Biomedical subjects

H Moch

Publications and source records attributed to H Moch.

At least 91 records · Page 5Linked to original sources

PubMed1998

Initiating genetic events in small renal neoplasms detected by comparative genomic hybridization.

PURPOSE: To identify the genetic alterations associated with renal adenomas. MATERIALS AND METHODS: We analyzed 37 renal adenomas obtained at autopsy (23 papillary and 14 non-papillary) by comparative genomic hybridization. RESULTS: In papillary tumors, the median number of gains and losses of genetic material per tumor was 2.0 and 1.0, respectively. Papillary tumors were characterized predominantly by gains of genetic material on chromosomes 7 (57%), 17 (35%), 16 (26%), 12 (26%), 3 (22%), 20 (22%) and loss of a sex chromosome (83%). In 6 papillary tumors less than or equal to 5 mm. in diameter, gain of chromosome 7 occurred in 4 specimens. Initiating events for papillary renal adenomas include gain of chromosome 7 and loss of a sex chromosome. In non-papillary tumors, the median number of gains and losses of genetic material per tumor was 1.0 and 1.0, respectively. Non-papillary tumors were characterized by loss of genetic material on chromosome 3p (50%), loss of a sex chromosome (36%) and a gain of chromosome 5 (43%). The initiating event for non-papillary renal adenomas is the loss of chromosome 3p. CONCLUSIONS: Renal adenomas demonstrate similar genetic alterations as clinically detected renal cell carcinomas. Their clinically indolent course may, in part, be a result of the lower number of genetic alterations per tumor than their clinically detected counterparts. Renal adenomas are thus small carcinomas which have not yet acquired the necessary genetic alterations leading to tumor progression.

Aged↗

PubMed1997

Altered expression of mdm-2 and its association with p53 protein status, tumor-cell-proliferation rate and prognosis in cervical neoplasia.

Recent results suggest that p53 inactivation is required for cervical-carcinoma development. The mdm-2 oncogene, which forms an auto-regulatory feedback loop with the normal p53 protein, has been found amplified in human carcinomas, thus abolishing the anti-proliferative function of p53. To investigate whether the mdm-2/p53 interaction plays a role in cervical neoplasms, we performed an immunohistochemical study in archival fixed, embedded specimens that included 178 pre-cancerous lesions (CIN) and invasive squamous-cell carcinomas of clinical stage IB. In addition to p53, we assessed the p53-associated protein, mdm-2, and the Ki-67 labelling index (LI). The presence of HPV was assessed by in situ DNA hybridization. Tumor expression of all nuclear proteins was scored as fraction of positive CIN or cancer nuclei. The analysis demonstrated a significant association of the Ki-67 LI with grade of atypia in cervical neoplasms. p53 accumulation and mdm-2 expression are higher in invasive carcinomas than in pre-cancerous lesions. No correlation was observed with HPV status. An inverse correlation was found between increased tumor-cell proliferation and mdm-2 expression in invasive carcinomas (p < 0.0001). mdm-2 expression was significantly associated with p53 accumulation (p < 0.02). However, the investigated nuclear proteins were not associated with overall survival in patients with invasive carcinomas. Cox stepwise-regression analysis revealed regional lymph node status and depth of invasion to be independent parameters.

Biomarkers, Tumor↗

PubMed1997

Marked genetic differences between stage pTa and stage pT1 papillary bladder cancer detected by comparative genomic hybridization.

Little is known about the genetic changes underlying invasive tumor growth in bladder cancer. Because alterations that are linked to invasive tumor growth may be detectable in minimally invasive (stage pT1) but not in noninvasive (stage pTa) tumors, we searched for genetic differences between 28 pTa and 28 papillary pT1 bladder tumors by comparative genomic hybridization. Losses of 9q (54%), 9p (39%), and Y (28%) and gains of 1q (14%) were most prevalent in pTa tumors. These changes may play a role in the initiation of noninvasive papillary bladder cancer. The total number of aberrations was higher in pT1 tumors (6.5 +/- 5.4) than in pTa tumors (2.3 +/- 2.1; P = 0.0003), suggesting an increased genetic instability at stage pT1. Specific alterations, which were significantly more frequent in pT1 than in pTa tumors (P < or = 0.05), included deletions at 2q (36% of pT1 tumors), 8p (32%), and 11p (21%) and gains at 1q (54%), 8q (32%), 3p, 3q, 5p, 6p, and 10p (18% each). These loci are candidates for carrying genes involved in invasive tumor growth in bladder cancer. High-level amplifications at 1q22-24, 3p24-25, 6p22, 8p12, 8q21-22, 10p12.1-14, 11q13, 12q15-21, 13q31-33, Xp11-13, and Xq21-22.2 may pinpoint the location of oncogenes with relevance for bladder cancer.

Chromosome Aberrations↗

PubMed1997

The Heidelberg classification of renal cell tumours.

This paper presents the conclusions of a workshop entitled 'Impact of Molecular Genetics on the Classification of Renal Cell Tumours', which was held in Heidelberg in October 1996. The focus on 'renal cell tumours' excludes any discussion of Wilms' tumour and its variants, or of tumours metastatic to the kidneys. The proposed classification subdivides renal cell tumours into benign and malignant parenchymal neoplasms and, where possible, limits each subcategory to the most commonly documented genetic abnormalities. Benign tumours are subclassified into metanephric adenoma and adenofibroma, papillary renal cell adenoma, and renal oncocytoma. Malignant tumours are subclassified into common or conventional renal cell carcinoma; papillary renal cell carcinoma; chromophobe renal cell carcinoma; collecting duct carcinoma, with medullary carcinoma of the kidney; and renal cell carcinoma, unclassified. This classification is based on current genetic knowledge, correlates with recognizable histological findings, and is applicable to routine diagnostic practice.

Humans↗

PubMed1997

Angiogenesis in cervical neoplasia: microvessel quantitation in precancerous lesions and invasive carcinomas with clinicopathological correlations.

Recently, angiogenic properties have been shown in preinvasive cervical lesions. Our goal was to determine the angiogenesis in cervical intraepithelial neoplasia (CIN) and the relationship between microvessel counts, histopathological parameters, and clinical outcome in invasive cervical carcinoma. One hundred thirty-eight cervical specimens were evaluated; among these 20 were designated normal epithelium, 20 low-grade CIN, 40 high-grade CIN, and 58 invasive carcinoma. Histological sections immunostained for CD31 were quantitatively evaluated for microvessel density. The tumor proliferation rate was determined by the Ki-67 Labeling Index. Comparison of microvessel counts from normal epithelium with those from CIN and invasive carcinoma showed significant increases in precancerous lesions and invasive cancer (P < 0.0001). Microvessel density was found to be associated with the overall survival in women with invasive carcinoma (P < 0.01). There was a significant correlation of microvessel density (P < 0.05) with relapse-free survival in patients with regional lymph node metastasis. A Cox stepwise regression analysis revealed microvessel density, together with depth of invasion, regional lymph node status, and vascular invasion, to be a strong independent prognostic indicator for overall survival in patients with clinical stage IB cervical carcinoma.

Carcinoma, Squamous Cell↗

PubMed1997

p53 protein expression but not mdm-2 protein expression is associated with rapid tumor cell proliferation and prognosis in renal cell carcinoma.

The clinical course of renal cell carcinoma (RCC) is highly variable. Overexpression of the p53 protein has been suggested as a possible prognostic parameter in RCC. Overexpression of the mdm-2 oncogene product has been shown to interact with the p53 function. To investigate the immunohistochemical overexpression of mdm-2 protein in comparison with that of p53 protein in RCC, 50 nonpapillary pT3 RCCs were immunostained for p53 protein (DO-7) and mdm-2 (IF2). Tumor growth fraction (Ki-67 labeling index; MIB-1) was determined by immunohistochemistry. p53 positivity was detected in 16% of tumors. mdm-2 overexpression was seen in 30% of RCCs. There was a significant association between p53 and mdm-2 immunostaining (P = 0.0006), suggesting that mdm-2 protein may contribute to p53 protein stabilization in RCC. p53 overexpression was associated with a high Ki-67 LI (P = 0.0002), suggesting that p53 overexpression is involved in growth control in RCC. Survival analysis showed that Ki-67 LI (P = 0.04) and p53 overexpression were associated with poor prognosis (P = 0.0021), whereas mdm-2 overexpression was not related to patient outcome (P = 0.73). A Cox regression analysis revealed tumor stage (P < 0.001) and p53 overexpression (P < 0.05) to be independent prognostic parameters. It is concluded that p53 but not mdm-2 may be of practical relevance in predicting patient prognosis in RCC.

Carcinoma, Renal Cell↗

PubMed1997

DNA aberrations in urinary bladder cancer detected by flow cytometry and FISH.

Detection of molecular alterations is of potential significance for diagnosis and prognosis in bladder cancer. Fluorescence in situ hybridization (FISH) allows visualization and quantitation of genes and chromosomes on a cell by cell level and can easily be applied to urinary cells. To evaluate the sensitivity of FISH for detection of DNA aberrations in bladder cancer, formalin-fixed tissues of 293 tumors were examined by FISH and flow cytometry (FCM). Centromere probes for the chromosomes X, Y, 1, 7, 9, and 17 were used for FISH analysis. FISH was more sensitive for detection of quantitative DNA aberrations than FCM. An aberration of at least one chromosome was found in 107 of 108 tumors (99%), which were tetraploid, aneuploid, or multiploid, and in 29 of 49 tumors (59%), which were diploid, by FCM. The frequency of FISH aberrations showed greater differences between pTa (47%) and pT1 tumors (85%; P < 0.0001) than between stages pT1 and pT2-4 (98%). The marked genetic difference between pTa and pT1 tumors argues against the concept of grouping pTa and pT1 tumors together as "superficial bladder cancer." The frequency of tumors with chromosomal aberrations detected by FISH increased with the number of chromosomes examined. Aneusomy was seen in 68% of grade 1 tumors examined for > or = 4 chromosomes, suggesting that the cytological diagnosis of bladder cancer recurrences could be substantially improved by FISH.

Carcinoma, Transitional Cell↗

PubMed1997

DNA aneuploidy, S-phase fraction, nuclear p53 positivity, and survival in non-small-cell lung carcinoma.

Inactivation of the p53 gene plays a key role in tumour biology, probably through a disturbed cell cycle control and an increased genetic instability in p53-inactivated tumours. To learn more about the relationship between p53 alterations, proliferation and genetic instability (DNA aneuploidy) in lung cancer patients, specimens of 220 surgically resected lung carcinomas with clinical follow-up information were examined by immunohistochemistry (p53; CM1) and flow cytometry. Nuclear p53 positivity--found in 49.5% of the tumours--was associated with both high S-phase fraction (SPF) and DNA ploidy aberrations. SPF was higher in p53-positive tumours (15.9 +/- 10.2) than in p53-negative tumours (10.3 +/- 8.7; P = 0.03). The rate of p53 positivity was higher in 101 DNA-aneuploid and DNA-multiploid tumours (55%) than in 27 diploid and peridiploid carcinomas (33%; P = 0.0512). These results are consistent with an in vivo role of p53 inactivation for increased proliferative activity and development of genomic instability in lung cancer. There was no association between SPF and prognosis. Although prognosis was worse in DNA-aneuploid and multiploid tumours than in diploid, peridiploid and tetraploid carcinomas (P = 0.029), DNA ploidy was not an independent predictor of poor prognosis in multivariate analysis. These data show that DNA-flow cytometry has little prognostic value for patients with resected non-small-cell lung carcinoma.

Aneuploidy↗

PubMed1997

Epidermal growth factor receptor expression is associated with rapid tumor cell proliferation in renal cell carcinoma.

Epidermal growth factor receptor (EGF-r) expression and tumor cell proliferation rate have been proposed as potential prognostic parameters in renal cell carcinoma (RCC). In this study, immunohistochemical stains using antibodies to EGF-r and the cell proliferation marker Ki-67 (MIB-1) were used to study the relationship between EGF-r expression, tumor cell proliferation, and prognosis in 50 non-papillary RCC extending beyond the renal capsule (pT3). A high Ki-67 labeling index (LI) was associated with poor patient prognosis (P < .05). Thirty-eight cases (76%) expressed strong cell membrane immunoreactivity for EGF-r. There was a tendency toward a shortened survival for EGF-r-positive tumors (P = .08). Tumor growth fraction (Ki-67 LI) was significantly higher in EGF-r-positive tumors than in EGF-r-negative tumors (P < .05), suggesting that rapid tumor proliferation might be responsible for the poor prognosis associated with EGF-r-positive RCC.

Carcinoma, Renal Cell↗

PubMed1997

Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas.

Hereditary papillary renal carcinoma (HPRC) is a recently recognized form of inherited kidney cancer characterized by a predisposition to develop multiple, bilateral papillary renal tumours. The pattern of inheritance of HPRC is consistent with autosomal dominant transmission with reduced penetrance. HPRC is histologically and genetically distinct from two other causes of inherited renal carcinoma, von Hippel-Lindau disease (VHL) and the chromosome translocation (3;8). Malignant papillary renal carcinomas are characterized by trisomy of chromosomes 7, 16 and 17, and in men, by loss of the Y chromosome. Inherited and sporadic clear cell renal carcinomas are characterized by inactivation of both copies of the VHL gene by mutation, and/or by hypermethylation. We found that the HPRC gene was located at chromosome 7q31.1-34 in a 27-centimorgan (cM) interval between D7S496 and D7S1837. We identified missense mutations located in the tyrosine kinase domain of the MET gene in the germline of affected members of HPRC families and in a subset of sporadic papillary renal carcinomas. Three mutations in the MET gene are located in codons that are homologous to those in c-kit and RET, proto-oncogenes that are targets of naturally-occurring mutations. The results suggest that missense mutations located in the MET proto-oncogene lead to constitutive activation of the MET protein and papillary renal carcinomas.

Adult↗

PubMed1997

Chromosome 8p deletions are associated with invasive tumor growth in urinary bladder cancer.

Alterations of chromosome 8, including deletions of 8p, occur frequently in many tumors. In this study, fluorescence in situ hybridization was used to study the relationship between 8p deletions, 8q gains, and phenotype in bladder cancer. Cells from 87 tumors were examined by dual-labeling fluorescence in situ hybridization with a centromere 8 probe (pJM12) and P1 probes for 8p22, 8p12, 8q12, and 8q24. Both 8p22 deletions and 8q24 gains were strongly associated with tumor phenotype. There was a marked difference in 8p22 deletions between noninvasive (pTa) tumors (3/33) and minimally invasive (pT1) tumors (8/19; P = 0.005) whereas there was no significant difference between pT1 and muscle-invasive (pT2-4) tumors (19/35; P = 0.3926). Six tumors with 8p22 deletion were examined at 8p12. Three of these tumors showed no 8p12 deletion, narrowing down the site of a putative tumor suppressor gene distal to 8p12. In one other case, there was a marked increase in 8p12 copy number (> 40 per cell; amplification), suggesting the presence of an oncogene involved in bladder cancer at 8p12. The marked difference in 8p22 deletions between noninvasive (pTa) and minimally invasive (pT1) tumors is consistent with a role of a putative tumor suppressor gene on 8p for development of invasive tumor phenotype.

Chromosome Aberrations↗

PubMed1997

[Genomic changes in urinary bladder cancer].

Recent molecular studies on transitional cell carcinomas (TCC) of the urinary bladder suggest two genetically different tumor types with a varying degree of genomic instability-pTa (grade 1 and 2) tumors are usually "genetically stable". These tumors have rarely p53 alterations and contain only few genomic alterations (deletions, DNA sequence copy number gains, amplifications). Genomic changes in these tumors typically include losses of the chromosomes Y and 9 as well as 1q gains. TCC's with invasive growth pattern (pT1-4) are mostly "genetically instable". They have p53 alterations in about 50% of tumors, and often numerous DNA sequence copy number changes including deletions of 2q, 5q, 6q, 8p and 11p as well as gains at 1q, 3p, 3q, 5p, 6p, 8q und 10p. High level amplifications at various sites of the genome are also frequent in these "instable tumors". They may pinpoint the localization of overexpressed oncogenes. Further studies will have to investigate whether genetic analyses can add useful information to the currently used pathological (pTNM) and clinical (superficial/invasive) classifications of urinary bladder cancer.

Carcinoma, Transitional Cell↗

PubMed1996

[Acute kidney insufficiency in an alcoholic patient with liver cirrhosis].

We report on a 67-year-old patient who was hospitalized because of worsening of general condition, generalized edema and ascites with decompensated ethylic cirrhosis of the liver. On hospital admission renal failure was present which had developed within 5 months. In spite of intensive treatment with diuretics and repeated ascites punctures, fluid repletion reappeared repeatedly. Renal function remained stable for the first 10 days but worsened thereafter rapidly.

Aged↗

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

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

Comparative genomic hybridization for genetic analysis of renal oncocytomas.

Renal oncocytomas are uncommon tumors of the kidney that are considered to be of low malignant potential. Neither conventional cytogenetic nor restriction fragment length polymorphism analyses have identified consistent genetic alterations in their genomic DNA. The purpose of the present study was to identify the genetic alterations associated with the development of renal oncocytomas. We studied 13 renal oncocytomas by using comparative genomic hybridization, and we identified loss of genetic material from chromosomes 1 and/or 14 in six of these tumors. These alterations may represent early genetic events in the development of these tumors.

Adenoma, Oxyphilic↗

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

Renal cell carcinoma genetic analysis by comparative genomic hybridization and restriction fragment length polymorphism analysis.

PURPOSE: To compare comparative genomic hybridization (CGH) with restriction fragment length polymorphism (RFLP) analysis in renal cell carcinoma (RCC). MATERIALS AND METHODS: Fifteen RCC specimens were analyzed by both CGH and RFLP analysis at 18 loci. RESULTS: Restriction fragment length polymorphism analysis was informative on 90 chromosomal arms. Allelic imbalance was identified on 27 chromosomal arms by RFLP and on 26 arms by CGH. Data from CGH and RFLP demonstrated a high degree of concordance (p < 0.001). Comparative genomic hybridization identified previously documented areas of interest in RCC as well as potential new areas of interest including loss of genetic material on chromosome 2 and gains of genetic material on chromosome 16p. CONCLUSIONS: Comparative genomic hybridization can successfully be performed in RCC specimens. As it surveys the entire genome simultaneously, it may be more efficient than conventional cytogenetics or RFLP analysis in analyzing RCC.

Carcinoma, Renal Cell↗