Michelle Ferrari

Genomic Profiling Reveals Alternative Genetic Pathways of Prostate Tumorigenesis

Prostate cancer is clinically heterogeneous, ranging from indolent to lethal disease. Expression profiling previously defined three subtypes of prostate cancer, one (subtype-1) linked to clinically favorable behavior, and the others (subtypes-2 and -3) linked with a more aggressive form of the disease. To explore disease heterogeneity at the genomic level, we carried out array-based comparative genomic hybridization (array CGH) on 64 prostate tumor specimens, including 55 primary tumors and 9 pelvic lymph node metastases. Unsupervised cluster analysis of DNA copy number alterations (CNA) identified recurrent aberrations, including a 6q15-deletion group associated with subtype-1 gene expression patterns and decreased tumor recurrence. Supervised analysis further disclosed distinct patterns of CNA among gene-expression subtypes, where subtype-1 tumors exhibited characteristic deletions at 5q21 and 6q15, and subtype-2 cases harbored deletions at 8p21 (NKX3-1) and 21q22 (resulting in TMPRSS2-ERG fusion). Lymph node metastases, predominantly subtype-3, displayed overall higher frequencies of CNA, and in particular gains at 8q24 (MYC) and 16p13, and loss at 10q23 (PTEN) and 16q23. Our findings reveal that prostate cancers develop via a limited number of alternative preferred genetic pathways. The resultant molecular genetic subtypes provide a new framework for investigating prostate cancer biology and explain in part the clinical heterogeneity of the disease.

Prostate specific antigen in the diagnosis and treatment of adenocarcinoma of the prostate. IV. Anti-androgen treated patients.

Serum prostate specific antigen was determined (Yang polyclonal radioimmunoassay) in 45 patients after anti-androgen therapy for stage D2, untreated adenocarcinoma of the prostate. Of the patients 9 per cent had undetectable prostate specific antigen levels and 22 per cent were within the normal range (0.0 to 2.5 ng. per ml.), with a mean interval of 2 years since introduction of therapy. Multiple prostate specific antigen values following anti-androgen therapy were available in 36 of 45 patients. The majority of the patients demonstrated an initial, often dramatic decrease in prostate specific antigen levels during the first 6 months after introduction of therapy. After 6 months 21 of 29 patients (72 per cent) had increasing prostate specific antigen levels. Data suggest that serum prostate specific antigen determination 6 months after introduction of therapy is capable of distinguishing patients with a favorable and persisting response to anti-androgen therapy from those in whom a limited response can be expected.

THE MALE BULBOURETHRAL SLING PROCEDURE FOR POST-RADICAL PROSTATECTOMY INCONTINENCE

PURPOSE We evaluate the efficacy of the male bulbourethral sling procedure in the treatment of post-radical prostatectomy urinary incontinence. MATERIALS AND METHODS We reviewed the records of 64 consecutive men with severe post-prostatectomy incontinence who underwent the male bulbourethral sling procedure at Northwestern Memorial Hospital and Stanford University Hospital. Preoperatively 50% of the patients were completely incontinent (diapers, clamps or condom catheter), and the remainder required a mean of 4.7 pads per day. Data were collected by chart review, patient interviews at followup appointments and telephone interviews. Median followup was 18.1 months (mean 22.4, range 6.5 to 53.8). RESULTS Following a single sling procedure 36 patients (56%) became dry, and 5 (8%) were significantly improved. In 17 patients 23 retightening procedures were performed, which decreased the median followup to 16 months and increased the success rate to 75% (67% cured, 8% improved). The revision, erosion and infection rates were 27, 6 and 3%, respectively. CONCLUSIONS The male bulbourethral sling procedure is effective treatment for post-radical prostatectomy urinary incontinence. Patients who had received adjuvant radiation therapy demonstrated a lower continence rate than those who had not. Further followup is needed to assess long-term efficacy.

Prostate Specific Antigen in the Diagnosis and Treatment of Adenocarcinoma of the Prostate. II. Radiation Treated Patients

Serum prostate specific antigen was determined (Yang polyclonal radioimmunoassay) in 183 men after radiation therapy for adenocarcinoma of the prostate. A total of 163 men had received 7,000 rad external beam radiotherapy and 20 had been implanted with 125iodine seeds. Only 11 per cent of these 183 patients had undetectable prostate specific antigen levels at a mean interval of 5 years since completion of radiotherapy. Prostate specific antigen levels after radiotherapy were directly related to initial clinical stage and Gleason score before treatment. Multiple prostate specific antigen determinations were performed with time in 124 of 183 patients. During year 1 after radiotherapy prostate specific antigen levels were decreasing in 82 per cent of the patients but only 8 per cent continued to decrease beyond year 1. Of 80 patients observed greater than 1 year after completion of radiotherapy 51 per cent had increasing values and 41 per cent had stable values. Increasing prostate specific antigen values after radiotherapy were correlated with progression to metastastic disease and residual cancer on prostate biopsy. Total serum acid phosphatase levels were poorly related to prostate specific antigen levels, were less effective in discriminating patients with metastatic disease and provided no additional information beyond that provided by prostate specific antigen.

Early detection of residual prostate cancer after radical prostatectomy by an ultrasensitive assay for prostate specific antigen.

We evaluated the usefulness of an ultrasensitive immunoassay for prostate specific antigen (PSA), modified from the standard Yang Pros-Check PSA test and with a biological detection limit for PSA in serum of 0.07 ng./ml., to detect residual prostate cancer at an earlier date. We studied retrospectively serial frozen serum samples from 22 prostate cancer patients after radical prostatectomy who later had residual cancer with detectable PSA levels of 0.3 ng./ml. or more by the standard PSA test. As controls we studied 33 cystoprostatectomy patients (for bladder cancer) without histological evidence of prostate cancer and 23 patients after radical prostatectomy who had the highest probability of cure of the cancer. All control patients without cancer had PSA values (282 of 283 samples, 99.6%) of less than 0.1 ng./ml. This value was called the residual cancer detection limit. In the 22 patients with recurrent cancer the ultrasensitive assay detected cancer recurrence (PSA 0.1 ng./ml. or more) much earlier (median 202 and mean 310 days) than the standard assay (PSA 0.3 ng./ml. or more). On screening 187 current post-radical prostatectomy patients without evidence of cancer by the standard assay the ultrasensitive assay detected 21 (11.2%) with evidence of residual cancer, that is PSA level of 0.1 ng./ml. or more. We conclude that an ultrasensitive assay for PSA can detect residual cancer after radical prostatectomy much earlier than current immunoassays for PSA. Earlier detection of residual cancer may improve long-term survival by allowing for earlier institution of adjuvant therapy.

The case of Jeffrey Dahmer: sexual serial homicide from a neuropsychiatric developmental perspective.

Sexual serial homicidal behavior has received considerable attention during the last three decades. Substantial progress has been made in the development of methods aimed at identifying and apprehending individuals who exhibit these behaviors. In spite of these advances, the origins of sexual serial killing behavior remain for the most part unknown. In this article we propose a biopsychosocial psychiatric model for understanding the origins of sexual serial homicidal behavior from both neuropsychiatric and developmental perspectives, using the case of convicted serial killer Jeffrey Dahmer as the focal point. We propose that his homicidal behavior was intrinsically associated with autistic spectrum psychopathology, specifically Aspergers disorder. The relationship of Aspergers disorder to other psychopathology and to his homicidal behavior is explored. We discuss potential implications of the proposed model for the future study of the causes of sexual serial homicidal crime.

Prognostic significance of prostate cancer originating from the transition zone

PURPOSE Transition zone (TZ) cancers are reported to have better biochemical relapse-free survival (bRFS) after radical prostatectomy (RP) than cancers from the peripheral zone (PZ). To understand the influence of tumor location, we compared bRFS for TZ and PZ cancers stratified for risk using known clinical and pathological prognostic factors. PATIENTS AND METHODS The surgical pathology and outcomes of 494 patients were reviewed. Cancers originating from the TZ and PZ were identified from step sectioning of surgical specimens and tumor mapping. Univariate and multivariate analyses of bRFS after RP were compared. RESULTS TZ cancers were present in 89 (18%) patients. On univariate analysis, most factors predicted bRFS, although cancer location did not: 5-year bRFS was 85% for TZ vs. 77% for PZ (P = 0.12). However, on multivariate analysis, all factors except SV involvement were significant, including TZ cancer location (P = 0.04, HR = 1.88 [1.02-3.47]). Interestingly, TZ location was correlated with improved 5-year bRFS for cancers > 2 cc (81% for TZ vs. 65% for PZ, P = 0.017), for preop PSA >10 (80% for TZ vs. 59% for PZ, P = 0.027), and for PSAV > 2 (85% for TZ vs. 66% for PZ, P = 0.08). However, TZ cancers showed no difference in outcome for small volumes, low preop PSA, low PSAV, or high Gleason grade. CONCLUSIONS TZ cancers that are large, with high preop PSA, low Gleason scores, and high PSAV show better outcomes than their PZ counterparts. However, high-grade cancer tumor location had no apparent influence on outcome. Tumor location could be considered in subsets for optimal prognostication.

A Tri-Marker Proliferation Index Predicts Biochemical Recurrence after Surgery for Prostate Cancer

Prostate cancer exhibits tremendous variability in clinical behavior, ranging from indolent to lethal disease. Better prognostic markers are needed to stratify patients for appropriately aggressive therapy. By expression profiling, we can identify a proliferation signature variably expressed in prostate cancers. Here, we asked whether one or more tissue biomarkers might capture that information, and provide prognostic utility. We assayed three proliferation signature genes: MKI67 (Ki-67; also a classic proliferation biomarker), TOP2A (DNA topoisomerase II, alpha), and E2F1 (E2F transcription factor 1). Immunohistochemical staining was evaluable on 139 radical prostatectomy cases (in tissue microarray format), with a median clinical follow-up of eight years. Each of the three proliferation markers was by itself prognostic. Notably, combining the three markers together as a “proliferation index” (0 or 1, vs. 2 or 3 positive markers) provided superior prognostic performance (hazard ratio = 2.6 (95% CI: 1.4–4.9); P = 0.001). In a multivariate analysis that included preoperative serum prostate specific antigen (PSA) levels, Gleason grade and pathologic tumor stage, the composite proliferation index remained a significant predictor (P = 0.005). Analysis of receiver-operating characteristic (ROC) curves confirmed the improved prognostication afforded by incorporating the proliferation index (compared to the clinicopathologic data alone). Our findings highlight the potential value of a multi-gene signature-based diagnostic, and define a tri-marker proliferation index with possible utility for improved prognostication and treatment stratification in prostate cancer.

Comparison of prostate cancer tumor volume and percent cancer in prediction of biochemical recurrence and cancer specific survival

OBJECTIVES Tumor volume and percent cancer (ratio of tumor volume/prostate volume) have been proposed as predictors of biochemical recurrence and cancer specific survival after radical prostatectomy. However, their relative merits as prognosticators have not been tested. We therefore evaluated and compared tumor volume and percent cancer as independent predictors of biochemical recurrence and prostate cancer specific death after radical prostatectomy. METHODS AND MATERIALS A retrospective review of 739 patients who underwent radical prostatectomy for prostate cancer between 1984 and 2004 was conducted. Median follow-up was 91.7 months, and 22 patients died of prostate cancer. Univariate and multivariate analysis evaluated the following factors in predicting biochemical recurrence and prostate cancer specific death: tumor volume, prostate volume, percent cancer, Gleason score, percentage of Gleason grade 4/5, margin status, capsular invasion status, seminal vesicle invasion status, preoperative PSA, and lymph node status. RESULTS In univariate analysis, both tumor volume (P<0.001) and percent cancer (P<0.001) significantly correlated with biochemical recurrence. Since they are highly correlated, they did not predict outcome independently when included in the same model; however, both were highly predictive for biochemical recurrence in separate multivariate models (P=0.01 for both). Both also correlated with cancer specific survival as single variables; however, in separate multivariate models, only tumor volume (P=0.03) predicted death, while percent cancer did not (P=0.09). CONCLUSIONS Tumor volume and percent cancer are independent predictors of recurrence after radical prostatectomy. However, in our series, tumor volume predicted cancer specific death better than percent cancer. Therefore, accurate determination of tumor volume, along with other accepted pathologic indices, is sufficient and preferred over percent cancer for prognostication after radical prostatectomy.

Higher rates of upgrading and upstaging in older patients undergoing radical prostatectomy and qualifying for active surveillance

To determine pathological and oncological outcomes of patients diagnosed with low‐risk prostate cancer in two age cohorts who underwent radical prostatectomy (RP) and qualified for active surveillance (AS) according to Prostate Cancer Research International: Active Surveillance (PRIAS) criteria, as AS for low‐risk prostate cancer represents an acceptable management strategy especially for older patients.