Manabu Osanai

Pancreatic ductal adenocarcinoma derived from IPMN and pancreatic ductal adenocarcinoma concomitant with IPMN.

Objectives: Pancreatic ductal adenocarcinoma (PDAC) may derive from an intraductal papillary mucinous neoplasm (IPMN) of the pancreas or may develop in the pancreatic duct apart from IPMN. The purpose of this study was to define the clinicopathological features of these 2 entities and compare them with those of ordinary PDAC. Methods: Of 765 patients who had surgical resection for IPMN, 122 were diagnosed as having PDAC derived from IPMN and 31 with PDAC concomitant with IPMN. In addition, 7605 patients with PDAC who were registered in the Japan Pancreas Society pancreatic cancer registry were compared with the above patients. Results: Pancreatic ductal adenocarcinomas derived from IPMN and concomitant with IPMN were significantly smaller, less invasive, and less extensive than ordinary PDAC. The median survival of patients with the 2 conditions was significantly longer than for those with ordinary PDAC when compared overall or when limited to TS2 (2.0 cm < tumor size ≤ 4.0 cm) or TS3 (4.0 cm < tumor size ≤ 6.0 cm) cases. Conclusions: These findings suggest that PDAC concomitant with IPMN and PDAC derived from IPMN may have more favorable biological behaviors or be diagnosed earlier than ordinary PDAC.

Serine/Threonine Kinase AKT Is Frequently Activated in Human Bile Duct Cancer and Is Associated with Increased Radioresistance

The prognosis for patients with bile duct cancer (BDC) remains poor. Although BDC cells are essentially radioresistant, recent reports have suggested that radiation therapy, in addition to its palliative role in the management of BDC, may improve patient survival. A better understanding of the mechanisms that lead to cellular radioresistance may assist in the development of more effective BDC therapies based on radiotherapy in combination with radiosensitizing agents. The serine/threonine kinase AKT/protein kinase B, a downstream effector of phosphatidylinositol 3′-kinase, is a well-characterized kinase that is known to play a critical role in antiapoptotic signaling pathways. In this investigation, we sought to clarify the role of AKT signaling in the radioresistance in BDC cells. First, to examine whether activated AKT is expressed in BDCs, tumor specimens were obtained from 19 consecutive BDC cases. Immunohistochemical staining using an anti-phosphorylated-AKT antibody showed that phosphorylated (activated) AKT was expressed in cancer cells but not in neighboring normal mucosa in 16 cases (84.2%). Next, to evaluate the role of AKT activation in the regulation of BDC cell radiosensitivity, clonogenic assays were performed using the phosphatidylinositol 3′-kinase inhibitor LY294002 with and without irradiation. LY294002 inhibited AKT activation in BDC cells and, on irradiation, decreased clonogenic survival in a radiation dose-dependent manner. Only a small decrease in cell viability was observed in cells exposed to LY294002. Expression of constitutively active AKT in BDC cells resulted in decreased radiosensitivity, whereas a dominant-negative AKT increased radiosensitivity. Furthermore, constitutively active AKT also inhibited radiation-induced apoptosis. Collectively, these results indicate that activated AKT in BDC cells is associated with radioresistance and suggest that pharmacological or genetic modulation of AKT activity may have important therapeutic implications in BDC patients treated with radiation.

Predictors of malignancy in intraductal papillary mucinous neoplasm of the pancreas: analysis of 310 pancreatic resection patients at multiple high-volume centers.

Objectives The present study was a retrospective investigation of predictors of malignancy in intraductal papillary mucinous neoplasm (IPMN) of the pancreas. Methods The subjects were 310 patients who underwent pancreatic resection at 3 high-volume centers. Preoperative laboratory and imaging findings were analyzed in logistic regression analyses. Endoscopic ultrasonography measurements were essential for the size of mural nodules, and a central review was conducted for pathological diagnosis. Results Pathological diagnosis was benign IPMN in 150 cases and malignant in 160 (noninvasive carcinoma, n = 100; invasive, n = 60). In multivariate analysis, size of mural nodules, diameter of main pancreatic duct, and cyst size of branch pancreatic duct were independent predictors of malignancy, and areas under the receiver operating characteristic curve for these 3 factors were 0.798, 0.643, and 0.601, respectively. With 7 mm taken as the cutoff value for the size of mural nodules, the diagnosis of malignant IPMN had sensitivity of 74.3% and specificity of 72.7%. Carcinoma without nodules was present in 15 patients (15/160 [9.4%]). Conclusions The size of mural nodules measured with endoscopic ultrasonography showed high predictive ability. However, about 10% of carcinoma patients did not have nodules, and the handling of the diagnosis in such cases is a problem for the future.

Diagnostic Peroral Video Cholangioscopy Is an Accurate Diagnostic Tool for Patients With Bile Duct Lesions

BACKGROUND & AIMS We evaluated the diagnostic ability of a newly developed peroral video cholangioscopy (PVCS) in patients with pancreaticobiliary disorders. METHODS We retrospectively evaluated data from 144 patients with pancreaticobiliary disorders, collected from 5 tertiary referral centers. Endoscopic sphincterotomy (EST) or endoscopic papillary balloon dilation (EPBD) was performed before PVCS. We performed 2 types of PVCS, using a conventional therapeutic duodenoscope. If tissue samples were needed, cholangioscopy-assisted biopsy or fluoroscopy-guided biopsy was performed. RESULTS PVCS was advanced into the bile duct in all cases after patients received EST (n = 134 cases), EPBD (n = 2), a combination of EST and EPBD (n = 1), or without treatment of the major papilla (n = 7). Biopsy samples were collected successfully from 112 of 120 cases in which endoscopists considered tissue sampling necessary. Endoscopic retrograde cholangiopancreatography (ERCP)/biopsy correctly identified 83 of 96 malignant lesions and 19 of 24 benign lesions (accuracy = 85.0%; sensitivity = 86.5%; specificity = 79.2%; positive predictive value = 94.3%; negative predictive value = 59.4%). Endoscopic retrograde cholangiopancreatography (ERCP)/biopsy plus PVCS correctly identified 95 of 96 malignant lesions and 23 of 24 benign lesions (accuracy = 98.3%; sensitivity = 99.0%; specificity = 95.8%; positive predictive value = 99.0%; negative predictive value = 95.8%). Procedure-related complications included pancreatitis (4 cases, 2.8%) and cholangitis (6 cases, 4.3%). CONCLUSIONS PVCS is an accurate diagnostic tool for patients with pancreaticobiliary disorders; resolution was well-defined when combined with biopsy analysis. Prospective multicenter clinical trials should evaluate the clinical utility of PVCS in diagnosis of biliary tract diseases.

Peroral video cholangioscopy to evaluate indeterminate bile duct lesions and preoperative mucosal cancerous extension: a prospective multicenter study.

BACKGROUND AND STUDY AIMS Despite the development of peroral video cholangioscopy (PVCS), no prospective multicenter studies have been undertaken to investigate the diagnostic accuracy of PVCS in biliary tract diseases. Therefore, the aim of this study was to clarify the accuracy of PVCS in evaluating biliary tract lesions. PATIENTS AND METHODS This study was a prospective multicenter study at five tertiary referral centers in Japan and included 87 eligible patients with biliary tract diseases who underwent PVCS. The study evaluated the ability of PVCS to diagnose indeterminate biliary tract diseases, detect mucosal cancerous extension preoperatively in extrahepatic bile duct cancers, and predict adverse events. RESULTS The use of PVCS appearance alone correctly distinguished benign from malignant indeterminate biliary lesions in 92.1 % of patients whereas biopsy alone was accurate in 85.7 %. In extrahepatic bile duct cancer, mucosal cancer extended histologically at least 20 mm in 34.7 % (17/49) of patients. The accuracy rate of PVCS to evaluate the presence or absence of mucosal cancerous extension by endoscopic retrograde cholangiography (ERC) alone, ERC with PVCS, and ERC with PVCS + biopsy were 73.5 %, 83.7 %, and 92.9 %, respectively. Adverse events were seen in 6.9 % of PVCS patients, but no serious complications were observed. CONCLUSION PVCS enhanced the accurate diagnosis of biliary tract lesions by providing excellent resolution in combination with biopsy.

Large balloon dilation for the treatment of recurrent bile duct stones in patients with previous endoscopic sphincterotomy: preliminary results

Abstract Objective. Endoscopic sphincterotomy (ES) is an established method to treat common bile duct (CBD) stones. Inevitable sequence after ES is a substantial risk of recurrent choledocholithiasis and occasional difficulty in removal of large or multiple CBD stones after ES even when mechanical lithotripsy (ML) is employed. In turn, a new endoscopic technique, large balloon dilation (LBD) after ES, has been introduced. The objective was to analyze the efficacy and safety of LBD in patients with recurrent bile duct stones who have previously undergone ES. Patients and methods. From December 2007 to November 2009, 24 patients with recurrent choledocholithiasis and a history of ES were treated with LBD without additional ES. The size of the balloon for LBD was 15–20 mm and the duration of balloon dilation was 30 s. Results. Successful stone removal and complications such as perforation, pancreatitis, and bleeding were evaluated as procedure-related outcomes. Postoperative CBD stone recurrence was evaluated as the short term outcome. Complete duct clearance rate without using ML was 96% (23/24 patients) and all stone removal was achieved in one session. Failure to remove stones occurred in one (4.2%) patient. There were no procedure-related complications although one case of aspiration pneumonia occurred after the endoscopy. Recurrent choledocholithiasis after LBD was observed in 12.5% (3/24) of the cases overall. Conclusions. LBD is an effective and safe method in patients with recurrent choledocholithiasis not only to treat large stones but also to prevent further recurrence.

Clinical Features and Natural History of Serous Cystic Neoplasm of the Pancreas

Aims: To clarify the clinical features and the natural history of serous cystic neoplasm (SCN) of the pancreas. Methods: We retrospectively analyzed data from 30 patients affected by SCN. SCNs were classified as (1) microcystic type, (2) micro- and macrocystic type, and (3) macrocystic type according to the modified WHO classification. Eighteen patients who underwent serial radiographic imaging were identified, and tumor growth rate in these patients was evaluated. Results: The median age was 62 years, and the female:male ratio was 2:1. Twenty-five patients (83%) were asymptomatic and 5 (17%) were symptomatic. The median tumor size was 2.6 cm. Fifteen cases (50%) had the microcystic type, 7 (23%) the micro- and macrocystic type, and 8 (27%) the macrocystic type. Age, gender, symptoms, location or tumor size did not differ significantly among the three subtypes. Eighteen patients were followed up for a median of 58 months. Morphological changes were observed in 3 patients (17%) and enlargement of tumor size in 9 patients (50%) during the follow-up. The growth rate was 0.29 cm per year and doubling time was 3.5 years; these rates did not differ among morphological subtypes or size of tumors. Conclusions: In asymptomatic patients with a clear imaging diagnosis of SCN, nonoperative management with a careful follow-up should be recommended. Surgery should be suggested in only symptomatic patients, those with giant tumors (>10 cm), rapid growing or when the presence of a potentially malignant tumor cannot be excluded.

Endoscopic treatment of difficult common bile duct stones.

Recent developments in treatment devices and advancements in technology have made endoscopic treatment the first choice for bile duct stones. In endoscopic treatment, the stones are removed after expanding the papilla with endoscopic sphincterotomy or endoscopic papillary balloon dilatation. The devices used to remove bile duct stones include basket catheters, balloon catheters and mechanical lithotripters, and their employment varies depending on the clinical situation. Stone removal by endoscopy is superior to other options, although treatment can be difficult in some cases. The reasons are mainly large stones, a history of gastric surgery, and Mirizzi syndrome. For such difficult cases, various adjuvant treatments such as extracorporeal shock wave lithotripsy, electrohydraulic lithotripsy and lasers are recommended rather than using just a mechanical lithotripter. Recently, large‐diameter biliary orifice balloon dilation, a method in which the papilla is expanded using a large‐diameter balloon, allowing the stones to be removed, has been reported and is attracting increasing attention.

Bench-top testing of suction forces generated through endoscopic ultrasound-guided aspiration needles

Adequate needle size and tissue acquisition techniques for endoscopic ultrasound‐guided fine needle aspiration (EUS‐FNA) need further elucidation. Moreover, the actual negative pressure and suction forces of FNA needles remain unknown. We evaluated the suction forces of 19‐gauge, 22‐gauge, and 25‐gauge conventional FNA needles and side hole aspiration needles using conventional negative pressure and the slow pull technique.

Diagnostic ability of EUS-FNA for pancreatic solid lesions with conventional 22-gauge needle using the slow pull technique: a prospective study

Abstract Objective. Endoscopic ultrasonography-guided fine needle aspiration (EUS-FNA) using the slow pull technique (SP-FNA) has recently attracted attention as an effective tissue acquisition technique. However, efficacy of SP-FNA with a 22-gauge conventional needle remains unclear. The aim of this study is to evaluate the diagnostic ability of SP-FNA with a 22-gauge needle. Material and methods. Patients with a pancreatic solid lesion were prospectively enrolled in this study. SP-FNA was performed at two needle passes with a 22-gauge needle. One dedicated pathologist evaluated the obtained samples in terms of quantity (Grade 0: scant; Grade 1: inadequate; Grade 2: adequate), quality (Grade 0: poor; Grade 1: moderate; Grade 2: good), and blood contamination (Grade 0: significant; Grade 1: moderate; Grade 2: low), and provided a pathological diagnosis. Additional EUS-FNA was performed by applying suction (SA-FNA). The evaluation points were as follows: diagnostic accuracy of SP-FNA compared with that of SA-FNA, and the quantity, quality, and blood contamination level of SP-FNA-obtained samples. Results. We enrolled 40 cases. The diagnostic accuracy of SP-FNA was 90% (36/40). There was no significant difference in the accuracy between SP-FNA and SA-FNA (90% vs. 90%, p = 1.000). The samples obtained using SP-FNA were assessed as Grade 2 for quantity in 29 cases (73%), quality in 31 (78%), and blood contamination in 25 (63%). Conclusions. Adequate, high-quality, and unsubstantially blood-contaminated samples could be obtained using SP-FNA. The diagnostic ability of SP-FNA was 90%, which appeared to be similar to that of SA-FNA.