Effects on quality of life, anti-cancer responses, breast conserving surgery and survival with neoadjuvant docetaxel: a randomised study of sequential weekly versus three-weekly docetaxel following neoadjuvant doxorubicin and cyclophosphamide in women with primary breast cancer

<p>Abstract</p> <p>Background</p> <p>Weekly docetaxel has occasionally been used in the neoadjuvant to downstage breast cancer to reduce toxicity and possibly enhance quality of life. However, no studies have compared the standard three weekly regimen to the weekly regimen in terms of quality of life. The primary aim of our study was to compare the effects on QoL of weekly versus 3-weekly sequential neoadjuvant docetaxel. Secondary aims were to determine the clinical and pathological responses, incidence of Breast Conserving Surgery (BCS), Disease Free Survival (DFS) and Overall Survival (OS).</p> <p>Methods</p> <p>Eighty-nine patients receiving four cycles of doxorubicin and cyclophosphamide were randomised to receive twelve cycles of weekly docetaxel (33 mg/m²) or four cycles of 3-weekly docetaxel (100 mg/m²). The Functional Assessment of Cancer Therapy-Breast and psychosocial questionnaires were completed.</p> <p>Results</p> <p>At a median follow-up of 71.5 months, there was no difference in the Trial Outcome Index scores between treatment groups. During weekly docetaxel, patients experienced less constipation, nail problems, neuropathy, tiredness, distress, depressed mood, and unhappiness. There were no differences in overall clinical response (93% vs. 90%), pathological complete response (20% vs. 27%), and breast-conserving surgery (BCS) rates (49% vs. 42%). Disease-free survival and overall survival were similar between treatment groups.</p> <p>Conclusions</p> <p>Weekly docetaxel is well-tolerated and has less distressing side-effects, without compromising therapeutic responses, Breast Conserving Surgery (BCS) or survival outcomes in the neoadjuvant setting.</p> <p>Trial registration</p> <p>ISRCTN: <a href="http://www.controlled-trials.com/ISRCTN09184069">ISRCTN09184069</a></p

Organisms or biological individuals? Combining physiological and evolutionary individuality

International audienceThe definition of biological individuality is one of the most discussed topics in philosophy of biology, but current debate has focused almost exclusively on evolution-based accounts. Moreover, several participants in this debate consider the notions of a biological individual and an organism as equivalent. In this paper, I show that the debates would be considerably enriched and clarified if philosophers took into account two elements. First, physiological fields are crucial for the understanding of biological individuality. Second, the category of biological individuals should be divided into two subcategories: physiological individuals and evolutionary individuals, which suggests that the notions of organism and biological individual should not be used interchangeably. I suggest that the combination of an evolutionary and a physiological perspective will enable biologists and philosophers to supply an account of biological individuality that will be both more comprehensive and more in accordance with scientific practices

Validation and utility of ARDS subphenotypes identified by machine-learning models using clinical data: an observational, multicohort, retrospective analysis

International audienceTwo acute respiratory distress syndrome (ARDS) subphenotypes (hyperinflammatory and hypoinflammatory) with distinct clinical and biological features and differential treatment responses have been identified using latent class analysis (LCA) in seven individual cohorts. To facilitate bedside identification of subphenotypes, clinical classifier models using readily available clinical variables have been described in four randomised controlled trials. We aimed to assess the performance of these models in observational cohorts of ARDS. Methods: In this observational, multicohort, retrospective study, we validated two machine-learning clinical classifier models for assigning ARDS subphenotypes in two observational cohorts of patients with ARDS: Early Assessment of Renal and Lung Injury (EARLI; n=335) and Validating Acute Lung Injury Markers for Diagnosis (VALID; n=452), with LCA-derived subphenotypes as the gold standard. The primary model comprised only vital signs and laboratory variables, and the secondary model comprised all predictors in the primary model, with the addition of ventilatory variables and demographics. Model performance was assessed by calculating the area under the receiver operating characteristic curve (AUC) and calibration plots, and assigning subphenotypes using a probability cutoff value of 0·5 to determine sensitivity, specificity, and accuracy of the assignments. We also assessed the performance of the primary model in EARLI using data automatically extracted from an electronic health record (EHR; EHR-derived EARLI cohort). In Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure (LUNG SAFE; n=2813), a multinational, observational ARDS cohort, we applied a custom classifier model (with fewer variables than the primary model) to determine the prognostic value of the subphenotypes and tested their interaction with the positive end-expiratory pressure (PEEP) strategy, with 90-day mortality as the dependent variable. Findings: The primary clinical classifier model had an area under receiver operating characteristic curve (AUC) of 0·92 (95% CI 0·90–0·95) in EARLI and 0·88 (0·84–0·91) in VALID. Performance of the primary model was similar when using exclusively EHR-derived predictors compared with manually curated predictors (AUC=0·88 [95% CI 0·81–0·94] vs 0·92 [0·88–0·97]). In LUNG SAFE, 90-day mortality was higher in patients assigned the hyperinflammatory subphenotype than in those with the hypoinflammatory phenotype (414 [57%] of 725 vs 694 [33%] of 2088; p<0·0001). There was a significant treatment interaction with PEEP strategy and ARDS subphenotype (p=0·041), with lower 90-day mortality in the high PEEP group of patients with the hyperinflammatory subphenotype (hyperinflammatory subphenotype: 169 [54%] of 313 patients in the high PEEP group vs 127 [62%] of 205 patients in the low PEEP group; hypoinflammatory subphenotype: 231 [34%] of 675 patients in the high PEEP group vs 233 [32%] of 734 patients in the low PEEP group). Interpretation: Classifier models using clinical variables alone can accurately assign ARDS subphenotypes in observational cohorts. Application of these models can provide valuable prognostic information and could inform management strategies for personalised treatment, including application of PEEP, once prospectively validated. Funding: US National Institutes of Health and European Society of Intensive Care Medicine

Geoeconomic variations in epidemiology, ventilation management, and outcomes in invasively ventilated intensive care unit patients without acute respiratory distress syndrome: a pooled analysis of four observational studies

Background: Geoeconomic variations in epidemiology, the practice of ventilation, and outcome in invasively ventilated intensive care unit (ICU) patients without acute respiratory distress syndrome (ARDS) remain unexplored. In this analysis we aim to address these gaps using individual patient data of four large observational studies. Methods: In this pooled analysis we harmonised individual patient data from the ERICC, LUNG SAFE, PRoVENT, and PRoVENT-iMiC prospective observational studies, which were conducted from June, 2011, to December, 2018, in 534 ICUs in 54 countries. We used the 2016 World Bank classification to define two geoeconomic regions: middle-income countries (MICs) and high-income countries (HICs). ARDS was defined according to the Berlin criteria. Descriptive statistics were used to compare patients in MICs versus HICs. The primary outcome was the use of low tidal volume ventilation (LTVV) for the first 3 days of mechanical ventilation. Secondary outcomes were key ventilation parameters (tidal volume size, positive end-expiratory pressure, fraction of inspired oxygen, peak pressure, plateau pressure, driving pressure, and respiratory rate), patient characteristics, the risk for and actual development of acute respiratory distress syndrome after the first day of ventilation, duration of ventilation, ICU length of stay, and ICU mortality. Findings: Of the 7608 patients included in the original studies, this analysis included 3852 patients without ARDS, of whom 2345 were from MICs and 1507 were from HICs. Patients in MICs were younger, shorter and with a slightly lower body-mass index, more often had diabetes and active cancer, but less often chronic obstructive pulmonary disease and heart failure than patients from HICs. Sequential organ failure assessment scores were similar in MICs and HICs. Use of LTVV in MICs and HICs was comparable (42·4% vs 44·2%; absolute difference -1·69 [-9·58 to 6·11] p=0·67; data available in 3174 [82%] of 3852 patients). The median applied positive end expiratory pressure was lower in MICs than in HICs (5 [IQR 5-8] vs 6 [5-8] cm H2O; p=0·0011). ICU mortality was higher in MICs than in HICs (30·5% vs 19·9%; p=0·0004; adjusted effect 16·41% [95% CI 9·52-23·52]; p&lt;0·0001) and was inversely associated with gross domestic product (adjusted odds ratio for a US$10 000 increase per capita 0·80 [95% CI 0·75-0·86]; p&lt;0·0001). Interpretation: Despite similar disease severity and ventilation management, ICU mortality in patients without ARDS is higher in MICs than in HICs, with a strong association with country-level economic status

Search for flavour-changing neutral-current couplings between the top quark and the photon with the ATLAS detector at s=13 TeV

This letter documents a search for flavour-changing neutral currents (FCNCs), which are strongly suppressed in the Standard Model, in events with a photon and a top quark with the ATLAS detector. The analysis uses data collected in pp collisions at s=13 TeV during Run 2 of the LHC, corresponding to an integrated luminosity of 139 fb−1. Both FCNC top-quark production and decay are considered. The final state consists of a charged lepton, missing transverse momentum, a b-tagged jet, one high-momentum photon and possibly additional jets. A multiclass deep neural network is used to classify events either as signal in one of the two categories, FCNC production or decay, or as background. No significant excess of events over the background prediction is observed and 95% CL upper limits are placed on the strength of left- and right-handed FCNC interactions. The 95% CL bounds on the branching fractions for the FCNC top-quark decays, estimated (expected) from both top-quark production and decay, are B(t→uγ)<0.85(0.88−0.25+0.37)×10−5 and B(t→cγ)<4.2(3.40−0.95+1.35)×10−5 for a left-handed tqγ coupling, and B(t→uγ)<1.2(1.20−0.33+0.50)×10−5 and B(t→cγ)<4.5(3.70−1.03+1.47)×10−5 for a right-handed coupling