Intense lasers interacting with dense targets accelerate relativistic electron beams, which transport part of the laser energy into the target depth. However, the overall laser-to-target energy ...coupling efficiency is impaired by the large divergence of the electron beam, intrinsic to the laser-plasma interaction. Here we demonstrate that an efficient guiding of MeV electrons with about 30 MA current in solid matter is obtained by imposing a laser-driven longitudinal magnetostatic field of 600 T. In the magnetized conditions the transported energy density and the peak background electron temperature at the 60-μm-thick target's rear surface rise by about a factor of five, as unfolded from benchmarked simulations. Such an improvement of energy-density flux through dense matter paves the ground for advances in laser-driven intense sources of energetic particles and radiation, driving matter to extreme temperatures, reaching states relevant for planetary or stellar science as yet inaccessible at the laboratory scale and achieving high-gain laser-driven thermonuclear fusion.
Quasi-static magnetic-fields up to 800 T are generated in the interaction of intense laser pulses (500 J, 1 ns, ) with capacitor-coil targets of different materials. The reproducible magnetic-field ...peak and rise-time, consistent with the laser pulse duration, were accurately inferred from measurements with GHz-bandwidth inductor pickup coils (B-dot probes). Results from Faraday rotation of polarized optical laser light and deflectometry of energetic proton beams are consistent with the B-dot probe measurements at the early stages of the target charging, up to ns, and then are disturbed by radiation and plasma effects. The field has a dipole-like distribution over a characteristic volume of 1 mm3, which is consistent with theoretical expectations. These results demonstrate a very efficient conversion of the laser energy into magnetic fields, thus establishing a robust laser-driven platform for reproducible, well characterized, generation of quasi-static magnetic fields at the kT-level, as well as for magnetization and accurate probing of high-energy-density samples driven by secondary powerful laser or particle beams.
Efficacy of endocrine therapy in HR+/HER2- metastatic breast cancer could differ depending on the presence of BRCA1/2 germline mutation.
The ESME metastatic breast cancer platform (NCT03275311) is a ...French real world database. Multivariable models including a time-varying approach and landmark analyses assessed the association between time-dependent gBRCA status (categorised as gBRCAm, gBRCAwt (wild type), and untested), overall survival (OS), and first-line progression-free survival (PFS1).
A total of 170 patients were gBRCAm carriers, 676 gBRCAwt, and 12,930 were untested at baseline. In the multivariable analysis, gBRCAm carriers overall had a lower OS compared to gBRCAwt (adjusted HR 95% CI 1.26 1.03-1.55). gBRCAm patients treated with front-line endocrine therapy had lower adjusted OS (adjusted HR 95% CI = 1.54 1.03-2.32) and PFS1 (adjusted HR 95% CI 1.58 1.17-2.12) compared to gBRCAwt patients. However, for patients who received frontline chemotherapy, neither OS nor PFS1 differed between gBRCAm carriers and the other groups (HR versus gBRCAwt for OS: 1.12 0.88-1.41, p = 0.350; PFS1: 1.09 0.90-1.31, p = 0.379).
In this large cohort of HR+/HER2- MBC patients treated in a pre-CDK4/6 inhibitors era, gBRCAm status was associated with a lower OS and lower PFS following first-line endocrine therapy, but not following first-line chemotherapy.
Purpose
Older cancer patients are underrepresented in clinical trials. We aimed to evaluate the enrollment of older women aged 70 years old (yo) or over with metastatic breast cancer (MBC) in ...clinical trials.
Methods
We used the national Epidemio-Strategy and Medical Economics MBC Data Platform, a French multi-center real-life database. We selected MBC women over 70yo, without central nervous system metastases, with at least one line of systemic treatment, between January 1st, 2008 and December 31st, 2016, and had no other cancer in the 5 years before MBC. The primary objective was to evaluate the proportion of patients enrolled in clinical trials according to their age. Secondary objective was to identify variables associated with enrollment in older ones.
Results
5552 women were aged ≥ 70 (median 74yo; IQR 72–77). 14,611 were less than 70. Of the older ones, 239 (4%) were enrolled in a clinical trial during first line of treatment, compared with 1529 (10.5%) for younger ones. Multivariable analysis of variables predicting for enrollment during first line of treatment in older patients were younger age (OR 0.50 95%CI 0.33–0.76 for the 80–85yo class; OR 0.17 95%CI 0.06–0.39 for the 85yo and more class), good ECOG Performance Status (PS 0–1) (OR 0.15 95%CI 0.08–0.27 for the PS 2–4 class), HER2 + disease (OR 1.78 95%CI 1.27–2.48), type of treatment (chemotherapy/targeted therapy/immunotherapy OR 5.01 95%CI 3.13–8.18), and period (OR 1.65 95%CI 1.22–2.26 for 2012–2016, compared to 2008–2011).
Conclusion
In this large database, few older MBC patients were enrolled in a trial compared with younger ones.
The estimated rate of de novo metastatic breast cancer (dnMBC) at the time of diagnosis is between 5 to 12%. International guidelines recommend metastatic work-up (MWU) only in women with advanced ...breast cancer. The purpose of this study was to describe the characteristics and prognosis of patients with dnMBC diagnosed without an initial indication for MWU.
We conducted a retrospective, comparative study in dnMBC patients selected from the ESME-MBC cohort. Patients were treated in France between 2008 and 2016. We compared two populations: patients in whom dnMBC was diagnosed by staging although not indicated by guidelines (non-guideline staging NGS) and those in whom dnMBC was diagnosed by guideline staging (GS).
During the study period, 22,463 patients with MBC were included in the ESME cohort. Among them, 6698 were dnMBC patients. In 247 of these patients (6% of dnMBC and 1% of the overall population), dnMBC was diagnosed by non-guideline staging. Women in this group were significantly younger (57 vs. 59 years, p = 0.02) and had fewer metastatic sites at diagnosis than dnMBC-GS patients. The two groups were not significantly different in terms of the other characteristics. Overall survival (OS) and progression-free survival (PFS) were better in the dnMBC-NGS group than in the dnMBC-GS group. The impact on survival was confirmed by univariate and multivariate analysis (HR 1.83 1.31–2.57, p < 0.01).
This study provides the first description of a very specific population. These patients with dnMBC-NGS were younger and more likely to have oligometastatic disease with a better prognosis.
•T1/T2 N0 de novo metastatic breast cancer (MBC) represented 6% of all de novo MBC.•Metastatic diagnosis in this population implied an unrecommended workup.•These patients were younger with oligometastatic disease and had a better prognosis.•Locoregional therapy prior to diagnosis in this population did not change survival.
Leptomeningeal metastasis (LM) is a rare complication of metastatic breast cancer (MBC), with high morbidity/mortality rates. Our study aimed to describe the largest-to-date real-life population of ...MBC patients treated with intrathecal (IT) therapy and to evaluate prognostic models.
The Epidemiological Strategy and Medical Economics (ESME) MBC database (NCT03275311) includes all consecutive patients who have initiated treatment for MBC since 2008. Overall survival (OS) of patients treated with IT therapy was estimated using the Kaplan–Meier method. Prognostic models were constructed using Cox proportional hazards models. Performance was evaluated using C-index and calibration plots.
Of the 22 266 patients included in the database between 2008 and 2016, 312 received IT therapy and were selected for our analysis. Compared with non-IT-treated patients, IT-treated patients were younger at MBC relapse (median age: 52 years versus 61 years) and more often had lobular histology (23.4% versus 12.7%) or triple-negative subtype (24.7% versus 13.3%) (all P < 0.001). Median OS was 4.5 months 95% confidence interval (CI) 3.8-5.6 and 1-year survival rate was 25.6%. Significant prognostic factors associated with poorer outcome on multivariable analysis were triple-negative subtype (hazard ratio 1.81, 95% CI 1.32-2.47), treatment line ≥3 (hazard ratio 1.88, 95% CI 1.30-2.73), ≥3 other metastatic sites (hazard ratio 1.33, 95% CI 1.01-1.74) and IT cytarabine or thiotepa versus methotrexate (hazard ratio 1.68, 95% CI 1.28-2.22), while concomitant systemic therapy was associated with better OS (hazard ratio 0.47, 95% CI 0.35-0.62) (all P < 0.001). We validated two previously published prognostic scores, the Curie score and the Breast-graded prognostic assessment, both with C-index of 0.57.
MBC patients with LM treated with IT therapy have a poor prognosis. We could identify a subgroup of patients with better prognosis, when concomitant systemic therapy and IT methotrexate were used.
•The outcome of BC patients with IT-treated LM is poor, with a median OS of 4.5 months.•Concomitant systemic therapy may improve the outcome in IT-treated patients.•Patients treated with IT methotrexate had better outcome than those treated with IT cytarabine/thiotepa.•The Curie and Breast-graded prognostic assessment scores were prognostic for IT-treated patients.
Obesity and associated plethora of diseases constitute a major public health challenge worldwide. The conjunction of profound changes in our lifestyle and a thrifty genetic that evolved in an ...environment of food scarcity largely explains this epidemic situation. Food abundance promotes our specific appetite for the more palatable food generally rich in lipids. It is noteworthy that this attraction for fatty food is not specific to humans. Rats and mice also spontaneously prefer lipid-rich food in a free-choice situation. Detection of lipids in food requires the presence of specific sensors located in strategic places (e.g., oral cavity, small intestine, brain) whose activation results in a modulation of the eating behavior. Recent data strongly suggest that the glycoprotein CD36 plays a significant role in this sensing system.
Nous avons récemment montré qu’une obésité induite chez la souris par un régime riche en acides gras saturés perturbe la détection oro-sensorielle des lipides alimentaires. En effet, les souris ...obèses deviennent incapables de détecter correctement la présence de faibles concentrations de lipides lors de tests de double choix. Une corrélation inverse entre masse grasse et seuil de détection orale des lipides a été trouvée. Ce phénomène, dont l’origine est un dysfonctionnement de la cascade de signalisation CD36 dépendante dans la papille gustative caliciforme (CVP), est réversible puisqu’une perte de masse grasse induite par une restriction calorique permet une restauration du seuil de détection des lipides (Chevrot, Bernard et al. 2013). Des travaux récents indiquent qu’une injection massive de lipopolysaccharides (LPS) entraine une augmentation de l’expression de cytokines pro-inflammatoires ainsi qu’une diminution de la prolifération des cellules gustatives dans la CVP chez la souris mince (Cohn, Kim et al. 2010).
Le but de cette étude était de déterminer s’il existe un lien entre l’obésité induite par un régime riche en acides gras saturés, l’inflammation et la capacité de détection orale des lipides alimentaires.
Des souris C57Bl6 ont reçu pendant 4 semaines un régime « high fat » (HF) contenant 32 % (m/m) d’huile de palme, puis ont été soumises ou non à une phase de restriction calorique (60 % de l’apport journalier en régime HF). L’évolution de la composition corporelle déterminée par Echo-MRI ainsi que la quantité de lipopolysaccharides (LPS) plasmatique ont été mesurées. Des tests de comportement alimentaire en double choix ont été réalisés avec une solution témoin (0,3 % de gomme de xanthane) et une série de solutions huileuses (0,02 – 2 % d’huile de colza + 0,3 % de gomme de xanthane). Les quantités d’ARN messagers de différents gènes cibles, marqueurs de l’inflammation (IL1(β, CD68) ou du renouvellement cellulaire (Ki67) dans la CVP ont été analysées par RT-QPCR.
Les souris soumises au régime HF ont vu leur masse grasse significativement augmenter par rapport aux souris nourries avec un régime standard (35,0 % ± 1,7 vs 14,5 % ± 2,6, P<0,001), ce phénomène étant réversé par la restriction calorique. Les tests de doubles choix ont mis en évidence une diminution significative de la préférence pour les lipides alimentaires chez les souris obèses (e.g. pour une émulsion à 2 % de lipides, 76,33±4,4 % vs 97,44±0,6 % chez les témoins minces, P<0,001) avec un retour aux valeurs témoins chez les souris en restriction calorique (91,55±1,6% vs 97,44±0,6% chez les témoins, ns). On constate une augmentation significative de la quantité de LPS circulant chez les animaux obèses (31,42±2,3ng/ml) comparativement aux animaux témoins (23,18±2,4 ng/ml) ou en restriction calorique (14,21±1 ng/ml) démontrant que ce régime obésogène est pro-inflammatoire. Des corrélations positives entre masse grasse et LPS plasmatique ont été mises en évidence. En revanche, des corrélations inverses ont été trouvées entre masse grasse ou concentration plasmatique de LPS et préférence pour les lipides. L’analyse de l’expression de gènes cibles au niveau des CVP a permis de mettre en évidence une augmentation de la teneur en ARNm codant pour IL1β (cytokine pro-inflammatoire), et CD68 (marqueur d’invasion macrophagique) mais une diminution des ARNm Ki67 (marqueur de prolifération cellulaire).
Ces travaux montrent pour la première fois l’existence d’un lien entre l’obésité induite par un régime, l’attraction pour les lipides et l’inflammation au niveau de papilles gustatives (CVP).
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