Safety and Efficacy of Maintenance Therapy With a Nonspecific Cytochrome P17 Inhibitor (CYP17i) After Response/Stabilization to Docetaxel in Metastatic Castration-Resistant Prostate Cancer

BackgroundFrontline treatment of metastatic castration-resistant prostate cancer (mCRPC) consists of docetaxel-based chemotherapy. The median time to progression (TTP) from chemotherapy initiation is 6 to 8 months. Ketoconazole, a nonspecific cytochrome P17 inhibitor (CYP17i), blocks adrenal androgen synthesis. Low-dose ketoconazole (LDK), (200 mg three times daily [t.d.s]) has shown activity in mCRPC after progression to androgen deprivation. The role of a CYP17i after docetaxel treatment in the maintenance setting has been unexplored.MethodsWe identified 38 patients with mCRPC who showed progression to luteinizing hormone releasing–hormone agonists (LHRHa) and who were treated with a median of 7 cycles of frontline three-weekly docetaxel (75 mg/m²) plus prednisone (10 mg/d) and LHRHa. Medical charts of 20 patients who showed no progression to docetaxel were reviewed. After the last docetaxel cycle, 10 patients received LDK maintenance treatment plus prednisone (10 mg/d) and LHRHa, whereas 10 patients received LHRHa alone. TTP was the primary endpoint.ResultsAfter a follow-up of 27 months, disease in all patients receiving LHRHa alone progressed, whereas 8/10 patients progressed to maintenance therapy. Median TTP from docetaxel initiation was 11.5 months (95% confidence interval [CI], 6.3-16.6) for maintenance therapy and 9.2 months (95% CI, 8.5-9.9) for LHRHa alone (P = .047). The maintenance treatment was well tolerated. Only 1 patient experienced a grade 4 adverse event due to a nonsymptomatic pulmonary embolism.ConclusionThis is the first study evaluating a CYP17i for maintenance therapy after docetaxel therapy. We showed a 2-month significant benefit in TTP for patients with mCRPC treated with LDK maintenance therapy after docetaxel, with a favorable toxicity profile. A large prospective randomized study using a CYP17i is warranted.     

Effects of the Dating Matters® Comprehensive Prevention Model on Health- and Delinquency-Related Risk Behaviors in Middle School Youth: a Cluster-Randomized Controlled Trial

Teen dating violence (TDV) is associated with a variety of delinquent behaviors, such as theft, and health- and delinquency-related risk behaviors, including alcohol use, substance abuse, and weapon carrying. These behaviors may co-occur due to shared risk factors. Thus, comprehensive TDV-focused prevention programs may also impact these other risk behaviors. This study examined the effectiveness of CDC’s Dating Matters®: Strategies to Promote Healthy Teen Relationships (Dating Matters) comprehensive TDV prevention model compared to a standard-of-care condition on health- and delinquency-related risk behaviors among middle school students. Students (N?=?3301; 53% female; 50% black, non-Hispanic; and 31% Hispanic) in 46 middle schools in four sites across the USA were surveyed twice yearly in 6th, 7th, and 8th grades. A structural equation modeling framework with multiple imputation to account for missing data was utilized. On average over time, students receiving Dating Matters scored 9% lower on a measure of weapon carrying, 9% lower on a measure of alcohol and substance abuse, and 8% lower on a measure of delinquency by the end of middle school than students receiving an evidence-based standard-of-care TDV prevention program. Dating Matters demonstrated protective effects for most groups of students through the end of middle school. These results suggest that this comprehensive model is successful at preventing risk behaviors associated with TDV. clinicaltrials.gov Identifier: NCT01672541

     

Complete root coverage of Miller Class III recessions

Gingival recessions may be classified according to a number of different systems. One of the most frequently used systems both in the literature and everyday practice is that proposed by Preston D. Miller in 1985. This classification assigned recessions to four different classes and gave a prognosis with regard to complete root coverage for each of the four situations following surgical treatment. According to Miller himself, complete coverage may be predicted in both Class I and II recessions, whereas its attainment is unpredictable in Class III and impossible in Class IV. Given that complete root coverage is attained in some Class III recessions, an investigation was planned to determine the presurgical variables that could help predict these results. Presurgical, surgical, and postsurgical conditions were studied for 121 Class III recessions in 50 patients, of which 47% achieved complete root coverage. Following statistical analysis using linear regression techniques, it was observed that the outweighing variables that explained these results were: soft tissue interproximal integrity, the use of grafts with a thickness of greater than 2 mm, interproximal bone loss not exceeding 3 mm, and an initial recession width not greater than 3 mm. Complete root coverage is possible in some Class III recessions. The Miller classification could be extended if these findings are confirmed by further research.     

Guanidine-reactive agent phenylglyoxal induces DNA damage and cancer cell death

BackgroundDNA-damaging compounds (e.g., alkylating agents, cytotoxic antibiotics and DNA topoisomerase poisons) are the most widely used anticancer drugs. The inability of tumor cells to properly repair some types of DNA damage may explain why specific DNA-damaging drugs can selectively kill tumor cells. Phenylglyoxal is a dicarbonyl compound known to react with guanidine groups such as that of the DNA base guanine, therefore suggesting that phenylglyoxal could induce DNA damage and have anticancer activity.MethodsCellular DNA damage was measured by the alkaline comet assay and the γH2AX focus assay. Formation of topoisomerase I- and topoisomerase II-DNA complexes was assessed by the TARDIS assay, an immunofluorescence technique that employs specific antibodies to DNA topo I or topo II to detect the protein covalently bound to the DNA in individual cells. Cell growth inhibition and cytotoxicity were determined by XTT, MTT and clonogenic assays. Apoptosis was assessed by the Annexin V flow cytometry assay.ResultsPhenylglyoxal induced cellular DNA damage and formation of high levels of topoisomerase I- and topoisomerase II-DNA complexes in cells. These topoisomerase-DNA complexes were abolished by catalase pretreatment and correlated well with the induction of apoptosis. Phenylglyoxal-induced cell death was partially prevented by catalase pretreatment and was higher in lung cancer cells (A549) than in normal lung fibroblasts (MRC5). Mammalian cell lines defective in nucleotide excision repair (NER), homologous recombination (HR) and non-homologous end joining (NHEJ) were more sensitive to phenylglyoxal than parental cells; this suggests that phenylglyoxal may induce bulky distortions in the shape of the DNA double helix (which are repaired by the NER pathway) and DNA double-strand breaks (which are repaired by HR and NHEJ).ConclusionsThis report shows that phenylglyoxal is a new DNA-damaging agent with anticancer activity, and suggests that tumor cells with defects in NER, HR and NHEJ may be hypersensitive to the cytotoxic activity of phenylglyoxal.     

Psychosis after epilepsy surgery: report of three cases

Temporal lobe epilepsy surgery has become a successful alternative in patients with refractory epilepsy. However, the outcome of epilepsy surgery may be affected by the occurrence of postsurgical psychiatric symptoms, such as psychosis. This report describes three cases of refractory temporal lobe epilepsy and hippocampal sclerosis, which, after anterior temporal lobectomy, presented with acute psychosis. One of them had a history of acute psychosis, and all of them met criteria for Cluster A personality disorder (schizoid/schizotypal) during psychiatric assessment prior to surgery. The three cases had a good seizure outcome (Engel I), but, on follow-up during the first year after surgery, developed an acute psychotic episode compatible with schizoaffective disorder; brief psychotic disorder; and a delusional disorder, respectively, according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Treatment with low-dose risperidone was successful.     

Geochemical behavior of heavy metals in differents environments in Rodrigo de Freitas lagoon - RJ/Brazil

The accelerated urbanisation without a planning, brought several environmental problems to Rio de Janeiro coastal zone, especially in areas such as Rodrigo de Freitas lagoon, which receives a great amount of untreated sewage every day. To assess the nature, potentially sources and extent of heavy metal pollution in the lagoon, sediments from the surrounding streets, from the entrance of the main canal that drains to the lagoon and from the bottom of the lagoon were collected and analysed by a modified selective extraction procedure in order to study the geochemical partitioning and bioavailability of Zn, Cu, Cr, Ni and Pb in these three compartments. The present study verified an increase in the Cu, Pb and Zn concentrations in the north of the Rodrigo de Freitas lagoon. Despite the different levels of oxidation between the sediments accumulated in the streets and in the bottom of the lagoon, the geochemical partitioning of the heavy metals did not show any pattern of variation for the metals, except for the element Cu. No concentrations were found in the soluble phase of samples collected in the surfacial sediments of the lagoon, suggesting no bioavailability of heavy metals.