Expression of dihydropyrimidine dehydrogenase (DPD) and hENT1 predicts survival in pancreatic cancer.

BACKGROUND: Dihydropyrimidine dehydrogenase (DPD) tumour expression may provide added value to human equilibrative nucleoside transporter-1 (hENT1) tumour expression in predicting survival following pyrimidine-based adjuvant chemotherapy. METHODS: DPD and hENT1 immunohistochemistry and scoring was completed on tumour cores from 238 patients with pancreatic cancer in the ESPAC-3(v2) trial, randomised to either postoperative gemcitabine or 5-fluorouracil/folinic acid (5FU/FA). RESULTS: DPD tumour expression was associated with reduced overall survival (hazard ratio, HR = 1.73 [95% confidence interval, CI = 1.21-2.49], p = 0.003). This was significant in the 5FU/FA arm (HR = 2.07 [95% CI = 1.22-3.53], p = 0.007), but not in the gemcitabine arm (HR = 1.47 [0.91-3.37], p = 0.119). High hENT1 tumour expression was associated with increased survival in gemcitabine treated (HR = 0.56 [0.38-0.82], p = 0.003) but not in 5FU/FA treated patients (HR = 1.19 [0.80-1.78], p = 0.390). In patients with low hENT1 tumour expression, high DPD tumour expression was associated with a worse median [95% CI] survival in the 5FU/FA arm (9.7 [5.3-30.4] vs 29.2 [19.5-41.9] months, p = 0.002) but not in the gemcitabine arm (14.0 [9.1-15.7] vs. 18.0 [7.6-15.3] months, p = 1.000). The interaction of treatment arm and DPD expression was not significant (p = 0.303), but the interaction of treatment arm and hENT1 expression was (p = 0.009). CONCLUSION: DPD tumour expression was a negative prognostic biomarker. Together with tumour expression of hENT1, DPD tumour expression defined patient subgroups that might benefit from either postoperative 5FU/FA or gemcitabine.

[Economic aspects of inpatient treatment for decompensated liver cirrhosis: a prospective study employing an evidence-based clinical pathway]. / Gesundheitsökonomische Aspekte der stationären Behandlung von Patienten mit dekompensierter Leberzirrhose: eine prospektive Studie unter Nutzung eines evidenzbasierten Behandlungspfads.

The introduction of the G-DRG reimbursement system has greatly increased the pressure to provide cost effective treatment in German hospitals. Reimbursement based on diagnosis-related groups, which requires stratification of costs incurred is still not sufficiently discriminating the disease severity and severity in relation to the intensive costs in gastroenterology. In a combined retrospective and prospective study at a tertial referral centre we investigated whether this also applies for decompensated liver cirrhosis. In 2006, 64 retrospective cases (age 57 ± 12.9; ♂ 69.2 %, ♀ 29.8 %) with decompensated liver cirrhosis (ICD code K76.4) were evaluated for their length of hospitalisation, reimbursement as well as Child and MELD scores. In 2008, 74 cases with decompensated liver cirrhosis were treated in a prospective study according to a standardised and evidence-based clinical pathway (age 57 ± 12.2; 73 % ♂, ♀ 27 %). Besides a trend in the reduction of length of hospital stay (retrospective: 13.6 ± 8.6, prospective 13.0 ± 7.2, p = 0.85) overall revenues from patients treated according to a evidence-based clinical pathway were lower than the calculated costs from the InEK matrix. Costs of medication as a percentage of reimbursement amount increased with increasing severity. In both years we could demonstrate an inverse correlation between daily reimbursement and disease severity which precluded cost coverage. For the cost-covering hospital treatment of patients with decompensated liver cirrhosis an adjustment of the DRG based on clinical severity scores such as Child-Pugh or MELD is warranted, if evidence-based treatment standards are to be kept.

[Fulminant liver failure after administration of the herbal antidepressant Kava-Kava]. / Fulminantes Leberversagen nach Einnahme des pflanzlichen Antidepressivums Kava-Kava.

HISTORY AND CLINICAL FINDINGS: A 60 year-old woman was admitted to hospital because of jaundice, fatigue, weight loss over several months and icteric skin. Because of progressive liver failure, concomitant renal failure and progressive encephalopathy she was transferred to an intensive care unit. INVESTIGATIONS: Biochemical tests revealed acute liver failure with high levels of total and conjugated bilirubin (30 mg/dl) as well as aspartate aminotransferase (921 IU/l) and alanine aminotransferase (1350 IU/l) concentrations. Prothrombin time was less than 10 %. Serological tests could rule out viral hepatitis, metabolic or autoimmune causes of liver failure. On abdominal computed tomography and ultrasonography no pathological changes were detected. Above all portal vein thrombosis, ascites, focal lesions of the liver and extrahepatic cholestasis could be excluded. Liver histology showed extensive hepatocellular necrosis with intrahepatic cholestasis. TREATMENT AND CLINICAL COURSE: The patient's physical condition deteriorated. She had to be intubated because of respiratory insufficiency and encephalopathy stage IV. Because of progressive liver failure under conservative treatment the patient received an orthotopic liver transplant 11 days after admission. CONCLUSIONS: The exclusion of other causes and the histological diagnosis made Kava-Kava as the cause of acute liver failure most likely. This is the 18th case of Kava-Kava induced liver failure reported to the European regulatory authorities.

Effect of hyperthermia on premature intracellular trypsinogen activation in the exocrine pancreas.

Hyperthermia, raising the body temperature from normal to above 40 degrees C, has been shown to prevent pancreatitis in an experimental animal model of the disease, but the underlying cellular mechanisms of this protection remain unknown. We induced controlled hyperthermia in either laboratory rats and isolated pancreatic acini or, alternatively, raised the temperature of pancreatic homogenates in vitro from 37 to 41 degrees C. In vitro controlled hyperthermia of up to 41 degrees C increased the autoactivation-induced and enterokinase-induced trypsinogen activation as well as free trypsin activity. Conversely, in whole animal studies and in living acinar cells hyperthermia reduced or abolished premature intracellular trypsinogen activation in a time- and temperature-dependent manner and this protective effect was independent of either de novo protein synthesis, interference with acinar cell signal transduction, or confirmational changes in pancreatic trypsinogen. We conclude that hyperthermia, in a manner that is independent of the synthesis of pancreatic chaperone or heat shock proteins, can directly abolish the earliest initiating event involved in the onset of pancreatitis, namely the premature and intracellular activation of digestive zymogens.

Association of human protein-tyrosine phosphatase kappa with members of the armadillo family.

We have identified a human receptor-like protein-tyrosine phosphatase (PTP) in the mammary carcinoma cell line SK-BR-3, which represents the human homolog of murine PTPkappa (Jiang, Y.-P., Wang, H., D'Eustachio, P., Musacchio, J. M., Schlessinger, J., and Sap, J. (1993) Mol. Cell. Biol. 13, 2942-2951) and was therefore termed hPTPkappa. We show here that hPTPkappa expression is dependent on cell density and find it colocalized with two members of the arm family of proteins, beta-catenin and gamma-catenin/plakoglobin, at adherens junctions. Using both in vitro and in vivo binding assays, we demonstrate specific complex formation between endogenous hPTPkappa and beta- and gamma-catenin/plakoglobin. In addition, we present evidence that suggests that beta-catenin may represent a substrate for the catalytic activity of hPTPkappa. The identification of specific binding partners for this receptor-like PTP provides insight into the mechanisms of its biological action and suggests a role for hPTPkappa in the regulation of processes involving cell contact and adhesion such as growth control, tumor invasion, and metastasis.

Cloning, characterization, and differential expression of MDK2 and MDK5, two novel receptor tyrosine kinases of the eck/eph family.

Using a polymerase chain reaction-based strategy for the cloning of developmentally regulated receptor tyrosine kinases, we identified two novel members of the eck/eph-related subfamily which, in analogy with the recently identified mouse developmental kinase 1 (MDK1), were designated MDK2 and MDK5. MDK2 is highly homologous to the mouse kinase Myk-1 and the human kinase Htk, whereas MDK5 represents the mouse homologue of human Hek2. Northern blot analyses of adult mouse tissues revealed a 4.7 kb transcript of MDK2 and a 4.8 kb transcript of MDK5 in various organ systems, including lung, liver, kidney, intestine, muscle, heart, and, in the case of MDK5, also the brain. In addition to the full-length transcripts, smaller fragments were identified that probably represent truncated receptors. Northern blot analysis and in situ hybridization of mouse embryos indicated abundant expression during embryonic development, with preferential involvement of tissues of epithelial and endothelial origin for both kinases and of the spinal cord gray matter for MDK5. Unlike most other members of the eck/eph-related subfamily, the expression of MDK2 and MDK5 is not primarily restricted to neuronal structures, and their abundant presence in various organ systems during embryonic development suggests an important role in gestational growth and differentiation.

Effect of kinin inhibition in experimental acute pancreatitis.

Activation of the endogenous kinin system is a consistent observation in acute pancreatitis and has repeatedly been implicated in the pathophysiology of the disease. We have studied the effect of a potent bradykinin antagonist on the onset and development of acute pancreatitis in four unrelated animal models. Pancreatitis was induced in rats by either supramaximal stimulation with caerulein, intraductal injection of sodium taurocholate, or pancreatic duct ligation with secretin infusion, and in mice by feeding a choline-deficient, ethionine-supplemented diet. The potent, long-acting bradykinin antagonist HOE-140 was administered subcutaneously (0.1 mg/kg every 5 h). Effective kinin inhibition had no effect on pancreatitis-associated mortality, the extent of morphological damage and inflammation, or the intracellular distribution of lysosomal hydrolases. Pancreatic edema was only reduced in caerulein-induced pancreatitis, the only model in which edema formation was paralleled by increased vascular permeability. We conclude that, contrary to previous suggestions, kinins do not play a predominant role in the development of acute pancreatitis. Their participation is strictly limited to vascular events and does not involve the early cell biological alterations in pancreatic acinar cells.