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

Butyrate may reduce the risk of colorectal cancer and can be delivered to the colon using butyrylated high-amylose maize starch (HAMSB). This trial evaluated the effects of HAMSB on polyp burden in participants with familial adenomatous polyposis. This study was a randomized, double-blind, placebo-controlled crossover trial. In three 6-month periods, participants ingested 40 g/day of HAMSB or low-amylose starch, followed by the alternative, and then a washout. Participants underwent four video-recorded colonoscopies to assess polyp burden as the primary endpoint. At baseline, two distal bowel tattoos were placed: tattoo one where polyps were cleared at each scope and tattoo two where polyps were left in situ. Generalized linear mixed models were used to estimate the ratio of mean polyp counts in intervention compared with placebo periods. Seventy-two participants were randomized (33 female), with 49 completing the study. In the intention-to-treat analysis, HAMSB did not reduce mean global [0.9 fold change (FC); 95% confidence interval (CI), 0.77-1.06; P = 0.218] or small (<2.4 mm) polyp numbers (0.88 FC; 95% CI, 0.71-1.1; P = 0.267). There was a trend for the reduction of small polyps in tattoo one (0.72 FC; 95% CI, 0.5-1.03; P = 0.074). In the per-protocol analysis, there was a strong trend for HAMSB to reduce mean global small polyp numbers (0.79 FC; 95% CI, 0.62-1; P = 0.051). HAMSB may reduce polyp initiation in the distal bowel without causing regression or growth of existing polyps. However, 95% CIs indicate large uncertainty to the true direction of the treatment effect, and the P values provide only weak evidence against the null hypothesis of no treatment effect.

Prevention relevance: There is convincing evidence that dietary fiber reduces the risk of colorectal cancer possibly by production of butyrate during microbial fermentation of indigestible fiber. This study was designed to determine if a dietary supplement that delivers butyrate to the colon reduces polyp burden in participants with familial adenomatous polyposis.

The number of cancer preventive/interceptive agents utilized clinically remains disappointingly few. After nearly four decades of research in the development of these agents, we need to take advantage of the progress that has been made in our understanding of early-stage cancer and premalignant lesions to maximize efforts to prevent or intercept cancer. It is crucial to identify the high-risk population and the appropriate target pathways and to use animal models that accurately represent early-stage human lesions and demonstrate at least a 50% reduction in tumor development. Determination of the agent's physiochemical properties, toxicities, solubility, and accumulation in the intended target organ needs to be verified. Tolerability is important, as these agents will be administered for an extended period to healthy individuals at higher risk for cancer. Reduction of side effects through the use of lower concentrations of agents in drug combinations, alternative delivery systems, and different dosing schedules should be considered. Collaboration with industry partners early in the development process to facilitate the movement of agents into clinical trials, including the necessary investigational new drug-enabling toxicology studies, manufacturing, and commercialization, is crucial. Moving forward, cancer prevention/interception will likely rely on combinations of vaccines with chemo/immunopreventive agents to reduce cancer mortality.

Implications on the loss of lung cancer screening (LCS) coverage among Medicare recipients aged 77+ years have not been explored. We use a 2022 Behavioral Risk Factor Surveillance System dataset to examine LCS patterns of screen-eligible adults across three age groups: 65 to 70, 71 to 77, and 78 to 79 years. In descriptive analyses, LCS-eligible respondents are compared by screening status across each age category. In regression analyses, we explore various sociodemographic and health-related factors that may help explain age-related differences between these groups. Less than a third of our sample reported LCS in the last year (26.3%). Among eligible respondents, adults aged 78 to 79 years reported the highest LCS rates (32.0%), followed by adults aged 71 to 77 years (28.3%) and 65 to 70 years (24.2%). Respondents aged 78 to 79 years and 65 to 70 years with chronic obstructive pulmonary disease indicated significantly increased LCS odds [OR, 3.37; 95% confidence interval (CI), 1.12-10.11 and OR, 2.91; 95% CI, 1.98-4.27, respectively]. Respondents aged 78 to 79 years with history of a heart attack or kidney disease indicated significantly decreased LCS odds (OR, 0.08; 95% CI, 0.01-0.62 and OR, 0.06; 95% CI, 0.01-0.56, respectively). Respondents aged 71 to 77 years with coronary heart disease indicated a significantly decreased LCS odds (OR, 0.54; 95% CI, 0.30-0.96). Although loss of Centers for Medicare & Medicaid Services coverage for LCS is not associated with lower screening among Behavioral Risk Factor Surveillance System adults aged 78 to 79 years, clinicians should continue to consider the appropriateness of treatment for older LCS-eligible adults with chronic health conditions.

Prevention relevance: Persons who reach the age of 78 years are no longer eligible for LCS coverage from Medicare. This study fills an important knowledge gap by comparing LCS patterns among a nationally representative sample of Medicare-eligible adults aged 78 to 79 years with their younger counterparts aged 65 to 77 years, for whom Centers for Medicare & Medicaid Services covers LCS. See related Spotlight, p. 655.

Hernandez's analysis of Behavioral Risk Factor Surveillance System (BRFSS) data concludes that adults of 78 to 79 years of age, who are excluded from Medicare coverage of lung cancer screening, have the highest uptake (32%) for lung cancer screening. They join other studies based on BRFSS that report much higher uptake than previous studies based on other sources. Potential social desirability, recall, and age-related biases and respondent clinical confusion in BRFSS and other sources lead us to question Hernandez's conclusions and the usefulness of uptake measures. Measuring the portion of newly diagnosed lung cancers detected through screening in administrative data is more closely connected to health outcomes. See related article by Hernandez et al., p. 693.

Cancer cells exhibit metabolic flexibility between anaerobic glycolysis and oxidative phosphorylation. Preclinical data showed that metformin, an oxidative phosphorylation inhibitor, combined with fasting-induced hypoglycemia led to activation of the PP2A-GSK3ß-Mcl1 axis and inhibition of tumor growth. A window-of-opportunity trial was designed to evaluate the effect of metformin and nightly fasting on proliferation in invasive breast cancer (IBC) or DCIS. The primary endpoint is the pre/post treatment change of Ki67 in cancer tissue and the co-primary endpoint is the difference in post-treatment Ki67 in cancer adjacent DCIS or high-risk lesions. Participants with hormone receptor positive IBC or DCIS candidates to surgery are being accrued and randomized to either: 1) fasting for ≥ 16 hours nightly, plus nutritional counseling and daily metformin with Continuous Glucose Monitoring, or 2) Continuous Glucose Monitoring. The intervention lasts 4-6 weeks with gradual metformin ramp up to limit gastrointestinal disturbances. The safety of the combination was evaluated as a primary interim endpoint. The frequency of Dose Limiting Toxicity (≥G3 adverse events related to treatment) was assessed in the first 14 participants in the experimental arm. Most adverse events were low grade (G1: 50; 90.9%) and unrelated to the treatment (G1: 26 unrelated; 52%). No one discontinued treatment due to toxicity and no Dose Limiting Toxicities were observed, so the escalation phase of metformin was significantly shortened from 7 days to 3 days. The results of this project will expand knowledge of this prevention approach and possibly provide the basis for large-scale primary prevention studies in at-risk women.

Prophylactic treatment with selective estrogen receptor modulators (SERMs) and aroma-tase inhibitors (AIs) targeting the nuclear estrogen receptor (ER) can prevent the formation of ER-positive tumors in women at high risk for breast cancer but does not prevent ER-negative and triple-negative subtypes. In this study, we tested whether nuclear retinoid X receptor (RXR) ago-nists, IRX4204 and 9cUAB30, which have been evaluated in clinical trials, could prevent the de-velopment of ER-negative and triple-negative breast cancers (TNBCs). Our study demonstrates that IRX4204 significantly delays the formation of mammary tumors in three ER-negative mouse models: MMTV-ErbB2, C3(1)/SV40-TAg and Brca1-deficient with modest toxicities. In some of the MMTV-ErbB2 mice, IRX4204 completely prevented mammary tumor formation and 60% of the IRX4204 treated Brca1-deficient mice remained tumor free when all vehicle treated mice had formed tumors 9cUAB30 treatment also delays tumor formation in Brca1-deficient mice, albeit to a lesser extent. Biomarker analysis revealed that delayed tumors arising after IRX4204 treatment had decreased Ki-67 expression and increased infiltration of cytotoxic T-cells. Our pre-clinical study data support the further evaluation of use of RXR agonists for the prevention of TNBC.

The role of sex hormones in the sex difference between adiposity and cancer risk remains unclear. We examined body mass index (BMI) and visceral adipose tissue (VAT) estimated using a validated equation in relation to cancer incidence according to serum sex hormone-binding globulin (SHBG), testosterone, and estradiol among 451,500 UK Biobank participants. For cancers showing a sex-specific adiposity association, we used Cox regression to calculate multivariable HRs per increase between the 10th and 90th percentiles of adiposity according to low versus high sex hormone levels. We documented 42,949 cancers over a median follow-up of 13.1 years. BMI and VAT were more strongly associated with a higher risk of esophageal, liver, and colorectal cancers in males than in females. In males, BMI showed a stronger association with esophageal (HR for high vs. low SHBG = 2.38 vs. 1.62; Pinteraction = 0.04) and liver cancers (HR = 3.24 vs. 1.96; Pinteraction = 0.03) among those with high versus low SHBG, whereas an opposite pattern was observed for colorectal cancer (HR = 1.12 vs. 1.47; Pinteraction = 0.03). Among females, BMI was associated with a higher esophageal cancer risk in those with low (HR = 1.68) but not high SHBG (HR = 0.64; Pinteraction = 0.025); for liver cancer, results were similar but statistically nonsignificant. No interaction by estradiol or testosterone was detected. Similar results were observed for VAT. SHBG may be an important factor underlying the sex difference in adiposity-associated risk for colorectal, esophageal, and liver cancers.

Prevention relevance: Understanding the interactions between sex hormones and adiposity can help explain sex differences in cancer risk associated with body fat. Our findings suggest that SHBG may be a promising target for future research on strategies to reduce the risk of colorectal, esophageal, and liver cancers in individuals with excess adiposity.

Anal cytology and human papillomavirus (HPV) testing are the most common tools for anal cancer screening. We conducted an exploratory survey on the use of anal cytology in Italy. The Italian Society of Cytology (SICi) disseminated a questionnaire to its members and contacts on screened populations, departments collecting the samples, devices used, type of cytology (conventional or liquid based), professionals evaluating cytology, reporting system, use of anal cytology alone or in combination-test modality, diagnostic procedure for screen-positive individuals, and departments involved. Eighteen centers participated in the survey. In 15 centers (83.3%), anal cytology is performed on more than one at-risk population: men who have sex with men (MSM)/transgender women (TW) living with human immunodeficiency virus (LWH 13 centers, 72.2%), women with a history of gynecologic (pre)cancer (10 centers, 55.6%), women LWH (nine centers, 50.0%), men who have sex with women LWH, and MSM/TW not LWH (eight centers, 44.4%). Samples mostly come from infectious disease (nine, 50.0%) and sexually transmitted infection units (seven, 38.9%). A median of 140 samples (IQR, 30-500) are collected per year, with 13 centers (72.2%) using a cytobrush. Cytology is generally conventional (11 centers, 61.1%) and is mainly interpreted by histopathologists (66.7%) and biologists (55.6%). All centers use the Bethesda System for reporting cytology. Most of the centers use cytology in co-testing with HPV (10, 55.6%). Twelve centers (66.7%) perform high-resolution anoscopy, and the diagnostic procedure is frequently performed in general surgery (eight, 44.6%). Most of the centers employ anal cytology in people LWH and perform conventional cytology. Screening modality is variable, with more than half of the centers using cytology in co-testing with HPV. The use of high-resolution anoscopy is still suboptimal.

Prevention relevance: Screening for anal cancer prevention in Italy relies on heterogeneous and not fully satisfactory tools. Further efforts should be made to implement the optimal strategies in order to address the needs of the populations with the highest anal cancer risk.

Aberrant DNA methylation and copy number alterations (CNAs) drive Barrett's esophagus (BE) progression to esophageal adenocarcinoma (EAC); however, their combined utility for early detection is unclear. We aimed to identify and validate methylated DNA markers (MDMs) and CNAs to distinguish EAC/high-grade dysplasia (HGD) from non-dysplastic Barrett's esophagus (NDBE). In this multi-phase, multi-center study, we discovered and validated MDMs and quantified CNAs utilizing whole-genome methylation sequencing of esophageal brushings. DNA biomarkers identified from discovery were further validated in independent patients with paired esophageal brushing and swallowed capsule sponge samples. MDMs were filtered against a reduced representation bisulfite sequencing data set obtained from independent tissue samples to advance only concordant candidates. CNA burden was quantified using ichorCNA-derived aneuploidy scores (AS). Two hundred MDMs discovered in HGD (N=18) and EAC (N=18) versus NDBE brushing samples (N=18) were tested in independent samples (N=146). A 52-MDM panel achieved a cross-validated area under the receiver operating characteristic curve (AUC) 0.88 (95% CI: 0.82-0.95); the addition of AS improved discrimination of HGD/EAC from NDBE to 0.91 (95% CI: 0.86-0.97) AUC. At 80% specificity, the combined model detected 93% of EAC and 88% of HGD cases. In paired capsule sponge samples, a 58-MDM panel achieved a cross-validated AUC of 0.77 (95% CI: 0.66-0.88); a combined 58-MDM and AS model achieved AUC 0.80 (95% CI: 0.7-0.9). MDMs and AS discerned HGD/EAC from normal esophagus (NE)/NDBE in endoscopic brushing and capsule sponge samples. This approach may improve BE surveillance.