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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.

Supplementary Figure from Genome-Wide Catalogue of Chromosomal Aberrations in Barrett's Esophagus and Esophageal Adenocarcinoma: A High-Density Single Nucleotide Polymorphism Array Analysis

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Inflammation, as measured by the circulating inflammatory marker high-sensitivity C-reactive protein (hsCRP), has been associated with cardiovascular disease. However, data about CRP and risk of colorectal cancer have been conflicting. The Adenoma Prevention with Celecoxib (APC) trial showed that the anti-inflammatory drug celecoxib prevents recurrence of colorectal adenoma but increases risk of cardiovascular events. We examined whether serum hsCRP modified these results. We measured hsCRP from serum specimens provided at study entry by patients enrolled in the APC trial. Patients were stratified according to use of low-dose aspirin, randomized to receive 3 years of treatment with placebo, 200-mg-bid celecoxib, or 400-mg-bid celecoxib, and underwent follow-up colonoscopies at years 1 and 3. Among 1,680 patients, the estimated 3-year cumulative incidence of adenoma was 42% for patients with hsCRP 3 mg/L. The effect of celecoxib on adenoma recurrence did not vary among patients with high (>3 mg/L) compared with low (≤3 mg/L) hsCRP. However, among patients with high hsCRP, the RR of cardiovascular events compared with placebo was 2.27 (95% CI = 0.72–7.14) for those randomized to celecoxib 200-mg-bid and 3.28 (95% CI = 1.09–9.91) for 400-mg-bid. In contrast, among patients with low hsCRP, the corresponding RRs were 0.99 (95% CI = 0.53–1.83) and 1.11 (95% CI = 0.61–2.02). hsCRP may predict risk of celecoxib-associated cardiovascular toxicity but not adenoma recurrence or celecoxib treatment efficacy. Patients with low hsCRP may be a subgroup with a favorable risk-benefit profile for celecoxib chemoprevention. Cancer Prev Res; 4(8); 1172–80. ©2011 AACR.

Perspective from Aberrant Crypt Foci in the Adenoma Prevention with Celecoxib Trial

Perspective on this Article from Five-Year Efficacy and Safety Analysis of the Adenoma Prevention with Celecoxib Trial

Perspective on This Article from C-reactive Protein and Risk of Colorectal Adenoma According to Celecoxib Treatment

Supplementary Information from Five-Year Efficacy and Safety Analysis of the Adenoma Prevention with Celecoxib Trial

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.

Figures S1, S2, S3 and S4. APC and KRAS genotyping of crypts and bulk biopsies in adenomas from MAP, UPF, LS and cMMRD cases. Figures S5, S6 and S7. APC and KRAS genotyping of crypts and bulk biopsies in adenomas from SPO cases. Figure S8, S9 and S10. Hyerarchical clustering analysis of crypts based on KRAS genotyping results. Figure S11. Comparative analysis of mutant allele discrimination by (A) Light Cycler 480 (Roche) and (B) nanofluidic PCR using Dynamic array (Fluidigm). Figure S12. A. Comparative analysis of KRAS genotyping using whole genome amplified (WGA) DNA or pre-amplified DNA using 15 cycles of a nested PCR. Figure S13. Genotyping results including water controls of random KRAS hotspot mutation analysis after performing a pre-amplification step using a nested PCR apporach. Figure S14. Independent validation of KRAS hotspot mutation that have been detected by Nanofluidic Dynamic array using the Nanofluidic Digital PCR genotyping as an alternative approach. Figure S15. Independent validation of KRAS hotspot mutation that have been detected by Nanofluidic Dynamic array using the Nanofluidic Digital PCR genotyping as an alternative approach.

Table S1: Samples analyzed by DNA and RNA sequencing; Table S2: DNA (n=67) and RNA (n=48) sequencing quality metrics for each sample; Table S3: Exonic mutations in known lung adenocarcinoma drivers and other cancer associated genes; Table S4: Genes mutated in atypical adenomatous hyperplasias and lung adenocarcinomas; Table S5: Validation of specific BRAF, KRAS and EGFR mutations using digital PCR; Table S6: Genes differentially expressed among normal lung tissues, atypical adenomatous hyperplasias and lung adenocarcinomas; Table S7: Genes differentially expressed between BRAF-mutant, KRAS-mutant and BRAF/KRAS wild type atypical adenomatous hyperplasias; Table S8: Markers of immune signaling that are aberrantly expressed between normal lung tissues, atypical adenomatous hyperplasias and lung adenocarcinomas.

Purpose: The majority of genomic alterations causing intratumoral heterogeneity (ITH) in colorectal cancer are thought to arise during early stages of carcinogenesis as a burst but only after truncal mutations in APC have expanded a single founder clone. We have investigated if the initial source of ITH is consequent to multiple independent lineages derived from different crypts harboring distinct truncal APC and driver KRAS mutations, thus challenging the prevailing monoclonal monocryptal model.Experimental Design: High-depth next-generation sequencing and SNP arrays were performed in whole-lesion extracts of 37 familial adenomatous polyposis colorectal adenomas. Also, ultrasensitive genotyping of hotspot mutations of APC and KRAS was performed using nanofluidic PCRs in matched bulk biopsies (n = 59) and crypts (n = 591) from 18 adenomas and seven carcinomas and adjacent normal tissues.Results: Multiple co-occurring truncal APC and driver KRAS alterations were uncovered in whole-lesion extracts from adenomas and subsequently confirmed to belong to multiple clones. Ultrasensitive genotyping of bulk biopsies and crypts revealed novel undetected APC mutations that were prominent among carcinomas, whereas abundant wild-type APC crypts were detected in adenomas. KRAS mutational heterogeneity within crypts was evident in both adenomas and carcinomas with a higher degree of concordance between biopsy and crypt genotyping in carcinomas. Nonrandom heterogeneity among crypts was also observed.Conclusions: The striking degree of nonrandom intercrypt heterogeneity in truncal and driver gene mutations observed in adenomas and carcinomas is consistent with a polycryptal model derived from multiple independent initiation linages as the source of early ITH in colorectal carcinogenesis. Clin Cancer Res; 23(19); 5936–47. ©2017 AACR.

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.

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Figure S1: Mutation burden in atypical adenomatous hyperplasia and lung adenocarcinoma; Figure S2: Mutation burden in atypical adenomatous hyperplasia and lung adenocarcinoma based on tobacco history; Figure S3: Mutations in cancer driver genes in atypical adenomatous hyperplasia and lung adenocarcinoma; Figure S4: Representative validation of somatic mutations by digital PCR.

Table S1. Summary of adenomas with multiple APC and KRAS somatic hits identified by next-generation sequencing. Table S2. Clinical and pathologic characteristics of patients analyzed in this manuscript. Table S3. Analysis of APC, KRAS and 5q loss using AmpliSeq and SNP array TableS4. Number of normal mucosa, adenomas, tumors and crypts analyzed per case. NM; normal mucosa. Table S5. Analytical sensibility of Light Cycler® 480 (Roche) and dynamic array (Fluidigm) to detect KRAS mutations. Table S6. In silico of the APC somatic hits observed by next-generaiton sequencing that were labelled as VUS. B, benign; N, neutral; D, damaging; P, Probably damaging. Table S7. APC analysis of adenomas and carcinomas in bulk biopsies and isolated crypts. The analysis of adjancent normal mucosa was not performed. Table S8. KRAS genotyping results of adenomas and carcinomas by digital and dynamic array (Fluidigm) in bulk biopsies and isolated crypts Table S9. Primers and probes used in this manuscript.

Purpose: 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.Experimental Design: 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.Results: 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.Conclusion: Genetic polymorphisms in the microRNA pathway may predict prognosis in patients with stage III CRC treated with fluoropyrimidine-based chemotherapy. Clin Cancer Res; 18(14); 3982–91. ©2012 AACR.

Supplementary Materials and Methods (Includes reference to Table S9 and Figures S11-15)

Supplementary methods including detailed methods on specimen collection and evaluation; DNA and RNA isolation; deep DNA targeted sequencing and transcriptome sequencing; identification and validation of somatic mutations; and expression analysis.

Historical Perspective on this Article from Cancer Prevention: From 1727 to Milestones of the Past 100 Years

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]

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: Screening for colonic neoplasia has decreased the incidence of colorectal cancer in the United States in the past two decades. Whether personal history of noncolorectal cancer is a risk factor for colonic neoplasia has not been well studied. We assessed the risk of colorectal neoplasia in noncolorectal cancer survivors. Methods: We conducted a retrospective study of patients who had undergone colonoscopy for any indication between 2009 and 2018. Colonic adenoma detection rate and multivariate logistic regression were conducted to assess for the primary outcomes of the study. Results: The study included 9408 cancer patients and 3295 control patients. Colonic adenomas were detected in 4503 cancer patients (48%) and 950 cancer-free patients (29%). Histologic examination of these adenomas revealed tubulovillous features in 620 patients (5%) and villous in 153 (1%). High-grade dysplasia was detected in 1611 patients (13%). Invasive colorectal adenocarcinoma was detected in 455 patients (12%); this rate was highest in patients with multiple myeloma (14%). Multivariate analysis revealed that a personal history of noncolorectal cancer was associated with increased risk of adenoma (Odd ratio, 2.04; 95% CI, 1.84-2.26; P

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 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.

Aims: Cervical cancer incidence and mortality rates are approximately 55% higher in the Rio Grande Valley (RGV) along the Texas–Mexico border compared with the average rates in the US. Our aim was to improve cervical cancer prevention efforts in the RGV through a comprehensive multilevel intervention initiative focused on community education, patient navigation, and training of local providers. Methods: We initiated a program in the RGV which consisted of (1) community education, (2) patient navigation, and (3) a training/mentoring program for local medical providers including hands-on training courses coupled with telementoring using Project ECHO® (Extension for Community Health Outcomes). We assessed the number of women undergoing cervical cancer screening, diagnosis, and treatment at three participating clinics caring for underserved women in the region. Results: From November 2014 to October 2018, 14,846 women underwent cervical cancer screening. A total of 2030 (13.7%) women underwent colposcopy for abnormal results (179% increase over baseline) and 453 women underwent loop electrosurgical excision procedures (LEEPs) for treatment of cervical dysplasia. Invasive cancer was diagnosed in 39 women who were navigated to a gynecologic oncologist for treatment. Seven local medical providers were trained to perform colposcopy and/or LEEP. Project ECHO telementoring videoconferences were held every 2 weeks for a total 101 sessions with an average of 22 participants per session and a total of 180 patient cases presented and discussed. Conclusions: Our program led to a large number of women undergoing diagnosis and treatment of cervical dysplasia in the RGV. If sustained, we anticipate these efforts will decrease cervical cancer rates in the region. The program is currently being expanded to additional underserved areas of Texas and globally to low- and middle-income countries.

Germline mutations in the tumor suppressor Adenomatous Polyposis Coli (APC) define Familial Adenomatous Polyposis (FAP), the genetic predisposition to developing adenomatous polyps. Recent sequencing of FAP adenomas have challenged established dogma that APC mutations alone represent the adenoma mutational landscape because recurrent somatic mutations in non-WNT pathway genes were also discovered. In particular, one of these novel genes, CNOT3, presented E20K and E70K mutations that are predicted to be deleterious in silico. We utilized zebrafish embryos to determine if these mutations affect CNOT3 function and perform novel biology in an APC-dependent pathway in vivo. Human CNOT3 (hCNOT3) and E20K mRNA injection rescued zebrafish cnot3a knockdown lordosis phenotype while E70K did not. In the FAP apcmcr zebrafish model, we show that ctbp1, but not retinoic acid, regulates cnot3a expression. Injection of hCNOT3 and E20K, but not E70K, to homozygous apcmcr zebrafish initiated gut differentiation while cnot3a knockdown in wildtype embryos led to decreased intestinal development and differentiation. Finally, targeted sequencing of 37 additional FAP adenomas revealed CNOT3 mutations in 20% of these samples. Overall, our work supports a mechanism where CTBP1 regulates CNOT3 and that overall CNOT3 perturbation could work in concert with germline APC mutations in advancing adenomas to a more transformed state prior to progression to adenocarcinoma.

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.

Background: Cancer beliefs and perceptions of cancer risk affect the cancer continuum. Identifying underlying factors associated with these beliefs and perceptions in Texas can help inform and target prevention efforts. Methods: We developed a cancer-focused questionnaire and administered it online to a nonprobability sample of the Texas population. Weighted multivariable logistic regression analysis identified key factors associated with perceptions and beliefs about cancer. Results: The study population comprised 2,034 respondents (median age, 44.4 years) of diverse ethnicity: 45.5% were non-Hispanic white, 10.6% non-Hispanic black, and 35.7% Hispanic. Self-reported depression was significantly associated with cancer risk perceptions and cancer beliefs. Those indicating frequent and infrequent depression versus no depression were more likely to believe that: (i) compared to other people their age, they were more likely to get cancer in their lifetime [OR, 2.92; 95% confidence interval (CI), 1.95–4.39 and OR, 1.79; 95% CI, 1.17–2.74, respectively]; and (ii) when they think about cancer, they automatically think about death (OR, 2.05; 95% CI, 1.56–2.69 and OR, 1.46; 95% CI, 1.11–1.92, respectively). Frequent depression versus no depression was also associated with agreement that (i) it seems like everything causes cancer (OR, 1.67; 95% CI, 1.26–2.22) and (ii) there is not much one can do to lower one's chance of getting cancer (OR, 1.44; 95% CI, 1.09–1.89). Other predictors for perceived cancer risk and/or cancer beliefs were sex, age, ethnicity/race, being born in the United States, marital status, income, body mass index, and smoking. Conclusions: Depression and other predictors are associated with cancer risk perceptions and beliefs in Texas. Impact: Increased attention to reducing depression may improve cancer risk perceptions and beliefs.

Hyperpolarized magnetic resonance spectroscopy enables quantitative, non-radioactive, real-time measurement of imaging probe biodistribution and metabolism in vivo. Here, we investigate and report on the development and characterization of hyperpolarized acetylsalicylic acid (aspirin) and its use as a nuclear magnetic resonance (NMR) probe. Aspirin derivatives were synthesized with single- and double-(13)C labels and hyperpolarized by dynamic nuclear polarization with 4.7% and 3% polarization, respectively. The longitudinal relaxation constants (T(1)) for the labeled acetyl and carboxyl carbonyls were approximately 30 seconds, supporting in vivo imaging and spectroscopy applications. In vitro hydrolysis, transacetylation, and albumin binding of hyperpolarized aspirin were readily monitored in real time by (13)C-NMR spectroscopy. Hyperpolarized, double-labeled aspirin was well tolerated in mice and could be observed by both (13)C-MR imaging and (13)C-NMR spectroscopy in vivo.

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.

Cancer prevention is the most cost-effective, long-term strategy for the control of cancer. 1 , 2 It is now well established that approximately one-third to one-half of all adult cancers occurring in Western populations can be prevented through the adoption of “healthy lifestyles.” A comprehensive view of a healthy lifestyle includes adherence to published cancer prevention recommendations that seek to eliminate or minimize exposure to lifestyle risk factors, and the use of screening and early detection tests as well as molecular preventive agents (e.g., aspirin, tamoxifen, human papillomavirus [HPV] vaccine) when warranted. This chapter focuses on the epidemiology of lifestyle risk factors and their associated interventions, as well as on the use of molecular preventive agents. Screening and early detection are addressed in another chapter.

Although substantial progress is currently being made in the development of novel and more effective therapeutics, cancer remains a largely unsolved clinical problem with high mortality. Cancer incidence is on the rise in the United States and worldwide. Between 2005 and 2015, the number of cancer cases increased by 33%, owing in part to population aging, which contributed 16%, and population growth and changes in age-specific rates, which contributed the remainder. Cancer incidence and the societal cancer burden are expected to increase further. Beyond therapeutics, substantial reduction in cancer mortality necessitates improved understanding of cancer risk, implementation of effective preventive intervention strategies, and early detection of cancers that are likely to progress to avoid the problem of overdiagnosis, all of which represent substantial challenges that can be overcome. Identifying individuals at increased risk of developing a particular cancer type would allow for a range of preventive interventions to be implemented, from altered lifestyle and health behaviors to the use of vaccines, and early detection of particular cancer(s) for which these persons are at risk. A case in point is obesity, which is a risk factor for at least 13 different cancers. Elucidation of metabolic, immune, and other molecular profiles that contribute to the increased risk would allow for more focused screening strategies for persons with these risk profiles and would allow implementation of targeted preven­tion strategies aimed at the cancer(s) for which they are at risk.

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.

Purpose: The majority of genomic alterations causing intratumoral heterogeneity (ITH) in colorectal cancer are thought to arise during early stages of carcinogenesis as a burst but only after truncal mutations in APC have expanded a single founder clone. We have investigated if the initial source of ITH is consequent to multiple independent lineages derived from different crypts harboring distinct truncal APC and driver KRAS mutations, thus challenging the prevailing monoclonal monocryptal model. Experimental Design: High-depth next-generation sequencing and SNP arrays were performed in whole-lesion extracts of 37 familial adenomatous polyposis colorectal adenomas. Also, ultrasensitive genotyping of hotspot mutations of APC and KRAS was performed using nanofluidic PCRs in matched bulk biopsies (n = 59) and crypts (n = 591) from 18 adenomas and seven carcinomas and adjacent normal tissues. Results: Multiple co-occurring truncal APC and driver KRAS alterations were uncovered in whole-lesion extracts from adenomas and subsequently confirmed to belong to multiple clones. Ultrasensitive genotyping of bulk biopsies and crypts revealed novel undetected APC mutations that were prominent among carcinomas, whereas abundant wild-type APC crypts were detected in adenomas. KRAS mutational heterogeneity within crypts was evident in both adenomas and carcinomas with a higher degree of concordance between biopsy and crypt genotyping in carcinomas. Nonrandom heterogeneity among crypts was also observed. Conclusions: The striking degree of nonrandom intercrypt heterogeneity in truncal and driver gene mutations observed in adenomas and carcinomas is consistent with a polycryptal model derived from multiple independent initiation linages as the source of early ITH in colorectal carcinogenesis. Clin Cancer Res; 23(19); 5936–47. ©2017 AACR.