Search PubMed⌕ Search

Biomedical subjects

W Schmiegel

Publications and source records attributed to W Schmiegel.

At least 19 recordsLinked to original sources
PubMed2006

Basement membrane component laminin-5 is a target of the tumor suppressor Smad4.

The tumor suppressor Smad4 is involved in carcinogenesis mainly of the pancreas and colon. Functional inactivation of Smad4 is a genetically late event that occurs upon transition from premalignant stages to invasive and metastatic growth. Smad4 encodes an intracellular messenger common to all signalling cascades induced by members of the transforming growth factor-beta (TGF-beta) superfamily of cytokines. Despite extensive knowledge about the mechanisms of TGF-beta/Smad signal transduction, little is known about Smad4 targets involved in the transition to malignancy. The hallmark of invasive growth is a breakdown of the basement membrane (BM), a specialized sheet of extracellular matrix produced through cooperation of epithelial and stromal cells. Laminin-5, a heterotrimeric epithelial-derived BM component, is commonly lost in carcinomas but not in premalignant tumors. Herein, we report that in human colon and pancreatic tumor cells, Smad4 functions as a positive transcriptional regulator of all three genes encoding laminin-5. Coordinate re-expression of the three laminin-5 chains induced by reconstitution of Smad4 leads to secretion and deposition of the heterotrimeric molecule in BM-like structures. These data define the expression control of an essential BM component as a novel function for the tumor suppressor Smad4.

Adenocarcinoma↗
PubMed2006

Phase I study of the humanised anti-EGFR monoclonal antibody matuzumab (EMD 72000) combined with gemcitabine in advanced pancreatic cancer.

The humanised anti-epidermal growth factor receptor (EGFR) monoclonal antibody matuzumab (formerly EMD 72000) is active against pancreatic cancer in preclinical studies. This phase I study assessed the safety and potential benefit of combined treatment with matuzumab and standard-dose gemcitabine. Three groups of chemotherapy-naive advanced pancreatic adenocarcinoma patients (n=17) received escalating doses of matuzumab (400 mg weekly, 800 mg biweekly, or 800 mg weekly) and gemcitabine (1000 mg m-2 weekly in weeks 1-3 of each 4-week cycle). Toxicity, antitumour activity, pharmacokinetic (PK) parameters, and pharmacodynamic (PD) markers in skin biopsies were evaluated. Severe treatment-related toxicities were limited to grade 3 neutropenia (n=3), leucopenia (n=1), and decreased white blood cell count (n=1). Common study drug-related adverse events were skin toxicities (grade 2=6, grade 1=7) and fever (grade 1=4). Matuzumab inhibited phosphorylated EGFR and affected receptor-dependent signalling and transduction; effects were seen even in the lowest-dose group. Pharmacokinetic data were consistent with results of matuzumab monotherapy. Partial response (PR) or stable disease occurred in eight of 12 evaluated patients (66.7%), with three PRs among six evaluated patients in the group receiving 800 mg weekly. Matuzumab in biologically effective doses with standard gemcitabine therapy appears well tolerated. The combination is feasible and may have enhanced activity.

Adenocarcinoma↗
PubMed2005

[Colorectal carcinoma in elderly patients].

The median age of patients with newly diagnosed colorectal carcinoma is about 70 years. Due to a steady rise of the life expectancy in the Western world the group of patients being older than 70 to 75 years will grow substantially. This will result in increased numbers of colorectal cancers. Patients in this age group are underrepresented in controlled clinical trials if not excluded to begin with. This is particularly true for trials conducted for adjuvant or palliative chemotherapy for colorectal cancer. Partly due to this lack of data leading to uncertainty chemotherapy is offered tients. However, the present data for patients >70 years show equall effectivity with regard to tumor response. This is true for all standard chemotherapy agents, such as 5-FU, folinic acid, capecitabine, irinotecan and oxaliplatin. With respect to toxicity some trials show an increased risk in toxic side effects for 5-FU-based combination therapies. There are no age-specific differences for the other drugs. Therefore, patients who are older than 70 years should be offered state-of-the-art chemotherapy in the adjuvant as well as palliative setting. For a balanced treatment decision one has to take into account the overall performance and organfunction alongside the mental and social capacity of the elderly patient.

Aged↗
PubMed2005

Association between the promoter polymorphism T/C at position -159 of the CD14 gene and anti-inflammatory therapy in patients with inflammatory bowel disease.

Immune response to intestinal bacteria and genetic predisposition seem to play a crucial role in the pathogenesis of inflammatory bowel disease. A single nucleotide polymorphism in the promoter of the lipopolysaccharide-receptor CD14 gene (T/C at position -159) has recently been described. To evaluate the role of the CD14 gene in anti-inflammatory therapy, the functionally relevant T(-159)-->C promoter polymorphism has been genotyped in 72 patients with inflammatory bowel disease and associated with the cumulative steroid dose. Cumulative corticosteroid dose was significantly higher in ulcerative colitis patients with the TT genotype (2447.7 +/- 927.0 mg/yr) compared with the CT genotype (142.3 +/- 142.3 mg/yr, p=0.016) and the CC genotype (391.7 +/- 272.7 mg/yr, p=0.047). In contrast, in patients with Crohn's disease there was no significant difference of the cumulative corticosteroid doses between the various T(-159)-->C promoter CD14 genotypes. An altered immune response to lipopolysaccharides with influence on the anti-inflammatory therapy seems to play a role in the genetic predisposition to ulcerative colitis. Genetic stratification will lead to the development of individualized therapies in inflammatory bowel disease.

Adrenal Cortex Hormones↗
PubMed2005

[Evaluation of outpatient management in HNPCC].

The differential diagnostic assignment of patients with hereditary non-polyposis colorectal cancer among patients with non-familial colorectal carcinoma is difficult but essential to provide early sufficient cancer screening. In order to analyze the actual situation of outpatients, 36 gastroenterologists in private practice have been interviewed with respect to their experience concerning outpatients. The interview data revealed that care for patients with colorectal cancer is a fundamental component of their work. A third of the gastroenterologists deal with patients suffering from colorectal cancer before 45 years of age. Yet these gastroenterologists did not report a single HNPCC patient. Especially gastroenterologists with long lasting experience in private practice did not mention HNPCC patients at all. These results may indicate that identifying the cases at risk for HNPCC is difficult in daily routine work. The possibility of genetic diagnostics (and counselling) should be taken into consideration in individual cases. In consequence comprehensive screening programs can be initiated for patients and their families.

Adult↗
PubMed2005

alpha-Glucosidase inhibition (acarbose) fails to enhance secretion of glucagon-like peptide 1 (7-36 amide) and to delay gastric emptying in Type 2 diabetic patients.

AIM: Acarbose is able to enhance GLP-1 release and delay gastric emptying in normal subjects. The effect of alpha-glucosidase inhibition on GLP-1 has been less evident in Type 2 diabetic patients. The aim of this study was to investigate the possible influence of acarbose on GLP-1 release and gastric emptying in Type 2 diabetic patients after a mixed test meal. PATIENTS AND METHODS: Ten Type 2 diabetic patients were tested with 100 mg acarbose or placebo served with a mixed meal that was labelled with 100 mg 13C-octanoic acid. Plasma concentrations of glucose, insulin, C-peptide, glucagon, GLP-1 and GIP were determined over 6 h. Gastric emptying was measured by determining breath 13CO2 using infrared absorptiometry. Statistics repeated-measures anova. RESULTS: Gastric emptying rates (t1/2: 162 +/- 45 vs. 163 +/- 62 min, P = 0.65) and plasma concentrations (increasing from approximately 12 to approximately 25 pmol/l, P = 0.37) and integrated responses of GLP-1 (P = 0.37) were not changed significantly by acarbose treatment. Postprandial plasma glucose concentrations (P < 0.0001) and their integrated responses were lowered by acarbose (by 64%; P = 0.016). The plasma concentrations of insulin and C-peptide were reduced (P = 0.007 and 0.057, respectively) by acarbose, while glucagon was not changed (P = 0.96). GIP plasma concentrations (increasing with placebo from approximately 10 to approximately 85 pmol/l and with acarbose to approximately 55 pmol/l (P < 0.0001) and their integrated responses were significantly lowered (by 43%) by acarbose (P = 0.021). After 2 weeks of acarbose treatment (50 mg t.i.d. for the first and 100 mg t.i.d. for the second week, n = 6), similar results were found. CONCLUSIONS: In hyperglycaemic Type 2 diabetic patients, ingestion of acarbose with a mixed test meal failed to enhance GLP-1 release and did not influence gastric emptying.

Acarbose↗
PubMed2005

A case-control study of tyrosine phosphatase (PTPN22) confirms the lack of association with Crohn's disease.

In Crohn's disease (CD), the whole gastrointestinal tract can be affected by discontinuous and transmural inflammation. The terminal ileum and colon are especially prone to inflammation that comprises granulomata and later intestinal and perianal fistulas. Genome-wide linkage and epidemiological studies established genetic predisposition factors to CD. Recently, a variation of the intracellular protein tyrosine phosphatase nonreceptor-type 22 (PTPN22) was associated with several autoimmune diseases. Here, we analysed the functionally relevant polymorphism R620W (rs 2476601) of the PTPN22 gene in 146 patients suffering from CD using restriction fragment length polymorphism (RFLP) analyses. This study revealed evidence that PTPN22 variation may have no influence in the genetic predisposition to CD, at least not in another well-characterized Caucasian cohort.

Amino Acid Substitution↗
PubMed2004

The G2964A polymorphism of the STAT6 gene in inflammatory bowel disease.

BACKGROUND AND AIMS: Linkage of inflammatory bowel diseases to chromosome 12p13.2-q24.1 (IBD2) has been confirmed in several genome wide screens. The STAT6 gene is located within this chromosomal region. The transcription factor STAT6 is involved in the regulation of the TH1/TH2 immune response. Increased production of TH1 cytokines is crucial in the pathogenesis of Crohn's disease. PATIENTS AND METHODS: Therefore, we genotyped a single nucleotide polymorphism in the 3' untranslated region of the STAT6 gene (G2964A) in 243 patients with Crohn's disease, 100 patients with ulcerative colitis and 548 healthy controls. RESULTS: In comparison to controls, the G allele and the GG genotype frequencies were significantly increased only in Crohn's disease patients without a variation in the CARD15 gene (p<0.03 and p<0.02, respectively). CONCLUSIONS: Alterations in the STAT6 pathway may play a crucial role in the pathogenesis of distinct subgroups of patients with Crohn's disease.

Adult↗
PubMed2004

[Clinical utility of EUS-FNA in upper gastrointestinal and mediastinal disease].

BACKGROUND: Endoscopic ultrasound (EUS)-guided fine-needle aspiration biopsy (EUS-FNA) is increasingly used for the diagnosis of malignant and benign disease in the region of the upper GI tract. We prospectively investigated the clinical accuracy and safety of this method in unselected patients under routine conditions. PATIENTS AND METHODS: 101 consecutive patients (median 61.5 years; 56 female) were enrolled in the study, in whom a total of 106 tissue biopsies were obtained by using EUS-FNA. Major indications for EUS-FNA were suspicious lesions located in the mediastinum, esophagus, stomach, pancreas, liver, biliary system, adrenals or retroperitoneum. A longitudinal echoendoscope (HITACHI FG-34UX) equipped with a standard 22G -aspiration needle was used. The aspirated specimens were analyzed further by using standard cytology and/or histology. Lymph-node biopsies were additionally subjected to flow-cytometry (FACS-light-chain restriction). Surgery was used for reference (where available). In the remaining cases the final diagnosis obtained by the clinical course and all available imaging and histologic informations (ultrasound, CT, MRT) was used for reference. RESULTS: EUS-FNA caused no serious complications. In 6/106 specimen (5.6 %) no sufficient cell material could be aspirated. In the remaining 100 specimens EUS-FNA reached an overall sensitivity of 78 % and a specificity of 100 %, while the accuracy was 89 % and the positive and negative predictive values were 100 % and 81 %, respectively. The greatest diagnostic accuracy was achieved in mediastinal and retroperitoneal lesions, while the accuracy of EUS-FNA in pancreatic lesions and perigastric lymph nodes was distinctly smaller (<80 %). Addition of FACS studies in patients with suspected malignant lymphoma increased the diagnostic accuracy in the small number of patients included in the study. CONCLUSION: EUS-FNA improves the tissue-based diagnosis of suspicious lesions in locations that are difficult to access (e. g., posterior mediastinum). EUS-FNA is safe, while its diagnostic accuracy is relatively high. Our preliminary data suggest that flow-cytometry may improve the fine-needle based diagnosis of non-Hodgkin s lymphoma, which should be further investigated.

Adrenal Glands↗
PubMed2004

[Diagnostic utility of capsule endoscopy in occult gastrointestinal bleeding].

BACKGROUND AND OBJECTIVE: The video-capsule endoscopy (CE) of the small intestine is a novel innovative procedure for outpatient use that can detect even small lesions of the mucosa of the small intestine. Aim of this retrospective clinical study was to evaluate the diagnostic value of CE in a clinical routine setting. PATIENTS AND METHODS: Between July 2001 and October 2002 we investigated 42 patients with suspected gastrointestinal bleeding by CE. In all patients, the previous upper and lower endoscopy work-up was normal. In some cases additional procedures such as bloodpool scintigraphy, angiography, small-bowel enteroclysis or push-enteroscopy were performed. RESULTS: CE detected relevant pathological findings in 23 out of 42 Patients (55 %). The majority of findings in the CE consisted of angiodysplasia (n = 16), ulcer and haemorrhagical erosions (n = 10), one Ulcus Dieulafoy and additional polyps of the small intestine (n = 2). In 4 cases an inflammatory small-bowel disease was detected. These findings could be confirmed by Re-endoscopy. The information provided was helpful to direct further diagnostic and treatment options. In 14 cases (33 %) CE-findings steered additional diagnostic and therapeutic steps. We conclude that CE is safe and has a high diagnostic yield. CONCLUSION: M2A video CE is likely to become an integral part of the algorithm of diagnostic of occult gastrointestinal bleeding after exclusion of other causes of anemia and negative upper and lower endoscopy work-up.

Adult↗
PubMed2004

Blood glucose control in healthy subject and patients receiving intravenous glucose infusion or total parenteral nutrition using glucagon-like peptide 1.

AIMS: It was the aim of the study to examine whether the insulinotropic gut hormone GLP-1 is able to control or even normalise glycaemia in healthy subjects receiving intravenous glucose infusions and in severely ill patients hyperglycaemic during total parenteral nutrition. PATIENTS AND METHODS: Eight healthy subjects and nine patients were examined. The volunteers received, in six separate experiments in randomised order, intravenous glucose at doses of 0, 2 and 5mg kg(-1) min(-1), each with intravenous GLP-1 or placebo for 6 h. Patients were selected on the basis of hyperglycaemia (>150 mg/dl) during complete parenteral nutrition with glucose (3.2+/-1.4 mg kg(-1) min(-1)), amino acids (n=8; 0.9+/-0.2 mg kg(-1) min(-1)), with or without lipid emulsions. Four hours (8 a.m. to 12 a.m. on parenteral nutrition plus NaCl as placebo) were compared to 4 h (12 a.m. to 4 p.m.) with additional GLP-1 administered intravenously. The dose of GLP-1 was 1.2 pmol kg(-1) min(-1). Blood was drawn for the determination of glucose, insulin, C-peptide, GLP-1, glucagon, and free fatty acids. RESULTS: Glycaemia was raised dose-dependently by glucose infusions in healthy volunteers (p<0.0001). GLP-1 ( approximately 100-150 pmol/l) stimulated insulin and reduced glucagon secretion and reduced glucose concentrations into the normoglycaemic fasting range (all p<0.05). In hyperglycaemic patients, glucose concentrations during the placebo period averaged 211+/-24 mg/dl. This level was reduced to 159+/-25 mg/dl with GLP-1 (p<0.0001), accompanied by a rise in insulin (p=0.0002) and C-peptide (p<0.0001), and by trend towards a reduction in glucagon (p=0.08) and free fatty acids (p=0.02). GLP-1 was well tolerated. CONCLUSIONS: Hyperglycaemia during parenteral nutrition can be controlled by exogenous GLP-1, e.g. the natural peptide (available today), whereas the chronic therapy of Type 2 diabetes requires GLP-1 derivatives with longer duration of action.

Adult↗
PubMed2004

Oral capecitabine vs intravenous 5-fluorouracil and leucovorin: integrated efficacy data and novel analyses from two large, randomised, phase III trials.

This study evaluates the efficacy of capecitabine using data from a large, well-characterised population of patients with metastatic colorectal cancer (mCRC) treated in two identically designed phase III studies. A total of 1207 patients with previously untreated mCRC were randomised to either oral capecitabine (1250 mg m(-2) twice daily, days 1-14 every 21 days; n=603) or intravenous (i.v.) bolus 5-fluorouracil/leucovorin (5-FU/LV; Mayo Clinic regimen; n=604). Capecitabine demonstrated a statistically significant superior response rate compared with 5-FU/LV (26 vs 17%; P<0.0002). Subgroup analysis demonstrated that capecitabine consistently resulted in superior response rates (P<0.05), even in patient subgroups with poor prognostic indicators. The median time to response and duration of response were similar and time to progression (TTP) was equivalent in the two arms (hazard ratio (HR) 0.997, 95% confidence interval (CI) 0.885-1.123, P=0.95; median 4.6 vs 4.7 months with capecitabine and 5-FU/LV, respectively). Multivariate Cox regression analysis identified younger age, liver metastases, multiple metastases and poor Karnofsky Performance Status as independent prognostic indicators for poor TTP. Overall survival was equivalent in the two arms (HR 0.95, 95% CI 0.84-1.06, P=0.48; median 12.9 vs 12.8 months, respectively). Capecitabine results in superior response rate, equivalent TTP and overall survival, an improved safety profile and improved convenience compared with i.v. 5-FU/LV as first-line treatment for MCRC. For patients in whom fluoropyrimidine monotherapy is indicated, capecitabine should be strongly considered. Following encouraging results from phase I and II trials, randomised trials are evaluating capecitabine in combination with irinotecan, oxaliplatin and radiotherapy. Capecitabine is a suitable replacement for i.v. 5-FU as the backbone of colorectal cancer therapy.

Administration, Oral↗
PubMed2004

[Colorectal cancer: current treatment options].

Colorectal Cancer is one of the leading causes for cancer related death in the industrialized world. The 5 year overall survival is only 50 - 60 %, although 70 - 80% of the patients are potentially cured by surgical resection. During the last 10 years intensive clinical studies helped to establish the value of adjuvant therapy for colorectal cancer. The introduction of new chemotherapeutic agents like Irinotecan and Oxaliplatin, has led to a significant increase in tumor response and median survival in patients with colorectal carcinoma receiving adjuvant or palliative chemotherapy. In the later situation the sequential application of new combination therapies enables an overall survival of exceeding more than 20 month. In addition the targeted manipulation of molecular tumor mechanisms with new substances like monoclonal antibodies against the epidermal growth factor receptor or the vascular endothelial growth factor shows promising effects. Besides the encouraging improvement of treatment results the introduction of the new drugs has also led to more complexity within choice, strategy and conduction of specific therapies. This manuscript introduces actual treatment concepts and their impact on colorectal cancer.

Antibodies, Monoclonal↗