Biomedical subjects

J Kleeff

Publications and source records attributed to J Kleeff.

At least 19 recordsLinked to original sources

PubMed2006

Hsulf-1 regulates growth and invasion of pancreatic cancer cells.

BACKGROUND: Hsulf-1 is a newly identified enzyme with arylsulphatase activity that can regulate the sulphation state of cell-surface heparan sulphate proteoglycans (HSPGs). In vitro overexpression of this enzyme in pancreatic cancer cells decreases responsiveness to fibroblastic growth factor-2, as Hsulf-1 is up regulated in primary pancreatic adenocarcinoma. AIM: To further analyse the functions of the Hsulf-1 enzyme in vitro and in vivo with respect to growth, invasion and tumorigenicity. METHODS AND RESULTS: Transfection of Panc-1 pancreatic cancer cells with a full-length Hsulf-1 expression vector resulted in increased invasiveness and adhesiveness. An in vivo xenograft nude mouse tumour model showed a markedly reduced growth potential of Hsulf-1-expressing Panc-1 cells, which correlated with a considerably lower proliferation rate. Hsulf-1-positive nude mouse tumours showed better development of interstitial matrix structures, with increased blood vessel density in these tumours. In an orthotopic model, Hsulf-1-positive tumours exhibited enhanced local invasiveness. In human primary pancreatic cancers there was strong staining for sulphated HSPGs, which was markedly reduced in metastatic tissue samples. CONCLUSION: Hsulf-1-mediated desulphation of HSPGs reduces the growth ability of Panc-1 pancreatic cancer cells, but increases the basal invasiveness of these cells, suggesting an important role of this enzyme in pancreatic cancer progression.

Adenocarcinoma↗

PubMed2006

Molecular characterisation of pancreatic ductal adenocarcinoma in patients under 40.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) rarely affects people under 40. OBJECTIVES: To determine whether the clinical, pathomorphological and genetic features of PDAC occurring in young patients (<or=40 years) differ from those in elderly patients. METHODS: Clinical and pathomorphological data were obtained from seven patients presenting with PDAC, with age ranging from 35 to 40 years of age (mean 38 years). All tumours were characterised by using immunohistochemistry and molecular genetics. RESULTS: All seven patients were women and lacked an association to cancer-predisposing genetic syndromes. Four patients were smokers and one had non-hereditary chronic pancreatitis. Pathomorphologically, tumours in three patients displayed moderate differentiation and four showed poor differentiation including one adenosquamous carcinoma. All tumours showed overexpression of transforming growth factor beta1 and loss or significant reduction of Smad4. Accumulation of p53 and overexpression of epidermal growth factor receptor (EGFR) were seen in five and four patients, respectively. No expression of p16, oestrogen hormone receptor or progesterone receptor was found. Mismatch repair gene products (MutL homologue 1 (MLH1), MSH2 and MSH6) were expressed in all tumours. Mutational analyses showed K-ras mutations in only three of the seven tumours. CONCLUSION: A large clinical, pathomorphological and genetic overlap of PDAC in young patients aged under 40 is seen with that in elderly patients. The existence of yet undefined initiating events of pancreatic carcinogenesis is suggested by the low rate of K-ras mutations, in at least a subgroup of young patients.

Adult↗

PubMed2006

Tenascin C and annexin II expression in the process of pancreatic carcinogenesis.

Tenascin C (TNC) is a component of the provisional extracellular matrix (ECM) that characterizes solid tumours. Cell surface annexin II is a high-affinity receptor for large TNC splice variants. The aim of this study was to analyse whether TNC and annexin II play a role in the development of pancreatic ductal adenocarcinoma (PDAC). PDAC is characterized by a rich ECM populated by pancreatic stellate cells, which play a crucial role in pancreatic desmoplasia. The mRNA and protein levels of TNC and of annexin II were analysed in pancreatic tissues by DNA array, quantitative reverse transcriptase-polymerase chain reaction (QRT-PCR) and immunohistochemistry. TNC large splice variants were detected by RT-PCR. Enzyme linked immunosorbent assay (ELISA) was used to measure TNC levels in serum and culture supernatants. TNC and annexin II mRNA levels were significantly higher in pancreatic cancer tissues than in the normal pancreas. TNC expression was detected with increased frequency in the progression from PanIN-1 lesions to PDAC, and a parallel switch from cytoplasmic to cell surface expression of annexin II was observed. Large TNC transcripts were found in pancreatic cancer and in chronic pancreatitis, but not in the normal pancreas. TNC expression was demonstrated in pancreatic stellate cells, where it could be induced by tumour necrosis factor alpha (TNFalpha), transforming growth factor beta1 (TGF-beta1) and by cancer cell supernatants supplemented with TGF-beta1. In conclusion, the expression of TNC and cell surface annexin II increases in the progression from low-grade PanIN lesions to pancreatic cancer. Pancreatic stellate cells are identified as a source of TNC in pancreatic tissues, possibly under the influence of soluble factors released by the tumour cells.

Adenocarcinoma↗

PubMed2006

[Autoimmune pancreatitis--a surgical disease?].

The term autoimmune pancreatitis (AIP) describes a nonalcoholic, chronic lymphoplasmocytic pancreatitis. The lymphoplasmocytic infiltration is characterized by periductal localization of predominantly CD4-positive T cells, fibrosis, and acinar atrophy, frequently resulting in stenosis of the main pancreatic and distal common bile ducts. Imaging studies often reveal a diffuse narrowing of the pancreatic main duct and swelling of the pancreatic head wrongly suggesting the presence of a malignant tumor. Clinical signs include mild abdominal pain, jaundice, recurrent episodes of acute pancreatitis, and even new-onset diabetes mellitus. Additionally, AIP can be associated with other autoimmune diseases such as Sjögren's syndrome, primary sclerosing cholangitis, chronic inflammatory bowel diseases, and retroperitoneal fibrosis. Serological markers include autoantibodies and increased levels of gamma globulin and especially IgG4. Steroids seem to be effective in improving clinical symptoms as well as in the resolution of pancreatic and bile duct narrowing. This distinguishes AIP from other forms of pancreatitis and from pancreatic neoplasms. Further studies of the underlying pathophysiologic mechanisms, prognosis, and new diagnostic tools are needed to provide adequate and effective treatment in the future. In this article, we summarize the current knowledge about AIP and present 17 cases that underwent surgical resection at our institution from 2003 to 2004.

Adolescent↗

PubMed2006

[Results and significance of lymphadenectomy in pancreatic cancer].

Pancreatic adenocarcinoma is one of the most aggressive human solid tumors with a 5-year survival rate of less than 5%. The only chance for cure is complete resection of the tumor. This can be achieved in approximately 8-15% of all cases since solely localized tumors and a small part of locally advanced carcinomas may be resected. However, many patients suffer from a local relapse after surgical therapy. In order to improve the long-term survival of surgically treated patients, extended lymphadenectomy after partial duodenopancreatectomy was introduced. Some retrospective studies from the 80 s showed improved survival rates for those patients in whom extended lymphadenectomy was performed. However, these results were not confirmed in following randomised controlled prospective studies. Extended lymphadenectomy can be performed with slightly increased morbidity and equal mortality but survival is not improved. Therefore, standard lymphadenectomy is recommended in patients undergoing duodenopancreatectomy for pancreatic cancer. Extended lymphadenectomy (with retroperitoneal clearance) should only be accomplished within controlled clinical studies.

Adenocarcinoma↗

PubMed2005

Osteopontin influences the invasiveness of pancreatic cancer cells and is increased in neoplastic and inflammatory conditions.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies, with an overall 5-year survival rate of less than 5%. Invasive tumor growth and early metastasis are two important reasons for this dismal prognosis. Osteopontin (OPN) is a secretory protein with a variety of functions, for example in cell adhesion and migration, inflammatory reaction and apoptosis. In this study the functional role of OPN in human pancreatic cancer and its potential use as a disease marker were analyzed. By real time quantitative PCR, there was a 2.2-fold and 1.6-fold increase of OPN mRNA in pancreatic cancers (n = 23) and chronic pancreatitis samples (n = 22), respectively, compared to normal pancreatic tissues (n = 20). Immunohistochemical analysis demonstrated OPN staining in 60% of the primary pancreatic tumors and in 72% of the lymph node and liver metastases. ELISA analysis of serum samples obtained from pancreatic cancer patients (n = 70), chronic pancreatitis patients (n = 12), and healthy donors (n = 20) showed a 1.6-fold increase in OPN serum levels in patients with tumors and a 1.9-fold increase in patients with chronic pancreatitis. Recombinant human OPN significantly increased the invasiveness of pancreatic cancer cells, without having any impact on cell proliferation. In addition, down regulation of OPN by specific siRNA molecules decreased pancreatic cancer cell invasion. In conclusion, OPN serum levels in pancreatic cancer and chronic pancreatitis patients are not significantly different, thereby restricting its role as a prognostic or follow-up marker. Our results do suggest, however, that blockade of OPN might be useful as a therapeutic approach to inhibit invasion and metastasis of pancreatic cancer cells.

Adenocarcinoma↗

PubMed2004

[Kausch-Whipple pancreaticoduodenectomy. Technique and results].

The Kausch-Whipple operation is the standard procedure for resection of pancreatic head cancer, distal bile duct cancer, and periampullary cancers. It is also used for some cases of chronic pancreatitis. Traditionally, this operation is associated with high perioperative morbidity and mortality. The aim of our study was to present our current technique for Kausch-Whipple pancreaticoduodenectomy and to demonstrate that acceptable perioperative and long-term outcomes can be achieved by a standardised technique in a high-volume centre.

Follow-Up Studies↗

PubMed2004

Loss of heterozygosity in the HLA class I region in human pancreatic cancer.

An altered human leukocyte antigen (HLA) class I expression constitutes an important tumor-escape mechanism counteracting T-cell mediated immune responses. We utilized the technique of microsatellite analysis to characterize the loss of heterozygosity (LOH) in the HLA class I region in 24 samples of patients with human ductal pancreatic carcinoma. The expression of HLA class I and the infiltration by T cells were studied in parallel by standard immunohistochemistry. The present study demonstrates LOH in the HLA class I region in five patients with pancreatic carcinoma. Immunohistochemical analysis showed that pancreatic carcinomas were frequently characterized by a total or partial loss of expression in HLA class I antigen. The positive or negative LOH status corresponded with the expression analysis in eight cases. Reduction of HLA class I expression without LOH was found in 14 cases. Lymphocyte infiltration with CD3+, CD4+, and CD8+ T cells did not show significant differences between LOH-positive and LOH-negative tumors. In conclusion, LOH does not seem to be the only factor for the reduced expression of HLA class I antigen as well as for the T-cell infiltration in this type of tumor.

CD3 Complex↗

PubMed2004

RUNX3 expression in primary and metastatic pancreatic cancer.

AIM: Runx transcription factors are important regulators of lineage specific gene expression, cell proliferation, and differentiation. Runx3 expression is lost in a high proportion of gastric cancers, suggesting a tumour suppressive role in this malignancy. This study investigates the expression and localisation of Runx3 in pancreatic tissues. METHODS: Quantitative polymerase chain reaction was used to measure Runx3 mRNA. Immunohistochemistry was carried out to localise Runx3 in normal pancreatic tissues, and in primary and metastatic pancreatic ductal adenocarcinoma (PDAC). Basal and transforming growth factor beta1 (TGFbeta1) induced Runx3 expression was analysed in cultured pancreatic cancer cell lines. RESULTS: Runx3 expression was low to absent in normal pancreatic tissues, but increased in a third of cancer tissues. Runx3 was present only in islets in normal pancreas, whereas in pancreatic cancers, Runx3 was detected in the cancer cells of seven of 24 samples analysed. In addition, it was expressed by lymphocytes in six of the 16 cases with lymphocyte infiltration. In pancreatic cancer cell lines, Runx3 mRNA was present in Colo-357 and T3M4 cells, but was low to absent in the other cell lines tested. TGFbeta1 repressed Runx3 mRNA expressed in Colo-357 cells, and had no effect on Runx3 expression in the other pancreatic cancer cell lines. CONCLUSION: Runx3 expression is restricted to islets in the normal pancreas. In contrast, a considerable proportion of pancreatic tumours express Runx3, and its expression is localised in the tumour cells and in the infiltrating lymphocytes. Thus, Runx3 might play a role in the pathogenesis of PDAC.

Adenocarcinoma↗

PubMed2004

Expression analysis of MAC30 in human pancreatic cancer and tumors of the gastrointestinal tract.

Meningioma-associated protein, MAC30, is a protein with unknown function and cellular localization that is differentially expressed in certain malignancies. In the present study, the expression of MAC30 in a variety of normal and cancerous human gastrointestinal tissues, with special emphasis on pancreatic tissues was analyzed. Quantitative RT-PCR was utilized to compare MAC30 expression levels. In situ hybridization and immunohistochemistry were carried out to localize MAC30 mRNA and protein expression in normal and cancerous tissue samples of the esophagus, stomach, colon and pancreas. Furthermore, the effects of TGF-beta on the transcription of MAC30 mRNA were examined in pancreatic cancer cells. MAC30 mRNA was expressed in a wide variety of normal human tissues, being most abundant in testicular and gastric tissue samples. MAC30 mRNA levels were significantly increased in breast and colon cancer, but significantly decreased in pancreatic and renal cancer. TGF-beta down-regulated MAC30 mRNA levels in certain pancreatic cancer cells. MAC30 protein was localized in normal pancreatic tissues, mainly in acinar and islet cells, and in normal colon, gastric and esophageal tissues especially in the mucosal cells. MAC30 was strongly present in tubular complexes in pancreatic cancer tissues but weak to absent in pancreatic cancer cells of primary tumors and metastases. In contrast, esophageal, gastric and colon tumors displayed strong MAC30 immunoreactivity in the cancer cells. In conclusion, MAC30 is expressed in various normal and diseased human tissues. MAC30 up-regulation in certain tumors and down-regulation in others suggests that this protein plays a distinct role in human malignancies.

Adult↗

PubMed2003

Microarray-based identification of differentially expressed growth- and metastasis-associated genes in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) has an extremely poor prognosis. To improve diagnosis and treatment, key mechanisms of deregulated molecular functions have to be identified. Using microarray analysis, the expression patterns of 5600 human genes were assessed in PDAC by comparison with the normal pancreas and chronic pancreatitis (CP). The expression of 467 of 5600 genes was increased in PDAC in comparison to the normal pancreas, and the expression of 120 of these genes was not increased in CP. In addition, 341 of 5600 genes were expressed at decreased levels in PDAC tissues, of which 96 were decreased in comparison to both normal and CP tissues. Thus, a total of 808 of 5600 human genes were differentially expressed in pancreatic cancer. The identification of a large panel of altered genes in PDAC will stimulate additional studies that will lead to improved understanding of the molecular mechanisms underlying pancreatic malignant growth.

Adenocarcinoma↗

PubMed2003

[Central case management in surgery].

Up to now, in most surgical departments there has been no central patient management coordinating the admission, the diagnostic work-up, and the surgical procedures of patients with the resources available in the hospital. In future, however, it will be essential for surgical departments to establish such a central patient management, not only in view of the importance of patient-oriented medicine but also considering the planned introduction of diagnosis related groups. A central patient management will reduce preoperative and overall length of stay through adequate organisation and communication structures. In addition, a central patient management will make optimal use of the available resources in terms of operation rooms and hospital beds. In this article, we will present our basic concept of a central patient management in a surgical university department.

Diagnosis↗

PubMed2003

[Surgical standard therapy for cancer of the pancreas].

Approximately 150,000 people worldwide and 40,000 people in Europe die each year of pancreatic cancer,making it one of the five leading causes of cancer-related death and one of the most aggressive human tumors. Resection is still the only option that offers a chance of cure for pancreatic cancer patients. Recent studies have highlighted the correlation between the number of pancreatic resections per year and postoperative mortality. Thus, large centers of pancreatic surgery have mortality rates below 5%, whereas centers with lower caseloads have mortality rates exceeding 10%. Standards have been established for the surgical treatment of pancreatic cancer;however, these are often not based on evidence derived from randomized, controlled studies. Resection for pancreatic cancer is carried out if there are no metastases present and if the tumor is locally resectable; i.e., if there is no complex vessel invasion. However, an isolated infiltration of the portal vein is not considered a contraindication for surgery. At present, there are no evidenced-based data available on palliative (R2) resections,which might be a therapeutic option in centers with low morbidity/mortality. Three randomized controlled trials clearly show that the pylorus-preserving Whipple is equal to the classical Whipple in terms of oncological effectiveness, morbidity, and quality of life. Therefore, the pylorus-preserving Whipple is increasingly considered the standard operation for tumors of the pancreatic head. Based on randomized trials, extended lymph node dissection cannot generally be recommended for pancreatic cancer. Further prospective, randomized, multicenter trials have to be carried out in the upcoming years to find new approaches in the therapy of pancreatic cancer and to establish evidence-based treatment strategies for this disease.

Adenocarcinoma↗

PubMed2003

COMP is selectively up-regulated in degenerating acinar cells in chronic pancreatitis and in chronic-pancreatitis-like lesions in pancreatic cancer.

BACKGROUND: Chronic pancreatitis (CP) is an inflammatory disease of the pancreas characterized histomorphologically by progressive development of fibrosis and atrophy of the pancreatic parenchyma. Cartilage oligomeric matrix protein (COMP) is a member of the thrombospondin (TSP) family of extracellular glycoproteins that is expressed in CP tissues. In the present study, we characterized COMP mRNA and protein expression in the normal pancreas, chronic pancreatitis, and pancreatic cancer tissues. METHODS: 15 normal pancreatic tissues, 14 CP tissues and 14 pancreatic cancer tissues were analyzed by Northern blotting, Western blotting, in situ hybridization and immunohistochemistry. RESULTS: COMP mRNA and protein were detected at moderate to high levels in chronic pancreatitis tissues, at moderate levels in pancreatic cancer tissues, but at low levels in normal pancreatic tissues and in four pancreatic cancer cell lines. COMP mRNA signals and immunoreactivity were strongly present in the cytoplasm of degenerating acinar cells in CP tissues as well as in CP-like lesions in pancreatic cancer tissues. COMP protein was also present in the fibrotic tissue in CP. In contrast, COMP expression was weak to absent in the cytoplasm of cancer cells in pancreatic cancer tissues, and in ductal cells and islet cells in normal pancreatic tissues. CONCLUSION: COMP is preferentially expressed in degenerating acinar cells in CP and in CP-like areas in pancreatic cancer, suggesting a potential role of this gene in the course of acinar cell degeneration and dedifferentiation. COMP might thus serve as a marker for tissue destruction and disease activity in CP.

Adolescent↗

PubMed2003

How Helicobacter Pylori changed the life of surgeons.

Helicobacter Pylori infection has been identified as a pathogenic factor in a number of gastroduodenal diseases, most importantly in gastric and duodenal ulcer disease. This association and the development of H. PYLORI eradication therapies has had a tremendous influence on the surgical therapy for these disorders. Decades ago, surgery was the therapy of choice for gastric and duodenal ulcers. Now, however, the first line of therapy includes treatment of H. PYLORI infection, suppression of gastric acid secretion, and protection of gastric mucosal barriers combined with a range of endoscopic procedures. These developments have had a major impact on the indications for surgery in benign gastroduodenal diseases. In addition, advances in our understanding of the pathogenetic mechanisms of H. PYLORI infection have also changed our views of gastric mucosa-associated lymphoid tissue lymphoma, gastric cancer, and gastroesophageal reflux disease.

Digestive System Surgical Procedures↗

PubMed2003

Preferential expression of cystein-rich secretory protein-3 (CRISP-3) in chronic pancreatitis.

BACKGROUND: Chronic pancreatitis (CP) is a progressive inflammatory process resulting in exocrine and endocrine pancreatic insufficiency in advanced stages. Cysteine-rich secretory protein (CRISP-3) has been identified as a defense-associated molecule with predominant expression in the salivary gland, pancreas and prostate. AIMS: In this study, we investigated CRISP-3 expression in normal pancreatic tissues, chronic pancreatitis tissues, pancreatic cancer tissues and pancreatic cancer cell lines, as well as in other gastrointestinal organs. MATERIALS AND METHODS: 15 normal pancreatic tissues, 14 chronic pancreatitis tissues and 14 pancreatic cancer tissues as well as three pancreatic cancer cell lines were analyzed. Moreover, hepatocellular carcinoma and esophageal, stomach and colon cancers were also analyzed together with the corresponding normal controls. RESULTS: CRISP-3 was expressed at moderate to high levels in chronic pancreatitis tissues and at moderate levels in pancreatic cancer tissues but at low levels in normal pancreatic tissues, and was absent in three pancreatic cancer cell lines. CRISP-3 expression was below the level of detection in all cancerous gastrointestinal tissues and in all normal tissues except 2 of 16 colon tissue samples. CRISP-3 mRNA signals and immunoreactivity were strongly present in the cytoplasm of degenerating acinar cells and in small proliferating ductal cells in CP tissues and CP-like lesions in pancreatic cancer tissues. In contrast, CRISP-3 expression was weak to absent in the cytoplasm of cancer cells as well as in acinar cells and ductal cells in pancreatic cancer tissues and normal pancreatic tissues. CONCLUSION: These results reveal that the distribution of CRISP-3 in gastrointestinal tissues is predominantly in the pancreas. High levels of CRISP-3 in acinar cells dedifferentiating into small proliferating ductal cells in CP and CP-like lesions in pancreatic cancer suggests a role of this molecule in the pathophysiology of CP.

Adolescent↗

PubMed2003

Distribution of Indian hedgehog and its receptors patched and smoothened in human chronic pancreatitis.

Indian hedgehog (IHH) and its receptors patched (PTC) and smoothened (SMO) belong to the hedgehog family of signaling molecules, which are essential for a variety of patterning events during mammalian tIssue development. IHH plays a role in pancreas organogenesis and differentiation, as well as in the regulation of insulin production. In the present study, the expression of IHH and its receptors was analyzed in normal human pancreatic and chronic pancreatitis (CP) tIssues using Northern blotting, immunohistochemistry and Western blotting, and was correlated with clinicopathological parameters. In addition, the effects of inhibition and stimulation of the hedgehog signaling pathway on cell growth were determined in TAKA-1 normal pancreatic ductal cells. IHH mRNA was expressed in the normal human pancreas and CP tIssues, with slightly higher expression levels in CP. Using immunohistochemistry, IHH and its receptors were localized mainly in the islet cells of the normal pancreas. In CP, IHH and its receptors were present in the cells forming tubular complexes and in the islets with a different signal pattern compared with the islets in the normal pancreas. Correlation between diabetic and non-diabetic CP patients revealed no significant difference in IHH, SMO, or PTC immunoreactivity. Inhibition of hedgehog signaling in TAKA-1 pancreatic ductal cells using cyclopamine significantly reduced their growth through cell cycle arrest, while stimulation of the IHH pathway enhanced the growth of these cells. In conclusion, IHH and its receptors are expressed in the normal human pancreas and in CP, yet with a different distribution and cellular localization. IHH signaling may be involved in the pathogenesis of CP, i.e. in the formation and proliferation of tubular complexes and in islet cell dysfunction.

Adult↗

PubMed2002

[Central patient management in surgery].

Diagnosis-Related Groups↗