Breast cancer risk genes: association analysis in more than 113,000 women

BACKGROUNDGenetic testing for breast cancer susceptibility is widely used, but for many genes, evidence of an association with breast cancer is weak, underlying risk estimates are imprecise, and reliable subtype-specific risk estimates are lacking.METHODSWe used a panel of 34 putative susceptibility genes to perform sequencing on samples from 60,466 women with breast cancer and 53,461 controls. In separate analyses for protein-truncating variants and rare missense variants in these genes, we estimated odds ratios for breast cancer overall and tumor subtypes. We evaluated missense-variant associations according to domain and classification of pathogenicity.RESULTSProtein-truncating variants in 5 genes (ATM, BRCA1, BRCA2, CHEK2, and PALB2) were associated with a risk of breast cancer overall with a P value of less than 0.0001. Protein-truncating variants in 4 other genes (BARD1, RAD51C, RAD51D, and TP53) were associated with a risk of breast cancer overall with a P value of less than 0.05 and a Bayesian false-discovery probability of less than 0.05. For protein-truncating variants in 19 of the remaining 25 genes, the upper limit of the 95% confidence interval of the odds ratio for breast cancer overall was less than 2.0. For protein-truncating variants in ATM and CHEK2, odds ratios were higher for estrogen receptor (ER)-positive disease than for ER-negative disease; for protein-truncating variants in BARD1, BRCA1, BRCA2, PALB2, RAD51C, and RAD51D, odds ratios were higher for ER-negative disease than for ER-positive disease. Rare missense variants (in aggregate) in ATM, CHEK2, and TP53 were associated with a risk of breast cancer overall with a P value of less than 0.001. For BRCA1, BRCA2, and TP53, missense variants (in aggregate) that would be classified as pathogenic according to standard criteria were associated with a risk of breast cancer overall, with the risk being similar to that of protein-truncating variants.CONCLUSIONSThe results of this study define the genes that are most clinically useful for inclusion on panels for the prediction of breast cancer risk, as well as provide estimates of the risks associated with protein-truncating variants, to guide genetic counseling. (Funded by European Union Horizon 2020 programs and others.)Molecular tumour pathology - and tumour geneticsMTG1 - Moleculaire genetica en pathologie van borstkanke

Review on broodstock management and gamete quality in commercially important european species

International audienc

Efectos del parasitismo sobre el tejido branquial en peces cultivados: estudio parasitologico e histopatologico Effect of the parasitism on the gill tissue of cultivated fishes: parasitological and histopathological studies

<abstract language="eng">One hundred four out of 225 diagnosticated cases were myxosporidian, monogenean, Ichthyophthirius multifiliis Fouquet, 1876 and bacterial diseases in Piaractus mesopotamicus Holmberg, 1887 (pacu), Colossoma macropomum Cuvier, 1818 (tambaqui) and tambacu, at Aquaculture Center, Universidade Estadual Paulista (UNESP), Jaboticabal, São Paulo, Brazil, between 1992 and 1995. The gills were fixed in 10% buffered formalin solution to posterior histologic routine. It was observed Henneguya sp. cysts into the capillaries of the secondary lamellae, encapsulated by the respiratory epithelium cells. It provoked adherence of the adjacent lamellae, hyperplasia, congestion, oedema and epithelium displacement. Monogeneans infestations by Anacanthorus penilabiatus Boeger, Husak & Martins, 1995 and Ancyrocephalinae sub-family caused light inflammatory reaction and hyperplasia. In severe infestations was observed hyperplasia of primary lamellae, necrosis, oedema, respiratory epithelium displacement, ruptured pillar cells and telangiectasis. Response to I. multifiliis was limited to surrounding epithelial cells in young fishes and hyperplasia, necrosis, inflammatory infiltrate and oedema in old fishes. Such lesions iniciate hyperplasic and oedematous process that with inflammation of the parasitic sites, provoked alterations over gases and ions interchange surface and consequently fish metabolism

NBTXR3, a first-in-class radioenhancer hafnium oxide nanoparticle, plus radiotherapy versus radiotherapy alone in patients with locally advanced soft-tissue sarcoma (Act. In. Sarc): a multicentre, phase 2-3, randomised, controlled trial

Background Pathological complete response to preoperative treatment in adults with soft-tissue sarcoma can be achieved in only a few patients receiving radiotherapy. This phase 2-3 trial evaluated the safety and efficacy of the hafnium oxide (HfO2) nanoparticle NBTXR3 activated by radiotherapy versus radiotherapy alone as a pre-operative treatment in patients with locally advanced soft-tissue sarcoma.Methods Act. In. Sarc is a phase 2-3 randomised, multicentre, international trial. Adults (aged = 18 years) with locally advanced soft-tissue sarcoma of the extremity or trunk wall, of any histological grade, and requiring preoperative radiotherapy were included. Patients had to have a WHO performance status of 0-2 and a life expectancy of at least 6 months. Patients were randomly assigned (1:1) by an interactive web response system to receive either NBTXR3 (volume corresponding to 10% of baseline tumour volume at a fixed concentration of 53.3 g/L) as a single intratumoural administration before preoperative external-beam radiotherapy (50 Gy in 25 fractions) or radiotherapy alone, followed by surgery. Randomisation was stratified by histological subtype (myxoid liposarcoma vs others). This was an open-label study. The primary endpoint was the proportion of patients with a pathological complete response, assessed by a central pathology review board following European Organisation for Research and Treatment of Cancer guidelines in the intention-to-treat population full analysis set. Safety analyses were done in all patients who received at least one puncture and injection of NBTXR3 or at least one dose of radiotherapy. This study is registered with ClinicalTrials.gov, number NCT02379845, and is ongoing for long-term follow-up, but recruitment is complete.Findings Between March 3, 2015, and Nov 21, 2017, 180 eligible patients were enrolled and randomly assigned and 179 started treatment: 89 in the NBTXR3 plus radiotherapy group and 90 in the radiotherapy alone group. Two patients in the NBTXR3 group and one patient in the radiotherapy group were excluded from the efficacy analysis because they were subsequently discovered to be ineligible; thus, a total of 176 patients were analysed for the primary endpoint in the intention-to-treat full analysis set (87 in the NBTXR3 group and 89 in the radiotherapy alone group). A pathological complete response was noted in 14 (16%) of 87 patients in the NBTXR3 group and seven (8%) of 89 in the radiotherapy alone group (p=0.044). In both treatment groups, the most common grade 3-4 treatment-emergent adverse event was postoperative wound complication (eight [9%] of 89 patients in the NBTXR3 group and eight [9%] of 90 in the radiotherapy alone group). The most common grade 3-4 adverse events related to NBTXR3 administration were injection site pain (four [4%] of 89) and hypotension (four [4%]) and the most common grade 3-4 radiotherapy-related adverse event was radiation skin injury in both groups (five [6%] of 89 in the NBTXR3 group and four [4%] of 90 in the radiotherapy alone group). The most common treatment-emergent grade 3-4 adverse event related to NBTXR3 was hypotension (six [7%] of 89 patients). Serious adverse events were observed in 35 (39%) of 89 patients in the NBTXR3 group and 27 (30%) of 90 patients in the radiotherapy alone group. No treatment-related deaths occurred.Interpretation This trial validates the mode of action of this new class of radioenhancer, which potentially opens a large field of clinical applications in soft-tissue sarcoma and possibly other cancers. Copyright (C) 2019 Elsevier Ltd. All rights reserved.Molecular tumour pathology - and tumour geneticsMTG

Delay in diagnosis of influenza A (H1N1)pdm09 virus infection in critically ill patients and impact on clinical outcome

Background: Patients infected with influenza A (H1N1)pdm09 virus requiring admission to the ICU remain an important source of mortality during the influenza season. The objective of the study was to assess the impact of a delay in diagnosis of community-acquired influenza A (H1N1)pdm09 virus infection on clinical outcome in critically ill patients admitted to the ICU. Methods: A prospective multicenter observational cohort study was based on data from the GETGAG/SEMICYUC registry (2009–2015) collected by 148 Spanish ICUs. All patients admitted to the ICU in which diagnosis of influenza A (H1N1)pdm09 virus infection had been established within the first week of hospitalization were included. Patients were classified into two groups according to the time at which the diagnosis was made: early (within the first 2 days of hospital admission) and late (between the 3rd and 7th day of hospital admission). Factors associated with a delay in diagnosis were assessed by logistic regression analysis. Results: In 2059 ICU patients diagnosed with influenza A (H1N1)pdm09 virus infection within the first 7 days of hospitalization, the diagnosis was established early in 1314 (63.8 %) patients and late in the remaining 745 (36.2 %). Independent variables related to a late diagnosis were: age (odds ratio (OR) = 1.02, 95 % confidence interval (CI) 1.01–1.03, P < 0.001); first seasonal period (2009–2012) (OR = 2.08, 95 % CI 1.64–2.63, P < 0.001); days of hospital stay before ICU admission (OR = 1.26, 95 % CI 1.17–1.35, P < 0.001); mechanical ventilation (OR = 1.58, 95 % CI 1.17–2.13, P = 0.002); and continuous venovenous hemofiltration (OR = 1.54, 95 % CI 1.08–2.18, P = 0.016). The intra-ICU mortality was significantly higher among patients with late diagnosis as compared with early diagnosis (26.9 % vs 17.1 %, P < 0.001). Diagnostic delay was one independent risk factor for mortality (OR = 1.36, 95 % CI 1.03–1.81, P < 0.001). Conclusions: Late diagnosis of community-acquired influenza A (H1N1)pdm09 virus infection is associated with a delay in ICU admission, greater possibilities of respiratory and renal failure, and higher mortality rate. Delay in diagnosis of flu is an independent variable related to death