Resistance Analyses of Japanese Hepatitis C-Infected Patients Receiving Sofosbuvir or Ledipasvir/Sofosbuvir Containing Regimens in Phase 3 Studies.

High rates of sustained virologic response (SVR) has been achieved in Japanese patients with chronic hepatitis C virus (HCV) genotype (GT)1 and GT2 infection treated with ledipasvir/sofosbuvir (LDV/SOF) ±ribavirin (RBV) and SOF+RBV, respectively. We evaluated the effect of baseline HCV NS5A and NS5B resistance-associated variants (RAVs) on treatment outcome and characterized variants at virologic failure. Baseline deep sequencing for NS5A and NS5B genes was performed for all GT1 patients. Deep sequencing of NS5A (GT1 only) and NS5B (GT1 and GT2) was performed for patients who failed treatment or discontinued early with detectable HCV RNA (i.e., >25 IU/mL). In patients with HCV GT1 infection, 22.3% (GT1a: 2/11; GT1b: 74/330) had ≥1 baseline NS5A RAV. The most frequent NS5A RAVs in GT1b were Y93H (17.9%, 59/330) and L31M (2.4%, 8/330). Despite the presence of NS5A RAVs at baseline, 100% and 97% of patients achieved SVR12, compared with 100% and 99% for those with no NS5A RAVs with LDV/SOF and LDV/SOF+RBV, respectively. All patients with NS5B RAVs at baseline achieved SVR12. Of the 153 patients with GT2 infection (GT2a 60.1%, GT2b 39.9%), 3.3% (5/153) experienced viral relapse. No S282T or other NS5B RAVs were detected at baseline or relapse; no change in susceptibility to SOF or RBV was observed at relapse. In conclusion, LDV/SOF and SOF+RBV demonstrate a high barrier to resistance in Japanese patients with HCV GT1 and GT2 infection. The presence of baseline NS5A RAVs did not impact treatment outcome in GT1 Japanese patients treated with LDV/SOF for 12 weeks.

Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update.

Worldwide, some 240 million people have chronic hepatitis B virus (HBV), with the highest rates of infection in Africa and Asia. Our understanding of the natural history of HBV infection and the potential for therapy of the resultant disease is continuously improving. New data have become available since the previous APASL guidelines for management of HBV infection were published in 2012. The objective of this manuscript is to update the recommendations for the optimal management of chronic HBV infection. The 2015 guidelines were developed by a panel of Asian experts chosen by the APASL. The clinical practice guidelines are based on evidence from existing publications or, if evidence was unavailable, on the experts' personal experience and opinion after deliberations. Manuscripts and abstracts of important meetings published through January 2015 have been evaluated. This guideline covers the full spectrum of care of patients infected with hepatitis B, including new terminology, natural history, screening, vaccination, counseling, diagnosis, assessment of the stage of liver disease, the indications, timing, choice and duration of single or combination of antiviral drugs, screening for HCC, management in special situations like childhood, pregnancy, coinfections, renal impairment and pre- and post-liver transplant, and policy guidelines. However, areas of uncertainty still exist, and clinicians, patients, and public health authorities must therefore continue to make choices on the basis of the evolving evidence. The final clinical practice guidelines and recommendations are presented here, along with the relevant background information.

Effect of hepatic arterial infusion chemotherapy of 5-fluorouracil and cisplatin for advanced hepatocellular carcinoma in the Nationwide Survey of Primary Liver Cancer in Japan.

BACKGROUND: The efficacy of hepatic arterial infusion chemotherapy for the treatment of advanced hepatocellular carcinoma (HCC) remains unclear. METHODS: The outcome of 476 patients with HCC who underwent hepatic arterial infusion chemotherapy with 5-fluorouracil and cisplatin (HAIC) were compared with 1466 patients who did not receive active therapy. RESULTS: A survival benefit of the therapy after adjusting for known risk factors was observed (hazard ratio, 0.48; 95% CI, 0.41-0.56; P<0.0001). In propensity score-matched analysis (n=682), median survival time was longer for patients who underwent chemotherapy (14.0 months) than for patients who did not receive active treatment (5.2 months, P<0.0001). CONCLUSION: For advanced HCC, HAIC is considered to be an effective treatment.

A multicentre randomised phase II trial of gemcitabine alone vs gemcitabine and S-1 combination therapy in advanced pancreatic cancer: GEMSAP study.

BACKGROUND: This randomised phase II trial compared gemcitabine alone vs gemcitabine and S-1 combination therapy in advanced pancreatic cancer. METHODS: Patients were randomly assigned to 4-week treatment with gemcitabine alone (1000, mg m(-2) gemcitabine by 30-min infusion on days 1, 8, and 15) or gemcitabine and S-1 combination therapy (1000, mg m(-2) gemcitabine by 30-min infusion on days 1 and 15 and 40 mg m(-2) S-1 orally twice daily on days 1-15). The primary end point was progression-free survival (PFS). RESULTS: Between July 2006 and February 2009, 106 patients were enrolled. The PFS in gemcitabine and S-1 combination arm was significantly longer than in gemcitabine arm (5.4 vs 3.6 months), with a hazard ratio of 0.64 (P=0.036). Overall survival (OS) for gemcitabine and S-1 combination was longer than that for gemcitabine monotherapy (13.5 vs 8.8 months), with a hazard ratio of 0.72 (P=0.104). Overall, grade 3 or 4 adverse events were similar in both arms. CONCLUSION: Gemcitabine and S-1 combination therapy demonstrated longer PFS in advanced pancreatic cancer. Improved OS duration of 4.7 months was found for gemcitabine and S-1 combination therapy, though this was not statistically significant.

Recurrence-free survival more than 10 years after liver resection for hepatocellular carcinoma.

BACKGROUND: High recurrence rates after liver resection with curative intent for hepatocellular carcinoma (HCC) remain a problem. The characterization of long-term survivors without recurrence after liver resection may help improve the therapeutic strategy for HCC. METHODS: A nationwide Japanese database was used to analyse 20 811 patients with HCC who underwent liver resection with curative intent. RESULTS: The 10-year recurrence-free survival rate after liver resection for HCC with curative intent was 22.4 per cent. Some 281 patients were recurrence-free after more than 10 years. The HCCs measured less than 5 cm in 83.2 per cent, a single lesion was present in 91.7 per cent, and a simple nodular macroscopic appearance was found in 73.3 per cent of these patients; histologically, most HCCs showed no vascular invasion or intrahepatic metastases. Multivariable analysis revealed tumour differentiation as the strongest predictor of death from recurrent HCC within 5 years. CONCLUSION: Long-term recurrence-free survival is possible after liver resection for HCC, particularly in patients with a single lesion measuring less than 5 cm with a simple nodular appearance and low tumour marker levels.

Inhibition of renin-angiotensin system affects prognosis of advanced pancreatic cancer receiving gemcitabine.

BACKGROUND: The renin-angiotensin system (RAS) is thought to have a role in carcinogenesis, and RAS inhibition may prevent tumour growth. METHODS: We retrospectively investigated the impact of angiotensin I-converting enzyme inhibitors (ACEIs) and angiotensin II type-1 receptor blockers (ARBs) in 155 patients with pancreatic cancer receiving gemcitabine monotherapy. Patients were divided into three groups: the ACEI/ARB group (27 patients receiving an ACEI or ARB for hypertension (HT)), the non-ACEI/ARB with HT group (25 patients receiving antihypertensive drugs other than ACEIs or ARBs), and the non-HT group (103 patients receiving no antihypertensive drugs). RESULTS: Patient characteristics were not different, except for age and HT medications. Progression-free survival (PFS) was 8.7 months in the ACEI/ARB group, 4.5 months in the non-ACEI/ARB with HT group, and 3.6 months in the non-HT group. Overall survival (OS) was 15.1 months in the ACEI/ARB group, 8.9 months in the non-ACEI/ARB with HT group, and 9.5 months in the non-HT group. The use of ACEIs/ARBs was a significant prognostic factor for both PFS (P=0.032) and OS (P=0.014) in the multivariate analysis. CONCLUSIONS: The ACEIs/ARBs in combination with gemcitabine might improve clinical outcomes in patients with advanced pancreatic cancer. Prospective trials are needed to test this hypothesis.

Laboratory and imaging features of kidney involvement in autoimmune pancreatitis: incidence, correlation, and steroid therapy response.

AIM: Autoimmune pancreatitis (AIP) is a rare subtype of chronic pancreatitis. AIP has been suggested to be complicated by tubulointerstitial nephritis or glomerulonephritis, implying that the kidney is involved as a phenotype of IgG4-positive multi-organ lymphoproliferative syndrome; however, the clinical significance of this novel entity is not well-defined. METHODS: We conducted a retrospective cohort analysis of 47 (male, 39; female, 8) AIP patients. RESULTS: The patients (mean age, 70.3 +/- 9.5 years) had a mean observation period of 4.1 years. Before treatment, renal dysfunction with an eGFR of 30 and 15 ml/min/1.73 m2 developed only in 10.6% (5/47) and 2.1% (1/47) of the patients, respectively. Nevertheless, urinary N-acetyl-beta-D-glucosaminidase and alpha1-microglobulin levels were elevated in 78.6% (11/14) and 30.8% (4/13) of the patients, respectively. Renal involvement in contrast-enhanced CT imaging was present in 18.2% (8/44) of the patients and was associated with proteinuria (p = 0.04) and a decrease in eGFR (p < 0.01). Furthermore, a follow-up CT study (mean, 545 days) revealed improved kidney lesions in 80.0% (4/5) of the patients after oral corticosteroid administration. In contrast, first-time kidney involvements appeared newly in 3.6% (1/28) of the patients after steroid therapy for nonrenal AIP symptoms, and in 14.3% (1/7) of the patients under no specific therapy (p = 0.02). CONCLUSION: Although severe renal failure develops rarely in AIP patients, renal abnormalities have been significantly detected by biochemical and radiological tests. Oral corticosteroid administration, even when not targeting symptomatic nephropathy, can treat and prevent kidney involvements in AIP.

Influence of anti-HBc seropositivity on the risk of hepatocellular carcinoma in HCV-infected patients after adjusting for confounding factors.

It is controversial whether past hepatitis B virus infection constitutes an additional risk of hepatocellular carcinoma (HCC) among patients with hepatitis C virus (HCV). The incidence of HCC between 1994 and 2004 was analysed among 1262 patients who were only positive for HCV. The cumulative incidence of HCC was assessed by Kaplan-Meier analysis and the difference between two groups was assessed by the log-rank test. The effect of anti-HBc positivity on the risk of HCC was assessed with multivariate Cox proportional analysis. Anti-HBc was positive in 522 (41.4%) patients. The proportion of male patients (56.7 vs 46.8%, P < 0.001) and mean age (60.8 vs 56.9 years, P < 0.001) were significantly higher in the anti-HBc positive group. HCC developed in 339 patients (mean follow-up 7.0 years), with cumulative incidence rates at 3, 5 and 10 years of 12.7, 24.5 and 41.9% in the anti-HBc positive group and 10.6, 17.7 and 33.4% in the negative group, respectively (P = 0.005). However, anti-HBc seropositivity did not reach statistical significance in multivariate analysis including age and gender (hazard ratio, 1.06; 95% CI, 0.85-1.31; P = 0.63). Anti-HBc positivity and HCC incidence were confounded by male gender and older age.

Predictors of postoperative stricture after esophageal endoscopic submucosal dissection for superficial squamous cell neoplasms.

BACKGROUND AND STUDY AIMS: Although endoscopic submucosal dissection (ESD) is becoming accepted as an established treatment for superficial esophageal squamous cell neoplasms, the risks for developing postoperative stricture have not been elucidated. PATIENTS AND METHODS: This was a retrospective study at a single institution. From January 2002 to October 2008, 65 patients with high-grade intraepithelial neoplasms (HGINs) or m2 carcinomas treated by ESD were enrolled. Predictors of postoperative stricture were investigated by comparing results from 11 patients who developed strictures with those from 54 patients who did not. RESULTS: Significant differences between the two groups were observed in longitudinal diameter (45.0 +/- 15.9 mm vs. 31.5 +/- 13.6 mm) and circumferential diameter (37.2 +/- 8.6 mm vs. 26.8 +/- 9.7 mm) of the resected specimens, and the proportion of extension to the whole circumference of the lumen (< 1 / 2/ > 1 / 2/ > 3 / 4 : 2 / 4 / 5 vs. 40 / 13 / 1), histologic depth (HGIN/m2 : 2 / 9 vs. 41 / 13), and procedure time (85.6 +/- 42.8 minutes vs. 53.3 +/- 30.1 minutes). Multivariate analysis revealed that circumferential extension of > 3 / 4 (odds ration [OR]: 44.2; 95 % confidence interval [CI]: 4.4 - 443.6) and histologic depth to m2 (OR: 14.2; 95 %CI: 2.7 - 74.2) are reliable risk factors. Subanalysis for each category by combinations of these risk factors revealed that patients with lesions in > 3 / 4 of the circumferential area were associated with a high rate of postoperative stricture. By contrast, patients with HGIN lesions in < 3 / 4 extension have no probability of postoperative strictures. Additionally, subanalysis of patients with m2 lesions in < 3 / 4 circumferential extension revealed that circumferential diameter can be a reliable predictor for postoperative stricture. CONCLUSIONS: Circumferential extension and histologic depth are the reliable risk factors for postoperative strictures. In combination with circumferential diameter, we can perform effective and appropriate preventive balloon dilatations after esophageal ESD.

Standard steroid treatment for autoimmune pancreatitis.

OBJECTIVE: To establish an appropriate steroid treatment regimen for autoimmune pancreatitis (AIP). METHODS: A retrospective survey of AIP treatment was conducted in 17 centres in Japan. The main outcome measures were rate of remission and relapse. RESULTS: Of 563 patients with AIP, 459 (82%) received steroid treatment. The remission rate of steroid-treated AIP was 98%, which was significantly higher than that of patients without steroid treatment (74%, 77/104; p<0.001). Steroid treatment was given for obstructive jaundice (60%), abdominal pain (11%), associated extrapancreatic lesions except the biliary duct (11%), and diffuse enlargement of the pancreas (10%). There was no relationship between the period necessary to achieve remission and the initial dose (30 mg/day vs 40 mg/day) of prednisolone. Maintenance steroid treatment was given in 377 (82%) of 459 steroid-treated patients, and steroid treatment was stopped in 104 patients. The relapse rate of patients with AIP on maintenance treatment was 23% (63/273), which was significantly lower than that of patients who stopped maintenance treatment (34%, 35/104; p = 0.048). From the start of steroid treatment, 56% (55/99) relapsed within 1 year and 92% (91/99) relapsed within 3 years. Of the 89 relapsed patients, 83 (93%) received steroid re-treatment, and steroid re-treatment was effective in 97% of them. CONCLUSIONS: The major indication for steroid treatment in AIP is the presence of symptoms. An initial prednisolone dose of 0.6 mg/kg/day, is recommend, which is then reduced to a maintenance dose over a period of 3-6 months. Maintenance treatment with low-dose steroid reduces but dose not eliminate relapses.

Technical feasibility of endoscopic submucosal dissection for early gastric cancer in patients taking anti-coagulants or anti-platelet agents.

BACKGROUND: Endoscopic submucosal dissection is a novel technique that is expected to be a curative treatment for early gastric cancers. Anti-coagulants and anti-platelet agents are widely used, especially in elderly patients, to prevent thromboembolic disease. However, the feasibility of endoscopic submucosal dissection for such patients has not been investigated. AIMS: To determine the feasibility of endoscopic submucosal dissection for patients using anti-coagulant and anti-platelet agents via retrospective investigation of clinical outcomes. METHODS: Of 408 patients with 444 early gastric cancers consecutively treated by endoscopic submucosal dissection from January 2000 to December 2007 in our hospital, 47 patients with 56 early gastric cancers were receiving anti-coagulants or anti-platelet agents. All patients were classified into groups for high and low risk of thromboembolism. In 44 low-risk patients, these agents were stopped for 1 week before and after treatment. Only three high-risk patients underwent intravenous heparin replacement during the cessation period. RESULTS: Comparison with other patients showed no significant differences in complete en-bloc resection (96.4%) or perforation (1.8%). Postoperative bleeding requiring endoscopic treatment occurred for six early gastric cancers (10.7%) in the anti-coagulant and anti-platelet group; this frequency was slightly higher than that observed for other patients (5.2%). The healing of endoscopic submucosal dissection ulcers was not delayed by anti-coagulant and anti-platelet treatment (91% in the scarring stage) when checked at the 8th week after endoscopic submucosal dissection. CONCLUSION: The clinical outcomes of endoscopic submucosal dissection for early gastric cancers in patients receiving anti-coagulants or anti-platelet agents indicated that endoscopic submucosal dissection for low-risk patients could be a reliable technique with equivalent efficacy and risk in comparison with that for other early gastric cancer patients.

Outcomes of endoscopic submucosal dissection for early gastric cancer with special reference to validation for curability criteria.

BACKGROUND AND STUDY AIMS: Endoscopic submucosal dissection (ESD) is a novel, promising endoscopic technique for gastrointestinal neoplasms. We aimed to elucidate the feasibility of ESD as curative treatment for intestinal-type early gastric cancer (EGC) potentially without lymph-node metastases. PATIENTS AND METHODS: For the short-term analysis, 276 consecutive, intestinal-type EGCs, which fulfilled the criteria for node-negative EGC in 231 patients who had undergone ESD from January 2000 to March 2007, were retrospectively investigated. For the long-term analysis, 212 lesions checked by endoscopy later than 1 year or recurrence within 1 year after ESD were assessed for local recurrence, and 208 patients followed for over 1 year or to death within 1 year after ESD were assessed for metastases and survival. All lesions/patients were divided into three groups: intramucosal cancer without ulcerative findings (M-Ul[-]); intramucosal cancer with ulcerative findings, < or = 3 cm (M-Ul[+]); and slight invasive cancer into submucosa (< 500 microm), < or = 3 cm (SM1). RESULTS: En bloc and complete resection rates were 96.7 % and 91.7 %, respectively. During a median follow-up of 36 months (range 2 - 93 months), two local recurrences occurred (0.9 %), which were detected at 2 and 6 months after ESD, respectively. During a median follow-up of 38 months (range 6 - 97 months), the 5-year overall and disease-specific survival rates were 96.2 % and 100 %, respectively, with neither lymph node nor other-organ metastasis; one patient died due to other disease 6 months after ESD. No disease-related death occurred. No significant differences were found between the groups in short- and long-term analyses. CONCLUSIONS: The prognostic analyses demonstrated the validity of the criteria of node-negative intestinal-type EGC as curability criteria for ESD. ESD can be proposed as an alternative method to gastrectomy for the treatment of these EGCs.

Visceral fat accumulation is an independent risk factor for hepatocellular carcinoma recurrence after curative treatment in patients with suspected NASH.

BACKGROUND AND AIMS: Visceral fat accumulation reportedly increases the risk of hepatocellular carcinoma (HCC) development in patients with chronic liver disease. However, it has not been fully elucidated whether visceral fat accumulation increases the risk of HCC recurrence after curative treatment in patients with suspected non-alcoholic steatohepatitis (NASH). Therefore this was investigated in the current study. METHODS: 62 patients with naive HCC with suspected NASH were enrolled. All were curatively treated with percutaneous radiofrequency ablation between 1999 and 2006. The visceral fat area (VFA) was determined in each patient from CT images, taken at the time of HCC diagnosis. Patients were divided into two groups based on VFA: the high VFA group (>130 cm(2) in males, >90 cm(2) in females, n = 27) and the others (n = 35). The effects of VFA on HCC recurrence were analysed together with other factors including patients' background, tumour-related factors and liver function-related factors. RESULTS: The cumulative recurrence rates differed significantly between the two groups; 15.9, 56.5 and 75.1% at 1, 2 and 3 years, respectively, in the high VFA group, and 9.7, 31.1 and 43.1%, respectively, in the controls (p = 0.018). Multivariate analysis indicated visceral fat accumulation (risk ratio 1.08, per 10 cm(2), p = 0.046) and older age (risk ratio 1.06 per 1 year, p = 0.04) as independent risk factors of HCC recurrence. CONCLUSIONS: Visceral fat accumulation is an independent risk factor of HCC recurrence after curative treatment in patients with suspected NASH.

Feasibility of electrocautery snaring as the final step of endoscopic submucosal dissection for stomach epithelial neoplasms.

BACKGROUND: Endoscopic submucosal dissection (ESD) is a novel endoluminal technique that permits the resection of gastric neoplasms. AIM: To analyse the feasibility of snaring as the final step of ESD. PATIENTS AND METHODS: One hundred and ninety-nine consecutive gastric neoplasms resected by four ESD experts from January 2004 to May 2007 were investigated. Forty-five (22.6%) were finally resected finally using a snare. Rates of en bloc resection, complete (R0 plus en bloc) resection, mean operation time, and complications were assessed between the snaring and the non-snaring groups. RESULTS: En bloc resection rate was significantly lower and delayed bleeding rate was significantly higher in the snaring group than in the non-snaring group (91.1% [41/45] vs. 100% [154/154], 11.1% [5/45] vs. 1.9% [3/154], respectively), although complete resection rate (86.7% [39/45] vs. 92.9% [143/154]) and mean operation time (70.2 min vs. 75.8 min) were not significantly different between the two groups. Six perforation cases (3 [6.7%] in the snaring group, 3 [1.9%] in the non-snaring group) were observed, but snaring did not lead to perforation in any case. When the subjects were divided into small (< or = 2 cm) and large (> 2 cm) tumours, en bloc resection rate in large tumours was still significantly different between the groups (76.9% [10/13] vs. 100% [67/67]), whereas in small tumours it was no longer significantly different (96.9% [31/32] vs. 100% [87/87]). CONCLUSIONS: Snaring may facilitate successful ESD for smaller tumours, but multiple-piece resection should be taken into account especially for larger tumours.