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.

A pilot study of EUS-guided through-the-needle forceps biopsy (with video).

BACKGROUND AND AIMS: In EUS-guided FNA (EUS-FNA), small-caliber needles are preferable for optimal cytologic yield, whereas large ones are preferable when histologic specimens are needed. Because of the rigidity and friction induced by its large caliber, however, technical limitation does exist in a 19-gauge FNA needle. Recent development of miniature biopsy forceps enables EUS-guided through-the-needle forceps biopsy (EUS-TTNFB). The aim of this study is to evaluate safety and efficacy of EUS-TTNFB. METHODS: Eighteen sessions of EUS-TTNFB in 17 patients with solid lesions were performed by using a 0.75-mm biopsy forceps through a 19-gauge FNA needle. Technical feasibility, safety, and diagnostic yield of EUS-TTNFB were retrospectively studied. RESULTS: A total of 49 passes, a median of 3 passes per session, were performed, and the needle puncture, advancement and removal of the biopsy forceps, and subsequent EUS-FNA were technically successful in all patients. No adverse events were observed other than one case with hyperamylasemia without pancreatitis. Macroscopic histologic core by EUS-TTNFB was obtained at a rate of 71% per pass. The tissue acquisition rate by EUS-TTNFB alone was 67% per pass and 100% per session. When EUS-TTNFB and subsequent EUS-FNA were combined, the tissue acquisition rate was 94% per pass. The accuracy of combined EUS-TTNFB and EUS-FNA to diagnose malignancy was 88% per pass and 94% per session. With a single pass of EUS-TTNFB and EUS-FNA, the tissue acquisition rate was 89%, and the accuracy to diagnose malignancy was 83%. CONCLUSIONS: EUS-TTNFB was safe and technically feasible and provided additional tissue acquisition with a single puncture of a 19-gauge FNA needle.

Outcome of Long-term Maintenance Steroid Therapy Cessation in Patients With Autoimmune Pancreatitis: A Prospective Study.

OBJECTIVE: To predict the duration of steroid maintenance therapy required to achieve good prognosis in patients with autoimmune pancreatitis. PATIENTS AND METHODS: The study sample comprised 21 patients with autoimmune pancreatitis who met the following criteria: (1) they received steroid therapy (ST) for at least 3 years without clinical relapse; and (2) immunoglobulin (Ig) G<1600 mg/dL was observed in the past year with a prednisolone maintenance dose ≤5 mg. All patients could be diagnosed with international consensus diagnostic criteria. Patients were prospectively followed up after tapering and cessation of steroids. Clinical relapse was defined as the need to resume ST. Serological relapse was defined as having an IgG level of >1600 mg/dL. RESULTS: During the 43-month (range, 19 to 48 mo) follow-up period, clinical relapse occurred in 10 patients: pancreatic lesion in 4; coronary lesion in 2; submandibular lesion in 1; both pulmonary and renal lesions in 1; pulmonary, retroperitoneal, and submandibular lesions in 1; and bronchial asthma in 1. Serological relapse was observed in 12 patients. Although clinical and serological relapse occurred concomitantly in 3 patients, serological relapse preceded clinical relapse in 4 patients. Five patients experienced serological relapse alone, and no clinical or serological relapse occurred in 6 patients. According to Cox proportional hazard analysis, the duration of ST before tapering was a significant predictive parameter (hazard ratio, 0.969/month; 95% confidence interval, 0.940-0.998; P=0.038). CONCLUSIONS: ST cessation resulted in a high rate of clinical relapses, even in patients with long-term maintenance therapy. Therefore, it appears desirable to continue steroid maintenance therapy for a period >3 years to prevent relapse.

Cholecystectomy after endoscopic papillary balloon dilation for bile duct stones reduced late biliary complications: a propensity score-based cohort analysis.

BACKGROUND: Cholecystectomy after endoscopic sphincterotomy for bile duct stones with concomitant gallstones is known to reduce late biliary complications. Endoscopic papillary balloon dilation for bile duct stones develops fewer late biliary complications than endoscopic sphincterotomy, but no randomized controlled trials have been conducted about the role of cholecystectomy after endoscopic papillary balloon dilation. Therefore, we conducted this propensity score-matched analysis to compare cholecystectomy and wait-and-see approach after endoscopic papillary balloon dilation. METHODS: Propensity score matching extracted 147 pairs of patients with cholecystectomy after endoscopic papillary balloon dilation and with gallbladder left in situ with stones (wait-and-see) from 725 patients who underwent endoscopic papillary balloon dilation for bile duct stones. Late biliary complications such as recurrent bile duct stones and cholecystitis were evaluated. Cumulative incidence of late biliary complications was calculated treating death without biliary complications as a competing risk, and its prognostic factor was evaluated. RESULTS: The rates of late biliary complications were 5.4 and 25.2 % in the cholecystectomy after endoscopic papillary balloon dilation and wait-and-see groups: Recurrent bile duct stones rates were 4.1 and 19.0 %, and cholecystitis rates were 0.7 and 6.1 %. The cumulative incidences of biliary complications in the cholecystectomy after endoscopic papillary balloon dilation and wait-and-see approach were 3.1 versus 13.0 % at 1 year and 5.7 versus 28.0 % at 5 year after endoscopic papillary balloon dilation (p = 0.008). Subdistribution hazard ratio of late biliary complications in the wait-and-see group was 5.1 (p = 0.020). CONCLUSION: Cholecystectomy after endoscopic papillary balloon dilation for choledocholithiasis was associated with fewer late biliary complications. Prophylactic cholecystectomy should be offered to all surgically fit patients after endoscopic papillary balloon dilation for bile duct stones with concomitant gallstones.

Risk factors for post-ERCP pancreatitis in wire-guided cannulation for therapeutic biliary ERCP.

BACKGROUND: Wire-guided cannulation (WGC) was reported to decrease post-ERCP pancreatitis (PEP), but risk factors for PEP in WGC are not fully elucidated. OBJECTIVE: To evaluate the incidence and risk factors of PEP in WGC. DESIGN: Single-center retrospective study. SETTING: Academic center. PATIENTS: A total of 800 consecutive patients with a native papilla. INTERVENTIONS: Biliary therapeutic ERCP by using WGC. MAIN OUTCOME MEASUREMENTS: The rate of PEP and its risk factors. RESULTS: Biliary cannulation was successful by using WGC alone in 70.5%, and the final cannulation rate was 96.1%. Unintentional guidewire insertion and contrast material injection into the pancreatic duct (PD) during cannulation occurred in 55.3% and 21.8%, respectively. The incidence of PEP was 9.5% (mild 5.6%, moderate 2.9%, severe 1.0%). Multivariate analysis revealed a common bile duct (CBD) diameter of <9 mm (odds ratio [OR] 2.03; P = .006) and unintentional guidewire insertion into the PD (OR 2.25; P = .014) as risk factors for PEP. PD opacification was not a risk factor for PEP (OR 1.15; P = .642), but the incremental increase of the PEP rate was seen in patients with CBDs <9 mm: 4.6% without any PD manipulation, 8.3% with contrast material alone, 16.9% with guidewire alone, and 22.1% with both contrast material and guidewire. LIMITATIONS: Retrospective design in a single center. CONCLUSION: Unintentional PD manipulation was not uncommon in WGC. Guidewire insertion into the PD and a small CBD were risk factors for PEP in biliary therapeutic ERCP with the use of WGC.

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.

Disease-specific mortality among patients with intraductal papillary mucinous neoplasm of the pancreas.

BACKGROUND & AIMS: Intraductal papillary mucinous neoplasm (IPMN) of the pancreas is associated with synchronous and metachronous pancreatic cancer. However, the risk factors for pancreatic cancer-specific mortality have not been determined. We evaluated disease-specific mortality among patients with IPMNs harboring high-risk stigmata. METHODS: We analyzed data from 243 patients diagnosed with IPMN, with indications for surgery according to the consensus criteria, at the University of Tokyo Hospital from 1995 to January 2011. By using optimal matching and propensity scores based on 16 characteristics, we matched patients who underwent surgery at diagnosis with those who did not undergo surgery. A competing risk analysis was used to assess the risk of pancreatic cancer-specific mortality. RESULTS: Fifty-nine patients underwent surgery after diagnosis and 184 did not. After adjustment with propensity scores, detection of a hypo-attenuating area by computed tomography, which indicates invasive carcinoma, was associated significantly with pancreatic cancer-specific mortality (adjusted hazard ratio, 16.75; 95% confidence interval, 2.72-103.3; P = .002). Cyst diameter, main pancreatic duct diameter, and the presence of a mural nodule were not associated significantly with pancreatic cancer-specific mortality. Surgical management was found to reduce pancreatic cancer-specific mortality, especially in patients with hypo-attenuating areas (P = .038). CONCLUSIONS: Detection of a hypo-attenuating area by computed tomography significantly increases the risk for pancreatic cancer-specific mortality among IPMN patients with consensus indications for surgery. Surgical resection significantly reduces this risk.

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.

Short- and long-term outcomes of endoscopic papillary large balloon dilation with or without sphincterotomy for removal of large bile duct stones.

OBJECTIVE: Removal of large bile duct stones by endoscopic papillary large balloon dilation (EPLBD) with endoscopic sphincterotomy (EST) has been proven safe and effective. Little evidence supports the benefits of a preceding EST in reducing complications. Recent studies suggest that large bile duct stone removal by EPLBD alone may be safe and effective. MATERIAL AND METHODS: We removed large bile duct stones by EPLBD with EST from March 2008 to February 2010 and without EST from March 2010 to October 2011. Efficacy and safety of EPLBD with or without EST and late biliary complication outcomes were assessed. RESULTS: Forty-two patients (men/women, 27/15; mean age, 76 years) underwent EPLBD: 14 underwent EPLBD with EST and 28 underwent EPLBD without EST. The mean stone size was 14 mm (9-30 mm). Overall complete stone removal rate was 98%, with 83% achieved in 1 session. Complete duct clearance by EPLBD alone was achieved in 79%. Mechanical lithotripsy was required in 4 (10%) patients. Extracorporeal shock wave lithotripsy and electrohydraulic lithotripsy were required in 4 (10%) and 1 (2%) patients, respectively. Pancreatitis and perforation occurred in 2 (5%) and 1 (2%) patients, respectively. Patients treated by EPLBD with EST and by EPLBD alone did not differ in complication outcomes. Six (14%) patients had recurrent bile duct stones, with a significant correlation to dilated common bile duct (p = 0.0351). CONCLUSIONS: EPLBD is safe and effective in patients with large bile duct stones. Preceding EST may be unnecessary.

High single-session success rate of endoscopic bilateral stent-in-stent placement with modified large cell Niti-S stents for malignant hilar biliary obstruction.

BACKGROUND: Endoscopic bilateral self-expandable metallic stent (SEMS) placement in a stent-in-stent method for malignant hilar biliary obstruction is technically challenging. Technical difficulties in the initial placement and reinterventions for stent occlusion are disadvantages inherent to this stent-in-stent method. We previously reported the feasibility of Niti-S large cell D-type biliary stents (LCD). This multicenter prospective consecutive study evaluated the efficacy of bilateral SEMS placement using modified LCD with large and uniform cells, a slimmer delivery system and high radial force. PATIENTS AND METHODS: From July 2010 to June 2011, 26 consecutive patients with unresectable malignant hilar biliary obstruction underwent endoscopic bilateral placement of modified LCD in a stent-in-stent method at three tertiary hospitals. Ten patients had gallbladder cancer, eight had cholangiocarcinoma, four had lymph node metastasis, two had intrahepatic cholangiocarcinoma, and two had liver metastasis. RESULTS: Single-session and final technical success rate was 96% and 100%, respectively. Functional success rate was 89%. Stent occlusion occurred in 11 patients (42%) because of sludge (n = 7) or tumor ingrowth (n = 4). Endoscopic bilateral reintervention was technically easy and successful: six patients had stent clearance by balloon sweeping and five had plastic stent placement. According to Kaplan-Meier analysis, median survival and stent patency were 220 days and 157 days, respectively. CONCLUSIONS: Modified LCD achieved a high technical success rate both in the initial stent-in-stent placement and in bilateral reinterventions in patients with malignant hilar biliary obstruction.

Diabetes is a useful diagnostic clue to improve the prognosis of pancreatic cancer.

BACKGROUND/OBJECTIVES: Diabetes mellitus (DM) is recognized as a risk factor for pancreatic cancer (PaC) and expected to be a clue for early diagnosis. However, it is still obscure whether a diagnostic strategy using DM as a clue can improve the prognosis or not. METHODS: We retrospectively reviewed 540 patients with PaC, and investigated the prognosis with regard to the reasons for diagnosis. We compared patients diagnosed by imaging studies performed when DM was newly diagnosed or deteriorated, and patients diagnosed by symptoms. RESULTS: The prevalence of DM in PaC patients was 45% (256/540) and did not differ between disease stages. More than half of DM in PaC patients (150/256) were new-onset (<2 years in duration). One hundred sixty one patients (30%) were asymptomatic at PaC diagnosis. There were 38 patients diagnosed in association with DM (by new-onset DM, 16; by aggravation of long-standing DM, 22). Asymptomatic patients had smaller primary tumor and were diagnosed at an earlier stage. The prognosis of PaC patients complicated with DM did not differ from that of patients without DM; however, patients had better prognosis if they were diagnosed in association with DM alone (median survival time, 20.2 months), compared with patients diagnosed by symptoms (10.2 months, P < 0.01). CONCLUSIONS: Our analysis revealed that patients diagnosed in association with DM had better survival than symptomatic patients. Given the high prevalence of DM in PaC patients, DM can be a useful diagnostic clue for screening and lead to improvement of prognosis in PaC patients.

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.).

One-step, simultaneous triple endoscopic nasobiliary drainage for hilar biliary stricture.

The management of advanced hilar malignant and benign biliary strictures remains difficult regardless of the advances in endoscopic biliary stenting. Endoscopic nasobiliary drainage (ENBD) is suitable for the management, but the number of ENBD tubes is limited by the diameter of the accessory channel of the duodenoscope. In the present study,we demonstrated the feasibility and safety of one-step simultaneous triple ENBD insertion to manage hilar biliary strictures. A therapeutic duodenoscope with a 4.2-mm accessory channel was advanced into the duodenum. Three guidewires were advanced into three different intrahepatic bile ducts, none of which communicated with the others.Then, the three 5-Fr ENBD tubes were simultaneously inserted alongguidewire, one at a time. Three patients with hilar biliary stricture who suffered from acute cholangitis due to stent occlusion were successfully managed by one-step, simultaneous triple ENBD insertion.There were no procedure-related complications. One-step simultaneous triple ENBD is the most suitable drainage method for patients with advanced hilar biliary obstruction, especially in the setting of acute cholangitis due to occlusion of the previously placed stent.

Lower incidence of biliary carcinoma in patients with primary sclerosing cholangitis and high serum levels of immunoglobulin E.

BACKGROUND & AIMS: High serum levels of immunoglobulin (Ig)E often are detected in patients with primary sclerosing cholangitis (PSC), but the clinical significance is not known. METHODS: We analyzed data from 44 patients with PSC and known serum levels of IgE. They were divided into groups called high IgE (>170 IU/mL; n = 17) or normal IgE (n = 27). We compared occurrence of biliary carcinoma including cholangiocellular and gallbladder carcinoma, liver transplantation, and death between groups. RESULTS: The high IgE group had a later age of onset of PSC than the normal IgE group (54 ± 20 y vs 39 ± 16 y; P = .010); they also had a higher serum level of IgG (2078 ± 638 vs 1517 ± 475 mg/dL; P = .002) and IgG4 (104 ± 102 vs 38 ± 16 mg/dL; P = .002). Association with inflammatory bowel disease did not differ significantly between groups (5 of 17 vs 11 of 27; P = .661). No patient had biliary carcinoma in the high IgE group, but biliary carcinoma was observed during the follow-up period in 8 patients in the normal IgE group (0 of 17 vs 8 of 27; P = .016). The occurrence of biliary carcinoma, liver transplantation, or death did not differ between groups (4 of 17 vs 13 of 27; P = .124). CONCLUSIONS: High serum levels of IgE often are observed in older patients with PSC and are associated with a reduced incidence of biliary carcinoma.

Clinical utility of single-operator cholangiopancreatoscopy using a SpyGlass probe through an endoscopic retrograde cholangiopancreatography catheter.

BACKGROUND AND AIM: A single-operator cholangiopancreatoscopy was developed to overcome a problem in conventional peroral cholangiopancreatoscopy. The aim of this pilot study was to clarify the clinical utility of single-operator cholangiopancreatoscopy using a SpyGlass probe through an endoscopic retrograde cholangiopancreatography (ERCP) catheter. METHODS: Patients undergoing ERCP with a SpyGlass probe passed through a catheter were included in this study. The SpyGlass probe was inserted into the catheter following successful cannulation, and cholangiopancreatoscopy was performed by a single operator. We retrospectively analyzed the successful visualization rate of this technique. RESULTS: Fifteen patients were included in this study. SpyGlass cholangiopancreatoscopy was technically successful in all patients. Successful visualization was obtained in nine patients (60%). The median SpyGlass procedure time was 10 min. Cholangiopancreatoscopic diagnoses were as follows: bile duct carcinoma in three patients; intraductal papillary mucinous adenoma in two; and intraductal pancreatic stone, benign biliary stricture, gallbladder cholesterolosis, and gallbladder carcinoma in one each. There were no cases of post-ERCP pancreatitis. CONCLUSIONS: While the low rate of successful visualization must be improved, single-operator cholangiopancreatoscopy using a SpyGlass probe through an ERCP catheter is a safe and effective procedure.

Endoscopic removal of a spontaneously fractured biliary uncovered self-expandable metal stent.

Self-expandable metal stents (SEMS) are widely used for the palliative treatment of unresectable malignant biliary obstruction. However, the long-term durability of SEMSs in biliary strictures is not clear. We describe a case of endoscopic removal of spontaneously fractured uncovered biliary SEMS. A 59-year-old woman presented to our institution with a 1-year history of recurrent cholangitis. Her medical history included a proctectomy for rectal cancer and right hemihepatectomy for liver metastasis 10 years earlier. Five years after these operations, she developed a benign hilar stricture and had an uncovered SEMS placed in another hospital. Endoscopic retrograde cholangiopancreatography demonstrated that the SEMS was torn in half and the distal part of the stent was floating in the dilated common bile duct. The papillary orifice was dilated by endoscopic papillary large balloon dilation (EPLBD) using a 15-mm wire-guided balloon catheter. Subsequently, we inserted biopsy forceps into the bile duct and grasped the distal end of the broken SEMS under fluoroscopy. We successfully removed the fragment of the SEMS from the bile duct, along with the endoscope. The patient was discharged without complications. Placement of an uncovered biliary SEMS is not the preferred treatment for benign biliary strictures. Spontaneous fracture of an uncovered biliary SEMS is an extremely rare complication. We should be aware that stent fracture can occur when placing uncovered biliary SEMSs in patients with a long life expectancy. EPLBD is very useful for retrieving the fractured fragment of SEMS.

A case of pancreatic cancer after heart transplantation.

Malignancy is not uncommon with immunosuppressive therapy, but pancreatic cancer is infrequently complicated in recipients of heart transplantation. Here we report a transplant case diagnosed with pancreatic cancer 4 years and 8 months after the heart transplantation. We changed the immunosuppressive regimen after the malignancy was detected, and administered everolimus along with chemotherapy using S-1, an oral fluoropyrimidine prodrug. The patient lived for 8 months after the diagnosis, and received metallic stenting for the biliary and duodenal obstruction. Also, to the best of our knowledge, this is the first report about chemotherapy and endoscopic intervention for pancreatic cancer in a heart transplantation patient.

Reduced expression of RAS protein activator like-1 in gastric cancer.

RAS signaling is frequently deregulated in human neoplasms. However, RAS mutations have been found in only a small proportion of human gastric cancers, implicating other mechanisms in the activation of RAS signaling in gastric tumorigenesis. We have previously reported that decreased expression of RAS protein activator like-1 (RASAL1), a member of the RAS-GTPase-activating proteins that switch off RAS activity, contributes to colon tumor progression. In our study, we explored the involvement of decreased RASAL1 expression in gastric tumorigenesis. RASAL1 expression was reduced in 6 of 10 gastric cancer cell lines examined by immunoblotting. Knockdown of RASAL1 increased mitogen-activated protein kinase signaling in response to growth factor stimulation, and the forced expression of RASAL1 reduced proliferation of gastric cancer cells. Immunohistochemical analyses in primary gastric tumors showed that RASAL1 expression was reduced in 23 of 48 (48%) of the gastric cancers but in none of the adenomas (0/10). Methylation of the RASAL1 promoter region and loss of heterozygosity (LOH) at the RASAL1 locus were examined to investigate the causes of RASAL1 silencing. All cell lines with reduced RASAL1 had RASAL1 methylation, and two had LOH. In primary gastric cancers, methylation or LOH was detected in 50% (6/12) of those with reduced RASAL1. Furthermore, RASAL1 expression was restored in some cell lines by histone deacetylase inhibitor treatment. Our findings demonstrate that reduced RASAL1 expression, partly due to genetic and epigenetic changes, contributes to gastric carcinogenesis, and also re-emphasize the importance of RAS signaling in gastric cancer development.

Altered composition of fatty acids exacerbates hepatotumorigenesis during activation of the phosphatidylinositol 3-kinase pathway.

BACKGROUND & AIMS: Some clinical findings have suggested that systemic metabolic disorders accelerate in vivo tumor progression. Deregulation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway is implicated in both metabolic dysfunction and carcinogenesis in humans; however, it remains unknown whether the altered metabolic status caused by abnormal activation of the pathway is linked to the protumorigenic effect. METHODS: We established hepatocyte-specific Pik3ca transgenic (Tg) mice harboring N1068fs*4 mutation. RESULTS: The Tg mice exhibited hepatic steatosis and tumor development. PPARγ-dependent lipogenesis was accelerated in the Tg liver, and the abnormal profile of accumulated fatty acid (FA) composition was observed in the tumors of Tg livers. In addition, the Akt/mTOR pathway was highly activated in the tumors, and in turn, the expression of tumor suppressor genes including Pten, Xpo4, and Dlc1 decreased. Interestingly, we found that the suppression of those genes and the enhanced in vitro colony formation were induced in the immortalized hepatocytes by the treatment with oleic acid (OA), which is one of the FAs that accumulated in tumors. CONCLUSIONS: Our data suggest that the unusual FA accumulation has a possible role in promoting in vivo hepato-tumorigenesis under constitutive activation of the PI3K pathway. The Pik3ca Tg mice might help to elucidate molecular mechanisms by which metabolic dysfunction contributes to in vivo tumor progression.

Duodenal invasion is a risk factor for the early dysfunction of biliary metal stents in unresectable pancreatic cancer.

BACKGROUND: Although the placement of self-expandable metal stents (SEMSs) has been widely accepted as palliation for distal malignant biliary obstruction, the risk factors for their early dysfunction remain unclear. OBJECTIVE: To identify risk factors for early (<3 months) SEMS dysfunction in unresectable pancreatic cancer. DESIGN: A multicenter retrospective study. SETTING: Five tertiary referral centers. PATIENTS: Patients were included who underwent first-time SEMS placement for distal malignant biliary obstruction caused by pancreatic cancer between April 1994 and August 2010. MAIN OUTCOME MEASUREMENTS: Rates and causes of early dysfunction were evaluated, and risk factors were analyzed. RESULTS: In all, 317 eligible patients were identified. Covered SEMSs were placed in 82% of patients. Duodenal invasion was observed endoscopically in 37%. The median time to dysfunction was 170 days. The rates of all and early SEMS dysfunction were 55% and 31%, respectively. The major causes of SEMS dysfunction were food impaction and nonocclusion cholangitis (21% each) in early dysfunction and sludge (29%) in nonearly dysfunction. The rate of early dysfunction was 42% with duodenal invasion and 24% without duodenal invasion (P = .001). Early dysfunction caused by food impaction was more frequent in patients with duodenal invasion (10% and 4%, P = .053). Duodenal invasion was a risk factor (odds ratio 2.35; 95% CI, 1.43-3.90; P = .001) in a multiple logistic regression model. LIMITATIONS: A retrospective design. CONCLUSIONS: Duodenal invasion is a risk factor for early SEMS dysfunction in patients with pancreatic cancer.