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A 68-year-old man with hepatocellular carcinoma (HCC) visited his previous hospital due to abdominal pain and was diagnosed with ruptured HCC. Before visiting our hospital, he underwent HCC treatment at his previous hospital, but his tumors did not improve. Although he started treatment with sorafenib, the tumors rapidly grew. Subsequently, regorafenib was given, and the tumors shrank. After 22 months being treated with regorafenib, HCC reoccurred, with a new lung metastasis and a contrast-enhanced nodule on the peritoneal dissemination appearing. He underwent conversion surgery and survived for 4.5 years after his HCC was diagnosed.

Background We previously reported on the trends in the etiologies of hepatocellular carcinoma (HCC) diagnosed in patients between 1995 and 2009. The aims of our updated study were to evaluate the incidence, nonhepatitis B and nonhepatitis C viral (NBNC) etiologies, and clinical characteristics of HCCs occurring in patients between 1992 and 2018. Methods The study enrolled 2171 consecutive patients with HCC between 1992 and 2018. Their medical records were reviewed. The patients were divided into two groups, patients with early diagnoses from 1992 to 2009 and those with late diagnoses from 2010 to 2018. Results NBNC-HCC occurred in 514 patients (23.6%). The percentage of patients with HCC who had NBNC-HCC increased from 26.5% in 2009 to 46.3% in 2018. Patients with NBNC-HCC were older (median ages from 67 to 73 years). Type 2 diabetes mellitus (48.5–60.3%: P = 0.008), hypertension (48.5–57.4%: P = 0.047), and hyperlipidemia (39.2–53.8%: P = 0.001) increased significantly in recent years. The median FIB-4 index decreased (4.37–3.61: P = 0.026) and the median platelet count increased (15.1–17.9 × 104/μL: P = 0.013). Among the 514 patients with NBNC-HCC, 194 underwent hepatic resection for nonalcoholic steatohepatitis (NASH) (15%), alcoholic liver disease (ALD) (29%), and cryptogenic hepatitis (56%). Cirrhosis was detected in 72%, 39%, and 16% of patients with NASH, ALD, and cryptogenic hepatitis, respectively. The prevalence of cirrhosis in patients with NASH was significantly higher than the prevalence of cirrhosis in the other groups (P Conclusions The prevalence of NBNC-HCC has increased rapidly even in a regional university hospital. Metabolic syndrome may be an important risk factor for HCC. HCC was also found in patients with non-cirrhotic livers. The FIB-4 index may be a useful screening method for HCC in patients with NBNC.

While the preS1 region of the large hepatitis B surface protein plays an essential role in hepatitis B virus (HBV) infection, the effect of preS1 on liver fibrosis and hepatocarcinogenesis in chronic hepatitis B (CHB) patients is not well known. In this study, we measured serum preS1 levels by chemiluminescent immunoassay technology in 690 CHB patients and evaluated the correlation between serum preS1 levels and HBV, liver function markers and liver inflammation, fibrosis assessed by histological findings. Predictive factors for hepatocellular carcinoma (HCC) development in patients who had no previous history of HCC at the time of preS1 level measurement were also analysed. Median hepatitis B surface antigen (HBsAg) and preS1 levels were 3.08 log IU/mL and 98 ng/mL, respectively. PreS1 values were significantly correlated with serum HBsAg (p

Objective Lusutrombopag is a thrombopoietin receptor agonist that improves thrombocytopenia in patients with chronic liver disease scheduled to undergo invasive procedures. However, information on the efficacy of repeated lusutrombopag treatment and factors associated with the treatment is scarce. We analyzed the efficacy of repeated lusutrombopag treatment and the factors associated with a response to lusutrombopag. Methods Thirty-nine patients with chronic liver disease who received lusutrombopag treatment before undergoing invasive procedures were enrolled in this retrospective study. Of the 39 patients, 10 received lusutrombopag treatment multiple times for a total of 53 regimens of lusutrombopag treatment. Changes in platelet counts, the effects of repeated lusutrombopag treatment, and factors associated with response to lusutrombopag were analyzed. Results The median platelet count increased significantly from 4.5×104/μL before lusutrombopag treatment to 7.2×104/μL before the invasive procedure (p

Background and aim The aim of this study was to identify the factors that contribute to the maintenance of relative dose intensity (RDI) of lenvatinib in hepatocellular carcinoma (HCC) patients. Methods Thirty-two patients with advanced HCC treated with lenvatinib were enrolled. We evaluated the relationship between maintenance of RDI and various clinical data, parameters obtained by body composition measurements with bioelectrical impedance analysis (BIA) and grip strength at the start of lenvatinib treatment. Results Multivariate analysis showed that only the extracellular water to total body water ratio (ECW/TBW) ≤ 0.400 at initiation of treatment was associated with RDI ≥ 50% (odds ratio, 6.94; 95% confidence interval [CI], 1.00-48.00; P = 0.049). When the RDI was compared between ECW/TBW ≤ 0.400 group and ECW/TBW > 0.400 group, the RDI was significantly higher in the ECW/TBW ≤ 0.400 group at each of 0-4W, 4-6W, and 6-8W points. The P value at each point was 0.003, 0.003, and 0.005, respectively. On the other hand, multivariate analysis showed that only the ECW/TBW ≤ 0.400 at initiation of treatment was associated with the extension of duration until reduction or withdrawal of lenvatinib (hazard ratio, 4.86; 95% CI, 1.52-15.50; P = 0.007). Conclusion The extracellular water to total body water ratio, a parameter of body composition measurement by BIA, was significantly associated with the maintenance of RDI and the duration until reduction or withdrawal of lenvatinib in HCC patients. In addition to standard predictors such as Child-Pugh score and modified albumin-bilirubin grade that have been used to date, ECW/TBW might be a new predictor of RDI in HCC patients treated with lenvatinib.

Introduction: We evaluated the efficacy and safety of lenvatinib-transcatheter arterial chemoembolization (LEN-TACE) sequential therapy for patients (n = 88) with intermediate-stage hepatocellular carcinoma (HCC). Methods: Eighty-eight patients who obtained tumor control by LEN treatment were analyzed; 30 received LEN followed by TACE (LEN-TACE sequential therapy), and 58 received LEN monotherapy. Propensity score matching was performed, and the outcomes of 19 patients in the LEN-TACE group and 19 patients in the LEN-alone group were compared. Objective response rate (ORR), progression-free survival (PFS), overall survival (OS), incidence of adverse events (AEs), and change in albumin-bilirubin (ALBI) score were evaluated. Results: After matching, baseline characteristics were similar between the groups. The ORR was 63.2% with LEN-TACE group and 63.2% with the LEN-alone group. Multivariate analysis showed that addition of TACE during LEN treatment (hazard ratio [HR] 0.264, 95% confidence interval [CI] 0.087–0.802, p = 0.019) and Child-Pugh score 5 (HR 0.223, 95% CI 0.070–0.704, p = 0.011) were the significant factors for PFS. Median PFS was 11.6 months with LEN-TACE and 10.1 months with LEN-alone. The survival rate of the LEN-TACE group was significantly higher than that of the LEN-alone group (median survival time; not reached vs. 16.9 months, p = 0.007). The incidence of common LEN-associated AEs was similar between groups. Although elevated aspartate aminotransferase/alanine aminotransferase and fever were more frequent with LEN-TACE group, these events were manageable. Conclusion: For patients with intermediate-stage HCC, LEN-TACE sequential therapy may provide a deep response and favorable prognosis.

Introduction: The clinical outcome of ramucirumab in multi-molecular targeted agent (MTA) sequential therapy for unresectable hepatocellular carcinoma (u-HCC) was assessed in comparison with that of prior tyrosine kinase inhibitor (TKI) therapy. Methods: Sixteen patients who received ramucirumab as part of multi-MTA sequential therapy for u-HCC were enrolled in a retrospective, cohort study. Ramucirumab was started as 2nd line in 7 patients, 3rd line in 5 patients, and 4th line in 4 patients. Results: The overall response rate was 6.3%, the disease control rate (DCR) was 50.0%, median progression-free survival was 2.0 months (evaluated by mRECIST), median overall survival (OS) with ramucirumab was 7.9 months, and the median OS from 1st-line therapy was 28.1 months. One month after the start of ramucirumab, α-fetoprotein (AFP) decreased in 6 of 12 cases (50.0%), and the DCR in AFP-decreased cases was 83.3%. The DCR of ramucirumab was 66.7% in cases in which disease control was obtained by prior TKI therapy, whereas it was 0.0% in the cases in which disease control was not obtained by prior TKI therapy. Examining the adverse events, no new safety concerns were confirmed. Conclusion: The AFP response to ramucirumab and the treatment response to prior TKI therapy are associated with treatment response to ramucirumab.

Hepatocellular carcinoma (HCC) has limited systemic treatment options and a poor prognosis. The immune checkpoint inhibitor pembrolizumab was recently approved for the treatment of solid tumors with microsatellite instability (MSI). However, its clinical utility for the management of HCC remains to be clarified. Here, we present a case of unresectable HCC with MSI that showed an impressive response to pembrolizumab treatment. A 64-year-old man with chronic HCV infection was diagnosed with a large HCC. His severe liver dysfunction and poor performance status prevented any treatment option other than sorafenib. However, sorafenib failed after a few days due to the rapid progression of the tumor. Based on the finding of MSI in a biopsy specimen, immunotherapy using pembrolizumab was initiated. A dramatic improvement in his general condition and a reduction in tumor size were observed after the initiation of pembrolizumab treatment. Among a cohort of 50 consecutive patients with advanced HCC who were refractory to standard systemic therapy, MSI was found only in the present case. Immune checkpoint blockade therapy induced prominent anti-tumor effects in HCC with MSI. Screening for defects in DNA mismatch repair function may be warranted in HCC patients despite the low frequency of MSI.

AIM We analyzed the impact of hepatitis C virus eradication by direct-acting antiviral (DAA) therapy on the risk of development of hepatocellular carcinoma (HCC), prognosis, and portal hypertension in patients with liver cirrhosis. METHODS The rate of HCC development and overall survival after achievement of sustained virological response (SVR) in 173 DAA-treated compensated cirrhosis patients without HCC history were retrospectively compared with that of 125 cirrhosis patients who achieved SVR by interferon (IFN)-based therapy or that of 85 cirrhosis patients who failed to respond to anti-HCV therapy. Changes in esophagogastric varices (EGV) and incidence of portosystemic encephalopathy were analyzed in 87 consecutive cirrhosis patients. RESULTS The cumulative HCC development rates at 1, 3, and 5 years were 2%, 7%, and 7% for the DAA-SVR group, significantly lower than the 3%, 7%, and 18% for the non-SVR group (log-rank, P

Although direct-acting antivirals (DAAs) have significantly increased the sustained virological response (SVR) rates in chronic hepatitis C virus (HCV)-infected adult patients, the efficacy and safety for children remain unclear. We herein report three HCV-infected children who received DAA treatment. The patients were girls 10-13 years old who had been infected with genotype 1b HCV by vertical transmission based on a phylogenetic tree analysis. Two patients were treated with 12 weeks of ombitasvir/paritaprevir/ritonavir, and the other patient was treated with 8 weeks of glecaprevir/pibrentasvir. All children received DAA doses that were similar to the dosages for adult patients. None developed adverse events, and all children achieved an SVR.

Aim Pembrolizumab has been quickly approved in many countries for the treatment of patients with unresectable or metastatic, microsatellite instability-high (MSI-H) solid tumors, which have progressed following previous treatment and who have no satisfactory alternative treatment options. We aimed to determine the incidence of MSI-H tumors in Japanese patients with advanced hepatocellular carcinoma (HCC). Methods We investigated the incidence of MSI-H tumors in 82 consecutive Japanese patients with unresectable HCC that had progressed after standard of care treatment. Using a companion diagnostic sequencing kit (polymerase chain reaction analysis of five microsatellite markers: BAT25, BAT26, NR21, NR24 and MONO27), we analyzed 49 biopsy specimens and 33 resection specimens. Responses to pembrolizumab were assessed with the modified Response Evaluation Criteria in Solid Tumors. Results MSI-H tumors were found in only two patients (2.4%), in whom all five markers showed slight shortening. One patient had a complete response to pembrolizumab for over 10 months, and the other was a non-responder. Conclusions MSI-H tumor status was found in only two of 82 (2.4%) Japanese patients with advanced HCC, one of whom had a complete response to pembrolizumab. Thus, MSI status should be assessed in patients with HCC who progress after standard of care treatment.

We report a 46-year-old male patient with functional liver damage due to hepatitis B virus infection. A 12 cm hepatocellular carcinoma (HCC) in the left lobe and portal venous tumor thrombosis (PVTT) with vp4 (portal vein tumor thrombosis in the main trunk) were detected by computed tomography (CT). He underwent hepatic arterial infusion chemotherapy (HAIC) with cisplatin 100 mg for HCC and received radiation therapy (39 Gy/13 Fr) for PVTT with vp4. Follow-up CT showed reduction of HCC and reduced PVTT volume after 1 month of treatment. He then initiated lenvatinib therapy at 12 mg/day. One month later, follow-up CT showed no change in HCC size and a reduction in PVTT volume. Two months after initiating lenvatinib, follow-up CT showed no change in HCC, but further reduction in contrast effect and volume of PVTT. Three months after HAIC, he underwent drug-eluting-bead transcatheter arterial chemoembolization (DEB-TACE) with 100 mg of cisplatin (CDDP) for the HCC. After DEB-TACE, he received 12 mg/day with 5-days-on/2-days-off due to vomiting. One month after DEB-TACE, blood evaluation showed decreased tumor markers, and CT revealed that the HCC had grown slightly with no change in PVTT. Five months after HAIC, he underwent DEB-TACE with 100 mg of cisplatin for the HCC. A total of 150 days have passed since the start of lenvatinib treatment, and his Child-Pugh A status has been maintained.

Objective: Functional hepatic reserve is important when considering sequential tyrosine kinase inhibitor (TKI) therapy for patients with advanced hepatocellular carcinoma (HCC). We assessed albumin-bilirubin (ALBI) score and Child-Pugh class as indices of liver function during sorafenib and lenvatinib treatment. Methods: A total of 212 patients with advanced HCC and Child-Pugh class A status who initiated TKI treatment at our hospital were enrolled in this retrospective cohort study. A total of 74 of the 212 patients underwent blood testing before starting sorafenib treatment and every 2 months after treatment initiation. Results: In 74 patients, the median ALBI score before TKI treatment was –2.53, and after 2, 4, and 6 months it was –2.45, –2.44, and –2.36, respectively. ALBI scores tended to increase during TKI therapy. Among patients who experienced a time to progression ≤3.8 months, ALBI scores had increased 2 months after treatment initiation, and at 4 and 6 months, significant differences were observed (p < 0.01). In all 212 patients, during first-line TKI treatment, the Child-Pugh class deteriorated to B or C in 72.2% of the patients, and the median time to deterioration was 3.9 months. The factors in hepatic reserve deterioration were serum albumin ≤3.8 g/dL and the presence of macroscopic vascular invasion. The hepatic reserve of 68.0% of the patients with deterioration of liver function recovered to Child-Pugh class A following dose reduction, drug withdrawal, or treatment intended for recovery of liver function. Conclusion: ALBI scores deteriorate in patients treated with TKIs, suggesting that tumor progression induces these changes.

Transarterial chemoembolization (TACE) has been the standard treatment for intermediate-stage, unresectable hepatocellular carcinoma (u-HCC). However, with recent advances in systemic therapy and the emergence of the concept of TACE-refractory or -unsuitable, the effectiveness of systemic therapy, as well as TACE, has been demonstrated for patients judged to be TACE-refractory or -unsuitable. In this study, the efficacy of lenvatinib and its combination with TACE after lenvatinib was investigated in 140 patients with intermediate-stage u-HCC treated with lenvatinib mainly because of being judged to be TACE-refractory or -unsuitable. Median overall survival (OS) and progression-free survival (PFS) were 24.4 and 9.0 months, respectively, indicating a good response rate. In multivariate analysis, modified albumin–bilirubin (mALBI) grade and up to seven criteria were identified as independent factors for OS, and mALBI grade and tumor morphology were identified as independent factors for PFS. While 95% of all patients were TACE-refractory or -unsuitable, the further prognosis was prolonged by the combination with TACE after lenvatinib initiation. These findings suggest that systemic therapy should be considered for intermediate-stage u-HCC, even in patients judged to be TACE-refractory or -unsuitable. The use of TACE after the start of systemic therapy may further improve prognosis.

A 76-year-old man was diagnosed with multiple hepatocellular carcinomas (HCCs). He underwent right lobectomy and partial resection of the liver after transcatheter arterial embolization at our hospital. The pathology report was moderately differentiated HCC (fT4N0M0 Stage Iva, Vp1, Vv0). Follow-up CT revealed a lesion in the right ventricle 3 years after surgery. Moderately differentiated HCC was determined on myocardial biopsy, and the lesion was diagnosed as cardiac metastasis of HCC. No recurrence of HCC was observed in the liver. Radiation therapy (39 Gy/13 fr) was performed for the cardiac metastasis, and oral lenvatinib 8 mg/day was started. Evaluation by mRECIST on contrast-enhanced CT indicate a partial response (PR). Lenvatinib has been continued for 7 months. Cardiac metastasis of HCC is extremely rare; herein, we have also provided a literature reviews.

Trastuzumab emtansine (T-DM1) is an antibody–drug conjugate approved for use in the treatment of human epidermal growth factor receptor 2-positive metastatic breast cancer. Here, we present the cases of two patients with metastatic breast cancer who received T-DM1 monotherapy and developed noncirrhotic portal hypertension (NCPH). Patient 1 presented with ruptured gastric varices at 2 years and 5 months after T-DM1 treatment. Patient 2 presented with intrahepatic portal-hepatic venous shunt at 2 years and 6 months and portal-systemic shunt encephalopathy at 4 years and 11 months after T-DM1 treatment. In both the patients, liver biopsies revealed sinusoidal obstruction syndrome (SOS). T-DM1-induced hepatotoxicity can result from SOS. In long-term administration of T-DM1 the unfavorable events associated with chronic liver circulatory disorder due to SOS, such as NCPH, are concerning.

This study investigated time-course changes in skeletal muscle volume per year with tolvaptan in patients with refractory ascites that was unresponsive to loop diuretics and aldosterone antagonists. This retrospective study included 42 patients who received tolvaptan for refractory ascites and/or hepatic edema and underwent computed tomography (CT) before and ≥ 3 months after initiating tolvaptan. The time-course changes in skeletal muscle index per year [ΔSMI (%)] was calculated as follows: ΔSMI (%) = (SMI at final CT scan − SMI at initial CT scan)/SMI at initial CT scan × 100/years between CT scans. Eligible patients were 23 men and 19 women of median age of 71 years (range 21–94 years). The median follow-up period was 22.7 (range 3.5–54.6) months. ΔSMI (%) was significantly higher in the responders group than in the nonresponder group. Multivariate analysis showed the response to tolvaptan was an independent and significant factor associated with an increase in muscle mass [odds ratio (OR) 20.364; 95% CI 2.327–178.97; P = 0.006]. Overall survival with tolvaptan was significantly higher in the responder group than in the nonresponder group. Multivariate analysis showed that the response to tolvaptan treatment was a significant contributor to good prognosis (OR 3.884; 95% CI 1.264–11.931; P = 0.018). A significant negative correlation was observed between the dosage of furosemide and ΔSMI (%) (P = 0.014). Treatment of refractory ascites with tolvaptan may attenuate the progression of sarcopenia and improve the prognosis in patients with decompensated cirrhosis.

Although NS3/4 protease inhibitor glecaprevir (GLE) plus NS5A inhibitor pibrentasvir (PIB) therapy has a high efficacy for chronic hepatitis C virus (HCV)-infected patients with hemodialysis, some patients fail to respond to the therapy. Here, we report a hemodialysis genotype 2 HCV-infected patient who achieved sustained virological response (SVR) by 12 weeks of GLE/PIB therapy after failing to respond to 8 weeks of GLE/PIB therapy. A 44-year-old man with chronic genotype 2a HCV-infection without any evidence of cirrhosis and who was undergoing hemodialysis received GLE/PIB therapy. He completed 8 weeks of therapy, but his serum HCV relapsed after the end of therapy. No resistance-associated substitutions were detected in the NS3 region, but NS5A-C92C/S was detected by direct sequence analysis prior to the start of therapy and subsequently shifted to NS5A-C92S at the time of HCV relapse. Four months after initial GLE/PIB therapy, he started a 12-week course of GLE/PIB retreatment. Serum HCV RNA level became and remained undetectable during the therapy and never relapsed after the end of the treatment. Finally, he succeeded in achieving sustained virological response following 12 weeks of GLE/PIB retreatment.

We report a 74-year-old male patient with compensated cirrhosis after hepatic C virus eradication. After the patient underwent hepatectomy for hepatocellular carcinoma, multiple lung and lymph node metastases were detected by computed tomography. Computed tomography also revealed a portosystemic shunt from the superior mesenteric vein to the right testicular vein. He was administered lenvatinib (12 mg). Five days after the initiation of lenvatinib, he developed grade 3 hepatic encephalopathy, and his ammonia level increased. Lenvatinib was stopped, with improvement of the encephalopathy and decrease in ammonia level. When lenvatinib was restarted, grade 2 encephalopathy recurred which then improved upon stopping the drug. We thought that the encephalopathy was due to the portosystemic shunt, and occlusion of the shunt was performed. The day after shunt occlusion, lenvatinib (8 mg) was restarted, and the lenvatinib dose was increased to 12 mg at 2 days after shunt occlusion. Subsequently, the ammonia level remained stable and the patient remained alert and conscious. Lenvatinib was continued until the time of this report (40 days after shunt occlusion), and after 1 month of lenvatinib therapy, the computed tomography verified absence of the portosystemic shunt and stable disease of hepatocellular carcinoma.

Although the effect of levocarnitine (L‐carnitine) on hyperammonemia has been reported in patients with liver cirrhosis (LC), its effect on sarcopenia remains to be elucidated. We assessed the effects of L‐carnitine on sarcopenia in patients with LC. We retrospectively evaluated 52 patients with LC who were treated with L‐carnitine for more than 3 months between February 2013 and June 2017. Computed tomography was used to measure the cross‐sectional area of the skeletal muscles at the level of the third lumbar vertebra. The relative change in skeletal muscle index (SMI) per year (ΔSMI/year) was computed in each patient. We evaluated the relationship between ΔSMI/year and various parameters, such as age, sex, liver functional reserve, and dose of L‐carnitine. The median ΔSMI/year for all patients was −0.22%. The ΔSMI/year values in Child‐Pugh classes A, B, and C were not significantly different among the three groups. There was no significant relationship between ΔSMI/year and sex, age, body mass index, and sarcopenia. Multivariate analysis showed that only a high dose of L‐carnitine (odds ratio [OR], 4.812; 95% confidence interval [CI], 1.233‐18.784; P = 0.024) was associated with increased muscle mass. The L‐carnitine high‐dose group included a significantly larger number of patients with increased muscle mass compared with the low‐dose group (OR, 3.568; 95% CI, 1.138‐11.185; P = 0.027). Administration of L‐carnitine led to a significant and gradual reduction in serum ammonia levels. Conclusion: L‐carnitine seems to suppress the progression of sarcopenia dose dependently, and this was noted to be associated with the improvement of hyperammonemia in patients with LC.

Aim: This study investigated early tumor marker response and treatment response in patients with advanced hepatocellular carcinoma (HCC) treated with lenvatinib. Methods: Twenty patients with advanced HCC who received lenvatinib were enrolled in this retrospective study. α-Fetoprotein (AFP) and des-γ-carboxyprothrombin (DCP) levels were measured before treatment as well as 2 and 4 weeks after treatment. The objective response rate was evaluated by mRECIST at 6 weeks. Results: The response rate was 30% (complete response/partial response/stable disease/progressive disease: n = 0/6/6/8 cases) by mRECIST. At 4 weeks, the AFP levels of 12 patients (80%) were lower than at baseline. The AFP levels of 9 patients (60%) continued decreasing from 2 weeks to 4 weeks (sustained-reduction group). In this group, the response rate was 67%. The median AFP change rate was –39% at 4 weeks. In imaging responders, the AFP change rate significantly decreased (p = 0.02). The DCP change rate had no significant correlation with imaging response. The AFP-sustained-reduction group had significantly higher adherence to lenvatinib than the non-sustained-reduction group (p = 0.02). Conclusion: With lenvatinib therapy for HCC, the AFP levels of most patients had declined at 2 weeks, and at 4 weeks the AFP-sustained-reduction group demonstrated a higher objective response.

Bariatric surgery has been reported to improve non-alcoholic steatohepatitis (NASH), which is a frequent comorbidity in morbidly obese patients. We performed a retrospective cohort study to estimate the therapeutic effect of sleeve gastrectomy (SG), the most common bariatric surgery in Japan, on obese patients with NASH by comparing the findings of paired liver biopsies. Eleven patients who underwent laparoscopic SG for the treatment of morbid obesity, defined as body mass index (BMI) > 35 kg/m2, from March 2015 to June 2019 at Hiroshima University Hospital, Japan, were enrolled. All patients were diagnosed with NASH by liver biopsy before or during SG and were re-examined with a second liver biopsy 1 year after SG. The clinical and histological characteristics were retrospectively analyzed. One year after SG, body weight and BMI were significantly reduced, with median reductions in body weight and BMI of—22 kg and –7.9 kg/m2, respectively. Body fat was also significantly reduced at a median of 13.7%. Liver-related enzymes were also significantly improved. On re-examination by paired liver biopsy, liver steatosis improved in 9 of the 11 patients (81.8%), ruling out of the pathological diagnosis of NASH. However, fibrosis stage did not significantly improve 1 year after SG. The non-alcoholic fatty liver disease activity score was significantly reduced in 10 of 11 patients (90.9%). Pathological improvement or remission of NASH could be achieved in most morbidly obese Japanese patients 1 year after SG.

The preS1 region plays an essential role in hepatitis B virus (HBV) infection. We construct an antibody that binds to preS1 and a measurement system for serum preS1 in chronic HBV-infected patients.Hybridoma clones that produce anti-preS1 antibodies were obtained by the iliac lymph node method. Epitope mapping was conducted, and an enzyme-linked immunosorbent assay (ELISA)-based method was developed. Using this ELISA system, serum preS1 levels were measured in 200 chronic HBV-infected patients.Eight types of hybridomas were obtained, of which antibody 3-55 using amino acids 38-47 as the epitope showed high binding affinity to preS1. Serum preS1 levels measured by ELISA using 3-55 antibody were correlated with HBsAg, HBcrAg and HBV DNA levels. Among HBeAg-negative patients without antiviral therapeutic objective (HBV DNA3.3 log IU/mL or alanine aminotransferase ≤30 U/L), preS1 was significantly higher in subjects who had progressed to the point of requiring antiviral therapy compared to subjects who had maintained their status for the preceding three years (p0.01).We constructed an antibody against preS1 and an ELISA system capable of measuring serum preS1 levels. PreS1 may serve as a novel tool to predict the need for antiviral therapy in HBeAg-negative HBV-infected patients.

Introduction: This study compared clinical outcomes of 2nd- and 3rd-line regorafenib in patients with unresectable hepatocellular carcinoma. Methods: In this retrospective cohort study, 48 patients were treated with regorafenib for unresectable hepatocellular carcinoma. Thirty-five and 13 patients were initiated on 2nd- and 3rd-line therapy, respectively. We assessed the responses to and safety of the therapy. Results: There were no statistically significant differences in clinical characteristics at the start of 2nd- or 3rd-line regorafenib therapy. The overall response rate of 2nd- and 3rd-line regorafenib was 20 and 8%, respectively. The disease control rate was 57 and 54%, respectively. Median overall survival (mOS) from the start of 2nd-line regorafenib was 17.5 months. mOS from the start of 3rd-line regorafenib was not obtained. Median progression-free survival of 2nd- and 3rd-line regorafenib was 4.9 and 2.3 months, respectively. mOS from 1st-line therapy with tyrosine kinase inhibitor plus sorafenib-regorafenib-lenvatinib was 29.5 months; that with lenvatinib-sorafenib-regorafenib was not obtained. Patients on 3rd-line therapy tended to have better Child-Pugh scores and tumor factors at the start of 1st-line therapy than other patients. Conclusion: Patients on 2nd- and 3rd-line regorafenib showed favorable responses. Good Child-Pugh scores and tumor factors may be associated with a better response rate and OS.

Non-alcoholic steatohepatitis (NASH) may progress via liver fibrosis along with hepatic stellate cell (HSC) activation. A single nucleotide polymorphism (SNP; rs58542926) located in transmembrane 6 superfamily 2 (TM6SF2) has been reported to be significantly associated with fibrosis in patients with NASH, but the precise mechanism is still unknown. The present study aimed to explore the role of TM6SF2 in HSC activation in vitro. Plasmids producing TM6SF2 wild-type (WT) and mutant type (MT) containing E167K amino acid substitution were constructed, and the activation of LX-2 cells was analyzed by overexpressing or knocking down TM6SF2 under transforming growth factor β1 (TGFβ) treatment. Intracellular α-smooth muscle actin (αSMA) expression in LX-2 cells was significantly repressed by TM6SF2-WT overexpression and increased by TM6SF2 knockdown. Following treatment with TGFβ, αSMA expression was restored in TM6SF2-WT overexpressed LX-2 cells and was enhanced in TM6SF2 knocked-down LX-2 cells. Comparing αSMA expression under TM6SF2-WT or -MT overexpression, expression of αSMA in TM6SF2-MT overexpressed cells was higher than that in TM6SF2-WT cells and was further enhanced by TGFβ treatment. The present study demonstrated that intracellular αSMA expression in HCS was negatively regulated by TM6SF2 while the E167K substitution released this negative regulation and led to enhanced HSC activation by TGFβ. These results suggest that the SNP in TM6SF2 may relate to sensitivity of HSC activation.

Background: We previously reported the trends of etiologies of hepatocellular carcinoma (HCC) between 1995 and 2009. By updating this study, we aimed to evaluate the incidence of HCC with non- hepatitis B viral and non- hepatitis C viral (NBNC) etiologies and explore the clinical characteristics, also.Methods: Consecutive 2171 HCC patients at our institution were enrolled between 1992 and 2018 in this retrospective cohort study. A comparative study was conducted by dividing into two groups, an early group from 1992 to 2009 and a late group from 2010 to 2018.Results: NBNC-HCC account for 514 patients (23.6%). The proportion of NBNC-HCC has continued to increase from 26.5% in 2009 to 46.3% in 2018. NBNC-HCC were getting older (median ages, 67 to 73 years). Type 2 diabetes mellitus (48.5% to 60.3%: P=0.008), hypertension (48.5% to 57.4%: P=0.047), and hyperlipidemia (39.2% to 53.8%: P=0.001) has increased significantly in recent years. The median FIB-4 index have decreased (4.37 to 3.61: P=0.026) and the median platelet counts have increased (15.1 to 17.9: P=0.013) significantly. Among 514 NBNC-HCC, 194 patients underwent hepatic resection in which 14.9%, 29.3%, and 55.8% were based on nonalcoholic steatohepatitis (NASH), alcoholic liver disease (ALD), and cryptogenic, respectively. Cirrhosis was detected in 72.4%, 38.6%, and 15.5% of NASH, ALD and cryptogenic, respectively. The prevalence of cirrhosis in NASH were significantly higher than other groups (PConclusions: NBNC-HCC has rapidly been increasing in recent years even in regional university hospital. The presence of metabolic syndrome may be important risk factors. Furthermore, HCC from non-cirrhotic liver needs attention carefully. Accordingly, it is speculated that these patients should receive periodic surveillance for HCC development.

Immune checkpoint inhibitor (ICI) therapy has potent anti-cancer effects but is associated with immune-related adverse events (irAEs). We present a case who developed secondary sclerosing cholangitis following treatment with nivolumab for non-small cell lung cancer who did not respond to immunosuppressive treatments and died of liver failure. A 75 year-old male with lung cancer who had been treated with nivolumab for non-small cell lung cancer developed Grade 3 liver injury with significant elevation of hepatobiliary enzymes. Magnetic resonance cholangiopancreatography (MRCP) revealed diffuse dilatation of the common bile duct and multifocal stenosis with prestenotic dilatation from the perihilar to intrahepatic bile duct, consistent with sclerosing cholangitis. Histological findings represented an infiltration of mainly CD8-positive T cells around the bile ducts in the liver. Despite treatments with ursodeoxycholic acid, prednisolone, and mycophenolate mofetil, the sclerosing cholangitis did not improve, and the patient died due to liver failure and aggravation of lung cancer. These findings suggest that immune checkpoint inhibitors may lead to resistance to immunosuppressive treatment as well as pose a risk of life-threatening sclerosing cholangitis.

Background We previously reported the trends of etiologies of hepatocellular carcinoma (HCC) between 1995 and 2009. By updating this study, we aimed to evaluate the incidence of HCC with non- hepatitis B viral and non- hepatitis C viral (NBNC) etiologies and also explore the clinical characteristics. Methods Consecutive 2171 HCC patients at our institution were enrolled between 1992 and 2018 in this retrospective cohort study. A comparative study was conducted by dividing into two groups, an early group from 1992 to 2009 and a late group from 2010 to 2018. Results NBNC-HCC account for 514 patients (23.6%). The proportion of NBNC-HCC has continued to increase from 26.5% in 2009 to 46.3% in 2018. NBNC-HCC were getting older (median ages, 67 to 73 years). Type 2 diabetes mellitus (48.5–60.3%: P = 0.008), hypertension (48.5–57.4%: P = 0.047), and hyperlipidemia (39.2–53.8%: P = 0.001) has increased significantly in recent years. The median FIB-4 index have decreased (4.37 to 3.61: P = 0.026) and the median platelet counts have increased (15.1 to 17.9: P = 0.013) significantly. Among 514 NBNC-HCC, 194 patients underwent hepatic resection in which 14.9%, 29.3%, and 55.8% were based on nonalcoholic steatohepatitis (NASH), alcoholic liver disease (ALD), and cryptogenic, respectively. Cirrhosis was detected in 72.4%, 38.6%, and 15.5% of NASH, ALD and cryptogenic, respectively. The prevalence of cirrhosis in NASH were significantly higher than other groups (P

Although glucocorticoids have been used for immunosuppression of patients with primary hepatitis B virus (HBV) infection-induced severe hepatitis, the treatment is associated with a high frequency of adverse events. We conducted a pilot study for evaluating the efficacy and safety of abatacept, a cytotoxic T lymphocyte antigen-4 immunoglobulin (CTLA4), for acute hepatitis B. Five patients with severe acute hepatitis B (prothrombin activity ≤ 60%) were treated for immunosuppression by abatacept. Four patients received abatacept concurrently with methylprednisolone, and another patient was treated with abatacept alone. Rapid decrease in serum alanine aminotransferase levels, increase in prothrombin activity and improvement of general condition were obtained in four out of five patients. The patient with the most severe hepatitis underwent liver transplantation due to exacerbation of hepatitis in spite of treatment with both abatacept and methylprednisolone. None of the patients developed significant adverse events associated with the use of abatacept. Hepatitis B surface antigen (HBsAg) became negative in all five patients. The effect of abatacept and methylprednisolone for severe hepatitis B was compared using a mouse model. Rapid reduction in mouse serum HBV DNA and human albumin levels and elevation of serum interferon-gamma and granzyme A levels were observed in HBV-infected human hepatocyte-transplanted immunodeficient mice that were administered human peripheral blood mononuclear cells. These hepatocyte injuries were inhibited to a greater extent by abatacept compared to methylprednisolone. Abatacept might be an effective therapy alternative to methylprednisolone to reduce acute massive liver damage for patients with severe acute hepatitis caused by HBV infection.

Background: Although a strong antitumor effect of lenvatinib (LEN) has been noted for patients with unresectable hepatocellular carcinoma (HCC), there are still no reports on the prognosis for patients with disease progression after first-line LEN therapy. Methods: Patients (n = 141) with unresectable HCC, Child-Pugh class A liver function, and an Eastern Cooperative Oncology Group performance status (ECOG-PS) of 0 or 1 who were treated with LEN from March 2018 to December 2019 were enrolled. Results: One hundred and five patients were treated with LEN as first-line therapy, 53 of whom had progressive disease (PD) at the radiological evaluation. Among the 53 patients with PD, there were 27 candidates for second-line therapy, who had Child-Pugh class A liver function and an ECOG-PS of 0 or 1 at progression. After progression on first-line LEN, 28 patients were treated with a molecular targeted agent (MTA) as second-line therapy (sorafenib: n = 26; ramucirumab: n = 2). Multivariate analysis identified modified albumin-bilirubin grade 1 or 2a at LEN initiation (odds ratio 5.18, 95% confidence interval [CI] 1.465–18.31, p = 0.011) as a significant and independent factor for candidates. The median post-progression survival after PD on first-line LEN was 8.3 months. Cox hazard multivariate analysis showed that a low alpha-fetoprotein level (p = 0.003), a relative tumor volume p = 0.03), and switching to MTAs as second-line treatment after LEN (HR 0.299, 95% CI 0.12–0.746, p = 0.01) were significant prognostic factors. Conclusion: Among patients with PD on first-line LEN, good liver function at introduction of LEN was an important and favorable factor related to eligibility for second-line therapy. In addition, post-progression treatment with MTAs could improve the prognosis for patients who had been treated with first-line LEN.

AIM Combination therapy with sofosbuvir (SOF) plus velpatasvir (VEL) is approved for patients with hepatitis C virus (HCV)-related decompensated cirrhosis. We analyzed the real-world efficacy of SOF/VEL therapy. METHODS Thirty-three patients with HCV-related decompensated cirrhosis (25 and eight patients with Child B and C, respectively) were treated with SOF/VEL for 12 weeks. The HCV non-structural protein (NS)5A and NS5B drug resistance-associated substitutions (RASs) were determined by direct sequencing. RESULT Thirty-two of 33 patients completed the treatment, but the remaining patient discontinued the therapy during third week of the treatment due to aggravation of hepatic encephalopathy. Serum HCV-RNA became negative during the treatment in all patients but relapsed after the end of therapy in five patients. In total, 28 out of 33 patients (85%) achieved sustained virological response 12 weeks following completion of treatment (SVR12). The SVR12 rate was 96% in patients with Child B, but significantly lower, at 50%, in patients with Child C (P

Purpose In recent years, it has been reported that use of 18F-FDG PET-CT can reveal the degree of hepatocellular carcinoma malignancy. We evaluate the ability of a preoperative 18F-FDG PET-CT to predict the recurrence of extrahepatic metastasis of HCC after surgery. Methods We retrospectively examined 67 patients who received 18F-FDG PET-CT prior to curative hepatic resection for HCC between April 2010 and March 2016. Multivariate Cox regression analysis was performed to identify the factors associated with recurrence of extrahepatic metastasis of HCC after surgery. We also evaluated the sensitivity, specifity, positive predictive value, negative predictive value and accuracy of diagnosis of 18F-FDG PET-CT for recurrent extrahepatic metastasis of HCC after surgery. Results The multivariate analysis identified a tumor-to-normal liver standardized uptake value ratio (TNR) ≥ 1.53 (hazard ratio [HR], 0.037; P = 0.003), multiple tumor nodules (HR, 0.121; P = 0.007), and presence of microvascular invasion (HR, 0.094; P = 0.003) as independent predictors of distant metastasis recurrence. A TNR ≥ 1.53 showed a sensitivity of 91.7 %, specificity of 76.4 %, positive predictive value of 45.8 %, negative predictive value of 97.7 %, and accuracy of 79.1 % for diagnosing distant metastasis recurrence of HCC. In a binomial logistic regression analysis of tumor factors associated with a TNR ≥ 1.53, poor tumor differentiation and large tumor size were significant factors. Conclusion 18F-FDG PET-CT and microvascular invasion may be useful for predicting the recurrence of extrahepatic metastasis of HCC after surgery., アクセプト後にアブストラクトに変更あり

BACKGROUND AND AIM To examine the effect on recurrence and survival of treatment by interferon (IFN)-free direct-acting antivirals (DAA) for patients with hepatitis C virus (HCV)-associated hepatocellular carcinoma (HCC) who underwent primary curative treatment. METHODS This was a retrospective cohort study of 250 patients with HCV who had received curative treatment for primary HCC. As anti-HCV treatment after HCC treatment, 38 patients received IFN-free DAA therapy (DAA patients) and 94 received IFN-based therapy (IFN patients). The recurrence of HCC and overall survival of the patient groups were compared in a case-control study. RESULTS The cumulative HCC recurrence rates at 1, 3, and 5 years were 5%, 39%, and 39% for DAA patients and 0%, 46%, and 62% for IFN patients, respectively (P = 0.370). Multivariate analysis of the HCC recurrence identified treatment responses (sustained virological response [SVR]: hazard ratio [HR] 2.237; P = 0.003) as an independent predictive factor. The cumulative overall survival rates at 3 and 5 years were 96%, 96% for DAA patients and 93%, 73% for IFN patients, respectively ( P = 0.163). Multivariate analysis identified treatment responses (SVR: HR 8.742; P

Aim The aim of this study is to compare the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) between 5-fluorouracil (5-FU)-based continuous infusion chemotherapy and low-dose cisplatin (CDDP) monotherapy in patients with advanced hepatocellular carcinoma (HCC). Methods Patients were grouped according to HAIC regimen (5-FU group, n = 317/CDDP group, n = 66). A two-to-one match was created using propensity score analysis (5-FU group, n = 102/CDDP group, n = 51). After matching, response rate (RR) and adverse events as primary end-points, and survival and progression-free survival as secondary end-points, were analyzed. Results In the analysis of primary end-points, the RR in the 5-FU group was significantly higher than in the CDDP group (32.4% vs. 15.7%, P = 0.033). In patients with a Child-Pugh (CP) score of 5-7, the RR in the 5-FU group was significantly higher than that in the CDDP group (36.1% vs. 15.4%, P = 0.020). In those with a CP score of 8-9, there was no significant difference in RR between the two groups (15.8% vs. 16.6%, P = 1.000). The reservoir system-related complications were 9.8% in the 5-FU group, and there was no significant difference in the incidence of grade 3/4 adverse events between the two matched groups (P > 0.05). In terms of secondary end-points, the median survival time was 9.1 and 8.7 months for the 5-FU and CDDP groups, respectively (P = 0.4917). Progression-free survival was 3.9 months for the 5-FU group and 4.9 months for the CDDP group (P = 0.4). Conclusions 5-Fluorouracil-based continuous infusion chemotherapy could be suitable for advanced HCC patients with a CP score of 5-7 considering the treatment response.

Background Sustained virological response (SVR) rates for the treatment of chronic hepatitis C virus (HCV)-infected patients have drastically improved with the use of direct-acting antiviral (DAA) therapies; however, a small minority of patients still fails to eradicate the virus. We analyzed factors associated with SVR in DAA therapy and the effect of age and liver fibrosis on treatment response. Methods Nine hundred and eighteen patients with chronic HCV infection were treated with 24 weeks of daclatasvir plus asunaprevir (DCV + ASV) or 12 weeks of sofosbuvir plus ledipasvir (SOF + LDV), ombitasvir, paritaprevir plus ritonavir (OMB + PTV + r) or sofosbuvir plus ribavirin (SOF + RBV). Multivariate logistic regression analysis was used to identify factors associated with SVR. The effect of age and liver fibrosis on SVR was analyzed. Results The overall SVR rate was 95.4% (876 of 918 patients), and rates by DAA regimen were 93.4%, 95.7%, 100%, and 95.0% in DCV + ASV-treated, SOF + LDV-treated, OMB + PTV + r-treated, and SOF + RBV-treated patients, respectively. Patients older than 75 years achieved a similar SVR rate with those aged 75 years or younger (96.4% and 94.8%, respectively). Multivariate logistic regression analysis identified absence of DAA therapy history (odds ratio [OR], 3.868 for presence; P = 0.002) and FIB-4 index of less than 3.25 (OR, 5.042 for ≥3.25; P = 0.001) as independent predictors for SVR. SVR rates were significantly lower in patients with FIB4 index of 3.25 or more compared with those with less than 3.25, especially in sofosbuvir-based therapies such as SOF + LDV-treated or SOF + RBV-treated patients. Conclusion Both older and younger patients respond similarly to DAA therapy. Advanced liver fibrosis affects the virological response to sofosbuvir-based therapy.

Aim As second-line therapy, regorafenib has been shown to provide a survival benefit for patients with hepatocellular carcinoma (HCC) who progress on sorafenib. In this retrospective study, we assessed the clinical outcomes of sorafenib treatment failure with regard to second-line chemotherapy. Methods Patients (n = 160) with advanced HCC, Child-Pugh A liver function and Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1 treated with sorafenib between June 2009 and September 2016 were enrolled. Among 147 patients with progressive disease (PD), we defined those with Child-Pugh A liver function and ECOG PS 0-1 at progression as candidates for second-line chemotherapy and those who had tolerated sorafenib (≥400 mg/day for ≥20 of the last 28 days of treatment) as candidates eligible for regorafenib treatment. Results Among all 160 patients, median overall survival was 10 months, and median progression-free survival was 3.5 months. Among the 147 patients with PD, 74 (50.3%) were candidates for second-line chemotherapy, and 45 (30.6%) were eligible for regorafenib treatment. The median post progression survival of the candidates for second-line chemotherapy (8.8 months) was statistically longer (P = 0.0002) than that of the non-candidates (3.6 months). Predictive factors for candidates were absence of macroscopic vascular invasion (MVI) (odds ratio [OR], 0.39; P = 0.009) and serum albumin >3.5 g/dL (OR, 3.3; P = 0.005) at sorafenib initiation. Conclusion Among patients with PD on sorafenib, approximately 30% were eligible for regorafenib treatment, whereas few patients with MVI or hypoalbuminemia at sorafenib initiation were eligible for regorafenib treatment.

Background and aim Sorafenib is the standard treatment for patients with advanced hepatocellular carcinoma (HCC) with distant metastasis, unresectable HCC, and HCC refractory to transcatheter arterial chemoembolization (TACE) or with macroscopic vascular invasion (MVI). Also, hepatic arterial infusion chemotherapy (HAIC) has been used for advanced HCC in Southeast and East Asian countries. However, clearer information is needed for choosing appropriately between these therapies. Methods The subjects were 391 HAIC and 431 sorafenibs administered at our hospital and related hospitals. In this case, cases that satisfy the following three conditions were targeted: (i) no extrahepatic metastasis, (ii) Child-Pugh A, and (ii) not having received treatment of both HAIC and sorafenib during the course. As a result, 150 cases of HAIC and 134 cases of sorafenib were analyzed this time. Results Univariate and multivariate analyses were performed for the HAIC and sorafenib groups. TACE refractory status and MVI were factors contributing to overall survival (OS). Therefore, this study divided all cases according to those variables. The median survival time of MVI-positive and non-TACE refractory cases was significantly better with HAIC (13 months) versus sorafenib (6 months). However, in MVI-negative and TACE refractory cases, the median survival time of HAIC (8 months) was significantly poorer than for sorafenib (20 months). Conclusion Transcatheter arterial chemoembolization refractory status with HAIC and MVI with sorafenib were factors for poor prognosis. In particular, HAIC was significantly better than sorafenib as primary treatment in MVI and non-TACE refractory cases. It is necessary to consider these factors in treatment selection.