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INTRODUCTION: Patients with central nervous system malignancies have limited representation in studies evaluating DOACs for VTE treatment. This study evaluated the safety and efficacy of DOACs in comparison with LMWH for cancer-associated VTE in patients with primary brain tumors or secondary brain metastases. MATERIALS & METHODS: In this multicenter, retrospective cohort study, adult patients with a diagnosis of primary brain tumor or secondary brain metastases who received either a DOAC or LMWH for treatment of cancer-associated VTE were evaluated. The primary outcome was the cumulative incidence of any intracranial hemorrhage within a 6-month period following the initiation of anticoagulation. Secondary outcomes included the cumulative incidence of any bleeding event, and recurrent VTE events. RESULTS: Between January 1, 2012 and October 9, 2019, one-hundred eleven patients met inclusion criteria. The 6-month cumulative incidence of intracranial hemorrhage was 4.3% (95% CI, 0.74-13.2%) in the DOAC group, compared to 5.9% (95% CI, 1.5-14.9%) in the LMWH group (p = 0.61). The 6-month cumulative incidence of bleeding events was 14.3% (95% CI, 6.2-25.8%) in the DOAC group, compared to 27.8% (95% CI, 15.5-41.6%) in the LMWH group (p = 0.10). The 6-month cumulative incidence of recurrent VTE events was 5.6% in the DOAC group (95% CI, 1.5-14.2%), compared to 6.6% in the LMWH group (95% CI, 1.7-16.5%) (p = 0.96). No differences were found with respect to other secondary outcomes. CONCLUSION: There were no significant differences in bleeding or recurrent VTE events between DOACs and LMWH. These findings suggest DOACs may be safe and effective for VTE treatment in this patient population.
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Neoplasias Encefálicas , Tromboembolia Venosa , Anticoagulantes/efectos adversos , Neoplasias Encefálicas/complicaciones , Heparina de Bajo-Peso-Molecular/efectos adversos , Humanos , Estudios Retrospectivos , Tromboembolia Venosa/tratamiento farmacológicoRESUMEN
BACKGROUND: Although novel agents have changed the treatment landscape of multiple myeloma (MM), cytotoxic chemotherapy regimens continue to have a role in aggressive or rapidly progressive disease. In such cases, our institution has utilized a hyperfractionated cyclophosphamide regimen (termed mCAD), similar to hyper-CVAD, in which vincristine is omitted or replaced with a proteasome inhibitor (PI), either bortezomib or carfilzomib. On occasion, doxorubicin is also omitted because of patient history and provider preference. PATIENTS AND METHODS: We retrospectively reviewed the charts of adult patients with MM receiving mCAD regimens at our institution between 2012 and 2016 and analyzed utilization patterns, toxicity profiles, and clinical outcomes. RESULTS: A total of 131 patients received mCAD, including 9% for newly diagnosed MM (NDMM), 18% attempting to optimize response to frontline therapy (OPT-MM), and 73% for treatment of relapsed/refractory MM (RRMM). Renal dysfunction was common; 31% had estimated glomerular filtration rate < 50 mL/min and 14% were dialysis dependent. The overall response rate was 83%, 63%, and 67% with a median progression-free survival of 17.4, 23.7, and 4.2 months, respectively, for NDMM, OPT-MM, and RRMM. Median overall survival was not reached for NDMM or OPT-MM, and was 15.2 months for RRMM. Most patients (90%) bridged to subsequent therapy, including 32% who proceeded to autologous transplantation. Hematologic, infectious, and cardiac toxicities were common and were similar to those expected for cytotoxic chemotherapy. CONCLUSION: mCAD regimens were safe and active across patient groups, including patients with renal dysfunction. Most patients were able to bridge to subsequent therapy.
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Mieloma Múltiple/tratamiento farmacológico , Inhibidores de Proteasoma/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Inhibidores de Proteasoma/farmacología , Estudios RetrospectivosRESUMEN
Lenalidomide is often used in the maintenance setting for multiple myeloma and has been linked to the development of secondary primary malignancies. The mechanism of lenalidomide causing secondary malignancies has not been fully elucidated, but case reports and phase 3 trials have captured this uncommon occurrence. A case series describing development of secondary acute lymphoblastic leukemia in patients receiving lenalidomide maintenance therapy is presented. Based on data published in the literature thus far and commonalities among patients in this case series, secondary acute lymphoblastic leukemia is likely duration related rather than dose related. Increased cognizance of this secondary malignancy will allow for a more accurate characterization of its true incidence. Regimens for acute lymphoblastic leukemia can be used for management of secondary acute lymphoblastic leukemia with plan for stem cell transplantation. Further studies are needed to identify risk factors for development of secondary malignancy and the best management approach for these patients. Copyright © 2015 John Wiley & Sons, Ltd.
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Factores Inmunológicos/efectos adversos , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Talidomida/análogos & derivados , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Humanos , Lenalidomida , Masculino , Persona de Mediana Edad , Neoplasias Primarias Secundarias/tratamiento farmacológico , Neoplasias Primarias Secundarias/etiología , Estudios Retrospectivos , Factores de Riesgo , Trasplante de Células Madre , Talidomida/efectos adversos , Resultado del Tratamiento , Adulto JovenRESUMEN
We report the chloroplast genomes of a tree fern (Dicksonia squarrosa) and a "fern ally" (Tmesipteris elongata), and show that the phylogeny of early land plants is basically as expected, and the estimates of divergence time are largely unaffected after removing the fastest evolving sites. The tree fern shows the major reduction in the rate of evolution, and there has been a major slowdown in the rate of mutation in both families of tree ferns. We suggest that this is related to a generation time effect; if there is a long time period between generations, then this is probably incompatible with a high mutation rate because otherwise nearly every propagule would probably have several lethal mutations. This effect will be especially strong in organisms that have large numbers of cell divisions between generations. This shows the necessity of going beyond phylogeny and integrating its study with other properties of organisms.
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Evolución Biológica , Helechos/genética , Filogenia , Genética de Población , Genoma del Cloroplasto , Datos de Secuencia Molecular , Tasa de Mutación , Nueva ZelandaRESUMEN
The phylogenetic branching order of the green algal groups that gave rise to land plants remains uncertain despite its fundamental importance to understanding plant evolution. Previous studies have demonstrated that land plants evolved from streptophyte algae, but different lineages of streptophytes have been suggested to be the sister group of land plants. To better understand the evolutionary history of land plants and to determine the potential effects of "long-branch attraction" in phylogenetic reconstruction, we analyzed a chloroplast genome data set including three new chloroplast genomes from streptophyte algae: Coleochaetae orbicularis (Coleochaetales), Nitella hookeri (Charales), and Spirogyra communis (Zygnematales). We further applied a site pattern sorting method together with site- and time-heterogeneous models to investigate the branching order among streptophytes and land plants. Our chloroplast phylogenomic analyses support previous hypotheses based on nuclear data in placing Zygnematales alone, or a clade consisting of Coleochaetales plus Zygnematales, as the closest living relatives of land plants.
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Chlorophyta/genética , Embryophyta/genética , Genoma del Cloroplasto , Evolución Biológica , Chlorophyta/clasificación , ADN de Algas/genética , ADN de Cloroplastos/genética , Embryophyta/clasificación , Filogenia , Análisis de Secuencia de ADNRESUMEN
Effectors of the bacterial type III secretion system provide invaluable molecular probes to elucidate the molecular mechanisms of plant immunity and pathogen virulence. In this report, we focus on the AvrBs2 effector protein from the bacterial pathogen Xanthomonas euvesicatoria (Xe), the causal agent of bacterial spot disease of tomato and pepper. Employing homology-based structural analysis, we generate a three-dimensional structural model for the AvrBs2 protein and identify catalytic sites in its putative glycerolphosphodiesterase domain (GDE). We demonstrate that the identified catalytic region of AvrBs2 was able to functionally replace the GDE catalytic site of the bacterial glycerophosphodiesterase BhGlpQ cloned from Borrelia hermsii and is required for AvrBs2 virulence. Mutations in the GDE catalytic domain did not disrupt the recognition of AvrBs2 by the cognate plant resistance gene Bs2. In addition, AvrBs2 activation of Bs2 suppressed subsequent delivery of other Xanthomonas type III effectors into the host plant cells. Investigation of the mechanism underlying this modulation of the type III secretion system may offer new strategies to generate broad-spectrum resistance to bacterial pathogens.