A randomized controlled trial of lusutrombopag in Japanese patients with chronic liver disease undergoing radiofrequency ablation.

BACKGROUND: Thrombocytopenia represents an obstacle for invasive procedures in chronic liver disease (CLD) patients. We aimed to estimate the appropriate dose and evaluate the efficacy and safety of lusutrombopag for the treatment of thrombocytopenia before percutaneous liver radiofrequency ablation (RFA) for primary hepatic cancer in patients with CLD. METHODS: In this multicenter, randomized, double-blind, placebo-controlled study conducted in Japan, 61 CLD patients with platelet count < 50 × 103/µL at screening were randomized to placebo or lusutrombopag 2, 3, or 4 mg once daily for 7 days, followed by a 28-day post-treatment assessment period. The primary efficacy endpoint was the proportion of patients who did not require platelet transfusion before RFA. The pre-specified key secondary efficacy endpoint was the proportion of responders. Adverse events (AEs) and thrombosis-related AEs were evaluated. RESULTS: The proportion of patients who did not require platelet transfusion before RFA and that of responders were significantly higher (p < 0.01) in the 2-mg (80.0, 66.7%), 3-mg (81.3, 68.8%), and 4-mg groups (93.3, 80.0%) compared with the placebo group (20.0, 6.7%) and showed a dose-dependent effect. The incidence of AEs was 97.8 and 100% in the lusutrombopag (all groups) and placebo groups, respectively; no dose-related increase was observed. Four patients experienced thrombosis-related events (one each in the placebo and 2-mg groups, and two in the 4-mg group). A total of 16 (18%) adverse drug reactions occurred in the safety analysis set. CONCLUSIONS: Lusutrombopag 3 mg once daily for 7 days was effective without raising concerns about excessive increases in platelet count. CLINICAL TRIAL REGISTRATION: The study is registered at JapicCTI-121944.

Supplementation with branched-chain amino acids ameliorates hypoalbuminemia, prevents sarcopenia, and reduces fat accumulation in the skeletal muscles of patients with liver cirrhosis.

BACKGROUND: Liver cirrhosis induces marked metabolic disorders, protein-energy malnutrition, and sarcopenia. The objective of the study reported here was to investigate the effects of dietary branched-chain amino acids (BCAAs) on systemic glucose metabolism, skeletal muscle, and prognosis of patients with liver cirrhosis. METHODS: Japanese patients with liver cirrhosis (n = 21) were enrolled into a longitudinal study in which their diets were supplemented with BCAAs. We evaluated glucose metabolism and analyzed the skeletal muscle area index (SAI) and intramuscular adipose tissue content (IMAC) using computed tomography. RESULTS: After 48 weeks of supplementation with BCAAs, there were no changes in glucose metabolism and skeletal muscle findings. In patients with ameliorated hypoalbuminemia, IMAC was significantly decreased and SAI was preserved concomitant with decreasing 90- and 120-min post-challenge plasma glucose levels (P < 0.01 each). In patients without increased albumin levels, IMAC was significantly increased and the SAI was significantly decreased (P < 0.01 each). Liver-related event-free survival rates for 72 months were 63.6% in patients with decreased IMAC and 20.0% in patients with increased IMAC. CONCLUSIONS: Amelioration of hypoalbuminemia associated with BCAA supplementation correlated with decreased fat accumulation in skeletal muscle, maintenance of skeletal muscle mass, and improved glucose sensitivity, all factors which may contribute to improving the survival of patients with liver cirrhosis.

Seropositivity and Titers of Anti-Smooth Muscle Actin Antibody Are Associated with Relapse of Type 1 Autoimmune Hepatitis.

BACKGROUND It is important to avoid relapse in autoimmune hepatitis (AIH) because repeated multiple relapses have been associated with a worse prognosis. However, risk factors for relapse before initiation of treatment are not fully understood. The aim of this study was to find predictive markers for relapse of type 1 AIH. MATERIAL AND METHODS We reviewed the records of 53 patients diagnosed with type 1 AIH based on the revised scoring system proposed by the International Autoimmune Hepatitis Group (IAIHG) between 2009 and 2014 at 4 hospitals belonging to the Saga Study Group of Liver Diseases (SASLD). We analyzed the differences in background characteristics between patients with or without relapse. RESULTS All patients achieved remission after treatment, and 9 (17%) subsequently relapsed. The relapsed patients were significantly younger and had a higher positive rate of anti-smooth muscle antibody (ASMA) than the non-relapsed patients (100% vs. 25%, P=0.0012). Moreover, relapse rate increased with titer of ASMA, while titer of antinuclear antibody was not associated with relapse rate. CONCLUSIONS ASMA is a useful predictive marker for relapse of type 1 AIH during or after withdrawal of medical therapy. More careful attention should be paid to immunosuppressive therapy in patients with high titers of ASMA.

S-1 versus placebo in patients with sorafenib-refractory advanced hepatocellular carcinoma (S-CUBE): a randomised, double-blind, multicentre, phase 3 trial.

BACKGROUND: Unresectable advanced hepatocellular carcinoma is a heterogeneous disease, for which sorafenib is the first targeted agent approved for first-line therapy, and treatment options for patients with sorafenib-refractory advanced hepatocellular carcinoma are limited. We assessed the efficacy and safety of S-1, a chemotherapeutic agent based on fluorouracil, in patients with sorafenib-refractory advanced hepatocellular carcinoma. METHODS: We did a randomised, double-blind, placebo-controlled, phase 3 study done at 57 sites in Japan. Patients with advanced hepatocellular carcinoma who were ineligible for surgical or local-regional therapy and judged refractory to sorafenib (ie, had progressed on sorafenib or had discontinued sorafenib because of adverse events) were randomly assigned (2:1) to receive oral S-1 (weight-banded 80 mg/m2 [80-120 mg per day]), or placebo, twice per day for 28 days consecutively, followed by a minimum 14 day drug-free period. This cycle was repeated until disease progression or the patient became intolerant to the study treatment. Patients were stratified by site and presence or absence of extrahepatic metastasis or vascular invasion. The primary endpoint was overall survival, assessed in the full analysis set (ie, all patients who were treated with study drug except any individuals who were found not to have hepatocellular carcinoma or who were found to have active double cancer). Patients, medical staff, investigators, and the sponsor were masked to treatment assignment. Blinding was maintained even after study treatment concluded. This study is registered with JapicCTI, number JapicCTI-090920, and has been completed. FINDINGS: Between Oct 26, 2009, and Aug 22, 2012, we screened 399 patients. 65 patients were excluded due to not meeting criteria (n=61), declining to participate (n=3), or other reasons (n=1). 334 patients were randomly assigned to receive either S-1 (n=223) or placebo (n=111). One patient in the S-1 group did not receive treatment, and was thus excluded from analyses. At data cutoff, median follow-up was 32·4 months (IQR 24·0-34·7) in the S-1 group and 32·9 months (23·7-39·5) in the placebo group. Median overall survival was 11·1 months (95% CI 9·7-13·1) in the S-1 group and 11·2 months (9·2-12·8) in the placebo group (hazard ratio 0·86, 95% CI 0·67-1·10; p=0·220). The most frequently reported adverse events were skin hyperpigmentation (123 [55%] of 222 patients in the S-1 group vs nine [8%] of 111 patients in the placebo group), decreased appetite (104 [47%] vs 21 [19%]), fatigue (102 [46%] vs 20 [18%]), diarrhoea (77 [35%] vs 14 [13%]), and increased blood bilirubin (77 [35%] vs 14 [13%]). Serious adverse events were reported in 90 (41%) of 222 patients in the S-1 group and 24 (22%) of 111 patients in the placebo group. Five treatment-related deaths were reported in the S-1 group. INTERPRETATION: S-1 did not prolong overall survival in patients with sorafenib-refractory advanced hepatocellular carcinoma. Further research is needed to identify subgroups of patients who might benefit from S-1. FUNDING: Taiho Pharmaceuticals.

Ramucirumab as second-line treatment in patients with advanced hepatocellular carcinoma: Japanese subgroup analysis of the REACH trial.

BACKGROUND: REACH evaluated ramucirumab in the second-line treatment of patients with advanced hepatocellular carcinoma. In the intent-to-treat population (n = 565), a significant improvement in overall survival (OS) was not observed. In patients with an elevated baseline α-fetoprotein (AFP) level (400 ng/mL or greater), an improvement in OS was demonstrated. An analysis of the Japanese patients in REACH was performed. METHODS: An analysis was performed with the subset of the intent-to-treat population enrolled in Japan (n = 93). RESULTS: The median OS was 12.9 months for the ramucirumab arm (n = 45) and 8.0 months for the placebo arm (n = 48) [hazard ratio (HR) 0.621 (95 % confidence interval (CI) 0.391-0.986); P = 0.0416]. The median progression-free survival was 4.1 months for the ramucirumab arm and 1.7 months for the placebo arm [HR 0.449 (95 % CI 0.285-0.706); P = 0.0004]. The objective response rates were 11 % for the ramucirumab arm and 2 % for the placebo arm (P = 0.0817). The grade 3 or higher treatment-emergent adverse events occurring in more than 5 % of patients with a higher incidence for the ramucirumab arm (n = 44) than for the placebo arm (n = 47) were ascites (7% vs 2 %), hypertension (7 % vs 2 %), and cholangitis (7 % vs 0 %). In patients with a baseline AFP level of 400 ng/mL or greater, the median OS was 12.9 months for the ramucirumab arm (n = 20) and 4.3 months for the placebo arm (n = 22) [HR 0.464 (95 % CI 0.232-0.926); P = 0.0263]. CONCLUSIONS: In the Japanese patients in REACH, ramucirumab treatment improved OS, including in patients with a baseline AFP level of 400 ng/mL or greater; improvements in progression-free survival and objective response rate were also demonstrated. The safety profile of ramucirumab was acceptable and well tolerated in Japanese patients. ClinicalTrials.gov identifier NCT01140347.

Phase 2 study of lenvatinib in patients with advanced hepatocellular carcinoma.

BACKGROUND: Lenvatinib is an oral inhibitor of vascular endothelial growth factor receptor 1-3, fibroblast growth factor receptor 1-4, platelet-derived growth factor receptor alpha, RET, and KIT. This phase 2, single-arm, open-label multicenter study evaluated lenvatinib in advanced hepatocellular carcinoma (HCC). METHODS: Patients with histologically/clinically confirmed advanced HCC who did not qualify for surgical resection or local therapies received lenvatinib at a dosage of 12 mg once daily (QD) in 28-day cycles. The primary efficacy endpoint was time to progression (TTP) per modified Response Evaluation Criteria in Solid Tumors v1.1; secondary efficacy endpoints included objective response rate (ORR), disease control rate (DCR), and overall survival (OS). RESULTS: Between July 2010 and June 2011, 46 patients received lenvatinib at sites across Japan and Korea. The median TTP, as determined by independent radiological review, was 7.4 months [95 % confidence interval (CI): 5.5-9.4]. Seventeen patients (37 %) had partial response and 19 patients (41 %) had stable disease (ORR: 37 %; DCR: 78 %). Median OS was 18.7 months (95 % CI: 12.7-25.1). The most common any-grade adverse events (AEs) were hypertension (76 %), palmar-plantar erythrodysesthesia syndrome (65 %), decreased appetite (61 %), and proteinuria (61 %). Dose reductions and discontinuations due to AEs occurred in 34 (74 %) and 10 patients (22 %), respectively. Median body weight was lower in patients with an early (<30 days) dose withdrawal or reduction than in those without. CONCLUSIONS: Lenvatinib 12-mg QD showed clinical activity and acceptable toxicity profiles in patients with advanced HCC, but early dose modification was necessary in patients with lower body weight. Further development of lenvatinib in HCC should consider dose modification by body weight. TRIAL REGISTRATION ID: www.ClinicalTrials.gov NCT00946153.

Ramucirumab as Second-Line Treatment in Patients With Advanced Hepatocellular Carcinoma: Analysis of REACH Trial Results by Child-Pugh Score.

IMPORTANCE: REACH is the first phase 3 trial to provide information on hepatocellular cancer (HCC) in the second-line (postsorafenib) setting categorized by Child-Pugh score, a scoring system used to measure the severity of chronic liver disease. This exploratory analysis demonstrates the relationship between a potential ramucirumab survival benefit, severity of liver disease, and baseline α-fetoprotein (αFP). OBJECTIVE: To assess treatment effects and tolerability of ramucirumab by Child-Pugh score in patients with HCC enrolled in the REACH trial. DESIGN, SETTINGS, AND PARTICIPANTS: Randomized, double-blind, phase 3 trial of ramucirumab and best supportive care vs placebo and best supportive care as second-line treatment in patients with HCC enrolled between November 4, 2010 and April 18, 2013, from 154 global sites. Overall, 643 patients were randomized and included in this analysis; 565 patients considered Child-Pugh class A (Child-Pugh scores 5 and 6) and 78 patients considered class B (Child-Pugh scores 7 and 8). INTERVENTIONS: Ramucirumab (8 mg/kg) or placebo intravenously plus best supportive care every 2 weeks. MAIN OUTCOMES AND MEASURES: Overall survival (OS), defined as time from randomization to death from any cause. RESULTS: In the randomized population of 643 patients (mean [SD] age, 62.8 [11.1] years) in this analysis, a potential ramucirumab OS benefit was observed for patients with a Child-Pugh score of 5 (hazard ratio [HR], 0.80; 95% CI, 0.63-1.02; P = .06) but no apparent benefit for patients with Child-Pugh scores of 6 or 7 and 8. In patients with baseline αFP levels of 400 ng/mL (to convert ng/mL to µg/L, multiply by 1.0) or more, a ramucirumab OS benefit was significant for a score of Child-Pugh 5 (HR, 0.61; 95% CI, 0.43-0.87; P = .01) and Child-Pugh 6 (HR, 0.64; 95% CI, 0.42-0.98; P = .04), but was not significant for Child-Pugh 7 and 8. The overall safety profile of ramucirumab, regardless of Child-Pugh score, was considered manageable. Regardless of treatment arm, patients with Child-Pugh scores of 7 and 8 experienced a higher incidence of grade 3 or higher treatment-emergent adverse events, including ascites and asthenia, and special-interest events, including liver injury and/or failure and bleeding, compared with patients with Child-Pugh scores of 5 or 6. CONCLUSIONS AND RELEVANCE: In unselected patients, a trend for ramucirumab survival benefit was observed only for patients with a Child-Pugh score of 5. In patients with baseline αFP levels of 400 ng/mL or more, a ramucirumab survival benefit was observed for Child-Pugh scores of 5 and 6. Ramucirumab had a manageable toxic effect profile. These results support the ongoing REACH-2 study of ramucirumab in patients with advanced HCC with underlying Child-Pugh A cirrhosis and baseline αFP levels of 400 ng/mL or more. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01140347.

Peginterferon Lambda-1a/Ribavirin with Daclatasvir or Peginterferon Alfa-2a/Ribavirin with Telaprevir for Chronic Hepatitis C Genotype 1b.

The study objective was to compare the efficacy and safety of peginterferon lambda-1a combined with ribavirin/daclatasvir (Lambda/RBV/DCV), versus peginterferon alfa-2a combined with ribavirin/telaprevir (Alfa/RBV/TVR), in patients chronically infected with hepatitis C virus (HCV), genotype 1b. This was a prospective, randomized, open-label, phase 3 study (NCT01718158) in adults (aged ≥18 years) who were treatment naïve or prior relapsers to peginterferon alfa/ribavirin therapy. The primary endpoint was sustained virologic response at post-treatment follow-up week 12 (SVR12). Patients were randomized in a 2:1 ratio to receive 24 weeks of Lambda/RBV/DCV or response-guided 24 or 48 weeks of Alfa/RBV/TVR. Overall, 440 patients were treated (294 with Lambda/RBV/DCV; 146 with Alfa/RBV/TVR). The proportion of patients achieving SVR12 was 88.8% in the Lambda/RBV/DCV arm and 70.5% in the Alfa/RBV/TVR arm (difference between arms: 18.3%; 95% confidence interval: 9.9-25.7; P < 0.0001). Patients in the Lambda/RBV/DCV group had fewer rash-related adverse events (AEs), cytopenic abnormalities, flu-like symptoms, serious AEs, and discontinuations due to AEs, but more liver abnormalities than those in the Alfa/RBV/TVR group. In conclusion, treatment with Lambda/RBV/DCV led to higher SVR12 rates and a more favorable safety profile than Alfa/RBV/TVR in patients with chronic HCV, genotype 1b infection.

Impact of Body Weight Reduction via Diet and Exercise on the Anti-Viral Effects of Pegylated Interferon Plus Ribavirin in Chronic Hepatitis C Patients with Insulin Resistance: A Randomized Controlled Pilot Trial.

OBJECTIVE: Insulin resistance (IR) modifies the anti-viral effects of interferon (IFN) therapy in patients with chronic hepatitis C (CHC). This prospective study evaluated whether lifestyle interventions improve the anti-viral response to treatment with pegylated (PEG)-IFN plus ribavirin (RBV) in patients with CHC. METHODS: The study cohort consisted of 60 patients chronically infected with a high viral load of hepatitis C virus genotype 1b and a homeostasis model assessment of IR (HOMA-IR) value above 2. The patients were divided into two groups, an intervention group (n=26) and a control group (n=34). The patients in the intervention group were prescribed diet and exercise treatment for 3-6 months to reduce their body weight by ≥5% before starting treatment with PEG-IFN plus RBV. RESULTS: Diet and exercise significantly reduced the HOMA-IR values in the intervention group, from 3.4 to 2.5 (p=0.0009), especially among the 15 patients who achieved a body weight reduction of ≥5%. The viral disappearance rate at 12 weeks was significantly higher in the intervention group among the patients with a ≥5% weight reduction than in the control group (53.3% vs. 23.5%, p=0.01). However, the sustained viral response (SVR) rates were similar. CONCLUSION: Improvements in IR achieved through weight reduction via lifestyle interventions may enhance the early viral response to PEG-IFN plus RBV in patients with CHC. However, this intervention program has no effect on the SVR rate.

Efficacy and safety of telaprevir, pegylated interferon α-2b and ribavirin triple therapy in Japanese patients infected with hepatitis C virus genotype 1b.

Objective This study evaluated the efficacy and safety of triple therapy with telaprevir (TVR), pegylated interferon α-2b (PegIFN-α-2b) and ribavirin (RBV) in Japanese patients chronically infected with hepatitis C virus (HCV) genotype 1b in real-world clinical practice. Methods A total of 106 consecutive patients with HCV genotype 1b were treated with triple therapy for 12 weeks followed by dual therapy with PegIFN-α-2b and RBV for 12 weeks. The primary end point was sustained virological response (SVR), defined as undetectable serum HCV RNA at 24 weeks after the end of treatment. Results The overall SVR rate was 87.7% (93/106 patients). Age and body weight (BW) differed significantly between patients with and patients without SVR. Multivariate analysis showed that age <67 years [odds ratio (OR) 5.03, p=0.014] and BW ≥55 kg (OR 5.87, p=0.008) were independent pretreatment factors predictive of SVR. When posttreatment factors were included, age <67 years (OR 7.30, p=0.041), rapid virological response (OR 10.60, p=0.019) and continuation of therapy (OR 14.45, p=0.012) were each independently associated with SVR. Body weight <55 kg (OR 5.96, p=0.015) and TVR initial dose ≥41 mg/kg/day (OR 5.19, p=0.017) were each independently associated with discontinuation of therapy. Discontinuation rates decreased in inverse proportion to the percentage of patients with an initial TVR dose of 1,500 mg/day. Conclusion For TVR-based triple therapy, continuation of therapy is the most important predictor of SVR. Patients who are likely intolerant of standard-dose TVR should receive reduced initial doses of TVR to avoid discontinuation of therapy.

Factors Associated with Post-Progression Survival in Patients with Advanced Hepatocellular Carcinoma Treated with Sorafenib.

Sorafenib exerts modest antitumor activity in patients with advanced hepatocellular carcinoma (HCC), and radiological progressive disease (rPD) does not always correspond to so-called clinical progressive disease (cPD). We evaluated 101 patients who initiated sorafenib treatment for HCC and assessed post-progression survival (PPS) using the Cox proportional hazards model. PPS was calculated from the date of the first rPD until the date of death or the last follow-up. Using Cox model analysis of the 76 patients who experienced first rPD, we identified the Child-Pugh class, Eastern Cooperative Oncology Group performance status, the best antitumor response during treatment (using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1) and α-fetoprotein levels as independent factors affecting PPS. When these factors were used to define scores ranging from zero to five with a cutoff value of two, PPS of patients who received best supportive care (BSC) after rPD was not statistically significantly different from that of patients who received post-rPD therapy with scores ≥2 (p = 0.220). In contrast, the PPS for the post-rPD therapy group was significantly longer compared with the BSC patients with scores <2 (p < 0.001). Patients who scored ≥2 at their first rPD were judged cPD and as candidates for BSC.

Dose-finding trial of tolvaptan in liver cirrhosis patients with hepatic edema: A randomized, double-blind, placebo-controlled trial.

AIM: Liver cirrhosis represents the end stage of any chronic liver disease, and it is associated with hepatic edema such as ascites. Many patients with ascites do not respond to diuretic therapy or require administration of diuretics at high doses that can cause adverse events. This 7-day, multicenter, double-blind trial of tolvaptan was designed to determine the optimal dose of tolvaptan for producing the intended pharmacological effect in hepatic edema. METHODS: Liver cirrhosis patients with inadequate diuretic response despite having received a conventional diuretic therapy were enrolled in the trial. Participants were stratified randomly to four groups receiving tolvaptan at 7.5, 15 or 30 mg/day, or placebo as an add-on to conventional diuretics once daily for 7 days. Changes in bodyweight and abdominal circumference were analyzed. Serum sodium concentrations were measured. Safety assessment was performed. RESULTS: Tolvaptan at 7.5-30 mg/day reduced bodyweight and abdominal circumference compared with placebo. Serum sodium concentrations remained within the normal range in all tolvaptan groups. Serious adverse events were not observed, and most common adverse event was thirst. Tolvaptan at 7.5 mg/day showed the maximum change in bodyweight and abdominal circumference together with preferable tolerability. CONCLUSION: Tolvaptan at 7.5 mg/day was considered the optimal dose in liver cirrhosis patients with hepatic edema who showed inadequate response to conventional diuretics.

Tolvaptan for improvement of hepatic edema: A phase 3, multicenter, randomized, double-blind, placebo-controlled trial.

AIM: Hepatic edema is manifested by ascites, lower limb edema and intolerable symptoms. Some patients insufficiently respond to the conventional diuretic therapy. Therefore, a novel therapeutic option is required. We conducted a phase 3 study to confirm therapeutic effect of tolvaptan on hepatic edema associated with liver cirrhosis. METHODS: In our multicenter, randomized, double-blind, placebo-controlled trial, liver cirrhosis patients who showed insufficient response to conventional diuretics were randomly assigned to 7-day administration of either tolvaptan at 7.5 mg/day or placebo as an add-on therapy to conventional diuretics. The primary outcome was change in bodyweight from baseline. RESULTS: Of 164 eligible patients, 84 were assigned to tolvaptan and 80 to placebo. Change in bodyweight from baseline on the final dosing day was -0.44 kg (standard deviation [SD], 1.93) in the placebo group and -1.95 kg (SD, 1.77) in the tolvaptan group (P < 0.0001). Improvement rates for lower limb edema and ascites-related clinical symptoms were higher with tolvaptan than with placebo. Even in patients with low serum albumin (<2.5 g/dL), decrease in bodyweight was greater with tolvaptan than with placebo (P = 0.0163). In addition, tolvaptan significantly increased serum sodium concentration from baseline. CONCLUSION: Add-on therapy with tolvaptan was effective for the treatment of hepatic edema and ascites-related clinical symptoms. Furthermore, tolvaptan is expected to improve low serum sodium concentration and to exert its effect regardless of serum albumin level. Add-on therapy with tolvaptan is therefore considered to be a novel therapeutic option for hepatic edema.

Skin toxicities and survival in advanced hepatocellular carcinoma patients treated with sorafenib.

AIM: Sorafenib is the first small molecule with significant clinical activity for advanced hepatocellular carcinoma (HCC). However, intolerable adverse events are sometimes observed. On the other hand, it has been reported that some toxicities of molecular targeted drugs, such as skin toxicities and arterial hypertension, are correlated with good clinical outcomes in other cancers. METHODS: We identified the correlations between adverse events and prognosis for sorafenib therapy in all patients with HCC treated at the institutions of the Saga Liver Cancer Study Group. The toxicities were assessed using the Common Terminology Criteria for Adverse Events version 4.0. RESULTS: Ninety-four patients received sorafenib until August 2010. The overall incidence of treatment-related adverse events was 98% of patients. Skin toxicities, including palmar-plantar erythrodysesthesia syndrome, rash, pruritus and alopecia, were the most common adverse events and were observed in 58 patients (62%). Hypertension was observed in 23 patients (24%). The median survival time was 12.5 months among the total patients. The patients with skin toxicities showed significantly longer survival than the patients without these toxicities (hazard ratio, 0.449; 95% confidence interval, 0.256-0.786; P = 0.005). Hypertension had no correlation with survival. Skin toxicities were also significant prognostic factors in a multivariate analysis (hazard ratio, 0.522; 95% confidence interval, 0.274-0.997; P = 0.049), along with Child-Pugh class and α-fetoprotein level. The median development time for skin toxicities was 21 days. CONCLUSION: Skin toxicities occur commonly at the early phase in patients treated with sorafenib, and could be a promising surrogate marker for the treatment outcome.

Low-dose rectal diclofenac for prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis: a randomized controlled trial.

BACKGROUND: Acute pancreatitis is a common complication of endoscopic retrograde cholangiopancreatography (ERCP). Rectal nonsteroidal anti-inflammatory drugs (specifically, 100 mg of diclofenac or indomethacin) have shown promising prophylactic activity in post-ERCP pancreatitis (PEP). However, the 100-mg dose is higher than that ordinarily used in Japan. METHODS: We performed a prospective randomized controlled study to evaluate the efficacy of low-dose rectal diclofenac for the prevention of PEP. Patients who were scheduled to undergo ERCP were randomized to receive a saline infusion either with 50 mg of rectal diclofenac (diclofenac group) or without (control group) 30 min before ERCP. The dose of diclofenac was reduced to 25 mg in patients weighing <50 kg. The primary outcome measure was the occurrence of PEP. RESULTS: Enrollment was terminated early because the planned interim analysis found a statistically significant intergroup difference in the occurrence of PEP. A total of 104 patients were eligible for this study; 51 patients received rectal diclofenac. Twelve patients (11.5%) developed PEP: 3.9% (2/51) in the diclofenac group and 18.9% (10/53) in the control group (p = 0.017). After ERCP, the incidence of hyperamylasemia was not significantly different between the two groups. Post-ERCP pain was significantly more frequent in the control group than in the diclofenac group (37.7 vs. 7.8%, respectively; p < 0.001). There were no adverse events related to diclofenac. CONCLUSIONS: Low-dose rectal diclofenac can prevent PEP.

Effect of vitamin K2 on the recurrence of hepatocellular carcinoma.

UNLABELLED: Hepatocellular carcinoma (HCC) is characterized by frequent recurrence, even after curative treatment. Vitamin K2, which has been reported to reduce HCC development, may be effective in preventing HCC recurrence. Patients who underwent curative ablation or resection of HCC were randomly assigned to receive placebo, 45 mg/day, or 90 mg/day vitamin K2 in double-blind fashion. HCC recurrence was surveyed every 12 weeks with dynamic computed tomography/magnetic resonance imaging, with HCC-specific tumor markers monitored every 4 weeks. The primary aim was to confirm the superiority of active drug to placebo concerning disease-free survival (DFS), and the secondary aim was to evaluate dose-response relationship. Disease occurrence and death from any cause were treated as events. Hazard ratios (HRs) for disease occurrence and death were calculated using a Cox proportional hazards model. Enrollment was commenced in March 2004. DFS was assessed in 548 patients, including 181 in the placebo group, 182 in the 45-mg/day group, and 185 in the 90-mg/day group. Disease occurrence or death was diagnosed in 58, 52, and 76 patients in the respective groups. The second interim analysis indicated that vitamin K2 did not prevent disease occurrence or death, with an HR of 1.150 (95% confidence interval: 0.843-1.570, one-sided; P=0.811) between the placebo and combined active-drug groups, and the study was discontinued in March 2007. CONCLUSION: Efficacy of vitamin K2 in suppressing HCC recurrence was not confirmed in this double-blind, randomized, placebo-controlled study.

Body mass index is associated with age-at-onset of HCV-infected hepatocellular carcinoma patients.

AIM: To identify factors associated with the age at onset of hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC). METHODS: Five hundred and fifty-six consecutive patients positive for HCV antibody and treatment-naïve HCC diagnosed between 1995 and 2004 were analyzed. Patients were classified into three groups according to age at HCC onset: < 60 years (n = 79), 60-79 years (n = 439), or ≥ 80 years (n = 38). Differences among groups in terms of sex, body mass index (BMI), lifestyle characteristics, and liver function were assessed. Factors associated with HCC onset in patients < 60 or ≥ 80 years were analyzed by logistic regression analysis. RESULTS: Significant differences emerged for sex, BMI, degree of smoking and alcohol consumption, mean bilirubin, alanine aminotransferase (ALT), and γ-glutamyl transpeptidase (GGT) levels, prothrombin activity, and platelet counts. The mean BMI values of male patients > 60 years old were lower and mean BMI values of female patients < 60 years old were higher than those of the general Japanese population. BMI > 25 kg/m² [hazard ratio (HR), 1.8, P = 0.045], excessive alcohol consumption (HR, 2.5, P = 0.024), male sex (HR, 3.6, P = 0.002), and GGT levels > 50 IU/L (HR, 2.4, P = 0.014) were independently associated with HCC onset in patients < 60 years. Low ALT level was the only factor associated with HCC onset in patients aged ≥ 80 years. CONCLUSION: Increased BMI is associated with increased risk for early HCC development in HCV-infected patients. Achieving recommended BMI and reducing alcohol intake could help prevent hepatic carcinogenesis.

Efficacy and safety of radiofrequency ablation for elderly hepatocellular carcinoma patients.

AIM: This study was conducted to evaluate the efficacy and safety of radiofrequency ablation (RFA) therapy in elderly patients with hepatocellular carcinoma (HCC). METHODS: Four hundred and sixty-one patients with naïve HCC, including 107 elderly (aged ≥75 years) patients, who were treated with RFA between 2000 and 2007, were enrolled. Baseline characteristics, survival/recurrence rates and complications after RFA were compared between elderly and non-elderly patients. RESULTS: In the elderly group, the proportion of men, alcohol consumption, serum alanine aminotransferase and γ-glutamyl transpeptidase levels were significantly lower compared with those in the non-elderly group. There were no differences in Child-Pugh grade and tumor characteristics between the two groups. The cumulative survival rates in the elderly group were 82% at 3 years and 61% at 5 years, which was equivalent to the non-elderly group. Similarly, no differences were observed in recurrence rates. In multivariate analysis, Child-Pugh grade and tumor-related factors were significant factors associated with survival, but age was not. Although elderly patients had more extrahepatic comorbidities, their presence was not a factor associated with survival prognosis or complication after RFA. CONCLUSION: RFA treatment might be safe and effective in elderly patients, as well as non-elderly patients, with HCC.

Recurrent acute pancreatitis caused by a gastric duplication cyst communicating with an aberrant pancreatic duct.

A 38-year-old woman was hospitalized in August 2007. This visit was her fifth episode of acute pancreatitis. Computed tomography revealed a cystic structure located near the antrum. Communication between this structure and the pancreatic duct was revealed by endoscopic retrograde cholangiopancreatography. Ultrasonography revealed that the cyst wall had a layered structure. Thus, we regarded it as a gastric duplication cyst. We thought that the gastric duplication cyst communicating with an aberrant pancreatic duct was responsible for the recurrent acute pancreatitis. In August 2008, a cyst gastrostomy was performed between the gastric duplication cyst and the stomach. No recurrence of acute pancreatitis has since occurred.