Cancer prevention research (Philadelphia, Pa.)最新文献

The International Anal Neoplasia Society (IANS) has generated recommendations for anal cancer screening, identifying MSM living with HIV (MSM-LWH) ≥35 years and MSM-noHIV ≥45 years as groups to prioritize. Since high-resolution anoscopy (HRA) availability is still limited across Europe, a retrospective study was conducted to estimate the potential HRA referral rates of the 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 HPV natural history (SAIN project). 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 strategies evaluated were: cytology as a standalone test or with high-risk (hr)HPV triage; hrHPV (with/without HPV16 genotyping) as a standalone test or with cytology triage; co-testing 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 ASC-H/HSIL (4.9% and 9.5% for MSM-LWH and MSM-noHIV, respectively) and HPV16+ MSM (27% 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.

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. Thereby, LNG-IUS use is associated with potential endometrial cancer (EC) risk reduction, but current use patterns in the U.S. are unknown. We analyzed LNG-IUS use prevalence among women aged 18-50 using a weighted statistical analysis of the 2017-2019 National Survey of Family Growth. Summary statistics were stratified by race and ethnic group, known EC sociodemographic and health risk factors, and assessed statistically with bivariate Rao-Scott chi-square tests. A multivariable logistic regression model was developed to explore LNG-IUS use predictors. Current LNG-IUS use in the US was 6.9% (95% confidence interval [CI]: 5.9-8.1%). LNG-IUS use was lower in Hispanic women compared to White women (adjusted odds ratio [AOR] 0.7, 95% CI: 0.5-1.0]. Compared to 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 EC 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 EC, which will further highlight potential opportunities for population-level primary prevention to address the growing incidence of EC.

Despite increasing incidence of hepatocellular carcinoma (HCC) in vulnerable populations, accurate early detection tools are lacking. We aimed to investigate the associations between pre-diagnostic plasma metabolites and incident HCC in a diverse population. In a prospective, nested case-control study within the Southern Community Cohort Study (SCCS), we conducted pre-diagnostic liquid chromatography-mass spectrometry metabolomics 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 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 (Meff p<0.0004), including N-acetylmethionine (OR=0.46, 95% CI=0.31-0.66). Multiple pathways were enriched in HCC, including histidine and coenzyme A metabolism (FDR p<0.001). Random forest classifier identified ten metabolites for inclusion in HCC risk classification models, which improved HCC risk classification compared to 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. Pre-diagnostic 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.

The role of dietary fiber in colon cancer prevention remains controversial. We investigated its impact on anti-tumor immunity and the gut microbiota in APCmin/+ mice infected with Enterotoxigenic Bacteroides fragilis. Mice were fed high-fiber, low-fiber, or chow diets, and 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 to chow diet. However, the low-fiber diet significantly reduced tumor burden and improved survival. Mechanistically, high fiber increased pro-inflammatory cytokines and CD4+Foxp3+RORγt+IL-17A+ regulatory T cells, while low fiber enhanced anti-inflammatory cytokines and cytotoxic T-cells. High fiber enriched microbial taxa associated with IL-17A+RORγt+ Tregs 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.

Individuals living with 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 aged 40+ living with HIV in Tennessee were evaluated for the following HPV16 antibodies: L1, E1, E2, E4, E6, 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 seropositivity and 75 (3.2%) had high. HPV16 E6 seropositive men had nearly 2-fold greater odds of seropositivity against one additional HPV16 E antigen (OR: 1.67 [95% CI: 1.10-2.52]; P=0.015) and over 3-fold 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 to prior studies in HIV populations (range: 1.1% to 3.2%) and likely reflects the high incidence of HPV+OPSCC in the southeast region of the United States.

Body mass index (BMI) may misclassify obesity-related cancer (ORC) risk, as metabolic dysfunction can occur across BMI levels. We hypothesized that metabolic dysfunction at any BMI increases ORC risk compared with normal BMI without metabolic dysfunction. Postmenopausal women (n = 20,593) in the Women's Health Initiative with baseline metabolic dysfunction biomarkers [blood pressure, fasting triglycerides, high-density lipoprotein cholesterol, fasting glucose, homeostatic model assessment for insulin resistance (HOMA-IR), and high-sensitive C-reactive protein (hs-CRP)] were included. Metabolic phenotype (metabolically healthy normal weight, metabolically unhealthy normal weight, metabolically healthy overweight/obese, and metabolically unhealthy overweight/obese) was classified using four definitions of metabolic dysfunction: (i) Wildman criteria, (ii) National Cholesterol Education Program Adult Treatment Panel III, (iii) HOMA-IR, and (iv) hs-CRP. Multivariable Cox proportional hazards regression, with death as a competing risk, was used to assess the association between metabolic phenotype and ORC risk. After a median (IQR) follow-up duration of 21 (IQR, 15-22) years, 2,367 women developed an ORC. The risk of any ORC was elevated among metabolically unhealthy normal weight (HR = 1.12, 95% CI, 0.90-1.39), metabolically healthy overweight/obese (HR = 1.15, 95% CI, 1.00-1.32), and metabolically unhealthy overweight/obese (HR = 1.35, 95% CI, 1.18-1.54) individuals compared with metabolically healthy normal weight individuals using Wildman criteria. The results were similar using Adult Treatment Panel III criteria, hs-CRP alone, or HOMA-IR alone to define metabolic phenotype. Individuals with overweight or obesity with or without metabolic dysfunction were at higher risk of ORCs compared with metabolically healthy normal weight individuals. The magnitude of risk was greater among those with metabolic dysfunction, although the CIs of each category overlapped. Prevention Relevance: Recognizing metabolic dysfunction as a significant risk factor for ORCs underscores the importance of preventive measures targeting metabolic health improvement across all BMI categories.

The German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC) has successfully implemented risk-adapted breast cancer surveillance for women at high breast cancer risk in Germany. Women with a family history of breast and ovarian cancer but without pathogenic germline variants in recognized breast cancer risk genes are recommended annual breast imaging if their predicted 10-year breast cancer risk is 5% or higher, using the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) breast cancer risk model, as outlined in the current GC-HBOC guideline. However, women who initially do not meet this risk threshold may do so later, even if there is no new cancer in their family. To determine when this threshold is crossed, one could annually repeat BOADICEA calculations using an aging pedigree: the "prediction by aging pedigree" (AP) approach. Alternatively, we propose a simplified and more practical "'conditional probability" (CP) approach, which calculates future risks based on the initial BOADICEA assessment. Using data from 6,661 women registered with GC-HBOC, both methods were compared. Initially, 74% of women, ages 30 to 48 years, had a 10-year breast cancer risk below 5%, but 53% exceeded this threshold at an older age based on the AP approach. Among the women with an initial risk below the threshold, the CP approach revealed that 99% of women exceeded the 5% threshold at the same or an earlier age compared with the AP approach (88% of cases were within the same year or 1 year earlier). The CP approach has been implemented as a user-friendly web application. Prevention Relevance: The German Consortium for Hereditary Breast Cancer recommends annual breast imaging for women if their 10-year breast cancer risk is 5% or higher. Women who initially do not meet this risk threshold may do so later. We propose a simple method to determine future risks based on initial risk assessments.

Necroptosis triggers an inflammatory cascade associated with antimicrobial defense. No prospective human study has yet explored the role of necroptosis in colorectal cancer development. We conducted quantitative analysis of biomarkers for necroptosis [transient receptor potential cation channel subfamily M member 7 (TRPM7) and phosphorylated mixed lineage kinase domain-like protein], inflammation [cyclooxygenase-2 (COX-2)], apoptosis [BCL2-associated X (BAX) and terminal deoxynucleotidyl transferase dUTP nick end labeling], and cell proliferation (Ki67). This was done using tissue microarray biospecimens from the Cooperative Human Tissue Network and rectal biopsies from a longitudinal study within the Personalized Prevention of Colorectal Cancer Trial. In the human colorectal adenoma-carcinoma sequence, we observed an inverse expression trend between BAX and TRPM7; TRPM7 decreased from normal mucosa to small and large adenomas but significantly increased in early colorectal cancer stages (Ptrend = 0.004). It maintained high levels through all cancer stages. An increased COX-2 intensity in the epithelium was noted during tumorigenesis (Ptrend = 0.02) and was significantly associated with an elevated risk of metachronous polyps (odds ratio = 3.04; 95% confidence interval, 1.07-8.61; Ptrend = 0.02). The combined composite index scores of TRPM7 and COX-2 were strongly linked to 6- to 47-fold increased risks for metachronous adenoma/serrated polyps, whereas combined scores of phosphorylated mixed lineage kinase domain-like protein or TRPM7 with BAX were associated with an 11.5- or 13.3-fold elevated risk for metachronous serrated polyps. In conclusion, our findings suggest that COX-2 expression within normal-looking colorectal mucosa is significantly associated with an increased risk of metachronous colorectal polyp. Furthermore, our results propose the hypothesis that synergistic interactions among necroptosis, inflammation, and apoptosis could play a pivotal role in human colorectal tumorigenesis. Prevention Relevance: Our findings suggest that COX-2 expression and combined scores of COX-2, TRPM7, and BAX hold promise for predicting the risk of metachronous polyps and could potentially serve as a tool for assessing the effectiveness of chemopreventive agents in preventing colorectal cancer during intervention trials.

High genetic risk and alcohol consumption ≥1 drink/day are associated with increased breast cancer risk. However, the interaction between alcohol and genetics on breast cancer risk is poorly understood, including in populations not enriched with daily drinkers. We prospectively studied 5,651 White and Black postmenopausal women in the Atherosclerosis Risk in Communities study. Alcohol intake was assessed by a food frequency questionnaire. The 313-SNP polygenic risk score (PRS) was calculated. Breast cancer cases were ascertained primarily by cancer registry linkage through 2015. Multivariable Cox regression was used to estimate HRs and 95% confidence intervals (CI) for the association of PRS and current ethanol intake with breast cancer, and their interaction. Of these individuals, 50.6% were current drinkers, and of them, 50.8% drank <1 drink/week and 12.8% drank >7 drinks/week. A higher PRS was associated with a higher breast cancer risk among White (HR1-SD, 1.48; 95% CI, 1.34-1.65) and Black (HR1-SD, 1.15; 95% CI, 0.96-1.38) women. Positive associations were not observed between current ethanol intake and breast cancer risk (White: HR13 g/week, 1.00; 95% CI, 0.98-1.03; Black: HR, 0.83; 95% CI, 0.69-1.00). Among both White and Black women, PRS generally seemed to be positively associated with risk in drinkers and nondrinkers. There was no evidence of a PRS-ethanol intake interaction among White or Black women. Patterns in Black women were similar when using an 89-SNP PRS developed among African ancestry women. In conclusion, in a prospective analysis of White and Black postmenopausal women in a study population not enriched with daily drinkers, our findings suggest that alcohol drinking does not modify the PRS-based genetic risk of breast cancer. Prevention Relevance: Although our findings suggest that alcohol drinking does not modify the PRS-based genetic risk of breast cancer among White and Black women with lower alcohol intake, nevertheless, women should consider limiting alcohol consumption as a general cancer prevention strategy, as indicated in dietary guidelines.