T. Linhart

NFAT-Induced Histone Acetylation Relay Switch Promotes c-Myc-Dependent Growth in Pancreatic Cancer Cells

BACKGROUND & AIMS Induction of immediate early transcription factors (ITF) represents the first transcriptional program controlling mitogen-stimulated cell cycle progression in cancer. Here, we examined the transcriptional mechanisms regulating the ITF protein c-Myc and its role in pancreatic cancer growth in vitro and in vivo. METHODS Expression of ITF proteins was examined by reverse-transcription polymerase chain reaction and immunoblotting, and its implications in cell cycle progression and growth was determined by flow cytometry and [(3)H]-thymidine incorporation. Intracellular Ca(2+) concentrations, calcineurin activity, and cellular nuclear factor of activated T cells (NFAT) distribution were analyzed. Transcription factor complex formations and promoter regulation were examined by immunoprecipitations, reporter gene assays, and chromatin immunoprecipitation. Using a combination of RNA interference knockdown technology and xenograft models, we analyzed the significance for pancreatic cancer tumor growth. RESULTS Serum promotes pancreatic cancer growth through induction of the proproliferative NFAT/c-Myc axis. Mechanistically, serum increases intracellular Ca(2+) concentrations and activates the calcineurin/NFAT pathway to induce c-Myc transcription. NFAT binds to a serum responsive element within the proximal promoter, initiates p300-dependent histone acetylation, and creates a local chromatin structure permissive for the inducible recruitment of Ets-like gene (ELK)-1, a protein required for maximal activation of the c-Myc promoter. The functional significance of this novel pathway was emphasized by impaired c-Myc expression, G1 arrest, and reduced tumor growth upon NFAT depletion in vitro and in vivo. CONCLUSIONS Our study uncovers a novel mechanism regulating cell growth and identifies the NFAT/ELK complex as modulators of early stages of mitogen-stimulated proliferation in pancreatic cancer cells.

Prospective Evaluation of Duodenogastroesophageal Reflux in Gastroesophageal Reflux Disease Patients Refractory to Proton Pump Inhibitor Therapy

Background: Duodenogastroesophageal reflux (DGER) is considered an independent risk factor for complicated reflux disease (gastroesophageal reflux disease; GERD). However, the role of DGER in GERD patients refractory to proton pump inhibitors (PPI) remains poorly understood. Methods: 85 patients with clinical reflux symptoms and a history of ineffective response to PPIs were enrolled in the study. Patients with elevated reflux measurement (pH and/or Bilitec measurement; n = 47) received pantoprazole 80 mg for 8 weeks. Clinical outcome was defined as response (≤2 symptoms/week) or nonresponse (≥3 symptoms/week). Results: Of the 47 patients with elevated reflux measurement, 30 were classified as responders and 17 as nonresponders. Treatment with pantoprazole resulted in a significant reduction of acidic reflux in both PPI responders and PPI nonresponders. In contrast, DGER was only significantly reduced in the PPI responder group (22.8 ± 22.8 vs. 6.6 ± 10.8%; p < 0.05) but not in the PPI nonresponder group (24.5 ± 18.6 vs. 22.2 ± 12.7%; p > 0.05). Conclusions: The presented study firstly describes that nonresponsiveness to PPI is associated with a limited effect of PPIs on reducing DGER. Thus, persistent DGER may play a key role in mediating reflux symptoms refractory to high-dose PPIs.

Impact of Pantoprazole on Duodeno-Gastro-Esophageal Reflux (DGER)

BACKGROUND Duodeno-gastro-esophageal reflux (DGER) is considered as an independent risk factor for complicated reflux disease (GERD). Patients with Barretts esophagus have significantly higher levels of DGER than patients with uncomplicated GERD. However, the clinical response to conventional high-dose PPI therapy in patients with uncomplicated GERD and DGER is largely unknown. METHODS 30 patients with uncomplicated GERD and combined pathological reflux (acid and bile) were enrolled in the study. Clinical work-up included evaluation of clinical symptoms, esophageal manometry and upper endoscopy. After 6 - 8 weeks of treatment with Pantoprazole 80 mg/d pH measurement and Bilitec 2000 were repeated, and the pattern of symptoms was re-evaluated. RESULTS Under treatment with Pantoprazole 80 mg/d acid reflux was normalised in 28 patients (93 %). Similarly the mean percentage of DGER (time with an absorption greater than 0.14) was significantly reduced from 19.6 % (+/- 13.7) to 5.7 % (+/- 7.7, p < 0.05). In 15 patients (50 %) an elevated DGER persisted under treatment with Pantoprazole (DGER-NR group) whereas in 15 cases (50 %) a normalisation could be achieved (DGER-R group). The DGER-NR group had significantly higher levels of bile reflux before (and under) treatment compared to the DGER-R group: 22.9 % (9.98 %) vs. 15.6 % (0.72 %), respectively. Overall, the median quality of life index (QLI) improved from 4.78 (+/- 0.86) before to 8.04 +/- 1.84) under therapy. The clinical response under treatment was marikedly reduced in the DGER-NR group compared to the DGER-R group: QLI 7.3 vs. 8.9. Particularly heartburn and nocturnal coughing persisted. CONCLUSIONS Our data confirm that high-dose pantoprazole therapy effectively exerts acid suppression in GERD patients with combined pathological reflux. However, DGER could only normalised in 50 % of patients. High levels of DGER at diagnosis enhance the risk of persistent DGER under PPI therapy and are associated with a reduced clinical outcome.

Ungewöhnliche klinische Präsentation einer autoimmunen Pankreatitis Typ 1

HISTORY AND ADMISSION FINDINGS A-51-year-old man presented with increasingly severe upper abdominal pain, in reduced general state and mild weight loss. Ten years before the patient had undergone a Kausch-Whipple procedure (pancreaticoduodenectomy) for an inflammatory mass in the pancreas, at that time histologically identified as an inflammatory tumour with chronic pancreatitis. Since then he has had repeated episodes of stenosis of the biliary-digestive anastomosis, associated with acute cholangitis. Laboratory findings on admission revealed liver function tests that were moderately (AST, ALT) or markedly elevated (GGT and AP). INVESTIGATIONS Abdominal ultrasound revealed cuffing of the portal vein and its side-branches with low echogenicity. Magnetic resonance imaging showed periportal edema with irregular bile ducts. Initially the histological examination strongly suggested a peripheral malignant T-cell lymphoma. However, subsequent examination revealed a chronic IgG4-associated, lymphoplasmatic sclerosing inflammation of the biliary tract. TREATMENT AND COURSE Histological re-examination of the 10-year-old pancreatic resection specimens also showed severe lymphoplasmatic infiltrates suggesting a pancreatic manifestation of an IgG4-associated systemic disease (ISD), known nowadays as an type 1 autoimmune pancreatitis (AIP). Based on the initial diagnosis of an invasive periphere malignant T-cell lymphoma of the liver a pre-phase treatment with vincristine, prednisolone followed by one cycle of CHOEP were administered. This resulted in complete remission of the patients symptoms. Once the true diagnosis had been revised this treatment was immediately stopped. Since the patient remained symptom-free, the initially elevated laboratory parameters returned to normal and a remission of low echogenicity cuffing of the portal vein was observed and no further steroid treatment was administered. Ursodesocycholic acid was then given as the only drug, to prevent any further episodes of cholangitis. CONCLUSIONS Autoimmune pancreatitis continues to be frequently unrecognized in clinical practice. But because it responds well to corticosteroids, this clinical entity should be considered in the differential diagnosis of unclear inflammatory changes and strictures of the pancreatic and biliary tracts or even, if necessary, looked for retrospectively in resected pancreas specimens.

Ungewöhnliche klinischePräsentation einer autoimmunen Pankreatitis Typ1

HISTORY AND ADMISSION FINDINGS A-51-year-old man presented with increasingly severe upper abdominal pain, in reduced general state and mild weight loss. Ten years before the patient had undergone a Kausch-Whipple procedure (pancreaticoduodenectomy) for an inflammatory mass in the pancreas, at that time histologically identified as an inflammatory tumour with chronic pancreatitis. Since then he has had repeated episodes of stenosis of the biliary-digestive anastomosis, associated with acute cholangitis. Laboratory findings on admission revealed liver function tests that were moderately (AST, ALT) or markedly elevated (GGT and AP). INVESTIGATIONS Abdominal ultrasound revealed cuffing of the portal vein and its side-branches with low echogenicity. Magnetic resonance imaging showed periportal edema with irregular bile ducts. Initially the histological examination strongly suggested a peripheral malignant T-cell lymphoma. However, subsequent examination revealed a chronic IgG4-associated, lymphoplasmatic sclerosing inflammation of the biliary tract. TREATMENT AND COURSE Histological re-examination of the 10-year-old pancreatic resection specimens also showed severe lymphoplasmatic infiltrates suggesting a pancreatic manifestation of an IgG4-associated systemic disease (ISD), known nowadays as an type 1 autoimmune pancreatitis (AIP). Based on the initial diagnosis of an invasive periphere malignant T-cell lymphoma of the liver a pre-phase treatment with vincristine, prednisolone followed by one cycle of CHOEP were administered. This resulted in complete remission of the patients symptoms. Once the true diagnosis had been revised this treatment was immediately stopped. Since the patient remained symptom-free, the initially elevated laboratory parameters returned to normal and a remission of low echogenicity cuffing of the portal vein was observed and no further steroid treatment was administered. Ursodesocycholic acid was then given as the only drug, to prevent any further episodes of cholangitis. CONCLUSIONS Autoimmune pancreatitis continues to be frequently unrecognized in clinical practice. But because it responds well to corticosteroids, this clinical entity should be considered in the differential diagnosis of unclear inflammatory changes and strictures of the pancreatic and biliary tracts or even, if necessary, looked for retrospectively in resected pancreas specimens.

Unusual presentation of autoimmune pancreatitis type 1

HISTORY AND ADMISSION FINDINGS A-51-year-old man presented with increasingly severe upper abdominal pain, in reduced general state and mild weight loss. Ten years before the patient had undergone a Kausch-Whipple procedure (pancreaticoduodenectomy) for an inflammatory mass in the pancreas, at that time histologically identified as an inflammatory tumour with chronic pancreatitis. Since then he has had repeated episodes of stenosis of the biliary-digestive anastomosis, associated with acute cholangitis. Laboratory findings on admission revealed liver function tests that were moderately (AST, ALT) or markedly elevated (GGT and AP). INVESTIGATIONS Abdominal ultrasound revealed cuffing of the portal vein and its side-branches with low echogenicity. Magnetic resonance imaging showed periportal edema with irregular bile ducts. Initially the histological examination strongly suggested a peripheral malignant T-cell lymphoma. However, subsequent examination revealed a chronic IgG4-associated, lymphoplasmatic sclerosing inflammation of the biliary tract. TREATMENT AND COURSE Histological re-examination of the 10-year-old pancreatic resection specimens also showed severe lymphoplasmatic infiltrates suggesting a pancreatic manifestation of an IgG4-associated systemic disease (ISD), known nowadays as an type 1 autoimmune pancreatitis (AIP). Based on the initial diagnosis of an invasive periphere malignant T-cell lymphoma of the liver a pre-phase treatment with vincristine, prednisolone followed by one cycle of CHOEP were administered. This resulted in complete remission of the patients symptoms. Once the true diagnosis had been revised this treatment was immediately stopped. Since the patient remained symptom-free, the initially elevated laboratory parameters returned to normal and a remission of low echogenicity cuffing of the portal vein was observed and no further steroid treatment was administered. Ursodesocycholic acid was then given as the only drug, to prevent any further episodes of cholangitis. CONCLUSIONS Autoimmune pancreatitis continues to be frequently unrecognized in clinical practice. But because it responds well to corticosteroids, this clinical entity should be considered in the differential diagnosis of unclear inflammatory changes and strictures of the pancreatic and biliary tracts or even, if necessary, looked for retrospectively in resected pancreas specimens.