Toshitaka Sakai

INSL5 may be a unique marker of colorectal endocrine cells and neuroendocrine tumors.

Insulin-like peptide 5 (INSL5) is a member of the insulin superfamily, and is a potent agonist for RXFP4. We have shown that INSL5 is expressed in enteroendocrine cells (EECs) along the colorectum with a gradient increase toward the rectum. RXFP4 is ubiquitously expressed along the digestive tract. INSL5-positive EECs have little immunoreactivity to chromogranin A (CgA) and might be a unique marker of colorectal EECs. CgA-positive EECs were distributed normally along the colorectum in INSL5 null mice, suggesting that INSL5 is not required for the development of CgA-positive EECs. Exogenous INSL5 did not affect the proliferation of human colon cancer cell lines, and chemically-induced colitis in INSL5 null mice did not show any significant changes in inflammation or mucosal healing compared to wild-type mice. In contrast, all of the rectal neuroendocrine tumors examined co-expressed INSL5 and RXFP4. INSL5 may be a unique marker of colorectal EECs, and INSL5-RXFP4 signaling might play a role in an autocrine/paracrine fashion in the colorectal epithelium and rectal neuroendocrine tumors.

The roles of interferon regulatory factors 1 and 2 in the progression of human pancreatic cancer.

Objective Pancreatic cancer is one of the most malignant diseases worldwide. Interferon regulatory factor (IRF) 1 and IRF2 function as a tumor suppressor and oncoprotein, respectively, in several types of cancers. We investigated whether IRF1 and IRF2 are involved in the progression of pancreatic cancer. Methods We examined the expressions of IRF1 and IRF2 in pancreatic cancer specimens and analyzed the association with clinicopathologic features. We evaluated the biological effects of IRF1 and IRF2 using a pancreatic cancer cell line. Results The expression levels of IRF1 and IRF2 were decreased and increased, respectively, in the pancreatic cancer cells compared with those observed in the paired normal areas. A higher expression of IRF1 was associated with better features of tumor differentiation, infiltration depth, tumor size, and survival, whereas that of IRF2 was associated with a worse feature of tumor infiltration depth. Interferon regulatory factor 2–overexpressing PANC-1 cells exhibited an increase in cell growth, less apoptotic features, and chemoresistance to gemcitabine treatment. In contrast, IRF1-overexpressing cells exhibited the opposite characteristics. Conclusions Interferon regulatory factors 1 and 2 may regulate the progression of pancreatic cancer by functioning as an antioncoprotein and oncoprotein, respectively. These molecules may serve as potential targets of therapy.

Functional Roles of TGF-β1 in Intestinal Epithelial Cells Through Smad-Dependent and Non-Smad Pathways

Background and AimsTransforming growth factor-β1 (TGF-β1) is one of the growth factors expressed in the gut, and has been shown to play an important role in intestinal mucosal healing. We investigated the effects of TGF-β1 on the cellular functions of intestinal epithelial cells, and also evaluated its signaling pathways in these cells.MethodsWe used the rat IEC-6 intestinal epithelial cell line for these studies. The expression of TGF-β1/Smad signaling molecules was examined. We evaluated the effect of TGF-β1 on the proliferation and differentiation by the BrdU incorporation assay and real-time PCR. We manipulated the expression levels of Smad2 and Smad3 using an adenovirus system and small interfering RNA to examine the signaling pathways. The expression of Smad2 and Smad3 along the crypt-villus axis was also examined in the murine intestine.ResultsIEC-6 cells produced TGF-β1 and expressed functional TGF-β/Smad signaling molecules. The addition of TGF-β1 in the culture medium suppressed the proliferation and increased the expression of a differentiation marker of enterocytes, in a dose-dependent manner. The adenovirus-mediated and small interfering RNA-mediated studies clearly showed that the growth inhibitory effect and the promotion of differentiation were exerted through a Smad3-dependent and a Smad2-dependent pathway, respectively. IEC-6 cells exhibited upregulated expression of an inhibitory Smad (Smad7) as a form of negative feedback via a non-Smad pathway. Smad2 was predominantly expressed in villi, and Smad3 in crypts.ConclusionsTGF-β1 regulates the cellular functions of intestinal epithelial cells through both Smad-dependent and non-Smad pathways.

Efficacy of combined balloon-occluded retrograde transvenous obliteration and simultaneous endoscopic injection sclerotherapy.

OBJECTIVE We evaluated the efficacy and safety of balloon-occluded retrograde transvenous obliteration (B-RTO) performed using absolute ethanol with iodized oil (ET+LPD) and simultaneous endoscopic injection sclerotherapy (EIS) with cyanoacrylate (CA) for gastric varices (GVs). METHODS A total of 16 patients with endoscopically proven high-risk GVs treated using combined B-RTO with ET+LPD and EIS with CA between January 2007 and July 2012 were enrolled. RESULTS Twelve cases included GVs involving both the cardia and fundus, two cases included fundal varices and two cases included cardiac varices. In terms of the form of GVs, 10 cases involved F2 lesions and six cases involved F3 lesions. The flow vein was the left gastric vein in 13 cases and the posterior gastric vein in three cases. The drainage route was a splenorenal shunt in all cases. The average dose of ET+LPD was 12.0 mL, while that of CA was 2.45 mL. All complications were transient, and no major complications occurred after the procedures. None of the patients experienced bleeding or recurrence of gastric varices after the combined B-RTO and EIS procedures during an average follow-up period of 38.3 months. CONCLUSION Combined B-RTO with ET+LPD and simultaneous EIS with CA is considered to be an effective and safe procedure for treating GVs.

Branch Duct Intraductal Papillary Mucinous Neoplasms of the Pancreas Involving Type 1 Localized Autoimmune Pancreatitis with Normal Serum IgG4 Levels Successfully Diagnosed by Endoscopic Ultrasound-guided Fine-needle Aspiration and Treated without Pancreatic Surgery

We herein report a 68-year-old man with branch duct intraductal papillary mucinous neoplasms of the pancreas (BD-IPMNs) involving type 1 localized autoimmune pancreatitis (AIP) with normal serum IgG4 levels. Although he was referred to our medical center due to suspicion of pancreatic cancer concomitant with BD-IPMNs, endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) revealed a mass suspected of being pancreatic cancer to be type 1 AIP. Steroid administration notably reduced the mass. Although the clinical diagnosis of pancreatic masses in patients with IPMN can be occasionally challenging, performing a pathological examination by EUS-FNA may prevent unnecessary pancreatic surgery in cases of possible AIP.

Signet-ring Cell Carcinoma Derived from a Main Duct-type Intraductal Papillary Mucinous Neoplasm of the Pancreas: A Case Report with Long-term Follow-up

We herein report the case of a 74-year-old man who underwent surgery 9 years after his initial visit and who was pathologically diagnosed with signet-ring cell carcinoma (SRCC) derived from a main-duct-type intraductal papillary mucinous neoplasm (MD-IPMN). At the first imaging examination, only a small pancreatic cyst with mild dilation of the main pancreatic duct (MPD) was detected in the pancreatic head. Eventually, MD-IPMN with mural nodules and MPD dilation (30 mm) developed in the pancreatic body, while the pancreatic head cyst remained unchanged. Total pancreatectomy was performed and the MD-IPMN was pathologically diagnosed as SRCC derived from an intestinal-type MD-IPMN.

Usefulness of cholangioscopic-guided mapping biopsy using SpyGlass DS for preoperative evaluation of extrahepatic cholangiocarcinoma: a pilot study

Background and study aims  Evaluation of longitudinal tumor extent is indispensable for curative surgical treatment of extrahepatic cholangiocarcinoma. The aim of this study was to evaluate the usefulness and feasibility of cholangioscopic-guided mapping biopsy using a newly developed peroral digital cholangioscope, SpyGlass DS (SpyDS), for preoperative evaluation of extrahepatic cholangiocarcinoma. Patients and methods  Thirteen patients (mean age, 75 years; male 10, female 3) with extrahepatic cholangiocarcinoma who underwent cholangioscopic-guided mapping biopsy using SpyDS for preoperative evaluation were included in this study. Successful cholangioscopic-guided mapping biopsy was defined as the acquisition of specimens sufficient for histopathological diagnosis. Results  The mean number of biopsies was 5 per patient. The overall success rate for cholangioscopic-guided mapping biopsy was 88 % (59/67). The success rate for cholangioscopic-guided mapping biopsy from the confluence of the right and left hepatic ducts was 89 %, that from the B4 confluence was 93 %, that from the confluence of the right anterior and right posterior segmental ducts was 86 %, that from the intrapancreatic common bile duct was 67 %, and that from the main lesion was 100 %. The overall diagnostic accuracy of longitudinal tumor extent at the hepatic side, the duodenal side and overall by cholangioscopic findings and mapping biopsy, was 88 % (7/8), 88 % (7/8) and 88 % (7/8), respectively. Assessment according to location of the main lesion revealed that diagnostic accuracy in the patients with distal bile duct carcinoma was 100 % (5/5) and that in patients with perihilar bile duct carcinoma was 66 % (2/3). Complications after the procedure did not occur in any patients. Conclusions  Cholangioscopic-guided mapping biopsy using SpyDS is thought to be feasible for preoperative evaluation of extrahepatic cholangiocarcinoma.

EUS-guided Biliary Drainage for Malignant Perihilar Biliary Strictures after Further Transpapillary Intervention has been Judged to be Impossible or Ineffective

Objective Patients with perihilar malignancy often develop recurrence of infectious cholangitis, which makes further transpapillary intervention extremely difficult. As endoscopic ultrasound (EUS)-guided biliary drainage (EUS-BD) of an intrahepatic bile duct is a possible option for additional intervention, the aim of this study was to estimate the feasibility of such intervention. Methods and Patients Patients who had undergone EUS-BD after further transpapillary intervention was deemed impossible or ineffective were investigated in this study. Those who had not received previous interventions via the papilla were excluded. Procedure-related adverse events, clinical efficacy, and time to recurrence of jaundice or infectious cholangitis transthyretin (TTR) were evaluated. Results Seven patients were eligible for the study between 2007 and 2016 (7 men; mean age, 77 years; 4 with perihilar cholangiocarcinoma and 3 with intrahepatic cholangiocarcinoma). No procedure-related adverse events were observed. EUS-BD was clinically effective and enabled hospital discharge in 4 patients (57%). The TTR in these 4 clinically effective patients was 43, 105, 118, and 147 days after the procedure (median, 112 days). Conclusion EUS-BD was found to be safe and often effective in patients in whom additional transpapillary intervention had become difficult, although its efficacy was limited to a short period.

Soft surface irregularity of malignant perihilar biliary strictures in cholangiography as a risk factor for early dysfunction of multiple metal stents

BACKGROUND Multiple metal stents (multi-MS) in the perihilar bile duct often develop dysfunction in an unexpectedly short period. AIMS This study is aimed to identify the risk factors for shorter patency of multi-MS. METHODS Of 97 patients who underwent multi-MS placement, 68 patients were followed-up for >28 days were retrospectively analyzed. Univariate analyses with the log-rank test was performed on 20 factors, including two newly defined classifications of cholangiography: the R classification, which classifies the rough image (localized type [R1] or spreading type [R2]); and the S classification, which classifies the surface texture (soft irregularity [S1], solid irregularity [S2], or smooth [S3]). RESULTS Stent dysfunction occurred in 36 patients (53%) (median time, 209 days). Type S1 was a significant risk factor for short stent patency (median, 100 days in S1 [n=18]; 231 in S2 [n=38]; 356 in S3 [n=12], p<0.0001). On multivariate analysis, type S1 was again the only independent factor among the six factors (HR 4.8, p<0.001). CONCLUSION Soft surface irregularity of the perihilar malignancy in cholangiography was found to be a significant risk factor for a shorter time to dysfunction of multi-MS.

Capability of Radial- and Convex-Arrayed Echoendoscopes for Visualization of the Pancreatobiliary Junction

Background/Aims Although both radial- and convex-arrayed endoscopic ultrasonography (EUS) scopes are widely used for observational EUS examinations, there have been few comparative studies on their power of visualization. The aim of this study was to evaluate the capability of these EUS scopes for observation of the pancreatobiliary junction. Methods The rate of successful visualization of the pancreatobiliary junction was retrospectively compared between a radial-arrayed and a convex-arrayed echoendoscope, from a prospectively maintained database. Study periods were defined as January 2010 to December 2012 for the radial group, and February 2015 to October 2016 for the convex group because the respective scope was mainly used during those periods. Results During the study period, 1,660 cases with radial EUS and 1,984 cases with convex EUS were recruited. The success rates of observation of the pancreatobiliary junction were 80.0% and 89.5%, respectively (p<0.0001). Conclusions The capability of visualization of the pancreatobiliary junction in observational EUS was found to be better with a convex-arrayed than with a radial-arrayed echoendoscope.