Carboxypeptidase 4 gene variants and early-onset intermediate-to-high risk prostate cancer.

BACKGROUND: Carboxypeptidase 4 (CPA4) is a zinc-dependent metallocarboxypeptidase on chromosome 7q32 in a region linked to prostate cancer aggressiveness. CPA4 is involved in the histone hyperacetylation pathway and may modulate the function of peptides that affect the growth and regulation of prostate epithelial cells. We examined the association between genetic variation in CPA4 and intermediate-to-high risk prostate cancer. METHODS: We studied 1012 men (506 cases and 506 controls) from Cleveland, Ohio. All cases had Gleason > or = 7, clinical stage > or = T2c, or PSA > or = 10 ng/mL at diagnosis. Six CPA4 single-nucleotide polymorphisms were genotyped, and evaluated for their relation to prostate cancer. We also evaluated whether CPA4 variants influence risk of disease among men diagnosed at an earlier age (< 66 years). RESULTS: The nonsynonymous coding SNP (rs2171492, Cys303Gly) in CPA4 was associated with an increased risk of aggressive prostate cancer among younger patients (< 66 years). Specifically, men carrying the TT genotype had an approximately two-fold increased risk for being diagnosed with intermediate-to-high risk disease (Odds Ratio = 1.83, p = 0.04). In the overall population (all ages) none of the CPA4 SNPs demonstrated a statistically significant association with prostate cancer. CONCLUSION: Coding variation in CPA4 may confer increased risk of intermediate-to-high risk prostate cancer among younger patients. Further work is needed to identify the functional aspects of this variation and understand its biological effects on prostate cancer. Such work may translate into more precise screening of higher risk individuals as well as guiding clinicians and patients toward earlier and more definitive treatment modalities in patients genetically identified as higher risk.

The relationship between anxiety and time to treatment for patients with prostate cancer on surveillance.

PURPOSE: Little is known about psychosocial factors affecting the decision to move from surveillance to active treatment in men with localized prostate cancer. We examined the impact of cancer anxiety on the decision to move from surveillance to treatment. MATERIALS AND METHODS: We analyzed data from CaPSURE, a national observational prostate cancer registry. A total of 105 participants had localized disease, selected surveillance vs treatment and had at least 3 prostate specific antigen values available after baseline. Cancer anxiety was measured with a 3-item scale (alpha = 0.78). We calculated the rate of change in prostate specific antigen with time (prostate specific antigen velocity) and used the same formula to calculate the rate of change in cancer anxiety. We fit a Cox regression model to determine predictors of receiving treatment in the 3-year observation period, controlling for prostate specific antigen velocity, demographics and baseline clinical characteristics. RESULTS: Prostate specific antigen velocity and the cancer anxiety change rate were significant independent predictors of treatment receipt (HR 1.02, 95% CI 1.004, 1.035, each p <0.01). Men with higher prostate specific antigen velocity (1.51 ng/ml per year or greater) were significantly more likely to receive treatment than men with lower prostate specific antigen velocity (HR 3.18, 95% CI 1.122, 9.016). The 2 velocity measures correlated only modestly (r = 0.29, p <0.001). CONCLUSIONS: Rather than being based only on clinical presentation and disease progression, decisions about treatment receipt for some men are influenced by cancer related anxiety. Men should be provided with more psychosocial support to perhaps delay treatment and the ensuing decrements in health related quality of life.

Resident involvement in open radical prostatectomy: a review of urology surgical training.

PURPOSE: The Royal College of Physicians and Surgeons of Canada (RCPSC) and The American Accreditation Council for Graduate Medical Education (ACGME) general objectives mandate that all residents be competent to independently perform select surgical procedures. Unfortunately, no objective standardized measures presently exist for surgical training assessment. Operative logs have been implemented to quantify the number of cases the resident has been exposed to, however, these do not assess their degree of involvement or aptitude. An analysis of what exactly a resident performs, and how well, per case may assist in measuring their training progress. Herein, we evaluate a questionnaire to quantify the level of resident participation in radical retropubic prostatectomy (RRP) and assess whether resident perception of how much involvement in a case correlates with staff surgeons. METHODS AND MATERIALS: Identical, self-administered questionnaires were distributed simultaneously to the resident and staff urologist upon completion of radical prostatectomy. The questionnaire comprised of 14 items, which were completed independently by the resident and the staff urologist. The items assessed which of the 14 specific surgical steps were actually performed by the resident. An analysis was performed to assess the level of agreement. RESULTS: Among all cases performed between June 2002 and July 2003, 64 RRPs performed by two surgeons had completed questionnaires by both resident and staff. Twenty-one (32.8%) cases were performed with a senior resident (R4) and 43 (67.2%) cases were performed with a chief resident (R5). Twenty (31.3%) cases involved pelvic lymph node dissection. Resident performance of key surgical steps, namely dorsal venous ligation, urethral division, lateral pedicle dissection and urethrovesical anastamosis was 59.4%, 62.5%, 84% and 59.4% respectively. Global level of agreement between staff and resident responses was 94.9% (71.4%-100%). CONCLUSION: Our results suggest that there exists good agreement between resident perception of their level of involvement in RRP and staff validation. As such, a residents' assessment of their participation is likely to be accurate. Designation of performance of key operative steps into logs may be more relevant than recording simple exposure to index cases. Attempts at measuring quality of key operative steps in the future may be beneficial.

Time-resolved mass spectrometry of tyrosine phosphorylation sites in the epidermal growth factor receptor signaling network reveals dynamic modules.

Ligand binding to cell surface receptors initiates a cascade of signaling events regulated by dynamic phosphorylation events on a multitude of pathway proteins. Quantitative features, including intensity, timing, and duration of phosphorylation of particular residues, may play a role in determining cellular response, but experimental data required for analysis of these features have not previously been available. To understand the dynamic operation of signaling cascades, we have developed a method enabling the simultaneous quantification of tyrosine phosphorylation of specific residues on dozens of key proteins in a time-resolved manner, downstream of epidermal growth factor receptor (EGFR) activation. Tryptic peptides from four different EGFR stimulation time points were labeled with four isoforms of the iTRAQ reagent to enable downstream quantification. After mixing of the labeled samples, tyrosine-phosphorylated peptides were immunoprecipitated with an anti-phosphotyrosine antibody and further enriched by IMAC before LC/MS/MS analysis. Database searching and manual confirmation of peptide phosphorylation site assignments led to the identification of 78 tyrosine phosphorylation sites on 58 proteins from a single analysis. Replicate analyses of a separate biological sample provided both validation of this first data set and identification of 26 additional tyrosine phosphorylation sites and 18 additional proteins. iTRAQ fragment ion ratios provided time course phosphorylation profiles for each site. The data set of quantitative temporal phosphorylation profiles was further characterized by self-organizing maps, which resulted in identification of several cohorts of tyrosine residues exhibiting self-similar temporal phosphorylation profiles, operationally defining dynamic modules in the EGFR signaling network consistent with particular cellular processes. The presence of novel proteins and associated tyrosine phosphorylation sites within these modules indicates additional components of this network and potentially localizes the topological action of these proteins. Additional analysis and modeling of the data generated in this study are likely to yield more sophisticated models of receptor tyrosine kinase-initiated signal transduction, trafficking, and regulation.

Variations in PSA doubling time in patients with prostate cancer on "watchful waiting": value of short-term PSADT determinations.

OBJECTIVES: In watchful waiting patients with localized prostate cancer, the prostate-specific antigen doubling time (PSADT) has been suggested to correlate with disease progression and is often used to determine the need for therapy. In these studies, all available prostate-specific antigen data throughout the observation period were used to determine the PSADT. However, the correlation between the short-term and long-term assessments of PSADT in this population is unknown. Our aim was to determine the correlation between short-term PSADT measurements and long-term PSADT among men with prostate cancer on observation. METHODS: In a prospective cohort of 108 watchful waiting patients, the correlation of the overall PSADT with the PSADT measured during short-term intervals was analyzed. The level of agreement in classifying patients as having a rapid PSADT (24 months or less) was also evaluated. RESULTS: The median interval of observation was 36 months. According to the various methods used, the median PSADT was 82 months using all prostate-specific antigen values, 128 months using the first three values (early), 78 months using the last three values (late), and 144 months using the first and last values only (2-point). The PSADT measured over short-term intervals demonstrated a weak correlation with the overall PSADT (Spearman's rho 0.53 for early, 0.56 for late, and 0.50 for 2-point PSADT). A statistically significant agreement was noted in the classification of rapid PSADT between the overall PSADT measurement and early PSADT measurement (kappa 0.67). Less agreement was found in the classification, however, with the late and 2-point PSADT and the overall PSADT. CONCLUSIONS: In untreated patients with localized prostate cancer, the PSADT varies considerably depending on the interval evaluated.

Paper standard gamble: a paper-based measure of standard gamble utility for current health.

OBJECTIVES: To develop and validate a paper-based instrument that is simple to administer and produces a reliable estimate of patient standard gamble (SG) utilities for current health status. METHODS: A 1-page paper questionnaire instrument, paper standard gamble (PSG), was designed to estimate SG utilities. We performed two studies to assess the validity of PSG. First we compared PSG and SG utilities for current health in patients with prostate cancer. They randomly received either PSG followed by SG or vice versa, always with an intervening SF-12. In the second validity study, we assessed the test-retest reliability of PSG by administering it to prostate cancer patients twice, at least 2 weeks apart. RESULTS: In the first study, utilities were assessed in 64 men (32 per SG/PSG order group). A paired-comparison t test suggested no difference between SG and PSG (mean difference = -0.007; 95% confidence interval (Cl), -0.022 to 0.008). The concordance correlation coefficient was 0.92 (95% Cl, 0.79 to 0.99). In the second study, test and retest PSGs were available for 184 patients. The concordance correlation coefficient was 0.88 (95% Cl, 0.73 to 0.94). CONCLUSIONS: These data suggest that PSG may serve as a reliable substitute for SG when current health utility is of interest. PSG may have particular advantages for acquisition of health-related quality-of-life data in longitudinal studies.

Comparisons of nomograms and urologists' predictions in prostate cancer.

When applying nomograms to a clinical setting it is essential to know how their predictions compare with clinicians'. Comparisons exist outside of the prostate cancer literature. We reviewed these comparisons and conducted 2 experiments comparing predictions of clinicians with prostate cancer nomograms. By using Medline, we searched studies from January 1966 to July 1999 that compared human predictions with nomogram predictions. Next, we conducted 2 experiments: (1) 17 urologists were presented with 10 case vignettes and asked to predict the 5-year recurrence-free probabilities for each patient; (2) case presentations of 63 prostate cancer patients (including full clinical histories with complete diagnostic data and surgical findings) were made to a group of 25 clinicians who were asked to predict organ-confined disease. We found 22 published studies comparing human experts with nomograms, greater than half (13 of 22) showed the nomogram performing above the level of the human expert. Our first experiment showed urologist modification of 165 nomogram predictions led to a decrease in prediction accuracy (c-index decreased from.67 to.55, P <.05). In our second experiment, clinician predictions of organ-confined disease were comparable to the nomogram (area under the receiver operating characteristic curve [AUC] 0.78 and 0.79, respectively). A mixed-model suggests the nomogram did not augment clinician prediction accuracy (doctor excess error 1.4%, P =.75, 95% confidence interval [CI]: -10.9% to 8.2%). Our data suggest that nomograms do not seem to diminish predictive accuracy and they may be of significant benefit in certain clinical decision making settings.