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Y Fradet

Publications and source records attributed to Y Fradet.

At least 73 records · Page 4Linked to original sources
PubMed1995

The etiology of bladder cancer--are there any new clues or predictors of behavior?

It is well documented that the etiology of bladder cancer involves environmental factors. Most chemical carcinogens probably affect the urothelial cells via their presence in the urine. As an important cofactor, cell proliferative activity may be increased by urinary bladder infection, irritation by bladder stones or through the action of a variety of endogenously produced direct acting chemicals or agents. Among the known causative factors, avoidable major ones are occupational exposure to certain chemicals such as benzidine and 4-aminobiphenyl, cigarette smoking and bilharzial infection, which could be eradicated by a combination of praziquantel, antihelminth therapy, education and improvements in social welfare. An anticarcinogenic drug, cyclophosphamide, used as an immunosuppressive agent also seems to be associated with a high risk of idiopathic induction of bladder cancer and physicians should therefore pay particular attention to its diverse effects when considering its prescription. In contrast to the above, the consumption of coffee and tea including artificial sweeteners is now thought unlikely to be major risk. So far there is no good biochemical tool to predict individual exposure to bladder carcinogens/or relative risk of bladder cancer development. However, acetylation capacity can be applied to assess susceptibility to carcinogenic amines in people exposed in their working environment. Progress in molecular biological analysis will hopefully bring to light etiology-specific DNA damage in the bladder tumors and prove useful for prediction of tumor behavior in the near future.

Diet↗
PubMed1995

Downstaging by combination therapy with flutamide and an LHRH agonist before radical prostatectomy.

A total of 161 patients diagnosed as having stage B (134 patients) or C (27 patients) prostate cancer were randomly assigned to radical prostatectomy alone or to 3 months of neoadjuvant combination therapy with the anti-androgen flutamide and an LHRH agonist before radical prostatectomy. Neoadjuvant combination therapy before radical prostatectomy decreased cancer positive surgical margins from 33.8% in the control group to only 7.8%, thus leaving 92.2% of patients with negative margins at surgery for a 39.2% increase in specimen confined disease. Although on average the final stage determined at histopathological examination of the surgical specimen was more advanced than predicted at initial diagnosis in 33.8% of control patients, an opposite observation was made in the group of men who received the 3 month neoadjuvant combination therapy where the final stage, instead of being more advanced, was less advanced than at diagnosis in an average of 21.1% of men for a net 54.9% improvement of staging in favour of combination therapy. On the other hand, organ confined disease increased from 49.3% to 77.8% of patients after 3 months of combination therapy, for a 57.9% increase in the incidence of organ confined disease. Although long term follow up of these patients is required to determine the impact on survival, the marked influence of neoadjuvant combination therapy on the stage of the disease suggests the possibility of a major improvement in the morbidity and mortality from prostate cancer.

Aged↗
PubMed1995

[Ipsilateral adrenalectomy in the surgical treatment of renal carcinoma].

OBJECTIVES: To assess the value of ipsilateral adrenalectomy during radical nephrectomy for the treatment of renal cell carcinoma as a function of preoperative computed tomography findings. METHODS: Between May 1985 and June 1994, 194 patients underwent radical nephrectomy for renal cell carcinoma in our institution. Preoperative radiological reports and postoperative pathological reports were reviewed for 185 patients. RESULTS: 148 patients underwent abdominal computed tomography before surgery. 94 adrenalectomies were performed in this group of patients. None of the 77 patients in whom computed tomography showed a normal adrenal gland had adrenal metastasis on the definitive histological examination. 17 patients had an adrenal mass on computed tomography, 3 of which proved to be neoplastic. Preoperative CT had a sensitivity of 100%, a specificity of 82%, a positive predictive value of 18% and a negative predictive value of 100%. The 185 files reviewed included 114 adrenalectomies, including 4 adrenal glands invaded by renal cell carcinoma (3.5%). In these 4 cases, the smallest diameter of the renal tumour was 4 cm and the minimum pathological stage was T3. CONCLUSIONS: It therefore appears justified not to perform adrenalectomy during nephrectomy, in the presence of a renal tumour and negative adrenal computed tomography.

Adenocarcinoma↗
PubMed1995

Tumor-associated antigens as prognostic factors for recurrence in 382 patients with primary transitional cell carcinoma of the bladder.

This prospective study was designed to assess the prognostic value of tumor-associated antigens, designated 19A211, M344, T138, and T43, with respect to recurrence of primary superficial bladder cancer. Between September 1990 and April 1992, all patients with primary superficial bladder tumors treated by endoscopic resection in 15 participating hospitals were enrolled. Immunostaining for 19A211 and M344 was performed on paraffin-embedded material, and for T43 and T138 on frozen tissue. Antigenic expression was evaluated blindly by a single pathologist. Patients were followed up with the standard schedule of control cystoscopies. Cox regression was used to estimate hazard ratios (HRs) for first recurrence, and Poisson regression was used to estimate recurrence rate ratios and tumor rate ratios adjusted for primary tumor characteristics. By March 1994, 2254 follow-up cystoscopies had been performed on 368 of the 382 study patients, and tumor recurrence was detected in 55.7% of patients. Positivity to 19A211 was detected in 90% of primary tumors, its expression being associated with a decrease in first recurrence hazard ]HR, 0.65; 95% confidence interval (CI), 0.42-1.03] and in recurrence rate (recurrence rate ratio, 0.70; 95% CI, 0.53-0.92). Positivity to T138 was detected in 15% of tumors, and its expression was associated with an increase in first recurrence hazard (HR, 1.43; 95% CI, 0.92-2.22) and in recurrence rate (recurrence rate ratio, 1.31; 95% CI, 1.00-1.72). Positivity to M344 was detected in 71% of tumors, and its expression was associated with an increase in tumor rate (tumor rate ratio, 1.77; 95% CI, 1.41-1.97). T43 expression was not associated with recurrence end points. In conclusion, recurrence of superficial bladder cancer was associated with antigenic expression of 19A211, T138, and M344, independently of primary tumor characteristics.

Adult↗
PubMed1995

Human papillomavirus in transitional cell carcinoma of the urinary bladder

The presence of human papillomavirus (HPV) was detected in transitional cell carcinoma of the urinary bladder. PCR amplification of DNA from 71 tumors, using consensus primers for a fragment of the L1 gene, detected 6 strongly positive tumors (through ethidium bromide staining of a gel) and 22 moderately positive tumors (through Southern blotting of the amplified DNA) for a total of 28 (39%) of the tumors. The presence of HPV was correlated with grade but not stage of the tumors. Typing of HPV was performed on 31 tumors: all positive tumors contained HPV 16 DNA except for one Ta tumor which contained HPV 11 DNA. Our data also showed a large variability in the sensitivity of HPV DNA detection, depending on sample fixation, DNA preparation, and amplification conditions, which may explain in large part the discrepancies reported in the literature on the association of HPV to bladder cancer. Because of the low HPV DNA copy number observed in bladder tumors, our results suggest that HPV should ideally be tested on fresh or frozen tumor material, that SDS detergent should be avoided for the preparation of DNA, and that the amplification conditions are critical for optimal detection.

Journal Article↗
PubMed1994

Influence of the diagnostic modality on the pathological stage of clinically localized prostatic cancer.

The pathological stage at surgery is one of the most reliable prognostic indicators in patients with prostate cancer. We examined the influence of the modality of diagnosis and the prostatic-specific antigen (PSA) level on the rate of organ-confined cancer, positive surgical margins and lymph node metastasis in 345 patients treated by radical surgery. The mean PSA and Gleason score were significantly lower in patients detected by screening (n=144) compared to patients detected by routine examination (n=102) or because of urological symptoms (n=89) while the mean age was similar in the three groups (62.5 years). The rate of lymph node metastasis was correlated with the PSA level and ranged from 0% in patients with a normal PSA level (< 4 mg/L) up to 33% in patients with a PSA above 20 mg/L, screened patients had a significantly lower rate of lymph node metastasis. Thus the diagnostic modality may be an important prognostic factor to consider in clinical staging.

Journal Article↗
PubMed1993

Bladder cancer risk assessment with quantitative fluorescence image analysis of tumor markers in exfoliated bladder cells.

BACKGROUND: The detection of potentially highly curable low-grade bladder cancers by noninvasive techniques remains an unsolved problem. Conventional cytology detects such tumors with 50% sensitivity, and addition of DNA measurements to cytology only improves sensitivity incrementally. Tumor-associated antigens potentially offer an additional diagnostic marker. METHODS: In this study, the M344 antibody against a tumor-associated antigen expressed mainly by low-grade tumor cells was tested for its sensitivity and specificity, alone and in combination with DNA ploidy and cytology. Voided urine samples from 69 asymptomatic control subjects, urines and bladder washings from 59 patients with cancer, and 195 symptomatic control patients were collected. Cells were double-labeled with M344 monoclonal antibody and Hoechst. Each case was blinded, and the number of positive cells was scored by two independent observers. RESULTS: High-grade and low-grade transitional cell carcinomas (TCC) were detected with equal efficiency (78%, P < 0.001 versus symptomatic control patients). Urine samples proved higher specificity in detecting cancers. Patients being monitored for recurrence, but without current detectable cancer, were intermediates between control subjects and patients with cancer, suggesting that this marker also responds to dysplasia or field disease. Patients with outlet obstruction did not significantly differ from patients with previous TCC (P = 0.95). When combined with DNA ploidy measurements and cytology, the sensitivity for low-grade and high-grade tumors was 88% and 95%, respectively. CONCLUSIONS: The M344 antibody potentially could improve the specificity and sensitivity of detection of low-grade bladder tumors in symptomatic and asymptomatic patients as well as monitoring for recurrence, therapeutic response, and assessment of individual risk.

Antibodies, Monoclonal↗
PubMed1993

Alterations in phenotypic biochemical markers in bladder epithelium during tumorigenesis.

Phenotypic biochemical markers of oncogenesis and differentiation were mapped in bladder biopsies to investigate changes that occur in bladder tumorigenesis and to identify markers for increased bladder cancer risk. Touch preparations from biopsy specimens from 30 patients were obtained from tumors, the adjacent bladder epithelium, and random distant bladder epithelium. Markers, including DNA ploidy, epidermal growth factor receptor (EGFR), and oncoproteins, were quantified in individual cells by using quantitative fluorescence image analysis. Cluster analysis revealed the markers fell into three independent groups: (i) G-actin and EGFR; (ii) ploidy, cytology, and p185 (HER-2/neu oncoprotein) (ERBB2); and (iii) p300, a low-grade tumor antigen. Each marker displayed a gradient of abnormality from distant field to adjacent field to tumor. Different patterns for each marker suggested a developmental sequence of bladder cancer oncogenesis; G-actin was altered in 58% of distant biopsies (vs. 0/6 normals, P < 0.001), ploidy and cytology were altered in < 20% of distant fields and approximately 80% of tumors, and the other markers were intermediate. Patterns of EGFR and p185 suggest low-and high-grade tracks diverge early (P < 0.05 by Mann-Whitney U test for EGFR and ANOVA for p185). In conclusion, this study shows that a sequence of phenotypic changes accompanies development and progression of bladder cancers. Biochemical alterations in cells of the bladder field are often detectable before abnormal pathology, and markers previously thought to be limited to tumors were found in the field. The hierarchy of expression may be useful in identifying high-risk patients, assessing completeness of response to therapy, and monitoring and predicting recurrence.

Analysis of Variance↗
PubMed1993

Flow and image cytometry for DNA analysis in bladder washings: improved concordance by using internal reference for flow.

Using flow or image cytometry, we compared the DNA distribution of cells from bladder washings from 52 patients with bladder cancer. For image cytometry, urothelial nuclei (recognized visually) were analyzed for DNA content using polymorphonuclear nuclei as internal diploid reference. For flow cytometry, two methods can be used: either all cells can be analyzed, as commonly performed, or urothelial cells can be analyzed alone, after specific detection. In this flow cytometry study, cells were doubly stained for panurothelial antigens T16 and for DNA. All the cells were first analyzed using peripheral lymphocytes as an external reference; 79% of the results were similar with results obtained from image analysis. For discordant results, flow-cytometric data were reprocessed to identify immunologically stained urothelial cells; one additional case became concordant with image cytometry when only urothelial cells were analyzed, with lymphocytes as diploid reference; a better concordance (94%) was found when the nonurothelial cells of the samples served as a diploid reference instead of peripheral lymphocytes. This suggests that we achieved an improvement of the flow-cytometric evaluations for ploidy assessment, and we conclude that, on these conditions, flow or image analysis can be considered as equivalent methods for DNA content studies of tumors.

Adult↗
PubMed1993

Downstaging of localized prostate cancer by neoadjuvant therapy with flutamide and lupron: the first controlled and randomized trial.

Although the only opportunity to cure prostate cancer is treatment at an early stage, radical prostatectomy has remained relatively unpopular because 40-50% of prostate cancers estimated at diagnosis as confined to the prostate are found to be at a more advanced stage following histopathological analysis of the surgical specimen. This first prospective, randomized trial investigated the potential advantages of 3-month neoadjuvant combination therapy with flutamide and lupron before radical prostatectomy vs. prostatectomy alone in early stage prostate cancer. Cancer-positive margins were reduced from 38.5% (25 of 65) in control patients to only 13.0% (10 of 77) in men who received neoadjuvant combination therapy with the antiandrogen flutamide and the luteinizing hormone-releasing hormone (LHRH) super-agonist Lupron before radical prostatectomy (p = 0.006). Moreover, comparison of the final stage determined by histopathological examination of the surgical specimen with that estimated at diagnosis showed that a more advanced stage (upstaging) was found in 53.8% of controls, but patients who received combination therapy had an opposite effect: a more favorable stage than expected at diagnosis was found in 23.4% of cases (downstaging), a 77.2% advantage of neoadjuvant combination therapy. The concern about radical prostatectomy, underestimation of stage, is thus markedly improved by 3-month neoadjuvant therapy with flutamide and a LHRH superagonist. Cancer-negative margins are expected to be accompanied by a life expectancy not different from that of men of similar age with no prostate cancer; therefore, the present data, combined with efficient detection of early stage prostate cancer, offer the basis for dramatic improvement in the morbidity and mortality of prostate cancer.

Adenocarcinoma↗
PubMed1992

Antibody drug carrier for immunotherapy of superficial bladder cancer: ultrastructural studies.

Superficial bladder cancer represents a promising target for intravesical, antibody-guided therapy. The construction of an optimum antibody-cytotoxic drug conjugate depends mostly on the appropriate selection of a monoclonal antibody (mAb). We have used immunogold labeling and SEM to specifically map the distribution of antigens expressed on three bladder cancer cell lines and on the luminal surface of biopsies from human transitional cell carcinoma of various grades and from normal bladder mucosa. The 48-127 mAb, which recognizes a M(r) 54,000 surface glycoprotein (gp54), was found to be very promising as a potential drug carrier. This antibody reacts with the surface of cells from low- and high-grade tumors; it does not react with the normal urothelium. Labeling of normal bladder mucosa was observed, however, on microvillous intermediate urothelial cells occasionally exposed by small areas of desquamation. The 48-127 mAb could target drugs to all areas of transformed urothelium while avoiding drug delivery to the normal, undesquamated bladder mucosa. Kinetics of gp54/48-127/gold complexes were tested in vitro with T24 and RT4 human bladder carcinoma cell lines incubated in the presence of the 48-127 mAb directly conjugated with 17.7-nm gold particles. Internalization of the gp54/48-127/gold complex was readily demonstrated by transmission electron microscopy. These results suggest that the 48-127 mAb represents a valuable drug carrier for intravesical therapy, allowing specific tumor targeting and internalization of various cytotoxic agents.

Aged↗
PubMed1992

Strategies of chemoprevention based on antigenic and molecular markers of early and premalignant lesions of the bladder.

Using monoclonal antibodies, we have identified a series of tumor-associated antigens selectively expressed on tumor subtypes with distinct clinical behaviours. The mucinous antigen M344 and the gp200 surface antigen 19A211 are preferentially expressed on papillary superficial tumors and carcinoma in situ lesions of the bladder. The combination of these two antigenic markers in immunocytology and flow cytometry studies of exfoliated cells has improved the sensitivity of detection for bladder tumors. Moreover, the detection of M344- and 19A211-positive exfoliated cells from previously treated but currently tumor-free patients appears to be predictive of tumor recurrence on follow-up. These results, as well as results of bladder mapping studies in tumor patients, suggest that these antigenic changes occur in a premalignant stage and may provide tools to monitor the efficacy of chemopreventive measures. Other markers, such as the surface antigen T138 and the soluble molecules autocrine motility factor (AMF) and tumor collagenase stimulating factor (TCSF), are produced by primary or recurrent tumors with a higher metastatic potential. They may be useful in identifying high risk patients for distant failure. The highly restricted antigen 19A211 is also expressed on cervix condylomas and carcinoma. This observation led us to investigate a possible viral etiology of some bladder cancers. Using PCR techniques, we detected the presence of human papillomavirus (HPV) 16 DNA sequences in a significant proportion of bladder tumors. HPV positivity was inversely correlated with the presence of p53 mutations in exons 5-9 of the same tumors as measured by PCR-SSCP technique. This combination of markers may provide a basis for chemoprevention strategies targeted to distinct etiological events.

Antigens, Neoplasm↗
PubMed1992

Intermediate endpoint biomarkers for chemoprevention.

The understanding of intermediate endpoint biomarker expression in relation to the sequential events in bladder tumorigenesis establishes a useful approach for evaluating chemopreventive agents. Biomarkers may be genotypic or phenotypic and function as biomarkers of susceptibility, exposure, effect, or disease. This paper reviews several years of research on biomarkers and their use in monitoring chemoprevention therapy. In initial animal experiments, mice were dosed with N-butyl-N-(4-hydroxybutyl)nitrosamine (OH-BBN) while co-administering N-(4-hydroxyphenyl)retinamide (4-HPR). 4-HPR did not statistically reduce tumor incidence, but did affect tumor differentiation and, consequently, nuclear size and DNA ploidy. These results suggest that nuclear size and ploidy may function as intermediate endpoint biomarkers of effect for oncogenesis and that epigenetic as well as genetic mechanisms may be primary in the oncogenic process. Early biomarkers of effect which occur prior to genetic effects or chromosome aberration may portend a higher probability of being modulated by differentiating agents such as retinoids. In vitro studies demonstrated that RPMI-7666 cells cultured with a phorbol ester tumor promoter (12-O-tetradecanoyl-phorbol-13-acetate) could be redifferentiated with 13-cis-retinoic acid and dimethyl sulfoxide (DMSO). F-actin, a cytoskeletal biomarker with a presumed function in the epigenetic mechanisms of carcinogenesis, could also be normalized in HL-60 cells treated with 4-HPR or DMSO. A clinical evaluation of F-actin in patients with varying degrees of risk confirmed the value of F-actin as a differentiating biomarker useful for bladder cancer risk assessment. The clarification of when the phenotypic changes of F-actin occur in the oncogenic process was achieved when a variety of biochemical changes were mapped in the patients with bladder cancer. These studies confirmed that G-actin, a reciprocal form of F-actin, is increased relatively early in bladder cancer oncogenesis when multiple biomarkers are quantitated in the field, adjacent area, and the tumor. Comparison of each individual biomarker's expression from field, adjacent to tumor, and tumor, and subsequent cluster analysis of these biomarkers, indicated that the possible sequence of phenotypic expression of biomarkers in bladder cancer oncogenesis is from G-actin, to p300 antigen, to epidermal growth factor receptor (EGFR), to p185 (neu oncogene product), to DNA aneuploidy and, finally, to visual morphology.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1992

Radioimmunodetection of human bladder tumor xenografts in nude mice with radiolabeled monoclonal antibodies.

The tumor targeting potential of two monoclonal antibodies (mAbs) reacting with growth-regulated surface glycoproteins of human bladder cancer was investigated. The mAb T16 reacts more intensely with stationary cells while the mAb T43 is preferentially reactive with exponentially growing cells. The test target was T24 human bladder cancer cells grown subcutaneously in 30 nude mice. Controls for tumor specificity were human lung cancer cells grown on the contralateral side. Purified mAb's T16 and T43, and Om5, a non-reactive control, were radiolabeled with 131-Iodine and injected intravenously in doses ranging from 50 to 300 microCi in tumor-bearing animals. Consistent images of the bladder cancer xenografts were obtained at 48 and 72 hours with tumors as small as 0.1 gm. High resolution tumor images were obtained only with the reactive antibodies and according to their in vitro specificity. These results demonstrate that the two mAbs T16 and T43 can specifically and sensitively localize human bladder cancer cells in vivo.

Animals↗