Terumasa Hisano

Evaluation of pancreatic endocrine and exocrine function in patients with autoimmune pancreatitis.

Objectives: Up to now, the characteristics of pancreatic endocrine and exocrine functions in autoimmune pancreatitis (AIP) are still unclear. The aim of this study is to evaluate pancreatic functions in AIP compared with those of chronic pancreatitis (CP). Methods: Twelve patients with AIP and 25 patients with CP were examined for exocrine and endocrine pancreas. Exocrine function was evaluated by a secretin test. Concerning endocrine function, insulin secretion (C-peptide response) was examined with the glucagon tolerance test and glucagon secretion was examined with the arginine tolerance test. Pathological examination of pancreatic tissues was done on the operative specimens of AIP and CP that could not be clinically excluded from pancreatic cancer. Results: For the secretin test, 8.3% of patients with AIP showed 1-factor abnormality, which was a reduction in volume, and 41.7% showed 2-factor abnormalities, which were a reduction in volume and amylase output. On the other hand, 44.0% of patients with CP showed only 1-factor abnormality, which was the reduction in the maximum bicarbonate concentration. Autoimmune pancreatitis accompanied with diabetes mellitus showed a reduction both in &Dgr;C-peptide response (&bgr;-cell response) and &Dgr;glucagon (&agr;-cell response). Histologically, AIP showed lymphoplasmatic cells infiltration surrounding the pancreatic ducts, but basement membranes were intact. Moreover, basement membranes of the duct were injured in CP. Furthermore, islet cells in AIP were revealed as almost intact even though they were surrounded by fibrosis. Conclusions: These findings indicate that exocrine dysfunction with AIP is different from CP because AIP induces stenosis of the pancreatic ducts, but ductal cells that possess the function of bicarbonate secretion are intact, and that endocrine dysfunction with AIP was secondary pancreatic diabetes.

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.

Increased expression of T‐plastin gene in cisplatin‐resistant human cancer cells: identification by mRNA differential display

The cellular resistance to the potent anticancer agent cis‐diamminedichloroplatinum(II) (cisplatin) is thought to be mediated by multiple mechanisms. The technique of differential display of mRNAs was applied to various cisplatin‐resistant cell lines and the corresponding parental sensitive human bladder, prostatic, and head and neck cancer cells in order to identify genes that underlie cisplatin resistance. Twenty‐four clones were confirmed by Northern blot analysis to be expressed differentially between resistant and the corresponding sensitive cells. Partial DNA sequences of the eight clones that showed a threefold or greater increase in expression in either the resistant cells (seven clones) or sensitive cells (one clone) revealed that two were derived from the T‐plastin gene and one from the tissue factor gene. The abundance of T‐plastin mRNA in cisplatin‐resistant T24/DDP10 cell was ∼12 times that in the parental T24 cells. Transfection of T24/DDP10 cells with a vector encoding full‐length T‐plastin antisense RNA demonstrated that reduced T‐plastin expression was associated with increased sensitivity to cisplatin. These results are consistent with the hypothesis that several mechanisms participate cooperatively in the acquisition of cisplatin resistance in human cancer.

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.

Overexpression of Multidrug Resistance Protein Gene in Human Cancer Cell Lines Selected for Drug Resistance to Epipodophyllotoxins

Overexpression of either the multidrug resistance 1 (MDR1) gene or multidrug resistance protein (MRP) gene is involved in acquisition of multidrug‐resistant phenotypes in human cancer cells. In this study we examined whether selection for resistance to the epipodophyllotoxins, etoposide/teniposide (VP16/VM26), could induce overexpression of MDR1 or MRP. We have previously isolated two VP16/VM26‐resistant KB cell lines. Two VP16/VM26‐resistant KB cell lines, KB/VM‐1 and KB/VM‐4, which were selected by stepwise exposure to VM26 had decreased accumulation of [3H]VP16 and increased levels of MRP, but no apparent expression of MDR1 gene was observed. Another VP16/VM26‐resistant KB cell line, KB/VP‐4, which was further isolated from a VP16‐resistant KB cell line, KB/VP‐2, had decreased accumulation of [3H]VP16 and showed overexpression of MRP gene, but not that of MDR1 gene. We also isolated a VP16‐resistant cell line, IN157/VP‐1, from a human glioma cell line IN157. IN157/VP‐1 cells showed decreased accumulation of [3H]VP16 and overexpression of MRP gene, but not of MDR1. These findings suggest that selection for resistance to VP16/VM26, preferentially induces overexpression of MRP gene.

Predictive factors for colonic diverticular rebleeding: a retrospective analysis of the clinical and colonoscopic features of 111 patients.

Background/Aims Colonic diverticular bleeding can stop spontaneously or be stopped by endoscopic hemostasis. We analyzed the clinical and colonoscopic features of patients with colonic diverticular bleeding to establish the predictive factors for rebleeding. Methods A total of 111 patients (median age, 72 years) with colonic diverticular bleeding in Aso Iizuka Hospital between April 2007 and July 2010 were enrolled. Age, sex, body mass index (BMI), comorbidity, medication, location of bleeding, colonoscopic findings and hemostatic methods were analyzed retrospectively from the hospital records. Results The most common sites of bleeding were the ascending (39.6%) and sigmoid (29.7%) colon. Overt rebleeding occurred in 30 patients (27.0%). Spontaneous hemostasis was seen in 81 patients (73.0%), and endoscopic hemostatic treatment was performed in 30 patients. The BMI in the patients with colonic diverticular rebleeding was significantly higher than in patients without rebleeding. Colonoscopic findings of actively bleeding or nonbleeding visible vessels in the responsible diverticula were more frequent in the group with rebleeding. Conclusions A higher BMI and colonoscopic findings of actively bleeding or nonbleeding visible vessels can be used as predictive factors for colonic diverticular rebleeding. Patients with such findings should be carefully followed up after hemostasis of the initial colonic diverticular bleeding.

Intramural Hematoma of the Cecum as the Lead Point of Intussusception in an Elderly Patient with Hemophilia A: Report of a Case

Hemophilia A is a congenital bleeding disorder characterized by a deficiency of coagulation factor VIII. Intramural hematoma of the colon is a very rare complication of this disease. We report a case of intramural hematoma of the cecum serving as the lead point of intussusception in a 65-year-old man with hemophilia A. The patient presented with right-sided abdominal pain and bloody stool. Palpation of his abdomen revealed a fist-sized mass. Abdominal computed tomography (CT) showed a circular mass with concentric rings, consistent with an intussuscepted intestine. Because his activated partial thromboplastin time (APTT) was prolonged, we gave him a continuous infusion of factor VIII during and after surgery. Laparotomy revealed an irreducible colo-colic intussusception and we identified a cecal hematoma as the lead point. After an unsuccessful attempt at Hutchinsons maneuver, we performed right colectomy. We report this case to illustrate the necessity of monitoring APTT in patients with hemophilia A who undergo surgery.

Endoscopic submucosal dissection for esophageal granular cell tumor using the clutch cutter

Endoscopic submucosal dissection (ESD) with a knife is a technically demanding procedure associated with a high complication rate. The shortcomings of this method are the deficiencies of fixing the knife to the target lesion, and of compressing it. These shortcomings can lead to major complications such as perforation and bleeding. To reduce the risk of complications related to ESD, we developed a new grasping type scissors forceps (Clutch Cutter®, Fujifilm, Japan) which can grasp and incise the targeted tissue using an electrosurgical current. Esophagogastroduodenoscopy on a 59-year-old Japanese man revealed a 16mm esophageal submucosal nodule with central depression. Endoscopic ultrasonography demonstrated a hypoechoic solid tumor limited to the submucosa without lymph node involvement. The histologic diagnosis of the specimen obtained by biopsy was granular cell tumor. It was safely and accurately resected without unexpected incision by ESD using the CC. No delayed hemorrhage or perforation occurred. Histological examination confirmed that the granular cell tumor was completely excised with negative resection margin.We report herein a case of esophageal granular cell tumor successfully treated by an ESD technique using the CC.

Paclitaxel-Based Chemotherapy for Advanced Pancreatic Cancer after Gemcitabine-Based Therapy Failure: A Case Series of 5 Patients

Background/Objectives: Gemcitabine (GEM) is a gold-standard chemotherapy agent for advanced pancreatic cancer. Because of the malignant character of the disease, nearly all patients show disease progression despite treatment with GEM-based chemotherapy; therefore, second-line chemotherapy may be beneficial for these patients. We report a retrospective analysis of 5 patients with advanced pancreatic cancer, treated with a paclitaxel-containing regimen as second-, third- or fourth-line chemotherapy after various therapies, such as a GEM-based regimen, S-1 regimen, and chemoradiation. We retrospectively analyzed the efficacy and adverse events, and evaluated the paclitaxel-containing regimens. A review of the literature is also discussed. Results: The median overall survival from the start of salvage therapy was 10.7 months. The disease control rate of the paclitaxel-containing regimen according to RECIST criteria was 60%, including complete response in 0 patients, partial response in 3, and stable disease in 2. Two patients had malignant ascites at the start of this salvage therapy, and in both of them the ascites and clinical complaints improved. Grade 3 and 4 hematological adverse events were observed in 2 patients and 1 patient, respectively. Conclusion: Salvage paclitaxel-based therapy could be beneficial to advanced pancreatic cancer patients who maintain good performance status after several chemotherapy failures.