Yusuke Niina

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.

The Current Strategy for Managing Pancreatic Neuroendocrine Tumors in Multiple Endocrine Neoplasia Type 1

Multiple endocrine neoplasia type 1 (MEN1) is an inherited autosomal dominant disease presenting with pancreatic neuroendocrine tumors (pNETs), parathyroid tumors, or pituitary tumors. Using the PubMed database, we reviewed the literature on information regarding the proper diagnosis and treatment of MEN1-associated pNET. Many cases of MEN1-associated pNET are functioning pNETs. Gastrinomas and insulinomas tend to occur frequently in the duodenum and pancreas, respectively. In addition to diagnostic imaging, the selective arterial secretagogue injection test (SASI test) is useful for localizing functioning pNET. The standard treatment is surgical resection. However, in the case of a functioning pNET, the tumor should first be accurately located using the SASI test before an appropriate surgical method is selected. In cases of a MEN1-associated non-functioning pNET that exceeds 2 cm in diameter, the incidence of distant metastasis is significantly increased, and surgery is recommended. In cases of unresectable pNET, a somatostatin analog has been shown to demonstrate antitumor effects and is considered to be a promising treatment. In addition, molecular-targeted drugs have recently been found to be effective in phase III clinical trials.

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.

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.

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.

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 Hashimotos 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.

Large area of walled-off pancreatic necrosis successfully treated by endoscopic necrosectomy using a grasping-type scissors forceps.

Endoscopic necrosectomy (EN) for walled‐off pancreatic necrosis (WOPN) is less invasive than surgical treatment and has become the first choice for pancreatic abscess. EN is usually carried out with several devices including snares, baskets, and grasping forceps. Occasionally, we have encountered cases in which EN has not been satisfactorily carried out, and there is pressure for further innovation in EN. Here, we describe a case of a large area of WOPN that was successfully treated by EN with endoscopic submucosal dissection and associated techniques, which facilitated removal of necrotic tissues. A 60‐year‐old man was referred to our hospital for WOPN as a complication of necrotizing pancreatitis. As a result of his complicating conditions including ischemic heart disease, uncontrollable arrhythmia, chronic renalfailure, and persistent pleural effusion, he was deemed a poor surgical candidate. Although EN with conventional devices was carried out for five sessions, we could not remove the dense and massive necrotic tissues. At the sixth EN session, the Clutch Cutter device (Fujifilm, Tokyo, Japan) was used to remove the necrotic tissues, without major complications. This is believed to be the first report of EN using the Clutch Cutter for successful treatment of WOPN.

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.

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 Wirsungs 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.

Paclitaxel-Based Chemotherapy for Advanced Pancreatic Cancer after Gemcitabine-Based Therapy Failure: A Case Series of 5 Patients

Background/Objectives: Gemcitabine (GEM) is a gold-standard chemotherapy agent for advanced pancreatic cancer. Because of the malignant character of the disease, nearly all patients show disease progression despite treatment with GEM-based chemotherapy; therefore, second-line chemotherapy may be beneficial for these patients. We report a retrospective analysis of 5 patients with advanced pancreatic cancer, treated with a paclitaxel-containing regimen as second-, third- or fourth-line chemotherapy after various therapies, such as a GEM-based regimen, S-1 regimen, and chemoradiation. We retrospectively analyzed the efficacy and adverse events, and evaluated the paclitaxel-containing regimens. A review of the literature is also discussed. Results: The median overall survival from the start of salvage therapy was 10.7 months. The disease control rate of the paclitaxel-containing regimen according to RECIST criteria was 60%, including complete response in 0 patients, partial response in 3, and stable disease in 2. Two patients had malignant ascites at the start of this salvage therapy, and in both of them the ascites and clinical complaints improved. Grade 3 and 4 hematological adverse events were observed in 2 patients and 1 patient, respectively. Conclusion: Salvage paclitaxel-based therapy could be beneficial to advanced pancreatic cancer patients who maintain good performance status after several chemotherapy failures.