Therapeutic resistance remains the principal problem in acute myeloid leukemia (AML). We used area under receiver-operating characteristic curves (AUCs) to quantify our ability to predict therapeutic ...resistance in individual patients, where AUC=1.0 denotes perfect prediction and AUC=0.5 denotes a coin flip, using data from 4601 patients with newly diagnosed AML given induction therapy with 3+7 or more intense standard regimens in UK Medical Research Council/National Cancer Research Institute, Dutch-Belgian Cooperative Trial Group for Hematology/Oncology/Swiss Group for Clinical Cancer Research, US cooperative group SWOG and MD Anderson Cancer Center studies. Age, performance status, white blood cell count, secondary disease, cytogenetic risk and FLT3-ITD/NPM1 mutation status were each independently associated with failure to achieve complete remission despite no early death ('primary refractoriness'). However, the AUC of a bootstrap-corrected multivariable model predicting this outcome was only 0.78, indicating only fair predictive ability. Removal of FLT3-ITD and NPM1 information only slightly decreased the AUC (0.76). Prediction of resistance, defined as primary refractoriness or short relapse-free survival, was even more difficult. Our limited ability to forecast resistance based on routinely available pretreatment covariates provides a rationale for continued randomization between standard and new therapies and supports further examination of genetic and posttreatment data to optimize resistance prediction in AML.
The Atacama Large Millimeter/submillimeter Array (ALMA) radio telescope has commenced science observations of the Sun starting in late 2016. Since the Sun is much larger than the field of view of ...individual ALMA dishes, the ALMA interferometer is unable to measure the background level of solar emission when observing the solar disk. The absolute temperature scale is a critical measurement for much of ALMA solar science, including the understanding of energy transfer through the solar atmosphere, the properties of prominences, and the study of shock heating in the chromosphere. In order to provide an absolute temperature scale, ALMA solar observing will take advantage of the remarkable fast-scanning capabilities of the ALMA 12 m dishes to make single-dish maps of the full Sun. This article reports on the results of an extensive commissioning effort to optimize the mapping procedure, and it describes the nature of the resulting data. Amplitude calibration is discussed in detail: a path that uses the two loads in the ALMA calibration system as well as sky measurements is described and applied to commissioning data. Inspection of a large number of single-dish datasets shows significant variation in the resulting temperatures, and based on the temperature distributions, we derive quiet-Sun values at disk center of 7300 K at
λ
=
3
mm
and 5900 K at
λ
=
1.3
mm
. These values have statistical uncertainties of about 100 K, but systematic uncertainties in the temperature scale that may be significantly larger. Example images are presented from two periods with very different levels of solar activity. At a resolution of about
25
″
, the 1.3 mm wavelength images show temperatures on the disk that vary over about a 2000 K range. Active regions and plages are among the hotter features, while a large sunspot umbra shows up as a depression, and filament channels are relatively cool. Prominences above the solar limb are a common feature of the single-dish images.
This paper describes a new Heterodyne Array Receiver Program (HARP) and Auto-Correlation Spectral Imaging System (ACSIS) that have recently been installed and commissioned on the James Clerk Maxwell ...Telescope. The 16-element focal-plane array receiver, operating in the submillimetre from 325 to 375 GHz, offers high (three-dimensional) mapping speeds, along with significant improvements over single-detector counterparts in calibration and image quality. Receiver temperatures are ∼120 K across the whole band, and system temperatures of ∼300 K are reached routinely under good weather conditions. The system includes a single-sideband (SSB) filter so these are SSB values. Used in conjunction with ACSIS, the system can produce large-scale maps rapidly, in one or more frequency settings, at high spatial and spectral resolution. Fully sampled maps of size can be observed in under 1 h. The scientific need for array receivers arises from the requirement for programmes to study samples of objects of statistically significant size, in large-scale unbiased surveys of galactic and extra-galactic regions. Along with morphological information, the new spectral imaging system can be used to study the physical and chemical properties of regions of interest. Its three-dimensional imaging capabilities are critical for research into turbulence and dynamics. In addition, HARP/ACSIS will provide highly complementary science programmes to wide-field continuum studies and produce the essential preparatory work for submillimetre interferometers such as the Submillimeter Array (SMA) and Atacama Large Millimeter/Submillimeter Array (ALMA).
Several different mutations collaborate with the fusion proteins in core-binding factor acute myeloid leukemia (CBF-AML) to induce leukemogenesis, but their prognostic significance remains unclear. ...We screened 354 predominantly younger (<60 years) adults with t(8;21) (n=199) or inv(16) (n=155) entered into UK MRC trials for KIT, FLT3 tyrosine kinase domain (FLT3(TKD)), N-RAS, K-RAS and c-CBL mutations and FLT3 internal tandem duplications (FLT3(ITD)) and assessed the impact of relative mutant level on outcome. Overall, 28% had KIT, 6% FLT3(ITD), 10% FLT3(TKD), 27% RAS and 6% CBL mutations. Mutant levels for all genes/loci were highly variable. KIT mutations were associated with a higher cumulative incidence of relapse but in multivariate analysis this was only significant for cases with a higher mutant level of 25% or greater (95% confidence interval (CI)=1.01-1.52, P=0.04). Similarly, only FLT3(ITD-HIGH) was a significant adverse factor for overall survival (OS; CI=1.27-5.39, P=0.004). Conversely, FLT3(TKD-HIGH) and CBL(HIGH) were both favorable factors for OS (CI= 0.31-0.89, P=0.01 and CI=0.05-0.85, P=0.02, respectively). KIT mutations were frequently lost at relapse, which is relevant to minimal residual disease detection and the clinical use of KIT inhibitors. These results indicate that relative mutant level should be taken into account when evaluating the impact of mutations in CBF-AML.
Observations of the Sun at millimeter and submillimeter wavelengths offer a unique probe into the structure, dynamics, and heating of the chromosphere; the structure of sunspots; the formation and ...eruption of prominences and filaments; and energetic phenomena such as jets and flares. High-resolution observations of the Sun at millimeter and submillimeter wavelengths are challenging due to the intense, extended, low-contrast, and dynamic nature of emission from the quiet Sun, and the extremely intense and variable nature of emissions associated with energetic phenomena. The Atacama Large Millimeter/submillimeter Array (ALMA) was designed with solar observations in mind. The requirements for solar observations are significantly different from observations of sidereal sources and special measures are necessary to successfully carry out this type of observations. We describe the commissioning efforts that enable the use of two frequency bands, the 3-mm band (Band 3) and the 1.25-mm band (Band 6), for continuum interferometric-imaging observations of the Sun with ALMA. Examples of high-resolution synthesized images obtained using the newly commissioned modes during the solar-commissioning campaign held in December 2015 are presented. Although only 30 of the eventual 66 ALMA antennas were used for the campaign, the solar images synthesized from the ALMA commissioning data reveal new features of the solar atmosphere that demonstrate the potential power of ALMA solar observations. The ongoing expansion of ALMA and solar-commissioning efforts will continue to enable new and unique solar observing capabilities.
Four retrospective studies have reported premature mortality in patients with hypopituitarism with standard mortality ratios (SMRs) varying between 1·20 and 2·17. Patients with hypopituitarism have ...complex endocrine deficiencies, and the mechanisms underpinning any excess mortality are unknown. Furthermore, the suggestion has emerged that endogenous growth-hormone deficiency might account for any excess mortality. We aimed to clarify these issues by doing a large prospective study of total and specific-cause mortality in patients with hypopituitarism.
We followed up 1014 UK patients (514 men, 500 women) with hypopituitarism from January, 1992, to January, 2000. 573 (57%) patients had non-functioning adenomas, 118 (12%) craniopharyngiomas, and 93 (9%) prolactinomas. SMRs were calculated as the ratio of observed deaths to the number of deaths in an age-matched and sex-matched UK population.
The number of observed deaths was 181 compared with the 96·7 expected (SMR 1·87 99% CI 1·62–2·16, p<0·0001). Univariate analysis indicated that mortality was higher in women (2·29 1·86–2·82) than men (1·57 1·28–1·93, p=0·002), in younger patients, in patients with an underlying diagnosis of craniopharyngioma (9·28 5·84–14·75 vs 1·61 1·30–1·99, p<0·0001), and in the 353 patients treated with radiotherapy (2·32 1·71–3·14 vs 1·66 1·30–2·13, p=0·004). Excess mortality was attributed to cardiovascular (1·82 1·30–2·54, p<0·0001), respiratory (2·66 1·72–4·11, p<0·0001), and cerebrovascular (2·44 1·58–4·18, p<0·0001) causes. There was no effect of hormonal deficiency on mortality, except for gonadotropin deficiency, which, if untreated was associated with excess mortality (untreated 2·97 2·13–4·13 vs treated 1·42 0·97–2·07, p<0·0001). Multiple regression analyses identified age at diagnosis, sex, a diagnosis of craniopharyngioma, and untreated gonadotropin deficiency as independent significant factors affecting mortality.
Patients with hypopituitarism have excess mortality, predominantly from vascular and respiratory disease. Age at diagnosis, female sex, and above all, craniopharyngioma were significant independent risk factors. Specific endocrine-axis deficiency, with the exception of untreated gonadotropin deficiency, does not seem to have a role.
Upregulation of the immunosuppressive cell surface glycoprotein, CD200, is a common feature of acute myeloid leukemia (AML) and is associated with poor patient outcome. We investigated whether CD200 ...overexpression on AML cells could specifically compromise patient natural killer (NK) cell anti-tumor responses. We found that CD200(hi) patients showed a 50% reduction in the frequency of activated NK cells (CD56(dim)CD16(+)) compared with CD200(lo) patients. Additionally, NK receptor expression (NKp44 and NKp46) on these cells was also significantly downregulated in CD200(hi) patients. To assess whether NK cell activity was directly influenced by CD200 expression, we examined the effect of ectopic expression of CD200. These assays revealed that both NK cell cytolytic activity and interferon-γ response were significantly reduced toward CD200(+) leukemic targets and that these targets showed increased survival compared with CD200(-) cells. Similarly, NK cells isolated from AML patients were less functionally active toward CD200(hi) autologous blasts from both cytolytic and immunoregulatory perspectives. Finally, blocking CD200 alone was sufficient to recover a significant proportion of NK cell cytolytic activity. Together, these findings provide the first evidence that CD200 has a direct and significant suppressive influence on NK cell activity in AML patients and may contribute to the increased relapse rate in CD200(+) patients.
Therapy-related acute promyelocytic leukemia (t-APL) is relatively rare, with limited data on outcome after treatment with arsenic trioxide (ATO) compared to standard intensive chemotherapy (CTX). We ...evaluated 103 adult t-APL patients undergoing treatment with all-trans retinoic acid (ATRA) alone (n=7) or in combination with ATO (n=24), CTX (n=53), or both (n=19). Complete remissions were achieved after induction therapy in 57% with ATRA, 100% with ATO/ATRA, 78% with CTX/ATRA, and 95% with CTX/ATO/ATRA. Early death rates were 43% for ATRA, 0% for ATO/ATRA, 12% for CTX/ATRA and 5% for CTX/ATO/ATRA. Three patients relapsed, two developed therapy-related acute myeloid leukemia and 13 died in remission including seven patients with recurrence of the prior malignancy. Median follow-up for survival was 3.7 years. None of the patients treated with ATRA alone survived beyond one year. Event-free survival was significantly higher after ATO-based therapy (95%, 95% CI, 82-99%) as compared to CTX/ATRA (78%, 95% CI, 64-87%; P=0.042), if deaths due to recurrence of the prior malignancy were censored. The estimated 2-year overall survival in intensively treated patients was 88% (95% CI, 80-93%) without difference according to treatment (P=0.47). ATO when added to ATRA or CTX/ATRA is feasible and leads to better outcomes as compared to CTX/ATRA in t-APL.
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