Report on Prostate Cancer Tumor Marker Workshop 1999.
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Antigens, Neoplasm↗
Biomedical subjects
A W Partin
Publications and source records attributed to A W Partin.
Quantitative nuclear grade (QNG): a new image analysis-based biomarker of clinically relevant nuclear structure alterations.
This review addresses the potential clinical value of using quantitative nuclear morphometry information derived from computer-assisted image analysis for cancer detection and predicting outcomes such as tumor stage, recurrence, and progression. Today's imaging technology uses sophisticated hardware platforms coupled with powerful and user-friendly software packages that are commercially available as complete image analysis systems. There are many different mathematically derived nuclear morphometric descriptors (NMD's) (i.e. texture features) that can be calculated by these image analysis systems, but for the most part, these NMD's quantify nuclear size, shape, DNA content (ploidy), and chromatin organization (i.e. texture, both Markovian and non-Markovian) parameters. We have utilized commercially available image analysis systems and the NMD's calculated by these systems to create a mathematical solution, termed quantitative nuclear grade (QNG), for making clinical, diagnostic, and prognostic outcome predictions in both prostate and bladder cancer. A separate computational model is calculated for each outcome of interest using well-characterized and robust training, testing, and validation patient sample sets that adequately represent the selected population and clinical dilemma. A specific QNG solution may be calculated either by non-parametric statistical methods or non-linear mathematics employed by artificial neural networks (ANNs). The QNG solution, a measure of genomic instability, provides a unique independent variable to be used alone or to be included in an algorithm to assess a specific clinical outcome. This approach of customization of the nuclear morphometric descriptor (NMD) information through the calculation of a QNG solution mathematically adjusts for redundancy of features and reduces the complexity of the inputs used to create decision support tools for patient disease management. J. Cell. Biochem. Suppl. 35:151-157, 2000.
Area Under Curve↗
Prediction of locoregional extension and metastatic disease in prostate cancer: a review.
Despite efforts to enhance the accuracy of prediction of extraprostatic disease, approximately 40% of the men undergoing radical prostatectomy are found at surgery to have non-organ-confined cancer. Predictive algorithms based on multivariate regression analysis and neural networks are widely available and are superior to our standard empirical methods of clinical staging. These algorithms have been validated in diverse and well-characterized patient groups. For enhancement of the predictive value, data input must be standardized and improved input variables must be incorporated. In addition to the three "classic" staging parameters, i.e., pretreatment prostate-specific antigen (PSA), biopsy pathology, and digital rectal examination, new variables now show promise in predicting disease extent and may be integrated in future predictive models. This review focuses on our present methods for prediction of locoregional spread and distant metastases in men with clinically localized prostate cancer.
Algorithms↗
Cancer cells engineered to secrete granulocyte-macrophage colony-stimulating factor using ex vivo gene transfer as vaccines for the treatment of genitourinary malignancies.
When irradiated and administered intradermally as vaccines, cancer cells engineered to secrete high levels of granulocyte-macrophage colony-stimulating factor (GM-CSF) by gene transfer elicit potent anticancer immune responses in a variety of animal tumor models. Upon vaccination, antigens present in the cancer cells are phagocytosed and processed by skin dendritic cells. These dendritic cells then prime anticancer immune responses by presenting antigenic peptides to T cells. The immune responses generated are capable of eradicating small but lethal cancer cell inocula with minimal toxicity in preclinical animal tumor studies. To develop this vaccination strategy for the treatment of human genitourinary cancers, we have conducted phase I clinical trials using human genitourinary cancer cells as sources of cancer cell antigens. In the first human clinical trial of genetically engineered cancer cell vaccines, a phase I clinical trial of kidney cancer cell vaccines (n = 18), kidney cancer cells were removed at surgery, propagated briefly in vitro, and then genetically modified to secrete high levels of GM-CSF via ex vivo transduction with the retrovirus MFG-GM-CSF. After irradiation, the kidney cancer cells were administered as vaccines to 18 patients with advanced kidney cancers. Vaccine treatment, which caused few side effects, nonetheless appeared to trigger anticancer immune responses manifest as conversion of delayed-type hypersensitivity (DTH) skin responses against irradiated autologous cancer cells after vaccination. Biopsies of vaccine sites yielded findings reminiscent of biopsies from preclinical animal model studies, with evidence of vaccine cell recruitment of dendritic cells, T cells, and eosinophils. One patient with measurable kidney cancer metastases treated at the highest vaccine dose level experienced a partial treatment response. The bioactivity of GM-CSF-secreting autologous cancer cell vaccines was confirmed in a phase I clinical trial for prostate cancer (n = 8). Vaccine cells were prepared from surgically harvested prostate tumors by ex vivo transduction with MFG-GM-CSF in a manner similar to that used for the kidney cancer trial. Vaccine treatment was well tolerated and associated with induction of anticancer immunity as assessed using DTH skin testing. In addition, new antiprostate cancer cell antibodies were detected in serum samples from treated men as a consequence of vaccination. These first clinical trials of GM-CSF-secreting cancer cell vaccines for the treatment of genitourinary cancers have demonstrated both safety and bioactivity, in that very few side effects have been seen and anticancer immune responses have been detected. Future clinical studies will be required to assess vaccine treatment efficacy, refine vaccination dose and schedule, define the appropriate clinical context for the use of such vaccines, and ascertain optimal combinations involving vaccines and other local or systemic anticancer treatments.
Adult↗
Does sextant prostate biopsy provide adequate sampling for early detection of prostate cancer?
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Biopsy↗
What does prostate-specific antigen recurrence mean?
The return of the prostate-specific antigen (PSA) to a detectable serum level (PSA recurrence) is usually the first sign of recurrent disease after radical prostatectomy. PSA recurrence generally occurs in men who are otherwise asymptomatic and may occur as late as 5 to 10 years after surgery. Men in this situation want to know what this means regarding the likelihood of clinical disease recurrence and, ultimately, survival. An evaluation for recurrent disease is warranted but generally does not reveal objective signs of clinical disease in the majority of men. Although select men may benefit from salvage local therapy, a PSA recurrence is most often an early sign of distant disease present since the time of surgery. The decision whether or not to initiate systemic therapy in these men is difficult and controversial. Fortunately, recent developments in determining the significance of a PSA recurrence may help the patient and his physician to make a more informed decision regarding treatment options.
Algorithms↗
The role of free prostate-specific antigen in prostate cancer detection.
Prostate-specific antigen (PSA) is the most important serum tumor marker for prostate cancer detection. Free PSA is one of the many molecular forms of PSA that have been identified. Percent free PSA improves the specificity (elimination of unnecessary biopsies) for prostate cancer detection in men with nonsuspicious digital prostate examination and total serum PSA ranges between 4 and 10 ng/mL. Further study is necessary to determine the optimal clinical utility of percent free PSA in men with a total serum PSA level of less than 4 ng/mL. In addition, the level of free PSA may be affected by many factors, including age, prostate volume, prostate manipulation, sample handling, and type of assay used.
Age Factors↗
Probability of prostate cancer detection based on results of a multicenter study using the AxSYM free PSA and total PSA assays.
OBJECTIVES: The determination of the percentage of free prostate-specific antigen (%fPSA) enhances the specificity of prostate cancer (CaP) detection. This study was undertaken to assess the performance of %fPSA in differentiating benign prostate disease from CaP and to determine the CaP probability estimates using the AxSYM Free PSA and AxSYM Total PSA assays. METHODS: In this prospective study, 297 men, 50 years old or older, with a total PSA level between 4 and 10 ng/mL and a nonsuspicious digital rectal examination were enrolled at 10 clinical sites. All subjects underwent at least sextant prostate biopsies to establish the diagnosis. fPSA and total PSA (tPSA) levels were determined using the AxSYM Free PSA and AxSYM Total PSA assays. Percent fPSA values were compared with tPSA values to determine the appropriate cutoffs for prostate biopsy and to calculate the CaP probability estimates. RESULTS: The strongest predictor of CaP in a logistic regression model was %fPSA (odds ratio 2.29), which contributed significantly more than age or tPSA to the predictive model. In this study population, a %fPSA cutoff of 26.4% would have detected 96% of subjects with CaP (sensitivity) and would have eliminated 27.4% of unnecessary biopsies (specificity). CaP probability estimates ranged from 9% to 69% and increased as the %fPSA value decreased. Men with a %fPSA level of 10% or lower had a 69% probability of CaP, and men with a %fPSA level of greater than 26% had a 9% probability of CaP. CONCLUSIONS: Percent fPSA values can help differentiate CaP from benign prostate disease and reduce unnecessary biopsies in 27% of men 50 years old or older whose digital rectal examination was normal and whose tPSA level was between 4 and 10 ng/mL. A %fPSA result can assist the physician and patient in determining the probability of CaP and assessing the need for prostate biopsy.
Biopsy↗
Transurethral radiofrequency therapy for benign prostatic hyperplasia using a novel saline-liquid conductor: the virtual electrode.
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Catheter Ablation↗
Percentage of free PSA in black versus white men for detection and staging of prostate cancer: a prospective multicenter clinical trial.
OBJECTIVES: In predominately white populations, measurement of the percentage of free prostate-specific antigen (%fPSA) has been shown to enhance the specificity of total PSA testing for prostate cancer while maintaining high sensitivity and to aid in prostate cancer staging. This study evaluated whether the %fPSA cutoff that maintained a 95% sensitivity in a white population yielded the same sensitivity and specificity in a black population and whether %fPSA was useful in predicting postoperative pathologic features in blacks. METHODS: We evaluated 647 white and 79 black men, prospectively enrolled at prostate cancer screening and surgical referral centers. Subjects were 50 to 75 years old with digital rectal examination findings that were not suspicious for prostate cancer and total PSA values between 4.0 and 10.0 ng/mL. All had undergone needle biopsy of the prostate. Hybritech's Tandem total and free PSA assays were used. RESULTS: Ninety-five percent sensitivity was attained with a %fPSA cutoff of 25% in both races. Use of this cutoff could have avoided unnecessary biopsies in 20% of white and 17% of black subjects (P = 0.69). In receiver operating characteristic (ROC) curve analysis, the area under the curve (AUC) for %fPSA was significantly higher than for total PSA in both blacks (0.76 versus 0.56, P <0.01) and whites (0.70 versus 0.54, P <0.001). In both races, higher %fPSA values indicated a lower risk of cancer and also predicted favorable pathologic features in radical prostatectomy specimens. CONCLUSIONS: A 25% fPSA cutoff detected 95% of cancers and reduced unnecessary biopsies in both races. Higher %fPSA values were associated with favorable postoperative histopathologic findings in both races.
Aged↗
Needle biopsy of recurrent adenocarcinoma of the prostate after radical prostatectomy.
The objective of this study was to evaluate needle biopsy of recurrent prostate cancer after radical prostatectomy. We evaluated 37 cases of recurrent prostate cancer after radical prostatectomy that were diagnosed by needle biopsy between March 1984 and July 1998. Fifteen were from consultations in which contributors were uncertain of the diagnosis, and 22 were from men who had come to The Johns Hopkins Hospital for treatment. The median interval from radical prostatectomy to biopsy showing recurrent tumor was 40 months. There was no correlation between the interval to recurrence and either pathologic features of the biopsy and radical prostatectomy or various clinical features. The mean extent of adenocarcinoma in the biopsies was 3.2 mm (range, 0.1 to 18 mm; median, 2 mm). The length of recurrent cancer on biopsy correlated with an abnormal rectal examination (P = .001). The mean Gleason score for the recurrent tumors was 6.5, which correlated with the grade of the radical prostatectomy cancer (P = .005). The cancers often lacked overt histologic features of malignancy. Benign prostatic acini were seen in five cases (14%), usually separate from the cancer. In 5 (33%) of the consultation cases, we would not have been able to diagnose cancer if not for the fact that atypical prostate glands should not be present after radical prostatectomy. In well-sampled radical prostatectomies, margins were almost always positive, as was extraprostatic extension. In cases with less sampling, there was a higher incidence of organ-confined disease and margin-negative disease implying suboptimal processing of the radical prostatectomy. After radical prostatectomy, recurrent cancer on needle biopsies may be focal and difficult to diagnose and must be assessed differently than in patients who have not had surgery.
Adenocarcinoma↗
The prognostic significance of tertiary Gleason patterns of higher grade in radical prostatectomy specimens: a proposal to modify the Gleason grading system.
The Gleason grading system of prostatic adenocarcinoma does not account for the existence of a tertiary (third most prevalent) pattern, and there are no studies concerning the latter's prognostic influence. The authors analyzed 114 radical prostatectomies with small tertiary components, which mostly occupied less than 5% of whole tumors. These specimens were compared with a prostatectomy database comprised of 2,276 cases without a tertiary component. The pathologic stages of "typical" Gleason score 5 to 6 tumors (Gleason scores 2 + 3 = 5, 3 + 2 = 5, 3 + 3 = 6), which contained tertiary patterns 4 or 5, were significantly higher than those of "typical" Gleason score 5 to 6 tumors without pattern 4 (p = 0.018) but lower than those of "typical" Gleason score 7 tumors (p = 0.021; Gleason scores, 3 + 4 = 7, 4 + 3 = 7). Typical Gleason score 7 tumors with a tertiary pattern 5 showed significantly worse pathologic stages than typical Gleason score 7 tumors (p = 0.008) without pattern 5 and were not different statistically from typical Gleason score 8 (Gleason score, 4 + 4 = 8) tumors. Both typical Gleason score 5 to 6 and 7 tumors with tertiary components revealed significantly higher progression rates than typical Gleason score 5 to 6 tumors (p <0.0001) and Gleason score 7 tumors (p = 0.003) without tertiary components, and progressed like typical Gleason score 7 and 8 tumors respectively. Tertiary high-grade components have an adverse impact on biologic behavior. The authors propose that the Gleason system for radical prostatectomy specimens be modified to take into account small volumes of patterns 4 and 5, which are important prognostically.
Adenocarcinoma↗
Diagnosis of localized prostate cancer: 10 years of progress.
Advances in the diagnosis of early stage disease, and particularly the introduction of prostate-specific antigen (PSA) testing, have had a dramatic effect on the presentation and clinical management of prostate cancer during the past ten years. As a result, there have been significant epidemiological changes in countries where early diagnosis is recommended. The importance of PSA testing for the diagnosis of localized prostate cancer has become well established in clinical practice and this is reflected by improved outcomes from definitive treatment. The contribution of PSA-related parameters and molecular forms of PSA both to cancer detection and prediction of pathological stage continue to be explored. Concerns about the reliability of the standard sextant biopsy technique for cancer detection relate to the need for re-biopsy in a growing number of patients with negative biopsies and an increasing proportion of patients with low volume, multifocal disease. In men with cancer, additional prognostic information can be derived from biopsy findings, with important therapeutic implications. This relates also to the need for reliable markers indicating pathological stage and risk of progression. The opportunities for the prevention of prostate cancer have grown with improved understanding of its biology and the genetic basis of the early steps associated with malignant transformation. In the future, the need for therapeutic intervention is likely to be most influenced by successful prevention strategies.
Biopsy↗
In vivo measurement of tumor conductiveness with the magnetic bioimpedance method.
A noninvasive electromagnetic method has been developed that can effectively measure the in-vivo conductivity difference between rat tumor lines having a low and high metastatic potential. These tumor lines are used in the study of human prostate tumor.
Animals↗
Minilaparotomy radical retropubic prostatectomy: updated technique and results.
The purpose of this article is to reduce the incisional morbidity associated with standard radical retropubic prostatectomy using the minilaparotomy incision developed for pelvic lymph-node dissection, which was applied to radical retropubic prostatectomy. More than 522 patients underwent minilaparotomy radical retropubic prostatectomy from 1991 to 1997. Preoperative evaluation included history, physical examination, prostate-specific antigen (PSA), and Gleason's grade. Postoperative follow-up included serial PSA measurements and a determination of continence. The surgical technique is described in detail. Two hundred sixty-five patients responded to the mailed questionnaire out of a total 522 patients. Satisfactory continence, defined as 0 to 1 pad per day, was achieved in 85% of patients, and 83% of patients had a PSA < 0.2 at an average follow-up of 2.6 years. There was no operative mortality, and overall complication rate was similar to other surgeons. The typical patient was discharged home 3 days postoperatively. Minilaparotomy radical retropubic prostatectomy compares favorably with standard radical retropubic prostatectomy.
Humans↗
Effects of a saw palmetto herbal blend in men with symptomatic benign prostatic hyperplasia.
PURPOSE: We tested the effects of a saw palmetto herbal blend in men with symptomatic benign prostatic hyperplasia (BPH) via a randomized, placebo controlled trial. MATERIALS AND METHODS: We randomized 44 men 45 to 80 years old with symptomatic BPH into a trial of a saw palmetto herbal blend versus placebo. End points included routine clinical measures (symptom score, uroflowmetry and post-void residual urine volume), blood chemistry studies (prostate specific antigen, sex hormones and multiphasic analysis), prostate volumetrics by magnetic resonance imaging, and prostate biopsy for zonal tissue morphometry and semiquantitative histology studies. RESULTS: Saw palmetto herbal blend and placebo groups had improved clinical parameters with a slight advantage in the saw palmetto group (not statistically significant). Neither prostate specific antigen nor prostate volume changed from baseline. Prostate epithelial contraction was noted, especially in the transition zone, where percent epithelium decreased from 17.8% at baseline to 10.7% after 6 months of saw palmetto herbal blend (p <0.01). Histological studies showed that the percent of atrophic glands increased from 25. 2% to 40.9% after treatment with saw palmetto herbal blend (p <0.01). The mechanism of action appeared to be nonhormonal but it was not identified by tissue studies of apoptosis, cellular proliferation, angiogenesis, growth factors or androgen receptor expression. We noted no adverse effects of saw palmetto herbal blend. When the study was no longer blinded, 41 men elected to continue therapy in an open label extension. CONCLUSIONS: Saw palmetto herbal blend appears to be a safe, highly desirable option for men with moderately symptomatic BPH. The secondary outcome measures of clinical effect in our study were only slightly better for saw palmetto herbal blend than placebo (not statistically significant). However, saw palmetto herbal blend therapy was associated with epithelial contraction, especially in the transition zone (p <0.01), indicating a possible mechanism of action underlying the clinical significance detected in other studies.
Aged↗
Complexed prostate specific antigen provides significant enhancement of specificity compared with total prostate specific antigen for detecting prostate cancer.
PURPOSE: Determining serum total prostate specific antigen (PSA) has proved to be a valuable diagnostic aid for detecting prostatic carcinoma, although the lack of specificity has limited its usefulness. Studies indicate that the use of percent free PSA would improve specificity while maintaining sensitivity. Since complexed PSA represents the major proportion of measurable PSA in serum, we determined whether it represents a single test alternative to the use of percent free PSA for the early detection of prostate cancer. MATERIALS AND METHODS: Archival serum was obtained from 385 men with no evidence of malignancy on biopsy and 272 with biopsy confirmed prostate cancer. We determined the concentration and proportion of total, complexed and free PSA. RESULTS: Receiver operating characteristics analysis using total PSA results from all samples (range 0.32 to 117 ng./ml.) indicated that the areas under the curve for complexed PSA alone as well as the free-to-total and complexed-to-total PSA ratios were similar and significantly greater than those for total PSA alone. Within the range of 85% to 95% sensitivity receiver operating characteristics analysis revealed that the specificity of complexed PSA was higher than that of total PSA and equivalent to that of the free-to-total PSA ratio. We noted a similar improvement in specificity in the 4 to 10 ng./ml. total PSA range. Using published cutoff values for complexed, total and percent free PSA when total PSA was in the 4 to 10 ng./ml. range the sensitivity and specificity of complexed and percent free PSA were similar. Within the 4 to 10 ng./ml. total PSA range the population of patients with no evidence of malignancy and complexed PSA below the upper limit was different with respect to total PSA from that with no evidence of malignancy and free PSA greater than 25%. CONCLUSIONS: The measurement of complexed PSA represents an alternative to the use of percent free PSA, although the patient populations identified by the 2 tests are different.
Humans↗
Correlation of serum prostate specific antigen and quantitative immunohistochemistry.
PURPOSE: Serum prostate specific antigen (PSA) in patients with prostate carcinoma is influenced by prostate size, transition zone volume, and tumor differentiation and volume. Immunohistochemistry studies have demonstrated an inverse correlation between PSA staining intensity and tumor grade, yet to our knowledge tissue expression of PSA has never been correlated with serum PSA. MATERIALS AND METHODS: In 47 radical prostatectomy cases serum PSA was corrected for gland size and tumor volume. Standard immunohistochemistry staining techniques were applied to specimens using monoclonal antibodies to PSA and cytokeratin CAM5.2. Color images of PSA and CAM5.2 immunohistochemistry stained slides were digitally acquired and analyzed using a standard image analysis system. Representative tumor foci in each slide were imaged with a 20x objective and 10x eyepiece. Staining extent and intensity of the tumor epithelium were measured, and stromal elements and luminal areas were excluded from analysis. For each case quantitative PSA staining intensity was expressed relative to keratin staining in adjacent benign epithelium. RESULTS: Gland volume and tumor volume independently correlated with serum PSA. Furthermore, tissue PSA intensity inversely correlated with histological grade of the tumor (p <0.00001). After gland size, tumor volume and grade were considered, corrected quantitative tissue PSA intensity did not significantly correlate with corrected serum PSA. CONCLUSIONS: Immunohistochemistry expression of tissue PSA in prostate carcinoma cannot be used to explain variations in serum PSA. This discrepancy may relate to differences between the amount of PSA produced by prostatic tumors and the amount secreted, and/or the sensitivity of detecting various tissue isoforms of PSA with immunohistochemistry.
Adenocarcinoma↗