HBV with precore and basal core promoter mutations exhibits a high replication phenotype and causes ER stress-mediated cell death in humanized liver chimeric mice.

BACKGROUND AND AIMS: Mutations within the precore (PC) and basal core promoter (BCP) regions of the HBV genome are associated with fulminant hepatitis and HBV reactivation. These mutations may enhance viral replication, but little is known about whether they directly induce damage to the liver. We investigated mechanisms of direct cytopathic effects induced by the infection with PC/BCP mutants in the absence of immune response in vitro and in vivo . APPROACH AND RESULTS: Mice with humanized livers and hepatocytes derived from humanized mice were infected with either wild-type or mutant-type PC/BCP HBV, and the HBV replication and human hepatocyte damage were evaluated. HBV proliferated vigorously in mice with PC/BCP-mutant infection, and the severe loss of human hepatocytes with a slight human ALT elevation subsequently occurred only in PC/BCP mutant mice. In PC/BCP mutant infection, the accumulation of HBsAg in humanized livers colocalized with the endoplasmic reticulum, leading to apoptosis through unfolded protein response in HBV-infected hepatocytes. RNA-sequencing revealed the molecular characteristics of the phenotype of PC/BCP mutant infection in a humanized mouse model. Reduced ALT elevation and higher HBV DNA levels in this model are consistent with characteristics of HBV reactivation, indicating that the hepatocyte damage in this model might mimic HBV reactivation followed by hepatocyte damage under immunosuppressive conditions. CONCLUSION: PC and BCP mutations were associated with enhanced viral replication and cell death induced by ER stress using HBV infection models. These mutations might be associated with liver damage in patients with fulminant hepatitis or HBV reactivation.

Outcomes of Patients with Child-Pugh B and Unresectable Hepatocellular Carcinoma Undergoing First-Line Systemic Treatment with Sorafenib, Lenvatinib, or Atezolizumab Plus Bevacizumab.

INTRODUCTION: Systemic therapy is recommended for patients with Child-Pugh A in hepatocellular carcinoma (HCC). We analyzed the outcomes of a cohort of patients with HCC who received either sorafenib (Sor), lenvatinib (Len) or atezolizumab plus bevacizumab (Atezo + Bev) as first-line systemic therapy for HCC, with the aim of identifying prognostic factors for survival. METHODS: A total of 825 patients with advanced HCC and Child-Pugh A or B received either Sor, Len or Atezo + Bev as first-line systemic therapy. Liver function was assessed according to the Child-Pugh score and the modified albumin-bilirubin (mALBI) grade. RESULTS: Prognosis was analyzed according to liver function such as Child-Pugh classifications, scores, and mALBI grades that worsened with a decline in liver function (p <0.001 for all). A Child-Pugh score of 7 was a factor significantly associated with OS. In patients with a Child-Pugh score of 7, an mALBI grade of 3 was an independent predictor of OS. In Child-Pugh B patients with HCC, receiving Atezo + Bev was identified as a factor associated with PFS. CONCLUSION: Determining the hepatic reserve of patients with unresectable HCC might be useful for identifying patents suitable for systemic treatment for HCC. Atezo + Bev might prolong the PFS of patients with a Child-Pugh score of 7.

Novel drug resistance-associated substitutions against pibrentasvir emerged in genotype 1b hepatitis C virus-infected human hepatocyte transplanted mice.

Combination therapy with glecaprevir and pibrentasvir (PIB) has high efficacy for patients with hepatitis C virus (HCV) infection except among those who experienced NS5A-P32 deletion (del) mutation during prior DAA treatment failure. However, some patients fail to achieve SVR through combination treatment even in the absence of NS5A-P32del. We analyzed emergence of NS5A resistance-associated substitutions (RASs) against PIB using HCV-infected mice. Male human hepatocyte transplanted mice were infected with genotype 1b wild-type HCV. Mice were treated with PIB, resulting in a transient decrease in serum HCV RNA levels but followed by relapse during the treatment. Direct sequence analysis showed emergences of various mutations in the NS5A region, including L31V/P32del, L31F/P32del/Y93H, NS5A-P29del/Y85C, and NS5A-F37Y. PIB was less effective in mice with NS5A-F37Y mutations compared to mice with wild-type HCV. NS5A-F37Y showed 5.4-fold resistance to PIB relative to wild-type based on analysis using HCV subgenomic replicon systems. The present in vivo and in vitro studies identified NS5A-F37Y as a novel RAS against PIB and showed the possibility of emergence of various NS5A RASs including P29del, P32del and F37Y following PIB treatment. These mutations might emerge and lead to failure to respond to DAA therapies including PIB-based regimens in chronic hepatitis C patients.

Abatacept treatment for patients with severe acute hepatitis caused by hepatitis B virus infection-Pilot study.

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.

Real-world efficacy of sofosbuvir plus velpatasvir therapy for patients with hepatitis C virus-related decompensated cirrhosis.

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 < 0.05). In genotype 1b HCV-infected patients, all eight patients without baseline NS5A RASs, but only three of seven patients with RASs, achieved SVR12. Multivariate analysis identified Child B (odds ratio, 35.8 for Child C; P = 0.045) as an independent predictor of SVR12. Median serum albumin levels significantly increased only in patients who achieved SVR12. Child-Pugh scores improved in 16 of 28 patients (57%) following achievement of SVR12. CONCLUSION: The effect of SOF/VEL therapy is lower for patients with Child C. Improvement of hepatic function is expected after viral eradication with SOF/VEL therapy in patients with decompensated cirrhosis.

Correlation between Early Tumor Marker Response and Imaging Response in Patients with Advanced Hepatocellular Carcinoma Treated with Lenvatinib.

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.

Primary liver carcinoma with sarcomatous changes: Analysis of 10 cases.

Primary liver carcinoma with sarcomatous change is a rare malignancy associated with high aggressiveness and poor prognosis. However, the characteristics of these types of tumors are still unknown. The aim of this study was to assess the imaging features, prognostic significance, and clinicopathological characteristics of patients with these tumors. Of 1070 patients who underwent surgical resection of primary liver carcinoma at Toranomon Hospital (Tokyo, Japan) from 2003 to 2017, 10 patients were diagnosed with primary liver carcinoma containing sarcomatous component. This study included all 10 patients. We evaluated the percentage of the sarcomatous component in each tumor. Patients were classified into two groups: the low percentage group (area of sarcomatous changes ≤30%) and high percentage group (area sarcomatous component ≥70%). We also divided patients into two groups based on the combination of the percentage of sarcomatous tissue and tumor size (≥40 mm or <40 mm). The overall survival rate of patients with ≥70% sarcomatous component and ≥40 mm tumor was significantly worse than that of patients with ≤30% sarcomatous tissue or <40 mm tumor size (P = 0.0059). The results confirmed the poor prognosis of patients with sarcomatous changes in primary liver carcinoma, especially those with large sarcomatous component and large tumor size. Radical resection in the early stage is recommended to improve prognosis.

Predictors of treatment efficacy and liver stiffness changes following therapy with Sofosbuvir plus Ribavirin in patients infected with HCV genotype 2.

While the combination therapy of ribavirin (RBV) and sofosbuvir (SOF) is effective in genotype 2 HCV infection, the predictors of treatment efficacy and posttreatment changes in α-fetoprotein (AFP) and liver stiffness (markers of hepatocellular carcinoma), remain unclear. In this study, 302 patients with chronic HCV genotype 2 infection were treated with SOF (400 mg) plus RBV (400-1000 mg; based on body weight) for 12 weeks. We evaluated the efficacy and safety of treatment, as well as measured serum AFP, liver stiffness, and controlled attenuation parameter (CAP, a surrogate marker of steatosis) at baseline and within 48 weeks of treatment completion. The intention-to-treat analysis showed a sustained virological response (SVR) rate of 95.7%. None of the patients discontinued treatment due to side effects. Multivariate analysis identified pretreatment (no treatment with interferon), level of AFP (AFP; <10 µg/L), and RBV/body weight (BW) ratio (≥9.0 mg/kg) as independent predictors of SVR. The SVR rate in patients with two predictors of poor response (AFP ≥10 µg/L and RBV/BW ratio <9.0 mg/kg) was significantly lower than in other patients. In the SVR group, posttreatment AFP level and liver stiffness were significantly lower than at baseline. CAP tended to be higher after treatment than at baseline in all patients. SOF plus RBV combination therapy achieved a high SVR rate and was safe in HCV genotype 2 infected patients. Treatment reduced AFP levels and improved liver stiffness, but increased CAP.

Comparison of hepatic arterial infusion chemotherapy between 5-fluorouracil-based continuous infusion chemotherapy and low-dose cisplatin monotherapy for advanced hepatocellular carcinoma.

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.

Analysis of Lenvatinib's Efficacy against Intermediate-Stage Unresectable Hepatocellular Carcinoma.

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.

In vitro analysis of hepatic stellate cell activation influenced by transmembrane 6 superfamily 2 polymorphism.

Non­alcoholic 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 LX­2 cells was analyzed by overexpressing or knocking down TM6SF2 under transforming growth factor ß1 (TGFß) treatment. Intracellular α­smooth muscle actin (αSMA) expression in LX­2 cells was significantly repressed by TM6SF2­WT overexpression and increased by TM6SF2 knockdown. Following treatment with TGFß, αSMA expression was restored in TM6SF2­WT overexpressed LX­2 cells and was enhanced in TM6SF2 knocked­down LX­2 cells. Comparing αSMA expression under TM6SF2­WT or ­MT overexpression, expression of αSMA in TM6SF2­MT overexpressed cells was higher than that in TM6SF2­WT cells and was further enhanced by TGFß 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 TGFß. These results suggest that the SNP in TM6SF2 may relate to sensitivity of HSC activation.

Efficacy of Lusutrombopag for Thrombocytopenia in Patients with Chronic Liver Disease Scheduled to Undergo Invasive Procedures.

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<0.01), and patients undergoing 49 of the 53 (92%) treatment regimens succeeded in undergoing invasive procedures without needing platelet transfusions. In patients who received lusutrombopag treatment repeatedly, the median platelet count significantly increased following the second administration of lusutrombopag, and the effects of lusutrombopag were similar between the first and second administration. A multivariate analysis identified the absence of diabetes mellitus (odds ratio, 5.56 for presence; p=0.04) as a significant and independent predictor of a response to lusutrombopag. Conclusion Lusutrombopag treatment significantly increased platelet counts in patients with chronic liver disease, making it possible to receive invasive procedures. The treatment produced identical effects when it was repeated. The efficacy of lusutrombopag might be decreased in patients with diabetes mellitus.

Real-word efficacy of sofosbuvir, velpatasvir plus ribavirin therapy for chronic hepatitis patients who failed to prior DAA therapy with NS5A-P32 deletion mutated HCV infection.

The hepatitis C virus (HCV) NS5A-P32 deletion (P32del) confers potent resistance to NS5A inhibitors. Chronic hepatitis C patients in whom NS5A-P32del variants had emerged during prior direct-acting antiviral (DAA) therapy with an NS5A inhibitor show poor response to DAA retreatment. Here, we report three patients with HCV NS5A-P32del infection who were treated with sofosbuvir, velpatasvir plus ribavirin (SOF/VEL + RBV) in a real-world setting. The patients developed HCV NS5A-P32del, L31F + P32del, or L31V + P32del variants following failure of daclatasvir plus asunaprevir (DCV/ASV) therapy. One of the patients failed to respond to subsequent DCV/ASV and beclabuvir therapy, and the remaining two patients failed to respond to subsequent glecaprevir and pibrentasvir therapy. All three patients completed 24-week SOF/VEL + RBV therapy. Serum HCV RNA became negative at the end of the therapy in all three patients. Two patients with NS5A-P32del and NS5A-L31F + P32del achieved sustained virological response 12 weeks after completion of treatment (SVR12), but HCV relapsed in the remaining NS5A-L13V + P32del patient. Direct sequence analysis detected no additional variants within either the NS5A or NS5B regions at the time of relapse. In conclusion, three patients with prior NS5A-P32del-associated DAA treatment failure received 24 weeks of SOF/VEL + RBV therapy, and two of the patients achieved SVR12.

Successful retreatment with 12 weeks of glecaprevir and pibrentasvir for a genotype 2a HCV-infected hemodialysis patient who failed to respond to 8 weeks of prior glecaprevir and pibrentasvir therapy.

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.

Management of refractory ascites attenuates muscle mass reduction and improves survival in patients with decompensated cirrhosis.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: Treatment of refractory ascites with tolvaptan may attenuate the progression of sarcopenia and improve the prognosis in patients with decompensated cirrhosis.

Three Children Treated with Direct-acting Antivirals for Chronic Hepatitis C Virus Genotype 1b Infection.

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.

Sinusoidal obstruction syndrome post-treatment with trastuzumab emtansine (T-DM1) in advanced breast cancer.

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.

Skeletal Muscle Loss during Tyrosine Kinase Inhibitor Treatment for Advanced Hepatocellular Carcinoma Patients.

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

Preoperative PET-CT is useful for predicting recurrent extrahepatic metastasis of hepatocellular carcinoma after resection.

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.

Circulating cytokines and angiogenic factors based signature associated with the relative dose intensity during treatment in patients with advanced hepatocellular carcinoma receiving lenvatinib.

BACKGROUND: Although lenvatinib was recently approved for treatment of advanced unresectable hepatocellular carcinoma (HCC) based on the phase III REFLECT trial, no biomarkers for management of lenvatinib treatment have been established. The aim of this study is to identify predictive biomarkers for the management of lenvatinib treatment in advanced HCC patients. METHODS: A total of 41 patients with advanced HCC were enrolled in this retrospective study. Serum levels of 22 circulating cytokines and angiogenic factors (CAFs) were measured by multiplex Luminex assay. Profiles of CAFs, clinical chemistry/hematology parameters, and clinical background were evaluated to explore biomarkers associated with clinical outcomes. RESULTS: Relative dose intensity (RDI) decreased significantly between weeks 1-2 and 3-4 (p < 0.001), and RDI during weeks 3-4 was a prominent indicator of progression-free survival (PFS). A signature based on baseline serum levels of nine CAFs associated with low RDI was identified. In a multivariate Cox regression analysis, patients with a favorable 9-CAFs signature [hazard ratio (HR) 0.42, 95% confidence interval (CI) 0.18-0.96, p = 0.040] had lower risk, and Child-Pugh grade B (HR 1.6, 95% CI 1.1-8.3, p = 0.026) and presence of macrovascular invasion (MVI; HR 2.9, 95% CI 1.0-8.3, p = 0.045) had higher risk of shorter PFS. CONCLUSION: This study demonstrates that RDI is an important predictive factor for longer PFS during lenvatinib treatment. In this hypothesis-generating exploratory analysis, we report that a CAF-signature associated with adverse events and RDI could predict PFS, which might contribute to improved management of lenvatinib treatment in HCC patients.