Clinical impact of bile-derived exosomal microRNAs as novel diagnostic and prognostic biomarkers for biliary tract cancers.

Sampling of bile juice during endoscopic retrograde cholangiopancreatography (ERCP) has potential benefit of being amenable to the identification of novel biomarkers in liquid biopsy. This study reports the results of a global investigation of exosomal microRNAs (miRNAs) in bile to identify potential biomarkers for biliary tract cancers (BTCs). Eighty-eight bile samples collected during ERCP (45 BTC and 43 noncancer control samples) were enrolled in this study. Eleven BTC samples and nine control samples were assigned as the discovery set. Exosomes in bile and serum samples were collected using a glass membrane column with size-controlled macroporous glass (MPG), and exosomal miRNA expression profiles were evaluated using comprehensive miRNA microarray analysis (3D-Gene). For validation, exosomal miRNA in the bile samples of 34 BTCs and 34 controls were comprehensively evaluated using 3D-Gene. In the discovery set, eight exosomal miRNAs in bile were identified as significant aberrant expression markers, while no miRNA with aberrant expression in serum was identified. In a comparison of the discovery and validation sets, miR-451a and miR-3619-3p were identified as reproducible upregulated markers, and the combination of the two bile miRNAs showed an excellent area under the curve (0.819) value for diagnosing BTCs. In addition, high miR-3619-3p expression in bile reflects poorer prognosis of BTCs (hazard ratio = 2.89). The MPG-extracted exosomal miRNAs in bile aspirated during ERCP provide a convenient new approach for diagnosing biliary diseases. Bile-derived miRNA analysis with miR-451a and miR-3619-3p represents a potentially valuable diagnostic strategy for identifying BTCs as well as a predictive indicator of BTC prognosis.

One-step versus two-step distal self-expandable metal stent placement: A multicenter prospective randomized trial.

BACKGROUND AND AIM: Two methods of transpapillary covered self-expandable metal stent (SEMS) placement are used for distal malignant biliary obstruction (MBO): after initial drainage by plastic stent (two-step method) and without previous drainage (one-step method). METHODS: In total, 90 patients with unresectable pancreatic cancer and distal MBO were enrolled in this prospective multicenter randomized study and allocated to one-step (n = 45) and two-step (n = 45) groups. The main outcome was the time to recurrent biliary obstruction (TRBO). Secondary outcomes were the rates of early and late adverse events, survival time, the time required for bilirubin level reduction, and cost-effectiveness. RESULTS: The median TRBO did not differ significantly between the one-step and two-step groups (not available vs 314 days, P = 0.134). SEMS migration occurred significantly more frequently in the two-step group (14.3% vs 0%, P = 0.026). No significant difference was observed between groups in early (7.3% vs 14.3%, P = 0.483) or late (12.2% and 11.9%, P = 1) adverse events other than RBO, survival time (P = 0.104), or the median number of days required to reach a bilirubin level considered to be acceptable for chemotherapy administration (<3 mg/dL; P = 0.881). The total costs of stent placement and reintervention were significantly lower in the one-step SEMS group (3347 vs 5465 US dollars, P < 0.001). CONCLUSIONS: The superiority of TRBO with two-step SEMS placement was not demonstrated. One-step SEMS placement might be a promising method from the viewpoints of cost-effectiveness and less invasiveness (UMIN-CTR clinical trial registration number: UMIN000016010).

Factors That Affect Stent-Related Complications in Patients with Malignant Obstruction of the Esophagus or Gastric Cardia.

BACKGROUND/AIMS: Self-expandable metallic stent (SEMS) placement is effective for dysphagia that results from malignant obstruction of the esophagus or gastric cardia; however, stent-related complications may be life-threatening. Thus, the goal of this study was to identify risk factors associated with complications following esophageal stenting. METHODS: Of the 71 patients who underwent SEMS placement for dysphagia as a result of malignant stricture of the esophagus or gastric cardia, 53 patients with squamous cell carcinoma or adenocarcinoma, without previous SEMS placement, without a fistula, and without recurrent tumor after surgery were retrospectively identified. The occurrence of stent-related complications was used as an endpoint. RESULTS: Stent-related complications were identified in 26 patients (49.1%), and major complications occurred in 14 patients (26.4%). The use of an Ultraflex stent (odds ratio [OR], 6.81; 95% confidence interval [CI], 1.54 to 30.00; p=0.011) and prior chemotherapy (OR, 6.13; 95% CI, 1.46 to 25.70; p=0.013) were significantly associated with stent-related complications. Moreover, the use of an Ultraflex stent (OR, 19.60; 95% CI, 2.26 to 170.00; p=0.007) and prior radiation (OR, 25.70; 95% CI, 2.37 to 280.00; p=0.008) significantly increased the risk of major complications. CONCLUSIONS: The use of an Ultraflex stent and prior radiation and/or chemotherapy may represent risk factors for complications following esophageal SEMS placement.

Bleeding risk of endoscopic ultrasound-guided fine-needle aspiration in patients undergoing antithrombotic therapy.

OBJECTIVES: Bleeding events related to endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) are rare. However, for patients treated with antithrombotic agents, the bleeding risk of EUS-FNA is uncertain. Hence, the aim of this study was to assess the bleeding event rate associated with EUS-FNA in patients receiving antithrombotic treatment. METHODS: A retrospective study was conducted in 742 consecutive patients who underwent EUS-FNA for solid lesions between 2008 and 2015. We compared the bleeding event rates among patients who were not administered antithrombotic agents, those whose agent use was discontinued, those who continued treatment with aspirin or cilostazol, and those who were administered heparin as a replacement. RESULTS: There were 131 patients (17.7 %) treated with antithrombotic agents. Seven experienced bleeding events, and the overall bleeding event rate was 0.9 % (7/742). All bleeding events were intraoperative; there were no postoperative bleeding episodes. Subgroup analysis by antithrombotic agent revealed bleeding event rates of 1.0 % (6/611), 0 % (0/62), 1.6 % (1/61), and 0 % (0/8) for the non-administration, discontinuation of agents, continuation of aspirin or cilostazol, and heparin replacement groups, respectively. Only one severe bleeding event necessitated hemostatic treatment (1/742; 0.1 %); this occurred in a patient in the non-administration group, and there were no severe bleeding events in patients receiving antithrombotic treatment. CONCLUSIONS: The present study found a low incidence of EUS-FNA-related bleeding in patients receiving antithrombotic treatment. The bleeding event rate was low even in patients who underwent EUS-FNA while continuing aspirin or cilostazol.

Feasibility of the placement of a novel 6-mm diameter threaded fully covered self-expandable metal stent for malignant hilar biliary obstructions (with videos).

BACKGROUND AND AIMS: Uncovered self-expandable metal stents (USEMSs) are used to treat unresectable malignant hilar biliary obstructions (MHBOs). However, ingrowth is not prevented, and reintervention is often troublesome. A novel 6-mm threaded fully covered self-expandable metal stent (T-FCSEMS) is available that may mitigate these issues. We aimed to clarify the safety and efficacy of T-FCSEMS placement for MHBO. METHODS: Thirty patients underwent T-FCSEMS placements for MHBOs between 2014 and 2015. T-FCSEMSs were used for initial stenting in 17 patients (initial group) and for reinterventions for USEMS occlusions caused by ingrowth in 13 patients (reintervention group). The technical success rates, times to recurrent biliary obstruction, and the reintervention success rates were evaluated. RESULTS: The technical success rates were 94% (16/17) and 92% (12/13) in the initial group and reintervention group, respectively. Intrahepatic bile duct occlusions caused liver abscesses 8 days and 22 days after T-FCSEMS placements in 2 cases (7%) in the initial group, in which T-FCSEMSs were placed across the intrahepatic bile duct bifurcation. The median times to recurrent biliary obstruction were 210 days in the initial group after bilateral placement and 112 days and 152 days in the reintervention group after bilateral and unilateral placements, respectively. During reintervention, T-FCSEMS removal was successful in all patients in whom it was attempted, and the success rate of endoscopic reintervention was 100% in both groups. CONCLUSIONS: T-FCSEMS placement is a promising option for both initial stenting and reintervention for MHBO. However, we should consider the possibility of intrahepatic bile duct occlusion.

Reintervention for stent occlusion after bilateral self-expandable metallic stent placement for malignant hilar biliary obstruction.

BACKGROUND AND AIM: Endoscopic reintervention for stent occlusions following bilateral self-expandable metallic stent (SEMS) placement for malignant hilar biliary obstruction (MHBO) is challenging, and time to recurrent biliary obstruction (RBO) of the revisionary stent remains unclear. We aimed to clarify a suitable reintervention method for stent occlusions following bilateral SEMS placement for MHBO. METHODS: Between 2002 and 2014, 52 consecutive patients with MHBO who underwent endoscopic reintervention for stent occlusion after bilateral SEMS placement were enrolled at two university hospitals and one tertiary care referral center. We retrospectively evaluated the technical and functional success rates of the reinterventions, and the time to RBO of the revisionary stents. RESULTS: Technical and functional success rates of the reinterventions were 92% (48/52) and 90% (43/48), respectively. Univariate analysis did not determine any significant predictive factors for technical and functional failures. Median time to RBO of the revisionary stents was 68 days. Median time to RBO was significantly longer for revisionary SEMS placement than for plastic stent placement (131 days vs 47 days, respectively; log-rank test, P = 0.005). Revisionary SEMS placement was the only independent factor that was significantly associated with a longer time to RBO of the revisionary stent in the multivariate Cox proportional hazards analysis (hazard ratio 0.37; 95% confidence interval 0.14-0.95; P = 0.039). CONCLUSION: Revisionary SEMS placement is a suitable endoscopic reintervention method for stent occlusion following bilateral SEMS placement from the perspective of time to RBO of the revisionary stent.

Long-term outcomes of endoscopic gallbladder stenting in high-risk surgical patients with calculous cholecystitis (with videos).

BACKGROUND AND AIMS: Recently, endoscopic gallbladder stenting (EGBS) has been performed to prevent recurrences in high-risk surgical patients with cholecystitis. However, evidence regarding the long-term outcomes of EGBS is sparse. We investigated the cholecystitis recurrence rate in high-risk surgical patients with acute calculous cholecystitis and compared the cholecystitis recurrence rates in patients in whom EGBS was performed with those in patients who were observed after percutaneous drainage. METHODS: We studied 64 consecutive high-risk surgical patients with acute calculous cholecystitis who required gallbladder decompression between 2007 and 2014. We divided the patient cohort into patients who underwent observation after percutaneous drainage between 2007 and 2011 (OAPD group) and those who underwent EGBS between 2012 and 2014 (EGBS group), and we compared the groups. RESULTS: The technical success rate of EGBS was 82.9% based on the intention-to-treat analysis. The cholecystitis recurrence rates were 17.2% in the OAPD group and 0% in the EGBS group, a difference that was significant (P = .043). There was also a significant difference between the groups with respect to the time to recurrent cholecystitis, which was determined by using Kaplan-Meier analysis (P = .015). The overall biliary event rates were 24.1% in the OAPD group and 9.1% in the EGBS group, and no significant difference was noted (P = .207). CONCLUSION: EGBS reduced the recurrence of cholecystitis in high-risk surgical patients with calculous cholecystitis. However, stent-related adverse events may occur, and modifications are necessary to reduce these.

Assessment of Factors Affecting the Usefulness and Diagnostic Yield of Core Biopsy Needles with a Side Hole in Endoscopic Ultrasound-Guided Fine-Needle Aspiration.

BACKGROUND/AIMS: A barbed puncture needle with a side hole was recently developed to improve sample quality and quantity in endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA). In this study, we retrospectively assessed the usefulness of this puncture needle. METHODS: Factors affecting diagnostic yield, safety, and diagnostic accuracy were investigated in 76 patients who consecutively underwent EUS-FNA for neoplastic lesions at our hospital between January and December 2013. RESULTS: The procedure was successful in all cases; the rates of sample collection and determination of the correct diagnosis were 92.1% and 89.5%, respectively. The mean number of needle passes required for diagnosis was 1.1. Complications included mild intraluminal bleeding in two patients (2.6%). Multivariate analysis revealed that lesion size (≤20 mm) was significantly associated with a decreased chance of determining the correct diagnosis. CONCLUSIONS: Core biopsy needles with a side hole are safe and provide a satisfactory diagnostic yield. However, the side hole may potentially reduce the rate of making the correct diagnosis in small lesions.

Localized IgG4-related Cholecystitis Mimicking Gallbladder Cancer.

We encountered a case of localized IgG4-cholecystitis mimicking gallbladder cancer with focal/segmental type1 autoimmune pancreatitis (AIP). In this case, we were unable to exclude a diagnosis of gallbladder cancer and thus performed radical cholecystectomy. Type1 AIP is often associated with gallbladder lesions, accompanied by generally diffuse, circumferential thickening of the gallbladder wall. Although localized IgG4-related cholecystitis is extremely rare, differentiating this condition from gallbladder cancer is often very difficult.

Solid pseudopapillary neoplasm of the pancreas associated with familial adenomatous polyposis.

A man in his thirties visited our hospital for an evaluation of a 12×10-mm pancreatic solid tumor that was accidentally detected on computed tomography performed for follow-up of familial adenomatous polyposis (FAP). We diagnosed the patient with a solid pseudopapillary neoplasm (SPN) based on endoscopic ultrasound-guided fine-needle aspiration, and he underwent pancreaticoduodenectomy. Small SPN tumors appear as solid tumors, without typical features of SPN, making the definitive diagnosis more difficult. The genetic background of FAP patients can predispose them to SPN, and imaging of the pancreas should be performed at prescribed intervals in FAP patients.

Chemotherapy treatment of a pregnant woman with progressive gastric cancer.

We herein describe a rare case of gastric cancer that was treated with chemotherapy during pregnancy. A woman in her thirty's at 23 weeks of gestation was admitted to the hospital with epigastralgia and left cervical lymph node swelling. She had been previously diagnosed with metastatic adenocarcinoma at another hospital. Findings from a CT scan and esophagogastroduodenoscopy revealed progressive gastric cancer, and the pathology indicated poorly differentiated adenocarcinoma. Chemotherapy was administered at 24 weeks of gestation, without the development of severe toxicity. At 32 weeks of gestation, a healthy baby girl (birth weight 1,442 g, Apgar score 7/8) was delivered by caesarean section. The child continued to show no abnormalities at 12 months after delivery.

Local administration of amphotericin B and percutaneous endoscopic necrosectomy for refractory fungal-infected walled-off necrosis: a case report and literature review.

Walled-off necrosis (WON) caused by fungal infection is very rare, and its treatment is more difficult than that of bacterial infection. We present the first case of a patient with refractory fungal-infected WON treated with percutaneous endoscopic necrosectomy and local administration of amphotericin B.A Japanese man in his 30s was hospitalized with severe necrotizing pancreatitis and multiple organ failure. Computed tomography imaging of the abdomen 1 month after the onset of pancreatitis revealed infected WON. Percutaneous drainage revealed purulent necrotic fluid, and culture of the fluid revealed the presence of Candida albicans and C glabrata. WON was treated by percutaneous endoscopic necrosectomy and local administration of amphotericin B. Consequently, the patient's condition improved, and Candida species were not detected in subsequent cultures.The combination of endoscopic necrosectomy with local administration of amphotericin B may be effective in treating refractory fungal-infected WON.

Difficult diagnoses of two cases of double cancer involving malignant lymphoma with peritoneal localization and malignant abdominal tumor.

We encountered two cases of malignant lymphoma with peritoneal localization complicated by sigmoid colon cancer and hepatocellular carcinoma. Multiple primary cancers were suspected on the basis of differences in absorption values on computed tomography (CT) and differences in the degree of accumulation on positron emission tomography CT; however, a definitive diagnosis based on these findings alone was difficult. Endoscopic ultrasound-guided fine-needle aspiration was useful for determining the diagnosis and treatment strategy. In cases of double cancers involving malignant lymphoma with peritoneal localization and malignant abdominal tumor, differentiation and staging are often difficult, which increases the risk of selecting the wrong treatment strategy. Therefore, care must be taken when diagnosing these diseases.

[Two cases of distal duodenal gastrointestinal stromal tumor diagnosed by endoscopic ultrasound-guided fine-needle aspiration biopsy].

Gastrointestinal stromal tumor (GIST) of the duodenum is rare. Obtaining tissue samples of GIST in the duodenum is difficult, especially when the tumor is located in the distal duodenum. Thus, preoperative pathological diagnosis often becomes difficult. We performed endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) biopsy for two cases with submucosal tumors in the third portion of the duodenum. Tissue samples were successfully obtained and diagnosed as GIST. Partial duodenectomy was performed in the two patients. Thus, we believe that EUS-FNA is a potentially useful diagnostic aid for submucosal tumors in the third portion of the duodenum, and it should be attempted before more invasive approaches.

[A case of intraductal papillary mucinous carcinoma found with acute obstructive suppurative pancreatic ductitis and liver abscess, and associated with a pancreatobiliary fistula].

We report a rare case of intraductal papillary mucinous carcinoma (IPMC) with acute obstructive suppurative pancreatic ductitis (AOSPD), liver abscess, and pancreatobiliary fistula formation. A man in his sixties was admitted to our hospital with a chief complain of high grade fever and anorexia. CT and MRI revealed a multilocular cystic lesion in the pancreatic head, fistula formation between the common bile duct and this cystic lesion, and multiple liver abscess. We performed endoscopic nasopancreatic drainage for the AOSPD, endoscopic biliary drainage for the biliary flow obstruction, and percutaneous transhepatic drainage for the liver abscess. Klebsiella pneumoniae was detected in the culture of pancreatic juice and liver abscess, but not in the bile and blood culture. These culture studies revealed that the liver abscess was caused by AOSPD. The patient underwent pancreaticoduodenectomy for the IPMC. The pathological diagnosis was IPMC.

[Gadolinium as an alternative radiocontrast agent in patients with allergy to iodine-based contrast provide for useful diagnostic imagings and safely treatment of biliary tract diseases].

Diagnosis and treatment of biliary tract disease requires an intraductal radiocontrast agent. Although iodine-based contrast medium is commonly used, some patients show severe allergy to iodinated contrast agent. We have retrospectively reviewed the usefulness and safety of gadolinium as an alternative radiocontrast agent in 3 patients with allergy to iodine-based contrast medium in the diagnosis and treatment of biliary tract diseases. In case 1, percutaneous transhepatic biliary drainage and cholangiography were performed successfully and it was possible to visualize an intrahepatic bile duct stone. Percutaneous transhepatic cholangioscopic lithotomy was performed and the intrahepatic bile duct stone was removed. In case 2, endoscopic biliary lithotripsy was performed. In case 3, percutaneous transhepatic cholangiography and cholangioscopy provided a diagnosis of moderately differentiated carcinoma. He underwent pancreatoduodenectomy. Postoperative cholangiograms were also obtained successfully. Gadolinium contrast agent is an alternative to iodine-based cholangiography for the patients with allergy to iodine.