New insights into predictors of autoimmune pancreatitis relapse after steroid therapy.

OBJECTIVES: While autoimmune pancreatitis (AIP) responds well to steroid therapy, the high relapse rate in type 1 AIP remains a critical problem. The present study examined predictors of relapse of type 1 AIP following steroid therapy. MATERIALS AND METHODS: Nine factors potentially predictive of relapse were analyzed in 81 AIP patients receiving steroid therapy with follow-up ≥ 12 months. The rate of serum IgG4 decrease following steroid therapy was calculated by dividing the difference between serum IgG4 values before and at two months after the start of steroid by the IgG4 value before steroid. RESULTS: A relapse occurred in 11 patients (13.5%) during a median of 38 months. Multivariate analysis revealed that the presence of IgG4-related retroperitoneal fibrosis (HR: 5.59; 95% CI: 1.42-22.0; p = 0.014) and the low rate of serum IgG4 decrease after steroid therapy (HR: 0.048; 95% CI: 0.005-0.46; p = 0.008) were significant, independent predictors of AIP relapse. The cut-off value based on receiver operating characteristic curve data for the rate of serum IgG4 decrease before and at two months after steroid therapy distinguishing patients with and without a relapse was 0.65. Using this cut-off value, the area under the curve, sensitivity, and specificity were found to be 0.63, 0.73, and 0.60, respectively. CONCLUSION: The low rate of serum IgG4 decrease after the start of steroid therapy and the presence of IgG4-related retroperitoneal fibrosis were predictive of type 1 AIP relapse. Cautious, gradual tapering of steroid dosage and longer maintenance therapy are recommended for patients with these factors.

Role of advanced endoscopy in the management of inflammatory digestive diseases (pancreas and biliary tract).

The progress of endoscopic diagnosis and treatment for inflammatory diseases of the biliary tract and pancreas have been remarkable. Endoscopic ultrasonography (EUS) and EUS-elastography are used for the diagnosis of early chronic pancreatitis and evaluation of endocrine and exocrine function in chronic pancreatitis. Notably, extracorporeal shock wave lithotripsy and electrohydraulic shock wave lithotripsy have improved the endoscopic stone removal rate in patients for whom pancreatic stone removal is difficult. Studies have reported the use of self-expanding metal stents for stent placement for pancreatic duct stenosis and EUS-guided pancreatic drainage for refractory pancreatic duct strictures. Furthermore, EUS-guided drainage using a double-pigtailed plastic stent has been performed for the management of symptomatic pancreatic fluid collection after acute pancreatitis. Recently, lumen-apposing metal stents have led to advances in the treatment of walled-off necrosis after acute pancreatitis. EUS-guided biliary drainage is an alternative to refractory endoscopic biliary drainage and percutaneous transhepatic biliary drainage for the treatment of acute cholangitis. The placement of an inside stent followed by switching to uncovered self-expanding metal stents in difficult-to-treat cases has been proposed for acute cholangitis by malignant biliary obstruction. Endoscopic transpapillary gallbladder drainage is an alternative to percutaneous transhepatic gallbladder drainage for severe and some cases of moderate acute cholecystitis. EUS-guided gallbladder drainage has been reported as an alternative to percutaneous transhepatic gallbladder drainage and endoscopic transpapillary gallbladder drainage. However, it is important to understand the advantages and disadvantages of each drainage method and select the optimal drainage method for each case.

Pancreatic duct epithelial malignancy suggested by large focal pancreatic parenchymal atrophy in cystic diseases of the pancreas.

BACKGROUND: /Objectives: A cystic lesion is common in the pancreas. Focal pancreatic parenchymal atrophy (FPPA) has been reported as a sign of high-grade pancreatic intraepithelial neoplasia/carcinoma in situ (HGP/CIS). Some cystic lesions accompany FPPA. However, the relationship between a cystic lesion, FPPA, and the histopathological background of the pancreatic duct is unknown. METHODS: We retrospectively evaluated the data of 98 patients with a cystic lesion who underwent serial pancreatic juice aspiration cytologic examination (SPACE) because of accompanying FPPA, increased size of the cystic lesion, and pancreatic duct stricture at the base. RESULTS: The clinical diagnosis of a cystic lesion was intraductal papillary mucinous neoplasia (IPMN) and cysts in 72 (73.5%) and 26 (26.5%) patients, respectively. Ninety of the 98 patients (91.8%) had FPPA. Positive results (adenocarcinoma and suspicion) on SPACE were observed in 56 of all cases (57.1%), 48 of IPMN (66.7%), 8 of cysts (30.8%), and 54 of FPPA (59.3%), and were significantly associated with IPMN (p = 0.002) and the large FPPA (>269.79 mm2,p = 0.0001); moreover, these disorders are considerably related (p = 0.0003). Fifty patients (51.0%) with positive results on SPACE underwent surgery, with the histopathological diagnosis of epithelial malignancy in 42 patients (42.9%, 42/50, 84%). Many cystic lesions clinically diagnosed as IPMN were dilated branches covered by pancreatic intraepithelial neoplasia. CONCLUSIONS: Positive results on SPACE were significantly associated with the clinical diagnosis of IPMN and the large FPPA. Moreover, these disorders are significantly related. Surgery owing to positive results could lead to the histopathological diagnosis of HGP/CIS.

Reducing relapse through maintenance steroid treatment can decrease the cancer risk in patients with IgG4-sclerosing cholangitis: Based on a Japanese nationwide study.

OBJECTIVE: IgG4-related sclerosing cholangitis (IgG4-SC) is recognized as a benign steroid-responsive disease; however, little is known about the risk of development of cancer in patients with IgG4-SC and about how to counter this risk. DESIGN: We conducted a retrospective review of the data of 924 patients with IgG4-SC selected from a Japanese nationwide survey. The incidence, type of malignancy, and risk of malignancy in these patients were examined. Then, the standardized incidence ratio (SIR) of cancer in patients with IgG4-SC was calculated. RESULTS: Relapse was recognized in 19.7% (182/924) of patients, and cancer development was noted in 15% (139/924) of patients. Multivariate analysis identified only relapse as an independent risk factor for the development of cancer. In most of these patients with pancreato-biliary cancer, the cancer developed within 8 years after the diagnosis of IgG4-SC. The SIR for cancer after the diagnosis of IgG4-SC was 12.68 (95% confidence interval [CI] 6.89-8.79). The SIRs of cancers involving the biliary system and pancreas were 27.35 and 18.43, respectively. The cumulative survival rate was significantly better in the group that received maintenance steroid treatment (MST) than in the group that did not; thus, MST influenced the prognosis of these patients. CONCLUSION: Among the cancers, the risk of pancreatic and biliary cancers is the highest in these patients. Because of the elevated cancer risk, surveillance after the diagnosis and management to prevent relapse are important in patients with IgG4-SC to reduce the risk of development of cancer.

Focal pancreatic parenchyma atrophy is a harbinger of pancreatic cancer and a clue to the intraductal spreading subtype.

BACKGROUND/OBJECTIVES: Radiological evidence of focal pancreatic parenchymal atrophy (FPPA) may presage early pancreatic ductal adenocarcinoma (PDAC) development. We aimed to clarify the incidence of FPPA and the clinicopathological features of PDAC with FPPA before diagnosis. METHODS: Data on endoscopic ultrasound-guided fine-needle biopsies and surgical samples from 170 patients with pancreatic cancer histologically diagnosed between 2014 and 2019 were extracted from the pathology database of Komagome Hospital and Juntendo University hospital and retrospectively evaluated together with 51 patients without PDAC. RESULTS: FPPA was identified in 47/170 (28%) patients before PDAC diagnosis and in 2/51 (4%) patients in the control group (P < 0.01). The median duration from FPPA detection to diagnosis was 35 (interquartile range [IQR]:16-63) months. In 24/47 (51%) patients with FPPA, the atrophic area resolved. The lesion was in the head and body/tail in 7/40 and 67/56 of the patients with (n = 47) and without FPPA (n = 123), respectively (P < 0.001). Histopathologically confirmed non-invasive lesions in the main pancreatic duct and a positive surgical margin in the resected specimens occurred in 53% vs. 21% (P = 0.078) and 29% vs. 3% (P = 0.001) of the groups, respectively. The PDAC patients with FPPA accompanied by a malignant pancreatic resection margin had high-grade pancreatic intraepithelial neoplasia. CONCLUSIONS: FPPA occurred in 28% of the PDAC group at 35 months prediagnosis. The FPPA area resolved before PDAC onset. Benchmarking previous images of the pancreas with the focus on FPPA may enable prediction of PDAC. PDAC with FPPA involves widespread high-grade pancreatic intraepithelial neoplasia requiring a wide surgical margin for surgical excision.

Nationwide epidemiological survey of immunoglobulin G4-related disease with malignancy in Japan.

BACKGROUND AND AIM: To clarify the clinicoepidemiological characteristics of immunoglobulin G4 (IgG4)-related disease (IgG4-RD) with malignancy, a nationwide epidemiological survey was conducted. METHODS: Immunoglobulin G4-related disease patients with malignancy who had visited selected hospitals in Japan were surveyed. The study consisted of two stages: the number of IgG4-RD patients with malignancy was estimated by the first questionnaire and their clinicoepidemiological characteristics were assessed by the second questionnaire. RESULTS: The frequencies of autoimmune pancreatitis (AIP), IgG4-related sialadenitis, IgG4-related eye disease, IgG4-related kidney disease, and IgG4-related retroperitoneal fibrosis were 44.7%, 20.8%, 14.0%, 5.16%, and 5.12%, respectively. The overall prevalence of malignant disease in IgG4-RD cases was estimated to be 10 900 per 100 000 cases, which was significantly higher than that of malignant disease in the general population. The prevalence of malignant lymphoma in IgG4-RD cases was the highest and was estimated to be 1985 per 100 000 cases. IgG4-related kidney disease had the highest frequency of malignant disease (17.1%). In data from 200 patients, 61 (30.5%) cases of cancer were found 2 years or more before the IgG4-RD diagnosis, 92 cases (46%) during the 1 year preceding or following IgG4-RD diagnosis, and 62 cases of cancer (31%) 2 or more years following IgG4-RD diagnosis. CONCLUSIONS: The nationwide survey for IgG4-RD with malignancy in Japan showed that IgG4-RD may be related with malignant diseases.

Pancreatic cancer in patients with autoimmune pancreatitis: A scoping review.

BACKGROUND: Chronic pancreatitis is a known risk factor of pancreatic cancer (PDAC). A similar association has been suggested but not demonstrated for autoimmune pancreatitis (AIP). OBJECTIVE: The aim of our study was to identify and analyse all published cases of AIP and PDAC co-occurrence, focusing on the interval between the diagnoses and the cancer site within the pancreas. METHODS: Relevant studies were identified through automatic searches of the MEDLINE, EMBASE, Scopus, and Web of Science databases, and supplemented by manual checks of reference lists in all retrieved articles. Missing/unpublished data were obtained from the authors of relevant publications in the form of pre-prepared questionnaires. RESULTS: A total of 45 cases of PDAC in AIP patients were identified, of which 12 were excluded from the analysis due to suspicions of duplicity or lack of sufficient data. Thirty-one patients (94%) had type 1 AIP. Synchronous occurrence of PDAC and AIP was reported in 11 patients (33%), metachronous in 22 patients (67%). In the metachronous group, the median period between diagnoses was 66.5 months (2-186) and a majority of cancers (86%) occurred more than two years after AIP diagnosis. In most patients (70%), the cancer originated in the part of the pancreas affected by AIP. CONCLUSIONS: In the literature, there are reports on numerous cases of PDAC in AIP patients. PDAC is more frequent in AIP type 1 patients, typically metachronous in character, and generally found in the part of the pancreas affected by AIP.

Gallbladder wall thickening in patients with IgG4-related diseases, with special emphasis on IgG4-related cholecystitis.

OBJECTIVES: Gallbladder (GB) wall thickening sometimes occurs in patients with autoimmune pancreatitis (AIP), a condition for which the name, IgG4-related cholecystitis, was proposed. We examined the radiological findings of the GB in patients with IgG4-related diseases and clinical features of patients with GB wall thickening and presented a hypothesis of its pathogenesis. MATERIALS AND METHODS: GB wall thickening was defined by thickness ≥ 4 mm. GB wall thickness was examined in 258 patients with IgG4-related disease. Clinical and imaging findings of 200 patients with AIP with and without GB wall thickening were then compared. RESULTS: GB wall thickening was detected in 58 patients (29%) with AIP and two patients with isolated IgG4-related sclerosing cholangitis. In the 60 GBs examined, wall thickening was diffuse, with the walls possessing a smooth inner surface. No GB wall thickening was detected among the 56 patients with IgG4-related disease without AIP or IgG4-related sclerosing cholangitis. Bile duct stenosis was detected in 56 patients (97%) with AIP with GB wall thickening. Intraductal ultrasonography indicated cystic duct wall thickening connected to bile duct wall thickening in 11 of 14 (79%) patients with AIP or IgG4-related sclerosing cholangitis with GB wall thickening. Forty-eight patients in whom IgG4-related cholecystitis was diagnosed experienced resolution of the GB wall thickening after receiving steroid therapy. CONCLUSIONS: Most cases of GB wall thickening in IgG4-related diseases are closely associated with IgG4-related sclerosing cholangitis and may be a manifestation of IgG4-related disease throughout the biliary tract, including the bile duct, cystic duct, and GB.

Focal parenchymal atrophy of pancreas: An important sign of underlying high-grade pancreatic intraepithelial neoplasia without invasive carcinoma, i.e., carcinoma in situ.

OBJECTIVES: Diagnosing high-grade intraepithelial neoplasia without invasion, traditionally referred to as carcinoma in situ (CIS), is essential for improving prognosis. We examined the imaging findings of patients with and without CIS to identify significant aspects for the diagnosis of CIS. METHODS: Forty-six patients strongly suspected of early pancreatic cancer without nodule on imaging (CIS group, n = 27; non-malignant group, n = 19) were retrospectively evaluated according to ten factors of computed tomography/magnetic resonance imaging (CT/MRI), endoscopic ultrasonography (EUS), and endoscopic retrograde cholangiopancreatography (ERCP) using hierarchical cluster and univariate analyses. RESULTS: Two clusters were formed by hierarchical cluster analysis. One cluster consisted of 83.3% CIS cases with similar image findings such as focal pancreatic parenchymal atrophy (FPPA) on CT/MRI, main pancreatic duct (MPD) stricture surrounded by hypoechoic areas on EUS, and MPD stricture with upstream MPD dilation on ERCP. On univariate analysis, the CIS and non-malignant groups had FPPA on CT/MRI in 15 (55.6%) and 3 (15.8%) cases (p = 0.013), and MPD stricture surrounded by hypoechoic areas on EUS in 20 (74.1%) and 4 (21.1%) cases (p = 0.001), respectively. MPD stricture surrounded by hypoechoic areas was observed in 80% (12/15) of CIS cases with FPPA on CT/MRI and correlated with FPPA. Moreover, FPPA and MPD stricture surrounded by hypoechoic areas had histopathologically observed fibrosis or fat replacement due to pancreatic parenchymal atrophy. CONCLUSIONS: FPPA and MPD stricture surrounded by hypoechoic areas are significant findings for the diagnosis of CIS.

Efficacy and limitations of the histological diagnosis of type 1 autoimmune pancreatitis with endoscopic ultrasound-guided fine needle biopsy with large tissue amounts.

OBJECTIVES: We examined the efficacy and limitations of acquiring large specimens by endoscopic ultrasound-guided fine needle biopsy (EUS-FNB) for diagnosing type 1 autoimmune pancreatitis (AIP). METHODS: Patients from 12 institutions with non-neoplastic diseases or pancreatic ductal adenocarcinoma (PDAC) with large EUS-FNB specimens were investigated. Slides stained with hematoxylin-eosin, elastic, IgG4, and IgG stains were evaluated. The IgG4- and IgG-positive cell numbers were counted in three foci. The diagnoses were based on the Japan Pancreas Society 2011 (JPS 2011) criteria and the International Consensus Diagnostic Criteria (ICDC). RESULTS: We analyzed 85 non-neoplastic (definite type 1 AIP in 73/85 based on the ICDC) cases and 64 PDAC cases. IgG4-positive cells were numerous (>10 in 85.9%), and the IgG4/IgG ratios were high (>40% in 81.2%). Plasma cell crushing by an artifact caused unsuccessful immunostaining, notably in smaller samples. Tissue lengths were an important factor for the presence of storiform fibrosis and obliterative phlebitis, but storiform fibrosis was equivocal even in large tissues. A definite or possible histological diagnosis was achieved in 45.9% (39/85) and 41.2% (35/85), respectively, and contributed to the definite final diagnosis of type 1 AIP in 33.3% (ICDC) and 55.6% (JPS 2011) in cases with segmental/focal lesions. In the PDAC group, >10 IgG4-positive cells was rare (2/58), but elastic stains revealed fibrous venous occlusions in 10.3% (6/58). CONCLUSIONS: EUS-FNB with large tissue amounts was useful for diagnosing type 1 AIP, notably by facilitating successful IgG4 immunostaining, but definite diagnosis may not be achieved even in cases with large specimens.

Guidance for diagnosing autoimmune pancreatitis with biopsy tissues.

The biopsy-based diagnosis of autoimmune pancreatitis (AIP) is difficult but is becoming imperative for pathologists due to the increased amount of endoscopic ultrasound-guided biopsy tissue. To cope with this challenge, we propose guidance for the biopsy diagnosis of type 1 AIP. This guidance is for pathologists and comprises three main parts. The first part includes basic issues on tissue acquisition, staining, and final diagnosis, and is intended for gastroenterologists as well. The second part is a practical guide for diagnosing type 1 AIP based on the AIP clinical diagnostic criteria 2018. Inconsistent histological findings, tips for evaluating IgG4 immunostaining and key histological features including the ductal lesion and others are explained. Storiform fibrosis and obliterative phlebitis are diagnostic hallmarks but are sometimes equivocal. Storiform fibrosis is defined as spindle-shaped cells, inflammatory cells and fine collagen fibers forming a flowing arrangement. Obliterative phlebitis is defined as fibrous venous obliteration with inflammatory cells. Examples of each are provided. The third part describes the differentiation of AIP from pancreatic ductal adenocarcinoma (PDAC), focusing on histological features of acinar-ductal metaplasia in AIP, which is an important mimicker of PDAC. This guidance will help standardize pathology reports of pancreatic biopsies for diagnosing type 1 AIP.

Impaired expression of innate immunity-related genes in IgG4-related disease: A possible mechanism in the pathogenesis of IgG4-RD.

Background: IgG4-related disease (IgG4-RD) is characterized by elevated serum IgG4 and tissue infiltration by IgG4-positive plasma cells. The pathogenesis of this disease is not clear. Transcriptome analysis was performed to identify genes over- and under-expressed in patients with IgG4-RD.Method: DNA microarray analysis was performed using RNA from peripheral blood mononuclear cells of two patients with IgG4-RD and four healthy individuals. Genes showing a greater than threefold change in expression in IgG4-RD patients following steroid therapy were identified. Four genes related to innate immunity such as transcobalamin I (TCN1), secretory leukocyte peptidase inhibitor (SLPI), bactericidal/permeability-increasing protein (BPI) and lactotransferrin (LTF) were assessed by real-time PCR in 15 IgG4-RD patients and 13 healthy individuals.Result: DNA microarray analysis identified 30 genes showing a greater than threefold change in expression in IgG4-RD patients following steroid therapy. Real-time RT-PCR showed that the levels of mRNAs encoding TCNI and SLPI, except for BPI and LTF, were significantly lower in patients with IgG4-RD than in healthy people. The levels of all four mRNAs in patients with IgG4-RD were significantly increased after steroid treatment.Conclusion: These results indicate that reduction in expression of innate immunity-related genes may participate in the pathogenesis of IgG4-RD that steroid treatment may rectify impaired innate immunity as well as acquired immunity.

Diagnosis and Treatment of IgG4-Related Disease.

It is critical to differentiate IgG4-related disease (IgG4-RD) from malignant tumor and similar disease of the affected organ to apply appropriate therapy and avoid unnecessary surgery. IgG4-RD is diagnosed on combination of typical radiological findings; elevation of serum IgG4 levels; histopathological findings of abundant infiltration of IgG4-positive plasma cells and lymphocytes, storiform fibrosis , and obliterative phlebitis ; association with other IgG4-related diseases; and response to steroids. Histopathological approach is particularly recommended. Systemic glucocorticoids are currently the first-line approach for IgG4-RD, and the indications are symptoms. The initial recommended dose of oral prednisolone for induction of remission is 0.6 mg/kg/day, administered for 2-4 weeks. This dose is gradually tapered to a maintenance dose of 2.5-5 mg/day over a period of 2-3 months. As IgG4-RD sometimes relapses after steroids, maintenance therapy is usually performed in Japan. However, as IgG4-RD patients are typically elderly and are at high risk of developing steroid-related complications, cessation of the medication should be attempted at least within 3 years. For relapsed IgG4-RD, re-administration or dose up of steroid is effective, but the addition of immunomodulatory drugs such as azathioprine has been considered to be appropriate. B cell depletion with rituximab (an anti-CD20 antibody) is effective, even in many patients in whom treatment with immunomodulatory drugs was unsuccessful. The short-term clinical, morphological, and functional outcomes of most IgG4-RD patients treated with steroid therapy are good, but the long-term outcomes are less clear due to several unknown factors such as relapse, developed fibrosis, and associated malignancy.

Randomised controlled trial of long-term maintenance corticosteroid therapy in patients with autoimmune pancreatitis.

OBJECTIVE: Corticosteroid has been established as the standard therapy for autoimmune pancreatitis (AIP), but the requirement for maintenance corticosteroid therapy is controversial. We conducted a randomised controlled trial to clarify the efficacy of maintenance corticosteroid therapy in patients with AIP. DESIGN: We conducted a multicentre, tertiary setting, randomised controlled trial. After the induction of remission with the initial oral prednisolone (PSL) treatment, maintenance therapy with PSL at 5-7.5 mg/day was continued for 3 years or withdrawn at 26 weeks. The primary endpoint was relapse-free survival over 3 years and the secondary endpoint was serious corticosteroid-related complications. All analyses were performed on an intention-to-treat basis. RESULTS: Between April 2009 and March 2012, 49 patients with AIP were randomly assigned to the maintenance therapy group (n=30) or the cessation group (n=19). Baseline characteristics were not different between the two groups. Relapses occurred within 3 years in 11 out of 19 (57.9%) patients assigned to the cessation group, and in 7 of 30 (23.3%) patients in the maintenance therapy group. The relapse rate over 3 years was significantly lower in the maintenance therapy group than that in the cessation group (p=0.011). The relapse-free survival was significantly longer in the maintenance therapy group than that in the cessation group (p=0.007). No serious corticosteroid-related complications requiring discontinuation of PSL were observed. CONCLUSIONS: Maintenance corticosteroid therapy for 3 years may decrease relapses in patients with AIP compared with those who discontinued the therapy at 26 weeks. TRIAL REGISTRATION NUMBER: UMIN000001818; Results.

Pancreatic cancer.

Pancreatic cancer is a highly lethal disease, for which mortality closely parallels incidence. Most patients with pancreatic cancer remain asymptomatic until the disease reaches an advanced stage. There is no standard programme for screening patients at high risk of pancreatic cancer (eg, those with a family history of pancreatic cancer and chronic pancreatitis). Most pancreatic cancers arise from microscopic non-invasive epithelial proliferations within the pancreatic ducts, referred to as pancreatic intraepithelial neoplasias. There are four major driver genes for pancreatic cancer: KRAS, CDKN2A, TP53, and SMAD4. KRAS mutation and alterations in CDKN2A are early events in pancreatic tumorigenesis. Endoscopic ultrasonography and endoscopic ultrasonography-guided fine-needle aspiration offer high diagnostic ability for pancreatic cancer. Surgical resection is regarded as the only potentially curative treatment, and adjuvant chemotherapy with gemcitabine or S-1, an oral fluoropyrimidine derivative, is given after surgery. FOLFIRINOX (fluorouracil, folinic acid [leucovorin], irinotecan, and oxaliplatin) and gemcitabine plus nanoparticle albumin-bound paclitaxel (nab-paclitaxel) are the treatments of choice for patients who are not surgical candidates but have good performance status.

International consensus for the treatment of autoimmune pancreatitis.

BACKGROUND AND AIMS: The International Consensus Diagnostic Criteria (ICDC) for AIP has proposed two distinctive type of AIP, type 1 and type 2, and enabled us first to differentiate two types of AIP each other. By initial steroid treatment for induction of remission, remission can be successfully induced in almost all subjects with type 1 and type 2 AIP. As relapse rate in type 1 AIP is significantly higher than in type 2 AIP, there has been ongoing debate on how to treat effectively relapse of type 1 AIP. METHODS: By a modified Delphi approach, a panel of international experts has proposed an international consensus on the treatment of AIP after intense discussion and deliberation during an international consensus symposium of the International Association of Pancreatology (IAP) 2016. RESULTS: Individual statements for nine clinical questions with recommendation levels and the therapeutic strategy have been proposed. CONCLUSION: The recommendations are based on the available evidence, and eastern and western experts' opinions to find standard treatment of AIP worldwide. These recommendations can be tailored according to the local expertise and context in the management of individual patients.

Revisions of international consensus Fukuoka guidelines for the management of IPMN of the pancreas.

The management of intraductal papillary mucinous neoplasm (IPMN) continues to evolve. In particular, the indications for resection of branch duct IPMN have changed from early resection to more deliberate observation as proposed by the international consensus guidelines of 2006 and 2012. Another guideline proposed by the American Gastroenterological Association in 2015 restricted indications for surgery more stringently and recommended physicians to stop surveillance if no significant change had occurred in a pancreatic cyst after five years of surveillance, or if a patient underwent resection and a non-malignant IPMN was found. Whether or not it is safe to do so, as well as the method and interval of surveillance, has generated substantial debate. Based on a consensus symposium held during the meeting of the International Association of Pancreatology in Sendai, Japan, in 2016, the working group has revised the guidelines regarding prediction of invasive carcinoma and high-grade dysplasia, surveillance, and postoperative follow-up of IPMN. As the working group did not recognize the need for major revisions of the guidelines, we made only minor revisions and added most recent articles where appropriate. The present guidelines include updated information and recommendations based on our current understanding, and highlight issues that remain controversial or where further research is required.

The Treatment of IgG4-Related Diseases in the Hepatobiliary-Pancreatic System.

An accurate diagnosis should be made before treatment of autoimmune pancreatitis and immunoglobulin G4-related sclerosing cholangitis. Once a diagnosis has been established, steroids are the standard therapy and symptoms are the major indications. Before steroid therapy, obstructive jaundice and hyperglycemia should be controlled. An initial dose of 0.6 mg/kg/d of oral prednisolone is administered for 2 to 4 weeks, and is gradually tapered over 2 to 3 months. After steroid therapy has begun, blood and imaging tests are performed periodically. Patients with a poor response to steroids should be reevaluated on suspicion of malignancy. To prevent relapse, maintenance therapy using low-dose prednisolone (2.5-5 mg/d) for 1 to 3 years is recommended in Japan. Proximal biliary stricture is reported to be a predictor of relapse. Readministration and dose-up of steroids are effective for relapses. In Western countries, immunosuppressive drugs and rituximab have also been shown to be effective. The optimal treatment regimen should be addressed in future randomized, controlled clinical trials.

IgG4-related disease.

IgG4-related disease is a protean condition that mimics many malignant, infectious, and inflammatory disorders. This multi-organ immune-mediated condition links many disorders previously regarded as isolated, single-organ diseases without any known underlying systemic condition. It was recognised as a unified entity only 10 years ago. Histopathology is the key to diagnosis. The three central pathology features of IgG4-related disease are lymphoplasmacytic infiltration, storiform fibrosis, and obliterative phlebitis. The extent of fibrosis is an important determinant of responsiveness to immunosuppressive therapies. IgG4-related disease generally responds to glucocorticoids in its inflammatory stage, but recurrent or refractory cases are common. Important mechanistic insights have been derived from studies of patients treated by B-cell depletion. Greater awareness of this disease is needed to ensure earlier diagnoses, which can prevent severe organ damage, disabling tissue fibrosis, and even death. Identification of specific antigens and T-cell clones that drive the disease will be the first steps to elucidate the pathogenesis of IgG4-related disease.