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Hepatitis B virus (HBV) chronically infects an estimated 300 million people, and standard treatments are rarely curative. Infection increases the risk of liver cirrhosis and hepatocellular carcinoma, and consequently, nearly 1 million people die each year from chronic hepatitis B. Tools and approaches that bring insights into HBV biology and facilitate the discovery and evaluation of antiviral drugs are in demand. Here, we describe a method to initiate the replication of HBV, a DNA virus, using synthetic RNA. This approach eliminates contaminating background signals from input virus or plasmid DNA that plagues existing systems and can be used to study multiple stages of HBV replication. We further demonstrate that this method can be uniquely applied to identify sequence variants that confer resistance to antiviral drugs.

Background: Hepatocellular carcinoma (HCC) patient-derived xenograft (PDX) models hold potential to advance knowledge in HCC biology to help improve systemic therapies. Beside hepatitis B virus-associated tumors, HCC is poorly established in PDX., Methods: PDX formation from fresh HCC biopsies were obtained and implanted intrahepatically or in subrenal capsule (SRC). Mouse liver injury was induced in immunodeficient Fah -/-  mice through cycling off nitisinone after HCC biopsy implantation, versus continuous nitisinone as non-liver injury controls. Mice with macroscopically detectable PDX showed rising human alpha1-antitrypsin (hAAT) serum levels, and conversely, no PDX was observed in mice with undetectable hAAT., Results: Using rising hAAT as a marker for PDX formation, 20 PDX were established out of 45 HCC biopsy specimens (44%) reflecting the four major HCC etiologies most commonly identified at Memorial SloanKettering similar to many other institutions in the United States. PDX was established only in severely immunodeficient mice lacking lymphocytes and NK cells. Implantation under the renal capsule improved PDX formation two-fold compared to intrahepatic implantation. Two out of 18 biopsies required murine liver injury to establish PDX, one associated with hepatitis C virus and one with alcoholic liver disease. PDX tumors were histologically comparable to biopsy specimens and 75% of PDX lines could be passaged., Conclusions: Using cycling off nitisinone-induced liver injury, HCC biopsies implanted under the renal capsule of severely immunodeficient mice formed PDX with 57% efficiency as determined by rising hAAT levels. These findings facilitate a more efficient make-up of PDX for research into subset-specific HCC., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

To repurpose therapeutics for fibrolamellar carcinoma (FLC), we developed and validated patient-derived xenografts (PDX) from surgical resections. Most agents used clinically and inhibitors of oncogenes overexpressed in FLC showed little efficacy on PDX. A high-throughput functional drug screen found primary and metastatic FLC were vulnerable to clinically available inhibitors of TOPO1 and HDAC and to napabucasin. Napabucasin's efficacy was mediated through reactive oxygen species and inhibition of translation initiation, and specific inhibition of eIF4A was effective. The sensitivity of each PDX line inversely correlated with expression of the antiapoptotic protein Bcl-xL, and inhibition of Bcl-xL synergized with other drugs. Screening directly on cells dissociated from patient resections validated these results. This demonstrates that a direct functional screen on patient tumors provides therapeutically informative data within a clinically useful time frame. Identifying these novel therapeutic targets and combination therapies is an urgent need, as effective therapeutics for FLC are currently unavailable. SIGNIFICANCE: Therapeutics informed by genomics have not yielded effective therapies for FLC. A functional screen identified TOPO1, HDAC inhibitors, and napabucasin as efficacious and synergistic with inhibition of Bcl-xL. Validation on cells dissociated directly from patient tumors demonstrates the ability for functional precision medicine in a solid tumor. This article is highlighted in the In This Issue feature, p. 2355 ., (©2021 The Authors; Published by the American Association for Cancer Research.)

Objectives: Our program routinely used fluorodeoxyglucose-positron emission tomography/computed tomography as part of the liver transplant evaluation of patients with hepatocellular carcinoma. The aim of this study was to evaluate the role of this imaging modality in the pretransplant work-up., Materials and Methods: This was a retrospective chart review of our liver transplant database from January 2011 to December 2014 for all patients with hepatocellular carcinoma who underwent a liver transplant. Collected data included age, sex, cause of liver disease, imaging modality, fluorodeoxyglucose-positron emission tomography/computed tomography results, explant tissue analysis, type of transplant, and transplant outcome., Results: During the study period, 275 liver transplants were performed. Fifty-three patients had hepatocellular carcinoma; 41 underwent fluorodeoxyglucose-positron emission tomography/computed tomography. Twenty-nine patients underwent living-donor liver transplant, and 12 patients underwent deceased-donor liver transplant. One of the 41 patients with negative FDG-imaging results had no evidence of hepatocellular carcinoma in the explant and was excluded from the study. The patients' average age was 58 years (range, 22-72 y), and 28 patients were men. The cause of liver disease was hepatitis C virus in 24 patients, cryptogenic cirrhosis in 12 patients, and hepatitis B virus in 5 patients. One patient had no hepatocellular carcinoma on explants and was excluded from the study. Twenty-five patients had hepatocellular carcinoma that met the Milan criteria, 7 were within the UCSF (University of California, San Francisco) criteria, and 8 exceeded the UCSF criteria. Of the 40 patients, 11 had positive fluorodeoxyglucose-positron emission tomography/computed tomography results (27.5%) with evidence of hepatocellular carcinoma in the explant; the remaining 29 patients (72.5%) had negative results. The fluorodeoxyglucose-positron emission tomography/computed tomography results were positive in 16% (4 of 21) of patients who met the Milan criteria, 28% (2 of 7) of patients who met the UCSF criteria and 62% (5 of 8) of patients who exceeded the UCSF criteria., Conclusions: Fluorodeoxyglucose-positron emission tomography/computed tomography has a low degree of use in patients with hepatocellular carcinoma that falls within the Milan criteria and should not be routinely used as part of the liver transplant work-up.

Recognizing the significant prevalence of hepatocellular carcinoma (HCC) in Saudi Arabia, and the difficulties often faced in early and accurate diagnoses, evidence-based management, and the need for appropriate referral of HCC patients, the Saudi Association for the Study of Liver diseases and Transplantation (SASLT) formed a multi-disciplinary task force to evaluate and update the previously published guidelines by the Saudi Gastroenterology Association. These guidelines were later reviewed, adopted and endorsed by the Saudi Oncology Society (SOS) as its official HCC guidelines as well. The committee assigned to revise the Saudi HCC guidelines was composed of hepatologists, oncologists, liver surgeons, transplant surgeons, and interventional radiologists. Two members of the task force served as guidelines editors. A wide based search on all published reports on all aspects of the epidemiology, natural history, risk factors, diagnosis, and management of HCC was performed. All available literature was critically examined and available evidence was then classified according to its strength. The whole document and the recommendations were then discussed in detail by members and consensus was obtained. All recommendations in these guidelines were based on the best available evidence, but were tailored to the patients treated in Saudi Arabia. We hope that these guidelines will improve HCC patient care and enhance the multidisciplinary care needed for these patients.