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Uproleselan (GMI-1271) is a novel E-selectin antagonist that disrupts cell survival pathways, enhances chemotherapy response, improves survival in mouse xenograft and syngeneic models, and decreases chemotherapy toxicity in vivo. A phase 1/2 study evaluated the safety, tolerability, and antileukemic activity of uproleselan (5-20 mg/kg) with MEC (mitoxantrone, etoposide, and cytarabine) among patients with relapsed/refractory (R/R) acute myeloid leukemia (AML). Among the first 19 patients, no dose-limiting toxicities were observed. The recommended phase 2 dose (RP2D) was 10 mg/kg twice daily. An additional 47 patients with R/R AML were treated with uproleselan at the RP2D plus MEC. At the RP2D, the remission rate (complete response [CR]/CR with incomplete count recovery [CRi]) was 41% (CR, 35%), and the median overall survival (OS) was 8.8 months. In a separate cohort, 25 newly diagnosed patients age ≥60 years received uproleselan at the RP2D plus cytarabine and idarubicin (7 + 3). In these frontline patients, the CR/CRi rate was 72% (CR, 52%), and the median OS was 12.6 months. The addition of uproleselan was associated with low rates of oral mucositis. E-selectin ligand expression on leukemic blasts was higher in patients with relapsed vs primary refractory AML and in newly diagnosed older patients with high-risk cytogenetics and secondary AML. In the R/R cohort, E-selectin expression >10% was associated with a higher response rate and improved survival. The addition of uproleselan to chemotherapy was well tolerated, with high remission rates, low induction mortality, and low rates of mucositis, providing a strong rationale for phase 3 randomized confirmatory studies. This trial was registered at www.clinicaltrials.gov as #NCT02306291.
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Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Glicolipídeos/administração & dosagem , Leucemia Mieloide Aguda , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Intervalo Livre de Doença , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Feminino , Glicolipídeos/efeitos adversos , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Mitoxantrona/administração & dosagem , Mitoxantrona/efeitos adversos , Taxa de SobrevidaRESUMO
The influence of demographic characteristics and social determinants on cancer outcomes is widely recognized in various malignancies but remains understudied in myelofibrosis (MF). This study aims to investigate social and demographic variables associated with MF survival. We retrospectively reviewed data of biopsy-proven MF patients from the Surveillance, Epidemiology and End Results (SEER) database (2000-2021) and Montefiore Medical Center (2000-2023), an underserved inner-city hospital. The SEER cohort included 5,403 MF patients and was predominantly Non-Hispanic (NH) White (82%) with a median age of 69 years. The age-adjusted incidence rate of MF was 0.32 cases per 100,000 person-years, increasing annually by 1.3% from 2000 to 2021. Two- and five- year overall survival rates were 69% and 42%, respectively. Worse cause-specific survival was associated with older age, male sex, and diagnosis before 2011 (year of Ruxolitinib approval). NH-Black ethnicity, unmarried status and lower median income were independent predictors of worse overall survival. The single-center analysis included 84 cases, with a median age of 66 years. NH-White patients comprised 37% of the sample, followed by NH-Black (28.5%). Two- and five- year overall survival rates were 90% and 61%, respectively, with NH-Black patients exhibiting the lowest median survival, although the difference was not statistically significant. Age was a significant predictor of worse survival in this cohort. NH-Black and Hispanic patients lived in areas with higher socioeconomic and demographic stress compared to NH-White patients. Overall, this study highlights the association of social and demographic factors with MF survival and emphasizes the need for equitable healthcare and further exploration of social-demographic factors affecting MF survival.
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INTRODUCTION: Myeloid malignancies are a heterogeneous group of clonal bone marrow disorders that are complex to manage in the community and therefore often referred to subspecialists at tertiary oncology referral centers. Many patients do not live in close proximity to tertiary referral centers and are unable to commute long distances due to age, comorbidities, and frailty. Interventions that minimize the travel time burden without compromising quality of care are an area of unmet need. We describe a cancer care delivery model for patients with myeloid malignancies that is built around telehealth and enables this vulnerable population access to care at an NCI-designated cancer center while receiving majority of their care close to home. METHODS AND MATERIALS: We report on a cohort of patients with myeloid malignancies who were co-managed by a general community oncologist and an academic leukemia subspecialist at Montefiore Einstein Cancer Center in New York. Patients were initially referred to our institute for a second opinion by community practices that are in partnership with Montefiore Health System, and initial visits were in-person or via telehealth. Treatment plans were made after discussion with patient's local community oncologist. Patients then continued to receive majority of their treatment and supportive care including transfusion support with their local oncologist, and follow-up visits were mainly via telehealth with the academic leukemia subspecialist. RESULTS: Our cohort of 12 patients had a median age of 81 years (range, 59-88 years). Patients remained on active treatment for a median time of 357 days (range, 154-557 days). Most of our patients had a performance status of ECOG 2 or higher. Three patients had myelodysplastic syndromes, 7 patients had acute myeloid leukemia, and 2 patients had myelofibrosis. The median number of hospitalizations over the total treatment time period was one. CONCLUSION: We demonstrate a shared academic and community care co-management model for the treatment of myeloid malignancies in elderly, frail patients using telehealth as a backbone with a very low hospitalization rate.
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COVID-19 , Atenção à Saúde , Gerenciamento Clínico , Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Mielofibrose Primária , Idoso , Idoso de 80 Anos ou mais , Humanos , Pessoa de Meia-Idade , COVID-19/epidemiologia , COVID-19/terapia , Atenção à Saúde/métodos , Idoso Fragilizado , Acessibilidade aos Serviços de Saúde , Hospitalização/estatística & dados numéricos , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/epidemiologia , Síndromes Mielodisplásicas/epidemiologia , Síndromes Mielodisplásicas/terapia , Pandemias , Mielofibrose Primária/epidemiologia , Mielofibrose Primária/terapia , Telemedicina , Cidade de Nova Iorque/epidemiologia , Centros Médicos Acadêmicos , Serviços de Saúde Comunitária , ComorbidadeRESUMO
This article marks the 30th anniversary of the Supreme Court of New Jersey's Baby M decision by offering a critical analysis of surrogacy policy in the United States. Despite fundamental changes in both science and society since the case was decided, state courts and legislatures remain bitterly divided on the legality of surrogacy. In arguing for a more uniform, permissive legal posture toward surrogacy, the article addresses five central debates in the surrogacy literature. First, should the legal system accommodate those seeking conception through surrogacy, or should it prohibit such arrangements? Second, if surrogacy is permitted, what steps can be taken to minimize the potential exploitation of women who are willing to rent their wombs for income? Third, what criteria should govern the eligibility to serve as a surrogate mother and an intended parent? Fourth, what principle(s) should serve as the basis for determining the parentage of children born through surrogacy? Fifth, is regulatory uniformity in the surrogacy realm desirable? Is it achievable? The article concludes that courts and legislatures should accept the validity of surrogacy contracts, determine parentage according to intent, and identify transparent criteria for the eligibility of both surrogates and intended parents.
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Declaração de Nascimento/legislação & jurisprudência , Contratos/legislação & jurisprudência , Mães/legislação & jurisprudência , Mães Substitutas/legislação & jurisprudência , Direitos da Mulher/legislação & jurisprudência , Feminino , Humanos , Gravidez , Técnicas de Reprodução Assistida/legislação & jurisprudência , Estados UnidosAssuntos
Delegação Vertical de Responsabilidades Profissionais/ética , Ética Médica , Consentimento Livre e Esclarecido/legislação & jurisprudência , Papel do Médico , Humanos , Equipe de Assistência ao Paciente/ética , Equipe de Assistência ao Paciente/legislação & jurisprudência , Pennsylvania , Governo Estadual , Estados UnidosRESUMO
CPX-351 is a liposomal formulation of cytarabine:daunorubicin designed to deliver synergistic drug ratios to leukemia cells. In this phase 2 study, newly diagnosed older acute myeloid leukemia (AML) patients were randomized 2:1 to first-line CPX-351 or 7+3 treatment. The goal was to determine efficacy and identify patient subgroups that may benefit from CPX-351 treatment. Response rate (complete remission + incomplete remission) was the primary end point, with event-free survival (EFS) and overall survival (OS) as secondary end points. The 126 patients entered were balanced for disease and patient-specific risk factors. Overall, CPX-351 produced higher response rates (66.7% vs 51.2%, P = .07), meeting predefined criteria for success (P < .1). Differences in EFS and OS were not statistically significant. A planned analysis of the secondary AML subgroup demonstrated an improved response rate (57.6% vs 31.6%, P = .06), and prolongation of EFS (hazard ratio [HR] = 0.59, P = .08) and OS (HR = 0.46, P = .01). Recovery from cytopenias was slower after CPX-351 (median days to absolute neutrophil count ≥1000: 36 vs 32; platelets >100 000: 37 vs 28) with more grade 3-4 infections but without increase in infection-related deaths (3.5% vs 7.3%) or 60-day mortality (4.7% vs 14.6%), indicating acceptable safety. These results suggest a clinical benefit with CPX-351, particularly among patients with secondary AML, and provide the rationale for a phase 3 trial currently underway in newly diagnosed secondary AML patients. This study is registered at Clinicaltrials.gov as #NCT00788892.
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Antibióticos Antineoplásicos/uso terapêutico , Antimetabólitos Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Citarabina/uso terapêutico , Idoso , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Daunorrubicina/administração & dosagem , Daunorrubicina/efeitos adversos , Daunorrubicina/uso terapêutico , Intervalo Livre de Doença , Feminino , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Lipossomos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: CPX-351 is a liposome-encapsulated fixed-molar-ratio formulation of cytarabine and daunorubicin that exploits molar ratio-dependent drug-drug synergy to enhance antileukemic efficacy. METHODS: This phase II study randomized 125 patients 2:1 to CPX-351 or investigators' choice of first salvage chemotherapy. Patients with acute myeloid leukemia (AML) in first relapse after initial Complete Remission (CR) lasting ≥1 month were stratified per the European Prognostic Index (EPI) into favorable, intermediate, and poor-risk groups based on duration of first CR, cytogenetics, age, and transplant history. Control salvage treatment was usually based on cytarabine and anthracycline, often with 1 or more additional agents. Survival at 1 year was the primary efficacy end point. RESULTS: Patient characteristics were well balanced between the 2 study arms. Improvements in efficacy outcomes were observed following CPX-351, but did not meet prospectively defined statistical criteria for 1-year survival improvement in the overall population. Subset analyses of the EPI-defined poor-risk strata demonstrated higher response rates (39.3% vs 27.6%) and improvements in event-free survival (HR, 0.63; P = .08) and overall survival (HR, 0.55; P = .02). Also, 60-day mortality was lower in the CPX-351 study arm for poor-risk patients (16.1% vs 24.1%). CONCLUSIONS: Taken together, the data suggest possible improved outcomes in CPX-351-treated first relapse AML patients with EPI-defined poor-risk disease.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Terapia de Salvação/métodos , Adulto , Idoso , Aminoglicosídeos/administração & dosagem , Amsacrina/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Cladribina/administração & dosagem , Citarabina/administração & dosagem , Daunorrubicina/administração & dosagem , Intervalo Livre de Doença , Etoposídeo/administração & dosagem , Feminino , Gemtuzumab , Humanos , Injeções , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/mortalidade , Lipossomos , Masculino , Pessoa de Meia-Idade , Mitoxantrona/administração & dosagem , Recidiva , Indução de Remissão , Medição de Risco , Resultado do Tratamento , Vidarabina/administração & dosagem , Vidarabina/análogos & derivadosRESUMO
Tipifarnib (T) exhibits modest activity in elderly adults with newly diagnosed acute myelogenous leukemia (AML). Based on preclinical synergy, a phase 1 trial of T plus etoposide (E) yielded 25% complete remission (CR). We selected 2 comparable dose levels for a randomized phase 2 trial in 84 adults (age range, 70-90 years; median, 76 years) who were not candidates for conventional chemotherapy. Arm A (T 600 mg twice a day × 14 days, E 100 mg days 1-3 and 8-10) and arm B (T 400 mg twice a day × 14 days, E 200 mg days 1-3 and 8-10) yielded similar CR, but arm B had greater toxicity. Total CR was 25%, day 30 death rate 7%. A 2-gene signature of high RASGRP1 and low aprataxin (APTX) expression previously predicted for T response. Assays using blasts from a subset of 40 patients treated with T plus E on this study showed that AMLs with a RASGRP1/APTX ratio of more than 5.2 had a 78% CR rate and negative predictive value 87%. This ratio did not correlate with outcome in 41 patients treated with conventional chemotherapies. The next T-based clinical trials will test the ability of the 2-gene signature to enrich for T responders prospectively. This study is registered at www.clinicaltrials.gov as #NCT00602771.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Farmacogenética , Idoso , Idoso de 80 Anos ou mais , Proteínas de Ligação a DNA/genética , Etoposídeo/administração & dosagem , Feminino , Seguimentos , Fatores de Troca do Nucleotídeo Guanina/genética , Humanos , Leucemia Mieloide Aguda/mortalidade , Masculino , Proteínas Nucleares/genética , Prognóstico , Quinolonas/administração & dosagem , RNA Mensageiro/genética , Indução de Remissão , Estudos Retrospectivos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Taxa de SobrevidaRESUMO
BACKGROUND: Tosedostat is a novel oral aminopeptidase inhibitor with clinical activity in a previous phase 1-2 study in elderly patients with relapsed or refractory acute myeloid leukaemia (AML). We aimed to compare two dosing regimens of tosedostat. METHODS: In this randomised phase 2 study, patients aged 60 years or older with AML that had relapsed after a first complete remission lasting less than 12 months, or had achieved no previous complete remission, were randomly assigned (1:1) to receive as first salvage tosedostat 120 mg once daily for 6 months or 240 mg once daily for 2 months followed by 120 mg for 4 months. Randomisation was by block method via an interactive web response system using a randomisation schedule generated by an external vendor, with no stratification. The study was open label. The primary endpoint was the proportion of patients who obtained a complete remission or complete remission with incomplete platelet recovery. Analyses included all patients randomly assigned to treatment groups who received at least one oral dose of tosedostat. The study is registered with ClinicalTrials.gov, number NCT00780598. FINDINGS: 38 patients were randomly assigned to receive tosedostat 120 mg and 38 to receive the tosedostat 240 mg to 120 mg regimen. 38 patients in the 120 mg group and 35 in the 240 mg to 120 mg group received tosedostat. Seven patients (10%) had complete remission or complete remission with incomplete platelet recovery: two (5%) in the 120 mg group and five (14%) in the 240 mg to 120 mg group. The most common grade 3 or worse adverse events were febrile neutropenia (11 [29%] patients in the 120 mg group and ten [29%] of the 240 mg to 120 mg group), thrombocytopenia (eight [21%] and eight [23%] patients), fatigue (seven [18%] and eight [23%] patients), dyspnoea (five [13%] and seven [20%] patients), and pneumonia (four [11%] and six [17%] patients). There were five fatal adverse events deemed to be treatment-related: three in the 120 mg group and two in the 240 mg to 120 mg group. The events were acute hepatitis, respiratory failure, pneumonia, atrial fibrillation, and left ventricular dysfunction. INTERPRETATION: Tosedostat, at either dose schedule, has activity in older patients with relapsed or refractory AML. Additional studies of tosedostat including combination with hypomethylating agents and low-dose cytarabine in patients with high-risk myelodysplastic syndromes and AML are ongoing or planned. FUNDING: Chroma Therapeutics.
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Anemia Refratária/tratamento farmacológico , Glicina/análogos & derivados , Ácidos Hidroxâmicos/administração & dosagem , Leucemia Monocítica Aguda/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Anemia Refratária/patologia , Citarabina/administração & dosagem , Intervalo Livre de Doença , Feminino , Glicina/administração & dosagem , Glicina/efeitos adversos , Humanos , Ácidos Hidroxâmicos/efeitos adversos , Leucemia Monocítica Aguda/patologia , Masculino , Pessoa de Meia-Idade , Recidiva , Indução de RemissãoRESUMO
Recent advances in graft-versus-host disease (GVHD) prophylaxis including post-transplant cyclophosphamide (PTCy) and abatacept have significantly improved outcomes following HLA-mismatched allogenic hematopoietic stem cell transplantation (allo-HSCT) and have tremendous potential for reducing racial disparities in donor availability. A recent small study employing bone marrow as the source of stem cells showed similar outcomes after 5/8 versus 7/8 matches and is currently being tested in a larger study using peripheral blood stem cells. In this study, we examine real-world alternative donor HSCT options for a minority-predominant cohort in the Bronx, NY, focusing on the availability of lesser-matched (5/8 to 7/8) donors. Records of patients who underwent HLA typing at Montefiore Medical Center (2019 to 2022) were reviewed. The National Marrow Donor Program registry was queried to evaluate the availability of donors with at least 99% likelihood of HLA match at various levels (5/8, 6/8, 7/8, 8/8). Two hundred forty-one patients were included, 70% were non-White. Although the availability of ≥7/8 donors was less common in non-White patients, 100% of patients from each group had at least one or more 5/8 and 6/8 HLA-matched donors and more than 80% of these patients had >100 potential 5/8 and 6/8 HLA-matched donors. There was no statistical difference by race or ethnicity in the mean number of donors at 5/8 and 6/8 HLA-match levels. We demonstrate through real-world data that patients from diverse ethnic and racial backgrounds have access to 5/8 and 6/8 HLA-matched donors for allo-HSCT, potentially eliminating disparities in donor availability and allowing prioritization of other donor selection characteristics such as donor age, sex, ABO, and B leader matching. Further work is needed to study whether the use of mismatched donors offers a more potent graft-versus malignancy effect and optimal GVHD prophylaxis.
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Transplante de Células-Tronco Hematopoéticas , Teste de Histocompatibilidade , Doadores não Relacionados , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Transplante de Células-Tronco Hematopoéticas/estatística & dados numéricos , Adulto , Doença Enxerto-Hospedeiro/prevenção & controle , Grupos Minoritários/estatística & dados numéricos , Estudos de Coortes , Antígenos HLA/imunologia , IdosoRESUMO
This phase I study evaluated the maximal tolerated dose of CPX-351 when administered sequentially with allogeneic hematopoietic stem cell transplantation (HSCT) in patients with refractory acute leukemia. CPX-351 is a novel liposomal formulation that combines cytosine arabinoside (ara-c) and daunorubicin in a fixed molar ratio of 5:1. Patients in cohorts of 3 were treated with CPX-351 followed by fludarabine and busulfan (Bu/Flu) conditioning at 4-week (schedule A) or 3-week (schedule B) intervals. CPX-351 doses were escalated in 20-U/m(2) increments starting at 60 U/m(2) for 3 doses. Of the 36 patients enrolled, 29 were able to undergo HSCT, and the other 7 (the majority on schedule A) did not proceed to HSCT because of rapid disease progression. The maximal tolerated dose of CPX-351 was not reached at the 120 U/m(2) × 3 dose level. All 29 patients who proceeded to HSCT demonstrated adequate neutrophil and platelet engraftment. The median follow-up on the study for all 36 patients was 205 days (range, 20 to 996 days). The 1-year cumulative incidence of relapse for the 36 patients was 60.1% (95% confidence interval [CI], 43.4% to 77.3%), and that of nonrelapse mortality was 23.8% (95% CI, 10.9% to 47.4%). The 1-year overall survival and leukemia-free survival were 37% (95% CI, 21% to 53%) and 27% (95% CI, 13% to 43%), respectively. Our data suggest that a phase II trial should incorporate CPX-351 120 U/m(2) × 3 dosing on schedule B. Patients with good performance status and those who achieve effective cytoreduction from CPX-351 derived the greatest benefit.
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Bussulfano/uso terapêutico , Citarabina/uso terapêutico , Daunorrubicina/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda/terapia , Agonistas Mieloablativos/uso terapêutico , Condicionamento Pré-Transplante , Vidarabina/análogos & derivados , Adulto , Idoso , Estudos de Casos e Controles , Esquema de Medicação , Quimioterapia Combinada , Feminino , Seguimentos , Humanos , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Agonistas Mieloablativos/farmacocinética , Prognóstico , Recidiva , Análise de Sobrevida , Transplante Homólogo , Vidarabina/uso terapêuticoRESUMO
We present the first reported infection caused by Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacter gergoviae. The patient had leukemia and neutropenia and died of septic shock from KPC-producing E. gergoviae bacteremia. The emergence of KPCs in additional species of Enterobacteriaceae is alarming and may disproportionately affect patients with hematologic malignancies.
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Proteínas de Bactérias/metabolismo , Infecções por Enterobacteriaceae/diagnóstico , Enterobacteriaceae/enzimologia , Enterobacteriaceae/isolamento & purificação , Leucemia/complicações , Neutropenia/complicações , Choque Séptico/diagnóstico , beta-Lactamases/metabolismo , Idoso , Antibacterianos/farmacologia , Infecções por Enterobacteriaceae/complicações , Infecções por Enterobacteriaceae/microbiologia , Infecções por Enterobacteriaceae/patologia , Evolução Fatal , Humanos , Masculino , Testes de Sensibilidade Microbiana , Choque Séptico/complicações , Choque Séptico/microbiologia , Choque Séptico/patologiaRESUMO
It seems strange, but after 40 years of experience using cytosine arabinoside (ara-C) and daunorubicin, leukemia doctors are still unsure as to how much of each drug they should use to treat their patients with acute myeloid leukemia (AML).
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We conducted an open-label phase 1 study exploring the feasibility, safety, and biologic activity of epigenetic priming with decitabine before standard induction chemotherapy in patients with less-than-favorable risk of acute myelogenous leukemia (AML). We directly compared the clinical and DNA-hypomethylating activity of decitabine delivered at 20 mg/m² by either a 1-hour infusion (Arm A) or a continuous infusion (Arm B) for 3, 5, or 7 days before a single, standard induction with infusional cytarabine (100 mg/m² for 7 days) and daunorubicin (60 mg/m² × 3 doses). Toxicity was similar to that of standard induction chemotherapy alone. Although we did not identify a maximum tolerated dose, there was more gastro-intestinal toxicity with 7 days of decitabine priming. Decitabine induced DNA hypomethylation at all dose levels and there was a trend toward greater hypomethylation in CD34(+) bone marrow cells when decitabine was delivered by a short pulse (Arm A). Twenty-seven subjects (90%) responded to therapy: 17 with complete remission (57%) and 10 with partial remission (33%). Of the patients with partial remission to protocol treatment, 8 achieved remission to their next therapy, bringing the overall complete remission rate to 83%. We conclude that epigenetic priming of intensive chemotherapy can be safely delivered in an attempt to improve response rates. This trial was registered at www.clinicaltrials.gov as NCT00538876.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Metilação de DNA/efeitos dos fármacos , Leucemia Mieloide/tratamento farmacológico , Leucemia Mieloide/genética , Doença Aguda , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Azacitidina/administração & dosagem , Azacitidina/efeitos adversos , Azacitidina/análogos & derivados , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Daunorrubicina/administração & dosagem , Daunorrubicina/efeitos adversos , Decitabina , Diarreia/induzido quimicamente , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Febre/induzido quimicamente , Humanos , Infecções/induzido quimicamente , Estimativa de Kaplan-Meier , Leucemia Mieloide/patologia , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Neutropenia/induzido quimicamente , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVES: To study relationships between median wrist and forearm sonographic measurements and median nerve conduction studies. METHODS: The study population consisted of a prospective convenience sample of healthy adults. Interventions included high-resolution median nerve sonography and median motor and sensory nerve conduction studies. Main outcome measures included median motor nerve compound muscle action potential amplitude, distal latency, and conduction velocity; sensory nerve action potential amplitude and distal latency; and sonographic median nerve cross-sectional area. Median motor nerve and sensory nerve conduction studies of the index finger were performed using standard published techniques. A second examiner blinded to nerve conduction study results used a high-frequency linear array transducer to measure the cross-sectional area of the median nerve at the distal volar wrist crease (carpal tunnel inlet) and forearm (4 cm proximally), measured in the transverse plane on static sonograms. The outer margin of the median nerve was traced at the junction of the hypoechoic fascicles and adjacent outer connective tissue layer. RESULTS: Fifty median nerves were evaluated in 25 participants. The compound muscle action potential amplitude with wrist stimulation was positively related to the cross-sectional area, with the area increasing by 0.195 mm(2) for every millivolt increase in amplitude in the dominant hand (95% confidence interval, 0.020, 0.370 mm(2); P < .05) and 0.247 mm(2) in the nondominant hand (95% confidence interval, 0.035, 0.459 mm(2); P < .05). There was no significant linear association between the wrist median cross-sectional area and median motor and sensory distal latencies. Conduction velocity through the forearm was not significantly linearly associated with the forearm area or forearm-to-wrist area ratio (tapering ratio). The wrist area was inversely related to the sensory nerve action potential amplitude. CONCLUSIONS: Although associations were found between median nerve conduction study amplitudes and sonographic nerve measurements, they were not found for other parameters. Studying these relationships may increase our understanding of when to best use these procedures.
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Aumento da Imagem/métodos , Nervo Mediano/diagnóstico por imagem , Nervo Mediano/fisiologia , Condução Nervosa/fisiologia , Ultrassonografia/métodos , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Valores de Referência , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Estatística como AssuntoRESUMO
PURPOSE: Venetoclax (VEN) added to the hypomethylating agents (HMA) decitabine or azacitidine is the new standard of care for elderly patients with acute myeloid leukemia (AML) and is being evaluated in myelodysplastic syndrome (MDS). Current dosing of HMA/VEN relies on leukemia suppression through cytotoxicity which also impacts normal hematopoiesis. A regimen using once-weekly low-dose decitabine (LDDec) has demonstrated activity in myeloid malignancies. To overcome the severe myelosuppression often seen with HMA/VEN, we evaluated a once-weekly dosing regimen of VEN and LDDec in elderly and/or frail patients who were felt less likely to tolerate severe myelosuppression. PATIENTS AND METHODS: This is a retrospective, single-center analysis of patients with AML, MDS, or chronic myelomonocytic leukemia treated with a once-weekly LDDec/VEN regimen. We also compare this regimen with a cohort treated with standard dosing HMA/VEN. RESULTS: In a retrospective cohort of 39 patients, the overall response rate for patients receiving LDDec/VEN for first-line AML and MDS was 88% and 64%, respectively. In patients with TP53 mutations, the composite complete response rate was 71% and the median overall survival was 10.7 months. When compared with 36 patients receiving standard dose HMA/VEN, the LDDec/VEN patients had a longer time on therapy (175 vs. 78 days; P = 0.014) and a trend toward a higher rate of transfusion independence (47% vs. 26%; P = 0.33). Neutropenic fever occurred in 31% of patients, with a median of one hospitalization at any point during treatment. CONCLUSIONS: This preliminary clinical experience, although retrospective, provides proof-of-activity of noncytotoxic DNA methyltransferase 1-targeting by allowing frequent, sustained drug exposure often not possible with standard HMA/VEN regimens.
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Survey data suggest that many people fear genetic discrimination by health insurers or employers. In fact, such discrimination has not yet been a significant problem. This article examines the fear and reality of genetic discrimination in the United States, describes how Congress sought to prohibit such discrimination by passing the Genetic Information Nondiscrimination Act of 2008 (GINA), and explores the implications of GINA for general internists and their institutions. It concludes that medical providers and health care institutions must be familiar with the general intent and specific terms of GINA, and should continue to collect genetic information that can contribute to the high quality provision of medical treatment. Not doing so violates their medical mission and diminishes the quality of care patients deserve.
Assuntos
Privacidade Genética/legislação & jurisprudência , Legislação Médica , Medicina de Precisão/métodos , Preconceito , Política Pública , Testes Genéticos/legislação & jurisprudência , Humanos , Estados UnidosRESUMO
The farnesyltransferase inhibitor tipifarnib exhibits modest activity against acute myelogenous leukemia. To build on these results, we examined the effect of combining tipifarnib with other agents. Tipifarnib inhibited signaling downstream of the farnesylated small G protein Rheb and synergistically enhanced etoposide-induced antiproliferative effects in lymphohematopoietic cell lines and acute myelogenous leukemia isolates. We subsequently conducted a phase 1 trial of tipifarnib plus etoposide in adults over 70 years of age who were not candidates for conventional therapy. A total of 84 patients (median age, 77 years) received 224 cycles of oral tipifarnib (300-600 mg twice daily for 14 or 21 days) plus oral etoposide (100-200 mg daily on days 1-3 and 8-10). Dose-limiting toxicities occurred with 21-day tipifarnib. Complete remissions were achieved in 16 of 54 (30%) receiving 14-day tipifarnib versus 5 of 30 (17%) receiving 21-day tipifarnib. Complete remissions occurred in 50% of two 14-day tipifarnib cohorts: 3A (tipifarnib 600, etoposide 100) and 8A (tipifarnib 400, etoposide 200). In vivo, tipifarnib plus etoposide decreased ribosomal S6 protein phosphorylation and increased histone H2AX phosphorylation and apoptosis. Tipifarnib plus etoposide is a promising orally bioavailable regimen that warrants further evaluation in elderly adults who are not candidates for conventional induction chemotherapy. These clinical studies are registered at www.clinicaltrials.gov as #NCT00112853.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Etoposídeo/administração & dosagem , Leucemia Mieloide Aguda/tratamento farmacológico , Quinolonas/administração & dosagem , Administração Oral , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/administração & dosagem , Farnesiltranstransferase/antagonistas & inibidores , Células HL-60 , Humanos , Células Jurkat , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/epidemiologia , Células Tumorais Cultivadas , Células U937RESUMO
In most U.S. jurisdictions, clinicians providing informal "curbside" consults are protected from medical malpractice liability due to the absence of a doctor-patient relationship. A recent Minnesota Supreme Court case, Warren v. Dinter, offers the opportunity to reassess whether the majority rule is truly serving the best interests of patients.