Trametinib: First Global Approval Wright, Cameron J. M.; McCormack, Paul L.
Drugs (New York, N.Y.),
07/2013, Letnik:
73, Številka:
11
Journal Article
Recenzirano
Trametinib is an orally bioavailable mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitor with antineoplastic activity. The compound specifically binds to MEK1 and MEK2, resulting in ...inhibition of growth factor-mediated cell signalling and cellular proliferation in various cancers. Originally developed by Japan Tobacco, GlaxoSmithKline has licensed exclusive worldwide rights to the compound and conducted development in a number of different cancer types. Trametinib, as a monotherapy, has been approved in the US for the treatment of unresectable or metastatic malignant melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test. The compound, as a monotherapy, has also been submitted for regulatory review in the EU for BRAF mutation-positive malignant melanoma, and is in phase III development in Europe, Argentina, Canada and Oceania. Phase II development is underway for pancreatic cancer, non-small cell lung cancer and relapsed or refractory leukaemias. GlaxoSmithKline is also developing trametinib for use in combination with dabrafenib in BRAF V600 mutation-positive metastatic cutaneous melanoma; the combination is at the preregistration stage in the EU and a phase III clinical programme is underway worldwide. Phase II development for this combination is also underway in colorectal cancer. Several phase I trials have also been initiated to evaluate trametinib in combination with other drugs for the treatment of various solid tumours and haematological malignancies. A paediatric oral solution formulation has been assessed against the oral tablet formulation in a phase I trial. This article summarizes the milestones in the development of trametinib leading to this first approval for unresectable or metastatic BRAF mutation-positive malignant melanoma.
ABSTRACT
The Galaxy And Mass Assembly Survey (GAMA) covers five fields with highly complete spectroscopic coverage (>95 per cent) to intermediate depths (r < 19.8 or i < 19.0 mag), and collectively ...spans 250 deg2 of equatorial or southern sky. Four of the GAMA fields (G09, G12, G15, and G23) reside in the European Southern Observatory (ESO) VST KiDS and ESO VISTA VIKING survey footprints, which combined with our GALEX, WISE, and Herschel data provide deep uniform imaging in the $FUV/NUV/u/g/r/i/Z/Y/J/H/K_s/W1/W2/W3/W4/P100/P160/S250/S350/S500$ bands. Following the release of KiDS DR4, we describe the process by which we ingest the KiDS data into GAMA (replacing the SDSS data previously used for G09, G12, and G15), and redefine our core optical and near-infrared (NIR) catalogues to provide a complete and homogeneous data set. The source extraction and analysis is based on the new ProFound image analysis package, providing matched-segment photometry across all bands. The data are classified into stars, galaxies, artefacts, and ambiguous objects, and objects are linked to the GAMA spectroscopic target catalogue. Additionally, a new technique is employed utilizing ProFound to extract photometry in the unresolved MIR–FIR regime. The catalogues including the full FUV–FIR photometry are described and will be fully available as part of GAMA DR4. They are intended for both standalone science, selection for targeted follow-up with 4MOST, as well as an accompaniment to the upcoming and ongoing radio arrays now studying the GAMA 23h field.
The Cryogenic Dark Matter Search low ionization threshold experiment (CDMSlite) searches for interactions between dark matter particles and germanium nuclei in cryogenic detectors. The experiment has ...achieved a low energy threshold with improved sensitivity to low-mass ( < 10 GeV / c 2 ) dark matter particles. We present an analysis of the final CDMSlite dataset, taken with a different detector than was used for the two previous CDMSlite datasets. This analysis includes a data “salting” method to protect against bias, improved noise discrimination, background modeling, and the use of profile likelihood methods to search for a dark matter signal in the presence of backgrounds. We achieve an energy threshold of 70 eV and significantly improve the sensitivity for dark matter particles with masses between 2.5 and 10 GeV / c 2 compared to previous analyses. We set an upper limit on the dark matter-nucleon scattering cross section in germanium of 5.4 × 10 − 42 cm 2 at 5 GeV / c 2 , a factor of ~ 2.5 improvement over the previous CDMSlite result.
NIDDK, JDRF, and the Diabetic Neuropathy Study Group of EASD sponsored a meeting to explore the current status of animal models of diabetic peripheral neuropathy. The goal of the workshop was to ...develop a set of consensus criteria for the phenotyping of rodent models of diabetic neuropathy. The discussion was divided into five areas: (1) status of commonly used rodent models of diabetes, (2) nerve structure, (3) electrophysiological assessments of nerve function, (4) behavioral assessments of nerve function, and (5) the role of biomarkers in disease phenotyping. Participants discussed the current understanding of each area, gold standards (if applicable) for assessments of function, improvements of existing techniques, and utility of known and exploratory biomarkers. The research opportunities in each area were outlined, providing a possible roadmap for future studies. The meeting concluded with a discussion on the merits and limitations of a unified approach to phenotyping rodent models of diabetic neuropathy and a consensus formed on the definition of the minimum criteria required for establishing the presence of the disease. A neuropathy phenotype in rodents was defined as the presence of statistically different values between diabetic and control animals in 2 of 3 assessments (nocifensive behavior, nerve conduction velocities, or nerve structure). The participants propose that this framework would allow different research groups to compare and share data, with an emphasis on data targeted toward the therapeutic efficacy of drug interventions.
ABSTRACT
Boyajian’s star is an apparently normal main-sequence F-type star with a very unusual light curve. The dipping activity of the star, discovered during the Kepler mission, presents deep, ...asymmetric, and aperiodic events. Here we present high-resolution spectroscopic follow-up during some dimming events recorded post-Kepler observations, from ground-based telescopes. We analyse data from the HERMES, HARPS-N, and FIES spectrographs to characterize the stellar atmosphere and to put some constraints on the hypotheses that have appeared in the literature concerning the occulting elements. The star’s magnetism, if existing, is not extreme. The spots on the surface, if present, would occupy 0.02 per cent of the area, at most. The chromosphere, irrespective of the epoch of observation, is hotter than the values expected from radiative equilibrium, meaning that the star has some degree of activity. We find no clear evidence of the interstellar medium or exocoments being responsible for the dimmings of the light curve. However, we detect at 1–2σ level, a decrease of the radial velocity of the star during the first dip recorded after the Kepler observations. We claim the presence of an optically thick object with likely inclined and high impact parameter orbits that produces the observed Rossiter–McLaughlin effect.
Background The Society of Thoracic Surgeons (STS) creates risk-adjustment models for common cardiothoracic operations for quality improvement purposes. Our aim was to update the lung cancer resection ...risk model utilizing the STS General Thoracic Surgery Database (GTSD) with a larger and more contemporary cohort. Methods We queried the STS GTSD for all surgical resections of lung cancers from January 1, 2012, through December 31, 2014. Logistic regression was used to create three risk models for adverse events: operative mortality, major morbidity, and composite mortality and major morbidity. Results In all, 27,844 lung cancer resections were performed at 231 centers; 62% (n = 17,153) were performed by thoracoscopy. The mortality rate was 1.4% (n = 401), major morbidity rate was 9.1% (n = 2,545), and the composite rate was 9.5% (n = 2,654). Predictors of mortality included age, being male, forced expiratory volume in 1 second, body mass index, cerebrovascular disease, steroids, coronary artery disease, peripheral vascular disease, renal dysfunction, Zubrod score, American Society of Anesthesiologists rating, thoracotomy approach, induction therapy, reoperation, tumor stage, and greater extent of resection (all p < 0.05). For major morbidity and the composite measure, cigarette smoking becomes a risk factor whereas stage, renal dysfunction, congestive heart failure, and cerebrovascular disease lose significance. Conclusions Operative mortality and complication rates are low for lung cancer resection among surgeons participating in the GTSD. Risk factors from the prior lung cancer resection model are refined, and new risk factors such as prior thoracic surgery are identified. The GTSD risk models continue to evolve as more centers report and data are audited for quality assurance.
Background The purpose of this analysis was to revise the model for perioperative risk for esophagectomy for cancer utilizing The Society of Thoracic Surgeons General Thoracic Surgery Database to ...provide enhanced risk stratification and quality improvement measures for contributing centers. Methods The Society of Thoracic Surgeons General Thoracic Surgery Database was queried for all patients treated for esophageal cancer with esophagectomy between July 1, 2011, and June 30, 2014. Multivariable risk models for major morbidity, perioperative mortality, and combined morbidity and mortality were created with the inclusion of surgical approach as a risk factor. Results In all, 4,321 esophagectomies were performed by 164 participating centers. The most common procedures included Ivor Lewis (32.5%), transhiatal (21.7%), minimally invasive esophagectomy, Ivor Lewis type (21.4%), and McKeown (10.0%). Sixty-nine percent of patients received induction therapy. Perioperative mortality (inpatient and 30-day) was 135 of 4,321 (3.4%). Major morbidity occurred in 1,429 patients (33.1%). Major morbidities include unexpected return to operating (15.6%), anastomotic leak (12.9%), reintubation (12.2%), initial ventilation beyond 48 hours (3.5%), pneumonia (12.2%), renal failure (2.0%), and recurrent laryngeal nerve paresis (2.0%). Statistically significant predictors of combined major morbidity or mortality included age more than 65 years, body mass index 35 kg/m2 or greater, preoperative congestive heart failure, Zubrod score greater than 1, McKeown esophagectomy, current or former smoker, and squamous cell histology. Conclusion Thoracic surgeons participating in The Society of Thoracic Surgeons General Thoracic Surgery Database perform esophagectomy with low morbidity and mortality. McKeown esophagectomy is an independent predictor of combined postoperative morbidity or mortality. Revised predictors for perioperative outcome were identified to facilitate quality improvement processes and hospital comparisons.
This article presents an analysis and the resulting limits on light dark matter inelastically scattering off of electrons, and on dark photon and axionlike particle absorption, using a ...second-generation SuperCDMS high-voltage eV-resolution detector. The 0.93 g Si detector achieved a 3 eV phonon energy resolution; for a detector bias of 100 V, this corresponds to a charge resolution of 3% of a single electron-hole pair. The energy spectrum is reported from a blind analysis with 1.2 g-days of exposure acquired in an above-ground laboratory. With charge carrier trapping and impact ionization effects incorporated into the dark matter signal models, the dark matter-electron cross section σe is constrained for dark matter masses from 0.5 to 104 MeV / c2; in the mass range from 1.2 to 50 eV / c2 the dark photon kinetic mixing parameter ϵ and the axioelectric coupling constant gae are constrained. The minimum 90% confidence-level upper limits within the above-mentioned mass ranges are σe = 8.7 × 10−34 cm2, ϵ = 3.3 × 10−14, and gae = 1.0 × 10−9.
Since the introduction of new growth charts in the mid 1990s, there has been confusion about which charts should be used, with many districts using more than one version. Because of this uncertainty, ...an expert working party, the Growth Reference Review Group, was convened by the Royal College of Paediatrics and Child Health to provide guidance on the validity and comparability of the different charts currently in use. This paper describes the technical background to the construction and evaluation of growth charts and outlines the group's findings on the validity of each growth reference in relation to contemporary British children. The group concluded that for most clinical purposes the UK90 reference is superior and for many measures is the only usable reference that can be recommended, while the original Tanner–Whitehouse and the Gairdner–Pearson charts are no longer reliable for use at any age. After the age of 2 the revised Buckler–Tanner references are still suitable for assessing height. There are presently no reliable head circumference reference charts for use beyond infancy. The group propose that apart from refinements of chart design and layout, the new UK90 reference should now be “frozen”, with any future revisions only undertaken after careful planning and widespread consultation
Background The aim of this study is to create models for perioperative risk of lung cancer resection using the STS GTDB (Society of Thoracic Surgeons General Thoracic Database). Methods The STS GTDB ...was queried for all patients treated with resection for primary lung cancer between January 1, 2002 and June 30, 2008. Three separate multivariable risk models were constructed (mortality, major morbidity, and composite mortality or major morbidity). Results There were 18,800 lung cancer resections performed at 111 participating centers. Perioperative mortality was 413 of 18,800 (2.2%). Composite major morbidity or mortality occurred in 1,612 patients (8.6%). Predictors of mortality include the following: pneumonectomy ( p < 0.001), bilobectomy ( p < 0.001), American Society of Anesthesiology rating ( p < 0.018), Zubrod performance status ( p < 0.001), renal dysfunction ( p = 0.001), induction chemoradiation therapy ( p = 0.01), steroids ( p = 0.002), age ( p < 0.001), urgent procedures ( p = 0.015), male gender ( p = 0.013), forced expiratory volume in one second ( p < 0.001), and body mass index ( p = 0.015). Conclusions Thoracic surgeons participating in the STS GTDB perform lung cancer resections with a low mortality and morbidity. The risk-adjustment models created have excellent performance characteristics and identify important predictors of mortality and major morbidity for lung cancer resections. These models may be used to inform clinical decisions and to compare risk-adjusted outcomes for quality improvement purposes.
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