Differential preventive activity of sulindac and atorvastatin in Apc+/Min-FCCCmice with or without colorectal adenomas.

OBJECTIVE: The response of subjects to preventive intervention is heterogeneous. The goal of this study was to determine if the efficacy of a chemopreventive agent differs in non-tumour-bearing animals versus those with colorectal tumours. Sulindac and/or atorvastatin was administered to Apc+/Min-FCCC mice with known tumour-bearing status at treatment initiation. DESIGN: Male mice (6-8 weeks old) underwent colonoscopy and received control chow or chow with sulindac (300 ppm), atorvastatin (100 ppm) or sulindac/atorvastatin. Tissues were collected from mice treated for 14 weeks (histopathology) or 7 days (gene expression). Cell cycle analyses were performed on SW480 colon carcinoma cells treated with sulindac, atorvastatin or both. RESULTS: The multiplicity of colorectal adenomas in untreated mice bearing tumours at baseline was 3.6-fold higher than that of mice that were tumour free at baseline (P=0.002). Atorvastatin completely inhibited the formation of microadenomas in mice that were tumour free at baseline (P=0.018) and altered the expression of genes associated with stem/progenitor cells. Treatment of tumour-bearing mice with sulindac/atorvastatin led to a 43% reduction in the multiplicity of colorectal adenomas versus untreated tumour-bearing mice (P=0.049). Sulindac/atorvastatin increased the expression of Hoxb13 and Rprm significantly, suggesting the importance of cell cycle regulation in tumour inhibition. Treatment of SW480 cells with sulindac/atorvastatin led to cell cycle arrest (G0/G1). CONCLUSIONS: The tumour status of animals at treatment initiation dictates response to therapeutic intervention. Atorvastatin eliminated microadenomas in tumour-free mice. The tumour inhibition observed with Sul/Atorva in tumour-bearing mice was greater than that achieved with each agent.

A Community-Based Randomized Trial of Hepatitis B Screening Among High-Risk Vietnamese Americans.

OBJECTIVES: To evaluate the effectiveness of a community-based liver cancer prevention program on hepatitis B virus (HBV) screening among low-income, underserved Vietnamese Americans at high risk. METHODS: We conducted a cluster randomized trial involving 36 Vietnamese community-based organizations and 2337 participants in Pennsylvania, New Jersey, and New York City between 2009 and 2014. We randomly assigned 18 community-based organizations to a community-based multilevel HBV screening intervention (n = 1131). We randomly assigned the remaining 18 community-based organizations to a general cancer education program (n = 1206), which included information about HBV-related liver cancer prevention. We assessed HBV screening rates at 6-month follow-up. RESULTS: Intervention participants were significantly more likely to have undergone HBV screening (88.1%) than were control group participants (4.6%). In a Cochran-Mantel-Haenszel analysis, the intervention effect on screening outcomes remained statistically significant after adjustment for demographic and health care access variables, including income, having health insurance, having a regular health provider, and English proficiency. CONCLUSIONS: A community-based, culturally appropriate, multilevel HBV screening intervention effectively increases screening rates in a high-risk, hard-to-reach Vietnamese American population.

Biomarkers in Colorectal Cancer Screening.

Colorectal cancer (CRC) is the third most common cause of cancer death in men and women in the United States. The main goals of screening are to prevent carcinogenesis (via adenoma detection and removal) and detect cancer at an early, curable stage. CRC mortality is steadily dropping in the United States, partly because of greater screening utilization. However, nearly 1 in 3 average-risk people are not up to date with standard CRC screening recommendations. This review surveys a wide range of CRC biomarkers in various stages of development, which may offer attractive risk stratification tools; a few have reached the commercial stage. If widely accepted, these tools may contribute to shift CRC screening practices away from 1-step colonoscopy to a 2-step risk stratification process of predictive biomarker measurements followed by colonoscopy for lower-risk patients with a positive result. Such strategies could potentially increase the rate of CRC screening.

Multilevel and multicomponent intervention to promote colorectal cancer screening among underserved Vietnamese Americans: A cluster randomized trial.

Purpose: The fecal immunochemical test (FIT) is a non-invasive method for colorectal cancer (CRC) screening, particularly effective in underserved Vietnamese American communities with low screening rates. This study reports on a culturally tailored multilevel intervention, incorporating FIT, aimed at increasing CRC screening among these populations aged 50 or above in the Greater Philadelphia metropolitan area. Methods: From 2017 to 2020, we conducted a two-arm cluster randomized controlled trial to test the efficacy of a culturally tailored, multicomponent multilevel intervention aimed at increasing CRC screening uptake via enhanced self-awareness and self-efficacy, improved access to care, and changes in social norms and removal of stigma. The intervention group received multicomponent, multilevel CRC intervention including provision of a FIT self-sampling kit, with intervention approaches informed by the Centers for Disease Control's Clinical Preventive Services (CPS) Guidelines for adults 50+. The control group received only the CPS education. Results: The study sample consisted of 746 eligible Vietnamese American participants recruited from 20 community-based organizations, with 95% having limited English proficiency. At 12-month follow-up, the intervention group showed substantially higher rates of FIT completion (89.56% vs. 7.59%, p < .001) and any CRC testing (91.48% vs. 42.41%, p < .001) compared to the control group. Conclusion: The results suggest that the community-based, culturally-tailored multilevel intervention, which incorporates with FIT self-testing, effectively enhances CRC screening among low-income Vietnamese Americans. Additionally, these results underscore the significance of community-oriented strategies, like collaborating with relevant community-based organizations, in achieving CRC screening targets.

The effect of social determinants of health on utilization of surgical treatment for hepatocellular carcinoma patients.

BACKGROUND: A paucity of data exists on how social determinants of health (SDOH) influence treatment for Hepatocellular carcinoma (HCC). We investigated associations between SDOH (healthcare access, education, social/community context, economic stability, and built/neighborhood environment) and receipt of surgery. METHODS: The Pennsylvania Liver Cancer Registry was linked with neighborhood SDOH from the American Community Survey. Multilevel logistic regression models with patient and neighborhood SDOH variables were developed. RESULTS: Of 9423 HCC patients, 2393 were stage I. Only 36.3% of stage I patients received surgery. Black patients had significantly lower odds of surgery vs Whites (OR = 0.73; p < 0.01), but not after adjustments for SDOH. All 5 SDOH domains were associated with odds of surgery overall; 2 domains were associated in Stage I patients, social context (e.g., racial concentration, p = 0.03) and insurance access (p < 0.01). CONCLUSIONS: SDOH impact utilization of surgery for HCC. Findings can guide healthcare professionals to create programs for populations at risk for poor liver cancer outcomes.

Improving Long-Term Adherence to Monitoring/Treatment in Underserved Asian Americans with Chronic Hepatitis B (CHB) through a Multicomponent Culturally Tailored Intervention: A Randomized Controlled Trial.

BACKGROUND: Although Asian Americans make up 6% of the U.S. population, they account for 58% of Americans with chronic hepatitis B (CHB). Yet, adherence to monitoring and antiviral treatment guidelines among Asian American CHB patients remains suboptimal. METHODS: The purpose of this study was to evaluate the efficacy of a multicomponent intervention on adherence to CHB monitoring among Asian Americans with CHB. The intervention components included virtual patient education, patient navigation, and mobile health reminders delivered by bilingual community health educators. Chi-square test and t-test were used to compare demographic characteristics and two CHB measures: CHB clinical follow-up and CHB laboratory monitoring by the time of the 12-month follow-up assessment. A generalized linear mixed-effects model (GLMM) was fitted to assess the effectiveness of the intervention. RESULTS: The study sample consisted of 358 Chinese and Vietnamese Americans living with CHB, including 181 in the intervention group and 177 in the control group. The intervention group had a significantly higher rate of CHB clinical follow-up (86.2%) and CHB laboratory monitoring (79.0%) than did the control group (54.2% and 45.2%, respectively). Results of the GLMM showed significant intervention effects on CHB clinical follow-up (odds ratio = 7.35, 95% confidence interval = 4.06-13.33) and CHB laboratory monitoring (odds ratio = 6.60, 95% confidence interval = 3.77-11.56) at the 12-month follow-up assessment. CONCLUSION: The multicomponent intervention was effective in improving adherence to CHB monitoring among Asian Americans. Additional implementation research is needed to better understand and apply effective interventions to other underserved populations.

Examining the Influencing Factors of Chronic Hepatitis B Monitoring Behaviors among Asian Americans: Application of the Information-Motivation-Behavioral Model.

Background: Compared to non-Hispanic whites, Asian Americans are 60% more likely to die from the disease. Doctor visitation for chronic hepatitis B (CHB) infection every six months is an effective approach to preventing liver cancer. Methods: This study utilized baseline data from an ongoing randomized controlled clinical trial aimed at improving long-term adherence to CHB monitoring/treatment. Guided by the information-motivation-behavioral skills (IMB) model, we examined factors associated with CHB monitoring adherence among Asian Americans with CHB. Multivariable logistic regression was conducted to test the associations. Results: The analysis sample consisted of 382 participants. Multivariable logistic regression showed that HBV knowledge (OR = 1.24, p < 0.01) and CHB-management motivation (OR = 1.06, p < 0.05) are significant predictors of having a doctor's visit in the past six months. Both factors were positively associated with the likelihood of having had blood tests for HBV in the past six months. Conclusion: We found that greater HBV-related knowledge and CHB-management motivation are significantly associated with performing CHB-monitoring behaviors in the past six months. The findings have critical implications for the development and implementation of evidence-based interventions for CHB monitoring and liver cancer prevention in the Asian American community.

Factors Associated with Hepatitis B Medication Adherence and Persistence among Underserved Chinese and Vietnamese Americans.

BACKGROUND: Hepatitis B virus (HBV) infection disproportionately affects Asian Americans in the United States, while this population faces low adherence to HBV treatment. Using the information-motivation-behavioral skills model (IMB), the study aims to examine medication adherence and persistence among Chinese and Vietnamese people with HBV. METHODOLOGY: Study participants were recruited between March 2019 and March 2020 and were enrolled through multiple recruitment approaches in the Greater Philadelphia Area and New York City. The study is an assessment of the baseline data on medication adherence, HBV-related knowledge, motivation of HBV medication treatment, self-efficacy about HBV medication treatment, and socioeconomic status. RESULTS: Among 165 participants, 77.6% were Chinese and 22.4% were Vietnamese Americans. HBV-related knowledge/information, motivation, and self-efficacy were all positively associated with having medium/high medication adherence. Multilevel mixed-effects generalized linear regression revealed that living more than 10 years in the U.S. (OR = 4.24; p = 0.028) and greater information-knowledge about HBV (OR = 1.46; p = 0.004) were statistically associated with higher odds of medium/high medication adherence. Moreover, greater HBV-related knowledge/information (OR = 1.49; p = 0.023) and greater motivation towards HBV treatment adherence (OR = 1.10; p = 0.036) were both associated with a higher likelihood of medication persistence. CONCLUSION: Our findings provided significant implications in designing behavioral interventions focused on self-efficacy, information, and motivation to promote better medication adherence among Asian Americans living with HBV.

Liver Cancer Incidence and Area-Level Geographic Disparities in Pennsylvania-A Geo-Additive Approach.

Many neighborhood socioeconomic index measures (nSES) that capture neighborhood deprivation exist but the impact of measure selection on liver cancer (LC) geographic disparities remains unclear. We introduce a Bayesian geoadditive modeling approach to identify clusters in Pennsylvania (PA) with higher than expected LC incidence rates, adjusted for individual-level factors (age, sex, race, diagnosis year) and compared them to models with 7 different nSES index measures to elucidate the impact of nSES and measure selection on LC geospatial variation. LC cases diagnosed from 2007-2014 were obtained from the PA Cancer Registry and linked to nSES measures from U.S. census at the Census Tract (CT) level. Relative Risks (RR) were estimated for each CT, adjusted for individual-level factors (baseline model). Each nSES measure was added to the baseline model and changes in model fit, geographic disparity and state-wide RR ranges were compared. All 7 nSES measures were strongly associated with high risk clusters. Tract-level RR ranges and geographic disparity from the baseline model were attenuated after adjustment for nSES measures. Depending on the nSES measure selected, up to 60% of the LC burden could be explained, suggesting methodologic evaluations of multiple nSES measures may be warranted in future studies to inform LC prevention efforts.

Towards precision public health: Geospatial analytics and sensitivity/specificity assessments to inform liver cancer prevention.

OBJECTIVES: Liver cancer (LC) continues to rise, partially due to limited resources for prevention. To test the precision public health (PPH) hypothesis that fewer areas in need of LC prevention could be identified by combining existing surveillance data, we compared the sensitivity/specificity of standard recommendations to target geographic areas using U.S. Census demographic data only (percent (%) Hispanic, Black, and those born 1950-1959) to an alternative approach that couples additional geospatial data, including neighborhood socioeconomic status (nSES), with LC disease statistics. METHODS: Pennsylvania Cancer Registry data from 2007-2014 were linked to 2010 U.S. Census data at the Census tract (CT) level. CTs in the top 80th percentile for 3 standard demographic variables, %Hispanic, %Black, %born 1950-1959, were identified. Spatial scan statistics (SatScan) identified CTs with significantly elevated incident LC rates (p-value<0.05), adjusting for age, gender, diagnosis year. Sensitivity, specificity, and positive predictive value (PPV) of a CT being located in an elevated risk cluster and/or testing positive/negative for at least one standard variable were calculated. nSES variables (deprivation, stability, segregation) significantly associated with LC in regression models (p < 0.05) were systematically evaluated for improvements in sensitivity/specificity. RESULTS: 9,460 LC cases were diagnosed across 3,217 CTs. 1,596 CTs were positive for at least one of 3 standard variables. 5 significant elevated risk clusters (CTs = 402) were identified. 324 CTs were positive for a high risk cluster AND standard variable (sensitivity = 92%; specificity = 37%; PPV = 17.4%). Incorporation of 3 new nSES variables with one standard variable (%Black) further improved sensitivity (93%), specificity (62.9%), and PPV (26.3%). CONCLUSIONS: We introduce a quantitative assessment of PPH by applying established sensitivity/specificity assessments to geospatial data. Coupling existing disease cluster and nSES data can more precisely identify intervention targets with a liver cancer burden than standard demographic variables. Thus, this approach may inform prioritization of limited resources for liver cancer prevention.

Mechanisms of hepatocellular carcinoma progression.

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver. It is the second leading cause of cancer-related deaths worldwide, with a very poor prognosis. In the United States, there has been only minimal improvement in the prognosis for HCC patients over the past 15 years. Details of the molecular mechanisms and other mechanisms of HCC progression remain unclear. Consequently, there is an urgent need for better understanding of these mechanisms. HCC is often diagnosed at advanced stages, and most patients will therefore need systemic therapy, with sorafenib being the most common at the present time. However, sorafenib therapy only minimally enhances patient survival. This review provides a summary of some of the known mechanisms that either cause HCC or contribute to its progression. Included in this review are the roles of viral hepatitis, non-viral hepatitis, chronic alcohol intake, genetic predisposition and congenital abnormalities, toxic exposures, and autoimmune diseases of the liver. Well-established molecular mechanisms of HCC progression such as epithelial-mesenchymal transition, tumor-stromal interactions and the tumor microenvironment, cancer stem cells, and senescence bypass are also discussed. Additionally, we discuss the roles of circulating tumor cells, immunomodulation, and neural regulation as potential new mechanisms of HCC progression. A better understanding of these mechanisms could have implications for the development of novel and more effective therapeutic and prognostic strategies, which are critically needed.

Community-Clinical Linkage Intervention to Improve Colorectal Cancer Screening Among Underserved Korean Americans.

Korean Americans report the lowest and declined rates of colorectal cancer (CRC) screening, compared to general population in the United States. The present study aimed to evaluate the efficacy of a community-based multifaceted intervention designed to improve CRC screening among Korean Americans. A cluster-randomized trial involving 30 Korean church-based community organizations (n = 925) was conducted. Fifteen churches were assigned to intervention (n=470) and the other 15 to control (n = 455) groups. Main components of the intervention included interactive group education, patient navigation, physician engagement, and provision of fecal immunochemical test (FIT) kit. CRC screening rates were assessed at a 12-month follow-up. Participants in the intervention group were significantly more likely to receive CRC screening (69.3%) as compared with those in the control group (16%). The intervention was particularly effective in promoting FIT among the more disadvantaged individuals in the Korean American community. Regression analysis revealed that controlling for the intervention effect, male gender, high school education, annual income of $20,000-40,000 were significantly associated with increased screening by FIT, whereas English inefficiency was significantly and lack of health insurance was marginally significantly associated with decreased screening by colonoscopy/sigmoidoscopy. Culturally and linguistically appropriate multifaceted intervention combining FIT provision with community-clinical linkage has a potential to be a cost-effective and practical approach to effectively targeting hard-to-reach disadvantaged minority populations and enhance CRC screening to reduce cancer disparities.

Psychosocial Predictors of HBV Screening Behavior among Vietnamese Americans.

OBJECTIVE: We evaluated the influence of psychosocial factors on HBV screening. METHODS: Sample consisted of 1716 Vietnamese participants in our previous HBV intervention trial, recruited from 36 community-based organizations in Pennsylvania, New Jersey, and New York City between 2009 and 2014. Using the Health Belief Model and Social Cognitive Theory, we measured self-efficacy, knowledge, perceived barriers, perceived benefits, perceived severity, and risk susceptibility. Analysis of covariance was used to compare pre- and post-intervention changes of psychosocial variables. Structural equation modeling was used to explore the direct and indirect effects of the psychosocial variables on HBV screening. RESULTS: Knowledge, self-efficacy, perceived benefits, and perceived barriers were directly associated with HBV screening; knowledge had the strongest effect. Perceived severity and risk susceptibility had indirect association with HBV screening through other variables. Indirect paths among the 6 psychosocial variables were also identified. CONCLUSION: To promote HBV screening among Vietnamese Americans, intervention efforts should focus on increasing knowledge, self-efficacy, and perceived benefits, decreasing perceived barriers, and accounting for the dynamic cognitive processing.

Description of a new hepatitis C risk assessment tool.

BACKGROUND: Because of the low prevalence of hepatitis C virus (HCV) infection in the general population, mass screening would be expensive and of low yield. Some researchers advocate targeted screening of persons at elevated HCV risk. METHODS: This cross-sectional study aimed to develop a patient-administered tool to assess HCV infection risk. Two hundred seven patients with unknown HCV status from a general medicine practice and 222 HCV-positive patients from a hepatology practice completed a 72-item survey about demographic, social, and clinical risk factors for HCV infection. General medicine patients also underwent HCV serologic testing. RESULTS: Three (1.5%) of 207 general medicine patients had positive HCV antibody test results. These patients plus the 222 hepatology patients were significantly more likely than HCV-negative patients to report an array of factors. In a multivariable model, 7 factors remained significantly associated with HCV infection: sex with a prostitute or an injecting drug user, exposure to blood products, refusal as a blood donor or as a life insurance applicant, witnessing illicit drug use, and self-reported HBV infection. A simplified model that assigned 1 point for each factor present predicted HCV infection as well as a weighted model (based on chi(2) testing and receiver operating characteristic curve comparison). In a population with a 2% prevalence of HCV infection, people who identified 2 risk factors had a 10% chance of HCV infection, whereas those with 4 or more risk factors had a 50% chance. CONCLUSIONS: A self-administered 72-item questionnaire can stratify patients into HCV risk groups. If validated in other primary care populations, this instrument could help target HCV screening.

Detection of colorectal adenomas using a bioactivatable probe specific for matrix metalloproteinase activity.

A significant proportion of colorectal adenomas, in particular those that lack an elevated growth component, continue to escape detection during endoscopic surveillance. Elevation of the activity of matrix metalloproteinases (MMPs), a large family of zinc endopeptidases, in adenomas serves as a biomarker of early tumorigenesis. The goal of this study was to assess the feasibility of using a newly developed near-infrared bioactivatable probe (MMPSense 680) that reports the activity of a broad array of MMP isoforms to detect early colorectal adenomas. Adenomatous polyposis coli (Apc)(+/Min-FCCC) mice that spontaneously develop multiple colorectal adenomas were injected with MMPSense 680, and the colons were imaged in an IVIS Spectrum system ex vivo. Image analyses were correlated with histopathologic findings for all regions of interest (ROIs). The biochemical basis of fluorescent signal was investigated by immunohistochemical staining of MMP-7 and -9. A strong correlation (Kendall = 0.80) was observed between a positive signal and the presence of pathologically confirmed colonic adenomas; 92.9% of the 350 ROIs evaluated were classified correctly. The correlation between two independent observers was 0.87. MMP-7 expression was localized to epithelial cells of adenomas and microadenomas, whereas staining of MMP-9 was found in infiltrating polymorphonuclear leukocytes within the adenomas. MMPSense 680 identifies colorectal adenomas, both polypoid and nonpolypoid, in Apc(+/Min-FCCC) mice with high specificity. Use of this fluorescent probe in combination with colonoscopy could aid in preventing colorectal neoplasias by providing new opportunities for early detection and therapeutic intervention.

Focal distribution of hepatitis C virus RNA in infected livers.

BACKGROUND: Hepatitis C virus (HCV) is a plus-strand RNA virus that replicates by amplification of genomic RNA from minus strands leading to accumulation of almost one thousand copies per cell under in vitro cell culture conditions. In contrast, HCV RNA copy numbers in livers of infected patients appear to be much lower, estimated at a few copies per cell. METHODOLOGY/PRINCIPAL FINDINGS: To gain insights into mechanisms that control HCV replication in vivo, we analyzed HCV RNA levels as well as expression of interferon beta (IFNbeta) and several interferon stimulated genes (ISGs) from whole liver sections and micro-dissected subpopulations of hepatocytes in biopsy samples from 21 HCV-infected patients. The results showed that intrahepatic HCV RNA levels range form less than one copy per hepatocyte to a maximum of about eight. A correlation existed between viral RNA levels and IFNbeta expression, but not between viral RNA and ISG levels. Also, IFNbeta expression did not correlate with ISGs levels. Replication of HCV RNA occurred in focal areas in the liver in the presence of a general induction of ISGs. CONCLUSION/SIGNIFICANCE: The low average levels of HCV RNA in biopsy samples can be explained by focal distribution of infected hepatocytes. HCV replication directly induces IFNbeta, which then activates ISGs. The apparent lack of a correlation between levels of IFNbeta and ISG expression indicates that control of the innate immune response during HCV infections depends on multiple factors.

Proteomic analyses of pancreatic cyst fluids.

OBJECTIVES: There are currently no diagnostic indicators that are consistently reliable, obtainable, and conclusive for diagnosing and risk-stratifying pancreatic cysts. Proteomic analyses were performed to explore pancreatic cyst fluids to yield effective diagnostic biomarkers. METHODS: We have prospectively recruited 20 research participants and prepared their pancreatic cyst fluids specifically for proteomic analyses. Proteomic approaches applied were as follows: (1) matrix-assisted laser-desorption-ionization time-of-flight mass spectrometry peptidomics with LC/MS/MS (HPLC-tandem mass spectrometry) protein identification; (2) 2-dimensional gel electrophoresis; (3) GeLC/MS/MS (tryptic digestion of proteins fractionated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and identified by LC/MS/MS). RESULTS: Sequencing of more than 350 free peptides showed that exopeptidase activities rendered peptidomics of cyst fluids unreliable; protein nicking by proteases in the cyst fluids produced hundreds of protein spots from the major proteins, making 2-dimensional gel proteomics unmanageable; GeLC/MS/MS revealed a panel of potential biomarker proteins that correlated with carcinoembryonic antigen (CEA). CONCLUSIONS: Two homologs of amylase, solubilized molecules of 4 mucins, 4 solubilized CEA-related cell adhesion molecules (CEACAMs), and 4 S100 homologs may be candidate biomarkers to facilitate future pancreatic cyst diagnosis and risk-stratification. This approach required less than 40 microL of cyst fluid per sample, offering the possibility to analyze cysts smaller than 1 cm in diameter.