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Biomedical subjects

Z F Zhang

Publications and source records attributed to Z F Zhang.

At least 91 records · Page 5Linked to original sources
PubMed1996

Chromosome 3 allelic losses and microsatellite alterations in transitional cell carcinoma of the urinary bladder.

A deletion analysis of chromosome 3 was conducted in 72 cases of transitional cell carcinoma of the urinary bladder using seven microsatellites spanning the 3p arm and two additional microsatellites in 3q. Results showed that 19 of 72 (26.4%) cases had deletions in one or more 3p regions. Two regions of frequent deletion were identified: 3p12-14 and 3p21-23. Less frequent deletions at 3p24.2-25 were also observed. Deletions at 3p were weakly correlated with tumor grade, but strongly with pathological stage. Among 70 cases with histological grade available, 4 of 29 (13.8%) grade 1 and 2 tumors, and 15 of 41 (36.6%) grade 3 tumors showed allelic losses in one or more of the 3p regions studied (P = 0.055). Among 69 cases with pathological stage available, none of 27 superficial carcinomas (pTa, pTis, and pT1) showed 3p deletions, whereas 18 of 42 (42.9%) muscle invasive lesions (pT2, pT3, and pT4) displayed allelic losses at 3p (P < 0.001). In addition, 12 cases showed microsatellite instability, but there was no correlation between abnormalities and tumor grade or stage. No correlation was found between deletions at 3p21-23 and microsatellite instability. In conclusion, deletions at three discrete regions of 3p were identified in bladder carcinoma, suggesting the involvement of candidate tumor suppressor genes residing in these regions. Moreover, detection of allelic losses in these regions was associated with higher tumor grade and more advanced stage, suggesting their potential involvement in bladder tumor progression.

Biomarkers, Tumor↗
PubMed1996

Familial and nutritional risk factors for p53 overexpression in colorectal cancer.

Although familial and dietary factors are recognized as important risk determinants for colorectal tumorigenesis, the specific causes of colorectal cancer remain unclear. Studies of p53 genetic alterations have provided clues concerning the etiology of many cancers. This study was designed to determine whether overexpression of the p53 protein is associated with familial and dietary risk factors. Epidemiological data were obtained from 163 colorectal cancer cases and 326 healthy controls. Tumors of all patients were analyzed immunohistochemically for p53 overexpression using an avidin-biotin immunoperoxidase procedure and polyclonal anti-p53 antibody CM1. Of patient tumors, 44.8% showed p53 nuclear reactivity. Colorectal cases versus controls were three times more likely to report a family history of colorectal cancer [odds ratio (OR), 3.12; 95% confidence interval (CI), 1.77-5.52]. Only cruciferous vegetables exhibited a significant inverse association (OR, 0.59; 95% CI, 0.34-1.02; trend test, P = 0.03) for the highest versus lowest quartiles. Both meat and beef displayed an elevated increase in risk. When cases with p53 overexpression (p53 positive) were compared with cases without p53 overexpression (p53 negative), etiological heterogeneity was suggested for family history of colorectal cancer (OR, 0.39; 95% CI, 0.16-0.93), cruciferous vegetables (trend test, P = 0.12), and beef consumption (trend test, P = 0.08). To estimate the individual relative risks for p53-dependent and p53-independent pathways, each p53 subtype was compared with controls. Cruciferous vegetables exhibited a significant association (OR, 0.37; 95% CI, 0.17-0.82; trend test, P = 0.03) when p53 positive cases were compared with controls. When p53 negative cases were compared with controls, a significant increase in risk was observed for family history of cancer (OR, 4.46; 95% CI, 2.36-8.43) and beef (OR, 3.17; 95% CI, 1.83-11.28; trend test, P = 0.006). The p53 (positive) dependent pathway was characterized by an inverse association with cruciferous vegetables, and p53-independent tumors were characterized by family history and beef consumption. These data may indicate the significance of linking epidemiology and molecular biology in assessing specific etiological pathways.

Adenocarcinoma↗
PubMed1996

Adenocarcinomas of the esophagus and gastric cardia: medical conditions, tobacco, alcohol, and socioeconomic factors.

Adenocarcinomas of the esophagus and gastric cardia have increased in incidence over the past 10-15 years in Western countries. The cause for this increase in incidence is still unknown. Our study was designed to investigate potential risk factors for adenocarcinomas of the esophagus and gastric cardia and to compare the risk profiles of a group of patients with this cancer with those having distal stomach cancer. We studied 95 incident cases with the pathological diagnosis of adenocarcinomas of the esophagus and gastric cardia, 67 patients with adenocarcinomas of the distal stomach, and 132 cancerfree controls. Patients were seen at Memorial Sloan-Kettering Cancer Center from November 1, 1992 to November 1, 1994. Epidemiological data were collected by a modified National Cancer Institute Health Habits History Questionnaire. Risk factors were analyzed using Mantel-Haenszel methods and a logistic regression model. Hypertension was associated with a 2-fold increased risk of adenocarcinomas of esophagus and gastric cardia after controlling for age, sex, race, education, pack-years of smoking, alcohol use, body mass index, and total dietary intake of calories. Increased risk of adenocarcinomas of esophagus and gastric cardia was associated with age, male gender, and Caucasian race. Tobacco smoking was related to a modest risk of adenocarcinomas of esophagus and gastric cardia. In contrast, the risk of distal stomach cancer was associated with stomach ulcers and pack-years of cigarette smoking. Iron deficiency was significantly associated with increased risk of both adenocarcinomas of the esophagus and gastric cardia and adenocarcinomas of the distal stomach. No obvious associations were identified for occupational exposures, family history of cancer, and physical activities. This study suggests that medical conditions such as hypertension and iron deficiency may be related to the risk of adenocarcinomas of esophagus and gastric cardia and confirms the moderate risk associated with tobacco smoking. Our results indicated an etiological heterogeneity with respect to risk factors identified between adenocarcinomas of esophagus and gastric cardia and those of the distal stomach.

Adenocarcinoma↗
PubMed1995

Deletion of the p16 and p15 genes in human bladder tumors.

BACKGROUND: Two genes, p16 (also known as CDKN2, INK4A, or MTS1) and p15 (also described as INK4B or MTS2), are found in tandem at chromosome 9p21. These genes are designated as candidate tumor suppressor genes because they encode proteins that function as negative cell cycle regulators. (The encoded polypeptides inactivate specific cyclin-protein kinase complexes that are required for progression through the cell cycle.) Molecular genetic studies have revealed that deletion of the p16 and p15 genes occurs frequently in cancer cell lines and in certain malignant neoplasms. PURPOSE: We evaluated the frequency of p16 and p15 gene alterations in a well-characterized cohort of human transitional cell bladder cancers, and we explored potential associations between alterations in these genes and tumor stage and/or grade. METHODS: Tumor tissue and normal tissue from 110 patients with transitional cell carcinoma of the urinary bladder were examined. The status of the p16 and p15 genes in these tissues was determined by Southern blotting and hybridization with gene-specific probes, by coupled polymerase chain reaction and single-strand conformation polymorphism analysis (PCR-SSCP), and by sequencing DNA fragments produced during PCR. Associations between alterations in the genes and tumor stage and/or grade were evaluated using the two-tailed Fisher's exact test. RESULTS: Homozygous deletion (both alleles lost) of the p16 and the p15 genes was observed in 11 and nine bladder tumors, respectively. Eight of the 11 tumors exhibiting complete loss of the p16 gene also displayed homozygous deletion of the p15 gene. Exclusive loss of either gene was detected in only three tumors. Hemizygous deletion (one allele lost, also referred to as loss of heterozygosity [LOH] of the p16 and/or p15 genes was observed in eight tumors. Rearrangement of the two genes was indicated in three additional tumors. No point mutations were identified in either gene. The overall frequency of alteration in this cohort of bladder tumors was approximately 18% for each gene (in 20 [18.3%, 95% confidence interval (CI) = 11.1%-25.6%] of 109 informative tumors for the p16 gene and in 18 [18%, 95% CI = 10.5%-25.5%] of 100 informative tumors for the p15 gene). A statistically significant association between p16 gene alteration and bladder tumors of low stage (P < .01) and grade (P < .01) was observed; a significant association between p15 gene alteration and tumors of low stage (P < .01) was also detected. CONCLUSIONS: Alteration of the p16 and p15 genes, especially coincident homozygous deletion, appears to be a common event in bladder cancer.

Aged↗
PubMed1995

Methodology for evaluating the incidence of second primary cancers with application to smoking-related cancers from the Surveillance, Epidemiology, and End Results (SEER) program.

The Surveillance, Epidemiology, and End Results (SEER) database is used to estimate the standardized incidence ratios (SIRs) of second primaries for all pairs of smoking-related cancers and to interpret the results in the context of our knowledge of the known effects of smoking on the incidence of each of the individual cancers. In evaluating the simultaneous incidence of two cancers, one must recognize the inherent duality of the two relevant SIRs linking the two cancers (e.g., A and B), namely, the SIRs of A following B and B following A. Under fairly general assumptions, the two SIRs are seen to be equal, and departures from equality suggest changes in risk status or the introduction of new risk factors after the incidence of the first primary. Based on these observations, a methodological strategy is developed. The data reveal several clear patterns. First, short-term incidence is uniformly much greater than long-term incidence. Second, the SIRs are consistently much higher for women than for men, for every pair of cancers studied. Third, the magnitudes of the SIRs are generally high and often substantially higher than would be expected on the basis of the known risks of smoking. Exceptionally high SIRs are observed between kidney and bladder cancer and between head and neck and esophageal cancer. Various influences may affect these high observed SIRs, including artifactual influences such as diagnostic, surveillance, and misclassification biases, and the effect of different exposure prevalences on subsequent SIRs, which may to some extent explain the strong sex differences. However, these artifacts do not appear to explain the magnitude of the observed SIRs, especially the very strong associations between kidney and bladder cancer and between head and neck and esophageal cancer. It seems likely that other factors play a role, including, possibly, host susceptibility factors or additional common risk factors other than smoking. Although multiple primary cancers are rare, they represent an especially fruitful population for detailed epidemiologic study.

Evaluation Studies as Topic↗
PubMed1995

Trichomonas vaginalis and cervical cancer. A prospective study in China.

The relationship between Trichomonas vaginalis infection and cervical cancer was investigated prospectively in a cohort of 16,797 women aged 25 years or more who were followed from 1974 to 1985 within the framework of a cervical screening program in Jingan, China. Personal interviews were conducted by trained interviewers when the women first entered the screening program. At initial screening, 421 (2.51%) women had a positive cytologic diagnosis of T. vaginalis infection. Ninety-nine incident cases of pathologically confirmed squamous cell carcinoma were identified from the cohort, with a total of 140,018 person-years of observation. T. vaginalis infection was found to contribute to the risk of cervical cancer, as determined by crude estimates and after adjustment for potential confounding effects. In a multiple proportional hazards model, the relative risk for cervical cancer was 3.3 (95% confidence interval: 1.5 to 7.4) among women with T. vaginalis infection. Furthermore, in the multivariate analysis, increased risk of cervical cancer was associated with the following factors: number of extramarital sexual partners of both the subjects and their spouses, cigarette smoking, and irregular menstruation. Having a large number of negative Pap smears was associated with lower risk. This study suggests that there might be an association between T. vaginalis infection and the risk of cervical cancer, but only 4 to 5% of cervical cancer in Chinese women may be attributable to T. vaginalis infection.

Adult↗
PubMed1995

Toxicity study of hepatic artery infusion chemotherapy with massive dose FUDR in rats.

Hepatic artery infusion (HAI) of fluoroudeoxyuridine (FUDR) has been shown to be effective in the treatment of liver metastases from colorectal cancer. However, local toxicity is the most serious limitation of this therapy. The aetiology of HAI toxicity remains unclear. To assess the HAI toxicity, forty-eight non-tumour-bearing, healthy BD-IX rats were randomized to control or treatment groups. The control group (n = 24) received heparinized saline alone (200 u heparin kg-1 day-1) and the treatment group (n = 24) received 6.7 mg FUDR kg-1 day-1 (equivalent to the human dose of 1.0 kg-1 day-1) via HAI for 28 days. Blood samples were collected for haematologic and biochemical analysis twice a week (on days 3 and 7). Toxicity was evaluated by determination of mortality, body weight, white blood cell (WBC) count, serum glutamic oxaloacetic transaminase (SGOT), alkaline phosphatase (ALP), total bilirubin and blood urea nitrogen (BUN), and creatinine. No significant differences in WBC, SGOT, BUN and creatinine levels were found between the group receiving FUDR treatment and the control group. Significantly higher total bilirubin levels, mortality and body weight loss were found in the FUDR-treated group than in the control group. A multivariate analysis revealed that total bilirubin level was the only significant predictor of mortality in the FUDR treatment group. These results suggested that biliary tract damage seems to be the principal toxicity of HAI FUDR chemotherapy.

Alkaline Phosphatase↗
PubMed1995

Family history of cancer, body weight, and p53 nuclear overexpression in Duke's C colorectal cancer.

To examine the hypothesis that colorectal carcinomas with and without TP53 mutations may be characterised by aetiological heterogeneity, we analysed a group of 107 patients with primary Dukes' C colorectal cancer seen at the Memorial Sloan-Kettering Cancer Center (MSKCC) from 1986 to 1990. We assessed p53 overexpression using the monoclonal antibody PAb 1801, and identified 42 (39%) patients displaying p53-positive phenotype, defined as > or = 25% of positive cells. Patients with two or more first-degree relatives with cancer had an odds ratio (OR) of 2.9 (95% CI 1.0-8.3) for p53 overexpression in comparison with those without a family history of cancer (trend test, P = 0.11). A possible association between body weight and p53 overexpression was observed. The ORs were 1.9 for the second quartile, 1.9 for the third quartile and 3.4 for the highest quartile in comparison with the lowest quartile (trend test, P = 0.06). No association between occupational physical activity, smoking, drinking, parity and p53 overexpression was identified. The results suggest that p53 overexpression may be related to genetic predisposition to colorectal cancer, and p53-positive and p53-negative colorectal cancers may be controlled by different aetiological pathways.

Age Factors↗
PubMed1995

Detection of circulating tumor cells in patients with localized and metastatic prostatic carcinoma: clinical implications.

PURPOSE: To determine the frequency with which prostate-specific antigen (PSA)-positive cells can be detected in the peripheral blood of patients with prostatic cancer in different stages and with different sensitivities to hormonal therapy. PATIENTS AND METHODS: Peripheral blood from 107 men with prostatic cancer and 27 non-prostate cancer controls was analyzed for PSA mRNA using reverse-transcriptase polymerase chain reaction (RT-PCR) and Southern blotting. RESULTS: The lower limit of detection was one PSA-producing cell diluted into 1 x 10(6) blood mononuclear cells. The test detected PSA mRNA in four of 25 patients (16%) with clinically organ-confined (T1-2) disease, three of 10 (30%) with T3-4 or N+ tumors, and 25 of 72 (35%) with distant metastases. None of the control samples were positive. An increase in positivity was observed with increasing PSA levels. Within the subgroup of patients with distant metastases, positivity was observed in six of 16 patients (38%) with normal or undetectable PSA levels after hormonal therapy and, overall, in 37% of patients (21 of 57) with androgen-independent disease. CONCLUSION: An RT-PCR-based assay for PSA mRNA can detect circulating cells in the peripheral blood of patients with prostatic cancer. The frequency of positivity increases with tumor stage. A unique observation was the detection of cells in patients with no measurable PSA on hormonal therapy. This suggests that continued seeding of distant sites may still be occurring in these patients, despite seemingly successful therapy. The relationship between continued seeding, disease progression, and survival will require further study.

Base Sequence↗
PubMed1995

Prognostic value of p53 nuclear overexpression in patients with invasive bladder cancer treated with neoadjuvant MVAC.

PURPOSE: This study sought to examine the prognostic role of p53 nuclear overexpression in muscle-invasive bladder cancer because of its correlation with progression of superficial bladder cancer. PATIENTS AND METHODS: Ninety of 111 patients treated with neoadjuvant methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) with a median follow-up duration of 5.8 years were evaluated. p53 nuclear overexpression was determined by immunohistochemistry on deparaffinized tissue sections. Patients were stratified into two groups according to the percent of tumor cells with positive nuclear reactivity. Overexpression was defined as tumors with > or = 20% cells with positive nuclear reactivity and nonoverexpression as tumors with less than 20% reactivity. RESULTS: Nuclear overexpression was observed in 47 patients and nonoverexpression in 43 patients. Patients whose tumors had p53 overexpression had a significantly higher proportion of cancer deaths. A multivariate analysis that evaluated the pretreatment variables p53 nuclear overexpression, age, sex, palpable mass, prechemotherapy tumor stage, performance status, ureteral obstruction, tumor size, multifocality, and grade showed that p53 overexpression had independent significance for survival (P = .001; relative risk ratio, 3.1). The impact of p53 overexpression on survival was predominantly in T2 and T3a tumors. Long-term survival was evident in seven of 17 patients (41%) with p53 overexpression versus 20 of 26 (77%) in whom p53 was not overexpressed (P = .007). CONCLUSION: p53 nuclear overexpression has independent prognostic value for survival in patients with invasive bladder cancer treated with neoadjuvant chemotherapy.

Adult↗
PubMed1995

Intravesical bacillus Calmette-Guérin therapy prevents tumor progression and death from superficial bladder cancer: ten-year follow-up of a prospective randomized trial.

PURPOSE: Superficial bladder tumors (stage Ta, T1, and Tis) may progress to invade the bladder muscle and cause death from metastatic cancer. Transurethral tumor resection (TURB) is the standard therapy for such tumors, but surgery alone may not prevent tumor progression. Intravesical therapy is widely used as an adjunct to TURB. Bacillus Calmette-Guérin (BCG) is the most active intravesical agent, but whether BCG prevents tumor progression and death from bladder cancer is unknown. PATIENTS AND METHODS: Between 1978 and 1981, 86 high-risk patients with superficial bladder cancer were randomly assigned to receive either TURB (n = 43) or TURB plus BCG (n = 43). Adverse tumor features for progression were equally distributed between the two groups. BCG was administered weekly for 6 weeks. Patients were evaluated every 3 to 6 months thereafter for progression to muscle invasion or metastasis. Control (TURB) patients with recurrent superficial tumors were eligible for crossover to the BCG arm. All patients have been monitored until event or for a minimum of 10 years (range, 10 to 14). RESULTS: The 10-year progression-free rate was 61.9% (95% confidence interval [CI], 47.2% to 76.7%) for patients treated with BCG and 37% (95% CI, 22.9% to 53.1%) for control patients. The median progression-free interval was not reached for the BCG group and was 46 months for the control group (P = .0063). Of 18 control patients crossed over to BCG (median, 29 months), 15 did not show tumor progression. TURB plus BCG resulted in a 10-year disease-specific survival rate of 75%, compared with 55% with TURB alone (P = .03). CONCLUSION: This study shows that intravesical therapy with BCG delays tumor progression and death from tumor in patients who present with superficial bladder cancer.

BCG Vaccine↗
PubMed1995

Risk factors and p53 nuclear overexpression in early stage intestinal-type adenocarcinoma of the stomach.

In order to investigate the relationship between altered patterns of p53 expression and risk factors for stomach cancer, we have analyzed a group of 35 patients with early stage intestinal-type adenocarcinoma of the stomach. We assessed p53 nuclear overexpression by immunohistochemistry, using monoclonal antibody PAb 1801, and identified 15 out of 35 patients (43%) displaying nuclear overexpression of p53 protein. Significantly elevated odds ratios (O.R.) were observed for greater body mass index (highest quartile versus lowest quartile: O.R. = 7.9; 95% confidence interval (CI): 1.1 to 56.1) and younger age (< 60 vs. > or = 70 years: O.R. = 10; 95% CI, 1.43 to 50). The odds ratio for p53 overexpression in cigarette smokers was 2.8 (95% CI: 0.7 to 11.6) but not statistically significant. These data indicate that p53 mutations may be involved in the early stages of gastric carcinogenesis, especially in the development of intestinal-type adenocarcinoma.

Adenocarcinoma↗
PubMed1995

Elevated tissue inhibitor of metalloproteinase 1 RNA in colorectal cancer stroma correlates with lymph node and distant metastases.

Tissue inhibitor of metalloproteinase (TIMP) inhibits the proteolytic activity of several matrix metalloproteinases centrally involved in tumor invasion and metastases. The purpose of this study was to determine the origin of TIMP-1 mRNA production in both human colorectal cancer (CRC) and metastatic liver lesions as well as define the relationships between TIMP-1 RNA expression and standard clinicopathological variables of CRC. Total cellular RNA, extracted from 56 CRC and 10 liver metastases, were examined by Northern blot hybridization. The mean/normal mucosa fold increase of TIMP-1 RNA was significantly elevated in both CRC (12.1 +/- 1.7) and liver metastases (10.0 +/- 3.6). No relationship was noted between TIMP-1 expression and tumor size, location nor differentiation. Based on lymph node metastases status, significantly higher TIMP-1 RNA levels were found in CRC with metastases than in those without metastases (15.6 +/- 3.3 versus 7.9 +/- 1.3) (P = 0.04). Similarly, TIMP-1 RNA levels were higher in primary CRC with distant metastases than those without distant metastases (17.6 +/- 4.1 versus 9.3 +/- 1.9) (P = 0. 04). In situ hybridization localized TIMP-1 mRNA predominantly in tumor stroma within spindle fibroblast-like cells rather than in cancer cells themselves. The correlation between the increased TIMP-1 mRNA level and advanced CRC stage noted in this study reflects a possible growth-promoting function for TIMP-1 in human CRC.

Aged↗
PubMed1994

Prostate adenocarcinoma in men younger than 50 years. A retrospective review of 151 patients.

BACKGROUND: Prostate adenocarcinoma is predominantly a disease of older men. Males younger than 50 years account for 1% of all patients with prostate cancer. The authors retrospectively examined cases of prostate adenocarcinoma in patients younger than 50 years of age to determine the natural history and prognosis of this malignancy in the younger population. METHODS: The medical records of 151 patients were reviewed, with particular attention to age and year at diagnosis, race, symptoms at presentation, family history of prostate cancer, histologic grade, clinical and pathologic stage, treatment modality, and clinical outcome. RESULTS: Univariate analyses demonstrated a significant correlation between higher disease stage (P = 0.0001), higher tumor grade (P = 0.0001), earlier year of diagnosis (P = 0.01), symptoms at presentation (P = 0.0001), and race (P = 0.01) with shorter disease-specific survival. However, multivariate analysis revealed that only stage and grade were statistically significant predictors for poor prognosis after controlling for other variables. With a one-unit increase of stage or grade, the risk of death from disease increases 2.2 or 1.9 times, respectively. CONCLUSION: These data suggest that patients younger than 50 years with prostate cancer present with similar symptomatology, histologic grade, and disease stage as the older population. Patients with disease confined to the prostate have a relatively good disease-specific survival but remain at risk for death even 15 years after diagnosis. When carcinoma escapes the confines of the prostate, the prognosis is uniformly poor.

Adult↗
PubMed1994

Altered patterns of MDM2 and TP53 expression in human bladder cancer.

BACKGROUND: The TP53 gene maps to the short arm of chromosome 17 (17p13.1) and encodes for a nuclear phosphoprotein of 53 kd (p53) involved in cell cycle control. The MDM2 gene is located on the long arm of chromosome 12 (12q13-14), and it encodes for a nuclear protein (Mdm2) of 90 kd of molecular mass. Genetic alterations in the TP53 gene have been reported as frequent events in bladder cancer and are associated with disease progression. The MDM2 gene has been shown to be amplified and overexpressed in sarcomas; however, these changes have not yet been analyzed in neoplastic lesions of the urinary bladder. PURPOSE: We undertook the present study in order to determine the frequency of MDM2 and TP53 abnormalities in bladder tumors, as well as to examine the clinical relevance of identifying their altered patterns of expression in patients affected with bladder cancer. METHODS: We analyzed a cohort of 87 patients affected by bladder tumors. Altered patterns of expression of Mdm2 proteins were determined using an immunohistochemical assay with monoclonal antibody 2A10, and MDM2 gene amplifications were studied by Southern blotting. Mutant p53 proteins were identified using monoclonal antibody PAb1801. The presence of intragenic mutations in the TP53 gene were assessed utilizing single-strand conformation polymorphism and further characterized by sequencing. Associations were assessed statistically by the two-tailed Fisher's exact test. RESULTS: Twenty-six of 87 cases had abnormally high levels of Mdm2 proteins; however, only one case showed an MDM2 amplification. Thirty-six of 87 cases displayed p53 nuclear overexpression. Sixteen cases had abnormally high levels of both Mdm2 and p53 proteins. There was a strong statistical association between Mdm2 and p53 overexpression (Fisher's exact test: P = .018). Moreover, there was a striking association between Mdm2 overexpression and low-stage, low-grade bladder tumors (Fisher's exact test: P = .0005). CONCLUSIONS: The results suggest that aberrant Mdm2 and p53 phenotypes are frequent events in bladder cancer and may be involved in tumorigenesis or tumor progression in urothelial neoplasias. IMPLICATIONS: This study is the first to report altered patterns of MDM2 expression in human bladder tumors and demonstrates that aberrant Mdm2 and p53 phenotypes may be important diagnostic and prognostic markers in patients affected by bladder cancer.

Aged↗
PubMed1994

p53 mutations in human bladder cancer: genotypic versus phenotypic patterns.

The objective of this study was to characterize the pattern of p53 mutations in bladder cancer. The sensitivity and specificity to detect these mutations using clinical material was assessed for the following assays: immunohistochemistry, restriction-fragment-length polymorphism, single-strand-conformation polymorphism, and sequencing. Discrepancies of reported results aimed at the identification of genetic alterations in the p53 gene may be due to differences in methodology, as well as to deficient morphological evaluation of the source of tissue utilized. In order to address these critical issues, we have implemented a novel experimental design that permits analysis by molecular genetics and immunopathology techniques in any given tissue specimen, allowing morphological correlation with genotypic and phenotypic characteristics of the tissue analyzed. Forty-two patients affected with bladder tumors in whom paired normal and tumor tissues were available were used for the present study. Nuclear immunoreactivities were observed in 26 out of 42 bladder tumors analyzed. Abnormal shifts in mobility were noted in 14 of the 42 cases in distinct exons, with one tumor revealing 3 mutations. There was a strong association between p53 nuclear over-expression and 17p LOH, as well as p53 nuclear over-expression and detection of mutations by SSCP and sequencing. According to receiver-operating-curve statistical analysis, the accuracy of detecting p53 mutations by IHC was estimated to be 90.3%. It is our conclusion that, when properly used, this is a highly sensitive and specific method with simple application using clinical material.

Antibodies, Monoclonal↗
PubMed1994

Association of P53 nuclear overexpression and tumor progression in carcinoma in situ of the bladder.

We investigated the prevalence and clinical relevance of p53 nuclear overexpression, as detected by antibody PAb1801 and immunohistochemistry, in 33 patients with carcinoma in situ of the bladder. Median followup was 124 months. Disease progressed in 16 patients (48%) during followup. The association between p53 nuclear overexpression and tumor progression was assessed by multivariate analysis, controlling for possible confounding variables, such as patient age and sex, presence of associated stage Ta bladder tumor and adjuvant bacillus Calmette-Guerin therapy. Patients were stratified into 2 groups according to the per cent of tumor cells displaying p53 nuclear overexpression: group 1-18 with less than 20% tumor cells positive and group 2-15 with 20% or more tumor cells positive. Disease progressed in 3 patients (16.7%) in group 1 and in 13 (86.7%) in group 2 (p < 0.0001). Detection of p53 nuclear overexpression in 20% or more tumor cells was the only independent marker of tumor progression in univariate and multivariate analyses (p = 0.004, adjusted relative risk 8.6, 95% confidence interval 2 to 40). Death specifically from bladder cancer was also associated with this altered pattern of p53 expression (p = 0.01, Fisher's exact test). We conclude that p53 nuclear overexpression is an early event in bladder cancer, occurring in 48% of cases of carcinoma in situ of the bladder. Our results also suggest that p53 nuclear overexpression offers significant clinical information and may be a useful tool in the selection of therapy for patients with carcinoma in situ of the bladder.

Aged↗