Matthias Löhr

International Consensus Diagnostic Criteria for Autoimmune Pancreatitis: Guidelines of the International Association of Pancreatology

Objectives: To achieve the goal of developing international consensus diagnostic criteria (ICDC) for autoimmune pancreatitis (AIP). Methods: An international panel of experts met during the 14th Congress of the International Association of Pancreatology held in Fukuoka, Japan, from July 11 through 13, 2010. The proposed criteria represent a consensus opinion of the working group. Results: Autoimmune pancreatitis was classified into types 1 and 2. The ICDC used 5 cardinal features of AIP, namely, imaging of pancreatic parenchyma and duct, serology, other organ involvement, pancreatic histology, and an optional criterion of response to steroid therapy. Each feature was categorized as level 1 and 2 findings depending on the diagnostic reliability. The diagnosis of type 1 and type 2 AIP can be definitive or probable, and in some cases, the distinction between the subtypes may not be possible (AIP-not otherwise specified). Conclusions: The ICDC for AIP were developed based on the agreement of an international panel of experts in the hope that they will promote worldwide recognition of AIP. The categorization of AIP into types 1 and 2 should be helpful for further clarification of the clinical features, pathogenesis, and natural history of these diseases.

Islet Pathology and the Pathogenesis of Type 1 and Type 2 Diabetes mellitus Revisited

The present review draws attention to the diversity of islet lesions seen in human type 1 and type 2 diabetes. This heterogeneity of islet changes is best demonstrated by immunocytochemistry. In type 1 diabetes the endocrine pancreas is characterized by selective loss of B cells, which most likely results from a slowly acting autoimmune process depending on the presence of both genetic and environmental factors. The process starts years before overt diabetes develops and manifests when the B-cell volume is reduced by about 80%. In type 2 diabetes B cells are always present, regardless of the duration and severity of the disease, but lack any signs of functional activity. This reflects a secretory defect of the B cells which obviously becomes evident under the conditions of obesity, hyperinsulinism and insulin resistance. Obese but non-diabetic subjects show, in parallel to their hyperinsulinism, an increased B cell volume, suggesting that under prediabetic conditions the B cells have still the capacity to respond to increased functional demands by enhanced proliferation. In manifest diabetes the B cells have lost their proliferative potential. Whether this is due to an inherent defect or the consequence of a functional disturbance, is not clear. The development of islet amyloidosis most likely represents an associated functional abnormality of the B cell.

Genetic profile of 22 pancreatic carcinoma cell lines. Analysis of K-ras, p53, p16 and DPC4/Smad4.

Abstract. The K-ras, p53, p16 and DPC4 genes are among those most frequently altered in pancreatic ductal carcinoma. We analyzed 22 cell lines for alterations in these genes by direct sequence analysis and methylation-specific polymerase chain reaction. These cell lines showed mutations in K-ras and p53 at frequencies of 91% and 95%, respectively. Alterations in p16INK4a were found in all cases and included nine homozygous deletions, seven mutations and promoter methylation in six cases. Eight cell lines (36%) had an alteration of DPC4, including one mutation and seven homozygous deletions. The most typical mutational profile involved K-ras, p53, and p16INK4a, concurrently aberrated in 20 cases (91%). Eight cell lines had alterations in all four genes. Inactivation of DPC4 was always accompanied by alteration of all of the other three genes. This comprehensive data regarding the cumulative genetic alterations in pancreatic carcinoma cell lines will be of great value for studies involving drug sensitivity or resistance that may be associated with inactivation of a particular gene or molecular pathway.

Chymotrypsin C (CTRC) variants that diminish activity or secretion are associated with chronic pancreatitis.

Chronic pancreatitis is a persistent inflammatory disease of the pancreas, in which the digestive protease trypsin has a fundamental pathogenetic role. Here we have analyzed the gene encoding the trypsin-degrading enzyme chymotrypsin C (CTRC) in German subjects with idiopathic or hereditary chronic pancreatitis. Two alterations in this gene, p.R254W and p.K247_R254del, were significantly overrepresented in the pancreatitis group, being present in 30 of 901 (3.3%) affected individuals but only 21 of 2,804 (0.7%) controls (odds ratio (OR) = 4.6; confidence interval (CI) = 2.6–8.0; P = 1.3 × 10−7). A replication study identified these two variants in 10 of 348 (2.9%) individuals with alcoholic chronic pancreatitis but only 3 of 432 (0.7%) subjects with alcoholic liver disease (OR = 4.2; CI = 1.2–15.5; P = 0.02). CTRC variants were also found in 10 of 71 (14.1%) Indian subjects with tropical pancreatitis but only 1 of 84 (1.2%) healthy controls (OR = 13.6; CI = 1.7–109.2; P = 0.0028). Functional analysis of the CTRC variants showed impaired activity and/or reduced secretion. The results indicate that loss-of-function alterations in CTRC predispose to pancreatitis by diminishing its protective trypsin-degrading activity.

A comprehensive characterization of pancreatic ductal carcinoma cell lines: towards the establishment of an in vitro research platform

There are a large number of stable pancreatic ductal carcinoma cell lines that are used by researchers worldwide. Detailed data about their differentiation status and growth features are, however, often lacking. We therefore attempted to classify commonly used pancreatic carcinoma cell lines according to defined cell biological criteria. Twelve pancreatic ductal adenocarcinoma cell lines were cultured as monolayers and spheroids and graded according to their ultrastructural features. The grading system was based on the integrity of membrane structures and on the presence of mucin granules, cell organelles, nuclear and cellular polymorphism, cell polarity, and lumen formation. On the basis of the resulting scores the cell lines were classified as well, moderately, or poorly differentiated. In addition, immunocytochemistry was performed for the markers cytokeratin 7, 8, 18, 19, carcinoembryonic antigen, MUC1 MUC2, MUC5, and MUC6. The population doubling time of monolayer cultures, determined by a tetrazolium salt based proliferation assay was correlated with the ultrastructural grade. The grading of the ultrastructural features of the monolayers, and particularly of the spheroids, revealed that Capan-1 and Capan-2 cells were well differentiated; Colo357, HPAF-2, Aspc-1, A818-4, BxPc3, and Panc89 cells were moderately differentiated and PancTu-I, Panc1, Pt45P1, and MiaPaCa-2 cells poorly differentiated. Membrane-bound MUC1 staining was a characteristic of well differentiated cell lines. The population doubling time of the monolayer cultures was related to the differentiation grade. No relationship was found between the p53, K-ras, DPC4/Smad4, or p16INK4a mutation status and the grade of differentiation. We conclude that the proposed ultrastructural grading system combined with the proliferative activity provides a basis for further comparative studies of pancreatic ductal adenocarcinoma cell lines.

Nodal/Activin Signaling Drives Self-Renewal and Tumorigenicity of Pancreatic Cancer Stem Cells and Provides a Target for Combined Drug Therapy

Nodal and Activin belong to the TGF-β superfamily and are important regulators of embryonic stem cell fate. Here we investigated whether Nodal and Activin regulate self-renewal of pancreatic cancer stem cells. Nodal and Activin were hardly detectable in more differentiated pancreatic cancer cells, while cancer stem cells and stroma-derived pancreatic stellate cells markedly overexpressed Nodal and Activin, but not TGF-β. Knockdown or pharmacological inhibition of the Nodal/Activin receptor Alk4/7 in cancer stem cells virtually abrogated their self-renewal capacity and in vivo tumorigenicity, and reversed the resistance of orthotopically engrafted cancer stem cells to gemcitabine. However, engrafted primary human pancreatic cancer tissue with a substantial stroma showed no response due to limited drug delivery. The addition of a stroma-targeting hedgehog pathway inhibitor enhanced delivery of the Nodal/Activin inhibitor and translated into long-term, progression-free survival. Therefore, inhibition of the Alk4/7 pathway, if combined with hedgehog pathway inhibition and gemcitabine, provides a therapeutic strategy for targeting cancer stem cells.

Long-term outcomes of autoimmune pancreatitis: a multicentre, international analysis

Objective Autoimmune pancreatitis (AIP) is a treatable form of chronic pancreatitis that has been increasingly recognised over the last decade. We set out to better understand the current burden of AIP at several academic institutions diagnosed using the International Consensus Diagnostic Criteria, and to describe long-term outcomes, including organs involved, treatments, relapse frequency and long-term sequelae. Design 23 institutions from 10 different countries participated in this multinational analysis. A total of 1064 patients meeting the International Consensus Diagnostic Criteria for type 1 (n=978) or type 2 (n=86) AIP were included. Data regarding treatments, relapses and sequelae were obtained. Results The majority of patients with type 1 (99%) and type 2 (92%) AIP who were treated with steroids went into clinical remission. Most patients with jaundice required biliary stent placement (71% of type 1 and 77% of type 2 AIP). Relapses were more common in patients with type 1 (31%) versus type 2 AIP (9%, p<0.001), especially those with IgG4-related sclerosing cholangitis (56% vs 26%, p<0.001). Relapses typically occurred in the pancreas or biliary tree. Retreatment with steroids remained effective at inducing remission with or without alternative treatment, such as azathioprine. Pancreatic duct stones and cancer were uncommon sequelae in type 1 AIP and did not occur in type 2 AIP during the study period. Conclusions AIP is a global disease which uniformly displays a high response to steroid treatment and tendency to relapse in the pancreas and biliary tree. Potential long-term sequelae include pancreatic duct stones and malignancy, however they were uncommon during the study period and require additional follow-up. Additional studies investigating prevention and treatment of disease relapses are needed.

International consensus guidance statement on the management and treatment of IgG4-related disease

A. Khosroshahi, Z. S. Wallace, J. L. Crowe, T. Akamizu, A. Azumi, M. N. Carruthers, S. T. Chari, E. Della-Torre, L. Frulloni, H. Goto, P. A. Hart, T. Kamisawa, S. Kawa, M. Kawano, M. H. Kim, Y. Kodama, K. Kubota, M. M. Lerch, M. L€ ohr, Y. Masaki, S. Matsui, T. Mimori, S. Nakamura, T. Nakazawa, H. Ohara, K. Okazaki, J. H. Ryu, T. Saeki, N. Schleinitz, A. Shimatsu, T. Shimosegawa, H. Takahashi, M. Takahira, A. Tanaka, M. Topazian, H. Umehara, G. J. Webster, T. E. Witzig, M. Yamamoto, W. Zhang, T. Chiba, and J. H. Stone

European experts consensus statement on cystic tumours of the pancreas.

Cystic lesions of the pancreas are increasingly recognized. While some lesions show benign behaviour (serous cystic neoplasm), others have an unequivocal malignant potential (mucinous cystic neoplasm, branch- and main duct intraductal papillary mucinous neoplasm and solid pseudo-papillary neoplasm). European expert pancreatologists provide updated recommendations: diagnostic computerized tomography and/or magnetic resonance imaging are indicated in all patients with cystic lesion of the pancreas. Endoscopic ultrasound with cyst fluid analysis may be used but there is no evidence to suggest this as a routine diagnostic method. The role of pancreatoscopy remains to be established. Resection should be considered in all symptomatic lesions, in mucinous cystic neoplasm, main duct intraductal papillary mucinous neoplasm and solid pseudo-papillary neoplasm as well as in branch duct intraductal papillary mucinous neoplasm with mural nodules, dilated main pancreatic duct >6mm and possibly if rapidly increasing in size. An oncological partial resection should be performed in main duct intraductal papillary mucinous neoplasm and in lesions with a suspicion of malignancy, otherwise organ preserving procedures may be considered. Frozen section of the transection margin in intraductal papillary mucinous neoplasm is suggested. Follow up after resection is recommended for intraductal papillary mucinous neoplasm, solid pseudo-papillary neoplasm and invasive cancer.

Autoimmune Pancreatitis : Pathological, Clinical, and Immunological Features

Introduction In recent years a type of chronic pancreatitis has been described that is clearly distinct from alcoholic chronic pancreatitis. It is characterized by its special pathology, immunologic features, clinical presentation, and steroid responsiveness. Because of its histologic hallmarks, i.e., ductal and periductal infiltration by lymphocytes, plasma cells, and granulocytes, it has been called duct-destructive chronic pancreatitis. The frequent association of this type of pancreatitis with other autoimmune diseases such as Sjögrens disease and a number of other immune phenomena has led to the concept that it is an autoimmune disease. Hence, the term autoimmune pancreatitis has been introduced and will be used in this review. Aims This review focuses on the pathology and related clinical and immunologic features of this new type of pancreatitis. Conclusions As the ability to diagnose autoimmune pancreatitis on the basis of clinical, imaging, and laboratory findings improves, it seems likely that fewer patients with this diagnosis will undergo resection. Thus, there is a need to accumulate and study additional retrospective series of patients undergoing resection because of mass-forming chronic pancreatitis.