Nobuo Toda

A prospective randomised study of “covered” versus “uncovered” diamond stents for the management of distal malignant biliary obstruction

Background and aim: Covered self-expandable metal stents (EMS) were recently developed to overcome tumour ingrowth in conventional EMS. However, supporting evidence for the efficacy of covered EMS is lacking. Patients and methods: We enrolled 112 patients with unresectable distal biliary malignancies. They were randomly assigned to polyurethane covered (n = 57) or original diamond stent (n = 55). Results: Stent occlusion occurred in eight patients (14%) after a mean of 304 days in the covered group, and in 21 patients (38%) after a mean of 166 days in the uncovered group. The incidence of covered EMS occlusion was significantly lower than that of uncovered EMS (p = 0.0032). The cumulative stent patency of covered stents was significantly higher than that of uncovered stents (p = 0.0066). No tumour ingrowth occurred in the covered group while it was observed in 15 patients in the uncovered group. In subgroup analysis, the cumulative patency of the covered EMS was significantly higher in pancreatic cancer (p = 0.0363) and metastatic lymph nodes (p = 0.0354). There was no significant difference in survival between the two groups. Acute cholecystitis was observed in two of the covered group and in none of the uncovered group. Mild pancreatitis occurred in five of the covered group and in one of the uncovered group. Conclusions: Covered diamond stents successfully prevented tumour ingrowth and were significantly superior to uncovered stents for the treatment of patients with distal malignant biliary obstruction. However, careful attention must be paid to complications specific to covered self-expandable metal stents, such as acute cholecystitis and pancreatitis.

Ledipasvir and sofosbuvir fixed-dose combination with and without ribavirin for 12 weeks in treatment-naive and previously treated Japanese patients with genotype 1 hepatitis C: an open-label, randomised, phase 3 trial

BACKGROUND Compared with other countries, patients with chronic hepatitis C infection in Japan tend to be older, have more advanced liver disease, and are more likely to have been previously treated for hepatitis C. We aimed to assess the efficacy and safety of an all-oral, fixed-dose combination of the hepatitis C virus NS5A inhibitor ledipasvir and the NS5B nucleotide polymerase inhibitor sofosbuvir with and without ribavirin for 12 weeks in treatment-naive and previously treated Japanese patients with chronic genotype 1 hepatitis C virus infection. METHODS In this randomised, open-label study, we enrolled patients from 19 clinical Japanese centres. Patients were randomly assigned (1:1) to receive either ledipasvir (90 mg) and sofosbuvir (400 mg) or ledipasvir, sofosbuvir, and ribavirin (dosed according to the Japanese Copegus product label-ie, patients ≤60 kg received 600 mg daily, patients >60 kg to ≤80 kg received 800 mg daily, and patients >80 kg received 1000 mg daily) orally once daily for 12 weeks. After completion or early discontinuation of treatment, patients were followed up off-treatment for 24 weeks. Eligible patients were at least 20 years of age with chronic genotype 1 hepatitis C virus infection with serum hepatitis C virus RNA concentrations of at least 5 log10 IU/mL, creatinine clearance of at least 1·0 mL/s, and a platelet count of at least 50 × 10(9) per L. An interactive web response system was used to manage patient randomisation and treatment assignment. Randomisation was stratified by the presence or absence of cirrhosis for treatment-naive patients and stratified by presence or absence of cirrhosis and by previous treatment category (relapser or breakthrough, non-responder, or interferon-intolerant) for previously treated patients. Within each strata, patients were sequentially assigned to either treatment with ledipasvir-sofosbuvir or ledipasvir-sofosbuvir plus ribavirin in a 1:1 ratio with block size of 4. The primary endpoint was sustained virological response 12 weeks after completion of treatment (SVR12) assessed in all patients who were randomly assigned and received at least one dose of study drug; safety outcomes were assessed in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT01975675. FINDINGS Between Oct 15, 2013 and Dec 13, 2013, 341 patients were randomly assigned to treatment groups and received at least one dose of study treatment. SVR12 was achieved in all 171 (100%) patients (83 of 83 treatment naive and 88 of 88 treatment experienced) receiving ledipasvir-sofosbuvir (95% CI 98-100) and 167 (98%) of 170 patients (80 of 83 treatment naive and 87 of 87 treatment experienced) receiving ledipasvir-sofosbuvir plus ribavirin (95% CI 95-100). Of the 76 patients with baseline NS5A resistant variants, 75 (99%) achieved SVR12. Two (1·2%) of 170 patients in the ledipasvir-sofosbuvir plus ribavirin group discontinued treatment because of adverse events. The most common adverse events were nasopharyngitis (50 [29·2%] of 171), headache (12 [7·0%] of 171), and malaise (nine [5·3%] of 171) in patients receiving ledipasvir-sofosbuvir; and nasopharyngitis (40 [23·5%] of 170), anaemia (23 [13·5%] of 170), and headache in those receiving ledipasvir-sofosbuvir and ribavirin (15 [8·8%] of 170). INTERPRETATION Although existing regimens for the treatment of hepatitis C virus are effective for many patients, medical needs remain unmet, particularly in Japan where the population with hepatitis C virus genotype 1 is generally older and treatment-experienced, with advanced liver disease. The efficacy, tolerability, and absence of drug-drug interactions of ledipasvir-sofosbuvir suggest that it could be an important option for treatment of genotype 1 hepatitis C virus in Japanese patients. FUNDING Gilead Sciences.

Involvement of the biliary system in autoimmune pancreatitis: a follow-up study

BACKGROUND & AIMS The aim of this study was to define the bile duct changes associated with autoimmune pancreatitis. METHODS Eight patients with autoimmune pancreatitis were followed for a mean of 4 years. The clinical features of these patients, including extrapancreatic bile duct changes, were examined by using biochemical parameters and several imaging modalities. Pathologic features of the pancreas and liver were examined by using the biopsy specimens of 7 patients. RESULTS Diffuse or focal narrowing of the main pancreatic duct was observed in all patients. Histologic examination of the pancreas showed lymphoplasmacyte infiltration with severe fibrosis and acinar cell depletion. In 6 patients extrapancreatic bile duct changes such as stricture of the bile duct at hilus or intrahepatic area were observed. In 2 patients abnormalities in the bile duct and pancreas were detected simultaneously at diagnosis, and changes in the bile duct were observed later in 4 patients. Lymphoplasmacyte infiltration and fibrosis were observed in the portal area of all 7 liver biopsy samples. Five of the patients with bile duct changes received steroid therapy, and the pathological changes improved. CONCLUSIONS Extrapancreatic bile duct changes are frequently associated with autoimmune pancreatitis. Similar pathogenic mechanism might produce the biliary tract and pancreatic abnormalities in autoimmune pancreatitis resulting in a similar histopathology in the liver and pancreas and response to steroid therapy.

Measurement of radial and axial forces of biliary self-expandable metallic stents

BACKGROUND Efforts to understand the properties of self-expandable metallic stents (SEMSs) through their mechanical properties have progressed. Among them, radial force (RF) is well known as an expanding force, but axial force (AF) has not been measured before. Correlations of these properties to clinical results are not well known. OBJECTIVE We measured RF and AF of 14 different SEMSs and discussed the results in terms of clinical implications. DESIGN Experimental study. SUBJECTS Measurement of RF and AF of 14 different covered and uncovered SEMSs. METHODS RF was measured with an RF measurement machine manufactured by Machine Solution, and AF was measured with in-house equipment. RESULTS Measurements of RF in the process of expansion showed characteristic patterns closely related to the structures and materials of SEMSs. Results of AF measurement can be classified into 3 groups: high, medium, and low AF, depending on the type of SEMS. AF decreased with an increase of the length of stents. A plot of RF against AF revealed 3 distinguished RF/AF combinations and indicated the importance of understanding the properties by not only RF or AF individually but also by RF/AF combination. LIMITATIONS In vitro study using measurement equipment. CONCLUSION It was demonstrated that a combination of RF and AF is more effective than RF or AF individually in understanding the clinical implications of SEMSs. More work is needed to correlate mechanical properties with clinical results by designing model experiments.

Quantitative analysis of K-ras gene mutation in pancreatic tissue obtained by Endoscopic ultrasonography-guided fine needle aspiration: Clinical utility for diagnosis of pancreatic tumor

OBJECTIVES:Endoscopic ultrasonography-guided fine needle aspiration (EUS-FNA) has become established in the diagnosis of pancreatic cancer. The combination of pathological diagnosis and analysis for mutant K-ras gene was investigated to improve the accuracy of diagnosis.METHODS:EUS-FNA was performed in 34 patients with pancreatic masses (26 adenocarcinomas and eight chronic pancreatitis). Mutant ras gene was analyzed semiquantitatively in the specimens obtained by EUS-FNA as well as in pancreatic juice obtained by ERCP.RESULTS:Mutant gene was detected at high amounts (more than 2% of total ras genes) in 20 of 26 (77%) specimens of EUS-FNA and in 12 of 19 (63%) of pancreatic juice in cases with pancreatic carcinoma. Cytological diagnosis of malignancy by EUS-FNA was found in 16 of 26 (62%) patients with pancreatic cancer. Accurate diagnosis of the carcinoma was 21 of 26 (81%) by combined cytology and molecular method of EUS-FNA, and increased to 23 of 26 (88%) by adding molecular analysis of pancreatic juice. In contrast, mutant gene was absent or low level despite suspicious cytology in patients with benign pancreatic lesion.CONCLUSION:Quantitative analysis of mutant ras gene supplemented conventional cytology of EUS-FNA and ERCP. Detection of mutation at high amounts may represent pancreatic cancer, whereas its absence increased the possibility of benign lesion.

Sofosbuvir plus ribavirin in Japanese patients with chronic genotype 2 HCV infection: an open‐label, phase 3 trial

Genotype 2 hepatitis C virus (HCV) accounts for up to 30% of chronic HCV infections in Japan. The standard of care for patients with genotype 2 HCV – peginterferon and ribavirin for 24 weeks – is poorly tolerated, especially among older patients and those with advanced liver disease. We conducted a phase 3, open‐label study to assess the efficacy and safety of an all‐oral combination of the NS5B polymerase inhibitor sofosbuvir and ribavirin in patients with chronic genotype 2 HCV infection in Japan. We enrolled 90 treatment‐naïve and 63 previously treated patients at 20 sites in Japan. All patients received sofosbuvir 400 mg plus ribavirin (weight‐based dosing) for 12 weeks. The primary endpoint was sustained virologic response at 12 weeks after therapy (SVR12). Of the 153 patients enrolled and treated, 60% had HCV genotype 2a, 11% had cirrhosis, and 22% were over the aged 65 or older. Overall, 148 patients (97%) achieved SVR12. Of the 90 treatment‐naïve patients, 88 (98%) achieved SVR12, and of the 63 previously treated patients, 60 (95%) achieved SVR12. The rate of SVR12 was 94% in patients with cirrhosis and in those aged 65 and older. No patients discontinued study treatment due to adverse events. The most common adverse events were nasopharyngitis, anaemia and headache. Twelve weeks of sofosbuvir and ribavirin resulted in high rates of SVR12 in treatment‐naïve and previously treated patients with chronic genotype 2 HCV infection. The treatment was safe and well tolerated by patients, including the elderly and those with cirrhosis.

Ulinastatin for pancreatitis after endoscopic retrograde cholangiopancreatography: A randomized, controlled trial

BACKGROUND & AIMS Pancreatitis remains the major complication of endoscopic retrograde cholangiopancreatography (ERCP), and hyperenzymemia after ERCP is common. Because ulinastatin, a protease inhibitor, has proved effective in the treatment of acute pancreatitis, the aim of this study was to assess the efficacy of ulinastatin for the prevention of post-ERCP pancreatitis and hyperenzymemia. METHODS In a multicenter, randomized, double-blind, placebo-controlled trial, patients undergoing a first ERCP were randomized to receive ulinastatin (150,000 U) or placebo by intravenous infusion for 10 minutes starting immediately before ERCP. All patients were hospitalized at least 24 hours after ERCP for evaluation of clinical symptoms. Serum pancreatic enzyme levels were measured before and at 4 and 18 hours after ERCP. The primary end point was the incidence of post-ERCP pancreatitis and the secondary objective was the occurrence of hyperenzymemia. RESULTS A total of 406 patients were enrolled (204 in the ulinastatin group and 202 in the placebo group). There were no differences between the 2 groups regarding baseline characteristics, details of fluoroscopic findings, or endoscopic procedure. The incidence of hyperenzymemia was significantly lower in the ulinastatin group than in the placebo group (amylase, P = .011; lipase, P = .008). Six patients in the ulinastatin group and 15 patients in the placebo group developed pancreatitis (2.9% vs. 7.4%, P = .041). There was no case of severe pancreatitis in either group. Patients who received ulinastatin did not present any side effects related to the medication. CONCLUSIONS Prophylactic short-term administration of ulinastatin decreases the incidence of pancreatitis and hyperenzymemia after ERCP.

High‐rate pulmonary involvement in autoimmune pancreatitis

Autoimmune pancreatitis (AIP) has extrapancreatic complications such as Sjögrens syndrome, retroperitoneal fibrosis and sclerosing cholangitis. We studied 30 patients with AIP. Of these, we identified pulmonary involvement in four patients during follow up. Among them, two patients had respiratory failure. They showed good response to steroid therapy, but a higher dose of prednisolone was necessary to maintain remission than that required in biliary involvement. Elevation of immunoglobulin G4 and Krebs von den Lungen‐6 levels were characteristic of pulmonary involvement. They may be useful for early detection of pulmonary complication.

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.

Pancreatic Mass Lesions Associated with Raised Concentration of IgG4

Autoimmune pancreatitis (AIP) is a recognized benign disease characterized by irregular narrowing of the pancreatic duct, swelling of parenchyma, lymphoplasmacytic infiltration and fibrosis, and a favorable response to corticosteroid treatment. In this condition, the whole pancreas is diffusely affected. Recently, however, a few cases with locally affected lesions were reported, with some of them showing features similar to cancer. We reviewed 138 patients with pancreatic mass lesion, of which 17 were not initially diagnosed despite examinations. Serum IgG4 levels were elevated in seven of them. Their biopsy specimens had a similar appearance to those of AIP. We considered that they should be diagnosed as AIP or conditions related to AIP. Among the 10 patients without elevated IgG4, 4 patients were diagnosed as pancreatic cancer after follow-up, 1 presented with an islet cell tumor, 1 presented AIP with sclerosing cholangitis, and the other 4 had chronic pancreatitis.