Prognostic value of Ki67 in localized prostate carcinoma: a multi-institutional study of >1000 prostatectomies.

BACKGROUND: Expanding interest in and use of active surveillance for early state prostate cancer (PC) has increased need for prognostic biomarkers. Using a multi-institutional tissue microarray resource including over 1000 radical prostatectomy samples, we sought to correlate Ki67 expression captured by an automated image analysis system with clinicopathological features and validate its utility as a clinical grade test in predicting cancer-specific outcomes. METHODS: After immunostaining, the Ki67 proliferation index (PI) of tumor areas of each core (three cancer cores/case) was analyzed using a nuclear quantification algorithm (Aperio). We assessed whether Ki67 PI was associated with clinicopathological factors and recurrence-free survival (RFS) including biochemical recurrence, metastasis or PC death (7-year median follow-up). RESULTS: In 1004 PCs (∼4000 tissue cores) Ki67 PI showed significantly higher inter-tumor (0.68) than intra-tumor variation (0.39). Ki67 PI was associated with stage (P<0.0001), seminal vesicle invasion (SVI, P=0.02), extracapsular extension (ECE, P<0.0001) and Gleason score (GS, P<0.0001). Ki67 PI as a continuous variable significantly correlated with recurrence-free, overall and disease-specific survival by multivariable Cox proportional hazard model (hazards ratio (HR)=1.04-1.1, P=0.02-0.0008). High Ki67 score (defined as ⩾5%) was significantly associated with worse RFS (HR=1.47, P=0.0007) and worse overall survival (HR=2.03, P=0.03). CONCLUSIONS: In localized PC treated by radical prostatectomy, higher Ki67 PI assessed using a clinical grade automated algorithm is strongly associated with a higher GS, stage, SVI and ECE and greater probability of recurrence.

Acceptability of an Internet treatment decision support program for men with prostate cancer.

We have implemented a customized Internet decision support system designed to engage men in the decision-making process for the management of localized prostate cancer. The system is delivered to patients in the patient education room of the UWMC Prostate Oncology Center. The system interactively guides the patient through a series of surveys, and delivers multi-media interaction modeling and decision support output, both of which are customized for the patient's preferences. The system is currently implemented on an open source platform.

Serial prostate specific antigen, free-to-total prostate specific antigen ratio and complexed prostate specific antigen for the diagnosis of prostate cancer.

PURPOSE: The free-to-total prostate specific antigen (PSA) ratio and complexed PSA have been introduced as adjuncts to total PSA for prostate cancer screening. Little data exist on the use of these tests for serial PSA screening. We compared serial total PSA, the free-to-total PSA ratio and calculated complexed PSA in men diagnosed with prostate cancer and matched controls in a population based study. MATERIALS AND METHODS: We identified 90 men diagnosed with prostate cancer between 1988 and 1996 with at least 3 serial serum samples obtained at 2-year intervals who were participants in the beta-Carotene and Retinol Efficacy Trial for the prevention of lung cancer. Samples were available up to 10 years before diagnosis. A total of 90 age matched men from the same cohort without prostate carcinoma were identified as controls. Free and total PSA was measured by the Abbott AxSYM system. RESULTS: Baseline demographics of cases and controls were similar. At baseline and diagnosis the men with prostate cancer had higher total and complexed PSA, and a lower free-to-total PSA ratio than controls. Mean followup was 5.2 years in cases and 5.5 in controls. The yearly change in PSA parameters in cases versus controls was 20.7% versus 3.5% for total, -3.4% versus 0.2% for free-to-total and 21.5% versus 3.4% for complexed PSA (p <0.0001). At diagnosis PSA alone was estimated to perform with more than 90% specificity in our model. CONCLUSIONS: In this population based study total PSA was superior to the free-to-total PSA ratio for predicting the development of prostate cancer. While serial changes in free-to-total PSA ratios with time were statistically significantly different in men diagnosed with prostate cancer and controls, the magnitude of these serial changes were slight enough to render them clinically insignificant.

Naturally occurring prostate cancer antigen-specific T cell responses of a Th1 phenotype can be detected in patients with prostate cancer.

BACKGROUND: Cytotoxic T cells (CTL) are considered one of the primary effector cell populations in antitumor immunity. Recent studies, however, have demonstrated the critical importance of helper T cells (Th), specifically interferon gamma (IFN gamma)-secreting Th1 cells, either by supporting an appropriate CTL environment or by recruiting other effector cells. We evaluated whether patients with prostate cancer have naturally occurring Th-cell responses specific for two prostate cancer-associated antigens, prostate-specific antigen (PSA) and prostatic acid phosphatase (PAP), and whether Th1-type responses to these antigens could be detected. METHODS: Peripheral blood mononuclear cells (PBMC) were collected from 80 patients with prostate cancer and 20 male controls without prostate disease. Th-cell responses were evaluated by measuring antigen-specific proliferation. IFN gamma and IL-5 secretion in response to antigen stimulation was determined by enzyme-linked immunosorbent assay. RESULTS: T cell proliferative responses specific for PSA and PAP could be detected in patients with prostate cancer. Six percent (5/80) of patients had T cell responses specific for PSA and 11% (9/80) for PAP. T cell responses specific for PSA were more prevalent in patients with metastatic disease (P = 0.02), whereas responses specific for PAP could be detected in patients irrespective of disease stage. IFN gamma-producing Th cells, specific for both PSA and PAP, could be identified in patients with prostate cancer. CONCLUSIONS: Patients with prostate cancer can have detectable Th-cell responses specific for the prostate cancer-associated proteins PSA and PAP. The presence of antigen-specific Th1 immune responses in prostate cancer patients suggests that an immune environment capable of supporting antigen-specific CTL may exist in vivo. Prostate 47:222-229, 2001.

Role of transrectal ultrasonography in prostate brachytherapy.

Modern brachytherapy has been made possible by advances in ultrasound technology. This technology allows accurate determination of gland size, determination of the relation to the pubic arch, and real-time placement of the radioactive sources. A thorough familiarity with transrectal ultrasonography thus is required to produce high-quality implants consistently.

Intermittent androgen suppression in the LuCaP 23.12 prostate cancer xenograft model.

BACKGROUND: Intermittent androgen suppression (IAS) has been proposed as a method of delaying the onset of androgen-independent growth in prostate cancer. While several pilot studies have demonstrated the feasibility of such a treatment, no study to date has defined the effect of IAS on survival. METHODS: We developed an IAS protocol for mice bearing the LuCaP 23.12 human prostate cancer xenograft, with each cycle consisting of 1 week of androgen replacement with a testosterone pellet followed by 3 weeks of androgen withdrawal. Mice that responded to castration with a 40% or greater decrease in serum prostate-specific antigen (PSA) were randomized to treatment with either continuous androgen suppression (CAS) or IAS. Serum PSA, tumor volume, and overall survival were monitored. RESULTS: A total of 75 mice met the randomization criteria. There was no significant difference of survival between animals treated with CAS or IAS (185 vs. 239 days, P = 0.1835). Serum PSA showed evidence of cycling with hormonal manipulation. No cycling was noted in tumor volume. CONCLUSIONS: IAS is not associated with a decrease in survival compared to CAS, yet in patients may offer quality-of-life improvements. Further studies of IAS in the setting of Institutional Review Board (IRB) approved clinical trials should be encouraged. Prostate 43:63-70, 2000. Published 2000 Wiley-Liss, Inc.

Analysis and sorting of prostate cancer cell types by flow cytometry.

BACKGROUND: Prostate tumor heterogeneity as manifested by differential expression of markers can be attributed to multiple types of cancer cells populating a tumor. Does the composition differ between primary tumor and metastasis? How can one isolate the different cancer cell types to study? What is the relationship among cancer cell types? METHODS: Flow cytometry keying on the prostate epithelial cell surface markers CD57 and CD44 was applied to analyze and sort single cells prepared from tumor tissue samples by collagenase digestion. In normal tissue, CD57 is found on luminal cells and CD44 on basal cells. RESULTS: CD57(+) and CD44(+) cells were sorted from various prostate tumor tissue specimens. The CD57(+) cancer cell type was found to predominate in primary tumors, while the CD44(+) cancer cell type was found to predominate in two visceral metastases. All tumors could be characterized by a ratio of CD57(+) and CD44(+) cancer cells. CONCLUSIONS: Two types of prostate cancer cells, CD57(+) and CD44(+), were identified. The finding that most primary tumors contain a predominantly CD57(+) cancer cell population agrees with the argument that cancer cells arise from the transformation of CD57(+) luminal cells. However, CD44(+) cancer cells are also present in some primary tumors; and in some metastases, they, and not CD57(+) cells, constitute a predominant population.

The relationship between serial measurements of the level of a bladder tumor associated antigen and the potential for recurrence.

PURPOSE: We evaluate the relationship between a serially assessed quantitative diagnostic marker (QDM) and the hazard function for the diagnosis of recurrence of bladder cancer. The marker is based on a bladder tumor associated antigen (BTA TRAK) assay. We present a rigorous approach to the evaluation of diagnostic markers to be used for recurrence monitoring. MATERIALS AND METHODS: Archival voided urine samples serially collected from 187 patients with a prior diagnosis of transitional cell carcinoma of the bladder were measured for BTA TRAK, an assay performed in clinical laboratories. All patients had been treated for stage Ta or T1 transitional cell carcinoma and were undergoing periodic assessments for recurrence. The results from the QDM were not used in case management. Time to histologically confirmed recurrence of transitional cell carcinoma was modeled using proportional hazard regression with the serial measurements of QDM levels and other variables as covariates. QDM levels are in the model as a time dependent covariate on the base 10 logarithmic scale. RESULTS: The estimated hazard ratio for QDM level indicated a 60% increase in the hazard for the diagnosis of recurrence for each 10-fold increment in the marker level (p = 0.013). CONCLUSIONS: A statistically significant relationship between the serially assessed QDM levels and the hazard for the diagnosis of recurrence has been established but the definition of optimum strategies for use of this relationship in clinical practice will require further study. Meanwhile, a prudent action based on the statistical relationship would be to shorten surveillance intervals for patients with high QDM levels.

Serum percent free prostate-specific antigen in metastatic prostate cancer.

OBJECTIVES: To define the serum prostate-specific antigen (PSA) isoform profile in patients who have prostate cancer but do not have a prostate gland, that is, men who have had a previous radical prostatectomy (RP) and subsequently persistent disease as evidenced by elevated PSA. PSA can be reliably measured in the serum in two major isoforms: PSA complexed to alpha1-antichymotrypsin and uncomplexed free PSA (fPSA). Multiple investigations have illustrated the usefulness of the free/total PSA proportion (percent fPSA) in differentiating prostate cancer from benign prostate disease in patients who still have their prostate gland in situ. METHODS: Sera were evaluated from 52 men who underwent RP and postoperatively had increased PSA. fPSA and total PSA (tPSA) concentrations were determined using the Abbott AxSYM PSA assays. Percent fPSA was calculated for all patients. RESULTS: Median tPSA was 5.45 ng/mL (range 0.93 to 214.99). Median fPSA was 0.69 ng/mL (range 0.11 to 54.93); the median percent fPSA was 13.3% (range 3.9% to 62.9%). There were 27 (52%) patients with percent fPSA less than 15%, 25 (48%) patients with greater than 15%, and 7 (13%) with greater than 30%. No significant relationship was found between percent fPSA and grade, stage, and severity of disease. Percent fPSA was significantly increased in patients who received hormonal, radiation, or combination treatment versus those who received no treatment (P = 0.02 to 0.0007). CONCLUSIONS: Serum percent fPSA in men after RP with persistent prostate cancer encompasses a wide range of values with no clear stratifying factor or factors. These observations and further serial studies in patients with progressive metastatic disease may be important in determining the mechanism(s) for lower percent fPSA in men with newly diagnosed prostate cancer.

Transition zone prostate specific antigen density: lack of use in prediction of prostatic carcinoma.

PURPOSE: Among the new approaches to enhance the performance of prostate specific antigen (PSA) testing in a biopsy population is the use of the free-to-total PSA as well as the transition zone density, which is calculated by dividing the PSA by the transition zone volume. We compare these manipulations of the PSA to PSA alone in a biopsy population. MATERIALS AND METHODS: We evaluated 917 consecutive men who underwent ultrasound guided biopsy for an elevation in serum PSA or abnormality on digital rectal examination. Total PSA was measured using the Tandem-E or Tandem-R method. Prostate gland volume and transition zone were measured with ultrasound and calculated using the prolate ellipsoid formula. RESULTS: In the overall PSA range 276 men had carcinoma (30.0% of the population), while in the PSA 4.0 to 10.0 ng./ml. range 141 of 477 had cancer (29.6%). Receiver operating characteristics analysis and analysis of variance were performed. In the overall PSA series the Tandem total PSA performed as well as any PSA index to predict carcinoma. In the restricted range of total PSA 4.0 to 10.0 ng./ml. total PSA density as well as transition zone density were more predictive than PSA alone. In both PSA ranges the volume of benign glands was significantly larger than in the prostates exhibiting carcinoma. There was no statistically significant difference in outcomes of analyses between different investigators or different sites of investigation (Veterans Affairs versus university based hospitals). CONCLUSIONS: In this biopsy population transition zone PSA density did not add to the information available with total PSA and gland volume. Neither investigator nor site bias contributed to the failure of transition zone PSA density or PSA density to predict prostatic carcinoma.

Oral bropirimine immunotherapy of bladder carcinoma in situ after prior intravesical bacille Calmette-Guérin.

OBJECTIVES: Bropirimine is an oral immunomodulator that has demonstrated anticancer activity in transitional cell carcinoma in situ (CIS) in both the bladder and upper urinary tract. Activity also has been documented in patients after prior therapy with bacille Calmette-Guérin (BCG). To more accurately estimate bropirimine's efficacy in BCG-resistant bladder CIS, a Phase II trial was performed. A separate analysis was performed in additional patients intolerant of BCG toxicity. METHODS: Patients received bropirimine 3.0 g/day by mouth for 3 consecutive days, weekly, for up to 1 year. Bladder biopsies and cytologic examination were performed quarterly. Complete response (CR) required negative biopsy and cytology results. RESULTS: Twenty-one of 86 patients entered were not evaluable. CR was seen in 21 (32%; 95th percentile confidence interval [CI], 21% to 44%) of 65 evaluable patients, including 14 (30%, CI 17% to 43%) of 47 BCG-resistant, and 7 (39%, CI 16% to 61%) of 18 BCG-intolerant patients. Overall, by intent-to-treat analysis, CR was thus seen in 21 (24%) of 86 subjects. Most BCG-resistant patients were failures to BCG without relapse, and had received 12 to 36 (median 12) BCG treatments; intolerant patients had received 4 to 11 treatments (median 6). Response duration ranged from 65 to 810 days, with median not yet reached (but greater than 12 months). Thirteen (15%) of 86 stopped bropirimine due to toxicity. Progression to invasive or metastatic disease during or immediately after therapy was documented in only 4 patients (6%), all nonresponders. CONCLUSIONS: Bropirimine may be an alternative to cystectomy for some patients with bladder CIS who have failed or have not tolerated BCG. Further evaluation to improve responses and durability is warranted.

The value of a reverse transcriptase polymerase chain reaction assay in preoperative staging and followup of patients with prostate cancer.

PURPOSE: The reverse transcriptase polymerase chain reaction (RT-PCR) assay is an extremely sensitive technique of detecting cells expressing prostate specific antigen (PSA). Controversy exists regarding the ability of peripheral blood PSA RT-PCR testing to reflect pathological staging or treatment outcome. We examine the phenomenology of RT-PCR results in patients with prostate cancer, with particular emphasis on the RT-PCR test before and after radical prostatectomy, and correlations with pathological staging and treatment outcome. MATERIALS AND METHODS: Peripheral blood was obtained from a wide variety of patients with and without prostate cancer, including before and after radical prostatectomy. After ribonucleic acid isolation, complementary deoxyribonucleic acid was generated and amplified with a hot-start technique. RT-PCR results were compared with pathological stage, Gleason score, tumor volume and disease-free status. Correlations between preoperative and postoperative RT-PCR tests were also made. RESULTS: The RT-PCR test was positive in 1 of 56 controls (1.8%) without suspicion of prostate cancer. A positive test was obtained in 12 of 65 men (18.5%) with a suspicion of prostate cancer but a negative biopsy. Before radical prostatectomy a positive test was obtained in 13 of 75 men (17.3%) with pT2 disease versus 10 of 46 (21.7%) with pT3 disease. There was no significant difference in serum PSA, Gleason score or tumor volume between the men with positive or negative results. With repetitive testing an increasing percentage of men had at least 1 positive test preoperatively. With a median followup of 8 months 6 of the 7 patients in whom radical prostatectomy failed had had negative RT-PCR before treatment. Of patients with known metastatic disease or failed primary treatment a positive test was obtained in 32 to 75%. Radical prostatectomy and prostate needle biopsy appeared to have a negligible effect on RT-PCR tests immediately following these procedures. Following radical prostatectomy results were variable but many men who are RT-PCR positive preoperatively become RT-PCR negative postoperatively. CONCLUSIONS: The PSA RT-PCR test in our laboratory cannot be used preoperatively to predict pathological stage of prostate cancer or treatment failure. Most cases that are positive preoperatively become negative postoperatively. While increasing tumor burden increases the likelihood of positive tests, there appears to be significant sampling error associated with the use of this test in the peripheral blood.

Early detection of recurrent prostate cancer with an ultrasensitive chemiluminescent prostate-specific antigen assay.

OBJECTIVES: Treatment failure after radical prostatectomy is most commonly heralded by an increase in serum prostate-specific antigen (PSA) to detectable levels. We evaluated the clinical utility of an ultrasensitive chemiluminescent PSA assay. METHODS: We evaluated the assay in banked sera obtained from 170 men after radical prostatectomy. Controls consisted of 142 females, 29 men who had undergone cystoprostatectomy without evidence of prostate cancer, and 25 men without evidence of recurrent disease at least 5 years after prostatectomy for organ-confined disease. Lead time to diagnosis of recurrence was based on comparisons with the IMx or Tandem E assays using a cutoff of 0.1 ng/mL (100 pg/mL). RESULTS: The biologic level of detection of this assay is 8 pg/mL. Serum PSA levels were undetectable in 82.4% of females, 86.2% of the cystoprostatectomy patients, and 96% of the radical prostatectomy controls. After radical prostatectomy, PSA levels were undetectable at last check in 104 of 168 (61.9%) men. In the 24 men with prostate cancer recurrence, the enhanced sensitivity of 8 pg/mL provided a mean lead time based on conservative calculations of 12.7 to 22.5 months over conventional assays. Thirty-four of the 41 men with detectable PSA levels and no evidence of disease recurrence had PSA levels of 30 pg/mL or less. CONCLUSIONS: PSA levels are undetectable in most men who do not have recurrence of disease after radical prostatectomy. Low but detectable serum PSA levels less than or equal to 30 pg/mL can be produced by nonmalignant sources of PSA. PSA assays with enhanced sensitivity can detect recurrent prostate cancer with significant lead time over conventional assays.

Cell-cell interaction in prostate gene regulation and cytodifferentiation.

To examine the role of intercellular interaction on cell differentiation and gene expression in human prostate, we separated the two major epithelial cell populations and studied them in isolation and in combination with stromal cells. The epithelial cells were separated by flow cytometry using antibodies against differentially expressed cell-surface markers CD44 and CD57. Basal epithelial cells express CD44, and luminal epithelial cells express CD57. The CD57+ luminal cells are the terminally differentiated secretory cells of the gland that synthesize prostate-specific antigen (PSA). Expression of PSA is regulated by androgen, and PSA mRNA is one of the abundant messages in these cells. We show that PSA expression by the CD57+ cells is abolished after prostate tissue is dispersed by collagenase into single cells. Expression is restored when CD57+ cells are reconstituted with stromal cells. The CD44+ basal cells possess characteristics of stem cells and are the candidate progenitors of luminal cells. Differentiation, as reflected by PSA production, can be detected when CD44+ cells are cocultured with stromal cells. Our studies show that cell-cell interaction plays an important role in prostatic cytodifferentiation and the maintenance of the differentiated state.

Improved detection of recurrent bladder cancer using the Bard BTA stat Test.

OBJECTIVES: To evaluate the BTA stat Test in the detection of recurrent bladder cancer. METHODS: Sensitivity and specificity were determined using frozen voided urine samples from patients with recurrent bladder cancer, volunteers, patients with nonurologic conditions, and patients with a history of bladder cancer but free of disease. Results of cytology and the original BTA Test were compared with the sensitivity of the BTA stat Test in a large subgroup of the patients with cancer. RESULTS: The BTA stat Test detected 147 (67%) of 220 recurrent cancers. For those urine samples with previous cytologic and BTA Test results available, cytology had a sensitivity of 23%, the BTA Test 44%, and the BTA stat Test 58% for detection of recurrent cancer (P < 0.001, stat versus cytology). The specificity of the BTA stat Test was 72% for benign genitourinary disease and 95% in healthy volunteers. CONCLUSIONS: The BTA stat Test has high sensitivity and is significantly superior to voided urine cytologic analysis in the detection of recurrent bladder cancer.

Detection of circulating prostate cells by reverse transcriptase-polymerase chain reaction of human glandular kallikrein (hK2) and prostate-specific antigen (PSA) messages.

OBJECTIVES: To investigate the clinical value of human glandular kallikrein (hK2) reverse transcriptase-polymerase chain reaction (RT-PCR) for detection of prostate cells in circulation and to compare the results with those obtained from prostate-specific antigen (PSA) RT-PCR. METHODS: We examined peripheral blood (PB) and bone marrow (BM) samples of 13 patients with advanced-stage prostate cancer and 63 patients with clinically localized disease for the presence of circulating prostate cells. An RT-PCR protocol with a two-step amplification cycle and hot-start conditions was used. RESULTS: The limit of detection of the PCR portion is similar for PSA and hK2 (5 to 10 copies of the plasmid containing the cDNA). The RT-PCR limit of detection is one LNCaP cell in 10(8) peripheral blood mononuclear cells (PMBC) for PSA, and one LNCaP cell in 10(7) PMBC for hK2. Of the BM samples obtained prior to radical prostatectomy, 71.4% were positive for PSA mRNA and 41.3% were positive for hK2 mRNA. In PB, the PSA positivity was 19% and hK2 positivity 12.7%. In advanced-stage patients, there were 76.9% PSA-positive samples in BM versus 38.5% hK2-positive samples; 46.2% of patients were positive in PB for PSA versus 30.8% for hK2. CONCLUSIONS: We have developed a sensitive RT-PCR protocol for detection of hK2 mRNA and evaluated the suitability of hK2 mRNA in comparison with PSA mRNA as an additional marker for detection of prostate cells in circulation. Combining results of these two tests increased the sensitivity of detection.

Cytochrome P4501A (CYP1A) induction in rat and man by the benzodioxino derivative, fluparoxan.

1. Fluparoxan is an alpha 2-adrenoceptor antagonist that has a relatively planar, tricyclic structure and was considered a potential substrate and inducer of cytochrome P4501A (CYP1A) enzymes. 2. Structure-activity analysis indicated some potential for CYP1A interaction, although its greater log P and molecular depth, compared with many CYP1A inducers, suggested fluparoxan would be a weak ligand for the aryl hydrocarbon (Ah) receptor and only a weak inducer. 3. In vitro, fluparoxan showed little affinity for the CYP1A enzymes. The compound was not metabolized by human CYP1A1 or 1A2 heterologously expressed in yeast and its rate of metabolism in rat and human microsomes was unaffected by the addition of the 1A inhibitor alpha-naphthoflavone. Furthermore, Ki's for fluparoxan against EROD activity were > 4000-fold higher than those of alpha-naphthoflavone. 4. In vivo, however, fluparoxan did show some capacity for CYP1A induction. In rat, hepatic EROD activity increased approximately 40-fold with seven once-daily oral doses of fluparoxan (50 mg/kg, solution), and immunoblotting studies confirmed induction of CYP1A2, though not of 1A1. In man, administration of 11 twice-daily oral doses of fluparoxan (8 mg tablet) produced some reduction in plasma levels of orally administered phenacetin and in the ratio of phenacetin AUC/urinary paracetamol, consistent with increased O-deethylation.

Early tumor cell dissemination in patients with clinically localized carcinoma of the prostate.

Because a significant number of patients with pathologically organ-confined carcinoma of the prostate subsequently develop recurrent disease, metastasis may occur much earlier than previously believed. We have used a reverse transcription-PCR assay for prostate-specific antigen mRNA and an immunocytochemical staining method for cytokeratins to test this hypothesis in paired peripheral blood (PB) and bone marrow (BM) specimens from 71 patients with clinically localized disease before radical prostatectomy, 14 patients with advanced-stage carcinoma of the prostate, and 30 controls (young healthy volunteers, patients without prostate disease, and patients with benign prostatic hyperplasia). Controls were negative in BM and PB. Fifty-six% of patients with organ-confined tumors (pT2) and 73% of those with extracapsular extension (pT3) were positive in the BM versus 16% of those with pT2 tumors and 27% of those with pT3 tumors in the PB. Patients with advanced-stage disease were positive in 86% of BM versus 71% of PB. The sensitivity of the immunocytochemistry assay to detect tumor cells was lower as compared with the reverse transcription-PCR assay. The results suggest that tumor cell dissemination occurs early during disease progression. Prostate cells seem to preferentially concentrate in the BM rather than the PB, which may be due to sequestration there by homing mechanisms. As the rate of detection in the BM exceeds the proportion of patients with subsequently progressing disease, we hypothesize that only a subset of these cells can survive in the BM and evolve to clinically apparent disease.

Clinical evaluation of the BTA TRAK assay and comparison to voided urine cytology and the Bard BTA test in patients with recurrent bladder tumors. The Multi Center Study Group.

OBJECTIVES: To assess the clinical performance of the BTA TRAK assay and to compare it with that of voided urine cytology (VUC) and the Bard BTA test (BTA) in the detection of recurrent bladder cancer (BC). METHODS: The study was performed on randomly selected archival voided urine samples for many of which VUC and/or BTA information was available. Sensitivity was determined in samples from patients with histologically confirmed recurrent BC. Specificity was determined in samples from healthy volunteers, patients with three categories of current medical conditions, and patients with a history of BC but no current evidence of disease. RESULTS: The TRAK assay was positive in 156 of 216 samples for patients diagnosed with BC, for an overall sensitivity of 72%. Mean values increased with progressing grade and stage of disease. In the comparison between TRAK and VUC, the overall sensitivities were 68% and 25%, respectively (P < 0.001). For Stages Ta and T1 and for all tumor grades, the sensitivity of the TRAK assay was significantly greater than that of VUC (P < 0.001). TRAK sensitivity was also significantly better than that of BTA (73% versus 58%, P = 0.005). The specificity of the TRAK assay ranged from 75% in samples from patients with genitourinary disease to 97% in healthy volunteers. CONCLUSIONS: The TRAK assay is superior to VUC and the original BTA test in the detection of BC. The results of the study indicate that the TRAK assay may be a useful adjunct to cystoscopy in the management of patients with recurrent BC.