Search

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. Prevention Relevance: 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.

Minimally invasive molecular biomarkers have been applied to the early detection of multiple cancers in large scale case-control and cohort studies. These demonstrations of feasibility herald the potential for permanent transformation of current cancer screening paradigms. This commentary discusses the major opportunities and challenges facing the preclinical development and clinical validation of multicancer early detection test strategies. From a diverse set of early detection research perspectives, the authors recommend specific approaches and highlight important questions for future investigation.

Colorectal cancer is the second most common cancer in Brazil. Yet, a nationally organized colorectal screening program is not implemented. Barretos Cancer Hospital (BCH) is one of the largest Brazilian institution that cares for underserved patients. BCH developed a fecal immunochemical test (FIT)-based organized colorectal cancer screening program to improve colorectal cancer outcomes. This study aims to present the quality/performance measures of the first 2 years of the FIT-based colorectal cancer screening program and its impact on the colorectal cancer disease stage. Between 2015 and 2017, a total of 6,737 individuals attending the Outpatient Department of Prevention or the Mobile Unit of BCH, which visits 18 cities of Barretos county, ages 50 to 65 years, were personally invited by a health agent/nurse practitioner. Exclusion criteria were personal history of colorectal cancer, adenomatous polyps, inflammatory bowel disease, and colonoscopy, or flexible sigmoidoscopy performed in the past 5 years. European Union (EU) guidelines for colorectal cancer screening programs were evaluated. Overall, 92.8% returned the FIT, with an inadequate examination rate of 1.5%. Among the 6,253 adequately tested, 12.5% had a positive result. The colonoscopy compliance and completion rates were 84.6 and 98.2%, respectively. The PPVs were 60.0%, 16.5%, and 5.6% for adenoma, advanced adenoma, and cancer, respectively. Stage distribution of screen-detected cancers shows earlier stages than clinically diagnosed colorectal cancer cancers reported at BCH and Brazilian cancer registries. Our colorectal cancer screening program achieved desirable quality metrics, aligned with the EU guidelines. The observed shift toward earlier colorectal cancer stages suggests an exciting opportunity to improve colorectal cancer–related cancers in Brazil.

The 2010 report of the President's Cancer Panel concluded that the burden of cancer from chemical exposures is substantial, while the programs for testing and regulation of carcinogens remain inadequate. New research on the role of early life exposures and the ability of chemicals to act via multiple biological pathways, including immunosuppression, inflammation, and endocrine disruption as well as mutagenesis, further supports the potential for chemicals and chemical mixtures to influence disease. Epidemiologic observations, such as higher leukemia incidence in children living near roadways and industrial sources of air pollution, and new in vitro technologies that decode carcinogenesis at the molecular level, illustrate the diverse evidence that primary prevention of some cancers may be achieved by reducing harmful chemical exposures. The path forward requires cross-disciplinary approaches, increased environmental research investment, system-wide collaboration to develop safer economic alternatives, and community engagement to support evidence-informed action. Engagement by cancer researchers to integrate environmental risk factors into prevention initiatives holds tremendous promise for reducing the rates of disease. See all articles in this CEBP Focus section, “Environmental Carcinogenesis: Pathways to Prevention.”

Background: Regular physical activity (PA) is associated with a lower risk of several types of cancers. However, two-thirds of overweight/obese adults are not sufficiently active; this, in combination with the unfavorable effect of excess body weight, puts them at a greater risk for cancer. One reason that these individuals do not engage in enough PA may be their lack of motivation to change their current behavior due to the perception of putting in effort for possible future gain without obvious short-term benefits. There is a need for innovative ways to help individuals recognize the immediate health benefits of PA and thus increase their motivation. Methods: This pilot intervention tested a PA education module that included a one-on-one counseling session highlighting the acute effects of PA on glucose patterns, followed by a 10-day self-monitoring period with a continuous glucose monitor (CGM) and a Fitbit tracker. Participants rated the acceptability of the education module on a 5-point Likert scale and completed surveys assessing stages of change for motivational readiness. Results: Nineteen overweight/obese adults (84% female) completed the study. Participants gave high ratings to the counseling session for improving their PA-related knowledge (mean = 4.22), increasing motivation (mean = 4.29), and providing personally relevant information (mean = 4.35). The summary acceptability scores for the self-monitoring period were 4.46 for CGM and 4.51 for Fitbit. Participants reported a significant decrease in the precontemplation stage and an increase in the action stage (P < 0.05). Conclusions: CGM is a feasible tool for PA interventions. Impact: Information from CGM could be used as biological-based feedback to motivate PA. See all articles in this CEBP Focus section, “Modernizing Population Science.”

Background and aims Hispanics are disproportionately affected by non-alcoholic fatty liver disease, liver fibrosis, cirrhosis, and hepatocellular carcinoma. Preventive strategies and non-invasive 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 (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 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 pro-inflammatory environment. These microbiome signatures, together with NCK2 polymorphisms, may have utility in risk modeling and disease prevention in this high-risk population.

E-cigarettes have the ability to deliver nicotine in a manner that is similar to, and, theoretically, safer than, combusted tobacco. However, these devices are extremely heterogeneous and regulation has struggled to keep up with their rapid evolution. A compilation of early data suggest that e-cigarettes may contain numerous toxic substances, including known carcinogens. However, there are few data available on the short- and long-term health effects of e-cigarettes, including any potential effect on cancer risk. Until more is known, e-cigarettes should not be considered a safe alternative to combusted tobacco use.

Background Genomic investigation of atypical adenomatous hyperplasia (AAH), the only known precursor lesion to lung adenocarcinomas (LUAD), presents challenges due to the low mutant cell fractions. This necessitates sensitive methods for detection of chromosomal aberrations to better study the role of critical alterations in early lung cancer pathogenesis and the progression from AAH to LUAD. Methods We applied a sensitive haplotype-based statistical technique to detect chromosomal alterations leading to allelic imbalance (AI) from genotype array profiling of 48 matched normal lung parenchyma, AAH and tumor tissues from 16 stage-I LUAD patients. To gain insights into shared developmental trajectories among tissues, we performed phylogenetic analyses and integrated our results with point mutation data, highlighting significantly-mutated driver genes in LUAD pathogenesis. Findings AI was detected in nine AAHs (56%). Six cases exhibited recurrent loss of 17p. AI and the enrichment of 17p events were predominantly identified in patients with smoking history. Among the nine AAH tissues with detected AI, seven exhibited evidence for shared chromosomal aberrations with matched LUAD specimens, including losses harboring tumor suppressors on 17p, 8p, 9p, 9q, 19p, and gains encompassing oncogenes on 8q, 12p and 1q. Interpretation Chromosomal aberrations, particularly 17p loss, appear to play critical roles early in AAH pathogenesis. Genomic instability in AAH, as well as truncal chromosomal aberrations shared with LUAD, provide evidence for mutation accumulation and are suggestive of a cancerized field contributing to the clonal selection and expansion of these premalignant lesions. Fund Supported in part by Cancer Prevention and Research Institute of Texas (CPRIT) grant RP150079 (PS and HK), NIH grant R01HG005859 (PS) and The University of Texas MD Anderson Cancer Center Core Support Grant.

Purpose Increasingly, cancer centers are delivering population-based approaches to narrow the gap between known cancer prevention strategies and their effective implementation. Leveraging successful healthy community initiatives, MD Anderson developed Be Well Communities™, a model that implements evidence-based actions to directly impact people’s lives. Methods In partnership with local organizations, MD Anderson’s Be Well Communities team executed and evaluated 16 evidence-based interventions to address community priorities in healthy diets, physical activity, and sun safety. Evaluation included assessing the effectiveness of evidence-based interventions, stakeholders’ perceptions of collaboration, and the population-level impact on dietary and physical activity behaviors among students using the School Physical Activity and Nutrition Survey and the System for Observing Fitness Instruction Time. Two-tailed t-tests were used to compare tested parameters at baseline and follow-up. p values less than .05 were considered significant. Results This model achieved its early outcomes, including effectively implementing evidence-based interventions, building strong partnerships, increasing access to healthy foods, improving the built environment, and increasing healthy food and water consumption and moderate to vigorous physical activity among students (p Conclusions Be Well Communities is an effective model for positively impacting community health which could be leveraged by others to deliver evidence-based actions to improve population health.

Background: 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. Methods: 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. Results: 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); P < 0.001; 5.7 (2.2–15.2); P < 0.001; and 3.7 (1.5–9.3); P = 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 PNPLA3 rs738409 homozygous genotype. Conclusions: 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. Impact: 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.

ObjectiveCancer care providers’ (CCPs) attitudes towards smoking cessation are influenced by many factors, including their smoking status and knowledge. Our objective was to assess CCPs’ characteristics, tobacco use and smoking cessation practices in two Latin American cancer centres.DesignCross-sectional survey.SettingsTwo urban cancer centres located in Colombia and Mexico.ParticipantsA total of 238 CCPs.MeasuresOnline survey consisted of 28 close-ended questions adapted from the 2012 International Association for the Study of Lung Cancer survey and the Global Adult Tobacco Survey developed by the WHO. Means, frequencies and proportions were reported for each country. Factors associated to providing of smoking cessation treatment or referral at initial visit were evaluated using logistic regression.ResultsCurrent smoking prevalence was 10.5% and 12.3% among Colombian and Mexican CCPs, respectively. Around three quarters of the Colombian (86.4%) and Mexican CCPs (66.1%) considered to have inadequate training in smoking cessation. Approximately two-thirds of Colombian (67.5%) and Mexican CCPs (63.9%) reported always or most of the time asking patients about tobacco use during the initial visit. In Colombia and Mexico, the most relevant barriers for providing cessation services were (1) difficulties for motivating patients with cancer, (2) patient resistance in quitting smoking, (3) lack of local resources or referral centres for smoking cessation and (4) lack of training in smoking cessation. CCPs appointed at Instituto Nacional de Cancerología were less likely to provide cessation treatment or referral to their patients if they had less than 50% of their time devoted to patient care and were former or current smokers. The regression model for Instituto de Cancerología did not retain statistically significant variables.ConclusionOur findings highlight an urgent need for assisting Latin American CCPs in their quitting efforts as well as expanding formal smoking cessation training specifically tailored to these professionals for improving patients’ cancer prognosis and quality of life.

Background Non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin and sulindac are effective for colorectal cancer prevention in humans and some animal models, but concerns over gastro-intestinal (GI) ulceration and bleeding limit their potential for chemopreventive use in broader populations. Recently, the combination of aspirin with a phospholipid, packaged as PL-ASA, was shown to reduce GI toxicity in a small clinical trial. However, these studies were done for relatively short periods of time. Since prolonged, regular use is needed for chemopreventive benefit, it is important to know whether GI safety is maintained over longer use periods and whether cancer prevention efficacy is preserved when an NSAID is combined with a phospholipid. Methods As a first step to answering these questions, we treated seven to eight-week-old, male and female C57B/6 Apcmin/+ mice with the NSAID sulindac, with and without phosphatidylcholine (PC) for 3-weeks. At the end of the treatment period, we evaluated polyp burden, gastric toxicity, urinary prostaglandins (as a marker of sulindac target engagement), and blood chemistries. Results Both sulindac and sulindac-PC treatments resulted in significantly reduced polyp burden, and decreased urinary prostaglandins, but sulindac-PC treatment also resulted in the reduction of gastric lesions compared to sulindac alone. Conclusions Together these data provide pre-clinical support for combining NSAIDs with a phospholipid, such as phosphatidylcholine to reduce GI toxicity while maintaining chemopreventive efficacy.

BACKGROUND. Optimal hepatitis C virus (HCV) screening strategies for cancer patients have not been established. We compared the performance of selective HCV screening strategies. METHODS. We surveyed patients presenting for first systemic anticancer therapy during 2013–2014 for HCV risk factors. We estimated the prevalence of positivity for HCV antibody (anti-HCV) and examined factors associated with anti-HCV status using Fisher’s exact test or Student’s t-test. Sensitivity was calculated for screening patients born during 1945–1965, patients with ≥1 other risk factor, or both cohorts (“combined screening”). RESULTS. We enrolled 2,122 participants. Median age was 59 years (range, 18–91); 1,138 participants were women. Race/ethnicity distribution was white non-Hispanic, 76% (n=1616); Hispanic, 11% (n=233); black non-Hispanic, 8% (n=160); Asian, 4% (n=78); other, 2% (n=35). Primary cancer distribution was non-liver solid tumor, 78% (n=1,664); hematologic cancer, 20% (n=422); liver cancer, 1% (n=28). Prevalence of anti-HCV was 1.93% (95% CI, 1.39%–2.61%). Over 28% of patients with detectable HCV RNA were unaware of infection. Factors significantly associated with anti-HCV positivity included less than a bachelor’s degree, birth in 1945–1965, chronic liver disease, injection drug use, and blood transfusion or organ transplant before 1992. A total of 1,315 participants (62%), including 39 of 41 with anti-HCV, reported ≥1 risk factor. Sensitivity was 80% (95% CI, 65–91%) for birth-cohort-based, 68% (95% CI, 52–82%) for other-risk-factor-based, and 95% (95% 83–99%) for combined screening. CONCLUSION. Combined screening still missed 5% of patients with anti-HCV. These findings favor universal HCV screening to identify all HCV-infected cancer patients.

Background Gene expression-based profiling of colorectal cancer (CRC) can be used to identify four molecularly homogeneous consensus molecular subtype (CMS) groups with unique biologic features. However, its applicability to colorectal premalignant lesions remains unknown. Patients and methods We assembled the largest transcriptomic premalignancy dataset by integrating different public and proprietary cohorts of adenomatous and serrated polyps from sporadic (N = 311) and hereditary (N = 78) patient populations and carried out a comprehensive analysis of carcinogenesis pathways using the CMS random forest (RF) classifier. Results Overall, transcriptomic subtyping of sporadic and hereditary polyps revealed CMS2 and CMS1 subgroups as the predominant molecular subtypes in premalignancy. Pathway enrichment analysis showed that adenomatous polyps from sporadic or hereditary cases (including Lynch syndrome) displayed a CMS2-like phenotype with WNT and MYC activation, whereas hyperplastic and serrated polyps with CMS1-like phenotype harbored prominent immune activation. Rare adenomas with CMS4-like phenotype showed significant enrichment for stromal signatures along with transforming growth factor-β activation. There was a strong association of CMS1-like polyps with serrated pathology, right-sided anatomic location and BRAF mutations. Conclusions Based on our observations made in premalignancy, we propose a model of pathway activation associated with CMS classification in colorectal carcinogenesis. Specifically, while adenomatous polyps are largely CMS2, most hyperplastic and serrated polyps are CMS1 and may transition into other CMS groups during evolution into carcinomas. Our findings shed light on the transcriptional landscape of premalignant colonic polyps and may help guide the development of future biomarkers or preventive treatments for CRC.

According to the Pan American Health Organization, noncommunicable diseases, including cancer, are the leading causes of preventable and premature death in the Americas. Governments and health care systems in Latin America face numerous challenges as a result of increasing morbidity and mortality from cancer. Multiple international organizations have recognized the need for collaborative action on and technical support for cancer research and control in Latin America. The Center for Global Health at the US National Cancer Institute (NCI-CGH) is one entity among many that are working in the region and has sought to develop a strategy for working in Latin America that draws on and expands the collaborative potential of engaged, skilled, and diverse partners. NCI-CGH has worked toward developing and implementing initiatives in collaboration with global partners that share the common objectives of building a global cancer research community and translating research results into evidence-informed policy and practice. Both objectives are complementary and synergistic and are additionally supported by an overarching strategic framework that is focused on partnerships and science diplomacy. This work highlights the overall strategy for NCI-CGH engagement in Latin America through partnerships and diplomacy, and highlights selected collaborative efforts that are aimed at improving cancer outcomes in the region.

ObjectiveThere 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.DesignWhole-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.ResultsSimilar 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.ConclusionThe 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.

Background Use of e-cigarettes for tobacco cessation efforts is a growing trend in the United States. However, little is known about the factors that determine the use of e-cigarettes for this specific purpose. Methods This study examined current and former cigarette smokers that reported ever using e-cigarettes. Data were obtained from a 2018 Texas population health assessment survey (n = 569) and weighted to be representative to Texas. A multivariable logistic regression was used to assess the socio-demographic and behavioral correlates of using e-cigarettes for tobacco cessation. Results Overall, 41.3% of e-cigarette users reported using them for tobacco cessation. Among ever e-cigarette users, Non-Hispanic blacks (aOR: 0.21; 95% CI, 0.07–0.64), males (aOR: 0.40; 95% CI, 0.20–0.80), and individuals not confident in obtaining health information (aOR: 0.38; 95% CI, 0.15–0.96) were less likely to use e-cigarettes for tobacco use cessation. Conversely, among ever e-cigarette users, odds of using e-cigarettes for tobacco cessation were higher among those who were 35–44 years old (aOR: 3.68, 95% CI: 1.26–10.71), those who received advice to quit smoking from a healthcare professional (aOR: 2.77, 95% CI, 1.36–5.64), and those with more than 5 years since their last routine checkup (aOR: 3.91; 95% CI, 1.23–12.45). Conclusion Findings from this study suggest that both health behaviors and sociodemographic factors predict use of e-cigarettes for the purpose of tobacco cessation. Furthermore, the relationship between use of e-cigarettes as a cessation device and being advised to quit tobacco use by a healthcare professional calls for additional investigation.

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/aims:Trust is the cornerstone of clinical trial recruitment and retention. Efforts to decrease barriers and increase clinical trial participation among diverse populations have yielded modest results. There is an urgent need to better understand the complex interactions between trust and clinical trial participation. The process of trust-building has been a focus of intense research in the business community. Yet, little has been published about trust in oncology clinical trials or the process of building trust in clinical trials. Both clinical trials and business share common dimensions. Business strategies for building trust may be transferable to the clinical trial setting. This study was conducted to understand and utilize contemporary thinking about building trust to develop an Integrated Model of Trust that incorporates both clinical and business perspectives.Methods:A key word–directed literature search of the PubMed, Medline, Cochrane, and Google Search databases for entries dated between 1 January 1985 and 1 September 2015 was conducted to obtain information from which to develop an Integrated Model of Trust.Results:Successful trial participation requires both participants and clinical trial team members to build distinctly different types of interpersonal trust to effect recruitment and retention. They are built under conditions of significant emotional stress and time constraints among people who do not know each other and have never worked together before. Swift Trust and Traditional Trust are sequentially built during the clinical trial process. Swift trust operates during the recruitment and very early active treatment phases of the clinical trial process. Traditional trust is built over time and operates during the active treatment and surveillance stages of clinical trials. The Psychological Contract frames the participants’ and clinical trial team members’ interpersonal trust relationship. The “terms” of interpersonal trust are negotiated through the psychological contract. Contract renegotiation occurs in response to cyclical changes within the trust relationship throughout trial participation.Conclusion:The Integrated Model of Trust offers a novel framework to interrogate the process by which diverse populations and clinical trial teams build trust. To our knowledge, this is the first model of trust-building in clinical trials that frames trust development through integrated clinical and business perspectives. By focusing on the process, rather than outcomes of trust-building diverse trial participants, clinical trials teams, participants, and cancer centers may be able to better understand, measure, and manage their trust relationships in real time. Ultimately, this may foster increased recruitment and retention of diverse populations to clinical trials.

The recent pace, extent, and impact of paradigm-changing cancer prevention science has been remarkable. The American Association for Cancer Research (AACR) convened a 3-day summit, aligned with five research priorities: (i) Precancer Atlas (PCA). (ii) Cancer interception. (iii) Obesity-cancer linkage, a global epidemic of chronic low-grade inflammation. (iv) Implementation science. (v) Cancer disparities. Aligned with these priorities, AACR co-led the Lancet Commission to formally endorse and accelerate the NCI Cancer Moonshot program, facilitating new global collaborative efforts in cancer control. The expanding scope of creative impact is perhaps most startling—from NCI-funded built environments to AACR Team Science Awarded studies of Asian cancer genomes informing global primary prevention policies; cell-free epigenetic marks identifying incipient neoplastic site; practice-changing genomic subclasses in myeloproliferative neoplasia (including germline variant tightly linked to JAK2 V617F haplotype); universal germline genetic testing for pancreatic cancer; and repurposing drugs targeting immune- and stem-cell signals (e.g., IL-1β, PD-1, RANK-L) to cancer interception. Microbiota-driven IL-17 can induce stemness and transformation in pancreatic precursors (identifying another repurposing opportunity). Notable progress also includes hosting an obesity special conference (connecting epidemiologic and molecular perspectives to inform cancer research and prevention strategies), co-leading concerted national implementation efforts in HPV vaccination, and charting the future elimination of cancer disparities by integrating new science tools, discoveries and perspectives into community-engaged research, including targeted counter attacks on e-cigarette ad exploitation of children, Hispanics and Blacks. Following this summit, two unprecedented funding initiatives were catalyzed to drive cancer prevention research: the NCI Cancer Moonshot (e.g., PCA and disparities); and the AACR-Stand Up To Cancer bold “Cancer Interception” initiative.

Children and adolescents of Mexican descent residing in Hidalgo County (TX) were evaluated for exposure to organochlorine (OC) and organophosphate (OP) pesticides. A convenience sample of 60 participants enrolled in our pilot study. The lipid-adjusted serum concentrations of nine OC metabolites and creatinine-adjusted urinary concentrations of six OP metabolites were measured and compared with data from the Centers for Disease Control and Prevention’s Fourth Report on Human Exposure to Environmental Chemicals. Descriptive statistics were used to summarize the concentration levels for each metabolite. Study participants were aged 5–18 years. For most of the OC and OP metabolites, our findings showed that participants had concentration levels within the distributional range of the national data. However, notable outlying levels (greater than the 95th percentile in the Fourth Report) were identified for the following OC metabolites: gamma-hexachlorocyclohexane, p,p′-dichlorodiphenyldichloroethene, and p,p′-dichlorodiphenyltrichloroethane. Among the children aged 5–11 years, one child had an outlying value for the OP metabolite: dimethylphosphate. Our findings on the levels of OC and OP pesticide exposure enhances the credibility of national estimates, and can serve as baselines for children and adolescents of Mexican descent residing in Lower Rio Grande Valley. Furthermore, our study contributes to the lacunae of knowledge regarding environmental exposures and presses further investigation of outlying OC and OP exposure levels.

Objective: Despite declining cigarette smoking rates in the US, there is a continued need for tobacco prevention education campaigns to reach young adults. Recognizing the need for improved tobacco control messaging, the University of Texas (UT) System engaged The University of Texas at Austin Center for Health Communication to develop a brand and message that would strengthen tobacco control efforts at its 14 institutions. Methods: This article describes the iterative process involved in creating a brand for tobacco control, including an environmental scan, identifying potential message themes, and creating and refining logos. Results: This article highlights the process of developing a system-wide tobacco control brand. Specifically, the process included coordinating an interdisciplinary team with content and design experts, and presenting ideas to stakeholders for serial feedback and refinement, among others. Conclusions: Ultimately, this project offers a model for other systems of higher education interested in pursuing similar initiatives.

Annually, there are 1.6 million new cases of cancer and nearly 600,000 cancer deaths in the United States alone. The public health burden associated with these numbers has motivated enormous research efforts into understanding the root causes of cancer. These efforts have led to the recognition that between 40% and 45% of cancers are associated with preventable risk factors and, importantly, have identified specific molecular mechanisms by which these exposures modify human physiology to induce or promote cancer. The increasingly refined knowledge of these mechanisms, which we summarize here, emphasizes the need for greater efforts toward primary cancer prevention through mitigation of modifiable risk factors. It also suggests exploitable avenues for improved secondary prevention (which includes the development of therapeutics designed for cancer interception and enhanced techniques for noninvasive screening and early detection) based on detailed knowledge of early neoplastic pathobiology. Such efforts would complement the current emphasis on the development of therapeutic approaches to treat established cancers and are likely to result in far greater gains in reducing morbidity and mortality.

Various clinical and epidemiologic studies show that nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin and cyclooxygenase inhibitors (COXIBs) help prevent cancer. Since eicosanoid metabolism is the main inhibitory targets of these drugs the resulting molecular and biological impact is generally accepted. As our knowledge base and technology progress we are learning that additional targets may be involved. This review attempts to summarize these new developments in the field.

Background & Aims Despite the significant association between obesity and several cancers, it has been difficult to establish an association between obesity and hepatocellular carcinoma (HCC). Patients with HCC often have ascites, making it a challenge to determine body mass index (BMI) accurately, and many factors contribute to the development of HCC. We performed a case–control study to investigate whether obesity early in adulthood affects risk, age of onset, or outcomes of patients with HCC. Methods We interviewed 622 patients newly diagnosed with HCC from January 2004 through December 2013, along with 660 healthy controls (frequency-matched by age and sex) to determine weights, heights, and body sizes (self-reported) at various ages before HCC development or enrollment as controls. Multivariable logistic and Cox regression analyses were performed to determine the independent effects of early obesity on risk for HCC and patient outcomes, respectively. BMI was calculated, and patients with a BMI of 30 kg/m 2 or greater were considered obese. Results Obesity in early adulthood (age, mid-20s to mid-40s) is a significant risk factor for HCC. The estimated odds ratios were 2.6 (95% confidence interval [CI], 1.4–4.4), 2.3 (95% CI, 1.2−4.4), and 3.6 (95% CI, 1.5–8.9) for the entire population, for men, and for women, respectively. Each unit increase in BMI at early adulthood was associated with a 3.89-month decrease in age at HCC diagnosis ( P Conclusions Early adulthood obesity is associated with an increased risk of developing HCC at a young age in the absence of major HCC risk factors, with no effect on outcomes of patients with HCC.

Background and aim Although Non-steroidal anti-inflammatory drugs reduce colorectal adenoma burden in familial adenomatous polyposis (FAP), the utility of combining chemopreventive agents in FAP is not known. We conducted a randomised trial of celecoxib (CXB) versus CXB+diflouromethylornithine (DFMO) to determine the synergistic effect, if any. Methods The primary endpoint was % change in adenoma count in a defined field. Secondary endpoints were adenoma burden (weighted by adenoma diameter) and video review of entire colon/rectal segments. Adverse event (AEs) were monitored by National Cancer Institution toxicity criteria. Results 112 subjects were randomised: 60 men and 52 women at a mean age of 38 years. For the 89 patients who had landmark-matched polyp counts available at baseline and 6 months, the mean % change in adenoma count over the 6 months of trial was −13.0% for CXB+DFMO and −1.0% for CXB (p=0.69). Mean % change in adenoma burden was −40% (CXB+DFMO) vs −27% (CXB) (p=0.13). Video-based global polyp change was −0.80 for CXB+DFMO vs −0.33 for CXB (p=0.03). Fatigue was the only significant AE, worse on the CXB arm (p=0.02). Conclusions CXB combined with DFMO yielded moderate synergy according to a video-based global assessment. No significant difference in adenoma count, the primary endpoint, was seen between the two study arms. No evidence of DFMO-related ototoxicity was seen. There were no adverse cardiovascular outcomes in either trial arm and no significant increase in AEs in the CXB+DFMO arm of the trial. Differences in outcomes between primary and secondary endpoints may relate to sensitivity of the endpoint measures themselves. Trial registration number ClinicalTrials.gov number N01-CN95040.

Platelets can serve as "first responders" in cancer and metastasis. This is partly due to bioactive lipid metabolism that drives both platelet and cancer biology. The two primary eicosanoid metabolites that maintain platelet rapid response homeostasis are prostacyclin made by endothelial cells that inhibits platelet function, which is counterbalanced by thromboxane produced by platelets during activation, aggregation, and platelet recruitment. Both of these arachidonic acid metabolites are inherently unstable due to their chemical structure. Tumor cells by contrast predominantly make more chemically stable prostaglandin E2, which is the primary bioactive lipid associated with inflammation and oncogenesis. Pharmacological, clinical, and epidemiologic studies demonstrate that non-steroidal anti-inflammatory drugs (NSAIDs), which target cyclooxygenases, can help prevent cancer. Much of the molecular and biological impact of these drugs is generally accepted in the field. Cyclooxygenases catalyze the rate-limiting production of substrate used by all synthase molecules, including those that produce prostaglandins along with prostacyclin and thromboxane. Additional eicosanoid metabolites include lipoxygenases, leukotrienes, and resolvins that can also influence platelets, inflammation, and carcinogenesis. Our knowledge base and technology are now progressing toward identifying newer molecular and cellular interactions that are leading to revealing additional targets. This review endeavors to summarize new developments in the field.

Platelets serve as "first responders" during normal wounding and homeostasis. Arising from bone marrow stem cell lineage megakaryocytes, anucleate platelets can influence inflammation and immune regulation. Biophysically, platelets are optimized due to size and discoid morphology to distribute near vessel walls, monitor vascular integrity, and initiate quick responses to vascular lesions. Adhesion receptors linked to a highly reactive filopodia-generating cytoskeleton maximizes their vascular surface contact allowing rapid response capabilities. Functionally, platelets normally initiate rapid clotting, vasoconstriction, inflammation, and wound biology that leads to sterilization, tissue repair, and resolution. Platelets also are among the first to sense, phagocytize, decorate, or react to pathogens in the circulation. These platelet first responder properties are commandeered during chronic inflammation, cancer progression, and metastasis. Leaky or inflammatory reaction blood vessel genesis during carcinogenesis provides opportunities for platelet invasion into tumors. Cancer is thought of as a non-healing or chronic wound that can be actively aided by platelet mitogenic properties to stimulate tumor growth. This growth ultimately outstrips circulatory support leads to angiogenesis and intravasation of tumor cells into the blood stream. Circulating tumor cells reengage additional platelets, which facilitates tumor cell adhesion, arrest and extravasation, and metastasis. This process, along with the hypercoagulable states associated with malignancy, is amplified by IL6 production in tumors that stimulate liver thrombopoietin production and elevates circulating platelet numbers by thrombopoiesis in the bone marrow. These complex interactions and the "first responder" role of platelets during diverse physiologic stresses provide a useful therapeutic target that deserves further exploration.

There is a dearth of knowledge about the pathogenesis of premalignant lung lesions, especially for atypical adenomatous hyperplasia (AAH), the only known precursor for the major lung cancer subtype adenocarcinoma (LUAD). In this study, we performed deep DNA and RNA sequencing analyses of a set of AAH, LUAD, and normal tissues. Somatic BRAF variants were found in AAHs from 5 of 22 (23%) patients, 4 of 5 of whom had matched LUAD with driver EGFR mutations. KRAS mutations were present in AAHs from 4 of 22 (18%) of patients. KRAS mutations in AAH were only found in ever-smokers and were exclusive to BRAF-mutant cases. Integrative analysis revealed profiles expressed in KRAS-mutant cases (UBE2C, REL) and BRAF-mutant cases (MAX) of AAH, or common to both sets of cases (suppressed AXL). Gene sets associated with suppressed antitumor (Th1; IL12A, GZMB) and elevated protumor (CCR2, CTLA-4) immune signaling were enriched in AAH development and progression. Our results reveal potentially divergent BRAF or KRAS pathways in AAH as well as immune dysregulation in the pathogenesis of this premalignant lung lesion. Cancer Res; 77(22); 6119–30. ©2017 AACR.

Background & Aims Environmental factors have been identified that affect risk of hepatocellular carcinoma (HCC), but little is known about the effects of sex hormones on liver cancer development or outcome. The authors investigated whether menopause hormone therapy (MHT) affects risk, age at onset, or outcome of HCC. Methods We performed a case–control study of 234 female patients treated for HCC at a tertiary medical center and with 282 healthy women (controls) from January 1, 2004 through May 31, 2015. We collected detailed information on environmental exposures, ages of menarche and menopause, hysterectomies, and uses of birth control and MHT. We performed multivariable logistic and Cox regression analyses to determine the independent effects of factors associated with women on risk and clinical outcome in HCC. The primary outcomes were effect of MHT on HCC risk, the relationship between MHT with hepatitis virus infection on HCC development, and effect of MHT on age at HCC onset or survival after diagnosis of HCC. Results The estimated adjusted odds ratio (AOR) for HCC in women who ever used estrogen was 0.53 (95% confidence interval [CI], 0.32–0.88). This association was supported by the older age of HCC onset among estrogen users (mean, 64.5 ± 0.9 years) vs nonusers (mean 59.2 ± 1.1 years; P = . 001) and the reduced risk of HCC among long-term users (more than 5 years) (AOR, 0.36; 95% CI, 0.20–0.63). Users of estrogen also had a reduced risk for hepatitis-associated HCC: AOR for users, 4.37 (95% CI, 1.67–11.44) vs AOR for nonusers, 17.60 (95% CI, 3.88–79.83). Estrogen use reduced risk of death from HCC (hazard ratio, 0.55; 95% CI, 0.40–0.77; P = . 01). Median overall survival times were 33.5 months for estrogen users (95% CI, 25.7–41.3 months) and 24.1 months for nonusers (95% CI, 19.02–29.30 months; P = . 008). Conclusion In a case–control study of women with HCC vs female control subjects at a single center, we associated use of estrogen MHT with reduced risk of HCC and increased overall survival times of patients with HCC. Further studies are needed to determine the benefits of estrogen therapy for women and patients with HCC, and effects of tumor expression of estrogen receptor.

Progress in cancer chemoprevention has been hindered by a lack of validated biomarkers of risk and interventive response. The identification of accurate, reliable, and easily measurable risk and response biomarkers within the field of cancer prevention could dramatically alter our approach to the disease. Colorectal cancer is associated with substantial morbidity and a limited 5-year survival rate for late-stage disease. The identification of biomarkers to predict (i) those most at risk of clinically significant colorectal neoplasia in conjunction with or building upon current risk models and/or (ii) those most likely to respond to potential colorectal chemopreventive agents, such as aspirin and NSAIDs, would significantly advance colorectal cancer risk management. Urinary PGE-M is an established indicator of systemic prostaglandin E2 production and has previously been demonstrated to predict risk of advanced colorectal neoplasia in a handful of studies. In the July 2014 issue, Bezawada and colleagues confirmed those earlier risk associations and demonstrated that PGE-M can also predict responsiveness to aspirin/NSAIDs in a small subset of women undergoing lower endoscopy in the Nurse's Health Study. PGE-M has the potential to define subsets of the population that may derive greater chemopreventive benefit from NSAIDs, as well as the potential to optimize the use of expensive and/or invasive screening tests. Additional larger and more diverse prospective studies meeting the criteria for phase IV biomarker studies are needed to advance the development of PGE-M as a noninvasive biomarker of both risk and chemopreventive response in populations at risk for colorectal cancer. Cancer Prev Res; 7(10); 969–72. ©2014 AACR.

This year marks the 50th anniversary of the 1964 Surgeon General's Report on Smoking and Health . This landmark publication found a definitive, causal link between smoking and lung cancer in men, and, along with the subsequent reports, spurred a series of important public health initiatives that

Celecoxib and low-dose aspirin might decrease risk of breast cancer recurrence.In the Canadian Cancer Trials Group MA.27, postmenopausal hormone receptor-positive breast cancer patients were randomly assigned (2 × 2) to adjuvant exemestane or anastrozole, and celecoxib or placebo. Low-dose aspirin of 81 mg or less was a stratification factor. Due to concerns about cardiac toxicity, celecoxib use was stopped in December 2004, while stratification by aspirin use was removed through protocol amendment. We examined the effects of celecoxib and low-dose aspirin on event-free survival (EFS), defined as time from random assignment to time of locoregional or distant disease recurrence, new primary breast cancer, or death from any cause; distant disease-free survival (DDFS); and overall survival (OS). All statistical tests were two-sided.Random assignment to celecoxib (n = 811, 50.0%) or placebo (n = 811, 50.0%) was discontinued after 18 months (n = 1622). At a median of 4.1 years' follow-up, among 1622 patients, 186 (11.5%) patients had an EFS event: 80 (4.9%) had distant relapse, and 125 (7.7%) died from any cause. Celecoxib did not statistically significantly impact EFS, DDFS, or OS in univariate analysis (respectively, P = .92, P = .55, and P = .56) or multivariable analysis (respectively, P = .74, P = .60, and P = .76). Low-dose aspirin use (aspirin users n = 476, 21.5%; non-aspirin users n = 1733, 78.5%) was associated in univariate analyses with worse EFS (hazard ratio [HR] = 1.48, 95% confidence interval [CI] = 1.12 to 1.96, P = 0.006) and worse OS (HR = 1.87, 95% CI = 1.35 to 2.61, P.001). After adjusting for baseline characteristics and treatment arm, aspirin use showed no statistical association with EFS (P = .08) and DDFS (P = .82), but was associated with statistically worse OS (HR = 1.67, 95% CI = 1.13 to 2.49, P = .01).Random assignment to short-term (≤18 months) celecoxib as well as use of low-dose aspirin showed no effect on DDFS and EFS in multivariable analysis. Low-dose aspirin increased "all-cause" mortality, presumably because of higher preexisting cardiovascular risks.

Measures shown to improve the adenoma detection during colonoscopy (excellent bowel preparation, cecal intubation, cap fitted colonoscope to examine behind folds, patient position change to optimize colon distention, trained endoscopy team focusing on detection of subtle flat lesions, and incorporation of optimum endoscopic examination with adequate withdrawal time) are applicable to clinical practice and, if incorporated are projected to facilitate comprehensive colonoscopy screening program for colon cancer prevention. To determine adenoma and serrated polyp detection rate under conditions designed to optimize quality parameters for comprehensive screening colonoscopy. Retrospective analysis of data obtained from a comprehensive colon cancer screening program designed to optimize quality parameters. Academic medical center. Three hundred and forty-three patients between the ages of 50 years and 75 years who underwent first screening colonoscopy between 2009 and 2011 among 535 consecutive patients undergoing colonoscopy. Comprehensive colonoscopy screening program was utilized to screen all patients. Cecal intubation was successful in 98.8% of patients. The Boston Bowel Preparation Scale for quality of colonoscopy was 8.97 (95% confidence interval [CI]; 8.94, 9.00). The rate of adenoma detection was 60% and serrated lesion (defined as serrated adenomas or hyperplastic polyps proximal to the splenic flexure) detection was 23%. The rate of precancerous lesion detection (adenomas and serrated lesions) was 66%. The mean number of adenomas per screening procedure was 1.4 (1.2, 1.6) and the mean number of precancerous lesions (adenomas or serrated lesions) per screening procedure was 1.6 (1.4, 1.8). Retrospective study and single endoscopist experience. A comprehensive colonoscopy screening program results in high-quality screening with high detection of adenomas, advanced adenomas, serrated adenomas, and multiple adenomas.

Barrett's esophagus is the precursor lesion of esophageal adenocarcinoma, whose progression follows sequential stages. However, the low progression rate and the inadequacy and subjective interpretation of histologic grading in predicting Barrett's esophagus progression call for more objective biomarkers that can improve risk prediction. We conducted a genome-wide profiling of 754 human microRNAs (miRNA) in 35 normal epithelium, 34 Barrett's esophagus, and 36 esophageal adenocarcinoma tissues using TaqMan real-time PCR-based profiling. Unsupervised hierarchical clustering using 294 modestly to highly expressed miRNAs showed clear clustering of two groups: normal epithelium versus Barrett's esophagus/esophageal adenocarcinoma tissues. Moreover, there was an excellent clustering of Barrett's metaplasia (without dysplasia) tissues from normal epithelium tissues. However, Barrett's esophagus tissues of different stages and esophageal adenocarcinoma tissues were interspersed. There were differentially expressed miRNAs at different stages. The majority of miRNA aberrations involved upregulation of expression in Barrett's esophagus and esophageal adenocarcinoma tissues, with the most dramatic alterations occurring at the Barrett's metaplasia stage. Known oncomiRs, such as miR-21, miR-25, and miR-223, and tumor suppressor miRNAs, including miR-205, miR-203, let-7c, and miR-133a, showed progressively altered expression from Barrett's esophagus to esophageal adenocarcinoma. We also identified a number of novel miRNAs that showed progressively altered expression, including miR-301b, miR-618, and miR-23b. The significant miRNA alterations that were exclusive to esophageal adenocarcinoma but not Barrett's esophagus included miR-375 downregulation and upregulation of five members of the miR-17-92 and its homologue clusters, which may become promising biomarkers for esophageal adenocarcinoma development. Cancer Prev Res; 6(3); 196–205. ©2013 AACR.

BACKGROUND Cancer has traditionally been considered a single disease, but it is now known to be far more complex, with an unfolding etiology. In less than 2 centuries, hundreds—if not thousands—of drugs for the treatment of cancer and for palliative care have been developed and tested, with 143 having achieved approval by the US Food and Drug Administration (MediLexicon International; “Cancer Drugs & Oncology Drugs,” http://www.medilexicon.com/drugs-list/cancer.php). Just 13 agents have been approved, however, for treating precancerous lesions or for reducing risk. CONTENT Nonsteroidal antiinflammatory drugs, vitamins, food constituents and spice components, antidiabetic drugs, ω-3 fatty acids, and fiber are just a few of the many classes of compounds that have been tested for their cancer-preventive potential. We highlight some of the agents that have been scrutinized by way of randomized clinical trials in humans for their cancer prevention potential. We summarize the major definitive cancer chemoprevention studies that (a) were successful in demonstrating efficacy and ultimately received regulatory approval; (b) were not successful in demonstrating efficacy or had unacceptable toxicities, but from which the field has learned important lessons; and (c) showed compelling efficacy against surrogate end points but failed to achieve regulatory approval because of a lack of consensus regarding the relevance of those end points to clinical benefit. SUMMARY Chemopreventive studies have provided new insights into early disease pathogenesis, stimulated new risk assessments and models, fostered important research in end point biomarkers, and led to 13 approved agents. The development of safe and effective chemopreventive agents holds tremendous potential for reducing the burden of cancer.

Cutaneous squamous cell carcinoma (cuSCC) comprises 15–20% of all skin cancers, accounting for over 700,000 cases in USA annually. Most cuSCC arise in association with a distinct precancerous lesion, the actinic keratosis (AK). To identify potential targets for molecularly targeted chemoprevention, here we perform integrated cross-species genomic analysis of cuSCC development through the preneoplastic AK stage using matched human samples and a solar ultraviolet radiation-driven Hairless mouse model. We identify the major transcriptional drivers of this progression sequence, showing that the key genomic changes in cuSCC development occur in the normal skin to AK transition. Our data validate the use of this ultraviolet radiation-driven mouse cuSCC model for cross-species analysis and demonstrate that cuSCC bears deep molecular similarities to multiple carcinogen-driven SCCs from diverse sites, suggesting that cuSCC may serve as an effective, accessible model for multiple SCC types and that common treatment and prevention strategies may be feasible., Cutaneous squamous cell of the skin is a common neoplasm that frequently arises from precancerous actinic keratoses. Here, the authors carry out genomic analysis on matched sets of human lesions and compare with those in ultraviolet treated mice and identify conserved drivers of tumour development.

In this issue of JAMAOncology, Cao et al1 present an analysis ofaspirinuse for cancerprevention in lightof the recentUSPreventive Services Task Force (USPSTF) draft recommendation2 regarding the use of aspirin for prevention of colorectal cancer (CRC) in individuals at risk for cardiovascular disease. The USPSTF does not recommend aspirin use for the sole purpose of CRC prevention, but rather acknowledges an additional benefit of aspirin use among a group of individuals who are already likely to benefit from aspirin for the preventionof cardiovascular events.Advancing theuseof aspirin as a truecancer chemopreventiveagentwould typically requireadditional data fromdedicated randomized clinical trials regarding theabilityofaspirin toprotectagainst cancerswith thedefinition of an effective dose, the frequency and duration of treatment, and theclinicalpopulationat risk. Inaddition, aswe haveseenwiththeUSFoodandDrugAdministration’spriorconsideration of other agents for possible CRC and polyp prevention effects, the impact of such agents in the context of establishedandeffective screeningmodalities, suchas colonoscopy with polypectomy, is also important. Cao and colleagues1 attempt to address several important issuesusing2of the largest andbest-characterizedcohorts, the Nurses’ Health Study and theHealth Professionals Follow-up Study. The strengths of these cohorts include their size; the length and completeness of follow-up; the availability of reasonable, albeit self-reported,dataonaspirinuse,dose, andduration; and their thorough ascertainment of cancer incidence. In addition, the cohorts are broadly representative of the US general population in terms of prevalence of risk factors and screening rates. The investigative team iswell versed in the issues surrounding the use of aspirin as a potential preventive agent in the general population andhas experience in performing careful observational evaluations of aspirin’s effects on cancer risk.3 Their findings are generally consistent with earlier reported preventive effects of aspirin on gastrointestinal (GI) tract cancers.4 In the combined cohort analysis, regular aspirin users experienced a statistically significant 15% reduction in the risk for all GI tract cancers, with a significant 19% reduction in the risk for CRC and a nonsignificant 15% reduction in the risk for gastroesophageal cancer. They also demonstrate that protection against GI tract cancers occurs at relatively low doses (0.5-1.5 standard tablets per week) that were used for various other reasons (eg, cardioprotection, headache, arthritis, musculoskeletal pain), with greater risk reduction seen at increasing doses and with longer duration of use and 6 years suggested as the minimum duration of use needed to realize cancerprotective benefits. The associations seen with GI tract cancers and CRC were not modified by any of the numerous lifestyle and clinical variables examined. A small but statistically significant 3% reduction in overall cancer incidence (relative risk, 0.97; 95% CI, 0.94-0.99) was also seen among regular aspirin users, although this reduction is largely driven by the lower incidence of GI tract cancers within this group. Regular aspirin use was not associated with a reduced risk for breast, advanced prostate, or lung cancers in these analyses. Despite these careful analyses, perhaps the most important andunique contributions of this study1 are the team’s assessmentof aspirin’s potential population-wide impact and its absolute benefits in the context of screening. They calculated the proportion of incident cancers that could have been prevented with regular aspirin use, or the partial populationattributable risk, and found that 8.0% of all GI tract cancers and 10.8%ofCRCs couldhavebeenpreventedwith regular aspirin use. In addition, their findings suggest that regular aspirin use could have prevented 33 CRCs per 100000 personyears (17.0% of CRCs) among those who did not have lower endoscopy, and another 18 CRCs per 100000 person-years (8.5%) could have beenprevented among thosewhodid have lower endoscopy. This finding is important because it suggests that aspirinusemaycomplementCRCscreeningandmay haveanabsolutebenefit regardlessofendoscopystatus, a critical insight that few other studies have provided thus far. As the authors note, CRC screening rates remain suboptimal in theUnited States and, according to their calculations, regular aspirin use could prevent 9800 CRCs among the nearly 30 million age-eligible individuals who remain unscreened.1 Given the rising rates of CRC in low-resource settings where screening with endoscopy is often not feasible, the findings suggest that aspirin may serve as a relatively low-cost primary prevention modality to complement the wellestablished but underused preventive benefits of CRC screening with polypectomy. Although the analysis by Cao and colleagues1 provides more context to the use of aspirin as a CRC-preventive agent, the studyprovidesnoassessmentof thepotential harmsof aspirin in these cohorts and does not assess the full range of aspirin’s benefits beyond its cancer-preventive effects. Moreover, aspirin’s long-term effects, if any, on cancer and overall mortality are not addressed, although earlier observational studies suggest inverse associationswith cancer-specific and all-cause mortality.3,5,6 To reflect accurately the often complex, real-world clinical scenarios inwhichphysicians andpatients contemplate the use of aspirin, any truly informative analysis of its usemust weigh its cumulative benefits against its cumulative risks. Few studies are capable of such an assessment, but 2 ongoing randomized clinical trials of aspirin Related article page 762 Research Original Investigation Effect of Long-term Use of Aspirin on the Risk for Cancer

We investigated whether single nucleotide polymorphisms within ultraconserved elements (UCEs) are associated with susceptibility to overall colorectal cancer (CRC) and susceptibility to tumor site-specific CRC. The study included 787 CRC patients and 551 healthy controls. The study comprised of a training set (520 cases and 341 controls) and a replication set (267 cases and 210 controls). We observed associations in rs7849 and rs1399685 with CRC risk. For example, a dose-dependent trend (per-allele odds ratio (OR), 0.78; 95% confidence interval (CI), 0.63–1.00; P for trend = 0.05) associated with the variant allele of rs7849 in the training set. The significant trend toward a decrease in CRC risk was confirmed in the replication set (per-allele OR, 0.72; 95% CI, 0.52–0.99; P for trend = 0.044). When stratified by tumor location, for left-sided CRC (LCRC) risk, significant association was observed for the variant-containing genotypes of rs1399685 (OR, 1.77; 95% CI, 1.02–3.06) and the risk was replicated in the replication population (OR, 2.04; 95% CI, 1.02–4.07). The variant genotypes of rs9784100 and rs7849 conferred decreased risk but the associations were not replicated. Three right-sided CRC (RCRC) susceptibility loci were identified in rs6124509, rs4243289 and rs12218935 but none of the loci was replicated. Joint effects and potential higher order gene–gene interactions among significant variants further categorized patients into different risk groups. Our results strongly suggest that several genetic variants in the UCEs may contribute to CRC susceptibility, individually and jointly, and that different genetic etiology may be involved in RCRC and LCRC.

Aspirin and celecoxib prevent colorectal adenoma recurrence. Genetic variants in the UGT1A6 enzyme are associated with delayed aspirin metabolism and greater chemopreventive efficacy. We examined the effect of combining aspirin and celecoxib in relation to UGT1A6 T181A and R184S variants among 1,647 patients in the Adenoma Prevention with Celecoxib (APC) trial who were stratified according to the use of low-dose aspirin after removal of adenomas and randomized to placebo, 200-mg twice daily, or 400-mg twice daily celecoxib for 3 years. Patients underwent follow-up colonoscopies at 1 and 3 years to assess on-treatment efficacy. At 5 years, 538 patients underwent a colonoscopy to assess risk of recurrence after treatment was discontinued for at least 1 year. During treatment, the relative risk (RR) of recurrent adenoma was 0.68 [95% confidence interval (CI), 0.59–0.79] for 200-mg twice daily celecoxib and 0.54 (95% CI, 0.46–0.64) for 400-mg twice daily celecoxib compared with placebo. Aspirin use was not independently associated with recurrent adenoma (RR, 0.98, 95% CI, 0.86–1.15). These results did not vary according to UGT1A6 genotype. However, among those with a variant UGT1A6 genotype on aspirin, the RR of adenoma was 1.60 (95% CI, 0.81–3.15) after withdrawal of 200-mg twice daily and 1.98 (95% CI, 1.06–3.70) after withdrawal of 400-mg twice daily celecoxib compared with withdrawal of placebo. In contrast, there was no increased risk associated with discontinuing celecoxib among any other groups. Concurrent use of low-dose aspirin does not influence the efficacy of celecoxib in adenoma prevention. However, discontinuing celecoxib among aspirin-using individuals who initially developed adenoma despite a UGT1A6 variant genotype resulted in rapid reemergence of disease. Cancer Prev Res; 5(1); 61–72. ©2011 AACR.

Our current understanding of tumourigenesis suggests that cancer develops as a series of cumulative genetic and epigenetic derangements across time culminating in a clone of cells differing from its population of origin in terms of cellular identity, growth control, and its contextual relationship to its environment. Our increasing knowledge of the timing, sequence, frequency, and specific implications of these changes provides unique opportunities for earlier identification of aberrations and preventive interventions. Here we discuss the fundamentals of cancer prevention including the targets, cohorts, agents, endpoints, mechanistic biomarkers, designs, and strategies employed in preventive drug development. There have been many notable successes in this field such as the identification and development of tamoxifen and raloxifene for breast cancer risk reduction, instillational BCG and valrubicin for treatment of preinvasive bladder cancer, and a variety of topical and systemic agents that effectively treat preinvasive neoplastic lesions of the skin. A variety of null or negative developmental endeavours have occurred as well, including trials of beta-carotene for lung cancer prevention, nutritional modifications for colorectal adenoma prevention, and most recently, selenium and alpha-tocopherol for prostate cancer prevention. A third category of prevention trials can be summarized as investigationally successful, but not achieving regulatory success. The development of finasteride and dutasteride for prostate cancer prevention, and celecoxib for colorectal neoplasia prevention fall into this category. In less than four decades, cancer chemoprevention has transformed from a concept to an achievable reality.

IMPORTANCE: Colorectal carcinomas in patients with Lynch syndrome (LS) arise in a background of mismatch repair (MMR) deficiency, display a unique immune profile with upregulation of immune checkpoints, and response to immunotherapy. However, there is still a gap in understanding the pathogenesis of MMR-deficient colorectal premalignant lesions, which is essential for the development of novel preventive strategies for LS. OBJECTIVE: To characterize the immune profile of premalignant lesions from a cohort of patients with LS. DESIGN, SETTING, AND PARTICIPANTS: Whole-genome transcriptomic analysis using next-generation sequencing was performed in colorectal polyps and carcinomas of patients with LS. As comparator and model of MMR-proficient colorectal carcinogenesis, we used samples from patients with familial adenomatous polyposis (FAP). In addition, a total of 47 colorectal carcinomas (6 hypermutants and 41 nonhypermutants) were obtained from The Cancer Genome Atlas (TCGA) for comparisons. Samples were obtained from the University of Texas MD Anderson Cancer Center and "Regina Elena" National Cancer Institute, Rome, Italy. All diagnoses were confirmed by genetic testing. Polyps were collected at the time of endoscopic surveillance and tumors were collected at the time of surgical resection. The data were analyzed from October 2016 to November 2017. MAIN OUTCOMES AND MEASURES: Assessment of the immune profile, mutational signature, mutational and neoantigen rate, and pathway enrichment analysis of neoantigens in LS premalignant lesions and their comparison with FAP premalignant lesions, LS carcinoma, and sporadic colorectal cancers from TCGA. RESULTS: The analysis was performed in a total of 28 polyps (26 tubular adenomas and 2 hyperplastic polyps) and 3 early-stage LS colorectal tumors from 24 patients (15 [62%] female; mean [SD] age, 48.12 [15.38] years) diagnosed with FAP (n = 10) and LS (n = 14). Overall, LS polyps presented with low mutational and neoantigen rates but displayed a striking immune activation profile characterized by CD4 T cells, proinflammatory (tumor necrosis factor, interleukin 12) and checkpoint molecules (LAG3 [lymphocyte activation gene 3] and PD-L1 [programmed cell death 1 ligand 1]). This immune profile was independent of mutational rate, neoantigen formation, and MMR status. In addition, we identified a small subset of LS polyps with high mutational and neoantigen rates that were comparable to hypermutant tumors and displayed additional checkpoint (CTLA4 [cytotoxic T-lymphocyte-associated protein 4]) and neoantigens involved in DNA damage response (ATM and BRCA1 signaling). CONCLUSIONS AND RELEVANCE: These findings challenge the canonical model, based on the observations made in carcinomas, that emphasizes a dependency of immune activation on the acquisition of high levels of mutations and neoantigens, thus opening the door to the implementation of immune checkpoint inhibitors and vaccines for cancer prevention in LS.

We evaluated the association between energy balance and risk of bladder cancer and assessed the joint effects of genetic variants in the mammalian target of rapamycin (mTOR) pathway genes with energy balance. The study included 803 Caucasian bladder cancer patients and 803 healthy Caucasian controls matched to cases by age (±5 years) and gender. High energy intake [odds ratio, 1.60; 95% confidence interval (95% CI), 1.23-2.09] and low physical activity (odds ratio, 2.82; 95% CI, 2.10-3.79) were each associated with significantly increased risk of bladder cancer with dose-response pattern (Ptrend < 0.001). However, obesity (body mass index, ≥30) was not associated with the risk. Among 222 single nucleotide polymorphisms, 28 single nucleotide polymorphisms located in six genes of mTOR pathway were significantly associated with the risk. Further, the risk associated with high energy intake and low physical activity was only observed among subjects carrying a high number of unfavorable genotypes in the pathway. Moreover, when physical activity, energy intake, and genetic variants were analyzed jointly, the study population was clearly stratified into a range of low- to high-risk subgroups as defined energy balance status. Compared with subjects within the most favorable energy balance category (low energy intake, intensive physical activity, low number of unfavorable genotypes), subjects in the worst energy balance category (high energy intake, low physical activity, and carrying ≥7 unfavorable genotypes) had 21.93-fold increased risk (95% CI, 6.7-71.77). Our results provide the first strong evidence that physical activity, energy intake, and genetic variants in the mTOR pathway jointly influence bladder cancer susceptibility and that these results have implications for bladder cancer prevention. Cancer Prev Res; 3(4); 505–17. ©2010 AACR.

The rich, multidisciplinary history of cancer prevention recounted here begins with surgical and workplace recommendations of the 1700s and ends with 2009 results of the enormous (35,535 men) Selenium and Vitamin E [prostate] Cancer Prevention Trial (SELECT). This history comprises a fascinating array of chemopreventive, vaccine, surgical, and behavioral science research, both preclinical and clinical. Preclinical milestones of cancer prevention include the 1913 and 1916 mouse studies by Lathrop and Loeb of cancer development associated with pregnancy or cancer prevention through castration (oophorectomy), preventing chemically induced mouse carcinogenesis as early as 1929, energy restriction studies in the 1940s, the 1950s discoveries and later molecular characterizations of field cancerization and multistep carcinogenesis, and the effects of angiogenesis inhibition in genetically engineered mice reported in 2009. The extraordinary panoply of clinical research includes numerous large and smaller chemoprevention studies of nutritional supplements, other dietary approaches, a Bacillus Calmette-Guérin trial in 1976, molecular-targeted agents, and agents to prevent infection-related cancers such as hepatitis B virus vaccine to prevent liver cancer in 1984. Clinical surgical prevention includes removal of intraepithelial neoplasia detected by screening (including Pap testing developed in 1929 and culposcopy for cervical premalignancy and colonoscopy and polypectomy to prevent colorectal cancer begun in the 1960s) and prophylactic surgeries, such as in Lynch syndrome patients begun in 1977. Behavioral studies include smoking cessation and control beginning in the 1950s, obesity control rooted in studies of 1841, and genetic-counseling and cancer-survivorship studies. This history of pioneering events may help in better understanding who we are and what we want to achieve as cancer prevention researchers and practitioners. [Cancer Res 2009;69(13):5269–84]

Background & Aims Aberrant crypt foci (ACF) are the putative precursor of colorectal adenomas. However, there are limited data available on the prevalence and risk factors for ACF. Methods Subjects from the Prostate, Lung, Colorectal and Ovarian cancer screening trial were recruited for an ACF study, with subjects with adenoma history being oversampled. By using a standardized protocol of magnified chromoendoscopy with methylene blue staining (up to the middle rectal fold), ACF were photo-documented and removed for histologic evaluation. Results A total of 505 (66% male; 55% ≥70 y) subjects from 4 institutions were examined; 42% had no adenoma, 32% had nonadvanced distal adenoma, and 25% had advanced distal adenoma at the baseline Prostate, Lung, Colorectal and Ovarian cancer screening trial examination (8.2 years before ACF examination on average). A total of 68% of this population had 1 or more ACF, 43% had 1 to 3, 19% had 4 to 6, and 5% had 7 or more. Baseline adenoma status was not associated with ACF prevalence (range, 66%–69%) or mean number of ACF (range, 3.1–3.5). Of 143 endoscopic ACF examined histologically, 68.5% were confirmed to be ACF. In a logistic model, current (odds ratio [OR], 2.6; 95% confidence interval [CI], 1.2–5.6) and former smoking (OR, 1.6; 95% CI, 1.1–2.5) were associated with higher ACF prevalence; a body mass index greater than 30 was associated with lower prevalence (OR, 0.53; 95% CI, 0.35–0.8). Age, sex, family history of colorectal cancer, and aspirin/nonsteroidal anti-inflammatory drug use were not associated significantly with ACF prevalence. Conclusions ACF prevalence and number were not associated with adenoma history, and only 68.5% of endoscopic ACF were confirmed histologically. These results raise concern about the use of ACF as a surrogate marker of colorectal cancer risk.

Aberrant crypt foci (ACF) are the earliest visible neoplastic lesions in the colorectum. The natural history of these lesions and their role in the adenoma-carcinoma sequence are unknown. We studied ACF in a subset of patients randomized to placebo (n = 17), celecoxib (200 mg twice daily; n = 15), or celecoxib (400 mg twice daily; n = 13) in the Adenoma Prevention with Celecoxib (APC) trial. Magnification chromoendoscopy was done to identify, count, and biopsy ACF within the rectum at baseline and after 8 to 12 months of treatment. A total of 655 ACF were identified in 45 patients. We examined 70 of these ACF histologically, and all 70 were nondysplastic. Cohort characteristics and APC trial treatment results for substudy patients were similar to those of the overall APC trial. There was no significant modulation of ACF by celecoxib (versus placebo; P = 0.77). Immunohistochemical comparison of ACF with adjacent normal mucosa showed that ACF had an increased proliferative index as determined by Ki-67 (P < 0.0001), but lacked other features of neoplasia such as increased cyclooxygenase-2 expression and microvessel density, nuclear localization of β-catenin, or decreased expression of the tumor suppressors SMAD4, Estrogen Receptor α, or MGMT. Only baseline SMAD4 expression in ACF correlated with posttreatment adenoma recurrence (independent of treatment arm; P = 0.01). The presence or number of nondysplastic ACF did not correlate with a higher risk of synchronous advanced or recurrent adenomas. Our overall results indicated that nondysplastic ACF were not accurate surrogate endpoint biomarkers of recurrent colorectal adenomas in the APC trial.

Background— Observational studies and randomized trials have reported increased cardiovascular risk associated with cyclooxygenase-2 inhibitors. Prior placebo-controlled randomized studies had limited ability to assess the relationship of either celecoxib dose or pretreatment cardiovascular status to risk associated with celecoxib. Our aim was to assess the cardiovascular risk associated with celecoxib in 3 dose regimens and to assess the relationship between baseline cardiovascular risk and effect of celecoxib on cardiovascular events. Methods and Results— We performed a patient-level pooled analysis of adjudicated data from 7950 patients in 6 placebo-controlled trials comparing celecoxib with placebo for conditions other than arthritis with a planned follow-up of at least 3 years. Patients were administered celecoxib in 3 dose regimens: 400 mg QD, 200 mg BID, or 400 mg BID. From the pooled data, we calculated a hazard ratio for all dose regimens combined and individual hazard ratios for each dose regimen and examined whether celecoxib-related risk was associated with baseline cardiovascular risk. The primary end point was the combination of cardiovascular death, myocardial infarction, stroke, heart failure, or thromboembolic event. With 16 070 patient-years of follow-up, the hazard ratio for the composite end point combining the tested doses was 1.6 (95% CI, 1.1 to 2.3). The risk, which increased with dose regimen ( P =0.0005), was lowest for the 400-mg-QD dose (hazard ratio, 1.1; 95% CI, 0.6 to 2.0), intermediate for the 200-mg-BID dose (hazard ratio, 1.8; 95% CI, 1.1 to 3.1), and highest for the 400-mg-BID dose (hazard ratio, 3.1; 95% CI, 1.5 to 6.1). Patients at highest baseline risk demonstrated disproportionately greater risk of celecoxib-related adverse events ( P for interaction=0.034). Conclusions— We observed evidence of differential cardiovascular risk as a function of celecoxib dose regimen and baseline cardiovascular risk. By further clarifying the extent of celecoxib-related cardiovascular risk, these findings may help guide treatment decisions for patients who derive clinical benefit from selective cyclooxygenase-2 inhibition.

Background: The Wnt/β-catenin signaling pathway plays a key role in stem cell maintenance in the colorectum. Rare high-penetrance genetic mutations in components of this pathway result in familial colorectal cancer, yet the impact of common, germline variants remains unknown. Methods: We assessed 172 variants in 26 genes from the Wnt/β-catenin pathway in 809 colorectal cancer cases and 814 healthy controls, followed by replication of the top findings in another 691 cases and 775 controls. In silico informatic tools were used to predict functional effects of variants. Results: Eighteen SNPs in the pathway were significantly associated with colorectal cancer risk (P < 0.05) in the discovery phase. We observed a significant dose-response increase in colorectal cancer risk by number of risk genotypes carried (P = 4.19 × 10−8). Gene-based analysis implicated CSNK1D (P = 0.014), FZD3 (P = 0.023), and APC (P = 0.027) as significant for colorectal cancer risk. In the replication phase, FZD3:rs11775139 remained significantly associated with reduced risk with a pooled OR of 0.85 [95% confidence interval (CI), 0.76–0.94, P = 0.001]. Although borderline significant in the replication population, APC:rs2545162 was highly significant in the pooled analysis—OR, 1.42; 95% CI, 1.16–1.74; P = 0.00085. Functional assessment identified several potential biologic mechanisms underlying these associations. Conclusions: Our findings suggest that common germline variants in the Wnt/β-catenin pathway may be involved in colorectal cancer development. Impact: These variants may be informative in colorectal cancer risk assessment to identify individuals at increased risk who would be candidates for screening. Cancer Epidemiol Biomarkers Prev; 25(3); 540–6. ©2016 AACR.