The combination of bortezomib with chemotherapy to treat relapsed/refractory acute lymphoblastic leukaemia of childhood

Achieving complete remission (CR) in childhood relapsed/refractory acute lymphoblastic leukaemia (ALL) is a difficult task. Bortezomib, a proteasome inhibitor, has invitro activity against ALL blasts. A phase I-II trial, reported by the Therapeutic Advances in Childhood Leukaemia and Lymphoma (TACL) consortium, demonstrated that bortezomib with chemotherapy has acceptable toxicity and remarkable activity in patients with relapsed ALL failing 2-3 previous regimens. We evaluated bortezomib in combination with chemotherapy in 30 and 7 children with B-cell precursor (BCP) and T-cell ALL, respectively. Bortezomib (13mg/m(2)/dose) was administered intravenously on days 1, 4, 8, and 11. Chemotherapy agents were the same as those used in the TACL trial, consisting of dexamethasone, doxorubicin, vincristine and pegylated asparaginase. Three patients (81%) died due to infections. Twenty-seven patients (729%) achieved CR or CR with incomplete platelet recovery (CRp). Fourteen had minimal residual disease (MRD) lower than 01%. Twenty-two of 30 BCP-ALL patients (733%) and 5/7 patients (71%) with T-cell ALL achieved CR/CRp. The 2-year overall survival (OS) is 313%; CR/CRp patients with an MRD response had a remarkable 2-year OS of 684%. These data confirm that the combination of bortezomib with chemotherapy is a suitable/effective option for childhood relapsed/refractory ALL

Chemical Cartography with APOGEE: Large-scale Mean Metallicity Maps of the Milky Way

We present Galactic mean metallicity maps derived from the first year of the SDSS-III APOGEE experiment. Mean abundances in different zones of Galactocentric radius (0 < R < 15 kpc) at a range of heights above the plane (0 < |z| < 3 kpc), are derived from a sample of nearly 20,000 stars with unprecedented coverage, including stars in the Galactic mid-plane at large distances. We also split the sample into subsamples of stars with low and high-[{\alpha}/M] abundance ratios. We assess possible biases in deriving the mean abundances, and find they are likely to be small except in the inner regions of the Galaxy. A negative radial gradient exists over much of the Galaxy; however, the gradient appears to flatten for R < 6 kpc, in particular near the Galactic mid-plane and for low-[{\alpha}/M] stars. At R > 6 kpc, the gradient flattens as one moves off of the plane, and is flatter at all heights for high-[{\alpha}/M] stars than for low-[{\alpha}/M] stars. Alternatively, these gradients can be described as vertical gradients that flatten at larger Galactocentric radius; these vertical gradients are similar for both low and high-[{\alpha}/M] populations. Stars with higher [{\alpha}/M] appear to have a flatter radial gradient than stars with lower [{\alpha}/M]. This could suggest that the metallicity gradient has grown steeper with time or, alternatively, that gradients are washed out over time by migration of stars.Comment: 16 pages, 12 figures, submitted to A

Very Metal-poor Stars in the Outer Galactic Bulge Found by the Apogee Survey

Despite its importance for understanding the nature of early stellar generations and for constraining Galactic bulge formation models, at present little is known about the metal-poor stellar content of the central Milky Way. This is a consequence of the great distances involved and intervening dust obscuration, which challenge optical studies. However, the Apache Point Observatory Galactic Evolution Experiment (APOGEE), a wide-area, multifiber, high-resolution spectroscopic survey within Sloan Digital Sky Survey III (SDSS-III), is exploring the chemistry of all Galactic stellar populations at infrared wavelengths, with particular emphasis on the disk and the bulge. An automated spectral analysis of data on 2,403 giant stars in twelve fields in the bulge obtained during APOGEE commissioning yielded five stars with low metallicity([Fe/H]$\le-1.7$), including two that are very metal-poor [Fe/H]$\sim-2.1$ by bulge standards. Luminosity-based distance estimates place the five stars within the outer bulge, where other 1,246 of the analyzed stars may reside. A manual reanalysis of the spectra verifies the low metallicities, and finds these stars to be enhanced in the $\alpha$-elements O, Mg, and Si without significant $\alpha$-pattern differences with other local halo or metal-weak thick-disk stars of similar metallicity, or even with other more metal-rich bulge stars. While neither the kinematics nor chemistry of these stars can yet definitively determine which, if any, are truly bulge members, rather than denizens of other populations co-located with the bulge, the newly-identified stars reveal that the chemistry of metal-poor stars in the central Galaxy resembles that of metal-weak thick-disk stars at similar metallicity.Comment: 6 pages, 3 figures, 2 table

The Milky Way's circular velocity curve between 4 and 14 kpc from APOGEE data

We measure the Milky Way's rotation curve over the Galactocentric range 4 kpc <~ R <~ 14 kpc from the first year of data from the Apache Point Observatory Galactic Evolution Experiment (APOGEE). We model the line-of-sight velocities of 3,365 stars in fourteen fields with b = 0 deg between 30 deg < l < 210 deg out to distances of 10 kpc using an axisymmetric kinematical model that includes a correction for the asymmetric drift of the warm tracer population (\sigma_R ~ 35 km/s). We determine the local value of the circular velocity to be V_c(R_0) = 218 +/- 6 km/s and find that the rotation curve is approximately flat with a local derivative between -3.0 km/s/kpc and 0.4 km/s/kpc. We also measure the Sun's position and velocity in the Galactocentric rest frame, finding the distance to the Galactic center to be 8 kpc < R_0 < 9 kpc, radial velocity V_{R,sun} = -10 +/- 1 km/s, and rotational velocity V_{\phi,sun} = 242^{+10}_{-3} km/s, in good agreement with local measurements of the Sun's radial velocity and with the observed proper motion of Sgr A*. We investigate various systematic uncertainties and find that these are limited to offsets at the percent level, ~2 km/s in V_c. Marginalizing over all the systematics that we consider, we find that V_c(R_0) 99% confidence. We find an offset between the Sun's rotational velocity and the local circular velocity of 26 +/- 3 km/s, which is larger than the locally-measured solar motion of 12 km/s. This larger offset reconciles our value for V_c with recent claims that V_c >~ 240 km/s. Combining our results with other data, we find that the Milky Way's dark-halo mass within the virial radius is ~8x10^{11} M_sun.Comment: submitted to Ap

The APOKASC Catalog: An Asteroseismic and Spectroscopic Joint Survey of Targets in the Kepler Fields

We present the first APOKASC catalog of spectroscopic and asteroseismic properties of 1916 red giants observed in the Kepler fields. The spectroscopic parameters provided from the Apache Point Observatory Galactic Evolution Experiment project are complemented with asteroseismic surface gravities, masses, radii, and mean densities determined by members of the Kepler Asteroseismology Science Consortium. We assess both random and systematic sources of error and include a discussion of sample selection for giants in the Kepler fields. Total uncertainties in the main catalog properties are of order 80 K in Teff , 0.06 dex in [M/H], 0.014 dex in log g, and 12% and 5% in mass and radius, respectively; these reflect a combination of systematic and random errors. Asteroseismic surface gravities are substantially more precise and accurate than spectroscopic ones, and we find good agreement between their mean values and the calibrated spectroscopic surface gravities. There are, however, systematic underlying trends with Teff and log g. Our effective temperature scale is between 0-200 K cooler than that expected from the Infrared Flux Method, depending on the adopted extinction map, which provides evidence for a lower value on average than that inferred for the Kepler Input Catalog (KIC). We find a reasonable correspondence between the photometric KIC and spectroscopic APOKASC metallicity scales, with increased dispersion in KIC metallicities as the absolute metal abundance decreases, and offsets in Teff and log g consistent with those derived in the literature. We present mean fitting relations between APOKASC and KIC observables and discuss future prospects, strengths, and limitations of the catalog data.Comment: 49 pages. ApJSupp, in press. Full machine-readable ascii files available under ancillary data. Categories: Kepler targets, asteroseismology, large spectroscopic survey

The Second APOKASC Catalog: The Empirical Approach

We present a catalog of stellar properties for a large sample of 6676 evolved stars with APOGEE spectroscopic parameters and \textit{Kepler} asteroseismic data analyzed using five independent techniques. Our data includes evolutionary state, surface gravity, mean density, mass, radius, age, and the spectroscopic and asteroseismic measurements used to derive them. We employ a new empirical approach for combining asteroseismic measurements from different methods, calibrating the inferred stellar parameters, and estimating uncertainties. With high statistical significance, we find that asteroseismic parameters inferred from the different pipelines have systematic offsets that are not removed by accounting for differences in their solar reference values. We include theoretically motivated corrections to the large frequency spacing ($\Delta \nu$) scaling relation, and we calibrate the zero point of the frequency of maximum power ($\nu_{\rm max}$) relation to be consistent with masses and radii for members of star clusters. For most targets, the parameters returned by different pipelines are in much better agreement than would be expected from the pipeline-predicted random errors, but 22\% of them had at least one method not return a result and a much larger measurement dispersion. This supports the usage of multiple analysis techniques for asteroseismic stellar population studies. The measured dispersion in mass estimates for fundamental calibrators is consistent with our error model, which yields median random and systematic mass uncertainties for RGB stars of order 4\%. Median random and systematic mass uncertainties are at the 9\% and 8\% level respectively for RC stars.Comment: 29 pages, 26 figures. Submitted ApJSupp. Comments welcome. For access to the main data table (Table 5) use https://www.dropbox.com/s/k33td8ukefwy5tv/APOKASC2_Table5.txt?dl=0; for access to the individual pipeline values (Table 6) use https://www.dropbox.com/s/vl9s2p3obftrv8m/APOKASC2_Table6.txt?dl=

Identifying Contributions to the Stellar Halo from Accreted, Kicked-Out, and In Situ Populations

[Abridged] We present a medium-resolution spectroscopic survey of late-type giant stars at mid-Galactic latitudes of (30$^{\circ}<|b|<60^{\circ}$), designed to probe the properties of this population to distances of $\sim$9 kpc. Because M giants are generally metal-rich and we have limited contamination from thin disk stars by the latitude selection, most of the stars in the survey are expected to be members of the thick disk ($\sim$-0.6) with some contribution from the metal-rich component of the nearby halo. Here we report first results for 1799 stars. The distribution of radial velocity (RV) as a function of l for these stars shows (1) the expected thick disk population and (2) local metal-rich halo stars moving at high speeds relative to the disk, that in some cases form distinct sequences in RV-$l$ space. High-resolution echelle spectra taken for 34 of these "RV outliers" reveal the following patterns across the [Ti/Fe]-[Fe/H] plane: seventeen of the stars have abundances reminiscent of the populations present in dwarf satellites of the Milky Way; eight have abundances coincident with those of the Galactic disk and more metal-rich halo; and nine of the stars fall on the locus defined by the majority of stars in the halo. The chemical abundance trends of the RV outliers suggest that this sample consists predominantly of stars accreted from infalling dwarf galaxies. A smaller fraction of stars in the RV outlier sample may have been formed in the inner Galaxy and subsequently kicked to higher eccentricity orbits, but the sample is not large enough to distinguish conclusively between this interpretation and the alternative that these stars represent the tail of the velocity distribution of the thick disk. Our data do not rule out the possibility that a minority of the sample could have formed from gas {\it in situ} on their current orbits.Comment: 43 pages, 9 figures, 4 tables, published in the Astrophysical Journa

Trastuzumab-lapatinib as neoadjuvant therapy for HER2-positive early breast cancer: Survival analyses of the CHER-Lob trial.

AIM: The Cher-LOB randomised phase II study showed that the combination of lapatinib-trastuzumab plus chemotherapy increases pathologic complete response (pCR) rate compared with chemotherapy plus either trastuzumab or lapatinib. Here, we report the post hoc survival analysis as per treatment arm, pCR and biomarkers. METHODS: The Cher-LOB study randomised 121 patients with human epidermal growth factor receptor 2-positive, stage II-IIIA breast cancer. A specific protocol to collect recurrence-free survival (RFS) and overall survival (OS) data was designed. Tumour-infiltrating lymphocytes (TILs) and PAM50-intrinsic subtyping were evaluated at baseline. RESULTS: At 9-year median follow-up, a trend towards RFS improvement with lapatinib-trastuzumab over trastuzumab was observed (hazard ratio [HR] 0.44, 95% confidence interval [CI] 0.18-1.05). Combining treatment arms, pCR was significantly associated with both RFS (HR 0.12, 95% CI 0.03-0.49) and OS (HR 0.12, 95% CI 0.03-0.49). TILs were significantly associated with RFS (HR = 0.978 for each 1% increment). Luminal-A subtype was a significant and independent predictor of improved RFS as compared with other PAM50-based intrinsic subtypes at the multivariate analysis including the most relevant clinicopathologic variables (HR 0.29, 95% CI 0.09-0.94, p = 0.040). CONCLUSIONS: Cher-LOB trial survival analysis confirmed the prognostic role of pCR and TILs and showed a signal for a better outcome with lapatinib-trastuzumab over trastuzumab. TRIAL REGISTRATION: NCT00429299

The Bulge Metallicity Distribution from the APOGEE Survey

The Apache Point Observatory Galactic Evolution Experiment (APOGEE) provides spectroscopic information of regions of the inner Milky Way, which are inaccessible to optical surveys. We present the first large study of the metallicity distribution of the innermost Galactic regions based on high-quality measurements for 7545 red giant stars within 4.5 kpc of the Galactic center, with the goal to shed light on the structure and origin of the Galactic bulge. Stellar metallicities are found, through multiple Gaussian decompositions, to be distributed in several components, which is indicative of the presence of various stellar populations such as the bar or the thin and the thick disks. Super-solar ([Fe/H] = +0.32) and solar ([Fe/H] = +0.00) metallicity components, tentatively associated with the thin disk and the Galactic bar, respectively, seem to be major contributors near the midplane. A solar-metallicity component extends outwards in the midplane but is not observed in the innermost regions. The central regions (within 3 kpc of the Galactic center) reveal, on the other hand, the presence of a significant metal-poor population ([Fe/H] = −0.46), tentatively associated with the thick disk, which becomes the dominant component far from the midplane ($| Z| \geqslant +0.75$ kpc). Varying contributions from these different components produce a transition region at +0.5 kpc $\leqslant \,| Z| \,\leqslant \ +1.0\,\mathrm{kpc}$, characterized by a significant vertical metallicity gradient

CHEMICAL CARTOGRAPHY with APOGEE: METALLICITY DISTRIBUTION FUNCTIONS and the CHEMICAL STRUCTURE of the MILKY WAY DISK

Using a sample of 69,919 red giants from the SDSS-III/APOGEE Data Release 12, we measure the distribution of stars in the [/Fe] versus [Fe/H] plane and the metallicity distribution functions (MDFs) across an unprecedented volume of the Milky Way disk, with radius 3 < R < 15 kpc and height kpc. Stars in the inner disk (R < 5 kpc) lie along a single track in [/Fe] versus [Fe/H], starting with -enhanced, metal-poor stars and ending at [/Fe] ∼ 0 and [Fe/H] ∼ +0.4. At larger radii we find two distinct sequences in [/Fe] versus [Fe/H] space, with a roughly solar- sequence that spans a decade in metallicity and a high- sequence that merges with the low- sequence at super-solar [Fe/H]. The location of the high- sequence is nearly constant across the disk