Pascal O. Berberat

Pancreatic cancer: the potential clinical relevance of alterations in growth factors and their receptors.

Molecular alterations play a key role in the pathogenesis of gastrointestinal cancers. In the present paper we describe relevant molecular alterations in human pancreatic adenocarcinomas. Overexpression of growth factor receptors (EGF receptor, c-erbB2, c-erbB3, TGFβ receptor I–III), growth factors (EGF, TGFα, TGFβ-1-3, aFGF, bFGF), adhesion molecules (ICAM-1, ELAM-1) and gene mutations (p53, K-ras, DCC, APC) are present in a significant number of these tumors. These changes stimulate tumor growth and enhance the metastatic behavior of pancreatic cancer cells and thereby may contribute to shorter postoperative survival following tumor resection.

Galectin-1 and galectin-3 in chronic pancreatitis.

Galectin-1 and galectin-3 have important functions in cell-cell interactions, cell adhesion to extracellular matrix, the organization of extracellular matrix, and tissue remodeling. To assess their potential role in chronic pancreatitis (CP), we examined their expression by Northern blot analysis, in situ hybridization, immunohistochemistry, and Western blot analysis in normal and CP pancreatic tissues. Northern blot analysis revealed a 4.5-fold increase of galectin-1 mRNA (p < 0.01) and a 3.8-fold increase of galectin-3 mRNA (p < 0.01) in CP samples compared with normal controls. In situ hybridization analysis of normal pancreas indicated low abundance of galectin-1 mRNA in fibroblasts, whereas galectin-3 mRNA was moderately present in ductal cells. CP samples exhibited moderate to intense galectin-1 mRNA signals in fibroblasts, whereas galectin-3 mRNA signals were intense in the cells of ductular complexes and weak in the degenerating acinar cells. In addition, intense galectin-1 and galectin-3 mRNA signals were present in nerves of normal and CP samples. Immunohistochemistry showed a distribution pattern of galectin-1 and galectin-3 similar to that described for in situ hybridization. Relative quantification of galectin-1 and galectin-3 protein by immunoblotting revealed an increase of 3.2-fold and 3.0-fold, respectively, in CP compared with normal controls. There was a significant correlation between galectin-1 and fibrosis and between galectin-3 and fibrosis and the density of ductular complexes. Up-regulation of galectin-1 in fibroblasts and galectin-3 in ductular complexes suggests a role of these lectins in tissue remodeling in CP. Galectin-1 might participate in ECM changes, whereas galectin-3 seems to be involved in both ECM changes and ductular complex formation.

Diagnosis and staging of pancreatic cancer by positron emission tomography.

Abstract. The detection of pancreatic cancer or the discrimination between pancreatic cancer and chronic pancreatitis remains an important diagnostic problem. Several imaging modalities are now used to diagnose pancreatic cancer, including transabdominal ultrasonography (US), contrast-enhanced computed tomography (CT), magnetic resonance imaging (MRI), endoscopic retrograde cholangiopancreatography (ERCP), endoscopic ultrasonography, and selective angiography. None of these six methods is perfect: Each has advantages and disadvantages, and their sensitivity and specificity are in a high range. In 1990 positron emission tomography (PET) was first applied to diagnose pancreatic cancer. This new diagnostic modality is based on functional changes in the pancreatic cancer cells caused by enhanced glucose metabolism. Increased glucose utilization is one of the characteristics of malignantly transformed cells, independent of their origin. The technical development of PET has allowed this new procedure to be used for clinical evaluation. Using 2-(18F)-fluoro-2-deoxy-d-glucose, PET can identify pancreatic cancer and differentiate pancreatic cancer from chronic pancreatitis with a sensitivity of 85% to 98% and a specificity of 53% to 93%. However, high sensitivity and high specificity are strongly dependent on the tumor stage. At present PET is still experimental and is available only in specialized centers. It may represent a new and noninvasive diagnostic procedure for the detection and the staging of pancreatic cancer. Further clinical studies, especially including patients with early tumor stages (small tumor size), are needed. This review discusses the possibilities and limits of PET and evaluates its importance in the future.

Prevention and Treatment of Complications in Pancreatic Cancer Surgery

Pancreatic cancer is the fourth leading cause of death from malignant disease in Western industrialized countries. It is a devastating disease with a very poor prognosis and has a death rate roughly equal to its incidence rate. As this tumor is resistant to all medical treatment options, such as radio- and chemotherapy, radical surgical resection is the only chance of cure so far. Significant advances have been made over the past decades in pancreaticoduodenectomy, which is the standard operation in patients with pancreatic head cancer or periampullary cancer. In specialized centers the operative mortality has fallen under 5%. However, the postoperative complication rates after this demanding procedure are still between 30 and 40%. Complications are mainly due to the technical difficulty of performing a safe and proper anastomosis between the stomach or small bowel and the soft pancreas. This article reviews the treatment of the complications most frequently occurring after pancreatic cancer surgery, such as leakage of pancreatic anastomosis, pancreatic fistula, abscess and hemorrhage. Furthermore, we discuss the management of these complications and how complications following pancreatic surgery can be prevented.

Influences of the lysosomal associated membrane proteins (Lamp-1, Lamp-2) and Mac-2 binding protein (Mac-2-BP) on the prognosis of pancreatic carcinoma.

Lamps and Mac‐2‐BP are ligands of galectin‐3, and they were suggested to influence tumor proliferation and metastasis formation. The authors studied the expression of Lamp‐1, Lamp‐2, and Mac‐2‐BP in pancreatic carcinoma and evaluated their influence on patient prognosis.

The Role of Octreotide in the Prevention of Complications following Pancreatic Resection

Postoperative complications following major pancreatic surgery are mainly due to the difficulties of performing a safe and proper anastomosis between the stomach or small bowel and the pancreas. Continuous pancreatic juice secretion and the often soft structure of the pancreatic parenchyma are major risk factors. The present paper summarizes the results of six previously published, placebo-controlled, double-blind trials and one open randomized trial analyzing the efficacy of octreotide in preventing postoperative complications in patients who undergo major pancreatic surgery. Patients were given either octreotide (3×100–150 µg subcutaneously/day) or a placebo perioperatively for 5–7 days starting at least 1 h before operation. The patients were monitored postoperatively for typical postoperative complications such as: leakage of the anastomosis, pancreatic fistula, abscess, fluid collection, shock, sepsis, pulmonary insufficiency, renal insufficiency, bleeding, postoperative pancreatitis, and death. Six of the seven studies showed significantly fewer postoperative complications in the octreotide group in comparison with the placebo group (p<0.05). The effectiveness of octreotide was most apparent in the prevention of secretion-related complications such as fistula, fluid collection and leakage of the anastomosis. These studies demonstrated that inhibition of perioperative pancreatic secretion is a viable treatment concept in patients undergoing major pancreatic surgery. The perioperative and prophylactic application of octreotide in patients who undergo major pancreatic resection reduces the postoperative complication rate significantly.

Transforming growth factor betas and their receptors in human liver cirrhosis

Background Transforming growth factor betas (TGF-βs) are a group of homologous polypeptides that exert pleiotropic effects on various cell types and stimulate the formation of extracellular matrix and fibrosis. To evaluate whether TGF-β isoforms (TGF-β1, TGF-β2 and TGF-β3) and their receptors (types l-lll) are also of importance in the pathophysiology of liver cirrhosis, we analysed their concomitant expression and localization in human liver cirrhosis. Patients Cirrhotic liver tissue samples were obtained from 17 patients (four women, 13 men) with a median age of 41 years (range 22–67). Normal liver tissues from ten patients (seven women, three men) with a median age of 55 years (range 45–75) served as controls. Methods The tissues were fixed in Bouins solution and paraffin-embedded for histological analysis. For RNA analysis, freshly obtained tissue samples were snapfrozen in liquid nitrogen and stored at −80°C until analysed. Northern blot analysis was used to examine the expression of TGF-β1, β2 and β3 and their receptors, type I (TβR-I), type II (TβR-ll) and type III (TβR-lll). Immunohistochemistry was performed to determine the localization of the corresponding proteins in the normal and the cirrhotic liver. Results Northern blot analysis revealed enhanced expression (P<0.05) of TGF-β1 (twofold increase), TGF-β2 (threefold increase) and TGF-β3 (8.5-fold increase) and of TβR-ll (threefold increase) mRNA in liver cirrhosis in comparison with normal controls. In contrast, TβR-l (ALK-5) and TβR-lll mRNA expression showed no significant changes. No TGF-β isoform immunoreactivity was present in hepatocytes in either normal livers or in liver cirrhosis. However, in liver cirrhosis, intense TGF-β1 immunoreactivity was present in bile duct and ductular epithelial cells (including ductular proliferations) and In inflammatory cells. In a few sinusoidal lining cells, faint TGF-β1 and moderate TGF-β2 immunoreactivity was present TGF-β3 immunostaining was present in bile duet and ductular epithelial cells, in inflammatory cells and in fibroblast-like spindle cells in liver cirrhosis. For TβR-l and TβR-ll, the immunoreactivity was localized in hepatocytes and biliary cells in normal and cirrhotic liver tissues, with higher intensity for TβR-ll in the cirrhotic liver. Conclusion Enhanced expression of all three TGF-β isoforms and of TβR-ll in liver cirrhosis suggests, their involvement in this fibrotic disorder. The higher immunoreactivity of the three TGF-β isoforms in the bile duct epithelial cells in cirrhotic tissues suggests a possible role of these cells in the pathogenesis of liver cirrhosis.

The Duodenum-Preserving Pancreatic Head Resection: An Organ-Preserving Operation in Chronic Pancreatitis

Patients with chronic pancreatitis often develop inflammatory enlargement of the pancreatic head. This may lead to a variety of complications on pancreatic neighboring organs often necessitating pancr

Nerve Growth Factor (NGF) steuert das Nervenwachstum und die Schmerzsymptomatik bei chronischer Pankreatitis

Neben der Destruktion des Pankreasparenchyms, mit nachfolgender exokriner Pankreasinsuffizienz, sind chronische Oberbauchschmerzen ein zweites klinisches Leitsymptom der chronischen Pankreatitis (CP). In der Schmerzgenese bei chronischer Pankreatitis werden Nervenveranderungen eine zunehmende Bedeutung beigemessen [1–4]. Bei chronischer Pankreatitis ist die Anzahl der Pankreasnerven erhoht, der Nervendurchmesser deutlich vergrosert, und das Perineurium weist deutliche Schadigungen auf [2]. Weiterfuhrende Untersuchungen zeigten, dass die Pankreasnerven aktiv wachsen, und das das Nervenwachstum und die perineurale Entzundungszellinfiltration mit der Oberbauch-Schmerzintensitat der CP Patienten korrelieren [4].

Sind TGF-βs ein Reparatur- und Regenerations-Promotor nach akuter Pankreatitis?

Die akute Pankreatitis kann in eine milde (odematose) und eine schwere Verlaufsform eingeteilt werden. Die milde Pankreatitis ist histomorphologisch durch ein Gewebsodem charakterisiert, welches nach der akuten Entzundungsphase resorbiert wird und zu keinem Funktionsverlust des Organs fuhrt. Im Gegensatz dazu kommt es bei den schweren Verlaufsformen zur Ausbildung von intra- und extrapankreatischen Nekrosen, die uber Defektbildungen ausheilen [1]. Aus Autopsiestudien weis man, das die nekrotischen Pankreasareale uber Granulationsgewebe in Bindegewebe umgewandelt werden. Eine Geweberegeneration, wie sie zum Beispiel bei der Leber bekannt ist, findet im humanen Pankreas nicht statt. Die molekularen Mechanismen, die zu dieser Fibrogenese nach akuter nekrotisierender Pankreatitis beitragen sind bisher nicht bekannt.