IgG4-related chronic rhinosinusitis: A new clinical entity of nasal disease

Conclusion: IgG4-related disease involves nasal manifestations with chronic rhinosinusitis (CRS). This type of sinusitis is a new clinical entity of nasal disease associated with a high level of serum IgG4 for which steroid therapy is effective. Objectives. To confirm whether IgG4-related disease has distinctive chronic rhinosinusitis. Methods: We compared serum IgG4 levels as well as nasal computed tomography (CT) and clinicopathological findings before and after glucocorticoid treatment in 31 patients diagnosed as having IgG4-related disease with nasal manifestations. To evaluate immunohistochemical findings of nasal mucosa, we compared them with IgG4-related CRS and common CRS. Results: All patients had levels of high serum IgG4. Ten of the 31 patients had nasal obstruction, nasal discharge, postnasal discharge, hyposmia, and dull headache. They also demonstrated sinus lesions on radiological findings. After glucocorticoid treatment, serum IgG and IgG4 levels were markedly decreased and along with improvement of the symptoms, nasal sinus CT findings also revealed improvement of the sinus opacification. In immunohistochemical examination, the magnitude of IgG4-positive plasma cell infiltration in common CRS was almost the same as in the IgG4-related CRS group. Therefore, in nasal mucosa immunocytochemical positive staining for IgG4 is not specific for definition of IgG4-related disease.ArticleACTA OTO-LARYNGOLOGICA. 131(5):518-526 (2011)journal articl

Combination Chemotherapy with Low-dose 5-FU, Cisplatin, and Gemcitabine for Gemcitabine-Refractory Pancreatic Cancer

Background : No single agent or combination therapy for advanced pancreatic cancer has been reported superior to single-agent GEM, and an effective second-line chemotherapy option is needed for patients who are resistant to first-line GEM therapy. Methods :We analyzed six patients who had disease progression following first-line gemcitabine therapy. Patients received second-line chemotherapy with low dose cisplatin, 5-fluorouracul or S-1,and gemcitabine every 21 days. Results : Two patients showed a partial response (33.3%) and two showed stable disease. Four patients (66.6%) showed a prolonged survival time with partial responses or stable disease.Median survival times were 7 and 11 months from the start of second-line therapy and the start of first-line gemcitabine therapy,respectively. In addition, all patients reported relief from pain and had a favorable performance status. The major toxicities of leucopenia, stomatitis, and diarrhea were found in one patient each.Conclusion : This second-line chemotherapy regimen is an effective option for patients with gemcitabineresistant pancreatic cancer.Article信州医学雑誌 57(6): 247-253(2009)journal articl

Chromosome Scaffold is a Double-Stranded Assembly of Scaffold Proteins

Poonperm, R., Takata, H., Hamano, T. et al. Chromosome Scaffold is a Double-Stranded Assembly of Scaffold Proteins. Sci Rep 5, 11916 (2015). https://doi.org/10.1038/srep11916

Association of Autoimmune Hepatitis with Src homology 2 adaptor protein 3 Gene Polymorphisms in Japanese Patients

Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease characterized by an autoimmune reaction to hepatocytes. The Src homology 2 adaptor protein 3 (SH2B3) gene is a member of the SH2B family of adaptor proteins that has been implicated in the integration and regulation of multiple signaling events. SH2B3 is involved in cytokine signaling pathways and serves as a negative mediator of T-cell receptor signaling. Genome-wide association analyses in Caucasians have linked a missense mutation at rs3184504 in SH2B3 with AIH. Accordingly, four selected single nucleotide polymorphisms (SNPs) in the SH2B3 gene were genotyped in 158 patients with AIH, 327 patients with primary biliary cholangitis, 160 patients with autoimmune pancreatitis, and 325 healthy subjects of Japanese descent. Although the functional rs3184504 was non-polymorphic in 952 subjects, the frequency of the minor rs11065904 T allele was significantly decreased in AIH patients compared with healthy controls (odds ratio [OR] = 0.68; corrected P = 0.025). Haplotype 2 (rs2238154 A, rs11065904 T, and rs739496 G) was associated with resistance to AIH (OR 0.67, P = 0.021) as well as to autoimmune pancreatitis (OR = 0.70, P = 0.035). Our findings suggest that an SNP and haplotype in SH2B3 are associated with AIH.ArticleJournal of Human genetics. 62: 963-967. (2017)journal articl

The Utility of Serum IgG4 Concentrations as a Biomarker

IgG4-related disease is a new disease entity involving IgG4 in its clinical presentation and having 6 characteristic features: (1) systemic involvement; (2) solitary or multiple lesions showing diffuse or localized swelling, masses, nodules, and/or wall thickening on imaging; (3) high serum IgG4 concentration >135 mg/dL; (4) abundant infiltration of lymphoplasmacytes and IgG4-bearing plasma cells; (5) a positive response to corticosteroid therapy; and (6) complications of other IgG4-related diseases. To date, most IgG4-related diseases have been recognized as extrapancreatic lesions of autoimmune pancreatitis. This paper will discuss the utility of IgG4 as a biomarker of IgG4-related diseases, including in the diagnosis of autoimmune pancreatitis and its differentiation from pancreatic cancer, in the prediction of relapse, in the long-term follow-up of patients with autoimmune pancreatitis and normal or elevated IgG4 concentrations, and in patients with autoimmune pancreatitis and extrapancreatic lesions, as well as the role of IgG4 in the pathogenesis of IgG4-related disease

International Consensus Diagnostic Criteria for Autoimmune Pancreatitis and Its Japanese Amendment Have Improved Diagnostic Ability over Existing Criteria

Objectives. The recent International Consensus Diagnostic Criteria (ICDC) for autoimmune pancreatitis (AIP) and its Japanese amendment developed by the Japanese Pancreas Society (JPS 2011) may have overcome the drawbacks of earlier criteria and achieved a higher diagnostic ability for AIP. The aim of the present study is to evaluate this possibility and identify the underlying causes of this change. Methods. We compared the diagnostic abilities of the ICDC and JPS 2011 with those of the Japanese diagnostic criteria 2006 (JPS 2006), Korean diagnostic criteria (Korean), Asian diagnostic criteria (Asian), and HISORt diagnostic criteria in 110 patients with AIP and 31 patients with malignant pancreatic cancer. Results. The ICDC achieved the highest diagnostic ability in terms of accuracy (95.0%), followed by JPS 2011 (92.9%), Korean (92.2%), HISORt (88.7%), Asian (87.2%), and JPS 2006 (85.1%). Nearly all criteria systems exhibited a high specificity of 100%, indicating that the enhanced diagnostic ability of the ICDC and JPS 2011 likely stemmed from increased sensitivity brought about by inclusion of diagnostic items requiring no endoscopic retrograde pancreatography. The diagnostic ability of JPS 2011 was nearly equivalent to that of the ICDC. Conclusions. The ICDC and JPS 2011 have improved diagnostic ability as compared with earlier criteria sets because of an increase in sensitivity.ArticleGASTROENTEROLOGY RESEARCH AND PRACTICE. 2013:456965 (2013)journal articl

Long-Term Follow-Up of Autoimmune Pancreatitis: Characteristics of Chronic Disease and Recurrence

Autoimmune pancreatitis is a unique disease, characterized by lymphoplasmacytic inflammation in the acute stages. However, the active clinical features are unlikely to persist for long periods. Through long-term follow-up, we investigated the disease course in 51 patients with autoimmune pancreatitis. We found recurrence in 21 (41%) patients and pancreatic stone formation in 9 (18%) patients. Pancreatic stone formation was significantly more frequent in the recurrence group (7/21, 33%), compared with the nonrecurrence group (2/30, 7%). Moreover, we found high serum immunoglobulin G4 concentrations in 13 of 175 (7.4%) patients with ordinary chronic pancreatitis. This suggested that pancreatic stone formation is closely associated with recurrence and that autoimmune pancreatitis might transform into ordinary chronic pancreatitis after several recurrences. We found that the immune complex level, with a cutoff value of 10 mu g/dL, served as a good predictor of recurrence, with high sensitivity (61.9%), specificity (70.0%), and efficacy (66.7%). We also confirmed that HLA and cytotoxic T-lymphocyte antigen-4 polymorphisms were useful predictors for AIP recurrence.ArticleCLINICAL GASTROENTEROLOGY AND HEPATOLOGYjournal articl

Mechanisms of Lower Bile Duct Stricture in Autoimmune Pancreatitis

Objectives We attempted to clarify the mechanism underlying lower bile duct stricture in autoimmune pancreatitis. Methods Imaging and histologic finding of the bile duct were assessed for 73 patients with autoimmune pancreatitis to clarify whether IgG4-related biliary inflammation or pancreatic head swelling is associated with lower bile duct stricture. Results Lower bile duct stricture was found in 59 (81%) patients. Pancreatic head swelling was significantly more frequent among patients with lower bile duct stricture than those patients without lower bile duct stricture (53 [90%] vs 4 [29%]; P < 0.01). Intraductal ultrasonography findings revealed lower bile duct wall thickening in 21 (95%) of the 22 patients with lower bile duct stricture, and the lower bile duct wall of the patients with pancreatic head swelling was significantly thicker than those patients without pancreatic head swelling (P = 0.028). Among the 38 patients with lower bile duct biopsies, 14 (37%) exhibited abundant IgG4-bearing plasma cell infiltration. Among the patients with lower bile duct stricture, an IgG4-related inflammation seemed to exert a dominant effect under limited conditions, including concomitant middle bile duct stricture and neither pancreatic swelling nor pancreatic duct stricture in the head region. Conclusions Both pancreatic head swelling and IgG4-related biliary inflammation affect lower bile duct stricture, which may be included in IgG4-related sclerosing cholangitis. Pancreatic head swelling affects IgG4-related biliary wall thickening.ArticlePANCREAS. 43(2):255-260 (2014)journal articl

Radiologic Findings of IgG4-Related Disease

Autoimmune pancreatitis (AIP), characterized by an autoimmune phenomenon of prominent lymphocytes, IgG4-bearing plasma cell infiltration and storiform fibrosis, has been widely reported as a specific type of chronic pancreatitis. Typical image findings of this disease are reported as diffuse pancreatic swelling and a capsule-like rim on CT or MRI. However, AIP presents with a variable morphology, such as focal, segmental and multifocal swellings. Because imaging findings for AIP can look like those of pancreatic cancer, AIP has often been treated with unnecessary surgical resection. In addition, AIP is complicated by the involvement of various other organs besides the pancreas that show lymphoplasmacytic infiltration and fibrosis. These are frequently misdiagnosed as inherent lesions of corresponding organs. Furthermore, these extra-pancreatic lesions show systemic distribution and share common features of IgG4- bearing plasma cell infiltration as well as favorable responses to corticosteroid, indicating the presence of systemic condition, IgG4-related diseases. AIP is now recognized as an IgG4-related disease. Detailed evaluations of imaging findings of CT, MRI and Gallium-67 (Ga-67) scintigraphy for the involvement of these various organs are useful for a correct diagnosis of this systemic disease.ArticleCurrent Immunology Reviews. 7(2):186-203 (2011)journal articl

Radiologic Findings of IgG4-Related Disease

Autoimmune pancreatitis (AIP), characterized by an autoimmune phenomenon of prominent lymphocytes, IgG4-bearing plasma cell infiltration and storiform fibrosis, has been widely reported as a specific type of chronic pancreatitis. Typical image findings of this disease are reported as diffuse pancreatic swelling and a capsule-like rim on CT or MRI. However, AIP presents with a variable morphology, such as focal, segmental and multifocal swellings. Because imaging findings for AIP can look like those of pancreatic cancer, AIP has often been treated with unnecessary surgical resection. In addition, AIP is complicated by the involvement of various other organs besides the pancreas that show lymphoplasmacytic infiltration and fibrosis. These are frequently misdiagnosed as inherent lesions of corresponding organs. Furthermore, these extra-pancreatic lesions show systemic distribution and share common features of IgG4- bearing plasma cell infiltration as well as favorable responses to corticosteroid, indicating the presence of systemic condition, IgG4-related diseases. AIP is now recognized as an IgG4-related disease. Detailed evaluations of imaging findings of CT, MRI and Gallium-67 (Ga-67) scintigraphy for the involvement of these various organs are useful for a correct diagnosis of this systemic disease.ArticleCurrent Immunology Reviews. 7(2):186-203 (2011)journal articl