1Archivio Italiano di Urologia e Andrologia 2021; 93, 1 ORIGINAL PAPER No conflict of interest declared. DOI: 10.4081/aiua.2021.1.1 South America and East Asia continue to vaccinate against TB, while other countries rely on targeted vaccination of only high-risk groups (5-7). For more than thirty years; BCG material has also served as the standard intravesical immunotherapy agent in the treatment of non-muscle inva- sive urinary bladder cancer (NMIBC) following transurethral resection (TUR) (8, 9). This combined approach to NMIBC offers the most successful treatment for bladder cancer to date (8, 10). In the past, the BCG vaccine was examined for its anti-cancer properties, which even until today are not well understood. However, it is speculated that BCG has anti-neoplastic properties through its ability to upreg- ulate immunologic cytokine expression within the urinary bladder and induce a form of trained immunologic mem- ory (11). Presently, urinary bladder neoplasms remain in the top 10 most common cancers around the world (12). Furthermore, incidence rates of bladder cancer have been increasing over the past twenty years, and the rates of bladder cancer are higher in first world countries (13). In these same countries, TB vaccination programs have ceased or target high-risk individuals, including immi- grants from TB endemic areas and a select few indige- nous populations living in highly crowded conditions (4-6). The role of BCG in the preventing recurrence of NMIBC when combined with TUR is well established and standard of care. However, it is presently unknown if the BCG vaccine given in early childhood actually serves as a protective mechanism for the development of bladder cancer in later life and whether or not increased rates of bladder cancer correlate with decreased BCG vaccination in various nations. This scoping literature review serves to summarize what is presently known of the connection between bladder cancer and BCG vaccination, and whether previous BCG immunization has any protective mechanisms for blad- der cancer development in later life. Results from this review will inform future research endeavors in the area of urinary bladder cancer prevention. METHODS Rationale The rationale of this scoping literature review is to estab- lish whether there is existing literature examining the link Background: The Bacillus Calmette-Guerin (BCG) vaccine has long been used for the prevention of tuberculosis (TB) around the world. BCG is also used as an immunotherapy agent for the treatment of non-mus- cle invasive urinary bladder cancer. This scoping literature review and preliminary data analysis aims to summarize the literature correlating infantile BCG vaccination with the inci- dence of future bladder cancer. Methods: Studies were identified by a formal literature search of MEDLINE and Cochrane Central Registrar of Controlled Trials following PRISMA guidelines. Preliminary data analysis was conducted on publicly accessible data summarizing the impact of gender, BCG vaccination, and socio-economic effects on crude and age-standardized rates of bladder cancer. Results: As part of our analysis, preliminary regression models demonstrated BCG vaccination status, gender, and socio-eco- nomic status to have statistically significant effects on crude and age-standardized rates of bladder cancer incidence. BCG vacci- nation was associated with a 35-37% lower age-standardized rate of bladder cancer incidence. Conclusions: There is very little literature examining the rela- tionship between prior BCG vaccination and rates of bladder cancer incidence. Our limited data analysis indicates that a relationship does exist between infantile BCG vaccination and later bladder cancer development, although extensive future investigation is needed in this area. KEY WORDS: BCG; Bladder cancer; BCG vaccine; Cancer prevention. Submitted 28 December 2020; Accepted 29 December 2020 INTRODUCTION The Bacillus Calmette-Guerin (BCG) vaccine is a live atten- uated strain of Mycobacterium bovis that has been used for the prevention of tuberculosis (TB) (1). As part of the World Health Organization Global Expanded Immunization Program, since the mid 1900’s, the BCG vaccine has remained as one of the most widely used vaccines around the world (2, 3). Implementation of this vaccine has resulted in significantly decreased rates of TB globally (2, 3). In most western countries, immunization cam- paigns in the early 20th century have led to near eradica- tion of TB and thus discontinuation of BCG vaccination programs (4-6). Currently, select countries, primarily in Bacillus Calmette-Guerin vaccine and bladder cancer incidence: Scoping literature review and preliminary analysis Summary Sabrina Trigo 1, Kaitlin Gonzalez 1, Livio Di Matteo 2, Asmaa Ismail 1, Hazem Elmansy 1, Walid Shahrour 1, Owen Prowse 1, Ahmed Kotb 1 1 Northern Ontario School of Medicine, Thunder Bay, ON, Canada; 2 Department of Economics, Lakehead University, Thunder Bay, ON, Canada. Archivio Italiano di Urologia e Andrologia 2021; 93, 1 S. Trigo, K. Gonzalez, L. Di Matteo, A. Ismail, H. Elmansy, W. Shahrour, O. Prowse, A. Kotb 2 between the BCG vaccine and rates of bladder cancer. We also aimed to summarize the impact of gender, BCG vaccination, and socio-economic effects on the crude and age-standardized rates of bladder cancer. The relationship between crude and age standardized rates of bladder can- cer incidence versus the aforementioned variables and other confounders was examined to investigate if an inverse relationship between current bladder cancer inci- dence and current use of BCG vaccines is related. Retrieval of studies A comprehensive virtual literature search was conducted in MEDLINE and the Cochrane Central Registrar of Controlled Trials using PRISMA guidelines for scoping lit- erature reviews. A protocol was created for this literature search but was not submitted for publication. This article is a review and consists solely of a literature search and analysis of publicly accessible information. It did not include patient data, thus was exempt from Research ethics board approval. The literature search was per- formed on September 6, 2020. The search was conducted for articles pertaining to the BCG vaccine and bladder can- cer published in the English language. Search terms used included “bladder cancer” or “urinary bladder neoplasm” and “bcg vaccine” or “bcg” or “mycobacterium bovis”. Two Reviewers independently reviewed titles, abstracts, full articles, and reference lists of articles selected for full-text review. Decision to include an article at any stage of the review was made by consensus, if there was a discrepancy a third reviewer served as a tiebreaker. At each stage of review, all studies were carefully assessed for relevance. Inclusion and exclusion criteria In this analysis, we used the following inclusion criteria: (1) original research from randomized controlled trials, cohort studies, case-control studies, observational stud- ies, or correlational studies; (2) patients vaccinated with BCG prior to bladder cancer diagnosis; (3) reported bladder cancer incidence or associated mortality. We did not consider review articles and guidelines or studies that included unvaccinated patients where the outcome of interest was not a bladder neoplasm. External data analysis Both linear and log-linear regression analysis was con- ducted using data obtained from the Cancer Incidence in Five Continents, Vol. 10, the BCG World Atlas, and the International Monetary Fund (IMF) World Economic Outlook Database to describe the impact of BCG vaccina- tion on bladder cancer rates. Next, we obtained the age standardized and crude bladder cancer incidence rates for females and males from 70 countries between 2003 and 2007. Additional variables of interest were subse- quently assigned to these countries, which included the following: If the country has current Bacillus-Calmette- Guerin (BCG) vaccination programs for TB (1 yes, 0 no); whether the national share of 1-year-olds vaccinated for BCG exceeded 80% (1 yes, 0 no); if the country never had a vaccination program or had or discontinued uni- versal BCG vaccination (1 yes, 0 no); the national share of 1-year-olds immunized for BCG in both 1985 and 2015 (%); the median per capita Gross Domestic Product (GDP) from 2003-07; the median unemployment rate from 2003-07; and, the median government spending to GDP (%) from 2003-07. If we accept that current rates of international BCG vaccination are an acceptable proxy for past levels, then the using country having current BCG vaccination for TB (1 yes, 0 no) and National Share of 1 Y Old’s Immunized (BCG) (WHO) in 2015 > 80% can be used as the TB vaccine variables. As well, we can also use another variable defined as Country Never Had or Discontinued Universal BCG (1 yes, 0 no). This variable may be better at picking up the lagged effects over time of TB vaccine use. RESULTS Literature search Our search resulted in 680 articles. Forty-two duplicates were identified and removed. Six hundred and thirty- eight articles underwent title screening. Subsequently, sixteen abstracts were reviewed, followed by 3 full-text articles and corresponding reference lists. Three articles were found to be of relevance to our work, however only one publication examined the relationship between BCG vaccination and bladder cancer. The identified study examined the relationship between childhood BCG vacci- nation and the subsequent development of lung cancer as the primary outcome of interest and bladder cancer as a secondary outcome. This article found BCG vaccination to not be associated with a decreased rate of bladder can- cer (HR, 1.34; 95% CI, 0.22-8.03). The study demon- strated that the rate of lung cancer was significantly lower in those who received the BCG vaccine compared to those who had received the placebo (18.2 vs 45.4 cases per 100 000 person-years; hazard ratio, 0.38; 95% CI, 0.20-0.74; p = .005), controlling for sex, region, alcohol overuse, smoking, and tuberculosis. No other types of malignant neoplasms were significantly different between the 2 groups; notably, leukemia and lymphoma rates were similar in the BCG group vs placebo group (HR, 0.80; 95% CI, 0.35-1.82). Ten individuals had a second malignant neoplasm, including cancers of the skin, breast, uterus, ovary, and pancreas and leukemia. The study was a retrospective review of a clinical trial that had assigned participants to a vaccine group using systematic stratification of participants based on school age, district, and sex. The participants (n = 2963) were subsequently randomized by alternation. The original study occurred at 9 sites in 5 US states in between 1935 and 1998 and involved indigenous and Alaskan school children with no prior evidence of tuberculosis infection. One cohort received a single intradermal BCG injection and the other, a saline placebo. The outcome of interest was diag- nosis of cancer following BCG vaccination. Data exploration Age standardized and crude bladder cancer incidence rates for males and females for 70 international geograph- ic units for the period 2003-07 were obtained and addi- tional variables assigned for these national units. These variables include: country has current bcg vaccination for tuberculosis (1 yes, 0 no), country never had or discon- tinued universal BCG (1 yes, 0 no), national share of 1 y olds immunized (BCG) (WHO) in 2015 > 80%, BCG immunization coverage among 1-year-olds (WHO 2017) (%) in 1985, BCG immunization coverage among 1-year- olds (WHO 2017) (%) in 2015, Median Per Capita GDP 2003-07, Median Unemployment Rate 2003-07 and Median Government Spending to GDP (%) 2003-07. Given that bladder cancer is primarily a disease of age and TB vaccination occurs early in life, one can hypoth- esis that any relationship between rates of vaccination and bladder cancer incidence is a lagged one with cur- rent bladder cancer incidence rates a function of rates of vaccination and coverage 30 to 50 years ago. On the other hand, current rates of vaccination may be a suit- able proxy for past rates and useful as a determining vari- able. As well, for some of these variables, it was not pos- sible to assign a value. Therefore, while the upper bound size of the dataset is 140 observations, some of the analy- sis would inevitably be restricted to dataset size of just over half the total number of observations. In any event, the analysis is exploratory and very pre- liminary. If we accept that current rates of international BCG vaccination are an acceptable proxy for past levels, then using country has current BCG vaccination for tuberculosis (1 yes, 0 no) and national share of 1 y olds immunized (BCG) (WHO) in 2015 > 80% can be used as the TB vaccine variables. We can look at the relation- ship between crude and age standardized rates of blad- der cancer incidence versus these variables as well as other confounders to see if an inverse relationship between current bladder cancer incidence and current use of TB vaccine. As well, we can also use another vari- able defined as Country Never Had or Discontinued Universal BCG (1 yes, 0 no). This variable may be better at picking up the lagged effects over time of TB vaccine use. As well, a variable was generated called National Share of 1 y olds immunized (BCG) (WHO 2017) in 1985 > 50% (1 if > 50%, 0 if < 50% or country never had or discontinued universal BCG = 1). This exploratory analysis will be confined to those variables for which the most observations are available. In terms of results, locally weighted scatterplot smoothing (LOWESS) univariate plots of age standardized bladder cancer incidence versus whether there is current univer- sal BCG vaccination [county has current BCG vaccina- tion for tuberculosis (1 yes, 0 no)] is quite negative for males and slightly negative for females (Figure 1). Plots of the age-standardized incidence rates versus GDP appears to show a hump-shaped relationship for both males and females suggesting rising incidence as GDP rises and then a decline at higher levels of GDP (Figure 2). This can be interpreted as rising incidence during ris- ing socio-economic status as captured by per capita GDP but then a leveling off and decline. However, these plots do not control for confounding factors. Regression analysis is conducted regressing both crude and age-standardized bladder cancer rates controlling for whether male or female incidence, GDP and GDP squared (to model the potential hump-shaped effect of the eco- nomic status variable) and BCG vaccination variables. The regressions are for linear and log-linear models. In the lin- ear models for the determinants of both cruse and age standardized incidence, the first set uses current universal BCG vaccination [county has current BCG vaccination for tuberculosis (1 yes, 0 no)] while the second set uses never or past BCG vaccination [Country Never Had or Discontinued Universal BCG (1 yes, 0 no)] as the BCG variables. The third set uses whether the percent of 1 year olds vaccinated with BCG in 1985 was greater than 50% [national share of 1 y olds immunized (BCG) (WHO 2017) in 1985 > 50% (1 if > 50%, 0 if < 50% or country 3Archivio Italiano di Urologia e Andrologia 2021; 93, 1 Bacillus Calmette-Guerin vaccine and bladder cancer incidence Figure 1. Age standardized bladder cancer incidence rate (2003-07) versus percent of one year old getting BCG vaccination in 1985. A: Males (lowess asrw currentbcgvacc if males=1). Males that did not receive BCG vaccine had a higher incidence rate of bladder cancer. B: Females (lowess asrw currentbcgvacc if males=0). Females that did not receive BCG vaccine had a slightly higher incidence rate of bladder cancer. Figure 2. Age standardized bladder cancer incidence rate (2003-07) versus median per capita GDP (2003-07). A: Males (lowess asrw medpercapgdp2003 07 if males=1, bwidth 0.5). There was a rise in the incidence rate of bladder cancer with increasing income to a certail level, after which, the incidence rate was declining. B: Females (lowess asrw medpercapgdp2003 07 if females=1, bwidth 0.5). There was a rise in the incidence rate of bladder cancer with increasing income to a certail level, after which, the incidence rate was declining Archivio Italiano di Urologia e Andrologia 2021; 93, 1 S. Trigo, K. Gonzalez, L. Di Matteo, A. Ismail, H. Elmansy, W. Shahrour, O. Prowse, A. Kotb 4 never had or discontinued universal BCG = 1)]. The log- linear models are for the age-standardized rates only. They are of interest, because being log-linear, the coefficients can be interpreted as percentages and therefore allow for interpretation of magnitudes of the effects. In general, the models suggest that gender, BCG vaccina- tions and socio-economic effects have statistically signifi- cant effects on crude and age-standardized rates of blad- der cancer incidence at the 5 and 10 percent level. The log-linear models suggest that all other things given, males have just over 4 times the rate of bladder cancer relative to females while the BCG vaccination variables are associated with a 35-37 percent lower age-standard- ized rate of bladder cancer incidence after controlling for both gender and GDP. When never having BCG or past BCG TB vaccinations is the included vaccination variable, the results show a 20 percent higher rate of bladder can- cer incidence, but the effect is not statistically significant. Meanwhile, controlling for gender and BCG vaccination, incidence rises and peaks at approximately $10,000 in per capita GDP (in PPP$) and then begins to decline. There does seem to be some relationship between rates of TB vaccine inoculation and longer-term bladder can- cer incidence in the results from this data. These results are interesting but should be interpreted with extreme caution given the relatively small size of the data set as well as the single point in time nature of the data. These are only the 2003-07 incidence rates and the data set could be expanded to include the 2008-12 data. However, the ultimate limitation is the lack of fine gran- ularity that would be provided by a much larger data set consisting of individuals over time – a time series micro- data panel – with corresponding data on BCG vaccina- tion and other individual level socio-economic charac- teristics. Whether such a data set exists or could be constructed would be interesting. Table 1 illustrate data retrieved from studies countries. COUNTRY Total Crude ASR M F Current Never Percent BCG Percent BCG Percent BCG Percent BCG MedPer Med MedG/GDP cases rate (W) BCG or past 1 yr old 1 yr old 1 yr old 1 yr old Cap GDP unemployment 2003-07 vacc BCG 2015 > 80% 1985 1985 > 50% 2015 2003-07 rate 2003-07 MALES Algeria 203 5.60 8.60 1 0 1 0 1 86 1 99 12495.6 15.265 30.765 Argentina 1238 15.75 14.93 1 0 1 0 1 90 1 99 15741.187 11.575 24.426 Australia 12300 21.38 14.90 1 0 0 1 0 0 40460.543 5.042 34.681 Austria 7271 36.40 20.30 1 0 0 1 0 90 1 41363.055 5.225 50.378 Bahrain 77 6.60 11.60 1 0 43218.759 5.6 24.923 Belarus 4406 19.30 14.40 1 0 1 0 1 0 97 11173.37 1.704 46.515 Belgium 12617 61.50 32.00 1 0 0 1 0 0 39592.405 8.267 48.933 Brazil 3906 7.38 10.68 1 0 1 0 1 63 1 99 12424.455 11.5 39.239 Bulgaria 5237 27.90 15.60 1 0 1 0 1 99 1 97 13086.906 10.177 34.301 Canada 24778 31.00 18.90 1 0 0 1 0 0 40588.876 6.758 38.662 Chile 267 7.17 8.07 1 0 1 0 1 96 1 93 16958.13 9.3 20.137 China 9172 8.37 6.17 1 0 1 0 1 64 1 99 5669.225 4.2 18.074 Columbia 451 4.50 4.85 1 0 1 0 1 76 1 90 9286.189 12.042 28.103 Costa Rica 486 4.50 5.40 1 0 1 0 1 82 1 83 11110.728 6.495 16.658 Croatia 3338 31.20 18.10 1 0 1 0 1 0 98 19252.067 17.583 46.815 Cuba 235 14.30 8.30 1 0 1 0 1 98 1 99 Cyprus 645 34.30 22.50 1 0 0 0 0 0 35179.581 4.55 39.127 Czech Rep 8094 32.40 19.80 1 0 0 0 0 0 98 25577.306 7.77 42.273 Denmark 6464 48.20 26.20 1 0 0 1 0 80 1 43342.624 4.8 51.242 Ecuador 190 3.65 4.55 1 0 0 1 1 99 1 88 8616.508 7.095 21.213 Egypt 1231 12.30 19.00 1 0 1 0 1 80 1 96 9132.877 10.917 30.638 Estonia 763 24.60 15.70 1 0 1 0 1 90 1 95 22409.357 8.031 33.771 Finland 3358 26.10 14.20 1 0 0 1 0 83 1 38798.265 8.475 48.331 France 7627 36.80 19.36 1 0 0 0 0 82 1 37551.869 8.825 52.985 Germany 24476 47.88 23.31 1 0 0 0 0 0 38597.366 10.042 46.791 Iceland 230 30.50 20.40 1 0 0 0 0 41633.012 2.875 41.303 India 3381 2.10 2.92 1 0 1 0 1 8 0 87 3258.168 26.659 Iran 133 5.40 8.50 1 0 1 0 1 79 1 99 16089.323 11.3 19.848 Ireland 2009 19.40 14.20 1 0 1 0 0 80 1 77 48034.889 4.775 33.343 Israel 5033 30.60 25.40 1 0 0 1 0 68 1 26340.356 11.2 43.685 Italy 35154 68.32 32.61 1 0 0 1 0 0 37066.895 7.692 47.144 Jamaica 58 3.70 4.10 1 0 1 0 1 51 1 99 8549.17 11.225 31.349 Japan 10877 26.78 11.69 1 0 1 0 1 85 1 84 35664.003 4.425 34.598 Kuwait 87 3.60 7.70 1 0 1 0 1 0 99 71142.748 1.37 31.914 Latvia 1040 24.70 16.30 1 0 1 0 1 0 94 17601.947 10.05 33.478 Table 1. Details of countries included in our analysis. A table illustrating all retrieved data is included as a supplementary material. 5Archivio Italiano di Urologia e Andrologia 2021; 93, 1 Bacillus Calmette-Guerin vaccine and bladder cancer incidence Libya 174 7.30 14.90 1 0 1 0 1 87 1 99 36946.588 33.699 Lithuania 1930 24.20 16.30 1 0 1 0 1 0 97 18443.757 8.324 33.424 Malawi 139 5.90 13.30 1 0 1 0 1 87 1 90 802.359 26.394 Malaysia 313 5.45 7.18 1 0 1 0 1 95 1 99 18241.829 3.55 25.884 Malta 390 38.90 23.90 1 0 1 0 0 65 1 27147.829 6.942 42.322 New Zealand 1617 16.00 9.90 1 0 0 0 0 0 30803.692 3.875 37.066 Norway 4467 38.90 21.40 1 0 0 0 0 0 63455.303 4.471 41.485 Phillipines 622 2.05 4.45 1 0 1 0 0 76 1 80 4835.821 11.35 19.532 Poland 4843 29.40 20.00 1 0 1 0 1 95 1 94 16982.21 17.745 44.395 Portugal 174 29.00 21.70 1 0 1 0 0 82 1 32 26384.19 7.582 45.31 Qatar 19 3.80 7.60 1 0 1 0 1 76 1 97 124151.906 28.727 Korea 11962 9.80 9.60 1 0 1 0 1 47 0 98 26340.46 3.55 19.202 Russia 1745 17.00 11.70 1 0 1 0 1 0 96 19374.661 7.15 29.598 Saudi Arabia 266 2.70 5.60 1 0 1 0 1 89 1 98 45699.25 5.822 29.453 Serbia 3997 30.30 16.20 1 0 1 0 1 0 98 11017.344 19.53 41.9 Singapore 680 7.90 7.10 1 0 1 0 1 93 1 99 62638.987 3.125 12.379 Slovakia 2810 21.50 16.30 1 0 0 0 0 0 90 19940.36 16.358 38.762 Slovenia 1457 29.60 18.10 1 0 0 0 0 93 1 26804.884 6.342 41.814 South Africa 12 0.50 0.70 1 0 1 0 0 70 1 69 10999.622 24.65 27.175 Spain 16120 61.37 33.52 1 0 0 1 0 0 33299.088 9.153 38.315 Sweden 8256 36.80 17.50 1 0 0 1 0 16 0 24 41206.175 7.042 51.302 Switzerland 4108 38.77 20.38 1 0 0 1 0 0 51299.143 3.691 32.896 Thailand 1388 5.07 4.90 1 0 1 0 1 80 1 99 11772.887 1.858 19.331 Netherlands 1243 48.00 28.70 1 0 0 1 0 0 44098.7 5.014 42.135 Tunisia 883 12.00 12.90 1 0 1 0 1 90 1 97 8802.959 12.819 24.166 Turkey 3607 23.58 22.43 1 0 1 0 1 76 1 95 15744.75 9.488 34.31 Uganda 31 0.70 2.60 1 0 1 0 1 37 0 93 1559.811 18.776 UK (England) 46707 37.70 19.60 1 0 0 1 0 0 75 37585.365 5 37.943 UK, Northern Ireland 1250 29.60 18.30 1 0 0 1 0 0 75 37585.365 5 37.943 UK, Scotland 5271 42.90 22.50 1 0 0 1 0 0 75 37585.365 5 37.943 UK, Wales 3103 43.10 20.50 1 0 0 1 0 0 75 37585.365 5 37.943 Ukraine 21497 19.80 13.40 1 0 1 0 0 0 39 7300.773 7.185 43.658 Uruguay 1103 23.00 15.80 1 0 1 0 1 92 1 98 12872.245 12.142 29.186 USA 60100 29.50 20.80 1 0 0 1 0 0 49412.962 5.083 33.931 Zimbabwe 75 2.60 9.40 1 0 1 0 1 76 1 90 2065.22 8.542 FEMALES Algeria 6 0.20 0.20 0 1 1 0 1 86 1 99 12495.6 15.265 30.765 Argentina 5 0.15 0.23 0 1 1 0 1 90 1 99 15741.187 11.575 24.426 Australia 1204 1.87 1.05 0 1 0 1 0 0 40460.543 5.042 34.681 Austria 49 0.20 0.10 0 1 0 1 0 90 1 41363.055 5.225 50.378 Bahrain 0 0.00 0.00 0 1 43218.759 5.6 24.923 Belarus 310 1.20 0.50 0 1 1 0 1 0 97 11173.37 1.704 46.515 Belgium 73 0.30 0.10 0 1 0 1 0 0 39592.405 8.267 48.933 Brazil 159 0.37 0.45 0 1 1 0 1 63 1 99 12424.455 11.5 39.239 Bulgaria 260 1.30 0.50 0 1 1 0 1 99 1 97 13086.906 10.177 34.301 Canada 395 0.50 0.20 0 1 0 1 0 0 40588.876 6.758 38.662 Chile 1 0.03 0.03 0 1 1 0 1 96 1 93 16958.13 9.3 20.137 China 78 0.09 0.07 0 1 1 0 1 64 1 99 5669.225 4.2 18.074 Columbia 14 0.10 0.08 0 1 1 0 1 76 1 90 9286.189 12.042 28.103 Costa Rica 1 0.00 0.00 0 1 1 0 1 82 1 83 11110.728 6.495 16.658 Croatia 133 1.20 0.50 0 1 1 0 1 0 98 19252.067 17.583 46.815 Cuba 11 0.70 0.50 0 1 1 0 1 98 1 99 Cyprus 4 0.20 0.10 0 1 0 0 0 0 35179.581 4.55 39.127 Czech Rep 153 0.60 0.20 0 1 0 0 0 0 98 25577.306 7.77 42.273 Denmark 87 0.60 0.30 0 1 0 1 0 80 1 43342.624 4.8 51.242 Ecuador 5 0.10 0.10 0 1 0 1 1 99 1 88 8616.508 7.095 21.213 Egypt 16 0.20 0.30 0 1 1 0 1 80 1 96 9132.877 10.917 30.638 Estonia 32 0.90 0.30 0 1 1 0 1 90 1 95 22409.357 8.031 33.771 Finland 161 1.20 0.40 0 1 0 1 0 83 1 38798.265 8.475 48.331 France 88 0.46 0.18 0 1 0 0 0 82 1 37551.869 8.825 52.985 Archivio Italiano di Urologia e Andrologia 2021; 93, 1 S. Trigo, K. Gonzalez, L. Di Matteo, A. Ismail, H. Elmansy, W. Shahrour, O. Prowse, A. Kotb 6 DISCUSSION There was one study we identified in our scoping litera- ture review that discussed the relationship between child- hood BCG vaccination and subsequent development of lung cancer and secondarily, bladder cancer development. The study occurred at 9 sites in 5 American states between 1935 and 1998 and involved Indigenous schoolchildren with no prior evidence of TB infection. One cohort received a single intradermal BCG injection and the other a saline placebo. BCG vaccination was found not to be associated with a decreased rate of bladder cancer. The authors, however, noted significant limitations to their findings given their small sample size, and therefore this association may be masked (14). Findings of our literature search yielding 1 article was expected and indicate that additional studies are required in this area. In support of future studies examining the relationship between bladder cancer devel- opment and previous BCG vaccination, we performed a preliminary exploration of data, the results of which were discussed above. Racial variation of bladder cancer Bladder cancer is the 9th most common malignancy, with five hundred and fifty thousand new cases annually worldwide. Geographically, there is significant variation Germany 181 0.40 0.13 0 1 0 0 0 Ó 0 38597.366 10.042 46.791 Iceland 2 0.30 0.10 0 1 0 0 0 41633.012 2.875 41.303 India 186 0.18 0.21 0 1 1 0 1 8 0 87 3258.168 26.659 Iran 5 0.20 0.20 0 1 1 0 1 79 1 99 16089.323 11.3 19.848 Ireland 19 0.20 0.10 0 1 1 0 0 80 1 77 48034.889 4.775 33.343 Israel 32 0.20 0.10 0 1 0 1 0 68 1 26340.356 11.2 43.685 Italy 216 0.43 0.13 0 1 0 1 0 0 37066.895 7.692 47.144 Jamaica 1 0.10 0.00 0 1 1 0 1 51 1 99 8549.17 11.225 31.349 Japan 47 0.11 0.01 0 1 1 0 1 85 1 84 35664.003 4.425 34.598 Kuwait 2 0.10 0.20 0 1 1 0 1 0 99 71142.748 1.37 31.914 Latvia 26 0.50 0.20 0 1 1 0 1 0 94 17601.947 10.05 33.478 Libya 1 0.00 0.10 0 1 1 0 1 87 1 99 36946.588 33.699 Lithuania 91 1.00 0.40 0 1 1 0 1 0 97 18443.757 8.324 33.424 Malawi 3 0.10 0.20 0 1 1 0 1 87 1 90 802.359 26.394 Malaysia 4 0.08 0.05 0 1 1 0 1 95 1 99 18241.829 3.55 25.884 Malta 2 0.20 0.10 0 1 1 0 0 65 1 27147.829 6.942 42.322 New Zealand 47 0.40 0.30 0 1 0 0 0 0 30803.692 3.875 37.066 Norway 139 1.20 0.50 0 1 0 0 0 0 63455.303 4.471 41.485 Phillipines 8 0.00 0.05 0 1 1 0 0 76 1 80 4835.821 11.35 19.532 Poland 106 0.55 0.25 0 1 1 0 1 95 1 94 16982.21 17.745 44.395 Portugal 8 1.30 0.50 0 1 1 0 0 82 1 32 26384.19 7.582 45.31 Qatar 0 0.00 0.00 0 1 1 0 1 76 1 97 124151.906 28.727 Korea 64 0.10 0.00 0 1 1 0 1 47 0 98 26340.46 3.55 19.202 Russia 41 0.30 0.10 0 1 1 0 1 0 96 19374.661 7.15 29.598 Saudi Arabia 4 0.00 0.10 0 1 1 0 1 89 1 98 45699.25 5.822 29.453 Serbia 195 1.40 0.70 0 1 1 0 1 0 98 11017.344 19.53 41.9 Singapore 4 0.00 0.00 0 1 1 0 1 93 1 99 62638.987 3.125 12.379 Slovakia 100 0.70 0.30 0 1 0 0 0 0 90 19940.36 16.358 38.762 Slovenia 51 1.00 0.40 0 1 0 0 0 93 1 26804.884 6.342 41.814 South Africa 0 0.00 0.00 0 1 1 0 0 70 1 69 10999.622 24.65 27.175 Spain 242 0.88 0.35 0 1 0 1 0 0 33299.088 9.153 38.315 Sweden 286 1.30 0.50 0 1 0 1 0 16 0 24 41206.175 7.042 51.302 Switzerland 28 0.21 0.11 0 1 0 1 0 0 51299.143 3.691 32.896 Thailand 163 0.72 0.63 0 1 1 0 1 80 1 99 11772.887 1.858 19.331 Netherlands 325 0.80 0.40 0 1 0 1 0 0 44098.7 5.014 42.135 Tunisia 5 0.10 0.10 0 1 1 0 1 90 1 97 8802.959 12.819 24.166 Turkey 49 0.33 0.25 0 1 1 0 1 76 1 95 15744.75 9.488 34.31 Uganda 0 0.00 0.00 0 1 1 0 1 37 0 93 1559.811 18.776 UK (England) 371 0.30 0.10 0 1 0 1 0 0 75 37585.365 5 37.943 UK, Northern Ireland 17 0.40 0.20 0 1 0 1 0 0 75 37585.365 5 37.943 UK, Scotland 60 0.50 0.20 0 1 0 1 0 0 75 37585.365 5 37.943 UK, Wales 26 0.30 0.20 0 1 0 1 0 0 75 37585.365 5 37.943 Ukraine 1871 1.50 0.60 0 1 1 0 0 0 39 7300.773 7.185 43.658 Uruguay 10 0.20 0.10 0 1 1 0 1 92 1 98 12872.245 12.142 29.186 USA 702 0.30 0.20 0 1 0 1 0 0 49412.962 5.083 33.931 Zimbabwe 0 0.00 0.00 0 1 1 0 1 76 1 90 2065.22 8.542 7Archivio Italiano di Urologia e Andrologia 2021; 93, 1 Bacillus Calmette-Guerin vaccine and bladder cancer incidence in the incidence of NMIBC. Asian countries are found to have the lowest incidence of bladder cancer, while North American and Western European countries have the high- est rates. Pursuant to our previous discussion, Asian countries have universal BCG vaccination programs, while many western countries do not. The incidence of bladder cancer also tends to increase as GDP increases, before levelling off and declining at higher levels of GDP. There are also racial and ethnic variations in the inci- dence of bladder cancer where it is twice as likely to occur in white males compared to African American or Hispanic men (15). BCG vaccination worldwide In 2010, a database was compiled of immunization pro- tocols; among the 180 countries with available data, 157 countries recommend universal BCG vaccination, while the remaining 23 countries have either stopped BCG vaccination due to a reduction in TB incidence, or never recommended mass BCG immunization and instead favored selective vaccination of “at risk” groups. The United States and Canada only recommended BCG immunization for high-risk groups and do not advocate for universal BCG vaccination. In contrast, other coun- tries such as the United Kingdom had universal vaccina- tion programs against TB. The M. tuberculosis genome was initially published in 1921, and since this time comparative genomic studies have demonstrated the evolution of BCG vaccine strains. In other words, there are genetic differences in the anti- genic proteins utilized in different vaccines over the years, which may translate into variations in efficacy over time. In spite of these differences, we have observed a 35-37% lower age-standardized rate of bladder cancer incidence in countries that vaccinate with the BCG vaccine, even after controlling for both gender and GDP (17). Early childhood BCG vaccination and its anti-neoplastic effects Although the BCG vaccine is efficacious against childhood TB, its efficacy would be expected to diminish with time and provide variable protection in adulthood. Existing lit- erature surrounding BCG immunization and leukemia gives some indication that long-lasting anti-neoplastic properties of the vaccine may exist, despite the waning immunity of the vaccine against TB. Specifically, these findings were summarized in a meta-analysis combining multiple studies. The aforementioned review indicated that early life-vaccination is associated with lower rates of child- hood leukemia (17). Another study demonstrated a reduced incidence of lung adenocarcinoma and squamous cell cancer with infantile BCG vaccination (14). Limitations The findings presented in this scoping literature review and preliminary data exploration should be interpreted with extreme caution given the relatively small data set as well as data giving a sole snapshot of statistics. However, the ultimate limitation is the lack of fine gran- ularity that would be provided by a much larger data set consisting of individuals over time, such as with a time series microdata panel. A time series microdata panel, which would ideally have corresponding data on BCG vaccination and other individual level socio-economic characteristics and co-founding variables for bladder car- cinogenesis such as smoking. CONCLUSIONS Bladder cancer remains one of the most common malig- nancies globally. Prior work suggests there may be a pro- tective relationship between BCG vaccination and rates of certain cancers. 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Correspondence Sabrina Trigo, MD - strigo@nosm.ca Kaitlin Gonzalez, MD - kquinlan@nosm.ca Asmaa Ismail, MD - asmaaismail0782@gmail.com Hazem Elmansy - hazemuro100@yahoo.com Walid Shahrour - walid.shahrour@gmail.com Owen Prowse - owenprowse@rogers.ca Ahmed Kotb, MD (Corresponding Author) drahmedfali@gmail.com Assistant Professor Urology Department, Northern Ontario School of Medicine, Thunder Bay Regional Health Science Centre 980 Oliver Rd, Thunder Bay, ON, Canada, P7B 6V4 Livio Di Matteo, PhD - ldimatte@lakeheadu.ca Department of Economics, Lakehead University, Thunder Bay, ON, Canada