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

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

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

Background: Hepatitis B virus (HBV) infection disproportionately affects Asian Amer- icans 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 assess- ment of the baseline data on medication adherence, HBV-related knowledge, motivation of HBV med- ication 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 im- plications in designing behavioral interventions focused on self-efficacy, information, and motivation to promote better medication adherence among Asian Americans living with HBV

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 (IFNb) 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 IFNb expression, but not between viral RNA and ISG levels. Also, IFNb 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 IFNb, which then activates ISGs. The apparent lack of a correlation between levels of IFNb and ISG expression indicates that control of the innate immune response during HCV infection

Detection of Colorectal Adenomas Using a Bioactivatable Probe Specific for Matrix Metalloproteinase Activity1

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

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

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

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

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. 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. 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). SDOH impact utilization of surgery for HCC. Findings can guide healthcare professionals to create programs for populations at risk for poor liver cancer outcomes. •Neighborhood SDOH domains related to built environment, education, economics, social context affect utilization of HCC surgery.•Black patients had significantly lower odds of surgery vs Whites but not after adjustments for SDOH.•Any patients with insurances other than private insurance had lower odds of surgery for HCC