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Biomedical subjects

W R Fair

Publications and source records attributed to W R Fair.

At least 37 records · Page 2Linked to original sources
PubMed1999

Effect of neoadjuvant hormonal therapy on prostatic intraepithelial neoplasia and its prognostic significance.

PURPOSE: We studied the effect of neoadjuvant hormonal therapy on prostatic intraepithelial neoplasia in patients undergoing radical prostatectomy and assessed the effect of prostatic intraepithelial neoplasia on disease recurrence as measured by serum prostate specific antigen (PSA). MATERIALS AND METHODS: A total of 278 patients with clinically localized prostate cancer were included in phase II and III studies evaluating radical prostatectomy alone versus radical prostatectomy following neoadjuvant hormonal therapy at Memorial Sloan-Kettering Cancer Center between October 1991 and August 1996. Patient data related to prostatic intraepithelial neoplasia were analyzed. RESULTS: Of 275 evaluable patients 145 (52.7%) had prostatic intraepithelial neoplasia. Of 50 patients treated with neoadjuvant hormonal therapy (hormone group) 22 (44%) had a lower incidence of prostatic intraepithelial neoplasia compared to 69 of 80 controls (86.3%) (chi-square test p<0.0001). Of 262 patients (95.3%) with followup PSA 44 (16.8%) had PSA recurrence at a median followup of 32 months, with a median time to recurrence of 30 months. PSA recurrence was noted in 23 of 145 patients with compared to 21 of 130 without prostatic intraepithelial neoplasia (chi-square test p = 0.95), and did not significantly differ between the hormone group (25 of 142, 17.6%) and controls (19 of 130, 14.6%) (chi-square test p = 0.45). CONCLUSIONS: While patients treated with neoadjuvant hormonal therapy had significantly lower incidence of prostatic intraepithelial neoplasia, neither prostatic intraepithelial neoplasia nor neoadjuvant hormonal therapy significantly affected PSA recurrence at a median followup of 32 months.

Antineoplastic Agents, Hormonal↗
PubMed1999

Prostate specific antigen doubling time after radical prostatectomy: effect of neoadjuvant androgen deprivation therapy.

PURPOSE: We determined the predictors of prostate specific antigen (PSA) doubling time in patients with relapse after radical prostatectomy as well as whether PSA doubling time is shorter in those treated versus not treated with neoadjuvant androgen deprivation therapy. MATERIALS AND METHODS: We calculated PSA doubling time in 204 patients with PSA relapse after radical prostatectomy who were or were not treated with neoadjuvant androgen deprivation therapy. Analysis of covariance was used to determine the effect of clinical and pathological parameters on PSA doubling time, and the proportion of variability explained by these parameters. RESULTS: Clinical stage, and combined clinical stage and margin status, clinical stage and androgen deprivation therapy status, androgen deprivation therapy status and time to PSA relapse, and androgen deprivation therapy status and pretreatment PSA were significant predictors of PSA doubling time. Any variable or combination of variables explained up to only 21% of PSA doubling time variability. When stratified by pretreatment PSA, clinical stage and biopsy grade, the difference in doubling times in patients treated with or without neoadjuvant androgen deprivation therapy was significant only for 4.1 to 10 ng./ml. PSA. In this group mean doubling time plus or minus standard deviation in patients receiving neoadjuvant androgen deprivation therapy and those treated only with radical prostatectomy was 7.6+/-1.0 and 15.4+/-2.6 months, respectively. CONCLUSIONS: Our study indicates that it is difficult to predict PSA doubling time in an individual. The small proportion of variability in PSA doubling time explained by the interaction of androgen deprivation therapy status and other variables indicates that these factors are not clinically significant.

Androgen Antagonists↗
PubMed1999

The impact of primary stage on survival in patients with lymph node positive bladder cancer.

PURPOSE: Contemporary series indicate that survival of cystectomy candidates with node positive bladder cancer is favorable when the primary tumor is confined to the bladder wall and lymph node involvement is minimal. However, these series lack node negative controls with a similar tumor stage to determine accurately the true impact of pelvic lymphadenectomy and radical cystectomy on survival. MATERIALS AND METHODS: We retrospectively analyzed disease specific survival in 686 consecutive cystectomy candidates of whom 193 (28.1%) had node positive disease at radical cystectomy. To correct for bias towards higher P category in the node positive group we subdivided groups into organ and nonorgan confined categories to compare outcome between node negative and node positive cases. RESULTS: The frequency of organ confined disease in node positive cases was 22.8% compared to 59.2% in node negative cases. Although when analyzing the entire group disease specific survival was significantly decreased in node positive cases, after correction for P stage we found no statistically significant differences in survival between N0 and N1 cases in the organ confined group (p = 0.4267). Differences between N0 and N1 cases in nonorgan confined disease were statistically significant (p = 0.0276). Significance levels were more pronounced when cases with N2 or N3 categories were compared with node negative cases. Comparison of survival between node negative and N2 or N3 in either group revealed significant differences indicating limited impact of surgery alone at this disease stage. CONCLUSIONS: Patients with N1 disease seem to benefit from pelvic lymphadenectomy and radical cystectomy as evidenced by similar outcome in those with node negative disease and similar P stage of the primary tumor. However, the observed benefit rapidly disappears when more than 1 lymph node is involved and additional therapy other than surgery seems appropriate.

Adult↗
PubMed1999

Vitamin E inhibits the high-fat diet promoted growth of established human prostate LNCaP tumors in nude mice.

PURPOSE: Prostate cancer has become an important public health problem in the Western world. It is currently the most common diagnosed cancer and the second leading cause of cancer deaths among North American men. Prostate cancer possesses a unique descriptive epidemiology which suggests that environmental factors (such as dietary fat consumption) play a pivotal role in tumor progression. Data from our institution have demonstrated that diets high in fat content can accelerate the growth of human LNCaP prostate cancer cells. One of the hypothesized mechanisms of dietary fat induced growth is oxidative stress. Our purpose was to determine the effect of supplemental Vitamin E, a potent intracellular antioxidant, on the high-fat promoted growth of transplanted LNCaP cells in the athymic mouse. MATERIALS AND METHODS: Tumors were induced by subcutaneous injection of 10(6) LNCaP cells. Mice were fed a control diet consisting of 40.5% of total calories from dietary fat. Once tumors were formed, PSA values were obtained and animals were randomized into 4 groups of 12. The animals were then assigned to one of 4 dietary plans. Group 1 received the control diet of 40.5%-kcal fat. Group 2 received the 40.5%-kcal fat diet plus supplemental Vitamin E. Group 3 received a diet of 21.2%-kcal fat. Group 4 received the 21.2%-kcal fat diet plus supplemental Vitamin E. Food intake, animal weights, and tumor volumes were recorded weekly. Survival analyses with time to a target volume of 0.523 cm.3 (defined as failure) were used to compare tumor growth among the 4 groups. Two-sided tests (log rank test) with alpha set at 0.05 were used to determine significance. RESULTS: Tumor growth rates were highest in the animals fed a 40.5%-kcal fat diet (p <0.05 group 1). Tumors in animals fed 40.5%-kcal fat plus Vitamin E, 21.2%-kcal fat, and 21.2%-kcal fat plus Vitamin E, experienced statistically indistinguishable growth rates. No significant differences were noted in total ingested calories, animal weight gain or initial PSA levels. CONCLUSIONS: These data suggest that the mechanism of dietary fat induced growth of human prostate cancer cells is mediated by oxidative stress. It also raises the possibility of a therapeutic benefit of vitamin E in preventing prostate cancer.

Animals↗
PubMed1999

The role of dietary manipulation in biochemical recurrence of prostate cancer after radical prostatectomy.

In 1999, we continue to be faced with difficulties in treating prostate cancer, which remains the leading cause of cancer and the second leading cause of cancer-related deaths in men. In the prostate-specific antigen (PSA) era, we must also determine which therapies, if any, are appropriate for the treatment of a biochemical or PSA relapse. In view of the limited number of efficacious and durable treatments for prostate cancer recurrence, the medical community has had to investigate nontraditional therapies. In the recent past, an expanding body of evidence has implicated certain nutrients in carcinogenesis and cancer progression. This article discusses the role of diet in prostate carcinogenesis and the rationale for dietary manipulation as a treatment strategy for the prevention of primary and secondary (recurrent) prostate cancer.

Diet↗
PubMed1999

Pelvic lymph node dissection can be curative in patients with node positive bladder cancer.

PURPOSE: We analyze outcome in a large cohort of patients with bladder cancer metastatic to the regional lymph nodes using disease specific survival as the end point. MATERIALS AND METHODS: To identify predictors for outcome a large series of 193 consecutive patients with regional lymph node metastases operated on from 1980 to 1990 at Memorial Sloan-Kettering Cancer Center was retrospectively analyzed. RESULTS: Among various clinical and pathological parameters, univariate and multivariate analyses identified only P (p = 0.0001) and N categories (p = 0.0006) as parameters predicting disease specific survival. In patients who received chemotherapy or irradiation either as part of a nonrandomized clinical protocol or on an ad hoc basis no beneficial impact on disease specific survival could be demonstrated. Survival was also not affected by pathological grade and other histological parameters, since pathological features in patients with node positive bladder cancer are uniformly shifted towards high grade lesions with vascular or lymphatic invasion and a solid appearance on histological analysis. CONCLUSIONS: Nodal metastases carry a poor prognosis despite pelvic lymphadenectomy and radical cystectomy. Nevertheless, some node positive cases with otherwise localized bladder cancer and/or low N category appear to benefit from surgery. Our findings of improved outcome in some individuals with node positive disease should be considered in the design of clinical trials evaluating the effects of adjuvant or neoadjuvant treatment strategies, and emphasize the importance of randomized studies to assess the results of these approaches.

Actuarial Analysis↗
PubMed1998

Mapping, genomic organization and promoter analysis of the human prostate-specific membrane antigen gene.

Prostate-specific membrane antigen (PSMA) is a 100 kDa type II transmembrane protein with folate hydrolase and NAALAdase activity. PSMA is highly expressed in prostate cancer and the vasculature of most solid tumors, and is currently the target of a number of diagnostic and therapeutic strategies. PSMA is also expressed in the brain, and is involved in conversion of the major neurotransmitter NAAG (N-acetyl-aspartyl glutamate) to NAA and free glutamate, the levels of which are disrupted in several neurological disorders including multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's disease and schizophrenia. To facilitate analysis of the role of PSMA in carcinoma we have determined the structural organization of the gene. The gene consists of 19 exons spanning approximately 60 kb of genomic DNA. A 1244 nt portion of the 5' region of the PSMA gene was able to drive the firefly luciferase reporter gene in prostate but not breast-derived cell lines. We have mapped the gene encoding PSMA to 11p11-p12, however a gene homologous, but not identical, to PSMA exists on chromosome 11q14. Analysis of sequence differences between non-coding regions of the two genes suggests duplication and divergence occurred 22 million years ago.

Antigens, Surface↗
PubMed1998

Dose escalation with three-dimensional conformal radiation therapy affects the outcome in prostate cancer.

PURPOSE: Three-dimensional conformal radiation therapy (3D-CRT) is a technique designed to deliver prescribed radiation doses to localized tumors with high precision, while effectively excluding the surrounding normal tissues. It facilitates tumor dose escalation which should overcome the relative resistance of tumor clonogens to conventional radiation dose levels. The present study was undertaken to test this hypothesis in patients with clinically localized prostate cancer. METHODS AND MATERIALS: A total of 743 patients with clinically localized prostate cancer were treated with 3D-CRT. As part of a phase I study, the tumor target dose was increased from 64.8 to 81 Gy in increments of 5.4 Gy. Tumor response was evaluated by post-treatment decrease of serum prostate-specific antigen (PSA) to levels of < or = 1.0 ng/ml and by sextant prostate biopsies performed > or = 2.5 years after completion of 3D-CRT. PSA relapse-free survival was used to evaluate long-term outcome. The median follow-up was 3 years (range: 1-7.6 years). RESULTS: Induction of an initial clinical response was dose-dependent, with 90% of patients receiving 75.6 or 81.0 Gy achieving a PSA nadir < or = 1.0 ng compared with 76% and 56% for those treated with 70.2 Gy and 64.8 Gy, respectively (p < 0.001). The 5-year actuarial PSA relapse-free survival for patients with favorable prognostic indicators (stage T1-2, pretreatment PSA < or = 10.0 ng/ml and Gleason score < or = 6) was 85%, compared to 65% for those with intermediate prognosis (one of the prognostic indicators with a higher value) and 35% for the group with unfavorable prognosis (two or more indicators with higher values) (p < 0.001). PSA relapse-free survival was significantly improved in patients with intermediate and unfavorable prognosis receiving > or = 75.6 Gy (p < 0.05). A positive biopsy at > or = 2.5 years after 3D-CRT was observed in only 1/15 (7%) of patients receiving 81.0 Gy, compared with 12/25 (48%) after 75.6 Gy, 19/42 (45%) after 70.2 Gy, and 13/23 (57%) after 64.8 Gy (p < 0.05). CONCLUSIONS: The data provide evidence for a significant effect of dose escalation on the response of human prostate cancer to irradiation and defines new standards for curative radiotherapy in this disease.

Aged↗
PubMed1998

Clinical stage I testis cancer: long-term outcome of patients on surveillance.

PURPOSE: The long-term outcome results of a prospective surveillance trial for clinical stage I nonseminomatous germ cell tumors of the testis (NSGCT) are reported in an effort to define the natural history of clinical stage I testis cancer treated with orchiectomy alone, and to determine if a subset of patients exists that may be suitable for surveillance. MATERIALS AND METHODS: Between September 1979 and December 1987, 105 patients were entered into the study. Patients with persistent elevation of serum tumor markers (AFP, BHCG, and LDH) following orchiectomy, stage T2-T4 primary tumors, any evidence of metastases and pure choriocarcinoma or pure seminoma on histology were excluded from study. Enrolled patients underwent periodic physical examination, serological testing and radiological imaging according to an established protocol. RESULTS: Median followup was 11.3 years. Of the patients 78 (74.3%) have remained disease-free and 27 (25.7%) have experienced relapse. Of the patients with relapse 24 are currently disease-free after treatment for relapse for a median duration of 10.8 years and 3 (2.8%) died of disease. All relapses occurred within 24 months of orchiectomy (median 5 months). Significant predictors of relapse during surveillance were a predominant embryonal carcinoma histology (p = 0.016) and vascular invasion (p = 0.0005). In patients with neither embryonal carcinoma nor vascular invasion the relapse rate was 12%, and no patients died of disease. CONCLUSIONS: With extended followup 74% of men with clinical stage I (T1) nonseminomatous germ cell tumor of the testis were cured by orchiectomy alone, and cure rates approached 90% when patients with predominant embryonal carcinoma histology or vascular invasion were excluded from surveillance. These findings support management by surveillance alone in a highly select cohort of men who have clinical stage I (T1) nonseminomatous germ cell tumor of the testis, normal serum markers following orchiectomy and neither predominant embryonal carcinoma or vascular invasion on histology.

Adolescent↗
PubMed1998

Early prostate cancer detection and potential for surgical cure in men with poorly differentiated tumors.

OBJECTIVES: Long-term cure after radical prostatectomy has been reported for men with organ-confined poorly differentiated prostate cancer. However, organ-confined rates have been disappointingly low, ranging from 8% to 18% in earlier series, which have consisted primarily of patients not screened for prostate-specific antigen (PSA). Recently, it has been our impression that a greater number of patients with poorly differentiated tumors have had organ-confined disease than earlier reports would have led us to predict. METHODS: To test this hypothesis, we reviewed the results of surgical staging in men with poorly differentiated tumors (Gleason score 8 to 10) entered into our prospective data base between August 1992 and June 1996. RESULTS: Of 109 men undergoing operation during the study period, 64 underwent exploration for planned radical prostatectomy with no previous therapy and comprise the study cohort. In 92%, the initial presentation was an elevated PSA level (median 10.8 ng/mL). We observed an organ-confined rate of 30% and found preoperative PSA levels of 10 ng/mL or less to be a significant predictor of organ-confined disease (45% versus 17%, P = 0.016, chi-square test). On preliminary follow-up (median 31 months), 84% of men with organ-confined tumors are free of PSA relapse, similar to that seen in 233 men with organ-confined moderately differentiated tumors undergoing operation during the study period (P = 0.12, log-rank test). CONCLUSIONS: Early prostate cancer detection, as reflected by PSA levels of 10 ng/mL or less, is associated with a higher organ-confined rate in men with poorly differentiated tumors. On preliminary follow-up, PSA relapse rates were lower in men with pathologically confirmed, organ-confined, poorly differentiated disease.

Adult↗
PubMed1998

Repeat transrectal ultrasound-guided prostate biopsy: a strategy to improve the reliability of needle biopsy grading in patients with well-differentiated prostate cancer.

OBJECTIVES: Gleason grade from prostate needle biopsy (PNB) specimens is important in guiding therapeutic decision making in patients with localized prostate cancer. Recent data from our institution suggest a significant discordance between Gleason grading from PNB versus the actual pathologic grade at radical prostatectomy (RRP). Of most concern is that a substantial proportion of patients with Gleason score of 6 or less from PNB actually have Gleason score of 7 or more at RRP. Under classic measurement theory, one useful way to improve the reliability of an inherently unreliable test is to repeat it. We investigated this strategy in an effort to reduce undergrading errors. METHODS: The control group of patients (n = 51) from our neoadjuvant androgen deprivation protocol was used as the test (two-biopsy) group in this study. These patients underwent two separate PNBs before RRP. We used the highest Gleason score from the two biopsies in these patients and compared the error rates with a concurrent group of patients treated at our institution (n = 226) who had only one set (single-biopsy group) of prostate biopsies. All pathologic slides were reviewed at our institution. Any PNB grade of 6 or less that was scored as 7 or more on final pathology was considered significant. RESULTS: Mean age, prostate-specific antigen levels, and stage distribution were not significantly different between these two groups. In the single-biopsy group, 165 patients had PNB Gleason score of 6 or less. Of these patients, 63 (38%) had final pathologic grade of 7 or more. In the two-biopsy group, 37 patients had PNB Gleason score of 6 or less. Of these patients, only 7 (19%) had final pathologic grade of 7 or more (P = 0.04). CONCLUSIONS: Prostate rebiopsy minimizes the inherent unreliability of PNB derived grade and should be considered for patients in whom watchful waiting or nomogram-based therapy has been selected.

Biopsy, Needle↗
PubMed1998

Incidence and clinical significance of false-negative sextant prostate biopsies.

PURPOSE: Since most patients do not undergo repeat sextant prostate biopsies after a biopsy is positive for prostate cancer, the true incidence of false-negative biopsies is not well defined. We assess the incidence and clinical significance of false-negative sextant prostate biopsies in patients undergoing radical prostatectomy. MATERIALS AND METHODS: A total of 118 patients with biopsy proved prostate cancer underwent repeat sextant prostate biopsy before enrollment in a prospective randomized trial of radical prostatectomy with or without neoadjuvant hormonal therapy. Clinical parameters were assessed to determine potential sources of bias. Pathological parameters and prostate specific antigen relapse-free survival rates were compared to determine the clinical significance of false-negative biopsies. RESULTS: Of the 118 patients 27 (23%) had a negative repeat sextant biopsy. Except for initial clinical stage, no differences were noted in the clinical or pathological parameters, or prostate specific antigen relapse rates in patients with negative versus positive repeat biopsies. CONCLUSIONS: Our findings suggest that this 23% incidence of false-negative biopsies represents significant cancer. This relatively high incidence is important to consider in treatment modalities in which prostate biopsy may be performed to determine response to therapy.

Biopsy, Needle↗
PubMed1998

Site specific predictors of positive margins at radical prostatectomy: an argument for risk based modification of technique.

PURPOSE: We identify patients at high risk for positive bladder neck, apical or posterior margins who may benefit from technical modifications, such as excision of the bladder neck or wide excision of the neurovascular bundles. MATERIALS AND METHODS: We studied 242 patients with clinically localized prostate cancer undergoing radical prostatectomy with or without neoadjuvant androgen deprivation therapy between June 1992 and August 1997 who had a sextant biopsy available for review. Multivariate logistic regression analysis was used to develop models for prediction of positive bladder neck, apical, and right and left posterior margins based on clinical parameters. From these models patients at low and high risk for positive margins were identified. RESULTS: The incidence of positive margins was 36% with 69% solitary sites. Patients with a prostate specific antigen of greater than 10 ng./ml. had a higher incidence (16%) of positive bladder neck margins. Patients with 3 or more positive cores who did not receive neoadjuvant androgen deprivation therapy had a higher incidence (24%) of positive apical margins. A nomogram incorporating pretreatment serum prostate specific antigen, number of ipsilateral positive cores and whether androgen deprivation therapy was used identified patients at high risk for positive posterior margins. CONCLUSIONS: The nomograms presented identify patients at high risk for positive margins at various sites who may benefit from modification of surgical technique based on risk.

Adenocarcinoma↗
PubMed1997

Evaluation of the tetracycline-repressible transactivator system for inducible gene expression in human prostate cancer cell lines.

BACKGROUND: Studies of genes that may inhibit growth or induce death of cells are facilitated greatly by tightly controlled expression of those genes. A promising system for control of transgene expression over a wide range is the tetracycline-repressible transactivator (tTA) system developed by Gossen and Bujard [Proc Natl Acad Sci USA 1992;89:5547-5551]. We investigated the effectiveness of this system in three well-established human prostate cancer cell lines. METHODS: LNCaP, PC-3, and Tsu-Pr1 cells were transfected with a vector coding for the tTA protein and/or a luciferase reporter vector, and luciferase activity was measured in the presence and absence of tetracycline or the tTA protein. RESULTS: In the absence of tetracycline, the tTA system yielded high levels of luciferase activity in all three cell lines. Background luciferase activity in the presence of tetracycline was nearly undetectable in LNCaP cells, moderate in Tsu-Pr1 cells, and more than 20-fold higher in PC-3 than in Tsu-Pr1 cells. Similar background activity was observed in Tsu-Pr1 and PC-3 cells, even in the absence of the transactivator protein. CONCLUSIONS: The tTA system should be useful for stable transfection of cytotoxic transgenes in LNCaP cells and for control of transgene expression over a wide range in Tsu-Pr1 and PC-3 cells.

Cell Line↗
PubMed1997

Prostate-specific membrane antigen.

BACKGROUND: In an effort to discover new prostate-specific antigens (PSAs) to enhance our understanding of the functions and behavior of the prostate and the complex processes involved in prostate tumor progression, the structure and function of the PSM antigen has been elucidated. METHODS: The PSM antigen was recognized using the 7E11-C5.3 monoclonal antibody, generated against the LNCaP human prostate adenocarcinoma cell line. The PSM cDNA was isolated by PCR, using tryptic peptides of immunoprecipitated PSM to design degenerate primers. RESULTS: The prostate specific membrane antigen (PSM) is a 100 KD glycoprotein which appears to be a type II integral membrane protein. The protein and cDNA have been extensively characterized and the findings reviewed in the report. CONCLUSIONS: PSM, a new prostate antigen is valuable as a marker for hematogenous micro-metastatic tumor dissemination as detected in RT-PCR assays of peripheral blood. PSM has many properties that may be potentially useful as a molecular target in monoclonal antibody directed strategies of tumor imaging and therapy.

Alternative Splicing↗