Search

We report on a search for persistent radio emission from the one-off fast radio burst (11(B) 20190714A, as well as from two repeating FRBs, 20190711A and 20171019A, using the MeerKAT radio telescope. For FRB 20171019A, we also conducted simultaneous observations with the High-Energy Stereoscopic System (H.E.S.S.) in very high-energy gamma rays and searched for signals in the ultraviolet, optical, and X-ray bands. For this FRB, we obtain a UV flux upper limit of 1.39 x 10(-16) erg cm(-2) s(-1) angstrom(-1), X-ray limit of similar to 6.6 x 10(-14) erg cm(-2) s(-1) and a limit on the very high energy gamma-ray flux Phi(E > 120 GeV) < 1.7 x 10(-12) erg cm(-2) S-1. We obtain a radio upper limit of similar to 15 mu Jy beam(-1) for persistent emission at the locations of both FRBs 20190711A and 20171019A with MeerKAT. However, we detected an almost unresolved (ratio of integrated flux to peak flux is similar to 1.7 beam) radio emission, where the synthesized beam size was similar to 8 arcsec size with a peak brightness of similar to 53 mu Jy beam(-1) at MeerKAT and similar to 86 mu Jy beam(-1) at e-MERLIN, possibly associated with FRB 20190714A at z = 0.2365. This represents the first detection of persistent continuum radio emission potentially associated with a (as-yet) non- repeating FRB. If the association is confirmed, one of the strongest remaining distinction between repeaters and non-repeaters would no longer be applicable. A parallel search for repeat bursts from these FRBs revealed no new detections down to a fluence of 0.08 Jy ms for a 1 ms duration burst.

We report on a search for persistent radio emission from the one-off Fast Radio Burst (FRB) 20190714A, as well as from two repeating FRBs, 20190711A and 20171019A, using the MeerKAT radio telescope. For FRB 20171019A we also conducted simultaneous observations with the High Energy Stereoscopic System (H.E.S.S.) in very high energy gamma rays and searched for signals in the ultraviolet, optical, and X-ray bands. For this FRB, we obtain a UV flux upper limit of 1.39x10^-16 erg/cm^-2/s/Amstrong, X-ray limit of ~ 6.6x10^-14 erg/cm^-2/s and a limit on the very-high-energy gamma-ray flux (Phi) (E > 120 GeV) < 1.7 x 10^-12 erg/cm^-2/s. We obtain a radio upper limit of ~15 microJy/beam for persistent emission at the locations of both FRBs 20190711A and 20171019A, but detect diffuse radio emission with a peak brightness of ~53 microJy/beam associated with FRB 20190714A at z = 0.2365. This represents the first detection of the radio continuum emission potentially associated with the host (galaxy) of FRB 20190714A, and is only the third known FRB to have such an association. Given the possible association of a faint persistent source, FRB 20190714A may potentially be a repeating FRB whose age lies between that of FRB 20121102A and FRB 20180916A. A parallel search for repeat bursts from these FRBs revealed no new detections down to a fluence of 0.08 Jy ms for a 1 ms duration burst., Comment: 15 pages, 9 figures

We report on a search for persistent radio emission from the one-off Fast Radio Burst (FRB) 20190714A, as well as from two repeating FRBs, 20190711A and 20171019A, using the MeerKAT radio telescope. For FRB 20171019A we also conducted simultaneous observations with the High Energy Stereoscopic System (H.E.S.S.) in very high energy gamma rays and searched for signals in the ultraviolet, optical, and X-ray bands. For this FRB, we obtain a UV flux upper limit of 1.39x10^-16 erg/cm^-2/s/Amstrong, X-ray limit of ~ 6.6x10^-14 erg/cm^-2/s and a limit on the very-high-energy gamma-ray flux (Phi) (E > 120 GeV) < 1.7 x 10^-12 erg/cm^-2/s. We obtain a radio upper limit of ~15 microJy/beam for persistent emission at the locations of both FRBs 20190711A and 20171019A, but detect diffuse radio emission with a peak brightness of ~53 microJy/beam associated with FRB 20190714A at z = 0.2365. This represents the first detection of the radio continuum emission potentially associated with the host (galaxy) of FRB 20190714A, and is only the third known FRB to have such an association. Given the possible association of a faint persistent source, FRB 20190714A may potentially be a repeating FRB whose age lies between that of FRB 20121102A and FRB 20180916A. A parallel search for repeat bursts from these FRBs revealed no new detections down to a fluence of 0.08 Jy ms for a 1 ms duration burst., Comment: 15 pages, 9 figures

Cosmological N-body simulations show that Milky Way-sized galaxies harbor a population of unmerged dark matter (DM) subhalos. These subhalos could shine in gamma-rays and eventually be detected in gamma-ray surveys as unidentified sources. We performed a thorough selection among unidentified Fermi-Large Area Telescope Objects (UFOs) to identify them as possible tera-electron-volt-scale DM subhalo candidates. We search for very-high-energy (E greater than or similar to 100 GeV) gamma-ray emissions using H.E.S.S. observations toward four selected UFOs. Since no significant very-high-energy gamma-ray emission is detected in any data set of the four observed UFOs or in the combined UFO data set, strong constraints are derived on the product of the velocity-weighted annihilation cross section sigma v by the J factor for the DM models. The 95% confidence level observed upper limits derived from combined H.E.S.S. observations reach sigma vJ values of 3.7 x 10(-5) and 8.1 x 10(-6) GeV(2 )cm(-2 )s(-1) in the W (+) W (-) and tau (+) tau (-) channels, respectively, for a 1 TeV DM mass. Focusing on thermal weakly interacting massive particles, the H.E.S.S. constraints restrict the J factors to lie in the range 6.1 x 10(19)-2.0 x 10(21) GeV(2 )cm(-5) and the masses to lie between 0.2 and 6 TeV in the W (+) W (-) channel. For the tau (+) tau (-) channel, the J factors lie in the range 7.0 x 10(19)-7.1 x 10(20) GeV(2 )cm(-5) and the masses lie between 0.2 and 0.5 TeV. Assuming model-dependent predictions from cosmological N-body simulations on the J-factor distribution for Milky Way-sized galaxies, the DM models with masses >0.3 TeV for the UFO emissions can be ruled out at high confidence level.

Context. Supernova remnants (SNRs) are commonly thought to be the dominant sources of Galactic cosmic rays up to the knee of the cosmic-ray spectrum at a few PeV. Imaging Atmospheric Cherenkov Telescopes have revealed young SNRs as very-high-energy (VHE, >100 GeV) gamma-ray sources, but for only a few SNRs the hadronic cosmic-ray origin of their gamma-ray emission is indisputably established. In all these cases, the gamma-ray spectra exhibit a spectral cutoff at energies much below 100 TeV and thus do not reach the PeVatron regime. Aims. The aim of this work was to achieve a firm detection for the oxygen-rich SNR LMC N132D in the VHE gamma-ray domain with an extended set of data, and to clarify the spectral characteristics and the localization of the gamma-ray emission from this exceptionally powerful gamma-ray-emitting SNR. Methods. We analyzed 252 h of High Energy Stereoscopic System (H.E.S.S.) observations towards SNR N132D that were accumulated between December 2004 and March 2016 during a deep survey of the Large Magellanic Cloud, adding 104 h of observations to the previously published data set to ensure a > 5 sigma detection. To broaden the gamma-ray spectral coverage required for modeling the spectral energy distribution, an analysis of Fermi-LAT Pass 8 data was also included. Results. We unambiguously detect N132D at VHE with a significance of 5.7 sigma. We report the results of a detailed analysis of its spectrum and localization based on the extended H.E.S.S. data set. The joint analysis of the extended H.E.S.S and Fermi-LAT data results in a spectral energy distribution in the energy range from 1.7 GeV to 14.8 TeV, which suggests a high luminosity of N132D at GeV and TeV energies. We set a lower limit on a gamma-ray cutoff energy of 8 TeV with a confidence level of 95%. The new gamma-ray spectrum as well as multiwavelength observations of N132D when compared to physical models suggests a hadronic origin of the VHE gamma-ray emission. Conclusions. S

This paper provides an overview of the Curiosity rover's exploration at Vera Rubin ridge (VRR) and summarizes the science results. VRR is a distinct geomorphic feature on lower Aeolis Mons (informally known as Mount Sharp) that was identified in orbital data based on its distinct texture, topographic expression, and association with a hematite spectral signature. Curiosity conducted extensive remote sensing observations, acquired data on dozens of contact science targets, and drilled three outcrop samples from the ridge, as well as one outcrop sample immediately below the ridge. Our observations indicate that strata composing VRR were deposited in a predominantly lacustrine setting and are part of the Murray formation. The rocks within the ridge are chemically in family with underlying Murray formation strata. Red hematite is dispersed throughout much of the VRR bedrock, and this is the source of the orbital spectral detection. Gray hematite is also present in isolated, gray-colored patches concentrated toward the upper elevations of VRR, and these gray patches also contain small, dark Fe-rich nodules. We propose that VRR formed when diagenetic event(s) preferentially hardened rocks, which were subsequently eroded into a ridge by wind. Diagenesis also led to enhanced crystallization and/or cementation that deepened the ferric-related spectral absorptions on the ridge, which helped make them readily distinguishable from orbit. Results add to existing evidence of protracted aqueous environments at Gale crater and give new insight into how diagenesis shaped Mars' rock record.

This paper provides an overview of the Curiosity rover's exploration at Vera Rubin ridge (VRR) and summarizes the science results. VRR is a distinct geomorphic feature on lower Aeolis Mons (informally known as Mount Sharp) that was identified in orbital data based on its distinct texture, topographic expression, and association with a hematite spectral signature. Curiosity conducted extensive remote sensing observations, acquired data on dozens of contact science targets, and drilled three outcrop samples from the ridge, as well as one outcrop sample immediately below the ridge. Our observations indicate that strata composing VRR were deposited in a predominantly lacustrine setting and are part of the Murray formation. The rocks within the ridge are chemically in family with underlying Murray formation strata. Red hematite is dispersed throughout much of the VRR bedrock, and this is the source of the orbital spectral detection. Gray hematite is also present in isolated, gray-colored patches concentrated toward the upper elevations of VRR, and these gray patches also contain small, dark Fe-rich nodules. We propose that VRR formed when diagenetic event(s) preferentially hardened rocks, which were subsequently eroded into a ridge by wind. Diagenesis also led to enhanced crystallization and/or cementation that deepened the ferric-related spectral absorptions on the ridge, which helped make them readily distinguishable from orbit. Results add to existing evidence of protracted aqueous environments at Gale crater and give new insight into how diagenesis shaped Mars' rock record.

Background. MM-015 is a pivotal phase 3 randomized, double-blind, placebocontrolled trial designed to compare melphalan-prednisone-lenalidomide (MPR) induction followed by lenalidomide maintenance (MPR-R) with fixed cycle MPR and melphalan-prednisone (MP) induction in transplant-ineligible newly diagnosed multiple myeloma (NDMM) patients. Interim results demonstrated unprecedented progression-free survival (PFS) improvement (Palumbo A, et al. Blood 2011). Aims. Examine efficacy and safety in patients 65-75 years as a protocol-specified age group. Methods. Dosing and schedule have been described. Efficacy and PFS data are provided through the last adjudicated assessment (median follow-up of 27 months). The median follow-up for safety and overall survival (OS) is 41 months. Results. A total of 152, 153, and 154 patients were randomized to MPR-R, MPR, and MP, respectively. Median PFS was significantly improved with MPR-R (31 months) vs. MPR (14 months; P<.001) and MP (13 months; P<.001). A landmark analysis calculating PFS from the time of maintenance entry demonstrated that lenalidomide maintenance significantly prolonged median PFS (26 months from maintenance entry) vs. placebo (7 months) (HR=0.34; P<.001). Lenalidomide maintenance extended PFS independent of induction response (partial response vs. very good partial response or better), ISS stage (I/II vs. III) and age (65-75 years vs. >75 years). Patients aged 65-75 years were evenly distributed: 76% MPR-R patients (116/152), 76% MPR (116/153), and 75% MP (116/154). In these, MPR-R significantly prolonged median PFS vs. MPR and MP (Figure). Importantly, MPR induction alone improved PFS vs. MP (Figure). Lenalidomide maintenance reduced the progression rate by 65% (P<.001). PFS improvements were noted in all patient subgroups (renal function, induction response, and ISS stage), and an OS trend has been observed (Figure). MPR induction had a manageable safety profile, allowing 67% of patients to reach maintenance. The

The efficacy of a fixed-dose rituximab schedule was prospectively explored in primary/acute refractory, relapsed or chronic (platelet count >10 x 109/l and <=50 x 109/l) idiopathic thrombocytopenic purpura (ITP). Patients received two doses of rituximab (1000 mg) on days 1 and 15 and were followed-up on weeks 1-8, 12, 26, 39 and 52. A total of 122 patients were included in the safety population; efficacy was analysed in 108 patients. Overall response rate (ORR) at week 8, defined as the proportion of patients achieving complete response (CR; platelet count >150 x 109/l) or partial response (PR; platelet count >50 x 109/l) was 44%. Therapeutic response, defined as achieving a response at week 8, with at least a minor response (MR; platelet count >30 x 109/l), sustained up to weeks 26 and 52 and accompanied by a reduction in ITP medications, was achieved in 44% (week 26) and 35% (week 52) of patients, respectively. Treatment was well tolerated with no safety concerns. While this study failed to meet its primary endpoint of an ORR of 50%, the efficacy of two fixed doses of rituximab appear to provide similar efficacy to the standard 375 mg/m2 four-dose schedule in relapsed/chronic ITP.Copyright © 2014 John Wiley & Sons Ltd.

Background. Idiopathic thrombocytopenic purpura (ITP) is an auto-immune disorder characterized by low platelet count and mucocutaneous bleeding. Post-acute presentation, 25-30% adult patients develop chronic ITP, up to 30% of whom become refractory to corticosteroids and require additional therapy. B-cells play an important pathophysiological role in auto-immune disease. Rituximab depletes CD20+ B-cells and an exploratory dosing regimen based on lymphoma therapy (375 mg/m2 weekly intravenous x4) has shown promising efficacy (~38% overall response rate-ORR) in adults with chronic and relapsing ITP. We explored the effectiveness of an abbreviated fixed dose rituximab schedule that has been approved in rheumatoid arthritis. Rituximab is not currently approved for the treatment of ITP. Aims. The primary objective was to determine the ORR at week 8 in adults (>=18 years), with chronic or relapsing ITP (platelet count >10x109/L and <=50x109/L) according to the ASH guidelines, who received rituximab 1000mg on days 1 and 15. Secondary objectives included time to, duration of and incidence of therapeutic response (defined below). Methods. After obtaining informed consent, patients received scheduled rituximab and were followed-up for at least 12 weeks. Evaluations were at mandatory follow-up visits on weeks 8, 12, 26, 39 and 52. ORR was defined as the proportion of patients achieving complete response (CR, platelet count >150x109/L) or partial response (PR, >50x109/L) at week 8 with 2 consecutive measurements, confirmed at least 2 weeks apart. Minor response (MR) was defined as platelet count >30x109/L. Simon's 2-stage design was used to determine if the ORR was more likely to be <=38% or >=50%. At least 50 out of 108 responders (46%) were required to conclude, with 95% confidence and 80% power, that the ORR was more likely to be >=50%. Duration of response was determined for patients with a response (MR/PR/CR) at week 8. Time to response was defined as time from first ritux

The efficacy of a fixed-dose rituximab schedule was prospectively explored in primary/acute refractory, relapsed or chronic (platelet count >10 x 109/l and <=50 x 109/l) idiopathic thrombocytopenic purpura (ITP). Patients received two doses of rituximab (1000 mg) on days 1 and 15 and were followed-up on weeks 1-8, 12, 26, 39 and 52. A total of 122 patients were included in the safety population; efficacy was analysed in 108 patients. Overall response rate (ORR) at week 8, defined as the proportion of patients achieving complete response (CR; platelet count >150 x 109/l) or partial response (PR; platelet count >50 x 109/l) was 44%. Therapeutic response, defined as achieving a response at week 8, with at least a minor response (MR; platelet count >30 x 109/l), sustained up to weeks 26 and 52 and accompanied by a reduction in ITP medications, was achieved in 44% (week 26) and 35% (week 52) of patients, respectively. Treatment was well tolerated with no safety concerns. While this study failed to meet its primary endpoint of an ORR of 50%, the efficacy of two fixed doses of rituximab appear to provide similar efficacy to the standard 375 mg/m2 four-dose schedule in relapsed/chronic ITP.Copyright © 2014 John Wiley & Sons Ltd.

Summary: Lumiliximab is a chimeric monoclonal antibody that targets CD23 on the surface of chronic lymphocytic leukaemia (CLL) B-cells. Early phase clinical studies with lumiliximab alone and in combination with fludarabine, cyclophosphamide and rituximab (FCR) established its potential efficacy and tolerability. The 152CL201 trial [Lumiliximab with fludarabine, cyclophosphamide and rituximab (FCR) versus FCR alone in subjects with relapsed CLL; LUCID] was a phase 2/3, randomized (1:1), open-label, multicentre study of lumiliximab in combination with FCR versus FCR alone in patients with relapsed CLL. Six hundred and twenty-seven patients were randomized to either arm. Overall the combination of lumiliximab with FCR was not significantly better than FCR alone (overall response rate 71% vs. 72%, complete response rate 16% vs. 15%, median progression-free survival 24.6 vs. 23.9 months respectively, for FCR with and without lumiliximab). There was a slightly increased incidence of adverse events with lumiliximab but these increases did not appear to lead to differences in eventual outcomes. An interim analysis failed to show sufficient efficacy of the combination of lumiliximab with FCR. The study was therefore stopped early for lack of efficacy. Despite the eventual outcome, the LUCID trial is one of the largest studies that provides valuable insight into the efficacy and tolerability of FCR as a therapeutic option for patients with relapsed CLL.Copyright © 2014 John Wiley & Sons Ltd.

Background. MM-015 is a pivotal phase 3 randomized, double-blind, placebocontrolled trial designed to compare melphalan-prednisone-lenalidomide (MPR) induction followed by lenalidomide maintenance (MPR-R) with fixed cycle MPR and melphalan-prednisone (MP) induction in transplant-ineligible newly diagnosed multiple myeloma (NDMM) patients. Interim results demonstrated unprecedented progression-free survival (PFS) improvement (Palumbo A, et al. Blood 2011). Aims. Examine efficacy and safety in patients 65-75 years as a protocol-specified age group. Methods. Dosing and schedule have been described. Efficacy and PFS data are provided through the last adjudicated assessment (median follow-up of 27 months). The median follow-up for safety and overall survival (OS) is 41 months. Results. A total of 152, 153, and 154 patients were randomized to MPR-R, MPR, and MP, respectively. Median PFS was significantly improved with MPR-R (31 months) vs. MPR (14 months; P<.001) and MP (13 months; P<.001). A landmark analysis calculating PFS from the time of maintenance entry demonstrated that lenalidomide maintenance significantly prolonged median PFS (26 months from maintenance entry) vs. placebo (7 months) (HR=0.34; P<.001). Lenalidomide maintenance extended PFS independent of induction response (partial response vs. very good partial response or better), ISS stage (I/II vs. III) and age (65-75 years vs. >75 years). Patients aged 65-75 years were evenly distributed: 76% MPR-R patients (116/152), 76% MPR (116/153), and 75% MP (116/154). In these, MPR-R significantly prolonged median PFS vs. MPR and MP (Figure). Importantly, MPR induction alone improved PFS vs. MP (Figure). Lenalidomide maintenance reduced the progression rate by 65% (P<.001). PFS improvements were noted in all patient subgroups (renal function, induction response, and ISS stage), and an OS trend has been observed (Figure). MPR induction had a manageable safety profile, allowing 67% of patients to reach maintenance. The

Background. Idiopathic thrombocytopenic purpura (ITP) is an auto-immune disorder characterized by low platelet count and mucocutaneous bleeding. Post-acute presentation, 25-30% adult patients develop chronic ITP, up to 30% of whom become refractory to corticosteroids and require additional therapy. B-cells play an important pathophysiological role in auto-immune disease. Rituximab depletes CD20+ B-cells and an exploratory dosing regimen based on lymphoma therapy (375 mg/m2 weekly intravenous x4) has shown promising efficacy (~38% overall response rate-ORR) in adults with chronic and relapsing ITP. We explored the effectiveness of an abbreviated fixed dose rituximab schedule that has been approved in rheumatoid arthritis. Rituximab is not currently approved for the treatment of ITP. Aims. The primary objective was to determine the ORR at week 8 in adults (>=18 years), with chronic or relapsing ITP (platelet count >10x109/L and <=50x109/L) according to the ASH guidelines, who received rituximab 1000mg on days 1 and 15. Secondary objectives included time to, duration of and incidence of therapeutic response (defined below). Methods. After obtaining informed consent, patients received scheduled rituximab and were followed-up for at least 12 weeks. Evaluations were at mandatory follow-up visits on weeks 8, 12, 26, 39 and 52. ORR was defined as the proportion of patients achieving complete response (CR, platelet count >150x109/L) or partial response (PR, >50x109/L) at week 8 with 2 consecutive measurements, confirmed at least 2 weeks apart. Minor response (MR) was defined as platelet count >30x109/L. Simon's 2-stage design was used to determine if the ORR was more likely to be <=38% or >=50%. At least 50 out of 108 responders (46%) were required to conclude, with 95% confidence and 80% power, that the ORR was more likely to be >=50%. Duration of response was determined for patients with a response (MR/PR/CR) at week 8. Time to response was defined as time from first ritux

No large prospective trial of bortezomib (Btz)/dexamethasone (Dex) from cycle (C) 1 in relapsed (r) multiple myeloma (MM) has been published, despite common use and data showing that adding Dex to Btz in patients (pts) with SD or PD improves overall response (OR). While Btz maintenance (mnt) improves time to progression (TTP) in untreated pts, there is limited data in rMM. 20 sites enrolled 100 rMM pts (Karnofsky>=60, platelets>=50?109/L and eGFR>=20mL/min) requiring 2nd line therapy (or 3rd line if prior thalidomide (Thal) and/or Dex monotherapy) in a Phase 2 study of IV Btz (1.3mg/m2; Day (D)1,4,8+11) plus PO Dex (20mg; D1,2,4,5,8,9,11+12) for stable disease received Btz (1.3mg/m2;D1) and Dex (20mg;D1,2) q14d until progression. 35/100 pts completed at least 1 C of mnt. A prospectively defined matched analysis of the 1o endpoint OR and 2o endpoints (Complete Response (CR) and TTP) with the Btz-only arm of APEX was performed. The algorithm matched 90 BoMeR and APEX pts for prior (P) Dex, P Thal, time since last therapy, P transplant, and # of P regimens. Toxicity during induction was similar to APEX (Harrison, ASCO 2010). OR by EBMT criteria (CR, PR, MR) was 62% BoMeR vs 42% APEX (odds ratio (OdR) 0.44 (0.244-0.806)), >PR 56% BoMeR vs 36% APEX (OdR 0.44 (0.242- 0.804)), with >50% (100%) reduction in M-protein in 76% (30%) of BoMeR vs 51% (18%) APEX pts (n=67). The median TTP was signifi- cantly longer in BoMeR (300 days) vs. APEX (154 days) (p<0.001). The BoMeR protocol significantly improved OR, M-protein reduction and TTP for rMM pts vs APEX.

No large prospective trial of bortezomib (Btz)/dexamethasone (Dex) from cycle (C) 1 in relapsed (r) multiple myeloma (MM) has been published, despite common use and data showing that adding Dex to Btz in patients (pts) with SD or PD improves overall response (OR). While Btz maintenance (mnt) improves time to progression (TTP) in untreated pts, there is limited data in rMM. 20 sites enrolled 100 rMM pts (Karnofsky>=60, platelets>=50?109/L and eGFR>=20mL/min) requiring 2nd line therapy (or 3rd line if prior thalidomide (Thal) and/or Dex monotherapy) in a Phase 2 study of IV Btz (1.3mg/m2; Day (D)1,4,8+11) plus PO Dex (20mg; D1,2,4,5,8,9,11+12) for stable disease received Btz (1.3mg/m2;D1) and Dex (20mg;D1,2) q14d until progression. 35/100 pts completed at least 1 C of mnt. A prospectively defined matched analysis of the 1o endpoint OR and 2o endpoints (Complete Response (CR) and TTP) with the Btz-only arm of APEX was performed. The algorithm matched 90 BoMeR and APEX pts for prior (P) Dex, P Thal, time since last therapy, P transplant, and # of P regimens. Toxicity during induction was similar to APEX (Harrison, ASCO 2010). OR by EBMT criteria (CR, PR, MR) was 62% BoMeR vs 42% APEX (odds ratio (OdR) 0.44 (0.244-0.806)), >PR 56% BoMeR vs 36% APEX (OdR 0.44 (0.242- 0.804)), with >50% (100%) reduction in M-protein in 76% (30%) of BoMeR vs 51% (18%) APEX pts (n=67). The median TTP was signifi- cantly longer in BoMeR (300 days) vs. APEX (154 days) (p<0.001). The BoMeR protocol significantly improved OR, M-protein reduction and TTP for rMM pts vs APEX.

To assess the maternal haematological effects of betamethasone administered in late pregnancy, an automated full blood count was performed before and daily for 5 days after betamethasone in 25 women with a singleton pregnancy between 23 and 33 weeks' gestation. From a mean (+/- SD) baseline level of 11.0 +/- 2.2 x 109/L, the total white cell count increased significantly to 13.2 +/- 2.9 x 109/L and 13.5 +/- 3.1 x 109/L on the first and second day after treatment respectively, returning to baseline on day 3 (p < 0.0001, ANOVA). These changes represented a mean increase in the neutrophil count of 35% and a mean decrease in the lymphocyte count of 23%. While there was considerable intersubject variation in the extent of the changes, this study has quantified the leucocytosis induced by betamethasone in late pregnancy, information that may assist with the clinical evaluation of a woman at risk of preterm delivery.

Background: FLT3-ITD is a major risk factor for relapse and poor clinical outcome in AML. Markedly elevated levels of FLT3 ligand (FLT3L) occur after intensive chemotherapy and in patients with relapsed AML. In addition, elevated circulating FLT3L in relapsed/refractory FLT3-ITD+ AML has been proposed to limit the response to FLT3 inhibitors (Sato T, et al. Blood 2011; 3286). Novel agents including hypomethylating agents and mTOR inhibitors are being investigated as salvage options in AML but their impact on circulating FLT3 ligand is unknown. Aim(s): To investigate the effect of azacitidine in combination with mTOR inhibitors on FLT3 ligand levels in relation to clinical outcome in relapsed and refractory AML. Method(s): A phase Ib/II open label dose escalation study using azacitidine 75 mg/m2 sc daily on days 1-5 and 8-9 of each 28-day cycle with 2.5, 5 or 10 mg everolimus orally on days 5-21. Serum was sampled at baseline and on days 5, 12 19 and 25 of cycle 1 and FLT3 ligand measured quantitated by ELISA. Result(s): 37 patients, median age 65 years (range 17-78), with relapsed (73%) or refractory (27%) AML, after failing 1 (n=16), 2 (n=13) or 3 (n=8) previous lines of chemotherapy received azacitidine in combination with 2.5mg (n=6), 5mg (n=12) or 10mg (n=19) everolimus. Poor risk karyotype was present in 10/34 (29%) and FLT3-ITD in 4/16 (25%) of those evaluable. Clinical response was 32% (2 CR, 10 PR). At a median follow up of 252 days, median OS is 211 days (194d in primary refractory and 211d in relapsed AML) and median PFS 178 days. 3/5 patients treated for relapsed AML after allo-SCT had clinical responses and remain alive at 245, 252 and 525 days. In comparison to the typically large increase in FLT3L in a patient given intensive HiDAC-based induction chemotherapy (Figure 1), only 4/26 patients given azacitidine + everolimus had FLT3L levels above 1000 pg/ml within the first month of therapy (Figure 2). Furthermore, patients A, B and C (Figure 2) achieved

Background: Idiopathic thrombocytopenic purpura (ITP) is an autoimmune disorder characterized by low platelet count and mucocutaneous bleeding. Approximately 25-30% of adult patients with acute ITP develop chronicity; 30% of chronic ITP patients become refractory to corticosteroids and require additional therapy. As B-cells play an important pathophysiological role in autoimmune disease, rituximab, a chimeric anti-CD20 monoclonal antibody which depletes CD20+ B-cells has been used in chronic ITP. A dosing regimen based on lymphoma therapy (375 mg/m2 weekly x 4) has shown efficacy (~38% Overall Response Rate-ORR) in adults in this context. Whether this schedule is optimal in autoimmune disease, in which the burden of pathological B-cells is low, is unknown. In this study we explored an abbreviated rituximab schedule, consistent with the approved rheumatoid arthritis dosing. We also explored inherited polymorphisms in FcGammaR3A (FCGR3A) as it has been shown to correlate with response to rituximab. AIM: The primary objective of this study was to determine the ORR, at week 8, among adults (>= 18 years) with chronic or relapsing ITP (platelet count > 10 x 109/L and <= 50 x 109/L) according to the ASH guidelines, who received rituximab 1000 mg intravenous (IV) on days 1 and 15. A laboratory sub-study investigated the relationship between the FCGR3A-V/F158 polymorphisms and response to rituximab. METHOD(S): Patients received planned doses of rituximab and were followed-up for a minimum of 12 weeks. Assessments and procedures at mandatory follow-up visits occurring on weeks 8, 12, 26, 39 and 52 included physical examination, vital signs, FBC and serum chemistry. ORR was defined as the proportion of patients achieving a Complete Response (CR, platelet count > 150x109/L) or Partial Response (PR, > 50 x 109/L) at weeks 8 and 12 with 2 consecutive measurements, confirmed at least 2 weeks apart. Simon's 2-stage design was used to determine if the ORR was more likely to be <= 38

In this prospective, multicenter, non-randomized study for patients with stage I-II Hodgkin lymphoma, group 1 (without risk-factors [RF]) had three cycles of ABVD chemotherapy (adriamycin, bleomycin, vinblastine, and dacarbazine) and group 2 (any of bulk, extranodal site, >3 regions, raised erythrocyte sedimentation rate [ESR]) and group 3 (B-symptoms) received four cycles. Involved field radiotherapy (IFRT) 30 Gy was given after adequate chemotherapy response. Five-year overall survival and freedom from progression (FFP) were 96% (95% confidence interval [CI] 91-98%) and 90% (84-94%), respectively. Five-year FFP was 97% (90-99%), 89% (75-95%), and 73% (52-86%) for groups 1, 2, and 3, respectively. In patients with RF, chemotherapy responses of complete response unconfirmed (CRu), partial response (PR), and stable disease (SD) were associated with FFP of 90%, 86%, and 62% (p=0.17), and CR/no CR on functional imaging with FFP of 90%/67%, respectively (p=0.05). The 97% FFP in group 1 compares favorably with previously reported results from cooperative trial groups. Intensification of therapy warrants study in patients with RF and a poor chemotherapy response. © 2011 Informa UK, Ltd.

Background: Initial therapy for patients with acute promyelocytic leukemia most often involves the combination of all-trans-retinoic acid with anthracycline-based chemotherapy. The role of non-anthracycline drugs in induction and consolidation is less well-established and varies widely between different cooperative group protocols. Design and Methods: In an attempt to minimize relapse and maximize survival for patients with newly diagnosed acute promyelocytic leukemia, the Australasian Leukaemia and Lymphoma Group utilized all-trans-retinoic acid and idarubicin as anti-leukemic therapy for both induction and consolidation. The protocol (known as APML3) was subsequently amended to incorporate maintenance with all-trans-retinoic acid, methotrexate and 6-mercaptopurine. Result(s): Eight (8%) of 101 patients died within 30 days, and 91 (90%) achieved complete remission. With a median estimated potential follow-up of 4.6 years, 4-year overall survival was 84%, and 71% of the patients remained in remission at 4 years. The cumulative incidence of all relapses was 28.1%, with 15 of the 25 relapses initially identified as an isolated molecular relapse. Both FLT3 mutations (internal tandem duplications and codon 835/836 kinase domain mutations) and increased white cell count at diagnosis were associated with inferior overall survival, but in multivariate analyses only FLT3 mutations remained significant (hazard ratio 6.647, P=0.005). Maintenance therapy was significantly associated with improved remission duration (hazard ratio 0.281, P<0.001) and disease-free survival (hazard ratio 0.290, P<0.001). Conclusion(s): The combination of all-trans-retinoic acid and just two cycles of idarubicin followed by triple maintenance produced durable remissions in most patients, but patients with high-risk disease, especially those with FLT3 mutations, require additional agents or alternative treatment approaches. The significant reduction in relapse seen after the addition of maintenance

To assess the maternal haematological effects of betamethasone administered in late pregnancy, an automated full blood count was performed before and daily for 5 days after betamethasone in 25 women with a singleton pregnancy between 23 and 33 weeks' gestation. From a mean (+/- SD) baseline level of 11.0 +/- 2.2 x 109/L, the total white cell count increased significantly to 13.2 +/- 2.9 x 109/L and 13.5 +/- 3.1 x 109/L on the first and second day after treatment respectively, returning to baseline on day 3 (p < 0.0001, ANOVA). These changes represented a mean increase in the neutrophil count of 35% and a mean decrease in the lymphocyte count of 23%. While there was considerable intersubject variation in the extent of the changes, this study has quantified the leucocytosis induced by betamethasone in late pregnancy, information that may assist with the clinical evaluation of a woman at risk of preterm delivery.

Background: FLT3-ITD is a major risk factor for relapse and poor clinical outcome in AML. Markedly elevated levels of FLT3 ligand (FLT3L) occur after intensive chemotherapy and in patients with relapsed AML. In addition, elevated circulating FLT3L in relapsed/refractory FLT3-ITD+ AML has been proposed to limit the response to FLT3 inhibitors (Sato T, et al. Blood 2011; 3286). Novel agents including hypomethylating agents and mTOR inhibitors are being investigated as salvage options in AML but their impact on circulating FLT3 ligand is unknown. Aim(s): To investigate the effect of azacitidine in combination with mTOR inhibitors on FLT3 ligand levels in relation to clinical outcome in relapsed and refractory AML. Method(s): A phase Ib/II open label dose escalation study using azacitidine 75 mg/m2 sc daily on days 1-5 and 8-9 of each 28-day cycle with 2.5, 5 or 10 mg everolimus orally on days 5-21. Serum was sampled at baseline and on days 5, 12 19 and 25 of cycle 1 and FLT3 ligand measured quantitated by ELISA. Result(s): 37 patients, median age 65 years (range 17-78), with relapsed (73%) or refractory (27%) AML, after failing 1 (n=16), 2 (n=13) or 3 (n=8) previous lines of chemotherapy received azacitidine in combination with 2.5mg (n=6), 5mg (n=12) or 10mg (n=19) everolimus. Poor risk karyotype was present in 10/34 (29%) and FLT3-ITD in 4/16 (25%) of those evaluable. Clinical response was 32% (2 CR, 10 PR). At a median follow up of 252 days, median OS is 211 days (194d in primary refractory and 211d in relapsed AML) and median PFS 178 days. 3/5 patients treated for relapsed AML after allo-SCT had clinical responses and remain alive at 245, 252 and 525 days. In comparison to the typically large increase in FLT3L in a patient given intensive HiDAC-based induction chemotherapy (Figure 1), only 4/26 patients given azacitidine + everolimus had FLT3L levels above 1000 pg/ml within the first month of therapy (Figure 2). Furthermore, patients A, B and C (Figure 2) achieved

In this prospective, multicenter, non-randomized study for patients with stage I-II Hodgkin lymphoma, group 1 (without risk-factors [RF]) had three cycles of ABVD chemotherapy (adriamycin, bleomycin, vinblastine, and dacarbazine) and group 2 (any of bulk, extranodal site, >3 regions, raised erythrocyte sedimentation rate [ESR]) and group 3 (B-symptoms) received four cycles. Involved field radiotherapy (IFRT) 30 Gy was given after adequate chemotherapy response. Five-year overall survival and freedom from progression (FFP) were 96% (95% confidence interval [CI] 91-98%) and 90% (84-94%), respectively. Five-year FFP was 97% (90-99%), 89% (75-95%), and 73% (52-86%) for groups 1, 2, and 3, respectively. In patients with RF, chemotherapy responses of complete response unconfirmed (CRu), partial response (PR), and stable disease (SD) were associated with FFP of 90%, 86%, and 62% (p=0.17), and CR/no CR on functional imaging with FFP of 90%/67%, respectively (p=0.05). The 97% FFP in group 1 compares favorably with previously reported results from cooperative trial groups. Intensification of therapy warrants study in patients with RF and a poor chemotherapy response. © 2011 Informa UK, Ltd.

Background: Idiopathic thrombocytopenic purpura (ITP) is an autoimmune disorder characterized by low platelet count and mucocutaneous bleeding. Approximately 25-30% of adult patients with acute ITP develop chronicity; 30% of chronic ITP patients become refractory to corticosteroids and require additional therapy. As B-cells play an important pathophysiological role in autoimmune disease, rituximab, a chimeric anti-CD20 monoclonal antibody which depletes CD20+ B-cells has been used in chronic ITP. A dosing regimen based on lymphoma therapy (375 mg/m2 weekly x 4) has shown efficacy (~38% Overall Response Rate-ORR) in adults in this context. Whether this schedule is optimal in autoimmune disease, in which the burden of pathological B-cells is low, is unknown. In this study we explored an abbreviated rituximab schedule, consistent with the approved rheumatoid arthritis dosing. We also explored inherited polymorphisms in FcGammaR3A (FCGR3A) as it has been shown to correlate with response to rituximab. AIM: The primary objective of this study was to determine the ORR, at week 8, among adults (>= 18 years) with chronic or relapsing ITP (platelet count > 10 x 109/L and <= 50 x 109/L) according to the ASH guidelines, who received rituximab 1000 mg intravenous (IV) on days 1 and 15. A laboratory sub-study investigated the relationship between the FCGR3A-V/F158 polymorphisms and response to rituximab. METHOD(S): Patients received planned doses of rituximab and were followed-up for a minimum of 12 weeks. Assessments and procedures at mandatory follow-up visits occurring on weeks 8, 12, 26, 39 and 52 included physical examination, vital signs, FBC and serum chemistry. ORR was defined as the proportion of patients achieving a Complete Response (CR, platelet count > 150x109/L) or Partial Response (PR, > 50 x 109/L) at weeks 8 and 12 with 2 consecutive measurements, confirmed at least 2 weeks apart. Simon's 2-stage design was used to determine if the ORR was more likely to be <= 38

Background: Initial therapy for patients with acute promyelocytic leukemia most often involves the combination of all-trans-retinoic acid with anthracycline-based chemotherapy. The role of non-anthracycline drugs in induction and consolidation is less well-established and varies widely between different cooperative group protocols. Design and Methods: In an attempt to minimize relapse and maximize survival for patients with newly diagnosed acute promyelocytic leukemia, the Australasian Leukaemia and Lymphoma Group utilized all-trans-retinoic acid and idarubicin as anti-leukemic therapy for both induction and consolidation. The protocol (known as APML3) was subsequently amended to incorporate maintenance with all-trans-retinoic acid, methotrexate and 6-mercaptopurine. Result(s): Eight (8%) of 101 patients died within 30 days, and 91 (90%) achieved complete remission. With a median estimated potential follow-up of 4.6 years, 4-year overall survival was 84%, and 71% of the patients remained in remission at 4 years. The cumulative incidence of all relapses was 28.1%, with 15 of the 25 relapses initially identified as an isolated molecular relapse. Both FLT3 mutations (internal tandem duplications and codon 835/836 kinase domain mutations) and increased white cell count at diagnosis were associated with inferior overall survival, but in multivariate analyses only FLT3 mutations remained significant (hazard ratio 6.647, P=0.005). Maintenance therapy was significantly associated with improved remission duration (hazard ratio 0.281, P<0.001) and disease-free survival (hazard ratio 0.290, P<0.001). Conclusion(s): The combination of all-trans-retinoic acid and just two cycles of idarubicin followed by triple maintenance produced durable remissions in most patients, but patients with high-risk disease, especially those with FLT3 mutations, require additional agents or alternative treatment approaches. The significant reduction in relapse seen after the addition of maintenance

Background On the basis of promising results that were reported in several phase 2 trials, we investigated whether the addition of the monoclonal antibody rituximab to first-line chemotherapy with fludarabine and cyclophosphamide would improve the outcome of patients with chronic lymphocytic leukaemia. Methods Treatment-naive, physically fit patients (aged 30-81 years) with CD20-positive chronic lymphocytic leukaemia were randomly assigned in a one-to-one ratio to receive six courses of intravenous fludarabine (25 mg/m(2) per day) and cyclophosphamide (250 mg/m(2) per day) for the first 3 days of each 28-day treatment course with or without rituximab (375 mg/m(2) on day 0 of first course, and 500 mg/m(2) on day 1 of second to sixth courses) in 190 centres in 11 countries. Investigators and patients were not masked to the computer-generated treatment assignment. The primary endpoint was progression-free survival (PFS). Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00281918. Findings 408 patients were assigned to fludarabine, cyclophosphamide, and rituximab (chemoimmunotherapy group) and 409 to fludarabine and cyclophosphamide (chemotherapy group); all patients were analysed. At 3 years after randomisation, 65% of patients in the chemoimmunotherapy group were free of progression compared with 45% in the chemotherapy group (hazard ratio 0.56 [95% CI 0.46-0.69], p<0.0001); 87% were alive versus 83%, respectively (0.67 [0.48-0.92]; p=0.01). Chemoimmunotherapy was more frequently associated with grade 3 and 4 neutropenia (136 [34%] of 404 vs 83 [21%] of 396; p<0.0001) and leucocytopenia (97 [24%] vs 48 [12%]; p<0.0001). Other side-effects, including severe infections, were not increased. There were eight (2%) treatment-related deaths in the chemoimmunotherapy group compared with ten (3%) in the chemotherapy group. Interpretation Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab improves progression-free

Background On the basis of promising results that were reported in several phase 2 trials, we investigated whether the addition of the monoclonal antibody rituximab to first-line chemotherapy with fludarabine and cyclophosphamide would improve the outcome of patients with chronic lymphocytic leukaemia. Methods Treatment-naive, physically fit patients (aged 30-81 years) with CD20-positive chronic lymphocytic leukaemia were randomly assigned in a one-to-one ratio to receive six courses of intravenous fludarabine (25 mg/m(2) per day) and cyclophosphamide (250 mg/m(2) per day) for the first 3 days of each 28-day treatment course with or without rituximab (375 mg/m(2) on day 0 of first course, and 500 mg/m(2) on day 1 of second to sixth courses) in 190 centres in 11 countries. Investigators and patients were not masked to the computer-generated treatment assignment. The primary endpoint was progression-free survival (PFS). Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00281918. Findings 408 patients were assigned to fludarabine, cyclophosphamide, and rituximab (chemoimmunotherapy group) and 409 to fludarabine and cyclophosphamide (chemotherapy group); all patients were analysed. At 3 years after randomisation, 65% of patients in the chemoimmunotherapy group were free of progression compared with 45% in the chemotherapy group (hazard ratio 0.56 [95% CI 0.46-0.69], p<0.0001); 87% were alive versus 83%, respectively (0.67 [0.48-0.92]; p=0.01). Chemoimmunotherapy was more frequently associated with grade 3 and 4 neutropenia (136 [34%] of 404 vs 83 [21%] of 396; p<0.0001) and leucocytopenia (97 [24%] vs 48 [12%]; p<0.0001). Other side-effects, including severe infections, were not increased. There were eight (2%) treatment-related deaths in the chemoimmunotherapy group compared with ten (3%) in the chemotherapy group. Interpretation Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab improves progression-free

The combination of cyclophosphamide, vincristine, and prednisone (CVP) is one of several standard treatment options for advanced follicular lymphoma. This, like similar chemotherapeutic regimens, induces response rates of 60% to 80%, with a median response duration of under 2 years. Rituximab, a chimeric monoclonal antibody against CD20, is active in follicular lymphoma, both as monotherapy and in combination with chemotherapy. Previously untreated patients with stages III to IV follicular lymphoma were randomly assigned to receive either 8 cycles of CVP plus rituximab (R-CVP; n = 162) or CVP (n = 159). Overall and complete response rates were 81% and 41% in the R-CVP arm versus 57% and 10% in the CVP arm, respectively (P < .0001). At a median follow-up of 30 months, patients treated with R-CVP had a very significantly prolonged time to progression (median 32 months versus 15 months for CVP; P < .0001). Median time to treatment fail-ure was 27 months in patients receiving R-CVP and 7 months in the CVP arm (P < .0001). Rituximab did not add significantly to the toxicity of CVP. The addition of rituximab to the CVP regimen significantly improves the clinical outcome in patients with previously untreated advanced follicular lymphoma, without increased toxicity. (C) 2005 by The American Society of Hematology.

The single crystal growth of rare earth silicates was investigated for the purpose of tunable laser hosts. Silicates of the type R2Si05, where R = La, Gd, Y, were prepared from stoichiometric melts and doped with Ce3+ activators. Seed crystals were obtained from crystallized melt sections or by growth on an iridium wire. Cathodoluminescence experiments on both powders and single crystals showed wavelength shifts with different rare earth ions. The Gd, Y, and mixed crystals of Gd-Y silicates gave good bright emission with Ce3+. The emission is broad band and covers the wavelength range of 370-525 micron. The peak emission can be centered near 450-460 micron by other compositions. Larger single crystals for laser hosts are under development. (Author)

The single crystal growth of rare earth silicates was investigated for the purpose of tunable laser hosts. Silicates of the type R2SiO5, where R = La, Gd, Y, Lu, were prepared from stoichiometric melts and doped with Ce(3+) activators. Seed crystals were obtained from crystallized melt sections or by growth on an iridium wire. These seeds were utilized in standard Czochralski type growth to obtain larger single crystals. Cathodoluminescence experiments on both powders and single crystals showed wavelength shifts with different rare earth ions. The Gd, Y, and mixed crystals of Gd-Y silicates gave good bright emission with Ce(3+). The emission is broad band and covers the wavelength range of 370-525nm. The peak emission can be centered near 450-460nm by other compositions. Larger single crystals for laser hosts are under development. Keywords: Tunable lasers; Rare earth silicates; Czochralski growth; Laser crystals.

This paper provides an overview of the Curiosity rover's exploration at Vera Rubin ridge and summarizes the science results. Vera Rubin ridge (VRR) is a distinct geomorphic feature on lower Aeolis Mons (informally known as Mt. Sharp) that was identified in orbital data based on its distinct texture, topographic expression, and association with a hematite spectral signature. Curiosity conducted extensive remote sensing observations, acquired data on dozens of contact science targets, and drilled three outcrop samples from the ridge, as well as one outcrop sample immediately below the ridge. Our observations indicate that strata composing VRR were deposited in a predominantly lacustrine setting and are part of the Murray formation. The rocks within the ridge are chemically in family with underlying Murray formation strata. Red hematite is dispersed throughout much of the VRR bedrock, and this is the source of the orbital spectral detection. Gray hematite is also present in isolated, gray‐colored patches concentrated towards the upper elevations of VRR, and these gray patches also contain small, dark Fe‐rich nodules. We propose that VRR formed when diagenetic event(s) preferentially hardened rocks, which were subsequently eroded into a ridge by wind. Diagenesis also led to enhanced crystallization and/or cementation that deepened the ferric‐related spectral absorptions on the ridge, which helped make them readily distinguishable from orbit. Results add to existing evidence of protracted aqueous environments at Gale crater and give new insight into how diagenesis shaped Mars’ rock record.

This paper provides an overview of the Curiosity rover's exploration at Vera Rubin ridge and summarizes the science results. Vera Rubin ridge (VRR) is a distinct geomorphic feature on lower Aeolis Mons (informally known as Mt. Sharp) that was identified in orbital data based on its distinct texture, topographic expression, and association with a hematite spectral signature. Curiosity conducted extensive remote sensing observations, acquired data on dozens of contact science targets, and drilled three outcrop samples from the ridge, as well as one outcrop sample immediately below the ridge. Our observations indicate that strata composing VRR were deposited in a predominantly lacustrine setting and are part of the Murray formation. The rocks within the ridge are chemically in family with underlying Murray formation strata. Red hematite is dispersed throughout much of the VRR bedrock, and this is the source of the orbital spectral detection. Gray hematite is also present in isolated, gray‐colored patches concentrated towards the upper elevations of VRR, and these gray patches also contain small, dark Fe‐rich nodules. We propose that VRR formed when diagenetic event(s) preferentially hardened rocks, which were subsequently eroded into a ridge by wind. Diagenesis also led to enhanced crystallization and/or cementation that deepened the ferric‐related spectral absorptions on the ridge, which helped make them readily distinguishable from orbit. Results add to existing evidence of protracted aqueous environments at Gale crater and give new insight into how diagenesis shaped Mars’ rock record.