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Helmut Friess

Publications and source records attributed to Helmut Friess.

At least 109 records · Page 6Linked to original sources
PubMed2004

Differential expression of connective tissue growth factor in inflammatory bowel disease.

Inflammatory bowel disease consists of Crohn's disease (CD) and ulcerative colitis (UC). A major clinical problem in some patients is to differentiate clearly between these entities, which is important when planning appropriate medical and surgical treatment. Connective tissue growth factor (CTGF), a novel peptide involved in fibrotic disorders, was analyzed in the present study in CD and UC patients to evaluate its possible role in these two disorders. Twenty-five normal human intestinal tissue samples were obtained through an organ donor program. CD tissues were obtained from 28 individuals undergoing partial intestinal resection (17 small bowel; 11 large bowel) due to complications of the disease. UC tissue samples were obtained from 16 patients undergoing colectomy due to complications of the disease. Expression of CTGF was studied by Northern blot analysis. In situ hybridization was used to localize mRNA moieties in the tissue samples. Northern blot analysis revealed an average 5-fold increase in CTGF mRNA expression in 89% (25/28) of CD tissue samples by comparison with normal controls (p < 0.0001). In contrast, in UC samples CTGF mRNA levels were comparable to those of normal controls. However, UC tissue samples exhibited enhanced TGF-beta1 mRNA levels (4-fold; p < 0.05). In situ hybridization in CD samples showed CTGF mRNA localized especially in fibroblasts within the submucosal layer, around lymph follicles and in some areas of intense damage in the proximity of the luminal surface, whereas inflammatory cells were devoid of any CTGF mRNA signal. The present data indicate that CTGF plays a different role in IBD and might be useful, especially in those cases with unusual disease presentation, to better differentiate UC and CD. In addition, our data indicate a crucial role for CTGF in CD, where fibrosis and stenosis are frequent complications that require surgery.

Adolescent↗
PubMed2004

Indian hedgehog signaling pathway: expression and regulation in pancreatic cancer.

Pancreatic cancer is an aggressive malignancy that exhibits a number of genetic and epigenetic alterations. Indian hedgehog (Ihh) and its 2 signaling receptors, patched (Ptc) and smoothened (Smo), are involved in pancreatic development and regulation of beta-cell function as well as in certain human tumors. In the current study, we analyzed the expression, distribution and function of Ihh and its receptors in pancreatic cancer. Quantitative RT-PCR and immunohistochemistry were utilized to analyze the expression, localization and transcriptional regulation of Ihh, Ptc and Smo. The effects of inhibition and stimulation of the hedgehog signaling pathway on pancreatic cancer cell growth were examined by the MTT cell growth assay. By quantitative RT-PCR, Ihh, Ptc and Smo mRNA levels were increased 35-, 1.2- and 1.6-fold, respectively, in pancreatic cancer tissues in comparison to normal pancreatic tissues. By immunohistochemistry, Ihh, Ptc and Smo were expressed in the islet cells of normal and cancerous tissues and in pancreatic cancer cells. The growth of pancreatic cancer cells was dose-dependently inhibited by the hedgehog antagonist cyclopamine through G0/G1 arrest. In contrast, Ihh agonists exhibited no significant effect on pancreatic cancer cell growth. TGF-beta1 repressed Ihh transcription in a TGF-beta1-responsive pancreatic cancer cell line, but had no effect on the other tested cell lines. In conclusion, Ihh and its receptors Ptc and Smo are expressed in pancreatic cancer, and blockage of hedgehog signaling results in inhibition of pancreatic cancer cell growth, suggesting that aberrant activation of the Ihh signaling pathway contributes to tumor development in this malignancy.

Adult↗
PubMed2004

Thioredoxin is downstream of Smad7 in a pathway that promotes growth and suppresses cisplatin-induced apoptosis in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive human malignancy in which Smad7 is commonly overexpressed. Analysis by differential display identified thioredoxin-1 (TRX) as a gene whose basal expression is increased in COLO-357 pancreatic cancer cells engineered to overexpress Smad7. To delineate the biological consequences of TRX overexpression, we assessed TRX mRNA levels in PDAC and studied the effects of increased TRX levels in Smad7-overexpressing cells. By northern blotting, TRX mRNA levels were increased in PDAC samples by comparison with the normal pancreas. Moreover, analysis of laser-captured pancreatic cancer cells revealed parallel increases in Smad7 and TRX mRNA levels. Retroviral infection of an antisense TRX cDNA suppressed TRX protein levels and blunted the increased capacity of Smad7-overexpressing cells to form colonies in soft agar. 1-Methyl-propyl-2-imidazolozyl disulfide, a TRX inhibitor, markedly suppressed the growth of sham-transfected COLO-357 cells and enhanced the growth inhibitory actions of cis-diamminedichloroplatinum(II) (CDDP). CDDP also induced apoptosis, as evidenced by induction of DNA laddering, PARP cleavage, and caspase-3/9 activities. These pro-apoptotic actions were greatly attenuated in Smad7-overexpressing cells, which exhibited a more prolonged association of TRX with the apoptosis inducer apoptosis signal-regulating kinase-1, and enhanced nuclear factor kappaB activation in response to CDDP. These findings suggest that TRX is downstream of Smad7 in a pathway that confers a growth advantage to pancreatic cancer cells and that increases their resistance to CDDP-mediated apoptosis, implying novel regulatory functions for Smad7.

Antineoplastic Agents↗
PubMed2004

Enhanced expression of 14-3-3sigma in pancreatic cancer and its role in cell cycle regulation and apoptosis.

14-3-3sigma belongs to the 14-3-3 family of proteins, which are involved in the modulation of diverse signal transduction pathways. Loss of 14-3-3sigma expression has been observed in a number of human cancers, suggesting that it may have a role as a tumor suppressor gene. The aim of the study was to investigate the expression and the functional role of 14-3-3sigma in pancreatic ductal adenocarcinoma (PDAC). Expression of 14-3-3sigma was analyzed using laser capture microdissection (LCM), quantitative real-time-PCR (QRT-PCR), DNA arrays, immunohistochemistry and western blot analysis. The role of 14-3-3sigma in apoptosis and cell cycle regulation was evaluated by western blotting, immunoprecipitation and FACS analysis. By QRT-PCR, 14-3-3sigma mRNA levels were 54-fold increased in pancreatic adenocarcinoma in comparison with normal pancreatic samples and localized in pancreatic cancer cells as determined by LCM. In pancreatic cancer cells, the degree of 14-3-3sigma expression was not decisive for the maintenance of G(2)/M cell cycle checkpoint or induction of apoptosis. Responses to radiation or apoptosis-inducing agents were neither accompanied by a significant 14-3-3sigma accumulation nor by a change in association of 14-3-3sigma with cdc2, bad and bax. In conclusion, the marked over-expression of 14-3-3sigma in PADC together with multiple known genetic and epigenetic alterations of potential 14-3-3sigma interacting partners suggests an important role of aberrant 14-3-3sigma downstream signaling in pancreatic cancer.

14-3-3 Proteins↗
PubMed2004

Moxifloxacin penetration into human gastrointestinal tissues.

OBJECTIVE: Moxifloxacin is a recently developed fourth-generation methoxyquinolone with a broad spectrum of activity against both Gram-positive and Gram-negative aerobic bacteria and anaerobes. The aim of the present study was to assess the penetration of moxifloxacin into gastrointestinal (GI) mucosal tissues to evaluate its potential role as an antimicrobial drug in bacterial infections of the GI tract. PATIENTS AND METHODS: Twenty-eight patients undergoing GI-tract surgery received 400 mg of moxifloxacin twice pre-operatively [eight patients orally (po) and 20 patients intravenously (iv)], of whom 22 completed the study. Mucosal tissues (three stomach, three small bowel and 16 colon) and serum samples were collected and moxifloxacin concentrations were measured by HPLC. RESULTS: The highest tissue concentrations were detected in the mucosa of the stomach (10.9 +/- 5.1 mg/kg), followed by colon mucosa (7.8 +/- 7.1 mg/kg after iv; 6.6 +/- 3.6 mg/kg after po) and small bowel mucosa (5.4 +/- 0.5 mg/kg). The tissue-to-serum ratio of moxifloxacin was 2.0 +/- 1.6 in the small bowel mucosa, 5.8 +/- 3.4 and 6.8 +/- 3.9 in the colon mucosa after po and iv administration, respectively, and 9.7 +/- 5.7 in the stomach mucosa. CONCLUSION: Moxifloxacin penetrates into and accumulates in the mucosa of the stomach, small bowel and colon. The clinical applicability of moxifloxacin administration for bacterial GI-tract infections should be investigated in controlled trials.

Adult↗
PubMed2004

A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer.

BACKGROUND: The effect of adjuvant treatment on survival in pancreatic cancer is unclear. We report the final results of the European Study Group for Pancreatic Cancer 1 Trial and update the interim results. METHODS: In a multicenter trial using a two-by-two factorial design, we randomly assigned 73 patients with resected pancreatic ductal adenocarcinoma to treatment with chemoradiotherapy alone (20 Gy over a two-week period plus fluorouracil), 75 patients to chemotherapy alone (fluorouracil), 72 patients to both chemoradiotherapy and chemotherapy, and 69 patients to observation. RESULTS: The analysis was based on 237 deaths among the 289 patients (82 percent) and a median follow-up of 47 months (interquartile range, 33 to 62). The estimated five-year survival rate was 10 percent among patients assigned to receive chemoradiotherapy and 20 percent among patients who did not receive chemoradiotherapy (P=0.05). The five-year survival rate was 21 percent among patients who received chemotherapy and 8 percent among patients who did not receive chemotherapy (P=0.009). The benefit of chemotherapy persisted after adjustment for major prognostic factors. CONCLUSIONS: Adjuvant chemotherapy has a significant survival benefit in patients with resected pancreatic cancer, whereas adjuvant chemoradiotherapy has a deleterious effect on survival.

Aged↗
PubMed2004

Microcystic tubulopapillary carcinoma of the pancreas: a new tumor entity?

An unusual pancreatic tumor with microcystic and tubulopapillary features was observed in a 53-year-old woman. The tumor presented as a large, focally cystic mass in the head of the pancreas, which compressed the surrounding structures. The histological and immunohistochemical analysis revealed a neoplasm that could not be assigned to any of the known pancreatic tumor types. At the molecular level, the tumor showed inactivation of the DPC4/SMAD4 gene, deletion of exon 1 of the p16(INK4A) gene and a point mutation at codon 34 (GGA>AGA) of beta-catenin. Transcriptional profiling analyses and subsequent correspondence cluster analysis demonstrated that the transcriptional profile of the tumor differed distinctly from that of ductal adenocarcinomas, pancreatic cystic tumors and normal pancreatic tissues. These data suggest that the neoplasm most likely represents a new pancreatic tumor entity, which we would like to refer to as microcystic tubulopapillary tumor.

Adenocarcinoma↗
PubMed2004

Oligoclonal T-cell populations in an inflammatory pseudotumor of the pancreas possibly related to autoimmune pancreatitis: an immunohistochemical and molecular analysis.

Inflammatory pseudotumors (IPT), also known as inflammatory myofibroblastic tumors (IMT), are benign inflammatory processes that may have an infectious etiology and are very rare in the pancreatico-biliary region. Recent studies suggest a biological distinction between IPT and IMT, the latter being a true neoplastic process. We describe a case of pancreatic IPT, originally diagnosed as malignancy, which presumably recurred 4 months after the operation. Histologically, the tumor consisted of a smooth muscle actin and CD68-positive spindle cell population and a more abundant mononuclear inflammatory cell population, primarily composed of macrophages and T-lymphocytes. Inflammatory cells were the source of connective tissue growth factor and transforming growth factor-beta1 and tended to accumulate around nerves and blood vessels, as well as around residual pancreatic parenchymal elements, where an intense angiogenetic response was detected. Comparative genomic hybridization analysis of the tumor showed no chromosomal imbalances. Polymerase chain reaction-based analysis of T-cell receptor gamma gene rearrangement revealed an oligoclonal pattern. These findings suggest that the pathogenesis of aggressive cases of IPT could be related to the development of an intense and self-maintaining immune response, with the emergence of clonal populations of T-lymphocytes. The relation of the pancreatic IPT to autoimmune pancreatitis is emphasized.

Adenocarcinoma↗
PubMed2004

Expression and functional significance of CDC25B in human pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related deaths. Deregulation of cell-cycle control is thought to be a crucial event in malignant transformation, and CDC25 phosphatases are a family of cyclin-dependent kinase activators, which act at different points of the cell cycle, including G1-S and G2-M transition. Here, we investigated the expression and functional significance of CDC25s in PDAC. CDC25B mRNA expression levels in human pancreatic tissue samples were analysed by cDNA array, quantitative PCR and Northern blotting. Immunohistochemistry was carried out to localize and quantify CDC25B expression. Two specific CDC25B inhibitors were utilized to determine the functional relevance of CDC25B. By quantitative RT-PCR, CDC25B mRNA was overexpressed in pancreatic cancer (7.5-fold) in comparison to the normal pancreas. Strong nuclear CDC25B immunoreactivity was present in both pancreatic and metastatic cancer samples, and there was a marked increase of the percentage of positive cells in primary cancer (48.6+/-16.3%) and metastatic tissues (71.7+/-3.1%) compared to normal samples (8.3+/-1.8%). Two CDC25B inhibitors reduced the growth of pancreatic cancer cell lines, resulting in the accumulation of phosphorylated CDC2 and G2/M arrest. These findings demonstrate an important role of CDC25B in cell-cycle progression, raising the possibility that inhibition of CDC25B may have therapeutic potential in pancreatic cancer.

Adenocarcinoma↗
PubMed2004

Antiangiogenic activity of genistein in pancreatic carcinoma cells is mediated by the inhibition of hypoxia-inducible factor-1 and the down-regulation of VEGF gene expression.

BACKGROUND: Previous reports indicate that Genistein, a naturally occurring isoflavonoid, exhibits strong antiangiogenic activity. The underlying mechanism of inhibition, however, remains unclear. Among the biologic effects of Genistein are the inhibition of tyrosine kinases and the inhibition of hypoxic activation of hypoxia-inducible factor-1 (HIF-1), one of the main regulators of VEGF gene expression. METHODS: Hypoxic cell culture was performed in a modular incubator chamber. Vascular endothelial growth factor (VEGF) protein secretion was measured using the enzyme-linked immunosorbent assay, binding of DNA by HIF-1 was measured using the electrophoretic mobility shift assay, and mRNA quantification was performed using Northern blot analysis. Pancreatic carcinoma was studied in an orthotopic murine model. Angiogenesis in vivo was quantified by staining xenograft tumors for endothelial cell markers. RESULTS: VEGF protein secretion was dose-dependently suppressed with increasing doses of Genistein. Furthermore, treatment of pancreatic carcinoma cells with Genistein led to impaired activation of HIF-1 under hypoxic culture conditions. Northern blot analysis indicated that VEGF mRNA expression decreased upon treatment with Genistein, both under normoxic and hypoxic culture conditions. In vivo, Genistein inhibited tumor growth for xenograft pancreatic carcinoma cells, whereas extensive hypoxia was observed in xenograft tumors and was not influenced by Genistein therapy. Similarly, decreased VEGF mRNA levels were observed in Genistein-treated Capan-1 xenograft tumors. CONCLUSIONS: The current study indicates that the previously reported antiangiogenic activity of Genistein probably is mediated by the inhibition of HIF-1, an important regulator of VEGF gene homeostasis, particularly under low-oxygen conditions. Therefore, this bioactive compound may well be beneficial to patients with pancreatic carcinoma.

Animals↗
PubMed2004

Still any role for transduodenal local excision in tumors of the papilla of Vater?

Tumors of the papilla and ampulla of Vater are rare neoplasms which are usually detected at an early stage due to their symptoms. The accurate preoperative histological diagnosis and staging of ampullary tumors is often difficult and inconclusive, leading to controversy over the adequate treatment of these lesions. Three procedures are currently being used to treat such tumors. Pancreatoduodenectomy (PD) is a procedure with low morbidity and mortality at experienced centers, and is considered the treatment of choice for invasive carcinoma and large benign ampullary lesions with suspicion of malignancy. Transduodenal local excision (TDE) of ampullary tumors is a relatively simple procedure with operative morbidity and mortality rates comparable to PD. TDE is challenged at endoscopic centers by endoscopic snare excision (ESE). Due to technical advances, the safety and outcomes of ESE for ampullary tumors have improved in recent years. ESE and TDE represent adequate methods for treatment of benign tumors and also for small malignant tumors detected at an early stage if the diagnosis and stage have been accurately established preoperatively. Due to the safety of PD and the technical advances of ESE, TDE is reserved for selected patients. Randomized controlled studies are needed to establish the correct indications for PD, TDE, and ESE.

Adenocarcinoma↗
PubMed2004

Pancreatic lesions in von Hippel-Lindau syndrome: report of a case.

von Hippel-Lindau (VHL) syndrome is a rare autosomal inherited disorder. A germline mutation predisposes carriers to the development of multiple tumors, the most common of which are hemangioblastoma, renal cell carcinoma, pheochromocytoma, and islet cell and cystic tumors of the pancreas, the kidney, and epididymis. Visceral manifestations, such as cystadenoma of the pancreas, occur late in its course. We report the case of a 20-year old woman who presented with vomiting and dizziness, most probably caused by a palpable mass in the upper abdomen, diagnosed as pancreatic cysts. She had undergone surgery for cerebellar hemangioblastoma 4 years previously. In view of her young age, preservation of pancreatic function was crucial because of the expense of enzyme therapy and the difficulties with follow-up. Therefore, we performed cyst enucleation and distal pancreatectomy, which relieved her symptoms. She has been well with no sign of recurrence for 18 months. This case highlights that a well-prepared surgical procedure can cure a patient with pancreatic cysts caused by VHL, living in difficult socioeconomic conditions.

Adult↗
PubMed2004

Inflammatory response after abdominal surgery.

Surgical manipulation of the gut elicits an inflammatory cascade within the intestinal muscularis that contributes to postoperative bowel dysmotility. A range of cytokines is sequentially released into the peritoneal fluid following abdominal surgery, their concentrations reflecting the magnitude of surgical trauma. The overproduction of inflammatory mediators might have detrimental effects on organ function and contribute to the enhanced risk of anastomotic leakage in the presence of sepsis. Specific cellular immune functions such as the microbicidal activity of peritoneal phagocytes are depressed after elective surgery, imposing a risk of infectious complications. Laparoscopic surgery decreases the local and systemic production of cytokines and acute-phase reactants, and better preserves peritoneal immunity compared with open surgery. As concluded from animal studies, the gas used for the pneumoperitoneum may possess substantial immunomodulatory activity.

Abdomen↗
PubMed2004

Tumor hypoxia correlates with metastatic tumor growth of pancreatic cancer in an orthotopic murine model.

BACKGROUND: The role of tumor hypoxia has become a major focus in cancer research since it influences both local and systemic tumor growth. Oxygen measurements taken in human pancreatic cancer have shown extremely low oxygen tension. The aim of this study was to develop an orthotopic model for pancreatic cancer that mimics the specific tumor microenvironment and to evaluate the role of tumor oxygenation in local tumor growth and systemic dissemination in this model. MATERIALS AND METHODS: We used two established human pancreatic cancer cell lines for xenobiotic tumor induction. After subcutaneous tumor formation one small tumor piece was transplanted into the pancreatic parenchyma of mice of the different study groups. Upon orthotopic tumor induction tumor oxygenation was measured with the Eppendorf histograph. Histological evaluation was performed with pimonidazole, an in vivo marker of hypoxia. RESULTS: The tumor take rate was 100% in this model. Metastatic tumor dissemination occurred within the abdominal cavity, and distant metastasis were observed in the lung parenchyma. Oxygen measurements taken in various abdominal organs and xenograft tumor showed a high variation between different organs and xenografted tumors. Tumor oxygenation correlated well with the metastatic score in this model. Furthermore hypoxia was found both in the tumor center and also at the rim of a growing tumor mass. A high number of hypoxic cells were detectable in metastases located in the lung parenchyma. CONCLUSION: This study provides experimental evidence that tumor hypoxia influences metastatic disease progression and supports recent assumptions that tumor hypoxia is actively involved in progression of pancreatic cancer. It further demonstrates that tumor hypoxia is not only found in the center of a tumor mass, but also occurs at the invasion front.

Abdominal Neoplasms↗
PubMed2004

Cell wounding in early experimental acute pancreatitis.

It is well established that damage to the outer membrane of cells is a common phenomenon allowing abnormal transmission of substances into the cytosol. Penetration of albumin into acinar cells has been detected in experimental acute pancreatitis, raising the possibility that membrane damage is a very early event, potentially representing the first changes leading to pancreatitis. To determine if direct damage to the cell membrane is a key factor during induction of acute pancreatitis, thus altering the balance of extra- and intracellular substances, fluorescein-dextran was administered with supramaximal doses of caerulein via the jugular vein or by injection directly into the pancreas. This tracer rapidly penetrates into cells. Two patterns of tracer penetration are observed: cytosolic and vesicular/vacuolar. Fluorescein-dextran administered intravenously with caerulein penetrates into the cytosol of acinar cells within 10 min. Strong cytoplasmic fluorescence occurs within 5 min after direct injection. It may be concluded that supramaximal caerulein, administered in vivo, damages the cell membrane of acinar cells, allowing large molecules to enter the cytosol. Thus Ca(2+) and other substances may enter the cells in abnormally high concentrations, initiating the cellular changes characteristic of pancreatitis. The results raise the question whether membrane wounding may play a role in the initiation of human pancreatitis.

Acute Disease↗
PubMed2004

Heidelberg's first experiences in establishing a living-donation liver transplantation programme.

BACKGROUND: Since indications for liver transplantation (LTx) have increased and the shortage of brain dead transplant organs continues, an increase in deaths related to extended waiting periods can be documented. Living-related LTx (LRLTx) is a good alternative that can help compensate the shortness of organs for transplantation and can reduce waiting periods and deaths related to a long waiting list. We started a LRLTx programme at the transplantation centre, Department of Surgery at the University of Heidelberg to increase our transplantation activities. In this article we present our primary experiences and protocol. METHODS: From September 2002 to June 2003, three LRLTx were performed. Indications in recipients were hepatocellular carcinoma in two cases and liver cirrhoses due to hepatitis B in one patient. Two patients received the right liver (segments V-VIII) of their donors. One patient received the complete liver collected as a Domino LTx. All liver transplants were performed without the use of a venous bypass. RESULTS: The peri- and post-operative courses of our donors were without complications, except for an infected intraabdominal bilioma, which was drained interventionally. The donors were fully able to work after the operation. The coordinative and logistical work should not be underestimated. CONCLUSIONS: This therapy should only be offered and performed in centres with excellent expert knowledge in liver and transplantation surgery.

Adult↗