Efficacy and safety of chemoradiation therapy using one-shot cisplatin via hepatic arterial infusion for advanced hepatocellular carcinoma with major macrovascular invasion: a single-arm retrospective cohort study.

BACKGROUND: Patients with hepatocellular carcinoma (HCC) and macrovascular invasion (MVI) who receive systemic chemotherapy have a poor prognosis. This study aimed to determine if one-shot cisplatin (CDDP) chemotherapy via hepatic arterial infusion (HAI) combined with radiation therapy (RT) prior to systemic chemotherapy could improve the outcomes of these patients. METHODS: This study consisted of 32 HCC patients with the following eligibility criteria: (i) portal vein invasion 3/4 and/or hepatic vein invasion 2/3; (ii) received one-shot CDDP via HAI; (iii) received RT for MVI, (iv) a Child-Pugh score ≤ 7; and (v) an Eastern Clinical Oncology Group Performance Status score of 0 or 1. To determine the therapeutic effect, we collected information on patient characteristics and took contrast-enhanced computed tomography at the start of the therapy and every 2 to 4 months after the start of therapy. We evaluated the overall response of the tumor and tumor thrombosis according to modified Response Evaluation Criteria in Solid Tumors. We assessed patient data using the Mann-Whitney U and Fisher exact tests and evaluated overall survival and progression-free survival using the log-rank test. RESULTS: The overall response rate at the first evaluation performed a median of 1.4 weeks after HAI was 16% for the main intrahepatic tumor and 59% for the MVI. The best responses were the same as those of the first-time responses. The duration of median survival was 8.6 months, and progression-free survival of the main intrahepatic tumor was 3.2 months. Predictive factors for overall survival were the relative tumor volume in the liver and the first therapeutic response of MVI. There were no severe adverse events or radiation-induced hepatic complications. CONCLUSIONS: One-shot CDDP via HAI and RT were well tolerated and showed immediate and favorable control of MVI. Thus, this combination shows potential as a bridging therapy to systemic chemotherapy.

Efficacy and Safety of Lenvatinib-Transcatheter Arterial Chemoembolization Sequential Therapy for Patients with Intermediate-Stage Hepatocellular Carcinoma.

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.

Increasing incidence of non-HBV- and non-HCV-related hepatocellular carcinoma: single-institution 20-year study.

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 < 0.001). Overall, 70% of the non-malignant liver tissue of patients with NBNC-HCC was not involved with cirrhosis. On the other hand, the median FIB-4 index in patients with cryptogenic HCC was 2.56, which was a significantly lower value than those values in the other groups of patients. The FIB-4 index considered as one of useful screening of HCC. 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.

Extracellular water to total body water ratio obtained by bioelectrical impedance analysis determines the dose intensity of lenvatinib for the treatment of patients with advanced hepatocellular carcinoma.

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.

Trends in Hepatic Functional Reserve of Patients with Hepatocellular Carcinoma Treated with Tyrosine Kinase Inhibitors.

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.

Analysis of Post-Progression Survival in Patients with Unresectable Hepatocellular Carcinoma Treated with Lenvatinib.

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 (<400 ng/mL; hazard ratio [HR] 0.297, 95% CI 0.099-0.886, p = 0.003), a relative tumor volume <50% at the time of progression (HR 0.204, 95% CI 0.07-0.592, 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.

Incidence of microsatellite instability-high hepatocellular carcinoma among Japanese patients and response to pembrolizumab.

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.

Pruritus in patients with chronic liver disease and serum autotaxin levels in patients with primary biliary cholangitis.

BACKGROUND: Pruritus is a common symptom seen in patients with chronic liver disease. However, frequency and severity of pruritus in patients with chronic liver disease is unclear. We investigated frequency, severity and predictive factors of pruritus in these patients from a large cohort. METHODS: A total of 2477 patients with chronic liver disease without allergies or skin diseases were investigated for itch frequency and severity. Itch severity was self-assessed using pruritus scores using the numerical rating scale (NRS). Multivariate regression analysis was performed to identify factors associated with pruritus. Serum autotaxin levels were measured in patients with primary biliary cholangitis (PBC), and the relationship to liver fibrosis and pruritus was analyzed. RESULTS: The frequency of pruritus in patients with chronic liver disease was significantly higher than in subjects without liver disease (29.8 and 16.2%, respectively, P < 0.001). NRS was high in patients with chronic liver disease, especially in those with PBC, as is generally expected. Multivariate analysis identified lower albumin, higher eosinophil count, and etiology of PBC as independent factors associated with severe pruritus (≥5 points of NRS). In patients with PBC, serum autotaxin levels were significantly correlated with liver fibrosis markers such as platelet count and liver stiffness, and hepatobiliary enzymes such as total bilirubin, aspartate aminotransferase and alkaline phosphatase. However, no significant correlations between serum autotaxin levels and frequency and severity of pruritus were observed in patients with PBC. CONCLUSION: The frequency of pruritus was high in patients with chronic liver disease. Reduction of liver function is associated with severe pruritus based on the large number of patients with chronic liver disease. Serum autotaxin is useful for assessing liver fibrosis and severity of cholangitis; however, it is not a predictive marker for severe pruritus in patients with PBC.

Ultrashort-Segment Embolization of High-Flow Vessels Using a Coil Packing Technique in an Amplatzer Vascular Plug.

PURPOSE: To report an experimental study and clinical case using a coil packing technique that hastens occlusion of an Amplatzer Vascular Plug 1 (AVP1) in short-segment embolization of high-flow target vessels. TECHNIQUE: An experimental vascular stenosis model was made of 12-mm soft polyvinyl chloride tubing. Under continuous pulsatile flow, a 12-mm AVP1 was deployed in the 4-mm-diameter stenosis. Before detachment of the AVP1, a 2.2-F microcatheter was inserted into the AVP1 through its mesh via a 6-F delivery guiding sheath in parallel with the delivery wire. Hydrogel microcoils were deployed tightly in the AVP1 and the plug was detached. After the procedure, the pulsatile saline flow was nearly obliterated. In the first clinical case, a 64-year-old man with a thoracic aortic stent-graft and single vessel debranching for type B aortic dissection developed a residual type II endoleak via the left subclavian artery. This coil packing technique in an AVP1 was employed to successfully embolize the leak. CONCLUSION: Based on the experimental study and the first experience in vivo, tight coil packing of an AVP1 might be a robust technique for ultrashort-segment embolization.

Complete response to short-term sorafenib treatment alone for hepatocellular carcinoma with bone, lymph node, and peritoneum metastases.

We report a 60-year-old male patient who developed extrahepatic metastases in bone, peritoneum, and lymph nodes (confirmed by computed tomography and positron emission tomography-computed tomography) after hepatectomy for hepatocellular carcinoma. He was treated with sorafenib (800 mg/day) but developed grade 3 hand-foot syndrome. He continued to be treated with sorafenib but at a lower dose (400 mg/week). The response to sorafenib therapy was graded as complete response at 6 months by the Response Evaluation Criteria in Solid Tumors. Sorafenib was continued for 8 months and the patient remained in complete response for 11 months. Further reporting of similar cases should help design treatment strategies and evaluate predictors of the response to sorafenib therapy.

Development of hepatocellular carcinoma in patients with hepatitis C virus infection who achieved sustained virological response following interferon therapy: A large-scale, long-term cohort study.

BACKGROUND: We assessed the risk factors for the development of hepatocellular carcinoma (HCC) following successful eradication of hepatitis C virus (HCV) with interferon (IFN) therapy in a long-term, large-scale cohort study. METHODS: We reviewed 1094 consecutive patients with HCV who achieved sustained virological response (SVR) following IFN therapy between January 1995 and September 2013. RESULTS: During the observation period (median 50 months: range 13-224), 36 (3%) of 1094 patients developed HCC after SVR. The median period from SVR to diagnosis of HCC was 37 months (range 17-141), and the cumulative rates of HCC at 5, 10, and 15 years were 4%, 6%, and 12%, respectively. Multivariate analysis identified old age (≥60 years, HR, 3.1: 95%CI, 1.3-6.6: P = 0.009), male sex (HR, 12.0: 95%CI, 2.8-50.0: P < 0.0001), advanced fibrosis stage (F3/4, HR, 3.2: 95%CI, 1.6-7.2: P < 0.0001), and alpha-fetoprotein ≥10 ng/mL at 1 year after SVR (HR, 7.8: 95%CI, 2.9-16.8: P < 0.0001) as significant and independent risk factors for post-SVR HCC. CONCLUSIONS: Older age and male sex (host factors), advanced fibrosis stage (pre-IFN treatment factor), and higher alpha-fetoprotein values (post-treatment factor) were significantly associated with HCC development after HCV eradication.

Usefulness of combining gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging and contrast-enhanced ultrasound for diagnosing the macroscopic classification of small hepatocellular carcinoma.

OBJECTIVE: Non-simple nodules in hepatocellular carcinoma (HCC) correlate with poor prognosis. Therefore, we examined the diagnostic ability of gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (EOB-MRI) and contrast-enhanced ultrasound (CEUS) for diagnosing the macroscopic classification of small HCCs. METHODS: A total of 85 surgically resected nodules (≤30 mm) were analyzed. HCCs were pathologically classified as simple nodular (SN) and non-SN. By evaluating hepatobiliary phase (HBP) of EOB-MRI and Kupffer phase of CEUS, the diagnostic abilities of both modalities to correctly distinguish between SN and non-SN were compared. RESULTS: Forty-six nodules were diagnosed as SN and the remaining 39 nodules as non-SN. The area under the ROC curve (AUROCs, 95% confidence interval) for the diagnosis of non-SN were EOB-MRI, 0.786 (0.682-0.890): CEUS, 0.784 (0.679-0.889), in combination, 0.876 (0.792-0.959). The sensitivity, specificity, and accuracy were 64.1%, 95.7%, and 81.2% in EOB-MRI, 56.4%, 97.8%, and 78.8% in CEUS, and 84.6%, 95.7%, and 90.6% in combination, respectively. High diagnostic ability was obtained when diagnosed in both modalities combined. The sensitivity was especially statistically significant compared to CEUS. CONCLUSION: Combined diagnosis by EOB-MRI and CEUS can provide high-quality imaging assessment for determining non-SN in small HCCs. KEY POINTS: • Non-SN has a higher frequency of MVI and intrahepatic metastasis than SN. • Macroscopic classification is useful to choose the treatment strategy for small HCCs. • Diagnostic ability for macroscopic findings of EOB-MRI and CEUS were statistically equal. • The diagnosis of macroscopic findings by individual modality has limitations. • Combined diagnosis of EOB-MRI and CEUS provides high diagnostic ability.

Sustained virological response to antiviral therapy improves survival rate in patients with recurrent hepatitis C virus infection after liver transplantation.

AIM: Previous European and North American studies analyzed the relationship between survival rate and sustained virological response (SVR) to interferon (IFN) therapy in patients with recurrent hepatitis C viral (HCV) infection after liver transplantation (LT). The present study was designed to define the same relationship in Japanese patients who had undergone LT. METHODS: Forty-seven patients (genotype 1, 40; genotype 2, 7) with recurrent HCV after LT were treated with pegylated interferon (PEG IFN) or IFN/ribavirin (RBV). In possible, within 3 months after LT, patients started treatment with PEG IFN-α-2b or IFN-α-2b s.c. once weekly combined with RBV (200 mg/day). RESULTS: The SVR rate was 51% (24/47) for all patients, 42.5% (17/40) for genotype 1 and 100% (7/7) for genotype 2. The median follow-up period was 71 months (range, 24-152). The survival rate of 24 patients who achieved SVR was 95% at 5 years and 92% at 10 years. These rates were significantly better than those of 23 patients who did not achieve SVR (82% at 5 years, 58% at 10 years) (P = 0.027). Two patients of the SVR group died during follow up (due to hepatocellular carcinoma in one and chronic rejection in one), while six non-SVR patients died during the same period (three died due to liver failure by recurrent HCV). CONCLUSION: SVR following IFN therapy contributes to improvement of survival rate in patients with recurrent post-LT HCV infection.

Role of 3-D conformal radiotherapy for major portal vein tumor thrombosis combined with hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma.

AIM: To evaluate the response, survival and safety on 3-D conformal radiotherapy (3D-CRT) for major portal vein tumor thrombosis (PVTT) combined with hepatic arterial infusion chemotherapy (HAIC) for advanced hepatocellular carcinoma (HCC). METHODS: In this retrospective study, 83 advanced HCC patients treated with HAIC who met the following criteria were enrolled: (i) PVTT of the main trunk or first branch of the portal vein; (ii) no extrahepatic metastasis; (iii) Child-Pugh score of 5-7; (iv) performance status of 0 or 1; and (v) no history of sorafenib treatment. The response, overall survival (OS), time to treatment failure (TTF), post-progression survival (PPS) and safety were compared between HAIC combined with 3D-CRT for PVTT (RT group, n = 41) and HAIC alone (non-RT group, n = 42). RESULTS: The objective response of PVTT was significantly higher in the RT group (56.1%) than in the non-RT group (33.3%), while that of intrahepatic tumor and OS were not significantly different between groups. Median OS, TTF and PPS were significantly longer in the RT group than in the non-RT group (8.6 and 5.0 months, 5.0 and 2.7 months, and 5.3 and 1.5 months, respectively) among intrahepatic tumor non-responders to HAIC, whereas those were not significantly different between groups among intrahepatic tumor responders to HAIC. By multivariate analysis, the combination of 3D-CRT with HAIC was an independent contributing factor for OS (hazard ratio, 3.2; 95% confidence interval, 1.692-6.021; P < 0.001) among intrahepatic HCC non-responders to HAIC. CONCLUSION: 3D-CRT for PVTT combined with HAIC could provide survival benefit to non-responder to HAIC.

Effect of prolonged administration of pegylated interferon/ribavirin therapy in genotypes 2a and 2b: propensity score-matched analysis.

BACKGROUND AND AIM: Chronic hepatitis C genotype 2 patients show high susceptibility to pegylated interferon plus ribavirin therapy (PEG/RBV). However, the differences in response to therapy between genotypes 2a and 2b, and the efficacy of prolonged therapy for refractory patients have not been evaluated. We investigated the differences in response to PEG/RBV between each genotype and examined the efficacy of prolonged therapy. METHODS: A total of 343 chronic hepatitis patients infected with hepatitis C virus (HCV) genotype 2 (2a: n = 195; 2b: n = 148) were enrolled in this study. All patients received PEG/RBV for 24 (24 week group, n = 242) or more weeks (prolonged group, n = 101). We analyzed the differences in virological response between genotypes 2a and 2b. Clinical and virological factors of patients in the 24-week group and the prolonged treatment group were matched using propensity score analysis, and the efficacy of prolonged therapy established by comparing time of serum HCV disappearance for each genotype. RESULTS: Virological response tended to be higher for genotype 2a compared with genotype 2b; however, there was no significant difference in sustained virological response rates between genotypes (2a: 78.3%; 2b: 70.2%; P = 0.19). After propensity score matching, the adjusted P-value for sustained virological response rate was significantly different for genotype 2b patients with undetectable HCV-RNA between weeks 5 and 8, and for genotype 2a patients with detectable HCV-RNA at week 8. CONCLUSION: Prolonged therapy with PEG/RBV may be effective when serum HCV-RNA is detectable at week 4 and week 8 for genotype 2b and 2a patients, respectively.

Effects of bisphosphonate zoledronic acid in hepatocellular carcinoma, depending on mevalonate pathway.

BACKGROUND AND AIM: Zoledronic acid (ZOL) is a nitrogen-containing bisphosphonate and is used to reduce cancer-induced osteolysis. We reported previously that ZOL delayed both the growth and pain progression of bone metastases from hepatocellular carcinoma. The present study was designed to evaluate the effects of ZOL on hepatoma cell lines and the molecular mechanisms of such effects. METHODS: Cell viability assay, scratch assay, immunohistochemistry, Western blotting, and flow cytometry analysis were performed using Huh7 and HepG2 cells treated with and without ZOL. RESULTS: ZOL reduced cell growth in a dose-dependent manner and prevented cell migration when used at a concentration exceeding 10 µM. Immunohistochemistry showed that the inhibitory effects of ZOL on hepatoma cell progression was not due to the suppression of Ras and RhoA expression but due to inhibition of their translocation from the cytosol to the cell membrane, which terminates mevalonate pathway. Immunoblotting and flow cytometry showed that ZOL inhibited the mitogen-activated protein kinase pathway (MAPK) and induced apoptosis of hepatoma cells. CONCLUSIONS: Our results indicated that ZOL prevented cell growth and metastasis based on direct antitumor effects in hepatoma cells. The use of ZOL could not only suppress the progression to bone metastatic lesions but also prevented growth of primary hepatocellular carcinoma.

Ultradeep sequencing study of chronic hepatitis C virus genotype 1 infection in patients treated with daclatasvir, peginterferon, and ribavirin.

Direct-acting antivirals (DAAs) are either part of the current standard of care or are in advanced clinical development for the treatment of patients chronically infected with hepatitis C virus (HCV) genotype 1, but concern exists with respect to the patients who fail these regimens with emergent drug-resistant variants. In the present study, ultradeep sequencing was performed to analyze resistance to daclatasvir (DCV), which is a highly selective nonstructural protein 5A (NS5A) inhibitor. Eight patients with HCV genotype 1b, who were either treatment naive or prior nonresponders to pegylated interferon plus ribavirin (Rebetol; Schering-Plough) (PEG-IFN/RBV) therapy, were treated with DCV combined with PEG-IFN alpha-2b (Pegintron; Schering-Plough, Kenilworth, NJ) and RBV. To identify the cause of viral breakthrough, the preexistence and emergence of DCV-resistant variants at NS5A amino acids were analyzed by ultradeep sequencing. Sustained virological response (SVR) was achieved in 6 of 8 patients (75%), with viral breakthrough occurring in the other 2 patients (25%). DCV-resistant variant Y93H preexisted as a minor population at higher frequencies (0.1% to 0.5%) in patients who achieved SVR. In patients with viral breakthrough, DCV-resistant variant mixtures emerged at NS5A-31 over time that persisted posttreatment with Y93H. Although enrichment of DCV-resistant variants was detected, the preexistence of a minor population of the variant did not appear to be associated with virologic response in patients treated with DCV/PEG-IFN/RBV. Ultradeep sequencing results shed light on the complexity of DCV-resistant quasispecies emerging over time, suggesting that multiple resistance pathways are possible within a patient who does not rapidly respond to a DCV-containing regimen. (This study has been registered at ClinicalTrials.gov under registration no. NCT01016912.).

Two patients treated with pegylated interferon/ribavirin/telaprevir triple therapy for recurrent hepatitis C after living donor liver transplantation.

It is difficult to use protease inhibitors in patients with recurrent hepatitis C virus (HCV) infection after liver transplantation (LT) due to interaction with immunosuppressive drugs. We report our experience with two patients treated with telaprevir (TVR) combined with pegylated interferon/ribavirin (PEG IFN/RBV) for recurrent HCV genotype 1 infection after LT. The first was a 63-year-old man with HCV-related liver cirrhosis, who failed to respond to IFN-ß plus RBV after LT. Treatment was switched to PEG IFN-α-2b plus RBV and TVR was started. The donor had TT genotype of interleukin (IL)-28 single nucleotide polymorphisms (SNP) (rs8099917). The recipient had TT genotype of IL-28 SNP (rs8099917). Completion of 12-week triple therapy was followed by PEG IFN-α-2b plus RBV for 36 weeks. Finally, he had sustained viral response. The second was a 70-year-old woman with HCV-related liver cirrhosis and hepatocellular carcinoma. She failed to respond to PEG IFN-α-2b plus RBV after LT, and was subsequently switched to PEG IFN-α-2b/RBV/TVR. Genotype analysis showed TG genotype of IL-28 SNP for the donor, and TT genotype of IL-28 SNP for the recipient. Serum HCV RNA titer decreased below the detection limit at 5 weeks. However, triple therapy was withdrawn at 11 weeks due to general fatigue, which resulted in HCV RNA rebound 4 weeks later. Both patients were treated with cyclosporin, starting with a small dose to avoid interactions with TVR. TVR is a potentially suitable agent for LT recipients who do not respond to PEG IFN-α-2b plus RBV after LT.

Non-invasive liver fibrosis score calculated by combination of virtual touch tissue quantification and serum liver functional tests in chronic hepatitis C patients.

AIM: Acoustic radiation force impulse (ARFI) technology, involving the shear wave velocity (SWV) with virtual touch tissue quantification (VTTQ), are currently available for the assessment of liver fibrosis, while there is no index derived from the combination of SWV and blood tests. The aim of this study was to develop a new index for assessment of liver fibrosis. METHODS: The subjects were 176 consecutive patients with hepatitis C (training set [n = 120] and validation set [n = 56]) who underwent liver biopsy in our institution. RESULTS: In the training set, SWV, international normalized ratio (INR) and alanine aminotransferase (ALT) correlated independently and significantly with fibrosis. According to this, we developed the VIA index = -1.282 + 0.965 × SWV + 1.785 INR + 0.00185 ALT. The areas under the receiver-operator curve (AUROC) of the VIA index were 0.838 for the diagnosis of significant fibrosis (≥F2), 0.904 for the severe fibrosis (≥F3) and 0.958 for the cirrhosis (F4) in the training set. While in the validation set, AUROC of the VIA index were 0.917 for F2 or higher, 0.906 for F3 or higher and 1.000 for F4, respectively. AUROC of the VIA index was improved compared to SWV alone, equivalent for VIA for the diagnosis of F2 or higher, and superior to that of FIB-4 index and aspartate aminotransferase-to-platelet ratio index for the diagnosis of F3 or higher and F4. CONCLUSION: The VIA index is potentially more useful for assessment of liver fibrosis than SWV alone, and easily and accurately measures liver fibrosis stage.