[Role of social medicine within the German Federal Employment Agency]. / Aufgabe des Arztes in der Sozialmedizin am Beispiel der Bundesagentur für Arbeit.

Social medicine deals with the interrelationships between health and society-as a cross-sectional subject within medicine and a bridging subject at the interfaces to other specialist disciplines. In the public and within the health system, social medicine still does not receive the attention it should be given, despite to its medical and socioeconomic importance. A significant proportion of social medicine specialists in Germany work as experts for social security providers. Using the example of the Medical Specialist Service ("Ärztlichen Dienstes", ÄD) of the German Federal Employment Agency ("Bundesagentur für Arbeit", BA), the medical tasks in social medicine are outlined. About 350 full-time medical employees nationwide as well as other contracted physicians support the specialists of the employment agencies and job centers to integrate those seeking training, jobs and employees with health restrictions into the labor market or maintaining an existing integration. In each individual case, they assess the extent of the health restrictions, the performance/earning ability, the suitability for training and professions as well as the requirement and type of vocational rehabilitation services. The ÄD's approximately 500,000 expert opinions each year are not only of far-reaching importance for the BA's affected customers, but also contribute to the responsible, effective, and accurate use of social system resources.

Influence of change in surgical practice for benign thyroid disease on postsurgical outcome-Single-center experience in 1400 patients.

PURPOSE: To evaluate the rate of surgical complications during the change from subtotal resection to hemithyroidectomy or thyroidectomy over a period of 17 years. METHODS: All operations for benign goiter at our hospital were analyzed for the periods 1996-2002 (Group 1) and 2003-2012 (Group 2). The groups were compared for recurrent laryngeal nerve damage, hypocalcemia, and other surgical complications directly postoperatively. RESULTS: In total, 1462 patients were operated on for goiter between 1996 and 2012. There were 1219 patients who underwent a primary thyroid operation, whereas 50 patients had surgery for recurrence. Postoperative histology revealed thyroid cancer in 193 patients (13.2%). In Group 1, 42.7% of all operated lobes were performed as lobectomies and 57.3% as subtotal resections; in Group 2, 74.4% were performed as lobectomies and 25.6% as subtotal resections. No differences were found for reduced vocal cord function (2.4% vs. 1.9%, p = 0.746) and recurrent laryngeal nerve paralysis in the postoperative laryngoscopy (2.9% vs. 1.8%, p = 0.675). Postoperative hypoparathyroidism was detected in 13.66% in Group 1 and in 19.80% in Group 2 after bilateral resections (p = 0.037). There was no difference in the rate of reoperations for cancer between both groups (43.4% vs. 52.1%, p = 0.182). CONCLUSION: Surgical practice changed from subtotal to lobectomies for benign goiter over a period of 17 years without change in laryngeal nerve damage but with increasing rates of postoperative hypocalcemia.

Taurolidine induces epithelial-mesenchymal transition via up-regulation of the transcription factor Snail in human pancreatic cancer cell lines.

PURPOSE: The taurine derivative taurolidine (TRD) exerts anti-neoplastic effects in a variety of tumor models. On the other hand, TRD at low doses was shown to reduce cell-cell adhesion, a prerequisite for metastasis. The aim of this study was to elucidate the effects of low-dose TRD on pancreatic cancer. METHODS: Human pancreatic cancer cell lines representing diverse states of differentiation were exposed to TRD for 24 h. Cell viability was assessed by MTT assay and trypan blue staining, apoptosis by caspase-3/7 activity, and flow-cytometric cell cycle analysis. Expression of Snail and E-cadherin was analyzed by polymerase chain reaction and Western blotting. RESULTS: MTT-tested viability of all pancreatic cancer cell lines decreased dose-dependently up to 50 % of the untreated control. In contrast to staurosporine TRD (100 and 250 µM) did not induce apoptosis but increased the percentage of cells in G1/G0 arrest. Correlation of MTT test and trypan blue staining revealed a decreased adherence of vital tumor cells at 250 µM TRD. This was associated with reduced expression of the adhesion molecule E-cadherin and an increased expression of the transcription factor Snail, a regulator of epithelial-mesenchymal transition (EMT). CONCLUSION: Low-dose TRD reduces not only viability but also cell-cell adherence and E-cadherin expression of pancreatic cancer cells, whereas the expression of the EMT inducer Snail was increased. By induction of these EMT hallmarks, low-dose TRD may promote metastasis in pancreatic cancer.

Non-invasive quantification of anti-angiogenic therapy by contrast-enhanced MRI in experimental pancreatic cancer.

BACKGROUND: Currently, early changes of tumor vasculature after angiogenesis inhibition can only be evaluated by histopathology, a method not suitable in a clinical setting. PURPOSE: To quantify effects of different angiogenesis inhibitors on the microvasculature of orthotopically implanted pancreatic cancers by contrast-enhanced magnetic resonance imaging (MRI) in order to establish a non-invasive technique for monitoring antiangiogenic cancer treatment. MATERIAL AND METHODS: DSL-6A/C1 pancreatic cancers were implanted in the pancreas of 109 Lewis rats. Three weeks later, antiangiogenic treatment was initiated by administration of Bevacizumab (n = 38) or Suramin (n = 27) while the control group (n = 44) remained untreated. Dynamic MRI was performed 24 h, 1 week, and 4 weeks after treatment initiation. Fractional tumor plasma volume (fPV, %) and vascular permeability (K(PS), mL/min/100 cc) were calculated based on the MRI data by using a pharmacokinetic model. RESULTS: Twenty-four hours after the initial dose, a significant decline in K(PS) was observed in the Bevacizumab group compared to the control and Suramin group (0.002 ± 0.008; 0.057 ± 0.046 and 0.064 ± 0.062 (mean ± SD); P < 0.05). At 1 week, fPV was significantly smaller in Bevacizumab and Suramin treated tumors compared to control tumors (6.25 ± 2.74, 7.47 ± 3.44, and 15.10 ± 9.97, respectively; P < 0.05). Differences in tumor volumes were first observed after 4 weeks of treatment with significantly larger control tumors (4380.3 ± 1590.6 vs. 869.6 ± 717.2 and 1676.5 ± 2524.1 mm(3); P < 0.05). CONCLUSION: Dynamic MRI can quantify antiangiogenic effects on tumor microvasculature before changes in tumor volumes are detectable. Thus, this technique is a reasonable addition to morphological MRI and may be applied as an alternative to histopathology.

In vitro and in vivo antitumor activity of cetuximab in human gastric cancer cell lines in relation to epidermal growth factor receptor (EGFR) expression and mutational phenotype.

BACKGROUND: Targeting the epidermal growth factor receptor (EGFR) pathway is an important approach for a variety of tumors. This study assessed the effect of cetuximab, an anti-EGFR monoclonal antibody, on three gastric cancer cell lines with different phenotypes in vitro and in a therapeutic orthotopic murine gastric cancer model. METHODS: Three human gastric cancer cell lines (AGS, MKN-45, NCI-N87) were evaluated for cell surface EGFR expression, and K-ras and BRAF mutations. In vitro, the effects of cetuximab, carboplatin, irinotecan, and docetaxel were investigated. Orthotopic tumors derived from MKN-45 and NCI-N87 were established in nude mice. After 4 weeks, the animals received cetuximab (1 mg/kg, weekly i.p.) or carboplatin (20 mg/kg, weekly i.p.), or both agents. The volume of the primary tumor and local and systemic tumor spread were determined at autopsy at 14 weeks. Tumor sections were immunostained for EGFR, as well as stained for CD31 to analyze microvessel density. RESULTS: Cell surface expression of EGFR was found only in AGS and NCI-N87 cells. AGS cells displayed a codon 12 K-ras mutation, and all three cell lines were BRAF wild-type. In vitro, cetuximab significantly reduced cell viability and proliferation only in EGFR-positive/K-ras wild-type NCI-N87 cells (-48%). In vivo, cetuximab in combination with carboplatin synergistically reduced tumor volume (-75%), dissemination (-63%), and vascularization (-47%) in NCI-N87 xenografts. Tumors derived from EGFR-negative MKN-45 cells were unaffected by cetuximab. CONCLUSIONS: Cetuximab is effective in K-ras wild-type, EGFR-expressing gastric cancer cell lines and xenografts. In vivo, the combination of cetuximab with carboplatin displayed synergistic antitumor activity.

Genes associated with epithelial-mesenchymal transition: possible therapeutic targets in ductal pancreatic adenocarcinoma?

Epithelial to mesenchymal transition (EMT) is a biological process that allows well-differentiated, polarized epithelial cells to undergo a conversion to motile, unpolarized mesenchymal cells. EMT plays crucial roles during implantation, embryogenesis, and organ development (Type 1 EMT), is associated with tissue regeneration and organ fibrosis (Type 2 EMT), and involved in cancer invasion, metastasis, and drug resistance (Type 3 EMT). Since aggressiveness and drug resistance are hallmarks of ductal pancreatic cancer, significant effort has been undertaken in recent years to elucidate molecular EMT mechanisms in this dismal malignancy. This represents a formidable challenge for several reasons: EMT is a dynamic process, both with regard to spatial and temporal heterogeneity. Moreover, EMT is induced and regulated by a complex network of traditional signaling pathways and new players like microRNAs. Interestingly, similar molecular characteristics link EMT-type cells also to the concept of cancer stem cells. This review tries to integrate the current knowledge regarding EMT and pancreatic cancer; furthermore to outline not only the perspective on novel EMT-associated therapeutic targets, but also on overcoming drug resistance by interfering with EMT.

A novel antiangiogenic approach for adjuvant therapy of pancreatic carcinoma.

INTRODUCTION: Surgical therapy remains the only curative option for pancreatic ductal adenocarcinoma. But even after complete resection, almost all patients suffer from local tumor recurrence. Current standard adjuvant therapy with gemcitabine does not impressively affect the recurrence rate. The aim of this study was to evaluate a novel anti-angiogenic adjuvant treatment strategy by targeting the vascular endothelial growth factor receptor (VEGFR). We assayed the effects of a novel VEGFR inhibitor (ZK261991) on pancreatic carcinoma. ZK261991 is a highly selective and potent VEGFR-kinase inhibitor, which is orally available. METHODS: We used a previously established nude mouse orthotopic pancreatic cancer resection model. Subcutaneous donor tumor fragments (1 mm(3)) derived from human pancreatic cancer cell lines HPAF-2 and AsPC-1 were implanted in the pancreatic tail of 48 nude mice. Fourteen days afterwards, all mice underwent a histologically confirmed curative tumor resection followed by daily adjuvant oral therapy with ZK261991 (50 mg/kg; n = 24) vs. placebo (n = 24). The mice were sacrificed after 12 weeks of therapy or in case of defined endpoints. All sacrificed mice underwent autopsy. A dissemination score (local and systemic tumor spread), size of recurrent tumor mass, survival, and weight loss/gain were surveyed. RESULTS: Kaplan-Meier analysis of survival showed a significant benefit for mice treated with ZK261991 after HPAF-2 tumor resection: 83.8 days (95% CI 73.9-93.6) vs. 60.9 days (95% CI 48.9-73.0), p = 0.006. Adjuvant treatment with ZK261991 of AsPC-1-derived tumors showed a tendency towards a benefit compared to control but no significant difference: 75.8 days (95% CI 59.7-91.9) vs. 65.7 days (95% CI 51.6-79.7). There were no significant differences in dissemination score and size of recurrent tumor mass between the treatment groups. CONCLUSION: Adjuvant anti-angiogenic therapy with the novel VEGFR-inhibitor ZK261991 resulted in a significant survival benefit after curative tumor resection in a clinically relevant orthotopic animal model of pancreatic cancer. Combination of anti-angiogenic treatment with cytotoxic agents may further improve the results of adjuvant therapy.

Specific targeting of tumor endothelial cells by a shiga-like toxin-vascular endothelial growth factor fusion protein as a novel treatment strategy for pancreatic cancer.

PURPOSE: Tumor endothelial cells express vascular endothelial growth factor receptor 2 (VEGFR-2). VEGF can direct toxins to tumor vessels through VEGFR-2 for antiangiogenic therapy. This study aimed to selectively damage the VEGFR-2-overexpressing vasculature of pancreatic cancer by SLT-VEGF fusion protein comprising VEGF and the A subunit of Shiga-like toxin which inhibits protein synthesis of cells with high VEGFR-2 expression. EXPERIMENTAL DESIGN: Expression of VEGF and VEGF receptors was evaluated in human pancreatic cancer cells (AsPC-1, HPAF-2) and in normal human endothelial cells (HUVEC) by reverse transcription-polymerase chain reaction. Cells were treated with SLT-VEGF (0.1-10 nM), and cell viability, proliferation, and endothelial tube formation were assessed. Orthotopic pancreatic cancer (AsPC-1, HPAF-2) was induced in nude mice. Animals were treated with SLT-VEGF fusion protein alone or in combination with gemcitabine. Treatment began 3 days or 6 weeks after tumor induction. Primary tumor volume and dissemination were determined after 14 weeks. Microvessel density and expression of VEGF and VEGF receptors were analyzed by immunohistochemistry. RESULTS: SLT-VEGF did not influence proliferation of pancreatic cancer cells; HUVECs (low-level VEGFR-2) reduced their proliferation rate and tube formation but not their viability. SLT-VEGF fusion protein reduced tumor growth and dissemination, increasing 14-week survival (AsPC-1, up to 75%; HPAF-2, up to 83%). Results of gemcitabine were comparable with SLT-VEGF monotherapy. Combination partly increased the therapeutic effects in comparison to the respective monotherapies. Microvessel density was reduced in all groups. Intratumoral VEGFR-2 expression was found in endothelial but not in tumor cells. CONCLUSIONS: SLT-VEGF is toxic for tumor vasculature rather than for normal endothelial or pancreatic cancer cells. SLT-VEGF treatment in combination with gemcitabine may provide a novel approach for pancreatic cancer.

Gangrenous intrathoracic appendicitis, a rare cause of right-sided chest pain: report of a case.

Diaphragmatic hernias are becoming increasingly common due to radiofrequency ablation of malignant liver tumors. Most patients eventually present with symptoms caused by bowel obstruction. A 54-year-old woman with pleuritic pain and fever had a right-sided enterothorax probably caused by hemihepatectomy several years before. The patient was diagnosed with perforated gangrenous intrathoracic appendicitis during an emergency laparotomy for suspected incarceration of her diaphragmatic hernia. She was treated with an appendectomy and suturing of her right hemidiaphragm. An acquired diaphragmatic hernia should therefore be surgically repaired as soon as it is diagnosed in order to avoid complications.

Fluid resuscitation with human albumin or hydroxyethyl starch--are there differences in the healing of experimental intestinal anastomoses?

OBJECTIVES: Restoration of the macro- and microcirculation is important for the healing of gastrointestinal anastomoses. Colloids and crystalloids are widely used for blood volume therapy. We evaluated the effects of human albumin, hydroxyethyl starch (HES) 130/0.4 and saline on the microcirculation and on wound healing in colon anastomoses in rats. MATERIAL AND METHODS: Male Wistar rats received a colonic end-to-end anastomosis. The animals were randomized into three groups and a single 3-ml dose of either 20% human albumin, 6% HES 130/0.4 or 0.9% saline was applied intravenously. Six, 24, 48, 96 h and 2 weeks after the procedure, 10 animals per group were reanesthetized. Measurements of capillary blood flow, vessel permeability and anastomosis bursting pressure were performed. The amounts of vascular endothelial growth factor (VEGF) and IL-6 in the plasma were determined by enzyme-linked immunosorbent assays, and the mRNA levels of VEGF and collagen types I and III were measured by real-time polymerase chain reaction. RESULTS: No significant differences were found between albumin, HES 130/0.4 and saline in capillary blood flow, vessel permeability and anastomotic bursting pressure in this rat model. Concentrations of collagen I and III mRNA were significantly elevated after 96 h in animals that had received HES 130/0.4 or albumin. RNA and protein levels of VEGF and interleukin-6 were unaffected by therapy. CONCLUSIONS: Human albumin, which is still widely used in the clinical setting, had no advantage over HES 130/0.4 and saline with regard to anastomotic healing in this animal model. Nevertheless, we prefer HES 130/0.4 because it is more effective for volume therapy than saline and has a better availability and is less expensive than human albumin.

Long-term outcome of "prophylactic therapy" for familial medullary thyroid cancer.

BACKGROUND: About one quarter of all medullary thyroid cancers (MTC) are determined genetically due to a mutation in the RET proto-oncogene. The most common site of mutation is in codon 634. Therapeutic approaches toward patients at risk for the development of MTC identified by family screening programs range from total thyroidectomy to total thyroidectomy with lymphadenectomy of all 4 compartments. METHODS: We report 17 patients (median age, 13 years; range, 4-36) carrying a mutation in codon 634 of the RET proto-oncogene who were operated on prophylactically at our department. All patients underwent thyroidectomy with bilateral cervicocentral lymphadenectomy. Current calcitonin level, overall survival, and disease-free survival were analyzed by contacting general practitioners and patients. RESULTS: Tumor classification was as follows: C-cell hyperplasia, 18% (n = 3); T1 (<1 cm), 71% (n = 12); and T1 (>1 cm), 12% (n = 2). Only 2 patients had lymph node metastases (12%). These patients developed recurrent disease (median observation time, 147 months; range, 90-181). In 1 patient, the calcitonin level normalized after unilateral cervicolateral lymphadenectomy. The other patient (9 years old at primary operation) still has a persistently increased serum calcitonin level after 140 months of follow-up despite several operations for MTC. CONCLUSION: Total thyroidectomy with bilateral cervicocentral lymphadenectomy is sufficient as routine "prophylactic therapy" for patients with mutations in codon 634 of the RET proto-oncogene. Cervicolateral lymphadenectomy is indicated if calcitonin remains elevated after primary surgery. Prophylactic thyroidectomy should be performed before the development of lymph node metastases.

An orthotopic nude mouse model for preclinical research of gastric cardia cancer.

PURPOSE: A clinically relevant animal model for cancer of the esophagogastric junction does not exist. This study aimed to establish an orthotopic mouse model for human gastric cancer of the distal stomach and the gastric cardia. MATERIALS AND METHODS: Human gastric cancer cell lines AGS, MKN-45, and NCI-N87 were injected subcutaneously into nude mice. These donor tumors were harvested after 4 weeks and minced into small tumor fragments. One donor tumor fragment was orthotopically implanted into the submucosa of either gastric cardia or distal stomach in other mice. The animals were killed 4, 8, and 12 weeks after tumor implantation. Volume of the primary tumor and local and systemic tumor spread were determined. RESULTS: The implantation technique resulted in a tumor take rate of 100%. An artificial dissemination of tumor cells into the abdominal cavity due to the procedure was not observed. CONCLUSIONS: We report for the first time the development of a clinically relevant mouse model for human gastric cancer of the gastric cardia and the distal stomach. Primary tumor growth and local and systemic spread progressed continuously during the observation period and mimic the human situation of this disease. This model may be suitable to evaluate novel treatment strategies for this malignancy.

Intravital microscopic characterization of suramin effects in an orthotopic immunocompetent rat model of pancreatic cancer.

OBJECTIVES: We investigated the effect of suramin on tumor growth and spread in an immunocompetent, orthotopic rat model of pancreatic cancer and analyzed the tumor vasculature by intravital microscopy. METHODS AND METHODS: In vitro, rat ductal pancreatic cancer cells (DSL-6A) were incubated with suramin (10-800 microg/ml), and cell proliferation was assessed. In vivo, DSL-6A tumors were induced in the pancreas of Lewis rats. Animals received suramin (60 mg/kg, weekly i.p.) or the vehicle (controls). Treatment started after 3 days. Intravital microscopy after 1, 4, and 8 weeks quantified diameter, density, and permeability of tumor vessels. Primary tumor volume, local infiltration, and metastatic spread were determined at autopsy. Microvessel density was analyzed by immunohistochemistry. RESULTS: In vitro, proliferation was inhibited by suramin up to 95%. In vivo, all controls developed extensive tumor growth and spread. No tumor was detectable in half of the suramin-treated animals after 8 weeks; tumor dissemination was almost completely depressed. Suramin therapy resulted in a complete regression of tumor macrovessels and a significant reduction of microvessel density. CONCLUSION: Suramin significantly reduces primary tumor growth and dissemination in a clinically relevant rat model of pancreatic cancer and seems to play an important role for the inhibition of tumor angiogenesis.

Effect of anastomosis level on continence performance and quality of life after colonic J-pouch reconstruction.

Total mesorectal excision (TME) has become the recommended method for treatment of cancer in the middle or lower third of the rectum. Thus very low anastomoses are necessary to preserve continence, and pouch reconstruction is favored. It is unclear whether the level of anastomosis is important for continence and quality of life in colonic J-pouch reconstruction. In this investigation all patients were included who underwent curative elective anterior continuity resection with colorectal or coloanal J-pouch reconstruction for primary rectal cancer between January 2001 and December 2004. Exclusion criteria were distant metastases and any signs of recurrence at the time of investigation. Evaluation of continence performance by Wexner and Holschneider questionnaire and quality of life using the QLQ-C30 and QLQ-CR38 (EORTC) questionnaires was done 220 +/- 38 days after closure of the protective Ileostomy, which was performed 106 +/- 48 days after primary intervention. Fifty-two patients (79%) were analyzed. Colopouch rectal anastomosis was performed in eighteen cases and colopouch anal anastomosis in thirty-four cases. Fifty percent of the patients in both groups were continent for solid stool. Patients with a colopouch anal anastomosis had a significantly higher rate of incontinence for liquid stool, however. They took stool-regulating medicine more frequently and complained of fecal soiling and a restricted quality of life. Patients with a colopouch anal anastomosis had a significantly lower score on the most important points of the QLQ-C30 (emotional functioning, social functioning, pain, and quality of life). The same applied to the QLQ-CR38 for body image and problems with defecation. The quality of life of patients with a colopouch anal anastomosis was still considered acceptable compared with reference data for the normal healthy population, however. Both continence and quality of life are substantially affected by the level of the anastomosis after colonic pouch reconstruction. This suggests preservation of a small part of the rectum when oncologically feasible and performing a colopouch rectal anastomosis.

Epithelial to mesenchymal transition: expression of the regulators snail, slug, and twist in pancreatic cancer.

PURPOSE: Epithelial to mesenchymal transitions are vital for tumor growth and metastasis. Several inducers of epithelial to mesenchymal transition are transcription factors that repress E-cadherin expression, such as Snail, Slug, and Twist. In this study, we aimed to examine the expression of these transcription factors in pancreatic cancer. EXPERIMENTAL DESIGN: The expression of Snail, Slug, and Twist was detected by immunohistochemistry in tissue samples from patients with pancreatic ductal adenocarcinoma. Five human pancreatic cancer cell lines (AsPC-1, Capan-1, HPAF-2, MiaPaCa-2, and Panc-1) were analyzed by reverse transcription-PCR, real-time PCR, and Western blotting. An orthotopic nude mouse model of pancreatic cancer was applied for in vivo experiments. RESULTS: Seventy-eight percent of human pancreatic cancer tissues showed an expression of Snail, and 50% of the patients displayed positive expression of Slug. Twist showed no or only weak expression. Snail expression was higher in undifferentiated cancer cell lines (MiaPaCa-2 and Panc-1) than in more differentiated cell lines (Capan-1, HPAF-2, AsPC-1). Expression of Slug was detected in all cell lines with different intensities. Twist was not expressed. After exposure to hypoxia, the Twist gene was activated in all five pancreatic cancer cell lines. CONCLUSIONS: The transcription factors Snail and Slug are expressed in pancreatic cancer but not in normal tissue, suggesting a role in the progression of human pancreatic tumors. Twist, activated by hypoxia, may play an important role in the invasive behavior of pancreatic tumors.

Suramin inhibits not only tumor growth and metastasis but also angiogenesis in experimental pancreatic cancer.

Suramin inhibits the proliferation of several human tumors in vivo and in vitro. In this study, the effects of Suramin on proliferation and angiogenesis were investigated in human pancreatic cancer cell lines and in an orthotopic nude mouse model of human pancreatic cancer. The effects of Suramin on proliferation, viability, cell cycle, and apoptosis were studied in five human pancreatic cancer cell lines. Suramin inhibited the proliferation of pancreatic cancer cells in a dose-dependent manner and reduced viability at high concentrations. Cell cycle analysis revealed a decreased S-phase fraction in most cell lines, whereas the apoptotic fraction was not notably different. In vivo treatment with Suramin significantly reduced pancreatic tumor size (MiaPaCa-2, -74%; AsPC-1, -41%; and Capan-1, -49%) and metastatic spread (MiaPaCa-2, -79%; AsPC-1, -34%; and Capan, -38%). As a parameter for angiogenic activity, vascular endothelial growth factor (VEGF) secretion was measured, revealing reduced VEGF concentrations under Suramin treatment in both cell culture medium and ascites. Also, microvessel density quantified in primary tumors was reduced in animals treated with Suramin. Therefore, Suramin inhibits the proliferation of human pancreatic cancer in vitro and in vivo. The therapeutic effects seem to involve cell cycle kinetics and may be in part related to the antiangiogenic action of the drug.

Risk factors for clinical anastomotic leakage and postoperative mortality in elective surgery for rectal cancer.

BACKGROUND AND AIMS: Clinical anastomotic leakage remains a major problem after anterior or low anterior resection for rectal cancer. The aim of this study was to assess the association between risk factors and anastomotic leakage and postoperative mortality. MATERIALS AND METHODS: Two hundred seventy-six elective anterior or low anterior resections with anastomosis were performed and documented on-line from January 1995 to December 2004. Univariate and multivariate analyses with Bonferroni adjustment were carried out to identify relevant risk factors. RESULTS: The rate of anastomotic leakage was 14.9% (41 of 276 patients) with a mortality of 12.2% (5 of 41 patients). Overall mortality was 2.5% (7 of 276 patients). Multiple regression analysis showed that smokers had an increased risk of anastomotic leakage [odds ratio (OR), 6.42; 95% confidence interval (CI), 2.68-15.36] as well as patients with coronary heart disease (OR, 7.79; 95% CI, 2.52-24.08). Smokers (OR, 13.20; 95% CI, 2.48-7.24) and patients with coronary heart disease (OR, 23.46; 95% CI, 4.33-27.04) also had an increased risk of postoperative mortality in the univariate analysis as well as patients with anastomotic leakage (OR, 16.25; 95% CI, 3.04-16.92). CONCLUSIONS: Smoking and coronary heart disease are important risk factors for anastomotic leakage and postoperative mortality after elective resection for rectal cancer.

Selective inhibition of endothelin receptor A as an anti-angiogenic and anti-proliferative strategy for human pancreatic cancer.

Endothelin-1 (ET-1) plays a major role in tumor proliferation and angiogenesis of various types of cancer acting through endothelin receptors A and B (ET(R)A and ET(R)B). The aim of this study was to analyze the ET-1/ET(R) system in human pancreatic cancer cell lines and to evaluate the effect of a selective endothelin A inhibitor in vitro and in vivo in an orthotopic mouse model. Three different human pancreatic cancer cell lines, MiaPaCa-2, AsPC-1, and Panc-1, were studied. We found that proliferation of human pancreatic carcinoma cells expressing ET(R)A was significantly reduced with a selective antagonist. Hypoxic conditions led to improved results compared to a normoxic environment (MiaPaCa-2: -53% vs. -18%; AsPC-1: -54% vs. -46%). Proliferation of ET(R)A negative Panc-1 cells was not decreased. In vivo, the selective ET(R)A inhibition resulted in reduced angiogenesis as measured by lower microvessel densities (MiaPaCa-2: -47%; AsPC-1: -55%). The blockade of ET(R)A decreased the volume (MiaPaCa-2: -87%; AsPC-1: -28%) and metastatic spread (MiaPaCa-2: -95.5%; AsPC-1: -27%) of receptor-positive tumors, thereby increasing survival in experimental pancreatic cancer. ET(R)A blockade did not show an effect on ET(R)A negative Panc-1 tumors. Therefore, targeting ET(R)A with a selective antagonist might provide a new approach to reducing proliferation and angiogenesis in human pancreatic cancer.

VEGF antisense therapy inhibits tumor growth and improves survival in experimental pancreatic cancer.

BACKGROUND: Vascular endothelial growth factor (VEGF), a key mediator of angiogenesis, is overexpressed in pancreatic cancer. This study evaluated VEGF production in pancreatic cancer cells and the effect of VEGF antisense on growth and angiogenesis of human pancreatic cancer in a nude mouse model. METHODS: In vitro: VEGF in cell culture supernatant of pancreatic cancer cells (AsPC-1, poorly differentiated; HPAF-2, moderately differentiated) was assessed by enzyme-linked immunosorbent assay. In vivo: A VEGF antisense oligonucleotide (AS-3) was synthesized. One-mm(3) fragments of subcutaneous pancreatic cancer donor tumors were implanted into the pancreas of nude mice also receiving AS-3 (10 mg/kg/day) or vehicle intraperitoneally for 14 weeks. Primary tumor volume, metastasis, and VEGF in plasma and ascites were determined at autopsy. Microvessel density was analyzed in CD31-stained tumors. RESULTS: In vitro: Both pancreatic cancer cell lines secreted VEGF protein (AsPC-1, 4200 +/- 40 pg/10(6) cells; HPAF-2, 8120 +/- 60 pg/10(6) cells). In vivo: AS-3 reduced tumor volume in the HPAF-2 group (860 +/- 140 vs 3830 +/- 590 mm(3)) and metastatic spread in both groups (AsPC-1, 6.5 +/- 0.8 vs 16.7 +/- 0.9 points; HPAF-2, 2.5 +/- 0.2 vs 8.3 +/- 1.5 points). Tumor volume was not different in the AsPC-1 group (1050 +/- 80 vs 1400 +/- 150 mm(3)). Survival was increased in the AsPC-1 group. Plasma levels of VEGF and microvessel density in tumors were significantly reduced in treated animals. Only control animals (50%) developed ascites with high VEGF concentrations. CONCLUSIONS: Human pancreatic cancer cells secrete VEGF at biologically relevant high levels. AS-3 therapy normalizes plasma VEGF and decreases neoangiogenesis, thereby reducing tumor growth and metastasis and improving survival. AS-3-treated animals developed no ascites, suggesting decreased vascular permeability by reducing VEGF expression in pancreatic cancer cells.