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Objective To validate the 17-gene Oncotype DX Genomic Prostate Score (GPS) as a predictor of adverse pathology (AP) in African American (AA) men and to assess the distribution of GPS in AA and European American (EA) men with localized prostate cancer. Methods The study populations were derived from 2 multi-institutional observational studies. Between February 2009 and September 2014, AA and EA men who elected immediate radical prostatectomy after a ≥10-core transrectal ultrasound biopsy were included in the study. Logistic regressions, area under the receiver operating characteristics curves (AUC), calibration curves, and predictive values were used to compare the accuracy of GPS. AP was defined as primary Gleason grade 4, presence of any Gleason pattern 5, and/or non-organ-confined disease (≥pT3aN0M0) at radical prostatectomy. Results Overall, 96 AA and 76 EA men were selected and 46 (26.7%) had AP. GPS result was a significant predictor of AP (odds ratio per 20 GPS units [OR/20 units] in AA: 4.58; 95% confidence interval (CI) 1.8-11.5, P = .001; and EA: 4.88; 95% CI 1.8-13.5, P = .002). On multivariate analysis, there was no significant interaction between GPS and race (P >.10). GPS remained significant in models adjusted for either National Comprehensive Cancer Network (NCCN) risk group or Cancer of the Prostate Risk Assessment (CAPRA) score. In race-stratified models, area under the receiver operating characteristics curves for GPS/20 units was 0.69 for AAs vs 0.74 for EAs (P = .79). The GPS distributions were not statistically different by race (all P >.05). Conclusion In this clinical validation study, the Oncotype DX GPS is an independent predictor of AP at prostatectomy in AA and EA men with similar predictive accuracy and distributions.

Purpose Large cell neuroblastomas (LCN) are frequently seen in recurrent, high-risk neuroblastoma but are rare in primary tumors. LCN, characterized by large nuclei with prominent nucleoli, predict a poor prognosis. We hypothesize that LCN can be created with high-dose intra-tumoral chemotherapy and identified by a digital analysis system. Methods Orthotopic mouse xenografts were created using human neuroblastoma and treated with high-dose chemotherapy delivered locally via sustained-release silk platforms, inducing tumor remission. After recurrence, LCN populations were identified on H&E sections manually. Clusters of typical LCN and non-LCN cells were divided equally into training and test sets for digital analysis. Marker-controlled watershed segmentation was used to identify nuclei and characterize their features. Logistic regression was developed to distinguish LCN from non-LCN. Results Image analysis identified 15,000 nuclei and characterized 70 nuclear features. A 19-feature model provided AUC > 0.90 and 100% accuracy when > 30% nuclei/cluster were predicted as LCN. Overall accuracy was 87%. Conclusions We recreated LCN using high-dose chemotherapy and developed an automated method for defining LCN histologically. Features in the model provide insight into LCN nuclear phenotypic changes that may be related to increased activity. This model could be adapted to identify LCN in human tumors and correlated with clinical outcomes.

Diagnosis of prostate cancer (PCa) typically relies on needle biopsies, which are routinely archived in paraffin after formalin fixation and may contain valuable risk or prognostic information. The objective of this study was to determine the feasibility of mRNA and miRNA expression analysis in laser-capture microdissected (LCM) formalin-fixed paraffin-embedded archived prostate biopsies compared to the gold standard of frozen tissue. We analyzed the expression of compartment-specific and PCa-related genes in epithelial and stromal tissues collected from paired sets of archived prostate biopsies and frozen radical prostatectomy specimens from three patients. Our results showed appropriate compartment-specific and PCa-related expression with good within patient agreement between the FFPE biopsies and the frozen tissue. The potential for both mRNA and micro-RNA expression profiling in the biopsies was also demonstrated using PCR arrays which showed high correlation between the biopsy and frozen tissue, notwithstanding sensitivity limitations for mRNA detection in the FFPE specimen. This is the first study to compare RNA expression from biopsy and frozen tissues from the same patient and to examine miRNA expression in LCM-collected tissue from prostate biopsies. With careful technique and use of appropriate controls, RNA profiling from archived biopsy material is quite feasible showing high correlation to frozen tissue.

The study was designed to determine the process and limitations by which estrone sulfate may be a precursor of estradiol in the parenchymal cells of the normal breast. The concentration of estrone sulfate in breast nipple aspirate fluid was 1000-fold greater than that of estradiol. Concentrations of 3H-estrone sulfate in parenchymal cells were only 0.20-0.33 times that of the 1.0 nM concentration in the medium, while 3H-estrone achieved concentrations up to 24 times that in the medium at 37 degrees C. Nevertheless, estrone sulfate added to the medium was linearly converted within a 1000-fold concentration range to estrone in intact cells with a mean half-time of conversion of 628 min per 10(6) cells. Homogenized cells had a half-time of 246 min per 10(6) cells. Thus, the time for entry of estrone sulfate into cells reduced the rate by approximately 55%. In split samples, the Vmax values (+/- S.D.) for intact and homogenized cells were 12.6 +/- 1.4 and 18.3 nmol/h mg DNA, respectively (P

Imatinib inhibits the ABL tyrosine kinase and is effective for the treatment of chronic myeloid leukemia (CML). ABL activates GPx-1, an enzyme associated with protection against oxidative DNA damage and disease. Enzyme activity was assessed in sample pairs consisting of mononuclear cells obtained from patients before and after imatinib therapy. Control sample sets obtained from patients not receiving imatinib showed little change in GPx activity over a several month interval. Five of 7 sample sets obtained from imatinib-receiving patients showed changes in GPx activity greater than 30%. One sample decreased 42% while 4 others increased 33% to 208%. Patients with the largest increase in activity were female and had the lowest baseline levels of GPx activity. Changes in GPx activity may influence the clinical outcome of patients being treated for CML.

A high calcium intake, mainly from dairy products, may increase prostate cancer risk by lowering concentrations of 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], a hormone thought to protect against prostate cancer. The results of epidemiologic studies of this hypothesis are inconclusive.We investigated the association between dairy product and calcium intakes and prostate cancer risk in the Physicians' Health Study, a cohort of male US physicians.At baseline, the men answered abbreviated dietary questionnaires. During 11 y of follow-up, we documented 1012 incident cases of prostate cancer among 20885 men. We estimated dairy calcium intake on the basis of consumption of 5 major dairy products and used logistic regression to estimate relative risk.At baseline, men who consumed600 mg Ca/d from skim milk had lower plasma 1,25(OH)(2)D(3) concentrations than did those consumingor =150 mg Ca/d [71 compared with 85 pmol/L (30.06 compared with 35.64 pg/mL); P = 0.005]. Compared with men consumingor =0.5 daily servings of dairy products, those consuming2.5 servings had a multivariate relative risk of prostate cancer of 1.34 (95% CI: 1.04, 1.71) after adjustment for baseline age, body mass index, smoking, exercise, and randomized treatment assignment in the original placebo-controlled trial. Compared with men consumingor =150 mg Ca/d from dairy products, men consuming600 mg/d had a 32% higher risk of prostate cancer (95% CI: 1.08, 1.63).These results support the hypothesis that dairy products and calcium are associated with a greater risk of prostate cancer.

PURPOSE: To explore agreement on cancer occurrence and site among Medicare Part A, Massachusetts Cancer Registry, and death certificates. METHODS: We linked these data sources with the cohort of the population-based East Boston Senior Health Project, a component of the National Institute on Aging’s Established Populations for Epidemiologic Studies of the Elderly. The cohort consists of 905 subjects dying between January 1986 and December 1990. RESULTS: We detected the following agreements on cancer occurrence: hospitalization data and death certificates (kappa = 0.70), hospitalization and cancer registry data (kappa = 0.59), and cancer registry and death certificate data (kappa = 0.50). Measures of agreement changed little when the analyses were stratified by age, sex, calendar year and place of death, autopsy performance, cigarette smoking or alcohol consumption. Site-specific agreements were higher for colorectal and respiratory tract cancer compared to breast and prostate across all three comparisons. CONCLUSIONS: The results should assist epidemiologists to better understand the strengths and limitations of these data sources.

We evaluated the beliefs of second-year medical students regarding critical issues in the AIDS epidemic before and after an intensive two-day training symposium. Paired responses, collected for three consecutive years, were available for 187 students. Our results indicate that, although the students generally held progressive beliefs on prevention and public policy prior to training, a significant minority held views that differ from expert opinion. After the training experience, we observed substantial shifts of opinion on several issues. For example, among those who initially believed that physicians should record results of HIV testing in patient charts without patient permission, 45% shifted to disagreement. On mandatory premarital testing, 43% of those initially supporting it shifted to disagreement. On some issues, such as contact tracing, where expert opinion is less clear, student opinion moved very little overall. Over the three-year period, we found evidence of a trend towards less concern over HIV transmission to men from causal sex with infected female partners and a trend towards acceptance of glove-wearing when handling all blood specimens. In conclusion, we demonstrate that the beliefs of medical students concerning difficult issues posed by the AIDS epidemic can be changed substantially in the short-term by a specially designed intensive educational program. Reinforcement and persistence of these changes should now be a concern for medical educators.

Informed consent for prostate-specific antigen (PSA) testing? No. No, but the issues are complex, and the idea cannot be dismissed casually. In the end, informed consent in this instance would benefit neither the medical provider nor the patient. My negative response relies on a few assumptions or definitions that I should explain. First, by informed consent, we usually mean written, as opposed to verbal consent. We explicitly mean a deliberate, formal process that culminates in a signature indicating consent. Second, we need to make a distinction between informal consent in the clinical as opposed to the research context. In the clinical context—where PSA belongs—informed consent is essentially a contract between provider and patient in which the benefit for the provider is some degree of protection from the accusation of wrongdoing, and for the patient the benefits are a guarantee of information and preservation of personal rights and autonomy (considered a value in our culture). In the research context, the contract is similar, but the patient is being offered a procedure that, by definition, does not have established clinical benefit, and this radically changes the risk/ benefit equation. We require (written) informed consent in the clinical setting when the physician recommends a procedure with enough risk that the physician would like, or needs to have, some medicolegal protection in case of an adverse event, and—from the patient’s point of view— enough risk is present to consider the option of refusing the procedure and therefore a need to receive enough information about the risks and benefits to make the decision. It is important to note that the notion of “sufficient risk” implies a continuum involving subjective judgments and perceptions by all parties concerned. For example, we perceive auscultation of the heart in an asymptomatic patient by a primary care physician as a procedure that does not require informed consent, even though the predictive value might be very low and the procedure conceivably could do more harm than good for the patient. The risk of a procedure is a combination of the probability of an adverse event and its severity. For PSA testing, there are three types of risk: two common, but relatively less severe ones—anxiety and unnecessary biopsy (which entails cost, risk, and discomfort); and one less common but very severe injury— unnecessary treatment. Interestingly, unnecessary treatment is a matter for lawsuits in many situations (eg, the patient requiring a gallstone removal who receives a leg amputation), but, in this situation, unnecessary treatment for prostate cancer cannot be a matter for a lawsuit, be