Junya Gibo

Treatment for autoimmune pancreatitis: consensus on the treatment for patients with autoimmune pancreatitis in Japan.

Autoimmune pancreatitis (AIP) has been characterized by unique clinical imaging, immunological findings, and the effectiveness of steroid therapy. A set of clinicopathological criteria for AIP was proposed by the Japan Pancreatic Society in 2002, and AIP has come to be widely recognized among general digestive clinicians. However, the indication of steroid therapy for AIP is still not well established, and furthermore the therapeutic doses and method of administration of steroid therapy is also unclear. Recently, an epidemiological survey of all the treatments used for AIP in Japan was conducted by the Research Committee of Intractable Pancreatic Diseases, and their report “Consensus for a Treatment of Autoimmune Pancreatitis” was produced. In a comparison of the results of steroid therapy and nonsteroid therapy for AIP in relation to the rate of complete remission, the recurrence rate, and the period needed to guarantee complete remission, it was thought that the administration of a steroid should be a standard therapy for AIP. However, if the diagnosis of AIP is still uncertain, steroid therapy should be given with caution. In addition, even when AIP still appears to be possible after a course of steroid therapy, a re-evaluation should be carried out taking pancreatic carcinoma into consideration. An initial steroid dose of 30–40 mg per day is recommended. With continuous and careful observations of the clinical manifestations, laboratory data, and imaging findings after administration of the initial dose of steroid for 2–4 weeks, the quantity of steroid can be reduced gradually to a maintenance dose in 2–3 months, and then reduced to 2.5–5 mg per day after remission. The recommended period of maintenance treatment is still unclear, but the administration of the steroid could be stopped after a period of about 6–12 months of treatment, although the patient should be monitored for clinical manifestations of improvement. In addition, the patients progress should be followed taking recurrence into consideration. In order to evaluate the effectiveness of steroid therapy, follow-up observations should include biochemical examinations of blood findings such as serum γ-globulin, IgG, and IgG 4, imaging findings, and clinical manifestations such as jaundice and abdominal discomfort.

Anti-monocyte chemoattractant protein 1 gene therapy attenuates experimental chronic pancreatitis induced by dibutyltin dichloride in rats

Background: Monocyte chemoattractant protein 1 (MCP-1) is a member of the C-C chemokine family and exerts strong chemoattractant activity in monocytes, macrophages, and lymphocytes. Rat pancreatic fibrosis induced by dibutyltin dichloride (DBTC) is considered to be an appropriate chronic pancreatitis model histologically and enzymatically, as has demonstrated in a previous study. Aim: We examined the effect of human dominant negative inhibitor of MCP-1 (mutant MCP-1) on progression of chronic pancreatitis induced by DBTC in a rat model. Methods: We used the experimental model of chronic pancreatitis induced by DBTC in rats. Mutant MCP-1 or empty plasmid at a dose of 50 µg/body weight was administrated into rat thigh muscles on days 4, 11, and 18 after administration of DBTC. On days 14 and 28, we evaluated the effect of mutant MCP-1 morphologically and biochemically. Results: The mutant MCP-1 treated group inhibited early pancreatic inflammation and later pancreatic fibrosis histologically, and showed a decrease in serum MCP-1 concentration, intrapancreatic hydroxyproline, α-smooth muscle actin, and an increase in intrapancreatic amylase and protein content compared with the empty plasmid treated group. The mutant MCP-1 group also inhibited intrapancreatic mRNA expression of cytokines and chemokines. Conclusions: : Our findings suggest that monocyte/macrophage recruitment and the systemic MCP-1 signal pathway contribute to progression of chronic pancreatitis, and that blockade of MCP-1 may suppress the development of pancreatic fibrosis.

Camostat mesilate attenuates pancreatic fibrosis via inhibition of monocytes and pancreatic stellate cells activity

Camostat mesilate (CM), an oral protease inhibitor, has been used clinically for the treatment of chronic pancreatitis in Japan. However, the mechanism by which it operates has not been fully understood. Our aim was to evaluate the therapeutic efficacy of CM in the experimental pancreatic fibrosis model induced by dibutyltin dichloride (DBTC), and we also determined the effect of CM on isolated monocytes and panceatic stellate cells (PSCs). In vivo, chronic pancreatitis was induced in male Lewis rats by single administration of 7 mg/kg DBTC and a special diet containing 1 mg/g CM was fed to the DBTC+CM-treated group from day 7, while the DBTC-treated group rats were fed a standard diet. At days 0, 7, 14 and 28, the severity of pancreatitis and fibrosis was examined histologically and enzymologically in both groups. In vitro, monocytes were isolated from the spleen of a Lewis rat, and activated with lipopolysaccharide stimulation. Thereafter, the effect of CM on monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-α (TNF-α) production from monocytes was examined. Subsequently, cultured rat PSCs were exposed to CM and tested to see whether their proliferation, MCP-1 production and procollagen α1 messenger RNA expression was influenced by CM. In vivo, the oral administration of CM inhibited inflammation, cytokines expression and fibrosis in the pancreas. The in vitro study revealed that CM inhibited both MCP-1 and TNF-α production from monocytes, and proliferation and MCP-1 production from PSCs. However, procollagen α1 expression in PSCs was not influenced by CM. These results suggest that CM attenuated DBTC-induced rat pancreatic fibrosis via inhibition of monocytes and PSCs activity.

The role of monocyte chemoattractant protein-1 in experimental chronic pancreatitis model induced by dibutyltin dichloride in rats.

Introduction Recently, dibutyltin dichloride (DBTC) was reported to induce pancreatic fibrosis within 28 days in rats, but it is not clear that the induced condition should be considered chronic pancreatitis. Aim and Methodology The aim of this study was to clarify whether the pancreatic fibrosis induced by DBTC can be regarded as chronic pancreatitis. Furthermore, we examined the relation of monocyte chemoattractant protein–1 (MCP-1) to the development of pancreatic fibrosis in this model. DBTC solution was injected into the right jugular vein in rats, and biochemical and histologic changes were measured at days 1, 3, 7, 14, and 28. Results Microscopically, inflammatory cell infiltration was evident in the pancreas at days 1 and 3, mononuclear cell infiltration was observed at days 7, 14, and 28, and pancreatic fibrosis was pronounced 7 days later. At day 28, interstitial fibrosis and atrophy of the gland and ductlike tubular complex had progressed. DBTC produced a significant decrease in the contents of pancreatic protein and amylase, whereas the pancreatic hydroxyproline content increased. Serum and pancreatic MCP-1 concentration significantly increased compared with the control group. Furthermore, the expression of PDGF mRNA in the pancreas increased following the MCP-1 elevation. Conclusions These results suggest that this experimental model of pancreatic fibrosis induced by DBTC in rats was useful as a chronic pancreatitis model and that MCP-1 may play an important role in the development of pancreatic fibrosis.

Improved techniques for double-balloon-enteroscopy-assisted endoscopic retrograde cholangiopancreatography

AIM To investigate the clinical outcome of double balloon enteroscopy (DBE)-assisted endoscopic retrograde cholangiopancreatography (DB-ERCP) in patients with altered gastrointestinal anatomy. METHODS Between September 2006 and April 2011, 47 procedures of DB-ERCP were performed in 28 patients with a Roux-en-Y total gastrectomy (n = 11), Billroth II gastrectomy (n = 15), or Roux-en-Y anastomosis with hepaticojejunostomy (n = 2). DB-ERCP was performed using a short-type DBE combined with several technical innovations such as using an endoscope attachment, marking by submucosal tattooing, selectively applying contrast medium, and CO₂ insufflations. RESULTS The papilla of Vater or hepaticojejunostomy site was reached in its entirety with a 96% success rate (45/47 procedures). There were no significant differences in the success rate of reaching the blind end with a DBE among Roux-en-Y total gastrectomy (96%), Billroth II reconstruction (94%), or pancreatoduodenectomy (100%), respectively (P = 0.91). The total successful rate of cannulation and contrast enhancement of the target bile duct in patients whom the blind end was reached with a DBE was 40/45 procedures (89%). Again, there were no significant differences in the success rate of cannulation and contrast enhancement of the target bile duct with a DBE among Roux-en-Y total gastrectomy (88 %), Billroth II reconstruction (89%), or pancreatoduodenectomy (100%), respectively (P = 0.67). Treatment was achieved in all 40 procedures (100%) in patients whom the contrast enhancement of the bile duct was successful. Common endoscopic treatments were endoscopic biliary drainage (24 procedures) and extraction of stones (14 procedures). Biliary drainage was done by placement of plastic stents. Stones extraction was done by lithotomy with the mechanical lithotripter followed by extraction with a basket or by the balloon pull-through method. Endoscopic sphincterotomy was performed in 14 procedures with a needle precutting knife using a guidewire. The mean total duration of the procedure was 93.6 ± 6.8 min and the mean time required to reach the papilla was 30.5 ± 3.7 min. The mean time required to reach the papilla tended to be shorter in Billroth II reconstruction (20.9 ± 5.8 min) than that in Roux-en-Y total gastrectomy (37.1 ± 4.9 min) but there was no significant difference (P = 0.09). A major complication occurred in one patient (3.5%); perforation of the long limb in a patient with Billroth II anastomosis. CONCLUSION Short-type DBE combined with several technical innovations enabled us to perform ERCP in most patients with altered gastrointestinal anatomy.

Solid pancreatic hamartoma

A case of solid pancreatic hamartoma in a 58‐year‐old Japanese woman is presented. She had no symptoms, and a pancreatic mass was incidentally found on screening ultrasonography 4 months before admission. The patient was not alcoholic and had no history of pancreatitis. Physical examination and laboratory data were unremarkable. Preoperative imaging demonstrated a nodule in the body of the pancreas, measuring 2.0 cm in maximum diameter, which showed marked delayed enhancement during dynamic CT. The patient underwent a distal pancreatectomy under the preoperative diagnosis of pancreatic endocrine tumor and had an uneventful postoperative course. A well‐demarcated solid nodule, 1.9 cm in diameter, was evident in the body of the pancreas. Microscopically, the lesion was composed of non‐neoplastic, disarranged acinar cells and ducts embedded in a sclerotic stroma with elongated spindle cells, lacking discrete islets. The stromal spindle cells were immunoreactive for CD34 and CD117. The histological diagnosis was solid hamartoma of the pancreas. There was no recurrence 5 months after surgery. Herein is reported a case of solid hamartoma of the pancreas and review of the literature. A search through the literature found only two cases of solid hamartoma of the pancreas, among the 14 cases previously reported as pancreatic hamartoma.

IS-741 attenuates local migration of monocytes and subsequent pancreatic fibrosis in experimental chronic pancreatitis induced by dibutyltin dichloride in rats

Objectives: Chronic pancreatitis consists of excessive leukocyte infiltration and fibrosis. IS-741 has been reported to be an antiinflammatory drug through an inhibitory action on cell adhesion. In this study, we investigated whether IS-741 could inhibit the progression of pancreatic fibrosis through monocyte infiltration. Moreover, we investigated the effect of IS-741 on rat pancreatic stellate cells (PSCs). Methods: Chronic pancreatitis was induced by dibutyltin dichloride in rats. From days 7 to 28 after dibutyltin dichloride application, IS-741 or distilled water was administered. At days 14 and 28, histological [hematoxylin-eosin stain and immunostain for ED1 and &agr; smooth muscle actin (&agr;-SMA)] and biochemical evaluations (intrapancreatic amylase, protein, cytokines, chemokines, and &agr;-SMA) were performed. In vitro, rat PSCs were incubated with cytokine, chemokine, and growth factor simultaneously with IS-741, and their proliferation and activation were examined. Results: Histologically, IS-741 inhibited pancreatic fibrosis and decreased the number of ED1- and &agr;-SMA-positive cells. The intrapancreatic expression of cytokines, chemokine, and &agr;-SMA were also decreased. In vitro, IS-741 has no direct effect on the proliferation, &agr;-SMA expression, and collagen synthesis of PSCs. Conclusions: These results suggest that IS-741 suppressed macrophage infiltration and subsequent pancreatic fibrosis and that the infiltration of monocytes into pancreas is essential for pancreatic fibrosis.Abbreviations: IS-741 - N-(2-sulfonylamino-5-trifluoromethyl-3-pyridyl) carboxamide derivative, MCP-1 - monocyte chemoattractant protein 1

Endoscopic submucosal dissection using the "Clutch Cutter" for early esophageal squamous cell carcinoma.

BACKGROUND AND STUDY AIMS To reduce the risk of complications related to the use of knives in endoscopic submucosal dissection (ESD), we developed the Clutch Cutter which can grasp and incise targeted tissue using electrosurgical current, similarly to a biopsy technique. The study aim was to evaluate the efficacy and safety of ESD using the Clutch Cutter for early esophageal squamous cell carcinoma. PATIENTS AND METHODS ESD using the Clutch Cutter was performed on 32 consecutive patients with early esophageal squamous cell carcinoma. Therapeutic efficacy and safety were assessed. RESULTS All lesions were treated easily and safely without unintended incision. En bloc resection was obtained in all patients. Histologically negative margins were obtained in 26/32 patients (81%). Endoscopic perforation due to the hood in one patient (3%), mediastinitis without endoscopic perforation in one patient (3%), and post-ESD stricture in 5 patients (16%) were observed. All were successfully managed conservatively. CONCLUSIONS ESD using the Clutch Cutter appears to be a safe, easy, and technically efficient method for resecting early esophageal squamous cell carcinomas.

Endoscopic Submucosal Dissection for Early Gastric Cancer using the Clutch Cutter: a large single-center experience

Background and study aims: The Clutch Cutter (CC) was developed to reduce the risk of complications related to endoscopic submucosal dissection (ESD) using knives. The CC is able to grasp and coagulate and/or incise the targeted tissue using electrosurgical current, like a biopsy technique. The aim of this study was to evaluate the efficacy and safety of ESD using the CC (ESD-CC) for early gastric cancer (EGC). Patients and methods: From June 2007 to March 2014, 325 consecutive patients with a diagnosis of EGC were enrolled in this prospective study. They had all satisfied the Japanese gastric cancer treatment guidelines for ESD indication, namely confirmation by preliminary endoscopy, endoscopic ultrasound, and endoscopic biopsies. The CC was used for all steps of ESD (marking, circumferential marginal incision, submucosal dissection, and hemostatic treatment). The therapeutic efficacy and safety were assessed. Results: The en-bloc resection rate was 99.7 % (324/325) and the R0 resection rate was 95.3 % (310/325). The mean operating time was 97.2 minutes. Perforation during ESD-CC occurred in one case (0.3 %), which was managed with conservative medical treatment after endoscopic closure of the perforation. Post-ESD-CC bleeding occurred in 11 cases (3.4 %), which were successfully treated by endoscopic hemostatic treatment. The R0 resection rate was significantly low in tumors > 20 mm (88.9 %), and in the exclusion indication group (73.7 %). Significant differences were seen in the mean operating time, depending upon tumor size, histologic type, location, and indication criteria. Conclusions: ESD-CC is a technically efficient, safe, and easy method for resecting EGC.

Immediate detection of endoscopic retrograde cholangiopancreatography-related periampullary perforation: Fluoroscopy or endoscopy?

AIM To investigate the causes and intraoperative detection of endoscopic retrograde cholangiopancreatography (ERCP)-related perforations to support immediate or early diagnosis. METHODS Consecutive patients who underwent ERCP procedures at our hospital between January 2008 and June 2013 were retrospectively enrolled in the study (n = 2674). All procedures had been carried out using digital fluoroscopic assistance with the patient under conscious sedation. For patients showing alterations in the gastrointestinal anatomy, a short-type double balloon enteroscope had been applied. Cases of perforation had been identified by the presence of air in or leakage of contrast medium into the retroperitoneal space, or upon endoscopic detection of an abdominal cavity related to the perforated lumen. For patients with ERCP-related perforations, the data on medical history, endoscopic findings, radiologic findings, diagnostic methods, management, and clinical outcomes were used for descriptive analysis. RESULTS Of the 2674 ERCP procedures performed during the 71-mo study period, only six (0.22%) resulted in perforations (male/female, 2/4; median age: 84 years; age range: 57-97 years). The cases included an endoscope-related duodenal perforation, two periampullary perforations related to endoscopic sphincterotomy, two periampullary perforations related to endoscopic papillary balloon dilation, and a periampullary or bile duct perforation secondary to endoscopic instrument trauma. No cases of guidewire-related perforation occurred. The video endoscope system employed in all procedures was only able to immediately detect the endoscope-related perforation; the other five perforation cases were all detected by subsequent digital fluoroscope applied intraoperatively (at a median post-ERCP intervention time of 15 min). Three out of the six total perforation cases, including the single case of endoscope-related duodenal injury, were surgically treated; the remaining three cases were treated with conservative management, including trans-arterial embolization to control the bleeding in one of the cases. All patients recovered without further incident. CONCLUSION ERCP-related perforations may be difficult to diagnose by video endoscope and digital fluoroscope detection of retroperitoneal free air or contrast medium leakage can facilitate diagnosis.