Citations

Hepatitis B virus (HBV) genotype E (HBV‐E) accounts for the majority of chronic hepatitis B (CHB) infections in West Africa. We aimed to determine factors associated with HBV‐E‐induced hepatocellular carcinoma (HCC) in West Africa. Data on patients from Burkina Faso who were hepatitis B surface antigen positive (HBsAg+) and had CHB were analyzed. HBV viral load and hepatitis B e antigen (HBeAg) status were measured in 3,885 individuals with CHB without HCC (CHB HCC−) and 59 individuals with CHB with HCC (CHB HCC+). HBV genotyping was performed for 364 subjects with CHB HCC− and 41 subjects with CHB HCC+. Overall, 2.5% of the CHB HCC− group was HBeAg+ compared with 0% of the CHB HCC+ group. Of the 364 patients who were CHB HCC− with available genotyping, the frequencies of HBV genotypes E and C/E were 70.3% and 12.9%, respectively. Age (odds ratio [OR] for older age, 1.08; 95% confidence interval [CI], 1.06‐1.10 per 1‐year increase in age), male sex (OR, 2.03; 95% CI, 1.11‐3.69), and HBV viremia (OR, 1.48; 95% CI, 1.31‐1.67 per 1 log10 IU/mL) were each associated with HCC diagnosis. Patients with genotype E had a lower HBeAg prevalence (6.3% vs. 14.9%), lower HBV viral load, and higher prevalence of cirrhosis (14.5% vs. 4.8%) than patients with genotype C/E. Conclusion: HBV‐E is the most common circulating strain (70.3%) in West African patients. HCC was associated with older age, male sex, and high HBV viral load. It is expected that these results will further inform guidance on clinical management of HBV infection in West Africa.

Abstract Background: Upamostat is an orally available small molecule serine protease inhibitor that is a highly potent inhibitor of trypsin 1, trypsin 2 and trypsin 3 (PRSS1/2/3) as well as urokinase-type plasminogen activator (uPA) which are expressed in many cancers and mediate cell migration, invasion and tissue remodeling. Opaganib (ABC294640), a novel, orally available small molecule is a specific inhibitor of sphingosine kinase 2 (SPHK2), which phosphorylates sphingosine to sphingosine-1-phosphate (S-1-P). While proliferation induced by S-1-P is regulated by both sphingosine kinase 1 (SPHK1) and SPHK2, SPHK2 appears to be more involved in cancer. We aimed to investigate the potential antitumor effect of upamostat and opaganib, individually and in combination, on cholangiocarcinoma (CCA) patient derived xenografts (PDX) in nude mice. Methods: PAX165, a PDX from a surgically resected CCA, expresses substantial levels of SPHK2, PRSS1, PRSS2 and PRSS3. 4 groups of 18 mice were treated with either drug or both. Mouse weights and tumor volumes were measured. In addition, experiments were conducted using the chorioallantoic membrane (CAM) of chicken embryos. Results: Table 1 shows the average tumor size for the control, upamostat, opaganib, and upamostat+opaganib groups at the study end point (Day 42). Tumor volumes in the upamostat, opaganib, and upamostat+opagnib groups were significantly decreased compared to the control group. The CAM experiments are ongoing and will be presented at the AACR Annual Meeting. Change in tumor volumes (mean) of CCA PDX after opaganib, upamostat or combination treatmentControlOpaganibUpamostatOpaganib+UpamostatPre-treatment129.9128.7118.8126.8Day 42198.6102.093.3186.09Percent change Day 0-42+53%-21%-21%-32%P value vs. control0.00020.00100.0008 Conclusion: This preclinical study demonstrated that upamostat and opaganib resulted in tumor regression in mice. Body weights of the mice showed no significant inter- or intra- group differences. The combination of upamostat and opaganib treatment showed greater regression compared to either upamostat or opaganib alone. Studies are underway to identify the molecular mechanisms of their interaction. Citation Format: Faizal Z. Asumda, Mohamed A. Hassan, Yo Han Kim, Nellie A. Campbell, Xin Luo, Daniel R. O'Brien, Sarah A. Buhrow, Joel M. Reid, Michael J. Moore, Vered Katz Ben-Yair, Reza Fathi, Mark L. Levitt, Fabrice Lucien-Matteoni, Jennifer L. Leiting, Mark J. Truty, Lewis R. Roberts. Effects of upamostat and opaganib on cholangiocarcinoma patient derived xenografts [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3078.

Background: Patients with cholangiocarcinoma often have indwelling biliary stents or catheters which are prone to obstructions and/or infections; studies show that 20–40% present with fever and/or jaundice requiring urgent treatment in the outpatient setting for which there are no uniform guidelines. The goal was to develop an expert panel consensus on this topic using the modified RAND/UCLA Delphi process to rate treatment appropriateness. Methods: Thirteen expert physicians from relevant specialties, geography, and practice settings were recruited for the panel. Patient scenarios were developed and panelists rated the therapies before and after a face-to-face discussion. The appropriateness of various therapies was rated on a scale from 1–9 and classified as appropriate, inappropriate, or uncertain. Scenarios with greater than 2 (>2) ratings of 1–3 (inappropriate) and greater than 2 (>2) ratings of 7–9 (appropriate) were considered to have disagreement and were not assigned an appropriateness rating. Results: Panelists were from all US regions and the UK (8%) and had practiced for a mean 16.5 years (4–33 years). Panelists rated 480 scenarios before the meeting and re-rated 288 of the clinical scenarios after the meeting. The panelists agreed that ongoing treatment with chemotherapy did not influence decision-making and, therefore, 192 scenarios were excluded from the final list. Disagreement decreased from 37.5% before to 10.4% after the meeting. Consensus on stent/tube manipulation and inpatient antibiotic therapy was obtained and summarized in patients as “appropriate” or “maybe appropriate” based on a patient’s bilirubin level at presentation. Conclusions: The Delphi process produced consensus guidelines to fill an unmet need in the urgent management of ascending cholangitis in patients with cholangiocarcinoma.

We report for the first time that in wild-type (WT) mice, fast-food diet (FFD) induced a threefold increase in hepatic Sulf2 mRNA and a 2.2-fold increase in sulfatase 2 (SULF2) protein expression compared with WT mice on standard chow diet (SC). We showed that knockout of SULF2 ameliorates FFD-induced obesity, hyperlipidemia, steatohepatitis, and fibrosis. These data, along with work from other laboratories, suggest that SULF2 may be critical to the ability of the liver to progress to nonalcoholic steatohepatitis and fibrosis in conditions of overnutrition.

4577 Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide. Though biannual ultrasound surveillance with or without alpha-fetoprotein (AFP) testing is recommended for at-risk patients, its sensitivity for early-stage HCC detection is suboptimal. We therefore evaluated performance of a biomarker panel incorporating methylated DNA markers (MDMs) and proteins for early HCC detection in at-risk patients with chronic liver disease. Methods: In an international, multicenter, case-control study, blood specimens were collected from patients with HCC per AASLD criteria and controls matched for age and liver disease etiology. All patients had underlying cirrhosis or chronic HBV infection. Whole blood was collected in cell-free DNA stabilizing and serum-separation tubes and shipped to a central laboratory for processing. The levels of 5 MDMs, AFP, and AFP-L3 were assessed along with age and sex. We used 537 samples in a 5-fold validation for developing a LASSO regression algorithm to classify samples as HCC positive or negative. Model robustness was tested by perturbing the data in silico and analyzing results with the predictive algorithm. Algorithm performance was compared to AFP alone and the GALAD score (Gender, Age, AFP-L3, AFP, and DCP). Results: The study included 136 HCC cases (81 early-stage—BCLC stage 0/A) and 401 controls. With specificity set at 89%, we developed a model using sex, AFP, and 3 MDMs (HOXA1, TSPYL5, B3GALT6) with higher sensitivity (70%) for early-stage HCC compared to GALAD (54%) or AFP (31% at 20 ng/mL or 52% at ≥7.7 ng/mL) (Table). The AUC for the HCC marker panel was 0.91 (95% CI 0.89 – 0.94) compared to GALAD (0.88; 95% CI 0.85 – 0.91) or AFP (0.84; 95% CI 0.81 – 0.87). The panel performed similarly in viral (AUC = 0.94) and non-viral (AUC = 0.89) etiologies. Conclusions: The robust algorithm based on novel blood-based biomarkers presented here provides higher sensitivity for early-stage HCC compared to other available blood-based biomarkers and, therefore, could significantly impact HCC clinical management and patient outcomes. Further clinical studies to validate the algorithm are ongoing. Clinical trial information: NCT03628651 . [Table: see text]

AbstractDeficient intake of micronutrients involved in one‐carbon metabolism (eg, choline, methionine, vitamin B12 and folic acid) leads to hepatocellular carcinoma (HCC) development in rodents, but is under‐investigated in humans. We investigated the association between one‐carbon metabolism‐related micronutrient intake and HCC risk in a prospective cohort of 494 860 participants with 16 years of follow‐up in the NIH‐AARP study. Dietary intakes and supplement use were ascertained at baseline using a food‐frequency questionnaire. Total intake (diet plus supplements) of the following one‐carbon metabolism‐related micronutrients were calculated: folate, methionine and vitamins B2 (riboflavin), B3 (niacin), B6 and B12. These micronutrients were examined both individually and simultaneously, with adjustment for covariates. Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Over the 16‐year follow‐up period, 647 incident HCC cases were diagnosed. When examined individually, higher total vitamin B3 intake was associated with a lower HCC risk (HRQ5 vs Q1 = 0.60; 95% CI = 0.42‐0.85; Ptrend = .008), and the association remained significant when all six micronutrients were examined simultaneously (HRQ5 vs Q1 = 0.32; 95% CI = 0.18‐0.55; Ptrend < .0001). Among participants with >3 years of follow‐up, higher total vitamin B3 intake was again associated with lower risk (HRQ5 vs Q1 = 0.37; 95% CI = 0.20‐0.68; Ptrend = .001), whereas higher total vitamin B6 intake was associated with higher risk (HRQ5 vs Q1 = 2.04; 95% CI = 1.02‐4.07; Ptrend = .04). Restricted cubic spline analyses showed a dose‐response inverse association between total vitamin B3 intake and HCC risk, and dose‐response positive association between total vitamin B6 intake and HCC risk. The study suggests that higher vitamin B3 intake is associated with lower HCC risk, whereas higher vitamin B6 intake is associated with increased risk.

Abstract Background: End-stage liver disease (ESLD) is a major burden on public health, particularly in sub-Saharan Africa, where hepatitis B virus (HBV) is an important risk factor. We aimed to describe clinical characteristics of ESLD from cirrhosis or hepatocellular carcinoma (HCC) and the performance of aspartate aminotransferase (AST) - platelet ratio index (APRI) and alpha fetoprotein (AFP) in Ghana. Methods: We performed an observational cross-sectional study in outpatient hepatology clinics at three teaching hospitals in Ghana, West Africa. One hundred and forty-one HCC, 216 cirrhosis and 218 chronic HBV patients were recruited by convenience sampling. Sociodemographic, history and examination, laboratory, and disease staging information were shown using descriptive statistics. Performance of the APRI score in diagnosis of cirrhosis and Alpha fetoprotein in the diagnosis of HCC was determined using AUROC analysis.Results: Median age at presentation was 44 years for HCC and 46 years for cirrhosis. HBV was found in 69.5% of HCC and 47.2% of cirrhosis cases, and HCV in 6.4% and 3.7% respectively. APRI cut-off of 2 had sensitivity of 45.4% and specificity of 95% in diagnosis of cirrhosis, and cut-off of 1 had sensitivity of 75.9% and specificity of 89%. AUC of AFP was 0.88 (95% CI 0.81-0.94) in diagnosis of HCC. Low monthly income was associated with lower odds of undertaking AFP. Thirty one percent of cirrhotic persons were Child-Pugh C, and 67.9% of HCC patients had advanced or terminal disease at presentation. Conclusions: Our findings emphasize the young age of ESLD patients in Ghana and the advanced nature at presentation. It highlights shortcomings in surveillance and the need for policies to address the burden and improve outcomes in Ghana.