Low Rates of Retention Into Hepatocellular Carcinoma (HCC) Surveillance Program After Initial HCC Screening.

GOALS: To evaluate rates and predictors of retention into hepatocellular carcinoma (HCC) surveillance beyond initial screening among underserved cirrhosis patients. BACKGROUND: Although initial HCC screening among cirrhosis patients remains low, few studies have evaluated retention to HCC surveillance beyond initial screening. METHODS: We retrospectively evaluated all consecutive adults with cirrhosis from 2014 to 2017 at a single underserved safety net hospital system to determine rates of HCC surveillance at 6 months and at 1 year beyond initial screening. Rates of HCC surveillance was stratified by sex, race/ethnicity, and etiology of liver disease. Multivariate Cox proportional hazards models evaluated predictors of retention into HCC surveillance. RESULTS: Among 235 cirrhosis patients [hepatitis C virus: 35.7%, hepatitis B virus (HBV): 15.7%, alcoholic cirrhosis: 36.2%, nonalcoholic steatohepatitis (NASH): 8.1%], mean age of cirrhosis diagnosis was 54.2±8.9 years. Overall, 74.8% received initial screening within 1 year of cirrhosis diagnosis. Among those who completed initial screening, 47.6% [95% confidence interval (CI), 41.4-54.2) received second surveillance within 1 year. On multivariate analyses, patients with NASH and HBV were significantly more likely to receive second HCC surveillance compared with hepatitis C virus, HBV (hazard ratio, 2.32; 95% CI, 1.18-4.56; P=0.014) and NASH (hazard ratio, 2.49; 95% CI, 1.22-5.11; P=0.012). No sex or race-specific/ethnicity-specific differences in HCC surveillance retention were observed. CONCLUSIONS: Although overall rates of initial HCC screening among cirrhosis patients is nearly 75%, retention into continued HCC surveillance is poor, with less than half of patients undergoing subsequent HCC surveillance. Cirrhosis patients with HBV and NASH were more likely to be retained into HCC surveillance.

Advanced Hepatocellular Carcinoma Tumor Stage at Diagnosis in the 1945-1965 Birth Cohort Reflects Poor Use of Hepatocellular Carcinoma Screening.

Individuals from the 1945-1965 birth cohort account for the majority of hepatocellular carcinoma (HCC) cases in the United States. Understanding trends in HCC among this birth cohort is vital given the increasing burden of chronic liver disease among this group. We retrospectively evaluated trends and disparities in HCC tumor stage at the time of diagnosis among the 1945-1965 birth cohort in the United States using the Surveillance, Epidemiology, and End Results (SEER) cancer registry. Tumor stage at the time of HCC diagnosis was assessed using Milan criteria and SEER HCC staging systems. Among 38,045 patients with HCC within the 1945-1965 birth cohort (81.6% male, 50.1% non-Hispanic white, 16.2% African American, 12.6% Asian, 19.8% Hispanic), 66.2% had Medicare or commercial insurance, 27.2% had Medicaid, and 6.6% were uninsured. During the period 2004-2006 to 2013-2014, the number of patients with HCC from the 1945-1965 birth cohort increased by 58.7% (5.9% increase per year). While the proportion of patients with HCC within the Milan criteria increased with time (36.4% in 2003-2006 to 46.3% in 2013-2014; P < 0.01), less than half were within the Milan criteria. On multivariate analysis within the Milan criteria, men were 12% less likely to have HCC compared to women, and African Americans were 27% less likely to have HCC compared to non-Hispanic whites (odds ratio, 0.73; 95% confidence interval, 0.68-0.78; P < 0.01). Conclusion: From 2004 to 2014, the burden of newly diagnosed HCC among the 1945-1965 birth cohort increased by 5.9% per year. While improvements in earlier staged HCC at diagnosis were observed, the majority of patients with HCC among the 1945-1965 birth cohort were beyond the Milan criteria at diagnosis; this may reflect poor utilization or suboptimal performance of HCC screening tests.

African-Americans with Cirrhosis Are Less Likely to Receive Endoscopic Variceal Screening Within One Year of Cirrhosis Diagnosis.

BACKGROUND: Esophageal variceal hemorrhage is a complication of cirrhosis that carries high mortality, and can be reduced with timely endoscopic variceal screening and treatment. AIM: We aim to evaluate overall rates of and disparities in receipt of endoscopic variceal screening among an ethnically diverse urban safety-net hospital. METHODS: All consecutive adults with cirrhosis (7/1/2014 to 12/31/2015) were retrospectively evaluated to determine the rates of receiving esophageal variceal screening within 6 months and within 1 year after cirrhosis diagnosis. Race-/ethnicity-specific differences in rates of variceal screening were compared using chi-square testing and multivariate regression methods. RESULTS: Among 157 patients (65% male, 33.8% Hispanic, 22.3% African-American, 44.6% alcoholic liver disease, 29.9% chronic HCV), 56.8% received variceal screening within 6 months and 65.8% received screening within 1 year. Compared to non-Hispanic whites with cirrhosis, African-Americans (52.2 vs. 76.2%, p < 0.05), Asians (57.1 vs. 76.2%, p < 0.05), and Hispanics (43.9 vs. 76.2%, p < 0.05) were all significantly less likely to receive endoscopic variceal screening within 6 months after cirrhosis diagnosis. On multivariate analysis, African-Americans with cirrhosis were 66% less likely to receive variceal screening compared to non-Hispanic whites (HR 0.34, 95% CI 0.15-0.77, p < 0.01). CONCLUSION: Among adults with cirrhosis at a community-based safety-net hospital system, overall first-time variceal screening remains suboptimal. African-Americans were the least likely to receive timely variceal screening. These findings are particularly concerning given the significant barriers that ethnic minorities and safety-net populations already face in timely access to medical care.

Cirrhosis Patients with Nonalcoholic Steatohepatitis Are Significantly Less Likely to Receive Surveillance for Hepatocellular Carcinoma.

BACKGROUND: Disparities in receipt of hepatocellular carcinoma (HCC) surveillance contribute to disparities in overall survival outcomes. AIM: We aim to evaluate disparities in receipt of routine HCC surveillance among patients with cirrhosis in a large urban safety-net hospital. METHODS: Consecutive adults (age ≥ 18) with cirrhosis from July 1, 2014, to December 31, 2015, were retrospectively evaluated to determine rates of receiving appropriate HCC surveillance within 6 months and 1 year after diagnosis of cirrhosis. Rates of HCC surveillance were stratified by sex, race/ethnicity, and liver disease etiology. Multivariate Cox proportional hazards models were utilized to evaluate for predictors of receiving appropriate HCC surveillance. RESULTS: Among 157 cirrhosis patients enrolled [hepatitis C virus (HCV): 29.9%, hepatitis B virus: 13.4%, alcoholic cirrhosis: 44.6%, nonalcoholic steatohepatitis (NASH): 8.9%], mean age of cirrhosis diagnosis was 53.8 ± 9.0 years. Among these patients, 49% received (n = 77) HCC surveillance within 6 months and 78% (n = 123) were surveyed within 1 year of cirrhosis diagnosis. On multivariate analyses, patients with NASH cirrhosis were significantly less likely to receive HCC surveillance compared with chronic HCV cirrhosis patients (HR 0.44, 95% CI 0.19-0.99, p < 0.05). No significant sex-specific or race/ethnicity-specific disparities in receipt of HCC surveillance were observed. CONCLUSION: Among a diverse safety-net hospital population, sub-optimal HCC surveillance rates were observed: Only 49% of cirrhosis patients received HCC surveillance within 6 months, and 78% of cirrhosis patients received HCC surveillance within 1 year. Differences in rates of HCC screening by liver disease etiology were observed.

PTH1 receptor is involved in mediating cellular response to long-chain polyunsaturated fatty acids.

The molecular pathways by which long chain polyunsaturated fatty acids (LCPUFA) influence skeletal health remain elusive. Both LCPUFA and parathyroid hormone type 1 receptor (PTH1R) are known to be involved in bone metabolism while any direct link between the two is yet to be established. Here we report that LCPUFA are capable of direct, PTH1R dependent activation of extracellular ligand-regulated kinases (ERK). From a wide range of fatty acids studied, varying in chain length, saturation, and position of double bonds, eicosapentaenoic (EPA) and docosahexaenoic fatty acids (DHA) caused the highest ERK phosphorylation. Moreover, EPA potentiated the effect of parathyroid hormone (PTH(1-34)) in a superagonistic manner. EPA or DHA dependent ERK phosphorylation was inhibited by the PTH1R antagonist and by knockdown of PTH1R. Inhibition of PTH1R downstream signaling molecules, protein kinases A (PKA) and C (PKC), reduced EPA and DHA dependent ERK phosphorylation indicating that fatty acids predominantly activate G-protein pathway and not the ß-arrestin pathway. Using picosecond time-resolved fluorescence microscopy and a genetically engineered PTH1R sensor (PTH-CC), we detected conformational responses to EPA similar to those caused by PTH(1-34). PTH1R antagonist blocked the EPA induced conformational response of the PTH-CC. Competitive binding studies using fluorescence anisotropy technique showed that EPA and DHA competitively bind to and alter the affinity of PTH1 receptor to PTH(1-34) leading to a superagonistic response. Finally, we showed that EPA stimulates protein kinase B (Akt) phosphorylation in a PTH1R-dependent manner and affects the osteoblast survival pathway, by inhibiting glucocorticoid-induced cell death. Our findings demonstrate for the first time that LCPUFAs, EPA and DHA, can activate PTH1R receptor at nanomolar concentrations and consequently provide a putative molecular mechanism for the action of fatty acids in bone.

Apparent PKA activity responds to intermittent hypoxia in bone cells: a redox pathway?

We studied hypoxia-induced dynamic changes in the balance between PKA and PKA-counteracting phosphatases in the microfluidic environment in single cells using picosecond fluorescence spectroscopy and intramolecular fluorescence resonance energy transfer (FRET)-based sensors of PKA activity. First, we found that the apparent PKA activity in bone cells (MC3T3-E1 cells) and endothelial cells (bovine aortic endothelial cells) is rapidly and sensitively modulated by the level of O(2) in the media. When the O(2) concentration in the glucose-containing media was lowered due to O(2) consumption by the cells in the microfluidic chamber, the apparent PKA activity increases; the reoxygenation of cells under hypoxia leads to a rapid ( approximately 2 min) decrease of the apparent PKA activity. Second, lack of glucose in the media led to a lower apparent PKA activity and to a reversal of the response of the apparent PKA activity to hypoxia and reoxygenation. Third, the apparent PKA activity in cells under hypoxia was predominantly regulated via a cAMP-independent pathway since 1) changes in the cAMP level in the cells were not detected using a cAMP FRET sensor, 2) the decay of cAMP levels was too slow to account for the fast decrease in PKA activity levels in response to reoxygenation, and 3) the response of the apparent PKA activity due to hypoxia/reoxygenation was not affected by an adenylate cyclase inhibitor (MDL-12,330A) at 1 mM concentration. Fourth, the immediate onset of ROS accumulation in MC3T3-E1 cells subjected to hypoxia and the sensitivity of the apparent PKA activity to redox levels suggest that the apparent PKA activity change during hypoxia and reoxygenation in this study can be linked to a redox potential change in response to intermittent hypoxia through the regulation of activities of PKA-counteracting phosphatases such as protein phosphatase 1. Finally, our results suggest that the detection of PKA activity could be used to monitor responses of cells to hypoxia in real time.