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Introduction:Proteinuria is one of the adverse events of atezolizumab plus bevacizumab combination therapy (Atezo + Bev) and can cause interruption in the use of Bev. However, the risk factors for proteinuria in patients with hepatocellular carcinoma (HCC) who are receiving Atezo + Bev have not yet been investigated. The aim of this study was to identify the risk factors for early onset of proteinuria in Atezo + Bev for patients with unresectable HCC. Methods:Sixty-four patients with Child-Pugh scores of 5–7, an Eastern Cooperative Oncology Group performance status of 0 or 1, and low level of proteinuria (1+ or less on a dipstick test and urine protein-to-creatinine ratio (UPCR) less than 2.0 g/g Cr) at the initiation of therapy were analyzed. The level of proteinuria was evaluated based on the Common Terminology Criteria for Adverse Events version 5.0. We adopted the UPCR for the quantitative test instead of a 24-h urine collection. The incidence of proteinuria and changes in liver function were retrospectively investigated. Results:The cumulative incidence of proteinuria over a 24-week period was 34.4%. Multivariate analysis showed that a low estimated glomerular filtration rate (hazard ratio [HR], 3.807; 95% confidence interval [CI], 1.579–9.180; p= 0.003), treatment for hypertension (HR, 6.224; 95% CI, 1.614–24.010; p= 0.008), and high systolic blood pressure (SBP) (HR, 2.649; 95% CI, 1.133–6.194; p= 0.025) were risk factors for proteinuria. Serum albumin levels and albumin-bilirubin scores in patients with proteinuria worsened. In addition, a mean SBP ≥135 mm Hg during treatment was the only risk factor for the development of severe proteinuria (UPCR >2 g/g Cr). Conclusion:Our study found that controlling blood pressure is extremely important for the management of proteinuria in patients with HCC who are receiving Atezo + Bev.

Benign recurrent intrahepatic cholestasis (BRIC) is a group of genetically heterogeneous autosomal recessive liver disorders characterized by recurrent episodes of jaundice and pruritus. BRIC is divided into two groups, BRIC type 1 (BRIC1) and BRIC type 2 (BRIC2), caused by mutations in the ATP8B1and ABCB11genes. We show that novel nonsense mutations in ATP8B1(c.2989G>A, c.1547T>A) are the cause of BRIC1. A 16-year-old girl presented with severe jaundice. Acute and chronic liver diseases with infectious (hepatitis virus), metabolic, and autoimmune etiologies were excluded. Imaging revealed normal intra- and extra-hepatic bile ducts. Liver biopsy revealed severe intrahepatic bile stasis with bile plugs. She had similar symptoms at the age of 0 years. The BRIC criteria were satisfied, and ATP8B1and ABCB11gene analyses performed. Surprisingly, novel nonsense variants of the ATP8B1gene (c.2989G>A and c.1547T>A) in heterozygosis were found, which were identified in each of her parents. Therefore, the compound heterozygote was thought to cause BRIC1 in these patients. Genetic mutations that differ from those already known may help diagnose patients with BRIC.

Background:Sarcopenia, defined as the loss of skeletal muscle mass (MM), physical performance, and strength, has been associated with poor clinical outcomes in hepatocellular carcinoma (HCC) patients treated with several therapies. As systemic therapies, including molecular targeted agents, have a strong impact on sarcopenia, we aimed to review the impact of sarcopenia in patients receiving systemic therapies, especially sorafenib and hepatic arterial infusion chemotherapy (HAIC). Summary:Several studies have demonstrated that sarcopenia is associated with poor clinical outcomes in patients receiving sorafenib or lenvatinib, while HAIC has no association with overall survival (OS) and sarcopenia. Furthermore, based on our previous study, we developed the management of sorafenib score (MS score) to stratify patients’ survival according to the positivity of three parameters (skeletal MM, disease control of sorafenib, and post-sorafenib therapy), ranging from 0 to 3. Patients with an MS score ≥2 (median survival time [MST], 16.4 months) showed significantly longer survival than those with an MS score ≤1 (MST, 8.4 months) (p< 0.001). This result indicates that patients need at least two positive parameters to prolong OS. Although performance status (PS) has been used in the Barcelona Clinic Liver Cancer staging system, we consider that the assessment of sarcopenia has the potential to replace PS. Key Messages:Sarcopenia is associated with poor clinical outcomes in patients of HCC receiving sorafenib or lenvatinib. The MS score, based on the positivity of three prognostic factors, including skeletal MM, in patients receiving sorafenib, can be a reliable indicator of prolonged survival.

Background:Overall survival of patients with advanced hepatocellular carcinoma (HCC) with Vp4 (tumor thrombosis of the main trunk or bilobar of the portal vein) is extremely poor. Purpose:The purpose of this study is to clarify the prognosis of hepatic arterial infusion chemotherapy (HAIC) combined with radiation therapy (RT) for advanced HCC with Vp4 and to analyze the factors that contribute to the prognosis. Methods:In this retrospective cohort study, 51 HCC patients who were treated with HAIC and RT for portal vein tumor thrombosis and met the following criteria were enrolled: (i) with Vp4; (ii) Child-Pugh score of 5–7; (iii) Eastern Cooperative Oncology Group performance status of 0 or 1; (iv) no history of systemic therapy; and (v) from September 2004 to April 2019. Results:Median overall survival and median progression-free survival were 12.1 and 4.2 months, respectively. Multivariate analysis showed >50% of relative tumor volume in the liver (HR, 3.027; p= 0.008) and extrahepatic spread with (HR, 3.773; p= 0.040) as significant and independent factors of OS. The total overall response rate (ORR) was 19.6%; ORR in main tumor was 13.7%; and ORR in Vp4 was 51.0%. None of the patients who received HAIC combined with RT for advanced HCC with Vp4 developed hepatic failure. This combination therapy of HAIC with RT was safe and well tolerated in all cases. Conclusion:Combination therapies of HAIC and RT might be good therapy for advanced HCC with Vp4.

Introduction:The measurement of body composition such as the skeletal muscle index (SMI) has been reported to be useful for predicting prognosis in hepatocellular carcinoma (HCC). In this study, we analyzed skeletal muscle change during sorafenib and lenvatinib therapy and the association between SMI and prognosis. Methods:A total of 67 patients with advanced HCC and Child-Pugh grade A status treated with tyrosine kinase inhibitors (TKIs) at Hiroshima University between September 2009 and December 2018 were enrolled in this retrospective cohort study. Patients underwent computed tomography (CT) imaging before starting sorafenib treatment and 1–3 months after treatment initiation. Results:In all patients, the median SMI was 45.3 cm2/m2 before TKI treatment and 42.1 cm2/m2 after treatment; 54 of 67 (80.6%) patients experienced SMI loss. The median ΔSMI was –1.5 cm2/m2/months, and no difference in ΔSMI was observed between patients receiving sorafenib and lenvatinib. No significant differences were observed in median ΔSMI between patients with and without progressive disease (–2.35 and –1.1 cm2/m2/months, respectively), albumin-bilirubin grade 1 and 2 group disease (–1.7 and –1.5 cm2/m2/months, respectively), and relative dose intensity ≤80 and >80 (–1.8 and –1.2 cm2/m2/months, respectively). Conclusion:This report demonstrated that patients receiving TKI treatment experienced a significant loss of skeletal muscle mass regardless of disease progression, hepatic reserve, or which TKI (sorafenib or lenvatinib) they received.