Gene expression profile predicts outcome after anthracycline-based adjuvant chemotherapy in early breast cancer

International audiencePrognosis of early beast cancer is heterogeneous. Today, no histoclinical or biological factor predictive for clinical outcome after adjuvant anthracycline-based chemotherapy (CT) has been validated and introduced in routine use. Using DNA microarrays, we searched for a gene expression signature associated with metastatic relapse after adjuvant anthracycline-based CT without taxane. We profiled a multicentric series of 595 breast cancers including 498 treated with such adjuvant CT. The identification of the prognostic signature was done using a metagene-based supervised approach in a learning set of 323 patients. The signature was then tested on an independent validation set comprising 175 similarly treated patients, 128 of them from the PACS01 prospective clinical trial. We identified a 3-metagene predictor of metastatic relapse in the learning set, and confirmed its independent prognostic impact in the validation set. In multivariate analysis, the predictor outperformed the individual current prognostic factors, as well as the Nottingham Prognostic Index-based classifier, both in the learning and the validation sets, and added independent prognostic information. Among the patients treated with adjuvant anthracycline-based CT, with a median follow-up of 68 months, the 5-year metastasis-free survival was 82% in the "good-prognosis" group and 56% in the "poor-prognosis" group. Our predictor refines the prediction of metastasis-free survival after adjuvant anthracycline-based CT and might help tailoring adjuvant CT regimens

Reduced plantar-flexors extensibility but improved selective motor control associated with age in young children with unilateral cerebral palsy and equinovalgus gait

Background:Children with spastic cerebral palsy gradually lose muscle extensibility but the interplay between the muscular and neurological components of the condition is unclear especially in the pathophysiology of equinovalgus gait. Aim:This study aimed to quantify the muscular and neurological disorders in young children with unilateral cerebral palsy, and to investigate the role of the peroneus longus (PL) in equinovalgus gait. Design, setting and population:This was an observational study with prospective assessments of 31 children (median age: 2.9 years, range: 2-6) from outpatient clinic in a tertiary teaching hospital. Methods:Clinical measures of plantar flexor extensibility (XV1), stretch response (XV3), and active ankle dorsiflexion angle (XA) were obtained as well as walking velocity and electromyography of tibialis anterior (TA), gastrocnemius medialis (GM) and PL during walking. Results:We found reduced extensibility of the triceps surae on the paretic side (effect size r = 0.73, p < 0.001 for soleus and r = 0.68, p < 0.001 for gastrocnemius) and a correlation between reduced triceps surae extensibility and earlier stretch response (rho = 0.5, p = 0.004). During the swing phase, there was major co-contraction between TA and GM/PL, and significantly larger activation of PL compared to GM (r = 0.46, p = 0.011). Both GM and PL activation decreased with age. Conclusions:Our results suggest gradual deterioration of the muscular disorder and a link between the muscular and neurological disorders, although plantar flexor co-contraction improved with age. The PL was more activated than the GM and may be considered an intervention target to treat equinovalgus gait

Prendre une ville au XVIe siècle

Depuis 1993, un groupe interdisciplinaire réunit à l'Université de Provence d'Aix des chercheurs travaillant tous sur le XVIe siècle et dans des domaines différents : histoire, littérature française, histoire des arts, littérature italienne, littérature espagnole. Ils livrent ici leurs regards croisés sur le thème « Prendre une ville au XVIe siècle ». Il ne s'agit pas d'un traité d'art militaire ou de poliorcétique, mais d'une réflexion sur un champ vaste qui va du factuel à l'imaginaire : une façon de rompre le carcan du cloisonnement en disciplines et de restituer, si possible, la richesse d'une réalité toujours difficile à saisir et toujours grosse de promesses : ne reste-t-il pas encore bien des citadelles à prendre

Cost-Effectiveness Analysis of Trastuzumab (Herceptin) in HER2-Overexpressed Metastatic Breast Cancer

International audienceOBJECTIVE:In women with Human Epidermal growth Receptor 2 (HER2)-positive metastatic breast cancer (MBC), Trastuzumab has become the standard of care but previous studies have raised doubts about its economic acceptability. We carried out the first cost-effectiveness study for Trastuzumab in MBC patients, in France, that is based on observed resource use and outcomes in clinical practice.METHODS:We retrospectively analyzed 47 HER2-positive MBC patients in a before-and-after design study. Nineteen patients did not receive Trastuzumab ("before" Trastuzumab introduction in clinical practice) and 28 patients received Trastuzumab (the "after" population). Direct medical costs were estimated on the basis of the physical quantities reported in the patient medical records, for the period from first metastatic progression until death or date of patient last news. Monetary values (2002 French francs) were attributed to these quantities on the basis of unit costs and incremental cost-effectiveness ratios were calculated.RESULTS:In the Trastuzumab group, median overall survival was significantly higher (37 months vs. 19 months in the non-Ttrastuzumab group, P = 0.001) but total treatment costs were 3 times higher (€ 39,608 vs. € 12,795). The cost per additional life-year saved by Trastuzumab treatment was estimated to be € 27,492 (95% confidence interval: € 20,964-€ 34,020/year of life [bootstrapped estimation]).CONCLUSIONS:Our data suggest that despite its high unit price, Trastuzumab should be considered cost-effective in MBC patients to the extent that its incremental cost per life-year saved remains lower than gross domestic product per capita in countries like France

Diagnostic performance of one-step nucleic acid amplification for intraoperative sentinel node metastasis detection in breast cancer patients.

International audienceThe purpose of this prospective multicenter study was to assess one-step nucleic acid amplification (OSNA) for intraoperative sentinel lymph node (SLN) metastasis detection in breast cancer patients, using final histology as the reference standard. OSNA results were also compared to intraoperative histology SLN evaluation and to standard clinicopathological risk markers. For this study, fresh SLNs were cut in four blocks, and alternate blocks were used for OSNA and histology. CK19 mRNA copy number was categorized as strongly positive, positive, or negative. Positive histology was defined as presence of macrometastasis or micrometastasis. When discrepancies occurred, the entire SLNs were subjected to histological studies and the node lysates to additional molecular studies. Five hundred and three SLN samples from 233 patients were studied. Mean time to evaluate two SLNs was 40 minutes. Sensitivity per patient was 91.4% (95%CI, 76.9%-98.2%), specificity 93.3% (95%CI, 88.6%-96.6%), positive likelihood ratio 13.7, and negative likelihood ratio 0.1. Sensitivity was 63.6% for frozen sections and 47.1% for touch imprint cytology. Both methods were 100% specific. Positive histology and positive OSNA were significantly associated with highest clinical stage, N1 status, and vascular invasion; and OSNA results correlated with HER2/neu status and benefited patients with negative histology. These findings show that OSNA assay can allow detection of SLN metastasis in breast cancer patients intra-operatively with a good sensitivity thus minimizing the need for second surgeries for axillary lymph node detection

Recent Improvements in Geant4 Electromagnetic Physics Models and Interfaces

An overview of the electromagnetic (EM) physics of the Geant4 toolkit is presented Two sets of EM models are available: the 'Standard' initially focused on high energy physics (HEP) while the 'Low-energy' was developed for medical, space and other applications The 'Standard' models provide a faster computation but are less accurate for keV energies, the 'Low-energy' models are more CPU time consuming A common interface to EM physics models has been developed allowing a natural combination of ultra-relativistic, relativistic and low-energy models for the same run providing both precision and CPU performance Due to this migration additional capabilities become available The new developments include relativistic models for bremsstrahlung and e+e- pair production, models of multiple and single scattering, hadron/ion ionization, microdosimetry for very low energies and also improvements in existing Geant4 models In parallel, validation suites and benchmarks have been intensively developed (author

COVID-19 outcomes in patients with inflammatory rheumatic and musculoskeletal diseases treated with rituximab: a cohort study

International audienceBackground: Various observations have suggested that the course of COVID-19 might be less favourable in patients with inflammatory rheumatic and musculoskeletal diseases receiving rituximab compared with those not receiving rituximab. We aimed to investigate whether treatment with rituximab is associated with severe COVID-19 outcomes in patients with inflammatory rheumatic and musculoskeletal diseases.Methods: In this cohort study, we analysed data from the French RMD COVID-19 cohort, which included patients aged 18 years or older with inflammatory rheumatic and musculoskeletal diseases and highly suspected or confirmed COVID-19. The primary endpoint was the severity of COVID-19 in patients treated with rituximab (rituximab group) compared with patients who did not receive rituximab (no rituximab group). Severe disease was defined as that requiring admission to an intensive care unit or leading to death. Secondary objectives were to analyse deaths and duration of hospital stay. The inverse probability of treatment weighting propensity score method was used to adjust for potential confounding factors (age, sex, arterial hypertension, diabetes, smoking status, body-mass index, interstitial lung disease, cardiovascular diseases, cancer, corticosteroid use, chronic renal failure, and the underlying disease [rheumatoid arthritis vs others]). Odds ratios and hazard ratios and their 95% CIs were calculated as effect size, by dividing the two population mean differences by their SD. This study is registered with ClinicalTrials.gov, NCT04353609.Findings: Between April 15, 2020, and Nov 20, 2020, data were collected for 1090 patients (mean age 55·2 years [SD 16·4]); 734 (67%) were female and 356 (33%) were male. Of the 1090 patients, 137 (13%) developed severe COVID-19 and 89 (8%) died. After adjusting for potential confounding factors, severe disease was observed more frequently (effect size 3·26, 95% CI 1·66-6·40, p=0·0006) and the duration of hospital stay was markedly longer (0·62, 0·46-0·85, p=0·0024) in the 63 patients in the rituximab group than in the 1027 patients in the no rituximab group. 13 (21%) of 63 patients in the rituximab group died compared with 76 (7%) of 1027 patients in the no rituximab group, but the adjusted risk of death was not significantly increased in the rituximab group (effect size 1·32, 95% CI 0·55-3·19, p=0·53).Interpretation: Rituximab therapy is associated with more severe COVID-19. Rituximab will have to be prescribed with particular caution in patients with inflammatory rheumatic and musculoskeletal diseases