Fulminant type 1 diabetes mellitus associated with Coxsackievirus type B1 infection during pregnancy: a case report.

BACKGROUND: Fulminant type 1 diabetes is characterized by an intrinsic insulin deficiency resulting from the severe destruction of pancreatic ß cells and it rapidly leads to ketoacidosis. However, the association between fulminant type 1 diabetes in pregnancy and specific viral infections has not been reported. CASE PRESENTATION: The patient in this study was a 31-year-old Japanese woman, and at 30 weeks of pregnancy she was admitted with marked fatigue. Fetal bradycardia was noted, and the child was delivered by emergency cesarean section but was stillborn. The maternal blood sugar level was high (427 mg/dL), but the glycated hemoglobin value was 6.2%; therefore, fulminant type 1 diabetes was suspected. Serum antibody testing confirmed a Coxsackievirus B1 infection. The patient in this case had fulminant type 1 diabetes in pregnancy associated with Coxsackievirus B1. CONCLUSION: This case highlights that fulminant type 1 diabetes in pregnancy may be associated with Coxsackievirus B1 infection.

Diagnostic Challenge in Pancreatic Sarcoidosis Using Endoscopic Ultrasonography.

We herein report a 55-year-old woman who presented with erythema and bilateral hilar lymphadenopathy 4 months prior to the detection of pancreatic lesions on an ultrasound. A skin biopsy showed evidence of sarcoidosis. The largest lesion in the tail of the pancreas was hypoechoic on endoscopic ultrasonography (EUS). The lesion was initially iso-enhanced on contrast enhanced-EUS (CE-EUS) but subsequently became hypoenhanced. The lesion revealed heterogeneous components of both soft and hard tissue on EUS elastography. She was ultimately diagnosed with pancreatic sarcoidosis based on the presence of noncaseating granulomas seen on pancreatic tissue retrieved through an EUS-guided fine needle aspiration biopsy.

Efficacy of chemotherapy in elderly patients with unresectable pancreatic cancer: a multicenter review of 895 patients.

BACKGROUND: The efficacy of chemotherapy for unresectable pancreatic cancer has improved. However, it is occasionally difficult to make treatment decisions for elderly patients. We reviewed the outcomes of elderly patients with unresectable pancreatic cancer by using a large cohort and evaluated whether they had received chemotherapy and the reason why. METHODS: Data for 895 pancreatic cancer patients who were treated using chemotherapy or best supportive care were analyzed considering demographics, clinical stage, treatment, and outcome. Data were analyzed using the chi-square test, Student t-test, or Mann-Whitney U-test, as appropriate. Outcomes were analyzed using the Kaplan-Meier method. Differences in survival were analyzed using the log-rank test. RESULTS: The median survival time was significantly shorter in elderly patients (≥65 years) than in younger patients (<65 years) (181 vs. 263 days, P = 0.0001). The median survival time of patients treated with chemotherapy was not significantly different between the elderly and the younger group (274 days vs. 333 days, P = 0.09), and nor was that of patients choosing best supportive care (84 days vs. 78 days, P = 0.83). These results held true even when the age cut-off between younger and elder patients was increased to 70, 75, and 80 years. Elderly patients treated with chemotherapy had a significantly longer median survival time than those choosing best supportive care (274 vs. 86 days, P < 0.0001); a significantly greater proportion of elderly patients chose best supportive care compared to younger patients (47.8 vs. 25.8%, P < 0.0001). The reason for choosing best supportive care was established in 261 elderly patients (82.9%); 133 (51.0%) met the eligibility criteria for chemotherapy, but of these, 78 (58.6%) were not informed about their disease. The treatment preferences of elderly patients were not always considered; they often received only best supportive care per family members preference (N = 65, 48.8%) or because the physician based their treatment decision only on the patient's age (N = 68, 51.1%). CONCLUSIONS: Chemotherapy appears effective for elderly pancreatic cancer patients with unresectable disease, but treatment needs to be optimized to improve prognosis.

Difficulty in management of intraductal papillary mucinous neoplasm-associated pancreatobiliary fistulas and the role of "pig-nose" appearance and intraductal ultrasonography in diagnosis.

Pancreatobiliary fistulas associated with intraductal papillary mucinous neoplasms (IPMN) often develop obstructive jaundice and cholangitis; thus, early diagnosis is important. However, computed tomography and cholangiography, the current methods for detecting pancreatobiliary fistulas, are not always effective. We previously reported a case of IPMN-associated pancreatobiliary fistula and proposed a potential new diagnostic marker: the "pig-nose" appearance of the duodenal papilla, which results from dilated pancreatic and bile ducts and can be visualized via endoscopy. In this study, we report another three cases of IPMN-associated pancreatobiliary fistulas detected by a different technology, intraductal ultrasonography (IDUS). As with our previously reported case, we confirmed the utility of the "pig-nose" appearance and IDUS in the diagnosis of IPMN-associated pancreatobiliary fistulas. In addition, we found it difficult to manage biliary obstruction that resulted from the flow of mucinous material through pancreatobiliary fistulas. The obstruction was treated with endoscopic nasal biliary drainage (ENBD), but this was not always successful. In two of our cases, additional treatment with a large diameter fully covered metal stent failed to improve jaundice. Therefore, we conclude that standard endoscopic stenting may not be effective, and that alternative endoscopic methods or surgery may be necessary.

Carbonic Anhydrate I Epitope Peptide Improves Inflammation in a Murine Model of Inflammatory Bowel Disease.

BACKGROUND: Carbonic anhydrase I (CA I), a major cecal bacterial antigen, improves inflammatory bowel disease (IBD) symptoms in a murine model. The aim of this study was to identify the responsible epitope region within the CA I protein and evaluate its effect on inflammation using a murine IBD model. METHODS: Candidate peptides within the CA I protein sequence that interact with major histocompatibility complex class II were chosen and their immune responses were evaluated using mesentery lymph nodes (MLNs) from a CD4CD25 T-cell transfer murine colitis model. Mice were treated with regulatory dendritic cells (Reg-DCs)-pulsed CA I peptide. We assessed their clinical signs, histopathology, induction of cytokines and transcription factors, and generation of CD103CD11c dendritic cells and regulatory T cells (Tregs). RESULTS: We identified 4 candidate epitope peptides of CA I. Among these, Reg-DCs pulsed with CA I 58-73 peptide (Reg-DCsCA I 58-73) alone ameliorated colitis. Reg-DCsCA I 58-73-treated mice showed higher mRNA expression levels of forkhead box protein 3, aldehyde dehydrogenase family 1a2, transforming growth factor-ß, and interleukin (Il)10, when compared with lower mRNA expression of retinoic acid-related orphan receptor gamma and Il17a in MLNs. Compared with control mice, these mice also showed higher numbers of Foxp3CD4CD25 Tregs and CD103CD11c dendritic cells in MLNs and colon. Administration of Reg-DCsCA I 58-73 induced antigen-specific Tregs in MLNs of colitic mice. CONCLUSIONS: CA I 58-73 peptide induces antigen-specific therapeutic effect in a murine IBD model using Reg-DCs, indicating that CA I 58-73 is a candidate epitope for IBD immunotherapy.

Utility of Contrast-Enhanced Transabdominal Ultrasonography to Diagnose Early Chronic Pancreatitis.

Purpose. The purpose of this study was to establish the relationship between the grade of chronic pancreatitis (CP) and pancreatic blood flow as measured by contrast-enhanced transabdominal ultrasonography (CEUS) and to diagnose early CP easily. Methods. This pilot study was conducted in 8 patients with CP, 7 patients with early CP, and 6 control participants. After injecting 0.015 mL/kg of perflubutane by manual bolus, values in one region of interest (ROI) in pancreatic parenchyma and one ROI including the superior mesenteric artery (SMA) were measured. Results. The ratio of blood flow in the SMA and pancreatic parenchyma increased with grade of CP and was significantly higher in patients with CP (5.41; 2.10-11.02) than in patients with early CP (2.46; 1.41-5.05) and control participants (2.32; 1.25-3.04) (P = 0.0279, P = 0.0142, resp.). The ratio of blood flow in the SMA and pancreatic parenchyma correlated with grade of CP (rs = 0.5904, P = 0.0048). Conclusion. The ratio of blood flow correlates with grade of CP on CEUS. This safe and convenient method may be useful to diagnose early CP.

Phlegmonous gastritis associated with group A streptococcal toxic shock syndrome.

Phlegmonous gastritis (PG) is a rare, acute, severe infectious disease of the gastric wall that is often fatal due to Streptococcus spp. A 77-year-old man with diabetes and a gastric ulcer was urgently admitted due to prolonged nausea and vomiting. Computed tomography revealed widespread diffuse thickening of the gastric wall, and PG was suspected. The patient expired less than 9 hours after admission despite intensive treatments. Later, an analysis of the blood and gastric juice revealed group A streptococcus (GAS) and virulence factors associated with toxic shock syndrome (TSS). We herein diagnosed a patient with an extremely aggressive course of PG caused by GAS TSS.

Signet-ring cell carcinoma of the gallbladder complicated by pulmonary tumor thrombotic microangiopathy.

Biliary drainage was performed in a 71-year-old man with obstructive jaundice of unknown origin; however, he died due to acute pulmonary failure. At autopsy, proliferation of adenocarcinoma cells was observed in the gallbladder mucosa transitioning from isolated signet-ring cell carcinoma (SRCC) to the subserosa and bile ducts without growth toward the gallbladder lumen. Furthermore, fibrocellular intimal proliferation, tumor emboli and organized thrombi were observed in the small pulmonary arteries. The final diagnosis was gallbladder carcinoma complicated by SRCC associated pulmonary tumor thrombotic microangiopathy (PTTM). PTTM may present as rapidly progressive dyspnea, and a high level of clinical suspicion is required to make the differential diagnosis.

Improvement of long-term outcomes in pancreatic cancer and its associated factors within the gemcitabine era: a collaborative retrospective multicenter clinical review of 1,082 patients.

BACKGROUND: Although the outcomes of pancreatic cancer have been improved by gemcitabine, the changes in its characteristics and long-term outcomes within the gemcitabine era remain unclear. This study was conducted to identify clinical characteristics of pancreatic cancer patients within the gemcitabine era. METHODS: A retrospective chart review was performed at 10 centers for 1,248 consecutive patients who were ever considered to have a diagnosis of pancreatic cancer between 2001 and 2010. Data collected included demographics, diagnosis date, clinical stage, treatment, and outcome 1,082 patients met the inclusion criteria and were analyzed further. The chi-square test, Student's t-test, and Mann-Whitney U-test were used for statistical analysis. Outcomes were analyzed using the Kaplan-Meier method and Cox proportional hazards regression. Differences in survival analyses were determined using the log-rank test. RESULTS: The distribution of clinical stages was: I, 2.2% II, 3.4% III, 13% IVa, 27% and IVb, 55%. Chemotherapy alone was administered to 42% of patients and 17% underwent resection. The 1-, 3-, and 5-year survival rates were 39%, 13%, and 6.9%, respectively. The median survival time was 257 days, but differed considerably among treatments and clinical stages. Demographics, distribution of clinical stage, and cause of death did not differ between groups A (2001-2005, n=406) and B (2006-2010, n=676). However, group B included more patients who underwent chemotherapy (P<0.0001) and fewer treated with best supportive care (P=0.0004), mirroring improvements in this group's long-term outcomes (P=0.0063). Finally, factors associated with long-term outcomes derived from multivariate analysis were clinical stage (P<0.0001), location of the tumor (P=0.0294) and treatments (surgery, chemotherapy) (<0.0001). CONCLUSIONS: Long-term outcomes in pancreatic cancer has improved even within the gemcitabine era, suggesting the importance of offering chemotherapy to patients previously only considered for best supportive care. Most patients are still diagnosed at an advanced stage, making clinical strategy development for diagnosing pancreatic cancer at earlier stages essential.

Increased B cell-activating factor promotes tumor invasion and metastasis in human pancreatic cancer.

B cell-activating factor (BAFF) is a cytokine belonging to the tumor necrosis factor (TNF) superfamily. It has been reported that BAFF is elevated in patients with autoimmune pancreatitis and contributes to the malignant potential of blood cancers and solid tumors. In this study, clinical evidence of increased BAFF levels in patients with pancreatic ductal adenocarcinoma (PDAC) was obtained, and the roles and mechanisms of BAFF in PDAC were clarified in human tissues of PDAC and from in vitro data of PDAC cell lines. Serum levels of BAFF in patients with PDAC were significantly higher than in healthy subjects (p = 0.0121). Patients with UICC stage IV PDAC (T1-4, N0-1, M1) had significantly higher levels of serum BAFF compared to patients with PDAC (p = 0.0182). BAFF was remarkably expressed in infiltrating B lymphocytes surrounding pancreatic cancer in human pancreatic tissues, suggesting that BAFF may play a role in progression of pancreatic cancer. PDAC cell lines were cultured with human recombinant BAFF, and morphology and gene expression were analyzed; pancreatic cancer cells changed to a fibroblast-like morphology, and showed altered gene expression of E-cadherin, vimentin and Snail. These BAFF-induced changes reflect enhanced cell motility and invasion. BAFF-R-overexpressing cell clones confirmed the association between these BAFF-induced changes and epithelial-mesenchymal transition (EMT)-related genes. BAFF was elevated in patients with metastatic advanced PDAC and induced alterations in PDAC cells via regulation of EMT-related genes. Elucidation of the precise role and mechanism of control of BAFF may lead to new therapeutic approaches with the aim of improving pancreatic cancer survival.

Oral administration of carbonic anhydrase I ameliorates murine experimental colitis induced by Foxp3-CD4+CD25- T cells.

IBDs are thought to involve uncontrolled innate and adaptive immunity against intestinal self-antigens and bacterial antigens. Mouse CA I is a major cecal bacterial antigen in fecal extracts and is implicated in the pathogenesis of IBD. We show here that oral tolerization to CA I induced antigen-specific protection from intestinal inflammation in a murine model. Oral administration of CA I but not irrelevant antigen (KLH) ameliorated CD4(+)CD25(-) T cell transfer murine colitis and DSS-induced murine colitis. Next, we investigated the mechanisms involved in the therapeutic effects of oral administration, such as induction of ALDH1a2, transcription factors, cytokines, CD103(+)CD11c(+) DCs, and generation of Tregs. Oral administration of CA I induced ALDH1a2 mRNA expression in the MLN and colon. When compared with PBS-treated mice, CA I-treated mice had higher Foxp3(+)CD4(+)CD25(+) Treg and CD103(+)CD11c(+) DC numbers in the MLN and colon; had higher TGF-ß production in the MLN and colon; had lower RORγt mRNA expression in the MLN and colon; and had lower IL-17 mRNA expression and production in the MLN. These results demonstrate that oral administration of CA I induced antigen-specific immune tolerance by generating Foxp3(+)CD4(+)CD25(+) Tregs and inhibiting Th17 cells in a murine colitis model, thus suggesting that oral tolerization with CA I is an effective therapeutic strategy for IBD regulation.

Rapid alternative absorption of dietary long-chain fatty acids with upregulation of intestinal glycosylated CD36 in liver cirrhosis.

BACKGROUND: Dietary long-chain fatty acid (LCFA) intake is an important risk factor for hepatic inflammation and hepatocarcinogenesis. An alternate route of dietary LCFA absorption has been suggested in patients with liver cirrhosis (LC). OBJECTIVE: We aimed to determine this alternate route and to identify its mechanism. DESIGN: Twenty healthy control subjects and 47 patients with LC-n = 23 with portal hypertension [PH(+)LC] and 24 without portal hypertension [PH(-)LC)]-were enrolled. [¹³C]Palmitate (an LCFA) and octanoate (a medium-chain fatty acid [MCFA]) were administered by using gastrointestinal endoscopy. Breath ¹³CO2 was measured to quantify metabolized fatty acids. We also examined intestinal specimens of patients in these groups. RESULTS: A more rapid increase in metabolized palmitate, which showed a pattern similar to that of octanoate metabolism, was observed in patients with LC than in healthy control subjects. The increase in the PH(-)LC group was higher than that in the PH(+)LC group. However, the concentration of metabolized palmitate increased with treatment of the PH(+)LC group with a portal-systemic shunt. Morphologic changes such as expanded lymph and blood vessels were present, and glycosylated CD36 increased in the jejunum of the PH(+)LC group. This group had high serum concentrations of glucagon-like peptide-2. These data suggest that dietary LCFAs, similar to MCFAs, are absorbed via blood vessels in patients with LC. CONCLUSIONS: Rapid absorption of LCFAs by an alternative method occurred in patients with LC. This altered LCFA processing is likely related to upregulation of intestinal glycosylated CD36 and could contribute to pathogenesis in patients with LC.

Regulatory dendritic cells pulsed with carbonic anhydrase I protect mice from colitis induced by CD4+CD25- T cells.

Inflammatory bowel disease (IBD), which is characterized by a dysregulated intestinal immune response, is postulated to be controlled by intestinal self-antigens and bacterial Ags. Fecal extracts called cecal bacterial Ag (CBA) have been implicated in the pathogenesis of IBD. In this study, we identified a major protein of CBA related to the pathogenesis of IBD and established a therapeutic approach using Ag-pulsed regulatory dendritic cells (Reg-DCs). Using two-dimensional gel electrophoresis and MALDI-TOF mass spectrometry, carbonic anhydrase I (CA I) was identified as a major protein of CBA. Next, we induced colitis by transfer of CD4(+)CD25(-) T cells obtained from BALB/c mice into SCID mice. Mice were treated with CBA- or CA I-pulsed Reg-DCs (Reg-DCs(CBA) or Reg-DCs(CA1)), which expressed CD200 receptor 3 and produced high levels of IL-10. Treatment with Reg-DCs(CBA) and Reg-DCs(CA1) ameliorated colitis. This effect was shown to be Ag-specific based on no clinical response of irrelevant Ag (keyhole limpet hemocyanin)-pulsed Reg-DCs. Foxp3 mRNA expression was higher but RORγt mRNA expression was lower in the mesenteric lymph nodes (MLNs) of the Reg-DCs(CA1)-treated mice compared with those in the MLNs of control mice. In the MLNs, Reg-DCs(CA1)-treated mice had higher mRNA expression of IL-10 and TGF-ß1 and lower IL-17 mRNA expression and protein production compared with those of control mice. In addition, Reg-DCs(CBA)-treated mice had higher Foxp3(+)CD4(+)CD25(+) and IL-10-producing regulatory T cell frequencies in MLNs. In conclusion, Reg-DCs(CA1) protected progression of colitis induced by CD4(+)CD25(-) T cell transfer in an Ag-specific manner by inducing the differentiation of regulatory T cells.

Epithelial cyst arising in an intrapancreatic accessory spleen: a diagnostic dilemma.

An epithelial cyst in an intrapancreatic accessory spleen (ECIAS) is a rare disease that is commonly misdiagnosed preoperatively. To identify the clinical and imaging features of ECIAS, we reviewed the relevant medical literature. Twenty-one cases of ECIAS were identified, including our own. The cases were mainly diagnosed as mucinous cystic neoplasm (MCN) preoperatively based on clinical and imaging features, such as, a woman in middle age; elevation of serum CA19-9 levels; location in the tail of the pancreas; and a solid component resembling a mural nodule. ECIAS is another lesion to be considered in the differential diagnosis of MCN.

Clinical significance of B cell-activating factor in autoimmune pancreatitis.

OBJECTIVES: Overexpression of B Cell-activating factor (BAFF) is involved in autoimmunity, but little is known about its role in autoimmune pancreatitis (AIP). The aim of this study was to investigate the role of BAFF in the diagnosis and pathogenesis of AIP. METHODS: Patients with AIP (n = 19) were compared with 2 disease control groups (chronic pancreatitis [n = 17] and pancreatic cancer [n = 15]) and a healthy subject group (n = 19). Serum BAFF levels were assessed using an enzyme-linked immunosorbent assay. The expressions of BAFF and BAFF receptor in the pancreatic tissue of patients with AIP were estimated using immunohistochemistry. RESULTS: Mean serum BAFF levels were higher in the patients with AIP than in the patients with chronic pancreatitis, the patients with pancreatic cancer, and the healthy subjects (P < 0.0001 for all groups). Using the cutoff value of 1389 pg/mL, the sensitivity and specificity to differentiate AIP from disease and healthy controls were 89.5% and 92.2%, respectively. Glucocorticoid therapy decreased serum BAFF levels below 1389 pg/mL in all patients with AIP (P < 0.0001). B Cell-activating factor and BAFF receptor were expressed on cells infiltrating the pancreas of patients with AIP. CONCLUSIONS: B Cell-activating factor could be a novel marker for diagnosis and treatment response in AIP and may contribute to its pathogenesis.

A case of serous cystadenoma of the pancreas with a central stellate scar detected on contrast-enhanced ultrasound with perflubutane.

An asymptomatic 66-year-old woman was admitted to our hospital for detailed evaluation of a 63-mm mass in the tail of the pancreas detected on abdominal computed tomography (CT). Abdominal ultrasound (US) revealed a hypoechoic solid mass, but on contrast-enhanced ultrasound (CE-US) with perflubutane, a stellate structure within the tumor, characteristic of a serous cystadenoma, was observed. A distal pancreatectomy was performed, and histologic examination confirmed a serous cystadenoma of the pancreas. This case highlights the usefulness of CE-US with perflubutane for diagnosis of pancreatic serous cystadenomas.