RESUMO
BACKGROUND: Understanding the impact of clonal hematopoiesis of indeterminate potential (CHIP) and mosaic chromosomal alterations (mCAs) on solid tumor risk and mortality can shed light on novel cancer pathways. METHODS: The authors analyzed whole genome sequencing data from the Trans-Omics for Precision Medicine Women's Health Initiative study (n = 10,866). They investigated the presence of CHIP and mCA and their association with the development and mortality of breast, lung, and colorectal cancers. RESULTS: CHIP was associated with higher risk of breast (hazard ratio [HR], 1.30; 95% confidence interval [CI], 1.03-1.64; p = .02) but not colorectal (p = .77) or lung cancer (p = .32). CHIP carriers who developed colorectal cancer also had a greater risk for advanced-stage (p = .01), but this was not seen in breast or lung cancer. CHIP was associated with increased colorectal cancer mortality both with (HR, 3.99; 95% CI, 2.41-6.62; p < .001) and without adjustment (HR, 2.50; 95% CI, 1.32-4.72; p = .004) for advanced-stage and a borderline higher breast cancer mortality (HR, 1.53; 95% CI, 0.98-2.41; p = .06). Conversely, mCA (cell fraction [CF] >3%) did not correlate with cancer risk. With higher CFs (mCA >5%), autosomal mCA was associated with increased breast cancer risk (HR, 1.39; 95% CI, 1.06-1.83; p = .01). There was no association of mCA (>3%) with breast, colorectal, or lung mortality except higher colon cancer mortality (HR, 2.19; 95% CI, 1.11-4.3; p = .02) with mCA >5%. CONCLUSIONS: CHIP and mCA (CF >5%) were associated with higher breast cancer risk and colorectal cancer mortality individually. These data could inform on novel pathways that impact cancer risk and lead to better risk stratification.
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The aim of this study was to evaluate the prognostic impact of FLT3-ITD in core-binding factor acute myeloid leukemia (CBFAML) in an international, multicenter survey of 97 patients of whom 52% had t(8;21)(q22;q22) and 48% had inv(16)(p13q22)/t(16;16)(p13;q22). The median age of the patients was 53 years (range, 19-81). Complete remission after anthracycline-based induction (n=86) and non-intensive therapy (n=11) was achieved in 97% and 36% of the patients, respectively. The median follow-up was 4.43 years (95% confidence interval [95% CI]: 3.35-7.39 years). The median survival after intensive and non-intensive treatment was not reached and 0.96 years, respectively. Among intensively treated patients, inv(16) with trisomy 22 (n=11) was associated with a favorable 4-year relapse-free survival rate of 80% (95% CI: 59-100%) as compared to 38% (95% CI: 27-54%; P=0.02) in all other patients with CBFAML/ FLT3-ITD (n=75). Overall, 24 patients underwent allogeneic hematopoietic cell transplantation (HCT), 12 in first complete remission and 12 after relapse. Allogeneic HCT in first complete remission was not beneficial (P=0.60); however, allogeneic HCT seemed to improve median survival in relapsed patients compared to that of patients treated with chemotherapy (not reached vs. 0.6 years, respectively; P=0.002). Excluding patients with inv(16) with trisomy 22, our data indicate that compathe outcome of CBF-AML patients with FLT3-ITD may be inferior to that of patients without FLT3-ITD (based on previously published data), suggesting that prognostically CBF-AML patients with FLT3-ITD should not be classified as favorable-risk. FLT3-inhibitors may improve the outcome of these patients.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Adulto , Idoso , Idoso de 80 Anos ou mais , Fatores de Ligação ao Core/genética , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Pessoa de Meia-Idade , Mutação , Prognóstico , Indução de Remissão , Estudos Retrospectivos , Adulto Jovem , Tirosina Quinase 3 Semelhante a fms/genéticaRESUMO
Gilteritinib is approved for the treatment of relapsed/refractory (R/R) acute myeloid leukemia (AML) with an FLT3-mutation (FLT3mut+ ). However, the gilteritinib phase 3 ADMIRAL study (Perl et al NEJM 2019) was conducted prior to widespread adoption of either midostaurin as a component of standard intensive induction and consolidation or posttransplant FLT3 inhibitor maintenance. We performed a retrospective analysis using data from 11 US centers and where we identified 113 patients who received gilteritinib alone or as combination therapy for the treatment of R/R FLT3mut+ AML. The composite complete remission (CR) rate (CRc, defined as CR + CRi + CR with incomplete platelet recovery [CRp]) was 48.7% (n = 55). The CRc rate after treatment with gilteritinib in patients who were treated with only prior 7+3 and midostaurin with or without consolidation was 58% with a median survival of 7.8 months. Survival was longest in patients who obtained a CR, particularly a cMRD (clinical minimal or measurable residual disease) negative response; this remained significant after censoring at the time of stem cell transplant. The mitogen-activated protein kinase pathway activating mutations that are known for gilteritinib resistance (NRAS, KRAS, and PTPN11) had lower CRc (35% vs. 60.5%) and lower median overall survival than patients' whose leukemia did not express these mutations (4.9 months vs. 7.8 months) (HR 2.4; 95% CI 1. 5.4) p value <.01.
Assuntos
Compostos de Anilina/administração & dosagem , Leucemia Mieloide Aguda , Mutação , Pirazinas/administração & dosagem , Estaurosporina/análogos & derivados , Tirosina Quinase 3 Semelhante a fms , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Feminino , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/enzimologia , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Recidiva , Estudos Retrospectivos , Estaurosporina/administração & dosagem , Taxa de Sobrevida , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Tirosina Quinase 3 Semelhante a fms/genéticaRESUMO
ABSTRACT: Acute myeloid leukemia (AML) is a heterogeneous malignancy with outcomes largely predicted by genetic abnormalities. Mutations of NPM1 are common in AML, occurring in â¼30% of cases, and generally considered a favorable risk factor. Mutations highly specific for secondary AML (sMut) have been shown to confer poor prognosis, but the overall impact of these mutations in the setting of favorable-risk AML defined by mutant NPM1 remains unclear. In this multicenter study of patients with AML (n = 233) with NPM1 mutation at diagnosis, we observed that patients with sMut had worse overall survival (OS) than those without sMut (15.3 vs 43.7 months; P = .002). Importantly, this finding persisted in the European LeukemiaNet (ELN) 2017-defined favorable risk subset (14.7 months vs not reached; P < .0001). Among patients who achieved NPM1 measurable residual disease (MRD) negativity, longer OS was observed in the entire cohort (P = .015) as well as in both the sMut subset (MRD negative: median OS (mOS) 73.9 months vs MRD positive: 12.3 months; P = .0170) and sMut ELN 2017-favorable subset (MRD negative: mOS 27.3 vs MRD positive: 10.5 months; P = .009). Co-occurrence of sMut and mutant NPM1 confers a poor prognosis in AML.
Assuntos
Leucemia Mieloide Aguda , Segunda Neoplasia Primária , Humanos , Leucemia Mieloide Aguda/patologia , Mutação , Proteínas Nucleares/genética , Nucleofosmina , PrognósticoRESUMO
We conducted a multi-center study to analyze factors predicting survival among patients with TP53-mutated (m) AML receiving allogeneic hematopoietic stem cell transplant (allo-HSCT) in the recent era. Out of 370 TP53m AML patients, 68 (18%) patients were bridged to allo-HSCT. The median age of the patients was 63 years (range, 33-75), 82% of patients had complex cytogenetics and 66% of patients had multi-hit TP53m. Forty three percent received myeloablative conditioning and 57% received reduced intensity conditioning. The incidence of acute graft versus host disease (GVHD) was 37% and chronic GVHD was 44%. The median event-free survival (EFS) from the time of allo-HSCT was 12.4 months (95% CI: 6.24-18.55) and median overall survival (OS) was 24.5 months (95% CI: 21.80-27.25). In multivariate analysis utilizing variables that showed significance in univariate analysis, complete remission at day 100 post allo-HSCT retained significance for EFS (HR: 0.24, 95% CI: 0.10-0.57, p = 0.001) and OS (HR: 0.22, 95% CI: 0.10-0.50, p ≤ 0.001). Similarly, occurrence of chronic GVHD retained significance for EFS (HR: 0.21, 95% CI: 0.09-0.46, p ≤ 0.001) and OS (HR: 0.34, 95% CI: 0.15-0.75, p = 0.007). Our report suggests that allo-HSCT offers the best opportunity to improve long-term outcome among patients with TP53m AML.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Humanos , Adulto , Pessoa de Meia-Idade , Idoso , Terapia de Salvação , Transplante Homólogo/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/complicações , Doença Enxerto-Hospedeiro/patologia , Estudos Retrospectivos , Condicionamento Pré-Transplante/métodos , Proteína Supressora de Tumor p53/genéticaRESUMO
The most promising alternatives to heart transplantation are left ventricular assist devices and artificial hearts; however, their use has been limited by thrombotic complications. To reduce these, sintered titanium (Ti) surfaces were developed, but thrombosis still occurs in approximately 7.5% of patients. We have invented a rapid-seeding technology to minimize the risk of thrombosis by rapid endothelialization of sintered Ti with human cord blood-derived endothelial cells (hCB-ECs). Human cord blood-derived endothelial cells were seeded within minutes onto sintered Ti and exposed to thrombosis-prone low fluid flow shear stresses. The hCB-ECs adhered and formed a confluent endothelial monolayer on sintered Ti. The exposure of sintered Ti to 4.4 dynes/cm for 20 hr immediately after rapid seeding resulted in approximately 70% cell adherence. The cell adherence was not significantly increased by additional ex vivo static culture of rapid-seeded sintered Ti before flow exposure. In addition, adherent hCB-ECs remained functional on sintered Ti, as indicated by flow-induced increase in nitric oxide secretion and reduction in platelet adhesion. After 15 day ex vivo static culture, the adherent hCB-ECs remained metabolically active, expressed endothelial cell functional marker thrombomodulin, and reduced platelet adhesion. In conclusion, our results demonstrate the feasibility of rapid-seeding sintered Ti with blood-derived hCB-ECs to generate a living antithrombotic surface.
Assuntos
Células Endoteliais/fisiologia , Coração Auxiliar/efeitos adversos , Sistemas Automatizados de Assistência Junto ao Leito , Trombose/prevenção & controle , Células Cultivadas , Sangue Fetal/citologia , Humanos , Adesividade Plaquetária , TitânioRESUMO
BACKGROUND: Pim1 kinase plays an important role in cell division, survival, and commitment of precursor cells towards a myocardial lineage, and overexpression of Pim1 in ckit+ cardiac stem cells (CSCs) enhances their cardioreparative properties. OBJECTIVES: The authors sought to validate the effect of Pim1-modified CSCs in a translationally relevant large animal preclinical model of myocardial infarction (MI). METHODS: Human cardiac stem cells (hCSCs, n = 10), hckit+ CSCs overexpressing Pim1 (Pim1+; n = 9), or placebo (n = 10) were delivered by intramyocardial injection to immunosuppressed Yorkshire swine (n = 29) 2 weeks after MI. Cardiac magnetic resonance and pressure volume loops were obtained before and after cell administration. RESULTS: Whereas both hCSCs reduced MI size compared to placebo, Pim1+ cells produced a â¼3-fold greater decrease in scar mass at 8 weeks post-injection compared to hCSCs (-29.2 ± 2.7% vs. -8.4 ± 0.7%; p < 0.003). Pim1+ hCSCs also produced a 2-fold increase of viable mass compared to hCSCs at 8 weeks (113.7 ± 7.2% vs. 65.6 ± 6.8%; p <0.003), and a greater increase in regional contractility in both infarct and border zones (both p < 0.05). Both CSC types significantly increased ejection fraction at 4 weeks but this was only sustained in the Pim1+ group at 8 weeks compared to placebo. Both hCSC and Pim1+ hCSC treatment reduced afterload (p = 0.02 and p = 0.004, respectively). Mechanoenergetic recoupling was significantly greater in the Pim1+ hCSC group (p = 0.005). CONCLUSIONS: Pim1 overexpression enhanced the effect of intramyocardial delivery of CSCs to infarcted porcine hearts. These findings provide a rationale for genetic modification of stem cells and consequent translation to clinical trials.
Assuntos
Proteínas Fúngicas/genética , Regulação da Expressão Gênica , Proteínas Quinases Ativadas por Mitógeno/genética , Infarto do Miocárdio/cirurgia , Miócitos Cardíacos/citologia , Transplante de Células-Tronco/métodos , Animais , Modelos Animais de Doenças , Feminino , Proteínas Fúngicas/biossíntese , Humanos , Proteínas Quinases Ativadas por Mitógeno/biossíntese , Infarto do Miocárdio/enzimologia , Infarto do Miocárdio/genética , SuínosRESUMO
The overall goal of this method is to describe a technique to subject adherent cells to laminar flow conditions and evaluate their response to well quantifiable fluid shear stresses. Our flow chamber design and flow circuit (Fig. 1) contains a transparent viewing region that enables testing of cell adhesion and imaging of cell morphology immediately before flow (Fig. 11A, B), at various time points during flow (Fig. 11C), and after flow (Fig. 11D). These experiments are illustrated with human umbilical cord blood-derived endothelial progenitor cells (EPCs) and porcine EPCs. This method is also applicable to other adherent cell types, e.g. smooth muscle cells (SMCs) or fibroblasts. The chamber and all parts of the circuit are easily sterilized with steam autoclaving. In contrast to other chambers, e.g. microfluidic chambers, large numbers of cells (> 1 million depending on cell size) can be recovered after the flow experiment under sterile conditions for cell culture or other experiments, e.g. DNA or RNA extraction, or immunohistochemistry (Fig. 11E), or scanning electron microscopy. The shear stress can be adjusted by varying the flow rate of the perfusate, the fluid viscosity, or the channel height and width. The latter can reduce fluid volume or cell needs while ensuring that one-dimensional flow is maintained. It is not necessary to measure chamber height between experiments, since the chamber height does not depend on the use of gaskets, which greatly increases the ease of multiple experiments. Furthermore, the circuit design easily enables the collection of perfusate samples for analysis and/or quantification of metabolites secreted by cells under fluid shear stress exposure, e.g. nitric oxide (Fig. 12).