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Biomedical subjects

W F Whitmore

Publications and source records attributed to W F Whitmore.

At least 19 recordsLinked to original sources

Conservative management of localized prostatic cancer.

Radical prostatectomy (RP), irradiation (RT), early endocrine therapy (EET), and expectant treatment (DT) are strategies for the management of clinically localized prostatic cancer. EET has not been systematically studied, but warrants prospective exploration. DT in uncontrolled studies results in disease-specific survival rates at 10 years that appear comparable to those achieved following RP or RT and may be considered a management option in patients with limited life expectancy. Serial observations in untreated patients provide a clinical indication of the rate of tumor progression, but better indicators of growth rate, metastatic potential, and responsiveness to a particular therapy are needed. Decision analysis may ultimately provide a practical supplement to clinical judgment in the choice of treatment.

Humans

Expectant management of localized prostatic cancer.

Seventy-five patients with clinical Stage B histologically proven prostatic cancer accumulated over a 40-year period and receiving no therapy for at least 1 year after histologic diagnosis were retrospectively reviewed. Twenty-nine patients had Stage B1 lesions, 37 had B2, and nine had B3 lesions; median follow-up for these patients was 124, 120, and 96 months, respectively. Five ultimately received pelvic lymph node dissection with iodine-125 implantation, 23 had transurethral resection of the prostate, and 18 had endocrine therapy. Of those tumors which progressed, 18 of 19 (95%) B1, 26 of 29 (90%) B2, and four of four (100%) B3 lesions demonstrated local progression first. Six of 29 (21%) B1, 17 of 37 (46%) B2, and two of nine (22%) B3 tumors developed recognized distant metastasis. Actuarial survival at 15 years was 67%, 39%, and 63% for patients with B1, B2, and B3 lesions, respectively. These data indicate the varied and potentially protracted course of patients with clinical Stage B prostatic cancer.

Adenocarcinoma

The effect of local control on metastatic dissemination in carcinoma of the prostate: long-term results in patients treated with 125I implantation.

The study evaluates the effect of the locally recurring tumor on the incidence of metastatic disease in early stage carcinoma of the prostate. The probability of distant metastases was studied in 679 patients with Stage B-C/N0 carcinoma of the prostate treated at MSKCC between 1970 and 1985 (median follow-up of 97 months). Patients were staged with pelvic lymph node dissection and treated with retropubic 125I implantation. The actuarial distant metastases free survival (DMFS) for patients at risk at 15 years after initial therapy was 37%. Cox proportional hazard regression analysis of covariates affecting the metastatic outcome showed that local failure, used in the model as a time dependent variable, was the most significant covariate, although stage, grade, and implant volume were also found to be independent variables. The relative risk of metastatic spread subsequent to local failure was 4-fold increased compared to the risk without evidence of local relapse. The 15-year actuarial DMFS in 351 patients with local control was 77% compared to 24% in 328 patients who developed local relapses (p less than 0.00001). The relation of distant spread to the local outcome was observed regardless of stage, grade, or implant dose. Even stage B1/N0-Grade I patient with local control showed a 15-year actuarial DMFS of 82%, compared to 22% in patients with local relapse; p less than 0.00001). The median local relapse-free survival (LRFS) in the 268 patients with local recurrences who did not receive hormonal therapy before distant metastases were detected was 51 months, compared to a median of 71 months for DMFS in the same patients (p less than 0.001), consistent with the possibility that distant dissemination may develop secondary to local failure. Furthermore, distant metastases in patients with local control, apparently already existing as micrometastases before treatment, were detected earlier (median DMFS of 37 months) than in patients with local relapse (median DMFS of 54 months; p = 0.009). These data suggest that the existence and re-growth of local residual disease in localized prostatic carcinoma promotes an enhanced spread of metastatic disease, and that early and complete eradication of the primary tumor is required if a long term cure is to be achieved, although the clinical expression of secondary metastases may not become apparent for 6.5 years or more in one-half of the patients.

Adenocarcinoma

'Local recurrence' and 'disease-free survival'. Doubtful parameters when comparing non-randomized studies of prostate cancer.

We reviewed recent literature on studies with external radiation of prostatectomy for localized prostate cancer considering the definitions of 'local recurrence' and 'disease-free survival' and the reporting of patients lost to follow-up. Among studies evaluating external radiation, 5/71 (29%) mention that prostate biopsy is used for some patients in determining local recurrence, versus 6/11 (55%) for prostatectomy. Several studies, 15/28 (54%), present figures for disease-free survival without giving a definition of the parameter. In the majority of the reports no comments are made relative to patients lost to follow-up. Three authors consider patients lost to follow-up as dead with disease. Considerations regarding 'local recurrence' and 'disease-free survival' warrant caution in the interpretation of data based on such parameters. In a comparison of non-randomized studies of localized prostate cancer, cancer-specific survival with prostate cancer death defined as 'death wtih diagnosed distant metastases' may be a robust parameter.

Clinical Trials as Topic

Locoregional prostatic cancer. Advances in management.

Conceptual advances include attempts to achieve uniformity among systems for characterizing and reporting experiences with prostatic cancer, better understanding of the zonal anatomy of the prostate, and recognition of probable precursor lesions to prostatic cancer. Prostatic-specific antigen, transrectal ultrasonography, and fine-needle aspiration biopsy are major innovations in diagnosis and staging of prostatic cancer. The varied and unpredictable behavior of prostatic cancer has stimulated the search for reliable indicators of the biologic potential of the disease. Management of localized prostatic cancer remains controversial. A nerve-sparing technique of radical retropubic prostatectomy accomplishes total removal of the prostate with possible preservation of sexual potency. Linear accelerator irradiation is an acceptable alternative treatment. Interstitial irradiation with a variety of radionuclides remains under investigation using ultrasound to enhance distribution of radiation sources. Endocrine therapy may prove especially advantageous if administered before development of bone metastasis.

Combined Modality Therapy

125iodine reimplantation for locally progressive prostatic carcinoma.

We treated 13 patients with a second 125iodine implant for local recurrence of prostatic carcinoma. All patients had biopsy proved palpable recurrence without evidence of distant metastases. Full doses of irradiation were used (median matched peripheral dose 170 Gy.). Six patients had complete regression of palpable recurrence, 2 had partial regression, 2 had no apparent response and 3 were unevaluable for local response. Actuarial freedom from local disease progression at 5 years was 51%. Despite a relatively high rate of local disease control the actuarial rate of distant metastases reached 100% at 6 years after reimplantation. There were 2 severe rectal complications and 4 instances of mild to moderate urinary incontinence among the 13 patients. Local regression of recurrent prostatic carcinoma may be achieved with 125iodine reimplantation but most patients still had distant metastases.

Brachytherapy

Neoadjuvant chemotherapy in invasive bladder cancer: the evolving role of surgery.

The role of an operation in patients receiving neoadjuvant chemotherapy for clinically localized but invasive transitional cell carcinoma of the bladder currently is evolving. An operation is essential for case selection and evaluation of local response but it also contributes to bladder preservation and survival. The procedure that is necessary to select for and assess response to chemotherapy may itself alter the actual or proceed to evolution of invasive bladder cancer. Neoadjuvant chemotherapy is a reasonable therapeutic strategy in selected patients but it remains to be seen whether the results will prove to be superior to those achieved with standard endoscopic and open operations.

Antineoplastic Combined Chemotherapy Protocols

Review of an 8-year experience with modifications of endoscopic suspension of the bladder neck for female stress urinary incontinence.

Several modifications of endoscopic suspension of the bladder neck for treatment of female stress urinary incontinence have been used during an 8-year period. Of 154 patients treated 25 failures occurred, for an over-all success rate of 84%. Fifteen patients had postoperative complications for an over-all complication rate of 9.8%. Hospital stay decreased steadily throughout the review period to a current average of 2.2 days, with many patients presently undergoing an operation on an outpatient basis.

Adult

Enhanced bladder cancer detection with the Lewis X antigen as a marker of neoplastic transformation.

Recent evidence indicates that the Lewis X determinant is a tumor-associated antigen in the urothelium. Immunohistochemical analyses on frozen and deparaffinized, formalin-fixed tissue sections have demonstrated that the Lewis X antigen is not detected in normal adult urothelium except for occasional umbrella cells. However, papillomas and transitional cell carcinomas express this blood group-related antigen in more than 90% of the cases regardless of the grade or stage of the tumor, or the blood type or secretor status of the individual. To determine the presence of Lewis X antigen on exfoliated bladder epithelial cells we used an anti-Lewis X monoclonal antibody (P-12) and the avidin-biotin-peroxidase technique on 129 bladder barbotage specimens. Of 40 controls 34 were negative for Lewis X antigen, for a specificity of 85%. The 89 bladder tumor patients consisted of 14 with papilloma, 13 with flat carcinoma in situ, 49 with transitional cell carcinoma, and 13 with a positive cytology and negative biopsy results. Of these 89 patients 76 were considered positive for Lewis X antigen, for an over-all sensitivity 85.4%. The sensitivity for cytology alone was 61.2%. However, the combination of a positive cytology and/or positive Lewis X antigen result yielded a sensitivity of 93.2%. The data suggest that immunocytological detection of the Lewis X antigen on exfoliated bladder cells enhances the detection of urothelial tumor cells, particularly from low grade and low stage neoplasms.

Antibodies, Monoclonal

The response of patients with superficial bladder cancer to a second course of intravesical bacillus Calmette-Guerin.

Of 347 patients who received an initial 6-week course of intravesical bacillus Calmette-Guerin for superficial transitional cell carcinoma of the bladder 28 (8%) were treated with another course. Subsequent progression of disease (muscle infiltration, metastasis or local progression) occurred in 13 patients (46%). Of the 15 patients (54%) without progression 10 (36%) had a complete response and 5 (33%) had new tumors, and they were rendered free of disease after transurethral resection. The median duration of response to course 1 of bacillus Calmette-Guerin was shorter for patients with disease progression after course 2 than for those with no progression (15 and 27 months, respectively, p equals 0.05). The median followup after course 2 was 31.2 months (range 15.6 to 56.4 months). The median interval between courses 1 and 2 of intravesical bacillus Calmette-Guerin was 21.6 months (range 3.6 to 78.8 months). The interval from course 2 of bacillus Calmette-Guerin to progression correlated with the duration of response to course 1 of treatment (p equals 0.01). It appears that a subsequent treatment with bacillus Calmette-Guerin is most likely to be useful in patients who have a sustained response to the initial treatment.

Administration, Intravesical

Voided urine flow cytometry in screening high-risk patients for the presence of bladder cancer.

Fifty-nine patients with a history of bladder cancer were evaluated with three serially voided urines for flow cytometry and cytology within the 24 hours preceding cystoscopy, bladder wash, and biopsy. Evaluation of the 32 patients with biopsy proven cancer revealed that for one, two, and three voided urine specimens, the sensitivity of flow cytometry in detecting bladder cancer was 29%, 35%, and 41%, respectively, whereas the sensitivity of voided urine cytology was 44%, 53%, and 57%, respectively. Bladder wash flow cytometry had a sensitivity of 76%. Interpretation of the voided urine flow cytometry was based on a control group of 80 volunteers with negative voided urine cytology. The control group demonstrated that a minimum of 1500 analyzable cells was necessary for a reliable histogram. Considering all 59 patients, voided urine flow cytometry, bladder wash flow cytometry, and voided urine cytology were acceptable for analysis in 53%, 93%, and 100% of the specimens, respectively. Voided urine specimens appear less suitable than bladder irrigation specimens for evaluation by flow cytometry. Voided urine flow cytometry is less sensitive in detecting bladder cancer than voided urinary cytology or bladder wash flow cytometry and is not effective for use as a bladder cancer screening test.

Cystoscopy

Current therapy of bladder cancer.

Bladder cancer includes a heterogeneous spectrum of neoplasms for which a variety of surgical and/or radiation treatments has been applied. Local control is generally achieved with the appropriately selected treatment. With superficial neoplasms, new tumor formation is the principal problem and has resulted in the development of intravesical instillations utilizing biologic response modifiers or chemotherapy. With muscle-infiltrating neoplasms, distant metastasis is the principal problem and has stimulated the evolution of systemic chemotherapy. Progress in systemic treatment has resulted in combination chemotherapies capable of inducing protracted complete responses in some patients. Pilot studies of such chemotherapy with or without irradiation and with or without surgery in patients with muscle-infiltrating tumors have the objectives of improving survival and/or of bladder preservation. Tumor heterogeneity requires more detailed specification to facilitate more rational and less empirical selection of the optimal therapy, especially in view of an increasing number of apparent treatment options.

Humans

Selection of treatment for muscle infiltrating transitional cell bladder cancer.

1. Cancers of the bladder are heterogeneous. 2. A variety of surgical and radiation treatments has been useful in local tumor control. 3. Rational selection for optimal local therapy requires definition of more specific selection criteria. 4. The favorable effects of chemotherapy in patients with advanced bladder cancer warrant clinical investigation of such treatment in adjuvant and neoadjuvant settings while the search for more effective chemotherapy continues.

Antineoplastic Agents

Natural history of low-stage prostatic cancer and the impact of early detection.

An expanding and increasingly older population, a rising incidence of prostate cancer, and uncertainties regarding treatment effectiveness have made this disease a target of special concern. The natural history of the cancer must be a consequence of host-tumor interactions, but little is known for sure about this subject. The growth rate of the tumor is determined by many factors, including genetic instability. At present, tumor grade, volume, and ploidy are the most useful techniques for judging the growth rate and metastatic potential. Stage A1 tumors generally are indolent, whereas stage A2 tumors are more aggressive. The natural history of stage B lesions is not well documented. The author asks two questions (Is cure necessary in those in whom it may be possible? Is cure possible in those in whom it may be necessary?) and reviews the problems inherent in screening for prostate cancer at this time.

Humans

Analysis of a mouse monoclonal antibody that reacts with a specific region of the human proximal tubule and subsets renal cell carcinomas.

Murine monoclonal antibody (mAb) F31 detects a heat-stable antigen (URO-8) found in the acidic lipid fraction of renal cancer cell extracts. Serological analysis of mAb F31 reactivity was assayed on 176 human cell lines. mAb F31 reacted with 38 of 45 renal cancers, a subpopulation of cells in primary cultures of normal renal epithelia, and two of 13 colon, two of 15 lung, and four of five ovarian cancers. No other epithelial, hematopoietic, or neuroectodermal cell lines tested were reactive. Immunofluorescence and immunoperoxidase analyses of fresh frozen tissue sections revealed mAb F31 reactivity in kidney, gastrointestinal tract, biliary canaliculi, bronchial epithelium, and skin. Within the kidney, mAb F31 immunoreactivity was confined to the straight portion of the proximal tubule. A panel composed of previously characterized mAbs as well as mAb F31 defines the antigenic phenotype of proximal convoluted tubular cells as URO-2+/URO-3+/URO-4+/URO-10+/URO-8-/URO-5-; proximal straight tubular cells as URO-2+/URO-3+/URO-4+/URO-10-/URO-8+/URO-5-; and cells of the descending thin limb of Henle as URO-2-/URO-3+ or -/URO-4+/URO-10-/URO-8-/URO-5+. While adult proximal tubular cells demonstrated reciprocal expression of URO-8 and URO-10, fetal kidney proximal tubule progenitor cells coexpressed both antigens (URO-10+/URO-8+). Fifty renal cancer specimens were typed with these antibodies. Fourteen cases were URO-10+/URO-8-, ten cases were URO-10-/URO-8+, and 25 cases expressed both antigens (URO-10+/URO-8+). These phenotypes are consistent with derivation of these particular subsets from the proximal convoluted tubule, the pars recta, or a proximal tubule progenitor cell, respectively. Only one specimen failed to express either URO-8 or URO-10.

Antibodies, Monoclonal

Detection of bladder carcinoma in females by flow cytometry and cytology.

The sensitivity of bladder wash flow cytometry (BWFCM), voided urinary cytology (VUC), and cytology of catheterized urine obtained at the time of cystoscopy (CUC) were reviewed on all women evaluated for bladder cancer at Memorial Sloan-Kettering Cancer Center between June 1985 and December 1986. This comprised sixty-four episodes of pathologically proven bladder cancer in 48 women. Considering positive and suspicious results jointly the sensitivities of BWFCM, CUC and 3 VUC were 75%, 64% and 56%, respectively. If only positive results were considered (i.e., suspicious results considered as negative), the sensitivities of BWFCM, CUC and 3 VUC were 64%, 31% and 32%, respectively. The sensitivities of these tests are less than for a predominantly male population, presumably related to the presence of squamous epithelium and greater frequency of pyuria. However, bladder wash flow cytometry and conventional cytology are still a very valuable addition to cystoscopic examination, and the combination of BWFCM with conventional cytology is more sensitive than either procedure alone.

Adult