Background: New therapeutic options for metastatic pancreatic cancer are urgently needed. In pancreatic cancer, overexpression of the epidermal growth factor receptor 2 (HER2) has been reported in up to 45%. This multicentre phase II study investigated the efficacy and toxicity of the HER2 antibody trastuzumab combined with capecitabine in the patients with pancreatic cancer and HER2 overexpression. Methods: Primary endpoint was progression-free survival (PFS) after 12 weeks. A total of 212 patients were screened for HER2 expression. Results: Immunohistochemical (IHC) HER2 expression was: 83 (40%) grade 0, 71 (34%) grade 1, 31 (15%) grade 2, 22 (11%) grade 3. A total of 17 patients with IHC +3 HER2 expression or gene amplification could be assessed for the treatment response. Grade 3/4 treatment toxicities were: each 7% leucopenia, diarrhoea, nausea and hand-foot syndrome. Progression-free survival after 12 weeks was 23.5%, median overall survival (OS) 6.9 months. Conclusion: This study demonstrates +3 HER2 expression or gene amplification in 11% of patients. Contrary to breast and gastric cancer, only 7 out of 11 (64%) patients with IHC +3 HER2 expression showed gene amplification. Although the therapy was well tolerated, PFS and OS did not perform favourably compared with standard chemotherapy. Together, we do not recommend further evaluation of anti-HER2 treatment in patients with metastatic pancreatic cancer.

Due to the lack of donor organs for orthotopic liver transplantation (OLT) in Germany, a larger proportion of patients advance to multi-organ failure (MOF) before OLT. Twenty-three patients on the waiting list for OLT were admitted to our intensive care unit (ICU) from January 2007 until September 2009. They consisted of 16 men and 7 women of median (25th-75th percentile) age of 60 years (54-65). Acute Physiology and Chronic Health Evaluation (APACHE II) score upon ICU admission was 26 (19-34); Model of End-Stage Liver Disease (MELD) score was 29 (22-41); Sequential Organ Failure Assessment (SOFA) score was 12 (8-16). The 90-day mortality rate was 39%. A decrease in MELD score during the first 48 hours (-2 [-5-0] vs 2 [-1-4]; P=.019) was associated with survival. Thirteen patients underwent transplantation from the ICU. By the time of the OLT, the MELD scores had deteriorated to 38 (33-39) and SOFA scores to 19 (18-19). All patients were mechanically ventilated and received hemodynamic support with catecholamines. Ten of 13 patients (77%) received renal replacement therapy and/or single pass albumin dialysis. Eight of 13 patients (62%) had a SOFA score of 3 or 4 (organ failure) in each of the respective subscores for the cardiovascular, renal, and respiratory systems at the time of OLT. The 90-day mortality rate after OLT was 38% and the 1-year-mortality rate was 54%. Patients who did not survive 90 days post OLT showed lower MELD scores on admission (33 [18-35] vs 44 [32-46]; P=.045), an increased MELD during the first 48 hours (3 [1-4] vs -2 [-8-1]; P=.002), and a longer ICU stay before OLT (32 [18-37] vs 8 [2-15]; P=.006). In conclusion, OLT may be successful treatment for cirrhotic patients with MOF. Outcomes of MOF in cirrhotic patients may improve after OLT but are generally worse than acceptable. A shorter ICU waiting time seemed to be beneficial.

BACKGROUND:Radical esophagectomy with lymphadenectomy remains the only curative therapy for patients with resectable esophageal squamous cell cancer (ESCC), however, combined treatment modalities may improve survival. Based upon more than 1300 consecutive esophageal resections, we present our current multidisciplinary ESCC approach with analysis in the context of recently published RCTs. METHODS:Subject to tumor staging, patients with resectable ESCC receive either a neoadjuvant radiochemotherapy (uT3N+) or are referred to primary surgery (uT1/2N0). By Medline searches (1997-2009), all published RCTs containing multimodal ESCC therapy concepts were identified and a systematic review was generated. RESULTS:From July 2007 to June 2009, 62 patients with ESCC were treated in our department (40 multimodal treatment concept, 21 primary surgery, 1 definite radiochemotherapy). The R0 resection rate was 78%, in hospital mortality 4.8%. 60% of patients showed a good response to neoadjuvant treatment. 18-month follow-up data revealed absence of tumor recurrence in 7 patients (18%). Our approach is aligned to the current published literature including 12 studies in this review. In line with our institutional experience, neodjuvant radiochemotherapy tends to improve overall survival and increases the likelihood of R0 resection. However, postoperative morbidity and mortality rates are increased. Adjuvant treatment failed to demonstrate any improvement in prognosis. For palliation, concurrent radiochemotherapy is the treatment of choice. CONCLUSION:The MRI approach can be aligned to the most recent published data. Surgical resection remains the principle treatment for patients with resectable ESCC. Although multimodal therapy concepts tend to improve survival rates, postoperative morbidity and mortality rates are increased.

Acute liver failure is a life threatening disease mostly triggered by drug-induced or toxic liver damage or viral hepatitis. Herpes Simplex virus (HSV) hepatitis is rare and accounts for only 1% of all acute liver failures. The importance of HSV-induced acute fiver failure is based oil its extremely severe clinical course with lethality rates of almost 75%. HSV hepatitis is just one or several clinical manifestations of HSV sepsis leading more frequently to encephalitis, pneumonia and esophagitis. Local herpes infection or recurrence of dermal lesions (herpes labialis, herpes genitalis), however, is common and account for the high prevalence of HSV-1 or HSV-2 infection in adults. Another rare entity is visual dissemination, which mostly affects immunocompromised patients. Compromised cellular immunity IS 1 Major risk factor for HSV sepsis because of either primary infection or reactivation of occult chronic HSV infection. Delayed diagnosis without antiviral therapy significantly contributes to the unfavorable outcome. Typically, anicteric hepatitis is seen in patients with HSV hepatitis. Because Or its low incidence, however, and the lack of dermal manifestations,, HSV hepatitis is rarely considered in the context of acute liver failure. In addition, diagnostic tests might not always be available. Therefore, it is a generally accepted Consensus to begin antiviral therapy pre-emptively with acyclovir ill cases of acute liver failure of unknown origin, ill which high urgency (HU) liver transplantation remains the only therapeutical option. Even ill the case of early specific therapy. sepsis may prevail and the indication for HU transplantation Must be evaluated carefully. The outcome after liver transplantation for HSV-induced liver failure with reported survival rates of more than 40% is good. Because of file risk of recurrence. lifelong prophylaxis with acyclovir is recommended.

Benign and low malignant tumors of the middle pancreatic segment can be resected by extended pancreaticoduodenectomy or distal pancreatic resection. Both procedures involve unavoidably extensive loss of normal pancreatic parenchyma, leading to deteriorated endocrine and exocrine pancreatic function. Segmental pancreatic resection represents an organ-preserving surgical procedure. Normal pancreatic tissue can be preserved as only the tumor with a pancreatic segment is resected. Several reports confirm lower mortality and minimal risk of postoperative endocrine or exocrine insufficiency than with standard pancreatic resections. The indication should be limited exclusively to benign or low malignant pancreatic tumors, metastases from other tumors, and focal chronic pancreatitis, as this type of resection cannot be deemed oncologic. Segmental pancreatic resections are technically more demanding and therefore should be performed in experienced centers.

Both vascular and nerval development are triggered physiologically by similar signals in order to maintain neurovascular supply to the different organ systems. During the development of pancreatic carcinomas, on the other hand, numerous new blood vessels and nerves emerge. As speculated recently, the Notch-Pathway (Notch-1/4, Jagged-1/2, Delta-1/2) plays an important role in this process.

Background Pancreatic cancer is the fourth commonest cause of death from cancer in men and women. Advantages in surgical techniques, radiation therapy techniques, chemotherapeutic regimes, and different combined-modality approaches have yielded only a modest impact on the prognosis of patients with pancreatic cancer. Thus there is clearly a need for additional strategies. One approach involves using the identification of a number of molecular targets that may be responsible for the resistance of cancer cells to radiation or to other cytotoxic agents. As such, these molecular determinants may serve as targets for augmentation of the radiotherapy or chemotherapy response. Of these, the epidermal growth factor receptor (EGFR) has been a molecular target of considerable interest and investigation, and there has been a tremendous surge of interest in pursuing targeted therapy of cancers via inhibition of the EGFR. Methods/design The PARC study is designed as an open, controlled, prospective, randomized phase II trial. Patients in study arm A will be treated with chemoradiation using intensity modulated radiation therapy (IMRT) combined with gemcitabine and simultaneous cetuximab infusions. After chemoradiation the patients receive gemcitabine infusions weekly over 4 weeks. Patients in study arm B will be treated with chemoradiation using intensity modulated radiation therapy (IMRT) combined with gemcitabine and simultaneous cetuximab infusions. After chemoradiation the patients receive gemcitabine weekly over 4 weeks and cetuximab infusions over 12 weeks. A total of 66 patients with locally advanced adenocarcinoma of the pancreas will be enrolled. An interim analysis for patient safety reasons will be done one year after start of recruitment. Evaluation of the primary endpoint will be performed two years after the last patient's enrolment. Discussion The primary objective of this study is to evaluate the feasibility and the toxicity profile of trimodal therapy in pancreatic adenocarcinoma with chemoradiation therapy with gemcitabine and intensity modulated radiation therapy (IMRT) and EGFR-targeted therapy using cetuximab and to compare between two different methods of cetuximab treatment schedules (concomitant versus concomitant and sequential cetuximab treatment). Secondary objectives are to determine the role and the mechanism of cetuximab in patient's chemoradiation regimen, the response rate, the potential of this combined modality treatment to concert locally advanced lesions to potentially resectable lesions, the time to progression interval and the quality of life.

Calcium is a key mediator of hormone-induced enzyme secretion in pancreatic acinar cells. At the same time, abnormal Ca(2+) responses are associated with pancreatitis. We have recently shown that inhibition of phosphatidylinositol 3-kinase (PI3-kinase) by LY-294002 and wortmannin, as well as genetic deletion of PI3-kinase-gamma, regulates Ca(2+) responses and the Ca(2+)-sensitive trypsinogen activation in pancreatic acinar cells. The present study sought to determine the mechanisms of PI3-kinase involvement in Ca(2+) responses induced in these cells by CCK and carbachol. The PI3-kinase inhibitors inhibited both Ca(2+) influx and mobilization from intracellular stores induced by stimulation of acini with physiological and pathological concentrations of CCK, as well as with carbachol. PI3-kinase inhibition facilitated the decay of cytosolic free Ca(2+) concentration ([Ca(2+)](i)) oscillations observed in individual acinar cells. The PI3-kinase inhibitors decreased neither CCK-induced inositol 1,4,5-trisphosphate [Ins(1,4,5)P(3)] production nor Ins(1,4,5)P(3)-induced Ca(2+) mobilization, suggesting that the effect of PI3-kinase inhibition is not through Ins(1,4,5)P(3) or Ins(1,4,5)P(3) receptors. PI3-kinase inhibition did not affect Ca(2+) mobilization induced by thapsigargin, a specific inhibitor of sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA). Moreover, SERCA blockade with thapsigargin abolished the effects of pharmacological and genetic PI3-kinase inhibition on [Ca(2+)](i) signals, suggesting SERCA as a downstream target of PI3-kinase. Both pharmacological PI3-kinase inhibition and genetic deletion of PI3-kinase-gamma increased the amount of Ca(2+) in intracellular stores during CCK stimulation. Finally, addition of the PI3-kinase product phosphatidylinositol 3,4,5-trisphosphate to permeabilized acini significantly attenuated Ca(2+) reloading into the endoplasmic reticulum. The results indicate that PI3-kinase regulates Ca(2+) signaling in pancreatic acinar cells through its inhibitory effect on SERCA.

Qualitätssicherungsmaßnahmen sind seit dem GSG von 1988 gesetzlich verankert, deren Bedeutung durch die GKV-Gesundheitsreform 2000 deutlich gestärkt und die Verantwortung zur Sicherung und Weiterentwicklung der Qualität den Leistungserbringer übertragen worden. Seit Jahren unterhält die DGC verschiedenste Qualitätssicherungsprogramme. Qualitätssichernde Maßnahmen befassen sich hauptsächlich mit Aspekten der Struktur-, Prozess- und vor allem Ergebnisqualität. Eine wichtige Neuregelung für Krankenhäuser ist die Verpflichtung zur Einführung und Weiterentwicklung eines einrichtungsinternen Qualitätsmanagement-Systems. Im Gegensatz zur Qualitätssicherung ist Qualitätsmanagement (QM) ist eine Managementmethode, die Qualität in den Mittelpunkt der Bemühungen des gesamten Klinikpersonals rückt. Ein funktionierendes QM-System ist charakterisiert durch ständiges Bestreben, die Bedürfnisse der Patienten, Angehörigen, Mitarbeiter und zuweisenden Ärzte (Stakeholders) einer Klinik zu berücksichtigen. Die Einführung eines funktionierenden QM-Systems bis spätestens 01.01.2005 ist nicht nur für alle Einrichtungen des Gesundheitswesens gesetzlich vorgeschrieben, sondern kann auch für eine Steigerung der Effizienz und Effektivität sehr nützlich sein. Ziel: Im Rahmen dieses Vortrages sollen die wesentlichen Merkmale von QM-Systemen im allgemeinen, die Abgrenzung zur Qualitätssicherung und der weitere Weg zum sog. Total Quality Management (TQM) einer chirurgischen Klinik erläutert werden. Weiterhin werden die wichtigsten QM-Systeme, das der European Foundation for Quality Management (EFQM), der DIN EN ISO 9001:2000, sowie die Zertifizierungen nach KTQ und nach DIN EN ISO 9001:2000 vergleichend dargestellt. Darüber hinaus werden die unterschiedlichen Zielsetzungen dieser Systeme herausgestellt. Weiterhin wird auf die Notwendigkeit einer institutionelle Einbindung moderner QM-Systeme im Rahmen eines bereichsübergreifenden Management-Konzepts einer Klinik (z.B. Balanced Scorecard, Corporate Identity etc.) und im besonderen von chirurgischen Kliniken eingegangen. Schluβfolgerung: Ein funktionierendes QM in chirurgischen Kliniken ist essentiell, um neuen gesetzlichen Anforderungen und Forderungen der Politik und Krankenkassen erfolgreich und proaktiv zu begegnen. Als zentraler klinischer Leistungserbringer muss die Chirurgie im Rahmen der QM-Implementierung anderen Abteilungen einen Schritt voraus sein, um nicht von diesen (z.B. Anästhesie) bevormundet zu werden.

blot arrays of >18,000 murine EST sequences (Mouse GDA, Incyte Genomics).Differential expression of selected ESTs was confirmed by RNase protection assay using riboprebes prepared from sequenced linearized plasmids from which the ESTs were derived.Relative expression levels of pancreatic transcripts were compared to the pancreatic housekeeping transcript of murine acidic ribosomal protein PO (mARP).RESULTS: A sequence identified as mouse prostatic secretory glycoprotein (MPSG), a serine protease inhibitor, was found to be overexpressed 2.3-fold in the array analysis.The plasmid containing this EST (Incyte Genomics) was sequenced and the insert was established to be a full-length sequence of MPSG, now termed SPINK3.Following a single 6 hr treatment with cerulein, 50/~g/kg/hr, SPINK3 mRNA increased 2 to 2.5-fold at 24-72 hr over the relatively abundant basal transcript levels.The induction of SPINK3 was dose-dependent: no induction followed physiologic or sub-injurious cerulein stimulation (0.1 to 5/~g/kg/hr) whereas 10-50/~g/kg/hr induced a 1.8 to 2.6-fold increase in SPINK3 mRNA levels at 24 hr.CONCLUSION: These experiments identified pancreatic SPINK3 as a gene induced following acute or repetitive pancreatic injury in the mouse.Genetic polymorphisms of a similar serine protease inhibitor, SPINK1, may confer an increased risk of chronic pancreatitis (PfOtzer, Gastro 119:615, 2000).Therefore, pancreatic SPINK3, which we show here to have abundant basal transcript levels in the mouse and to be induced by injury, could be another protease inhibitor important in preventing repetitive acinar cell injury by prematurely activated digestive enzymes.