Noninvasive Detection of Clinically Significant Prostate Cancer Using Circulating Tumor Cells.

PURPOSE: Prostate specific antigen testing results in unnecessary biopsy and over diagnosis with consequent overtreatment. Tissue biopsy is an invasive procedure associated with significant morbidity. More accurate noninvasive or minimally invasive diagnostic approaches should be developed to avoid unnecessary prostate biopsy and over diagnosis. We investigated the potential of using circulating tumor cell analysis in cancer diagnosis, particularly to predict clinically significant prostate cancer in prebiopsy cases. MATERIALS AND METHODS: We enrolled 155 treatment naïve patients with prostate cancer and 98 before biopsy for circulating tumor cell enumeration. RNA was extracted from circulating tumor cells of 184 patients for gene expression analysis. The Kruskal-Wallis and Spearman rank tests, multivariate logistic regression and the random forest method were applied to assess the association of circulating tumor cells with aggressive prostate cancer. RESULTS: Of patients with localized prostate cancer 54% were scored as having positive circulating tumor cells, which was associated with a higher Gleason score (p=0.0003), risk group (p <0.0001) and clinically significant prostate cancer (p <0.0001). In the prebiopsy group a positive circulating tumor cell score combined with prostate specific antigen predicted clinically significant prostate cancer (AUC 0.869). A 12-gene panel prognostic for clinically significant prostate cancer was also identified. When combining the prostate specific antigen level, the circulating tumor cell score and the 12-gene panel, the AUC of clinically significant prostate cancer prediction was 0.927. Adding those data to cases with available multiparametric magnetic resonance imaging data significantly increased prediction accuracy (AUC 0.936 vs 0.629). CONCLUSIONS: Circulating tumor cell analysis has the potential to significantly improve patient stratification by prostate specific antigen and/or multiparametric magnetic resonance imaging for biopsy and treatment.

Polymeric nanoparticles for increased oral bioavailability and rapid absorption using celecoxib as a model of a low-solubility, high-permeability drug.

PURPOSE: To demonstrate drug/polymer nanoparticles can increase the rate and extent of oral absorption of a low-solubility, high-permeability drug. METHODS: Amorphous drug/polymer nanoparticles containing celecoxib were prepared using ethyl cellulose and either sodium caseinate or bile salt. Nanoparticles were characterized using dynamic light scattering, transmission and scanning electron microscopy, and differential scanning calorimetry. Drug release and resuspension studies were performed using high-performance liquid chromatography. Pharmacokinetic studies were performed in dogs and humans. RESULTS: A physical model is presented describing the nanoparticle state of matter and release performance. Nanoparticles dosed orally in aqueous suspensions provided higher systemic exposure and faster attainment of peak plasma concentrations than commercial capsules, with median time to maximum drug concentration (Tmax) of 0.75 h in humans for nanoparticles vs. 3 h for commercial capsules. Nanoparticles released celecoxib rapidly and provided higher dissolved-drug concentrations than micronized crystalline drug. Nanoparticle suspensions are stable for several days and can be spray-dried to form dry powders that resuspend in water. CONCLUSIONS: Drug/polymer nanoparticles are well suited for providing rapid oral absorption and increased bioavailability of BCS Class II drugs.

Obesity and hypertension among children after treatment for acute lymphoblastic leukemia.

BACKGROUND: The purpose was to determine the prevalence and treatment-related risk factors for obesity and hypertension among childhood acute lymphoblastic leukemia (ALL) survivors treated with contemporary therapy. METHODS: In a single-center longitudinal study, serial body mass indices (BMI) and blood pressure (BP) measurements of children ages 2-20 at time of ALL diagnosis and enrolled on pediatric cooperative group trials from 1993-2003 were abstracted from medical records and converted to population-referenced z-scores. RESULTS: Among 165 study participants, BMI z-scores increased significantly between diagnosis (median age 4.8 years) and therapy completion. At the end of therapy, 17.0% of survivors were overweight (BMI of 25-29, or 85-94% for age), 21.2% were obese (BMI >or=30, or >or=95% for age), and 15.3% had BP meeting stage 1+ hypertension thresholds (systolic or diastolic BP >or=140/90 mm Hg, or 95% for age and height plus 5 mm Hg). These proportions were found to be unchanged 2-3 years later. In multivariate analysis, the highest level of corticosteroid exposure was associated with both obesity (odds ratio [OR] 6.0; 95% confidence interval [95% CI], 1.2-28.5) as well as stage 1+ hypertension (OR 2.4; 95% CI, 1.2-5.1) compared with the lowest level. Females also were more likely to have increased BMI and elevated BP compared with males. Treatment intensity and cranial radiotherapy were not found to be associated with BMI or BP changes. CONCLUSIONS: Despite reductions in the use of cranial radiotherapy, contemporary childhood survivors of ALL remain at an increased risk of obesity and hypertension at least several years after the completion of treatment, with those exposed to higher doses of corticosteroids at greater risk.

7-Oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamides: synthesis and biological activity of a new class of highly potent inhibitors of human cytomegalovirus DNA polymerase.

We report a new class of non-nucleoside antivirals, the 7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamides, some of which possess remarkable potency versus a broad spectrum of herpesvirus DNA polymerases and excellent selectivity compared to human DNA polymerases. A critical factor in the level of activity is hypothesized to be conformational restriction of the key 2-aryl-2-hydroxyethylamine sidechain by an adjacent methyl group.

Self-care autonomy and outcomes of intensive therapy or usual care in youth with type 1 diabetes.

OBJECTIVE: This article evaluated whether deviation from developmentally appropriate self-care autonomy moderated the effects of intensive therapy (IT) or usual care (UC) on glycosylated hemoglobin (HbA(1C)) in 142 youths with diabetes. METHODS: Youths received an autonomy/maturity ratio (AMR) score at baseline that was a ratio of standardized scores on measures of self-care autonomy to standardized scores on measures of psychological maturity and were categorized by tertile split into low, moderate, and high AMR. RESULTS: Higher baseline AMR was associated with higher baseline HbA(1C) for IT and UC. Baseline AMR scores predicted glycemic outcomes from UC; the high AMR tertile showed deteriorating glycemic control over time, whereas the low AMR tertile maintained better glycemic control. All three AMR groups derived equal glycemic benefit from IT. CONCLUSION: Children with inordinate diabetes self-care autonomy may fare poorly in UC but these same children may realize less glycemic deterioration during IT.

Self-management competence as a predictor of outcomes of intensive therapy or usual care in youth with type 1 diabetes.

OBJECTIVE: This article evaluates prediction of HbA(1c) during an 18-month randomized trial of intensive therapy (IT) versus usual care (UC) for type 1 diabetes in 142 youth. RESEARCH DESIGN AND METHODS: Patients received a composite score for self-management competence (SMC) that combined standardized scores on baseline measures of diabetes knowledge, treatment adherence, and quality of health care interactions. They were categorized by tertiles split into low, moderate, and high SMC levels. RESULTS: IT yielded very similar mean HbA(1c) levels in all three SMC groups. However, in UC patients, HbA(1c) increased markedly for low-SMC youth but not for moderate- and high-SMC youth during the trial. Compared with the mean HbA(1c) of their UC counterparts, low-SMC patients realized greater glycemic benefit from IT than did the moderate- or high-SMC youth. Baseline SMC was more strongly correlated with HbA(1c) for UC than IT. CONCLUSIONS: All three SMC groups realized similar glycemic benefits from IT. The mean HbA(1c) levels of low-SMC patients in the UC group increased markedly over 18 months, whereas HbA(1c) levels of low-SMC patients in the IT group did not differ significantly from that of moderate- and high-SMC patients. Relative to their UC counterparts, low-SMC patients derived greater glycemic benefit from IT than did moderate- or high-SMC youth. SMC may be more critical to the success of UC than IT. Perhaps more importantly, patients should not be denied access to IT on the basis of limited competence in diabetes self-management.

Broad-spectrum antiviral activity of PNU-183792, a 4-oxo-dihydroquinoline, against human and animal herpesviruses.

We identified a novel class of 4-oxo-dihydroquinolines represented by PNU-183792 which specifically inhibit herpesvirus polymerases. PNU-183792 was highly active against human cytomegalovirus (HCMV, IC(50) value 0.69 microM), varicella zoster virus (VZV, IC(50) value 0.37 microM) and herpes simplex virus (HSV, IC(50) value 0.58 microM) polymerases but was inactive (IC(50) value >40 microM) against human alpha (alpha), gamma (gamma), or delta (delta) polymerases. In vitro antiviral activity against HCMV was determined using cytopathic effect, plaque reduction and virus yield reduction assays (IC(50) ranging from 0.3 to 2.4 microM). PNU-183792 antiviral activity against both VZV (IC(50) value 0.1 microM) and HSV (IC(50) ranging from 3 to 5 microM) was analyzed using plaque reduction assays. PNU-183792 was also active (IC(50) ranging 0.1-0.7 microM) in cell culture assays against simian varicella virus (SVV), murine cytomegalovirus (MCMV) and rat cytomegalovirus (RCMV). Cell culture activity was compared with the appropriate licensed drugs ganciclovir (GCV), cidofovir (CDV) and acyclovir (ACV). PNU-183792 was also active against both GCV-resistant and CDV-resistant HCMV and against ACV-resistant HSV. Toxicity assays using four different species of proliferating mammalian cells indicated PNU-183792 was not cytotoxic at relevant drug concentrations (CC(50) value >100 microM). PNU-183792 was inactive against unrelated DNA and RNA viruses indicating specificity for herpesviruses. In animals, PNU-183792 was orally bioavailable and was efficacious in a model of lethal MCMV infection.