OLIGOPELVIS GETUG P07, a Multicenter Phase II Trial of Combined High-dose Salvage Radiotherapy and Hormone Therapy in Oligorecurrent Pelvic Node Relapses in Prostate Cancer.

BACKGROUND: Oligorecurrent pelvic nodal relapse in prostatic cancer is a challenge for regional salvage treatments. Androgen depriving therapies (ADTs) are a mainstay in metastatic prostate cancer, and salvage pelvic radiotherapy may offer long ADT-free intervals for patients harboring regional nodal relapses. OBJECTIVE: To assess the efficacy of the combination of ADT and salvage radiotherapy in men with oligorecurrent pelvic node relapses of prostate cancer. DESIGN, SETTING, AND PARTICIPANTS: We performed an open-label, phase II trial of combined high-dose intensity-modulated radiotherapy and ADT (6 mo) in oligorecurrent (five or fewer) pelvic node relapses in prostate cancer, detected by fluorocholine positron-emission tomography computed tomography imaging. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was 2-yr progression-free survival defined as two consecutive prostate-specific antigen levels above the level at inclusion and/or clinical evidence of progression as per RECIST 1.1 and/or death from any cause. RESULTS AND LIMITATIONS: Between August 2014 and July 2016, 67 patients were recruited in 15 centers. Half of the patients had received prior prostatic irradiation. The median age was 67.7 yr. After a median follow-up of 49.4 mo, 2- and 3-yr progression-free survival rates were 81% and 58%, respectively. Median progression-free survival was 45.3 mo. The median biochemical relapse-free survival (BRFS) was 25.9 mo. At 2 and 3 yr, the BRFS rates were 58% and 46%, respectively. Grade 2 + 2-yr genitourinary and gastrointestinal toxicities were 10% and 2%, respectively. CONCLUSIONS: Combined high-dose salvage pelvic radiotherapy and ADT appeared to prolong tumor control in oligorecurrent pelvic node relapses in prostate cancer with limited toxicity. After 3 yr, nearly half of patients were in complete remission. Our study showed initial evidence of benefit, but a randomized trial is required to confirm this result. PATIENT SUMMARY: In this report, we looked at the outcomes of combined high-dose salvage pelvic radiotherapy and 6-mo-long hormone therapy in oligorecurrent pelvic nodal relapse in prostatic cancer. We found that 46% of patients presenting with oligorecurrent pelvic node relapses in prostate cancer were in complete remission after 3 yr following combined treatment at the cost of limited toxicity.

Anticariogenic activities of Libidibia ferrea, gallic acid and ethyl gallate against Streptococcus mutans in biofilm model.

ETHNOPHARMACOLOGICAL RELEVANCE: In Brazil, ethnopharmacological studies show that Libidibia ferrea (Mart. ex Tul.) L. P. Queiroz is commonly used in folk medicine as an antifungal, antimicrobial and anti-inflammatory. In the Amazon region, the dried fruit powder of L. ferrea are widely used empirically by the population in an alcoholic tincture as an antimicrobial mouthwash in oral infections and the infusion is also recommended for healing oral wounds. However, there are few articles that have evaluated the antimicrobial activity against oral pathogens in a biofilm model, identifying active compounds and mechanisms of action. AIM OF THE STUDY: The aim of this study was to evaluate the antimicrobial and anti-adherence activities of the ethanolic extract, fractions and isolated compounds (gallic acid and ethyl gallate) of the fruit and seed of L. ferrea against Streptococcus mutans. The inhibition of acidicity/acidogenicity and the expression of the S. mutans GTF genes in biofilms were also evaluated. MATERIALS AND METHODS: Minimal Inhibitory Concentration (MIC), Minimum Bactericidal Concentration (MBC) and Minimum Inhibitory Concentration of Cell Adhesion (MICA) were evaluated with ethanolic extract (EELF), fractions, gallic acid (GA) and ethyl gallate (EG) against S. mutans. Inhibition of biofilm formation, pH drop and proton permeability tests were conducted with EELF, GA and EG, and also evaluated the expression of the GTF genes in biofilms. The compounds of dichloromethane fraction were identified by GC-MS. RESULTS: This is the first report of shikimic, pyroglutamic, malic and protocatechuic acids identified in L. ferrea. EELF, GA and EG showed MIC at 250 µg/mL, and MBC at 1000 µg/mL by EELF. EELF biofilms showed reduced dry weight and acidogenicity of S. mutans in biofilms. GA and EG reduced viable cells, glucans soluble in alkali, acidogenicity, aciduricity and downregulated expression of gtfB, gtfC and gtfD genes in biofilms. SEM images of GA and EG biofilms showed a reduction of biomass, exopolysaccharide and microcolonies of S. mutans. CONCLUSIONS: The ethanolic extract of fruit and seed of L. ferrea, gallic acid and ethyl gallate showed great antimicrobial activity and inhibition of adhesion, reduction of acidogenicity and aciduricity in S. mutans biofilms. The results obtained in vitro validate the use of this plant in ethnopharmacology, and open opportunities for the development of new oral anticariogenic agents, originated by plants that can inhibit pathogenic biofilm that leads to the development of caries.

Toxicity of binary mixtures of Al2O3 and ZnO nanoparticles toward fibroblast and bronchial epithelium cells.

The objective of this study was to examine the cytotoxic effects of binary mixtures of Al2O3 and ZnO NPs using mouse fibroblast cells (L929) and human bronchial epithelial cells (BEAS-2B) as biological test systems. The synergistic, additive, or antagonistic behavior of the binary mixture was also investigated. In toxicity experiments, cellular morphology, mitochondrial function (MTT assay), apoptosis, nuclear size and shape, clonogenic assays, and damage based upon oxidative stress parameters were assessed under control and NPs exposure conditions. Although Abbott modeling results provided no clear evidence of the binary mixture of Al2O3 and ZnO NPs exhibiting synergistic toxicity, some specific assays such as apoptosis, nuclear size and shape, clonogenic assay, activities of antioxidant enzymatic enzymes catalase, superoxide dismutase, and levels of glutathione resulted in enhanced toxicity for the mixtures with 1 and 1.75 toxic units (TU) toward both cell types. Data demonstrated that co-presence of Al2O3 and ZnO NPs in the same environment might lead to more realistic environmental conditions. Our findings indicate cytotoxicity of binary mixtures of Al2O3 and ZnO NPs produced greater effects compared to toxicity of either individual compound.

Crystalline phase-dependent toxicity of aluminum oxide nanoparticles toward Daphnia magna and ecological risk assessment.

Aluminum oxide nanoparticles (Al2O3 NPs) can be found in different crystalline phases, and with the emergence of nanotechnology there has been a rapid increase in the demand for Al2O3 NPs in different engineering areas and for consumer products. However, a careful evaluation of the potential environmental and human health risks is required to assess the implications of the release of Al2O3 NPs into the environment. Thus, the objective of this study was to investigate the toxicity of two crystalline phases of Al2O3 NPs, alpha (α-Al2O3 NPs) and eta (η-Al2O3 NPs), toward Daphnia magna and evaluate the risk to the aquatic ecology of Al2O3 NPs with different crystalline phases, based on a probabilistic approach. Different techniques were used for the characterization of the Al2O3 NPs. The toxicity toward Daphnia magna was assessed based on multiple toxicological endpoints, and the probabilistic species sensitivity distribution (PSSD) was used to estimate the risk of Al2O3 NPs to the aquatic ecology. The results obtained verify the toxic potential of the NPs toward D. magna even in sublethal concentrations, with a more pronounced effect being observed for η-Al2O3 NPs. The toxicity is associated with an increase in the reactive oxygen species (ROS) content and deregulation of antioxidant enzymatic/non-enzymatic enzymes (CAT, SOD and GSH). In addition, changes in MDA levels were observed, indicating that D. magna was under oxidative stress. The most prominent chronic toxic effects were observed in the organisms exposed to η-Al2O3 NPs, since the lowest LOEC was 3.12 mg/L for all parameters, while for α-Al2O3 NPs the lowest LOEC was 6.25 mg/L for longevity, growth and reproduction. However, the risk assessment results indicate that, based on a probabilistic approach, Al2O3 NPs (alpha, gamma, delta, eta and theta) only a very limited risk to organisms in surface waters.

Banana fruits with high content of resistant starch: Effect of genotypes and phosphorus fertilization.

Banana fertilization practices aim to increase agricultural yield and the effects of these practices on fruit components have not been well explored. This study aimed to evaluate the effects of phosphate fertilizer levels on production parameters and accumulation of dry matter, phosphorus, starch and resistant starch in green fruits. Four banana genotypes were cultivated under the same cultural practices, with varying levels of phosphate fertilizers during three production cycles. Bunches were harvested and evaluated for total fruit mass, average finger mass and yield. Fresh green fruit pulps were analyzed for dry matter, phosphorus, starch and resistant starch content. The results showed that the effects of phosphate fertilizer were genotype dependent and that the increase of P2O5 rates applied in banana fertilization promoted an increase in fruit production with higher levels of phosphorus, starch and resistant starch.

Toxicological Evaluation and Quantification of Ingested Metal-Core Nanoplastic by Daphnia magna Through Fluorescence and Inductively Coupled Plasma-Mass Spectrometric Methods.

There are few studies on nanoplastic that propose quantification of the amount ingested combined with evaluation of the toxic effects on aquatic organisms. We propose 2 methods to quantify the amount of polystyrene nanoplastic (PSNP) ingested by Daphnia magna: fluorescence intensity, where a fluorescent monomer (F) is added to the PSNP and quantified through fluorescence light microscopy, and total aluminum quantification, where PSNP is synthesized with Al2 O3 metal-core nanoparticles and used for quantification of the nanoplastic ingested by the organism Daphnia magna using inductively coupled plasma-mass spectrometry. In addition, the PSNP was functionalized with palmitic acid to simulate the environmental conditions leading to biological and chemical transformations. Acute and chronic toxicity tests were performed with fluorescent PSNP (PSNP/F) and palmitic acid-functionalized PSNP/F (PSNP/F-PA). The ingestion quantified was higher by factors of 2.8 and 3.0 for PSNP/F-PA and 1.9 and 1.7 for PSNP/F applying the fluorescence intensity and total Al quantifying methods, respectively, when compared to PSNP. These results are consistent with the data obtained in the toxicity tests, which showed an approximately 3 times increase in the adverse effect of PSNP/F-PA on the mobility and reproduction of the organisms. Thus, the strong inhibition of D. magna reproduction caused by PSNP/F-PA in the chronic toxicity tests could be associated with a greater amount of this nanoplastic being ingested by the organisms. Environ Toxicol Chem 2019;38:2101-2110. © 2019 SETAC.

Early Toxicity of a Phase 2 Trial of Combined Salvage Radiation Therapy and Hormone Therapy in Oligometastatic Pelvic Node Relapses of Prostate Cancer (OLIGOPELVIS GETUG P07).

PURPOSE: Limited pelvic nodal relapse of prostatic cancer is a paramount challenge for locoregional salvage treatments. Salvage whole pelvis radiation therapy as considered in the BLINDED trial is an attractive option, but there are concerns about its toxicity. This article describes early toxicity with the technique. METHODS AND MATERIALS: BLINDED was a prospective multicenter phase 2 trial investigating high-dose salvage pelvic irradiation with an additional dose to the fluorocholine-based positron emission tomography-positive pelvic lymph nodes, combined with 6-month androgen blockade. The prescribed dose was 54 Gy in 1.8 Gy fractions with up to 66 Gy in 2.2 Gy fractions to the pathologic pelvic lymph nodes. Early toxicity was defined as toxicity until 1 year after radiation therapy. Patients quality of life was assessed using the European Organisation for Research and Treatment of Cancer questionnaires (QLQ-C30 and QLQ-PR25). RESULTS: Seventy-four patients were recruited in 15 French radiation oncology departments between August 2014 and July 2016. Seven were excluded before treatment because of violation of the inclusion criteria. The intention-to-treat analysis therefore included 67 patients. Half had received prior prostatic irradiation. Median age was 67.7 ± 6.5 years. Grade 2 acute urinary toxicity was observed in 9 of 67 patients (13.4%), and grade 2 1-year toxicity occurred in 4 of 67 patients (6%). Three patients (4.4%) had grade 3 urinary toxicity. Grade 2 acute digestive toxicity was observed in 10 of 67 patients (14.9%), and grade 2 1-year toxicity occurred in 4 of 67 patients (6%). Patients with prior prostate bed irradiation did not exhibit increased urinary or digestive toxicity. The European Organisation for Research and Treatment of Cancer questionnaire scores at 1 year did not worsen significantly. CONCLUSIONS: The acute and 1-year toxicity of the BLINDED protocol was satisfactory, even in patients with a history of prostatic irradiation.