After primary treatment for clinically localized prostate cancer, biochemical recurrence is usually the first evidence of either local recurrence or metastatic progression. This poses a diagnostic dilemma for both the patient and the physician regarding future therapy. Prostate-specific antigen doubling time (PSADT) is a useful tool in this clinical setting. There have been multiple reports of the utility of PSADT in men with isolated biochemical recurrence after either radical prostatectomy or external-beam radiation therapy. Early observations of PSADT in men with recurrence are reviewed and the current literature is summarized to allow physicians to make an accurate assessment of a patient's risk of progression after isolated biochemical recurrence.

Adenocarcinoma↗

PubMed2003

Quantitative alterations in nuclear structure predict prostate carcinoma distant metastasis and death in men with biochemical recurrence after radical prostatectomy.

BACKGROUND: Microscopic histologic grade has been the best predictor of prostate carcinoma (PCa) progression in men after surgical therapy. The ability to predict accurately, at the time of surgery, which patients are likely to develop metastatic PCa would enable optimization of disease management with adjuvant therapy. The authors assessed the ability of pathologic, nuclear morphometric, and chromatin parameters to predict metastatic PCa progression and/or death in 227 men with biochemical recurrence and long-term follow-up after undergoing radical prostatectomy. METHODS: Multivariate logistic regression (LR) was used to calculate quantitative nuclear grade (QNG) solutions using the variances of 60 nuclear morphometric descriptors (NMDs) of nuclear size, shape, DNA content, and chromatin organization that predicted distant metastasis and/or PCa-specific death. An LR model also was generated to predict this outcome using a combination of pathologic variables and the best QNG solution. Cox proportional hazards models were generated, and Kaplan-Meier plots were used to display three risk groups based on pathology, QNG, and a combination of these variables. RESULTS: A multivariate LR model using pathology retained lymph node (LN) status, seminal vesicle status, and prostatectomy Gleason score, yielding an area under the curve-receiver operator characteristic (AUC-ROC) of 75% with an accuracy of 59% at 90% sensitivity. The best QNG solution used the variance of 25 NMDs, yielding an AUC-ROC of 84% and an accuracy of 70% at 90% sensitivity. The combined pathology-QNG model retained LN status, prostatectomy Gleason score, and QNG, yielding an AUC-ROC of 86% with an accuracy of 76% at 90% sensitivity. The Cox proportional hazards models produced the following significant univariate and multivariate hazard ratios: QNG, 3.5 and 2.9, respectively; LN, 2.7 and 1.8, respectively; and prostatectomy Gleason score, 2.8 and 2.1, respectively. CONCLUSIONS: Alterations in the structure of tumor nuclei measured by computer-assisted image analysis were strong predictors of PCa progression and death in men with long-term follow-up who had biochemical recurrence after undergoing radical prostatectomy. QNG solutions can serve as a new supplemental biomarker for accurate prediction of PCa progression at the time of surgery.

Adenocarcinoma↗

PubMed2003

A neurocomputational model for prostate carcinoma detection.

BACKGROUND: Current guidelines for prostate carcinoma screening rely primarily on the digital rectal examination (DRE) and prostate specific antigen (PSA). Well described patient risk factors for prostate carcinoma also include age, ethnicity, family history, and complexed PSA. However, due to the nonlinear relation of each of these variables with prostate carcinoma, it is difficult to predict reliably each patient's risk based on linear univariate analysis. The authors investigated a neural network to model the risk of prostate carcinoma by seven readily available clinical features. METHODS: The database for the current study comprised 3268 men recently evaluated for the early detection of prostate carcinoma. The seven clinical features evaluated included age, race, family history, International Prostate Symptom Score (IPSS), DRE, and total and complexed PSA. Three hundred forty-eight subjects in the dataset included men with determined prostate biopsy outcomes and for whom at least 6 of 7 features were available. The dataset was divided randomly into a training set (60%) and a test set (40%), with n1/n2 cross-validation used to evaluate model accuracy, and was modeled with linear and quadratic discriminant function analysis and a neural computational system. After a model with acceptable goodness of fit was achieved, reverse regression analysis using Wilks's generalized likelihood ratio test was performed to evaluate the statistical significance of each input variable. RESULTS: The receiving operating characteristic (ROC) area for the neural computational system in the test set was 0.825, whereas total PSA and complexed PSA alone had ROC areas of 0.678 and 0.697, respectively. The ROC area of logistic regression in the test set was 0.510, linear discriminant function analysis was 0.674, and quadratic discriminant function analysis was 0.011. All were significantly less than the ROC area of the neural computational model (all Ps < 0.002). Reverse regression based on Wilks's generalized likelihood ratio test demonstrated each input feature to be highly significant to the model (all Ps << 0.000001). CONCLUSIONS: The authors modeled a combination of well described patient risk factors for prostate carcinoma using a neural computational system with acceptable goodness of fit. They demonstrated that each of the seven variates on which the model was based was critically significant to model performance. The authors presented this model for clinical use and suggested that clinicians use it in deciding to perform prostate biopsy.

Age Factors↗

PubMed2003

Quantitative biopsy pathology for the prediction of pathologically organ-confined prostate carcinoma: a multiinstitutional validation study.

BACKGROUND: Quantitative biopsy pathology with prostate specific antigen significantly improves the prediction of pathologic stage in patients with clinically localized prostate carcinoma (PCa). The authors recently reported a computational model for predicting patient specific likelihood of organ confinement of PCa using biopsy pathology and clinical data. The current study validates the initial models and presents an new, improved tool for clinical decision making. METHODS: The authors assessed 10 biopsy pathologic parameters and 2 clinical parameters using data from two institutions. Of 1287 patients, 798 men had pathologically organ confined (OC) PCa, 282 men had nonorgan-confined disease with capsular penetration (NOC-CP) only, and 207 men showed seminal vesicle or lymph node invasion (NOC-AD) after undergoing pelvic lymphadenectomy and radical prostatectomy. Patient input data were evaluated by ordinal logistic (OLOGIT) and neural network (NN) models; and the likelihood of developing OC, NOC-CP, or NOC-AD disease was calculated for the combined and separate data sets and was compared with the results from original presentation. In addition, a new two-output model was constructed (OC/NOC-CP vs. NOC-AD). RESULTS: The three-output OLOGIT and NN models predicted OC disease with 95.0% and 98.6% accuracy, respectively, for the combined data set and with 93.0% and 98.6% accuracy, respectively, on subset analysis. The combined accuracy for predicting OC, NOC-CP, and NOC-AD disease in the entire validation set was 66.7% for OLOGIT model and 66.0% for the NN model. The two-output OLOGIT and NN models correctly predicted 94.9% and 100.0% of all OC/NOC-CP disease, respectively. CONCLUSIONS: Both computation models predicted OC PCa with an accuracy of 93.0-98.6% when they were validated with two different data sets. The OLOGIT and NN-based, two-output model permitted an appropriate treatment decision for 85.2-90.2% of patients. These data support the use of quantitative pathology and clinical data-based decision modeling to manage patients with clinically localized PCa.

Biopsy↗

PubMed2003

Microarrays of tumor cell derived proteins uncover a distinct pattern of prostate cancer serum immunoreactivity.

The broad characterization of the immune responses elicited by tumors has valuable applications in diagnostics and basic research. We present here the use of microarrays of tumor-derived proteins to profile the antibody repertoire in the sera of prostate cancer patients and controls. Two-dimensional liquid chromatography was used to separate proteins from the prostate cancer cell line LNCaP into 1760 fractions. These fractions were spotted in microarrays on coated microscope slides, and the microarrays were incubated individually with serum samples from 25 men with prostate cancer and 25 male controls. The amount of immunoglobulin bound to each fraction by each serum sample was quantified. Statistical analysis revealed that 38 of the fractions had significantly higher levels of immunoglobulin binding in the prostate cancer samples compared to the controls. Two fractions showed higher binding in the control samples. The significantly higher immunoglobulin reactivity from the prostate cancer samples may reflect a strong immune response to the tumors in the prostate cancer patients. We used multivariate analysis to classify the samples as either prostate cancer or control. In a cross-validation study, recursive partitioning classified the samples with 84% accuracy. A decision tree with two levels of partitioning classified the samples with 98% accuracy. Additional studies will allow further characterization of tumor antigens in prostate cancer and their significance for diagnosis. These results suggest that microarrays of fractionated proteins could be a powerful tool for tumor antigen discovery and cancer diagnosis.

Antibodies, Neoplasm↗

PubMed2003

Volume indexes of total, free, and complexed prostate-specific antigen enhance prediction of extraprostatic disease extension in men with nonpalpable prostate cancer.

OBJECTIVES: To analyze the ability of volume-adjusted total, complexed, and free prostate-specific antigen (PSA) to predict organ-confined cancer at radical prostatectomy in patients with nonpalpable disease. METHODS: Collected sera were assayed for total PSA (tPSA), complexed PSA (cPSA), and free PSA (fPSA) in 78 men who underwent radical prostatectomy with nonpalpable prostate cancer. The pathologic results (organ-confined versus extraprostatic extension [EPE]), tPSA, cPSA, fPSA/tPSA ratio, cPSA/tPSA ratio, fPSA/cPSA ratio, tPSA density (tPSAD), cPSA density (cPSAD), and fPSA density (fPSAD) were compared by the Mann-Whitney U test and receiver operating characteristic curves. RESULTS: Fifteen men (19.2%) had pathologic EPE. After stratifying the patients on the basis of the Beckman tPSA, the cPSAD, tPSAD, and fPSAD were significant predictors of EPE when comparing their respective medians in individuals with tPSA greater than 4.0 ng/mL. Statistically significant differences were noted between patients with and without EPE for tPSAD (P = 0.0015), cPSAD (P = 0.0018), and fPSAD (P = 0.0022), but not for the fPSA/tPSA, cPSA/tPSA, and fPSA/cPSA ratios. The area under the receiver operating characteristic curve was similar for tPSA (0.539) and cPSA (0.542), as it was for tPSAD (0.708), cPSAD (0.700), and fPSAD (0.731). The specificity and diagnostic accuracy of tPSAD, cPSAD, and fPSAD were significantly greater than those of tPSA and cPSA (specificity P <0.001; diagnostic accuracy P <0.05). CONCLUSIONS: In men with nonpalpable prostate cancer, the density parameters of tPSA, cPSA, and fPSA performed equivalently and appeared to enhance the predictability of EPE.

Adenocarcinoma↗

PubMed2003

Proenzyme psa for the early detection of prostate cancer in the 2.5-4.0 ng/ml total psa range: preliminary analysis.

OBJECTIVES: To determine the clinical utility of using proenzyme prostate-specific antigen (pPSA) for early detection of prostate cancer in the 2.5 to 4.0 ng/mL total PSA range. pPSA, the precursor form of PSA that contains a 7 amino acid leader peptide, and truncated forms such as [-2]pPSA and [-4]pPSA can be measured in serum by research immunoassay. METHODS: Archival serum from 119 men (noncancer, 88; cancer, 31), obtained before biopsy and in the total PSA range of 2.5 to 4.0 ng/mL, were assayed for total PSA, free PSA (fPSA), and pPSA. pPSA was defined as the sum of the [-2], [-4], and [-7] forms, and the percent pPSA (%pPSA) was defined as pPSA/fPSA. RESULTS: pPSA averaged 4.6% +/- 0.4% (SEM) of total PSA and 39.3% +/- 3.5% of fPSA. PSA and %fPSA values were similar between the noncancer and cancer groups, and %pPSA tended to be higher in the cancer group (50.1% +/- 4.4%) compared with the noncancer group (35.5% +/- 6.7%; P = 0.07). Using receiver operating characteristic analysis to assess clinical utility, the area under the curve for %pPSA was 0.688 compared with 0.567 for %fPSA. At a fixed sensitivity of 75%, the specificity was significantly greater for %pPSA at 59% compared with %fPSA at 33% (P <0.0001). CONCLUSIONS: In the 2.5 to 4.0 ng/mL total PSA range, 75% of cancers can potentially be detected with 59% of unnecessary biopsies being spared using %pPSA; use of %fPSA would result in sparing only 33% of unnecessary biopsies. A large prospective clinical trial is needed to confirm these preliminary findings.

Adult↗

PubMed2003

Identification and preliminary clinical evaluation of a 50.8-kDa serum marker for prostate cancer.

OBJECTIVES: To identify a 50.8-kDa biomarker to perform a preliminary clinical evaluation of its utility as an aid in the early detection of prostate cancer. METHODS: The 50.8-kDa protein, previously called NMP48, was partially purified from the serum of an individual with prostate cancer and identified by peptide mass fingerprinting of tryptic peptides from an in-gel digest. Serum samples were obtained from men with biopsy-confirmed prostate cancer, high-grade prostatic intraepithelial neoplasia, and benign histologic features, from men with clinically defined benign prostatic hyperplasia, and from controls without prostatic disease. These samples were analyzed for the presence of the biomarker by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry. RESULTS: The 50.8-kDa protein was identified by peptide mass fingerprinting as being related to vitamin D-binding protein. It was found in 96% of the sera from individuals with prostate cancer (n = 52) including 11 of 12 specimens that exhibited prostate-specific antigen values of less than 4 ng/mL. The 50.8-kDa protein was found in 10 of 19 samples from men with prostatic intraepithelial neoplasia; however, it was not detected in the sera of 5 (75%) of 20 individuals with benign prostatic histologic features, 7 (70%) of 10 with clinical benign prostatic hyperplasia, 8 (80%) of 10 patients who had previously undergone radical prostatectomy, or 48 (96%) of 50 specimens from healthy controls. CONCLUSIONS: Although the study cohort was relatively small, the data suggest that an assay for the 50.8-kDa protein may be useful for the early detection of prostate cancer. Additional elucidation of its structure may yield insight into the development of this disease.

Amino Acid Sequence↗

PubMed2003

Immunohistochemical staining of prostate cancer with monoclonal antibodies to the precursor of prostate-specific antigen.

OBJECTIVES: To characterize the immunohistochemical staining (IHS) of precursor forms of prostate-specific antigen (pro-PSA) forms in prostate cancer, high-grade prostatic intraepithelial neoplasia (HGPIN), and benign tissue from the peripheral and transition zones. Pro-PSA have previously been shown to be more concentrated in prostate cancer tissue extracts than in benign tissue. METHODS: Prostate needle biopsies showing HGPIN (22 sections, 11 patients) and adenocarcinoma (30 sections, 21 patients) and 17 radical prostatectomy and 3 open prostatectomy specimens were identified from the surgical pathology files of Johns Hopkins Hospital. IHS was performed on formalin-fixed, paraffin-embedded sections using one monoclonal antibody (mAB) against pro-PSA with a truncated pro-leader peptide containing two amino acids, [-2]pPSA, and a second mAB against native pro-PSA ([-5/-7]pPSA). RESULTS: The mABs were specific for both benign and malignant prostatic glandular tissue and did not stain stromal, vascular, or colonic tissue when present in the specimens. All sections with HGPIN and/or adenocarcinoma showed staining with both mABs. HGPIN was strongly positive in most cases (66.1%). The native pro-PSA mAB showed little differential between cancer and benign glands, and the mAB to the truncated [-2]pPSA stained cancer tissue more strongly than benign tissue. Benign atrophic glands often showed negative or weak/patchy staining. No difference was found in the staining pattern between benign glands in the peripheral zone and transition zone. CONCLUSIONS: This study is the first to demonstrate that mABs to pro-PSA can be used as specific IHS for benign and malignant prostatic tissue. [-2]pPSA appears to be preferentially more concentrated in cancer tissue than in benign glands, correlating with previous tissue extract studies. Unlike previous studies with PSA staining, the IHS for pro-PSA remained uniform among the different tumor grades. Therefore, pro-PSA may be a useful marker in differentiating high-grade prostate adenocarcinoma from other non-prostate carcinomas.

Adenocarcinoma↗

PubMed2003

Long-term cancer control of radical prostatectomy in men younger than 50 years of age: update 2003.

OBJECTIVES: To compare the cancer control in men younger than 50 years with that in older men treated with radical retropubic prostatectomy (RRP) for localized prostate cancer in a contemporary series. In the 1970s and 1980s, men younger than 50 years old represented approximately 1% of newly diagnosed prostate cancer cases. However, with the widespread use of serum prostate-specific antigen (PSA) testing and increased public awareness of prostate cancer, this figure has risen (3.7% to 4%). Previous studies, mostly carried out before the PSA era, reported conflicting data with respect to cancer control for these younger men treated with RRP. METHODS: We analyzed the data from 2897 men who underwent RRP between April 1982 and September 2001. Preoperative PSA level, clinical and pathologic stage, and biochemical recurrence were compared between 341 men younger than 50 years old and 2556 men 50 years old or older. Disease-free (PSA less than 0.2 ng/mL) survival rates were compared using Kaplan-Meier analysis. Pathologic staging was compared using logistic regression analysis. RESULTS: Men younger than 50 years old had pathologic variables and 5, 10, and 15-year biochemical disease-free survival rates comparable to men aged 50 to 59 years (88%, 81%, and 69% versus 87%, 78%, and 71%, respectively). However, younger men had a lower incidence of extraprostatic extension (25% versus 31%; P <0.02), seminal vesicle involvement (2% versus 6%; P <0.03), and positive surgical margins (3% versus 9%; P <0.03), a greater organ-confined disease rate (65% versus 49%; P <0.0001), and a trend toward greater 5, 10, and 15-year biochemical disease-free survival rates, which did not reach statistical significance, compared with men aged 60 to 69 years (84%, 74%, and 67%, respectively; P <0.09). Furthermore, younger men not only had a lower rate of extraprostatic extension (25% versus 36%; P <0.001), seminal vesicle involvement (2% versus 10%; P <0.001), and positive surgical margins (3% versus 9%; P <0.001) and a greater organ-confined disease rate (65% versus 36%; P <0.0001), they also demonstrated significantly (P <0.003) greater 5, 10, and 15-year biochemical disease-free survival rates compared with men aged 70 years or older (72%, 58%, and 58%, respectively). CONCLUSIONS: Men diagnosed with prostate cancer who are younger than 50 years of age and are candidates for RRP tend to have a greater probability of organ-confined disease than older men. Younger men also demonstrate greater long-term cancer control rates than older men.

Adenocarcinoma↗

PubMed2003

Expectant management of localized prostate cancer.

Explore the source record for details and available documents.

Adenocarcinoma↗

PubMed2003

Probability of biochemical recurrence by analysis of pathologic stage, Gleason score, and margin status for localized prostate cancer.

OBJECTIVES: The Partin tables provide pretreatment information regarding the probability of various pathologic stages (eg, organ confined, extraprostatic extension, and seminal vesicle or lymph node involvement). Although the pathologic stage serves as an excellent surrogate for outcome after radical prostatectomy (RRP), many patients and physicians want to know how the predictions made from the Partin tables can be translated into long-term biochemical recurrence-free survival. In this work, we go beyond the pathologic outcomes predicted by the Partin nomograms to provide long-term biochemical recurrence-free estimates on the basis of the pathologic data obtained at RRP to help counsel patients after surgery for prostate cancer. METHODS: The study group comprised 1955 men treated by one surgeon with RRP and pelvic lymph node dissection for clinically localized disease (1989 to 2001). The patients were followed up for at least 1 year postoperatively, and the disease-free survival rates were determined using Kaplan-Meier analysis. RESULTS: The pathologic stages were as follows: organ confined in 57%, extraprostatic extension in 35%, seminal vesicle involvement in 4%, and lymph node involvement in 4%. The prostatectomy Gleason score distribution was as follows: 2 to 4 in 1%, 5 to 6 in 63%, 7 in 30%, and 8 to 10 in 6%. Overall, a positive surgical margin was present in 9.8%. On the basis of the prostatectomy Gleason score, pathologic stage, and surgical margin status, the probability of long-term biochemical recurrence-free survival was divided into four groups: excellent, good, moderate, and low. CONCLUSIONS: These simple to use and explain risk groups can be used to predict long-term biochemical recurrence-free survival from pathologic stage data obtained at surgery or predicted from the Partin tables, along with surgical margin status and Gleason score information obtained at RRP.

Adenocarcinoma↗