Faculty Bibliography

Originally, prostate-specific membrane antigen (PSMA) was described in benign and malignant prostate cells. On the basis of recent reports that this antigen also is expressed in normal renal proximal tubular cells and in the neovascular endothelium associated with renal carcinoma, we used a nested reverse transcriptase-polymerase chain reaction assay to evaluate whether PSMA-expressing cells might be present in specimens of peripheral blood obtained from renal cancer patients, benign renal tumor patients, and healthy volunteers. Our reverse transcriptase-polymerase chain reaction PSMA assay had a sensitivity of detecting 1 lymph node prostate cancer (LNCaP) per 10(7) lymphocytes. None of the 20 non-renal cancer controls were positive for PSMA mRNA, whereas 11 of 50 patients (22%) with diagnosed renal cancer were positive. Despite a comparative increase of PSMA positivity with stage, no statistical correlation was found. However, 44% of PSMA-positive patients had tumor size greater than 12 cm, versus only 9% in patients negative for PSMA (P = .03), and 67% of positive PSMA patients were found to have vascular invasion versus only 16% of patients negative for PSMA (P = .006; odds ratio, 10.8). This preliminary study suggests the possibility that PSMA expression in peripheral blood might be a useful biomarker for detecting or monitoring the progression of renal cancer in patients.

PURPOSE: We evaluated the independent response rate of dexamethasone before docetaxel and estramustine administration as measured by changes in serum prostate specific antigen (PSA) in patients with androgen independent prostate cancer. MATERIALS AND METHODS: A total of 12 patients received 20 mg. dexamethasone orally every 6 hours for 3 doses repeated every 3 weeks before starting cytotoxic therapy with estramustine and docetaxel. After progression on dexamethasone 280 mg. estramustine orally 3 times daily on days 1 to 5 and 70 mg./m.2 docetaxel intravenously for 1 hour on day 2 were given. RESULTS: None of the patients initially treated with dexamethasone monotherapy (median 1 cycle, range 1 to 5) had a PSA decline of 50% or greater. Median PSA increase on monotherapy was 47% (range 0% to 22%). On estramustine and docetaxel therapy PSA decreased 50% or greater in 11 patients (92%, 95% confidence intervals [CI] 60 to 99) and 80% or greater in 7 (58%, 95% CI 29 to 84), and normalized in 5 (42%, 95% CI 16 to 71), with a median duration of response of 153 (range 42 to 371), 132 (range 84 to 287) and 84 (range 21 to 174) days, respectively. Median times to reach 50% and 80% decreases in baseline PSA were 21 (range 21 to 209) and 63 (range 21 to 138) days, respectively. In 9 patients (75%, 95% CI 43 to 93) PSA decreased at least 50% by week 9. Of 4 patients with bidimensionally measurable disease 3 had a partial response. Median time to progression was 263 days (range 91 to 378). CONCLUSIONS: Administration of 20. mg. dexamethasone orally every 6 hours for 3 doses every 3 weeks does not significantly contribute to the PSA response rate of estramustine and docetaxel.

The reverse transcriptase-polymerase chain reaction (RT-PCR) assay is an extremely sensitive technique for the detection of circulating cells expressing prostate-specific antigen (PSA) in prostate cancer patients. This article reviews the literature on the use of this technique as a preoperative parameter to predict both extraprostatic disease and PSA recurrence after radical prostatectomy. Despite the relative consensus regarding the increase in RT-PCR-positivity with tumor stage (i.e., clinically localized vs metastatic prostate cancer), the use of RT-PCR as a clinical staging modality is controversial. To date, more than 16 institutions have evaluated the RT-PCR test in prostate cancer. Of these institutions, only two have reported the utility of RT-PCR as a staging modality and three have reported the utility of the test in predicting PSA recurrence. Before further conclusions are drawn regarding the clinical utility of RT-PCR in prostate cancer patients and its routine use is advocated, a larger patient population needs to be studied and followed for longer periods.

OBJECTIVES/OBJECTIVE:Angiogenesis is believed to play an important role in tumor progression and metastasis. Previous studies have suggested that the microvessel density (MVD) of prostate tumors may be of prognostic value. This study investigated the reliability of assessing MVD in radical prostatectomy specimens and its value as an independent prognostic indicator in men with clinically localized prostate cancer. METHODS:One hundred radical prostatectomy specimens from 1993 to 1995 were randomly selected for this study. Thirteen cases were excluded because the patients had undergone neoadjuvant hormonal therapy or tissue blocks were unavailable. The median follow-up time was 36 months. Tumor blocks were immunostained using the endothelial-specific antibody CD31. MVD was counted in areas with the greatest microvessel immunostaining, which were designated "hot spots." MVD was analyzed for associations with clinical and pathologic factors. In a subset of 60 cases, the same observer repeated the counts three times. RESULTS:Intraobserver reliability for MVD counting was excellent (reliability coefficient 0.82), demonstrating that this method could be reproduced by a single observer. MVD was not associated with Gleason sum, tumor stage, surgical margin status, or seminal vesicle invasion. Of the 87 patients, 20 (23%) had a prostate-specific antigen (PSA) failure during a 36-month median follow-up time. As expected, Gleason sum and tumor stage were strong predictors of PSA failure, with risk ratios of 2.1 and 2.3, respectively. In contrast, MVD was not associated with PSA failure. CONCLUSIONS:MVD, as determined by CD31, can be reliably measured by a single observer, but it is not a useful prognostic indicator for men with clinically localized prostate cancer.

PURPOSE/OBJECTIVE:We evaluated the role of perineural invasion identified on prostate needle biopsy as a predictor of prostate specific antigen (PSA) recurrence after radical prostatectomy. MATERIALS AND METHODS/METHODS:Between 1993 and 1998 radical prostatectomy was performed in 319 consecutive patients. Prostate needle biopsies were reviewed in all cases. We compared perineural invasion with other preoperative parameters, including digital rectal examination, PSA and biopsy Gleason score, for the ability to predict PSA recurrence with recurrence defined as any serum PSA level greater than 0.2 ng./ml. RESULTS:Perineural invasion was identified on 77 of 319 preoperative prostate biopsies (24%). There was PSA recurrence in 46 patients (14.4%) at a mean followup of 25.4 months (range 0.2 to 62.1). Perineural invasion statistically correlated with PSA recurrence. Kaplan-Meier analysis revealed disease-free survival rates of 24 versus 64% when perineural invasion was and was not present in the prostate biopsy (p = 0.0003, log rank 12.92). Multivariate analysis demonstrated that perineural invasion (p = 0.012) and PSA (p = 0.005) were independent preoperative predictive factors of PSA recurrence. When perineural invasion was compared with postoperative parameters, including disease stage, surgical margins and seminal vesicle invasion, it was not an independent predictor because it closely correlated with tumor stage. CONCLUSIONS:Perineural invasion on preoperative prostate needle biopsy is a strong independent predictor of PSA recurrence in patients in whom prostate cancer was treated with radical prostatectomy.

Reverse transcriptase polymerase chain reaction (RT-PCR) assay is a sensitive technique to detect circulating cells expressing prostate-specific antigen (PSA) in blood or bone marrow from patients with prostate cancer. When applied to prostate cancer patients at our institution, this technique identifies those patients with a greater likelihood of extra-prostatic disease. We evaluated RT-PCR PSA as a predictor of PSA recurrence and compared it with pre-operative (serum PSA, digital rectal examination, Gleason score on biopsy) and post-operative parameters (pathological findings). Three hundred nineteen men scheduled for radical prostatectomy had an enhanced RT-PCR PSA assay before surgery. The enhanced RT-PCR PSA protocol has been previously described. PSA recurrence was defined as any serum PSA value above 0.2 microgram/l. Forty-six patients had PSA recurrence. The mean follow-up was 25.4 months. Recurrence free survival was 53% for patients with positive RT-PCR PSA vs. 84% if RT-PCR PSA was negative. By using multivariate analyses, RT-PCR PSA status was not an independent predictor of PSA recurrence compared to pathological stage pT3, Gleason score on prostate specimen and serum PSA. If only pre-operative parameters were studied, serum PSA and RT-PCR PSA status were 2 independent pre-operative predictors of PSA recurrence compared with Gleason score on biopsy and digital rectal examination. Int. J. Cancer (Pred. Oncol.) 84:360-364, 1999.

OBJECTIVES/OBJECTIVE:The Columbia University experience of RT-PCR PSA as a predictive factor of stage and biochemical recurrence is reviewed by trying to explain its differences. PATIENTS AND METHODS/METHODS:319 patients were included between January 1993 and March 1998. Radical prostatectomy was performed in all patients by the same surgeon. The RT-PCR protocol has been previously described (Katz et al., Urology, 1994). Biochemical recurrence was defined by a PSA greater than or equal to 0.2 ng/ml. RESULTS:Histological examination diagnosed 218 pT2 and 101 pT3 tumours. Thirty-four of the 218 pT2 patients (16%) had a positive RT-PCR versus 51 of the 101 pT3 patients (51%, p < 0.001). Analysis of Kaplan-Meier curves showed an 84% recurrence-free survival when RT-PER was negative versus 47% when RT-PCR was positive (Log-rank test, p = 0.0002). Multivariate analysis showed that independent predictive factors of biochemical recurrence were stage (p = 0.004), Gleason score estimated on the operative specimen (p = 0.010) and serum PSA (p = 0.047); RT-PCR (p = 0.075), strongly correlated with stage, was not an independent predictive factor. By exclusively comparing preoperative parameters, PSA (p = 0.004) and RT-PCR (p = 0.006) were found to be independent predictive factors compared to digital rectal examination (p = 0.371) and Gleason score on biopsies (p = 0.076). CONCLUSION/CONCLUSIONS:In this institution, RT-PCR PSA is a predictive parameter of stage and biochemical recurrence. No consensus has yet been reached in the literature concerning the reference protocol, as each team has developed its own RT-PCR technique applied to its own patient population. Comparison of results is therefore difficult.

OBJECTIVES/OBJECTIVE:To evaluate the in vitro activity of PC-SPES, a complex phytotherapeutic agent, against prostate cancer cell lines, and to assess its activity in suppressing serum prostate specific antigen (PSA) level in patients with prostate cancer. PATIENTS AND METHODS/METHODS:Four variant prostate cancer cell lines (LNCaP and an apoptosis-resistant derivative, LNCaP-bcl-2, PC3 and DU145) were exposed to three different concentrations of PC-SPES extract. Cell viability was measured at 3, 4 and 5 days of exposure using a colorimetric assay and was compared with control cultures receiving aliquots of the ethanolic extraction medium alone. Clinically, a prospective study was initiated in patients with prostate cancer who refused conventional therapy or who had failed previous cryosurgery, radiation therapy and/or hormonal therapy. The patients were treated with PC-SPES (three capsules of 320 mg/day). The serum PSA responses and side-effects were evaluated. RESULTS:All cultured prostate cancer cell lines showed a significant dose-dependent reduction in cellular viability (compared with control cultures) by exposure to 4 and 6 microL of PC-SPES extract/mL of culture medium (P<0.001). In contrast to the hormone-insensitive cell lines tested (LNCaP-bcl-2, PC-3 and DU-145), only the hormone-sensitive cell line LNCaP was affected by the lowest dose of PC-SPES extract tested (2 microL/mL medium). In the prospective clinical trial of 33 patients, with a mean (range) follow-up of 6.8 (2-24) months after initiating PC-SPES therapy, serum PSA levels were lower in 87% at 2 months and in 78% at 6 months (n=18, P=0.026). The side-effects in these patients were nipple tenderness in two (6%) and leg clots requiring heparinization in two (6%). No gynaecomastia or hot flashes were observed in this group and the treatment was well tolerated. CONCLUSIONS:In this preliminary study, an extract of the phytotherapeutic agent PC-SPES was active in suppressing the growth of cultured hormone-sensitive and -insensitive prostate cancer cell lines. In the small clinical study, PC-SPES therapy decreased serum PSA levels in most patients. However, a longer follow-up and more patients will be required to evaluate the long-term efficacy of this new phytotherapy.

Recent advances in molecular technology have been applied to the detection, staging, and prognosis of prostate cancer. The reverse transcriptase-polymerase chain reaction (RT-PCR) is an exquisitely sensitive tool that allows for the detection of minimal quantities of cells. The assay has been studied clinically to distinguish metastatic prostate cancer patients from controls, and to preoperatively stage prostatic carcinoma; it also has been studied as a marker for postoperative recurrences. We review our experience at Columbia University and reports in the literature from other institutions to date. In addition, we provide our most recent data correlating the "enhanced" RT-PCR for PSA assay of peripheral blood specimens with final pathologic stage in 300 radical prostatectomy patients.

Tumor biomarkers (p53, bcl-2, Ki-67, and RT-PCR) were reviewed in the literature for their ability to predict prostate-specific antigen (PSA) biological recurrence after radical prostatectomy. All of them are strongly associated with PSA recurrence on univariate analysis. p53 seems to be better than current predictors, such as stage, grade, and positive surgical margins on multivariable analysis; further studies need to confirm bcl-2 and Ki-67 as better predictors of PSA recurrence. However, most of these studies were performed on radical prostatectomy specimens and will need to be confirmed on the preoperative prostate biopsy. The RT-PCR assay was strongly correlated with PSA recurrence and was one of the two best preoperative PSA recurrence predictors with serum PSA.