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

Epigenetic clocks can quantify DNA methylation by measuring the methylation levels at specific sites in the genome, which correlate with biological age (BA). Accelerated aging, where BA exceeds chronologic age, has been studied in relation to cancer development, but its utility in cancer prevention remains unclear. Accelerated aging holds promise as a tool to explain the increase in early-onset colorectal cancer (EOCRC). We investigate the association of accelerated aging and the presence of preneoplastic polyps (PNP) in the colon, defined as tubular adenomas and sessile serrated adenomas. In this study of persons under age 50 undergoing colonoscopy, we used peripheral blood samples to determine BA and age acceleration metrics. Age acceleration was determined by interrogating DNA methylation at specific CpG sites across the genome, which has been shown to correlate with age. We then conducted logistic regression analyses to evaluate the association between age acceleration and PNPs. In total, 51 patient samples were evaluated. We found that that the odds of harboring a PNP are 16% higher with 1 year of accelerated aging, as measured by GrimAge. However, the strongest risk factor for PNPs remained male sex. This represents one of the first studies to explore accelerated aging and PNP in patients under the age of 50. A risk-stratified approach to EOCRC screening would minimize unnecessary colonoscopies and minimize healthcare burden while addressing the increase in EOCRC. Our findings suggest that BA calculations with peripheral blood collections could be an important component of such a risk model. Prevention Relevance: Understanding the association of accelerated aging and colorectal PNPs presents an opportunity to develop a risk-stratified approach to colorectal cancer screening in young persons.

Given the female predominance of thyroid cancer (TC), particularly in the reproductive age range, female sex hormones have been proposed as an aetiology; however, previous epidemiological studies have shown conflicting results. We conducted a pooled analysis using individual data from 9 prospective cohorts in the Asia Cohort Consortium, to explore the association between 10 female reproductive and hormonal factors and TC risk. Using Cox proportional hazards models, cohort-specific hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated and then pooled using a random-effects model. Analyses were stratified by country, birth years, smoking status, body mass index, and TC risk based on age of diagnosis was also examined. Among 259,649 women followed for a mean 17.2 years, 1,353 incident TC cases were identified, 88% (n=1,140) being papillary TC. Older age at first delivery (≥26 vs 21-25 years) was associated with increased TC 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 TC 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 TC 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 non-significant inverse associations for China and Japan. Contextual and macrosocial changes in reproductive factors in Asian countries may influence thyroid cancer risk.

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 associated with an increased risk for 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 with 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, 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.

Gastric cancer is the fifth most common cancer and the fifth leading cause of cancer deaths worldwide. Chronic infection by the bacterium Helicobacter pylori is the most prominent gastric cancer risk factor, but only 1-3% of infected individuals will develop gastric cancer. Cigarette smoking is another independent gastric cancer risk factor, and H. pylori-infected smokers are at a 2-11-fold increased risk of gastric cancer development, but the direct impacts of cigarette smoke on H. pylori pathogenesis remain unknown. In this study, male C57BL/6 mice were infected with H. pylori and began smoking within one week of infection. The mice were exposed to cigarette smoke (CS) five days/week for 8 weeks. CS exposure had no notable impact on gross gastric morphology or inflammatory status compared to filtered-air (FA) exposed controls in mock-infected mice. However, CS exposure significantly blunted H. pylori-induced gastric inflammatory responses, reducing gastric atrophy and pyloric metaplasia development. Despite blunting these classic pathological features of H. pylori infection, CS exposures increased DNA damage within the gastric epithelial cells and accelerated H. pylori-induced dysplasia onset in the INS-GAS gastric cancer model. These data suggest that cigarette smoking may clinically silence classic clinical symptoms of H. pylori infection but enhance the accumulation of mutations and accelerate gastric cancer initiation.

We performed a clinical trial in patients with non-muscle-invasive (NMI) urothelial cancer randomized (2:1) to the EGFR tyrosine kinase inhibitor erlotinib or placebo (either orally once weekly × 3 doses prior to scheduled surgery) to assess for a difference in EGFR phosphorylation in tumor-adjacent normal urothelium <24 hours post-study dose and tolerance of weekly erlotinib therapy. Thirty-seven volunteers (6 female/31 male; mean age 70; 35 White/2 non-White) with confirmed or suspected NMI urothelial cancer were enrolled into either erlotinib (n = 24; 900 mg-13, 600 mg-11) or placebo (n = 13). IHC assessment of phosphorylated and total EGFR in tumor-adjacent normal urothelium (20 erlotinib and 9 placebo subjects) or tumor (21 erlotinib and 11 placebo subjects) at study end showed no significant difference between those receiving erlotinib or placebo. This was also true for other assessed tissue biomarkers (phosphorylated ERK, ERK, E-cadherin, p53, and Ki67). Adverse events were more common, in a dose-related fashion, in participants receiving erlotinib, e.g., 38% experienced grade 1 with rare grade 2 diarrhea and skin toxicity versus 8% in placebo. Clinically insignificant but statistically significant (P = 0.001) elevations in serum total bilirubin and creatinine were observed in participants receiving erlotinib. Serum erlotinib and metabolite concentrations (OSI-420) confirmed compliance in all subjects receiving erlotinib and did not significantly differ between the 600 and 900 mg doses. Despite compelling preclinical and clinical data for targeted EGFR inhibition in bladder cancer prevention, these data do not support the use of weekly erlotinib therapy to prevent progression of NMI bladder cancer. Prevention Relevance: We evaluated the potential of erlotinib in preventing cancer by performing a randomized, double-blind, placebo-controlled trial of weekly erlotinib therapy in participants undergoing surgical removal of suspected noninvasive bladder neoplasia. Weekly erlotinib therapy was tolerated with common grade 1 to 2 toxicities but without evidence of beneficial effect upon urothelial tissue. See related Spotlight, p. 7.

Patients with Li-Fraumeni syndrome (LFS) are recommended to follow a comprehensive surveillance protocol, but the demanding nature may limit adherence. We sought to identify barriers to adherence and to determine whether screening fatigue and financial hardship are contributors. A 39-item online survey was developed and distributed to patients presenting to a LFS clinic between 2017 and 2022. Of the 39 patients eligible, 20 responded to the survey (51%). Of the respondents, 75% reported they do not skip surveillance tests; however, this was not consistent when asked about specific tests, with only 65% and 40% up to date with colonoscopy and esophagogastroduodenoscopy, respectively. Hundred percent of those diagnosed within the last 5 years said they never skip tests, whereas only 50% of those diagnosed more than 5 years ago reported the same (P = 0.01). Barriers to adherence were reported by 85% and most commonly included finances (40%), time (25%), and difficulty scheduling (25%). Only 21% felt no financial stress, and 63% worried at least somewhat about their future financial situation because of LFS. Even with insurance, 65% felt their share of healthcare costs was too high. Adherence to rigorous cancer surveillance is imperfect and decreases over time among patients with LFS. Whereas number of tests was not a commonly cited barrier, time and difficulty scheduling were common and may contribute to screening fatigue. The degree of financial stress in the affluent population studied should raise even greater concern about financial strain in the LFS population in general. Prevention Relevance: Li-Fraumeni syndrome (LFS) essentially guarantees a cancer diagnosis in an affected individual's lifetime. Findings of this study reveal a difficulty for patients with LFS to adhere to recommended rigorous surveillance protocols and question how identified barriers can be broken down to reduce the morbidity and mortality of LFS.

While tobacco smoking is a risk factor in the development of oral squamous cell carcinoma (OSCC), only a fraction of smokers develop the disease. Compelling evidence shows that microbial community composition is associated with carcinogenesis, suggesting that the microbiome may play a role in cancer development of smokers. We previously showed that black raspberry (BRB) protects against OSCC induced by the tobacco constituent dibenzo[def,p]chrysene (DBP) via alteration of genetic and epigenetic markers in a manner consistent with its cancer preventive activity. In the present study, we conducted a mouse experiment to investigate the effects of BRB and DBP individually and in combination on the oral and gut microbiota. DBP-induced DNA damage in the mouse oral cavity is an essential step for the development of OSCC in mice. 16S rRNA gene sequencing revealed that BRB significantly increased microbial diversity and shifted microbiome composition in the gut and oral cavity, whereas DBP had no significant effect. In both gut and oral microbiota, Akkermansia muciniphila was significantly reduced after BRB treatment; however, this was not consistent with pure culture in vitro assays suggesting that the impact of BRB on A. muciniphila may be mediated through indirect mechanisms including the host or other microbes. Indeed BRB, but not DBP, was found to modulate the growth kinetics of human gut microbes in vitro including lactic acid bacteria and Bacteroides spp. The results of the current study further emphasize the interplay of microbiome and environmental factors in the development and prevention of OSCC. Prevention Relevance: Our work clearly demonstrates the modulatory impact of BRB on both gut and oral microbiomes within a DBP-induced OSCC mouse model and paves the way for future research examining a causal role of BRB-microbiota interactions at different stages of disease progression.

The study by Downs and colleagues targets patients with non-muscle-invasive bladder cancer (NMIBC) to explore secondary/tertiary cancer prevention strategies. Utilizing a "window-of-opportunity" design, erlotinib was evaluated for its effect on EGFR phosphorylation, although the unconventional dosing regimen failed to demonstrate efficacy. New opportunities in NMIBC prevention include targeting FGFR3 mutations with emerging FGFR inhibitors. A future trial design could focus on clinical outcomes such as tumor response and NMIBC recurrence while also evaluating FGFR3 inhibition in both tumor and adjacent normal bladder epithelia. See related article by Downs et al., p. 31.

Mammographic density is a strong risk factor for breast cancer and is reported clinically as part of Breast Imaging Reporting and Data System (BI-RADS) results issued by radiologists. Automated assessment of density is needed that can be used for both full-field digital mammography (FFDM) and digital breast tomosynthesis (DBT) as both types of exams are acquired in standard clinical practice. We trained a deep learning model to automate the estimation of BI-RADS density from a prospective Washington University clinic-based cohort of 9,714 women, entering into the cohort in 2013 with follow-up through October 31, 2020. The cohort included 27% non-Hispanic Black women. The trained algorithm was assessed in an external validation cohort that included 18,360 women screened at Emory from January 1, 2013, and followed up through December 31, 2020, that included 42% non-Hispanic Black women. Our model-estimated BI-RADS density demonstrated substantial agreement with the density as assessed by radiologists. In the external validation, the agreement with radiologists for category B 81% and C 77% for FFDM and B 83% and C 74% for DBT shows important distinction for separation of women with dense breast. We obtained a Cohen's κ of 0.72 (95% confidence interval, 0.71-0.73) in FFDM and 0.71 (95% confidence interval, 0.69-0.73) in DBT. We provided a consistent and fully automated BI-RADS estimation for both FFDM and DBT using a deep learning model. The software can be easily implemented anywhere for clinical use and risk prediction. Prevention Relevance: The proposed model can reduce interobserver variability in BI-RADS density assessment, thereby providing more standard and consistent density assessment for use in decisions about supplemental screening and risk assessment.