Junichi Sakagami

Interferon-gamma is causatively involved in experimental inflammatory bowel disease in mice.

Cytokines may be crucially involved in the pathogenesis of inflammatory bowel diseases (IBD), but it remains controversial whether interferon (IFN)‐γ, a typical proinflammatory cytokine, is an essential mediator to cause the disorders. In the present study, IFN‐γ–/– and wild‐type (WT) C57BL/6 mice were fed 2·5% dextran sodium sulphate (DSS) in drinking water for 7 days, in order to investigate DSS‐induced intestinal inflammation. The DSS‐treated WT mice exhibited a robust production of IFN‐γ in the gut, a remarkable loss of body weight, as well as high rate of mortality (60%). In striking contrast, IFN‐γ deficient mice did not develop DSS‐induced colitis, as indicated by the maintenance of body weight and survival rate of 100%. Severe intestinal inflammation was demonstrated exclusively in WT animals in terms of the shortening of the bowel as well as the elevation of the disease activity index, myeloperoxidase (MPO) activity and serum haptoglobin level. Histological study of DSS‐treated WT intestine revealed disruption of mucosal epithelium and massive infiltration of inflammatory cells, while the organ from IFN‐γ–/– mice remained virtually normal in appearance. Enzyme‐linked immunosorbent assay (ELISA) analyses indicated abundant production of three chemokines, i.e. monokine induced by interferon‐γ (MIG), interferon‐inducible protein 10 (IP‐10) and monocyte chemoattractant protein‐1 (MCP‐1), in the DSS‐irritated intestine of WT but not of IFN‐γ–/– mice. The present results demonstrate clearly that IFN‐γ plays indispensable roles in the initiation of DSS colitis, and some chemokines are produced in an IFN‐γ‐dependent fashion.

Involvement of IL-17A in the pathogenesis of DSS-induced colitis in mice

To investigate the etiological implication of IL-17A in inflammatory bowel disease (IBD), dextran sodium sulfate (DSS) was administered to the mice deficient for the IL-17A gene. They showed only faint manifestations of colitis, as revealed by body weight loss, shrinkage in the colon length, serum haptoglobin concentration, and disease activity index. Although the mortality rate of WT mice reached approximately 60%, more than 90% of the IL-17A KO mice survived the DSS treatment. Histological change was also marginal in the IL-17A KO intestine, in which epithelial damage and inflammatory infiltrates were not obvious and the myeloperoxidase activity elevated only slightly. G-CSF and MCP-1 were abundantly produced in WT mouse intestine, whereas the production of these chemokines was drastically hampered in IL-17A-null intestine. The present results show that IL-17A plays a pivotal role in the pathogenesis of DSS-induced colitis, while MCP-1 and G-CSF may be crucially involved in the IL-17A-induced inflammation.

Prediction of pancreatic anastomotic failure after pancreatoduodenectomy: The use of preoperative, quantitative computed tomography to measure remnant pancreatic volume and body composition

Objective: To determine whether remnant pancreatic volume (RPV), subcutaneous/visceral adipose tissue(SAT/VAT) area, and skeletal muscle (SM) area calculated from preoperative computed tomography (CT) can predict the occurrence of pancreatic anastomotic failure (PAF) after pancreatoduodenectomy (PD). Background: Increased body mass index, small main pancreatic duct, and soft pancreatic texture are well-established predictors of PAF after PD. The impact on PAF of anthropomorphic measurements, such as RPV and body composition, is unknown. Methods: In 173 patients undergoing PD from 2004 to 2009, cross sections of SAT/VAT/SM area were quantitated volumetrically, respectively, from preoperative CT. RPV was calculated from the CT as the sum of pancreatic tissue area to the left of the presumed pancreatic transection site. The predictive ability for multiple models using combinations of body mass index, RPV, SAT/VAT area, SM area, main pancreatic duct size, and pancreatic gland texture was described using a concordance index (c-index). Results: Clinically relevant PAF occurred in 22 patients (13%). Multivariate logistic regression analysis identified RPV (P = 0.0012), VAT area (P = 0.0003), and SM area (P = 0.0006) as independent predictors of PAF. Using previously identified risk factors, the best 2-predictor model (body mass index and pancreatic duct size) resulted in a c-index of 0.748. Using anthropomorphic factors, however, the 2-predictor model using VAT and SM areas revealed a superior c-index of 0.959. Conclusions: Our 2-predictor model using VAT area and SM area based on volumetric quantification using preoperative CT may offer clinical benefit as an objective prognostic measure to predict clinically relevant PAF after PD.

Randomised controlled trial of long-term maintenance corticosteroid therapy in patients with autoimmune pancreatitis

Objective Corticosteroid has been established as the standard therapy for autoimmune pancreatitis (AIP), but the requirement for maintenance corticosteroid therapy is controversial. We conducted a randomised controlled trial to clarify the efficacy of maintenance corticosteroid therapy in patients with AIP. Design We conducted a multicentre, tertiary setting, randomised controlled trial. After the induction of remission with the initial oral prednisolone (PSL) treatment, maintenance therapy with PSL at 5–7.5 mg/day was continued for 3 years or withdrawn at 26 weeks. The primary endpoint was relapse-free survival over 3 years and the secondary endpoint was serious corticosteroid-related complications. All analyses were performed on an intention-to-treat basis. Results Between April 2009 and March 2012, 49 patients with AIP were randomly assigned to the maintenance therapy group (n=30) or the cessation group (n=19). Baseline characteristics were not different between the two groups. Relapses occurred within 3 years in 11 out of 19 (57.9%) patients assigned to the cessation group, and in 7 of 30 (23.3%) patients in the maintenance therapy group. The relapse rate over 3 years was significantly lower in the maintenance therapy group than that in the cessation group (p=0.011). The relapse-free survival was significantly longer in the maintenance therapy group than that in the cessation group (p=0.007). No serious corticosteroid-related complications requiring discontinuation of PSL were observed. Conclusions Maintenance corticosteroid therapy for 3 years may decrease relapses in patients with AIP compared with those who discontinued the therapy at 26 weeks. Trial registration number UMIN000001818; Results.

Phase II trial of combined regional hyperthermia and gemcitabine for locally advanced or metastatic pancreatic cancer.

Purpose: Despite advances in cancer therapy, treating pancreatic cancer remains one of the major challenges in the field of medical oncology. We conducted this phase II study to evaluate the efficacy and safety of regional hyperthermia combined with gemcitabine for the treatment of unresectable advanced pancreatic cancer. Methods: Eligibility criteria included histologically proven, locally advanced or metastatic pancreatic cancer. Gemcitabine was administered intravenously at a dose of 1000 mg/m2 on days 1, 8, and 15 every 4 weeks. Regional hyperthermia was performed once weekly, 1 day preceding or following gemcitabine administration. The primary end point was the 1-year survival rate. Secondary objectives were determination of tumour response and safety. Results: We enrolled 18 patients with advanced pancreatic cancer between November 2008 and May 2010. The major grade 3–4 adverse events were neutropenia and anaemia; however, there were no episodes of infection. The objective response rate (ORR) and disease control rate (ORR + stable disease) were 11.1% and 61.1%, respectively. Median overall survival (OS) was 8 months, and the 1-year survival rate was 33.3%. Median OS of patients with locally advanced pancreatic cancer was 17.7 months. Conclusions: Regional hyperthermia combined with gemcitabine is well tolerated and active in patients with locally advanced pancreatic cancer.

Evidence-based clinical practice guidelines for chronic pancreatitis 2015.

Chronic pancreatitis is considered to be an irreversible progressive chronic inflammatory disease. The etiology and pathology of chronic pancreatitis are complex; therefore, it is important to correctly understand the stage and pathology and provide appropriate treatment accordingly. The newly revised Clinical Practice Guidelines of Chronic Pancreatitis 2015 consist of four chapters, i.e., diagnosis, staging, treatment, and prognosis, and includes a total of 65 clinical questions. These guidelines have aimed at providing certain directions and clinically practical contents for the management of chronic pancreatitis, preferentially adopting clinically useful articles. These revised guidelines also refer to early chronic pancreatitis based on the Criteria for the Diagnosis of Chronic Pancreatitis 2009. They include such items as health insurance coverage of high-titer lipase preparations and extracorporeal shock wave lithotripsy, new antidiabetic drugs, and the definition of and treatment approach to pancreatic pseudocyst. The accuracy of these guidelines has been improved by examining and adopting new evidence obtained after the publication of the first edition.

The effect of steroid pulse therapy on the development of acute pancreatitis induced by closed duodenal loop in rats

Background:Background: The aim of the present study was to evaluate the effect of a high dose of methylprednisolone (MP) on the development of acute pancreatitis (AP) in rats induced by closed duodenal loop (CDL). Methods: Pancreas web weight, volume of ascites, hematocrit, serum amylase activity, concentrations of interleukin (IL)-1β and IL-6, organ blood flow in both the pancreas and the kidney, and histological findings of the pancreas were studied 6 h after the induction of AP. Results: The intravenous administration of MP (30 mg/kg body weight) significantly reduced the increase in pancreas web weight, volume of ascites, hematocrit, serum amylase activity, concentrations of IL-1β and IL-6, histological edema, and necrosis observed in CDL pancreatitis. The administration of MP also apparently improved both the pancreatic and the renal blood flow. Conclusions: The present results suggest that these cytokines influence at least the progression of AP, and that the mechanism by which MP pulse therapy inhibits the development of AP partly involves the inhibition by MP of the release of the cytokines.

Successful management of severe L-asparaginase–associated pancreatitis by continuous regional arterial infusion of protease inhibitor and antibiotic

L‐asparaginase is a key drug in the treatment of childhood acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL). However, L‐asparaginase can cause a fatal complication of pancreatitis, and an effective treatment for L‐asparaginase–associated pancreatitis (AAP) has not been developed to date. The authors investigated whether rapidly treating children with AAP by continuous regional arterial infusion (CRAI) of protease inhibitor and antibiotic would quickly resolve AAP.

Relationship of plasma CCK to acinar cell regeneration in acute pancreatitis as studied by proliferating cell nuclear antigen

In order to elucidate the relationship of cholecystokinin to acinar cell regeneration, the current study examined the changes in plasma cholecystokinin and immunostaining of proliferating cell nuclear antigen in the pancreas of rats with acute necrotizing pancreatitis. Proliferating cell nuclear antigen immunohistochemistry has been used to examine the proliferation of cells in several types of tissues. We compared the usefulness of proliferating cell nuclear antigen immunostaining and the incorporation of 5-bromodeoxyuridine to demonstrate acinar cell proliferation in the pancreas of rats with acute necrotizing pancreatitis. We also examined the relationship between these labeling indices and plasma cholecystokinin concentrations. The labeling index of paraformaldehyde-fixed specimens stained with proliferating cell nuclear antigen showed biphasic peaks at 12 hr and day 7. On the other hand, the methanol-fixed specimens stained with proliferating cell nuclear antigen and specimens stained with bromodeoxyuridine showed monophasic peaks in their labeling indices on day 5. There was a linear correlation (r=0.808,P<0.001) between the labeling index of bromodeoxyuridine and that of methanol-fixed proliferating cell nuclear antigen during the entire experimental period. During the regenerating phase, plasma cholecystokinin bioactivity showed positive correlations with the labeling index of bromodeoxyuridine and that of methanol-fixed proliferating cell nuclear antigen,r=0.555 and 0.566, respectively (P<0.001). Immunostaining of methanol-fixed proliferating cell nuclear antigen may be a useful tool for analyzing proliferating acinar cells. Acinar cell proliferation correlates with the bioactivity of plasma cholecystokinin during the regenerating phase of acute pancreatitis.

Pathophysiologic studies of experimental chronic pancreatitis in rats induced by injection of zein-oleic acid-linoleic acid solution into the pancreatic duct

An experimental model of chronic pancreatitis was induced by a retrograde injection of a viscous solution consisting of zein-oleic acid-linoleic acid (0.05 ml/100 g body weight) into the rat pancreatic duct. Histologic and biochemical changes were investigated over a period of 6 months after induction of this model. The treated rats gained weight, but pancreatic weight decreased with time. Histologically, the widening of acinar lumen and cellular vacuolization occurred within 24 h at the parenchyma neighboring the small ducts filled with the injected solution. Degenerative parenchyma, interstitial edema, and inflammatory cell infiltration were pronounced 1 week later. Thereafter, duct-like tubular complex formation progressed, and the exocrine tissue exhibited marked atrophy of the gland with irregular fibrosis and fat replacement over a period of 6 months. Pancreatic contents of protein, amylase, DNA, and RNA markedly decreased, as did pancreatic weight, whereas hydroxyproline content increased. Oral administration of camostat did not affect pancreatic weight and contents of enzyme in this model. Urinary para-aminobenzoic acid (PABA) excretion in the BT-PABA test decreased to 54% at 6 weeks and 22% at 6 months. Although three quarters of pancreatic immunoreactive insulin (IRI) content was lost after 6 months, overt diabetes did not occur. The results suggest that an obstructive mechanism in the small ducts plays an important role in the genesis and development of chronic pancreatitis.