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Immune checkpoint inhibitors (ICIs) are monoclonal antibodies targeting immune checkpoint molecules. ICIs are an immunotherapy for the treatment of many advanced malignancies. The advent of ICIs has been a major breakthrough in the field of oncology, a fact recognized by the 2018 Nobel Prize in Physiology or Medicine being awarded for the discovery. The Food and Drug Administration approved the first ICI, ipilimumab, in 2011 for the treatment of metastatic melanoma. Seven ICIs are now used in clinical practice, including nivolumab and pembrolizumab for treatment of advanced hepatocellular carcinoma. ICIs are increasingly used across the spectrum of hepatobiliary neoplasia. The utility of ICI therapy has been limited by immune-related adverse reactions (irAEs) affecting multiple organ systems. Hepatotoxicity is an important irAE, occurring in up to 16% of patients receiving ICIs. Optimizing outcomes in patients receiving ICI therapy requires awareness of and familiarity with diagnosing and management of ICI-induced immune-mediated hepatotoxicity (IMH), including approaches to treatment and ICI dose management. The aim of this review article is to (1) provide a comprehensive, evidence-based review of IMH; (2) perform a systematic review of the management of IMH; and (3) present algorithms for the diagnosis and management of IMH., (© 2020 by the American Association for the Study of Liver Diseases.)

Aim: To assess the performance of BALAD, BALAD-2 and their component biomarkers in predicting outcome of hepatocellular carcinoma (HCC) patients after liver transplant., Methods: BALAD score and BALAD-2 class are derived from bilirubin, albumin, alpha-fetoprotein (AFP), Lens culinaris agglutinin-reactive AFP (AFP-L3), and des-gamma-carboxyprothrombin (DCP). Pre-transplant AFP, AFP-L3 and DCP were measured in 113 patients transplanted for HCC from 2000 to 2008. Hazard ratios (HR) for recurrence and death were calculated. Univariate and multivariate regression analyses were conducted. C-statistics were used to compare biomarker-based to predictive models., Results: During a median follow-up of 12.2 years, 38 patients recurred and 87 died. The HRs for recurrence in patients with elevated AFP, AFP-L3, and DCP defined by BALAD cut-off values were 2.42 (1.18-5.00), 1.86 (0.98-3.52), and 2.83 (1.42-5.61), respectively. For BALAD, the HRs for recurrence and death per unit increased score were 1.48 (1.15-1.91) and 1.59 (1.28-1.97). For BALAD-2, the HRs for recurrence and death per unit increased class were 1.45 (1.06-1.98) and 1.38 (1.09-1.76). For recurrence prediction, the combination of three biomarkers had the highest c-statistic of 0.66 vs. 0.64, 0.61, 0.53, and 0.53 for BALAD, BALAD-2, Milan, and UCSF, respectively. Similarly, for death prediction, the combination of three biomarkers had the highest c-statistic of 0.66 vs 0.65, 0.61, 0.52, and 0.50 for BALAD, BALAD-2, Milan, and UCSF. A new model combining biomarkers with tumor size at the time of transplant (S-LAD) demonstrated the highest predictive capability with c-statistics of 0.71 and 0.69 for recurrence and death., Conclusion: BALAD and BALAD-2 are valid in transplant HCC patients, but less predictive than the three biomarkers in combination or the three biomarkers in combination with maximal tumor diameter (S-LAD)., Competing Interests: Conflict-of-interest statement: Roberts LR has received grant funding from BTG, Gilead Sciences and Wako Life Sciences; Yamada H is an employee of Wako Life Sciences. There are no other potential conflicts of interest for the rest of the authors.

Growing evidence suggests that pretransplant alpha-fetoprotein (AFP) predicts outcomes of hepatocellular carcinoma (HCC) patients treated with liver transplantation. We aimed to determine whether pretransplant AFP, Lens culinaris agglutinin-reactive alpha-fetoprotein (AFP-L3), and des-gamma-carboxyprothrombin (DCP) predicted HCC recurrence after transplantation. A retrospective cohort study of 313 HCC patients undergoing transplantation between 2000 and 2008 was conducted, and 48 (15.3%) developed recurrence during a median follow-up of 90.8 months. The 127 patients with available serum drawn before transplantation were included; they included 86 without recurrence and 41 with recurrence. Serum was tested for AFP, AFP-L3%, and DCP in a blinded fashion with the μTASWako i30 immunoanalyzer. All biomarkers were significantly associated with HCC recurrence. The hazard ratios (HRs) were 3.5 [95% confidence interval (CI), 1.9-6.7; P < 0.0001] for DCP ≥ 7.5 ng/mL and 2.8 (95% CI, 1.4-5.4; P = 0.002) for AFP ≥ 250 ng/mL. The HR increased to 5.2 (95% CI, 2.3-12.0; P < 0.0001) when AFP ≥ 250 ng/mL and DCP ≥7.5 ng/mL were considered together. When they were combined with the Milan criteria, the HR increased from 2.6 (95% CI, 1.4-4.7; P = 0.003) for outside the Milan criteria to 8.6 (95% CI, 3.0-24.6; P < 0.0001) for outside the Milan criteria and AFP ≥ 250 ng/mL and to 7.2 (95% CI, 2.8-18.1; P < 0.0001) for outside the Milan criteria and DCP ≥7.5 ng/mL. Our findings suggest that biomarkers are useful for predicting the risk of HCC recurrence after transplantation. Using both biomarkers and the Milan criteria may be better than using the Milan criteria alone in optimizing the decision of liver transplantation eligibility., (© 2015 American Association for the Study of Liver Diseases.)

Transarterial chemoembolization (TACE) is a common treatment for patients with hepatocellular carcinoma (HCC) who are awaiting liver transplantation (LT). The aim of this study was to assess the impact of multiple TACE treatments on tumor necrosis, tumor recurrence, and survival in these patients. A retrospective analysis was performed for 104 consecutive patients undergoing LT for HCC from January 2002 to December 2009 who were treated with TACE before LT. The number of TACE treatments was not associated with tumor necrosis in the explant. After a median follow-up of 69 months (range = 0-123 months), 14 of the 104 patients (13%) developed recurrent HCC after LT. Recurrence had a significant relationship with a short interval between the diagnosis of HCC and LT (≤6 months) in univariate and multivariate analyses [P = 0.029, odds ratio (OR) = 19.2]. Patients subjected to a single TACE treatment were more likely to experience recurrence, although this finding was not confirmed in the multivariate analysis. No significant relationship was observed between tumor necrosis in the explant and recurrence. The mean overall survival was 102.8 months (95% confidence interval = 94.9-110.8 months) with 1-, 3-, and 5-year survival rates of 91%, 89%, and 84% respectively. In the univariate survival analysis, the presence of ascites before TACE, a waiting time ≤ 9 months, and tumor characteristics at the pathological examination were statistically associated with shorter survival. In the multivariate analysis, only vascular invasion (P < 0.001, OR = 7.99) remained independently associated with shorter survival. The number of TACE treatments was not associated with survival. In conclusion, multiple TACE treatments were not associated with a higher risk of recurrence or shorter survival. Continued use of TACE should be considered as indicated if the patient and lesions are suitable for retreatment. A shorter waiting time before LT is related to an increased risk of recurrence and decreased survival after LT for HCC. These data could reflect the presence of more aggressive tumor biology and may be useful for guiding organ allocation policy to consider a minimum observation period before LT for regions with shorter wait times., (© 2014 American Association for the Study of Liver Diseases.)

Determining risk for recurrence of hepatocellular carcinoma (HCC) following liver transplantation (LT) is an important clinical need. We assessed consecutive patients who underwent LT for HCC following sequential transarterial chemoembolization (TACE). Treatment response was assessed using modified response evaluation criteria in solid tumors (mRECIST) categories: complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD). Cox proportional hazard models were used to predict HCC recurrence. One hundred seventy-three patients underwent TACE and imaging to assess response prior to LT. TACE responses were: CR = 23.7%, PR = 24.3%, SD = 27.7% and PD = 24.3%. Five-year HCC recurrence rate was 5.3% in patients responding to TACE (CR/PR), versus 17.6%, among patients who did not respond (SD/PD, p = 0.014). In multivariate analysis, independent pre-LT predictors of recurrence were response to TACE and largest radiologic size of tumor (>3 cm vs. ≤3 cm). HCC recurrence rate for patients with tumor size >3 cm and no response to TACE was 35.8%, compared with 1.9% for patients with tumor size ≤3 cm and response to TACE (p = 0.0007). We conclude that mRECIST criteria and tumor size differentiate patients with high or low likelihood of HCC recurrence after LT. These findings raise the possibility of incorporating response to TACE and largest tumor size to identify patients at highest risk for HCC recurrence., (© Copyright 2014 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Branched-chain amino acids (BCAAs) are a group of essential amino acids comprising valine, leucine, and isoleucine. A low ratio of plasma BCAAs to aromatic amino acids is a physiological hallmark of liver cirrhosis, and BCAA supplementation was originally devised with the intention of normalizing amino acid profiles and nutritional status. However, recent studies on BCAAs have revealed that, in addition to their role as protein constituents, they may have a role as pharmacological nutrients for patients with chronic liver disease. Large-scale, multicenter, randomized, double-blinded, controlled trials on BCAA supplementation have been performed in Italy and Japan, and results demonstrate that BCAA supplementation improves not only nutritional status, but also prognosis and quality of life in patients with liver cirrhosis. Moreover, accumulating experimental evidence suggests that the favorable effects of BCAA supplementation on prognosis may be supported by unforeseen pharmacological actions of BCAAs. This review summarizes the possible effects of BCAAs on albumin synthesis and insulin resistance from clinical and basic viewpoints. We also review the newly discovered clinical impact of BCAAs on hepatocellular carcinoma and the prognosis and quality of life of patients with liver cirrhosis., (Copyright © 2011 American Association for the Study of Liver Diseases.)

Background & Aims: The percentage of Lens culinaris agglutinin-reactive (alpha)-fetoprotein (AFP-L3%) is proposed as a diagnostic and prognostic marker for hepatocellular carcinoma (HCC). We evaluated the utility of AFP-L3% for diagnosis of HCC in a US referral population., Methods: This retrospective study included 272 patients: 166 with HCC and 106 with benign liver disease (chronic liver disease, 77; benign liver mass, 29). The AFP-L3% was measured using a clinical auto-analyzer., Results: The AFP-L3% is not reported for a total alpha-fetoprotein (AFP) less than 10 ng/mL, and all patients with an AFP greater than 200 ng/mL had HCC; thus the AFP-L3% was noninformative for these patients. In patients with a total AFP of 10-200 ng/mL, an AFP-L3% greater than 10% had a sensitivity of 71% and a specificity of 63% for diagnosis of HCC. An AFP-L3% greater than 35% had a reduced sensitivity of 33%, but an increased specificity of 100%. The high specificity of the AFP-L3% cut-off of 35% allowed the confident diagnosis of an additional 10% of HCCs not diagnosed using an AFP cut-off of 200 ng/mL. After adjustment for AFP level, no association was observed between AFP-L3% and tumor size, stage, vascular invasion, grade, or survival., Conclusions: Patients with indeterminate total AFP values of 10-200 ng/mL present a diagnostic dilemma. We found that an AFP-L3% greater than 35% has 100% specificity for HCC in these patients. AFP-L3%, used in combination with AFP, may be a clinically useful adjunct marker for the diagnosis of HCC.

Inadvertent transmission of neoplastic cells from an organ donor can occur at the time of transplantation. Determination of recipient versus donor origin of a tumor is crucial for patient management. This report illustrates the use of microsatellite (MS) analysis to determine the origin of adenocarcinoma arising in a liver transplant. The study patient was a 42-year-old male who had received a liver transplant for hepatitis C and alcohol-related cirrhosis. At the 1-year follow-up visit, a 1.5-cm liver mass was identified during routine ultrasound of the vascular anastamoses. A liver biopsy showed a moderately differentiated adenocarcinoma. Tumor, donor, and recipient DNA were isolated from the paraffin-embedded liver biopsy, pretransplant donor liver biopsy, and the explant liver tissue, respectively. MS analysis was performed by polymerase chain reaction using 5 markers: D5S346, ACTC, D2S123, D18S34, and TP53. The allelic patterns of tumor DNA were identical to those of donor DNA and were distinct from the DNA profile of the recipient. The use of MS analysis clearly established that the adenocarcinoma was of donor origin., (Copyright 2002, Elsevier Science (USA). All rights reserved.)