4 1.68 (1.55,1.81) 2 1.38 (1.25,1.5) 2 medical college of wisconsin (mcw) pathologic stage gdf15. tumor, median (range) p n= gdf15. benign, median (range) p n= 2 1.5 (0.33,3) 0.589 36 1 (0,2.5) 0.101 36 3a 1.83 (0,3) 14 0.5 (0,2.5) 14 3b 1.75 (0.5,2.67) 6 0.88 (0,2.33) 6 4 -- 0 -- 0 pathologic stage nfκb. tumor, median (range) p n= nfκb. benign, median (range) p n= 2 2 (0.75,3) 0.206 35 1.73 (0.75,3) 0.860 36 3a 1.71 (0,2.83) 14 1.77 (0.17,2.88) 14 3b 2.42 (1,3) 6 1.92 (1.4,2.83) 6 4 -- 0 -- 0 n= number of informative cases www.companyofscientists.com/index.php/chd e19 cancer health disparities research supplemental table 4. racial disparity of expression of gdf15 and nfκb according to gleason grade group stratified by study site. henry ford african-american white american grade group gdf15. tumor, median (range) p n= gdf15. benign, median (range) p n= gdf15. tumor, median (range) p n= gdf15. benign, median (range) p n= 1 2.69 (0,3) 0.557 48 1.17 (0,3) 0.591 59 2.83 (0,3) 0.585 55 1.18 (0,2.88) 0.104 73 2 2.75 (0.5,3) 44 1.2 (0,3) 48 2.75 (0,3) 57 1.17 (0,3) 65 3 2.83 (0.17,3) 15 1.42 (0.06,3) 17 2.75 (1,3) 17 1.27 (0.13,3) 22 4 2.96 (1,3) 18 0.92 (0,3) 23 2.75 (0.5,3) 25 1.33 (0,3) 27 5 2.79 (0.75,3) 9 1.17 (0.25,3) 10 2.25 (1.15,3) 11 0.73 (0,2.5) 12 grade group nfκb. tumor, median (range) p n= nfκb. benign, median (range) p n= nfκb. tumor, median (range) p n= nfκb. benign, median (range) p n= 1 1.17 (0,3) 0.754 48 1.17 (0,2.67) 0.912 58 1.33 (0,3) 0.122 58 0.81 (0,2.5) 0.511 72 2 1.33 (0,3) 41 1 (0,2.25) 48 1.21 (0,3) 60 0.75 (0,2.5) 65 3 1.6 (0,3) 15 1.42 (0,2.33) 17 1.25 (0,3) 17 0.98 (0,2.12) 22 4 1.75 (0,2.88) 21 1.25 (0,3) 23 1.5 (0,2.92) 27 1.25 (0,2.08) 27 5 1.25 (0.36,3) 10 1.23 (0,1.8) 9 2.31 (0.17,3) 12 1.12 (0,2.83) 12 johns hopkins african-american white american grade group gdf15. tumor, median (range) p n= gdf15. benign, median (range) p n= gdf15. tumor, median (range) p n= gdf15. benign, median (range) p n= 1 2.38 (0.5,3) 0.867 56 1 (0,2.56) 0.872 56 1.81 (0,3) 0.174 56 1 (0,2.5) 0.007 56 2 2.5 (0.5,3) 41 1.21 (0,2.56) 41 1.5 (0,3) 39 0.63 (0,2.5) 40 www.companyofscientists.com/index.php/chd e20 cancer health disparities research 3 2.5 (0.5,3) 13 1.06 (0,2.56) 13 2.25 (0.5,3) 13 1.5 (0,2.5) 13 4 2.53 (2.12,2.83) 4 0.74 (0.67,2.35) 4 2.44(2.06,2.81) 5 1.81 (1,2.56) 5 5 2.38 (0.88,2.94) 23 1.44 (0.38,2.38) 23 1.88 (0.5,3) 22 1.34 (0.25,2.6) 22 grade group nfκb. tumor, median (range) p n= nfκb. benign, median (range) p n= nfκb. tumor, median (range) p n= nfκb. benign, median (range) p n= 1 1 (0,2.42) 0.019 55 0.33 (0,2.38) <0.00 01 56 1.5 (0.38,3) 0.034 55 0.5 (0,1.75) <0.000 1 56 2 1.19 (0,2.81) 41 0.42 (0.08,1.81) 41 1.5 (0.44,2.88) 39 0.44 (0,2.12) 40 3 1.62 (0.25,2.69) 13 0.75 (0.1,2.08) 13 1.38(0.75,2.69) 13 0.88 (0.25,2.5) 13 4 1.81 (0.83,2.94) 4 1.24 (0.75,1.62) 4 1.62 (0.69,2) 5 1.06 (0.58,1.69) 5 5 1.81 (0.25,2.69) 23 1.28 (0.38,2.52) 23 2.12(0.81,2.81) 22 1.31 (0.58,2.25) 22 medical college of wisconsin (mcw) african-american white american grade group gdf15. tumor, median (range) p n= gdf15. benign, median (range) p n= gdf15. tumor, median (range) p n= gdf15. benign, median (range) p n= 1 1.5 (1.5,2) 0.512 3 0.5 (0,1) 0.867 3 1 (0.5,1) 0.127 3 1 (0,1) 0.757 3 2 2 (1,3) 8 0.75 (0,1.5) 8 1 (0.5,1.5) 8 0.5 (0,2.5) 8 3 2.42 (0.67,3) 14 0.94 (0,1.5) 14 2.17 (0,3) 15 1 (0,2.5) 15 4 -- 0 -- 0 -- 0 -- 0 5 1.83 (1.5,2.17) 4 0.56 (0,2.33) 4 0.5 (0.5,0.5) 1 0.5 (0.5,0.5) 1 grade group nfκb. tumor, median (range) p n= nfκb. benign, median (range) p n= nfκb. tumor, median (range) p n= nfκb. benign, median (range) p n= 1 1 (0.75,1.5) 0.005 3 1.25 (0.8,1.8) 0.010 3 2.33 (1.67,3) 0.559 2 1.5 (1.5,1.5) 0.078 3 2 1.5 (1,2.83) 8 1.5 (0.17,2) 8 1.69 (1,2.75) 8 1.23 (0.75,2) 8 www.companyofscientists.com/index.php/chd e21 cancer health disparities research 3 2.17 (1,3) 14 2 (1.4,3) 14 2 (0,2.5) 15 2 (0.5,3) 15 4 -- 0 -- 0 -- 0 -- 0 5 2.5 (2.33,2.62) 4 2.17 (1.4,2.83) 4 2.25 (2.25,2.25) 1 1.83 (1.83,1.83) 1 n= number of informative cases supplemental table 5. racial disparity of expression of gdf15 and nfκb according to pathologic stage stratified by study site. henry ford african-american white american stage gdf15. tumor, median (range) p n= gdf15. benign, median (range) p n= gdf15. tumor, median (range) p n= gdf15. benign, median (range) p n= 2 2.83 (0,3) 0.528 113 1.21 (0,3) 0.080 134 2.82 (0,3) 0.009 130 1.25 (0,3) 0.042 161 3a 2.49 (1.04,3) 12 0.9 (0.06,1.7) 13 2.79 (0.167,3) 22 0.787 (0,3) 24 3b 2.88 (0.75,3) 8 1.25 (0.25,2.5) 9 2.08 (1.15,3) 12 1.12 (0.35,2.5) 13 4 2.79 (2.79,2.79) 1 1.94 (1.94,1.94) 1 1.42(1.42,1.42) 1 0.19 (0.19,0.19) 1 stage nfκb. tumor, median (range) p n= nfκb. benign, median (range) p n= nfκb. tumor, median (range) p n= nfκb. benign, median (range) p n= 2 1.45 (0,3) 0.545 115 1.16 (0,3) 0.773 114 1.38 (0,3) 0.244 138 0.9 (0,2.83) 0.432 160 3a 0.92 (0,3) 11 1.32 (0,1.92) 11 1.49 (0,3) 22 0.71 (0,2.5) 24 3b 1.75 (0,2.83) 8 0.91 (0,1.75) 8 1.62 (0.17,3) 13 1.25 (0.13,2.08) 13 4 0.36 (0.36,0.36) 1 0.67 (0.67,0.67) 1 0 (0,0) 1 0.75 (0.75,0.75) 1 johns hopkins african-american white american stage gdf15. tumor, median (range) p n= gdf15. benign, median (range) p n= gdf15. tumor, median (range) p n= gdf15. benign, median (range) p n= 2 2.5 (0.5,3) 0.496 92 1 (0,2.56) 0.813 92 2 (0,3) 0.162 91 1 (0,2.56) 0.974 91 3a 2.5 (0.5,3) 29 1 (0,2.56) 29 1.5 (0.5,2.69) 28 1 (0,2.6) 29 3b 2.31 (0.88,3) 15 1.06 (0.38,2.5) 15 1.81 (0.5,2.94) 15 1.02 (0.25,2.38) 15 4 1.31 (1.31,1.31) 1 1.69 (1.69,1.69) 1 1.5 (1.5,1.5) 1 0.63 (0.63,0.63) 1 www.companyofscientists.com/index.php/chd e22 cancer health disparities research stage nfκb. tumor, median (range) p n= nfκb. benign, median (range) p n= nfκb. tumor, median (range) p n= nfκb. benign, median (range) p n= 2 1.25 (0,2.94) 0.250 91 0.46 (0,2.38) 0.008 92 1.5 (0.38,3) 0.010 90 0.6 (0,2.5) 0.002 91 3a 1.12 (0,2.75) 29 0.5 (0,1.98) 29 1.5 (0.5,2.88) 28 0.5 (0,1.94) 29 3b 1.75 (0.25,2.69) 15 0.94 (0.42,2.52) 15 2.31 (0.83,2.81) 15 1.25 (0.58,2.25) 15 4 1.81 (1.81,1.81) 1 1.5 (1.5,1.5) 1 1.55 (1.55,1.55) 1 1.25 (1.25,1.25) 1 medical college of wisconsin (mcw) african-american white american stage gdf15. tumor, median (range) p n= gdf15. benign, median (range) p n= gdf15. tumor, median (range) p n= gdf15. benign, median (range) p n= 2 2 (1,3) 0.696 16 1 (0,1.5) 0.104 16 1 (0.33,3) 0.435 20 1 (0,2.5) 0.485 20 3a 2.25 (1,3) 8 0.5 (0,1) 8 1.58 (0,2.67) 6 0.42 (0,2.5) 6 3b 2 (0.67,2.67) 5 1.12 (0,2.33) 5 0.5 (0.5,0.5) 1 0.5 (0.5,0.5) 1 4 -- 0 -- 0 -- 0 -- 0 stage nfκb. tumor, median (range) p n= nfκb. benign, median (range) p n= nfκb. tumor, median (range) p n= nfκb. benign, median (range) p n= 2 1.56 (0.75,3) 0.589 16 1.68 (0.8,3) 0.546 16 2 (0.83,3) 0.101 19 1.75 (0.75,3) 0.281 20 3a 1.96 (1.5,2.83) 8 2.12 (0.17,2.88) 8 1.19 (0,2.17) 6 1.45 (0.5,2) 6 3b 2.5 (1,3) 5 2 (1.4,2.83) 5 2.25 (2.25,2.25) 1 1.83 (1.83,1.83) 1 4 -- 0 -- 0 -- 0 -- 0 n= number of informative cases note: with only 1 cases for stage 4, values are probably not representative. www.companyofscientists.com/index.php/chd e1 cancer health disparities research racial/ethnic disparities in thyroid cancer stratified by risk factors: a literature review kristiana rood1,2,3,**, ria t. laxa1,**, andrea shields4, hae-soo kim1,2, salma khan1,2,3,5,* 1division of biochemistry, loma linda university school of medicine, loma linda, ca 92350, usa. 2division of otolaryngology, loma linda university school of medicine, loma linda, ca 92350, usa. 3center for health disparities & molecular medicine, loma linda university school of medicine, loma linda, ca 92350, usa. 4department of pathology & human anatomy, loma linda university school of medicine, loma linda, ca 92350, usa. 5department of internal medicine, loma linda university school of medicine, loma linda, ca 92354, usa. loma linda university, mortensen hall, 11085 campus st, loma linda, ca 92350. *corresponding author: salma khan: salmakhan@llu.edu. **equally contributed. abstract in the united states, thyroid cancer incidence has increased dramatically within the last few decades. recent research suggests that this incidence along with cancer stage and mortality vary by race/ethnicity, highlighting health disparities in the united states. there are several risk factors for thyroid cancer incidence that may contribute to these disparities. the goal of this literature review is to analyze whether these potential risk factors impact incidence and aggressiveness differently by race/ethnicity, implicating their possible role in influencing thyroid cancer disparities in the united states. through pubmed searches, we have reviewed recent literature on u.s. populations. we found that chromosomal alterations/nonhereditary conditions, autoimmunity, thyroid nodules, and socioeconomic differences potentially impacted thyroid cancer incidence and aggressiveness by race/ethnicity, whereas sex disparities did not. several potential risk factors showed some variations by race/ethnicity but either did not specifically examine their relationship to thyroid cancer or did not impact thyroid cancer incidence and aggressiveness. other potential risk factors have not yet been studied regarding their influence on thyroid cancer incidence and outcomes for racial/ethnic groups in the united states. therefore, we identify a critical need for subsequent research to examine these potential risk factors for different racial/ethnic groups and contribute to our understanding of racial/ethnic health disparities in the united states. we also present several research areas relating to thyroid cancer health disparities that require further study. keywords: thyroid cancer, health disparities, incidence, mortality. citation: rood k et al (2023) racial/ethnic disparities in thyroid cancer stratified by risk factors: a literature review. cancer health disparities 7:e1-20. doi:10.9777/chd.2023.1004 mailto:salmakhan@llu.edu www.companyofscientists.com/index.php/chd e2 cancer health disparities research 1. introduction thyroid cancer incidence has increased dramatically over the last 30 years, and epidemiologists predict this cancer will become the fourth most prevalent cancer in the united states by 2030 (krook et al., 2015; la vecchia et al., 2015; rahib et al., 2014; reitzel et al., 2014; weeks et al., 2018). one study found that by 2008, thyroid cancer had already been one of the top five cancers in asian indian/pakistani, chinese, filipina, korean, and vietnamese women (gomez et al., 2013). furthermore, recent research suggests that this incidence varies by race/ethnicity (table 1) (magreni et al., 2015; suresh et al., 2015; weeks et al., 2018). in the united states, thyroid cancer incidence rates are the highest in non-hispanic european americans and the lowest in non-hispanic african americans (lim et al., 2017; magreni et al., 2015; reitzel et al., 2014; tortolero-luna et al., 2019; weeks et al., 2018; yu et al., 2010). however, when separating asian americans by subgroups, vietnamese, cambodian, and filipino americans are shown to have elevated thyroid cancer incidence rates; filipino americans, in particular, have higher thyroid cancer incidence rates than non-filipino asians and non-hispanic european americans (gomez et al., 2013; horn-ross et al., 2011; jin et al., 2016; megwalu et al., 2021; nguyen et al., 2017). table 1. age-adjusted thyroid cancer incidence rates and 95% confidence intervals (cis) by asian subgroup and non-hispanic (nh) whites, 2009-2011* (jin et al., 2016). chinese filipino japanese korean south asian vietnamese asian total nh white n rate (95% ci) n rate (95% ci) n rate (95% ci) n rate (95% ci) n rate (95% ci) n rate (95% ci) n rate (95% ci) n rate (95% ci) men 263 6.9 (6.17.8) 271 9.7 (8.511.0) 41 3.7 (2.65.2) 108 8.3 (6.810.1) 186 5.8 (4.96.8) 75 5.3 (4.16.7) 974 6.8 (6.47.3) 9,425 8.1 (7.98.3) women 920 20.8 (19.422.2) 1,108 28.5 (26.830.3) 153 (11.6 (9.713.9) 408 23.2 (21.025.6) 624 19.9 (18.321.7) 318 19.3 (17.221.7) 3,670 21.5 (20.822.2) 25,325 22.4 (22.122.7) *rates are average annual per 100,000 age-standardized to the 2000 us population; the number of cases may not add up to the total due to rounding. there are several risk factors for thyroid cancer incidence that may contribute to these disparities (konturek et al., 2016; la vecchia et al., 2015; weeks et al., 2018). a recent study by bogović et al. categorized the potential risk factors as either “high risk,” “low risk,” or “unclear” (bogović crnčić et al., 2020). high-risk factors included external radiation exposure (especially during infancy and childhood), chromosomal alterations, and hereditary conditions. low-risk factors included thyroid imaging with iodine, iodine deficiency, high thyroidstimulating hormone (tsh) level, autoimmunity, thyroid nodules, environmental pollutants, lifestyle/diet, and obesity/high bmi. the only unclear risk factor included was estrogen. another recent study by yildirim et al. mentioned metabolic syndrome and insulin resistance as important risk factors (yildirim simsir et al., 2020). additionally, sex and socioeconomic status may also be considered risk factors. the goal of this literature review is to analyze whether these potential risk factors impact incidence and aggressiveness differently by race/ethnicity, implicating their possible role in www.companyofscientists.com/index.php/chd e3 cancer health disparities research influencing thyroid cancer racial/ethnic disparities in the united states. 2. materials and methods to review recent research, a pubmed search was used, including articles published since 2010. each identified thyroid cancer risk factor, as informed by bogović et al. (bogović crnčić et al., 2020) and yildirim et al. (yildirim simsir et al., 2020), was used as a keyword: ‘radiation exposure’ or ‘ionizing radiation’, ‘chromosomal alterations’, ‘nonhereditary conditions’, ‘hereditary conditions’, ‘iodine’, ‘tsh’, ‘autoimmunity’, ‘thyroid nodules’, ‘environmental pollutants’ and ‘geospatial’, ‘lifestyle and diet’, ‘bmi’, ‘metabolic syndrome’, ‘insulin resistance’, ‘sex’, and ‘socioeconomic’. other keywords included: ‘effects of’, ‘thyroid’, ‘thyroid cancer’, ‘united states’, ‘health disparities’, ‘risk factors’, and ‘race and ethnicity’. articles were selected after screening titles and abstracts for relevancy, with a particular focus on research done in the united states. afterwards, the full text for each article was acquired. some potential risk factors such as radiation exposure, autoimmunity, chromosomal alterations/non-hereditary conditions, hereditary conditions, and thyroid nodules included publications since 2000 as the findings for these risk factors are less likely to change significantly within the last 20 years compared to the others. each potential risk factor was reviewed for whether they may impact thyroid cancer incidence and aggressiveness differently by racial/ethnic group, if no difference exists, or if further research is necessary to examine their relationship to health disparities. 3. risk factors potentially contributing to tc health disparities 3.1. genetic factors hereditary conditions influencing tc health disparities although more than 90% of thyroid cancers are sporadic, thyroid cancer has been shown to have a significant hereditary component with many hereditary forms exhibiting more aggressive courses. hereditary thyroid neoplasms are divided into those that arise from follicular cells, familial non-medullary thyroid carcinoma (fnmtc) and those arising from calcitonin-producing c cells, familial medullary thyroid carcinomas (fmtcs). fnmtcs are further divided into syndromes where non-thyroid tumors predominate, and those where non-medullary thyroid tumors predominate. the former includes familial adenomatous polyposis (fap), cowden syndrome (cs), carney complex (cnc), werner syndrome (ws), mccune-albright syndrome, pendred syndrome, and dicer1 syndrome. the latter group includes pure familial papillary thyroid carcinoma (fptc), fptc with multinodular goiter, and fptc with papillary renal cell carcinoma (guilmette and nosé, 2018). medullary thyroid cancer (mtc) is hereditary in 25% of cases, and commonly occurs as part of the multiple endocrine neoplasia ii syndromes, although a heritable mtc-only syndrome is reported. hereditary and sporadic mtc are both driven by mutations in the ret proto-oncogene; however, hereditary forms are more likely to present bilaterally and arise at an earlier age, with menii carrying a near 100% lifetime risk of developing mtc (guilmette and nosé, 2018). despite earlier presentation of hereditary mtc, one study found the overall 10-year survival to be 100% in hereditary mtc compared to 80% in sporadic mtc (xu et al., 2012). although hereditary mtc has been reported across varying ethnic groups, there www.companyofscientists.com/index.php/chd e4 cancer health disparities research is little research investigating the racial distribution of hereditary mtc. familial adenomatous polyposis (fap) is an autosomal disorder caused by a germline mutation in the adenomatous polyposis coli (apc) gene. around 2-12% of patients with fap develop ptc, with a 160-fold greater risk of developing ptc than unaffected individuals. more than 90% of the cases have a histologic variant, called cribriform-morular ptc (cmv-ptc), and they are more likely to affect females and present bilaterally. overall, the prognosis is good and only 10% of cmv-ptc cases are aggressive (guilmette and nosé, 2018). fap has been described in all races but there is little research comparing the prevalence between different racial groups. one study investigated the racial variation in apc mutations and found that the overall apc mutation rate was higher in asians and african americans compared to europeans (inra et al., 2015). further research is indicated to evaluate whether the risk of thyroid cancer with fap varies between racial/ethnic groups. out of all fnmtc, cowden syndrome (cs) is an autosomal dominant condition caused by a germline mutation in pten. although other genes have also been implicated in cs, intact pten virtually excludes the diagnosis. two-thirds of cs patients develop thyroid tumors, with the majority of follicular origin, including follicular adenoma and follicular carcinoma (guilmette and nosé, 2018). although most of the patients with cs reported in the literature are european (garofola et al., 2022), at present, the true racial distribution is not yet well described. carney complex (cnc) is a rare autosomal dominant syndrome with the majority harboring mutations in the prkar1a gene. up to 75% have multiple thyroid nodules but they are at minimal risk for developing thyroid malignancy. thyroid neoplasms within cnc patients are more likely to be found in young females and both follicular thyroid carcinoma and ptc can be seen (guilmette and nosé, 2018). there have been more than 750 reported cases with affected europeans, asians (from all continents), and african americans described (correa et al., 2015). werner syndrome (ws) is an autosomal recessive syndrome caused by wrn mutations leading to defects in dna repair and replication that leads to premature aging. thyroid cancer typically presents in the third decade, with a lower female to male ratio (2:1). they carry a three-fold increased risk for follicular carcinoma and a six-fold increased risk for anaplastic thyroid carcinoma (guilmette and nosé, 2018). there is a high prevalence of ws in japan, where ws has been reported up to 1 in 20,00040,000 live births compared to 1 in 100,000 births worldwide. in the united states the prevalence is estimated to be even less as 1 in 200,000 live births (sickles and gross, 2022). up to 18% of japanese patients with ws also develop thyroid cancer and europeans have an increased risk of ptc. the median life expectancy of ws patients is approximately 54 years, with thyroid cancers and cardiac diseases being the most common causes of death (guilmette and nosé, 2018). there are some cases of fnmtc in which genetics is not yet known. but it is believed that these cases are autosomal dominant and six potential chromosomal regions have been implicated. this category of fnmtc is diagnosed when three or more first-degree relatives have non-medullary thyroid cancer, usually ptc. the tumors are more likely to present at a younger age and have a more aggressive clinical course with a worse prognosis (guilmette and nosé, 2018). further research is indicated on the racial distribution within all these various types of fnmtc. www.companyofscientists.com/index.php/chd e5 cancer health disparities research 3.2. environmental factors 3.2.1. radiation exposure in tc health disparities the radiosensitivity of the thyroid gland is well documented (lubin et al., 2017). radiation exposure in childhood is associated with a higher risk of thyroid cancer than radiation exposure in adults (lee et al., 2019), and the risk increases from about 5 years after exposure (furukawa et al., 2013). radiation exposure in children increases their likelihood of developing papillary thyroid cancer later in life, which is the most common type of thyroid cancer (bogović crnčić et al., 2020; yildirim simsir et al., 2020). children and adolescents exposed to radioactive iodine from the chernobyl fallout have also shown a higher risk of thyroid cancer (furukawa et al., 2013). this trend has also been seen in animal models. it was reported that more radiation-induced thyroid tumors developed in 10-day-old infant rats than in adult rats (matsuumatsuyama et al., 2021). another study demonstrated that the thyroids of 1-week-old neonatal rats are more sensitive to ionizing radiation at 12 gy compared to those from adult rats (matsuu-matsuyama et al., 2021). increase in the use of imaging in medicine, such as ct examinations, is believed to play a role in the increased incidence of thyroid cancer in the united states (yildirim simsir et al., 2020). this means that differences in access to healthcare between patients of different ethnic groups may affect the population’s exposure to radiation, and therefore incidence of thyroid cancer. for example, in the 1970s and 80s, there were many medical professionals who came to the united states from the philippines. this group most likely had better access to ct examinations and had additional occupational exposure to ionizing radiation. in fact, one study reported that highly educated filipinos had higher proportionate mortality due to thyroid cancer than less educated filipinos (nguyen et al., 2017). on the other hand, in a single hospital study of 1,024 female nurses and 2,631 non-nurse females with both groups receiving their annual health examinations over a period of two years, generally no difference was found in incidence of thyroid cancer between the two groups (kim and woo, 2016). this suggests more research is needed to determine if this increased incidence among filipinos is due to job or socioeconomic statusrelated radiation exposure or if it is largely due to inherent biological factors within the filipina population. 3.2.2. iodine deficiency in tc health disparities the thyroid gland uses iodine to make thyroid hormones. when the body is low on iodine and there is a decrease in the level of thyroid hormones, the pituitary gland produces more tsh to compensate. however, tsh is a growth stimulating factor for thyroid follicular cells. this suggests that diets with insufficient intake of iodine could play a role in follicular thyroid cancer (bogović crnčić et al., 2020). however, low iodine diets are necessary prior to radioactive iodine (rai) treatment for thyroid cancer patients with a thyroidectomy (nguyen et al., 2017). studies showed that thyroid cancer patients on low-iodine diets before radioactive iodine (rai) treatment experienced enhanced uptake and maximized destruction of thyroid cancer cells (li et al., 2016; nguyen et al., 2017). however, in filipino americans who have a higher intake of iodine-rich foods such as seafood, dairy, grains, and eggs treatment was less effective compared to other patients preparing for rai treatment (herrick et al., 2018; nguyen et al., 2017). another study analyzed the median urinary iodine concentration (muic) of individuals in the united states as a measure of dietary iodine (herrick et al., 2018). non-hispanic asian women of reproductive age had low muic, and therefore mild iodine deficiency, compared to non-hispanic african www.companyofscientists.com/index.php/chd e6 cancer health disparities research american women of reproductive age despite both populations consuming similar amounts of dairy and grains (herrick et al., 2018). when looking at the total population of individuals ages 6 years and above, non-hispanic asians consumed more amounts of dairy and grains compared to nonhispanic african americans but continued to have lower muic (herrick et al., 2018). since asian individuals tend to consume more rice than other racial groups, it is possible that differences in the type of grain consumed by ethnic groups could influence iodine levels (herrick et al., 2018). additionally, this study found that non-hispanic asians consumed higher amounts of soy products compared to other racial groups and suggests that substances in these soy products could inhibit iodine uptake by the thyroid (herrick et al., 2018). these data suggest that differences in diet among racial/ethnic groups may impact dietary iodine levels and, therefore, rai treatment outcome. 3.2.3. environmental pollutants influencing tc health disparities populations are exposed to varying levels of harmful chemicals in the environment through water, air, food, or soil (yildirim simsir et al., 2020). a few of these chemicals – such as benzene, formaldehyde, and pesticides – have been linked to goiter and nodular goiter formation as well as papillary thyroid cancer (bogović crnčić et al., 2020; yildirim simsir et al., 2020). another set of chemicals, nitrates, are commonly found in readymade foods and, when at above-average levels, can affect iodine uptake and increase the risk of thyroid cancer (bogović crnčić et al., 2020). additionally, polybrominated diphenyl ethers (pbdes) found in many industrial materials may induce abnormal thyroid cell proliferation leading to a risk of thyroid cancer (bogović crnčić et al., 2020). considering residential segregation and racial/ethnic diversity by geographic level in the united states, a geospatial approach to cancer research could allow for a better understanding of whether environmental pollutants differentially impact certain racial/ethnic groups (korycinski et al., 2018; sahar et al., 2019). an example of this approach includes the application of geographic information science (giscience) to cancer research. this allows researchers to analyze spatial data, visualize cancer and risk factor data on a map, and investigate geographic disease patterns and clusters (sahar et al., 2019). most geospatial cancer research studies have been published after 2010 and are affiliated with nci-designated cancer centers (korycinski et al., 2018). additionally, despite this recently growing area of research, most of these studies have looked at other cancer types besides thyroid cancer – such as breast, prostate, and colorectal cancers (korycinski et al., 2018). one study done in vermont found no correlation between thyroid cancer incidence and proximity to tertiary healthcare centers or socioeconomic status (hanley et al., 2015). however, the researchers note that vermont has a population that is >95% european american and has >92% healthcare insurance coverage, providing little evidence for racial/ethnic minority groups (hanley et al., 2015). another study done in california found that disadvantaged communities, or dacs, had higher amounts of nitrate well contamination as well as a significant correlation between well contamination per square mile and thyroid cancer incidence (tariqi and naughton, 2021). in particular, there was a two times greater thyroid cancer incidence compared to non-dacs (tariqi and naughton, 2021). dacs tend to have a higher population density and amount of people per well, exposing a larger number of people to contaminated drinking water and suggesting that certain populations are disproportionately affected by environmental www.companyofscientists.com/index.php/chd e7 cancer health disparities research factors (tariqi and naughton, 2021). these studies highlight the importance of further geospatial research on thyroid cancer to address geographic and racial/ethnic cancer disparities in the united states. another area of consideration regarding environmental pollutants and their possible contribution to thyroid cancer racial/ethnic disparities is birthplace. one study – although limited by birthplace data – has looked at whether birthplace alters incidence rates of thyroid cancer among asians (horn-ross et al., 2011). researchers found that us-born chinese women had higher papillary thyroid cancer incidence rates than chinaborn chinese women, and a reverse trend was observed among filipino american and japanese american women (horn-ross et al., 2011). another study of five asian female subgroups in california from 1988 to 2004 showed that japan-born japanese women had a significantly higher papillary thyroid cancer incidence rate compared to us-born japanese women, and a reverse trend was observed among chinese and filipina american women (horn-ross et al., 2011). this study also found that foreign-born chinese, korean, vietnamese, and filipina american women had papillary thyroid cancer incidence rates that peaked at 70 years of age, whereas their us-born asian subgroup counterparts peaked during reproductive and menopausal years (horn-ross et al., 2011). overall, these findings suggest that exposures related to immigration and acculturation of these ethnic groups may have impacted their risk of thyroid cancer (horn-ross et al., 2011)(21). further research is needed that includes other racial/ethnic groups and analyzes how these factors could affect thyroid cancer incidence. 3.3. socioeconomic factors 3.3.1. radioiodine treatment within the last few decades, the use of rai treatment for thyroid cancer has increased (pasqual et al.). one study found that patients who had a thyroidectomy for low-risk papillary thyroid cancer were more likely to undergo rai treatment if they had lower healthcare access (marti et al., 2015). this includes those that are uninsured, in poverty, attained only a high school education, are nonenglish speaking, or unemployed. additionally, racial/ethnic minority populations are more likely to be uninsured and have decreased access to highquality care, whether due to geographic area or stereotyping by healthcare providers (artiga s, 2021; national research council panel on race and health in later, 2004). this suggests that some racial/ethnic minority populations of the united states may experience inappropriate use of rai treatment, an aggressive therapy for low-risk ptc (marti et al., 2015). when using rai for differentiated thyroid cancer (dtc) treatment, one recent study found that rai treatment increased the risk of leukemia and several types of solid cancer such as breast cancer, regardless of racial/ethnic group (pasqual et al.). however, rai treatment for dtc did not increase the risk of second thyroid cancer (pasqual et al.). this indicates that rai treatment may not be a risk factor for thyroid cancer which differentially impacts certain racial/ethnic groups. further studies could examine the racial/ethnic variations in rai treatment sensitivity or resistance to determine if these contribute to thyroid cancer health disparities. 3.3.2. diagnostic differences in tc health disparities many literature suggest that thyroid cancer’s racial/ethnic differences could be related to socioeconomic status and insurance coverage impacting dissimilar access to us-guided fna and www.companyofscientists.com/index.php/chd e8 cancer health disparities research computed tomography (ct) (brown et al., 2010; keegan et al., 2015; morris et al., 2013; reitzel et al., 2014; roche et al., 2016; stroup et al., 2012; weeks et al., 2018; zevallos et al., 2015). while thyroid cancer incidence has been increasing over time irrespective of socioeconomic status, a study in texas reports a difference in the rate of increase between low and high socioeconomic status ethnic groups (reitzel et al., 2014). in particular, the study found a low thyroid cancer incidence rate among low socioeconomic status non-hispanic african americans and hispanic americans and a high thyroid cancer incidence rate among high socioeconomic status non-hispanic african americans and hispanic americans (reitzel et al., 2014). similarly, a study in north dakota found that counties with higher median income levels had increasing incidence rates, likely due to detection bias associated with increased access to physicians (schwartz and klug, 2019). studies have also shown that among thyroid cancer patients, european americans (vs. noneuropean americans) have greater odds of having tumors <40mm, and this variability in diagnosis is likely due to differences between races in their access to medical care to detect these tumors; particularly, european americans tend to have and seek more access to medical care than racial/ethnic minority patients (national research council panel on race and health in later, 2004; weeks et al., 2018). however, once tumors increase to a size ≥40mm in other races/ethnicities, they become palpable, thus leading patients to seek medical attention similarly (weeks et al., 2018). regarding insurance coverage, it has been found that insured patients were 45% more likely to be diagnosed with small tumors compared to the uninsured (weeks et al., 2018). a study found that adolescent and young adult patients who were diagnosed between 2001 and 2010 had a worse overall survival if they had no medical insurance (keegan et al., 2015). another study found that ageadjusted thyroid cancer incidence rates were 2-3 times greater in uninsured hispanic americans than in uninsured european americans (weeks et al., 2018). the reverse incidence rate was found in insured hispanic americans compared to insured non-hispanic european americans (weeks et al., 2018). as mentioned previously, racial/ethnic minority populations are more likely to be uninsured (artiga s, 2021; national research council panel on race and health in later, 2004), therefore these findings suggest that access to medical care and insurance could influence incidence rates among racial/ethnic groups differentially. 3.4. metabolic factors obesity, metabolic syndrome, and insulin resistance in tc health disparities while there has been a rise in thyroid cancer incidence, the centers for disease control and prevention (cdc) reports that there has also been a rise in obesity in the united states; obesity prevalence has increased from 30.5% to 42.4% from 1999-2000 through 2017-2018, and the prevalence of severe obesity has increased from 4.7% to 9.2% (https://www.cdc.gov/obesity/data/ adult.html). besides being associated with a number of chronic diseases, such as diabetes mellitus and cardiovascular disease, studies have also shown that obesity puts individuals at a higher risk of thyroid cancer compared to those with normal weight (bogović crnčić et al., 2020; clinckspoor et al., 2011; franchini et al., 2022; hales et al., 2020; kushchayeva et al., 2022; ma et al., 2022; zhao et al., 2019). studies found that high bmi was significantly associated with the risk of papillary, follicular, and anaplastic, but not medullary, thyroid cancers (kitahara et al., 2016; zhao et al., 2019). furthermore, studies have shown that high bmi was associated with larger tumor size, multifocality, and https://www.cdc.gov/obesity/data/adult.html https://www.cdc.gov/obesity/data/adult.html www.companyofscientists.com/index.php/chd e9 cancer health disparities research advanced tumor-node-metastasis (tnm) stage (ma et al., 2022; zhao et al., 2019). in addition to high bmi, a waist circumference ≥109 cm has also been found as a strong predictor of thyroid cancer (lubin et al., 2017; ma et al., 2022). while one cohort study found that higher bmi was not associated with more aggressive tumor features and recurrence or persistence, this study looked at a 93% european american population at a single institution, therefore, the results may have been limited by the lack of racial/ethnic and socioeconomic diversity (paes et al., 2010). in these ongoing studies, it is important to recognize that obesity impacts some ethnic/racial groups more than others. in particular, nonhispanic african american adults have the highest prevalence of obesity (defined as a bmi of greater than or equal to 30) and severe obesity (defined as a bmi greater than or equal to 40) compared to other ethnic/racial groups (hales et al., 2020). by contrast, non-hispanic asian adults have the lowest prevalence of obesity (hales et al., 2020). despite having lower bmi’s than other racial/ethnic groups, asian americans tend to have high prevalence rates of metabolic syndrome, especially amongst filipinos and asian indians (palaniappan et al., 2011). filipinos and asian indians also tend to have a higher prevalence of obesity than non-hispanic european americans (palaniappan et al., 2011). this is particularly interesting considering the disproportionate impact filipinos face from thyroid cancer as well. therefore, further research is necessary to determine whether some factors which may impact obesity for a certain ethnic/racial group could impact that group’s risk for thyroid cancer. 3.5. behavioral factors lifestyle and diet in tc health disparities with the growing evidence that obesity may be associated with an increased risk of thyroid cancer, it is advised that individuals adopt a lifestyle that includes at least 60 min/day of moderate physical activity to reduce the incidence of obesity-related thyroid cancer (franchini et al., 2022; ma et al., 2022). some studies in the united states have found that higher levels of physical activity could reduce the risk of some cancers (bladder, breast, colon, endometrial, esophageal adenocarcinoma, and gastric cardia) while increasing the risk for some other cancers (lung, ovarian, pancreatic, and renal cancer) (friedenreich et al., 2021). however, these studies have not looked at the relationship between thyroid cancer, specifically, and physical activity (friedenreich et al., 2021). some research has been done to examine this relationship in korea; less physical activity in women was associated with a decreased risk of thyroid cancer, and a positive correlation was found between physical exercise and thyroid cancer (kim et al., 2021; lee et al., 2020). further research is needed to examine the relationship between physical activity and thyroid cancer among populations in the united states, especially since physical activity in the united states varies between racial/ethnic groups which could impact thyroid cancer outcomes. in particular, the cdc reports that hispanic adults have the lowest physical activity outside of work and non-hispanic asian adults have the highest. diets can vary by racial/ethnic group due to social and cultural differences between populations (satia, 2009). variations in iodine intake among racial/ethnic groups could be from differences in the consumption of seafood, dairy, grains, and eggs (bogović crnčić et al., 2020; herrick et al., 2018; nguyen et al., 2017). nitrate/nitrite intake can vary among racial/ethnic groups due to consumption of processed foods and meats, which is more common in certain racial/ethnic groups than others (said abasse et al., 2022). in particular, one study found that non-hispanic european americans were more likely than other racial/ethnic groups to consume excess processed meats (gudenkauf and www.companyofscientists.com/index.php/chd e10 cancer health disparities research thrift, 2021). this study also found that nonhispanic african americans had more cancer types attributable to processed meat consumption (gudenkauf and thrift, 2021). however, this study focused on non-hispanic european americans, non-hispanic african americans, and hispanics while grouping all other racial/ethnic groups together. further research is needed to examine differences in diet practices and nutrient intake among racial/ethnic subgroups since certain subgroups, such as filipino americans within the asian american population, tend to have high consumption of processed foods. social and cultural differences in diet could, therefore, place some racial/ethnic groups at a higher risk of thyroid cancer. it is worth noting that socioeconomic differences can play a role in access to ingredients and types of foods as well as how much physical activity individuals can realistically engage in due to barriers such as cost and time, placing minority populations at particular risk of thyroid cancer. some other lifestyle practices, such as smoking and alcohol consumption, could affect one’s risk of thyroid cancer. in the united states, one study examining smoking found that e-cigarette users had a higher prevalence of several cancer types including thyroid cancer compared to traditional smokers (chidharla et al., 2022). smoking and alcohol consumption habits vary by racial/ethnic group, as well, and could be due to social and cultural factors. according to the cdc, cigarette smoking prevalence is the highest in native americans and alaska natives and lowest among asian americans although within asian subgroups, koreans and vietnamese have high smoking prevalence (chartier and caetano, 2010). alcohol consumption tends to be most common in european americans, lowest in asian americans, and similar amongst native americans, hispanics, and african americans; however native americans tend to have the highest prevalence of heavy and binge drinking (chartier and caetano, 2010). these variations in smoking and alcohol consumption habits could contribute to the thyroid cancer health disparities seen between racial/ethnic groups in the united states, however, further research is needed to examine these relationships. 3.6. biological factors 3.6.1. thyroid-stimulating hormone (tsh) level in tc health disparities research suggests that thyroid stimulating hormone (tsh), also known as thyrotropin, mediates thyroid cell growth factors, such as igf-i and insulin (bogović crnčić et al., 2020). therefore, high levels of tsh may lead to an enlarged thyroid gland, or goiter (bogović crnčić et al., 2020; yildirim simsir et al., 2020). one study has found that higher levels of tsh is associated with a fourfold increase of thyroid cancer and a higher risk of advanced stage differentiated thyroid cancer (bogović crnčić et al., 2020). another study has found that even minimal elevations of serum tsh over time could lead to increased thyroid volume and goiter (yildirim simsir et al., 2020). obese individuals are at a higher risk of increased tsh levels and the development of goiter and papillary thyroid cancer (yildirim simsir et al., 2020). therefore, it is not surprising that tsh suppression therapy following radioiodine treatment can reduce the recurrence rate of differentiated thyroid cancer (bartenstein et al., 2014; kim et al., 2014; wang et al., 2022). however, further research is needed to look at whether levels of tsh vary by race/ethnicity in the united states. 3.6.2. sex in tc health disparities thyroid cancer is one of the most rapidly increasing types of cancer in both women and men (lim et al., 2017; rahbari et al., 2010; tortolero-luna et al., 2019; weeks et al., 2018). it is known that women are about three times more likely to be diagnosed with thyroid cancer than men, particularly through www.companyofscientists.com/index.php/chd e11 cancer health disparities research the finding of small tumors (<40mm) (rahbari et al., 2010; weeks et al., 2018). this places thyroid cancer as one of the top ten most diagnosed cancers in women as of 2018 (rahbari et al., 2010; weeks et al., 2018). furthermore, follicular and papillary thyroid cancers make up approximately 80% of thyroid cancer cases in women, and papillary thyroid cancer is three times more common in women than in men (horn-ross et al., 2011; rahbari et al., 2010). however, it is also known that men have a higher mortality rate compared to women (keegan et al., 2015; rahbari et al., 2010; tortolero-luna et al., 2019). additionally, men are more likely to have regional/distant stages of disease upon diagnosis, unfavorable clinicopathological characteristics such as angioinvasion, and a higher risk for recurrence of well-differentiated thyroid cancer (gajowiec et al., 2021; keegan et al., 2015; zahedi et al., 2020). while some studies have been looking at differences between men and women in hormonal regulation, androgen receptor gene expression, and certain somatic mutations, further research is needed to find if there are any strong associations with thyroid cancer (asban et al., 2019; chou et al., 2020; megwalu et al., 2021; o'connell et al., 2021; rahbari et al., 2010). when looking at whether sex as a risk factor for thyroid cancer varies by race/ethnicity, one study found a ratio of female to male incidence rates of 3:1 to 4:1 across racial/ethnic groups, including european americans, hispanics, asians, african americans, and native americans (weeks et al., 2018). it is likely that this higher incidence among women and the size of tumors upon diagnosis could be due to differences in access to medical care and women receiving more regular check-ups than men (rahbari et al., 2010; weeks et al., 2018). generally, however, there is a uniform 3:1 ratio of sex disparities across all ethnicities, suggesting that sex is a risk factor for thyroid cancer that does not differentially impact certain racial/ethnic groups. based on these findings, it is of interest to investigate differences in sex hormone levels among racial/ethnic groups. for example, a study found that african american men had higher sex hormone binding globulin (shbg) concentration and serum estradiol levels than hispanic american and european american men (rohrmann et al., 2007). serum testosterone levels did not differ between african american men and european american men, however hispanic american men had higher serum testosterone levels than the other racial/ethnic groups (rohrmann et al., 2007). another study looked at variations in hormone levels among overweight, glucose-intolerant, postmenopausal women (kim et al., 2012). this study found that, among women not using estrogen, non-hispanic european americans had higher baseline total and bioavailable estradiol and testosterone levels than hispanics, as well as higher baseline bioavailable estradiol and lower levels of shbg than african americans (kim et al., 2012). therefore, while sex differences exist across all racial/ethnic groups, it is still possible that variations in androgen and androgen receptor levels between racial/ethnic groups could contribute to the racial/ethnic disparity in thyroid cancer. future studies are required to investigate the correlation between androgen and thyroid cancer health disparities. 3.6.3. autoimmunity in tc health disparities autoimmune diseases (ad) are caused by inflammation of organs due to production of antibodies against self-structures and cytotoxic action of t cells (fröhlich and wahl, 2017). ad is prevalent in the population and is more common in women (≥85%) than in men. additionally, autoimmune thyroid disease (aitd) is one of the most common types (fröhlich and wahl, 2017). graves’ disease and hashimoto’s thyroiditis (ht) are www.companyofscientists.com/index.php/chd e12 cancer health disparities research examples of thyroid autoimmune diseases (umar et al., 2010). in graves’ disease, hyperthyroidism (low tsh and elevated free t4 concentrations) is caused by thyroid-stimulating autoantibodies to the tsh receptor (tshr) , which may lead to hyperfunction of the thyroid gland (umar et al., 2010). after delivering a baby, some patients may develop forms of autoimmune thyroid dysfunction, such as graves’ disease (inaba and akamizu, 2000). another is postpartum thyroiditis, which is also believed to be an autoimmune disorder, and its prevalence ranges from 3 to 8 percent of all pregnancies (inaba and akamizu, 2000). it is painless and occurs within 6 months after pregnancy, with a return to normal thyroid function typically within a year, although some patients develop permanent hypothyroidism as a result (inaba and akamizu, 2000). it is characterized by transient thyrotoxicosis followed by hypothyroidism or by one or the other occurring in the first year after parturition (inaba and akamizu, 2000). diagnostic tests reveal that serum tsh is suppressed, associated with an increase in serum ft3 and ft4 levels (inaba and akamizu, 2000). in ht, hypothyroidism (elevated tsh and low free t4 concentrations) is associated with thyroid peroxidase and thyroglobulin autoantibodies (mclachlan et al., 2007), and is thought to be caused by a tsh stimulation-blocking antibody (tsbab) which blocks the action of the tsh hormone causing damage to the thyroid gland (umar et al., 2010). retrospective pathological studies and fna cytological studies have shown an association between ht and papillary thyroid carcinoma (ptc) (boi et al., 2017). most pathological studies showed high prevalence of ptc in ht (boi et al., 2017). in most fnac studies, increased thyroid-stimulating hormone (tsh) levels were the main risk factor for malignancy (boi et al., 2017). additionally, several studies have shown an association between chronic inflammation and increased risk of developing differentiated thyroid cancers (dtcs) (pagano et al., 2018). this suggests that the inflammatory microenvironment is essential in cellular transformation and tumor progression (pagano et al., 2018). it has been demonstrated that inflammatory cells within the cancer site and activation of oncoprotein-mediated signaling in epithelial cancer cells influence thyroid cancer progression (pagano et al., 2018). racial disparities have been noted in autoimmune thyroid conditions (table 2). a study has shown that african americans and asians are much more likely to develop graves’ disease than european americans (mcleod et al., 2014). on the other hand, european americans have a greater risk of developing ht compared to other ethnic groups (mcleod et al., 2014). when evaluating thyroid function and autoimmunity in african american and european american women during pregnancy and the postpartum period, another study found that african american women always had lower tsh values than european american women (walker et al., 2005). these findings provide awareness of racial disparities in thyroid autoimmune disorders. table 2. racial disparities in autoimmune thyroiditis. www.companyofscientists.com/index.php/chd e13 cancer health disparities research european americans (ea) african americans (aa) asian americans graves’ disease (mcleod et al., 2014) less susceptible more susceptible more susceptible hashimoto thyroiditis (mcleod et al., 2014) more susceptible less susceptible less susceptible pregnancy/postpartum (walker et al., 2005) higher tsh values compared to aas lower tsh values compared to eas 3.6.4. thyroid nodule size in tc health disparities it is proposed that the dramatic increase in thyroid cancer incidence rates within the last few decades could be due to improved diagnostic techniques and the introduction of ultrasound-guided fineneedle aspiration (us-guided fna) into the united states healthcare system in the 1990s, which aids in detecting tumors that are not easily discovered by palpation (la vecchia et al., 2015; lim et al., 2017; tortolero-luna et al., 2019; weeks et al., 2018; zevallos et al., 2015). more sensitive diagnostic procedures, such as ct or mri scans (done for other medical problems), can detect nonpalpable, incidental thyroid nodules (itns) that might not otherwise have been found in the past (fisher and perrier, 2018). imaging studies can detect up to 10 times more nodules than by palpation, most of which are benign (fisher and perrier, 2018). approximately 5 to 15% of nodules are found to be malignant (alexander et al., 2012). for diagnostic purposes, nodules 1cm or larger in diameter prompt diagnostic us-guided fna, which is the only method routinely used for thyroid nodule evaluation (alexander et al., 2012; yoon et al., 2014). however, about 15 to 30% of thyroid nodules evaluated by fna are indeterminate, so it is unclear whether they are benign or malignant (alexander et al., 2012). indeterminate nodules are often referred for diagnostic surgery, though most of these nodules are shown to be benign (alexander et al., 2012). this exposes these patients to a 2 to 10% risk of serious surgical complications, and they could require thyroid hormone replacement therapy for life to overcome hypothyroidism (alexander et al., 2012). future work is needed for better diagnostic tools in preoperative diagnosis of thyroid cancer. autopsy studies estimate that thyroid nodules may be present in up to 50% to 60% of all adults (fisher and perrier, 2018). women are more frequently affected than men (4:1), and the prevalence of thyroid nodules in women increases with age (fisher and perrier, 2018). studies have been done exploring ethnicities affected. zheng et al. showed that thyroid nodules in african americans had consistently lower rates of harboring malignancy compared to other groups (zheng et al., 2022). among different ethnic groups represented in the study, the prevalence of thyroid malignancy was 24.0% of african americans, 52.1% of caucasian americans, 58.7% of hispanic americans, and 71.7% of asian americans (zheng et al., 2022). iwata et al. noted that african americans have a much lower incidence of thyroid cancer than other ethnic groups despite presenting with larger nodules, and european americans have a greater risk (iwata et al., 2018). this study aimed to see if there was a true difference in the thyroid cancer rates between these ethnicities, or if socioeconomic status perhaps played a role (iwata et al., 2018). they found that european americans have a higher incidence not only due to diagnostic bias, but also due to a true difference in cancer prevalence (iwata et al., 2018). another study aimed to determine whether patients of filipino descent are at increased risk of thyroid www.companyofscientists.com/index.php/chd e14 cancer health disparities research cancer compared to matched controls (clark et al., 2006). this group found that filipino patients with thyroid nodules are at significantly increased risk. thus, suspicion for malignancy should be high when evaluating these patients. recently, we showed a differential expression of vitamin d binding protein (dbp) in two different ethnic groups, which was related to advanced stage thyroid cancer in filipino americans compared to european americans (mull et al., 2021); higher dbp expression in european americans correlated to better prognosis. we further demonstrated that differential small non-coding rnas may potentially influence the poor prognosis in filipino americans versus european americans (rood et al., 2021). 3.6.5. chromosomal alterations/non-hereditary conditions influencing tc health disparities although germline mutations are very rare, somatic mutations play an important role in thyroid cancer oncogenesis. several genetic alterations have been implicated in the development of thyroid cancer, including activation of signaling pathways by either recombination events or point mutations, with some mutations associated with more aggressive forms (bogović crnčić et al., 2020; yildirim simsir et al., 2020). somatic mutations can cause dysregulation of mitogen-activated protein kinases (mapk), phosphoinositide 2 kinase-akt (pi3k-akt), and wingless-related integration site (wnt) cell signaling pathways (singh et al., 2021). they are some of the most common pathways associated with thyroid cancer (singh et al., 2021). both mapk and pi3k-akt pathways are coupled to the cell membrane receptor tyrosine kinase (rtk), which leads to downstream intracellular signaling and ultimately activation and deactivation of genes related to cell growth, proliferation, and survival (xing et al., 2013). the wnt pathway similarly leads to disordered cellular growth by preventing degradation of β-catenin, thus allowing its localization into the nucleus and subsequent activation of transcription factors involved in cellular proliferation and cell-cell adhesion (pai et al., 2017). activating point mutations of ras and braf and rearrangements of ret/ptc and ntrk genes within the mapk pathway, are common drivers of papillary thyroid cancer (ptc). in contrast, follicular thyroid cancer (ftc) frequently has alterations of the pi3kakt pathway such as activating mutations of pik3ca, ras, and akt1, and deactivating mutations of pten. other mutations such as p53 and tert promoter mutations, and wnt/β-catenin pathway alterations have been implicated in thyroid cancer disease progression and dedifferentiation (prete et al., 2020). there are few studies comparing the prevalence of these mutations across different racial/ethnic groups. one study evaluated radioiodine refractory thyroid (rair) cancers and found that european race/ethnicity was associated with a reduced odds ratio of radioiodine refractoriness (shobab et al., 2019). additionally, 50% of patients with rair had mutations in the ras/raf pathway; however, the prevalence of ras/raf mutation within europeans was not directly measured (shobab et al., 2019). another study performed whole-genome genotyping on european and african american patients with rair and found that the thyroglobulin, brca1, and the nsmce2 haplotypes were uniquely associated with african americans (hurst et al., 2019). differences in mutation can explain the established differences in the incidence of thyroid cancer among racial/ethnic groups. different mutations also carry varying prognoses. therefore, differences in chromosomal alterations between races/ethnicities can potentially contribute to the varying disease outcomes seen across racial/ethnic groups. additional studies are indicated to further explore the demographics and other racial/ethnic groups with common thyroid cancer mutations. www.companyofscientists.com/index.php/chd e15 cancer health disparities research 4. conclusions through this literature review, several risk factors are found to potentially impact thyroid cancer incidence and aggressiveness differently by racial/ethnic groups. chromosomal alterations/non-hereditary conditions, autoimmunity, thyroid nodules, and socioeconomic differences are identified as factors that vary by racial/ethnic group and influence thyroid cancer incidence and outcomes. some of these potential risk factors require further research to incorporate more racial/ethnic groups. the only risk factor that does not vary by racial/ethnic group is sex disparities. however, differences found in sex hormone levels between racial/ethnic groups may suggest their possible influence on thyroid cancer health disparities and necessitates further research. some studies on iodine deficiency, environmental pollutants, obesity/metabolic syndrome/insulin resistance, and lifestyle/diet as risk factors for thyroid cancer suggest that certain racial/ethnic groups could be differentially impacted. further research, however, is needed to specifically examine their relation to thyroid cancer or to clarify whether certain racial/ethnic groups are differentially impacted in the united states. additionally, while some racial/ethnic disparities exist in regards to the use of rai treatment, recent research suggests that this is not a risk factor for secondary thyroid cancer. other potential risk factors including radiation exposure, hereditary conditions, and tsh level have not yet been studied regarding their potential influence on thyroid cancer incidence and outcomes for different racial/ethnic groups in the united states. these should be given priority in future research work. 5. limitations a limitation of our literature review is that we did not perform a meta-analysis of potential factors contributing to thyroid cancer health disparities. however, we are currently gathering insight into the factors that may contribute to the differences in the genetic and epigenetic pathways of health disparities. additionally, the findings of our literature review are limited by the racial/ethnic groups that have been studied by the articles reviewed. in particular, some studies focused on two racial/ethnic populations only or may have grouped some racial/ethnic populations together. therefore, it is possible that variations in the potential thyroid cancer risk factors between racial/ethnic groups may have been limited by the lack of diversity in some of these studies. 6. future directions there are several areas of research which need to be addressed regarding thyroid cancer health disparities, as highlighted by this literature review. one such area of interest for our lab is the sex hormone-induced immune pathway in cancer cells. in future work, we will examine this pathway in relation to racial/ethnic groups in the united states to understand why filipino americans have higher tc incidence rates. additionally, although biologic differences were thought to be responsible for the difference in the severity and progression of thyroid cancer, no genetic or molecular level differences were reported so far. this literature review contributes to our knowledge of the several factors that may be correlated to the differential mirna expression we observe within ethnic groups. future work may include taking these factors into account in our statistical analysis in a larger cohort of patients. acknowledgements the authors would like to thank dr. reinhard schulte, md; dr. mia perez, md; celina r. yamauchi, bs; and dr. qudus lawal, md for contributing through conceptualization, reviewing, and editing of the manuscript. www.companyofscientists.com/index.php/chd e16 cancer health disparities research funding this research was supported by the department of otolaryngology and the national institute on minority health and health disparities (nimhd) [grant number p20md001632] (pi: deleon) from center for health disparities & molecular medicine, loma linda university school of medicine. this work was also supported by nimhd grant [grant number 5u54md007592]. author’s contribution conceptualization, kr, rl, sk; writing—original draft preparation, rl, kr, as, hsk, sk; writing— review and editing, rl, kr, as, hsk, sk; supervision, sk; funding acquisition, sk. all authors have read and agreed to the published version of the manuscript. conflicts of interest the authors declare that there is no conflict of interest regarding the publication of this article. consent all co-authors approve the submission of this manuscript. confirmation content of this manuscript has not been submitted for publication elsewhere, and is not under consideration for publication by any other journal. references autoimmune thyroiditis. arup consult®. alexander, e.k., 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(2022). comparing the rate and extent of malignancy in surgically excised thyroid nodules across race and ethnicity. the american journal of surgery 223, 617-623. 1. introduction 2. materials and methods 3. risk factors potentially contributing to tc health disparities 3.1. genetic factors hereditary conditions influencing tc health disparities 3.2. environmental factors 3.2.1. radiation exposure in tc health disparities 3.2.2. iodine deficiency in tc health disparities 3.2.3. environmental pollutants influencing tc health disparities 3.3. socioeconomic factors 3.3.1. radioiodine treatment 3.3.2. diagnostic differences in tc health disparities 3.4. metabolic factors obesity, metabolic syndrome, and insulin resistance in tc health disparities 3.5. behavioral factors lifestyle and diet in tc health disparities 3.6. biological factors 3.6.1. thyroid-stimulating hormone (tsh) level in tc health disparities 3.6.2. sex in tc health disparities 3.6.3. autoimmunity in tc health disparities 3.6.4. thyroid nodule size in tc health disparities 3.6.5. chromosomal alterations/non-hereditary conditions influencing tc health disparities 4. conclusions 5. limitations 6. future directions acknowledgements funding author’s contribution conflicts of interest consent confirmation www.companyofscientists.com/index.php/chd e1 cancer health disparities research breast and cervical cancer disparities in alabama: current scenario, ongoing efforts to reduce the disparity gaps, and what more we could be doing kiley caroline brady1#, claudia paige stephens1#, sarabjeet kour sudan2,3, ajay pratap singh2,3,4, santanu dasgupta2,3,4, seema singh2,3,4* 1frederick p. whiddon, college of medicine, university of south alabama, mobile, alabama, 36688; 2mitchell cancer institute, university of south alabama, mobile, al 36604, usa; 3department of pathology, college of medicine, university of south alabama, mobile, al 36617, usa; 4department of biochemistry and molecular biology, university of south alabama, mobile, al 36688 #equal contribution *corresponding author: seema singh, ph.d. email: seemasingh@southalabama.edu abstract over the years, we have made considerable progress in our understanding of the biology of various cancers leading to advancements in their management strategies. consequently, we have witnessed steady improvements in survival rates of cancer patients post-diagnosis. the progress; however, has been slow for some cancer types and the advances in cancer care have not benefited all the communities equally in the united states. the state of alabama has one of the most diverse demographics in the country and as a result, we witness significant health disparities among our populations. breast and cervical cancers are the two major cancer types that disparately affect the women in our state. here, we describe the extent of disparities in the diagnosis and death rates from these cancers in the state of alabama and discuss potential underlying causes affecting the health outcomes. we also discuss ongoing efforts undertaken to reduce the disparity gaps and provide a perspective for addressing these disparities more effectively. keywords: breast cancer, cervical cancer, cancer health disparities, african american, caucasian american. citation: brady kc et al (2022) breast and cervical cancer disparities in alabama: current scenario, ongoing efforts to reduce the disparity gaps, and what more we could be doing. cancer health disparities 6: e1-e10. doi:10.9777/chd.2022.1004. www.companyofscientists.com/index.php/chd e2 cancer health disparities research introduction cancer is the second leading cause of death in the nation, following only behind heart disease (nagai and kim, 2017). this year, nearly 1.9 million new cancer diagnoses and about 609,360 cancerrelated deaths are expected to occur in the united states (siegel et al., 2022). this number is 0.9% and 1% higher than the last year for overall cancer incidence and mortality, respectively (siegel et al., 2021, siegel et al., 2022). among the multiple cancers affecting women, breast cancer (bc) is the most common, with an overall annual incidence of 287,850 nationwide and an estimated death of 43,250 women (siegel et al., 2022). cervical cancer (cc) is another common malignancy that affects women with an expected 14,100 diagnoses this year alone in the united states and an estimated death of 4280 women according to the american cancer society (acs). while these statistics might be startling, the state of alabama has even higher allsite cancer incidence and mortality rates than the national average. from the years 2014-2018, the cancer incidence rate in alabama was 450.8 compared to 448.6 nationwide per 100,000 persons, and from 2015-2019 the mortality rate was 170.0 for alabama, compared to 152.4 per 100,000 in all states combined (profiles, 2014-2018). more importantly, significant health disparities are observed in these two cancer types in terms of disease incidence, aggressiveness, and mortality based on racial background, lifestyle, socioeconomic status (ses), and genetic background (yedjou et al., 2019). bc incidence has been lower among black women as compared to white women (seer, 2022a). in contrast, the mortality rate has been observed to be high in black women as compared to white women (seer, 2022a). in addition to racial background, bc disparity also exists due to ses and insurance status (newman and martin, 2007, bigby and holmes, 2005). similarly, cc disparity has been observed among different races in incidence and mortality rates between white and black women. the incidence and mortality rate of cc is found to be high in black women as compared to the white population (seer, 2022b). besides, women in rural areas have a higher incidence of cc as compared to women in urban areas (yu et al., 2019). in the sections below, we focus on the extent of bc and cc disparities in alabama and discuss possible underlying causes and the efforts that have been made to reduce the disparity gaps. we anticipate that our analysis will provide guidance in developing effective and collective approaches to address this significant clinical and social problem affecting women’s health in the state of alabama and nationwide. breast and cervical cancer disparities in alabama alabama is one of the southeastern states in the united states with diverse demographics. as per the most recent american community survey, alabama state has a diverse racial composition, as given in table 1 (worldpopulation, 2022). among gender distribution, there are 51.5% female and 48.5% male in alabama. in alabama only, there is an estimated 30,210 new cancer cases with a mortality of 10,520 in 2022 (siegel et al., 2022). as per state cancer profiles, bc is the most commonly diagnosed cancer in alabama after colorectal cancer and the second leading cause of cancer-related death in the state. from 2009-2018 the alabama statewide cancer registry (ascr) showed that the incidence of bc was higher for black women than for white women (126.5 vs. 118.1 per 100,000) (figure 1a). it is interesting since bc incidence is generally higher in white women than in black women. the incidence rate per 100,000 persons is 137.6 cases in white women as compared to 129.6 cases in women of black ethnicity (seer, 2022a). the mortality rates due to bc were also higher among black women www.companyofscientists.com/index.php/chd e3 cancer health disparities research than white women (28.0 vs. 19.9 per 100,000) (figure 1b). this difference in mortality rate is also greater compared to that observed in a nationwide comparison. as per the surveillance, epidemiology, and end results (seer) program, the mortality of black women is 28.0 compared to 19.9 in the white population. besides, black women have a low 5year survival rate compared to white women (moormeier, 1996). table 1. distribution of race in the state of alabama race percentage (%) white 67.50 black or african american 26.59 two or more races 2.44 some other races 1.53 asian 1.39 american indian and alaska native 0.51 native hawaiian or pacific islander 0.04 source: world population review. cc is the third most common women cancer globally and the second leading cause of cancerrelated mortalities in women between 20 to 39 years of age (abdalla et al., 2021, siegel et al., 2022). cc disparity has also been observed in incidence and mortality rates between white and black women. nationwide, the incidence of cc in black women is 9.0 cases per 100,000 women compared to 7.1 cases per 100,000 in women of white ethnicity. in addition, the death rate is different between white (2.0 cases per 100,000) and black women (3.4 cases per 100,000) (seer, 2022b). notably, the incidence of cc is significantly higher in alabama than in the united states average, with a rate of 9.0 versus 7.5, respectively. besides, the mortality rate of cc has also been significantly higher in alabama than in the usa, with a rate of 3.3 versus 2.3 (ascr, 2021). between black and white women, the incidence rate of cc in black women (10.2) is high as compared to white women (8.7) (figure 1a). additionally, black women have an approximately 1.5 times higher mortality rate due to cc than white women in the state of alabama (figure 1b) (ascr, 2021, abdalla et al., 2021). this disparity is of particular attention since cc is almost entirely preventable and treatable with proper vaccination, screening, and available treatments. human papillomavirus (hpv) infection is a significant cause of cervical carcinogenesis, and this malignancy is virtually ubiquitous in sexually active individuals (braaten and laufer, 2008, burd, 2003). vaccines are available to prevent hpv infection, and with timely screening, cc can be detected early at a more manageable stage (safaeian et al., 2007, thomas, 2016). thus, it becomes essential to understand the underlying reasons behind the unequal distribution of cancer among different races. figure1. incidence and mortality of breast and cervical cancer in alabama. (a) rate of incidence per 100,000 women with black and white racial background (b) rate of mortality per 100,000 women with black and white racial background. underlying causes of cervical and breast cancer disparities in alabama when discussing bc and cc, early detection and access to care are critical to decreasing the mortality rate. among various causes, lack of medical insurance is one of the reasons behind the disparity. about 31.6 million people in the us were uninsured as of 2020 (cha and cohen, 2022). to www.companyofscientists.com/index.php/chd e4 cancer health disparities research qualify for medicaid in alabama, you must be characterized in the low-income or very lowincome category, pregnant or responsible for a person under 18, disabled or have a disabled family member, blind, or over 65 years of age (alabama medicaid, https://www.benefits.gov /benefit/1618). although with the help of the affordable care act, there has been an increase in the availability of reasonable insurance options via medicaid expansion among black americans however, alabama is among the states that have chosen not to expand medicaid coverage following the acs, 2010 even though it has some of the lowest eligibility rates in the country (insurance, 2021) (health insurance.org). another important cause for the disparity is accessibility to health care facilities. even if low-income women in alabama could get medicaid coverage, healthcare access becomes the second hurdle in the way. the black belt describes a series of 17 counties in alabama that lack access to social and medical services, whose economy depends predominantly on agriculture, and have populations that are at least 50% black and a per capita income of around $13,000. as per 2021 poverty guidelines, the national poverty line for one individual in 2021 is $12,880 and $21,960 for a family of three. of the 17 counties that fall into the black belt, only 4 have at least one obstetrician-gynecologist as of 2018, as per the human rights watch report. proper gynecological care and screening for cc have fiveyear survival rates of 93% (flannery, 2018). limited screening of black women is also a factor contributing to the health disparities. mammogram screening has been shown to decrease 10-year mortality by 41% in bc patients (duffy et al., 2020). the hpv vaccine is the best way to prevent women from developing cc. still, black women who are statistically less likely to have a primary care provider have reduced access to this preventative measure. according to the kff analysis of the centers for disease control and prevention (cdc)'s 2020 behavioral risk factor surveillance system, in alabama, 15% of black women were reported to have no personal healthcare provider compared to 12% in the case of women with white racial backgrounds. the increased incidence of poverty in alabama’s black belt also contributes to the increase in incidence. while a pap smear is routine for many women, an alarming number of lower-income women, a larger percentage of whom are in this region are black, are unable to take time off work to receive this essential standard of care. as per the center for health journalism, 2016, the poverty rate was 32.7% for black individuals compared to 8.1% for white people in the region (barry-jester, 2016). while it cannot be doubted that income, insurance status, access, and other heavily economic reasons account for differences in care, even when black women are diagnosed, they are still more likely to die from cc even when compared to white women in their same socioeconomic class (abdalla et al., 2021). another issue that is particular to alabama is abstinence-only teaching in schools. education can empower the women with the understanding to go for screening and vaccinations when required to decrease the burden of cancer. in many alabama counties, a black belt, in particular, there is no fund in public schools due to state constitution restrictions. sexual health education has no importance, and it is left unregulated and unmonitored, which further increases the spread of cc (flannery, 2018). hence, it becomes imperative to provide education regarding sexually transmitted infections and strategies for their prevention and also provide sufficient funds for their implementation in the curriculum without any biasing (figure 2). www.companyofscientists.com/index.php/chd e5 cancer health disparities research figure 2. schematic diagram showing different factors involved in cancer health disparities in alabama. closing the disparity gaps: what we are doing and what more we could do ongoing remediation efforts: although the incidence and mortality rates for both bc and cc are alarming, they have not gone entirely unnoticed by the state. one measure to offset the cost and thereby increase diagnosis and treatment is the alabama breast and cc early detection program (abccedp). the abccedp provides free breast and cc screenings for women ages 40-64 at or below 250% of the federal poverty line, or an annual income of $33,975 for one individual. there are also certain instances where women of this income level can qualify at younger ages, such as a first-degree family history of bc or previous tubal ligation for cc screening (medicaid). this program helps bridge the gap for those who would not usually qualify for medicaid, thus allowing women of all races to receive necessary care. however, a program like abccedp is only helpful if women know about it. this is where the community health advisor program based at the university of alabama at birmingham (uab) has the potential to be more beneficial. as part of the deep south network for cancer control (dsn), this program trains individuals that are already leaders in their community to become community health advisors (chas) and community health advisors as research partners (charps). the dsn works to spread information regarding breast and cc screening and treatment. funded by the national cancer institute, this program helps build infrastructure, partners with state organizations and coalitions, and implements interventions in target communities where cancer disparities are disproportionately high (lisovicz et al., 2008). the thought process behind this model is that information will be more trusted and highly regarded if it comes from community pillars to whom people are already looking for information. the goal is to build a volunteer, grassroots community infrastructure that provides individuals in that community the opportunity to take control of their health and lessen healthcare disparities (uab, 2022). in the first three years of the programs, from 2001 to 2004, alabama charps reported a greater than 700% increase in referral screenings in targeted communities. it is evident that the program is working, and people are receptive to the work being done by the dsn and charps. more such programs need to be developed and federally or state-supported to reach and benefit communities across the state. moreover, the involvement of advocates from different communities, including minority groups, should be sought to enhance engagement and develop ways to maximize the reach and benefits. lessons from the parallel public health efforts: currently, the patterns of racial disparity, inequality, and exclusion all contribute to minority women being less likely to receive the reproductive health care services and follow-up they need. while efforts are in place to help combat these problems, more work is still required. the human rights watch identified four critical interventions that can be used to prevent, treat, and cure cc and the same could be applied to bc as well. these include i) vaccination ii) screening, iii) timely follow-up after www.companyofscientists.com/index.php/chd e6 cancer health disparities research abnormal test results, and iv) early treatment (flannery, 2018). the hpv vaccine is highly effective at reducing the incidence of cc compared to unvaccinated women (lei et al., 2020). currently, the national average for hpv vaccination in adolescents in this age group is 58.6%, and the alabama average is 52.9% (vaccination, 2022). working with systems already in place, such as the dsn and charp, and implementing new strategies to help remind patients and make access to vaccines easier will help increase vaccination rates across the state. cc screening is essential to detect cancer at an initial stage with high chances of cancer treatment. tests for hpv infection need to be done for screening for cc, and we should make every effort to increase the participation of minority women in the screening process. moreover, we should also develop ways to provide timely followup to the minority women, who come up with abnormal screening. finally, the women who are diagnosed with malignancy should be provided early and optimal treatment to enhance clinical outcomes. implementation hurdles and awareness issues: despite medical advances and recognition of cancer health disparities, multiple hurdles restrict the efforts targeted at reducing the existing disparities. the problem lies in rural communities where there is a lack of medical facilities. additionally, the cost of a visit is also high for those without insurance and for those living at or below the poverty line. for these people, choosing to take care of health problems that may not currently be causing issues may be trumped by basic needs such as food, shelter, and clothing. besides, it is essential to inform the public regarding their sexual and reproductive health. the cdc identified that fewer than 43% of high schools and 18% of middle schools teach the key topics for sexual health education in their curriculum (cdc, 2020). this population of adolescents and young adults make up a quarter of the world’s population and is the largest cohort of young people in history (nguyen et al., 2019). alabama’s current laws do not mandate that sex education be taught in schools. if it is introduced, the state approaches the conversation from a largely pure culture mindset, emphasizing abstinence-only teaching. while the state mandates that students receive hiv/aids education through a school program between the grades of 5-12, and efforts are currently being made to remove anti-homosexuality language in the laws, there is still no requirement for schools to cover these topics in their curriculum. cdc data suggests that nearly one-third of high school students in the state of alabama are sexually active, and these students are the most at risk for engaging in risky sexual behaviors that can lead to hiv infections, sexually transmitted diseases, and unintended pregnancies, which all have long-term effects on their health (profiles, 2016). by changing the beliefs, attitudes, and behaviors of this population regarding sexual and reproductive health, a shift can be made to change the culture around these topics. recent guidance from the american college of obstetrics and gynecologists suggests that taking a more holistic approach to sexual education may be a first step in overcoming social, economic, and political factors that have negative sexual, psychological, and social influences on reproductive health. while the state is making an effort to be more inclusive and encourage conversations regarding sexual health, future revisions should take a more biological approach and focus on setting clear health goals, reproductive development, consent, communication, recognizing and preventing sexual violence, human rights about lgbtq+ community and others (profiles, 2016). schools can use resources such as the cdc’s health education curriculum analysis tool to engage in more www.companyofscientists.com/index.php/chd e7 cancer health disparities research comprehensive conversations with their students and provide valuable information regarding sexual and reproductive health. by shifting away from the purist mindset and focusing on a research-based curriculum that addresses social pressures and influences and increases personal perceptions of the risks and harms of engaging in certain behaviors, the culture, and mindset around sexual and reproductive health will shift. moving forward: with this in mind, there are three critical areas that the state can focus on to increase access to care and decrease the burden among populations at the highest risk. by expanding the medicaid eligibility to cover adults earning 138% of the federal poverty line, medicaid enrollment would increase by 283,636 patients. while this would cost the state an average of $225.4 million per year above current expenditures, the state could see savings of up to $397.8 million (parcalabama, 2022). this increase in federal revenue would not only help alleviate the financial burden placed on low-income families but also reduces racial and ethnic disparities gaps, strengthens rural health care provider institutions, and would help the state economy. expanding medicaid eligibility would also create an estimated average of 20,083 new jobs annually for the following six years (parcalabama, 2022). this would seem to be a promising work opportunity for the growing number of medical students graduating each year. however, with the average medical student graduating with $194,280 in debt from a public institution, working in a rural community can be daunting, knowing the pay could be significantly reduced (calonia, 2022). that is why programs such as the university of alabama’s college of community health sciences rural medical scholars and rural community health scholars programs and the blue cross blue shield of alabama primary care physician network scholarship are being created to help offset the costs of medical education and encourage students to seek our rural positions (bcbs, 2018, zganjar, 2021). these programs target medical students from the four medical schools within the state who desire to work in underserved communities, such as the black belt, and provide better scholarship funding and specialized training to prepare these students for their work in these fields. by funding programs and rural medicine loan forgiveness programs, graduating medical students are incentivized to care for these populations in need without the fear of being unable to pay back the money used for their initial education. moreover, increasing the available obstetriciangynecologists in rural areas will help. transportation to these offices can still be a major issue for women seeking care. alabama is one of only three states that does not provide state funding for public transportation. many seniors, people with disabilities, and low-income families suffer from the lack of this facility. in 2018, the alabama state legislature created the public transportation trust fund to combat the lack of available transportation. however, no state funds had been allocated to the fund until february 2022. this initial transit funding is designed to help update current bus fleets and facilities and build new rail cars, tracks, and stations throughout the state. while this is a great first step, we must continue advocating for funding to be allocated to the state to improve transportation throughout the state. conclusion drastic differences in care between black and white women because of socioeconomic and geographic factors largely contribute to the racial cancer health disparities throughout the state of alabama. moreover, lack of information available to the public has made the mindset of many fall into the category of “if i don’t have to go, i won’t go”. in www.companyofscientists.com/index.php/chd e8 cancer health disparities research addition, the cost of missing work, traveling throughout the state, or expenses of the care itself far outweigh the perceived benefits. while efforts are being made throughout the state to increase access to care, alleviate financial burdens, and raise awareness regarding sexual and reproductive health, more work is still needed. there is also a need to understand the causes of health disparities beyond socioeconomic and geographical aspects. it is being increasingly recognized that there are significant differences in the tumor biology of minority patients. we all know that african american women are more likely to be diagnosed with an aggressive triple-negative breast tumor subtype, compared to caucasian american women, which likely also contributes to their greater mortality as per acs, 2022. there are other biological differences that have been reported between aa and ca women (deshmukh et al., 2017, deshmukh et al., 2015, olusola et al., 2019). clearly, we need to precisely characterize these differences in tumor biology and genetics and study their impact on patient outcomes. clinical trials testing new drugs should also enroll minority patients to determine if the drug efficacy is similar or different among diverse racial populations. altogether, by developing more awareness, developing ways to provide equal healthcare to all, and providing the right treatment based on the genetic makeup of the tumors, the state and the country at large, can succeed in reducing the prevalent health disparities in cancer. conflict of interest the authors declare that they have no conflict of interest. author contribution study design and oversight: ss, aps; data acquisition: cps, kcb, sks; writing original draft: cps, kcb, sks; review and supervision: sks, aps, sd, ss. acknowledgment this work was supported, in part, by funding from the nih/nci [r01ca231925 (ss), medical student summer research program of the whiddon college of medicine, (kcb, cps), and mitchell cancer institute, university of south alabama. references abdalla, e., habtemariam, t., fall, s., troy, r., tameru, b. & nganwa, d. 2021. a comparative study of health disparities in cervical cancer mortality rates through time between black and caucasian women in alabama and the us. int j 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https://parcalabama.org/wp-content/uploads/2022/01/economic-analysis-of-alabama-medicaid-expansion.pdf https://parcalabama.org/wp-content/uploads/2022/01/economic-analysis-of-alabama-medicaid-expansion.pdf https://www.cdc.gov/healthyyouth/policy/pdf/summary_report_factsheets/alabama.pdf https://www.cdc.gov/healthyyouth/policy/pdf/summary_report_factsheets/alabama.pdf https://statecancerprofiles.cancer.gov/ https://seer.cancer.gov/statfacts/html/cervix.html https://seer.cancer.gov/statfacts/html/cervix.html https://www.uab.edu/onealcancercenter/outreach/community-health-advisor-program https://www.uab.edu/onealcancercenter/outreach/community-health-advisor-program https://www.americashealthrankings.org/explore/annual/measure/immunize_hpv/state/al https://www.americashealthrankings.org/explore/annual/measure/immunize_hpv/state/al www.companyofscientists.com/index.php/chd e10 cancer health disparities research yedjou, c. g., sims, j. n., miele, l., noubissi, f., lowe, l., fonseca, d. d., alo, r. a., payton, m. & tchounwou, p. b. 2019. health and racial disparity in breast cancer. adv exp med biol, 1152, 31-49. yu, l., sabatino, s. a. & white, m. c. 2019. rural-urban and racial/ethnic disparities in invasive cervical cancer incidence in the united states, 2010-2014. prev chronic dis, 16, e70. zganjar, l. 2021. ua programs welcome students studying rural health care [online]. available: https://news.ua.edu/2021/10/ua-programs-welcomestudents-studying-rural-health-care [accessed 2022]. introduction breast and cervical cancer disparities in alabama underlying causes of cervical and breast cancer disparities in alabama closing the disparity gaps: what we are doing and what more we could do conclusion conflict of interest author contribution acknowledgment www.companyofscientists.com/index.php/chd e1 cancer health disparities research highlights from international conference on cancer health disparities murali m. yallapu1,2*, jorge teniente3, andrew tsin3,4, and subhash c. chauhan1,2* 1department of immunology and microbiology, school of medicine, university of texas rio grande valley, mcallen, tx, usa 2south texas center of excellence in cancer research, school of medicine, university of texas rio grande valley, mcallen, tx, usa 3office of research, school of medicine, university of texas rio grande valley, mcallen, tx, usa 4department of molecular sciences, school of medicine, university of texas rio grande valley, mcallen, tx, usa *corresponding author: murali m. yallapu, ph.d., e. mail: murali.yallapu@utrgv.edu. subhash. c. chauhan, ph.d., e. mail: subhash.chauhan@utrgv.edu abstract the first international conference on cancer health disparities (icchd) was held on august 13-14, 2021, in harlingen, tx, usa. this two-day icchd-2021 was organized by the university of texas rio grande valley, school of medicine (utrgv-som). about 200 national and international delegates from 10 countries attended this hybrid meeting in person and through online digital platforms. the event delegates were representatives from national institutes of health (nih), cancer prevention and research institute of texas (cprit), and the city of harlingen, in addition to clinicians, faculty, researchers, scientists, bioinformaticians, geneticists, bioethicists, and others. under the theme of cancer health disparities, this event featured a number of special talks and showcased the work done by researchers from a broad array of disciplines (academia, community, and health care) to identify gaps and/or solutions to multi-faceted heath and health disparity issues impacting minority and underserved populations across the country and worldwide. the conference was comprised of six sessions: session 1: introduction to the conference and tackling cancer health disparities; session 2: elimination of cancer health disparities; session 3: cancer cellular and molecular biology; session 4: diversity and inclusion in cancer research: session 5: poster and oral presentations, and early career investigator talks; session 6: an award ceremony and closing remarks. this conference report summarizes the meeting’s content, discussions, and conclusions. keywords: research symposium, cancer health disparities, cancer biology, drug delivery, medical research. citation: yallapu mm et al (2022) highlights from international conference on cancer health disparities .cancer health disparities 6:e1-9. doi:10.9777/chd.2022.1001 www.companyofscientists.com/index.php/chd e2 cancer health disparities research introduction the university of texas rio grande valley (utrgv) is located at the united states (us)-mexico border, a region predominately latino/hispanic. utrgv is the second largest hispanic-serving institution in the us and has a special focus on addressing health disparities in the rio grande valley, where approximately 1.4 million people reside. in view of the region’s urgent needs, the school of medicine (som) was founded in 2015 to provide improved health care, medical educational, and biomedical research. utrgv-som is strategically positioned to improve the lives and well-being of surrounding communities through innovative research and patient-centered care. utrgv-som attracting and supporting research that will help to address the health disparities of the rio grande valley (rgv) latino/hispanic population. as a part of its mission to educate a diverse group of medical students, residents, and future biomedical scientists, in 2017 the som began hosting an annual research symposium. to date, utrgv-som has successfully held three annual research symposiums on health disparities in the rio grande valley (1-3). these symposiums have provided continued medical education, promoted minority communities to participate in health and health disparities research, and advocated attention to health issues that affect hispanic and other underserved communities. considering the numerous cancer health disparities that exist in the rgv region, utrgv-som sought to focus the 4th annual utrgv-som research symposium on cancer health disparities. the research symposium titled the “international conference on cancer health disparities (icchd2021)” which was held during august 13-14, 2021. because the rgv region is a hot spot for several cancer heath disparities (liver, gall bladder, stomach and cervical), the national cancer institute (nci) of national institutes of health (nih) graciously sponsored this conference (1r13ca254453-01; principal investigators: subhash c. chauhan and andrew tsin) along with the utrgv-som. our scientific agenda showcased collaborative and community-engaged research in which researchers, practitioners, and communities (e.g., biomedical, clinical and translational science) discussed global cancer health disparities in a single forum. the icchd-2021 emphasized how the scientific and medical research community can interact with community health organizations/workers to discuss the common goal of addressing global minority health and health disparities. the research studies include many projects focused on health disparities among hispanic, african american, and american asian/indian populations. icchd-2021 included presentations including, but not limited to, the us, canada, mexico, latin american, and asian, african, and european countries. many utrgv-som teams conduct research and work with hispanic, african american, american indian, and american asian populations in the u.s. the icchd-2021 closely aligns with the mission of the nci and national institute on minority health and health disparities (nimhd), that is, to support global cancer research and cancer health disparity research to advance scientific knowledge and help all people live longer/maintain a quality lifestyle after cancer diagnosis/treatment. cancer health disparities impact millions of people across the us and around the globe (4-6). disparities in cancer burden/prevalence, incidence, and health outcomes are evident by race/ethnicity, geography, genetics, gender, culture, and sexual orientation. cancer health disparities are primarily due to not only to poor access to health care, comorbidities, chronic stress, and ancestry, but also correspond to cultural, socio-economic, biological, and environmental factors. thus, there is a critical need for research on global health disparities impacting disadvantaged populations. we are www.companyofscientists.com/index.php/chd e3 cancer health disparities research keenly aware of the need for a diverse scientific workforce to foster scientific innovation, global health, and community service. icchd-2021 was aimed to promote a robust learning environment, to improve the quality of research, and to advance participation of global health disparity populations who benefit from health research. the community outreach program during the icchd-2021 promoted information dissemination and enhanced public trust essential for the success of intervention programs to reduce and eliminate us-mexico border and global cancer health disparities. the prime objectives of icchd-2021 were 1) to provide a unique platform for open scientific discussions between basic, clinical, and translational cancer researchers from institutions on both sides of the us-mexico border and from other international institutions, 2) to introduce health disparities concepts and educate new investigators in global cancer health disparity research and organize community-based participatory research and outreach, and 3) to enable interprofessional and transdisciplinary partnerships to bring awareness and help eliminate minority health disparities in the u.s. and other countries. the icchd-2021 reports recent advances in understanding of the causes of cancer health disparities in rural populations and among various ethnicities. the icchd-2021 also focused on the roles of financial hardship and the tumor immune profile in causing outcome disparities and discuss evidence-based strategies to reduce these disparities. the icchd-2021 was comprised of six sessions and reported on various health disparitiesrelated topics, discussions, interaction, engagement, and collaboration among participants, administrators, state and federal officials, and stakeholders. despite the ongoing covid-19 pandemic, a total of 200 participants from more than 10 countries attended the icchd2021 either in-person or through digital online platforms. among these participants were several renowned faculty, researchers, scientists, and students from reputed institutions, centers, hospitals, and universities. overall, the majority of participants were from academic and research institutions. summary of the conference the icchd-2021 not only aligns with the mission of the nci global health center, but it is novel to the region and is one of the few health disparity research conferences in the us with an emphasis on cancer research in minority health and health disparities. the icchd-2021 opened a platform to transform the biomedical and health disparity research culture in the rio grande valley and beyond. access was broadened at the icchd-2021 through novel health disparity content and approaches, work with community health organizations and health workers, and simultaneous spanish interpretation of sessions. the icchd-2021 was comprised of six sessions: session 1: introduction to the conference and tackling cancer health disparities; session 2: elimination of cancer health disparities; session 3: cancer cellular and molecular biology; session 4: diversity and inclusion in cancer research: session 5: poster and oral presentations, and early career investigator talks; and session 6: an award ceremony and closing remarks. dr. subhash c. chauhan, professor and chairman of the department of immunology and microbiology and the director of south texas center of excellence in cancer research, school of medicine, utrgv, opened the conference by warmly welcoming and greeting to participants. he introduced dr. michael b. hocker, dean, school of medicine, utrgv; honorable christopher boswell, mayor, city of harlingen; and dr. parwinder grewal, www.companyofscientists.com/index.php/chd e4 cancer health disparities research executive vice president, research, graduate studies, and new program development, utrgv. they briefly shared the roles and engagement of the cancer center, school of medicine, city of harlingen, and university research and graduate programs addressing cancer and cancer health disparities in the rgv region, texas, the us, and around the globe. day 1 opened with two plenary presentations and two keynote talks by world renowned speakers. this session was moderated by dr. chauhan. dr. rina das, program officer, division of integrative biological and behavioral sciences, nimhd, presented on the topic “nimhd mission and programs in health disparities,” which delineated programs that exist for investigators, researchers, and students. next, dr. jose a. torres ruiz, chancellor at ponce health sciences university (phsu) in ponce, puerto rico, focused on “eliminating cancer health disparities through the phsu specialized center in health disparities.” he described the implementation of cancer health disparity research at the phsu. after this, dr. renu wadhwa, professor of the school of integrative and global majors, university of tsukuba, japan, presented on “experimental evidence to the bioactivities of propolis constituents, caffeic acid phenethyl ester and artepillin c presentation” which reports the feasibility of implementing natural agents for cancer prevention. as a concluding talk, dr. jamboor k. viswanatha, regents professor and vice president, and director of texas center for health disparities, university of north texas health science center, presented on “mien1 in regulation of migration and invasion in prostate and breast cancers” correlating how use of mien1 can be extended in tackling cancer health disparities. of equally high standards as the first session, day 2 started with a morning session on elimination of cancer health disparities moderated by dr. bilal hafeez, assistant professor, school of medicine, utrgv. dr. sunil saini, director of cancer research institute, himalayan institute hospital trust, swami rama himalayan university, india, presented his team work on “multitude of disparities in cancer care in india”. this work primarily relates to india where approximately 70% of the rural population have very limited access to cancer care and facilities. additionally, india needs specifically tailored cancer control strategies, taking into account the time, current trends, and resources available to patients. the next presentation was delivered by dr. junichi fujii, professor of biochemistry & molecular biology, yamagata university, japan. his presentation focused on “genetically modified mice that undergo both oxidative stress and endoplasmic reticulum stress spontaneously develop hepatocellular carcinoma” which confirmed the development of a suitable animal model that transitions from non-alcoholic steatohepatitis (nash) to hepatocellular carcinoma (hcc) progression. this dko model undergoes oxidative/er stress that would clarify the pathogenesis of hcc development initiated by non-alcoholic fatty liver disease (nafld). during the morning, a presentation was made by nationally renowned physician scientist, dr. daniel petereit, member of monument health cancer care institute, monument health, on a topic “the walking forward cancer disparity program: a model for community cancer control”. dr. petereit is a prominent researcher looking at cancer health disparities in the native american population of the northern plains. he presented his work of two decades on the cancer disparity program that was implemented in south dakota in collaboration with local ethnic groups. the final talk of this session was presented by dr. dulal panda, chair professor, department of biosciences & bioengineering, iit bombay, from india. his presentation on “inhibition of wnt/β-catenin signaling is a prominent www.companyofscientists.com/index.php/chd e5 cancer health disparities research antitumor activity of microtubule-targeting anticancer drugs” provided more understanding of the mechanism of anticancer action of microtubule targeted drugs towards development of antimitotic agents. the third session of the symposium was on cellular and molecular biology and determinants of cancer health disparities. this was the first breakout session, held during the morning of the second day. in hall a’s breakout session, dr. manish tripathi assistant professor, school of medicine, utrgv and dr. sheema khan, assistant professor, school of medicine, utrgv, were session moderators. first, dr. keshav singh, professor, department of genetics, uab school of medicine, presented a keynote talk on “mitochondrial determinants of cancer health disparities.” his work documents a number of findings that demonstrate how mitochondria contributes to determining cancer health disparities. dr. mehdi shakibaei, professor institute of anatomy, ludwig maximilian university, munich, from germany delivered a presentation on “calebin a decreases tumor microenvironment inducing emt in crc cells via modulation of nfkb/slug axis.” his team’s study indicates that the tumor microenvironment has a pivotal impact on tumor progression, and epithelial-mesenchymal transition is an extremely crucial initial event in the metastatic process in various cancers which can be prevented by employing a naturally occurring molecule, calebin a (an ingredient in curcuma longa). in the next presentation, dr. upender manne, director/ professor, anatomic pathology, university of alabama at birmingham school of medicine, presented recent outcomes of his study on “interplay of molecular factors and comorbid conditions in cancer disparities.” this work shows how distinct molecular alterations contribute to cancer health disparities, and he continues investigating various molecular factors and comorbid condition analyses through a grant from the center to reduce cancer health disparities branch of the national cancer institute (u54ca118948). in the concluding presentation, a breakout session was presented by dr. nadeem zafar, director, pathology and laboratory medicine service, va-washington, from seattle on the topic “promoting healthcare as a career for minority students to fight cancer health disparity,” which referred to a number of points on cancer disparities in terms of differences in cancer measures which can be minimized by education, frequent/annual medical visits/test, minority community awareness, and the welfare pipeline. dr. zafar’s work also emphasizes how awareness of healthcare careers for american minority populations can be enhanced by medical schools’ educational programs/components. in the morning breakout session in hall b, dr. subash gupta, assistant professor, institute of science, banaras hindu university, and dr. ajaikumar kunnumakkara, professor, department of biosciences and bioengineering, indian institute of technology guwahati, from india were session moderators. dr. subash gupta delivered the keynote presentation on the special topic “unraveling the long non-coding rna signatures for gall bladder cancer”. his team findings identified a distinct role of long non-coding rna for initiation, progression, and metastasis of cancer cells in vitro/in vivo models which needs to be further verified and investigated in human samples. dr. alok bharti, professor, department of zoology, university of delhi, india, delivered the next presentation on “plant-derived homeopathic preparations with anti-cervical cancer and antihuman papillomavirus activity as alternative to mitigate cancer health disparity”. his data supports the use of homeopathic preparations as a promising cost effective and safe alternative for cancer therapeutics against cervical cancer in lowresource settings. dr. anshika arora, assistant www.companyofscientists.com/index.php/chd e6 cancer health disparities research professor, swami rama himalayan university, india, described their team work on “association of nutritional status with failure to complete planned treatment in patients with hnscca prospective cohort study in a tertiary cancer center in northern india”. this study confirms that various nutritional parameters (weight, bmi, muac, weight loss, and sga score) are highly associated with failure to complete treatment. thus, it advises that disparities in the nutritional status of patients undergoing treatment for head and neck squamous cell carcinomas need to be acknowledged. another distinct talk on “disparities in occurrence of cancer due to different treatment modalities in rheumatoid arthritis patients” was delivered by dr. varsha gupta, assistant professor, department of biotechnology, institute of biosciences and biotechnology, chhatrapati shahu ji maharaj university, india. her study addresses disparities in the occurrence of various cancers with respect to different treatment modalities in rheumatoid arthritis patients. mr. erik steinfelder, director, biobanking market development, thermo fisher scientific, presented on “biobanking in cancer related research” and described how thermo fisher scientific can be part of cancer health disparity research. the last presentation on “health disparities in oral cancer” was given by dr. ajaikumar kunnumakkara, professor, indian institute of technology guwahati, india. he addressed the association of risk factors such as tobacco smoking, alcohol intake, areca nut, human papillomavirus (hpv), and poor oral hygiene on oral cancer etiology in eastern india. the fourth session in the afternoon on day 2 focused on cancer health disparities in the rgv and around the globe. in hall a, dr. subhash c. chauhan moderated the session. in this breakout session, dr. patty moore, director of academic research, cancer prevention and research institute of texas (cprit), presented a “cprit-overview” which broadened the horizons for investigators at texas institutions seeking to apply for and conduct cancer prevention and community outreach research. the second talk was by dr. vijian dhevan, general surgeon, ut health rgv, who presented on “cancer disparities in the lower rio grande valley”. this work discussed disparities among various types of cancers in the rgv region comparing them to the broader area of south texas, the state as a whole, and nationally. later, dr. rakesh kumar, distinguished professor, national chair in cancer research, rajiv gandhi centre for biotechnology, india, portrayed his life-time experience through the presentation “science and medicine: a priceless journey” which summarized the contribution of his laboratory over the past few decades to fundamental molecular events to cancer progression and metastasis. he also shared his thoughts on how these findings may offer new opportunities in health disparity cancer research. the other breakout session in hall b was moderated by dr. subash gupta and dr. ajaikumar kunnumakkara. dr. rajesh singh, associate professor, microbiology, biochemistry & immunology, morehouse school of medicine, presented a keynote talk titled “ccr5/ccl5 axis plays an essential role in liver cancer racial disparity”. this work explained the involvement of chemokines in various cancers and their stimulation of the chemokine receptors expressed in cancer cells. he proposed that blockage of the ccr5/ccl5 interaction could induce apoptosis, confirming that the ccr5/ccl5 interaction might be an interesting target for managing and treating hcc in humans and hcc associated disparities. the next work was presented by dr. eduardo c. lazcano-ponce, dean, el instituto nacional de salud pública, mexico, on the special topic “the epidemiologic panorama of cancer in mexico” which describes several key insights into cancer disparities across the country. later, dr. catherine kaschula, senior lecturer, www.companyofscientists.com/index.php/chd e7 cancer health disparities research stellenbosch university, south africa, from south africa delivered her presentation on “investigations into the cytotoxic mechanism of the garlic compound ajoene in cancer cells”. this study has identified and validated a number of targets, many of which contain reactive cysteines involved in the maintenance of cancer homeostasis. the concluding presentation of this session was delivered by dr. shailesh singh, professor, microbiology, biochemistry & immunology, morehouse school of medicine. his presentation focused on “associate of cc chemokines with breast cancer disparity”. his team concluded that there is a significant association of cc-chemokines in breast cancer progression and disparate disease outcome in african american (aa) compared to european american (ea) patients. the fifth session of the symposium included poster and oral presentations, and early career investigator talks focused on diversity and inclusion in cancer and health disparities research. there were about 127 poster and 61 oral presentations, out of which 1 high school, 11 undergraduate, 20 medical students, 36 graduate students, 15 residents, 8 fellows, 5 faculty, and 5 staff (poster presentations) and 16 flash talks and 30 oral videos (oral presentations). the early career investigator flash talks session was moderated by dr. murali yallapu, associate professor, school of medicine, utrgv. the flash talk topics included: gene-by-environment expression and calculation of the frailty index (dr. eron grant manusov); mind, body and race: a look into how implicit biases influence the perception of emotion (faiza ahmad, utrgv medical student); multiple rsv strains infecting hep-2 and a549 cells reveal cell line-dependent differences in resistance to rsv infection (dr. felipe-andres piedra); human ipsc derived cardiomyocyte model reveals the transcriptomic bases of covid-19 associated myocardial injury (miss. kashish kumar, high school student); production of codon optimized polyomavirus (dr. luis m. rodriguez martinez); center for diabetes and metabolism, a collaborative dream comes true (claudia munguia, mph); smoking and drinking activates nf-κb /il-6 axis to promote inflammation during cervical carcinogenesis (dr. vivek k. kashyap); development and validation of a simple clinical construct for prediction of new type 2 diabetes mellitus (xavier rios, undergraduate student); cross-linked nanocomplexes for drug delivery applications (sumeet s. chauhan, undergraduate student); potential involvement of a glycoprotein muc13 mucin in colorectal cancer health disparity (dr. manish k. tripathi); targeting tumor associated macrophages to improve the immunotherapy of pancreatic cancer (dr. bilal hafeez); therapeutic intervention using autologous exosomes for treatment of early-stage pancreatic cancer (dr. sheema khan); exploration of potential natural inhibitors against kras-g12d in pancan: protein centered pharmacophore htvs approach (dr. anupam dhasmana); mucin muc13 and yap1 correlate with poor survival in colorectal cancer (dr. sudhir kotnala); tuberculosis in elderly hispanics: bcg vaccination at birth is protective and diabetes is not a risk factor (dr. blanca i. restrepo); case report: chronic diabetes and covid-19: a perfect storm for reactivation tuberculosis (tb)? (dr. blanca i. restrepo); and addressing pkd1 in prostate cancer disparity: implication for drug repurposing dr. mohammed sikander). in all sessions, there is a window of two to five minutes discussion on all topics. during this question-and-answer session a topic relevant content was discussed. it was noticed that a highly engaged discussions among various participants and presenters. notable incidents are regarding cprit opportunities and development of new programs, cancer health disparity community engagement research queries, and delineating cancer biology in health disparity research, etc. www.companyofscientists.com/index.php/chd e8 cancer health disparities research the final session of the program included an award ceremony and closing remarks. dr. subhash c. chauhan and dr. murali yallapu described the various award category honors and selection criteria. a dedicated committee and chair oversaw the selection process and only works with technical excellence were recommended for an award. award categories included honors for significant technical expertise in both oral and poster presenters from undergraduate students (4), graduate students (7), medical students (3), resident fellows (5), postdoctoral fellows/staff scientists (5), and young investigators/ faculty (4). to encourage international participants, there was a separate category allotted for international participants (11). all work of technical excellence in posters and oral talks received a distinctive engraved award plaque and certificate signed by the conference chairman. at the final stage of the program, a vote of thanks to all participants and organizers was extended by dr. subhash c. chauhan (chairman of the scientific committee icchd-2021). he also provided a brief overview of the meeting, feedback received, and future plans. at the end of the meeting, dr. chauhan also announced the continuation of the “international conference on cancer health disparities” conference on an annual basis. conclusions the first two-day annual international conference on cancer health disparities (icchd) was conducted by the utrgv-som as the 4th annual research symposium. the icchd-2021 was held on august 13-14, 2021, at the harlingen convention center, harlingen, tx, usa, as hybrid event (both physical and virtual live programs). the conference was comprised of six sessions: introduction and tackling cancer health disparities; elimination of cancer health disparities; cancer cellular and molecular biology; diversity and inclusion in cancer research, poster, and oral presentations; early career investigator talks; followed by an award ceremony and closing remarks. a network of colleagues from academia, the community, and health care joined to promoted various themes of cancer health disparities via special talks, showcasing research work, and continuing professional development programs. the success of this program can be seen in the participation of ~200 delegates from more than 10 countries. this accomplishment resulted from the commitment and participation of volunteers, utrgv leadership, nih, cprit, as well as city officials, clinicians, faculty members, researchers, scientists, bioinformaticians, geneticists, bioethics, and other members. acknowledgement we acknowledge strong support and contributions from the utrgv-som, utrgv executive vice president of research, and the national cancer institute (nci/nih/nimhd). we also acknowledge anonymous sponsors who provided generous contributions for the successful hosting of this international event. the authors thank the scientific, event planning, and finance committees for their tremendous efforts in the organization of this event. these committees include, dr. subhash c. chauhan, dr. murali yallapu, dr. andrew tsin, dr. lisa trevino, dr. meena jaggi, dr. dae kim, dr. sheema khan, dr. bilal hafeez, dr. jennifer cahn, dr. juan lopez-alvarenga, dr. beatriz bautista, dr. anupam dhasmana, ms. ana i. martinez bulnes, mr. aaron de la cruz, mr. jorge teniente, mrs. edith kolahdouz, mrs. aniella perez, ms. dorian garcia, ms. stephanie sharpe, mr. loren clark, dr. vivek kashyap, dr. jay morrow, dr. paulina vega, dr. heriberto cantu, ms. elizabeth lim, mr. matt hidalgo, ms. sonal jha, dr. karen martirosyan, mr. javier zambrano, dr. manish tripathi, mrs. isabel nicasio. we also thank the university of texas rio grande valley and harlingen convention center in hosting the hybrid conference live and zoom www.companyofscientists.com/index.php/chd e9 cancer health disparities research meetings. additionally, funding support by somutrgv, and the national institute on minority health and health disparities (r13 ca254453 to subhash chauhan and andrew tsin). we aknowledge dr. jennifer cahn for proof reading this manuscript. conflicts of interest the authors have no conflicts of interest to report. authors' contributions m.m.y. drafted the manuscript. s.c.c., j.t, a.t., and mmy participated in review and edition of the manuscript. references 1. 2018 utrgv som research symposium program https://wwwutrgvedu/som/researchadministration/_files/documents/som%20research%20sy mposium-booklet%20final%2020180910pdf 2. 2017 utrgv som research symposium program. https://wwwutrgvedu/som/researchadministration/symposium/14584-som-researchsymposium-program-bookletpdf 3. 2019 utrgv som research symposium program. https://wwwgooglecom/search?client=firefox-b-1d&q=utrgv+2019+research+symposium 4. https://www.cancer.org/research/acs-researchhighlights/cancer-health-disparities-research.html. 5. aacr cancer health disparity progress report, the state of cancer health disparities in 2020. https://cancerprogressreportaacrorg/disparities/chd20contents/chd20-state-of-cancer-health-disparities-2020/ 6. williams f, zoellner n, hovmand ps. understanding global cancer disparities: the role of social determinants from system dynamics perspective. transdisciplinary journal of engineering & science 2016;7 introduction summary of the conference conclusions acknowledgement conflicts of interest authors' contributions www.companyofscientists.com/index.php/chd e1 cancer health disparities research strong tumor expression of aldh1a1 is associated with black race, metabolic disorders, and poor breast cancer outcomes steficah maosa1,2, lisa frerichs1, scott d. siegel, 1zachary schug3, jennifer sims-mourtada1 1cawley center for translational cancer research, helen f graham cancer center and research institute, christiana care health services, inc. newark, usa 2department of biological sciences, the university of delaware, newark, de, usa 3the wistar institute, philadelphia, pennsylvania, usa *corresponding author: jennifer sims-mourtada, email: jsimsmourtada@chrisitanacare.org abstract racial differences in tumor biology may explain worse breast cancer outcomes in black women relative to white women. this study provides a comparative racial analysis in black and white women in terms of aldehyde dehydrogenase1 member a1 (aldh1a1) expression and its association to clinicopathological features. expression of aldh1a1 in both tumor and stromal cells was assessed by immunohistochemistry in tissue microarrays containing 253 breast tumors including 161 tumors from white patients and 92 from black patients. relationships to clinicopathological features for strong and moderate to low aldh1a1 staining were determined using pearson’s chi square and an odds ratio was determined. survival and recurrence were analyzed using kaplan-meier curves and mantel log-rank tests. multivariate analysis was conducted using cox-proportional hazards tests. black, obese, and diabetic women showed higher staining intensity in both tumor and stromal tissue. strong tumor staining was associated with black race, advanced stage, high grade obesity and diabetes. strong stromal expression was associated with estrogen receptor positivity, and prediabetes/diabetes. patients with strong tumor aldh1a1 had shorter recurrence free and overall survival compared to those with moderate to low expression. when stratified by race, black women with strong tumor aldh1a1 expression had shorter recurrence free survival compared to white women. strong tumor aldh1a1 staining was an independent predictor of poor overall survival in both black and white women. these findings indicate that aldh1a1 expression is associated with poor outcomes in breast cancer, particularly in black women, and provide the first link between tumor aldh1a1 expression, obesity, and diabetes. keywords: breast cancer; aldh1a1, black women, metabolic disorders, obesity. citation: maosa s et al (2023) strong tumor expression of aldh1a1 is associated with black race, metabolic disorders, and poor breast cancer outcomes. cancer health disparities 7:e1-14, doi:10.9777/chd.2023.1003 www.companyofscientists.com/index.php/chd e2 cancer health disparities research introduction breast cancer accounts for a third of all cancers diagnosed in black women and is the leading cause of cancer death in this population (giaquinto et al., 2022). although incidence rates are comparable, black women are 41% more likely to die of breast cancer than white women and are twice as likely to be diagnosed with aggressive breast cancers such as triple negative or inflammatory breast cancers (giaquinto et al., 2022; stringer-reasor et al., 2021). higher mortality rates in black women are attributable to many factors including later stage of diagnosis, limited access to high quality care, unfavorable tumor characteristics, and increased prevalence of obesity and associated comorbidities (stringer-reasor et al., 2021). studies examining mortality rates in black and white women diagnosed with early stage breast cancer show that after controlling for non-biological factors such as socioeconomic status, treatment factors and tumor stage at diagnosis, black women still had higher mortality rates than white women (dietze et al., 2015; hershman et al., 2005; jatoi et al., 2003; silber et al., 2013). these findings indicate that racial molecular and genetic differences in tumor biology may play a role in poor survival rates among black women. however, racial differences in tumor biology and their interaction with other biological and non-biological risk factors are poorly understood. aldehyde dehydrogenases are detoxifying enzymes that play a critical role in metabolism of intracellular aldehydes. in particular, the aldh1 family has been implicated in the oxidation of retinol to retinoic acid which impacts differentiation state, treatment resistance, and anti-tumor immune responses(ayub et al., 2015; bazewicz et al., 2019; ginestier et al., 2007). strong aldh1 expressing cells are thought to be tumor initiating cells and are associated with other stem-cell markers and poor outcomes in breast cancer (ginestier et al., 2007). in triple negative breast cancer, aldh1 expression was significantly correlated with larger tumor size, later stage and is an independent prognostic factor(ma et al., 2017). strong aldh1 expression has been observed in breast cancers of black women and is associated with basal like features in this population (nalwoga et al., 2010). the aldh1 family is made up of several isoforms, with aldh1a1 and aldh1a3 being the most important for breast cancer progression and resistance (marcato et al., 2011b). although both are involved in the biosynthesis of retinoic acid, aldh1a1 has a broader role in the metabolism of intracellular and extracellular aldehydes (poturnajova et al., 2021). while our group and others have shown that aldh1a3 expression correlates with prognosis, the role of aldh1a1 has been controversial and may be dependent on cutoff levels used to score high and low (althobiti et al., 2020; opdenaker et al., 2014; sjostrom et al., 2015). strong mrna expression of aldh1a1 has been associated with good prognosis in triple negative breast cancer (liu et al., 2015). however, at the protein level, strong expression in tumor cells was associated with stage, triple negativity, and poor response to neoadjuvant chemotherapy(khoury et al., 2012), as well as worse prognosis (sjostrom et al., 2015). a recent study examining expression of aldh1a1 in 222 breast cancers from ghanian women reported tumor expression in 90% of tumors. although no association with clinicopathologic features was observed with aldh1a1 alone, significant associations with tumor stage and grade were observed in tumors with a large stem-like population indicated by strong staining of aldh1a1 and cd44 and weak cd24 expression (gyan et al., 2021). outcome analysis was not performed in this study. www.companyofscientists.com/index.php/chd e3 cancer health disparities research in addition to its possible role in breast cancer progression, expression of aldh1a1 has been linked to lipogenic adipogenesis, accumulation of visceral fat (reichert et al., 2011; yasmeen et al., 2013), and altered glucose tolerance (petrosino et al., 2014) in aldh1a1 knock-out mouse models. additionally, aldh1a1 expression in adipose tissue in both mice and humans is induced by a high-fat diet (landrier et al., 2017). pharmacological inhibition of aldh1a1 suppressed weight gain in a mouse model of diet-induced obesity and reduced genes involved in fatty acid synthesis in multiple tissues (haenisch et al., 2018). as obesity is strongly associated with breast cancer risk and outcomes, particularly in black women (dietze et al., 2018; micaily et al., 2021), we sought to investigate the relationship between aldh1a1 expression, metabolic disorders and breast cancer outcomes in black women compared to white women. methods patient samples and data paraffin embedded blocks of breast cancer tissue were obtained from the biorepository at the helen f. graham cancer center and research institute (hfgccri) under a protocol approved by the institutional review board of christianacare, newark, delaware. blocks were obtained from patients undergoing surgical resection from years 2007-2011 and were pathologically confirmed as invasive breast cancer tissue. paraffin tissues were constructed into 4x5 tissue microarrays (tma) with a 5 mm core size and cut as serial sections. clinicopathologic data was taken from patient charts. patients pathologic stage of iia or stronger were considered to have advanced breast cancer, consistent with a recent recommendation from the breast cancer surveillance study that found that this definition most accurately predicts 5 year survival (kerlikowske et al., 2021). obesity was determined by bmi at diagnosis. patients were coded as obese if their bmi was greater than or equal to 30. data regarding other co-morbidities such as blood glucose levels (normal or high (prediabetes) or a clinical diagnosis of diabetes mellitus at the time breast cancer occurrence was available in the biorepository database for a subset of patients n=130. immunohistochemical procedure paraffin-embedded slides were deparaffinized and rehydrated, and heat antigen epitope retrieval was performed for 16 hours at 60°c. slides were stained using a 1:100 dilution of aldh1a1 antibody (kiefer et al., 2012) (abcam, clone ep1933y) using the mouse and rabbit specific hrp/aec (abc) detection ihc kit (abcam, ab93705), following the manufacturer’s instructions. negative control slides were performed with the omission of antibody. slides were counterstained with hematoxylin. images were captured using a zeiss axio microscope using a 10x objective. segmentation of tumor and stromal cells and measurement of sum intensity per area was performed using zen blue. statistical analysis statistical analysis was done in graph pad prism 8 and ibm27 spss. comparisons of staining intensity were done using student’s t tests. staining intensities were divided into quartiles, with the top quartile considered to be strong aldh1a1 expression. relationships for strong and moderate to low expressing slides were determined using pearson’s chi square and an odds ratio was determined. survival and recurrence were analyzed using kaplan-meier curves and mantel log-rank tests. multivariate analysis was conducted using cox-proportional hazards tests. results patient characteristics this study was comprised of a cohort of 253 patients with invasive ductal carcinoma, including www.companyofscientists.com/index.php/chd e4 cancer health disparities research 161 white patients and 92 black patients. patient demographics and clinicopathologic characteristics are summarized in table 1. her2 receptor status was not known for all patients and was not included in this analysis. black patients were significantly more likely to have advanced stage (p=0.022) and have a bmi greater than 30 at diagnosis (p=0.013). no significant racial differences were observed in tumor grade and expression of hormone receptors in this cohort. table 1. comparison of patient characteristics between white and black patients. patient characteristics all white black p value number % number % number % samples 253 100 161 63.6 92 36.4 stage early stage 156 61.7 108 67.1 48 52.2 0.022* advanced 97 38.3 53 32.9 44 47.8 grade low-medium 74 29.2 54 33.5 23 25 0.164 high 179 70.8 110 68.3 69 75 hormone receptor expression hr+ 75 29.6 47 29.2 28 30.4 0.887 hr178 70.4 114 70.8 64 69.6 obesity non-obese 131 51.8 93 57.8 38 41.3 0.013* obese 122 48.2 68 42.2 54 58.7 diabetes normal blood glucose 99 76.10% 67 79.8 32 69.5 0.204 pre-diabetes/diabetes 31 23.80% 17 20.1 14 30.4 strong tumor aldh1a1 staining is associated with race, stage, obesity, and diabetes. tumor microarrays were constructed from paraffin embedded surgical sections and stained with an anti-aldh1a1 specific antibody. tumor and stromal staining were quantified as sum intensity per area. figure 1 shows representative samples with strong and low tumor and stromal staining. significantly stronger staining intensities were observed in tumor tissue from black women, obese women, and women with prediabetes/ diabetes (figure 2a, 2c and 2e). similarly, significantly stronger staining intensities of aldh1a1 were found in stroma of tumors from black women and women who were obese or had prediabetes or diabetes (figure 2b, 2d and 2f). strong tumor staining (specimens that were in the highest quartile) was associated with black race (or 1.625, ci 1.202-2.270, p=.004), advanced stage (or 1.454, ci 1.062-1.991, p=.037), strong grade (or 1.209, ci 1.036-1.441, p=.039), www.companyofscientists.com/index.php/chd e5 cancer health disparities research obesity (or 1.441, ci 1.122-1.825, p=0.009) and diabetes (or 1.599, ci 1.206-2.119, p=.001). although black women in our cohort were more likely to be obese and have advance cancer, the association with race remained even when controlling for stage (chi square 3.414, p=0.036) and obesity (chi square 3.328, p= 0.038). strong stromal expression was associated with black race (or 1.216, ci 0.843-1.624), estrogen receptor positivity (or 1.47, ci 0.996-2.190, p=0.004), obesity (or 1.287, ci 1.008-1.643, p=0.044), and prediabetes/diabetes (or 1.290, ci 0.970-1.1716, p=.038). no associations between race, stage and grade were observed with strong stromal staining. (table 2). figure 1. immunohistochemical analysis of aldh1a1. tumor sections showing strong (top quartile by staining intensity/area) and low/moderate (lower quartiles by staining intensity/area) tumor and stromal expression of aldh1a1 (red stain). nuclei were counterstained with hematoxylin (blue). images in panels were taken with a 10x objective. images in inserts were taken with 40x objective. www.companyofscientists.com/index.php/chd e6 cancer health disparities research figure 2. differential tumor and stromal expression of aldh1a1. expression of aldh1a1 expression in white vs black tumor (a.) and stroma (b.), non-obese vs obese tumor (c.) and stroma (d.), and non-diabetic vs prediabetic/diabetic tumors (e.) and stroma (f.) data is reported as sum red intensity per area. solid red lines represent quartiles, dotted red line represents mean. **** p<.0001; *** p<.001; * p<.05. table 2. association of aldh1a1 strong tumor and stromal expression with patient and tumor characteristics. strong expression of aldh1a1 tumor expression stromal expression or 95% ci p value or 95% ci p value race black 1.625 1.202-2.270 0.004** black 1.216 0.843-1.624 0.156 white 0.704 0.537-0.923 white 0.973 0.702-1.348 stage nonadvanced 0.762 0.584-0.994 0.037* nonadvanced 1.087 0.893-1.321 0.439 advanced 1.454 1.062-1.991 advanced 0.875 0.640-1.197 grade low-medium 0.572 0.330-03990 0.039* low-medium 1.222 0.829-1.802 0.325 high 1.209 1.036-1.411 high 0.921 0.786-1.079 estrogen receptor expression er+ 0.886 0.546-1.372 0.324 er+ 1.472 0.996-2.190 .004** er1.06 0.889-1.262 er0.851 0.725-1.970 obesity non-obese 0.669 0.471-0.940 0.009** non-obese 0.764 0.591-0.989 .044* obese 1.441 1.122-1.825 obese 1.287 1.008-1.643 prediabetes/ diabetes normal blood glucose 0.281 0.148-0.534 0.001** normal blood glucose 0.517 0.283-0.944 .038* pre-diabetes/ diabetes 1.599 1.206-2.119 pre-diabetes/ diabetes 1.29 0.970-1.716 www.companyofscientists.com/index.php/chd e7 cancer health disparities research strong tumor and stromal aldh1a1 staining are associated with poor outcomes to assess the role of strong tumor and stromal aldh1a1 in breast cancer outcomes, kaplan-meyer analysis was conducted. shorter recurrence free survival (rfs, p<0.001) and overall survival (os, p<0.001) were observed in women whose tumors had strong expression of aldh compared to those with moderate to low expression (figure 3a & b). interestingly, of those in the top quartile, black women had worse rfs compared to white women (p=0.011, figure 4a.). no racial differences were observed in rfs between women with moderate to low tumor expression of aldh1a1 (figure 4b.). race had no effect on overall survival in either expression groups (figure 4c&d) as shorter os was observed in both black and white women with strong aldh expression. figure 3. tumor aldh1a1 expression is associated with breast cancer outcomes. kaplan-meier survival curves showing shorter recurrence free survival (a.) and overall survival (b.) in patients with high expression of aldh1a1 (top quartile). black tick marks represent censured patients. a sample was considered to have strong staining if its staining index was in the top quartile. lower quartiles were considered to have low to moderate staining. sims mourtada, jennifer figures are missing title rfs on the axis www.companyofscientists.com/index.php/chd e8 cancer health disparities research figure 4. high aldh1a1 is associated with shorter rfs in black women compared to white women. (a.). when stratified by race shorter rfs is observed in black women with strong tumor (staining intensity in top quartile) aldh1a1 expression compared to white women. (b.) no difference in rfs was observed between black and white women with moderate to low tumor expression of aldh1a1 (staining intensity in lower 3 quartiles) (c.) no significant racial differences were observed in os in women with high or (d.) low to moderate tumor expression of aldh1a1. black tick marks represent censured patients. although a trend of shorter rfs and os was observed in women with strong aldh1a1 stromal expression compared to those with moderate to low stromal expression, this was not significant (figure 5a.&b.). no racial differences in outcomes were observed between black and white women with strong stromal aldh1a1 expression (figure 6a.-d.). multivariate analysis revealed that advanced stage, hormone receptor negativity, and strong tumor aldh1a1 expression were independently associated with worse survival outcomes. (table 3). figure 5. stromal aldh1a1 expression is not significantly associated with breast cancer outcomes. kaplan-meier survival curves showing shorter recurrence free survival (a.) and overall survival (b.) in patients with high expression of aldh1a1 (staining intensity in top quartile). black tick marks represent censured patients. www.companyofscientists.com/index.php/chd e9 cancer health disparities research figure 6. stromal expression is not associated with breast cancer outcomes when stratified by race. (a.). when stratified by race shorter rfs in black women with high stromal (staining intensity in top quartile) aldh1a1 expression compared to white women. (b.) no difference in rfs was observed between black and white women with moderate to low stromal expression of aldh1a1 (staining intensity in lower 3 quartiles) (c.) no significant racial differences were observed in os in women with high or (d.) low to moderate stromal expression of aldh1a1. black tick marks represent censured patients. discussion considerable data indicates that tumor biology may be a contributing factor to racial disparities in breast cancer. previous studies have reported increased expression of aldh1a1 in tumors of women with african ancestry (jiagge et al., 2018b). our findings confirm that expression of aldh1a1 is increased in breast tumor tissue from black women compared to those from white women. strong tumor expression of ald1a1 was associated with black race, high grade, advanced cancer stage, obesity, and diabetes. in contrast to previous studies, we did not find an association of between strong tumor aldh1a1 expression and estrogen receptor negativity. although aldh1a1 activity has been linked to metastatic behavior and treatment resistance (croker et al., 2017), the association between tumor aldh1a1 expression and survival is controversial. we observed poor rfs and os in women with strong tumor expression of aldh1a1. a multivariate analysis revealed that tumor, but not stromal, aldh1a1 expression is an independently associated with cancer outcomes. analyses stratified by race revealed worse overall survival in both black and white women with strong tumor aldh1a1 www.companyofscientists.com/index.php/chd e10 cancer health disparities research compared to those with moderate to low expression. however, among women with strong aldh1a1 staining, black women had shorter recurrence free survival compared to white women. members of the aldh1 family, including aldh1a1. have been associated with stemness in normal and malignant breast cells (douville et al., 2009; ginestier et al., 2007; ginestier et al., 2009; honeth et al., 2014; marcato et al., 2011a; schwartz et al., 2013). however, research on stemness in tumors of black women is limited (jiagge et al., 2018a). one study found that the overall number of cells expressing the stem cell markers cd44+/cd24 cells was elevated in tumors from black women (nakshatri et al., 2015). this study also found that black but not white tumors contained a distinct population of cd44+/cd24cells that showed differential gene expression which was like that of mammary stem cells and included upregulation of tgfβ/wnt and ctnbb1/nf-κb pathways and downregulation of the p53 and er pathway. additionally, gyan et al found that expression of the cd44+cd24population together with aldh1a is associated with aggressive tumor characteristics including high tumor grade and clinical prognostic staging in black women (gyan et al., 2021). another study found that tumor cells from black women exhibited a cancer stem like phenotype including increased growth and migration compared to tumor cells from white women (siddharth et al., 2021).in this study, tumor cells from black women also showed different gene expression patterns than those from white tumors, including elevated expression of stemness genes gli-1 and notch1. stromal expression of aldh1a1 has been investigated in only a few studies (bednarz-knoll et al., 2015; sjostrom et al., 2015) which report that expression of aldh1a in tumor stromal may be associated with improved outcomes in breast cancer. we found no association between strong stromal staining and outcomes in our study. however, we found that strong aldh1a1 stromal expression is associated with estrogen receptor positivity, obesity, and diabetes. although no associations between stromal staining and breast cancer subtypes have been reported, a positive association between strong stromal aldh1a1 expression and decreased basal markers in tumor cells has previously been observed (bednarz-knoll et al., 2015). further investigation of the prognostic significance of aldh1a1 stromal expression by breast cancer subtype is needed. metabolic disorders are associated with breast cancer risk and outcomes, particularly in black women(jones et al., 2003; zhao et al., 2020). previous studies have shown that in addition to its role in stemness and oxidative stress, aldh1a1 plays a key role in glucose tolerance and abdominal fat formation (ma et al., 2020; petrosino et al., 2014). further, increased expression of aldh1a1 has been linked to accumulation of visceral fat in murine models and mediates inflammatory responses to a high-fat diet in females (yasmeen et al., 2013). our findings are the first to show an association between metabolic disorders and aldh1a1 expression in tumors. the mechanisms driving increased expression of aldh1a1 in tumor and stroma cells, particularly in black women, have yet to be fully understood. functional polymorphisms in aldh1a1 have been identified and studied in the context of alcohol dependence (agarwal et al., 1981).the frequency of these alterations varies across different ethnic groups and several variants have strong prevalence among black individuals (crawford et al., 2014; ji et al., 2019; liu et al., 2011; spence et al., 2003). a three base-pair insertion with prevalence exclusively to black people was shown to increase expression of aldh1a1 (spence et al., 2003). to date, the role of www.companyofscientists.com/index.php/chd e11 cancer health disparities research aldh1a1 polymorphisms in breast cancer has not been well studied. additionally, aldh1a1 is regulated by factors that are also associated with breast cancer risk including decreased estrogen (petrosino, 2014), alcohol-associated inflammation (wang et al., 2017) and high fat diets (he et al., 2020; srinivasan et al., 2019). moreover, we and other groups have shown that tumor expression of aldh1a1 can be induced by activation of the il-6stat3 pathway (arnold et al., 2020; hellsten et al., 2011) and may be associated with chronic inflammation. our study has several limitations including a small sample size. although our findings show that high aldh1a1 expression is correlated with race and metabolic disorders including obesity and diabetes, these findings need to be confirmed in larger studies. we were able to obtain information on diabetes and blood glucose levels on a subset of patients; however, this information was missing in our biorepository database for many patients and warrants further study. due to the smaller sample size, we were not able to further stratify patients to compare differences among race in prediabetes and diabetes groups. although our analysis included stratification by receptor subtype, we were not able to classify patients according to molecular subtyping. racial differences have been reported in pam50 molecular subtypes, with black women having increased luminal b subtypes (troester et al., 2018). as aldh1a1 expression is associated to both luminal b and tnbc subtypes (althobiti et al., 2020) this could be a confounding factor. although our study investigated the association of stromal expression to race, comorbidities and outcomes, our study focused on staining index of the total stroma and did not determine differences by individual cell type. we did observe strong stromal staining in multiple cell types, which warrants further investigation. in conclusion, this study shows that aldha1a1 expression in breast tumor and stromal cells is associated with black race, obesity, and diabetes. when stratified by race, black women whose tumors express high levels of aldh1a1 have significantly shorter recurrence times than white women with strong aldh1a1 expression. moreover, aldh1a1 expression was found to be an independent driver of outcomes. these findings indicate that aldh1a1 is associated to disparities in breast cancer outcomes and provide the first link between tumor aldh1a1 expression, obesity, and diabetes. further study is needed to understand the mechanisms driving high aldh1a1 expression in these cohorts. financial support this work was supported by a grant from the lisa dean mosely foundation, and by the delaware inbre program, with a grant from the national institute of general medical sciences – nigms (p20 gm103446) from the national institutes of health and the state of delaware. acknowledgement the authors have no acknowledgements conflicts of interest the authors report no conficlts of interest authors' contributions kindly add. s.m.: experimental procedures and contributed to the writing of the draft, l.f.: performed experimetnal procedures and manuscript reveiw., s.d.s.: conceptualiztion, manuscript review and editing, z.s. conceptualization, manuscript review and editing, j.s.m.: conceptualization, statistical analysis, writing of the draft and review and editing of manuscript. www.companyofscientists.com/index.php/chd e12 cancer health disparities research references agarwal, d.p., harada, s., and goedde, h.w. 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https://www.ncbi.nlm.nih.gov/pubmed/32698183 https://www.ncbi.nlm.nih.gov/pubmed/32698183 introduction methods patient samples and data immunohistochemical procedure statistical analysis results patient characteristics strong tumor aldh1a1 staining is associated with race, stage, obesity, and diabetes. strong tumor and stromal aldh1a1 staining are associated with poor outcomes discussion financial support acknowledgement conflicts of interest authors' contributions www.companyofscientists.com/index.php/chd e1 cancer health disparities research racial/ethnic disparities in hpvassociated anogenital cancers among males in the united states: a populationbased retrospective cohort study seiichi villalona1, simone sukhdeo1, daisy reinoso1, antoinette m. stroup2,3, jeanne m. ferrante3,4* 1 rutgers robert wood johnson medical school, piscataway, nj, usa 2 department of biostatistics & epidemiology, rutgers school of public health, piscataway, nj, usa 3 rutgers cancer institute of new jersey, new brunswick, nj, usa 4 department of family medicine and community health, rutgers robert wood johnson medical school, new brunswick, nj, usa *corresponding author: jeanne m. ferrante, email: jeanne.ferrante@rutgers.edu abstract little is known regarding racial/ethnic differences in human papillomavirus (hpv)-associated anogenital cancer among males. this population-based retrospective cohort study included 39,601 males diagnosed with hpv-associated invasive penile and anorectal cancers between 2005-2016 from the north american association of central cancer registries. we evaluated the association of race/ethnicity with late-stage diagnosis, survival, and mortality of anogenital cancers among males in the united states using multivariable logistic regression and cox proportional hazard models. hispanic and non-hispanic (nh) black males had highest age-adjusted incidence of penile and anorectal cancer, respectively. higher odds of late-stage penile cancer were observed among nh black (adjusted odds ratios [aor] 1.22, 95% ci 1.071.39) and hispanic males (aor 1.17, 95% ci 1.04-1.31). higher odds of late-stage anorectal cancer were observed among nh black (aor 1.25, 95% ci 1.14-1.36) and nh other males (aor 1.29, 95% ci 1.01-1.66). compared to all other groups, nh black males had the lowest cumulative and mean survival of both cancers and higher cancer-specific mortality (penile adjusted hazards ratios [ahr] 1.23, 95% ci 1.01-1.49; anorectal ahr 1.25, 95% ci 1.10-1.42). there are different racial/ethnic disparities in health outcomes among males depending on site of hpv-associated anogenital cancer. interventions to increase hpv vaccination rates, early detection, and treatment of anogenital cancers in males are needed, particularly among men of color. keywords: human papillomavirus (hpv), anorectal cancer, penile cancer, males, racial/ethnic disparities. citation: villalona s et al (2022) racial/ethnic disparities in hpv-associated anogenital cancers among males in the united states: a population-based retrospective cohort study. cancer health disparities 6:e1-25. doi:10.9777/chd.2022.1006 www.companyofscientists.com/index.php/chd e2 cancer health disparities research introduction human papillomavirus (hpv)-associated cancers have become an increasing healthcare burden, accounting for over 46,000 cancer cases per year in the united states (centers for disease control and prevention, 2021). hpv infection often precedes the development of anogenital (ag) cancers, with approximately 64% of penile cancers and 91% of anal cancers attributable to hpv, particularly from oncogenic strains 16 and 18 (centers for disease control and prevention, 2021). in 2022, there will be an estimated 2,070 and 3150 new cases of penile and anorectal cancers, respectively, among males in the u.s.(siegel et al., 2022). while incidence of cervical cancer has been declining in females due to widespread use of papanicolaou smears, there has been a steady increase in hpv-associated cancers among males over the last few decades (liao et al., 2022), highlighting the importance of targeting male hpv-associated ag cancer in public health efforts. penile cancer comprises 0.2% of male-associated malignancies (siegel et al., 2022), with higher incidences observed in hispanic and nh black males (attalla et al., 2018; sharma et al., 2016b). one potential risk factor for hpv-associated penile cancer is lack of circumcision. the human papillomavirus infection in men (him) study reported that circumcision was associated with reduced risk of hpv detection across all viral strains tested (giuliano et al., 2010; giuliano et al., 2009). cultural differences in circumcision practice can create populations at greater risk for hpv infection and subsequent penile cancer. in the u.s., hispanic males have lower rates of circumcision relative to other ethnic groups, which may shift the healthcare burden of penile cancer disproportionately on the male hispanic population (colón-lópez et al., 2010). additional risk factors such as lack of insurance, lower education, and lower socioeconomic status (ses) may result in poorer prognosis and worse survival among hispanic males (attalla et al., 2018; sharma et al., 2016a). anal cancer incidence is rising among men (annual increase of 1.2%) while declining among women (3.2% annual decrease) (centers for disease control and prevention, 2020). notably, new cases are highest in nh black males with an annual average percentage increase of 3.40% between 2001-2017, and studies have shown poorer survival outcomes in this population (benard et al., 2008; fields et al., 2019; liao et al., 2022; patel et al., 2020). it has been suggested that the rising incidence of anal cancer parallels a rising incidence of hiv infection in racial minority populations and men who have sex with men (msm) due to hiv and hpv co-infection (walsh et al., 2015; ye et al., 2020). however, the trends in incidence of anal cancer and poorer survival in nh black males most likely result from a combination of socioeconomic status, insurance, and treatment factors, in addition to sexual practices and hiv status (bian et al., 2021; fields et al., 2019; gillis et al., 2020; goksu et al., 2020). prior studies of hpv-associated cancers in men have focused on select subpopulations (e.g. hivpositive men) or limited the inclusion of distinct minority groups. however, a more encompassing sample is necessary to explore the intersections of race/ethnicity, hpv-associated cancer incidence and outcomes, and social determinants of health (baughman and shah, 2016; bojko et al., 2018; goksu et al., 2020; gupta et al., 2017; ortiz et al., 2018; walsh et al., 2015). in this present study, we compared differences in stage at diagnosis, survival, and mortality of ag cancers in males among different racial/ethnic groups, while controlling for age, area poverty level, area of residence, and insurance status, all factors previously suggested to impact survival in males with ag cancers (attalla et al., 2018; bojko et al., 2018). to our knowledge, this www.companyofscientists.com/index.php/chd e3 cancer health disparities research is the largest population-based study to examine racial/ethnic disparities in incidence, late-stage diagnosis, survival and mortality of ag cancers among males across the u.s. identifying populations at risk is important to understand which men to target preventive interventions. materials and methods data and sample this is a population-based retrospective cohort study of males in the u.s. diagnosed with invasive anogenital (ag) cancers between 2005-2016 within the north american association of central cancer registries (naaccr) cancer in north america (cina) deluxe data file (north american association of central cancer registries, 2018). naaccr cina is the most comprehensive cancer incidence database, covering 93% of the u.s. population, and it includes all 18 surveillance, epidemiology, and end results (seer) registries. the database contains de-identified demographic, cancer type, and treatment information from population-based cancer registries across the u.s. and canada. for survival and mortality analyses, we used a subset of this data file, the cina survival dataset, which includes cancer registries that meet the surveillance, epidemiology, and end results (seer) standards for follow-up or ascertainment of deaths. data were accessed through the seer*stat software program and exported into the statistical package for the social sciences (spss) version 27 (ibm, armonk, new york) for advanced analyses. this study was approved by the institutional review boards at naaccr and rutgers, the state university of new jersey. we included males with tumors in the following anatomical sites under the international classification of diseases for oncology (icd-o)-3: rectum (c20.9); anus (c21.0); anal canal (c21.1); cloacogenic zone (c21.2); overlapping lesion of rectum, anus, and anal canal (c21.8); prepuce (c60.0); glans penis (c60.1); body of penis (c60.2); overlapping lesion of penis (c60.8); and penis (c60.9) for a total of 263,102 individual cases. we excluded persons <15 years of age (n=28); cases diagnosed at autopsy or by death certificate (n=1,538); and diagnosis in puerto rico (n=2,268). because cancer registries do not collect hpv status of cancers, we used standard centers for disease control and prevention definitions of hpvassociated cancers, i.e., icd-o-3 site codes (listed above) and histological codes (squamous cell carcinoma (scc) 8050-8084; 8120-8131) to identify hpv-associated ag cancers (centers for disease control and prevention, 2020). hpv-associated ag cancers were restricted to microscopically confirmed cases. stage at diagnosis stage at diagnosis was classified as local, regional, and distant based on the seer summary stage 1977/2000/derived variable. for the stage at diagnosis analyses, we excluded persons with unknown stage (n=21,212), resulting in a final analytic sample of 39,601 cases. we defined stage as “early” if the ag cancer was diagnosed with local stage disease, and “late” if the ag cancer was diagnosed with regional or distant stage disease (yang et al., 2018). survival and mortality we excluded cases diagnosed after december 31, 2011 (n=67,720) for our survival and mortality analyses in order to have at least 5 years of followup. we also excluded cases where ag cancer was not the first primary malignancy (n=44,196), had unknown cause of death (n=9,165), or unknown survival time (n=18,149), resulting in a final analytic sample of 15,244 cases. mean cancer-specific survival for each racial/ethnic group was generated within seer*stat using the actuarial method (ohnomachado, 2001), via the “seer cause-specific death classification” variable from the naaccr data file www.companyofscientists.com/index.php/chd e4 cancer health disparities research (north american association of central cancer registries, 2018). this variable takes into account cause of death information (icd-10 codes), site of original cancer diagnosis, tumor sequence, and diseases associated to the cancer of diagnosis, and it addresses known misclassifications in cause of death on death certificates for cancer (howlader et al., 2010). cases are categorized as: dead (attributable to this cancer diagnosis); alive or dead of other cause; and dead (missing/unknown cause of death) (howlader et al., 2010). in cancer-specific mortality analyses, persons who died of causes other than ag cancer were censored. covariates the main independent variable of interest, race/ethnicity, was based on self-report and categorized as nh white, nh black, hispanic, and nh other (asians/pacific islanders and american indians/alaskan natives) as classified in the naaccr research file (north american association of central cancer registries, 2018). other covariates considered in our analyses included: age at diagnosis, health insurance, county level attributes of residence (metropolitan/nonmetropolitan, percent of persons below poverty), geographic region of the u.s., and treatment modality. the naaccr cina research file categorizes age at diagnosis in 5-year intervals (e.g. 35-39, 40-44). we grouped this into three categories: <54, 55-64, 65+ years. health insurance categories included: private, medicare, medicaid, other (indian/public health service, military, tricare, veterans affairs, and insurance not otherwise specified), and no insurance or self-pay. metropolitan/non-metropolitan county designations were broadly based on population size (metropolitan has 50,000 persons or more). percent of persons below poverty was categorized as: <9.99%, 10-19.99%, and 20% or more below federal poverty levels. the four geographic regions of the u.s. were based on the u.s. census bureau: northeast, south, midwest, and west/pacific (united states census bureau, 2018). treatment modality included the first course of planned treatment and was categorized as: surgery only; radiation or chemotherapy only; surgery plus (radiation or chemotherapy); radiation and chemotherapy; all modalities; or no treatment. statistical analysis the number of new cases of hpv-associated ag cancer from 2005-2016 was extracted from seer*stat. age-adjusted incidence rates, stratified by disease stage, anatomic site (penile or anorectal), and race/ethnicity were calculated directly from seer*stat. bivariate relationship between demographic characteristics and latestage diagnosis was evaluated using χ2 tests and univariate logistic regression. adjusted odds ratios (aor) of late-stage diagnosis compared with early stage and corresponding 95% confidence intervals (cis) were calculated for each category of race/ethnicity using multivariable logistic regression, adjusting for age at diagnosis, insurance, metropolitan/non-metropolitan residence, area poverty, and geographic region. finally, interaction terms were included in our final model to examine how race/ethnicity modified the relationship between covariates and late-stage ag diagnosis. we used cox proportional hazards regression to generate adjusted cancer-specific survival curves for different racial/ethnic groups. we examined associations of race/ethnicity with mortality from ag cancers using cox proportional regression models to estimate the hazards of death from ag cancer (with 95% cis). we included the variables described above and stage at diagnosis as potential confounders in multivariable model 1. to determine the effect of treatment modality on the associations between race/ethnicity and ag cancer mortality, we www.companyofscientists.com/index.php/chd e5 cancer health disparities research added treatment to multivariable model 2. finally, to examine potential effect modification of race/ethnicity on the other variables, interaction terms were included in the final multivariable model 2. we conducted initial sensitivity analyses including and excluding cases with unknown race/ethnicity and unknown covariates. we additionally conducted sensitivity analyses of ag cancers as an aggregate sample and then stratified by anatomic site (penile and anorectal). results were similar with and without unknown race and other covariates, but different when stratified by anatomic site. therefore, we present multivariable models excluding missing values and separately for penile and anorectal cancers. results table 1 describes the characteristics of our study cohort stratified by race/ethnicity. most of our study sample consisted of nh white males (75%), aged 65+ (43.1%), residing in large metropolitan areas (82.3%), covered by medicare insurance (38.2%), living in counties with 10-19.99% poverty (69.2%), residing in the geographic south (38.6%), and with local disease stage at diagnosis (52.6%). a majority of the cases were anorectal cancers (63.1%). compared to other racial/ethnic groups, a higher proportion of hispanics (44.1%) and nh black (52.2%) males were less than 54 years of age. higher proportions of hispanic (23.1%) and nh black (22.6%) males had medicaid or no health insurance. nh black males represented the largest proportion of individuals living in counties with >20% of poverty (30.2%). hispanic (56.2%) and nh other (55.3%) males represented larger proportions of penile cancers, while nh black males (70.7%) represented the highest proportion of anorectal cancers. all bivariate relationships were statistically significant using χ2 tests (all p-values <0.01). table 1. characteristics of hpv-associated anogenital cancers in males, united states, 2005-2016 (n = 39,601). characteristic* total n (%) hispanic n (%) white nh n (%) black nh n (%) other, nh§ n (%) unknown n (%) overall 39,601 (100) 3,806 (9.6) 29,714 (75.0) 5,066 (12.8) 740 (1.9) 275 (0.7) age at diagnosis, years <54 12,436 (31.4) 1,679 (44.1) 7,772 (26.2) 2,643 (52.2) 224 (30.3) 118 (42.9) 55-64 10,089 (25.5) 883 (23.2) 7,761 (26.1) 1,182 (23.3) 195 (26.4) 68 (24.7) 65+ 17,076 (43.1) 1,244 (32.7) 14,181 (47.7) 1,241 (24.5) 321 (43.4) 89 (32.4) residence metropolitan 32,572 (82.3) 3,558 (93.5) 23,518 (79.1) 4,629 (91.4) 634 (85.7) 233 (84.7) non-metropolitan 6,419 (16.2) 232 (6.1) 5,633 (19.0) 425 (8.4) 96 (13.0) 33 (12.0) unknown 610 (1.5) 16 (0.4) 563 (1.9) 12 (0.2) 10 (1.4) 9 (3.3) insurance status private 8,748 (22.1) 829 (21.8) 6,818 (22.9) 895 (17.7) 168 (22.7) 38 (13.8) medicare 15,123 (38.2) 1,030 (27.1) 12,185 (41.0) 1,596 (31.5) 254 (34.3) 58 (21.1) www.companyofscientists.com/index.php/chd e6 cancer health disparities research medicaid 3,235 (8.2) 484 (12.7) 1,914 (6.4) 754 (14.9) 72 (9.7) 11 (4.0) other♦ 3,530 (8.9) 280 (7.4) 2,719 (9.2) 434 (8.6) 67 (9.1) 30 (10.9) no insurance/self-pay 2,097 (5.3) 397 (10.4) 1,261 (4.2) 388 (7.7) 39 (5.3) 12 (4.4) unknown 6,868 (17.3) 786 (20.7) 4,817 (16.2) 999 (19.7) 140 (18.9) 126 (45.8) % persons below poverty at residence < 9.9% 5,312 (13.4) 314 (8.3) 4,408 (14.8) 407 (8.0) 141 (19.1) 42 (15.3) 10-19.99% 27,396 (69.2) 2,738 (71.9) 20,873 (70.2) 3,115 (61.5) 481 (65.0) 189 (68.7) ≥ 20% 6,283 (15.9) 738 (19.4) 3,870 (13.0) 1,532 (30.2) 108 (14.6) 35 (12.7) unknown 610 (1.5) 16 (0.4) 563 (1.9) 12 (0.2) 10 (1.4) 9 (3.3) geographic region northeast 7,603 (19.2) 838 (22.0) 5,614 (18.9) 968 (19.1) 128 (17.3) 55 (20.0) south 15,267 (38.6) 1,375 (36.1) 11,042 (37.2) 2,625 (51.8) 151 (20.4) 74 (26.9) midwest 8,172 (20.6) 247 (6.5) 6,815 (22.9) 975 (19.2) 88 (11.9) 47 (17.1) west/pacific 8,559 (21.6) 1,346 (35.4) 6,243 (21.0) 498 (9.8) 373 (50.4) 99 (36.0) stage at diagnosis local 20,814 (52.6) 1,970 (51.8) 15,921 (53.6) 2,408 (47.5) 374 (50.5) 141 (51.3) regional 12,574 (38.6) 1,255 (33.0) 9,207 (31.0) 1,811 (35.7) 247 (33.4) 54 (19.6) distant 3,025 (7.6) 266 (7.0) 2,241 (7.5) 443 (8.7) 64 (8.6) 11 (4.0) unknown 3,188 (8.1) 315 (8.3) 2,345 (7.9) 404 (8.0) 55 (7.4) 69 (25.1) anatomical site penile 14,612 (36.9) 2,140 (56.2) 10,477 (35.3) 1,482 (29.3) 409 (55.3) 104 (37.8) anorectal 24,989 (63.1) 1,666 (43.8) 19,237 (64.7) 3,584 (70.7) 331 (44.7) 171 (62.2) treatment surgery only 15,431 (39.0) 1,940 (51.0) 11,251 (37.9) 1,745 (34.4) 375 (50.7) 120 (43.6) radiation or chemo 2,472 (6.2) 164 (4.3) 1,906 (6.4) 357 (7.0) 29 (3.9) 16 (5.8) surgery + (radiation or chemo) 3,834 (9.7) 411 (10.8) 2,801 (9.4) 532 (10.5) 73 (9.9) 17 (6.2) radiation + chemo 9,556 (24.1) 604 (15.9) 7,533 (25.4) 1,245 (24.6) 132 (17.8) 42 (15.3) all modalities 4,740 (12.0) 347 (9.1) 3,620 (12.2) 701 (13.8) 63 (8.5) 9 (3.3) no treatment 3,553 (9.0) 338 (8.9) 2,590 (8.7) 486 (9.6) 68 (9.2) 71 (25.8) nh, non-hispanic. chemo, chemotherapy. * all variables were statistically significant at p < 0.01 in bivariate analyses using χ2 tests. § includes asian, american indian, alaska native, and pacific islander www.companyofscientists.com/index.php/chd e7 cancer health disparities research ♦other insurance includes indian/public health service, military, tricare, veterans affairs, and insurance not otherwise specified. figure 1 describes the age-adjusted incidence rates of hpv-associated ag cases from 2005-2016 by race/ethnicity and stage, stratified by anatomic site. the incidence rate of penile cancer remained relatively stable for all groups, while there were slight increases in late stage anorectal cancers among nh black and nh white males. relative to the other groups, hispanics had the highest incidence rate of penile cancers irrespective of disease stage (1a, 1b), while nh black males had the highest incidence rate of anorectal cancers (1c, 1d). figure 1: incidence of hpv-associated anogenital cancers by stage among males, 2005-2016 (n= 36,413)† †cases with unknown tumor stage were excluded. stage at anogenital cancer diagnosis males with anorectal cancers had higher odds of late-stage diagnosis (aor 1.32, 95% ci 1.26-1.39) relative to penile cancers (data not shown). table 2 describes factors associated with late stage diagnosis of penile and anorectal cancers. compared to nh white males, higher odds of latestage penile cancers were observed in nh black (aor 1.22, 95% ci 1.07-1.39) and hispanic males (aor 1.17, 95% ci 1.04-1.31). other independent factors associated with late-stage diagnosis of penile cancer included having medicaid (aor 1.50, 95% ci 1.28-1.76) or no insurance (aor 1.54, 95% ci 1.30-1.82). among anorectal cancers, nh other (aor 1.29, 95% ci 1.01-1.66) and nh black males (aor 1.25, 95% ci 1.14-1.36) had higher odds of late-stage diagnosis relative to nh white males. additionally, males older than 55 years (55-64: aor 1.17, 95% ci 1.08-1.25; 65+: aor 1.10, 95% ci 1.01-1.19), as well as those with medicaid (aor 1.62, 95% ci 1.46-1.79), other (aor 1.12, 95% ci 1.02-1.24), or no www.companyofscientists.com/index.php/chd e8 cancer health disparities research insurance/self pay (aor 1.76, 95% ci 1.55-2.00) had higher odds of late-stage anorectal cancer diagnosis. residential characteristics (metropolitan/non-metropolitan, area poverty, and geographic region) were not associated with late stage diagnosis of penile or anorectal cancers. table 2. predictors of late stage hpv-associated anogenital cancers among males in the united states, 2005-2016 (n= 30,319)† characteristic penile cancers (n=11,533) anorectal cancers (n=18,786) race/ethnicity aor# (95% ci) aor# (95% ci) nh, white 1.00 1.00 hispanic/latino 1.17 (1.04, 1.31)* 0.94 (0.83, 1.06) nh, black 1.22 (1.07, 1.39)* 1.25 (1.14, 1.36)* nh, other§ 1.11 (0.88, 1.40) 1.29 (1.01, 1.66)* age at diagnosis (years) < 54 1.00 1.00 55-64 1.11 (0.99, 1.26) 1.17 (1.08, 1.25)* 65 + 0.91 (0.80, 1.04) 1.10 (1.01, 1.19)* insurance type private 1.00 1.00 medicare 1.12 (0.99, 1.26) 1.01 (0.93, 1.09) medicaid 1.50 (1.28, 1.76)* 1.62 (1.46, 1.79)* other♦ 0.98 (0.84, 1.14) 1.12 (1.02, 1.24)* no insurance/self pay 1.54 (1.30, 1.82)* 1.76 (1.55, 2.00)* residence large metropolitan 1.00 1.00 non-metropolitan 0.97 (0.87, 1.06) 1.01 (0.93, 1.10) % persons below poverty at residence < 9.9% 1.00 1.00 10-19.99% 0.98 (0.88, 1.10) 1.01 (0.92, 1.10) > 20% 0.92 (0.80, 1.07) 1.00 (0.89, 1.12) geographic region northeast 1.00 1.00 south 0.96 (0.85, 1.08) 1.03 (0.93, 1.13) midwest 1.01 (0.88, 1.15) 0.97 (0.88, 1.08) west/pacific 1.04 (0.91, 1.18) 1.07 (0.96, 1.18) hpv, human papillomavirus; nh, non-hispanic; aor, adjusted odds ratio; ci, confidence interval † cases with unknown stage and unknown covariates were excluded. www.companyofscientists.com/index.php/chd e9 cancer health disparities research # adjusted for all other variables in table * p ≤0.01 § includes asian, american indian, alaska native, and pacific islander ♦other insurance includes indian/public health service, military, tricare, veterans affairs, and insurance not otherwise specified. in interaction analyses for penile cancers, race/ethnicity modified the relationship between late-stage diagnosis and other factors (supplemental table 1). compared with their nh white counterparts of the same age group, hispanic males under the age of 55 (aor 1.51, 95% ci 1.26-1.80) and nh black males aged 65 and older (aor 1.77, 95% ci 1.20-2.61) had higher odds of late-stage diagnosis. nh black males with private insurance, living in large metropolitan or low poverty (<10% of population below poverty) areas, or who lived in the south or western/pacific regions were also found to have higher odds of late-stage diagnosis compared to nh white males. additionally, hispanic males were found to have higher odds of late-stage diagnosis when living in large metropolitan or low poverty areas and in the western/pacific region. interestingly, nh black males living in high poverty areas (>20% of population below poverty) had significantly lower odds of late-stage penile cancer compared to nh white males (aor 0.55, 95% ci 0.32-0.95). for anorectal cancer, the only significant finding was that nh other males aged 65 years and older were observed to have over 3 times higher odds of latestage diagnosis (aor 3.01, 95% ci 1.50-6.02) relative to nh white males in the same age group (results not shown). supplemental table 1: interactions of race/ethnicity with covariates, late-stage diagnosis from hpvassociated penile cancers among males in the united states, 2005-2016 (n=11,533) † characteristic aor (95% ci) p-value age at diagnosis (years) 0.01 < 54 nh, white 1.00 hispanic/latino 1.51 (1.26, 1.80) <0.01 nh, black 1.08 (0.85, 1.36) 0.53 nh, other§ 1.41 (0.90, 2.21) 0.13 55-64 nh, white 1.00 hispanic/latino 1.05 (0.77, 1.44) 0.74 nh, black 1.21 (0.84, 1.74) 0.30 nh, other 0.75 (0.36, 1.56) 0.45 65 + nh, white 1.00 hispanic/latino 0.73 (0.52, 1.02) 0.06 nh, black 1.77 (1.20, 2.62) <0.01 nh, other 0.80 (0.38, 1.69) 0.56 www.companyofscientists.com/index.php/chd e10 cancer health disparities research insurance type 0.67 private nh, white 1.00 hispanic/latino 1.14 (0.91, 1.41) 0.25 nh, black 1.37 (1.02, 1.83) 0.03 nh, other 1.08 (0.70, 1.67) 0.71 medicare nh, white 1.00 hispanic/latino 1.16 (0.82, 1.63) 0.40 nh, black 0.70 (0.47, 1.04) 0.08 nh, other 1.21 (0.59, 2.51) 0.60 medicaid nh, white 1.00 hispanic/latino 1.12 (0.76, 1.66) 0.57 nh, black 0.88 (0.54, 1.43) 0.60 nh, other 0.74 (0.32, 1.69) 0.48 other♦ nh, white 1.00 hispanic/latino 1.20 (0.78, 1.84) 0.41 nh, black 0.87 (0.53, 1.44) 0.59 nh, other 1.67 (0.65, 4.34) 0.29 no insurance/self pay nh, white 1.00 hispanic/latino 1.28 (0.86, 1.90) 0.23 nh, black 0.73 (0.43, 1.22) 0.23 nh, other 1.10 (0.39, 3.12) 0.86 residence 0.27 large metropolitan nh, white 1.00 hispanic/latino 1.31 (1.19, 1.46) <0.01 nh, black 1.25 (1.11, 1.42) <0.01 nh, other 1.20 (0.95, 1.50) 0.12 non-metropolitan nh, white 1.00 hispanic/latino 1.10 (0.74, 1.65) 0.64 nh, black 1.40 (0.96, 2.06) 0.08 www.companyofscientists.com/index.php/chd e11 cancer health disparities research nh, other 0.73 (0.34, 1.57) 0.42 % persons below poverty at residence 0.14 < 9.9% nh, white 1.00 hispanic/latino 1.51 (1.11, 2.07) 0.01 nh, black 1.68 (1.13, 2.50) 0.01 nh, other 1.31 (0.80, 2.14) 0.29 10-19.99% nh, white 1.00 hispanic/latino 0.87 (0.59, 1.28) 0.48 nh, black 0.62 (0.38, 1.00) 0.05 nh, other 0.96 (0.50, 1.84) 0.91 > 20% nh, white 1.00 hispanic/latino 0.77 (0.48, 1.22) 0.27 nh, black 0.55 (0.32, 0.95) 0.03 nh, other 1.29 (0.52, 3.23) 0.58 geographic region 0.02 northeast nh, white 1.00 hispanic/latino 1.12 (0.89, 1.39) 0.33 nh, black 1.07 (0.80, 1.42) 0.64 nh, other 1.34 (0.85, 2.10) 0.21 south nh, white 1.00 hispanic/latino 1.01 (0.55, 1.88) 0.97 nh, black 1.78 (1.10, 2.89) 0.02 nh, other 1.65 (0.96, 2.82) 0.07 midwest nh, white 1.00 hispanic/latino 0.83 (0.40, 1.73) 0.62 nh, black 0.49 (0.20, 1.22) 0.12 nh, other 1.29 (0.49, 3.40) 0.60 west/pacific nh, white 1.00 hispanic/latino 1.53 (1.05, 2.24) 0.03 www.companyofscientists.com/index.php/chd e12 cancer health disparities research nh, black 1.46 (1.00, 2.13) 0.05 nh, other 1.40 (0.85, 2.31) 0.18 or, odds ratio; aor, adjusted odds ratio; nh, non-hispanic † cases with unknown stage and unknown covariates were excluded. § includes asian, american indian, alaska native, and pacific islander ♦other insurance includes indian/public health service, military, tricare, veterans affairs, and insurance not otherwise specified. anogenital cancer survival and mortality figure 2 represents the adjusted cumulative survival of hpv-associated ag cancers. nh black males had lower cumulative (fig. 2) and mean survival times (table 3) relative to the other racial/ethnic groups for both penile and anorectal cancers. conversely, nh other males had higher cumulative (fig. 2) and mean survival (table 3) of penile cancers relative to the other racial/ethnic groups. figure 2: cumulative survival of hpv-associated anogenital cancers among males, 2005-2011 (n= 11,432)* www.companyofscientists.com/index.php/chd e13 cancer health disparities research *mantel-cox log rank tests for cumulative survival were statistically significant at p<0.01. table 3. mean survival of males with hpv-associated anogenital cancers by race/ethnicity, united states, 2005-2011 (n=11,258)* overall mean months (95% ci) hispanic mean months (95% ci) nh white mean months (95% ci) nh black mean months (95% ci) nh other§ mean months (95% ci) penile 102.94 (101.60-104.27) 105.62 (102.42-108.82) 102.91 (101.31-104.50) 95.68 (91.11-100.26) 112.05 (105.60-118.50) anorectal 98.10 (97.03-99.17) 100.81 (96.69-104.92) 99.28 (98.08-100.47) 90.64 (87.65-93.63) 95.53 (86.25-104.81) hpv, human papillomavirus; nh, non-hispanic *unadjusted; all log rank mantel-cox tests were statistically significant at p<0.01 § includes asian, american indian, alaska native, and pacific islander table 4 describes the predictors of ag cancerspecific mortality stratified by anatomic site. in multivariable analyses adjusting for all covariates except treatment (model 1), independent predictors of higher penile cancer-specific mortality included: nh black race, medicaid or medicare, regional or distant stage diagnosis, and residence in high poverty (20%) areas. penile cancer-specific mortality was significantly lower in males living in the geographic south and midwest compared to the northeast. after adjusting for treatment, there was an attenuation of mortality for stage at diagnosis (model 2). higher mortality was observed for all treatment groups compared to surgery alone, with individuals receiving no treatment experiencing more than 3.5 times higher cancerspecific mortality (ahr 3.54, 95% ci 2.61-4.80). www.companyofscientists.com/index.php/chd e14 cancer health disparities research among males with anorectal cancers, after adjusting for all covariates except treatment (model 3), independent predictors of higher cancer-specific mortality included: nh black race; all insurances compared to private; regional or distant stage at diagnosis; and residence in moderate to high poverty areas. similar relationships were found after adjustment for treatment (model 4) with a few notable exceptions. we found that residence in the western/pacific region became significantly higher than the northeast and a sizable attenuation of hazards for regional and distant stage. men who received no treatment experienced more than 4.5 times higher cancer-specific mortality (ahr 4.53, 95% ci 3.57,-5.74). table 4. predictors of cause-specific mortality from hpv-associated anogenital cancers among males in the united states, 2005-2011 (n=11,432)† penile cancers (n=4,383) anorectal cancers (n=7,049) multivariable model 1 multivariable model 2 multivariable model 3 multivariable model 4 characteristic ahr# (95% ci) ahr## (95% ci) ahr# (95% ci) ahr## (95% ci) race/ethnicity nh, white 1.00 1.00 1.00 1.00 hispanic/latino 0.84 (0.70, 1.02) 0.83 (0.69, 1.00) 0.95 (0.78, 1.15) 0.93 (0.76, 1.13) nh, black 1.25 (1.03, 1.51)* 1.23 (1.01, 1.49)* 1.29 (1.14, 1.46)* 1.25 (1.10, 1.42)* nh, other§ 0.72 (0.48, 1.09) 0.69 (0.45, 1.05) 0.97 (0.67, 1.40) 0.94 (0.65, 1.38) age at diagnosis (years) < 54 1.00 1.00 1.00 1.00 55-64 1.19 (0.99, 1.44) 1.21 (1.01, 1.46)* 1.04 (0.94, 1.17) 1.00 (0.90, 1.12) 65 + 1.17 (0.95, 1.44) 1.23 (0.99, 1.53) 1.09 (0.96, 1.24) 1.00 (0.88, 1.13) insurance type private 1.00 1.00 1.00 1.00 medicare 1.27 (1.04, 1.54)* 1.28 (1.05, 1.56)* 1.72 (1.51, 1.95)* 1.72 (1.50, 1.96)* medicaid 1.34 (1.05, 1.71)* 1.28 (1.00, 1.64)* 1.67 (1.44, 1.93)* 1.67 (1.44, 1.94)* other♦ 0.94 (0.74, 1.18) 0.91 (0.72, 1.15) 1.34 (1.16, 1.56)* 1.32 (1.14, 1.54)* no insurance/self pay 1.04 (0.80, 1.35) 1.06 (0.81, 1.38) 1.27 (1.07, 1.51)* 1.21 (1.01, 1.44)* stage at diagnosis local 1.00 1.00 1.00 1.00 regional 3.45 (3.02, 3.94)* 3.02 (2.63, 3.48)* 2.30 (2.08, 2.54)* 2.18 (1.96, 2.43)* distant 18.14 (14.65, 22.46)* 11.52 (9.08, 14.61)* 7.40 (6.58, 8.33)* 6.14 (5.41, 6.96)* residence large metropolitan 1.00 1.00 1.00 1.00 non-metropolitan 1.02 (0.88, 1.19) 1.03 (0.88, 1.20) 0.93 (0.82, 1.05) 0.91 (0.80, 1.04) % persons below poverty at residence www.companyofscientists.com/index.php/chd e15 cancer health disparities research < 9.9% 1.00 1.00 1.00 1.00 10-19.99% 1.10 (0.89, 1.35) 1.11 (0.90, 1.37) 1.26 (1.08, 1.46)* 1.24 (1.06, 1.45)* > 20% 1.33 (1.04, 1.70)* 1.33 (1.04, 1.71)* 1.42 (1.18, 1.70)* 1.38 (1.14, 1.67)* geographic region northeast 1.00 1.00 1.00 1.00 south 0.79 (0.65, 0.97)* 0.77 (0.63, 0.95)* 1.13 (0.97, 1.32) 1.16 (0.99, 1.35) midwest 0.74 (0.59, 0.93)* 0.73 (0.58, 0.93)* 1.05 (0.88, 1.26) 1.12 (0.94, 1.35) west/pacific 0.86 (0.69, 1.08) 0.84 (0.67, 1.05) 1.14 (0.97, 1.35) 1.21 (1.02, 1.44)* treatment modality surgery only 1.00 1.00 radiation or chemotherapy only 2.40 (1.72, 3.35)* 2.45 (1.99, 3.01)* surgery + radiation or chemotherapy 2.15 (1.80, 2.55)* 1.27 (0.97, 1.66) radiation + chemotherapy 1.86 (1.16, 2.96)* 1.50 (1.26, 1.79)* all modalities 2.06 (1.57, 2.71)* 1.23 (1.02, 1.49)* no treatment 3.54 (2.61, 4.80)* 4.53 (3.57, 5.74)* hpv, human papillomavirus; nh, non-hispanic; hr, hazards ratio; ahr, adjusted hazards ratio † cases with unknown stage and unknown covariates were excluded. # adjusted for all other variables excluding treatment modality ##adjusted for all other variables including treatment modality * p ≤0.01 § includes asian, american indian, alaska native, and pacific islander ♦other insurance includes indian/public health service, military, tricare, veterans affairs, and insurance not otherwise specified. in interaction analyses (supplemental table 2), race/ethnicity modified the relationship of penile cancer mortality and age, stage, residence in a metropolitan area, and geographic region. compared with nh white males of the same age group, nh black males less than age 55 years had higher hazards of death (ahr 1.53, 95% ci 1.092.14). relative to nh white males diagnosed at the same stage, lower cancer-specific mortality was observed in nh other (ahr 0.35, 95% ci 0.14-0.84) and hispanic males (ahr 0.45, 95% ci 0.21-0.97) with local and distant stage penile cancers, respectively. lower cancer-specific mortality was also observed in nh black males living in the midwest (aor 0.36, 95% ci 0.14-0.90) and hispanic males living in the northeast (aor 0.37, 95% ci 0.20-0.67) compared to nh white males living in those regions. for anorectal cancer mortality, there were no significant interactions between race/ethnicity and other variables. www.companyofscientists.com/index.php/chd e16 cancer health disparities research supplemental table 2: interactions of race/ethnicity with covariates, cancer-specific mortality from hpvassociated penile cancers among males in the united states, 2005-2011 (n=4,383)† penile cancer-specific mortality characteristic ahr (95% ci) p-value age at diagnosis (years) 0.44 < 54 nh, white 1.00 hispanic/latino 1.06 (0.79, 1.43) 0.70 nh, black 1.53 (1.09, 2.14) 0.01 nh, other§ 0.75 (0.33, 1.69) 0.48 55-64 nh, white 1.00 hispanic/latino 0.87 (0.53, 1.43) 0.58 nh, black 0.67 (0.39, 1.14) 0.14 nh, other 0.50 (0.09, 2.77) 0.43 65 + nh, white 1.00 hispanic/latino 1.01 (0.56, 1.78) 0.99 nh, black 1.25 (0.69, 2.25) 0.46 nh, other 1.44 (0.17, 12.00) 0.73 insurance type 0.31 private nh, white 1.00 hispanic/latino 0.79 (0.54, 1.16) 0.23 nh, black 1.16 (0.74, 1.81) 0.52 nh, other 0.70 (0.31, 1.59) 0.40 medicare nh, white 1.00 hispanic/latino 1.11 (0.61, 2.04) 0.73 nh, black 0.76 (0.39, 1.47) 0.42 nh, other 0.53 (0.06, 5.08) 0.58 medicaid nh, white 1.00 hispanic/latino 1.04 (0.55, 1.96) 0.91 nh, black 0.94 (0.45, 1.95) 0.87 www.companyofscientists.com/index.php/chd e17 cancer health disparities research nh, other 0.24 (0.04, 1.39) 0.11 other¶ nh, white 1.00 hispanic/latino 1.98 (0.98, 3.98) 0.06 nh, black 1.78 (0.88, 3.60) 0.11 nh, other 0.37 (0.02, 5.75) 0.48 no insurance/self pay nh, white 1.00 hispanic/latino 1.48 (0.75, 2.91) 0.26 nh, black 1.51 (0.71, 3.20) 0.28 nh, other -------- stage at diagnosis 0.01 local nh, white 1.00 hispanic/latino 0.81 (0.60, 1.07) 0.14 nh, black 1.20 (0.88, 1.62) 0.24 nh, other 0.35 (0.14, 0.84) 0.02 regional nh, white 1.00 hispanic/latino 0.79 (0.52, 1.19) 0.26 nh, black 1.06 (0.68, 1.65) 0.79 nh, other 2.21 (0.58, 8.41) 0.24 distant nh, white 1.00 hispanic/latino 0.45 (0.21, 0.97) 0.04 nh, black 0.80 (0.37, 1.70) 0.56 nh, other -------- residence 0.41 large metropolitan nh, white 1.00 hispanic/latino 0.86 (0.73, 1.02) 0.09 nh, black 1.31 (1.09, 1.57) 0.01 nh, other 0.63 (0.42, 0.96) 0.03 non-metropolitan nh, white 1.00 hispanic/latino 1.56 (0.87, 2.80) 0.14 www.companyofscientists.com/index.php/chd e18 cancer health disparities research nh, black 1.27 (0.75, 2.14) 0.38 nh, other 0.85 (0.22, 3.32) 0.82 % persons below poverty at residence 0.14 < 9.9% nh, white 1.00 hispanic/latino 0.24 (0.09, 0.64) 0.01 nh, black 1.01 (0.53, 1.93) 0.97 nh, other 0.35 (0.09, 1.40) 0.14 10-19.99% nh, white 1.00 hispanic/latino 3.50 (1.06, 11.62) 0.04 nh, black 1.72 (0.74, 4.01) 0.21 nh, other 0.63 (0.11, 3.60) 0.60 > 20% nh, white 1.00 hispanic/latino 3.71 (1.06, 13.03) 0.04 nh, black 1.45 (0.58, 3.61) 0.42 nh, other 2.43 (0.40, 14.92) 0.34 geographic region 0.01 northeast nh, white 1.00 hispanic/latino 0.37 (0.20, 0.67) 0.01 nh, black 0.91 (0.49, 1.69) 0.76 nh, other 0.45 (0.14, 1.43) 0.18 south nh, white 1.00 hispanic/latino 0.70 (0.33, 1.45) 0.34 nh, black 0.49 (0.23, 1.04) 0.06 nh, other 0.59 (0.07, 5.10) 0.63 midwest nh, white 1.00 hispanic/latino 0.44 (0.13, 1.47) 0.18 nh, black 0.36 (0.14, 0.90) 0.03 nh, other 3.27 (0.36, 30.07) 0.29 west/pacific nh, white 1.00 www.companyofscientists.com/index.php/chd e19 cancer health disparities research hispanic/latino 1.26 (0.61, 2.59) 0.53 nh, black 0.46 (0.17, 1.22) 0.12 nh, other 0.55 (0.09, 3.54) 0.53 treatment modality 0.54 surgery only nh, white 1.00 hispanic/latino 0.82 (0.67, 1.00) 0.05 nh, black 1.22 (0.98, 1.51) 0.07 nh, other 0.58 (0.35, 0.97) 0.04 radiation or chemotherapy only nh, white 1.00 hispanic/latino 1.74 (0.61, 4.91) 0.30 nh, black 2.21 (0.93, 5.23) 0.07 nh, other -------- surgery + (radiation or chemotherapy) nh, white 1.00 hispanic/latino 1.47 (0.91, 2.34) 0.11 nh, black 0.76 (0.44, 1.30) 0.32 nh, other 0.51 (0.12, 2.26) 0.38 radiation + chemotherapy nh, white 1.00 hispanic/latino -------- nh, black -------- nh, other -------- all modalities nh, white 1.00 hispanic/latino 1.18 (0.56, 2.49) 0.65 nh, black 1.17 (0.46, 3.00) 0.74 nh, other -------- no treatment nh, white 1.00 hispanic/latino 0.82 (0.67, 1.00) 0.05 nh, black 1.04 (0.47, 2.30) 0.92 nh, other -------- hr, hazards ratio; ahr, adjusted hazards ratio; nh, non-hispanic † cases with unknown stage and unknown covariates were excluded. www.companyofscientists.com/index.php/chd e20 cancer health disparities research § includes asian, american indian, alaska native, and pacific islander. ♦other insurance includes indian/public health service, military, tricare, veterans affairs, and insurance not otherwise specified. ---suppressed for unreliable estimates due to case counts below 6. discussion to our best knowledge, the present study is the most comprehensive examination of hpvassociated ag cancer health outcomes among males living across the united states. prior studies have focused on one particular outcome or did not include covariates such as insurance status or geographic region in their analyses (huang et al., 2020; osazuwa-peters et al., 2021; slopnick et al., 2016). this study contributes to the literature of hpv-associated ag cancers in specifically analyzing the disparities in incidence, late-stage, survival, and mortality among males of multiple racial/ethnic groups. previous incidence estimates of hpv-associated ag cancers in the united states have been based on study populations consisting primarily of nh white and nh black men due to sample size considerations and the relative rarity of penile and anal cancer compared to other cancer types (arora et al., 2017; baughman and shah, 2016; bian et al., 2021; centers for disease control and prevention, 2020). similar to other studies, nh white males represented the largest proportion of our study sample, regardless of anatomic site or stage (huang et al., 2020; osazuwa-peters et al., 2021), while nh black males had the highest incidence and mortality of anorectal cancers (arora et al., 2017; deshmukh et al., 2020; goksu et al., 2020). additionally, we found hispanic males had the highest age-adjusted incidence rate of penile cancers regardless of disease stage, and nh black males had later stage at diagnosis, lower survival, and higher mortality for both penile and anorectal cancers. furthermore, certain subgroups of hispanic and nh other males were found to have higher late stage diagnosis of penile (hispanics living in south and west/pacific) and anorectal cancer (nh other males 65 years and older). inclusion of hispanic and nh other males (asian, pacific islander, native american, alaskan native) and controlling for potential confounders contribute uniquely to the literature about male hpv-associated ag cancers, which can lead to more targeted interventions to reduce the incidence, later stage at diagnosis, and mortality in men of color. the lower survival and higher mortality rates among nh black males for both penile and anorectal cancers may be associated with delayed treatment initiation, later stage at diagnosis, lower rates of radiation therapy, and ses disparities (ahmad et al., 2019; attalla et al., 2018; baughman and shah, 2016; fields et al., 2019; goksu et al., 2020; gupta et al., 2017). however, our observed disparity in mortality persisted after controlling for stage, treatment, and markers of ses. a potential contributing factor may be hiv co-infection with hpv. studies have noted disporportionately higher rates of contracting hiv among nh black men, especially men who have sex with men (msm) relative to white men, and there has been a rise in the hiv-infection of nh black males over the last three decades (heckman et al., 1999; leeds and fang, 2016; millett et al., 2007). hiv is a known risk factor for anal cancer, and the coinfection of hiv and hpv represents a significant challenge to a progressively diminished immune system (burd, 2003). additional clinician-related challenges include a lack of formal recommendations for use of anal pap tests, relative infrequency of anal cancer cases, and lack of familiarity with the procedure and purpose of anal pap testing (liszewski et al., 2014). studies examining the potential cost-effectiveness of anal www.companyofscientists.com/index.php/chd e21 cancer health disparities research cytology screening have found that screening msm every 2–3 years would be cost-effective and have life-expectancy benefits, and that screening could be easily incorporated into a primary care practice (goldie et al., 2000; siddharthan et al., 2019). nh black msm are 80% less likely to report anal cancer screening relative to their nh white counterparts, and thus, less likely to benefit from early detection of anal cancer (hicks et al., 2019), potentially leading to later stage at diagnosis and higher mortality. though penile cancer incidence is rare, it can cause significant psychological distress, especially related to a man’s self-esteem and sexual function (harju et al., 2021). our study findings showing hispanic males having the highest age-adjusted incidence rates of penile cancer is consistent with previous studies (huang et al., 2020; ortiz et al., 2018). we also found hispanic males to be diagnosed at later stages compared with nh white males, particularly among hispanic males living in the south and west/pacific regions of the u.s. researchers partially attribute this to the lower rates of circumcision among hispanic males (colón-lópez et al., 2010), and lack of circumcision may be more prevalent among recent hispanic immigrants who predominantly reside in the south and western u.s. (passel et al., 2022). circumcision potentially has a protective mechanism by decreasing the likelihood of phimosis and by removing the foreskin as a site susceptible to the development of penile cancer (larke et al., 2011). this may be why hispanic males with hiv have higher penile cancer rates but lower anal cancer rates compared with nh white and black males with hiv (cruz et al., 2019; ortiz et al., 2018). no differences in mortality were observed between hispanic and nh white males for either ag cancer. however, interaction analyses revealed lower cancer-specific mortality in hispanic males with distant disease and those living in the northeasten region of the country relative to nh white males of the same disease stage and region, respectively. this trend recurs throughout cancer research and other disease studies and has led to the emergence of a "hispanic paradox" or "healthy migrant effect," which suggest that migration demands exerted a selective effect that leads to better health and mortality outcomes compared to nh white and nh black males in similarly disadvantaged conditions (thomson et al., 2013). however, extreme caution should be used when considering this hypothesis during health intervention planning because of the serious impact on health policy and likelihood of negatively impacting healthcare delivery to hispanic populations that may still be at risk, including msm and hiv-positive hispanic males. nh other males were observed to have the lowest age-adjusted incidence of penile and anorectal cancer among all groups. the population that compose nh other are under-studied, therefore, it is unclear why they have lower incidence of hpvassociated cancers and improved prognosis relative to other racial/ethnic groups. among men, asians and pacific islanders have the lowest incidence of hpv infection and lower probability of acquiring new hpv infections relative to other ethnic groups (schabath et al., 2013). additionally, asians have been found to have lower cancer-specific mortality of any cancer compared to nh white males in all insurance status categories (benard et al., 2008; pan et al., 2017). our study reveals additional health outcomes among nh other males with hpvassociated ag cancers, particularly in certain subgroups. for example, nh other males were found to have similar odds of late-stage diagnosis and risks of mortality from penile cancers relative to nh white males. however, those diagnosed at local stage had 0.35 times lower hazards of death compared to nh white males diagnosed at local stage. conversely, nh other males with anorectal cancer had 29% higher odds of late-stage diagnosis www.companyofscientists.com/index.php/chd e22 cancer health disparities research relative to nh white males; specifically, those older than 65 years of age had three times higher odds of late-stage diagnosis relative to nh white males of the same age group. future studies are necessary in understanding why certain subgroups of nh other males experience better outcomes in penile cancer, while other subgroups have worse outcomes for anorectal cancer. limitations though our study included several established variables contributing to stage at diagnosis and overall survival in male ag cancers across racial/ethnic groups, the naaccr database does not contain other information, such as sociocultural and behavioral factors as well as comorbidities that may impact our results. known risk factors for anal and penile cancer include anal intercourse, lack of circumcision, immunosuppression, hiv-infection, and solid-organ transplantation (amirian et al., 2013; clifford et al., 2020; van der zee et al., 2013). these factors may be differentially distributed across racial/ethnic groups and within subgroups of msm and those engaging in higher-risk sexual behaviors (amirian et al., 2013). additionally, hpv status was not molecularly determined but based on supposition that cancers at particular sites and histologies are associated with hpv (centers for disease control and prevention, 2020), which may have led to misclassification of cases and an overestimate of the number of ag squamous cell carcinomas in our cohort. furthermore, a limitation of the naaccr database is a lack of information on the immigration status or birthplace of individuals identified as hispanic or asian. since intragroup variability may be substantial among hispanics (martinez tyson et al., 2018) and asians (thompson et al., 2016), future studies are needed to disentangle and understand ag outcomes among different hispanic ethnicities and asian subgroups. conclusion this study highlights different racial/ethnic disparities in health outcomes among males depending on site of hpv-associated ag cancer. when considering the strong association between hpv and anal (>90%) and penile cancer (64%), as well as the potential reduction of cancer risk with hpv vaccination (stier et al., 2016), our findings call for increasing hpv immunizations among all males. additionally, increasing awareness of symptoms and signs of penile and anal cancer, as well as the utility of anal pap smears in high-risk populations may help to improve early detection, particularly in men of color. finally, improving access to treatment is paramount for decreasing mortality in males with hpv-associated ag cancers, especially for black men. author contributions sv, ams, and jmf designed the research study. sv, ams, jmf acquired and analyzed the data. all authors interpreted the data. sv, ss, dr drafted the manuscript. ams and jmf revised the manuscript critically for important intellectual content. all authors approved the final manuscript and agreed to be accountable for all aspects of the work. ethics approval this study was approved by the institutional review boards at the north american association of central cancer registries (naaccr) and rutgers, the state university of new jersey (pro2019001220). funding no funding was received for this research. conflict of interest ams received travel expenses while serving as president and representative-at-large of the board of directors for the north american association of central cancer registries (naaccr) and the www.companyofscientists.com/index.php/chd e23 cancer health disparities research naaccr communications steering committee. the other authors have no conflicts of interests to declare. acknowledgement the data underlying this article were provided by the north american association of central cancer registries, which granted access to the cancer in north america deluxe file. we thank anna petrova, md, phd, mph and ambarina faiz, md, phd for their feedback on the analysis as part of seiichi villalona’s distinction in research program at rutgers robert wood johnson medical school. references ahmad, t.r., susko, m., lindquist, k., and anwar, m. 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(2020). comorbidities associated with hpv infection among people living with hiv-1 in the southeastern us: a retrospective clinical cohort study. bmc infect dis 20, 1-9. https://www.census.gov/geographies/reference-maps/2010/geo/2010-census-regions-and-divisions-of-the-united-states.html https://www.census.gov/geographies/reference-maps/2010/geo/2010-census-regions-and-divisions-of-the-united-states.html https://www.census.gov/geographies/reference-maps/2010/geo/2010-census-regions-and-divisions-of-the-united-states.html introduction materials and methods data and sample stage at diagnosis survival and mortality covariates statistical analysis results stage at anogenital cancer diagnosis discussion limitations conclusion author contributions ethics approval funding conflict of interest acknowledgement www.companyofscientists.com/index.php/chd e1 cancer health disparities research psychosocial stress, glucocorticoid signaling and prostate cancer health disparities in african american men leanne woods-burnham1,#, laura stiel2, shannalee r. martinez1, evelyn s. sanchez-hernandez1, herbert c. ruckle3, frankis g. almaguel1,4, mariana c. stern5, lisa r. roberts6, david r. williams7, susanne montgomery1,,2, carlos a. casiano1.8* 1center for health disparities and molecular medicine and department of basic sciences, loma linda university school of medicine, loma linda, ca, usa; 2loma linda university school of behavioral health, loma linda, ca, usa; 3department of surgical urology, loma linda university school of medicine, loma linda, ca, usa; 4loma linda university cancer center, loma linda, ca, usa; 5departments of preventive medicine and urology, university of southern california keck school of medicine, los angeles, ca; 6loma linda university school of nursing, loma linda, ca, usa; 7department of social and behavioral sciences, harvard university school of public health; 8department of medicine, loma linda university school of medicine, loma linda, ca, usa. #current address: city of hope comprehensive cancer center, department of population sciences, division of health equities, 1500 east duarte rd, duarte ca 91010 *corresponding author: carlos a. casiano, email: ccasiano@llu.edu. abstract: recent advances in our understanding of racial disparities in prostate cancer (pca) incidence and mortality that disproportionately affect african american (aa) men have provided important insights into the psychosocial, socioeconomic, environmental, and molecular contributors. there is, however, limited mechanistic knowledge of how the interplay between these determinants influences prostate tumor aggressiveness in aa men and other men of african ancestry. growing evidence indicates that chronic psychosocial stress in aa populations leads to sustained glucocorticoid signaling through the glucocorticoid receptor (gr), with negative physiological and pathological consequences. compelling evidence indicates that treatment of castration-resistant prostate cancer (crpc) with anti-androgen therapy activates gr signaling. this enhanced gr signaling bypasses androgen receptor (ar) signaling and transcriptionally activates both ar-target genes and gr-target genes, resulting in increased prostate tumor resistance to anti-androgen therapy, chemotherapy, and radiotherapy. given its enhanced signaling in aa men, gr—together with specific genetic drivers—may promote crpc progression and exacerbate tumor aggressiveness in this population, potentially contributing to pca mortality disparities. ongoing and future crpc clinical trials that combine standard of care therapies with gr modulators should assess racial differences in therapy response and clinical outcomes in order to improve pca health disparities that continue to exist for aa men. keywords: african american, african ancestry, clinical trials, glucocorticoid receptor, glucocorticoid signaling, health disparities, prostate cancer, psychosocial stress citation: woods-burnham l et al (2020) psychosocial stress, glucocorticoid signaling, and prostate cancer health disparities in african american men. cancer health disparities 4:e1-e30. doi:10.9777/chd.2020.1005. www.companyofscientists.com/index.php/chd e2 cancer health disparities research introduction prostate cancer (pca) is the most commonly diagnosed cancer and the second leading cause of cancer mortality in men in the united states (u.s.) (siegel et al., 2020). approximately 191,930 men will be diagnosed with pca and 33,330 will die from this malignancy in the u.s. in 2020 (siegel et al., 2020). african-american (aa) men have the highest rates of pca incidence and mortality compared to men of other races and ethnicities in the u.s. (siegel et al., 2020). these disparities have also been reported in other populations of men with african ancestry (petersen et al., 2019; rebbeck, 2017). at time of diagnosis, aa men and african men show a greater frequency of high-risk prostate tumors compared to men from other racial groups, ultimately resulting in increased mortality (cuevas et al., 2019; petersen et al., 2019; rebbeck, 2017; woods-burnham et al., 2018a). emerging evidence supports the notion that these disparities stem from the interplay between multiple factors including socioeconomic status (ses), environment, and biology (abdalla et al., 1999; chornokur et al., 2011; desantis et al., 2019; moul et al., 1995). an emerging area in the field of pca health disparities research is the contribution of psychosocial stress or socioenvironmental adversity to an increased risk of tumor aggressiveness, particularly in aa men (cuevas et al., 2019; kantor et al., 2019; woods-burnham et al., 2018a). in this review we discuss recent studies linking psychosocial stress with increased glucocorticoid signaling in aa populations. we also discuss emerging evidence pointing to glucocorticoid signaling through the glucocorticoid receptor (gr) as critical for pca progression into the therapy-resistant advanced stage. we propose a model (fig. 1) that integrates psychosocial stress, glucocorticoid signaling, and pca progression in the context of pca health disparities. in this model, cumulative exposure to psychosocial stressors (e.g. discrimination, negative neighborhood effects, low ses, limited access to health care) contributes to sustained elevated levels of cortisol resulting in amplified gr signaling. this amplified gr signaling is further increased by anti-androgen therapy during pca treatment, leading to the activation of molecular mechanisms associated with pca aggressiveness and therapy resistance. www.companyofscientists.com/index.php/chd e3 cancer health disparities research fig. 1 psychosocial stress, glucocorticoid signaling, and prostate cancer progression in the context of health disparities. chronic or cumulative exposure of aa men to psychosocial stressors (e.g. discrimination, negative neighborhood effects, low ses, limited access to health care) contributes to sustained elevated levels of cortisol resulting in amplified gr signaling leading to the activation of molecular mechanisms associated with prostate tumor aggressiveness and therapy resistance. aa, african american; gr, glucocorticoid receptor; ses, socioeconomic status. prostate cancer health disparities aa men are more likely to be diagnosed and die from pca than european american (ea) men (siegel et al., 2020). while it is estimated that 1 in 9 ea men will be diagnosed with pca in their lifetime, the estimation rate in aa men is 1 in 7 (desantis et al., 2019). we recently reported that 1 in 3 aa men had elevated circulating psa in a random sample of 414 adult aa men from the community (woods-burnham et al., 2018b). the biological characteristics of prostate tumors are exaggerated in aa men compared to ea men at time of diagnosis, including higher psa levels, higher gleason scores, differential anatomical localization of the tumors, and advanced tumor stage (abdalla et al., 1999; chornokur et al., 2011; moul et al., 1995). moreover, aa men show a higher rate of errors at the time of biopsy, leading to under-detection of higher grade disease at the time of diagnosis, which may compromise their outcomes (sanchez-ortiz et al., 2006; sundi et al., 2013). multifactorial causes of pca health disparities. the causes of these racial disparities are complex and include the interplay between multiple factors such as ses, biological and genetic determinants, stress, diet, lifestyle, and access to healthcare (derouen et al., 2018; desantis et al., 2019; deshmukh et al., 2017; kelly et al., 2017; kinlock et al., 2016; krokschoen et al., 2017; mahal et al., 2017; singh and jemal, 2017; tsodikov et al., 2017; weprin et al., 2019). low ses directly affects diet, lifestyle, and access to healthcare, and therefore contributes significantly to cancer health disparities (bach et al., 2002; benjamins et al., 2016; desantis et al., 2019; ward et al., 2004). aas have been reported to suffer disparities for many cancer risk factors, such as lower dietary quality, greater rates of obesity, lower rates of physical activity, higher rates of exposure to endocrine disruptive chemicals, and higher prevalence of night-shift work (wang and chen, 2011). income inequalities also contribute to increased exposure to risk factors such as barriers to highquality cancer prevention, early detection, and cutting-edge treatment options (bach et al., 2002; benjamins et al., 2016; desantis et al., 2019; ward et al., 2004). the level of education affects potential income, and aas have lower percentages of college degrees and higher rates of poverty than eas (desantis et al., 2019). less education leading to lower income also affects neighborhood placement, and low ses neighborhoods are more likely to be targeted by marketing that promotes behaviors known to increase cancer risk (desantis et al., 2016). lower ses also translates to worse overall cancer survival rates for several reasons that include limited access to high-quality health care (bach et al., 2002; shavers and brown, 2002; ward et al., 2008; zeng et al., 2015). worse overall survival is also influenced by the fact that aas are more likely to be diagnosed with pca at advanced tumor stage, which limits treatment options and reduces their efficacy (arace et al., www.companyofscientists.com/index.php/chd e4 cancer health disparities research 2020; desantis et al., 2016). aa men also experience lower pca screening rates compared to non-aa men (misra-hebert et al., 2017). we recently reported that in a sample of 264 aa/black men over 45 years old living in the u.s. who met the american cancer society criteria for screening, only 49.6% had ever been screened and only 29.2% had a psa test within the last year, consistent with other reports of lower rates of screening among aa men (roberts et al., 2018). in another study of 414 aa/black men (mean age 48.9 years) living in the u.s., we found that less than half (45.2%) of the participants had discussed pca screening with their physicians, and detected higher-than-normal psa values in 29.1% of the men who had not discussed pca screening (woods-burnham et al., 2018b). even when provided the same pca treatment as ea men, aa men are more likely to experience delay in treatment administration and suffer greater postoperative complications (schmid et al., 2016). in addition, aas are less likely to enroll in clinical trials, preventing them from exposure to cutting-edge treatment options (murthy et al., 2004; wallace et al., 2011). co-morbidities affecting delivery of optimal treatment, including obesity, diabetes, and hypertension, are higher in aas and may exacerbate pca mortality (braithwaite et al., 2009; tammemagi et al., 2005; yancik et al., 1998). the current covid-19 pandemic has clearly exposed how these co-morbidities, combined with an adverse and stressful host-environment, have rendered aa populations more vulnerable during the pandemic (holmes et al., 2020). molecular determinants of prostate cancer disparities. although studies from the u.s. veteran administration health care system suggest that pca health disparities can be attenuated with better access to health care (daskivich et al., 2015; riviere et al., 2020), other studies indicate that these disparities persist even after controlling for ses, clinical setting, and access to care (du et al., 2011; kish et al., 2014; nettey et al., 2018). this suggests that molecular or biological determinants may also contribute to these disparities (bhardwaj et al., 2017; singh et al., 2017). genomic differences between aa and ea men with pca hint that genetic mediators may drive pca health disparities (batai et al., 2016; gusev et al., 2016; han et al., 2015; hoffman et al., 2001; powell et al., 2013; rand et al., 2016; reams et al., 2009; wallace et al., 2008; wang et al., 2017). this is supported by the identification of pca susceptibility loci for aa men in both linkage studies and genome-wide association studies (gwas) (gudmundsson et al., 2007; kote-jarai et al., 2011; yeager et al., 2007). interestingly, genetic variation on the chromosome 8q24 region, where the c-myc gene is located, has been consistently associated with pca risk, and ethnic specific mutations and haplotypes have been reported in african populations (chung et al., 2014; darst et al., 2020). in addition to inherited genomic factors linked to pca, there are also genetic alterations that are associated with pca risk (rebbeck, 2017). recent genomic studies on human prostate tumors have identified multiple oncogenic drivers of pca development. these include chromosomal translocations resulting in the generation of a fusion between the tmprss2 (a transmembrane serine protease) and erg (a member of the ets transcription factor family) genes, as well as mutations or alterations in genes associated with phosphoinositide 3-kinase(pi3k)-akt signaling, wnt/β-catenin pathway, transcription and epigenetic regulation (e.g. ets, foxa1, kmt2c/d, swi/snf complex members), ubiquitination (e.g. www.companyofscientists.com/index.php/chd e5 cancer health disparities research spop and cul3), dna repair (e.g. brca2, atm, cdk12), tumor suppression (e.g. tp53, pten), rasmapk signaling, and ar signaling (armenia et al., 2018; banerjee et al., 2018; frank et al., 2018; warner et al., 2019). the frequencies of mutations and alterations in these genetic drivers vary according to disease stage. the tmprss2:erg fusion has been found at lower frequencies in aa men (∼28%) and black men from africa (∼13%), compared to ea men (49%) (blackburn et al., 2019). aa and ea men also have significant differences in erg expression (yamoah et al., 2015). the prognostic values of tmprss2:erg fusion and erg expression are not clear, but the relationship with pca risk factors differs by tmprss2:erg translocation status (ahearn et al., 2016; netto, 2013). in addition, the association between obesity and worse pca outcome has been found in men harboring the tmprss2:erg (pettersson et al., 2013). by default, aa men, who have greater rates of obesity than ea men (rebbeck, 2017), harboring the tmprss2:erg translocation may have a poorer pca prognosis than ea men. interestingly, exome and whole-genome sequencing of aa prostate tumors revealed loss of function mutations in erf, an ets transcriptional repressor, lower frequency of erg fusions, pik3ca mutations and pten deletions, as well as increased frequency of spop mutations and expression of long non-coding rnas (lncrnas), compared to ea pca (huang et al., 2017; jaratlerdsiri et al., 2018; yuan et al., 2020). another recent study showed that tp53 mutations, mutations in the dna repair gene brca2, and deletions in cdkn1b (cyclin-dependent kinase inhibitor b1) are associated with increased risk of metastasis among aa men with pca (petrovics et al., 2019). however, another study showed that alterations in dna repair genes, including brca1/2 and atm, are less likely to be detected in aa patients with pca compared to ea patients (sartor et al., 2020). gene expression profiling of pca tumors have also revealed differences in tumor immunobiology between aa and ea men (wallace et al., 2008). for instance, genes associated with autoimmunity and inflammation, particularly those clustering in immune response, stress response, cytokine signaling, and chemotaxis pathways are differentially upregulated in aa prostate tumors (wallace et al., 2008). a recent study that integrated the genomic and transcriptomic landscape between aa pca and ea pca revealed an enrichment of highly expressed differentially expressed genes (degs) for immune-related pathways in aa men, compared to increased enrichment for pten/pi3k signaling in ea men (yuan et al., 2020). metastasis-promoting genes are also more highly expressed in aa prostate tumors, including autocrine mobility factor receptor, chemokine receptor 4, and matrix metalloproteinase 9 (wallace et al., 2008). inflammation associated genes such as il6, il8, il1b, cxcr4, and fasn were also found to be significantly expressed at higher levels in prostate tumors from aa compared to ea men (powell et al., 2013). the expression of many of these genes have been associated with diet and lifestyle, higher gleason scores, androgen receptor (ar) signaling, aggressive pca tumors, and metastasis (dubrovska et al., 2012; finley et al., 2009; jia et al., 2004; nguyen et al., 2010; powell et al., 2013; yang et al., 2004). consistent with the notion of differential expression of immune function-related genes between aa and ea men with pca, our group reported race-related differences in serum autoantibody responses to specific tumor www.companyofscientists.com/index.php/chd e6 cancer health disparities research associated antigens in pca patients (sanchez et al., 2016). the rna splicing landscape has also been explored as a potential biological determinant of pca health disparities (olender and lee, 2019; wang et al., 2017). a genome-wide analysis of differential splicing (ds) events in racially diverse prostate tumors revealed hundreds of ds events that were unique to aa pca and affected specific splice variants of several oncogenes such as pik3cd, fgfr3, tsc2, and rasgrp2 (olender and lee, 2019). validation studies showed that ectopic overexpression of a short splice variant of pik3cd, enriched in aa tumors, enhanced the aggressive properties of pca cells compared to the corresponding variant enriched in ea tumors. these results suggested that differential rna splicing may contribute to increased tumor aggressiveness in aa pca and could be exploited for developmental therapeutics in aggressive pca. given that androgens drive pca etiology and disease progression prior to metastatic crpc (mcrpc), several studies have also explored racial differences in androgen production and ar signaling (bosland and mahmoud, 2011; karakas et al., 2017; massengill et al., 2003; schatzl et al., 2003). these studies have shown that aa men have higher testosterone and active 5-alpha reductase levels than ea men, resulting in enhanced conversion of testosterone to the more potent dht (kheirandish and chinegwundoh, 2011; ross et al., 1992). the differential expression of epithelial and stromal ar in pca tissue is also emerging as a possible driver of castration resistance in patients receiving adt (karakas et al., 2017), and there is evidence that while nuclear ar levels are increased in aa pca patients compared to ea patients, stromal levels are decreased (li et al., 2008; singh et al., 2014). in addition, aa pca patients have higher frequency of germline and somatic ar mutations and their tumors show increased expression of specific ar target genes associated with tumor aggressive properties compared to those of ea pca men (gaston et al., 2003; jemal et al., 2006; karakas et al., 2017). african americans and psychosocial stress aas are exposed to more cumulative lifetime stressors than other racial/ethnic groups, which detrimentally alters psychological and physical health (cohen et al., 2006; young et al., 1991; zannas et al., 2015). the elevated levels of stress among aas can be due, among other factors, to social isolation, racial discrimination, perceived discrimination, and segregation (cacioppo and hawkley, 2003; cuevas et al., 2019; williams and collins, 2001). chronic stress leading to dysregulation of endogenous cortisol production via the hypothalamic-pituitary-adrenocortical (hpa) axis can enhance risk for metabolic disorders and cancer (cohen et al., 2006; steptoe et al., 2000; vedhara et al., 1999; zannas et al., 2015). as illustrated in fig. 2, when the hpa axis is activated, neurons in the paraventricular nucleus of the hypothalamus are triggered to release corticotropin-releasing hormone (crh) and arginine vasopressin, which stimulate the production and secretion of adrenocorticotropic hormone (acth) from the anterior pituitary gland, resulting in the synthesis and secretion of the steroid hormone cortisol, an endogenous glucocorticoid, from the adrenal cortex (joseph and whirledge, 2017; stephens and wand, 2012). a classical endocrine negative feedback loop inhibits further release of crh and acth in response to rising levels of cortisol, thus maintaining a physiological homeostasis under normal conditions (joseph and whirledge, 2017). www.companyofscientists.com/index.php/chd e7 cancer health disparities research in addition, the hpa axis tightly regulates glucose metabolism, cardiovascular function, cell proliferation and survival, growth, cognition and behavior, immune function, and reproduction directly through cortisol production (joseph and whirledge, 2017). cortisol is secreted diurnally, peaking early in the morning when blood glucose levels are at the lowest and tapering throughout the day (cohen et al., 2006). this diurnal rhythm is altered in response to chronically stressful situations (adam and gunnar, 2001; cohen et al., 2006). fig. 2. physiological response to stress. cortisol is secreted from the adrenal cortex in response to acute stress. a classical endocrine negative feedback loop inhibits further release of crh and acth in response to rising levels of cortisol to maintain a physiological homeostasis under normal conditions. chronic stress leading to dysregulation of endogenous cortisol production via the hpa axis can enhance risk for metabolic disorders and cancer. acth, adrenocorticotropic hormone; crh, corticotropin-releasing hormone; gr, glucocorticoid receptor; hpa, hypothalamic-pituitary-adrenocortical. chronic exposure to stressors is increased in individuals of low ses, and there is a positive association between low ses and stress in aa men (cohen et al., 2006; williams, 2003). low ses is defined by lower income, education, or occupational status, and often results in increased exposure to environmental stressors leading to stress-related dysregulation of physiological systems and increased risk for disease (adler et al., 1994; cohen et al., 2006; mcewen, 1998). however, even in aas who have high ses, racial disparities in health persist, suggesting that there are alternative sources of stress other than ses (farmer and ferraro, 2005). for example, a poor lipid profile characterized by high triglycerides, ldl cholesterol, and total cholesterol, as well as lower hdl cholesterol, actually increases in aas as education increases (knox et al., 1996). national data reveals that strikingly high levels of racial inequality in ses exist in the u.s., having changed little over time, and that aas continue to suffer from disproportionately lower ses (williams et al., 2010), which has been shown to influence emotions and behaviors that alter cortisol levels www.companyofscientists.com/index.php/chd e8 cancer health disparities research (adler et al., 1994). lower ses is also associated with greater perceived stress, depressive symptoms, negative affect, weak social networks and support, and sleep deprivation (cohen et al., 2006), factors linked to greater cortisol responses (leproult et al., 1997; polk et al., 2005; pruessner et al., 2003; seeman et al., 2001). however, whether lower ses by itself is associated with increased cortisol responses among aas remains to be unambiguously established. a major study by cohen and colleagues explored whether sesassociated dysregulation of cortisol diurnal rhythm is independent of race and occurs equally in aas and eas (cohen et al., 2006). this study reported that both lower ses (education and income) and being black were associated with higher evening levels of cortisol (cohen et al., 2006). these higher cortisol levels in aas were associated with poorer health practices (e.g. smoking), higher levels of depressive symptoms, poorer social networks and supports, and feelings of helplessness (cohen et al., 2006). this dysregulation has negative longterm repercussions for the health of aas (williams et al., 2010; williams and sternthal, 2010; zannas et al., 2015). employed aas are also more likely to be exposed to carcinogens and occupational hazards compared to other racial groups with matched education and job experience (kaufman et al., 1997; williams and sternthal, 2010). compounding these realities, aas have less purchasing power, as the costs of goods and services are highest in predominantly aa communities (kaufman et al., 1997; williams and sternthal, 2010). outside the workplace, aas are exposed to daily stressors within neighborhoods that are highly segregated (williams et al., 2010), the effects of which negatively impact the ses and health of aa residents (schulz et al., 2002; williams and collins, 2001). for instance, optimal health is jeopardized in economically-disadvantaged, segregated neighborhoods as nutrition suffers in the presence of higher cost, lower quality, and decreased availability of healthy foods (schulz et al., 2002; williams and collins, 2001). similarly, physical activity is reduced in the absence of suitable recreational facilities amid safety concerns (schulz et al., 2002; williams and collins, 2001). exposure to environmental toxins and poor-quality living conditions also exist in neighborhoods accustomed to institutional neglect and disinvestment (schulz et al., 2002; williams and collins, 2001). adding to these cumulative stressful events are frequent experiences of discrimination and incarceration among aas, which are associated with psychological distress and adverse physical health effects, including high incidence of chronic conditions such as hypertension, obesity, diabetes, substance abuse, and cancer (byrd, 2012; krieger et al., 2011). combined, these stressors are directly linked to elevated risk of illness and death among aas, and greatly contribute to existing racial disparities in health (acevedo-garcia et al., 2003; williams and collins, 2001). for example, aa men ages 57-85 may have worse metabolic outcomes than their ea counterparts due to chronic inflammation arising from cumulative, multi-dimensional stress experienced over their lives (das, 2013). interestingly, a study based in argentina of men ages 45-70 reported that uncontrollable stressful life events were inversely correlated with psa among men with low cortisol, but positively correlated with psa among men with high cortisol, suggesting that such events may be related to prostatic tumorigenic processes in men with high cortisol (gidron et al., 2011). www.companyofscientists.com/index.php/chd e9 cancer health disparities research glucocorticoid receptor signaling gr biology. the cellular and pharmacological actions of cortisol and other glucocorticoids are mediated by gr, although low levels of glucocorticoids can also stimulate the mineralocorticoid receptor (mr) (gomez-sanchez and gomez-sanchez, 2014; joseph and whirledge, 2017). gr is ubiquitously expressed throughout the human body, and signaling through this receptor regulates metabolism, growth, development, cardiovascular homeostasis, and cognition (biddie et al., 2012; oakley and cidlowski, 2013). synthetic glucocorticoids such as prednisone and dexamethasone have long been integral components of treatment regimens for inflammatory and autoimmune diseases as well as certain cancers (vandewalle et al., 2018). as a member of the nuclear receptor family (which also includes receptors for estrogen, progesterone, and androgen), gr has both genomic (regulating gene transcription by binding to glucocorticoid response elements, gres, in promoter regions) and non-genomic (modulating the function of intracellular kinases, including c-src) effects (oakley and cidlowski, 2013). in the absence of ligand binding, gr resides in the cytoplasm as part of a large multi-protein complex including chaperone heat shock proteins hsp90, hsp70, and p23 as well as immunophilins of the fk506 family including fk506-binding protein (fkbp) 51 and fkbp52 (grad and picard, 2007; joseph and whirledge, 2017; pratt and toft, 1997). upon ligand binding, a conformational change occurs releasing gr from the chaperone proteins and promoting its translocation into the nucleus where it exerts transcriptional regulation functions (joseph and whirledge, 2017). this nuclear translocation is promoted by signaling through the semaphorins sema4d/sema3c upon binding to their receptor plexinb1 (williamson et al., 2019). gr-mediated transcriptional control also extends to sequestration of other transcription factors (including nfkb and ap-1) to inhibit proinflammatory gene expression as well as tethering transcription factors to facilitate gene transcription (oakley and cidlowski, 2011; vandevyver et al., 2014). while most cells express gr, its genetic structure is highly complex, and tissue-specific control of gr signaling is conferred, to a large extent, by the type and level of gr expressed (ito et al., 2006). the gene encoding gr, nr3c1 (nuclear receptor subfamily 3 group c member 1), is composed of 9 exons; however, the major transcriptional start site is within exon 2 and only exons 2 through 9 encode protein (ito et al., 2006; vandevyver et al., 2014). exon 2 encodes the amino (n)-terminal modulatory domain, exons 3 and 4 encode the dna-binding domain, exon 5 codes for a hinge region, and exons 6-9 encode the carboxy (c)terminal ligand binding domain (kadmiel and cidlowski, 2013). the 13 currently-identified variants of exon 1, with 9 possible promoter regions, form the 5’-untranslated region (utr) and are thought to confer tissue specificity of gr expression (turner and muller, 2005). alternative splicing of gr mrna yields grα, grβ, grγ, gr-a, and gr-p. grα is expressed at higher levels in most cells, including cancer cells, than the other gr forms (biddie et al., 2012; vandevyver et al., 2014). grβ is a closely-related variant to grα, differing by ~35 amino acids within the ligand binding domain (fig. 3). in contrast to grα, grβ does not bind glucocorticoids and is constitutively located in the nucleus (biddie et al., 2012; kassel and herrlich, 2007; mata-greenwood et al., 2015). although it does not directly mediate transcription, www.companyofscientists.com/index.php/chd e10 cancer health disparities research grβ has been shown to regulate gene expression through dominant-negative effects on grα via heterodimer formation and also by epigenetically modifying chromatin structure through interactions with histone deacetylases (nicolaides et al., 2010; oakley and cidlowski, 2013). grγ, which makes up about 10% of total gr expression in most cells, is formed through alternative splicing between exons 3 and 4, with the incorporation of a single additional arginine nucleotide into the dna binding domain (morgan et al., 2016). this minor structural difference, while not affecting dna binding affinity or total gr occupancy of target genes, still confers different sequence specificity and target gene control (through variable allosteric signal interpretation) compared to grα (morgan et al., 2016). other notable aspects of grγ are a delayed ligand-induced nuclear import (unlike beta, resides in the cytoplasmic region) as well as a pro-cellular respiration function within mitochondria (morgan et al., 2016). the gr-a and gr-p isoforms are formed through removal of large portions of the ligand binding domain (exons 5-7 and exons 8-9, respectively) (oakley and cidlowski, 2013). comparatively less is known concerning these isoforms, but evidence suggests a ligandindependent ability to modulate grα function (oakley and cidlowski, 2013; vandevyver et al., 2014). a further layer of complexity in gr expression is introduced by 8 alternate translation initiation sites within exon 2, yielding a number of additional isoforms (oakley and cidlowski, 2013; vandevyver et al., 2014). these have been identified for grα and are predicted to exist for each of the other splice variants grβ, grγ, gr-a, and gr-p (oakley and cidlowski, 2013; vandevyver et al., 2014). furthermore, post-translational modifications of gr also regulate the receptor’s function in target cells (vandevyver et al., 2014). kinase activity (including mapk, cdk, ck2, gsk-3β) at serine residues within the n-terminal domain occurs following glucocorticoid exposure (oakley and cidlowski, 2013; vandevyver et al., 2014). these phosphorylation events may result in cytoplasmic sequestration (ser-203, -226, -404), degradation, or enhanced transcriptional activity (-211) (oakley and cidlowski, 2013; vandevyver et al., 2014). other gr modifications include the addition of a ubiquitin moiety at lysine 419, which targets gr for proteasomal degradation; sumoylation of lysines 277, 293, and 703, which modulate gr interactions with transcriptional co-regulators; and acetylation of lysines 494 and 495, which inhibit gr binding (and suppression) to nfkb, thus regulating gr’s anti-inflammatory function (oakley and cidlowski, 2013; vandevyver et al., 2014). in addition to modulating the level and form of gr expression, cells and tissues may also regulate immediate ligand availability (oakley and cidlowski, 2013). at the cellular level, the enzyme 11β-hydroxysteroid dehydrogenase type 2 (11βhsd2) catalyzes the inactivation of cortisol to cortisone, while the opposing type 1 enzyme (11βhsd1) reverses the reaction, promoting cortisol production (oakley and cidlowski, 2013). thus, the relative activities of these enzymes within a cell confer control over the local availability of cortisol. of note, most synthetic glucocorticoids are not inactivated by 11β-hsd2 and their activities are preserved despite cellular upregulation of 11βhsd2 (oakley and cidlowski, 2013). as grα is the biologically relevant isoform, all references henceforth to gr will imply grα (matagreenwood et al., 2015). gr encompasses three functional domains including an amino-terminal www.companyofscientists.com/index.php/chd e11 cancer health disparities research transactivation domain, a central dna-binding domain, and a carboxy-terminal ligand-binding domain (joseph and whirledge, 2017). there is a flexible hinge region that contains a nuclear localization signal between the dna-binding domain and the ligand-binding domain (fig. 3). it is within this flexible hinge region that genomic interactions occur (joseph and whirledge, 2017). in the nucleus, gr homodimers bind to gr response elements (gre) within promoter regions of target genes (luisi et al., 1991). the consensus gre sequences are comprised of two hexameric halfsites separated by a spacer of three nucleotides (e.g., agaacannntgttct) (strahle et al., 1987). once gr homodimers bind to gres, chromatin is remodeled, co-regulators are recruited, and grinduced transcription is initiated (joseph and whirledge, 2017). in addition to activation of grtarget genes, gr may also negatively repress genes (surjit et al., 2011). this occurs when gr binds to gres with consensus sequence ctcc(n)02ggaga and co-repressors are recruited (surjit et al., 2011). gr also mediates gene transcription via interactions with other transcription factors (joseph and whirledge, 2017). fig. 3 nr3c1 (gr) domain structure. the domain structure of grα is composed of an n-terminal modulatory domain, a dna-binding domain, a hinge region, a ligand-binding domain, and a c-terminal ligand binding domain. regions involved in transcriptional activation, dimerization, glucocorticoid binding, and dna binding are indicated. the nuclear localization signal is located within the flexible hinge region. for comparison, the domain structures of grβ and ar and its splice variant ar-v7 are included. note the structural similarities between these transcription factors. ar, androgen receptor, are, androgen response element; ce3, cryptic exon 3; dbd, dna-binding domain; dna, deoxyribonucleic acid; gr, glucocorticoid receptor; gre, glucocorticoid response element; lbd, ligand-binding domain; ntd, n-terminal domain. www.companyofscientists.com/index.php/chd e12 cancer health disparities research gr signaling in aas. gr signaling is triggered by a variety of physiological and environmental factors (joseph and whirledge, 2017). chronic stress resulting in sustained elevated glucocorticoid exposure throughout a lifetime has negative physiological consequences (cohen et al., 2006; joseph and whirledge, 2017; williams et al., 2010; zannas et al., 2015). constant gre binding induces local lasting changes in dna methylation, shaping subsequent responses to stressors and glucocorticoids (klengel et al., 2013; thomassin et al., 2001; wiench et al., 2011a; wiench et al., 2011b; zannas and west, 2014). it is therefore plausible that chronic stress confers cumulative effects on dna methylation sites with long-term epigenetic ramifications (zannas et al., 2015). profound changes in dna methylation are associated with aging-related diseases (bjornsson et al., 2008; christensen et al., 2009; hernandez et al., 2011; heyn et al., 2012; horvath, 2013; horvath et al., 2012; rakyan et al., 2010). because of this, several dna methylation-based predictors of aging have been recently developed (bocklandt et al., 2011; hannum et al., 2013; horvath, 2013; weidner et al., 2014). for example, a composite predictor comprised of 353 cytosine-phosphate-guanosine sites (cpgs) across the genome was shown to strongly correlate with chronological age across multiple human tissues (horvath, 2013). several studies have used this predictor to calculate accelerated epigenetic aging, defined as the difference between dna-methylation-predicted age and chronological age (boks et al., 2015; horvath, 2015; marioni et al., 2015a; marioni et al., 2015b). this accelerated epigenetic aging has been associated with cancer, obesity, ptsd, physical and cognitive decline, all-cause mortality, lower ses, and cumulative lifetime stress (boks et al., 2015; horvath, 2013; marioni et al., 2015a; zannas et al., 2015). cumulative lifetime stress has been associated with accelerated epigenetic aging in aas (zannas et al., 2015). this is attributed to altered gr signaling marked by an increased number of epigenetic clock cpgs located within functional gres, dynamic methylation changes following exposure to dexamethasone, and dynamic regulation by genes with enriched association for aging-related diseases which neighbored these cpgs (zannas et al., 2015). these results support a model of stressinduced accelerated epigenetic aging mediated by the lasting effects of chronic stressor exposure and aberrant glucocorticoid signaling on the epigenome (zannas et al., 2015). aas also appear to have amplified gr signaling and increased glucocorticoid resistance (frazier et al., 2010). this was reported in a study that explored the role of body weight and body composition in insulin resistance among participants who were treated with placebo or 4 mg dexamethasone (frazier et al., 2010). results revealed that aas were significantly more hyperinsulinemic after dexamethasone treatment than eas, indicated by higher peak insulin and postprandial insulin (frazier et al., 2010). aas were also found to be more insulin resistant as determined by fasting insulin and homeostatic model assessment (frazier et al., 2010). this hyperinsulinemia and increased insulin resistance in aas was independent of body weight or composition (body mass index, percent body fat, waist circumference), suggesting that amplified gr signaling was more prevalent in the aa study participants (frazier et al., 2010). in another study, aas showed increased activity in pro-inflammatory pathways and gr signaling, compared to eas, www.companyofscientists.com/index.php/chd e13 cancer health disparities research which was linked to exposure to discrimination (thames et al., 2019). taken together, the studies discussed above provide support for our model (fig. 1) which links chronic exposure to stressors (low ses, discrimination, neighborhood effects, lesser education status) to elevated cortisol and amplified gr signaling. this amplified gr signaling could be exacerbated during the current covid-19 pandemic, given the chronic psychosocial stress disproportionately affecting minority populations, particularly aas, during this pandemic (holmes et al., 2020). the implications of this increased gr signaling for pca progression and resistance to therapy is discussed below. gr signaling in pca. gr has recently emerged as a major driver of pca progression and resistance to ar-signaling inhibitor (arsi) therapy, chemotherapy, and radiotherapy (arora et al., 2013; beer et al., 2017; chen et al., 2019; claessens et al., 2017; kroon et al., 2016; li et al., 2017; montgomery et al., 2014; narayanan et al., 2016; puhr et al., 2018; sartor et al., 2014). a seminal study by sawyers and colleagues identified gr overexpression as a common feature of arsiresistant pca tumors using pre-clinical models and confirmed in patient samples (arora et al., 2013). gr overexpression in arsi-resistant pca cells and tissues have since been validated in cellular models of resistance and patient biospecimens (isikbay et al., 2014; li et al., 2017; puhr et al., 2018). growth factors produced in prostate stroma regulate glandular epithelial proliferation and differentiation, and steroid hormones including glucocorticoids are important modulators of stromal-epithelial cell signaling interactions in the prostate (hidalgo et al., 2011; taylor and risbridger, 2008). gr-mediated transcriptional activity has been found to be altered in carcinoma-associated stroma and confers cellspecific effects with the potential to induce antiandrogen therapy resistance (hidalgo et al., 2011; zhao et al., 2014). significant structural similarities (fig. 3) and transcriptomic overlap between ar and gr accounts for gr-mediated bypass of ar blockade (sahu et al., 2013). in addition, there is overlap in the transcription protein interactome of both nuclear receptors (lempiainen et al., 2017). induction of gr expression is also accompanied in arsi-resistant tissues by the loss of 11b-hsd2, resulting in increased stability of intratumoral cortisol (li et al., 2017). the implications of these initial findings have sparked great interest, as pca patients are routinely administered synthetic glucocorticoids (e.g. prednisone and dexamethasone) alongside arsi and taxane chemotherapy for palliative purposes (chi et al., 2017; collins et al., 2007; narayanan et al., 2016; tannock et al., 1989). furthermore, the mechanisms underlying arsi-resistance in pca and their contribution to disease progression had not been fully previously elucidated, and these findings paved the way for research on the role of gr in these processes (narayanan et al., 2016). while anti-androgen therapy is highly effective in producing an initial period of pca regression, mcrpc eventually develops for many patients, characterized by rapidly rising psa levels, even though circulating testosterone levels are in the typical castration range (<50 ng/dl) (chen et al., 2004; feldman and feldman, 2001; lamont and tindall, 2011; schrecengost and knudsen, 2013; sharifi, 2013). this means that ar-target genes are operating in the absence of androgen to stimulate pca cell survival, growth, and psa secretion www.companyofscientists.com/index.php/chd e14 cancer health disparities research (narayanan et al., 2016). to understand the prospect of gr bypassing the ar signaling pathway and directly activating ar-target genes (fig. 4), the similarities between ar and gr must be considered. ar and gr belong to the same intracellular receptor family of transcriptional regulators, and the dna binding domains of ar and gr are highly conserved with an 80% match in amino acid sequence (mangelsdorf et al., 1995; narayanan et al., 2016; rundlett and miesfeld, 1995). as shown in fig. 3 the domain structures of gr and ar are very similar. like gres, ar response elements (ares) in the promoter regions of ar-target genes are composed of a 15 base pair binding sequence comprised of two hexamer half-sites and separated by a 3 base pair spacer (bolton et al., 2007). this similarity allows gr to interact with ares and alter the expression of artarget genes in the absence of androgens (arora et al., 2013). while that study identified 52 common overlapping genes out of 105 ar signature genes and 121 gr signature genes, several canonical ar-target genes were found to be regulated by gr, including pca key genes klk3 (encoding psa) and tmprss2 (involved in fusions with erg in a race-related manner) (arora et al., 2013). also, gr expression is normally repressed in pca cells in the presence of ar, however this study demonstrated that ar blockade removes this gr inhibition and stimulates gr amplification (arora et al., 2013). intriguingly, the tmprss2 protein is a key receptor used by sars-cov-2 virus to infect host cells, which has prompted recent speculation that race-related and gender-related differences in ar signaling may explain in part the racial and gender variations in covid-19 deaths and that anti-androgen agents combined with tmprss2 inhibitors could potentially decrease disease severity (mccoy et al., 2020). fig. 4 the interplay between gr and ar in the context of pca. ar and gr belong to the same intracellular receptor family of transcriptional regulators and their dna binding domains are highly conserved. gres www.companyofscientists.com/index.php/chd e15 cancer health disparities research and ares in the promoter regions of gr-and ar-target genes are also similar and are composed of a 15 base pair binding sequence with 2 hexamer half-sites separated by a 3 base pair spacer. gr expression is normally repressed in pca cells in the presence of ar. however, an ar blockade removes gr inhibition and stimulates gr amplification allowing gr to interact with ares and alter the expression of ar-target genes. this complex ar-gr interplay creates a major clinical dilemma as the effects of glucocorticoids can be beneficial and/or harmful to patients. treatment options for prostate cancer patients the interplay between gr and ar in the context of pca treatment presents a major clinical dilemma because the effects of glucocorticoids are both beneficial and harmful to patients (arora et al., 2013; claessens et al., 2017; montgomery et al., 2014; narayanan et al., 2016; puhr et al., 2018; sartor et al., 2014). ar signaling has been traditionally considered as the key actionable driver of pca recurrence and progression (banerjee et al., 2018). because of this, targeting androgen biosynthesis and ar has been a standard of care for pca treatment for over seven decades (huggins and hodges, 1972). huggins and colleagues made the seminal observation that both surgical castration and estrogen administration resulted in regression of pca metastasis (huggins and hodges, 1972), which led to the development of androgen deprivation therapy (adt). both agonists and antagonists of luteinizing hormone-releasing hormone (lhrh) are typically used as first-line adt in patients with hormone-sensitive pca to decrease endogenous testosterone production through the hypothalamic-pituitary-testicular (hpt) axis. there are also first-line anti-androgens that bind to ar and inhibit its activity including flutamide, bicalutamide, and nilutamide (boccon-gibod et al., 1997; kolvenbag and nash, 1999; todd et al., 2005). while adt with first-line anti-androgens is initially successful in most pca patients who choose this option after biochemical recurrence, resistance to this therapy is inevitable, occurring within 18-24 months (asmane et al., 2011). prostatic epithelial cells demonstrate great plasticity in response to adt, giving rise to a highly heterogeneous coexistence of ar-positive and ar-negative cells (banerjee et al., 2018). a relatively short time after development of adt-resistance, the patient enters a disease stage referred to as mcrpc, which typically has a 5-year survival rate of 30% (scher et al., 2004; thoreson et al., 2014). therapeutic options for patients with mcrpc include arsi, immunotherapy, radiation therapy with radium223, and taxane-based chemotherapy with docetaxel (dtx) or cabazitaxel (cbz) plus the glucocorticoids dexamethasone or prednisone (arlen and gulley, 2005; corn et al., 2017; gilbert and parker, 2005). second-line, next-generation arsis such as enzalutamide and apalutamide have been developed during the past decade for pca patients who have failed lhrh agonists/antagonists or other first-line antiandrogens (banerjee et al., 2018). another clinically relevant arsi, abiraterone, is an inhibitor of androgen biosynthesis that acts by blocking the activity of cytochrome p450 17 alpha-hydroxylase (cyp17), a key enzyme that is essential for the generation of the androgen precursor dehydroepiandrosterone (dhea) (rehman and rosenberg, 2012). dtx and/or cbz can extend patient survival by a few months, but chemoresistance develops, www.companyofscientists.com/index.php/chd e16 cancer health disparities research curtailing the beneficial effects of these taxane drugs (arlen and gulley, 2005; corn et al., 2017; gilbert and parker, 2005). although not all pca patients that fail anti-androgen therapy undergo chemotherapy, results from the recent clinical trials chaarted and stampede showed that administering dtx together with anti-androgen therapy in newly diagnosed mcrpc patients provides a dramatic increase in overall survival advantage compared to adt alone (james et al., 2016; kyriakopoulos et al., 2018). other recent trials combining emerging therapies or modifying the sequence of available therapies have yielded promising results for the treatment of mcrpc (ku et al., 2019; schmid and omlin, 2020). because of the tumor heterogeneity observed within and among pca patients, developing effective therapies for this malignancy remains challenging (ku et al., 2019; maitland et al., 2019). despite the spectrum of therapeutic options for mcrpc which provide increased overall survival benefits with improved quality of life, this advanced stage of the disease still remains incurable due to the development of therapy resistance. a promising emerging therapy for mcrpc based on prostate specific membrane antigen (psma) theranostics, which combines positron emission tomography (pet) imaging with tumor targeting, is bringing hope to the diagnosis and treatment of men with advanced pca (kratochwil et al., 2019). psma is a transmembrane glycoprotein that is highly expressed in pca, particularly in high grade tumors or mcrpc, with minimal or no expression in normal tissues (silver et al., 1997). currently, a psma specific ligand labeled with a positron emitter is a desirable diagnostic tool for detecting metastatic disease at much lower psa levels than conventional imaging. patients with high psma tumor expression can then undergo targeted radioligand therapy using the same psma ligand labeled with a beta emitter (e.g. 177lutetium) or an alpha emitter (e.g. 225actinium) to selectively destroy the cancer cells without damaging normal tissues (baum and kulkarni, 2012). the implementation of psma theranostics in clinical practice has the potential to revolutionize mcrpc treatment and improve patient outcomes. prospective randomized clinical trials are currently underway worldwide to validate psma theranostics compared to available standard of care therapies for mcrpc. the optimal timing for administering this therapy relative to the sequence of other therapies has yet to be defined. glucocorticoids in pca treatment the synthetic glucocorticoids prednisone and dexamethasone are routinely used therapeutically and have much higher potency than cortisol in activating gr. for example, 4 mg of prednisone and 0.75 mg of dexamethasone provide the physiological equivalent of 20 mg of cortisol.(narayanan et al., 2016) prednisone is clinically used in doses of 5-10 mg once or twice per day and dexamethasone is used in doses at 0.75-1 mg once or twice per day (narayanan et al., 2016). when co-administered with taxane chemotherapy for pca, their potent antiinflammatory properties counteract pain, nausea, lack of appetite, fatigue, hypersensitivity, and fluid retention (de bono et al., 2010; dorff and crawford, 2013; lafeuille et al., 2013; schwartz, 2012; tannock et al., 2004). while the benefits of glucocorticoid coadministration to pca patients have been established, there is evidence that increased gr signaling could also be detrimental to these patients (arora et al., 2013; claessens et al., 2017; isikbay et al., 2014; kroon et al., 2016; li et al., 2017; www.companyofscientists.com/index.php/chd e17 cancer health disparities research montgomery et al., 2014; narayanan et al., 2016; puhr et al., 2018; sartor et al., 2014). one study by puhr et al. found that gr expression is initially reduced in primary pca tissue, but is restored in metastatic lesions (puhr et al., 2018). this group also found that genetic or pharmacological inhibition of gr impaired the proliferation and 3d spheroid-forming capabilities of pca cell lines (puhr et al., 2018). additionally, these investigators also reported that gr levels increase in dtxresistant pca cell lines and in tissues from patients who have been treated with dtx, and that patients who relapse with biochemical recurrence and have high gr levels experience shortened progressionfree survival (puhr et al., 2018). there are also reports that pca patients enrolled in clinical trials have worse overall survival outcomes when receiving glucocorticoids compared to patients not receiving glucocorticoids (montgomery et al., 2014; montgomery et al., 2015; narayanan et al., 2016). this trend was observed in the affirm phase 3 clinical trial evaluating the use of enzalutamide as well as in the cou-aa-301 phase 3 clinical trial in which patients were randomized to prednisone plus abiraterone after failing taxane chemotherapy (de bono et al., 2011; narayanan et al., 2016). on the other hand, recent results from the switch trial showed that in selected clinically stable mcrpc patients with limited disease progression, the combination of abiraterone with dexamethasone provided a benefit, measurable by psa decline and disease stabilization, to patients with normal ar status but not patients with ar aberrations (romero-laorden et al., 2018). one limitation of this study, however, was the lack of a molecular analysis that included predictive biomarkers such as the ar-v7 splicing variant (fig. 3), also implicated in both arsi and taxane resistance, and gr expression or signaling (romero-laorden et al., 2018). our group recently demonstrated the ability of liganded gr to upregulate the expression of clusterin (clu) and lens epithelium-derived growth factor of 75 kd (ledgf/p75), two stress oncoproteins previously established as key contributors to therapy resistance in various cancer types, in racially diverse preclinical pca cellular models (chun, 2014; djeu and wei, 2009; huang et al., 2007; july et al., 2002; koltai, 2014; matsumoto et al., 2013; mediavilla-varela et al., 2009; rios-colon et al., 2017; woods-burnham et al., 2018a). this upregulation could be reversed by blocking gr signaling with the steroidal antagonist mifepristone (ru-486) or gr knockdown (woodsburnham et al., 2018a). the particular observation of high endogenous clu expression in the aa pca cell line mda-pca-2b suggests that downstream effects of gr signaling such as the upregulation of genes associated with therapy-resistance may be exaggerated in aa pca patients, and is consistent with the emerging notion that gr signaling is enhanced in the aa population (frazier et al., 2010; woods-burnham et al., 2018a; zannas et al., 2015). our recent study also revealed higher median values of gr in aa prostate tissues compared to ea prostate tissues using the taylor and wallace datasets within the oncomine database, supporting the premise that aa men with pca may have enhanced intratumoral gr signaling (woods-burnham et al., 2018a). regardless of whether gr drives resistance to arsi by activating ar-target genes only or also by activating an independent transcriptome that drives therapy resistance, it is becoming very clear that gr plays a major role in the progression of mcrpc. there remains an urgent need, however, www.companyofscientists.com/index.php/chd e18 cancer health disparities research to further elucidate genes driven by gr signaling that are specifically associated with arsi-resistance while also identifying precise genes that have been linked to taxane chemotherapy. this is critical to our understanding of mechanisms by which gr may contribute to therapy resistance, supporting the development of novel therapeutic strategies. furthermore, given that aa men suffer from disproportionate pca incidence and mortality as well as an enhanced physiological response to glucocorticoids, additional studies are warranted to fully elucidate the interplay between gr signaling and pca tumor aggressiveness specifically in this racial/ethnic group. given the emerging role of gr signaling in pca progression, we propose that cumulative psychosocial stress leading to chronically elevated cortisol levels, increased gr expression, and sustained gr signaling in aa men over time could predispose them to develop aggressive pca tumors as well as prime them towards poor response to conventional treatments (fig. 1). therapeutic gr modulators. the emerging contribution of gr signaling to pca therapy resistance has led to increasing efforts to therapeutically target this signaling as a potential treatment for mcrpc. a phase i/ii clinical trial (nct02012296) is currently ongoing to determine if combination therapy with enzalutamide and mifepristone, a gr antagonist that delayed mcrpc in pre-clinical models, extends the time to psa progression. because complete antagonism of gr may introduce adverse systemic consequences, highly selective gr modulators (sgrms) that target this receptor in specific tissues are currently under development and are being evaluated in preclinical models of mcrpc (hunt et al., 2018; kach et al., 2017; nguyen et al., 2017). the specificity of these new generation modulators are often dependent upon their superior selectivity for gr over other steroid receptors, which is a characteristic of mifepristone (baulieu, 1991; hunt et al., 2018; kach et al., 2017; meijer et al., 2018; nguyen et al., 2017). for example, the sgrm cort118335 has a high gr affinity with only modest mr affinity (atucha et al., 2015; hunt et al., 2012; nguyen et al., 2017). this and another sgrm, cort108297, showed ability to block gr transcriptional activity and slow crpc progression in pre-clinical models, and unlike mifepristone did not affect ar signaling (kach et al., 2017). another sgrm, cort125134, was shown to reverse the effects of prednisone without binding to progesterone receptor (pr) and is well tolerated in humans. however, it should be noted that the overwhelming majority of study participants were ea males and the study did not take into account potential racial or ethnic differences in gr signaling (hunt et al., 2018). an additional determinant of the ability of gr modulators to bind to specific tissues is the presence or lack of gr co-regulators that may either serve as coactivators or corepressors (hunt et al., 2018; lonard and o'malley, 2012; meijer et al., 2018; nguyen et al., 2017). gres in different genes depend on particular sets of coactivators (lachize et al., 2009; meijer et al., 2018; zalachoras et al., 2016). selective gr modulators that act via gres may differ in their ability to induce interactions with other transcription factors that bind dna in the vicinity of the gres (meijer et al., 2018). the ability to treat a specific disease independently from all the other gr-dependent effects would be considered a “game changer” in medicine (de bosscher et al., 2016; meijer et al., 2018). to that end, sgrms are being introduced in clinical trials for pca patients. a current trial seeks to establish www.companyofscientists.com/index.php/chd e19 cancer health disparities research the recommended dose, safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of the specific gr antagonist oric-101 in combination with enzalutamide in mcrpc patients (nct04033328) (multani, 2019). a similar trial is underway to examine the same primary outcomes using a different gr antagonist, cort125281 (nct03437941) (shepherd, 2018). given the potential role of gr in promoting dtx resistance, future pre-clinical studies and clinical trials evaluating selective gr modulation in combination with taxane drugs for patients with mcrpc are warranted. conclusions and future perspectives emerging data support the notion that pca health disparities are influenced by the interplay between socioeconomic, psychosocial, health care, and biological/genetic factors. chronic and amplified gr signaling triggered by cumulative psychosocial stress may negatively influence health outcomes in aa men by promoting the activation of molecular pathways that contribute to pca progression (fig. 1). this enhanced gr signaling, combined with diminished access to health care and genetic drivers of pca that increase risk of aggressive disease in aa men may promote a more aggressive tumor phenotype, including the possibility of increased resistance to standard therapies (fig. 1). however, it remains to be determined if mcrpc therapies involving glucocorticoids such as dexamethasone or prednisone produce lower benefits in aa patients compared to ea patients. likewise, it remains to be determined if aa men with mcrpc may benefit more from combinatorial therapies involving gr antagonists such as mifepristone and sgrms compared to ea patients. critical for addressing these issues is the recruitment and retention of large numbers of aa pca patients to current and future clinical trials examining the contribution of glucocorticoids or gr antagonists to overall patient survival. it would therefore be of great interest to determine if there are racial differences in the outcomes of the switch trial (abiraterone plus dexamethasone), the nct02012296 trial (enzalutamide plus mifepristone), the nct03437941 trial (enzalutamide plus the gr antagonist cort125281), and the nct0403328 trial (enzalutamide plus the gr antagonist oric101). as our understanding of the contribution of gr signaling to pca progression and therapy resistance increases, clinicians and researchers must consider carefully the clinical implications of standard and upcoming treatments for pca that modulate gr function in aa men. it is probable that ongoing clinical trials may reveal race-related differential benefits, or harms, of modulating gr function for mcrpc treatment. this would necessitate clinical and socio-behavioral scientists working together to measure psychosocial indicators linked to increased gr signaling in aa pca patients. socio-behavioral scientists and clinicians could also implement novel community and clinic-based interventions to reduce chronic stress, which may result in attenuated gr signaling and, potentially, better outcomes for aa men, who are most at risk of developing aggressive pca. finally, preventive policy interventions targeting upstream determinants of ses including education, housing, urban planning, community development, employment, and income enhancements should be considered to ameliorate the discriminatory contributors to chronic psychosocial stress experienced by african american men. funding sources www.companyofscientists.com/index.php/chd e20 cancer health disparities research the authors acknowledge research support from the national institutes of health (nih) grants r21ca226654-01a1 (c.a.c) and p20md006988project 2 (c.a.c.), the loma linda university health (lluh) center for health disparities and molecular medicine (c.a.c. and s.m) and the lluh schools of medicine (c.a.c, h.c.r., f.g.a), behavioral health (s.m.), and nursing (l.r.r). l.w.b., s.r.m., and e.s.s.h. were supported by nih grant r25gm060507 and the llu-nih initiative for maximizing student development (imsd) graduate training program. e.s.s.h. is currently supported by nih grant r21ca226654-01a1s1. l.w.b. is currently supported by nih grant t32 ca186895. acknowledgements the authors thank dr. marino de leon, director of the lluh center for health disparities and molecular medicine, for his support of this work. we also thank the members of this center and many other colleagues for stimulating discussions leading to the writing of this comprehensive review paper. conflict of interest the authors declare that no competing or conflict of interests exist. the funders had no role in study design, writing of the manuscript, or decision to publish. authors’ contributions l.w.b., l.s., s.m., and c.a.c. contributed to the conceptual design of the original research topic. l.w.b. wrote the initial version of the manuscript and prepared fig. 1. s.r.m. wrote the sections on gr biology. h.r.c. contributed to the section on prostate cancer treatment options. f.g.a. wrote the section on psma theranostics. e.s.s.h. prepared figs. 2, 3, and 4, and cross-checked for accuracy the literature citations throughout the manuscript. m.c.s., l.r.r., and d.r.w. provided unique perspectives that guided the writing of sections related to socioeconomic and psychosocial aspects of pca. l.w.b., l.s., and c.a.c. edited the various drafts of the manuscript. all authors reviewed and approved the 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