Cop+Ed+fisse 2006 41Archivio Italiano di Urologia e Andrologia 2022; 94, 1 ORIGINAL PAPER No conflict of interest declared. sought to provide an overview of de novo T2 muscle invasive bladder cancer of patients who underwent a rad- ical cystectomy in Thunder Bay in order to identify the characteristics of patients with clinically localized muscle invasive bladder carcinoma and to determine their clini- cal and pathological outcomes. METHODS This is a cross-sectional study that retrospectively exam- ined the medical records of 59 patients with documented organ confined de novo T2 muscle invasive bladder can- cer confirmed on a diagnostic TURBT who underwent radical cystectomy over a 2 year-period. Clinical and pathological characteristics of TURBT and cystectomy were retrieved. The analysis was conducted using IBM SPSS Software (ver- sion 19.0, SPSS Inc., Illinois, USA). The continuous data was presented as mean or median with standard deviation and compared using independent t-test while the categorical data was in percentages and compared using the chi- square test. Statistical significance was defined as p < 0.05. A multi- variate regression analysis was performed to identify the significant risk factors for upstaging. RESULTS The mean age of the patients was 67 ± 8.8 years. Those aged under 60 years old accounted for 27.1% of the sam- ple. Eighty percent of patients were male. Based on final pathological results, upstaging was noted in 59.3% (T3 in 27.1% and T4 in 32.2%). Thirty-six percent had node-positive disease. Prostate ade- nocarcinoma was incidentally discovered in 20 (34%) of patients. Significant high-grade prostate cancer was found in 50% of patients. Twenty patients (34%) had their sur- gery delayed for more than 12 weeks. Overall, 14 patients received neoadjuvant chemotherapy (NAC) (Table 1). Younger patients (aged ≤ 60 years) had a higher prevalence of pathological upstaging (68.7% vs. 45.8%), as well as a higher chance of positive lymph nodes (37.5% vs. 34.9%), whereas older patients (age > 60) had a higher rate of inci- dental prostate cancer (34.9% vs. 31.3%). However, these findings were not statistically significant (Table 2). Upstaging was observed in 30% of patients who had sur- Objective: This study aimed to investigate the clinical and pathological characteristics of patients with de novo muscle-invasive bladder cancer (MIBC) who underwent radical cystectomy in Northern Ontario. Methods: This is a retrospective cross-sectional study of patients with de novo T2 MIBC who underwent radical cystectomy over a 2-year-period in Thunder Bay Regional Health Sciences Centre. Clinical and pathological characteristics of Trans Urethral Resection of Bladder Tumors and cystectomy speci- mens were analyzed. Results: Of the 59 patients aged 67 ± 8.8 years, predominated by males (80%), 27.1% were younger than age 60. After sur- gery, upstaging was noted in 59.3% (T3 in 27.1% and T4 in 32.2%) while node positive was noted in 36% of patients. Prostate adenocarcinoma was incidentally discovered in 20 (34%) of patients with 50% considered significant (Gleason score ≥ 7). Downstaging was found in those who had neoadju- vant chemotherapy (p = 0.001). Conclusions: The high prevalence of younger ages (less than 60), a high rate of upstaging, the presence of high-grade inci- dental prostate cancer, and lymph node positives in T2 de novo MIBC in Northern Ontario, warrants further investigation of potential causes and risk factors at individual, public, and popu- lation health levels in the region. KEY WORDS: Bladder cancer; Cystectomy; Northern Ontario. Submitted 10 November 2021; Accepted 8 December 2021 INTRODUCTION According to global cancer statistics, 3% of all new diag- nosed cancer and 2.1% of all cancer mortality are due to bladder cancer (1). Bladder cancer is linked to a number of important risk factors, the most prominent of which are smoking, occu- pational and environmental exposure to carcinogens, and conditions that cause chronic bladder irritation (2). Toxins found in the environment, such as aromatic amines like benzidine and 2-naphthylamine, have been linked to up to 27% of bladder cancers (3). A recent study could identify that patients older than 70- year-old with significant comorbidities have less favourable outcomes (4). The projected average annual new cases of bladder cancer in 2018-2022 in Ontario has been estimated at 1950 for males and 660 for females (5). With this knowledge, we Adverse pathological outcomes of patients with de novo muscle invasive bladder cancer in Northern Ontario Vahid Mehrnoush, Shahrzad Keramati, Asmaa Ismail, Waleed Shabana, Ahmed Zakaria, Hazem Elmansy, Walid Shahrour, Owen Prowse, Ahmed Kotb Urology Department, Northern Ontario School of Medicine, Thunder Bay Regional Health Centre, Ontario, Canada. DOI: 10.4081/aiua.2022.1.41 Summary Archivio Italiano di Urologia e Andrologia 2022; 94, 1 V. Mehrnoush, S.Keramati, A. Ismail, W. Shabana, A. Zakaria, H. Elmansy, W. Shahrour, O. Prowse, A. Kotb 42 gery delayed for more than 12 weeks, whereas upstaging was found in 74.3% of those who had surgery within 12 weeks, which is statistically different (p = 0.001). Not surprisingly, NAC was performed more in the delayed group (92.8%) (Table 3). A significant difference in upstag- ing was found between those who had NAC, 3 (21.4%), and those who did not, 11 (78.6 %) (p = 0.001). However, the invasion to the lymph nodes was not lower in those who received NAC compared to those who did not (Table 4). Multivariate regression analysis revealed that NAC was the only factor associated with upstaging, while there was no significant association with other risk fac- tor including age, gender, and waiting time to surgery (Table 5). The pathology in those who received NAC are approxi- mately 60% less likely to show upstaging (OR = -0.38, CI 95% = -0.74- -0.02) (Table 5). DISCUSSION The current case series in Northern Ontario draws atten- tion to the high prevalence of MIBT in patients younger Table 1. Characteristics of patients with preoperative T2 transitional cell carcinoma. Variable Value Mean age (years) 67 ± 8.8 (51-88) Age groups ≤ 60 16 (27.1%) > 61 43 (72.9%) Sex Males 47 (80.0%) Females 12 (20.0%) Stage T0 9 (15.3%) Ta/T1 6 (10.1%) T2 9 (15.3%) T3 16 (27.1%) T4 19 (32.2%) Positive Lymph Nods No 38 (64.0%) Yes 21 (36.0%) Incidental prostate cancer No 39 (66.0%) Yes 20 (34.0%) Grade of prostate cancer 3 + 3 10 (50.0%) 3 + 4 8 (40.0%) 4 + 3 2 (10.0%) Waiting time to surgery (weeks) Mean ± SD 13 ± 8 Wait time (weeks) < 6 21 (36.0%) 6- 12 18 (30.0%) > 12 20 (34.0%) Neoadjuvant chemotherapy (NAC) No 45 (76.0%) Yes 14 (24.0%) Table 2. Comparison of the findings based on age. Age < 60 > 60 P value n = 16 n = 43 Sex Males 13 (81.2%) 34 (79.1%) 1.0 Females 3 (18.8%) 9 (20.9%) Waiting time to surgery < 12 9 (56.2%) 30 (69.8%) 0.3 > 12 7 (43.8%) 13 (30.2%) Neoadjuvant chemotherapy (NAC) No 11 (68.7%) 34 (79.1%) 0.5 Yes 5 (31.3%) 9 (20.9%) Stage < T3 5 (31.3%) 19 (44.2%) 0.5 T3/ T4 11 (68.7%) 24 (45.8%) Lymph nodes invasion Negative 10 (62.5%) 28 (65.1%) 1.0 Positive 6 (37.5%) 15 (34.9%) Prostate cancer No 11 (68.7%) 28 (65.1%) 1.0 Yes 5 (31.3%) 15 (34.9%) Table 3. Comparison of operation waiting time categories against clinical and pathological staging. Waiting time to surgery < 12 weeks < 12 weeks P value n = 39 n = 20 Mean age 68 ± 8 65 ± 9 0.2 Stage < T3 10 (25.7%) 14 (70%) 0.001 T3/T4 29 (74.3%) 6 (30%) Lymph nodes Negative 23 (59%) 15 (75%) 0.2 Positive 16 (41%) 5 (25%) Neoadjuvant chemotherapy (NAC) Yes 1 (2.6%) 13 (65%) 0.001 No 38 (97.4%) 7 (35%) Table 4. Comparison of patients with or without neoadjuvant chemotherapy (NAC) against clinical and pathological staging. Neoadjuvant chemotherapy No Yes P value (NAC) n = 45 n = 14 Mean age (years) 68 ± 9 64 ± 7 0.1 Stage < T3 13 (28.9%) 11 (78.6%) 0.001 T3/T4 32 (71.1%) 3 (21.4%) Lymph nodes Negative 28 (62.2%) 10 (71.4%) 0.7 Positive 17 (37.8%) 4 (28.6%) Table 5. Multivariate regression analysis for factors associated with upstaging. Odds ratio 95% Confident interval P value Lower limit Upper limit Age -0.23 -0.51 0.04 0.097 Gender 0.04 -0.28 0.36 0.809 Neoadjuvant chemotherapy -0.38 -0.74 -0.02 0.041 * Waiting time to surgery -0.08 -0.44 0.28 0.659 * P-value < 0.05 is significant. 43Archivio Italiano di Urologia e Andrologia 2022; 94, 1 Muscle invasive bladder cancer in Northern Ontario than 60 years (27.1%), with a high rate of upstaging (68.7%) in this young group of patients. The findings indicate that approximately 60% of clinical- ly T2 MIBC were T3/T4 at final pathology. Another highlight is the high rate of clinically significant prostate cancer (50%) in patients with incidental prostate cancer. In terms of treatment, the findings showed that NAC was underutilized in Northern Ontario (76% did not receive NAC) and that no significant association was found between receiving NAC or delaying surgery and upstag- ing. The majority of our patients were male, which was con- sistent with the literature (80% male vs. 20% female). Our findings suggest that bladder cancer should not be emphasized in a purely geriatric population in Northern Ontario. The causes of bladder cancer in the younger age group, however, have not been well documented in the literature. According to the findings of a study conducted in Montreal (Canada), natural gas combustion products, aromatic amines, cadmium compounds, photographic products, acrylic fibers, polyethylene, titanium dioxide, and chlorine were found to have weak evidence of being risk factors for bladder cancer. Occupational exposures such as motor vehicle drivers, particularly among drivers in the motor transport indus- try, who were more likely to drive full time than drivers in other industries, textile dyers, construction painters, metal machinists and sheet metal workers, and aromatic amines were responsible for 6.5 percent of bladder cancer incidence (6). Another Canadian case control study dis- covered that miners, metal workers, mechanics, and male hairdressers were more likely to develop bladder cancer. They assumed that exposure to various combustion prod- ucts and/or oils was a common theme in these occupa- tions (7). Epidemiological studies in Canada and other countries, including the United States, Italy, and France discovered that carcinogenic chemicals in tap water, such as chloro- form and other trihalomethanes, are linked to an increased risk of bladder cancer (8, 9). Peculiar environmental conditions can also expose this population to risk factors. Northern Ontario is one of the leading mining regions for nickel, copper, uranium, zinc, gold, platinum, and silver. Northern Ontario's economy is built on forestry, transshipment, and manufacturing industries such as textile, steel, pulp, and paper. Moreover, Northern Ontario is the transshipment point of agriculture products across Canada (10). From the standpoint of public health, the high prevalence of younger age (60 years old) with MIBC in Northern Ontario appears to necessitate a transdisciplinary approach that includes medical, logistical, and municipal sectors to identify the risk factors and implement a multi- level strategy to address this issue. The findings of our study revealed that a high percentage of patients with clinically T2 MIBC turned into T3/T4 with positive lymph nodes after cystectomy, and that the majority of these patients undergo surgery in less than 12 weeks. According to the pathological results of radical cystectomy, 59.3% of patients were diagnosed at the most advanced stages (T3/T4), and 36% developed node-posi- tive disease. It is concerning to diagnose patients at such advanced stages. These findings also emphasize early investigation which leads to earlier diagnosis and intervention with the expec- tation of a better outcome. In our study; the use of NAC was associated with 60% less likely finding of upstaging on final pathology and so a part of adverse pathological outcomes may be explained by the underutilization of NAC. In general, delay in cancer diagnosis and treatment is classified into patient delay, health care provider delay, delay in service provider, and finally, treatment delay (11). It has been proposed that differences in socioeco- nomic status, rural or urban residency, and immigration status can all contribute to disparities in screening, diag- nosis staging on presentation, and treatment services (12). Despite enormous efforts to provide equity in health care, the distribution of the population due to the geo- graphic characteristics of Northern Ontario impede some regions from timely access and health monitoring. Moreover, there is only one hospital in all of Northern Ontario that provide urological cancer care. This results in a long waiting list, making timely access to equitable care more difficult for the population. Further research is also needed to investigate and identi- fy the factors associated with bladder cancer patients' delayed diagnosis and late-stage presentation in Northern Ontario. According to our findings, prostate cancer, which is the third leading cause of cancer death in Canadian males (5), was discovered incidentally (34%) during a cystectomy, which is consistent with literature reported 23-54% (13, 14). However, 50% of our patients had significant prostate cancer (Gleason score ≥ 7 out of 10), which is notably higher than literature. Djaladat et al. studied 1964 patients with primary transitional cell carcinoma of the bladder who underwent radical cystectomy. Thirty six percent of the patients (n = 559) had inciden- tal prostate cancer with the Gleason scores ≤ 6 for 458 (82%) patients (14). Another study by Mazzucchelli et al. found that the major- ity (81.3%) of incidentally detected prostate cancers by radical cystoprostoctomy had a Gleason score of 4 or less (15). Hiros et al. reported 68% of incidental prostate can- cer were low grade (Gleason scores less than 6) and 32% were high grade (16). One study found that overall survival for patients with incidental prostate cancer was lower than for patients without (28.1 ± 27.5 month vs 45.5 ± 35 month). Given the significant impact on overall survival, they highlight- ed the importance of paying closer attention to this con- current pathology (13). Therefore, given the high prevalence of high grade prostate cancer in our population, it may be practical to assign a greater importance to performing prostate cancer screening during bladder cancer work-up, regardless of the patients’ age. Furthermore, additional workup such as MRI to rule out prostate cancer is required if a patient chooses trimodal therapy. Radical cystectomy is the standard treatment for patients with MIBC (17). However, the time of performing cystec- tomy is controversial. Some literature has shown that cys- Archivio Italiano di Urologia e Andrologia 2022; 94, 1 V. Mehrnoush, S.Keramati, A. Ismail, W. Shabana, A. Zakaria, H. Elmansy, W. Shahrour, O. Prowse, A. Kotb 44 tectomy after 12 weeks is not associated with an unfavor- able outcome (18, 19) while a population-based study and the European Association of Urology have recommend- ed to not delay cystectomy for more than 3 months due to the increasing risk of progression and mortality (20). Based on Canadian Urological Association guideline, the optimal timing of radical cystectomy where NAC has not been administered is within six weeks of TURBT (21). According to our findings, upstaging was observed in 29 (74.3%) and 6 (30%) of patients who had surgery < 12 weeks and > 12 weeks, respectively. The lower likelihood of upstaging in > 12 week surgery waiting time can be interpreted that the delay in surgery for the sake of receiv- ing NAC does not negatively affect the staging and pro- gression. In our study, a lower upstaging rate was found in those who had NAC compared to those who did not (21.4% vs 71.1%). However, NAC did not significantly decrease the invasion to lymph nodes. The advantages of NAC in patients with MIBC have been reported in literature. NAC is recommended to improve the outcome of radical cystectomy which is the gold stan- dard of treatment in MIBC with a 5-year survival of about 50% (22). Accordingly, it seems that the rate of perioper- ative NAC in Ontario, Canada follows an increasing trend from 19% in 2009 to 27% in 2013 (23). However, the rate of perioperative NAC in our study was only 23.7%. Despite the survival benefit, practicing NAC has been underutilized in Northern Ontario. The finding of this study may prompt urologists and medical oncologists to incorporate NAC more frequently in their practice. Due to the lack of clinical outcomes, our findings cannot be interpreted as supporting or opposing the controversial opinions on surgery before or after 12 weeks. However, the findings suggest that the surgical delay of more than 12 weeks due to the NAC may not negatively impact the pathological outcomes. The interpretation of the current study's results may be limited by the small sample size. Furthermore, including only one center negatively affects the external validity of the results while having a positive impact on improving the internal validity of the study. 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Patterns of use of systemic chemotherapy for Medicare beneficiaries with urothelial bladder cancer. Urol Oncol. 2011; 29:252-58. 23. Booth CM, Karim S, Brennan K, et al. Perioperative chemother- apy for bladder cancer in the general population: Are practice pat- terns finally changing? Urol Oncol. 2018; 36:89.e13-89.e20. Correspondence Vahid Mehrnoush, MD vahidmehrnoush7@gmail.com Shahrzad Keramati, MD shz.keramati@gmail.com Asmaa Ismail, MD asmaaismail0782@gmail.com Waleed Shabana, MD waleed.shabana@gmail.com Ahmed Zakaria, MD aszakaria81@yahoo.com Hazem Elmansy, MD hazemuro100@yahoo.com Walid Shahrour, MD walid.shahrour@gmail.com Owen Prowse, MD owenprowse@rogers.ca Ahmed Kotb, MD, PhD, FRCS Urol, FEBU (Corresponding Author) drahmedfali@gmail.com Assistant Professor Northern Ontario School of Medicine TBRHSC 980 Oliver Road, Thunder Bay, ON, Canada. P7B 6V4