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

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 BOADICEA BC 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 aged 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 one year earlier). The CP approach has been implemented as a user-friendly web application.

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 to 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 (MHNW), metabolically unhealthy normal weight (MUNW), metabolically healthy overweight/obese (MHO), metabolically unhealthy overweight/obese (MUO)) was classified using four definitions of metabolic dysfunction: (1) Wildman criteria, (2) National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III), (3) HOMA-IR, and (4) 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 MUNW (HR 1.12, 95% CI: 0.90-1.39), MHO (HR 1.15, 95% CI: 1.00-1.32), and MUO (HR 1.35, 95% CI: 1.18-1.54) compared with MHNW using Wildman criteria. Results were similar using ATP 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 confidence intervals of each category overlapped.

Patients with Li-Fraumeni syndrome 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 respondents, 75% reported they do not skip surveillance tests, though this was not consistent when asked about specific tests, with only 65% and 40% up to date with colonoscopy and esophagogastroduodenoscopy, respectively. 100% of those diagnosed within the last 5 years said they never skip tests, whereas only 50% of those diagnosed over 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. 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. While 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.

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) altering 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 which 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.

Oxysterols are metabolites of cholesterol that regulate the homeostasis of cholesterol, fatty acids, and glucose. These metabolites are generated throughout the body, either enzymatically or from oxidative stress, and are detectable in peripheral circulation. We previously reported that circulating 27-hydroxycholesterol (27-OHC), an endogenous selective estrogen receptor modulator, may be a risk factor for colorectal adenomas. Here, in addition to 27-OHC, we report on four other circulating oxysterols: 25-hydroxycholesterol, 24(S)-hydroxycholesterol, 7ɑ-hydroxycholesterol, and 4β-hydroxycholesterol. Oxysterol concentrations were measured using liquid chromatography/mass spectrometry from fasting plasma collected at baseline from 1,246 participants of the Vitamin D/Calcium Polyp Prevention Study, a multicenter adenoma chemoprevention trial. To evaluate multiple oxysterols simultaneously, we used both log-linear regression and Bayesian kernel machine regression models developed for analyses of complex mixtures adjusted for potential confounding factors. Higher circulating 7ɑ-hydroxycholesterol was associated with higher adenoma risk (Bayesian kernel machine regression-based multivariable-adjusted risk ratios (RR; for the 75th vs. 25th percentile, 1.22; 95% credible interval, CI, 1.04-1.42). In contrast, higher circulating 4β-hydroxycholesterol was associated with lower risk of these polyps (RR, 0.84; 95% CI, 0.71-0.99). The positive association with advanced adenoma risk that we previously reported for circulating 27-OHC persisted when controlling for other oxysterols (RR, 1.26; 95% CI, 0.98-1.62), including among those with advanced adenomas at baseline (RR, 1.75; 95% CI, 1.01-3.06). Prevention Relevance: Circulating concentrations of multiple oxysterols measured at the time of an initial colorectal adenoma diagnosis may be risk factors for subsequent incidence of these lesions. Novel colorectal cancer prevention strategies may target oxysterol formation.

Vaginal dysbiosis is implicated in persistent human papillomavirus (HPV) infection and cervical cancer. Yet, there is a paucity of data on the vaginal microbiome in Native American communities. Here, we aimed to elucidate the relationships between microbiome, HPV, sociodemographic, and behavioral risk factors to better understand an increased cervical cancer risk in Native American women. In this pilot study, we recruited 31 participants (16 Native American and 15 non-Native women) in Northern Arizona and examined vaginal microbiota composition, HPV status, and immune mediators. We also assessed individuals' sociodemographic information and physical, mental, sexual, and reproductive health. Overall, microbiota profiles were dominated by common Lactobacillus species (associated with vaginal health) or a mixture of bacterial vaginosis-associated bacteria. Only 44% of Native women exhibited Lactobacillus dominance, compared with 58% of non-Native women. Women with vaginal dysbiosis also had elevated vaginal pH and were more frequently infected with high-risk HPV. Furthermore, we observed associations of multiple people in a household, lower level of education, and high parity with vaginal dysbiosis and abundance of specific bacterial species. Finally, women with dysbiotic microbiota presented with elevated vaginal levels of proinflammatory cytokines. Altogether, these findings indicate an interplay between HPV, vaginal microbiota, and host defense, which may play a role in the cervical cancer disparity among Native American women. Future longitudinal studies are needed to determine the mechanistic role of vaginal microbiota in HPV persistence in the context of social determinants of health toward the long-term goal of reducing health disparities between non-Hispanic White and Native American populations. Prevention Relevance: Cervical cancer disproportionally affects Native American women. Sociodemographic and behavioral factors might contribute to this disparity via alteration of vaginal microbiota. Here, we show the association between these factors and vaginal dysbiosis and immune activation, which can be implicated in high-risk HPV infection among Native American and other racial/ethnic populations.

In October 2023, Nigeria integrated the single-dose human papillomavirus (HPV) vaccine into its routine immunization program, aiming to protect 7.7 million girls aged 9 to 14 years. This milestone in the fight against HPV-related cancers, especially cervical cancer, faces significant challenges due to high vaccine rejection rates driven by misinformation and cultural barriers. Despite the vaccine's proven safety and efficacy, uptake remains low. This communication highlights the urgent need for a comprehensive public health education campaign to address these barriers. Proposed strategies include leveraging digital health technologies, integrating HPV education into school curricula, training community health workers, engaging religious and cultural leaders, and launching media campaigns featuring personal narratives. Implementing these evidence-based interventions is crucial for dispelling myths, misconceptions, and skepticism surrounding HPV vaccines. This will enhance acceptance and uptake, ultimately reducing cervical cancer mortality in Nigeria.

Currently, eight million people in the United States suffer from cancer and it is a major global health concern. Early detection and interventions are urgently needed for all cancers, including colorectal cancer. Colorectal cancer is the third most common type of cancer worldwide. Based on the diagnostic efforts to general awareness and lifestyle choices, it is understandable why colorectal cancer is so prevalent today. There is a notable lack of awareness concerning the impact of this cancer and its connection to lifestyle elements, as well as people sometimes mistaking symptoms for a different gastrointestinal condition. Artificial intelligence (AI) may assist in the early detection of all cancers, including colorectal cancer. The usage of AI has exponentially grown in healthcare through extensive research, and since clinical implementation, it has succeeded in improving patient lifestyles, modernizing diagnostic processes, and innovating current treatment strategies. Numerous challenges arise for patients with colorectal cancer and oncologists alike during treatment. For initial screening phases, conventional methods often result in misdiagnosis. Moreover, after detection, determining the course of which colorectal cancer can sometimes contribute to treatment delays. This article touches on recent advancements in AI and its clinical application while shedding light on why this disease is so common today.

Metformin administration has recently emerged as a candidate strategy for the prevention of head and neck squamous cell carcinoma (HNSCC). However, the intricate relationship between genetic alterations in HNSCC and metformin sensitivity is still poorly understood, which prevents the stratifications of patients harboring oral premalignant lesions that may benefit from the chemopreventive activity of metformin. In this study, we investigate the impact of prevalent mutations in HNSCC in response to metformin. Notably, we found that the expression of oncogenic HRAS mutants confers resistance to metformin in isogenic HNSCC cell systems and that HNSCC cells harboring endogenous HRAS mutations display limited sensitivity to metformin. Remarkably, we found that metformin fails to reduce activation of the mTOR pathway in HRAS oncogene expressing HNSCC cells in vitro and in vivo, correlating with reduced tumor suppressive activity. Mechanistically, we found that this process depends on the ability of HRAS to enhance glycolytic metabolism, thereby suppressing the requirement of oxidative phosphorylation to maintain the cellular energetic balance. Overall, our study revealed that HNSCC cells with oncogenic HRAS mutations exhibit diminished metformin sensitivity, thus shedding light on a potential mechanism of treatment resistance. This finding may also help explain the limited clinical responses to metformin in cancers with RAS mutations. Ultimately, our study underscores the importance of understanding the impact of the genetic landscape in tailoring precision cancer preventive approaches in the context of HNSCC and other cancers that are characterized by the presence of a defined premalignant state and, therefore, amenable for cancer interception strategies.