Clinical significance of circulating biomarkers of immune-checkpoint molecules with atezolizumab plus bevacizumab therapy in unresectable hepatocellular carcinoma.

BACKGROUND: The aims of this study were to identify clinically significant biomarkers of a response to atezolizumab plus bevacizumab (ATZ + BV) therapy and to develop target strategies against unresectable hepatocellular carcinoma (u-HCC). METHOD: We first investigated the potential of circulating tumor DNA (ctDNA) to serve as a biomarker for predicting the therapeutic outcome in 24 u-HCC patients treated with ATZ + BV therapy. Next, we analyzed levels of immune-related cytokines in blood samples from 134 u-HCC patients who received ATZ + BV. For this, serum immune-related molecules or cancer-immune cycle-related molecules that have been reported in HCC patient sera, namely CD274, LAG-3, CCL2, 4, 5, CXCL1, 9, 10, 12, 13, CX3CL1, CCR5, IFNγ and IL-6, 8 were measured using enzyme-linked immunosorbent assay. RESULTS: More than 1% of variant read frequency (VRF) mutations were found in TP53, APC, PIK3CA and VHL, although with no correlation with treatment response. Among the 15 cytokines evaluated, CXCL9 and LAG-3 levels were significantly different between patients with objective response (OR), stable disease (SD), and progressive disease (PD) following ATZ + BV treatment. Receiver-operating characteristic curve analyses of CXCL9 (cut-off value: 419.1 pg/ml) and LAG-3 (cut-off value: 3736.3 pg/ml) indicated areas of 0.779 and 0.697, respectively, for differentiating PD from non-PD and OR from non-OR. In multivariate analysis of progression-free survival (PFS) and overall survival (OS), high serum CXCL9 (hazard ratio (HR) and 95% confidence interval (CI): 0.412 (0.251-0.677) (p = 0.0005) for PFS and 0.252 (0.125-0.508) (p = 0.0001) for OS), and low serum LAG-3 (HR and 95% CI 0.419 (0.249-0.705) (p = 0.0011) for PFS and 0.294 (0.140-0.617) (p = 0.0012) for OS) were independent positive predictive factors. CONCLUSION: Although, as far as we examined, no ctDNA mutations in blood were found to be related to ATZ + BV treatment efficacy, serum CXCL9 and LAG-3 levels, which are related to the cancer-immune cycle, were associated with treatment efficacy and could be predictive markers of the efficacy of ATZ + BV treatment in HCC patients.

Evaluation of Skeletal Muscle Mass in Patients with Chronic Liver Disease Shows Different Results Based on Bioelectric Impedance Analysis and Computed Tomography.

OBJECTIVE: We aimed to evaluate the difference between computed tomography (CT)-based and bioelectrical impedance analysis (BIA)-based assessment of sarcopenia in patients with chronic liver disease (CLD). METHODS: We enrolled a total of 257 patients who were evaluated with or without sarcopenia. Sarcopenia was defined as a low skeletal muscle mass index (SMI) with low muscular strength by the Japan Society of Hepatology. To evaluate whether or not the different methods influence the diagnosis of sarcopenia for patients with CLD, we assessed the number and characteristics of mismatches between the low SMI using BIA and CT. We also compared the overall survival (OS) in patients with and without sarcopenia based on CT and BIA to evaluate the appropriate methods. RESULTS: The numbers of patients with low SMI using BIA or CT were 53 (20.6%) and 114 (44.3%) patients, respectively. Multivariate analysis revealed that hepatic ascites and body weight were independent factors of mismatch between SMI using BIA versus CT (hazard ratio [HR] 3.232, p < 0.001; HR 2.347, p = 0.005, respectively). The median OS in patients with sarcopenia based on CT was significantly lower than that in patients without sarcopenia (p = 0.006). In contrast, there was no difference between patients with sarcopenia based on BIA (p = 0.217). CONCLUSION: Muscle mass in patients with CLD may be overestimated by the BIA method compared to CT when assessing sarcopenia, especially in cases of fluid retention.

A case of successful treatment with lenvatinib in primary hepatoid adenocarcinoma of the gallbladder that was difficult to distinguish from hepatocellular carcinoma.

Hepatoid adenocarcinoma (HAC) is an adenocarcinoma with components similar to those of hepatocellular carcinoma. Primary HAC of the gallbladder is extremely rare; to our knowledge, there is no consensus on the treatment after diagnosis. We reported an 82-year-old Japanese female of primary HAC of the gallbladder with postoperative recurrence that responded to lenvatinib. A total of 9 months has passed since the start of chemotherapy with lenvatinib, and the patient is in good general condition. To establish an effective treatment for primary HAC of the gallbladder, further accumulation and investigation of cases are recommended.

Additional L-Carnitine Reduced the Risk of Hospitalization in Patients with Overt Hepatic Encephalopathy on Rifaximin.

BACKGROUND: Data regarding the additional effect on the recurrence of hepatic encephalopathy (HE) after oral L-carnitine administration are scarce. OBJECTIVE: This study aimed to assess the additional effects of L-carnitine in patients who were receiving rifaximin for HE. METHODS: This randomized study comprised a screening visit and a 12-week treatment period. Patients who fulfilled the eligibility criteria were randomized to either group A (additional rifaximin) or group B (additional L-carnitine and rifaximin). Group A received 1,200 mg/day of rifaximin. Group B received 1,500 mg/day of L-carnitine and rifaximin at 1,200 mg/day. The endpoints were the changes in the portal systemic encephalopathy (PSE) index and the admission rate from the baseline for the duration of the study in both groups. RESULTS: Eighty-three patients were randomized to either group A (n = 42) or group B (n = 41). In group A, the PSE index decreased from 0.35 ± 0.09 at baseline to 0.27 ± 0.11 on the final evaluation day (p = 0.001). In group B, the PSE index decreased from 0.37 ± 0.09 at baseline to 0.24 ± 0.11 on the final evaluation day (p = 0.001). Although there was not a significant reduction in the PSE index in group A compared to that in group B (p = 0.202), the admission rates were 30.9% and 9.8% in groups A and B, respectively. Additional L-carnitine significantly reduced the admission rate (p = 0.028). CONCLUSION: L-Carnitine addition reduced the risk of hospitalization for patients who received rifaximin for HE.

Safety and efficacy of atezolizumab plus bevacizumab in patients with unresectable hepatocellular carcinoma in early clinical practice: A multicenter analysis.

PURPOSE: To assess the impact of clinical factors on the safety and efficacy of atezolizumab plus bevacizumab (ATZ + BV) treatment in patients with unresectable hepatocellular carcinoma (u-HCC). METHOD: Ninety-four u-HCC patients who were treated with ATZ + BV at multiple centers were enrolled. We defined Child-Pugh (CP)-A patients who received ATZ + BV treatment as a first line therapy as the 'meets the broad sense of the IMbrave150 criteria' group (B-IMbrave150-in, n = 46), and patients who received ATZ + BV treatment as a later line therapy or CP-B patients (regardless of whether ATZ + BV was a first line or later line therapy) as the B-IMbrave150-out group (n = 48). Patients were retrospectively analyzed for adverse events (AEs) and treatment outcomes according to their clinical characteristics, including neutrophil lymphocyte ratio (NLR) at baseline. RESULTS: The overall incidence of AEs was 87.2% (82/94 patients). The frequency of interruption of ATZ + BV treatment due to fatigue was higher in CP-B than CP-A patients (p = 0.030). Objective response (OR) rates of the B-IMbrave150-in group (28.3%, 39.1%) were significantly higher than those of the B-IMbrave150-out group (8.3%, 18.8%; p = 0.0157, 0.0401) using Response Evaluation Criteria in Solid Tumors (RECIST) and modified RECIST, respectively. In multivariate analysis, NLR (hazard ratio (HR), 4.591; p = 0.0160) and B-IMbrave150 criteria (HR, 4.108; p = 0.0261) were independent factors associated with the OR of ATZ + BV treatment using RECIST. CONCLUSION: In real-world practice, ATZ + BV treatment might offer significant benefits in patients who meet B-IMbrave150 criteria or have low NLR.

Splenectomy for Torsion of a Wandering Spleen in a Patient with Myeloproliferative Disease.

We herein report a rare case of torsion of a wandering spleen in a patient with myeloproliferative disease. A 66-year-old Japanese woman presented to our hospital with abdominal pain and a fever. She had a medical history of polycythemia and secondary myelofibrosis. Abdominal enhanced computed tomography showed an enlarged spleen without enhancement in the lower pelvic region. The clinical diagnosis was severe torsion of a wandering spleen in a patient with myeloproliferative disease, necessitating surgical intervention. Splenectomy was performed after de-rotating to revascularize the spleen. After the operation, the platelet count gradually increased, and aspirin was administered to prevent thrombosis.

Prospective study for an independent predictor of prognosis in liver cirrhosis based on the new sarcopenia criteria produced by the Japan Society of Hepatology.

AIM: There are limited data from prospective studies showing the clinical usefulness of the new criteria for sarcopenia in liver disease produced by the Japan Society of Hepatology. Therefore, we aimed to evaluate the clinical usefulness of this new criteria for prognosis in cirrhotic patients. METHODS: This prospective study was performed at six centers. The 300 enrolled patients, aged more than 20 years with liver cirrhosis, were evaluated over a 3-year period for skeletal muscle mass index and grip strength. Sarcopenia was defined according to the Japan Society of Hepatology criteria by grip strength and computed tomography-based skeletal muscle mass index values. We investigated the correlation between sarcopenia and the survival rate of cirrhotic patients. RESULTS: Among the 300 assessed patients there were 99 (33%) patients with sarcopenia. The number of deaths in the sarcopenia and non-sarcopenia groups was 34 (34.3%) and 38 (18.9%), respectively (p = 0.002). Multivariate analysis confirmed that sarcopenia, decompensated phase, albumin-bilirubin grade, and hepatocellular carcinoma (HCC) stage 3/4 were independent factors correlated with death in patients with liver cirrhosis during the observation period. The interaction between sarcopenia and the presence of HCC was statistically significant (p < 0.001), and the presence of HCC had the highest hazard ratio of 6.665 for deaths in cirrhotic patients when non-sarcopenia and the absence of HCC were used as references. CONCLUSIONS: The new Japan Society of Hepatology criteria for sarcopenia are accurate predictors of poor prognosis in patients with liver cirrhosis.

A case of immune checkpoint inhibitor-associated myocarditis after initiation of atezolizumab plus bevacizumab therapy for advanced hepatocellular carcinoma.

In November 2020, atezolizumab plus bevacizumab became available for the treatment of hepatocellular carcinoma (HCC), and its efficacy is expected as a new treatment option for HCC. However, the occurrence of immune-related adverse events (irAEs) associated with the administration of immune checkpoint inhibitors is a major concern in clinical practice. We reported a case of irAE-induced myocarditis after the treatment for HCC. Based on the symptoms and echocardiographic findings, we suspected irAE-induced myocarditis and acute heart failure, and the patient was admitted to the hospital for further investigation and treatment. From starting the patient on therapy with methylprednisolone succinate sodium, the laboratory data and symptoms tended to improve. The patient was discharged to home on the 25th day of treatment. Because the number of patients with irAE myocarditis is expected to increase in clinical practice in the near future, further accumulation and investigation of cases are necessary.

Cartilage-hair Hypoplasia Complicated with Liver Cirrhosis Due to Chronic Intrahepatic Cholestasis.

We herein report a rare case of cartilage-hair hypoplasia (CHH) complicated with liver cirrhosis. A 20-year-old Japanese man with CHH was found incidentally to have liver cirrhosis and an esophageal varix. This patient had been treated for infections due to immunodeficiency since early childhood. He ultimately died of liver failure at 31 years of age. An autopsy revealed an abnormality of the interlobular bile ducts and intrahepatic cholestasis. Liver cirrhosis was thought to have been caused by chronic intrahepatic cholestasis due to biliary duct hypoplasia and changes in the intestinal microbiome. Therefore, CHH may cause biliary cirrhosis due to multiple effects.

Impact of Anti-GPIIb/IIIa Antibody-Producing B Cells as a Predictor of the Response to Lusutrombopag in Thrombocytopenic Patients with Liver Disease.

BACKGROUND: To make an accurate estimate of the response to thrombopoietin (TPO) receptor agonists for thrombocytopenia associated with chronic liver disease, we evaluated the influence of antiplatelet autoantibodies on the response to lusutrombopag in thrombocytopenic patients with liver disease. METHODS: A prospective study was conducted at 2 hospitals. Thrombocytopenic patients with liver disease received oral lusutrombopag 3.0 mg once daily for up to 7 days. We analyzed changes in platelet counts from baseline to the maximum platelet count on days 9-14. The definition of clinical response was a platelet count of ≥5 × 104/µL with an increased platelet count of ≥2 × 104/µL from baseline. We assessed the correlation between the response to treatment drug and antiplatelet autoantibodies measured by anti-GPIIb/IIIa antibody-producing B cells. RESULTS: Thirty patients received the trial drug. There were 25 responders and 5 nonresponders. The median change in platelet counts was 3.9 × 104/µL (95% CI 2.8-4.6, p < 0.0001). The correlation between change in platelet counts and the frequency of the anti-glycoprotein IIb/IIIa antibody-producing B cells was moderate (r = 0.414, 95% CI 0.064-0.674, p = 0.023). In multivariate analysis of factors affecting the change in platelet counts, the anti-GPIIb/IIIa antibody-producing B cells were identified as an independent factor (regression coefficient [B] = 0.089; CI 0.021-0.157, p = 0.013). CONCLUSION: Anti-GPIIb/IIIa antibody-producing B cells may be a predictor for TPO receptor agonists in patients with chronic liver disease.

Long-term observation in patients with esophageal varices after endoscopic variceal ligation accompanied with 24-hour pH monitoring.

AIM: Esophageal variceal ligation (EVL) is usually carried out to decrease the risk of hemorrhage. Several complications have been reported with the procedure, including bleeding from ligation-induced esophageal ulcers or heartburn. However, there is scant evidence for gastroesophageal reflux caused by EVL. The aim of this study was to assess 24-h pH monitoring in the esophagogastric junction before and after EVL and the bleeding rate for 18 months. METHODS: We undertook this single-center prospective trial in Kitasato University Hospital (Sagamihara, Japan). We included patients with cirrhosis who were Child-Pugh classification A or B, without uncontrollable hepatocellular carcinoma, and had F2 or larger esophageal varices, and/or were red color sign (RC) positive. The study period was from July 2012 through September 2017 for 32 patients enrolled in this study and followed up until March 2019. RESULTS: Baseline characteristics were: median Child-Pugh score, 6; and mean age, 64.3 years. Before and after EVL, the median 24-h under pH 4 holding time percentages of all patients were 0.6% (range, 0-5.6%) and 0.95% (range, 0-50.6%), respectively, without a significant difference (P = 0.107). We could not find any G3 or G4 adverse events during this study, and 75% of the patients who had already suffered from moderate gastroesophageal reflux became worse after EVL (P = 0.18) and required antacid therapies. There were no patients with hemorrhage from esophageal varices. CONCLUSIONS: Esophageal variceal ligation for esophageal varices did not significantly change gastroesophageal reflux. Therefore, acid suppressive therapy might be unnecessary for patients who do not suffer from gastroesophageal reflux after EVL.

Undifferentiated Embryonal Sarcoma of the Liver Identified after the Initial Diagnosis of a Hepatic Cyst.

Abdominal ultrasound in a 50-year-old Japanese man revealed a cystic lesion on the caudate lobe of the liver. Four-month follow-up imaging showed a rapid increase in the size of the cystic lesion. The patient underwent laparoscopic partial hepatectomy because of a suspicion and perceived risk that the lesion might be malignant. The initial histological diagnosis was a hepatic cyst. Eleven months later, computed tomography showed a giant cystic lesion in the abdominal cavity and multiple liver metastases. The patient underwent excision of the giant cystic lesion and a partial hepatectomy. Immunohistochemistry for the recurring lesion revealed undifferentiated embryonal sarcoma of the liver.

Portal hemodynamic effects of lenvatinib in patients with advanced hepatocellular carcinoma: A prospective cohort study.

AIM: Lenvatinib is an oral, multitargeted, tyrosine kinase inhibitor, which suppress tumor angiogenesis and tumor progression. It was non-inferior to sorafenib in overall survival in untreated advanced hepatocellular carcinoma (HCC). Sorafenib had a beneficial effect on portocollateral circulation with portal hypertension in translating and clinical studies. However, the hemodynamic effects of lenvatinib appear to be different from those of sorafenib because the efficacy of lenvatinib for vascular endothelial growth factor receptors and fibroblast growth factor receptors is different from that of sorafenib. This study was prospectively performed to evaluate the portal hemodynamic effect of lenvatinib in patients with advanced HCC using duplex Doppler ultrasonography. METHODS: In total, 28 Child-Pugh class A or B patients with advanced HCC received lenvatinib depending on body weight daily for 2 weeks. Primary outcomes were changes in the hemodynamics of the portal venous system using duplex Doppler ultrasonography before and after the 2-week administration of lenvatinib. RESULTS: The portal venous flow velocity (cm/s) significantly reduced (27 ± 12.1 vs. 22.6 ± 8.0, P = 0.019), while portal venous area (cm2 ) did not change after the 2-week administration (0.80 ± 0.36 vs. 0.82 ± 0.27, P = 0.665). Therefore, the congestion index (portal venous area/portal venous flow velocity), which reflects the pathophysiological hemodynamics of the portal venous system significantly worsened (0.037 ± 0.025 vs. 0.043 ± 0.024, P = 0.045). CONCLUSIONS: Considering that this was a short-term study, because lenvatinib could be an agent that aggravates portal hypertension, it will be necessary to verify its clinical effects for portal hypertension in future studies.