Colorectal cancer prevention Hawk, Ernest T; Levin, Bernard
Journal of clinical oncology,
01/2005, Letnik:
23, Številka:
2
Journal Article
Recenzirano
Colorectal cancer is the second leading cause of mortality in the United States. In the United States, the cumulative lifetime risk of developing colorectal cancer for both men and women is 6%. ...Despite advances in the management of this disease, the 5-year survival rate in the United States in only 62%. Because only 38% of patients are diagnosed when the cancers are localized to the bowel wall, it is likely that widespread implementation of screening could significantly improve the outcome. Colorectal cancer screening is cost effective, irrespective of the methods used. In addition to currently available methods (fecal occult blood, flexible sigmoidoscopy, colonoscopy, and double contrast barium enema), computed tomographic colonography (virtual colonoscopy) and stool-based molecular screening are under development. Four classes of chemopreventive compounds have demonstrated efficacy in reducing recurrent colorectal adenomas and/or cancer in randomized, controlled trials. They are selenium, calcium carbonate, hormone replacement therapy, and nonsteroidal anti-inflammatory drugs. The mechanisms of action of nonsteroidal anti-inflammatory drugs include inhibition of the cyclooxygenase system as well as cyclooxygenase-independent effects. Considerable effort is being expended to define chemopreventive activity, optimal dose, administration schedule, and toxicity for the coxibs in adenoma recurrence prevention trials. The threshold for tolerating toxicities is very low in asymptomatic individuals at minimally increased risk for colorectal neoplasia.
Coxibs, including celecoxib, and other nonsteroidal anti-inflammatory drugs (NSAID), including aspirin, are among the most promising cancer chemopreventive agents in development today. This article ...examines the data on the efficacy of these agents in animal model studies of cancer prevention carried out by the authors. The studies evaluated here are restricted to our rodent models of colon/intestinal, bladder, and nonmelanoma skin cancer, in which celecoxib and other NSAIDs were administered as either cancer preventive or therapeutic agents. These studies may shed light on several questions. Is celecoxib unique compared with other NSAIDs, and if so, what implications would this have for human use? Are standard NSAIDs (which inhibit both COX-1 and COX-2) as effective as celecoxib in animal studies? Is the efficacy of celecoxib in particular or NSAIDs in general due to their off-target effects or to their effects on COX-1 and COX-2? What is the likely efficacy of low-dose aspirin? Some questions raised by human trials and epidemiology are discussed and related to our observations in animal model studies. We also discuss the problem of cardiovascular (CV) events associated with coxibs and certain other NSAIDs and whether results in animal models are predictive of efficacy in humans. On the basis of epidemiologic studies and its CV profile, aspirin seems to be the most promising NSAID for preventing human colorectal, bladder, and skin cancer, although the animal data for aspirin are less clear. A comprehensive understanding of the results of coxibs and other NSAIDs in animal studies may help inform and shape human trials of these commonly employed, relatively inexpensive, and highly effective compounds.
Physical activity (PA) is a known behavior to reduce cancer risk and improve cancer survivorship, yet adherence to PA guidelines is poor among the general population and cancer survivors. The purpose ...of this study was to determine the extent to which patients referred for exercise consultation within a clinical cancer prevention setting were meeting aerobic and resistance physical activity (PA) guidelines and to identify factors associated with guideline adherence. Between 2013 and 2015, cancer prevention patients and cancer survivors were interviewed by an exercise physiologist within an Integrative Health Program at The University of Texas MD Anderson Cancer Prevention Center. PA adherence was defined as at least 150-minutes of moderate-intensity or 75-minutes of vigorous-intensity PA per week, along with resistance training at least 2 days per week. Logistic regression was used to determine factors associated with meeting or not meeting PA guidelines for aerobic exercise, resistance exercise, and aerobic and resistance exercise combined. Among 1,024 cancer prevention patients and survivors, 9% of patients adhered to guideline-based PA. Adherence to aerobic and resistance guidelines were 20% and 12%, respectively. Overweight or obesity was associated with not meeting guideline-based PA in both cancer prevention patients and cancer survivors. Among breast cancer survivors, combination treatment with surgery, radiation, and chemotherapy ('multimodal therapy') was robustly associated with not meeting aerobic guidelines (OR 2.20, 95% CI: 1.17 to 4.16). BMI and breast cancer treatment history are key determinants of PA behavior among cancer prevention patients and survivors. Poor adherence to PA guidelines is a key issue for cancer prevention patients and survivors, particularly obese patients and women who receive multimodal therapy for breast cancer. Identifying and connecting patients at highest risk of poor PA adherence with exercise programs is needed to improve PA, a key modifiable cancer risk factor.
Background and Aims
Hispanics are disproportionately affected by NAFLD, liver fibrosis, cirrhosis, and HCC. Preventive strategies and noninvasive means to identify those in this population at high ...risk for liver fibrosis, are urgently needed. We aimed to characterize the gut microbiome signatures and related biological functions associated with liver fibrosis in Hispanics and identify environmental and genetic factors affecting them.
Approach and Results
Subjects of the population‐based Cameron County Hispanic Cohort (CCHC; n = 217) were screened by vibration‐controlled transient elastography (FibroScan). Among them, 144 (66.7%) had steatosis and 28 (13.0%) had liver fibrosis. The gut microbiome of subjects with liver fibrosis was enriched with immunogenic commensals (e.g., Prevotella copri, Holdemanella, Clostridiaceae 1) and depleted of Bacteroides caccae, Parabacteroides distasonis, Enterobacter, and Marinifilaceae. The liver fibrosis‐associated metagenome was characterized by changes in the urea cycle, L‐citrulline biosynthesis and creatinine degradation pathways, and altered synthesis of B vitamins and lipoic acid. These metagenomic changes strongly correlated with the depletion of Parabacteroides distasonis and enrichment of Prevotella and Holdemanella. Liver fibrosis was also associated with depletion of bacterial pathways related to L‐fucose biosynthesis. Alcohol consumption, even moderate, was associated with high Prevotella abundance. The single‐nucleotide polymorphisms rs3769502 and rs7573751 in the NCK adaptor protein 2 (NCK2) gene positively associated with high Prevotella abundance.
Conclusion
Hispanics with liver fibrosis display microbiome profiles and associated functional changes that may promote oxidative stress and a proinflammatory environment. These microbiome signatures, together with NCK2 polymorphisms, may have utility in risk modeling and disease prevention in this high‐risk population.
The human papillomavirus (HPV) vaccine was indicated for the prevention of vulvovaginal cancers in 2008, but its impact on the incidence of vulvar cancers within the US is unknown. To determine this, ...we conducted a secondary analysis of 88,942 vulvar cancer cases among women 20+ years old using the US Cancer Statistics 2001-2018 databases. Data were stratified by tumor behavior (in situ or invasive), age (20-44, 45-64, 65+ years old), race/ethnicity (non-Hispanic White, non-Hispanic Black, Hispanic), and US census region (Northeast, South, Midwest, West), and incidence rates and average annual percentage changes (AAPC) were calculated by group. Reversing previous trends, the incidence of vulvar carcinoma in situ significantly decreased between 2001 and 2018 among women from all age groups, races/ethnicities, and regions (combined AAPC, -4.3; 95% confidence interval (CI), -4.7 to -3.8). The incidence of invasive vulvar squamous cell carcinoma decreased significantly among 20- to 44-year-old women (AAPC, -0.8; 95% CI, -1.3 to -0.3), but significantly increased among those 45 to 64 (AAPC, 2.3; 95% CI, 1.8-2.8) and 65+ years old (AAPC, 1.2; 95% CI, 1.1-1.4). Regardless of tumor behavior, incidence was highest among non-Hispanic Whites and the Midwest region. Overall, the significant declines in vulvar carcinoma in situ among all ages, as well as invasive vulvar cancer among younger women, are encouraging and complement other recent data suggesting HPV vaccinations are already reducing anal and cervical cancer incidence. Over time, further declines in vulvar carcinoma incidence are likely as uptake and completion rates of the HPV vaccine increase in the US.
We found evidence that HPV vaccinations likely contributed to a decrease in the incidences of vulvar carcinoma in situ and invasive vulvar carcinoma among 20- to 44-year-old women between 2001 and 2018. Our data add to the growing evidence that HPV vaccinations are reducing the incidence of HPV-related anogenital cancers.
There are few studies which characterised the molecular alterations in premalignant colorectal adenomas. Our major goal was to establish colorectal adenoma genome atlas and identify molecular markers ...of progression from colorectal adenoma to adenocarcinoma.
Whole-exome sequencing and targeted sequencing were carried out in 149 adenoma samples and paired blood from patients with conventional adenoma or sessile serrated adenoma to characterise the somatic mutation landscape for premalignant colorectal lesions. The identified somatic mutations were compared with those in colorectal cancer (CRC) samples from The Cancer Genome Atlas. A supervised random forest model was employed to identify gene panels differentiating adenoma from CRC.
Similar somatic mutation frequencies, but distinctive driver mutations, were observed in sessile serrated adenomas and conventional adenomas. The final model included 20 genes and was able to separate the somatic mutation profile of colorectal adenoma and adenocarcinoma with an area under the curve of 0.941.
The findings of this project hold potential to better identify patients with adenoma who may be candidates for targeted surveillance programmes and preventive interventions to reduce the incidence of CRC.
To evaluate the effects of single-nucleotide polymorphisms (SNP) in microRNA-related genes on clinical outcomes in patients with colorectal cancer (CRC) receiving first-line fluoropyrimidine-based ...chemotherapy.
Forty-one SNPs in 26 microRNA-related genes were genotyped in 1,097 patients with CRC recruited at the University of Texas MD Anderson Cancer Center (Houston, TX). Patients were enrolled between 1990 and 2008 and last follow-up was in 2010. The associations between genotypes and recurrence-free survival (RFS), progression-free survival (PFS), and overall survival (OS) stratified by clinical stage were analyzed in 741 newly diagnosed patients (diagnosed within 1 year) and replicated the findings in an additional 356 patients.
In patients with stage III disease, mir608: rs4919510 was associated with increased risk for both recurrence HR, 2.72; 95% confidence interval (CI), 1.38-5.33 and death (HR, 3.53; 95%CI, 1.42-8.73). The associations were confirmed in the replication set, and the combined HRs for training and replication sets were 1.65 (95% CI, 1.13-2.41) for recurrence and 1.96 (95% CI, 1.19-3.21) for death, respectively. The mir219-1:rs213210 showed consistent association with death in the training set (HR, 3.86; 95% CI, 1.33-11.22), the replication set (HR, 3.33; 95% CI, 1.39-7.98), and combined data set (HR, 3.22; 95% CI, 1.70-6.10). In combined analysis of these two SNPs, patients carrying the variant genotypes at both sites exhibited a 5.6-fold increased risk of death.
Genetic polymorphisms in the microRNA pathway may predict prognosis in patients with stage III CRC treated with fluoropyrimidine-based chemotherapy.
Lynch syndrome (LS) is a hereditary condition with a high lifetime risk of colorectal and endometrial cancers. Exercise is a non-pharmacologic intervention to reduce cancer risk, though its impact on ...patients with LS has not been prospectively studied. Here, we evaluated the impact of a 12-month aerobic exercise cycling intervention in the biology of the immune system in LS carriers.
To address this, we enrolled 21 patients with LS onto a non-randomized, sequential intervention assignation, clinical trial to assess the effect of a 12-month exercise program that included cycling classes 3 times weekly for 45 minutes versus usual care with a one-time exercise counseling session as control. We analyzed the effects of exercise on cardiorespiratory fitness, circulating, and colorectal-tissue biomarkers using metabolomics, gene expression by bulk mRNA sequencing, and spatial transcriptomics by NanoString GeoMx.
We observed a significant increase in oxygen consumption (VO2peak) as a primary outcome of the exercise and a decrease in inflammatory markers (prostaglandin E) in colon and blood as the secondary outcomes in the exercise versus usual care group. Gene expression profiling and spatial transcriptomics on available colon biopsies revealed an increase in the colonic mucosa levels of natural killer and CD8+ T cells in the exercise group that were further confirmed by IHC studies.
Together these data have important implications for cancer interception in LS, and document for the first-time biological effects of exercise in the immune system of a target organ in patients at-risk for cancer.
Hispanics in South Texas have high rates of hepatocellular carcinoma (HCC) and nonalcoholic fatty liver disease (NAFLD). Liver fibrosis severity is the strongest predictive factor of NAFLD ...progression to HCC. We examined the association between free fatty acids (FA) and advanced liver fibrosis or HCC in this population.
We quantified 45 FAs in plasma of 116 subjects of the Cameron County Hispanic Cohort, 15 Hispanics with HCC, and 56 first/second-degree relatives of Hispanics with HCC. Liver fibrosis was assessed by FibroScan.
Advanced liver fibrosis was significantly associated with low expression of very long chain (VLC) saturated FAs (SFA), odd chain SFAs, and VLC n-3 polyunsaturated FAs PUFA; AOR; 95% confidence interval (CI), 10.4 (3.7-29.6);
< 0.001; 5.7 (2.2-15.2);
< 0.001; and 3.7 (1.5-9.3);
= 0.005. VLC n3-PUFAs significantly improved the performance of the noninvasive markers for advanced fibrosis - APRI, FIB-4, and NFS. Plasma concentrations of VLC SFAs and VLC n-3 PUFAs were further reduced in patients with HCC. Low concentrations of these FAs were also observed in relatives of patients with HCC and in subjects with the
rs738409 homozygous genotype.
Low plasma concentrations of VLC n-3 PUFAs and VLC SFAs were strongly associated with advanced liver fibrosis and HCC in this population. Genetic factors were associated with low concentrations of these FAs as well.
These results have implications in identifying those at risk for liver fibrosis progression to HCC and in screening this population for advanced fibrosis. They also prompt the evaluation of VLC n-3 PUFA or VLC SFA supplementation to prevent cirrhosis and HCC.
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