550 research outputs found
An overview of treatment options for patients with relapsed/refractory multiple myeloma and renal impairment
Renal impairment (RI) is a relatively common complication of multiple myeloma, which increases in frequency as disease becomes more advanced and recovery of renal function becomes less likely as patients progress through lines of therapy. Clinical trials in the relapsed/refractory multiple myeloma (RRMM) setting have not uniformly included patients with RI or robustly reported their outcomes. Here, we review existing data among patients with RI and RRMM across drug classes (including immunomodulatory agents, proteasome inhibitors, monoclonal antibodies, antibody-drug conjugates, chimeric antigen receptor T-cell therapies, and exportin-1 inhibitor) to provide an improved understanding of available treatment options for this important population. We highlight data from pivotal clinical trials, including data relating to renal response (as defined by the International Myeloma Working Group) and discuss real-world experiences in patients with RI, where applicable. Despite substantial advances in RRMM treatment, the presence of RI remains associated with reduced overall survival. Consistent inclusion of patients with RI, and uniform reporting of their outcomes, should be encouraged in future prospective trials of treatments for RRMM
Unbiasing the density of TTV-characterised sub-Neptunes: Update of the mass-radius relationship of 34 Kepler planets
Transit Timing Variations (TTVs) can provide useful information on compact
multi-planetary systems observed by transits, by putting constraints on the
masses and eccentricities of the observed planets. This is especially helpful
when the host star is not bright enough for radial velocity follow-up. However,
in the past decades, numerous works have shown that TTV-characterised planets
tend to have a lower densities than RV-characterised planets. Re-analysing 34
Kepler planets in the super-Earth to sub-Neptunes range using the RIVERS
approach, we show that at least part of these discrepancies was due to the way
transit timings were extracted from the light curve, which had a tendency to
under-estimate the TTV amplitudes. We recover robust mass estimates (i.e. low
prior dependency) for 23 of the planets. We compare these planets the
RV-characterised population. A large fraction of these previously had a
surprisingly low density now occupy a place of the mass-radius diagram much
closer to the bulk of the known planets, although a slight shift toward lower
densities remains, which could indicate that the compact multi-planetary
systems characterised by TTVs are indeed composed of planets which are
different from the bulk of the RV-characterised population. These results are
especially important for obtaining an unbiased view of the compact
multi-planetary systems detected by Kepler, TESS, and the upcoming PLATO
mission
Melflufen for relapsed and refractory multiple myeloma
Introduction: The overall survival of patients with multiple myeloma has improved with the advent of novel agents; however, multiple myeloma remains incurable. Combinations of standard-of-care agents such as immunomodulators, proteasome inhibitors, and anti-CD38 monoclonal antibodies are increasingly used in earlier lines of therapy. Patients with disease that is refractory to multiple novel agents represent a population with high unmet medical need and for whom therapies with new mechanisms of action could be beneficial. Melphalan flufenamide (melflufen) has demonstrated encouraging activity in patients with relapsed and refractory multiple myeloma. Areas covered: This review provides an overview of the mechanism of action of melflufen, a first-in-class peptide-drug conjugate that targets aminopeptidases and rapidly delivers alkylating agents into tumor cells. It reviews key Phase I and II clinical trial data for melflufen in combination with dexamethasone as well as in triplet combinations with daratumumab or bortezomib. The safety profile of melflufen, which is characterized primarily by clinically manageable hematologic adverse events, is described. Expert opinion: Melflufen has potential to fill a gap in the myeloma treatment landscape by providing a new mechanism of action with clinically meaningful efficacy and a favorable safety profile in patients refractory to multiple novel agents
Temporal dynamics and developmental memory of 3D chromatin architecture at Hox gene loci
Hox genes are essential regulators of embryonic development. Their step-wise transcriptional activation follows their genomic topology and the various states of activation are subsequently memorized into domains of progressively overlapping gene products. We have analyzed the 3D chromatin organization of Hox clusters during their early activation in vivo, using high-resolution circular chromosome conformation capture. Initially, Hox clusters are organized as single chromatin compartments containing all genes and bivalent chromatin marks. Transcriptional activation is associated with a dynamic bi-modal 3D organization, whereby the genes switch autonomously from an inactive to an active compartment. These local 3D dynamics occur within a framework of constitutive interactions within the surrounding Topological Associated Domains, indicating that this regulation process is mostly cluster intrinsic. The step-wise progression in time is fixed at various body levels and thus can account for the chromatin architectures previously described at a later stage for different anterior to posterior levels.DOI: http://dx.doi.org/10.7554/eLife.02557.001
Epidemiology, clinical characteristics, and outcome of candidemia: experience in a tertiary referral center in the UK
SummaryObjectivesTo review the epidemiology of candidemia in a UK tertiary referral center.MethodsClinical and laboratory data from patients with candidemia were collected prospectively from October 1, 2005 to June 30, 2008 (a 33-month period).ResultsA total of 107 episodes were identified. The incidence was 10.9 episodes/100Â 000 bed-days. The most common predisposing factors were the use of broad-spectrum antibiotics (92%), the presence of an intravascular device (IVD) (82%), admission to an intensive care unit (ICU) (51%), and recent surgery (50%). Non-Candida albicans species accounted for 58% of the episodes, which is higher than the percentage reported from other UK centers. C. albicans was the most common species, accounting for 43% of episodes, followed by C. glabrata (31%) and C. parapsilosis (20%). Overall C. tropicalis, C. krusei, C. norvegensis, and C. lusitaniae caused 7% of episodes. The crude 30-day mortality rate was 37%. Advanced age (p = 0.003) and the presence of septic shock (p = 0.038) were associated with mortality.ConclusionsCandidemia continues to be associated with a high mortality. Preventative measures should be targeted against high-risk hospitalized patients, especially those in ICUs, the elderly, and those undergoing major surgery. Local surveillance of candidemia is important to optimize management
Uncovering the true periods of the young sub-Neptunes orbiting TOI-2076
Context. TOI-2076 is a transiting three-planet system of sub-Neptunes orbiting a bright (G = 8.9 mag), young (340 ± 80 Myr) K-type star. Although a validated planetary system, the orbits of the two outer planets were unconstrained as only two non-consecutive transits were seen in TESS photometry. This left 11 and 7 possible period aliases for each. Aims: To reveal the true orbits of these two long-period planets, precise photometry targeted on the highest-probability period aliases is required. Long-term monitoring of transits in multi-planet systems can also help constrain planetary masses through TTV measurements. Methods: We used the MonoTools package to determine which aliases to follow, and then performed space-based and ground-based photometric follow-up of TOI-2076 c and d with CHEOPS, SAINT-EX, and LCO telescopes. Results: CHEOPS observations revealed a clear detection for TOI-2076 c at P = 21.02538 - 0.00074 + 0.00084 d, and allowed us to rule out three of the most likely period aliases for TOI-2076 d. Ground-based photometry further enabled us to rule out remaining aliases and confirm the P = 35.12537 ± 0.00067 d alias. These observations also improved the radius precision of all three sub-Neptunes to 2.518 ± 0.036, 3.497 ± 0.043, and 3.232 ± 0.063 R⊕. Our observations also revealed a clear anti-correlated TTV signal between planets b and c likely caused by their proximity to the 2:1 resonance, while planets c and d appear close to a 5:3 period commensurability, although model degeneracy meant we were unable to retrieve robust TTV masses. Their inflated radii, likely due to extended H-He atmospheres, combined with low insolation makes all three planets excellent candidates for future comparative transmission spectroscopy with JWST. Photometric time series are only available at the CDS via anonymous ftp to ftp://cdsarc.u-strasbg.fr (130.79.128.5) or via http://cdsarc.u-strasbg.fr/viz-bin/cat/J/A+A/664/A15
Isatuximab plus pomalidomide and dexamethasone in relapsed/refractory multiple myeloma patients with renal impairment: ICARIA-MM subgroup analysis
The randomized, phase 3 ICARIA-MM study investigated isatuximab (Isa) with pomalidomide and dexamethasone (Pd) versus Pd in patients with relapsed/refractory multiple myeloma and ≥2 prior lines. This prespecified subgroup analysis examined efficacy in patients with renal impairment (RI; estimated glomerular filtration rate <60 mL/min/1.73 m²). Isa 10 mg/kg was given intravenously once weekly in cycle 1, and every 2 weeks in subsequent 28-day cycles. Patients received standard doses of Pd. Median progression-free survival (PFS) for patients with RI was 9.5 months with Isa-Pd (n = 55) and 3.7 months with Pd (n = 49; hazard ratio [HR] 0.50; 95% confidence interval [CI], 0.30–0.85). Without RI, median PFS was 12.7 months with Isa-Pd (n = 87) and 7.9 months with Pd (n = 96; HR 0.58; 95% CI, 0.38–0.88). The overall response rate (ORR) with and without RI was higher with Isa-Pd (56 and 68%) than Pd (25 and 43%). Complete renal response rates were 71.9% (23/32) with Isa-Pd and 38.1% (8/21) with Pd; these lasted ≥60 days in 31.3% (10/32) and 19.0% (4/21) of patients, respectively. Isa pharmacokinetics were comparable between the subgroups, suggesting no need for dose adjustment in patients with RI. In summary, the addition of Isa to Pd improved PFS, ORR and renal response rates
Bortezomib, Melphalan, and Dexamethasone for Light-Chain Amyloidosis
PURPOSE: Oral melphalan and dexamethasone (MDex) were considered a standard of care in light-chain (AL) amyloidosis. In the past decade, bortezomib has been increasingly used in combination with alkylating agents and dexamethasone. We prospectively compared the efficacy and safety of MDex and MDex with the addition of bortezomib (BMDex). METHODS: This was a phase III, multicenter, randomized, open-label trial. Patients were stratified according to cardiac stage. Patients with advanced cardiac stage (stage IIIb) amyloidosis were not eligible. The primary end point was hematologic response rate at 3 months. This trial is registered with ClinicalTrials.gov identifier NCT01277016. RESULTS: A total of 109 patients, 53 in the BMDex and 56 in the MDex group, received ≥ 1 dose of therapy (from January 2011 to February 2016). Hematologic response rate at 3 months was higher in the BMDex arm (79% v 52%; P = .002). Higher rates of very good partial or complete response rates (64% v 39%; hazard ratio [HR], 2.47; 95% CI, 1.30 to 4.71) and improved overall survival, with a 2-fold decrease in mortality rate (HR, 0.50; 95% CI, 0.27 to 0.90), were observed in the BMDex arm. Grade 3 and 4 adverse events (the most common being cytopenia, peripheral neuropathy, and heart failure) were more common in the BMDex arm, occurring in 20% versus 10% of cycles performed. CONCLUSION: BMDex improved hematologic response rate and overall survival. To our knowledge, this is the first time a controlled study has demonstrated a survival advantage in AL amyloidosis. BMDex should be considered a new standard of care for AL amyloidosis
Planetary system LHS 1140 revisited with ESPRESSO and TESS
Context. LHS 1140 is an M dwarf known to host two transiting planets at orbital periods of 3.77 and 24.7 days. They were detected with HARPS and Spitzer. The external planet (LHS 1140 b) is a rocky super-Earth that is located in the middle of the habitable zone of this low-mass star. All these properties place this system at the forefront of the habitable exoplanet exploration, and it therefore constitutes a relevant case for further astrobiological studies, including atmospheric observations. Aims. We further characterize this system by improving the physical and orbital properties of the known planets, search for additional planetary-mass components in the system, and explore the possibility of co-orbitals. Methods. We collected 113 new high-precision radial velocity observations with ESPRESSO over a 1.5-yr time span with an average photon-noise precision of 1.07 m s-1. We performed an extensive analysis of the HARPS and ESPRESSO datasets and also analyzed them together with the new TESS photometry. We analyzed the Bayesian evidence of several models with different numbers of planets and orbital configurations. Results. We significantly improve our knowledge of the properties of the known planets LHS 1140 b (Pb ∼ 24.7 days) and LHS 1140 c (Pc ∼ 3.77 days). We determine new masses with a precision of 6% for LHS 1140 b (6.48 ± 0.46 Mpdbl) and 9% for LHS 1140 c (mc = 1.78 ± 0.17 Mpdbl). This reduces the uncertainties relative to previously published values by half. Although both planets have Earth-like bulk compositions, the internal structure analysis suggests that LHS 1140 b might be iron-enriched and LHS 1140 c might be a true Earth twin. In both cases, the water content is compatible to a maximum fraction of 10-12% in mass, which is equivalent to a deep ocean layer of 779 ± 650 km for the habitable-zone planet LHS 1140 b. Our results also provide evidence for a new planet candidate in the system (md = 4.8 ± 1.1Mpdbl) on a 78.9-day orbital period, which is detected through three independent methods. The analysis also allows us to discard other planets above 0.5 Mpdbl for periods shorter than 10 days and above 2 Mpdbl for periods up to one year. Finally, our co-orbital analysis discards co-orbital planets in the tadpole and horseshoe configurations of LHS 1140 b down to 1 Mpdbl with a 95% confidence level (twice better than with the previous HARPS dataset). Indications for a possible co-orbital signal in LHS 1140 c are detected in both radial velocity (alternatively explained by a high eccentricity) and photometric data (alternatively explained by systematics), however. Conclusions. The new precise measurements of the planet properties of the two transiting planets in LHS 1140 as well as the detection of the planet candidate LHS 1140 d make this system a key target for atmospheric studies of rocky worlds at different stellar irradiations.With funding from the Spanish government through the "MarÃa de Maeztu Unit of Excellence" accreditation (MDM-2017-0737
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