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1.
JAMA Oncol ; 9(1): 112-121, 2023 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-36394838

RESUMO

Importance: Glioblastoma is the most lethal primary brain cancer. Clinical outcomes for glioblastoma remain poor, and new treatments are needed. Objective: To investigate whether adding autologous tumor lysate-loaded dendritic cell vaccine (DCVax-L) to standard of care (SOC) extends survival among patients with glioblastoma. Design, Setting, and Participants: This phase 3, prospective, externally controlled nonrandomized trial compared overall survival (OS) in patients with newly diagnosed glioblastoma (nGBM) and recurrent glioblastoma (rGBM) treated with DCVax-L plus SOC vs contemporaneous matched external control patients treated with SOC. This international, multicenter trial was conducted at 94 sites in 4 countries from August 2007 to November 2015. Data analysis was conducted from October 2020 to September 2021. Interventions: The active treatment was DCVax-L plus SOC temozolomide. The nGBM external control patients received SOC temozolomide and placebo; the rGBM external controls received approved rGBM therapies. Main Outcomes and Measures: The primary and secondary end points compared overall survival (OS) in nGBM and rGBM, respectively, with contemporaneous matched external control populations from the control groups of other formal randomized clinical trials. Results: A total of 331 patients were enrolled in the trial, with 232 randomized to the DCVax-L group and 99 to the placebo group. Median OS (mOS) for the 232 patients with nGBM receiving DCVax-L was 19.3 (95% CI, 17.5-21.3) months from randomization (22.4 months from surgery) vs 16.5 (95% CI, 16.0-17.5) months from randomization in control patients (HR = 0.80; 98% CI, 0.00-0.94; P = .002). Survival at 48 months from randomization was 15.7% vs 9.9%, and at 60 months, it was 13.0% vs 5.7%. For 64 patients with rGBM receiving DCVax-L, mOS was 13.2 (95% CI, 9.7-16.8) months from relapse vs 7.8 (95% CI, 7.2-8.2) months among control patients (HR, 0.58; 98% CI, 0.00-0.76; P < .001). Survival at 24 and 30 months after recurrence was 20.7% vs 9.6% and 11.1% vs 5.1%, respectively. Survival was improved in patients with nGBM with methylated MGMT receiving DCVax-L compared with external control patients (HR, 0.74; 98% CI, 0.55-1.00; P = .03). Conclusions and Relevance: In this study, adding DCVax-L to SOC resulted in clinically meaningful and statistically significant extension of survival for patients with both nGBM and rGBM compared with contemporaneous, matched external controls who received SOC alone. Trial Registration: ClinicalTrials.gov Identifier: NCT00045968.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Humanos , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Temozolomida/uso terapêutico , Estudos Prospectivos , Neoplasias Encefálicas/patologia , Recidiva , Células Dendríticas/patologia , Vacinação
3.
Hematol Oncol ; 35(1): 64-68, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26205037

RESUMO

The significance of HIV associated paraproteins and their risk of progression to hematological malignancies remains unclear. We compared the development of hematological malignancies among HIV+ (n = 266) and HIV- (n = 537) patients with monoclonal gammopathies. HIV+ and HIV- patients with a positive serum protein electrophoresis test (SPEP) were studied. HIV+ SPEP+ were more likely to have faint and oligoclonal paraproteins (F-SPEP) and less likely to have discrete bands (D-SPEP) compared to HIV- SPEP+. The incidence of hematological malignancies was significantly lower in the HIV+ compared to the HIV- (6.4% vs 15.4%, p < 0.0002). Upon subgroup analysis, the lower incidence of hematological malignancies was noted for HIV+ patients with F-SPEP but not for those with D-SPEP. Copyright © 2015 John Wiley & Sons, Ltd.


Assuntos
Infecções por HIV/complicações , Infecções por HIV/epidemiologia , Gamopatia Monoclonal de Significância Indeterminada/complicações , Gamopatia Monoclonal de Significância Indeterminada/epidemiologia , Algoritmos , Proliferação de Células , Progressão da Doença , Feminino , Infecções por HIV/imunologia , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/imunologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Gamopatia Monoclonal de Significância Indeterminada/imunologia , Razão de Chances , Prevalência , Análise de Regressão , Estudos Retrospectivos , Risco , Resultado do Tratamento
4.
J Fam Pract ; 65(5): 345-347, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-27275939

RESUMO

The patient denied recent trauma or any heavy lifting, but she'd lost 10 pounds over the previous month. What was causing her shoulder pain?

5.
Ann Hematol ; 95(4): 575-80, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26747296

RESUMO

The role of viral co-infections and paraproteins in the development of hematological malignancies (HMs) in HIV remains unclear. Using our large database of HIV+ patients, we investigated whether co-infection and paraproteinemia increase the risk of HM. Data on demographics, hepatitis B (HBV) and hepatitis C virus (HCV) co-infections, paraproteinemia, HIV characteristics, and biopsy proven malignant hematological disorders for HIV+ patients were collected over a 10-year period in a large urban hospital setting. We identified 10,293 HIV+ patients who were followed for a median duration of 53 months. Of the 10,293 patients with HIV, 229 (2.2 %) were diagnosed with a HM. Over 85 % of patients in both groups were tested; no significant difference in the prevalence of chronic HBV or HCV was noted between the HM positive (n = 229) and HM negative (n = 9992) patients. The serum protein electrophoresis test was performed for 1371 of the 10,221 patients. HM positive patients, compared to HM negative, were more likely to be tested for paraproteins (OR 3.3, 95 % CI 2.5-4.4) and more likely to have a discrete paraprotein band (OR 3.3, 95 % CI 1.2-8.9). Discrete paraproteins exclusively correlated with the development of plasma cell malignancies. Faint or oligoclonal protein bands were seen in high grade B cell lymphomas but did not show a significant correlation with HM development. Chronic hepatitis B or C infections did not correlate with the development of HM in HIV; however, viral influence on host gene transformation may have been impacted by anti-viral therapy limiting the duration of high viremic states.


Assuntos
Coinfecção/sangue , Infecções por HIV/sangue , Neoplasias Hematológicas/sangue , Hepatite B/sangue , Hepatite C/sangue , Paraproteínas/metabolismo , Adulto , Estudos de Coortes , Coinfecção/diagnóstico , Coinfecção/epidemiologia , Feminino , Seguimentos , Infecções por HIV/diagnóstico , Infecções por HIV/epidemiologia , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/epidemiologia , Hepatite B/diagnóstico , Hepatite B/epidemiologia , Hepatite C/diagnóstico , Hepatite C/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade
6.
J Hematol Oncol ; 6: 50, 2013 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-23841999

RESUMO

Myelodysplastic syndromes (MDS) are a group of hematologic disorders characterized by ineffective hematopoiesis that results in reduced blood counts. Although MDS can transform into leukemia, most of the morbidity experienced by these patients is due to chronically low blood counts. Conventional cytotoxic agents used to treat MDS have yielded some encouraging results but are characterized by many adverse effects in the predominantly elderly patient population. Targeted interventions aimed at reversing the bone marrow failure and increasing the peripheral blood counts would be advantageous in this cohort of patients. Studies have demonstrated over-activated signaling of myelo-suppressive cytokines such as TGF-ß, TNF-α and Interferons in MDS hematopoietic stem cells. Targeting these signaling cascades could be potentially therapeutic in MDS. The p38 MAP kinase pathway, which is constitutively activated in MDS, is an example of cytokine stimulated kinase that promotes aberrant apoptosis of stem and progenitor cells in MDS. ARRY-614 and SCIO-469 are p38 MAPK inhibitors that have been used in clinical trials and have shown activity in a subset of MDS patients. TGF-ß signaling has been therapeutically targeted by small molecule inhibitor of the TGF-ß receptor kinase, LY-2157299, with encouraging preclinical results. Apart from TGF-ß receptor kinase inhibition, members of TGF-ß super family and BMP ligands have also been targeted by ligand trap compounds like Sotatercept (ACE-011) and ACE-536. The multikinase inhibitor, ON-01910.Na (Rigosertib) has demonstrated early signs of efficacy in reducing the percentage of leukemic blasts and is in advanced stages of clinical testing. Temsirolimus, Deforolimus and other mTOR inhibitors are being tested in clinical trials and have shown preclinical efficacy in CMML. EGF receptor inhibitors, Erlotinib and Gefitinib have shown efficacy in small trials that may be related to off target effects. Cell cycle regulator inhibitors such as Farnesyl transferase inhibitors (Tipifarnib, Lonafarnib) and MEK inhibitor (GSK1120212) have shown acceptable toxicity profiles in small studies and efforts are underway to select mutational subgroups of MDS and AML that may benefit from these inhibitors. Altogether, these studies show that targeting various signal transduction pathways that regulate hematopoiesis offers promising therapeutic potential in this disease. Future studies in combination with high resolution correlative studies will clarify the subgroup specific efficacies of these agents.


Assuntos
Antineoplásicos/farmacologia , Síndromes Mielodisplásicas/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Animais , Citocinas/metabolismo , Inibidores Enzimáticos/farmacologia , Humanos , Síndromes Mielodisplásicas/metabolismo
7.
J Biol Chem ; 288(13): 8805-14, 2013 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-23306203

RESUMO

Differentiation of hematopoietic stem cells to red cells requires coordinated expression of numerous erythroid genes and is characterized by nuclear condensation and extrusion during terminal development. To understand the regulatory mechanisms governing these widespread phenotypic changes, we conducted a high resolution methylomic and transcriptomic analysis of six major stages of human erythroid differentiation. We observed widespread epigenetic differences between early and late stages of erythropoiesis with progressive loss of methylation being the dominant change during differentiation. Gene bodies, intergenic regions, and CpG shores were preferentially demethylated during erythropoiesis. Epigenetic changes at transcription factor binding sites correlated significantly with changes in gene expression and were enriched for binding motifs for SCL, MYB, GATA, and other factors not previously implicated in erythropoiesis. Demethylation at gene promoters was associated with increased expression of genes, whereas epigenetic changes at gene bodies correlated inversely with gene expression. Important gene networks encoding erythrocyte membrane proteins, surface receptors, and heme synthesis proteins were found to be regulated by DNA methylation. Furthermore, integrative analysis enabled us to identify novel, potential regulatory areas of the genome as evident by epigenetic changes in a predicted PU.1 binding site in intron 1 of the GATA1 gene. This intronic site was found to be conserved across species and was validated to be a novel PU.1 binding site by quantitative ChIP in erythroid cells. Altogether, our study provides a comprehensive analysis of methylomic and transcriptomic changes during erythroid differentiation and demonstrates that human terminal erythropoiesis is surprisingly associated with hypomethylation of the genome.


Assuntos
Eritropoese/fisiologia , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Antígenos CD34/biossíntese , Sítios de Ligação , Diferenciação Celular , Ilhas de CpG , Metilação de DNA , Epigênese Genética , Epigenômica , Eritrócitos/citologia , Citometria de Fluxo/métodos , Genoma Humano , Genômica , Humanos , Íntrons , Metilação , Análise de Sequência com Séries de Oligonucleotídeos , Células-Tronco/química
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