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Biomedical subjects

W R Fair

Publications and source records attributed to W R Fair.

At least 127 records · Page 7Linked to original sources
PubMed1993

Randomized trial of etoposide and cisplatin versus etoposide and carboplatin in patients with good-risk germ cell tumors: a multiinstitutional study.

PURPOSE: This multicenter, randomized phase III clinical trial evaluated the efficacy of etoposide plus carboplatin (EC) versus etoposide plus cisplatin (EP) in good-risk germ cell tumor (GCT) patients. PATIENTS AND METHODS: Between October 1986 and December 1990, 270 patients with good-risk GCTs were randomized to receive four cycles of either EP or EC. The etoposide dose in all patients was 100 mg/m2 on days 1 through 5. EP patients received cisplatin at 20 mg/m2 on days 1 through 5 and therapy was recycled at 21-day intervals. For EC patients, the carboplatin dose was 500 mg/m2 on day 1 of each cycle and the EC recycling interval was 28 days. RESULTS: Two hundred sixty-five patients were assessable: 131 patients treated with EC and 134 treated with EP. One hundred fifteen of 131 assessable patients (88%) treated with EC achieved a complete response (CR) versus 121 of 134 patients (90%) treated with EP (P = .32). Sixteen patients (12%) treated with EC relapsed from CR versus four patients (3%) treated with EP. Therefore, 32 patients (24%) who received carboplatin experienced an event (incomplete response [IR] or relapse) compared with 17 of 134 patients (13%) who received cisplatin (P = .02). At a median follow-up of 22.4 months, event-free and relapse-free survival were inferior for patients treated with EC (P = .02 and P = .005, respectively). No difference in overall survival was evident (P = .52). CONCLUSION: Two-drug therapy with EC using this dose and schedule was inferior to therapy with EP. Cisplatin remains as the standard platinum analog in the treatment of patients with good-risk GCTs. Carboplatin should be restricted to investigational trials in GCT.

Adolescent↗
PubMed1993

Molecular genetic alterations of chromosome 17 and p53 nuclear overexpression in human bladder cancer.

We set out to define the alterations of chromosome 17 in human bladder tumors and to correlate p53 nuclear over-expression with 17p deletions in those neoplasms. We studied 60 bladder tumors by restriction fragment-length polymorphism analysis directed at five different loci on chromosome 17. The same tumors were studied with a panel of mouse monoclonal antibodies (PAb1801, PAb240, and PAb1620) to mutant and wild-type p53 proteins using immunohistochemistry. Deletion of 17p correlated with grade (p = 0.039), stage (p = 0.004), and the presence of vascular invasion (p = 0.056). None of the pathologic parameters correlated with 17q deletions. p53 nuclear overexpression correlated with grade (p = 0.027), stage (p = 0.008), vascular invasion (p = 0.021), and the presence of nodal metastases (p = 0.007). In superficial (Ta) lesions, 17p was not deleted, whereas 55% of T1 and T2-T4 tumors showed a loss of heterozygosity. Mutations of p53 as detected by immunohistochemistry were seen in superficial as well as invasive tumors, whereas loss of heterozygosity was seen only in invasive tumors. A strong correlation was found between the presence of mutation and the loss of heterozygosity of the remaining allele (p = 0.0003). Additional follow-up and further studies are required to better define the role of p53 nuclear overexpression and 17p deletions as markers of tumor progression in human bladder cancer.

Alleles↗
PubMed1993

Use of neoadjuvant androgen deprivation therapy in clinically localized prostate cancer.

Radical prostatectomy is an excellent form of treatment of pathologically organ-confined prostatic carcinoma. However, most clinically localized prostatic cancers have pathologic evidence of extracapsular spread, limiting the effectiveness of radical surgery in curing this disease. To improve the organ-confined rate of prostate cancer, we studied the effect of preoperative or neoadjuvant androgen deprivation therapy (ADT). Our initial attempts focused on downstaging locally advanced tumors (T3) with neoadjuvant diethylstilbestrol (3 mg/d). Our study of 59 patients revealed that although there were significant clinical signs of downstaging, most patients still had extraprostatic disease. However, a subset of patients demonstrated marked pathologic regression, so we initiated a nonrandomized but controlled study of neoadjuvant ADT (goserelin acetate and flutamide for 3 months) followed by radical prostatectomy in patients with clinically localized prostate cancer. Of 72 control and 69 study patients, the rate of organ-confined disease was 48% and 74% (including 4% with no detectable residual carcinoma), respectively. In addition, the margin-positive rate was 33% and 10%, respectively. As demonstrated in the previous study, changes in serum prostate-specific antigen, transrectal ultrasonographic evaluations, and digital rectal examinations could not predict those patients with favourable pathology. Our results suggest that neoadjuvant ADT may improve the pathologic stage in some prostatic carcinomas and is worthy of further investigation in the efforts to augment the effectiveness of radical prostatectomy.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1993

Metallothionein gene expression in bladder cancer exposed to cisplatin.

Some 68% of bladder tumors will respond to cisplatin-based chemotherapy but only 30% will have a durable response. Recent studies have suggested that the metallothionein (MT) gene may produce cisplatin drug resistance in cell lines. To determine the role of MT gene overexpression in human tumors resistant to cisplatin, we evaluated 19 bladder tumors, seven of which had been exposed to cisplatin, for MT mRNA expression. By Northern analysis, four of the seven tumors exposed to cisplatin overexpressed the MT gene compared to untreated tumors. Of the three treated tumors without MT overexpression, one was a relapse 4 yr after the last dose of cisplatin and the other two received only one dose of chemotherapy. MT gene overexpression was found in some tumors that had failed cisplatin chemotherapy and may be a mechanism for drug resistance in bladder cancer.

Base Sequence↗
PubMed1992

Altered expression of the retinoblastoma gene product: prognostic indicator in bladder cancer.

BACKGROUND: It has been reported that 50%-70% of patients with bladder cancer experience recurrence after initial successful treatment and about 10%-20% of these patients die of the disease. Despite precise pathologic staging and grading, we are unable to predict clinical outcome in all patients. The retinoblastoma-susceptibility (RB) gene, a prototype of tumor suppressor genes, has recently been associated with development and/or progression of bladder cancer, as well as sarcoma and small-cell lung cancer. In transitional cell carcinomas of the bladder, we have observed altered expression of the Rb gene product--a nuclear phosphoprotein thought to function as a cell cycle regulator. PURPOSE: The aim of this study was to investigate the hypothesis that altered patterns of Rb expression correlate with prognosis in bladder cancer. METHODS: Expression of the RB gene was evaluated in specimens from 48 primary bladder tumors obtained by cystectomy or transurethral resection. Rb protein expression was correlated with disease outcome in these patients. Rb expression was examined by immunohistochemistry, using the mouse monoclonal antibody Rb-PMG3-245 on frozen tissue sections. Computerized image analysis was used to quantify the level of Rb protein in individual tumor cells. RESULTS: The overall 5-year disease-free survival was 66%, with a median follow-up of 42 months. Normal levels of Rb protein expression were found in 34 patients (Rb-positive group). A spectrum of altered patterns of expression from undetectable levels to heterogeneous expression, however, was observed in 14 patients (altered Rb group). Of the 38 patients with muscle-invasive tumors, 13 were categorized as having altered expression of Rb protein. Only one of 10 patients with superficial carcinomas had altered expression of Rb protein. The 5-year survival was significantly decreased in patients with altered Rb protein compared with the survival in patients with positive Rb expression (P less than .001). CONCLUSIONS: The results suggest that tumors exhibiting decreased expression of the RB gene-coded product (Rb protein) had a more aggressive biological behavior than those that expressed the Rb protein in the majority of their tumor cells. IMPLICATIONS: This study demonstrates that altered patterns of Rb protein expression may be an important prognostic variable in patients presenting with invasive bladder cancer.

Adult↗
PubMed1992

Growth regulation of human renal carcinoma cells: role of transforming growth factor alpha.

Findings of increased numbers of epidermal growth factor receptors (EGF-R) and increased expression of transforming growth factor alpha (TGF-alpha) in surgical specimens of human renal cell carcinoma have led to the proposal that growth of these tumors may be regulated by TGF-alpha in an autocrine manner. In the studies presented here, we have examined this hypothesis using two human renal carcinoma cell lines, SKRC-4 and SKRC-29. We demonstrated that both SKRC-4 and SKRC-29 cells were growth stimulated by greater than 35% when cultured in the presence of TGF-alpha or EGF and were inhibited by 29% to 46% if cultured in the presence of anti-EGF-R monoclonal antibody 225. Treatment of cells with TGF-alpha enhanced the levels of expression of EGF-R mRNA and TGF-alpha mRNA. In addition, incubation of cells with monoclonal antibody 225 significantly elevated the levels of excreted TGF-alpha species in the culture medium. Our findings suggest that proliferation of human renal carcinoma cells may be regulated by endogenously produced TGF-alpha and that this regulatory pathway can be interrupted using antibody to its receptor, EGF-R.

Carcinoma, Renal Cell↗
PubMed1992

Neoadjuvant hormonal manipulation: a strategy for chemoprevention trials.

Androgen ablation using hormonal manipulation is used extensively in metastatic prostate cancer; however, its use in localized disease combined with surgical extirpation of the gland has not been thoroughly and systematically investigated. The rationale for neoadjuvant therapy stems from the demonstrated effectiveness of androgen ablative therapy in metastatic disease and the high rate of "positive" surgical margins, especially in patients with Stage B2 disease. In addition, the essentially anecdotal clinical report of Scott and Boyd [1], using endocrine therapy plus radical prostatectomy in patients with Stage C disease, gives 15 year survival results comparable to those obtained by Jewett [2] in Stage 1 patients treated by radical prostatectomy. Finally, experimental observations in the androgen-sensitive mammary tumor (Shionogi) lend support to the concept of neoadjuvant hormonal manipulation. A pilot study of neoadjuvant endocrine therapy in 55 patients treated at Memorial Sloan-Kettering Cancer Center with 3 months of diethylstilbestrol (DES) (3 mg/day) prior to radical prostatectomy indicates marked reductions in prostate-specific antigen (PSA), although persistent evidence of adverse local tumor features was common. Some patients, however, exhibited evidence of significant downstaging. Whether or not any alteration in disease progression will accrue from demonstrated local downstaging is, of course, uncertain. However, clinical and laboratory effects of such treatment may provide a means for correlation with subsequent tumor behavior, and may prove useful in treatment decisions. Additionally, a decrease in the number of foci of grade 3 prostatic intraepithelial neoplasia (PIN-3) was noted in a small number of patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Androgens↗
PubMed1992

Chemoprevention of prostate cancer: guidelines for possible intervention strategies.

The "natural history" of prostate cancer may bedevil the development of guidelines for chemoprevention interventions. Can strategies be designed to direct agents to those lesions which have the potential to develop localized extension that may become symptomatic or metastatic disease? Of necessity our interventions will focus on the identification and quantification of appropriate biomarkers as intermediate endpoints, although no reliable endpoints for prostate cancer have yet been identified. The reduction of prostate cancer incidence may be the ultimate objective, but a decrease in the progression of microfocal or "latent" cancer may well be just as effective as prevention when the age of the target population and competing causes of death are taken into account. Early intervention strategies must focus on the analysis of the interactions of the chosen chemopreventive agents upon precancerous and cancerous cellular dynamics in the prostate. Whether the requirements of such molecular epidemiology necessitate a more deliberate strategy of Phase II studies or a high risk-high gain strategy of a broad Phase III study is open to debate. Factorial designs for proposed randomized chemoprevention trials may be desirable to test multiple chemopreventive agents simultaneously, provided knowledge of the biochemical synergism of the agents is solid. Stratification of study participants by degree of risk will ameliorate concerns regarding the precision targeting of lesions at different stages in the precancer/cancer continuum.

Androstenes↗
PubMed1992

Phase II evaluation of coumarin (1,2-benzopyrone) in metastatic prostatic carcinoma.

The unavailability of effective treatment of metastatic hormone refractory prostatic carcinoma warrants trials of new and promising treatments. Coumarin is an investigational new drug that has produced objective tumor regression in some patients with metastatic renal cell carcinoma and malignant melanoma. Coumarin has shown activity against prostatic carcinoma in the Dunning R-3327 rat prostatic adenocarcinoma model. Forty-eight patients with metastatic hormone naive (5 stage D1 and 10 stage D2) or hormone refractory (33 stage D3) prostatic carcinoma of average age 67.6 years (range 46-86) and ECOG performance status of 2 or better were given 3 grams coumarin daily by mouth and evaluated monthly for toxicity and response by rigid criteria in a multicenter trial. Toxicity was limited to asymptomatic SGOT elevations in 3 patients and nausea and vomiting in 4 patients that required cessation of therapy in 2. Eligibility and protocol violations removed 6 additional patients from response evaluation. There were no complete responses. Partial responses (3 of 40 patients, 8%) occurred in 2 patients with bidimentionally measurable disease and 1 patient with disease evaluable by bone scan and elevated prostate specific antigen and prostatic acid phosphatase. The remaining patients progressed after 1 to 12 (average 4.4) months. Coumarin is a relatively nontoxic drug that may warrant further trials in a subset of patients with prostatic carcinoma.

Adult↗
PubMed1992

Prognostic significance of antigenic heterogeneity, Gleason grade, and ploidy of lymph node metastases in patients with prostate cancer.

We retrospectively evaluated 51 prostate cancer patients found to have pelvic lymph node metastases at the time of pelvic lymphadenectomy and 125I implantation. All of them were followed until death or for a minimum of 70 months. Rabbit polyclonal anti-PSA, anti-PAP, anti-PSP-94, and mouse TURP-27 monoclonal antibodies were used in immunohistochemical evaluation of the metastatic lesions. In addition, Gleason grade and ploidy were assessed and correlated. No tumor with a Gleason grade of less than 7 could be found in the metastatic lymph nodes. Time to progression (P = .003), disease-specific survival (P = .009), and overall survival (P = .003) were significantly shorter in patients whose tumors had a primary Gleason pattern of 5 (grade 9 or 10). In the PSA study, patients whose tumors were reactive in more than 75% of cancer cells experienced significantly longer survival than those with less than 75% of cancer cells expressing PSA (P = .0006 log rank test). The means of overall survival +/- SEM were 71.5 +/- 5.0 and 34.9 +/- 5.4 months, respectively. Similar correlations were found with disease-specific survival and time to progression. Patterns of PAP expression and TURP-27 reactivity were not prognostically useful, whereas PSP-94 expression may add some additional information. These data suggest that evaluation of tissue PSA heterogeneity in lymph node metastases may offer additional prognostic information on prostate cancer patients. Better prediction of individual prognosis may be possible with the combined use of Gleason grade, flow cytometry, and PSA expression.

Adult↗
PubMed1992

The natural history of locally confined prostate cancer: a review.

The incidence of prostate cancer rises steeply in men over the age of 50 years. Mortality due to prostate cancer also increases, but not at the same rate as the incidence. In the U.S.A., a man has a lifetime risk of developing prostate cancer of about 1 in 11, but his risk of dying of the disease is about 1 in 22-33. Tumor DNA ploidy is one of the predictive features of the growth rate of prostate cancer. Patients with diploid tumors have a more favorable prognosis than those with aneuploid tumors, regardless of the stage or grade. Patients with stage A1 defined disease (less than 5% of the specimen being cancerous) have a relatively low risk of progression (about 12%) and death (about 3%). Evidence suggests that transurethral resection of the prostate (TURP) is effective in removing disease in about 62% of cases. Expectant management involves following a patient and giving hormonal therapy or TURP as necessary. Four studies with follow-up periods of 4-10 years have shown that the metastatic disease rate ranges from 9 to 37% and that deaths from prostate cancer range from 9 to 16%. Results from animal studies suggest that hormonal therapy only improves survival if it is given at the time of tumor implantation or shortly after, though it can be effective palliative treatment.

Humans↗
PubMed1992

Multicenter, randomized, double-blind, placebo controlled study to investigate the effect of finasteride (MK-906) on stage D prostate cancer.

A total of 28 untreated patients with asymptomatic, stage D prostate cancer was randomized in a double-blinded fashion to receive finasteride (10 mg. per day), a 5 alpha-reductase inhibitor or placebo. Patients were evaluated at 3-week intervals by rectal examination, and serum prostate specific antigen (PSA) and prostatic acid phosphatase (PAP) levels, and at 6-week intervals by bone scan and transrectal ultrasound determinations of prostatic volume. Patients stopped the medication at week 6 at the discretion of the investigator when PSA levels increased from baseline. After 12 weeks all patients were reevaluated. Of the patients 13 received finasteride and 15 received placebo. The 2 groups did not differ statistically with respect to patient age, initial PSA and PAP level, or the extent of metastases on initial bone scan. A statistically significant decrease in the median percentage change from baseline in PSA at weeks 3 and 6 occurred in the finasteride group compared to the placebo group (-22.9% versus -2.9% and -15.1% versus +11.7%, respectively, p less than 0.05). Finasteride had no effect upon PAP, serum testosterone, prostatic volume or appearance of bone scans. A decrease in serum PSA in the finasteride treatment group suggests that finasteride exerts a minor effect in patients with prostate cancer. This effect does not approach that seen with medical or surgical castration yet because of the potency preserving feature and the lack of toxicity finasteride may warrant further study in the treatment of prostate cancer.

5-alpha Reductase Inhibitors↗
PubMed1992

Distribution of retroperitoneal metastases after chemotherapy in patients with nonseminomatous germ cell tumors.

For patients with advanced nonseminomatous germ cell tumors a retroperitoneal lymph node dissection is routinely performed following chemotherapy if the serum tumor markers have returned to normal. Bilateral retroperitoneal lymph node dissection has been recommended because metastatic deposits may be widespread. The aim of this study was to describe the distribution of retroperitoneal metastases following chemotherapy in patients with nonseminomatous germ cell tumor and determine if the extent of the retroperitoneal lymph node dissection can be modified. We studied 113 patients who had initially bulky retroperitoneal disease and underwent retroperitoneal lymph node dissection following chemotherapy. For the purposes of this study teratoma and malignant germ cell tumor are referred to as tumor. The most common location of tumor was the para-aortic area (91%) in patients with a left primary tumor and the interaortocaval area (78%) in those with a right tumor. Tumor was located outside the boundaries of a modified retroperitoneal lymph node dissection in 14 of the 60 patients with residual disease but the tumor was present within a palpable mass in 6 of these 14 patients. If the residual mass was removed and a modified retroperitoneal lymph node dissection was performed only 9 of the 113 patients (8%) would have tumor left in the retroperitoneum. For a select group of patients with advanced nonseminomatous germ cell tumor treated with chemotherapy, resection of the residual mass combined with modified retroperitoneal lymph node dissection is appropriate.

Humans↗
PubMed1992

Evaluation of epidermal growth factor receptor DNA amplification and mRNA expression in bladder cancer.

The epidermal growth factor receptor has been implicated in the malignant transformation of cells because the v-erbB oncogene is a truncated form of the epidermal growth factor receptor. DNA amplification and/or mRNA overexpression of the epidermal growth factor receptor is associated with the malignant potential of several human epithelial tumors. To determine the frequency of epidermal growth factor receptor DNA amplification and mRNA overexpression in bladder cancer, we evaluated 12 bladder tumors for DNA amplification and another 14 bladder tumors for mRNA overexpression. By Southern hybridization, we found no evidence of DNA amplification or gene rearrangements in 12 bladder tumors. Five of 14 bladder tumors overexpressed epidermal growth factor receptor mRNA four to 15 fold compared to normal urothelium from the same bladder by Northern analysis. These findings suggest that epidermal growth factor receptor amplification and/or gene rearrangement occurs infrequently in bladder cancer. Epidermal growth factor receptor mRNA overexpression, however, is found in 36% of bladder tumors and may play a role in bladder tumorogenesis.

Blotting, Northern↗
PubMed1992

Bacillus Calmette-Guerin therapy for superficial bladder cancer: a 10-year followup.

We report the outcome of 61 patients with superficial bladder tumors who received bacillus Calmette-Guerin (BCG) therapy and were followed for at least 10 years (range 10 to 13 years). A total of 19 patients (31%) remains free of tumor and progression, 17 (28%) had interval superficial recurrences but no progression and 25 (41%) had progression, first identified as muscle invasion in 12, prostatic involvement in 8 or metastasis in 5. Most tumors recurred or progressed within the first 5 years. Of the 61 patients 33 (54%) are disease-free and with an intact bladder, 13 (21%) are alive after cystectomy, 2 (3%) died of other causes, 1 (2%) is alive with metastasis and 12 (20%) died of metastatic urothelial cancer (11 from the bladder or prostate and 1 from an upper tract tumor).

Adult↗
PubMed1992

Adult urological sarcoma.

From July 1982 to December 1989, 43 of 1,583 adults (2.7%) with soft tissue sarcoma admitted to the Memorial Sloan-Kettering Cancer Center (MSKCC) had tumors arising from the urinary tract and male genital tract (urological sarcoma). The most common site of origin of the tumor was paratesticular (14 patients), followed by the prostate/seminal vesicle (12), bladder (10) and kidney (7). The most common histological type was leiomyosarcoma (19 patients), followed by rhabdomyosarcoma (14), liposarcoma (5) and 5 other histological sarcoma categories (angiosarcoma, malignant fibrous histiocytoma, mesenchymoma and 2 undifferentiated sarcomas). Most of the tumors were high grade (86%) and more than half (56%) were greater than 5 cm. in diameter. A total of 9 patients (21%) presented with metastatic disease, 8 of whom had rhabdomyosarcoma. Complete resection with negative microscopic margins was possible in 58% of the patients. Actuarial relapse-free survival for all patients at 3 and 5 years was 55% and 40%, respectively. There were no significant differences in survival based on patient age, sex or histological tumor type. Favorable prognostic variables by univariate analysis included tumor diameter less than 5 cm., low histological grade, paratesticular or bladder tumor site and complete surgical resection. Application of the MSKCC sarcoma staging system, which is based on grade, size, depth and presence or absence of metastasis, was useful to predict survival. In our experience patients with stage 3 (high grade, greater than 5 cm., 15 patients) or stage 4 (metastatic disease, 9 patients) had a combined 3-year relapse-free survival rate of only 26% and they should be considered candidates for adjuvant treatment protocols.

Actuarial Analysis↗
PubMed1992

Abbott IMx evaluated for assay of prostate-specific antigen in serum.

We evaluated a new fully automated procedure for quantitative measurement of prostate-specific antigen (PSA) by the Microparticle Enzyme Immunoassay (MEIA) technology developed for the Abbott IMx automated immunoassay system. The performance characteristics of the Abbott IMx PSA assay (y) were evaluated and compared with those of the Hybritech Tandem-E PSA assay (x), a solid-phase two-site immunoenzymometric assay. PSA values for both assays were well correlated (r = 0.99); regression analysis yielded the equation y = 0.92x - 0.23 micrograms/L. The Abbott assay proved reliable and reproducible, as shown by the intra- and interassay coefficients of variation (2.0-3.4% and 3.1-4.7%, respectively). The assay gave a linear standard curve up to 100 micrograms/L and was very sensitive (detected PSA < 0.1 microgram/L). This analytical sensitivity was comparable with that of the Tandem-E PSA assay. Overall, the IMx PSA assay demonstrated the accuracy, precision, linearity, and intermethod correlation required for monitoring patients with prostate cancer.

Autoanalysis↗