Medical Sciences

Abstract The New England Bladder Cancer Study has recently reported an increased bladder cancer risk with occupational exposure to mononuclear aromatic organic solvents, including exposure to benzene, toluene, and xylene and their combination BTX. However, the mechanisms by which BTX influence bladder cancer are unclear. In this study, we evaluated the interaction between BTX and genetic markers in known bladder cancer susceptibility loci and in variants shown to impact the metabolism of these solvents. We used multivariate logistic regression to calculate the ORs, 95% confidence intervals, and P values for multiplicative interaction in 1,182 cases and 1,408 controls from a population-based case–control study from New England. Lifetime occupational exposure to benzene, toluene, xylene, and BTX were assessed using occupational histories and exposure-oriented modules in conjunction with a job–exposure matrix. Buccal cells from mouthwash samples were used to conduct genotyping. Subjects with the highest cumulative exposure to benzene and who carried a risk allele in rs72826305 (CASC15) had an increased risk of bladder cancer (OR = 2.56, 95% confidence interval, 1.28–5.12) compared with those never exposed with no risk alleles (P interaction = 0.03). Additional suggestive joint effects with benzene were evident for those carrying genetic risk variants in FGFR3 (P value = 0.01) and GSTT1 (P interaction = 0.007). Bladder cancer risk is higher among those exposed to BTX-containing solvents who also harbor common variants in CASC15, FGFR3, and GSTT1, adding to the evidence of a plausible link between these exposures and bladder cancer risk. Prevention Relevance: Our findings suggest that bladder cancer risk is higher among those exposed to BTX-containing solvents who also harbor common genetic polymorphisms associated with bladder cancer. The joint contribution of genetics and occupational exposures may play an important role in the etiology of bladder cancer.

Abstract Aspirin reduces colorectal cancer risk but has a potential for adverse effects. Recent preclinical data suggest that intermittent dosing of aspirin may minimize adverse effects while maintaining efficacy. We conducted a three-arm double-blind randomized placebo-controlled phase II trial. The primary objective of the study was to test for the equivalency of two aspirin schedules, i.e., the effects of daily aspirin 325 mg/day continuously (cont-ASA) for 12 weeks or intermittently and 3 weeks on/3 weeks off on biomarkers related to colorectal carcinogenesis in rectal mucosa. A placebo group enabled the estimation of spontaneous biomarker variation. Eighty-one participants were randomized, of whom forty-five were evaluable. For the primary endpoint of decrease in the Ki-67:BCL2-associated X ratio, we could not establish equivalence for the two treatment regimens and also found no significant difference between them. For the secondary endpoint, cont-ASA treatment was significantly more effective in reducing the Ki-67:terminal deoxyribonucleotidyl transferase–mediated dUTP nick end labeling ratio. Among exploratory endpoints, we found more reduction in epithelial COX-2 expression in the cont-ASA arm compared with the intermittent aspirin dosing arm. We did not observe significant differences in other secondary and exploratory endpoints. Intermittent aspirin dosing in 3-week cycles does not produce the same biologic effect as continuous dosing. Future studies should examine whether a 1-week on/1-week off schedule can maximize the efficacy and minimize the side effects. Prevention Relevance: In this three-arm double-blind randomized placebo-controlled phase II trial, we could not establish equivalence for daily aspirin 325 mg versus intermittent aspirin (3 weeks on/3 weeks off) on Ki-67:BCL2-associated X ratio. However, compared with intermittent aspirin administration, continuing aspirin was significantly more effective in reducing the Ki-67:terminal deoxyribonucleotidyl transferase–mediated dUTP nick end labeling ratio and COX-2 in rectal mucosa.

Abstract Experimental studies have shown that dietary isothiocyanates reduced cellular proliferative marker Ki-67 and increased apoptotic markers caspase-3 and terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling (TUNEL) in animals, but human data are lacking. The present study was to assess whether sulforaphane would stop/reverse the progression of bronchial histopathology, reduce the Ki-67 index, and/or increase caspase-3 and TUNEL indices in humans. A randomized clinical trial (NCT03232138) was conducted in former smokers. Forty-three subjects were randomly assigned to the placebo or the treatment with a potential daily dose of 95 μmol sulforaphane for 12 months. The endpoints were the changes in histopathology scores and Ki-67, caspase-3, and TUNEL indices in post- versus pretreatment bronchial biopsies. Thirty-seven participants (17 in the sulforaphane and 20 in the placebo group) completed the study. Supplementation of sulforaphane did not show significant impact on bronchial histopathology but significantly reduced the Ki-67 index with a 20% decrease in the sulforaphane group and a 65% increase in the placebo (P = 0.014). The difference was even greater in high-density (3+) positive Ki-67, with a 44% decrease in the sulforaphane group compared with a 71% increase in the placebo (P = 0.004). Higher bioavailability of sulforaphane was correlated with greater reduction of the Ki-67 index (P for trend = 0.019). Sulforaphane treatment had no impact on the caspase-3 or TUNEL index in bronchial biopsies. No severe adverse event was observed in the study participants. The findings of oral sulforaphane that significantly reduced the Ki-67 index in bronchial tissue support further development as a potential chemopreventive agent against lung cancer development. Prevention Relevance: High intake of cruciferous vegetables and their sulforaphane is associated with lower incidence of lung cancer in humans and animal models. This clinical trial has demonstrated that oral supplementation of sulforaphane for 12 months significantly reduced the Ki-67 index, a potential surrogate endpoint of biomarkers for lung cancer risk.

Abstract Colorectal cancer (CRC) is highly preventable with timely screening, but screening modalities are widely underused, especially among those of low individual-level socioeconomic status (SES). In addition to individual-level SES, neighborhood-level SES may also play a role in CRC screening completion through less geographic access to health care, transportation, and community knowledge of and support for screenings. We investigated the associations between neighborhood SES using a census tract-level measure of social and economic conditions with the uptake of colonoscopy and stool-based testing. We utilized data from the Southern Community Cohort Study, a large, prospective study of English-speaking adults aged 40-79 from the southeastern United States with 65% of participants identifying as non-Hispanic Black and 53% having annual household income <$15,000. Neighborhood SES was measured via a Neighborhood Deprivation Index compiled from principal component analysis of 11 census tract variables in the domains of education, employment, occupation, and poverty; screening was self-reported at the baseline interview (2002-2009) and follow-up interview (2008-2012). We found that participants residing in the lowest SES areas had lower odds of ever undergoing colonoscopy (ORQ5vsQ1=0.75; 95%CI=[0.68, 0.82]) or stool-based CRC testing (ORQ5vsQ1=0.71; 95%CI=[0.63, 0.80]), while adjusting for individual-level SES factors. Associations were consistent between neighborhood SES and screening in subgroups defined by race, sex, household income, insurance, or education (p>0.20 for all interaction tests). Our findings suggest that barriers to screening exist at the neighborhood level and that residents of lower SES neighborhoods may experience more barriers to screening using colonoscopy and stool-based modalities.

Abstract Diet affects cancer risk, and plant-derived polyphenols exhibit cancer-preventive properties. Walnuts are an exceptional source of polyphenolic ellagitannins, converted into urolithins by gut microflora. This clinical study examines the impact of urolithin metabolism on inflammatory markers in blood and colon polyp tissue. We evaluate the effects of walnut consumption on urinary urolithins, serum inflammatory markers, and immune cell markers in polyp tissues obtained from 39 subjects. Together with detailed food frequency data, we perform integrated computational analysis of metabolomic data combined with serum inflammatory markers and spatial imaging of polyp tissues using imaging mass cytometry. LC/MS-MS analyses of urine and fecal samples identify a widely divergent capacity to form nine urolithin metabolites in this patient population. Subjects with higher urolithin A formation exhibit lower levels of several key serologic inflammatory markers, including C-peptide, soluble form of intracellular adhesion molecule 1, sIL-6R, ghrelin, TRAIL, sVEGFR2, platelet-derived growth factor (PDGF), and MCP-2, alterations that are more pronounced in obese individuals for soluble form of intracellular adhesion molecule 1, epithelial neutrophil–activating peptide 78, leptin, glucagon-like peptide 1, and macrophage inflammatory protein 1δ. There is a significant increase in levels of peptide YY associated with urolithin A formation, whereas TNFα levels show an opposite trend, recapitulated in an in vitro system with ionomycin/phorbol 12-myristate 13-acetate–stimulated peripheral blood mononuclear cells (PBMC). Spatial imaging of colon polyp tissues shows altered cell cluster patterns, including a significant reduction of vimentin and CD163 expression associated with urolithin A. The ability to form urolithin A is linked to inflammation, warranting further studies to understand the role of urolithins in cancer prevention. Prevention Relevance: We evaluate cancer-protective effects of walnuts via formation of microbe-derived urolithin A, substantiating their functional benefits on serum inflammatory markers and immunologic composition of polyps in normal/obese subjects. Our approach incorporates personalized nutrition within the context of colonic health, providing the rationale for dietary inclusion of walnut ellagitannins for cancer prevention.

Abstract The Tribally Engaged Approaches to Lung Cancer Screening study aimed to codesign and test a community-based lung cancer screening (LCS) program within a large, tribally operated health system. In 2020 to 2021, we conducted a pre–post quasi-experimental pilot implementation study of a tailored and comprehensive LCS program in two Choctaw Nation of Oklahoma primary care clinics in rural Oklahoma. The program included screening quality assessment, academic detailing, practice facilitation, health system enhancements, technology support, centralized LCS coordination, and community outreach. Eligibility for LCS was based on the 2013 U.S. Preventive Services Task Force guidelines. Participants completed pre- and post-intervention surveys on their knowledge, attitudes, and experiences regarding LCS. All participant charts were extracted to determine LCS completion. Postimplementation semi-structured interviews of patients and clinicians were conducted, and practice facilitator notes were analyzed. Participants (N = 57) averaged 67 years, and 66% were current smokers. The proportion of participants who were up-to-date with LCS increased from 39% to 58% (P < 0.01). About 18% of patients reported improvement in general care choice and treatment discussions with their doctor, and about 40% reported an improvement in their awareness or understanding of lung cancer and receipt of LCS. We also identified several key facilitators and barriers to LCS implementation at the practice and health system levels. LCS acceptance and uptake improved significantly in this community-engaged pilot intervention which informed a subsequent cluster-randomized trial. Comprehensive and community-engaged LCS programs may have the potential to improve the delivery of LCS in underserved community settings. Prevention Relevance: Our community-engaged, multicomponent, and multilevel pilot implementation study significantly improved lung cancer screening rates in a rural, tribal health system. A key feature of this pilot study was a centralized screening coordination service supported by a population screening registry. We believe that our study is replicable in other settings.

Abstract Screening digital breast tomosynthesis (DBT) aims to identify breast cancer early when treatment is most effective leading to reduced mortality. In addition to early detection, the information contained within DBT images may also inform subsequent risk stratification and guide risk-reducing management. Using transfer learning we refined a model in the WashU cohort of 5,066 women with DBT screening (mean age 54.6) among whom 105 were diagnosed with breast cancer (26 DCIS). We applied the model to external data from the EMBED cohort of 7,017 women free from cancer (mean age 55.4) among whom 111 pathology confirmed breast cancer cases were diagnosed more than 6 months after initial DBT (17 DCIS). We obtained a 5-year area under the curve (AUC) = 0.75 (95% confidence interval (CI) = 0.73 – 0.78) in the internal validation. The model validated in external data gave an AUC = 0.72 (95% CI, 0.69 – 0.75). The AUC was unchanged when age and BI-RADS density are added to the model with synthetic DBT image. The model significantly outperforms the Tyrer-Cuzick model 5-year AUC 0.56 (95%CI 0.54, 0.58) (p<0.01). Our model extends risk prediction applications to synthetic DBT, provides 5-year risk estimates, and is readily calibrated to national risk strata for clinical translation and guideline driven risk management. The model could be implemented within any digital mammography program.

Abstract Oral cancer is a major global health problem. It is commonly diagnosed at an advanced stage, although often preceded by clinically visible oral mucosal lesions, termed oral potentially malignant disorders, which are associated with an increased risk of oral cancer development. There is an unmet clinical need for effective screening tools to assist front-line healthcare providers to determine which patients should be referred to an oral cancer specialist for evaluation. This study reports the development and evaluation of the mobile detection of oral cancer (mDOC) imaging system and an automated algorithm that generates a referral recommendation from mDOC images. mDOC is a smartphone-based autofluorescence and white light imaging tool that captures images of the oral cavity. Data were collected using mDOC from a total of 332 oral sites in a study of 29 healthy volunteers and 120 patients seeking care for an oral mucosal lesion. A multimodal image classification algorithm was developed to generate a recommendation of “refer” or “do not refer” from mDOC images using expert clinical referral decision as the ground truth label. A referral algorithm was developed using cross-validation methods on 80% of the dataset and then retrained and evaluated on a separate holdout test set. Referral decisions generated in the holdout test set had a sensitivity of 93.9% and a specificity of 79.3% with respect to expert clinical referral decisions. The mDOC system has the potential to be utilized in community physicians’ and dentists’ offices to help identify patients who need further evaluation by an oral cancer specialist. Prevention Relevance: Our research focuses on improving the early detection of oral precancers/cancers in primary dental care settings with a novel mobile platform that can be used by front-line providers to aid in assessing whether a patient has an oral mucosal condition that requires further follow-up with an oral cancer specialist.

Abstract The International Anal Neoplasia Society (IANS) has generated recommendations for anal cancer screening, identifying men who have sex with men (MSM) living with human immunodeficiency virus (HIV; MSM-LWH) ≥35 years and MSM not living with HIV (MSM-noHIV) ≥45 years as groups to prioritize. As high-resolution anoscopy (HRA) availability is still limited across Europe, a retrospective study was conducted to estimate the potential HRA referral rates of the Sexually Transmitted Infections (STI)/HIV center of a European capital city using IANS-recommended strategies. The study included participants in a program for the surveillance of anal intraepithelial neoplasia and anal human papillomavirus (HPV) natural history. MSM-LWH ≥35 years and MSM-noHIV ≥45 years with valid results for liquid-based anal cytology and HPV test at baseline were included. The following strategies were evaluated: cytology as a standalone test or with high-risk HPV (hrHPV) triage; hrHPV (with/without HPV16 genotyping) as a standalone test or with cytology triage; and cotesting with cytology and hrHPV (with/without HPV16 genotyping). Overall, 307 MSM were included (244 LWH, 79.5%). hrHPV as a standalone test led to the highest referral rate in both MSM-LWH and MSM-noHIV (74.6% and 55.6%, respectively). Cytology with hrHPV triage (without genotyping) and hrHPV with cytology triage resulted in the same referral rates (44.3% in MSM-LWH and 27.0% in MSM-noHIV). In settings with insufficient HRA capacity, only high-grade squamous intraepithelial lesions (HSIL) or atypical squamous cells-cannot exclude HSIL (4.9% and 9.5% for MSM-LWH and MSM-noHIV, respectively) and HPV16+ MSM (27.0% and 20.6%, respectively) would be referred to HRA. Adoption of IANS recommendations should balance the sensitivity of the screening algorithm and the HRA referral rate because the latter is a matter of concern in settings with limited HRA capacity. Prevention Relevance: Adopting the recent IANS recommendations for anal cancer screening in MSM may be challenging when HRA availability is limited. Estimating the HRA referral rates we would have using 12 different screening algorithms, we highlighted that application of these recommendations implies a careful analysis of the local resource capacity.

Abstract Despite increasing incidence of hepatocellular carcinoma (HCC) in vulnerable populations, accurate early detection tools are lacking. We aimed to investigate the associations between prediagnostic plasma metabolites and incident HCC in a diverse population. In a prospective, nested case–control study within the Southern Community Cohort Study, we conducted prediagnostic LC/MS metabolomic profiling in 150 incident HCC cases (median time to diagnosis, 7.9 years) and 100 controls with cirrhosis. Logistic regression assessed metabolite associations with HCC risk. Metabolite set enrichment analysis identified enriched pathways, and a random forest classifier was used for risk classification models. Candidate metabolites were validated in the UK Biobank (N = 12 incident HCC cases and 24 cirrhosis controls). In logistic regression analysis, seven metabolites were associated with incident HCC (MeffP < 0.0004), including N-acetylmethionine (OR = 0.46; 95% confidence interval, 0.31–0.66). Multiple pathways were enriched in HCC, including histidine and CoA metabolism (FDR P < 0.001). The random forest classifier identified 10 metabolites for inclusion in HCC risk classification models, which improved HCC risk classification compared with clinical covariates alone (AUC = 0.66 for covariates vs. 0.88 for 10 metabolites plus covariates; P < 0.0001). Findings were consistent in the UK Biobank (AUC = 0.72 for covariates vs. 0.88 for four analogous metabolites plus covariates; P = 0.04), assessed via nuclear magnetic resonance spectroscopy. Prediagnostic metabolites, primarily amino acid and sphingolipid derivatives, are associated with HCC risk and improve HCC risk classification beyond clinical covariates. These metabolite profiles, detectable years before diagnosis, could serve as early biomarkers for HCC detection and risk stratification if validated in larger studies. Prevention Relevance: Our findings support the need for larger prospective studies examining the role of prediagnostic plasma metabolomics for the preventive management of HCC in diverse patients across multiple etiologies of liver disease. This approach could improve HCC care by identifying metabolic changes years before diagnosis, potentially enhancing screening and early detection practices.

Abstract Individuals living with human immunodeficiency virus (HIV) are at a higher risk for developing human papillomavirus–driven oropharyngeal squamous cell carcinoma (HPV + OPSCC). There are no methods for early detection; however, HPV16 E6 antibodies have been identified as a promising early marker. The objective of this study was to evaluate the prevalence of HPV16 E6 antibodies among men living with HIV, with secondary objectives of analyzing clinical and serologic predictors of HPV16 E6 seropositivity. Banked blood specimens from 2,320 men ages ≥40 years living with HIV in Tennessee were evaluated for the following HPV16 antibodies: L1, E1, E2, E4, E6, and E7. HPV16 E6 antibody levels were further categorized as moderate or high. Demographic, clinical, and serologic determinants of HPV16 E6 seropositivity were evaluated using logistic regression. HPV16 L1 antibodies were most common (22.8%), followed by E4 (10.5%), E6 (5.6%), E2 (4.8%), and E7 (4.0%). Of the 130 HPV16 E6 seropositives, 55 (2.4%) had moderate and 75 (3.2%) had high seropositivity. HPV16 E6 seropositive men had nearly twofold greater odds of seropositivity against one additional HPV16 E antigen [OR: 1.67 (95% CI, 1.10–2.52); P = 0.015] and more than threefold greater odds of seroreactivity against two additional HPV16 E antigens [OR: 3.21 (95% CI, 1.40–7.33); P = 0.006]. HPV16 E6 seropositivity was not associated with the clinical or demographic factors evaluated. In the largest study to date, HPV16 E6 seroprevalence was elevated compared with prior studies in HIV populations (range: 1.1%–3.2%) and likely reflects the high incidence of HPV + OPSCC in the Southeast region of the United States. Prevention Relevance: Our findings fill an important gap, given that our study is the largest to date to evaluate HPV antibodies among men living with HIV and is the first study to do so in the Southeastern United States, the region with the highest prevalence of both HIV and HPV + OPSCC in the nation.

Abstract The role of dietary fiber in colon cancer prevention remains controversial. We investigated its impact on antitumor immunity and the gut microbiota in APCmin/+ mice infected with enterotoxigenic Bacteroides fragilis. Mice were fed high-fiber, low-fiber, or chow diets, and the tumor burden, survival, cytokines, microbiota, and metabolites were analyzed. Contrary to the belief that high fiber inhibits tumor progression, it had no significant impact compared with chow diet. However, the low-fiber diet significantly reduced the tumor burden and improved survival. Mechanistically, high fiber increased proinflammatory cytokines and CD4+Foxp3+RORγt+IL-17A+ regulatory T cells, whereas low fiber enhanced anti-inflammatory cytokines and cytotoxic T cells. High fiber enriched microbial taxa associated with IL-17A+RORγt+ regulatory T cells and altered metabolites, including reduced tryptophan and increased short-chain fatty acids and bile acids. Low fiber produced opposite effects. These findings suggest that dietary fiber’s effects on colon cancer depends on microbial infection and immune status, emphasizing the need for personalized dietary interventions in colon cancer management. Prevention Relevance: Dietary fiber’s impact on colon cancer progression highlights the need for personalized dietary approaches, considering microbial infection and immune status.

Abstract Levonorgestrel-releasing intrauterine system (LNG-IUS) use is approved by the FDA for contraception and heavy menorrhagia. More importantly, it effectively treats endometrial hyperplasia, a precursor to endometrial cancer. Therefore, LNG-IUS use is associated with potential endometrial cancer risk reduction, but current use patterns in the United States are unknown. We analyzed LNG-IUS use prevalence among women ages 18 to 50 years using a weighted statistical analysis of the 2017 to 2019 National Survey of Family Growth. Summary statistics were stratified by race and ethnic group and known endometrial cancer sociodemographic and health risk factors and assessed statistically with bivariate Rao–Scott χ2 tests. A multivariable logistic regression model was developed to explore LNG-IUS use predictors. Current LNG-IUS use in the United States was 6.9% [95% confidence interval (CI), 5.9%–8.1%]. LNG-IUS use was lower in Hispanic women compared with White women [adjusted OR (AOR), 0.7; 95% CI, 0.5–1.0]. Compared with women with ≤high school education, LNG-IUS use was higher for women with ≥college degree (AOR, 2.0; 95% CI, 1.3–3.1). Parous (AOR, 2.6; 95% CI, 1.7–3.9) and insured (AOR, 1.7; 95% CI, 1.0–3.1) women had higher odds of LNG-IUS use, whereas women with diabetes (AOR, 0.3; 95% CI, 0.1–0.7) had lower odds of LNG-IUS use. No differences in LNG-IUS use were observed by endometrial cancer risk factors of women’s body mass index, age of menarche, hypertension, and personal history of cancer. More research is needed to establish the potential benefits of LNG-IUS use on endometrial cancer, which will further highlight potential opportunities for population-level primary prevention to address the growing incidence of endometrial cancer. Prevention Relevance: This study describes the characteristics of American women using the LNG-IUS. Reproductive-age women (especially Hispanic, with lower education, nulliparous, uninsured, and with diabetes) have lower LNG-IUS use odds. These groups may benefit from LNG-IUS use for endometrial cancer primary prevention, conditioned that LNG-IUS use is proven effective in reducing endometrial cancer incidence.

Abstract Given the female predominance of thyroid cancer, particularly in the reproductive age range, female sex hormones have been proposed as an etiology; however, previous epidemiological studies have shown conflicting results. We conducted a pooled analysis using individual data from nine prospective cohorts in the Asia Cohort Consortium to explore the association between 10 female reproductive and hormonal factors and thyroid cancer risk. Using Cox proportional hazards models, cohort-specific hazard ratios (HR) and 95% confidence intervals (CI) were estimated and then pooled using a random-effects model. Analyses were stratified by country, birth years, smoking status, and body mass index, and thyroid cancer risk based on age of diagnosis was also examined. Among 259,649 women followed up for a mean of 17.2 years, 1,353 incident thyroid cancer cases were identified, with 88% (n = 1,140) being papillary thyroid cancer. Older age at first delivery (≥26 vs. 21–25 years) was associated with increased thyroid cancer risk (P-trend = 0.003; HR = 1.16; 95% CI, 1.03–1.31), particularly when diagnosed later in life (≥55 vs. < 55 years; P-trend = 0.003; HR = 1.19; 95% CI, 1.02–1.39). Among younger birth cohorts, women with more number of deliveries showed an increased thyroid cancer risk [P-trend = 0.0001, HR = 2.40; 95% CI, 1.12–5.18 (≥5 vs. 1–2 children)], and there was no substantial trend in older cohorts. Distinct patterns were observed for the number of deliveries and thyroid cancer risk across countries, with a significant positive association for Korea [P-trend = 0.0008, HR = 1.89; 95% CI, 1.21–2.94 (≥5 vs. 1–2 children)] and nonsignificant inverse associations for China and Japan. Contextual and macrosocial changes in reproductive factors in Asian countries may influence thyroid cancer risk. Prevention Relevance: This analysis of prospective cohort studies across three Asian countries highlights that older age at first birth is linked to increased thyroid cancer risk. As women delay motherhood, understanding these trends is vital for public health strategies addressing reproductive factors influencing thyroid cancer risk in these populations.