El cáncer hereditario en mujeres

Most cases of cancer are sporadic, whereas 5-10% are hereditary and about 20-30% of cancers tend to cluster in families. Families and individuals who are suspected of suffering from hereditary cancer need to undergo a process known as genetic counseling, which is of considerable importance in the prevention and early detection of malignant tumours. The most common hereditary cancer syndromes are: hereditary breast-ovarian cancer syndrome, familial adenomatous polyposis and Lynch syndrome. Genetic diagnosis allows clinicians to estimate the risks of developing different cancers in order to make decisions over surveillance and prophylactic surgery to reduce these risks. The ultimate goal is to reduce cancer mortality through early diagnosis and prevention.La mayoría de los casos de cáncer son esporádicos, entre un 20-30% presentan agregación familiar, mientras que solo el 5 -10% son de carácter hereditario. Las familias e individuos en los que se sospecha que padecen cáncer hereditario deben someterse a un proceso de asesoramiento genético, que es de gran importancia para la prevención y detección temprana de tumores malignos. Los síndromes más frecuentes de cáncer hereditario son el síndrome de mama-ovario hereditario, la poliposis adenomatosa familiar y el síndrome de Lynch. El diagnóstico genético facilita realizar una estimación de los riesgos de desarrollar diferentes cánceres, permitiendo tomar decisiones de vigilancia y preventivas que reducen estos riesgos. El objetivo final es reducir la mortalidad por cáncer mediante el diagnóstico precoz y la prevención

Metabolomic profile of neuroendocrine tumors (NETs) identifies methionine, porphyrin and tryptophan metabolism as key dysregulated pathways associated with patient survival

Objective: Metabolic profiling is a valuable tool to characterize tumor biology but remains largely unexplored in neuroendocrine tumors (NETs). Our aim was to comprehensively assess the metabolomic profile of NETs and identify novel prognostic biomarkers and dysregulated molecular pathways.Design and Methods: Multiplatform untargeted metabolomic profiling (GC-MS, CE-MS, and LC-MS) was performed in plasma from 77 patients with G1-2 extra-pancreatic NETs enrolled in the AXINET trial (NCT01744249) (study cohort) and from 68 non-cancer individuals (control). The prognostic value of each differential metabolite (n = 155) in NET patients (P < .05) was analyzed by univariate and multivariate analyses adjusted for multiple testing and other confounding factors. Related pathways were explored by Metabolite Set Enrichment Analysis (MSEA) and Metabolite Pathway Analysis (MPA).Results: Thirty-four metabolites were significantly associated with progression-free survival (PFS) (n = 16) and/or overall survival (OS) (n = 27). Thirteen metabolites remained significant independent prognostic factors in multivariate analysis, 3 of them with a significant impact on both PFS and OS. Unsupervised clustering of these 3 metabolites stratified patients in 3 distinct prognostic groups (1-year PFS of 71.1%, 47.7%, and 15.4% (P = .012); 5-year OS of 69.7%, 32.5%, and 27.7% (P = .003), respectively). The MSEA and MPA of the 13-metablolite signature identified methionine, porphyrin, and tryptophan metabolisms as the 3 most relevant dysregulated pathways associated with the prognosis of NETs.Conclusions: We identified a metabolomic signature that improves prognostic stratification of NET patients beyond classical prognostic factors for clinical decisions. The enriched metabolic pathways identified reveal novel tumor vulnerabilities that may foster the development of new therapeutic strategies for these patients

Mammographic density and breast cancer in women from high risk families

INTRODUCTION: Mammographic density (MD) is one of the strongest determinants of sporadic breast cancer (BC). In this study, we compared MD in BRCA1/2 mutation carriers and non-carriers from BRCA1/2 mutation-positive families and investigated the association between MD and BC among BRCA1/2 mutation carriers per type of mutation and tumor subtype. METHODS: The study was carried out in 1039 female members of BRCA1 and BRCA2 mutation-positive families followed at 16 Spanish Genetic Counseling Units. Participants' density was scored retrospectively from available mammograms by a single blinded radiologist using a 5-category scale (75 %). In BC cases, we selected mammograms taken prior to diagnosis or from the contralateral breast, whereas, in non-cases, the last screening mammogram was evaluated. MD distribution in carriers and non-carriers was compared using ordinal logistic models, and the association between MD and BC in BRCA1/2 mutation carriers was studied using logistic regression. Huber-White robust estimators of variance were used to take into account correlations between family members. A similar multinomial model was used to explore this association by BC subtype. RESULTS: We identified and scored mammograms from 341 BRCA1, 350 BRCA2 mutation carriers and 229 non-carriers. Compared to non-carriers, MD was significantly lower among BRCA2 mutation carriers (odds ratio (OR) =0.71; P-value=0.04), but not among BRCA1 carriers (OR=0.84; P-value=0.33). MD was associated with subsequent development BC (OR per category of MD=1.45; 95 % confidence interval=1.18-1.78, P-value<0.001), with no significant differences between BRCA1 and BRCA2 mutation carriers (P-value=0.48). Finally, no statistically significant differences were observed in the association of MD with specific BC subtypes. CONCLUSIONS: Our study, the largest to date on this issue, confirms that MD is an independent risk factor for all BC subtypes in either BRCA1 and BRCA2 mutation carriers, and should be considered a phenotype risk marker in this context.This work was supported by three research grants, PS09/01006, PS09/01024 and PS09/01721, from Spain’s Health Research Fund (Fondo de Investigación Sanitaria); and a grant from the Spanish Federation of Breast Cancer Patients (Federación Española de Cáncer de Mama) (FECMA 485 EPY 1170–10). The authors also acknowledge the contribution of the Asociación Española contra el Cáncer (AECC), Carlos III Health Institute; RTICC; and the Catalan Health Institute and Autonomous Government of Catalonia (grant numbers: RD06/0020/1051, RD06/0020/1050, RD12/0036/0008, RD12/0036/0031, PI10/01422, PI13/00285, PIE13/00022 and SGR290). This project was approved by the following ethical boards: Comité de Ética de la Investigación y de Bienestar Animal CEIyBA, Instituto de Salud Carlos III; Comité de Ética de la Investigación Clínica Hospital de la Santa Creu y Sant Pau, Barcelona; Comité de Ética de la Investigación Clínica Hospital Universitari de Girona Doctor Josep Trueta, Girona; Comité de Ética de la Fundación INCLIVA, Hospital Clínico Universitario, Valencia; Comité de Ética de la Investigación Clínica del Hospital Universitario 12 de Octubre, Madrid, and Comité de Ética de la Investigación Clínica del Hospital Ramón y Cajal, Madrid.S

A Phase II Study of BEZ235 in Patients with Everolimus-resistant, Advanced Pancreatic Neuroendocrine Tumours

BACKGROUND: This was a two-stage, phase II trial of the dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor BEZ235 in patients with everolimus-resistant pancreatic neuroendocrine tumours (pNETs) (NCT01658436). PATIENTS AND METHODS: In stage 1, 11 patients received 400 mg BEZ235 orally twice daily (bid). Due to tolerability concerns, a further 20 patients received BEZ235 300 mg bid. Stage 2 would be triggered by a 16-week progression-free survival (PFS) rate of ≥60% in stage 1. RESULTS: As of 30 June, 2014, 29/31 patients had discontinued treatment. Treatment-related grade 3/4 adverse events were reported in eight (72.7%) patients at 400 mg and eight (40.0%) patients at 300 mg, including hyperglycaemia, diarrhoea, nausea, and vomiting. The estimated 16-week PFS rate was 51.6% (90% confidence interval=35.7-67.3%). CONCLUSION: BEZ235 was poorly tolerated by patients with everolimus-resistant pNETs at 400 and 300 mg bid doses. Although evidence of disease stability was observed, the study did not proceed to stage 2.status: publishe

French multicentre observational study on SARS-CoV-2 infections intensive care initial management: the FRENCH CORONA study

International audienceAim: Describing acute respiratory distress syndrome patterns, therapeutics management, and outcomes of ICU COVID-19 patients and indentifying risk factors of 28-day mortality.Methods: Prospective multicentre, cohort study conducted in 29 French ICUs. Baseline characteristics, comorbidities, adjunctive therapies, ventilatory support at ICU admission and survival data were collected.Results: From March to July 2020, 966 patients were enrolled with a median age of 66 (interquartile range 58-73) years and a median SAPS II of 37 (29-48). During the first 24 h of ICU admission, COVID-19 patients received one of the following respiratory supports: mechanical ventilation for 559 (58%), standard oxygen therapy for 228 (24%) and high-flow nasal cannula (HFNC) for 179 (19%) patients. Overall, 721 (75%) patients were mechanically ventilated during their ICU stay. Prone positioning and neuromuscular blocking agents were used in 494 (51%) and 460 (48%) patients, respectively. Bacterial co-infections and ventilator-associated pneumonia were diagnosed in 79 (3%) and 411 (43%) patients, respectively. The overall 28-day mortality was 18%. Age, pre-existing comorbidities, severity of respiratory failure and the absence of antiviral therapy on admission were identified as independent predictors of 28-day outcome.Conclusion: Severity of hypoxaemia on admission, older age (> 70 years), cardiovascular and renal comorbidities were associated with worse outcome in COVID-19 patients. Antiviral treatment on admission was identified as a protective factor for 28-day mortality. Ascertaining the outcomes of critically ill COVID-19 patients is crucial to optimise hospital and ICU resources and provide the appropriate intensity level of care

Classical scholarship: the Byzantine contribution

Discusses the effect that Byzantine work has had on our perception of ancient Greek language and literature (especially Homer and drama)

Reading and Commenting on Aristotle

Questo studio esamina brevemente la ricezione Bizantina della filosofia di Aristotele. Include uno studio sui manoscritti principali del corpus aristotelicum e dei principali lettori di Aristotele