Octreotide LAR significantly lengthens time to tumor progression compared with placebo in patients with functionally active and inactive metastatic midgut NETs. Because of the low number of observed deaths, survival analysis was not confirmatory.
Pancreatic ductal adenocarcinoma (PDA) is an almost uniformly lethal disease. One explanation for the devastating prognosis is the failure of many chemotherapies, including the current standard of care therapy gemcitabine. Although our knowledge of the molecular events underlying multistep carcinogenesis in PDA has steadily increased, translation into more effective therapeutic approaches has been inefficient over the last several decades. Evidence for this innate resistance to systemic therapies was recently provided in an accurate mouse model of PDA by the demonstration that chemotherapies are poorly delivered to PDA tissues because of a deficient vasculature. This vascular deficiency correlated with the presence of a dense stromal matrix that is a prominent histological hallmark of PDA tumours. Therapeutic targeting of stromal cells decreased the stroma from pancreatic tumours, resulting in increased intratumoral perfusion and therapeutic delivery of gemcitabine. Stromal cells contained within the PDA tumour microenvironment therefore represent an additional constituent to neoplastic cells that should be critically evaluated for optimal therapeutic development in preclinical models and early clinical trials.
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.
Pancreatic ductal adenocarcinoma (PDA) exhibits one of the poorest prognosis of all solid tumours and poses an unsolved problem in cancer medicine. Despite the recent success of two combination chemotherapies for palliative patients, the modest survival benefits are often traded against significant side effects and a compromised quality of life. Although the molecular events underlying the initiation and progression of PDA have been intensively studied and are increasingly understood, the reasons for the poor therapeutic response are hardly apprehended. One leading hypothesis over the last few years has been that the pronounced tumour microenvironment in PDA not only promotes carcinogenesis and tumour progression but also mediates therapeutic resistance. To this end, targeting of various stromal components and pathways was considered a promising strategy to biochemically and biophysically enhance therapeutic response. However, none of the efforts have yet led to efficacious and approved therapies in patients. Additionally, recent data have shown that tumour-associated fibroblasts may restrain rather than promote tumour growth, reinforcing the need to critically revisit the complexity and complicity of the tumour-stroma with translational implications for future therapy and clinical trial design.
Chronic pancreatitis is a persistent inflammatory disease of the pancreas. The digestive protease trypsin plays a fundamental role in the pathogenesis. Here we analyzed the gene encoding the trypsindegrading enzyme chymotrypsin C (CTRC) in German subjects with idiopathic or hereditary chronic pancreatitis. Two alterations, p.R254W and p.K247_R254del, were significantly overrepresented in the pancreatitis group and were present in 30/901 (3.3%) affected individuals but only in 21/2,804 (0.7%) controls (OR=4.6; CI=2.6−8.0; P=1.3×10 −7 ). A replication study identified these two variants in 10/348 (2.9%) individuals with alcoholic chronic pancreatitis but only in 3/432 (0.7%) subjects with alcoholic liver disease (OR=4.2; CI=1.2−15.5; P=0.02). CTRC variants were also found in 10/71 (14.1%) Indian subjects with tropical pancreatitis but only in 1/84 (1.2%) control (OR=13.6; CI=1.7 −109.2; P=0.0028). Functional analysis of the CTRC variants revealed 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.Chronic pancreatitis is a continuing inflammatory disorder characterized by permanent destruction of the pancreatic parenchyma leading to maldigestion and diabetes mellitus due to exocrine and endocrine insufficiency. Penetrating insight into the pathomechanism came from relatively recent studies investigating the genes encoding cationic trypsinogen (PRSS1; OMIM 276000), anionic trypsinogen (PRSS2; OMIM 601564), and the pancreatic secretory trypsin inhibitor (SPINK1; OMIM 167790). Gain-of-function variants in PRSS1 have been linked to autosomal dominant hereditary pancreatitis and subsequently also to idiopathic chronic pancreatitis 1-4 . Recently, triplication of the PRSS1 locus has been observed in a subset of families with hereditary pancreatitis 5 . In vitro biochemical studies revealed that the majority of disease predisposing PRSS1 variants increase autocatalytic conversion of trypsinogen to active trypsin and probably promote premature intrapancreatic trypsin activation in vivo 6,7 . Consistent with the central pathophysiological role of trypsin, p.N34S and other loss-offunction alterations in the trypsin inhibitor SPINK1 predispose to idiopathic, tropical, and alcoholic chronic pancreatitis 8-15 . In contrast to pathogenic PRSS1 and SPINK1 variations, the p.G191R PRSS2 variant affords protection against chronic pancreatitis due to rapid autodegradation 16 . Taken together, genetic and biochemical evidence defines a pathological pathway in which a sustained imbalance between intrapancreatic trypsinogen activation and trypsin inactivation results in the development of chronic pancreatitis ( Supplementary Fig. 1).Because trypsin degradation serves as a protective mechanism against pancreatitis, we hypothesized that loss of function in trypsin degrading enzymes increases the risk for pancreatitis. We recently demonstrated that chymotrypsin C (CTRC) degrades all human tryps...
The nuclear factor of activated T cell (NFAT) proteins are a family of Ca 2 þ /calcineurin-responsive transcription factors primarily recognized for their central roles in T lymphocyte activation and cardiac valve development. We demonstrate that NFATc1 is commonly overexpressed in pancreatic carcinomas and enhances the malignant potential of tumor cells through transcriptional activation of the c-myc oncogene. Activated NFATc1 directly binds to a specific element within the proximal c-myc promoter and upregulates c-myc transcription, ultimately resulting in increased cell proliferation and enhanced anchorageindependent growth. Conversely, c-myc transcription and anchorage-dependent and -independent cell growth is significantly attenuated by inhibition of Ca 2 þ /calcineurin signaling or siRNA-mediated knock down of NFATc1 expression. Together, these results demonstrate that ectopic activation of NFATc1 and the Ca 2 þ /calcineurin signaling pathway is an important mechanism of oncogenic c-myc activation in pancreatic cancer.
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