Selective activation of the fatty acid synthesis pathway in human prostate cancer.

A substantial subset of breast, colorectal, ovarian, endometrial and prostatic cancers displays markedly elevated expression of immunohistochemically detectable fatty acid synthase, a feature that has been associated with poor prognosis and that may be exploited in anti-neoplastic therapy. Here, using an RNA array hybridisation technique complemented by in situ hybridisation, we report that in prostate cancer fatty acid synthase expression is up-regulated at the mRNA level together with other enzymes of the same metabolic pathway. Contrary to the observations that in many cell systems (including androgen-stimulated LNCaP prostate cancer cells) fatty acid and cholesterol metabolism are co-ordinately regulated so as to supply balanced amounts of lipids for membrane biosynthesis, storage or secretion, no changes in the expression of genes involved in cholesterol synthesis were found. These findings point to selective activation of the fatty acid synthesis pathway and suggest a shift in the balance of lipogenic gene expression in a subgroup of prostate cancers.

Modern prostate brachytherapy. Prostate specific antigen results in 219 patients with up to 12 years of observed follow-up.

BACKGROUND: The purported lack of long term modern prostate brachytherapy outcome data continues to lead many physicians to recommend other, more traditional treatments. This concern for long term results has encouraged the authors to supplement their earlier 10-year follow-up of patients receiving brachytherapy; in the process, an additional 77 patients (> 50%) were added to the original cohort, and the follow-up time was increased by 2 years. METHODS: Between January 1987 and September 1989, 229 patients with T1-T3 prostate carcinoma underwent transperineal prostate brachytherapy using iodine-125 (I-125). No patient received adjuvant hormone therapy. The median Gleason sum was 5 (range, 2-10). Of these patients, 147 were determined to have a high probability of organ-confined disease and were treated solely with an I-125 implant. The remaining 82 patients were determined to be at increased risk for extracapsular disease and received pelvic external beam radiation in addition to brachytherapy. All patients were followed continuously. Failure was defined as a positive biopsy, radiographic evidence of metastases, or three consecutive rises in prostate specific antigen (PSA) levels as defined by the American Society for Therapeutic Radiology and Oncology (ASTRO) consensus article. RESULTS: Excluding deaths from intercurrent disease, the median follow-up was 122 months (range, 18-144 months). Fourteen patients were excluded from analysis due to insufficient follow-up. Adopting the ASTRO definition of failure resulted in minimal change in survival when compared with the authors' previous study, which used a PSA level > 0.5 ng/mL as the failure point. Observed 10-year disease free survival (DFS) for the entire cohort was 70%. In the brachytherapy only group, the observed 10-year DFS was 66%, whereas those patients treated with the addition of external pelvic radiation achieved a DFS of 79%. None of the patients who were followed for the full 12 years failed between Years 10 and 12. Only 25% of the failures observed occurred > 5 years after treatment, thus confirming the durability of brachytherapy. CONCLUSIONS: Prostate brachytherapy provides excellent long term disease control with few late failures reported in the authors' program. The addition of external beam radiation appears to confer survival advantages in selected patients. Using the ASTRO failure criteria for long term follow-up resulted in no significant difference compared with using a PSA failure point of 0.5 ng/mL.

Follow-up ProstaScint scans verify detection of occult soft-tissue recurrence after failure of primary prostate cancer therapy.

BACKGROUND: A reliable imaging modality is required to uncover occult soft- tissue recurrence after failure of primary prostate cancer therapy. This retrospective study was done to evaluate the ability of the (111)Indium-labeled monoclonal antibody (ProstaScint(R)) scan in detection of prostatic bed recurrence and/or metastases to regional and/or distant lymph nodes. METHODS: One hundred sequential patients were evaluated with repeated ProstaScint(R) scans because of evidence of recurrence during the course of their disease. These 100 patients were followed closely from November 1994 and April 1999, and had concurrent bone scans and serum prostate-specific antigen (PSA) evaluations. They have had hormone therapy (n = 53) and/or experienced a rising PSA after radical prostatectomy (n = 38) or after radiation therapy (n = 56). Scan images were scored 0-3, where score 0 = negative, score 1= prostate bed uptake, score 2 = regional lymph node uptake, and score 3 = distant lymph node uptake. In each patient, the uptake of the follow-up scan(s) was compared to that of the initial scan. RESULTS: The median age was 70 years (range, 45-87), and 23 patients had a positive bone scan. The average PSA was 40.5 ng/ml (standard deviation, 223.5). There was 257 scans representing 100 patients. All patients had at least 2 scans, 35 patients had 3 scans, and 11 patients had 4 scans. No individual exhibited detectable adverse clinical reactions during or after the scan. The findings of the initial and consecutive scans were anatomically consistent in 79%, whereas in 21% there were skip metastases. In 24 patients the lesions progressed by scan and PSA, 10 patients showed progression of scan but no PSA progression, 49 patients showed no change, and 17 patients showed a remission related to adjuvant therapy. CONCLUSIONS: The consistency on repeating the scan (79%) and the high percentage of patients showing persistent uptake at the prostate bed (43%) as well as the percentage of detection of regional nodes (20%) and distant nodes (32%) reflects the importance of using the ProstaScint(R) scan in finding occult recurrences after primary treatment failure of prostate cancer. These results are similar to those reported earlier in autopsy series studies in similar populations.

Evaluation of prostate cancer patients receiving multiple staging tests, including ProstaScint scintiscans.

BACKGROUND: Multiple serum tests were performed on archival samples from patients who participated in trials to assess the ProstaScint scan staging ability. Traditional statistical analysis as well as artificial neural network (ANN) analysis were employed to evaluate individual patients and the group as a whole. The results were evaluated so that each factor was tested for prognostic value. METHODS: Data obtained from serum tests, bone scans, and ProstaScint scans were evaluated by traditional statistical methods and ANN to determine the individual value in clinical staging of prostate cancer. RESULTS: Two hundred seventy-five patients (180 postprostatectomy, 95 intact prostate) with prostate cancer (14 with distant metastases) were available for analysis. Data available included: clinical state (remission or progression), most recent clinical TNM stage, bone scan, and ProstaScint scan. Serum was tested for prostate-specific membrane antigen(PSMA), prostate-specific antigen(PSA), free PSA (fPSA), and complexed PSA (cPSA). Additional calculations included percent free PSA, and percent complexed PSA. Spearman individual statistical assessment for traditional group evaluation revealed no significant factors for T-stage. The free PSA and complex PSA had a significant association with node (N)-status. The distant metastases (M) stage correlated well with the bone scan and clinical stage. ANN analysis revealed no significant T-stage factors. N-stage factors showed a 95% sensitivity and 49% specificity. These factors included the presence or absence of a prostate, PSA serum levels, bone scan, and ProstaScint scans as major associated indicators. ANN analysis of the important variables for M-stage included ProstaScint scan score, and PSA levels (total, percent complexed, percent free, and fPSA). These factors were associated with a 95% sensitivity and 15% specificity level. CONCLUSIONS: Two hundred seventy-five patients receiving treatment for prostate cancer were evaluated by ANN and traditional statistical analysis for factors related to stage of disease. ANN revealed that PSA levels, determined by a variety of ways, ProstaScint scan, and bone scan, were significant variables that had prognostic value in determining the likelihood of nodal disease, or distant disease in prostate cancer patients.

Prostate-specific membrane antigen (PSMA): current benefits and future value.

We will review the evolution, benefits, and limitations of PSMA testing in the past, as well as its current and future value. Prostate cancer has been the most frequently diagnosed cancer and the second leading cause of cancer death in men in the United States. It has a wide spectrum of biological behavior between latent (indolent) and progressive (aggressive). Further identification of prostate-specific membrane antigen (PSMA) as a prognostic proliferation marker may enhance our understanding of the types of prostate cancer. A review of PSMA testing in the past as well as currently was conducted. Studies were reviewed that deal with detection of PSMA in serum and seminal fluid, reverse transcriptase-polymerase chain reaction (RT-PCR), immunoscintigraphy, and immunohistochemical assays. PSMA is expressed primarily in benign and cancerous prostatic epithelial cells. It is up-regulated in hormone resistant states, and in metastatic situations or other clinical situations where there is tumor recurrence or extension. Based on current results, PSMA detected in the serum by western blotting can assist in the identification, staging, and monitoring of metastatic prostate cancer. In addition, PSMA shows a promising role in directed imaging and therapy of recurrent or metastatic disease.

Detection of extraprostatic prostate cells utilizing reverse transcription-polymerase chain reaction.

This article reviews the utility of reverse transcription-polymerase chain reaction (RT-PCR) in prostate cancer. RT-PCR aims to detect occult micrometastases in non-prostatic sites. Due to its exquisite analytical sensitivity, RT-PCR is able to amplify and detect even low-level, prostate-specific messages present at these extraprostatic sites. In recent years, a fair amount of data on the clinical utility of the technique had been reported. The target tissues under investigation are peripheral blood, bone marrow aspirate, and lymph nodes. Favorite markers of choice are prostate-specific antigen (PSA), prostate-specific membrane antigen (PSMA), and human glandular kallikrein-2 (hK2). False positives among negative controls are low. For the most part, RT-PCR is inadequate in detecting tumor cells in the peripheral blood from patients who are known to have metastatic prostate cancer. All studies showed that RT-PCR could detect PSA, PSMA or hK2 mRNAs in the circulation of patients who have organ-confined or extraprostatic disease. Most studies showed that RT-PCR utilizing current markers could not be used as a prospective test to diagnose prostate cancer. However, a few studies also showed that the detection rate could be predictive and sensitive enough to differentiate patients with organ-confined disease from those with extraprostatic disease. Data from PSA- or PSMA-RT-PCR using lymph nodes as the tissue source is more encouraging. RT-PCR was able to detect PSA and/or PSMA positive samples that have not been detected by conventional pathology.

Modern prostate brachytherapy.

Of all the treatment options available for men with organ-confined prostate cancer, brachytherapy--permament implantation of radioactive seeds into the prostate gland--is the least disruptive for the patient, both physiologically and practically. Early brachytherapy represents the oldest technique for delivering radiation to the prostate gland, preceding external beam therapy of the prostate by several decades. Although there have not been, and are not likely to be, any definitive randomized studies comparing radical prostatectomy, external beam radiotherapy, and brachytherapy, treatment decisions will continue to be made on the basis of patient and physician preferences in conjunction with clinical probabilities. Long-term results in this series show that monotherapy with seed implants achieved disease-free survival of 66%; moreover, 79% of patients with higher grade disease who were treated with a combination of brachytherapy and external beam radiation also experienced long-term disease-free survival. The following article provides a brief historical review of prostate brachytherapy, rationale for treatments, patient selection criteria, up-to-date implant techniques, and long-term (12-year) outcome results.

Circulating levels of interleukin-6 in patients with hormone refractory prostate cancer.

BACKGROUND: Interleukin-6 (IL-6) is a cytokine that plays a central role in host defense due to its wide range of immune and hematopoietic activities. It is found in high levels in human ejaculate, and has recently been found to regulate prostate-specific protein expression in prostate cancer cells through nonsteroidal activation of the androgen receptor. IL-6 may be a candidate mediator of morbidity in patients with metastatic disease. We attempted to evaluate the potential of circulating IL-6 levels as a marker of disease progression. MATERIALS AND METHODS Serum IL-6, prostate specific antigen (PSA), percent free PSA (%fPSA), and prostate-specific membrane antigen (PSMA) were measured using commercially available assays in 407 men, including 15 controls. The rest of the study population had clinical or histologic evidence of prostate diseases, including 41 patients with chronic prostatitis, 167 with benign prostatic hyperplasia (BPH), 8 with high-grade prostatic intraepithelial neoplasia (PIN), 88 with localized prostate cancer, 22 with local recurrence after treatment of primary tumor, 4 with advanced untreated disease (nodal or bony metastases), 23 with advanced hormone dependent disease, and 39 with advanced hormone refractory disease (PSA > 1.0 ng/ml while on hormone treatment and/or evidence of disease progression). None had history of concurrent malignancy or acute inflammatory condition. Kruskal-Wallis analysis of variance and Spearman's correlation analysis were used for statistical analyses. RESULTS: Serum levels of IL-6 were significantly elevated in patients with clinically evident hormone refractory disease (5.7 +/- 1.9 pg/ml) and statistical significance was seen when comparing the elevated serum IL-6 levels to those in normal controls, prostatitis, BPH, and localized and recurrent disease, (P values < 0.01). Compared to serum levels of controls and BPH, PSA was significantly elevated in advanced untreated disease and hormone refractory groups (P < 0.05). Percent fPSA was significantly lower in all cancer patients but the hormone refractory. Serum PSMA was elevated in advanced untreated prostate cancer. Serum IL-6 showed positive correlation with PSMA and negative correlation with serum PSA but did not attain statistical significance. CONCLUSIONS: Serum IL-6 levels are significantly elevated in hormone-refractory prostate cancer patients and may be a surrogate marker of the androgen independent phenotype.

Follow-up evaluation of a phase II prostate cancer vaccine trial.

BACKGROUND: A phase II trial, involving infusions of autologous dendritic cells (DC) and two human histocompatibility antigen (HLA-A2)-specific prostate-specific membrane antigen (PSMA) peptides, was recently completed. Thirty percent of the participants, including subjects with hormone-refractory metastastic disease, and those with suspected local recurrence of prostate cancer, were identified as clinical responders. This report describes the follow-up evaluation of 19 responders in the two study groups. METHODS: After conclusion of the study, study participants were subjected to follow-up evaluations at 6-8-week intervals. Each responder was reevaluated for response status, and duration of response was determined. RESULTS: Subjects were observed for an average of 291 days (metastastic group, group A-2) and 557 days (local recurrence group, group B), which included the treatment and follow-up periods. The average duration of response was 149 days for group A-2, and 187 days for group B. A majority of responders (11/19; 58%) were still responsive at the end of the current follow-up. CONCLUSIONS: The responses observed may be significant and relatively durable. This study suggests that DC-based cancer vaccines in the future may provide an additional therapy for advanced prostate cancer.

Vaccine therapy for prostate cancer.

Vaccine therapy may provide an alternative for prostate cancer patients whose disease no longer responds to hormone therapy. Administration of dendritic cells pulsed with prostate-specific membrane antigen (PSMA) induces cellular immune responses against the tumor with virtually no adverse effects. About 30% of the evaluable patients were identified as partial responders, based on the National Prostate Cancer Project (NPCP) criteria. In addition, there was a 50% decrease of serum prostate-specific antigen or resolution of previously measurable lesions on imaging. Dendritic cell vaccine therapy may have a synergistic effect, when combined with other therapies.

GM-CSF as a systemic adjuvant in a phase II prostate cancer vaccine trial.

BACKGROUND: Recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF; Leukine [sargramostim], Immunex Corp., Seattle, WA) was administered to a subgroup of 44 patients in a phase II clinical trial for prostate cancer using DC pulsed with HLA-A2-specific prostate-specific membrane antigen (PSMA) peptides. Our purpose was to determine if GM-CSF caused any enhancement of patients' immune responses, including enhancement of clinical response to the DC-peptide treatment. This report compares the clinical responses to DC-peptide infusions with and without systemic GM-CSF treatment. METHODS: GM-CSF was administered by subcutaneous injection at a dose of 75 microg/m2/day for 7 days with each of six infusion cycles. Prefilled syringes were supplied to the patients for self-administration. RESULTS: One complete and 8 partial responders were identified among 44 patients who received GM-CSF, as compared to 2 complete and 17 partial responders among 51 patients who did not receive GM-CSF. For patients who received GM-CSF and were tested by delayed-type hypersensitivity (DTH) skin test, 3 cases of improved immune response were identified, compared to 5 cases of improvement in patients who did not receive GM-CSF. The main GM-CSF side effects reported were local reactions at the site of injection, fatigue, pain, and fever. Most reported side effects were of mild severity, with some cases of moderate severity leading to discontinuation of GM-CSF. CONCLUSIONS: Our results suggest GM-CSF as employed in this trial did not detectably enhance clinical response to DC-peptide infusions, or significantly enhance the measured immune response.

Phase II prostate cancer vaccine trial: report of a study involving 37 patients with disease recurrence following primary treatment.

BACKGROUND: A phase II trial was conducted to assess the efficacy of infusions of dendritic cells (DC) and two HLA-A2-specific prostate-specific membrane antigen (PSMA) peptides (PSM-P1 and -P2). This report describes the evaluation of 37 subjects admitted with presumed local recurrence of prostate cancer after primary treatment failure. METHODS: All subjects received six infusions of DC pulsed with PSM-P1 and -P2 at 6-week intervals. Clinical monitoring was conducted pre-, during, and post-phase II study. Data included: complete blood count, bone and total alkaline phosphatase, prostate markers, physical examination, performance status, bone scan, ProstaScint scan, and chest X-ray, as well as other assays to monitor cellular and humoral immune responses. RESULTS: One complete and 10 partial responders were identified from this group based on National Prostate Cancer Project criteria, or on a 50% reduction of prostate-specific antigen (PSA), or on a significant resolution in lesions (biopsy-proven when possible) on ProstaScint scan. CONCLUSIONS: About 30% of study participants in this group showed a positive response at the conclusion of the trial. This study suggests that DC-based cancer vaccines may provide an alternative therapy for prostate cancer patients whose primary treatment failed.

Infusion of dendritic cells pulsed with HLA-A2-specific prostate-specific membrane antigen peptides: a phase II prostate cancer vaccine trial involving patients with hormone-refractory metastatic disease.

BACKGROUND: A phase II trial was conducted to assess the efficacy of infusions of dendritic cells (DC) and two HLA-A2-specific PSMA peptides (PSM-P1 and -P2). This report describes thirty three subjects with hormone-refractory metastatic prostate cancer without prior vaccine therapy history who were evaluated and reported as a group. METHODS: All subjects received six infusions of DC pulsed with PSM-P1 and -P2 at six week intervals. Clinical monitoring was conducted pre-, during, and post- phase II study. Data collected include: complete blood count, bone and total alkaline phosphatase, prostate markers, physical examination, performance status, bone scan, ProstaScint scan, chest x-ray, as well as assays to monitor cellular immune responses. RESULTS: Six partial and two complete responders were identified in the phase II study based on NPCP criteria, plus 50% reduction of prostate-specific antigen (PSA), or resolution in previously measurable lesions on ProstaScint scan. CONCLUSIONS: Over 30% of study participants in this group showed a positive response at the conclusion of the trial. This study suggested that DC-based cancer vaccines may provide an alternative therapy for prostate cancer patients whose disease no longer responds to hormone therapy.

Current evaluation of the tissue localization and diagnostic utility of prostate specific membrane antigen.

BACKGROUND: Current statistics indicate that prostate carcinoma is the most common form of cancer diagnosed in American men, resulting in the second highest cancer death rate. Early diagnosis and accurate staging are imperative given that there is little effective treatment for metastatic disease, especially after androgen deprivation therapy fails. Identification of new biochemical markers for disease progression will provide important tools for diagnosis and monitoring. One such potential marker is prostate specific membrane antigen (PSMA). METHODS: A review was conducted to identify reports concerning evaluation of diagnostic applications of PSMA. RESULTS: PSMA is a membrane-bound glycoprotein that is highly restricted to the prostate. Immunohistochemical findings indicate that PSMA is a marker of epithelial cells of the prostate. This expression is increased in association with prostate carcinoma, particularly in hormone-refractory disease. Given its membrane-bound character, PSMA has been exploited as a marker for tumor detection by immunoscintiscanning with the 111In-labeled anti-PSMA monoclonal antibody 7E11.C5. Increased concentrations of 7E11.C5-reactive antigen are present in the serum of prostate carcinoma patients compared with healthy individuals; also, hematogenous circulating prostate carcinoma cells are detectable with reverse transcriptase-polymerase chain reaction analysis with primers specific for PSMA. New monoclonal antibodies specific for extracellular portions of the PSMA molecule currently are being utilized in applied studies. CONCLUSIONS: PSMA is a widely used marker for prostate epithelial cells. Its up-regulation in association with cancer, particularly in advanced cancer, is ideal for application as a prognostic marker. A variety of promising clinical applications utilizing PSMA have been or are being developed. In the future, these promise to have an important impact on cancer diagnosis and patient treatment.

ProstaScint scan may enhance identification of prostate cancer recurrences after prostatectomy, radiation, or hormone therapy: analysis of 136 scans of 100 patients.

BACKGROUND: Primary extraprostatic spread or failure after prostate cancer treatment can occur locally in the prostatic fossa and/or metastasize to regional and/or distant lymphatics and/or in bone. We evaluated the ability of the ProstaScint (Cytogen Corp., Princeton, NJ) scan to identify soft tissue recurrence of prostate cancer in patients who failed primary treatment, and we monitored their responses to a secondary treatment. METHODS: The 111indium-labeled monoclonal antibody (ProstaScint) was evaluated in a series of 136 consecutive scans associated with a complete set of relevant clinical and biochemical data. These scans represented 100 patients, imaged between November 1994-May 1998, who underwent a definitive prostate cancer treatment followed by evidence of recurrence. All patients had serum prostate-specific antigen (PSA), Western-blot serum prostate-specific membrane antigen (PSMA), and bone scans. Prostatic fossa and/or lymph node biopsies were available in 33 patients. RESULTS: Overall, no adverse reactions were related to any of the radioactive antibody infusions. The average age was 69 years (range, 48-89 years), serum PSA was 55.9 ng/ml (range, 0-2,185 ng/ml), and serum PSMA was 0.32 (relative intensity levels range, 0.04-0.55). The initial therapies given were radical prostatectomy (55 scans), prostate radiation (74 scans), and/or hormonal therapy (77 scans). Twelve patients exhibited a negative scan. Local recurrence alone was identified in 58 scans (42.6%). Lymph node metastases were identified in 66 scans (48.5%). Of these, 21 had regional metastases alone, and 45 had distant lymph node metastases. Ten scans showed skip lymph node metastases without regional failure. PSA significantly correlated with negative, pelvic, and extrapelvic scan findings (P < or = 0.02). PSMA correlated best with pelvic recurrence and extrapelvic metastases in prostatectomized patients. Thirty-four patients had repeated scans for monitoring treatment response. Of these patients, 19 (56%) showed progression on the second scan, consistent with persistent increase in PSA and PSMA levels in all but 2 patients. Another 11 patients showed no change, and 4 patients showed partial remission, suggesting a response to the salvage treatment. All 20 positive prostate biopsies and 4 of the 7 positive lymph node biopsies correlated with ProstaScint findings, whereas 4 of the 6 patients with a negative biopsy had negative scans (i.e., 89% sensitivity and 67% specificity). Bone metastases were identified in 42 bone scans; 45% of these showed no lymph node metastasis on ProstaScint. In another 24 patients (57%), bone metastases were detected on ProstaScint examinations.

Ten-year disease free survival after transperineal sonography-guided iodine-125 brachytherapy with or without 45-gray external beam irradiation in the treatment of patients with clinically localized, low to high Gleason grade prostate carcinoma.

BACKGROUND: The authors report observed 10-year brachytherapy results in the treatment of 152 consecutive patients with clinically organ-confined prostate carcinoma. METHODS: One hundred and fifty-two consecutive patients with T1-T3, low to high Gleason grade, prostate carcinoma were treated between January 1987 and June 1988 at Northwest Hospital in Seattle, Washington. Their median age was 70 years (range, 53-92 years). Of these 152 patients, 98 (64%) received an iodine-125 implant alone (Group 1), and the remaining 54 patients (36%), who were judged to have a higher risk of extraprostatic extension, also were treated with 45 gray (Gy) of external beam irradiation to the pelvis (Group 2). No patient underwent lymph node sampling, and none received androgen ablation therapy. Multivariate regression and the Mann-Whitney rank sum test were used for statistical analysis. Preoperative patient data with associated success or failure outcomes at 10 years after treatment were used for training and validating a back-propagation neural network prediction program. RESULTS: The average preoperative prostate specific antigen (PSA) value, clinical stage, and Gleason grade were 11.0 ng/mL, T2, and 5, respectively. The median posttreatment follow-up was 119 months (range, 3-134 months). Overall survival 10 years after treatment was 65%. At last follow-up only 3 of the 152 patients (2%) had died of prostate carcinoma. Ninety-seven patients (64%) remained clinically and biochemically free of disease at 10 years of follow-up and had an average PSA value of 0.18 ng/mL (range, 0.01-0.5 ng/mL). In these patients a period of 42 months was required to reach the average PSA (0.5 ng/mL). The median to last PSA follow-up was 95 months (range, 3-134 months). Postoperative needle biopsies were negative in 56% of patients, positive in 15% of patients, and not available in 29% of patients. Only 6% of patients developed bone metastasis. At 10 years there was no statistically significant difference in treatment outcome between patients who received iodine-125 alone, and those who received iodine-125 with 45-Gy external beam irradiation (P = 0.08). Nevertheless, in these two groups preoperative PSA, stage, and Gleason grade were significantly different (P < 0.01). In the artificial neural network analysis, pretreatment serum PSA was the most accurate predictor of disease-free survival. CONCLUSIONS: Percutaneous prostate brachytherapy is a valid and efficient option for treating patients with clinically organ-confined, low to high Gleason grade, prostate carcinoma. Observed 10-year follow-up documents serum PSA levels superior to those reported in several published external beam irradiation series, and comparable to those published in a number of published radical prostatectomy series.

Method for identifying prostate cells in semen using flow cytometry.

BACKGROUND: Prostate-specific antigen (PSA) cannot differentiate benign prostatic hyperplasia (BPH), from prostatitis, or prostate cancer in the range of 4.0-10 ng/ml. An accurate cytologic or histologic assessment is necessary to confirm the proper diagnosis. The nature of a biopsy tends to make it a selective test not frequently repeated. We are reporting a technique employing semen as a source for the differential diagnosis of prostate epithelial cells. METHODS: Eleven vasectomized and nonvasectomized prostate cancer patients provided semen samples (stage T1 to T2). Two patients provided repeat samples. In addition, 15 vasectomized or nonvasectomized individuals without evidence of disease provided semen samples. Three million cells fixed with 50% ethanol were stained by an antibody (7E11.C5) to prostate-specific membrane antigen (PSMA), Hybritech Antibody (399) to PSA, and cytokeratin 8 and 18. In addition to the antibodies described, a DNA stain To-Pro 3 was used to identify 2n-4n DNA containing cells. A dual laser, Becton Dickinson FACSCaliber cytometer, was used to analyze the samples. RESULTS: All semen specimens contained diploid, cytokeratin 18-positive epithelial cells regardless of disease status. A clear difference between prostate cancer and normal prostate cell samples was observed using staining with 7E11.C5. The ratio of prostatic cells in the total epithelial cell population (PSMA:cytokeratin ratios) was calculated for each specimen. A retrospective study of sixteen semen samples from 11 prostate cancer patients had a mean PSMA:cytokeratin ratio of 0.57, whereas the samples from 15 patients without evidence of cancer had a mean PSMA:cytokeratin ratio of 0.11. This difference was significant. PSA staining was variable and inconsistent. CONCLUSIONS: This report demonstrates that human semen contains prostate cells that can be characterized and used in the clinical diagnosis of prostate cancer.

Evaluation of phase I/II clinical trials in prostate cancer with dendritic cells and PSMA peptides.

BACKGROUND: A phase I trial involving patients with advanced prostate cancer was conducted to assess the safe administration of dendritic cells (DC) and HLA-A0201-specific prostate-specific membrane antigen (PSMA) peptides (PSM-P1 or -P2). Thirty-three of the phase I participants were subsequently enrolled in a phase II trial, which involved six infusions of DC pulsed with PSM-P1 and -P2 peptides. METHODS: Clinical monitoring was conducted up to 770 days from the start of the phase I study. Data collected included: complete blood count, bone and total alkaline phosphatase, prostate markers, physical examination, performance status, bone scan, ProstaScint scan, and chest X-ray, as well as assays to monitor cellular immune responses. RESULTS: Nine partial responders were identified in the phase II study based on National Prostate Cancer Project (NPCP) criteria, plus 50% reduction of prostate-specific antigen. Four of the partial responders were also responders in the phase I study, with an average response duration of 225 days. Their combined average total response period was over 370 days. Five other responders were nonresponders in the phase I study. Their average partial response period was 196 days. CONCLUSIONS: The responses observed in the phase I and II clinical trials were significant and of long duration. The partial-responder group included patients who continued to respond from phase I, as well as those who started to respond during the phase II trial.