Ken Kawabe

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.

Preliminary results of a Japanese nationwide survey of neuroendocrine gastrointestinal tumors

BackgroundWe conducted a nationwide survey to estimate the incidence of neuroendocrine gastrointestinal tumors (NETs) newly diagnosed in Japan from 2002 through 2004.MethodsData on 1541 patients, 514 pancreatic endocrine tumors (PETs) and 1027 gastrointestinal carcinoids (GICs), were collected and analyzed.ResultsNonfunctioning tumors (NF-PET) constituted 47.7% of PETs. Next in frequency were insulinoma (31.7%) and gastrinoma (8.6%). Malignancy was frequent in NF-PETs (46.1%) and gastrinomas (45.5%), but only 7.4% of insulinomas were malignant. The incidence of multiple endocrine neoplasia type-1 associated with PETs was 7.4%. The incidence of GICs was 28.8%, 5.2%, and 66.0% in foregut, midgut, and hindgut, respectively. Carcinoid syndrome and metastases were observed in only 1.7% and 5.6% of GICs, respectively.ConclusionsThe incidence of NETs in Japan was clarified by this preliminary study. Comparatively large differences in GICs between Japan and Western nations were present with regard to the location, symptomatic status, and prevalence of malignancy.

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.

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.

Sexually dimorphic expression of Dax-1 in the adrenal cortex

Background: The DAX‐1 (also known as AHC) gene encodes an unusual member of the nuclear receptor superfamily, and the gene product plays a pivotal role during gonadal and adrenal differentiation. Mutations of the human DAX‐1 gene cause X‐linked adrenal hypoplasia congenita associated with hypogonadotropic hypogonadism. However, the molecular mechanisms underlying the transcriptional regulation of the gene are not well understood.

Blocking of monocyte chemoattractant protein-1 (MCP-1) activity attenuates the severity of acute pancreatitis in rats

Background. Monocyte chemoattractant protein-1 (MCP-1) has been shown to affect the progression of various inflammatory disorders, including pancreatitis. To investigate the role of MCP-1 in acute pancreatitis and to seek possible therapeutic means, we evaluated the effect of a plasmid expression vector containing a dominant-negative mutant MCP-1 gene (mMCP-1). Methods. Two rat models of acute pancreatitis were employed that used either cerulein (for mild pancreatitis) or a mixture of 5% taurocholic acid and trypsin (for severe pancreatitis). At 6 h after induction of acute pancreatitis with or without injection of mMCP-1, serum amylase levels and cytokine levels, as well as morphological evaluation of the pancreas, were determined. Survival rates were also evaluated. Results. Severe pancreatitis was significantly reduced by mMCP-1 injection. mMCP-1 decreased serum levels of amylase, IL-6, IL-10, and LDH, and improved the survival rate 48 h after disease onset. Histopathological changes of pancreas and lungs were also improved by mMCP-1. Conclusions. MCP-1 appears to be involved in the progression of severe forms of acute pancreatitis. Our data suggested that MCP-1 is a candidate as a therapeutic target to treat acute pancreatitis.

Diagnostic and therapeutic single-operator cholangiopancreatoscopy in biliopancreatic diseases: Prospective multicenter study in Japan

AIM To assess the utility and safety of single-operator cholangiopancreatoscopy (SOCPS) using the SpyGlass system in widespread clinical application for biliary and pancreatic diseases. METHODS This study was a prospective case series conducted in 20 referral centers in Japan. There were 148 patients who underwent SOCPS; 124 for biliary diseases and 24 for pancreatic diseases. The attempted interventions were SOCPS examination, SOCPS-directed tissue sampling, and therapy for stone removal, among others. The main outcomes were related to the procedure success rate in terms of visualizing the target lesions, SOCPS-directed adequate tissue sampling, and complete stone removal. RESULTS A total of 148 patients were enrolled for the diagnosis of indeterminate biliary and pancreatic lesions or treatment of biliary and pancreatic disease. The overall procedure success rate of visualizing the target lesions was 91.2% (135/148). The overall procedural success rates of visualizing the target lesions of diagnostic SOCPS in the bile duct and pancreatic duct were 95.5% (84/89) and 88.2% (15/17), respectively. DIAGNOSIS the overall adequate tissue for histologic examination was secured in 81.4% of the 86 patients who underwent biopsy under SOCPS (bile duct, 60/75, 80.0%; pancreatic duct, 10/11, 90.9%). The accuracy of histologic diagnosis using SOCPS-directed biopsies in indeterminate bile duct lesions was 70.7% (53/75). In the pancreatic duct, the accuracy of SOCPS visual impression of intraductal papillary mucinous neoplasm was 87.5% (14/16). Stone therapy: complete biliary and pancreatic stone clearance combined with SOCPS-directed stone therapy using electrohydraulic lithotripsy or laser lithotripsy was achieved in 74.2% (23/31) and 42.9% (3/7) of the patients, respectively. Others: SOCPS using the SpyGlass system was used in cannulation of the cystic duct in two patients and for passing across the obstructed self-expandable metallic stent for a malignant biliary stricture in two patients. All procedures were successful in both SOCPS-guided therapies. The incidence of procedure-related adverse events was 5.4% (8/148). CONCLUSION SOCPS with direct visualization and biopsy for diagnosis and SOCPS-directed therapy for biliary and pancreatic diseases can be safely performed with a high success rate. The clinical trial was registered at UMIN CTR (http://www.umin.ac.jp). The registration identification number is UMIN000015155.

Epidemiological study of pancreatic diabetes in Japan in 2005: a nationwide study.

Objectives: There have been few epidemiological studies on pancreatic diabetes. In this study, we determined the incidence and pathology of pancreatic diabetes in Japan. Methods: We examined the epidemiology of pancreatic diabetes in Japan in 2005 by using a nationwide stratified random-sampling method. Especially, we focused on newly developed diabetes in association with the occurrence of pancreatic disease (true pancreatic diabetes). Results: A total of 19,500 individuals received treatment for true pancreatic diabetes, accounting for 0.8% of patients with diabetes. Prevalence was estimated to be 15.2 per 100,000 with an annual onset incidence of 1.1 per 100,000. With regard to the complications in true pancreatic diabetes, the incidence of retinopathy was lower than that in types 1 and 2 diabetes. Among true pancreatic diabetes with chronic pancreatitis, alcoholic pancreatitis was found in the largest sector. Furthermore, as many as 53.7% were continuous drinkers, and 66.7% received insulin therapy. The frequency of hypoglycemia was high in regular drinkers treated with insulin. Hypoglycemia was a major cause of death in patients who were on insulin and continuous drinkers. Conclusion: We clarified the epidemiology of pancreatic diabetes in Japan. Patients with chronic pancreatitis-associated pancreatic diabetes should receive lifestyle guidance focused on drinking cessation.

Efficacy of endoscopic ultrasonography and endoscopic ultrasonography-guided fine-needle aspiration for the diagnosis and grading of pancreatic neuroendocrine tumors

Abstract Background and aim: Pancreatic neuroendocrine tumors (pNETs) are histologically categorized according to the WHO 2010 classification by their mitotic index or Ki-67 index as G1, G2, or G3. The present study examined the efficacy of endoscopic ultrasonography (EUS) and EUS-guided fine-needle aspiration (EUS-FNA) in the diagnosis and grading of pNET. Methods: We retrospectively reviewed 61 pNETs in 51 patients who underwent EUS between January 2007 and June 2014. All lesions were pathologically diagnosed by surgical resection or EUS-FNA. We evaluated the detection rates of EUS for pNET and sensitivity of EUS-FNA, and compared the Ki-67 index between EUS-FNA samples and surgical specimens. EUS findings were compared between G1 and G2/G3 tumors. Results: EUS showed significantly higher sensitivity (96.7%) for identifying pNET than CT (85.2%), MRI (70.2%), and ultrasonography (75.5%). The sensitivity of EUS-FNA for the diagnosis of pNET was 89.2%. The concordance rate of WHO classification between EUS-FNA and surgical specimens was 69.2% (9/13). The concordance rate was relatively high (87.5%, 5/6) in tumors <20 mm but lower (57.1%; 4/7) in tumors ≥20 mm. Regarding EUS findings, G2/G3 tumors were more likely to be large (>20 mm), heterogeneous, and have main pancreatic duct (MPD) obstruction than G1 tumors. Multivariate analysis showed large diameter and MPD obstruction were significantly associated with G2/G3 tumors. Conclusions: EUS and EUS-FNA are highly sensitive and accurate diagnostic methods for pNET. Characteristic EUS findings such as large tumor size and MPD obstruction are suggestive of G2/G3 tumors and would be helpful for grading pNETs.