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Biomedical subjects

W Kuhn

Publications and source records attributed to W Kuhn.

At least 37 records · Page 2Linked to original sources
PubMed2001

Neoadjuvant chemotherapy followed by tumor debulking prolongs survival for patients with poor prognosis in International Federation of Gynecology and Obstetrics Stage IIIC ovarian carcinoma.

BACKGROUND: Patients with advanced ovarian carcinoma of International Federation of Gynecology and Obstetrics (FIGO) Stage IIIC should be treated by radical surgical tumor debulking with the goal of complete tumor resection. Prolonged median survival can be achieved in those patients entirely free of tumor after surgery by the administration of postsurgical platinum/taxane-based chemotherapy regimens. However, residual tumor is present in the majority of patients, which limits survival prognosis. Different therapy approaches should be utilized to improve prognosis in these patients. Neoadjuvant chemotherapy could induce "downstaging" of the tumor and thus improve operability. Here, evidence of large ascites volume (>500 mL) can be used to identify those patients who could benefit from neoadjuvant chemotherapy. METHODS: In a prospective, nonrandomized Phase II study, 31 patients with advanced FIGO Stage IIIC ovarian carcinoma and large ascites volume (>500 mL) received 3 cycles of platinum/taxane-based combination chemotherapy, followed by tumor debulking surgery and 3 additional cycles of platinum/taxane-based combination chemotherapy. During the same period, 32 patients with advanced FIGO Stage IIIC ovarian carcinoma and large ascites volume (>500 mL) received conventional therapy (tumor debulking surgery followed by 6 cycles of platinum/taxane-based combination chemotherapy). The two groups were investigated and compared with respect to tumor resection rates, blood transfusion requirements, morbidity, and mortality during surgery, duration of surgery, and median survival. RESULTS: The tumor resection rate in the patient group receiving neoadjuvant chemotherapy was significantly higher (P = 0.04) than that of the conventionally treated group; the median survival time of 42 months versus 23 months also was significantly longer (P = 0.007). Time spent in surgery, blood transfusion requirements, morbidity, and mortality during surgery were not significantly different. CONCLUSIONS: Patients with advanced ovarian carcinoma of FIGO Stage IIIC who will benefit only marginally from conventional therapy can be identified by evidence of large ascites volume. Higher tumor resection rates and longer median survival can be achieved in these patients by the use of neoadjuvant chemotherapy. A prospective randomized multicenter study currently is being performed by the Society for Gynecological Oncology in Germany to confirm these findings.

Aged↗
PubMed2001

Evaluation of the gamma-synuclein gene in German Parkinson's disease patients.

Mutations in the alpha-synuclein gene are responsible for an autosomal-dominantly inherited form of Parkinson's disease (PD) and alpha-synuclein was found to be the major component of Lewy bodies in PD. Because of the high homology to alpha-synuclein and the abundance in neuronal tissues, we investigated the gamma-synuclein gene in PD. We analyzed 262 German PD patients and 179 healthy German controls via two polymorphisms in the gamma-synuclein gene. No significant differences in the allelic or genotypic distributions of the investigated polymorphisms were observed between patients and controls. In addition no evidence for an increased risk of combined genotypes of polymorphisms in the gamma-synuclein and the alpha-synuclein gene was found. Therefore, our results do not support a major role of the gamma-synuclein gene in PD.

Aged↗
PubMed2001

Decrease of methionine and S-adenosylmethionine and increase of homocysteine in treated patients with Parkinson's disease.

Levodopa is administered with dopa decarboxylase inhibitors (DDI) to prevent its peripheral degradation. This increases conversion of levodopa to 3-O-methyldopa (3-OMD) by catechol-O-methyltransferase (COMT). S-adenosylmethionine (SAM), which is synthesized from adenosine triphosphate and methionine (MET), serves as methyl donor for this O-metabolisation of levodopa with resulting conversion of SAM to total homocysteine (tHcy) via S-adenosylhomocysteine (SAH). Previous studies showed augmented plasma levels of tHcy in long-term levodopa/DDI-treated patients with Parkinson's disease (PP). Objective of this study was to compare MET, SAM, levodopa, 3-OMD, tHcy and SAH in plasma of 20 levodopa/DDI treated PP and corresponding controls. A significant decrease of MET respectively SAM and an increase of tHcy appeared in PP. SAH with its short half-life did not differ. Levodopa/DDI long-term treatment contributes to altered levels of substrates of the O-methylation cycle in PP.

Aged↗
PubMed2001

Familial parkinsonism with synuclein pathology: clinical and PET studies of A30P mutation carriers.

BACKGROUND: The authors identified the second known mutation in the alpha-synuclein(SNCA) gene, an alanine-to-proline exchange in amino acid position 30 (A30P), that cosegregates with the disease in one German family with autosomal dominantly inherited parkinsonism (ADP). The authors studied carriers of the A30P mutation to compare the phenotype of this mutation with idiopathic PD (IPD) and to assess nigrostriatal dopaminergic function in symptomatic and preclinical mutation carriers. METHODS: The pedigree of the A30P family spans five generations with five affected individuals. The authors performed detailed neurologic examinations followed by mutation analysis in 11 living individuals. In three mutation carriers, two individuals with definite PD and one person at risk for PD, they used L-[18]F-fluoro-3,4-dihydroxyphenylalanine (F-DOPA), [11]C-raclopride (RAC), and [18]F-fluorodeoxyglucose (FDG) PET to investigate presynaptic dopaminergic function, dopamine D2 receptors, and cerebral energy metabolism. The authors studied the cognitive functions of carriers of the A30P mutation using neuropsychological screening. RESULTS: PET studies revealed striatal presynaptic dopaminergic alterations consistent with sporadic IPD in two affected family members and no evidence for nigrostriatal dopaminergic dysfunction in one presymptomatic mutation carrier. Neuropsychological testing in four mutation carriers provided evidence for cognitive impairment as a frequent and early symptom of the A30P mutation; this is also supported by regional cerebral energy metabolism alterations in the clinically presymptomatic subject. CONCLUSIONS: The phenotype of the A30P mutation in the SNCA gene is similar to that of sporadic IPD, including a high variability of the age at disease onset, ranging from 54 to 76 years. The follow-up of presymptomatic carriers of the A30P mutation may give insight into preclinical disease stages and early manifestations of PD.

Aged↗
PubMed2001

Integrity of the blood-cerebrospinal fluid barrier in early Parkinson's disease.

Dysfunction of the blood-cerebrospinal fluid barrier (BCB) has been implicated in the pathogenesis of Parkinson's disease (PD) and other neurodegenerative disorders. Therefore, we assayed serum and cerebrospinal fluid (CSF) from 30 parkinsonian patients and 30 controls for concentrations of albumin and IgG. The CSF/serum ratio for albumin (AQ), IgG (GQ), IgG-index as well as determination of oligoclonal bands were used to evaluate BCB function and to quantify humoral immune response within the central nervous system (CNS). Levels of AQ, GQ and IgG-index did not significantly differ in both groups. We found no dysfunction of the blood-CSF barrier or signs of local synthesis of IgG in the central nervous system of parkinsonian patients. Our data do not support the hypothesis of a dysfunctional BCB that contributes to pathophysiological mechanisms underlying PD.

Adult↗
PubMed2001

Expression of latent matrix metalloproteinase 9 (MMP-9) predicts survival in advanced ovarian cancer.

OBJECTIVE: Matrix metalloproteinases (MMPs) are frequently expressed in malignant tumors and play an important role in tumor invasion and metastasis. MMP-2 and MMP-9 expression has been correlated with poor survival in some tumors, but data for ovarian cancer are lacking, despite clinical trials with MMP inhibitors. The aim of this study was to assess activity of MMP-2 and MMP-9 and correlate it to prognosis in ovarian cancer. METHODS: MMP-2 and MMP-9 gelatinolytic activity was analyzed in 84 patients with advanced ovarian cancer FIGO stage III and 19 benign ovarian tumors by gelatin zymography. MMP-9 immunoreactivity was detected by immunohistochemistry and gelatinolytic activity was localized in ovarian cancer tissue by in situ zymography. RESULTS: were correlated with patient survival, with a median follow-up period of 55 months. Results. Median pro-MMP-9 activity was at 0.00 U/microg protein in benign ovarian tissues and 4.82 U/microg protein in ovarian cancer (P = 0.001); activated MMP-9 was not detected. Pro-MMP-2 expression in benign ovarian tissue did not differ from that of malignant ovarian tissue, whereas active MMP-2 was present in 52% of ovarian cancers, but absent in benign ovarian tissues. Analyzing all patients high pro-MMP-9 activity was associated with short overall survival (P = 0.019) while pro-MMP-2 and activated MMP-2 did not predict overall survival. When analyzing the subgroups of patients with and without residual tumor mass at the time of surgery, pro-MMP-9 was of prognostic value only in the subgroup of patients with no residual tumor mass. In univariate analysis pro-MMP-9 activity, residual tumor mass, age, ascites volume, and grading were of prognostic significance for overall survival. However, in multivariate analyses, including all biological and clinicopathologic variables, only pro-MMP-9 and residual disease remained statistically independent prognostic factors. In situ zymography localized gelatinolytic activity predominantly to the tumor cell nests displaying MMP-9 immunoreactivity. CONCLUSIONS: Pro-MMP-9 gelatinolytic activity, but not active MMP-2 or MMP-9, serves as a useful statistically independent prognostic factor in ovarian cancer FIGO stage III, thus helping to identify ovarian cancer patients with an aggressive form of the disease.

Adult↗
PubMed2001

The central catechol-O-methyltransferase inhibitor tolcapone increases striatal hydroxyl radical production in L-DOPA/carbidopa treated rats.

Inhibition of catechol catechol-O-methyltransferase (COMT) in the brains of subjects treated with L-DOPA (L-3,4-dihydroxylphenylalanine) and an aromatic amino acid decarboxylase (AADC) inhibitor is suggested to cause an increase of L-DOPA, which might lead to oxidative damage through enhanced formation of free radicals. To investigate this hypothesis, the acute effects of two doses of the systemically administered COMT inhibitors entacapone (peripheral) and tolcapone (peripheral and central) on the extracellular formation of hydroxyl radicals in vivo following treatment with L-DOPA and the AADC inhibitor carbidopa were examined. The formation of extracellular hydroxyl radicals were determined by the measurement of 2,3-dihydroxybenzoic acid (2,3-DHBA), a reaction product of hydroxyl radicals with sodium salicylate, using microdialysis in the striatum of anesthetised rats. The COMT inhibitors were administered together with 50 mg/kg i.p. carbidopa as 5% gum arabic suspensions intraperitoneally (i.p.) at doses of 0, 1.0, and 10 mg/kg body weight to a total of 36 male HAN-Wistars rats. L-DOPA was injected i.p. 40 min after drugs of interest. Microdialysis samples were collected every 20 min for 400 min at a perfusion rate of 1 microl/min. Systemically administered 10 mg/kg tolcapone, but not entacapone, induced an increase in hydroxyl radical formation in the striatum of anesthetised rats following treatment with L-DOPA/carbidopa. The increase in hydroxyl radical formation was reflected by higher extracellular concentrations of the hydroxylate product of salicylate, 2,3-DHBA, peaking at 192% of baseline at the end of the observation period. Similar results were also found using the AUC (area under the curve) value estimated for the observation period. We conclude that the increase in hydroxyl radical formation is likely to result from an increased rate of monoamine oxidase-mediated and non-enzymatic (autoxidation) dopamine metabolism following increased central availability caused by reduction in COMT-mediated metabolism. We cannot, however, exclude the possibility that hydroxyl radicals are produced by tolcapone as a result of uncoupling mitochondrial oxidative phosphorylation.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2001

Lipid hydroperoxides and free radical scavenging enzyme activities in preeclampsia and HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome: no evidence for circulating primary products of lipid peroxidation.

OBJECTIVE: Preeclampsia is reportedly accompanied by increased plasma lipid peroxidation. However, to date the assays that have been applied to measure lipid peroxides have been relatively nonspecific. A highly specific high-performance lipid chromatographic-chemiluminescence technique was used here to measure lipid hydroperoxides in plasma and red blood cells of patients with preeclampsia and HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome. STUDY DESIGN: Lipid peroxidation products, both lipid hydroperoxides and thiobarbituric acid reactive substances (TBARS), and free radical scavenging enzyme activities were measured in either plasma or erythrocytes of patients with normal pregnancies (n = 36), preeclampsia (n = 28), or HELLP syndrome (n = 10). RESULTS: Whereas lipid hydroperoxides were undetectable (<0.02 micromol/L), plasma TBARS and glutathione peroxidase activity in plasma and erythrocytes were significantly increased in patients with HELLP syndrome. There were no differences in glutathione transferase and reductase activities or superoxide dismutase activity between the groups. CONCLUSIONS: We were unable to corroborate results of studies that suggested that increased TBARS are representative of circulating plasma lipid hydroperoxides in preeclampsia. However, elevated glutathione peroxidase activity and TBARS are in line with increased oxidative stress in preeclampsia.

Adult↗
PubMed2001

Detection of serum autoantibodies to tumor suppressor gene p53 with a new enzyme-linked immunosorbent assay in patients with ovarian cancer.

Sera from 99 ovarian cancer patients were assayed for serum autoantibodies to p53 using a newly developed enzyme-linked immunosorbent assay (ELISA). Results were compared to the investigation using the former ELISA. The incidence of autoantibodies (25%) was lower using the newly developed ELISA as compared to the previous results (41%). The results were consistent in 79% of patients (P < .001). The incidence of autoantibodies was lower in patients with complete remission (19%) as compared to that of patients with recurrence (30%) and before primary surgery (26%). No statistically significant correlation was found among p53 serum autoantibody status and tumor stage, degree of malignancy, histologic subtype, and residual tumor after primary surgery. Use of the newly developed ELISA resulted in a higher consensus between immunohistochemically negative and autoantibody negative cases. Owing to further purifying of the prepared human recombinant p53. the newly developed ELISA seems to be of higher specificity as compared to the former ELISA.

Adenocarcinoma, Clear Cell↗
PubMed2001

The integration of anthracyclines in the treatment of advanced ovarian cancer.

Since the publication of the Gynecologic Oncology Group (GOG) protocol 111 in 1996, and the results of the Arbeitgemeinschaft Gyna kologische Onkologie (AGO) trial Ovar-3 and the GOG protocol 158, the combination of platinum and paclitaxel has been adopted as the standard therapy in advanced ovarian cancer. One option for achieving further progress in the first-line treatment of advanced ovarian cancer might be the addition of noncross-resistant drugs to the two-drug regimen. Meta-analysis showed a survival benefit for platinum-anthracycline based combinations as compared to platinum-based combinations without anthracyclines. An AGO phase I/II trial compared epirubicin in combination with carboplatin and paclitaxel in untreated patients with gynecological malignancies. Based on the results of this study a randomized phase III trial together with the French GINECO group was conducted. The trial started 11/97 and was closed 11/99. All 1281 patients were randomized. Currently, 1132 end-of-therapy reports have been issued. Nine hundred eighty nine (87%) patients completed six cycles of treatment. Treatment and toxicity data are available for these patients. Three hundred thirty five patients had a measurable residual tumor after initial debulking surgery. Response data of 228 patients (111 ET-Carbo, 117 Carbo-T) are available.

Antibiotics, Antineoplastic↗
PubMed2001

Increased expression of matrix metalloproteinases (MMP)-2, MMP-9, and the urokinase-type plasminogen activator is associated with progression from benign to advanced ovarian cancer.

Proteases are linked to the malignant phenotype of different solid tumors. Therefore, the expression of the matrix metalloproteinase (MMP)-2 and MMP-9 and of the serine protease urokinase-type plasminogen activator (uPA) and its inhibitor plasminogen activator inhibitor type 1 (PAI-1) in the progression of ovarian cancer was investigated. Gelatinolytic activity and protein expression of MMP-2 and MMP-9 were analyzed in tissue extracts of 19 cystadenomas and 18 low malignant potential (LMP) tumors, as well as 41 primary tumors of advanced ovarian cancer stage International Federation of Gynecology and Obstetrics IIIc/IV and their corresponding omentum metastases by quantitative gelatin zymography and Western blot. In the same tissue extracts, antigen levels of uPA and its inhibitor PAI-1 were determined by ELISA. Protein expression of pro-MMP-2 (72 kDa) and pro-MMP-9 (92 kDa as well as antigen levels of uPA and PAI-1 were low in benign ovarian tumors but increased significantly from LMP tumors to advanced ovarian cancers. The highest values of all of the proteolytic factors were detected in omentum metastases. Active MMP-2 enzyme (62 kDa) was detected only in ovarian cancer (66%) and corresponding metastases (93%) but never in benign or LMP tumors. The activation rate of MMP-2 to its active isoform was higher in the metastases. Comparing both proteolytic systems, higher PAI-1 concentrations were consistently found in cancers with high pro-MMP-9 expression. These data indicate that members of the plasminogen activator system, as well as the metalloproteinases MMP-2/9, increase with growing malignant potential of ovarian tumors. These findings are of particular relevance to the development of protease inhibitors as new therapeutic approaches in ovarian cancer.

Adult↗
PubMed2000

Breast imaging with positron emission tomography and fluorine-18 fluorodeoxyglucose: use and limitations.

PURPOSE: To evaluate the diagnostic value of positron emission tomography (PET) using fluorine-18 fluorodeoxyglucose (FDG) for the diagnosis of primary breast cancer. PATIENTS AND METHODS: Preoperatively, 144 patients with masses suggestive of breast cancer underwent PET imaging of the breast. To identify breast cancer by increased metabolic activity, parametric FDG-PET images were analyzed for increased tracer uptake applying conventional image reading (CIR) and sensitive image reading (SIR). One hundred eighty-five breast tumors were evaluated by histology, revealing 132 breast carcinomas and 53 benign masses. RESULTS: Breast carcinomas were identified with an overall sensitivity of 64.4% (CIR) and 80.3% (SIR). The increase in sensitivity (SIR) resulted in a noticeable decrease in specificity, from 94.3% (CIR) to 75.5% (SIR). At stage pT1, only 30 (68.2%) of 44 breast carcinomas were detected, compared with 57 (91.9%) of 62 at stage pT2. A higher percentage of invasive lobular carcinomas were false-negative (65.2%) compared with invasive ductal carcinomas (23.7%). Nevertheless, positive PET scans provided a high positive-predictive value (96.6%) for breast cancer. CONCLUSION: Partial volume effects and varying metabolic activity (dependent on tumor type) seem to represent the most significant limitations for the routine diagnostic application of PET. The number of invasive procedures is therefore unlikely to be significantly reduced by PET imaging in patients presenting with abnormal mammography. However, the high positive-predictive value, resulting from the increased metabolic activity of malignant tissue, may be used with carefully selected subsets of patients as well as to determine the extent of disease or to assess therapy response.

Breast Neoplasms↗
PubMed2000

Genetic analysis of the alpha2-macroglobulin gene in early- and late-onset Parkinson's disease.

Recent association studies investigating polymorphisms in the alpha2-macroglobulin (A2M) gene provided evidence for an involvement of this protease inhibitor in the pathogenesis of Alzheimer's disease (AD). The partially overlapping pathology between AD and Parkinson's disease (PD) led us to investigate the role of A2M in PD. We performed association studies in a large sample of 328 German PD patients and 322 closely matched healthy controls. Analyzing the Val1000Ile polymorphism and a pentanucleotide deletion in the 5' splice site of exon 18 of the A2M gene we found an excess of homozygosity for the A2M deletion in early-onset PD (EOPD) patients (age at onset < 50 years) compared to late-onset PD (LOPD) patients (age at onset > 50 years; p = 0.008, p(p)c = 0.064, chi2 = 7.017). Therefore our data might indicate an age at onset modulating effect of the homozygous A2M deletion in PD.

Age of Onset↗
PubMed2000

Mutation analysis and association studies of the UCHL1 gene in German Parkinson's disease patients.

Recently, an Ile93Met substitution has been identified in the ubiquitin carboxy-terminal hydrolase L1 (UCHL1) gene in a single German PD family with autosomal dominant inheritance. To determine whether mutations in the UCHL1 gene are causative for Parkinson's disease (PD) a detailed mutation analysis was performed in a large sample of German sporadic and familial PD patients. We found no disease-causing mutation in the coding region of the UCHL1 gene. Direct sequencing revealed six intronic polymorphisms in the UCHL1 gene. Analysis of an S18Y polymorphism in exon 3 of the UCHL1 gene in sporadic PD patients and controls showed carriers of allele 2 (tyrosine) significantly less frequent in patients with a reduced risk of 0.57 (CI = 0.36-0.88; p = 0.012, p(c) = 0.047, chi2 = 6.31). Our study shows that sequence variations in the coding region of UCHL1 are a rare event. A protective effect of a certain UCHL1 variant in the pathogenesis of sporadic PD is suggested, underlining the relevance of UCHL1 in neurodegeneration.

Aged↗
PubMed2000

Levodopa in plasma correlates with body weight of parkinsonian patients.

Background: Antiparkinsonian comedication and/or altered gastrointestinal motility and absorption influence plasma levels of levodopa. Another putative factor may represent body weight. The objective of our study was to examine the relationship between body weight and levodopa in plasma of parkinsonian patients.Methods: We enrolled 26 individuals into this trial on the resorption of levodopa. A standardized protocol was used, which eliminated influencing factors, such as comedication, activity, food and estimated levodopa plasma levels at fixed timepoints.Results: Levodopa amount (Spearman R=-0.48; p=0.013) and maximum concentration (Spearman R=-0.50; p=0.008) in plasma correlated negatively with body weight.Conclusion: Doses of levodopa should be considered in relation to body weight. Thus severe loss of weight may reduce the need for oral levodopa intake by parkinsonian subjects and may represent a putative factor in the occurrence of dyskineasia in these patients unless there is a concomitant reduction in the dose of oral levodopa.

Journal Article↗
PubMed2000

Identification of proteins from human cerebrospinal fluid, separated by two-dimensional polyacrylamide gel electrophoresis.

The aim of this work is to display the protein composition of the cerebrospinal fluid by two-dimensional (2-D) gel electrophoresis and identify it using different mass spectrometric techniques. This will enable us to present an overview of the proteins in human cerebrospinal fluid. The comparison of 2-D gels will help us to analyze the normal protein variability in healthy persons and specific protein variations in patients with different neurological diseases (e.g., morbus Alzheimer, chorea Huntington). However, it is not possible to carry out 2-D gel electrophoresis directly with human cerebrospinal fluid due to the high amount of salts, sugars and lipids present. In addition, the total amount of protein is only as high as 0.3-0.7 microg/microL. Therefore, concentration and desalting steps using precipitation and ultrafiltration are necessary. To date we have been able to identify more than 65 spots from 2-D gels using matrix assisted laser desorption/ionization-mass spectrometry and electrospray ionization-mass spectrometry.

Amino Acid Sequence↗
PubMed2000

Combined transvaginal B-mode and color Doppler sonography for differential diagnosis of ovarian tumors: results of a multivariate logistic regression analysis.

OBJECTIVE: Transvaginal sonography is limited in its ability to assess early stage cancers of the ovary as well as in distinguishing benign processes. As a method for characterization of tumor vascularization, color-coded Doppler sonography may be able to improve the diagnostic accuracy of B-mode sonography. METHODS: Preoperative transvaginal B-mode and Doppler sonography was performed in 63 patients with unclear adnexal lesions prior to operation. Using multiple logistic regression, the independent variables of each procedure were selected and combined to yield a diagnostic flow chart. The diagnostic accuracy of this decision matrix was tested on 257 patients with unclear adnexal tumors. RESULTS: In the 63 adnexal tumors investigated, the diagnostic impact of isolated sonomorphological assessment with evidence of a "solid area" was 78%. Using Doppler sonography, the best discrimination was achieved by displaying the vascular distribution ("central vascularization"). Combining these independent significant variables of the two procedures raised the diagnostic accuracy to 90% (sensitivity 86%, specificity 93%). The validity achieved by this combination was confirmed by the independent application of this method to the 257 adnexal tumors with unclear malignancy status (diagnostic accuracy 93%, sensitivity 92%, specificity 94%). CONCLUSIONS: The combination of sonography and Doppler sonography achieves high and reproducible diagnostic accuracy in preoperative malignancy status assessment of adnexal tumors. The additional use of Doppler sonography can thus provide significant aid both for differential diagnostics of adnexal lesions and for the choice of surgical route in the case of an existing indication for operative therapy.

Adnexal Diseases↗