Comparison of novel large-bore and conventional-bore covered self-expandable metal stents for malignant gastric outlet obstruction: Multicenter, retrospective study.

OBJECTIVES: Covered self-expandable metal stent (cSEMS) for gastric outlet obstruction (GOO) has been developed to overcome tumor ingrowth but is prone to be associated with an increased risk of migration. Clinical impact of the novel large-bore cSEMS for malignant GOO remains unclear. METHODS: A total of 117 patients undergoing endoscopic cSEMS placement for malignant GOO were enrolled in this multicenter retrospective study. Technical and clinical success, adverse events, recurrent GOO, and survival after stent placement were compared between 24 mm-cSEMS (n = 49) and 20 mm-cSEMS (n = 68). RESULTS: Patient characteristics were well-balanced and thus similar survival was observed between the two groups (136 days vs. 89 days, P = 0.60). Technical success rate of 100% and clinical success rate of 96% were achieved both in 24 mm-cSEMS and 20 mm-cSEMS, respectively. The median cumulative time to recurrent GOO was significantly longer in 24 mm-cSEMS than in 20 mm-cSEMS (380 days vs. 138 days, P = 0.01). The incidence of adverse events and recurrent GOO was comparable: 12% vs. 15% (P = 0.91), and 16% vs. 31% (P = 0.11); however, no stent migration was observed in 24 mm-cSEMS. In a subgroup analysis, the superiority of 24 mm-cSEMS to 20 mm-cSEMS was demonstrated in extrinsic cancers (380 days vs. 121 days, P = 0.01) but not in intrinsic cancers (151 days vs. not reached, P = 0.47). CONCLUSIONS: The 24 mm-cSEMS may improve time to recurrent GOO with ensuring acceptable safety in patients with malignant GOO.

Multicenter randomized trial of endoscopic papillary large balloon dilation without sphincterotomy versus endoscopic sphincterotomy for removal of bile duct stones: MARVELOUS trial.

BACKGROUND : Endoscopic papillary large balloon dilation (EPLBD) has been increasingly used for the management of large common bile duct (CBD) stones. Although EPLBD is often preceded by endoscopic sphincterotomy (EST), EPLBD alone without EST has been increasingly reported as an alternative to EST for large CBD stones. METHODS : This multicenter randomized trial was conducted at 19 Japanese institutions to compare the efficacy and safety of EPLBD alone versus EST for the removal of large (≥ 10 mm) CBD stones. The primary end point was complete stone removal in a single session. The secondary end points included: overall complete stone removal, lithotripsy use, procedure time, adverse events, and cost. RESULTS: 171 patients with large CBD stones were included in the analysis. The rate of single-session complete stone removal was significantly higher in the EPLBD-alone group than in the EST group (90.7 % vs. 78.8 %; P = 0.04). Lithotripsy use was significantly less frequent in the EPLBD group than in the EST group (30.2 % vs. 48.2 %; P = 0.02). The rates of early adverse events were comparable between the two groups: rates of overall adverse events were 9.3 % vs. 9.4 % and of pancreatitis were 4.7 % vs. 5.9 % in the EPLBD and EST groups, respectively. The procedure costs were $1442 vs. $1661 in the EPLBD and EST groups, respectively (P = 0.12). CONCLUSION : EPLBD without EST for the endoscopic treatment of large CBD stones achieved a significantly higher rate of complete stone removal in a single session compared with EST, without increasing adverse events.

Retrospective Comparative Study of Side-by-Side and Stent-in-Stent Metal Stent Placement for Hilar Malignant Biliary Obstruction.

BACKGROUND: In patients with unresectable hilar malignant biliary obstruction (MBO), bilateral metal stent placement is recommended. However, treatment selection between partially stent-in-stent (SIS) and side-by-side (SBS) methods is still controversial. STUDY: Clinical outcomes of bilateral metal stent placement by SBS and SIS methods for hilar MBO were retrospectively studied in four Japanese centers. While large-cell-type uncovered metal stents were placed above the papilla in SIS, braided-type uncovered metal stents were placed across the papilla in SBS. RESULTS: A total of 64 patients with hilar MBO (40 SIS and 24 SBS) were included in the analysis. Technical success rate was 100% in SIS and 96% in SBS. Functional success rate was 93% in SIS and 96% in SBS. Early adverse event rates were higher in SBS (46%) than in SIS (23%), though not statistically significant (P = 0.09). Post-procedure pancreatitis was exclusively observed in SBS group (29%). Recurrent biliary obstruction rates were 48% and 43%, and the median time to recurrent biliary obstruction was 169 and 205 days in SIS and SBS, respectively. CONCLUSIONS: Other than a trend to higher adverse event rates including post-procedure pancreatitis in SBS, clinical outcomes of SIS and SBS methods were comparable in patients with unresectable hilar MBO.

Early pancreatic stent placement in wire-guided biliary cannulation: A multicenter retrospective study.

BACKGROUND AND AIM: Guidewire insertion to a pancreatic duct under wire-guided cannulation (WGC) during endoscopic retrograde cholangiopancreatography (ERCP) is associated with a high incidence of post-ERCP pancreatitis (PEP). Pancreatic stent placement followed by WGC (PS-WGC) is considered for these cases to reduce PEP. This study was aimed to examine the effectiveness of PS-WGC compared with repeated WGC. METHODS: The consecutive data of patients without history of ERCP who underwent ERCP for biliary intervention were retrospectively collected from five centers. Patients without guidewire insertion to the pancreatic duct were excluded. Pancreatic stent was immediately placed after guidewire insertion to the pancreatic duct in the PS-WGC group. The association between the method of biliary cannulation (PS-WGC or repeated WGC) and PEP was analyzed using multivariable logistic regression model. RESULTS: A total of 590 patients (183 in the PS-WGC and 407 in the repeated WGC group) were included. PS-WGC decreased PEP (8.7% vs 19%, P = 0.001) and improved its severity (moderate and severe PEP; 2.2% vs 6.4%, P = 0.04) compared with repeated WGC. PS-WGC was associated with reduction of PEP in the multivariable model (Odds ratio 0.31, P < 0.001). The rates of difficult cannulation and overall successful biliary cannulation were not different between the two groups (66% vs 70%, P = 0.39 and 98% vs 96%, P = 0.21 in the PS-WGC and repeated WGC group, respectively). CONCLUSIONS: Pancreatic stent placement followed by WGC reduced PEP in patients with guidewire insertion to the pancreatic duct during WGC for native papilla compared with repeated WGC.

Endoscopic papillary large balloon dilation without sphincterotomy for users of antithrombotic agents: A multicenter retrospective study.

BACKGROUND AND AIM: With an aging population, an increasing number of individuals on antithrombotic agents are diagnosed with large bile duct stones. Studies have shown the effectiveness of endoscopic papillary large balloon dilation (EPLBD) for removal of large bile duct stones. EPLBD without endoscopic sphincterotomy (EST) may reduce the risk of procedure-related bleeding, but the safety of this procedure for users of antithrombotic agents remains unclear. METHODS: In this multicenter retrospective study, we included patients who underwent EPLBD without EST for bile duct stones between March 2008 and December 2017. We compared adverse events and other clinical outcomes between users and non-users of antithrombotic agents (antiplatelet agents and anticoagulants). RESULTS: We analyzed a total of 144 patients (47 users and 97 non-users of antithrombotic agents). Among the users, the agents were continued in 13% and were replaced with heparin in 62% during the periprocedural period. We did not observe clinically significant bleeding and thrombotic events irrespective of the use of antithrombotic agents. Overall rate of early adverse events did not differ between users and non-users (6.4% and 7.2%, P = 0.99). Procedural outcomes did not differ between the groups (necessity for lithotripsy, 28% vs. 29%; and complete stone removal in a single session, 72% vs. 71%, for users and non-users, respectively). CONCLUSIONS: Endoscopic papillary large balloon dilation without EST may be done without a substantial increase in procedure-related bleeding for users of antithrombotic agents. A larger study is required to refine the management strategy for those agents during the periprocedural period.

Antireflux covered metal stent for nonresectable distal malignant biliary obstruction: Multicenter randomized controlled trial.

BACKGROUND AND AIM: An antireflux metal stent (ARMS) for nonresectable distal malignant biliary obstruction (MBO) may prevent recurrent biliary obstruction (RBO) as a result of duodenobiliary reflux and prolong time to RBO (TRBO). Superiority of ARMS over conventional covered self-expandable metal stents (SEMS) has not been fully examined. METHODS: We conducted a multicenter randomized controlled trial to examine whether TRBO of an ARMS with a funnel-shaped valve was longer than that of a covered SEMS in SEMS-naïve patients. We enrolled 104 patients (52 patients per arm) at 11 hospitals in Japan. Secondary outcomes included causes of RBO, adverse events, and patient survival. RESULTS: TRBO did not differ significantly between the ARMS and covered SEMS groups (median, 251 vs 351 days, respectively; P = 0.11). RBO as a result of biliary sludge or food impaction was observed in 13% and 9.8% of patients who received an ARMS and covered SEMS, respectively (P = 0.83). ARMS was associated with a higher rate of stent migration compared with the covered SEMS (31% vs 12%, P = 0.038). Overall rates of adverse events were 20% and 18% in the ARMS and covered SEMS groups, respectively (P = 0.97). No significant between-group difference in patient survival was observed (P = 0.26). CONCLUSIONS: The current ARMS was not associated with longer TRBO compared with the covered SEMS. Modifications including addition of an anti-migration system are required to use the current ARMS as first-line palliative treatment of distal MBO (UMIN-CTR clinical trial registration number: UMIN000014784).

International study of endoscopic management of distal malignant biliary obstruction combined with duodenal obstruction.

OBJECTIVE: Endoscopic transpapillary or endoscopic ultrasound (EUS)-guided stent placement is used for nonresectable distal malignant biliary obstruction. We conducted a retrospective study to evaluate endoscopic biliary drainage in patients with duodenal obstruction. METHODS: We included consecutive patients who underwent endoscopic biliary drainage combined with a duodenal stent at 16 referral centers in four Asian countries. The primary outcome was time to recurrent biliary obstruction (TRBO). We assessed TRBO according to the sequence of biliary and duodenal obstruction (group 1/2/3, biliary obstruction first/concurrent/duodenal obstruction first, respectively) or the location of duodenal obstruction (type I/II/III, proximal to/affecting/distal to the ampulla, respectively). We also evaluated functional success and adverse events. RESULTS: We included 110 patients (group1/2/3, 67/29/14 patients; type I/II/III, 45/46/19 patients; endoscopic retrograde cholangiopancreatography [ERCP]/EUS-guided choledocoduodenostomy/EUS-guided hepaticogastrostomy, 90/10/10 patients, respectively). The median TRBO of all cases was 450 days (interquartile range, 212-666 days) and functional success was achieved in 105 cases (95%). The TRBO did not differ significantly by the timing or location of duodenal obstruction (p = .30 and .79, respectively). The TRBO of metal stents (n = 96) tended to be longer compared with plastic stents (n = 14, p = .083). Compared with ERCP, EUS-guided biliary drainage was associated with a higher rate of adverse events. CONCLUSION: Transpapillary or transmural endoscopic biliary drainage with a duodenal stent was effective, irrespective of the timing or location of duodenal obstruction. A prospective study is required considering the tradeoff of technical success rate, stent patency, and adverse events (ClinicalTrials.gov number, NCT02376907).

Multicenter study of endoscopic preoperative biliary drainage for malignant hilar biliary obstruction: E-POD hilar study.

BACKGROUND AND AIM: Endoscopic nasobiliary drainage (ENBD) is often recommended in preoperative biliary drainage (PBD) for hilar malignant biliary obstruction (MBO), but endoscopic biliary stent (EBS) is also used in the clinical practice. We conducted this large-scale multicenter study to compare ENBD and EBS in this setting. METHODS: A total of 374 cases undergoing PBD including 281 ENBD and 76 EBS for hilar MBO in 29 centers were retrospectively studied. RESULTS: Extrahepatic cholangiocarcinoma (ECC) accounted for 69.8% and Bismuth-Corlette classification was III or more in 58.8% of the study population. Endoscopic PBD was technically successful in 94.6%, and adverse event rate was 21.9%. The rate of post-endoscopic retrograde cholangiopancreatography pancreatitis was 16.0%, and non-endoscopic sphincterotomy was the only risk factor (odds ratio [OR] 2.51). Preoperative re-intervention was performed in 61.5%: planned re-interventions in 48.4% and unplanned re-interventions in 31.0%. Percutaneous transhepatic biliary drainage was placed in 6.4% at the time of surgery. The risk factors for unplanned procedures were ECC (OR 2.64) and total bilirubin ≥ 10 mg/dL (OR 2.18). In surgically resected cases, prognostic factors were ECC (hazard ratio [HR] 0.57), predraiange magnetic resonance cholangiopancreatography (HR 1.62) and unplanned re-interventions (HR 1.81). EBS was not associated with increased adverse events, unplanned re-interventions, or a poor prognosis. CONCLUSIONS: Our retrospective analysis did not demonstrate the advantage of ENBD over EBS as the initial PBD for resectable hilar MBO. Although the technical success rate of endoscopic PBD was high, its re-intervention rate was not negligible, and unplanned re-intervention was associated with a poor prognosis in resected hilar MBO.

Gemcitabine and S-1 versus gemcitabine and cisplatin treatment in patients with advanced biliary tract cancer: a multicenter retrospective study.

Objective This study aimed to compare the safety and efficacy of the combination therapy of gemcitabine and S-1 (GS) versus gemcitabine and cisplatin (GC) in patients with advanced biliary tract cancer (BTC). Methods In this multicenter retrospective cohort study, a total of 212 patients with advanced BTC receiving GS (n = 125) or GC (n = 87) between July 2006 and August 2015 were analyzed. The primary endpoint was overall survival (OS). The secondary endpoints were progression-free survival (PFS), objective tumor response, and safety. Results Patient characteristics were well balanced between the two groups, except for tumor size (the baseline sum of the largest diameter of the tumor: 6.3 cm in the GS group vs. 8.6 cm in the GC group, p = 0.01). Although the response rate was higher in the GS group than in the GC group (28.8% vs. 10.3%, p = 0.01), the median PFS and OS were comparable between the two groups (PFS of 5.6 vs. 7.6 months, p = 0.74; OS of 12.4 vs. 9.2 months, p = 0.20, respectively). Stomatitis and skin rash were more frequently observed in the GS group, whereas anemia, thrombocytopenia, nausea, and renal toxicity were more commonly observed in the GC group. Conclusion This study demonstrates that GS and GC are similar with regard to their safety and efficacy in patients with advanced BTC. GS could serve as an alternative treatment for advanced BTC as a first-line chemotherapy.

[Complete Response in a Patient with HER2-Positive Gastric Cancer and Multiple Lung Metastases with Trastuzumab-Containing Chemotherapy].

We report the case ofa 79-year-old Japanese woman diagnosed with human epidermal growth factor receptor 2 (HER2)-positive gastric cancer of the cardia with multiple lung metastases that showed complete response to trastuzumab-containing chemotherapy. First, we administered tegafur/gimeracil/oteracil (S-1) and cisplatin (CDDP) concurrently to the patient. Next, we switched to trastuzumab in combination with capecitabine and CDDP because gastric cancer tissue indicated HER2-positivity. Considering the patient's age and renal function, the dose of CDDP was decreased to 50% after starting the medication. Before the 2nd course of trastuzumab-containing chemotherapy, oral mucositis (Grade 3) and hand-foot syndrome (Grade 1) were observed. Therefore, a one-step dose reduction of capecitabine was necessary. After the 4th course, the primary gastric tumor was no longer visible endoscopically. After the 7th course, computed tomography (CT) showed the disappearance of all lung metastases. Accordingly, the patient was considered to be completely responsive to the medication. After the 12th course, recurrence of the tumor was not identified and at the request of the patient, the trastuzumab-containing chemotherapy was discontinued. Regular follow-up showed no evidence of recurrence 8 months after discontinuing treatment and the patient was in good condition 21 months after her initial diagnosis.

Early use of double-guidewire technique to facilitate selective bile duct cannulation: the multicenter randomized controlled EDUCATION trial.

BACKGROUND AND STUDY AIMS: There are no guidelines for the timing of conversion from a single-guidewire to a double-guidewire technique to facilitate selective bile duct cannulation and reduce post-endoscopic retrograde cholangiopancreatography pancreatitis (PEP), when using wire-guided cannulation. We investigated whether early conversion to the double-guidewire method, at first unintentional insertion of a guidewire into the pancreatic duct, facilitated selective bile duct cannulation and reduced PEP compared with repeated single-guidewire attempts. PATIENTS AND METHODS: A multicenter prospective randomized controlled trial included 274 patients with a naive papilla, undergoing endoscopic retrograde cholangiography (ERC) using wire-guided cannulation in whom there was unintentional insertion of the guidewire into the pancreatic duct. With the guidewire still in the duct, patients were randomly assigned to undergo the double-guidewire technique or repeated single-wire cannulation. Main outcomes were success rates for selective bile duct cannulation and PEP frequency. RESULTS: Success rates for selective bile duct cannulation within 10 attempts and 10 minutes were 75 % and 70 %, respectively, for the early double-guidewire (EDG) and repeated single-guidewire (RSG) cannulation groups (relative rate 1.07, 95 % confidence interval [95 %CI] 0.93 - 1.24, P = 0.42). Corresponding final selective bile duct cannulation rates were 98 % and 97 % (relative rate 1.01, 95 %CI 0.97 - 1.05, P = 1.00). PEP rates were 20 % and 17 %, respectively, for the EDG and RSG cannulation groups (relative risk 1.17, 95 %CI 0.71 - 1.94, P = 0.53). Double-guidewire cannulation was more effective in patients with malignant biliary stricture (relative rate 1.36, 95 %CI 1.05 - 1.77, P = 0.02). CONCLUSIONS: During therapeutic ERC using wire-guided cannulation, converting to a double-guidewire technique neither facilitated selective bile duct cannulation nor decreased PEP incidence compared with repeated use of a single-wire technique.

Clinical outcomes of secondary gastroduodenal self-expandable metallic stent placement by stent-in-stent technique for malignant gastric outlet obstruction.

BACKGROUND AND AIM: To evaluate the efficacy and safety of secondary gastroduodenal stent placement after first stent dysfunction for malignant gastric outlet obstruction. METHODS: We conducted a retrospective analysis to investigate the efficacy and safety of secondary stent-in-stent gastroduodenal stent placement. RESULTS: Among 260 patients who had been treated with first gastroduodenal stent placement for malignant gastric outlet obstruction, 29 patients (11.2%) were treated with secondary gastroduodenal stent placement because of first stent dysfunction. Pancreatic cancer was the major primary cancer (55.2%). A WallFlex duodenal stent was the most frequently inserted stent both as a first stent (75.9%) and as a secondary stent (62.1%). There were 22 patients (75.9%) that received gastroduodenal stents at the bending site (supraduodenal angle or infraduodenal angle). Technical and clinical success rates were 100% and 86.2%, respectively. Median eating period was 3.0 months, and median survival time was 3.5 months. As for related complications, gastrointestinal perforation, insufficient stent expansion, tumor ingrowth, tumor overgrowth, and cholangitis were experienced in 13.8% (four cases), 6.9% (two cases), 6.9% (two cases), 3.4% (one case), and 3.4% (one case), respectively. CONCLUSION: Secondary gastroduodenal stent placement might be effective for managing first stent dysfunction in malignant gastric outlet obstruction. However, gastrointestinal perforation was the major complication.

Detection of painless pancreatitis by computed tomography in patients with post-endoscopic retrograde cholangiopancreatography hyperamylasemia.

OBJECTIVES: Post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis is diagnosed on the basis of pancreatic pain and hyperamylasemia. However, because the diagnosis of abdominal pain is not objective, there may be some cases of painless pancreatitis among patients with post-ERCP hyperamylasemia (PEH). We reviewed the computed tomography (CT) findings of PEH cases to determine the incidence of painless pancreatitis. METHODS: Between July, 2005 and December, 2011, CT was performed in 91 patients with hyperamylasemia 18 h after ERCP. We reviewed the CT findings and graded the severity of pancreatitis according to the Balthazar grading system. Grades C, D, and E were defined as pancreatitis. RESULTS: Thirty-four patients (37%) had pancreatitis according to the CT findings. There was a significant difference in the serum amylase levels between the positive- and negative-CT finding groups (1306 ± 833 vs. 786 ± 315 IU/L, respectively; p = 0.0012). Receiver operating characteristic curve analysis showed that the amylase cut-off value for discriminating between the 2 groups was 795 IU/L (6.36 times the upper normal limit). CONCLUSIONS: Thirty-seven percent of PEH patients had painless pancreatitis. CT is useful to determine pancreatitis in patients taking analgesics, steroids, or anti-immunological drugs and those with diabetes mellitus and 18-h serum amylase levels of >6 times the normal upper limit.

Risk factors for covered metallic stent migration in patients with distal malignant biliary obstruction due to pancreatic cancer.

BACKGROUND AND AIM: Covered metallic stents (CMSs) were developed to overcome tumor ingrowth in uncovered metallic stents (UMSs) for malignant biliary obstruction, but superiority of CMSs over UMSs is still controversial due to the high migration rate in CMS. Therefore, we conducted this retrospective analysis to clarify risk factors for stent migration, including mechanical properties of CMSs. METHODS: Patients with unresectable pancreatic cancer, receiving CMS for distal malignant biliary obstruction in five tertiary care centers, were retrospectively studied. Univariate and multivariate analyses to identify prognostic factors for early (< 6 months) stent migration were performed using a proportional hazards model with death or stent occlusion without stent migration as a competing risk. Two mechanical properties were included in the analysis: axial force, the recovery force that leads to a CMS straightening, and radial force (RF), the expansion force against the stricture. RESULTS: Among 290 patients who received CMS placement for distal malignant biliary obstruction, stent migration rate was 15.2%. CMS migrated early (< 6 months) in 10.0% and distally in 11.7%, respectively. In the multivariate analysis, significant risk factors for early stent migration were chemotherapy (subdistribution hazard ratios [SHR] 4.46, P = 0.01), CMS with low RF (SHR 2.23, P = 0.03), and duodenal invasion (SHR 2.25, P = 0.02). CONCLUSION: CMS with low RF, chemotherapy, and duodenal invasion were associated with CMS migration from our study.

Metallic stent with high axial force as a risk factor for cholecystitis in distal malignant biliary obstruction.

BACKGROUND AND AIM: Tumor involvement to the orifice of cystic duct (OCD) is a risk factor for cholecystitis after self-expandable metallic stent (SEMS) placement, but its prevention is still difficult. We conducted this multicenter analysis to clarify a type of SEMS or a method to place SEMS which would decrease the incidence of cholecystitis after SEMS placement. METHODS: The incidence of cholecystitis was studied in consecutive patients receiving SEMS for distal malignant biliary obstruction in five tertiary care centers. Multiple logistic regression analysis was performed to evaluate risk factors for cholecystitis. RESULTS: A total of 376 patients who received SEMS placement for distal malignant biliary obstruction were analyzed. Tumor involvement to OCD was diagnosed in 25.3%. Overall incidence of cholecystitis was 6.9%. Cholecystitis was observed in 8.0% of 300 patients with covered SEMS, 16.8% of 95 patients with tumor involvement to OCD, 10.8% of 234 patients with SEMS of high axial force (AF), and 12.0% of 158 patients with SEMS length ≤ 60 mm. In the multivariate analysis, tumor involvement to OCD (odds ratio [OR] 5.40, P < 0.001), SEMSs with high AF (OR 5.33, P = 0.002), and SEMS length ≤ 60 mm (OR 3.19, P = 0.010) are risk factors. Among patients with tumor involvement to OCD, the incidence of cholecystitis in SEMS with high and low AF was 25.0% and 5.0%, respectively. CONCLUSION: This study with an expanded cohort reconfirmed tumor involvement to OCD as a risk factor for cholecystitis after SEMS placement. SEMS with low AF might decrease cholecystitis.

A multicenter phase II trial of gemcitabine and candesartan combination therapy in patients with advanced pancreatic cancer: GECA2.

BACKGROUND: Our retrospective study and phase I trial of gemcitabine and candesartan combination therapy suggested the inhibition of renin-angiotensin system potentially has a role in the treatment of advanced pancreatic cancer. The aim of this multicenter phase II trial was to assess the efficacy and toxicity of gemcitabine and candesartan combination therapy for advanced pancreatic cancer. METHODS: Chemotherapy-naive patients with histologically or cytologically proven advanced pancreatic cancer were enrolled. Gemcitabine was administered at a dose of 1,000 mg/m(2) over 30 min on days 1, 8, and 15 and oral candesartan at a dose of 16 mg in normotensive patients, and 8 mg initially in hypertensive patients, with dose escalation to 16 mg allowed, from days 1 to 28, repeated every 4 weeks. RESULTS: A total of 35 patients with advanced pancreatic cancer were enrolled. Overall response rate and disease control rate were 11.4 % and 62.9 %. The median PFS and OS were 4.3 and 9.1 months with 1-year survival rate of 34.2 %. The median PFS was significantly longer in patients receiving 16 mg compared with 8 mg of candesartan (4.6 vs. 3.5 months, p=0.031). Major severe toxicities were neutropenia (23 %), leukopenia (17 %) and thrombocytopenia (11 %). Grade 2 hypotension was observed in 3 patients (9 %) and candesartan was discontinued in 2 patients due to hypotension. Conclusions In this multicenter phase 2 trial, gemcitabine and candesartan combination therapy was tolerable but failed to demonstrate activity against advanced pancreatic cancer. (UMIN CTR: UMIN000005580).

Results of the Tokyo trial of prevention of post-ERCP pancreatitis with risperidone-2: a multicenter, randomized, placebo-controlled, double-blind clinical trial.

BACKGROUND: Our previous study suggested that a combination of ulinastatin and risperidone reduced post-ERCP pancreatitis (PEP) compared with ulinastatin alone. OBJECTIVE: The aim of this study was to evaluate the efficacy of risperidone alone for prevention of PEP. DESIGN: A multicenter, randomized, placebo-controlled, double-blind clinical trial. SETTING: Two academic hospitals and 5 referral hospitals in Tokyo and Saitama, Japan. PATIENTS: Patients undergoing therapeutic or interventional-diagnostic ERCP. INTERVENTION: The patients were randomized to receive 2 mg of oral risperidone or oral placebo at 0.5 to 2 hours before ERCP. MAIN OUTCOME MEASUREMENTS: The primary endpoint was the incidence of PEP. Secondary endpoints were the incidence of hyperenzymemia and enzyme levels (amylase, pancreatic amylase, lipase). Risk factors for PEP were evaluated. RESULTS: We initially enrolled 500 patients in the study (250 in the risperidone group and 250 in the placebo group), but 17 (11 in the risperidone and 6 in the placebo group) were excluded after randomization. PEP developed in 24 patients (10.0%) in the risperidone group and 21 patients (8.6%) in the placebo group (P = .587). Serum amylase levels at 3 hours after ERCP were lower in the risperidone group (P = .007 in a single test of hypothesis, significance removed by Bonferroni correction for multiple testing). In multivariate analysis, a small papilla of Vater, total procedure time ≥40 minutes, and stenosis of the intrahepatic duct were significantly associated with PEP. LIMITATIONS: Multiplicity of study centers and a relatively wide time range of drug administration time. CONCLUSION: Risperidone did not show a benefit in prevention of PEP in this trial. ( CLINICAL TRIAL REGISTRATION NUMBER: NCT000004592.).

A retrospective study of gemcitabine and cisplatin combination therapy as second-line treatment for advanced biliary tract cancer.

BACKGROUND: To evaluate the treatment outcome of gemcitabine and cisplatin combination therapy as second-line treatment for advanced biliary tract cancer. PATIENTS AND METHODS: Patients with advanced biliary tract cancer who were refractory to gemcitabine-based first-line chemotherapy were treated with gemcitabine and cisplatin combination therapy. Gemcitabine (1,000 mg/m(2)) and cisplatin (25 mg/m(2)) were administered intravenously on days 1 and 8, repeated every 3 weeks. RESULTS: Sixty patients were included. The tumor response and disease control rates were 1.7 and 58.3%, respectively. The median overall survival and time to progression were 6.7 months (95% CI 4.9-8.1) and 3.5 months (95% CI 2.5-5.0), respectively. Grade 3/4 toxicities included leucopenia (20%), neutropenia (25%), anemia (23%), thrombocytopenia (17%), nausea (2%), anorexia (2%), and liver dysfunction (2%). CONCLUSIONS: Gemcitabine and cisplatin combination therapy showed moderate efficacy and safety as second-line treatment for advanced biliary tract cancer that is refractory to gemcitabine-based first-line chemotherapy.

Japanese multicenter estimation of WallFlex duodenal stent for unresectable malignant gastric outlet obstruction.

AIM: This retrospective study estimated the efficacy and safety of the WallFlex duodenal stent for malignant gastric outlet obstruction (GOO) in Japan. METHODS: Forty-two consecutive patients with symptomatic malignant GOO were treated using WallFlex duodenal stents between January 2010 and October 2010. RESULTS: The technical and clinical success rates were 100% and 83.3%, respectively.The median gastric outlet obstruction scoring system increased significantly, from 0 to 2, after stent placement (P < 0.01).The median survival time was 3.3 months (95% confidence interval (CI), 1.8-6.0 months), and the median eating period was 3.0 months (95% CI, 1.1-4.3 months). Re-intervention was required in 11 patients (26.2%). The complication rate was 26.2%. The major complication was stent occlusion (23.8%) by tumor ingrowth, which occurred in nine (21.4%) patients, and tumor overgrowth, which occurred in one (2.4%) patient. Stentmigration, perforation, and food impaction without stent occlusion were not observed.The median survival time of the patients with stent occlusion was 11.7 months (95% CI, 2.2 months - not reached), and the median stent patency of these patients was 4.0 months (95% CI, 0.8-4.7 months).These patients were successfully treated with additional stent insertion using a stent-in-stent procedure. CONCLUSION: Duodenal stent placement using a WallFlex duodenal stent was safe and effective for managing malignant GOO.This stent is an uncovered metallic stent, and the major problem was stent occlusion due to tumor ingrowth. However, the occluded stent could be corrected by inserting an additional duodenal stent.

Phase I trial of gemcitabine and candesartan combination therapy in normotensive patients with advanced pancreatic cancer: GECA1.

Our retrospective study showed inhibition of the renin-angiotensin system was associated with better outcomes in patients with advanced pancreatic cancer receiving gemcitabine. The primary objective of this phase I study was to determine the recommended dose of candesartan in combination with gemcitabine in normotensive patients with advanced pancreatic cancer. Candesartan was given orally at an escalating dose (4, 8, 16, and 32 mg) q.d. daily, and gemcitabine was given 1000 mg/m(2) 30 min i.v. on days 1, 8, and 15, repeated every 4 weeks. Dose-limiting toxicity (DLT) was defined as grade 4 hematological toxicities, grade 2 hypotension, abnormal creatinine or potassium, and grade 3 or 4 other non-hematological toxicities. A standard "3+3" phase I dose-escalation design was used. A total of 14 patients (candesartan 4 mg, three patients; 8 mg, three patients; 16 mg, six patients; 32 mg, two patients) were enrolled. One of six patients at 16 mg showed DLT of grade 4 neutropenia and two of two patients at 32 mg showed DLT of grade 2 hypotension. Response rate and disease control rate were 0% and 79%, respectively. Progression-free survival and overall survival were 7.6 and 22.9 months, respectively. Candesartan 16 mg is the recommended dose in combination with gemcitabine in the treatment of advanced pancreatic cancer. (UMIN CTR: UMIN000002152).