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Bone Marrow Transplant ; 55(6): 1161-1168, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31992847


Prophylactic donor lymphocyte infusion (pDLI) is a potential intervention to prolong remission for patients receiving allogeneic hematopoietic stem cell transplantation (allo-SCT), however, the optimal timing and dose are unknown. We conducted a prospective trial exploring the feasibility of early withdrawal of immunosuppression (WOI) at day 60 followed by dose escalation of pDLI after alemtuzumab-based, T-cell depleted conditioning for patients with high-risk hematologic malignancies. pDLI were administered at day 75 to day 90 and again in 4-8 week intervals with receipt of up to 5 pDLI infusions. Fourty-six patients with matched-related donors (MRD) and 29 patients with matched-unrelated donors (MUD) were considered. Twenty-eight MRD patients were able to undergo WOI, 26 patients (93%) received at least 1 DLI, 16 patients (57%) received 3+, and 7 patients (25%) received 5 pDLI. Only 7 MUD patients were able to undergo WOI, 4 (57%) received at least 1 pDLI, 1 patient (14%) received 3 DLI, and no patients received all 5. Median PFS for patients on the study was 366 days. The estimated 2-year PFS and OS rates for all patients were 41% (95% CI, 32-54%) and 51% (95% CI, 41-63%) compared with 57% (95% CI, 41-77%) and 67% (95% CI, 52-86%) for patients who received at least one pDLI. In addition, MRD patients receiving pDLI had faster immune re-constitution and improved donor chimerism. Our trial proposes a novel dosage and treatment schedule for pDLI that is tolerable for patients who have received MRD allo-SCT and leads to improved outcomes.

J Thromb Thrombolysis ; 46(1): 1-6, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29611105


Non-valvular atrial fibrillation (NVAF) is common in older adults. Oral anticoagulation is indicated to reduce the risk of stroke and systemic embolism, but it also poses a risk of bleeding, particularly in the elderly. Direct oral anticoagulants (DOACs) provide an alternative to warfarin and their use in the treatment of AF is growing. We conducted a retrospective cohort study to assess the quality of DOAC prescribing in elderly patients with NVAF in a large academic health system and to compare practice with consensus best practice recommendations. We searched the electronic medical record for patients ≥ 65 years of age who were newly initiated on a DOAC for AF from January 2013 through December 2015. Patient and provider characteristics, baseline laboratory investigations, concomitant medications, and interval to first follow-up were recorded. 192 patients met eligibility criteria. The most commonly prescribed DOACs were rivaroxaban (65%) and apixaban (26%). Despite consensus recommendations that patients have a baseline creatinine, complete blood cell count, and coagulation studies prior to DOAC initiation, these tests were not performed in 18, 31, and 67% of patients, respectively. Consensus recommendations also suggest a follow-up visit within 1 month of DOAC initiation. However, only 39% of patients had a return visit within 6 weeks and 43% did not have follow-up within 12 weeks. DOAC prescribing in elderly patients with NVAF frequently fell short of quality standards. Interventions to enhance the quality of DOAC prescribing in this high-risk population are needed.

Anticoagulantes/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Padrões de Prática Médica/normas , Idoso , Idoso de 80 Anos ou mais , Inibidores do Fator Xa/uso terapêutico , Feminino , Humanos , Masculino , Guias de Prática Clínica como Assunto/normas , Pirazóis/uso terapêutico , Piridonas/uso terapêutico , Estudos Retrospectivos , Rivaroxabana/uso terapêutico
Nature ; 545(7652): 60-65, 2017 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-28397821


Despite the success of monotherapies based on blockade of programmed cell death 1 (PD-1) in human melanoma, most patients do not experience durable clinical benefit. Pre-existing T-cell infiltration and/or the presence of PD-L1 in tumours may be used as indicators of clinical response; however, blood-based profiling to understand the mechanisms of PD-1 blockade has not been widely explored. Here we use immune profiling of peripheral blood from patients with stage IV melanoma before and after treatment with the PD-1-targeting antibody pembrolizumab and identify pharmacodynamic changes in circulating exhausted-phenotype CD8 T cells (Tex cells). Most of the patients demonstrated an immunological response to pembrolizumab. Clinical failure in many patients was not solely due to an inability to induce immune reinvigoration, but rather resulted from an imbalance between T-cell reinvigoration and tumour burden. The magnitude of reinvigoration of circulating Tex cells determined in relation to pretreatment tumour burden correlated with clinical response. By focused profiling of a mechanistically relevant circulating T-cell subpopulation calibrated to pretreatment disease burden, we identify a clinically accessible potential on-treatment predictor of response to PD-1 blockade.

Linfócitos T CD8-Positivos/imunologia , Melanoma/tratamento farmacológico , Melanoma/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Carga Tumoral/imunologia , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/imunologia , Anticorpos Monoclonais Humanizados/farmacocinética , Anticorpos Monoclonais Humanizados/uso terapêutico , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/metabolismo , Feminino , Humanos , Antígeno Ki-67/imunologia , Antígeno Ki-67/metabolismo , Masculino , Melanoma/irrigação sanguínea , Melanoma/patologia , Estadiamento de Neoplasias , Fenótipo , Resultado do Tratamento
Lung Cancer ; 106: 1-7, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28285682


OBJECTIVES: Efficient use of nivolumab in non-small-cell lung cancer (NSCLC) has been limited by the lack of a definitive predictive biomarker. In patients with metastatic melanoma treated with ipilimumab, a pretreatment neutrophil-to-lymphocyte ratio (NLR)<5 has been associated with improved survival. This retrospective cohort study aimed to determine whether the pretreatment NLR was associated with outcomes in NSCLC patients treated with nivolumab. METHODS: We reviewed the medical records of all patients with previously treated advanced NSCLC who received nivolumab between March 2015 and March 2016 outside of a clinical trial at the University of Pennsylvania. Patients were dichotomized according to pretreatment NLR<5 vs. ≥5. Multivariable logistic regression and Cox proportional hazards models were used to assess the impact of pretreatment NLR on overall survival (OS), progression-free survival (PFS), and overall response rate (ORR). RESULTS: 175 patients were treated. Median age was 68 (range, 33-88); 54% were female. Twenty-five percent of patients had an Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≥2; 46% had received ≥2 prior systemic therapies. In multivariate analyses, pretreatment neutrophil-to-lymphocyte ratio (NLR) ≥5 was independently associated with inferior OS (median 5.5 vs. 8.4 months; HR 2.07, 95% CI 1.3-3.3; p=0.002) and inferior PFS (median 1.9 vs. 2.8 months; HR 1.43, 95% CI 1.02-2.0; p=0.04). CONCLUSIONS: In a cohort of patients with NSCLC treated with nivolumab in routine practice, pretreatment NLR≥5 was associated with inferior outcomes. It is unclear whether this marker is predictive or prognostic. Prospective studies are warranted to determine the utility of NLR in the context of other biomarkers of programmed death-1 (PD-1) therapy.

Anticorpos Monoclonais/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/imunologia , Neoplasias Pulmonares/imunologia , Linfócitos/imunologia , Neutrófilos/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Administração Intravenosa , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/administração & dosagem , Biomarcadores/sangue , Carcinoma Pulmonar de Células não Pequenas/patologia , Ensaios Clínicos como Assunto , Intervalo Livre de Doença , Feminino , Humanos , Imunoterapia/métodos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Nivolumabe , Prognóstico , Estudos Retrospectivos , Resultado do Tratamento
J Vasc Interv Radiol ; 26(2): 240-6, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25534637


PURPOSE: To determine whether hemodialysis patients with central venous stenosis (CVS) are more frequently symptomatic if they have grafts versus fistulas. MATERIALS AND METHODS: A retrospective review was performed of 500 consecutive discrete patients, half with fistulas and half with grafts, who had fistulograms performed over a 4-year period. All fistulograms were evaluated for CVS, which was graded into quartiles. The presence of collaterals was noted and graded. Patient records were analyzed for symptoms of CVS, including face, neck, breast, or limb swelling. Statistical analysis was performed to determine the association between access type, degree of stenosis, location of stenosis, and symptoms. RESULTS: Of 500 fistulograms, 31 were excluded because of inadequate or absent central imaging. Of the remaining 469 patients, 235 had fistulas and 234 had grafts. CVS was present in 51% of patients with fistulas (119 of 237) and 51% of patients with grafts (118 of 237). When CVS was present, 29% (35 of 119) of patients with fistulas were symptomatic versus 52% (62 of 118) of patients with grafts (P = .0005). Overall, only 15% of patients with fistulas in the entire cohort were symptomatic compared with 27% of patients with grafts (P = .002). Sex, access side, and transposition did not influence symptoms; however, patients with upper arm access were more likely than patients with forearm access to be symptomatic (P < .0001), independent of access type. CONCLUSIONS: CVS is more likely to be symptomatic in patients with grafts versus fistulas, and patients with upper arm access are more likely than patients with forearm access to be symptomatic.

Derivação Arteriovenosa Cirúrgica/estatística & dados numéricos , Cateterismo Venoso Central/estatística & dados numéricos , Complicações Pós-Operatórias/epidemiologia , Diálise Renal/estatística & dados numéricos , Doenças Vasculares/epidemiologia , Enxerto Vascular/estatística & dados numéricos , Comorbidade , Feminino , Humanos , Incidência , Falência Renal Crônica/epidemiologia , Falência Renal Crônica/terapia , Masculino , Pessoa de Meia-Idade , Pennsylvania/epidemiologia , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento