Kinase inhibitors for advanced medullary thyroid carcinoma

The recent availability of molecular targeted therapies leads to a reconsideration of the treatment strategy for patients with distant metastases from medullary thyroid carcinoma. In patients with progressive disease, treatment with kinase inhibitors should be offered

CO 2 Migration Monitoring Methodology in the Shallow Subsurface: Lessons Learned From the CO 2 FIELDLAB Project

International audienceA CO 2 migration field laboratory for testing of monitoring methods has been established in the glaciofluvial-glaciomarine Holocene deposits of the Svelvik ridge, near Oslo. A shallow CO 2 injection experiment was conducted in September 2011 in which approximately 1700 kg of CO 2 was injected at 18 m depth below surface. The objectives of this experiment were to (i) detect and, where possible, quantify migrated CO 2 concentrations, (ii) evaluate the sensitivity of the monitoring tools and (iii) study the impact of the vadose zone on measurements. This paper describes the injection, discusses the joint interpretation of the results and suggests some recommendations for further work

Seismic constraints on rotation of Sun-like star and mass of exoplanet

Rotation is thought to drive cyclic magnetic activity in the Sun and Sun-like stars. Stellar dynamos, however, are poorly understood owing to the scarcity of observations of rotation and magnetic fields in stars. Here, inferences are drawn on the internal rotation of a distant Sun-like star by studying its global modes of oscillation. We report asteroseismic constraints imposed on the rotation rate and the inclination of the spin axis of the Sun-like star HD 52265, a principal target observed by the CoRoT satellite that is known to host a planetary companion. These seismic inferences are remarkably consistent with an independent spectroscopic observation (rotational line broadening) and with the observed rotation period of star spots. Furthermore, asteroseismology constrains the mass of exoplanet HD 52265b. Under the standard assumption that the stellar spin axis and the axis of the planetary orbit coincide, the minimum spectroscopic mass of the planet can be converted into a true mass of 1.85 (+0.52,-0.42) M_Jupiter, which implies that it is a planet, not a brown dwarf.Comment: Published in Proceedings of the National Academy of Sciences (5 pages, 5 figures, 3 tables). Available at http://www.pnas.org/cgi/doi/10.1073/pnas.130329111

Gene expression profiling of human adrenocortical tumors using complementary deoxyribonucleic Acid microarrays identifies several candidate genes as markers of malignancy.

International audienceThe aim of this study was to identify predictor sets of genes whose over- or underexpression in human sporadic adrenocortical tumors would help to identify malignant vs. benign tumors and to predict postsurgical metastatic recurrence. For this, we analyzed the expression of 230 candidate genes using cDNA microarrays in a series of 57 well-characterized human sporadic adrenocortical tumors (33 adenomas and 24 carcinomas). We identified two clusters of genes (the IGF-II cluster containing eight genes, including IGF-II, and the steroidogenesis cluster containing six genes encoding steroidogenic enzymes plus eight other genes) whose combined levels of expression appeared to be good predictors of malignancy. This predictive value was as strong as that of the pathological score of Weiss. The analysis of the population of carcinomas (13 tumors) for genes whose expression would be strongly different between recurring and nonrecurring tumors allowed identification of 14 genes meeting these criteria. Among these genes, there are probably new markers of tumor evolution that will deserve additional validation on a larger scale. Taken together, these results show that the parallel analysis of the expression levels of a selected group of genes on microgram quantities of tumor RNA (a quantity that can be obtained from fine needle aspirations) appears as a complementary method to histopathology for the diagnosis and prognosis of evolution of adrenocortical carcinomas

What Is the Optimal Duration of Adjuvant Mitotane Therapy in Adrenocortical Carcinoma? An Unanswered Question

A relevant issue on the treatment of adrenocortical carcinoma (ACC) concerns the optimal duration of adjuvant mitotane treatment. We tried to address this question, assessing whether a correlation exists between the duration of adjuvant mitotane treatment and recurrence-free survival (RFS) of patients with ACC. We conducted a multicenter retrospective analysis on 154 ACC patients treated for ≥12 months with adjuvant mitotane after radical surgery and who were free of disease at the mitotane stop. During a median follow-up of 38 months, 19 patients (12.3%) experienced recurrence. We calculated the RFS after mitotane (RFSAM), from the landmark time-point of mitotane discontinuation, to overcome immortal time bias. We found a wide variability in the duration of adjuvant mitotane treatment among different centers and also among patients cared for at the same center, reflecting heterogeneous practice. We did not find any survival advantage in patients treated for longer than 24 months. Moreover, the relationship between treatment duration and the frequency of ACC recurrence was not linear after stratifying our patients in tertiles of length of adjuvant treatment. In conclusion, the present findings do not support the concept that extending adjuvant mitotane treatment over two years is beneficial for ACC patients with low to moderate risk of recurrence

A multi-site campaign to measure solar-like oscillations in Procyon. II. Mode frequencies

We have analyzed data from a multi-site campaign to observe oscillations in the F5 star Procyon. The data consist of high-precision velocities that we obtained over more than three weeks with eleven telescopes. A new method for adjusting the data weights allows us to suppress the sidelobes in the power spectrum. Stacking the power spectrum in a so-called echelle diagram reveals two clear ridges that we identify with even and odd values of the angular degree (l=0 and 2, and l=1 and 3, respectively). We interpret a strong, narrow peak at 446 muHz that lies close to the l=1 ridge as a mode with mixed character. We show that the frequencies of the ridge centroids and their separations are useful diagnostics for asteroseismology. In particular, variations in the large separation appear to indicate a glitch in the sound-speed profile at an acoustic depth of about 1000 s. We list frequencies for 55 modes extracted from the data spanning 20 radial orders, a range comparable to the best solar data, which will provide valuable constraints for theoretical models. A preliminary comparison with published models shows that the offset between observed and calculated frequencies for the radial modes is very different for Procyon than for the Sun and other cool stars. We find the mean lifetime of the modes in Procyon to be 1.29 +0.55/-0.49 days, which is significantly shorter than the 2-4 days seen in the Sun.Comment: accepted for publication in Ap

Sunitinib for metastatic progressive phaeochromocytomas and paragangliomas: results from FIRSTMAPPP, an academic, multicentre, international, randomised, placebo-controlled, double-blind, phase 2 trial

Background: No randomised controlled trial has ever been done in patients with metastatic phaeochromocytomas and paragangliomas. Preclinical and first clinical evidence suggested beneficial effects of sunitinib. We aimed to evaluate the safety and efficacy of sunitinib in patients with metastatic phaeochromocytomas and paragangliomas. Methods: FIRSTMAPPP is a multicentre, international, randomised, placebo-controlled, double-blind, phase 2 trial done at 14 academic centres across four European countries. Eligible participants were adults (aged ≥18 years) with sporadic or inherited progressive metastatic phaeochromocytomas and paragangliomas. Patients were randomly assigned (1:1) to receive either oral sunitinib (37·5 mg per day) or placebo. Randomisation was stratified according to SDHB status (mutation present vs wild type) and number of previous systemic therapies (0 vs ≥1). Primary endpoint was the rate of progression-free survival at 12 months according to real-time central review (Response Evaluation Criteria in Solid Tumours version 1.1). On the basis of a two-step Simon model, we aimed for the accrual of 78 patients, assuming a 20% improvement of the 12-month progression-free survival rate from 20% to 40%, to conclude that sunitinib is effective. Crossover from the placebo group was allowed. This trial is registered with ClinicalTrials.gov, number NCT01371201, and is closed for enrolment. Findings: From Dec 1, 2011, to Jan 31, 2019, a total of 78 patients with progressive metastatic phaeochromocytomas and paragangliomas were enrolled (39 patients per group). 25 (32%) of 78 patients had germline SDHx variants and 54 (69%) had used previous therapies. The primary endpoint was met, with a 12-month progression-free survival in 14 of 39 patients (36% [90% CI 23-50]) in the sunitinib group. In the placebo group, the 12-month progression-free survival in seven of 39 patients was 19% (90% CI 11-31), validating the hypotheses of our study design. The most frequent grade 3 or 4 adverse events were asthenia (seven [18%] of 39 and one [3%] of 39), hypertension (five [13%] and four [10%]), and back or bone pain (one [3%] and three [8%]) in the sunitinib and placebo groups, respectively. Three deaths occurred in the sunitinib group: these deaths were due to respiratory insufficiency, amyotrophic lateral sclerosis, and rectal bleeding. Only the latter event was considered drug related. Two deaths occurred in the placebo group due to aspiration pneumonia and septic shock. Interpretation: This first randomised trial supports the use of sunitinib as the medical option with the highest level of evidence for anti-tumour efficacy in progressive metastatic phaeochromocytomas and paragangliomas. Funding: French Ministry of Health, through the National Institute for Cancer, German Ministry of Education and Research, and the German Research Foundation within the CRC/Transregio 205/2, EU Seventh Framework Programme, and a private donator grant

The flare likelihood and region eruption forecasting (FLARECAST) project: flare forecasting in the big data & machine learning era

The European Union funded the FLARECAST project, that ran from January 2015 until February 2018. FLARECAST had a research-to-operations (R2O) focus, and accordingly introduced several innovations into the discipline of solar flare forecasting. FLARECAST innovations were: first, the treatment of hundreds of physical properties viewed as promising flare predictors on equal footing, extending multiple previous works; second, the use of fourteen (14) different machine learning techniques, also on equal footing, to optimize the immense Big Data parameter space created by these many predictors; third, the establishment of a robust, three-pronged communication effort oriented toward policy makers, space-weather stakeholders and the wider public. FLARECAST pledged to make all its data, codes and infrastructure openly available worldwide. The combined use of 170+ properties (a total of 209 predictors are now available) in multiple machine-learning algorithms, some of which were designed exclusively for the project, gave rise to changing sets of best-performing predictors for the forecasting of different flaring levels, at least for major flares. At the same time, FLARECAST reaffirmed the importance of rigorous training and testing practices to avoid overly optimistic pre-operational prediction performance. In addition, the project has (a) tested new and revisited physically intuitive flare predictors and (b) provided meaningful clues toward the transition from flares to eruptive flares, namely, events associated with coronal mass ejections (CMEs). These leads, along with the FLARECAST data, algorithms and infrastructure, could help facilitate integrated space-weather forecasting efforts that take steps to avoid effort duplication. In spite of being one of the most intensive and systematic flare forecasting efforts to-date, FLARECAST has not managed to convincingly lift the barrier of stochasticity in solar flare occurrence and forecasting: solar flare prediction thus remains inherently probabilistic