Hubble Space Telescope Observations of an Outer Field in Omega Centauri: A Definitive Helium Abundance

We revisit the problem of the split main sequence (MS) of the globular cluster omega Centauri, and report the results of two-epoch Hubble Space Telescope observations of an outer field, for which proper motions give us a pure sample of cluster members, and an improved separation of the two branches of the main sequence. Using a new set of stellar models covering a grid of values of helium and metallicity, we find that the best possible estimate of the helium abundance of the bluer branch of the MS is Y = 0.39 +/- 0.02. For the cluster center we apply new techniques to old observations: we use indices of photometric quality to select a high-quality sample of stars, which we also correct for differential reddening. We then superpose the color-magnitude diagram of the outer field on that of the cluster center, and suggest a connection of the bluer branch of the MS with one of the more prominent among the many sequences in the subgiant region. We also report a group of undoubted cluster members that are well to the red of the lower MS.Comment: 26 pages, 10 figures (4 in low resolution. AJ accepted on March 21, 201

Treatment of Acute Myeloid Leukemia with 20-30% Bone Marrow Blasts

The transition of patients with ≥20% <30% bone marrow (BM) blast from the FAB category of myelodysplasia to the family of acute myeloid leukemia (AML) according to the recent WHO classification has not resolved the argument as to whether the natural history and responsiveness to therapy of these diseases is comparable to that of AML with > 30% BM blast. These controversies are even more manifest when it comes to elderly patients in whom concern for intensive chemotherapy (IC) related toxicity is the critical determinant for the therapeutic choice. In fact, due to concerns of treatment-related morbidity and mortality associated with delivery of IC, approximately only 30% of all patients ≥65 years are considered eligible for this approach. Therefore, a great deal of attention has been dedicated to alternative agents such as hypomethylators (azacitidine and decitabine). Actually, these agents have shown efficacy with reduced toxicity when administered to elderly patients with 20–30% BM blasts and not eligible for IC. In the present review, we will discuss the clinical results achieved in the treatment of elderly patients with 20%–30% BM blasts AML using intensive chemotherapy (IC) or hypomethylating agents. Overall, our survey of the literature suggests that only controlled, randomized, clinical trials will answer the question as to whether hypomethylating agents has the potential to substitute for IC even in elderly patients with an optimal functional status

Clinical significance of bax/bcl-2 ratio in chronic lymphocytic leukemia

In chronic lymphocytic leukemia the balance between the pro-apoptotic and anti-apoptotic members of the bcl-2 family is involved in the pathogenesis, chemorefractoriness and clinical outcome. Moreover, the recently proposed anti-bcl-2 molecules, such as ABT-199, have emphasized the potential role of of bcl-2 family proteins in the context of target therapies. We investigated bax/bcl-2 ratio by flow cytometry in 502 patients and identified a cut off of 1.50 to correlate bax/bcl-2 ratio with well-established clinical and biological prognosticators. Bax/bcl-2 was 1.50 or over in 263 patients (52%) with chronic lymphocytic leukemia. Higher bax/bcl-2 was associated with low Rai stage, lymphocyte doubling time over 12 months, beta-2 microglobulin less than 2.2 mg/dL, soluble CD23 less than 70 U/mL and a low risk cytogenetic profile (P<0.0001). On the other hand, lower bax/bcl-2 was correlated with unmutated IGHV (P<0.0001), mutated NOTCH1 (P<0.0001) and mutated TP53 (P=0.00007). Significant shorter progression-free survival and overall survival were observed in patients with lower bax/bcl-2 (P<0.0001). Moreover, within IGHV unmutated (168 patients) and TP53 mutated (37 patients) subgroups, higher bax/bcl-2 identified cases with significant longer PFS (P=0.00002 and P=0.039). In multivariate analysis of progression-free survival and overall survival, bax/bcl-2 was an independent prognostic factor (P=0.0002 and P=0.002). In conclusion, we defined the prognostic power of bax/bcl-2 ratio, as determined by a flow cytometric approach, and highlighted a correlation with chemoresistance and outcome in chronic lymphocytic leukemia. Finally, the recently proposed new therapies employing bcl-2 inhibitors prompted the potential use of bax/bcl-2 ratio to identify patients putatively resistant to these molecules

Toward optimization of postremission therapy for residual disease-positive patients with acute myeloid leukemia

Purpose:Despite the identification of several baseline prognostic indicators, the outcome of patients with acute myeloid leukemia (AML) is generally heterogeneous. The effects of autologous (AuSCT) or allogeneic stem-cell transplantation (SCT) are still under evaluation. Minimal residual disease (MRD) states may be essential for assigning patients to therapy-dependent risk categories. Patients and Methods: By multiparametric flow cytometry, we assessed the levels of MRD in 142 patients with AML who achieved complete remission after intensive chemotherapy. Results: A level of 3.5 x 10(-4) residual leukemia cells (RLCs) after consolidation therapy was established to identify MRD-negative and MRD-positive cases, with 5-year relapse-free survival (RFS) rates of 60% and 16%, respectively (P <.0001) and overall survival (OS) rates of 62% and 23%, respectively (P=.0001). Of patients (n = 77) who underwent a transplantation procedure (56 AuSCT and 21 SCT procedures); 42 patients (55%) were MRD positive (28 patients who underwent AuSCT and 14 patients who underwent SCT) and 35 patients (45%) were MRD negative (28 patients who underwent AuSCT and seven who underwent SCT). MRD-negative patients had a favorable prognosis, with only eight (22%) of 35 patients experiencing relapse, whereas 29 (69%) of 42 MRD-positive patients experienced relapse (P <.0001). In this high-risk group of 42 patients, we observed that 23 (82%) of 28 of those who underwent AuSCT experienced relapse, whereas six (43%) of 14 who underwent SCT experienced relapse (P=.014). Patients who underwent SCT also had a higher likelihood of RFS (47% v 14%). Conclusion A threshold of 3.5 x 10(-4) RLCs postconsolidation is critical for predicting disease outcome. MRD-negative patients have a good outcome regardless of the type of transplant they receive. In the MRD-positive group, AuSCT does not improve prognosis and SCT represents the primary option

Star Counts in the Globular Cluster Omega Centauri. I. Bright Stellar Components

We present an extensive photometry on HB, RGB, and MSTO stars in Omega Cen. The central regions of the cluster were covered with a mosaic of F435W, F625W, and F658N-band data collected with ACS/HST. The outer reaches were covered with a large set of U,B,V,I-band data collected with the [email protected] ESO/MPI telescope. The final catalogue includes ~1.7 million stars. We identified ~3,200 likely HB stars and ~12,500 stars brighter than the subgiant branch and fainter than the RGB bumps. The HB morphology changes with the radial distance. The relative number of extreme HB stars decreases from ~30% to ~21% when moving from the center toward the outer regions of the cluster, while the fraction of less hot HB stars increases from ~62% to ~72%. We performed a detailed comparison between observed ratios of different stellar tracers and predictions based on canonical evolutionary models with a primordial helium (Y=0.23) content and metal abundances (Z=0.0002,0.001) that bracket the observed spread in metallicity of Omega Cen stars. We found that the empirical star counts of HB stars are on average larger (30%-40%) than predicted. Moreover, the rate of HB stars is 43% larger than the MSTO rate. The discrepancy between the rate of HB compared with the rate of RG and MSTO stars supports the evidence that we are facing a true excess of HB stars. The same comparison was performed by assuming a mix of stellar populations made with 70% of canonical stars and 30% of He-enhanced stars. The discrepancy between theory and observations decreases by a factor of two when compared with rates predicted by canonical He content models, but still 15%-25% (Y=0.42) and 15%-20% (Y=0.33) higher than observed. Furthermore, the ratio between HB and MSTO star counts are ~24% (Y=0.42) and 30% (Y=0.33) larger than predicted lifetime ratios.Comment: 54 pages, 17 figures,to be published in ApJ, see link at http://stellari.wiki.zoho.co

Near-IR period-luminosity relations for pulsating stars in ω\omega Centauri (NGC 5139)

$\omega$ Centauri (NGC 5139) hosts hundreds of pulsating variable stars of different types, thus representing a treasure trove for studies of their corresponding period-luminosity (PL) relations. Our goal in this study is to obtain the PL relations for RR Lyrae, and SX Phoenicis stars in the field of the cluster, based on high-quality, well-sampled light curves in the near-infrared (IR). $\omega$ Centauri was observed using VIRCAM mounted on VISTA. A total of 42 epochs in $J$ and 100 epochs in $K_{\rm S}$ were obtained, spanning 352 days. Point-spread function photometry was performed using DoPhot and DAOPHOT in the outer and inner regions of the cluster, respectively. Based on the comprehensive catalogue of near-IR light curves thus secured, PL relations were obtained for the different types of pulsators in the cluster, both in the $J$ and $K_{\rm S}$ bands. This includes the first PL relations in the near-IR for fundamental-mode SX Phoenicis stars. The near-IR magnitudes and periods of Type II Cepheids and RR Lyrae stars were used to derive an updated true distance modulus to the cluster, with a resulting value of $(m-M)_0 = 13.708 \pm 0.035 \pm 0.10$ mag, where the error bars correspond to the adopted statistical and systematic errors, respectively. Adding the errors in quadrature, this is equivalent to a heliocentric distance of $5.52\pm 0.27$ kpc.Comment: 10 pages, 8 figures, accepted for publication in A&

SN 2005cs in M51 I. The first month of evolution of a subluminous SN II plateau

Early time optical observations of supernova (SN) 2005cs in the Whirlpool Galaxy (M51), are reported. Photometric data suggest that SN 2005cs is a moderately under-luminous Type II plateau supernova (SN IIP). The SN was unusually blue at early epochs (U-B ~ -0.9 about three days after explosion) which indicates very high continuum temperatures. The spectra show relatively narrow P-Cygni features, suggesting ejecta velocities lower than observed in more typical SNe IIP. The earliest spectra show weak absorption features in the blue wing of the He I 5876A absorption component and, less clearly, of H$\beta$ and H$\alpha$. Based on spectral modelling, two different interpretations can be proposed: these features may either be due to high-velocity H and He I components, or (more likely) be produced by different ions (N II, Si II). Analogies with the low-luminosity, $^{56}$Ni-poor, low-velocity SNe IIP are also discussed. While a more extended spectral coverage is necessary in order to determine accurately the properties of the progenitor star, published estimates of the progenitor mass seem not to be consistent with stellar evolution models.Comment: 12 pages, 11 Figures. Accepted for publication in MNRA

High Incidence of Invasive Fungal Diseases in Patients with FLT3-Mutated AML Treated with Midostaurin: Results of a Multicenter Observational SEIFEM Study

The potential drug-drug interactions of midostaurin may impact the choice of antifungal (AF) prophylaxis in FLT3-positive acute myeloid leukemia (AML) patients. To evaluate the incidence of invasive fungal diseases (IFD) during the treatment of FLT3-mutated AML patients and to correlate it to the different AF prophylaxis strategies, we planned a multicenter observational study involving 15 SEIFEM centers. One hundred fourteen patients treated with chemotherapy + midostaurin as induction/reinduction, consolidation or both were enrolled. During induction, the incidence of probable/proven and possible IFD was 10.5% and 9.7%, respectively; no statistically significant difference was observed according to the different AF strategy adopted. The median duration of neutropenia was similar in patients with or without IFD. Proven/probable and possible IFD incidence was 2.4% and 1.8%, respectively, during consolidation. Age was the only risk factor for IFD (OR, 95% CI, 1.10 [1.03–1.19]) and complete remission achievement after first induction the only one for survival (OR, 95% CI, 5.12 [1.93–13.60]). The rate of midostaurin discontinuation was similar across different AF strategies. The IFD attributable mortality during induction was 8.3%. In conclusion, the 20.2% overall incidence of IFD occurring in FLT3-mutated AML during induction with chemotherapy + midostaurin, regardless of AF strategy type, was noteworthy, and merits further study, particularly in elderly patients

In vitro elimination of epidermal growth factor receptor-overexpressing cancer cells by CD32A-chimeric receptor T cells in combination with cetuximab or panitumumab

Cetuximab and panitumumab bind the human epidermal growth factor receptor (EGFR). Although the chimeric cetuximab (IgG1) triggers antibody-dependent-cellular-cytotoxicity (ADCC) of EGFR positive target cells, panitumumab (a human IgG2) does not. The inability of panitumumab to trigger ADCC reflects the poor binding affinity of human IgG2 Fc for the FcγRIII (CD16) on natural killer (NK) cells. However, both human IgG1 and IgG2 bind the FcγRII (CD32A) to a similar extent. Our study compares the ability of T cells, engineered with a novel low-affinity CD32A131R-chimeric receptor (CR), and those engineered with the low-affinity CD16158F-CR T cells, in eliminating EGFR positive epithelial cancer cells (ECCs) in combination with cetuximab or panitumumab. After T-cell transduction, the percentage of CD32A131R-CR T cells was 74 ± 10%, whereas the percentage of CD16158F-CR T cells was 46 ± 15%. Only CD32A131R-CR T cells bound panitumumab. CD32A131R-CR T cells combined with the mAb 8.26 (anti-CD32) and CD16158F-CR T cells combined with the mAb 3g8 (anti-CD16) eliminated colorectal carcinoma (CRC), HCT116FcγR+ cells, in a reverse ADCC assay in vitro. Crosslinking of CD32A131R-CR on T cells by cetuximab or panitumumab and CD16158F-CR T cells by cetuximab induced elimination of triple negative breast cancer (TNBC) MDA-MB-468 cells, and the secretion of interferon gamma and tumor necrosis factor alpha. Neither cetuximab nor panitumumab induced Fcγ-CR T antitumor activity against Kirsten rat sarcoma (KRAS)-mutated HCT116, nonsmall-cell-lung-cancer, A549 and TNBC, MDA-MB-231 cells. The ADCC of Fcγ-CR T cells was associated with the overexpression of EGFR on ECCs. In conclusion, CD32A131R-CR T cells are efficiently redirected by cetuximab or panitumumab against breast cancer cells overexpressing EGFR