Cronkhite-Canada Syndrome Complicated by Triple Primary Cancers.

We herein report a case of Cronkhite-Canada syndrome (CCS) complicated with triple primary cancers. The patient was diagnosed with CCS at 65 years of age. At 76 years of age, one of his colon polyps was diagnosed as adenocarcinoma. At 81 years of age, gastric carcinoma was detected. Weight loss and fatigue appeared one month before he visited our hospital. An examination revealed dilatation of the intrahepatic bile duct. Cholangiocarcinoma was diagnosed as a result of bile duct cytology. Patients with CCS should be monitored carefully for carcinoma of systemic organs as well as the gastrointestinal tract.

Pancreatic stellate cells and CX3CR1: occurrence in normal pancreas and acute and chronic pancreatitis and effect of their activation by a CX3CR1 agonist.

OBJECTIVES: Numerous studies suggest important roles of the chemokine, fractalkine (CX3CL1), in acute/chronic pancreatitis; however, the possible mechanisms of the effects are unclear. Pancreatic stellate cells (PSCs) can play important roles in pancreatitis, secreting inflammatory cytokines/chemokines, as well as proliferation. Therefore, we investigated CX3CL1 receptor (CX3CR1) occurrence in normal pancreas and pancreatitis (acute/chronic) tissues and the effects of CX3CL1 on activated PSCs. METHODS: CX3CR1 expression/localization in normal pancreas and pancreatitis (acute/chronic) tissues was evaluated with immunohistochemical analysis. CX3CR1 expression and effects of CX3CL1 on activated PSCs were examined with real-time polymerase chain reaction, BrdU (5-bromo-2-deoxyuridine) assays, and Western blotting. RESULTS: In normal pancreas, acinar cells expressed CX3CR1 within granule-like formations in the cytoplasm, whereas in acute/chronic pancreatitis, acinar, ductal, and activated PSCs expressed CX3CR1 on cell membranes. With activation of normal PSCs, CX3CR1 is increased. CX3CL1 activated multiple signaling cascades in PSCs. CX3CL1 did not induce inflammatory genes expression in activated PSCs, but induced proliferation. CONCLUSIONS: CX3CR1s are expressed in normal pancreas. Expression is increased in acute/chronic pancreatitis, and the CX3CR1s are activated. CX3CL1 induces proliferation of activated PSCs without increasing release of inflammatory mediators. These results suggest that CX3CR1 activation of PSCs could be important in their effects in pancreatitis, especially to PSC proliferation in pancreatitis where CX3CL1 levels are elevated.

PSCs and GLP-1R: occurrence in normal pancreas, acute/chronic pancreatitis and effect of their activation by a GLP-1R agonist.

There is increasing concern about the development of pancreatitis in patients with diabetes mellitus who received long-term glucagon-like peptide-1 (GLP-1) analog treatment. Its pathogenesis is unknown. The effects of GLP-1 agonists on pancreatic endocrine cells are well studied; however, there is little information on effects on other pancreatic tissues that might be involved in inflammatory processes. Pancreatic stellate cells (PSCs) can have an important role in pancreatitis, secreting various inflammatory cytokines/chemokines, as well as collagen. In this study, we investigated GLP-1R occurrence in normal pancreas, acute pancreatitis (AP)/chronic pancreatitis (CP), and the effects of GLP-1 analog on normal PSCs, their ability to stimulate inflammatory mediator secretion or proliferation. GLP-1 receptor (GLP-1R) expression/localization in normal pancreas and pancreatitis (AP/CP) tissues were evaluated with histological/immunohistochemical analysis. PSCs were isolated from male Wistar rats. GLP-1R expression and effects of GLP-1 analog on activated PSCs was examined with real-time PCR, MTS assays and western blotting. In normal pancreas, pancreatic ß cells expressed GLP-1R, with only low expression in acinar cells, whereas in AP or CP, acinar cells, ductal cells and activated PSCs expressed GLP-1R. With activation of normal PSCs, GLP-1R is markedly increased, as is multiple other incretin-related receptors. The GLP-1 analog, liraglutide, did not induce inflammatory genes expression in activated PSCs, but induced proliferation. Liraglutide activated multiple signaling cascades in PSCs, and the extracellular signal-regulated kinase pathway mediated the PSCs proliferation. GLP-1Rs are expressed in normal pancreas and there is marked enhanced expression in AP/CP. GLP-1-agonist induced cell proliferation of activated PSCs without increasing release of inflammatory mediators. These results suggest chronic treatment with GLP-1R agonists could lead to proliferation/chronic activation of PSCs, which may lead to important effects in the pancreas.

Endoscopic approach through the minor papilla for the management of pancreatic diseases.

AIM: To clarify the efficacy and safety of an endoscopic approach through the minor papilla for the management of pancreatic diseases. METHODS: This study included 44 endoscopic retrograde cholangiopancreatography (ERCP) procedures performed in 34 patients using a minor papilla approach between April 2007 and March 2012. We retrospectively evaluated the clinical profiles of the patients, the endoscopic interventions, short-term outcomes, and complications. RESULTS: Of 44 ERCPs, 26 were diagnostic ERCP, and 18 were therapeutic ERCP. The most common cause of difficult access to the main pancreatic duct through the major papilla was pancreas divisum followed by distortion of Wirsung's duct. The overall success rate of minor papilla cannulation was 80% (35/44), which was significantly improved by wire-guided cannulation (P = 0.04). Endoscopic minor papillotomy (EMP) was performed in 17 of 34 patients (50%) using a needle-knife (13/17) or a pull-type papillotome (4/17). EMP with pancreatic stent placement, which was the main therapeutic option for patients with chronic pancreatitis, recurrent acute pancreatitis, and pancreatic pseudocyst, resulted in short-term clinical improvement in 83% of patients. Mild post-ERCP pancreatitis occurred as an early complication in 2 cases (4.5%). CONCLUSION: The endoscopic minor papilla approach is technically feasible, safe, and effective when the procedure is performed in a high-volume referral center by experienced endoscopists.

Retroperitoneal fibrosis associated with immunoglobulin G4-related disease.

Retroperitoneal fibrosis is a rare disease characterized by the development of inflammation and fibrosis in the soft tissues of the retroperitoneum and other abdominal organs. Retroperitoneal fibrosis can be of 2 types: idiopathic and secondary. The recently advocated concept and diagnostic criteria of immunoglobulin G4 (IgG4)-related disease, derived from research on autoimmune pancreatitis (AIP), has led to widespread recognition of retroperitoneal fibrosis as a condition caused by IgG4-related disease. We now know that previously diagnosed idiopathic retroperitoneal fibrosis includes IgG4-related disease; however, the actual prevalence is unclear. Conversely, some reports on AIP suggest that retroperitoneal fibrosis is concurrently found in about 10% of IgG4-related disease. Because retroperitoneal fibrosis has no specific symptoms, diagnosis is primarily based on diagnostic imaging (computed tomography and magnetic resonance imaging), which is also useful in evaluating the effect of therapy. Idiopathic retroperitoneal fibrosis can occur at different times with other lesions of IgG4-related disease including AIP. Thus, the IgG4 assay is recommended to diagnose idiopathic retroperitoneal fibrosis. High serum IgG4 levels should be treated and monitored as a symptom of IgG4-related disease. The first line of treatment for retroperitoneal fibrosis is steroid therapy regardless of its cause. For patients with concurrent AIP, i.e., IgG4-related retroperitoneal fibrosis, the starting dose of steroid is usually 30-40 mg/d. The response to steroid therapy is generally favorable. In most cases, the pancreatic lesion and retroperitoneal fibrosis improve after the initial treatment. However, the epidemiology, treatment for recurring retroperitoneal fibrosis, and long-term prognosis are still largely unknown. Further analysis of such cases and research are necessary.

ERK pathway and sheddases play an essential role in ethanol-induced CX3CL1 release in pancreatic stellate cells.

The clinical course of chronic pancreatitis (CP) worsens with drinking, and pancreatic stellate cells (PSCs) have an important role in the pathogenesis of alcoholic CP. Chemokines recruit inflammatory cells, resulting in chronic pancreatic inflammation. Although serum levels of fractalkine (CX3CL1) are significantly elevated in patients with alcoholic CP, the mechanism of this elevation remains unclear. This study aims to determine the effects of cytokines, pathogen-associated molecular patterns (PAMPs), and ethanol and its metabolites on CX3CL1 secretion by PSCs. Male Wistar/Bonn Kobori (WBN/Kob) rats aged 15 to 20 weeks were used as rodent models of CP in vivo. PSCs were isolated from 6-week-old male Wistar rats. The effects of cytokines, PAMPs, and ethanol and its metabolites on chemokine production and activation of signaling pathways in PSCs in vitro were examined by real-time reverse transcription-polymerase chain reaction (RT-PCR), western blotting, and enzyme-linked immunosorbent assay. Expression of CX3CL1 and matrix metalloprotease (MMP)-2 was increased in the pancreas of WBN/Kob rats. The rat PSCs expressed CX3CL1, MMP-2, and a disintegrin and metalloprotease domain (ADAM) 17. Cytokines and PAMPs induced CX3CL1 release and activated extracellular signal-regulated kinase (ERK), MMP-9, and ADAM17. CX3CL1 release was suppressed by specific inhibitors of ERK, MMP, and ADAM, and ERK was associated with CX3CL1 transcription. Ethanol and phorbol myristate acetate synergistically increased CX3CL1 release. Real-time PCR and western blotting confirmed the synergistic activation of ERK and ADAM17. Ethanol synergistically increased CX3CL1 release via ERK and ADAM17 activation in PSCs. In conclusion, we demonstrated for the first time that ethanol synergistically increased CX3CL1 release from PSCs at least in part through activation of ERK mitogen-activated protein kinase and ADAM17. This might be one of the mechanisms of serum CX3CL1 elevation and disease progression in patients with alcoholic CP.

Cytosolic double-stranded DNA as a damage-associated molecular pattern induces the inflammatory response in rat pancreatic stellate cells: a plausible mechanism for tissue injury-associated pancreatitis.

Pancreatitis is an inflammatory disease of unknown causes. There are many triggers causing pancreatitis, such as alcohol, common bile duct stone, virus and congenital or acquired stenosis of main pancreatic duct, which often involve tissue injuries. Pancreatitis often occurs in sterile condition, where the dead/dying pancreatic parenchymal cells and the necrotic tissues derived from self-digested-pancreas were observed. However, the causal relationship between tissue injury and pancreatitis and how tissue injury could induce the inflammation of the pancreas were not elucidated fully until now. This study demonstrates that cytosolic double-stranded DNA increases the expression of several inflammatory genes (cytokines, chemokines, type I interferon, and major histocompatibility complex) in rat pancreatic stellate cells. Furthermore, these increase accompanied the multiple signal molecules genes, such as interferon regulatory factors, nuclear factor-kappa B, low-molecular-weight protein 2, and transporter associated with antigen processing 1. We suggest that this phenomenon is a plausible mechanism that might explain how cell damage of the pancreas or tissue injury triggers acute, chronic, and autoimmune pancreatitis; it is potentially relevant to host immune responses induced during alcohol consumption or other causes.

Relationship between pancreatic and/or extrapancreatic lesions and serum IgG and IgG4 levels in IgG4-related diseases.

OBJECTIVE: We aimed to investigate the relationship between the number of involved organs or regions and serum immunoglobulin G (IgG) and immunoglobulin G4 (IgG4) levels. METHODS: The number of pancreatic and/or extrapancreatic lesions and serum IgG and IgG4 levels were examined by groups in 46 patients with IgG4-related diseases at diagnosis prior to the initiation of steroid treatment: group A (one region involved, n=7), group B (two regions involved, n=11), group C (three regions involved, n=12), group D (four regions involved, n=9) and group E (five to seven regions involved, n=7). RESULTS: Both serum IgG and IgG4 levels increased with the number of inflamed regions. Mean serum IgG levels were 15.11, 18.65, 20.92, 23.29 and 30.98 g/L while the mean IgG4 levels were 3.99, 4.70, 4.70, 9.86 and 16.49 g/L in group A, B, C, D and E, respectively. Regression analysis also suggested that IgG4 was positively correlated with the number of regions involved. Additionally, serum IgG4 was higher in patients with multiple lesions when accompanied by sclerosing sialadenitis. CONCLUSION: Patients having IgG4-related disease with high serum IgG and IgG4 levels should be systematically examined for involved lesions.

Vasoactive intestinal peptide reduces oxidative stress in pancreatic acinar cells through the inhibition of NADPH oxidase.

Vasoactive intestinal peptide (VIP) attenuates experimental acute pancreatitis (AP) by inhibition of cytokine production from inflammatory cells. It has been suggested that reactive oxygen species (ROS) as well as cytokines play pivotal roles in the early pathophysiology of AP. This study aimed to clarify the effect of VIP on the oxidative condition in pancreas, especially pancreatic acinar cells (acini). Hydrogen peroxide (H(2)O(2))-induced intracellular ROS, assessed with CM-H(2)DCFDA, increased time- and dose-dependently in acini isolated from rats. Cell viability due to ROS-induced cellular damage, evaluated by MTS assay, was decreased with ≥100 µmol/L H(2)O(2). VIP significantly inhibited ROS production from acini and increased cell viability in a dose-dependent manner. Expression of antioxidants including catalase, glutathione reductase, superoxide dismutase (SOD) 1 and glutathione peroxidase was not altered by VIP except for SOD2. Furthermore, Nox1 and Nox2, major components of NADPH oxidase, were expressed in pancreatic acini, and significantly increased after H(2)O(2) treatment. Also, NADPH oxidase activity was provoked by H(2)O(2). VIP decreased NADPH oxidase activity, which was abolished by PKA inhibitor H89. These results suggested that VIP affected the mechanism of ROS production including NADPH oxidase through induction of a cAMP/PKA pathway. In conclusion, VIP reduces oxidative stress in acini through the inhibition of NADPH oxidase. These results combined with findings of our previous study suggest that VIP exerts its protective effect in pancreatic damage, not only through an inhibition of cytokine production, but also through a reduction of the injury caused by oxidative stress.

Bacterial DNA promotes proliferation of rat pancreatic stellate cells thorough toll-like receptor 9: potential mechanisms for bacterially induced fibrosis.

OBJECTIVES: We hoped to clarify the possible role of CpG DNA as a trigger factor for overt pancreatic inflammation of pancreatic stellate cells (PSCs). METHODS: Pancreatic stellate cells were isolated from the male Lewis rat. The expression of Toll-like receptor 9 (TLR9) messenger RNA and protein were evaluated by reverse transcription-polymerase chain reaction and immunofluorescent cytochemistry. Internalization of CpG DNA was analyzed by confocal laser scanning microscopy. Pancreatic stellate cells were incubated with CpG DNA, and then cell proliferation and migration were assessed. RESULTS: Constitutive expression of TLR9 occurs at the messenger RNA and protein levels. After several minutes of CpG DNA administration, CpG DNA was observed on the cell membrane surface and in the cytoplasm and found to be translocating into the perinucleus of PSCs. Pancreatic stellate cells migrated and proliferated in dose- and time-dependent manners in response to simulation by CpG DNA. Proliferation of PSCs was observed 3 hours after administration (earlier than platelet-derived growth factor-induced proliferation), suggesting that PSCs respond readily to provide innate immunity. Endosomal acidification inhibitors attenuated CpG DNA-induced signaling, leading to suppression of DNA synthesis by PSCs. CONCLUSIONS: Our findings demonstrate that bacterial DNA promotes migration and proliferation of PSCs and suggest that bacterial DNA can initiate and sustain pancreatic inflammation and fibrosis by means of TLR9.

Characteristics of pancreatic diabetes in patients with autoimmune pancreatitis.

OBJECTIVE: Although patients with autoimmune pancreatitis (AIP) tend to have concurrent diverse disorders, very few studies have focused on diabetes mellitus (DM) coexisting with AIP. METHODS: In total 102 AIP patients with DM were divided into three groups. Those with DM before the onset of AIP were labeled group A (n=35), those who developed DM and AIP simultaneously were labeled group B (n=58) and those who developed DM after steroid therapy for AIP were labeled group C (n=9). The characteristics of DM among the three groups were evaluated. RESULTS: No significant differences were noted in the age of DM onset among the three groups. However, the mean duration of DM was significantly longer in group A (8.7 years) than in groups B and C. AIP developed 6.8 years after DM onset in group A, whereas it developed 1.8 years after steroid therapy in group C. Group A had the highest rate (25.7%) of family members with a history of AIP. Levels of serum albumin, total cholesterol and triglyceride were significantly lower in group A. No correlations were found between glycated hemoglobin and benzoyl-tyrosyl para-aminobenzoic acid. Hypoglycemia was observed in 20% of patients under insulin therapy. Most of them were habitual drinkers and received no pancreatic enzymes. Group A showed a high prevalence of retinopathy, nephropathy and macrovascular disorders than group B. CONCLUSION: Aspects of AIP-associated pancreatic diabetes were clarified. AIP-associated DM must be controlled by a full assessment of the pancreatic endocrine and exocrine function.

A case of lipomatous pseudohypertrophy of the pancreas diagnosed by typical imaging.

CONTEXT: Lipomatous pseudohypertrophy of the pancreas is an extremely rare disease, and is characterized by the replacement of pancreatic acinar cells with adipose tissue, although the pancreatic duct and islets are preserved. CASE REPORT: We report the case of a 64-year-old female who was undergoing treatment for Hashimoto's disease at a nearby clinic. For the previous two years, she had experienced an unpleasant feeling in the upper abdominal area after eating oily foods. For the previous six months, she had also suffered from lower-back pain, and presented at our hospital. Abdominal computed tomography and magnetic resonance imaging revealed marked fat replacement over the entire pancreas. Endoscopic retrograde cholangiopancreatography revealed no anatomical abnormality or narrowing of the main pancreatic duct; the main pancreatic duct was normal up to the pancreatic tail and the branches of the pancreatic duct did not show any abnormalities. While the serum levels of the pancreatic enzymes were considerably low, according to the data of the pancreatic exocrine function test (N-benzoyl-tyrosyl-p-aminobenzoic acid test), endocrine function was maintained. On the basis of the abovementioned findings, we diagnosed lipomatous pseudohypertrophy of the pancreas. CONCLUSIONS: Lipomatous pseudohypertrophy of the pancreas is a very rare disease characterized by the disappearance of pancreatic exocrine tissue due to adipose tissue replacement, although the pancreatic duct and islets remain intact. Even though it has been suggested that the diagnosis of lipomatous pseudohypertrophy of the pancreas should be based on histological findings, this case indicated the possibility that lipomatous pseudohypertrophy of the pancreas may be diagnosed solely by typical imaging findings and serological data.

Orally active factor Xa inhibitors: investigation of a novel series of 3-amidinophenylsulfonamide derivatives using an amidoxime prodrug strategy.

A series of novel and potent 3-amidinophenylsulfonamide derivatives of factor Xa inhibitors were designed and synthesized using an amidoxime prodrug strategy. We focused on systemic clearance of parent compounds in rats, and performed in vivo pharmacokinetic screening. Incorporation of a carboxymethoxy group markedly improved systemic clearance (compound 43), and the related amidoxime 44 showed sufficient prodrug conversion. Compound 45, the double prodrug of 43, exhibited practicable bioavailability after oral administration in rats. Among the various compounds under investigation, KFA-1982 was selected for clinical development.

Characteristics of the hemostatic action of KFA-1411, an inhibitor of coagulation factor Xa (FXa), in humans and various animals.

This study examined a low-molecular-weight factor-Xa inhibitor, KFA-1411 (3-[N-(3-amidinophenyl)-N-[N-[4-[1-(1-iminoethyl)piperidin-4- yl]phenyl]carbamoylmethyl]aminomethyl]phenoxyacetic acid monosulfonate-dihydrate). KFA-1411 selectively inhibited FXa among the serine proteases in the human blood-coagulation cascade with a Ki value of 1.73 nM, (selectivity ratio, 15000 versus its action on thrombin). The anticoagulant action of KFA-1411 in human plasma almost equaled that of the selective thrombin inhibitor, argatroban. KFA-1411 did not inhibit platelet aggregation at the concentration at which it showed an anticoagulant action. In contrast, argatroban, heparin, and low-molecular-weight heparin (LMWH; dalteparin) inhibited thrombin-induced platelet aggregation at concentrations lower than those needed for their anticoagulant actions. The FXa-inhibiting action of KFA-1411 differed among animal species, the maximum effect being seen in humans, followed by monkeys and rabbits, with rats and mice showing about one-tenth the potency seen in humans. A species variation was also observed among the values obtained for KFA-1411 in respect of anticoagulant activity in plasma (monkeys again being closest to humans). These results indicate that KFA-1411 may exhibit antithrombotic efficacy without an unwanted platelet-related action in the future treatment of various thrombotic diseases. The experimental model of monkeys is recommended for estimation of the clinical effects and safety of KFA-1411 in humans.