Search PubMed⌕ Search

Biomedical subjects

G Sauter

Publications and source records attributed to G Sauter.

At least 109 records · Page 6Linked to original sources
PubMed1996

Genetic aberrations detected by comparative genomic hybridization are associated with clinical outcome in renal cell carcinoma.

The clinical behavior of renal cell carcinoma (RCC) cannot be predicted by histological and other markers. In this study, comparative genomic hybridization was used to evaluate whether the number of genomic aberrations has prognostic significance in 41 nonmetastatic clear cell RCC extending beyond the renal capsule. Losses were most prevalent at 3p (56%) and 9p and 13q (24% each). The number of DNA losses per tumor was associated with recurrence-free survival (P = 0.03). DNA gains most often involved chromosome 5q (17%) and chromosome 7 (15%). The number of DNA gains was not associated with clinical outcome. Loss of chromosome 9p was the only individual locus associated with recurrence (P = 0.04), suggesting that a tumor suppressor gene on chromosome 9p may play a role in RCC progression.

Carcinoma, Renal Cell↗
PubMed1996

Nuclear p53 overexpression is an independent prognostic parameter in node-negative non-small cell lung carcinoma.

The prognosis of operated patients with non-small cell lung cancer (NSCLC) is poor despite thorough pre-operative staging. An improved preselection is needed of patients likely to profit from surgery. This study was undertaken to evaluate the prognostic significance of nuclear p53 overexpression in a cohort of 247 surgically treated patients with NSCLC. It showed that the prevalence of immunohistochemically detectable p53 overexpression varied between different tumour types. p53 overexpression was equally frequent in large cell carcinoma (53 per cent) and in squamous cell carcinoma (54 per cent), but significantly less frequent in adenocarcinoma (34 per cent; P = 0.009). p53 overexpression was particularly rare in bronchioloalveolar carcinoma (positivity in 1 of 17 cases). These variations may reflect aetiological differences between the histological subtypes. p53 overexpression was also associated with high tumour grade (P = 0.0157) and the presence of lymph node metastasis (P = 0.0259), but not with advanced tumour stage. Survival analysis showed no difference in clinical outcome between p53-positive and p53-negative tumours within 101 node-positive tumours. In contrast, survival time was significantly better in p53-negative tumours than in p53-positive tumours within the group of 113 node-negative tumours (P = 0.032). Stepwise regression analysis showed that p53 overexpression is an independent prognostic factor in node-negative NSCLC.

Biomarkers, Tumor↗
PubMed1996

Ki67 labelling index: an independent predictor of progression in prostate cancer treated by radical prostatectomy.

The clinical course of prostate cancer is highly variable and cannot satisfactorily be predicted by histological criteria alone. Both tumour cell proliferation and neuroendocrine differentiation have been suggested as additional prognostic parameters, neuroendocrine differentiation being considered to enhance tumour cell proliferation. This study investigated the prognostic value of tumour cell proliferation [Ki67 labelling index (LI), MIB 1] and neuroendocrine differentiation and their relationship to each other. One hundred and thirty-seven paraffin-embedded radical prostatectomy specimens were examined. Neuroendocrine differentiation was found in 58 per cent of cases, but was not associated with pTN stage, Gleason score, Ki67 LI, or tumour progression. Ki67 LI was not significantly associated with pTN stage or with Gleason score. High grade (P = 0.0005), advanced local stage (P = 0.0004), positive lymph nodes (P = 0.02), and high Ki67 LI (P = 0.0203) were predictors of tumour progression if univariate analysis was performed, but Cox stepwise regression showed that only advanced local stage (P = 0.0025) and Ki67 LI (P = 0.0105) were independent predictors of tumour progression, the relative risk being 3.6 and 2.5, respectively. It is concluded that Ki67 is an important prognostic marker in prostate cancer with a potential for routine application.

Aged↗
PubMed1996

Molecular cytometry of cancer.

The application of molecular probes to diagnosis and prognosis of malignancies has redefined our perceptions of disease, allowing diagnosis by genotypic rather than phenotypic criteria. DNA analysis is especially useful when applied to pathological material in situ, because this allows the pathologist to combine information from both morphological and molecular observations. DNA in situ hybridization is a useful approach for the molecular pathologist, especially when combined with cytometric analysis. Potential clinical applications for in situ hybridization and the recently described technique of comparative genomic hybridization in tumor diagnosis and prognosis are described.

Chromosome Aberrations↗
PubMed1996

A constitutional de novo mutation in exon 8 of the p53 gene in a patient with multiple primary malignancies.

We report a constitutional point mutation of codon 278 in exon 8 of the TP53 gene that has not yet been described as a germ-line mutation. A 52-year-old female developed multiple primary malignancies (liposarcoma, breast cancer, malignant histiocytoma, occult adenocarcinoma). The mutation found in her tumour and peripheral blood lymphocyte DNA is a cytosine to thymine transition at the second position of codon 278 resulting in an amino acid exchange from proline to leucine in the DNA-binding domain. Evaluation of the patient's family revealed that both of her sons were affected by the same mutation. Although the patient's mother had died already, we were able to demonstrate by polymorphic microsatellite analysis that the defective allele originated from the maternal side. As four brothers and one sister had inherited the same allele, which however was wild type, we were able to show that the mutation must have occurred in the germ cells of the patient's mother and that it may therefore be called de novo. This explains the lack of a high cancer incidence in the family history. All tumours tested showed positive immunohistochemical staining for p53. Loss of heterozygosity was found in five of seven tumours, one showing chromosome 17 monosomy.

Alleles↗
PubMed1996

Tauroursodeoxycholic acid activates protein kinase C in isolated rat hepatocytes.

BACKGROUND & AIMS: Ursodeoxycholic acid (UDCA) improves liver function in patients with chronic cholestatic liver diseases by an unknown mechanism. UDCA is conjugated to taurine in vivo, and tauroursodeoxycholic acid (TUDCA) is a potent hepatocellular Ca2+ agonist and stimulates biliary exocytosis and hepatocellular Ca2+ influx, both of which are defective in experimental cholestasis. Protein kinase C (PKC) mediates stimulation of exocytosis in the liver. The aim of this study was to determine the effects of TUDCA on PKC in isolated hepatocytes. METHODS: The effect of TUDCA on the distribution of PKC isoenzymes within the hepatocyte was studied using immunoblotting and immunofluorescence techniques. In addition, the effect of TUDCA on the accummulation of sn-1,2-diacylglycerol (DAG), the intracellular activator of PKC, and hepatocellular PKC activity was studied using radioenzymatic techniques. RESULTS: Immunoblotting studies showed the presence of four isoenzymes (alpha, delta, epsilon, and zeta). The phorbol ester phorbol 12-myristate 13-acetate (1 mumol/L) induced translocation of alpha-PKC, delta-PKC, and epsilon-PKC from cytosol to a particulate membrane fraction, a key step for activation of PKC. TUDCA, but not taurocholic acid, selectively induced translocation of the alpha-PKC isoenzyme from cytosol to the membranes. In addition, TUDCA induced a significant increase in hepatocellular DAG mass and stimulated membrane-associated PKC activity. CONCLUSIONS: TUDCA might stimulate Ca(2+)-dependent hepatocellular exocytosis into bile in part by activation of alpha-PKC.

Animals↗
PubMed1996

Serum concentrations of 7alpha-hydroxy-4-cholesten-3-one reflect bile acid synthesis in humans.

Serum concentrations of 7alpha-hydroxy-4-cholesten-3-one (alpha-HC) have recently been shown to reflect the activity of cholesterol 7 alpha-hydroxylase in humans. To evaluate the relationship between alpha-HC in serum and bile acid synthesis, serum concentrations of alpha-HC, and rates of bile acid synthesis, as measured by the isotope dilution technique using gas chromatography-mass spectrometry, were determined simultaneously. Regression analysis revealed a positive linear correlation of serum alpha-Hc with synthesis of cholic acid (CA) (r = .59, P = .02), chenodeoxycholic acid (CDCA) (r = .75, P = .001), and total synthesis of both primary bile acids (r = .83, P < .001) in patients with gallstones and normal liver function (n = 15). alpha-HC was also correlated to input rates of deoxycholic acid (DCA) (r = .53, P <.05). Addition of patients with chronic cholestatic liver disease (n = 5) improved the correlation between serum alpha-HC and synthesis of CA (r = .75, P < .001), CDCA (r = .77, P < .001), and both primary bile acid combined (r = .87), P < .001). Our data are in agreement with the concept that synthesis of bile acids is regulated by cholesterol 7 alpha-hydroxylase activity and that alpha-HC in serum may serve as a convenient marker for the semiquantitative assessment of bile acid synthesis in humans.

Adult↗
PubMed1996

Prognostic significance of Bcl-2 in clinically localized prostate cancer.

The clinical course of prostate cancer is highly variable and cannot satisfactorily be predicted by histological criteria alone. To study the prognostic significance of Bcl-2 and p53 overexpression in prostate cancer, 137 consecutive radical prostatectomy specimens were examined by immunohistochemistry. Both Bcl-2 and p53 were associated with malignant phenotype. Bcl-2 expression was more frequent in pT3 tumors (31% positive) than in pT2 tumors (5% positive, P = 0.001). p53 overexpression (found in 8%) was associated with high Gleason score (P = 0.03) and increased tumor growth fraction (Ki67 labeling index (LI); P = 0.017). Survival analysis showed that Bcl-2 expression (P = 0.03), high Ki67 LI (P = 0.018), high grade (P = 0.0037), advanced local stage (P = 0.0005), and positive lymph nodes (P = 0.026) were predictors of progression. The combined analysis of Ki67 LI and Bcl-2 allowed the distinction of three groups with different clinical outcome. Prognosis was best in Bcl-2-negative tumors with low Ki67 LI, worst in Bcl-2-positive tumors with high Ki67 LI, and intermediate in the remaining tumors (P = 0.03). These data suggest that altered expression of both Bcl-2 and p53 play a role in prostate cancer progression. Combined analysis of factors regulating both apoptosis and cell proliferation may be relevant in prostate cancer.

Aged↗
PubMed1996

Patterns of epidermal growth factor receptor amplification in malignant gliomas.

Amplification of the gene for epidermal growth factor receptor (EGFR) is a common finding in malignant gliomas. We found that 18 of 29 grade 3 and grade 4 gliomas had EGFR amplification when assayed using fluorescence in situ hybridization. The amplification pattern suggests that the amplicon is contained within double minute chromosomes in most cases. EGFR copy number can differ by 20-fold in amplified cells within a single case. Polysomy 7 occurs frequently in both EGFR-amplified and -unamplified cells. More than one-third of the cases had < or = 10 percent of cells with amplified EGFR, and it is likely that these cases would not have been identified by methods that do not examine DNA on a cell by cell basis.

Brain Neoplasms↗
PubMed1995

Heterogeneity of chromosome 17 and erbB-2 gene copy number in primary and metastatic bladder cancer.

To study the relationship of tumor genomic heterogeneity with bladder cancer phenotype and p53 gene alterations, 138 primary bladder tumors were examined by dual labeling fluorescence in situ hybridization (FISH) using probes for chromosome 17 centromere (p17H8) and p53 (17p13.1). The number of different aneusomic populations > 5% (and monosomic populations > 20%) of cells served as a marker for heterogeneity. Nuclear p53 overexpression and Ki67 labeling index (Ki67 LI) were determined by immunohistochemistry. The number of aneusomic populations was 0 in 53 tumors, 1 in 18, 2 in 47, 3 in 9, and > 3 in 11 tumors. Presence of aneusomy was associated with tumor grade and stage (P < 0.0001 each). Ki67 LI was low in disomic tumors (11.0 +/- 7.7), higher in tumors with 1-3 aneusomic populations (17.4 +/- 11.3), and highest in tumors with > 3 aneusomic populations (25.8 +/- 10.9; P = 0.02 for > 3 vs. 1-3 populations). Aneusomy and heterogeneity were associated with p53 alterations. Aneusomy was seen in 35% of tumors with neither p53 expression nor p53 deletion but in 97% of tumors with both p53 deletion and expression. Nine of 11 tumors with > 3 aneusomic populations exhibited both p53 deletion and overexpression. To study genomic heterogeneity in tumor progression, two recurrences and three metastases of a tumor with known erbB-2 amplification were examined for centromere 17 and erbB-2 copy number. A considerable heterogeneity in centromere 17 and erbB-2 gene copy number was found in both recurrences and metastases, indicating a marked genomic instability in these metastatic cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Carcinoma, Transitional Cell↗
PubMed1995

Y chromosome loss detected by FISH in bladder cancer.

To examine the significance of Y chromosome losses in bladder cancer, fluorescence in situ hybridization (FISH) was used to determine its prevalence and associations with known parameters of malignancy. Cells were dissociated from formalin-fixed paraffin-embedded bladder tumors from 68 male patients and from 11 post-mortem bladder washes of male patients with a negative bladder cancer history, and were examined by FISH using centromeric probes for chromosomes X, Y, 7, 9, and 17. Nullisomy for chromosome Y was seen in 23 of 68 tumors (34%), monosomy in 28 of 68 tumors (41%), and polysomy in 17 of 68 tumors (25%). There was no association between chromosome Y loss and tumor grade, stage, tumor growth fraction (Ki67 LI), p53 immunostaining, and presence of p53 deletions. Patient age was higher for tumors with a Y loss (73.5 +/- 12.0 years) than for tumors without Y loss (66.6 +/- 10.8 years; p = 0.0207). In one normal bladder wash, a distinct subpopulation (38% of cells) with Y nullisomy was seen. These data suggest that Y loss is a frequent event that can occur early in bladder cancer, although there is no evidence for a role of Y loss in tumor progression.

Age Factors↗
PubMed1995

Chromosome-9 loss detected by fluorescence in situ hybridization in bladder cancer.

A loss of chromosome-9 material is one of the most frequent genomic aberrations known in bladder cancer. In order to better understand the role of chromosome-9 losses in bladder cancer, 125 formalin-fixed and 37 unfixed bladder tumors were examined using fluorescence in situ hybridization (FISH). A repetitive probe for a pericentromeric region on 9q12 (pHUR98) was applied for chromosome-9 copy-number enumeration. Under-representation of chromosome 9 was found in 74 of 162 cases. There was no association between loss of chromosome 9 and increased grade or stage, papillary growth pattern, p53 protein expression, or tumor-cell proliferation (Ki-67). These data show that chromosome-9 loss is an early event in bladder-cancer development, occurring independently of p53 alterations. In order to determine the prevalence of large sub-regional chromosome-9 deletions, dual hybridizations with pHUR98 and cosmid probes for 9q34, 9q22, and 9p21 were performed. Partial deletion was detected in only 1 of 36 cases for 9q34 and in 1 of 24 cases for 9p21. Surprisingly, amplification of the interferon alpha locus on 9p21 was seen in 1 of 24 tumors. The finding of 9p amplification may indicate the site of an oncogene relevant for bladder cancer.

Chromosome Deletion↗
PubMed1995

Identification of gains and losses of DNA sequences in primary bladder cancer by comparative genomic hybridization.

Comparative genomic hybridization (CGH) makes it possible to detect losses and gains of DNA sequences along all chromosomes in a tumor specimen based on the hybridization of differentially labeled tumor and normal DNA to normal human metaphase chromosomes. In this study, CGH analysis was applied to the identification of genomic imbalances in 26 bladder cancers in order to gain information on the genetic events underlying the development and progression of this malignancy. Losses affecting 11p, 11q, 8p, 9, 17p, 3p, and 12q were all seen in more than 20% of the tumors. The minimal common region of loss in each chromosome was identified based on the analysis of overlapping deletions in different tumors. Gains of DNA sequences were most often found at chromosomal regions distinct from the locations of currently known oncogenes. The bands involved in more than 10% of the tumors were 8q21, 13q21-q34, 1q31, 3q24-q26, and 1p22. In conclusion, these CGH data highlight several previously unreported genetic alterations in bladder cancer. Further detailed studies of these regions with specific molecular genetic techniques may lead to the identification of tumor suppressor genes and oncogenes that play an important role in bladder tumorigenesis.

Chromosome Mapping↗
PubMed1995

Patterns of p53, erbB-2, and EGF-r expression in premalignant lesions of the urinary bladder.

Frequent recurrences and multicentricity of bladder cancer suggest that alterations of the urothelium distant from the tumor may be relevant to prognosis. In this study immunohistochemistry and fluorescence in situ hybridization (FISH) were used to examine expression of p53, erbB-2, and epidermal growth factor receptor (EGF-r), genomic aberrations, and tumor cell proliferation (Ki67 LI) in normal and dysplastic urothelium. Biopsy specimens examined included normal urothelium (n = 40), mild dysplasia (n = 34), moderate dysplasia (n = 18) and carcinoma in situ (CIS; n = 20). Several different oncogene expression patterns were found, only some of which were associated with dysplasia. EGF-r expression was equally frequent in normal and dysplastic urothelium and showed a strong association with Ki67 LI (P < .0001). A purely superficial erbB-2 positivity was present in both normal and dysplastic biopsies. However, diffuse erbB-2 positivity and p53 overexpression were both associated with advanced dysplasia (P < .0001 each). FISH analysis showed erbB-2 gene amplification and p53 deletions in selected CIS, as well as a marked chromosome 17 copy number heterogeneity in all six CIS examined. These findings indicate a considerable genomic instability in bladder CIS. They show that both erbB-2 and p53 are altered during malignant transformation. Detectable oncogene expression alone, however, is not diagnostic of malignancy in bladder urothelium.

Adolescent↗
PubMed1995

Dormia baskets impacted in the bile duct: release by extracorporeal shock-wave lithotripsy.

BACKGROUND AND STUDY AIMS: Endoscopic extraction of bile duct stones may be complicated by impaction of the Dormia basket with captured stones, or rupture of the traction wire of the basket during mechanical lithotripsy. In an attempt to release impacted baskets by nonoperative means, we studied the efficacy of extracorporeal shock-wave lithotripsy in this dangerous clinical situation. PATIENTS AND METHODS: Fourteen extracorporeal shock-wave treatments were performed in 12 consecutive patients (eight women and four men; mean age 73.2 +/- 13.2 years, range 46-86 years) with an electrohydraulic shock-wave lithotriptor, using fluoroscopy (n = 13) or ultrasound (n = 1) for targeting. A total of 1845 +/- 334 (mean +/- SD) shock-wave discharges at a voltage of 22 +/- 4 kV were delivered per treatment. Nine treatment sessions (64%) were performed while patients were under general anesthesia. An attempt to extract the Dormia basket was made after disintegration of the captured stone had been confirmed by fluoroscopy. RESULTS: It was possible to remove the Dormia basket by nonsurgical means in 11 of the 12 patients (92%) after one treatment session, and after three treatment sessions in the remaining patient. Thus, disintegration of the stones allowed extraction of the Dormia basket in all patients. None of the patients needed surgical intervention. All patients were rendered free of bile duct stones after extracorporeal shock-wave lithotripsy and subsequent endoscopic removal of the fragments. No adverse effects of shock-wave therapy with subsequent extraction of the Dormia baskets were observed. CONCLUSION: Shock-wave therapy represents a primary nonsurgical therapeutic option in patients with either impacted Dormia baskets or broken devices which cannot be extracted by endoscopic means.

Aged↗
PubMed1995

Effect of dietary fiber on serum bile acids in patients with chronic cholestatic liver disease under ursodeoxycholic acid therapy.

During ursodeoxycholic acid therapy for chronic cholestatic liver disease, the serum levels of lithocholic acid increase about twofold. Lithocholic acid has been shown to be hepatotoxic in some animal species. Administration of psyllium hydrophilic mucilloid (PHM), a dietary fiber, has been reported to increase the bile acid mass excreted by the feces. We, therefore, studied the effect of PHM (3 x 3.25 g/day) on serum bile acids including lithocholic acid in 12 patients with primary sclerosing cholangitis (n = 7) and primary biliary cirrhosis (n = 5) receiving ursodeoxycholic acid therapy. After 2 and 6 weeks of treatment with PHM, the serum levels of ursodeoxycholic acid increased by 52.4 +/- 72.8% (p < 0.05) and 40.5 +/- 69.6% (NS), respectively. The absolute serum levels of lithocholic acid were not significantly changed. This led to a decrease of the relative amount of lithocholic acid as referred to total bile acids and to ursodeoxycholic acid in serum by 27.4 +/- 34.5% (p < 0.05) and 25.5 +/- 32.8% (p < 0.05), respectively, after 6 weeks of PHM treatment.

Adult↗
PubMed1995

Simvastatin added to ursodeoxycholic acid does not enhance disappearance of gallstone fragments after shock wave therapy.

Inhibitors of the HMG-CoA reductase have been shown to further reduce the biliary cholesterol saturation in patients treated with oral bile acids for cholesterol gallbladder stones. It was the aim of our study to evaluate the efficacy of simvastatin in addition to ursodeoxycholic acid in the dissolution of gallstone fragments after shock wave lithotripsy and adjuvant bile acid dissolution therapy. Eighteen patients with a single radiolucent gallbladder stone and a serum cholesterol of more than 250 mg/dl were randomly assigned to receive either ursodeoxycholic acid alone (750 mg per day, group A, n = 9) or in combination with simvastatin (20 mg per day, group B, n = 9) for the dissolution of the gallstone fragments generated by extracorporeal shock wave lithotripsy. The two groups were well matched regarding their baseline characteristics. At the primary end point of the study 6 months after lithotripsy, there was no difference between the groups in the rate of gallstone disappearance with 4 of 9 patients being stone free in each group. As evaluated by life table analysis, even further follow-up showed no significant difference between the groups (P = 0.8). In group B, serum cholesterol levels decreased by 22% at 3 months (P = 0.01 vs. baseline) and by 24% at six months (P = 0.02) during treatment while no significant change was observed in group A. With both regiments, no adverse effects were observed. While simvastatin added to ursodeoxycholic acid resulted in a decrease of elevated serum cholesterol levels in gallstone patients, it did not enhance stone disappearance after shock wave lithotripsy and adjuvant bile acid dissolution therapy.

Anticholesteremic Agents↗