The identification of chromosomal rearrangements involving the anaplastic lymphoma kinase (ALK) gene in ~3–5% of non–small cell lung cancer (NSCLC) tissues and the demonstration that the ...first‐in‐class ALK tyrosine kinase inhibitor, crizotinib, can effectively target these tumors represent a significant advance in the evolution of personalized medicine for NSCLC. Single‐arm studies demonstrating rapid and durable responses in the majority of ALK‐positive NSCLC patients treated with crizotinib have been followed by a randomized phase III clinical trial in which superiority of crizotinib over chemotherapy was seen in previously treated ALK‐positive NSCLC patients. However, despite the initial responses, most patients develop acquired resistance to crizotinib. Several novel therapeutic approaches targeting ALK‐positive NSCLC are currently under evaluation in clinical trials, including second‐generation ALK inhibitors, such as LDK378, CH5424802 (RO5424802802), and AP26113, and heat shock protein 90 inhibitors.
Clinical Pharmacology & Therapeutics (2013); 95 1, 15–23 advance online publication 13 November 2013. doi:10.1038/clpt.2013.200
The efficacy of the ALK inhibitor crizotinib as compared with standard chemotherapy as first-line treatment for advanced ALK-positive non-small-cell lung cancer (NSCLC) is unknown.
We conducted an ...open-label, phase 3 trial comparing crizotinib with chemotherapy in 343 patients with advanced ALK-positive nonsquamous NSCLC who had received no previous systemic treatment for advanced disease. Patients were randomly assigned to receive oral crizotinib at a dose of 250 mg twice daily or to receive intravenous chemotherapy (pemetrexed, 500 mg per square meter of body-surface area, plus either cisplatin, 75 mg per square meter, or carboplatin, target area under the curve of 5 to 6 mg per milliliter per minute) every 3 weeks for up to six cycles. Crossover to crizotinib treatment after disease progression was permitted for patients receiving chemotherapy. The primary end point was progression-free survival as assessed by independent radiologic review.
Progression-free survival was significantly longer with crizotinib than with chemotherapy (median, 10.9 months vs. 7.0 months; hazard ratio for progression or death with crizotinib, 0.45; 95% confidence interval CI, 0.35 to 0.60; P<0.001). Objective response rates were 74% and 45%, respectively (P<0.001). Median overall survival was not reached in either group (hazard ratio for death with crizotinib, 0.82; 95% CI, 0.54 to 1.26; P=0.36); the probability of 1-year survival was 84% with crizotinib and 79% with chemotherapy. The most common adverse events with crizotinib were vision disorders, diarrhea, nausea, and edema, and the most common events with chemotherapy were nausea, fatigue, vomiting, and decreased appetite. As compared with chemotherapy, crizotinib was associated with greater reduction in lung cancer symptoms and greater improvement in quality of life.
Crizotinib was superior to standard first-line pemetrexed-plus-platinum chemotherapy in patients with previously untreated advanced ALK-positive NSCLC. (Funded by Pfizer; PROFILE 1014 ClinicalTrials.gov number, NCT01154140.).
Millimeter observations of CO gas in planetesimal belts show a high detection rate around A stars, but few detections for later type stars. We present the first CO detection in a planetesimal belt ...around an M star, TWA 7. The optically thin CO (J = 3-2) emission is colocated with previously identified dust emission from the belt, and the emission velocity structure is consistent with Keplerian rotation around the central star. The detected CO is not well shielded against photodissociation, and must thus be continuously replenished by gas release from exocomets within the belt. We analyze in detail the process of exocometary gas release and destruction around young M dwarfs and how this process compares to earlier type stars. Taking these differences into account, we find that CO generation through exocometary gas release naturally explains the increasing CO detection rates with stellar luminosity, mostly because the CO production rate from the collisional cascade is directly proportional to stellar luminosity. More luminous stars will therefore on average host more massive (and hence more easily detectable) exocometary CO disks, leading to the higher detection rates observed. The current CO detection rates are consistent with a ubiquitous release of exocometary gas in planetesimal belts, independent of spectral type.
Massive galaxies in the early Universe have been shown to be forming stars at surprisingly high rates. Prominent examples are dust-obscured galaxies which are luminous when observed at sub-millimetre ...wavelengths and which may be forming stars at a rate of 1,000 solar masses (M ) per year. These intense bursts of star formation are believed to be driven by mergers between gas-rich galaxies. Probing the properties of individual star-forming regions within these galaxies, however, is beyond the spatial resolution and sensitivity of even the largest telescopes at present. Here we report observations of the sub-millimetre galaxy SMMJ2135-0102 at redshift z = 2.3259, which has been gravitationally magnified by a factor of 32 by a massive foreground galaxy cluster lens. This magnification, when combined with high-resolution sub-millimetre imaging, resolves the star-forming regions at a linear scale of only 100 parsecs. We find that the luminosity densities of these star-forming regions are comparable to the dense cores of giant molecular clouds in the local Universe, but they are about a hundred times larger and 107 times more luminous. Although vigorously star-forming, the underlying physics of the star-formation processes at z 2 appears to be similar to that seen in local galaxies, although the energetics are unlike anything found in the present-day Universe.
MET exon 14 alterations are oncogenic drivers of non-small-cell lung cancers (NSCLCs)
. These alterations are associated with increased MET activity and preclinical sensitivity to MET inhibition
. ...Crizotinib is a multikinase inhibitor with potent activity against MET
. The antitumor activity and safety of crizotinib were assessed in 69 patients with advanced NSCLCs harboring MET exon 14 alterations. Objective response rate was 32% (95% confidence interval (CI), 21-45) among 65 response-evaluable patients. Objective responses were observed independent of the molecular heterogeneity that characterizes these cancers and did not vary by splice-site region and mutation type of the MET exon 14 alteration, concurrent increased MET copy number or the detection of a MET exon 14 alteration in circulating tumor DNA. The median duration of response was 9.1 months (95% CI, 6.4-12.7). The median progression-free survival was 7.3 months (95% CI, 5.4-9.1). MET exon 14 alteration defines a molecular subgroup of NSCLCs for which MET inhibition with crizotinib is active. These results address an unmet need for targeted therapy in people with lung cancers with MET exon 14 alterations and adds to an expanding list of genomically driven therapies for oncogenic subsets of NSCLC.
We investigate the apparent discrepancy between gas and dust outer radii derived from millimeter observations of protoplanetary disks. Using 230 and 345 GHz continuum and CO image data from the ...Submillimeter Array for four nearby disk systems (HD 163296, TW Hydrae, GM Aurigae, and MWC 480), we examine models of circumstellar disk structure and the effects of their treatment of the outer disk edge. We show that for these disks, models described by power laws in surface density and temperature that are truncated at an outer radius are incapable of reproducing both the gas and dust emission simultaneously: the outer radius derived from the dust continuum emission is always significantly smaller than the extent of the molecular gas disk traced by CO emission. However, a simple model motivated by similarity solutions of the time evolution of accretion disks that includes a tapered exponential edge in the surface density distribution (and the same number of free parameters) does much better at reproducing both the gas and dust emission. While this analysis does not rule out the disparate radii implied by the truncated power law models, a realistic alternative disk model, grounded in the physics of accretion, provides a consistent picture for the extent of both the gas and dust.
Context. Deuterium fractionation has been used to study the thermal history of prestellar environments. Their formation pathways trace different regions of the disk and may shed light into the ...physical structure of the disk, including locations of important features for planetary formation. Aims. We aim to constrain the radial extent of the main deuterated species; we are particularly interested in spatially characterizing the high and low temperature pathways for enhancing deuteration of these species. Methods. We observed the disk surrounding the Herbig Ae star HD 163296 using ALMA in Band 6 and obtained resolved spectral imaging data of DCO+ (J = 3 − 2), DCN (J = 3 − 2) and N2D+ (J = 3 − 2) with synthesized beam sizes of 0.̋53 × 0.̋42, 0.̋53 × 0.̋42, and 0.̋50 × 0.̋39, respectively. We adopted a physical model of the disk from the literature and use the 3D radiative transfer code LIME to estimate an excitation temperature profile for our detected lines. We modeled the radial emission profiles of DCO+, DCN, and N2D+, assuming their emission is optically thin, using a parametric model of their abundances and our excitation temperature estimates. Results. DCO+ can be described by a three-region model with constant-abundance rings centered at 70 AU, 150 AU, and 260 AU. The DCN radial profile peaks at about 60 AU and N2D+ is seen in a ring at 160 AU. Simple models of both molecules using constant abundances reproduce the data. Assuming reasonable average excitation temperatures for the whole disk, their disk-averaged column densities (and deuterium fractionation ratios) are 1.6–2.6×1012 cm-2 (0.04–0.07), 2.9–5.2×1012 cm-2 (~0.02), and 1.6–2.5×1011 cm-2 (0.34–0.45) for DCO+, DCN, and N2D+, respectively. Conclusions. Our simple best-fit models show a correlation between the radial location of the first two rings in DCO+ and the DCN and N2D+ abundance distributions that can be interpreted as the high and low temperature deuteration pathways regimes. The origin of the third DCO+ ring at 260 AU is unknown but may be due to a local decrease of ultraviolet opacity allowing the photodesorption of CO or due to thermal desorption of CO as a consequence of radial drift and settlement of dust grains. The derived Df values agree with previous estimates of 0.05 for DCO+/HCO+ and 0.02 for DCN/HCN in HD 163296, and 0.3−0.5 for N2D+/N2H+ in AS 209, a T Tauri disk. The high N2D+/N2H+ confirms N2D+ as a good candidate for tracing ionization in the cold outer disk.
We present a suite of Atacama Large Millimeter Array (ALMA) interferometric molecular line and continuum images that elucidate, on linear size scales of ∼30-40 au, the chemical structure of the ...nearby, evolved, protoplanetary disk orbiting the close binary system V4046 Sgr. The observations were undertaken in the 1.1-1.4 mm wavelength range (ALMA Bands 6 and 7) with antenna configurations involving maximum baselines of several hundred meters, yielding subarcsecond-resolution images in more than a dozen molecular species and isotopologues. Isotopologues of CO and HCN display centrally peaked morphologies of integrated emission-line intensity, whereas the line emission from complex nitrile group molecules (HC3N, CH3CN), deuterated molecules (DCN, DCO+), hydrocarbons (as traced by C2H), and potential CO ice line tracers (N2H+, and H2CO) appears as a sequence of sharp and diffuse rings. The dimensions and morphologies of HC3N and CH3CN emission are suggestive of photodesorption of organic ices from the surfaces of dust grains, while the sequence of increasing radius of peak intensity represented by DCN (smallest), DCO+, N2H+, and H2CO (largest) is qualitatively consistent with the expected decline of midplane gas temperature with increasing disk radius. Empirical modeling indicates that the sharp-edged C2H emission ring lies at relatively deep disk layers, leaving open the question of the origin of C2H abundance enhancements in evolved disks. This study of the "molecular anatomy" of V4046 Sgr should serve as motivation for additional subarcsecond ALMA molecular line imaging surveys of nearby, evolved protoplanetary disks aimed at addressing major uncertainties in protoplanetary disk physical and chemical structure and molecular production pathways.
Resolved observations of millimeter-sized dust, tracing larger planetesimals, have pinpointed the location of 26 Edgeworth-Kuiper Belt analogs. We report that a belt's distance R to its host star ...correlates with the star's luminosity L , following with a low intrinsic scatter of ∼17%. Remarkably, our Edgeworth-Kuiper Belt in the solar system and the two CO snow lines imaged in protoplanetary disks lie close to this R-L relation, suggestive of an intrinsic relationship between protoplanetary disk structures and belt locations. To test the effect of bias on the relation, we use a Monte Carlo approach and simulate uncorrelated model populations of belts. We find that observational bias could produce the slope and intercept of the R-L relation but is unable to reproduce its low scatter. We then repeat the simulation taking into account the collisional evolution of belts, following the steady-state model that fits the belt population as observed through infrared excesses. This significantly improves the fit by lowering the scatter of the simulated R-L relation; however, this scatter remains only marginally consistent with the one observed. The inability of observational bias and collisional evolution alone to reproduce the tight relationship between belt radius and stellar luminosity could indicate that planetesimal belts form at preferential locations within protoplanetary disks. The similar trend for CO snow line locations would then indicate that the formation of planetesimals or planets in the outer regions of planetary systems is linked to the volatility of their building blocks, as postulated by planet formation models.
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