Estudio comparativo de la eficacia quirúrgica en la prostatectomía abierta y laparoscópica: reconstrucción virtual de la próstata y cuantificación del tejido periprostático / Comparative study of surgical efficacy in open versus laparoscopic prostatectomy: virtual prostate reconstruction and periprostatic tissue quantification

Introducción: La introducción de la cirugía laparoscópica como medio de realizar la prostatectomía radical precisa de un método objetivo para evaluar la idoneidad de este nuevo procedimiento quirúrgico. Los parámetros tradicionales, incluidos la incidencia de márgenes quirúrgicos positivos, son útiles, pero no suficientemente objetivos. Diferentes autores publican distintos criterios para definir los márgenes quirúrgicos positivos. Además, existen algunos artefactos técnicos que pueden ocurrir durante el procesamiento de la pieza quirúrgica por el patólogo, los cuales pueden dar lugar a márgenes falsamente positivos. Hemos usado un programa de modelización por ordenador acoplado al escaneado de las imágenes seriadas de cortes histológicos de la glándula completa, con el fin de determinar el porcentaje del tejido extracapsular que rodea a las glándulas prostáticas, tanto las extirpadas mediante la técnica abierta retropúbica como las extirpadas mediante laparoscopia. Este porcentaje puede considerarse un parámetro objetivo que potencialmente pueda predecir el beneficio de la cirugía en cuanto al control del cáncer, así como el éxito clínico del procedimiento quirúrgico. La correlación con los resultados clínicos a largo plazo, - supervivencia y recidiva bioquímica -servirán para validar en última instancia la utilidad clínica de este parámetro en años venideros. Materiales y métodos: Para este estudio se dispuso de un total de 32 piezas quirúrgicas de la próstata, incluidas 15 piezas de próstata de pacientes sometidos a prostatectomía radical abierta y 17 piezas de próstata de pacientes sometidos a prostatectomía laparoscópica. Después de la cirugía y de 24 horas de fijación en formol, se tomaron cortes seriados para realizar secciones completas (“whole mount”) de la próstata a intervalos de 5 mm de grosor. Un patólogo experto en uropatología revisó las secciones completas y dibujó los contornos de la cápsula prostática y del tumor en cada corte tisular. Las imágenes seriadas de la glándula completa y del tejido peri o extraprostático circundante se escanearon para producir imágenes digitales, utilizándose un programa informático para crear un archivo con información sobre la cápsula y un archivo con información sobre el tejido fibroadiposo circundante (extraprostático). Estos procedimientos permitieron la reconstrucción de un modelo tisular tridimensional de la cápsula prostática y del tejido extraprostático circundante. Se generaron dos archivos de nubes de puntos por separado, con la intención de representar modelos tanto de la cápsula como del tejido extraprostático y se usaron algoritmos de software para generar diferencias en las nubes de puntos y, de este modo, cuantificar la magnitud de la cobertura del tejido extracapsular, un parámetro que consideramos indicativo de la idoneidad de la técnica quirúrgica. Resultados: El porcentaje global de superficie de la glándula prostática cubierto por tejido fibroadiposo extracapsular fue estadísticamente mayor en las piezas extirpadas mediante la técnica laparoscópica, en comparación con la técnica retropúbica. Cuando se evaluó un análisis segmentario del porcentaje de cobertura de la glándula, se encontró que el porcentaje era significativamente mayor en los segmentos apical e inferolateral de las glándulas extirpadas sin preservación de los nervios y en el segmento apical de las glándulas extirpadas con preservación de los nervios para la prostatectomía laparoscópica. Conclusiones: En nuestra serie, la prostatectomía laparoscópica aportó una cobertura tisular extracapsular superior a la prostatectomía retropúbica. Del mismo modo, la prostatectomía laparoscópica aportó una cobertura tisular superior en las regiones inferolateral y apical de las glándulas extirpadas sin preservación de los nervios y en la región apical de las glándulas extirpadas con preservación de los nervios. Así pues, la idoneidad quirúrgica de esta técnica, en comparación con el procedimiento retropúbico, parece ser superior

Introduction: The introduction of laparoscopic surgery as a procedure to perform radical prostatectomy needs an objective method to evaluate the suitability of this new surgical procedure. The traditional parameters, including the incidence of positive surgical margins, are useful, but not sufficiently objective. Different authors publish different criteria to define positive surgical margins. In addition, there are some technical problems that may ocur during the processing of the surgical specimen by the pathologist, which can give false positive margins. We have used a computer modeling software in connection to scanned images from serial sections of the whole gland, to determine the percentage of extracapsular tissue that surrounds the prostate glands, removed by both, open retropubic and laparoscopic procedures. This percentage can be considered as an objective parameter which can potentially predict the benefit of surgery in predicting cancer control, as well as the clinical success of the surgical procedure. The correlation with the clinical results in the long term, survival and biochemical recurrence, will be useful to validate as a last resort the clinical utility of this parameter in the coming years. Materials and Methods: We had a total of 32 prostate surgical specimens, 15 from patients who underwent open retropubic prostatectomy and 17 from patients who underwent laparoscopic prostatectomy for this study. After surgery and 24 hours formol fixation, serial cuts were taken at 5 mm thickness intervals to make complete sections (“whole mount”) of the prostate. An expert uropathologist reviewed all the surgical sections and drew in each tissue cut the prostatic capsule and tumor contours. The serial images of the whole gland and surrounding prostate tissue were scanned to produce digital images, using a computer software to create a file with capsule information and a file with information on the surrounding fibroadipose tissue (extraprostatic). These procedures allowed the reconstruction of a threedimensional tissue model of the prostatic capsule and the surrounding extraprostatic tissue. Two separate point clouds files were generated, with the purpose of representing capsule and extraprostatic tissue models and software algorithms were used to generate differences in point clouds and thereby quantifying the extracapsular tissue coverage dimension, a parameter that we considered indicative of the adequeacy and feasibility of the surgical procedure. Results: The global percentage of prostate gland surface covered by extracapsular fibroadipose tissue was statistically higher in specimens removed by a laparoscopic procedure when compared to the open retropubic procedure. When a segmental analysis of the gland percentage of coverage was evaluated, it was found this percentage was significantly higher in the apical and inferolateral segments of those glands removed without nerves preservation and in the apical segments of those glands removed with nerves preservation for the laparoscopic prostatectomy. Conclusions: In our series, laparoscopic prostatectomy contributed superior extracapsular tissue coverage than retropubic prostatectomy. Similarly laparoscopic prostatectomy produced a superior tissue coverage in inferolateral and apical regions on those glands removed without nerve preservation and in the apical regions of those glands removed with nerve preservation

[Comparative study of surgical efficacy in open versus laparoscopic prostatectomy: virtual prostate reconstruction and periprostatic tissue quantification]. / Estudio comparativo de la eficacia quirúrgica en la prostatectomía abierta y laparoscópica: reconstrucción virtual de la próstata y cuantificación del tejido periprostático.

INTRODUCTION: The introduction of laparoscopic surgery as a procedure to perform radical prostatectomy needs an objective method to evaluate the suitability of this new surgical procedure. The traditional parameters, including the incidence of positive surgical margins, are useful, but not sufficiently objective. Different authors publish different criteria to define positive surgical margins. In addition, there are some technical problems that may ocur during the processing of the surgical specimen by the pathologist, which can give false positive margins. We have used a computer modeling software in connection to scanned images from serial sections of the whole gland, to determine the percentage of extracapsular tissue that surrounds the prostate glands, removed by both, open retropubic and laparoscopic procedures. This percentage can be considered as an objective parameter which can potentially predict the benefit of surgery in predicting cancer control, as well as the clinical success of the surgical procedure. The correlation with the clinical results in the long term--survival and bioche--mical recurrence--will be useful to validate as a last resort the clinical utility of this parameter in the coming years. MATERIALS AND METHODS: We had a total of 32 prostate surgical specimens, 15 from patients who underwent open retropubic prostatectomy and 17 from patients who underwent laparoscopic prostatectomy for this study. After surgery and 24 hours formol fixation, serial cuts were taken at 5 mm thickness intervals to make complete sections ("whole mount") of the prostate. An expert uropathologist reviewed all the surgical sections and drew in each tissue cut the prostatic capsule and tumor contours. The serial images of the whole gland and surrounding prostate tissue were scanned to produce digital images, using a computer software to create a file with capsule information and a file with information on the surrounding fibroadipose tissue (extraprostatic). These procedures allowed the reconstruction of a three dimensional tissue model of the prostatic capsule and the surrounding extraprostatic tissue. Two separate point clouds files were generated, with the purpose of representing capsule and extraprostatic tissue models and software algorithms were used to generate differences in point clouds and thereby quantifying the extracapsular tissue coverage dimension, a parameter that we considered indicative of the adequeacy and feasibility of the surgical procedure. RESULTS: The global percentage of prostate gland surface covered by extracapsular fibroadipose tissue was statistically higher in specimens removed by a laparoscopic procedure when compared to the open retropubic procedure. When a segmental analysis of the gland percentage of coverage was evaluated, it was found this percentage was significantly higher in the apical and inferolateral segments of those glands removed without nerves preservation and in the apical segments of those glands removed with nerves preservation for the laparoscopic prostatectomy. CONCLUSIONS: In our series. laparoscopic prostatectomy contributed superior extracapsular tissue coverage than retropubic prostatectomy. Similarly laparoscopic prostatectomy produced a superior tissue coverage in inferolateral and apical regions on those glands removed without nerve preservation and in the apical regions of those glands removed with nerve preservation. Therefore, the surgical suitability of this technique, when compared to the retropubic, seems to be higher

[Laparoscopic radical cystectomy with intracorporeal creation of a continent urinary diversion. Future or present?]. / Laparoskopische radikale Zystektomie mit intrakorporaler Anlage einer kontinenten Harnableitung. Zukunft oder Gegenwart?

Once laparoscopic radical prostatectomy has been mastered, the step to performing a radical cystectomy is not that far. The challenge is to create the urinary diversion by laparoscopy. In this report we describe our experience with 11 laparoscopic radical cystectomies and intracorporeal construction of a continent urinary diversion (Mainz pouch II) as a treatment option in patients with muscle-invading bladder cancer. All 11 procedures could be performed successfully. A conversion to open surgery was not required in any case. The mean surgery time was 6.7 h. Except for two pouch fistulas we did not observe any intra- or postoperative complications. The functional as well as the oncological results are convincing. Less morbidity and faster recovery are the main advantages of this minimally invasive procedure. In addition, the low levels of blood loss, fluid shifts, and electrolyte loss considerably reduce cardiovascular stress. Radical cystectomy and construction of a continent urinary diversion represent the limit of technically feasible laparoscopy and should be done exclusively in specialized centers.

Quantitation of serum prostate-specific membrane antigen by a novel protein biochip immunoassay discriminates benign from malignant prostate disease.

The lack of a sensitive immunoassay for quantitating serum prostate-specific membrane antigen (PSMA) hinders its clinical utility as a diagnostic/prognostic biomarker. An innovative protein biochip immunoassay was used to quantitate and compare serum PSMA levels in healthy men and patients with either benign or malignant prostate disease. PSMA was captured from serum by anti-PSMA antibody bound to ProteinChip arrays, the captured PSMA detected by surface-enhanced laser desorption/ionization mass spectrometry, and quantitated by comparing the mass signal integrals to a standard curve established using purified recombinant PSMA. The average serum PSMA value for prostate cancer (623.1 ng/ml) was significantly different (P < 0.001) from that for benign prostate hyperplasia (117.1 ng/ml) and the normal groups (age <50, 272.9 ng/ml; age >50, 359.4 ng/ml). These initial results suggest that serum PSMA may be a more effective biomarker than prostate-specific antigen for differentiating benign from malignant prostate disease and warrants additional evaluation of the surface-enhanced laser desorption/ionization PSMA immunoassay to determine its diagnostic utility.

Quality of life after treatment for localized prostate cancer: differences based on treatment modality.

PURPOSE: Brachytherapy with 103palladium (103Pd) is an increasingly administered treatment modality for localized prostate cancer. We compared general and disease specific health related quality of life after 103Pd treatment, radical prostatectomy and external beam radiation therapy given during the same time frame. MATERIALS AND METHODS: We performed a retrospective cross-sectional survey study of patients treated at a single community medical center between 1995 and 1999. We mailed 5 validated health related quality of life survey instruments to 269, 142 and 222 men who underwent radical prostatectomy, 103Pd treatment and external beam radiation therapy, respectively, with a response rate of greater than 80% in all groups. RESULTS: General health related quality of life assessed by the SF-36 showed the same scores in patients who underwent prostatectomy and 103Pd treatment. The University of California-Los Angeles Prostate Cancer Index was used to assess bowel, urinary and sexual function/bothersomeness. External beam radiation therapy reported was associated with worse bowel function and greater bowel bothersomeness. Prostatectomy was associated with worse urinary function compared to 103Pd and external beam radiation therapy. Prostatectomy was associated with worse sexual function than 103Pd or external beam radiation therapy, although nerve sparing surgery and erectile aids minimized the difference. American Urological Association symptom scores were initially higher for 103Pd but became equal to those in the other groups in patients treated greater than 12 months from survey time. Disease-free men who underwent prostatectomy and 103Pd brachytherapy were equally confident that cancer would not recur in the future. Satisfaction rates were equivalent and biochemical failure significantly decreased satisfaction in all groups. CONCLUSIONS: While general health related quality of life was mostly unaffected by the 3 most common treatments for prostate cancer, there were differences in bowel, urinary and sexual function. This information may aid patients in the decision making process.

Luteinizing hormone-releasing hormone monotherapy: a viable option for treatment of prostate cancer?

When addressing the appropriateness of luteinizing hormone-releasing hormone (LHRH) analog monotherapy as a method of androgen deprivation, it is important to look at the alternative option of androgen deprivation by combined androgen blockade (CAB). The randomized control trials studying CAB have been thoroughly analyzed and subjected to meta-analyses that have shown a small but significant difference in survival at 5 years. These findings have been subject to variable interpretations. Much like other treatment-option decisions for prostate cancer, it is mandatory to inform patients fully on the costs and benefits of monotherapy versus CAB and to incorporate the patient's concerns and preferences in the decision-making process. Currently, parameters to identify a subgroup of patients who might specifically benefit from a combined androgen deprivation treatment policy are not available. When using monotherapy, it is necessary to recognize several important facts. Castrate testosterone levels are not achieved or maintained in all patients. For some patients this may be a disadvantage. Additionally, before categorizing a patient as having an androgen-independent tumor, it is important to measure serum testosterone to ensure that LHRH analog monotherapy has achieved and maintained a castrate testosterone level.

Development of a novel proteomic approach for the detection of transitional cell carcinoma of the bladder in urine.

Development of noninvasive methods for the diagnosis of transitional cell carcinoma (TCC) of the bladder remains a challenge. A ProteinChip technology (surface enhanced laser desorption/ionization time of flight mass spectrometry) has recently been developed to facilitate protein profiling of biological mixtures. This report describes an exploratory study of this technology as a TCC diagnostic tool. Ninety-four urine samples from patients with TCC, patients with other urogenital diseases, and healthy donors were analyzed. Multiple protein changes were reproducibly detected in the TCC group, including five potential novel TCC biomarkers and seven protein clusters (mass range, 3.3 to 133 kd). One of the TCC biomarkers (3.4 kd) was also detected in bladder cancer cells procured from bladder barbotage and was identified as defensin. The TCC detection rates provided by the individual markers ranged from 43 to 70% and specificities from 70 to 86%. Combination of the protein biomarkers and clusters, increased significantly the sensitivity for detecting TCC to 87% with a specificity of 66%. Interestingly, this combinatorial approach provided sensitivity of 78% for detecting low-grade TCC compared to only 33% of voided urine or bladder-washing cytology. Collectively these results support the potential of this proteomic approach for the development of a highly sensitive urinary TCC diagnostic test.

Combined androgen blockade with nonsteroidal antiandrogens for advanced prostate cancer: a systematic review.

OBJECTIVES: Combined androgen blockade with medical or surgical castration plus a nonsteroidal antiandrogen for metastatic prostate cancer has been the subject of 20 randomized trials. The findings range from no expected increase in survival in 17 studies to an estimated 3.7 to 7 months' survival improvement noted in 3 studies. Most recently, a 1999 evidence report from the Agency for Healthcare Research and Quality and a 2000 overview from the Prostate Cancer Trialists Collaborative Group indicated that combined androgen blockade was associated with an approximately 3% to 5% increase in 5-year survival. We report herein a systematic review on combined androgen blockade performed by the Cochrane Collaborative Review Group on Prostate Diseases. METHODS: Controlled trials that included a randomization of immediate nonsteroidal antiandrogens with castration versus castration alone for metastatic prostate cancer and provided information on survival were reviewed. Information on overall survival, toxicity, progression-free survival, cancer-specific survival, and type of nonsteroidal antiandrogen and castration therapies was abstracted by two independent reviewers. RESULTS: Twenty trials (n = 6320 patients) were included. The pooled odds ratio (OR) for overall survival with combined androgen blockade was 1.03 (95% confidence interval [CI] 0.85 to 1.25; n = 4970 from 13 trials), 1.16 (95% CI 1.00 to 1.33; n = 5286 from 14 trials), and 1.29 (95% CI 1.11 to 1.50; n = 3550 from 7 trials) at 1, 2, and 5 years, respectively. Progression-free survival was improved at 1 year (OR = 1.38; 95% CI 1.15 to 1.67; n = 2278 from 7 trials). Cancer-specific survival was improved at 5 years (OR = 1.58; 95% CI 1.05 to 2.37; n = 781 from 2 trials). When analysis was limited to studies identified as being of high quality, the pooled OR for overall survival progressively increased but was not significant at any follow-up interval. CONCLUSIONS: We find that there is a 5% improvement in the percentage of men surviving at 5 years (30% vs. 25%) with combined androgen blockade with nonsteroidal antiandrogens as well as improvements in progression-free survival at 1 year. Appropriate patients with metastatic prostate cancer should be informed of the potential benefits, toxicities, and out-of-pocket expenditures.

Bilateral testicular lymphoma treated with chemotherapy and radiation without orchiectomy: complete response relapsed at 52 months in the vitreous humor.

We report the first detailed case of testicular lymphoma managed with chemotherapy and radiation without orchiectomy. A 60-year-old man with Stage II extralymphatic bilateral testicular lymphoma refused orchiectomy, but underwent cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy and radiation. He remained disease free for 52 months, when a solitary central nervous system relapse to the vitreous humor was diagnosed. The optimal therapy for testicular lymphoma is unclear but often includes orchiectomy with adjuvant chemotherapy and radiation. Stage I testicular lymphoma can be cured by surgery alone; however, the relapse rates for all stages of testicular lymphoma are high despite systemic therapy. For Stage II disease and higher, chemotherapy/radiation is recommended; orchiectomy may not be mandatory.

Overexpression of p53 in prostate carcinoma is associated with improved overall survival but not predictive of response to radiotherapy.

p53 gene mutations are among the most common specific genetic alterations in human cancer. Inactivation of p53 and subsequent protein accumulation has been implicated in a variety of human malignancies and associated with prostate cancer progression. In this study, we assessed p53 protein overexpression and gene mutations in prostate carcinoma and investigated associations between p53 alterations and clinicopathological parameters, survival, and response to radiotherapy. We evaluated 58 archival formalin-fixed, paraffin-embedded prostate carcinomas to detect abnormal p53 nuclear protein accumulation using immunohistochemistry. p53 mutational status of tumor DNA was evaluated using polymerase chain reaction-single-strand conformation polymorphism analysis of exons 5-9 and confirmed by direct DNA sequencing. Univariate and multivariate statistical analysis was used to determine the association of p53 status with clinical characteristics and response to radiotherapy. Overexpression of p53 was detected in 42 (72%) of 58 primary prostate carcinomas, but was undetectable in 7 samples of benign prostatic hyperplasias or 5 samples of normal prostate tissue. p53 exon 5-9 mutations were detected in 8 (14%) of 58 patient specimens. p53 mutational status, but not overexpression, was associated with higher Gleason scores (p=0.0145). Neither p53 overexpression nor mutation was associated with clinical stage, biochemical disease-free probability, or predictive of response to radiotherapy. p53 protein accumulation was inversely associated with improved overall survival (p=0.0108). Our studies demonstrate that p53 protein accumulation is a frequent alteration in prostate cancer. The disparity between p53 protein overexpression and p53 exon 5-9 mutations suggests the possibility of mutations outside this region or stabilization of wild-type p53 by alternative mechanisms. In our patient population, p53 protein overexpression or mutational status was not predictive of outcome in patients treated with radiation therapy. Additional studies are needed to further evaluate the association between p53 protein overexpression and improved overall survival.

Fifteen-year minimum follow-up of a prostate brachytherapy series: comparing the past with the present.

OBJECTIVES: To report the overall survival for 126 patients more than 15 years after iodine-125 interstitial therapy; to report the biochemical progression status for those alive and clinically without evidence of disease for longer than 15 years; to document the upward migration of grade by date of grade assignment; to compare the tumor stage and grade profile of this mature series with our current experience; and to clarify the prostate-specific antigen (PSA) data when this series is used as a historical comparison. METHODS: The records of 126 patients who underwent interstitial therapy more than 15 years previously were reviewed for assessment of the current TNM stage and Gleason grade and the current PSA level for patients clinically free of disease. The tumor grade and stage of these patients were compared with those of the first 126 patients treated by transrectal ultrasound-guided brachymonotherapy at our center between January 1995 and January 1999. The methodology of our 1993 publication was also reviewed. RESULTS: Of the 16 patients clinically free of disease (13 still alive and 3 dead of other causes more than 15 years after therapy), a review of the initial diagnostic needle biopsy was unable to confirm the presence of tumor in 3 patients. Of the remaining 13, 4 had a PSA level of 0.2 ng/mL or less, 4 a PSA level between 0.21 and 0.9 ng/mL, and 5 a PSA level between 1 and 2.5 ng/mL. Re-evaluation of the histopathologic findings using current criteria increased the Gleason score and World Health Organization grade. Patients currently selected for brachytherapy have a lower Gleason grade and TNM stage than recorded for patients treated in the past. The actuarial progression probability curves using the 0.5 or less cutpoint published in 1993 represented the best possible outcome and cannot serve as a historical control for current series comparisons. CONCLUSIONS: For patients who were alive and clinically free of disease longer than 15 years after therapy, the biochemical PSA levels were low. This may be attributed to the therapeutic radiation effect. Whether the improved technology of current transrectal ultrasound-guided implants can extend these favorable results from a small minority to a significant majority and whether it can approach the therapeutic results of radical prostatectomy may be partially answered with a longer follow-up of the current series. The histopathologic criteria have been refined, and upgrading from the initially assigned grade is common. In some cases, a prostate cancer diagnosis could not be confirmed. These findings limit the ability to match patients across time and institution. The results of our 1993 report of biochemical chemical progression-free probability 10 years after iodine-125 implantation cannot be used as a comparator for current studies. Ultimately, a valid comparison between treatment options will only be achieved through a randomized controlled trial.

Management of patients with Bacilli Calmette-Guérin-refractory carcinoma in situ of the urinary bladder: cost implications of a clinical trial for valrubicin.

OBJECTIVE: This study was undertaken to identify the expected first- and second-year clinical costs associated with intravesical valrubicin therapy, using a decision analytic model, for patients with Bacilli Calmette-Guérin (BCG)-refractory carcinoma in situ (CIS) of the urinary bladder. BACKGROUND: Cancer of the urinary bladder is the fourth most common malignancy in men and the sixth most common noncutaneous carcinoma overall. One histopathologic stage of bladder cancer is CIS, for which BCG intravesical immunotherapy is the first-line therapy. Radical cystectomy has been recommended for patients with CIS who do not respond to or become refractory to therapy with BCG. Surgery, however, may not be appropriate for all patients, especially those who are ineligible for the lengthy procedure because of advanced age or comorbidities and those who prefer alternative nonsurgical management. For these groups, intravesical valrubicin therapy is a plausible alternative. METHODS: Models were developed and populated with data from 1 open-label study of 90 patients, information from the medical literature, and input from clinical experts. The analysis was conducted from the payor perspective for direct costs only. RESULTS: Our data indicate that first- and second-year expected costs for valrubicin therapy are $19,912 and $23,496, respectively. Expected cost for radical cystectomy was also evaluated, since some patients may have no other option if drug therapy fails. CONCLUSION: Our cost-consequence analysis and clinical data provide decision-makers with tools to aid in global budgetary projections of fractional and total expected health care costs associated with the management BCG-refractory CIS of the urinary bladder.

The prognostic significance of S-phase analysis in stage Ta/T1 bladder cancer. A Southwest Oncology Group Study.

OBJECTIVES: An intergroup study (SWOG 8795) comparing two forms of adjunctive therapy (immuno and chemo), bacillus Calmette-Guerin (BCG) and mitomycin C (MMC), furnished preregistration index tumors for 244 patients with superficial, papillary stage Ta/T1 TCC. These were examined by flow cytometry to learn whether DNA ploidy or proliferation (low vs high S-phase fraction (SPF) helped to predict disease recurrence or progression. METHODS: Cell cycle analysis using commercially available (Multicycle) programs was performed on 249 Ta/T1 bladder cancers. Tumor grade, available for 223 cases, was assigned by a single study pathologist. The SWOG statistical office reviewed follow-up information and other data and performed statistical analysis. RESULTS: Disease recurrence occurred in half the cases studied. The most parsimonious model predictive of recurrence included only treatment arm and tumor grade, with the MMC arm and tumor grade greater than I indicating worse prognosis (p = 0. 014). Neither ploidy nor SPF predicted recurrence-free survival or contributed prognostic information that was additive to tumor grade. Within 5 years of follow-up, disease progression or death from bladder cancer occurred for 29/223 (13%) of patients. The most parsimonious model for progression-free survival included only grade greater than I (p<0.001) and high SPF (p = 0.029) (relative risk: tumor grade, 4.3, high SPF, 1.9). CONCLUSIONS: Knowledge of tumor proliferation (low versus high SPF) contributes prognostic information about tumor progression that is additive to tumor grade.

Flt3-ligand induces transient tumor regression in an ectopic treatment model of major histocompatibility complex-negative prostate cancer.

We assessed the in vivo efficacy of Flt3-ligand (Flt3-L) treatment in C57BL/6 mice bearing a well-established MHC class I-negative prostate carcinoma TRAMP-C1. Flt3-L immunotherapy was initiated approximately 30 days after tumor inoculation, a time when > or =80% of the mice had palpable TRAMP-C1 tumors. Treatment with Flt3-L at 10 microg/day for 21 consecutive days suppressed TRAMP-C1 tumor growth and induced tumor stabilization (P = 0.0337). Enhanced tumor regression was demonstrated at a higher dose of 30 microg/day (P < 0.0001). Tumors excised from mice treated with Flt3-L were smaller than carrier-treated controls and contained a more pronounced mixed inflammatory cell infiltrate primarily composed of mphi. In regressor nice, tumors reappeared at the site of injection when Flt3-L therapy was terminated. When the experiment was repeated with MHC class I-positive TRAMP-C1 cells, tumor stabilization and/or regression was again observed after treatment (P < 0.0001); however, once again, tumors reappeared after the termination of therapy despite an extended treatment schedule (35 days). MHC class I-negative variants were present in tumors isolated from carrier- and Flt3-L-treated mice, and this phenotype could be reversed by IFN-gamma treatment in vitro. Thus, Flt3-L treatment of mice with preexisting transplantable prostate tumors results in tumor regression that is dose-dependent and accompanied by a pronounced mixed-cell inflammatory tumor infiltrate. However, disease relapse was invariably observed after the termination of therapy, which suggests that Flt3-L treatment of advanced MHC- prostate cancers will require adjuvant modalities to achieve a durable response.

Outcomes after intravesical bacillus Calmette-Guerin are not affected by substaging of high grade T1 transitional cell carcinoma.

PURPOSE: Substaging of T1 bladder tumors into T1a and T1b based on invasion of the tumor superficial to and beyond the muscularis mucosa has been assigned prognostic significance. We determined whether outcomes after intravesical bacillus Calmette-Guerin (BCG) differ between stage T1a and T1b subcategories. MATERIALS AND METHODS: Retrospective pathological evaluation of the initial transurethral resection specimens of stage T1 bladder tumors was performed by 2 pathologists. Grade 1, 2 or 3 and stage T1a or T1b were assigned to each case. Followup was from the date of transurethral resection to date of death or the last visit. Kaplan-Meier probability and log rank test were used to evaluate recurrence and progression. RESULTS: Substaging was performed in 49 of the 55 patients (89%) with stage T1 disease. Disease was stage T1a in 32 (65%), stage T1b in 17 (35%), grade 3 in 45 (92%) and grade 2 in 4 (8%) cases. Maximum followup was 147 months (median 71) and 28 cases had a minimum of 5 years of followup. Recurrence was noted in 33 cases (67.3%), including 22 stage T1a (69%) and 11 stage T1b (65%), at a median followup of 11.3 and 8.6 months, respectively. Progression to a higher stage of disease was recorded in 12 cases (24.4%), including 7 (22%) stage T1a and 5 (29%) stage T1b, at a median followup of 108 and 120 months, respectively. The difference between T1a and T1b subcategories was not statistically significant in regard to recurrence-free (p = 0.7203) and progression-free (p = 0.574) outcomes. CONCLUSIONS: Substaging of T1 tumors did not affect response to BCG in regard to recurrence or progression. Therefore, intravesical BCG is effective for stages T1a and T1b disease.

Does prolonged combined androgen blockade have survival benefits over short-term combined androgen blockade therapy?

OBJECTIVES: To explore whether less than 120 days of an antiandrogen plus a luteinizing hormone-releasing hormone agonist resulted in a different survival outcome than 120 days or more of combined treatment in patients with Stage D2 prostate cancer. METHODS: Survival data were available from a previously published controlled trial that had evaluated the efficacy and tolerability of two antiandrogens, bicalutamide and flutamide, each combined with a monthly depot preparation of leuprolide or goserelin, in 813 patients with Stage D2 prostate cancer. Cox's proportional hazards regression model assessed the relative effects of the length of combined androgen blockade (CAB) therapy on survival. This analysis was repeated in the subset of patients who lived at least 2 years beyond the date of randomization. Data were obtained at a median follow-up of 160 weeks. RESULTS: A survival benefit was demonstrated for patients receiving prolonged CAB therapy, with a hazard ratio of 0.275 (95% confidence interval 0.213 to 0.355, P = 0.0001) in favor of patients who received 120 days or more of CAB therapy (median survival 1035 days versus 302 days for less than 120 days of therapy). This result was confirmed in the patients who lived at least 2 years, in whom the median survival time was increased by 35%. The hazard ratio for 120 days or more of CAB therapy versus less than 120 days was 0.415 (95% confidence interval 0.246 to 0.702, P = 0.001). CONCLUSIONS: The results of the present exploratory analysis suggest that prolonged (120 days or more) antiandrogen treatment as part of CAB therapy may result in a better survival outcome.