A Case of Wilson's Disease Suspected to Involve a Novel Genetic Mutation of ATP7B Gene, Requiring a Differential Diagnosis with Non-alcoholic Steatohepatitis.

A 19-year-old Japanese man was referred for a further evaluation of liver dysfunction. Despite the absence of symptoms or obesity, the liver biopsy results were consistent with non-alcoholic steatohepatitis. Subsequent investigations revealed low serum ceruloplasmin, increased urinary copper excretion, and a known mutation c.3809A>G (p.Asn1270Ser) in the copper-transporting enzyme P-type ATPase (ATP7B) gene, leading to a diagnosis of Wilson's disease. A previously unreported variant, i.e., c.3866A>T (p.Asp1289Val) was detected on the patient's other allele and was considered a novel mutation, classified as 'likely pathogenic' according to the American College of Medical Genetics guidelines.

A Case of Immune-Related Aseptic Meningitis during Atezolizumab plus Bevacizumab for Hepatocellular Carcinoma.

Introduction: Immune checkpoint inhibitors are sometimes associated with immune-related adverse events during or after treatment. Among these, aseptic meningitis is a rare and serious complication. We report the first case of atezolizumab-induced aseptic meningitis, which occurred during treatment for advanced hepatocellular carcinoma (HCC). Case Presentation: A 74-year-old woman diagnosed with advanced HCC and treated with first-line atezolizumab plus bevacizumab developed anorexia, fatigue, and fever, after three treatment cycles. Cerebrospinal fluid examination showed slightly increased cell count and protein level but no infection or malignancy. Contrast enhancement along the cerebral sulcus was evident in contrast-enhanced magnetic resonance imaging, and the patient was diagnosed with aseptic meningitis associated with atezolizumab. Steroid therapy soon improved her clinical symptoms, and the contrast enhancement along the cerebral sulcus disappeared. Conclusion: Clinicians should monitor to avoid serious immune-related adverse events, such as aseptic meningitis, in patients during treatment of HCC with immune checkpoint inhibitors and make the diagnosis as soon as possible.

Objective Response and Progression-Free Survival Contribute to Prolong Overall Survival in Atezolizumab plus Bevacizumab Treatment for Unresectable Hepatocellular Carcinoma.

INTRODUCTION: Atezolizumab plus bevacizumab (Atez/Bev) is a standard treatment for unresectable hepatocellular carcinoma (HCC) due to its good antitumor and survival prolongation effects. Post-progression survival (PPS) has been reported to be a great contributor in the treatment with tyrosine kinase inhibitors for unresectable HCC. This study aimed to clarify the significance of progression-free survival (PFS) or PPS of Atez/Bev treatment for HCC. METHODS: We analyzed the correlations of PFS and PPS with overall survival (OS) in studies of HCC patients treated with Atez/Bev and evaluated the contribution to OS in Atez/Bev treatment with patients at our institutions as clinical practice. RESULTS: Analysis of 18 studies involving 3,752 patients treated with Atez/Bev found that PPS had a stronger correlation with OS (R2 = 0.872, p < 0.001) than did PFS (R2 = 0.605, p = 0.001). Analysis of 80 patients with unresectable HCC treated with Atez/Bev found that presence of antitumor responses during Atez/Bev was the most significant contributor to OS, and post-progression treatment after Atez/Bev also significantly contribute to OS. CONCLUSION: The presence of antitumor response with tumor shrinkage during Atez/Bev treatment contributes to good OS through its durable response. Atez/Bev treatment could be considered as first-line treatment for unresectable HCC. However, there is a need for optimal biomarkers for good antitumor response.

Impact of post-progression survival in second-line treatment with molecular target agents for unresectable hepatocellular carcinoma.

AIM: Sequential therapies are essential to extend overall survival (OS) in patients with unresectable hepatocellular carcinoma (HCC). Several second-line treatments with molecular target agents have shown survival benefits. However, the significance of post-progression survival (PPS) in extending OS in patients with HCC given such treatments remains uncertain. METHODS: Through a systematic review of the literature in the PubMed database, this study investigated the correlation between PPS and OS and that between progression-free survival (PFS) and OS in patients with HCC given second-line treatments. RESULTS: In total, 3935 patients who had received second-line treatment with regorafenib, ramucirumab, or cabozantinib, which are approved molecular target agents, were identified. In the patients treated with regorafenib, PPS showed a strong correlation with OS (R2 = 0.729, R = 0.854, p < 0.001) whereas PFS showed a weak correlation (R2 = 0.218, R = 0.467, p = 0.021). In the patients treated with ramucirumab, PPS showed a strong correlation with OS (R2 = 0.800, R = 0.894, p = 0.016) whereas PFS showed a negligible correlation (R2 = 0.020, R = 0.140, p = 0.791). In the patients treated with cabozantinib, PPS showed a strong correlation with OS (R2 = 0.856, R = 0.925, p = 0.003) as did PFS (R2 = 0.946, R = 0.973, p < 0.001). CONCLUSIONS: PPS plays a more significant role than PFS in extending OS in patients given second-line treatment for unresectable HCC. Sequential therapies after disease progression in second-line treatment are essential to acquire good OS. Maintenance of hepatic reserve function and the patient's general condition is essential during systemic treatments for unresectable HCC.

An Autopsy Case of Ruptured Hepatic Angiosarcoma Treated by Transcatheter Arterial Embolization.

An 80-year-old Japanese man presented to our hospital with intra-abdominal hemorrhage due to a ruptured liver tumor. Transcatheter arterial embolization (TAE) temporarily achieved hemostasis, but he died following re-rupture 4 days later. Based on autopsy findings, the liver tumor was diagnosed as hepatic angiosarcoma. Embolic agents used during embolization were identified within the hepatic small interlobular arteries. However, there were no findings of tumor cell necrosis or ischemic change in the angiosarcoma. In the present case, TAE alone did not induce ischemia-induced tumor necrosis, suggesting that TAE might be unsuitable to treat hepatic angiosarcoma. Treatment optimization for ruptured hepatic angiosarcoma is desired.

Liver metastasis affects progression pattern during immune checkpoint inhibitors monotherapy in gastric cancer.

Introduction: The efficacy of immune checkpoint inhibitors (ICIs) is heterogeneous at each metastatic site, and tumor progression pattern is associated with survival; however, it remains unclear in gastric cancer (GC). Therefore, we aimed to clarify the progression pattern in response to ICIs in patients with GC, and we analyzed its mechanism focusing on the intratumoral immune cells. Methods: Patients who received ICIs were retrospectively classified into non-systemic and systemic progression groups based on their radiological assessments. Moreover, the best percentage change in target lesions from each organ was compared. Results: Among 148 patients, the non-systemic progression group showed a significant improvement in overall survival (OS) compared with the systemic progression group (median, 5.6 months vs. 3.3 months; HR, 0.53; 95%CI, 0.32-0.89; p = 0.012). Poor performance status (HR, 1.73, 95%CI, 1.00-2.87) and systemic progression (HR, 3.09, 95%CI, 1.95-4.82) were associated with OS. Of all metastatic sites, the liver showed the poorest percentage change, and liver metastasis (OR, 2.99, 95%CI, 1.04-8.58) was associated with systemic progression. Hence, intratumoral CD8+ T-cell density was lower in patients with liver metastasis than in those without liver metastasis after ICIs, although the density of CD4+ T-cells (Th1, Th17, and Treg) and CD163+ cells (TAM) were not significantly different. Conclusion: The new progression pattern was associated with OS in GC. Liver metastasis may be a predictive factor of systemic progression during ICIs by regulating intratumoral CD8+ T-cells.

Long term changes in thrombocytopenia and leucopenia after HCV eradication with direct-acting antivirals.

BACKGROUND: Thrombocytopenia due to hypersplenism is a major complication of hepatitis C virus (HCV)-associated cirrhosis. HCV eradication improves these complications in some patients, but the long-term effects of HCV eradication on these complications remain unclear, especially in patients treated with direct acting antivirals (DAAs). The aim was to evaluate long term changes in thrombocytopenia and leucopenia after HCV eradication with DAAs. METHODS: The present multicenter study retrospectively evaluated changes over 5 years in thrombocytopenia and leukocytopenia, as well as changes in liver fibrosis markers and spleen size, in 115 patients with HCV-cirrhosis treated with DAAs. RESULTS: Thrombocytopenia and leukocytopenia were improved 4 weeks after DAA administration, with thrombocytopenia show further gradual improvement over the next year. Fib-4 index was markedly reduced 1 year after DAA, followed by subsequent gradual reduction over the next 4 years. Spleen size showed gradual annual reductions, with patients experiencing spleen size reduction characterized at baseline by bilirubinemia. CONCLUSIONS: Rapid DAA-associated HCV eradication might lead to rapid disappearance of liver inflammation and bone marrow suppression due to HCV infection. HCV eradication may gradually improve portal hypertension, reducing spleen size.

A ruptured sarcomatoid hepatocellular carcinoma treated with combined immunotherapy.

Sarcomatoid hepatocellular carcinoma (sHCC) is a rare phenotype of HCC with extremely poor prognosis and no established pharmacological treatment. Interventional therapies such as radiofrequency ablation (RFA) or transcatheter arterial embolization (TAE) have been shown to limit the development of sHCC through mechanisms involving hypoxia-induced epithelial-mesenchymal transition. This report describes an 83-year-old man who developed sHCC 2 years after RFA treatment for HCC and experienced sHCC rupture. Following TAE-induced hematostasis, he was administered lenvatinib for tumor control. Although his physical status had improved, due to loss of fever and attenuation of arterial enhancement in the tumor, for 1 month after lenvatinib administration, tumor re-growth was observed 2 months after lenvatinib treatment. His general condition was preserved, and he was treated with 10 courses of atezolizumab plus bevacizumab (Atez+Bev), resulting in tumor shrinkage that was maintained for 3-8 months after Atez+Bev. Findings in this patient showed that combined immunotherapy was effective for sHCC. Further investigation in additional patients is required to maximize prognosis in patients with sHCC.

Impact of Post-progression Survival on Outcomes of Lenvatinib Treatment for Unresectable Hepatocellular Carcinoma: A Systematic Review and Retrospective Cohort Study.

BACKGROUND/AIM: Lenvatinib is a tyrosine kinase inhibitor (TKI) more effective against hepatocellular carcinoma (HCC) than sorafenib, making lenvatinib a first-line treatment option for patients with unresectable HCC. In patients treated with sorafenib, post-progression survival (PPS) rather than progression-free survival (PFS) is essential for overall survival (OS). However, the importance of PPS for OS in patients treated with lenvatinib is uncertain, and optimal treatment after lenvatinib failure has not yet been established. PATIENTS AND METHODS: The present study investigated the correlations of PFS and PPS with OS in studies of HCC patients treated with lenvatinib by weighted linear regression analysis. Furthermore, the contribution of treatment regimens after lenvatinib failure to OS were evaluated in daily clinical practice. RESULTS: An analysis of 20 studies with 4,054 patients found that PPS had a stronger correlation with OS (r=0.869, p<0.001) than did PFS (r=0.505, p=0.007). Analysis of 79 patients with unresectable HCC treated with first-line lenvatinib showed that subsequent treatment was the most significant contributor to OS. Second-line sorafenib was administered to 25 patients, with late transition to third-line treatment being highest among patients who received second-line treatment. CONCLUSION: PPS contributes significantly to OS in HCC treatment with TKIs, with multi-sequential treatment being a key determinant of longer OS.

Direct-acting antivirals for hepatitis C virus-infected patients with hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) in hepatitis C virus (HCV)-infected patients has a high risk of recurrence. Although eradication of HCV is expected to reduce this risk, the risk in patients with a history of HCC may be high after treatment with direct-acting antivirals (DAAs). AIM: To determine the risk factors for HCC recurrence in patients with HCV and a history of HCC. METHODS: The risk of HCC recurrence in patients with a history of HCC and/or of HCC occurrence in patients without a history of HCC after DAA therapy was retrospectively analyzed in 311 HCV patients treated at our institution and several neighboring hospitals. The frequency and predictors of HCC recurrence/ occurrence after DAA treatment were included in these analyses. The clinical course of HCC before and after DAA treatment was also evaluated. RESULTS: HCV patients with a history of HCC were older and had greater progression of liver fibrosis and diabetes than patients without a history of HCC. Median recurrence-free survival (RFS) was 1092 d in patients with a history of HCC, and post-DAA HCC recurrence/occurrence was observed in 29 patients (53.7%) with and 5 (1.9%) without a history of HCC over 6 years (P < 0.001). RFS in patients with a history of HCC did not differ significantly before and after DAA treatment. The frequency of HCC recurrence/occurrence in patients with a history of HCC was lower after than before DAA treatment. Multivariate analysis showed that the incidence rate of HCC recurrence/occurrence before DAA treatment was the only independent predictor of HCC recurrence/occurrence after DAA treatment. Liver function was well preserved and clinical course was good in patients with HCC recurrence/occurrence after DAA therapy. CONCLUSION: DAA therapy in patients infected with HCV is also effective in patients with a history of HCC. Curative treatment for HCC is desirable before DAA therapy. The frequency of HCC recurrence/occurrence before DAA therapy was associated with a significantly increased risk of HCC recurrence after DAA therapy. Careful observation after DAA therapy is required in patients with a history of HCC.

Chronic liver disease questionnaire to manage patients with chronic liver diseases.

BACKGROUND AND AIMS: Although patients with chronic liver disease (CLD) usually show few symptoms, they exhibit decreased health-related QOL (HRQOL) with occurrence complications including hepatocellular carcinoma (HCC). Health-related QOL is an important indicator in the management of CLD. The Chronic Liver Disease Questionnaire (CLDQ) was established as a tool for assessment of HRQOL. In this study, we evaluate its usefulness for the management of daily clinical practice. METHODS: Patients (N = 190, median age 70 years old) treated between 2016 and 2019 were registered and prospectively followed-up with annual CLDQ. Associations of liver function and development of factors for admission or death were evaluated. RESULTS: Of the 190 patients registered, median age 70 years old, 140 were Child-A, 121 were Fib-4 index >2.67 and showed 80 HCC. All 6 domains including Systemic Symptoms (SS) were negatively correlated with Child-Pugh score more than with albumin-bilirubin score and Fib-4 index. A hundred four admission events and 49 deaths were found during observation period, and median event-free survival was 34.3 months. Treatment for HCC was the most frequent cause of admission, and 37 liver-related deaths were found. Systemic Symptoms score 2 years after registration was decreased in both HCC- and non-HCC cohort. Systemic Symptoms decreased and SS < 4 might be predictive for event occurrence. CONCLUSIONS: CLDQ is useful to assess HRQOL in patients with CLD and is well correlated with liver function especially Child-Pugh. Chronic Liver Disease Questionnaire might be useful to predict the prognosis of CLD and can be a tool of management in clinical practice.

Successful Treatment with Crushed Sofosbuvir/Velpatasvir of a Patient with Decompensated Cirrhosis C and Thrombocytopenia.

A 36-year-old woman with decompensated liver cirrhosis type C was referred to our hospital to receive antiviral treatment for hepatitis C virus (HCV). She had been diagnosed with intractable epilepsy and cerebral palsy at birth and was managed by central venous nutrition and nasal gastric feeding. At age 34 years, she was diagnosed with thrombocytopenia, probably associated with HCV infection. She showed refractory ascites for several months and was therefore administered crushed sofosbuvir/velpatasvir tablets via a nasal gastric tube. Her HCV infection was successfully eradicated, her ascites disappeared, and thrombocytopenia improved with a marked decrease in platelet-associated IgG.

Intrahepatic Bile Duct Injury as a Hepatic Immune-Related Adverse Event after Immune-Checkpoint Inhibitor Treatment.

The increased use of immune-checkpoint inhibitors to treat various types of cancer has increased the incidence of immune-related adverse events (irAEs). Hepatic irAEs are frequent and can lead to serious conditions. Among the various types of hepatic irAEs reported to date, bile duct injury has been shown refractory to steroid treatment. This study describes 2 patients with hepatic irAEs manifesting as intrahepatic bile duct injury. Immunostaining with antibodies to both CD8 and cytokeratin-7 was useful for the diagnosis, and both patients were refractory to steroid treatment. Prompt diagnosis and active immunosuppressive therapies are required in such cases.

Drug-eluting Bead-Transcatheter Arterial Chemoembolization for Advanced Hepatocellular Carcinoma Refractory to Conventional Lipiodol-based Transcatheter Arterial Chemoembolization.

PURPOSE: To evaluate the potential of drug-eluting bead (DEB)-transcatheter arterial chemoembolization (TACE) as a treatment option for patients with refractory to conventional lipiodol-based TACE (c-TACE) especially with decreased liver function. PATIENTS AND METHODS: We retrospectively evaluated the treatment results of DEB-TACE for 89 HCC nodules in 27 patients with c-TACE refractory according to liver function. RESULTS: Although overall survival was significantly better in Child-Pugh A patients than in Child-Pugh B patients (median survival time, MST: 561 vs 347 days, p=0.031), progression-free survival was almost similar in both patients between Child-Pugh A and B (MST: 79 vs 87 days, p=0.534). Regarding antitumor response, the objective response rate (ORR) and disease-control rate (DCR) were 5.3/12.5% and 52.7/87.5% in Child-Pugh A/B, respectively. In each 89 HCC nodules, ORR and DCR were almost similar between Child-Pugh A and B (ORR, 20.3 vs 13.3%; DCR, 77.0 vs 73.3%, respectively). Adverse events of DEB-TACE were well-tolerated, and liver function was reserved during DEB-TACE procedures. CONCLUSION: DEB-TACE could be a therapeutic option for advanced HCC patients with c-TACE refractory and decreased liver function.

Factors correlated with drug use for constipation: perspectives from the 2016 open Japanese National Database.

BACKGROUND: The prevalence of chronic constipation is increased in females and with age or environmental (low temperature), racial, socioeconomic, and habitual risk factors. The impact of low outside temperature on constipation drug use remains unclear. Here, we investigated risk factors for constipation drug use by evaluating data from the Japanese National Database. METHODS: This ecological study used the 2016 open Japanese National Database of health insurance claims (prescriptions) to acquire the number of health insurance prescription claims in all 47 prefectures for drugs to relieve constipation, antihypertensives, vasodilators, as well as medical check-ups and questionnaire responses. Internet survey on room temperatures in 2010 were also used. Pearson correlation coefficients (r) between the number of population-based prescriptions for each item were calculated and multiple linear regression analysis (MLR) was performed. RESULTS: Prescriptions for magnesium laxatives significantly correlated with aging (r = 0.58), vasodilators (r = 0.53), being female (r = 0.43), antihypertensives (r = 0.39), and inversely with eating ≤2 h before bedtime (r = - 0.37), total crime rate (r = - 0.33), insomnia (r = - 0.33), and population density (r = - 0.31). Stimulant laxatives (sennoside and picosulfate) were significantly correlated with antihypertensives (r = 0.79), aging (r = 0.69), vasodilators (r = 0.67), and being female (r = 0.56), and were inversely associated with average outside temperature (r = - 0.62), total crime rate (r = - 0.52), average income (r = - 0.51), and 30-min of vigorous exercise (r = - 0.44). Fecal interventions were significantly correlated with aging (r = 0.55) and female (r = 0.59), and inversely correlated with population density (r = - 0.41) and total crime rate (r = - 0.38). MLR analysis identified aging as the only significant risk factor for magnesium laxative use (partial slope [ß] = 1241.0). Female sex and antihypertensives were independent risk factors for stimulant laxative prescriptions (ß = 44,547.0 and 0.2) and average outside temperature and 30-min of vigorous exercise were independent preventive factors (ß = - 616.8 and - 219.1). CONCLUSION: We identified associations of magnesium laxatives with aging, stimulant laxatives with female sex, antihypertensives, low outside temperature and less 30 min of vigorous exercise.

Perforation of the Small Intestine after Introduction of Lenvatinib in a Patient with Advanced Hepatocellular Carcinoma.

Lenvatinib is a first-line standard treatment for advanced hepatocellular carcinoma (HCC) with better anti-tumor effects than sorafenib, as shown by greater inhibition of the kinases of fibroblast growth factor receptor and vascular endothelial growth factor (VEGF) receptor. This report describes a patient with advanced HCC who experienced perforation of the small intestine 1 month after starting the treatment with lenvatinib. This patient likely had partial necrosis of a metastasis to the small intestine before starting lenvatinib treatment, with subsequent ischemic changes leading to perforation of the small intestine. Although metastasis of HCC to the small intestine is rare, patients with these metastases should be regarded as being at risk for perforation during lenvatinib treatment.