Masayuki Hijioka

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.

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 up‐to‐date review of epidemiological pancreatic neuroendocrine tumors in Japan

Pancreatic neuroendocrine tumors (PNETs) were considered an extremely rare disease. However, in recent years, the number of patients with PNET has increased rapidly. According to an epidemiological survey conducted in Japan, the number of treated patients with PNETs in 2010 was approximately 1.2‐times that in 2005, and the number of new incidences of non‐functional PNETs in 2010 was approximately 1.7‐times that in 2005. Among functional PNETs, insulinoma was most prevalent, followed by gastrinoma. To diagnose PNETs, correct histological diagnosis is most important. According to the World Health Organization 2010 classification criteria, neuroendocrine tumors (NETs) are categorized into well‐differentiated NETs and poorly differentiated neuroendocrine carcinomas (NECs). NECs accounted for 7.6% of all NETs, and functional and non‐functional PNETs accounted for 2.1% and 10.1%, respectively. Patients with distant metastasis accounted for 19.9%, and those with multiple endocrine neoplasia type 1 accounted for 4.3%. When treating PNETs, it is necessary to correctly evaluate the functionality and progression of tumors, the presence or absence of metastasis, and the degrees of differentiation and malignant potential of tumors. A new registration system from the Japan Neuroendocrine Tumor Society will start to be used in 2015, which will help further dissemination of Japanese epidemiological information to the world.

Serum chromogranin A is a useful marker for Japanese patients with pancreatic neuroendocrine tumors

Although chromogranin A (CGA) is a useful marker for pancreatic neuroendocrine tumors (pNET) in the West, its usefulness in Japanese populations is unclear. To assess this, we evaluated the serum CGA levels in 189 patients with various pancreatic diseases, including proven pNET (n = 69), pancreatic cancer (PC) (n = 50), chronic pancreatitis (CP) (n = 50) and autoimmune pancreatitis (AIP) (n = 20), and 112 normal controls (controls) using an ELISA kit. The mean CGA level of patients with pNET was significantly higher than any of the other groups (407.8 ± 984.6 ng/mL [pNET] vs 91.8 ± 101.8 ng/mL [PC], 93.6 ± 57.5 ng/mL [CP], 69.9 ± 52.4 ng/mL [AIP] and 62.5 ± 48.3 ng/mL [controls]). Limiting the analysis to patients not using proton pump inhibitors (PPI), the CGA level of patients with PC or CP was not significantly different compared with the controls. Discriminant analysis revealed that the best cut‐off value of CGA to distinguish patients with pNET from the controls was 78.7 ng/mL, with a sensitivity and specificity of 53.6% and 78.6%, respectively. In patients with pNET, significant factors associating with elevated CGA levels were tumor classification, tumor size, and the presence of liver metastases in univariate analysis as well as PPI use and the presence of liver metastases in multivariate analysis. We show that CGA is a useful marker for diagnosing pNET in Japanese populations and for distinguishing patients with pNET from patients with other pancreatic diseases. The increased use of CGA in Japan will likely be a helpful tool in managing these patients, as found in the West.

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.

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 β 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.

Long-term outcomes and prognostic factors in 78 Japanese patients with advanced pancreatic neuroendocrine neoplasms: a single-center retrospective study

OBJECTIVE Despite an increase in the number of Japanese patients with pancreatic neuroendocrine neoplasms, long-term outcomes and prognostic factors, especially for those with advanced disease, remain unclear. METHODS We retrospectively reviewed the medical records of 78 patients with unresectable pancreatic neuroendocrine neoplasms treated at our hospital from January 1987 to March 2015. Survival analyses were performed using Kaplan-Meier methods. Prognostic significance of several clinicopathological factors were analyzed by univariate and multivariate analyses using a Cox regression model. RESULTS Median overall survivals of pancreatic neuroendocrine tumor (n = 64) and pancreatic neuroendocrine carcinoma (n = 14) were 83.7 and 9.1 months, respectively (hazard ratio: 0.02, 95% confidence interval: 0.01-0.08, P < 0.001). Although no significant differences were observed using a Ki-67 cut-off value of 2% (hazard ratio: 0.46, 95% confidence interval: 0.16-1.13, P = 0.0989), a Ki-67 cut-off of 10% was a significant predictor in patients with pancreatic neuroendocrine tumor (hazard ratio: 9.95, 95% confidence interval, 3.01-32.97, P < 0.001). Treatment after the advent of targeted therapy (hazard ratio: 0.07, 95% confidence interval: 0.03-0.19, P < 0.001) and the presence of bone metastases (hazard ratio: 4.38, 95% confidence interval: 1.42-11.29, P = 0.013) were significant prognostic factors in patients with pancreatic neuroendocrine tumor evaluated by univariate analysis. Multivariate analysis also revealed that a Ki-67 index ≥10% (hazard ratio: 38.8, 95% confidence interval: 8.42-226.62, P < 0.001), approval of targeted therapy (hazard ratio: 0.02, 95% confidence interval: 0.00-0.11, P < 0.001) and bone metastases (hazard ratio: 5.56, 95% confidence interval: 1.10-24.00, P = 0.039) were independent prognostic factors. CONCLUSIONS We elucidated the long-term outcomes and prognostic factors in Japanese patients with advanced pancreatic neuroendocrine neoplasms.

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.

Biotherapy of pancreatic neuroendocrine tumors using somatostatin analogs.

Basically, pancreatic neuroendocrine tumor (PNET) should be treated surgically; however, in unresectable cases, a treatment that aims to improve the prognosis by inhibiting the growth of the tumor and control the clinical symptoms becomes necessary. In the case of functional tumors, the quality of life of patients is decreased by not only the symptoms with tumor invasion and/or metastasis but also by the symptoms of hormone excess. The efficacy of somatostatin analogs against the latter has been previously reported, and their sustained release formulations have been developed. Somatostatin analogs are recommended to treat the endocrine symptoms of functional PNET; however, in case they can cause hypoglycemia in patients with insulinoma. On the other hand, results from the PROMID study demonstrated a tumor‐stabilizing effect when octreotide LAR (long acting repeatable) was used to treat patients with advanced midgut NET; however, there has been no consensus regarding its antitumor effect for PNET. Additionally, a recent result from the CLARINET study suggests that lanreotide autogel has an antitumor effect against nonfunctional NET including PNET. Further clinical study results are awaited.

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.