Molecular mechanisms of the preventable causes of cancer in the United States.

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.

Genome-wide association study identifies high-impact susceptibility loci for HCC in North America.

BACKGROUND AND AIMS: Despite the substantial impact of environmental factors, individuals with a family history of liver cancer have an increased risk for HCC. However, genetic factors have not been studied systematically by genome-wide approaches in large numbers of individuals from European descent populations (EDP). APPROACH AND RESULTS: We conducted a 2-stage genome-wide association study (GWAS) on HCC not affected by HBV infections. A total of 1872 HCC cases and 2907 controls were included in the discovery stage, and 1200 HCC cases and 1832 controls in the validation. We analyzed the discovery and validation samples separately and then conducted a meta-analysis. All analyses were conducted in the presence and absence of HCV. The liability-scale heritability was 24.4% for overall HCC. Five regions with significant ORs (95% CI) were identified for nonviral HCC: 3p22.1, MOBP , rs9842969, (0.51, [0.40-0.65]); 5p15.33, TERT , rs2242652, (0.70, (0.62-0.79]); 19q13.11, TM6SF2 , rs58542926, (1.49, [1.29-1.72]); 19p13.11 MAU2 , rs58489806, (1.53, (1.33-1.75]); and 22q13.31, PNPLA3 , rs738409, (1.66, [1.51-1.83]). One region was identified for HCV-induced HCC: 6p21.31, human leukocyte antigen DQ beta 1, rs9275224, (0.79, [0.74-0.84]). A combination of homozygous variants of PNPLA3 and TERT showing a 6.5-fold higher risk for nonviral-related HCC compared to individuals lacking these genotypes. This observation suggests that gene-gene interactions may identify individuals at elevated risk for developing HCC. CONCLUSIONS: Our GWAS highlights novel genetic susceptibility of nonviral HCC among European descent populations from North America with substantial heritability. Selected genetic influences were observed for HCV-positive HCC. Our findings indicate the importance of genetic susceptibility to HCC development.

Be Well™ Acres Homes: a community-driven, evidence-based approach to reduce health inequities through sustained cross-sector partnership.

PURPOSE: Be Well Communities™ is MD Anderson's signature place-based approach for cancer prevention and control, working with communities to promote wellness and address modifiable risk factors for cancer. The purpose of this paper is to describe implementation of the planning phase of the Be Well Communities model in Acres Homes which began in 2019. METHODS: A community advisory group (Steering Committee) including residents, non-profit organizations, health care partners, city and county agencies, plus other stakeholders, was convened and aligned through a structured process to develop shared goals, foster multisector collaboration, as measured by a stakeholder survey administered twice, and enhance community capacity to improve health outcomes through development of a Community Action Plan. RESULTS: Clear, achievable goals were developed, multisector collaboration was enhanced, and more than 400 h of capacity building support led to a Community Action Plan initially focused on healthy eating and active living, including 15 evidence-based interventions led by 18 organizations. The majority (93%) of the Steering Committee reports that this plan reflects community priorities and will reach the residents most in need. CONCLUSION: By listening and developing trust, the Be Well Communities team successfully worked with Acres Homes residents and organizations to enhance community capacity to address health inequities in one of Houston's most diverse and historic communities.

Implementation of Universal Hepatitis C Virus Screening in a Tertiary Cancer Center.

BACKGROUND: The prevalence of chronic hepatitis C virus (HCV) infection in the United States is ≤1%. Universal HCV screening is recommended nationwide. Here we describe our experience implementing universal HCV screening at a cancer center. METHODS: In October 2016, universal HCV screening with HCV antibody (anti-HCV) was initiated for all new outpatients. Universal screening was promoted through widespread provider education, orders in the Epic electronic health records (EHRs), SmartSets, and automated EHR reminders. The effort focused on patients with solid tumors, because universal screening in patients with hematologic malignancies was already standard practice. Primary outcomes were the proportion of patients screened and the proportion of patients with reactive anti-HCV test results linked to HCV care. The secondary outcome was the incidence of HCV-associated hepatocellular carcinoma as a second primary malignancy (HCC-SPM) in patients with a history of other cancers before HCC diagnosis. Epic's Reporting Workbench Business Intelligence tools were used. Statistical significance was defined as P<.05 on chi-square analysis. RESULTS: From April 2016 through April 2023, 56,075 patients with solid tumors were screened for HCV, of whom 1,300 (2.3%) had reactive anti-HCV test results. The proportion of patients screened was 10.1% in the 6 months before study implementation and 34.4% in the last 6 months of the study (P<.001). HCV screening was ordered using SmartSets in 39,332 (45.8%) patients and in response to automated EHR reminders in 10,972 (12.8%) patients. Most patients with reactive anti-HCV test results were linked to care (765/1,300; 59%), most with proven HCV infection were treated (425/562; 76%), and most treated patients achieved sustained virologic response (414/425; 97%). The incidence of HCC-SPMs was 15% in historical controls treated from 2011 to 2017 and 5.7% following implementation of universal screening (P=.0002). CONCLUSIONS: Universal HCV screening can be successfully implemented in cancer hospitals using an EHR-based multipronged approach to eliminate HCV and prevent HCV-associated HCC-SPMs.

Reducing risk for chronic disease: evaluation of a collective community approach to sustainable evidence-based health programming.

BACKGROUND: Community initiatives can shape health behaviors, such as physical activity and dietary habits, across a population and help reduce the risk of developing chronic disease. To achieve this goal and impact health outcomes, Pasadena Vibrant Community aimed to engage communities in an ongoing dialogue about the importance of healthy behaviors, implement and advance community-based strategies to promote health, and improve diet and physical activity behaviors. The initiative was centered around a collaboration between a backbone organization, steering committee, and 7 collaborating organizations funded to implement multicomponent, evidence-based programs.. The common agenda was detailed in a community action plan, which included 19 interventions targeting healthy eating and active living among adults and youth in Pasadena, Texas. METHODS: A mixed methods evaluation of the initiative was conducted over 4 years. Data sources included document reviews of quarterly progress reports (n = 86) and supplemental data reports (n = 16) provided by collaborating organizations, annual Steering Committee surveys (n = 4), and interviews conducted with staff from a subset of Collaborating Organizations (n = 4). RESULTS: The initiative reached over 50,000 community members per year through 19 evidence-based interventions and impacted health outcomes, including knowledge and adoption of healthy eating practices and increased physical activity. Thirty-one systems-level changes were implemented during the initiative, including 16 environmental changes. Steering Committee meetings and shared goals enabled connections, communication, and cooperation, which allowed Collaborating Organizations to address challenges and combine resources to deliver their programs. CONCLUSIONS: Community initiatives can effectively permeate the community by reaching individuals, improving physical activity and dietary habits, and ensuring sustainability. Based on the experience reported here, the success of a community initiative can be facilitated if collaborating organizations come together to implement evidence-based interventions and tailor them to the community, and if they are empowered by significant leadership and supportive collaboration and aligned by a common agenda.

Institution-Wide Retreats Foster Organizational Learning and Action at a Comprehensive Cancer Center.

Providing safe and informed healthcare for sexual and gender minority (SGM) individuals with cancer is stymied by the lack of sexual orientation and gender identity (SOGI) data reliably available in health records and by insufficient training for staff. Approaches that support institutional learning, especially around sensitive topics, are essential for hospitals seeking to improve practices impacting patient safety and research. We engineered annual institutional retreats to identify and unify stakeholders, promote awareness of gaps and needs, identify initiatives, minimize redundant projects, and coordinate efforts that promote improvements in SGM cancer care, education, and research. The 2022 and 2023 retreats employed a 4-h hybrid format allowing virtual and in-person engagement. Retreat organizers facilitated small-group discussions for brainstorming among participants. We performed descriptive statistics from retreat evaluations. The retreats engaged 104 attendees from distinct departments and roles. Participants expressed robust satisfaction, commending the retreat organization and content quality. Notably, the first retreat yielded leadership endorsement and funding for a Quality Improvement pilot to standardize SOGI data collection and clinical staff training. The second retreat provided a platform for updates on focused efforts across the institution and for receiving direction regarding national best practices for SGM care and research. We report the processes and outcomes of institution-wide retreats, which served as a platform for identifying gaps in organizational healthcare practices and research for SGM individuals with cancer. The strategies described herein may be readily scaled at other cancer hospitals seeking to learn and enact system-wide practice changes that support the needs of SGM patients and families.

Gut microbiome features associated with liver fibrosis in Hispanics, a population at high risk for fatty liver disease.

BACKGROUND AND AIMS: Hispanics are disproportionately affected by NAFLD, liver fibrosis, cirrhosis, and HCC. Preventive strategies and noninvasive means to identify those in this population at high risk for liver fibrosis, are urgently needed. We aimed to characterize the gut microbiome signatures and related biological functions associated with liver fibrosis in Hispanics and identify environmental and genetic factors affecting them. APPROACH AND RESULTS: Subjects of the population-based Cameron County Hispanic Cohort (CCHC; n = 217) were screened by vibration-controlled transient elastography (FibroScan). Among them, 144 (66.7%) had steatosis and 28 (13.0%) had liver fibrosis. The gut microbiome of subjects with liver fibrosis was enriched with immunogenic commensals (e.g., Prevotella copri, Holdemanella, Clostridiaceae 1) and depleted of Bacteroides caccae, Parabacteroides distasonis, Enterobacter, and Marinifilaceae. The liver fibrosis-associated metagenome was characterized by changes in the urea cycle, L-citrulline biosynthesis and creatinine degradation pathways, and altered synthesis of B vitamins and lipoic acid. These metagenomic changes strongly correlated with the depletion of Parabacteroides distasonis and enrichment of Prevotella and Holdemanella. Liver fibrosis was also associated with depletion of bacterial pathways related to L-fucose biosynthesis. Alcohol consumption, even moderate, was associated with high Prevotella abundance. The single-nucleotide polymorphisms rs3769502 and rs7573751 in the NCK adaptor protein 2 (NCK2) gene positively associated with high Prevotella abundance. CONCLUSION: Hispanics with liver fibrosis display microbiome profiles and associated functional changes that may promote oxidative stress and a proinflammatory environment. These microbiome signatures, together with NCK2 polymorphisms, may have utility in risk modeling and disease prevention in this high-risk population.

Multicancer early detection test: Preclinical, translational, and clinical evidence-generation plan and provocative questions.

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.

A Comprehensive Program to Reduce Tobacco-related Cancers Through Actions by a National Cancer Institute-designated Cancer Center.

Tobacco use accounts for 30% of all cancer-related deaths worldwide and 20% in the US, despite effective, evidence-based interventions for reducing tobacco use and tobacco-related cancers and deaths. In 2012, to reduce the burden of tobacco-related cancer and associated population-level risks across Texas, The University of Texas MD Anderson Cancer Center initiated the EndTobacco® program to promote statewide cancer control activities. We created evidence-based initiatives, established selection criteria, and implemented actions involving policy, education, and tobacco treatment services. As a result, EndTobacco has supported, educated, and convened local and state coalitions in policymaking; provided tobacco treatment education to health professionals; implemented Texas' only certified tobacco treatment training program; and led an initiative to enhance the tobacco-free culture of the state's publicly funded university system. Supported by commitments from MD Anderson, we developed and implemented evidence-based actions for tobacco control tailored to the center's mission, values, expertise, resources, and partnerships. By 2021, the adult smoking rate in Texas dropped from 19.2% (2014) to 13.2%. Contributors to this drop include state tobacco control policies, programs and services from multiple agencies and associations, and EndTobacco activities that complement the statewide effort to prevent youth smoking initiation and increase quit attempts among youth and adults.

Molecular cancer prevention: Current status and future directions.

The heterogeneity and complexity of advanced cancers strongly support the rationale for an enhanced focus on molecular prevention as a priority strategy to reduce the burden of cancer. Molecular prevention encompasses traditional chemopreventive agents as well as vaccinations and therapeutic approaches to cancer-predisposing conditions. Despite challenges to the field, we now have refined insights into cancer etiology and early pathogenesis; successful risk assessment and new risk models; agents with broad preventive efficacy (eg, aspirin) in common chronic diseases, including cancer; and a successful track record of more than 10 agents approved by the US Food and Drug Administration for the treatment of precancerous lesions or cancer risk reduction. The development of molecular preventive agents does not differ significantly from the development of therapies for advanced cancers, yet it has unique challenges and special considerations given that it most often involves healthy or asymptomatic individuals. Agents, biomarkers, cohorts, overall design, and endpoints are key determinants of molecular preventive trials, as with therapeutic trials, although distinctions exist for each within the preventive setting. Progress in the development and evolution of molecular preventive agents has been steadier in some organ systems, such as breast and skin, than in others. In order for molecular prevention to be fully realized as an effective strategy, several challenges to the field must be addressed. Here, the authors provide a brief overview of the context for and special considerations of molecular prevention along with a discussion of the results from major randomized controlled trials.

Be Well Communities™: mobilizing communities to promote wellness and stop cancer before it starts.

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 < .001). 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.

Strategies to identify hepatitis C virus infection in patients receiving anticancer therapy: a cross-sectional study.

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 2122 participants. Median age was 59 years (range, 18-91); 1138 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); and other, 2% (n = 35). Primary cancer distribution was non-liver solid tumor, 78% (n = 1664); hematologic cancer, 20% (n = 422); and 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 1315 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.

Sulindac plus a phospholipid is effective for polyp reduction and safer than sulindac alone in a mouse model of colorectal cancer development.

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.

Bioactive lipid metabolism in platelet "first responder" and cancer biology.

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.

Real-Time Interrogation of Aspirin Reactivity, Biochemistry, and Biodistribution by Hyperpolarized Magnetic Resonance Spectroscopy.

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 (T1 ) 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.

The somatic mutation landscape of premalignant colorectal adenoma.

OBJECTIVE: There are few studies which characterised the molecular alterations in premalignant colorectal adenomas. Our major goal was to establish colorectal adenoma genome atlas and identify molecular markers of progression from colorectal adenoma to adenocarcinoma. DESIGN: Whole-exome sequencing and targeted sequencing were carried out in 149 adenoma samples and paired blood from patients with conventional adenoma or sessile serrated adenoma to characterise the somatic mutation landscape for premalignant colorectal lesions. The identified somatic mutations were compared with those in colorectal cancer (CRC) samples from The Cancer Genome Atlas. A supervised random forest model was employed to identify gene panels differentiating adenoma from CRC. RESULTS: Similar somatic mutation frequencies, but distinctive driver mutations, were observed in sessile serrated adenomas and conventional adenomas. The final model included 20 genes and was able to separate the somatic mutation profile of colorectal adenoma and adenocarcinoma with an area under the curve of 0.941. CONCLUSION: The findings of this project hold potential to better identify patients with adenoma who may be candidates for targeted surveillance programmes and preventive interventions to reduce the incidence of CRC.

Platelet "first responders" in wound response, cancer, and metastasis.

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.

Beyond COX-1: the effects of aspirin on platelet biology and potential mechanisms of chemoprevention.

After more than a century, aspirin remains one of the most commonly used drugs in western medicine. Although mainly used for its anti-thrombotic, anti-pyretic, and analgesic properties, a multitude of clinical studies have provided convincing evidence that regular, low-dose aspirin use dramatically lowers the risk of cancer. These observations coincide with recent studies showing a functional relationship between platelets and tumors, suggesting that aspirin's chemopreventive properties may result, in part, from direct modulation of platelet biology and biochemistry. Here, we present a review of the biochemistry and pharmacology of aspirin with particular emphasis on its cyclooxygenase-dependent and cyclooxygenase-independent effects in platelets. We also correlate the results of proteomic-based studies of aspirin acetylation in eukaryotic cells with recent developments in platelet proteomics to identify non-cyclooxygenase targets of aspirin-mediated acetylation in platelets that may play a role in its chemopreventive mechanism.

Estrogen Replacement Reduces Risk and Increases Survival Times of Women With Hepatocellular Carcinoma.

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.

Building trust and diversity in patient-centered oncology clinical trials: An integrated model.

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.