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OBJECTIVES/PURPOSE: Childhood cancer survival brings continued mental and physical health challenges both for the child and for the family. In this study, we investigated how parents viewed their roles in their child's health and symptom monitoring during the survivorship period. METHODS: Twenty-one parents of childhood cancer survivors (n = 18 mothers; parent mage = 49.78 years, child mage = 18.50 years; range = 12-25 years), whose children were at least one year off-treatment (m = 3.67 years; SD = 2.25; various diagnoses), completed semi-structured interviews. Interviews were recorded, transcribed, and analyzed using reflexive thematic analysis. RESULTS: Analyses generated three themes which reflect roles that parents may adopt in the context of monitoring symptoms in their childhood cancer survivor. "Vigilant Mama and Papa" (theme 1) described parents who expressed a strong sense of responsibility for protecting their child's health during survivorship resulting in careful monitoring of their child's symptoms and health. "Pragmatic Mamas and Papas" (theme 2) described parents who adopted an approach to symptom and health monitoring that emphasized moving past cancer and focusing on the future. Finally, "Encouraging Mamas and Papas" (theme 3) described parents who focused on educating and preparing their child to develop an autonomous approach to health and symptom self-monitoring as they transitioned to survivorship and adulthood. CONCLUSION: Parents take on varying roles in monitoring their child's symptoms and health after finishing childhood cancer treatment. IMPLICATIONS FOR CANCER SURVIVORS: Understanding the ways in which parents continue to be involved in their child's cancer journey helps researchers develop interventions to support dyadic coping in survivorship.
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OBJECTIVE: Scan-related anxiety ("scanxiety") refers to the fear, stress, and anxiety in anticipation of tests and scans in follow-up cancer care. This study assessed the feasibility of Ecological Momentary Assessment (EMA) for real-world, real-time capture of scanxiety using patients' personal smartphone. METHODS: Adolescent and Young Adult survivors of childhood cancer were prompted to complete EMA surveys on a smartphone app three times per day for 11 days (33 surveys total) around their routine surveillance scans. Participants provided structured feedback on the EMA protocol. RESULTS: Thirty out of 46 contacted survivors (65%) enrolled, exceeding the preregistered feasibility cutoff of 55%. The survey completion rate (83%) greatly exceeded the preregistered feasibility cutoff of 65%. Participants generally found the smartphone app easy and enjoyable to use and reported low levels of distress from answering surveys. Participants reported significantly more daily fear of cancer recurrence (FCR) and negative affect in the days before compared to the days after surveillance scans, aligning with the expected trajectory of scanxiety. Participants who reported greater FCR and scanxiety using comprehensive measures at baseline also reported significantly more daily FCR around their surveillance scans, indicating validity of EMA items. Bodily threat monitoring was prospectively and concurrently associated with daily FCR, thus warranting further investigation as a risk factor for scanxiety. CONCLUSIONS: Findings indicate the feasibility, acceptability, and validity of EMA as a research tool to capture the dynamics and potential risk factors for scanxiety.
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Sobreviventes de Câncer , Neoplasias , Adolescente , Criança , Avaliação Momentânea Ecológica , Estudos de Viabilidade , Humanos , Neoplasias/terapia , Smartphone , Sobreviventes , Adulto JovemRESUMO
Introduction: Ex vivo gene therapy for treatment of Inborn errors of Immunity (IEIs) have demonstrated significant clinical benefit in multiple Phase I/II clinical trials. Current approaches rely on engineered retroviral vectors to randomly integrate copy(s) of gene-of-interest in autologous hematopoietic stem/progenitor cells (HSPCs) genome permanently to provide gene function in transduced HSPCs and their progenies. To circumvent concerns related to potential genotoxicities due to the random vector integrations in HSPCs, targeted correction with CRISPR-Cas9-based genome editing offers improved precision for functional correction of multiple IEIs. Methods: We compare the two approaches for integration of IL2RG transgene for functional correction of HSPCs from patients with X-linked Severe Combined Immunodeficiency (SCID-X1 or XSCID); delivery via current clinical lentivector (LV)-IL2RG versus targeted insertion (TI) of IL2RG via homology-directed repair (HDR) when using an adeno-associated virus (AAV)-IL2RG donor following double-strand DNA break at the endogenous IL2RG locus. Results and discussion: In vitro differentiation of LV- or TI-treated XSCID HSPCs similarly overcome differentiation block into Pre-T-I and Pre-T-II lymphocytes but we observed significantly superior development of NK cells when corrected by TI (40.7% versus 4.1%, p = 0.0099). Transplants into immunodeficient mice demonstrated robust engraftment (8.1% and 23.3% in bone marrow) for LV- and TI-IL2RG HSPCs with efficient T cell development following TI-IL2RG in all four patients' HSPCs. Extensive specificity analysis of CRISPR-Cas9 editing with rhAmpSeq covering 82 predicted off-target sites found no evidence of indels in edited cells before (in vitro) or following transplant, in stark contrast to LV's non-targeted vector integration sites. Together, the improved efficiency and safety of IL2RG correction via CRISPR-Cas9-based TI approach provides a strong rationale for a clinical trial for treatment of XSCID patients.
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Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X , Animais , Camundongos , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/genética , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/terapia , Dependovirus , Sistemas CRISPR-Cas , Camundongos SCID , Células-Tronco HematopoéticasRESUMO
Therapy-related myeloid neoplasms (t-MN) are a distinct subgroup of myeloid malignancies with a poor prognosis that include cases of therapy-related myelodysplastic syndrome (t-MDS), therapy-related myeloproliferative neoplasms (t-MPN) and therapy-related acute myeloid leukemia (t-AML). Here, we report a series of patients with clinical features consistent with juvenile myelomonocytic leukemia (JMML), an overlap syndrome of MDS and myeloproliferative neoplasms that developed after treatment for another malignancy.
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Leucemia Mielomonocítica Juvenil , Síndromes Mielodisplásicas , Transtornos Mieloproliferativos , Segunda Neoplasia Primária , Humanos , Leucemia Mielomonocítica Juvenil/diagnóstico , Leucemia Mielomonocítica Juvenil/terapia , Síndromes Mielodisplásicas/induzido quimicamente , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/terapia , Segunda Neoplasia Primária/diagnósticoRESUMO
Children with chronic myeloid leukemia (CML) tend to present with higher white blood counts and larger spleens than adults with CML, suggesting that the biology of pediatric and adult CML may differ. To investigate whether pediatric and adult CML have unique molecular characteristics, we studied the transcriptomic signature of pediatric and adult CML CD34+ cells and healthy pediatric and adult CD34+ control cells. Using high-throughput RNA sequencing, we found 567 genes (207 up- and 360 downregulated) differentially expressed in pediatric CML CD34+ cells compared to pediatric healthy CD34+ cells. Directly comparing pediatric and adult CML CD34+ cells, 398 genes (258 up- and 140 downregulated), including many in the Rho pathway, were differentially expressed in pediatric CML CD34+ cells. Using RT-qPCR to verify differentially expressed genes, VAV2 and ARHGAP27 were significantly upregulated in adult CML CD34+ cells compared to pediatric CML CD34+ cells. NCF1, CYBB, and S100A8 were upregulated in adult CML CD34+ cells but not in pediatric CML CD34+ cells, compared to healthy controls. In contrast, DLC1 was significantly upregulated in pediatric CML CD34+ cells but not in adult CML CD34+ cells, compared to healthy controls. These results demonstrate unique molecular characteristics of pediatric CML, such as dysregulation of the Rho pathway, which may contribute to clinical differences between pediatric and adult patients.
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XMEN disease, defined as "X-linked MAGT1 deficiency with increased susceptibility to Epstein-Barr virus infection and N-linked glycosylation defect," is a recently described primary immunodeficiency marked by defective T cells and natural killer (NK) cells. Unfortunately, a potentially curative hematopoietic stem cell transplantation is associated with high mortality rates. We sought to develop an ex vivo targeted gene therapy approach for patients with XMEN using a CRISPR/Cas9 adeno-associated vector (AAV) to insert a therapeutic MAGT1 gene at the constitutive locus under the regulation of the endogenous promoter. Clinical translation of CRISPR/Cas9 AAV-targeted gene editing (GE) is hampered by low engraftable gene-edited hematopoietic stem and progenitor cells (HSPCs). Here, we optimized GE conditions by transient enhancement of homology-directed repair while suppressing AAV-associated DNA damage response to achieve highly efficient (>60%) genetic correction in engrafting XMEN HSPCs in transplanted mice. Restored MAGT1 glycosylation function in human NK and CD8+ T cells restored NK group 2 member D (NKG2D) expression and function in XMEN lymphocytes for potential treatment of infections, and it corrected HSPCs for long-term gene therapy, thus offering 2 efficient therapeutic options for XMEN poised for clinical translation.
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Proteínas de Transporte de Cátions/genética , Edição de Genes , Células-Tronco Hematopoéticas/metabolismo , Linfócitos/metabolismo , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/genética , Animais , Sistemas CRISPR-Cas , Proteínas de Transporte de Cátions/deficiência , Células Cultivadas , Feminino , Edição de Genes/métodos , Terapia Genética , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/patologia , Humanos , Linfócitos/patologia , Masculino , Camundongos Endogâmicos NOD , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/patologia , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/terapiaRESUMO
BACKGROUND: Prenatal immune development may play an important role in the etiology of childhood acute lymphoblastic leukemia (ALL). METHODS: Seven cytokines, IL1ß, IL4, IL6, IL8, GM-CSF, TNFα, and VEGF, were analyzed in blood spots collected at birth from 1,020 ALL cases and 1,003 controls participating in the California Childhood Leukemia Study. ORs and 95% confidence intervals (95% CI) associated with an interquartile range increment in cytokine levels were calculated using logistic regression, adjusting for sociodemographic and birth characteristics. RESULTS: We found that patients with ALL were born with higher levels of a group of correlated cytokines than controls [IL1ß: OR of 1.18 (95% confidence interval [CI], 1.03-1.35); IL8: 1.19 (1.03-1.38); TNFα: 1.15 (1.01-1.30); VEGF: 1.16 (1.01-1.33)], especially among children of Latina mothers (ORs from 1.31 to 1.40) and for ALL with high hyperdiploidy (ORs as high as 1.27). We found that neonatal cytokine levels were correlated with neonatal levels of endogenous metabolites which had been previously associated with ALL risk; however, there was no evidence that the cytokines were mediating the relationship between these metabolites and ALL risk. CONCLUSIONS: We posit that children born with altered cytokine levels are set on a trajectory towards an increased risk for subsequent aberrant immune reactions that can initiate ALL. IMPACT: This is the first study to evaluate the interplay between levels of immunomodulatory cytokines at birth, prenatal exposures, and the risk of childhood ALL.
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Citocinas/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Biomarcadores/sangue , California/epidemiologia , Estudos de Casos e Controles , Feminino , Humanos , Recém-Nascido , Masculino , Triagem Neonatal , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologia , Fatores de RiscoRESUMO
X-linked chronic granulomatous disease is an immunodeficiency characterized by defective production of microbicidal reactive oxygen species (ROS) by phagocytes. Causative mutations occur throughout the 13 exons and splice sites of the CYBB gene, resulting in loss of gp91phox protein. Here we report gene correction by homology-directed repair in patient hematopoietic stem/progenitor cells (HSPCs) using CRISPR/Cas9 for targeted insertion of CYBB exon 1-13 or 2-13 cDNAs from adeno-associated virus donors at endogenous CYBB exon 1 or exon 2 sites. Targeted insertion of exon 1-13 cDNA did not restore physiologic gp91phox levels, consistent with a requirement for intron 1 in CYBB expression. However, insertion of exon 2-13 cDNA fully restored gp91phox and ROS production upon phagocyte differentiation. Addition of a woodchuck hepatitis virus post-transcriptional regulatory element did not further enhance gp91phox expression in exon 2-13 corrected cells, indicating that retention of intron 1 was sufficient for optimal CYBB expression. Targeted correction was increased ~1.5-fold using i53 mRNA to transiently inhibit nonhomologous end joining. Following engraftment in NSG mice, corrected HSPCs generated phagocytes with restored gp91phox and ROS production. Our findings demonstrate the utility of tailoring donor design and targeting strategies to retain regulatory elements needed for optimal expression of the target gene.
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Doença Granulomatosa Crônica , Animais , Sistemas CRISPR-Cas , DNA Complementar , Éxons , Doença Granulomatosa Crônica/genética , Doença Granulomatosa Crônica/terapia , Células-Tronco Hematopoéticas , Humanos , Camundongos , NADPH Oxidase 2/genética , NADPH Oxidases/genéticaRESUMO
Lentivector gene therapy for X-linked chronic granulomatous disease (X-CGD) has proven to be a viable approach, but random vector integration and subnormal protein production from exogenous promoters in transduced cells remain concerning for long-term safety and efficacy. A previous genome editing-based approach using Streptococcus pyogenes Cas9 mRNA and an oligodeoxynucleotide donor to repair genetic mutations showed the capability to restore physiological protein expression but lacked sufficient efficiency in quiescent CD34+ hematopoietic cells for clinical translation. Here, we report that transient inhibition of p53-binding protein 1 (53BP1) significantly increased (2.3-fold) long-term homology-directed repair to achieve highly efficient (80% gp91phox+ cells compared with healthy donor control subjects) long-term correction of X-CGD CD34+ cells.
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Reparo do DNA , Edição de Genes/métodos , Terapia Genética/métodos , Doença Granulomatosa Crônica/terapia , Transplante de Células-Tronco Hematopoéticas , NADPH Oxidase 2/genética , Proteína 1 de Ligação à Proteína Supressora de Tumor p53/antagonistas & inibidores , Animais , Proteínas de Bactérias , Caspase 9 , Células Cultivadas , Reparo do DNA/genética , Dependovirus/genética , Éxons/genética , Vetores Genéticos/genética , Vetores Genéticos/uso terapêutico , Doença Granulomatosa Crônica/genética , Células-Tronco Hematopoéticas/enzimologia , Xenoenxertos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , NADPH Oxidase 2/deficiência , Fagócitos/metabolismo , RNA Guia de Cinetoplastídeos/genética , RNA Mensageiro/genética , Espécies Reativas de Oxigênio , Ribonucleoproteínas/genética , Deleção de Sequência , Streptococcus pyogenes/enzimologiaRESUMO
BACKGROUND AIM: X-linked MAGT1 deficiency with increased susceptibility to EBV-infection and N-linked glycosylation defect' (XMEN) disease is caused by mutations in the magnesium transporter 1 (MAGT1) gene. Loss of MAGT1 function results in a glycosylation defect that abrogates expression of key immune proteins such as the NKG2D receptor on CD8+ T and NK cells, which is critical for the recognition and killing of virus-infected and transformed cells, a biomarker for MAGT1 function. Patients with XMEN disease frequently have increased susceptibility to EBV infections and EBV-associated B cell malignancies, for which no specific treatment options are currently available. Experimental transfer of donor EBV-specific cytotoxic T cells may be beneficial but carries the risks of eliciting alloimmune responses. An approach for cell therapy to address viral infections and associated complications that avoids the risks of alloimmunity is needed. METHODS: Here the authors assess the feasibility and efficiency of correcting autologous lymphocytes from XMEN patients by MAGT1 mRNA electroporation (EP) that avoids genomic integration and can be scaled for clinical application. RESULTS AND CONCLUSIONS: Restoration of NKG2D expression was demonstrated in XMEN patient lymphocytes after MAGT1 mRNA electroporation that reach healthy donor levels in CD8+ T and NK cells at 1-2 days after EP. NKG2D expression persisted at â¼50% for 2 weeks after EP. Functionally, mRNA-correction of XMEN NK cells rescued cytotoxic activity also to healthy donor NK cell level. The restored NKG2D receptor expression and function were unaffected by cryopreservation, which will make feasible repeat infusions of MAGT1 mRNA-corrected autologous XMEN CD8+ T and NK cells for potential short term therapy for XMEN patients without the risks of alloimmunization.
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Proteínas de Transporte de Cátions , Infecções por Vírus Epstein-Barr , Neoplasias , Terapia Baseada em Transplante de Células e Tecidos , Herpesvirus Humano 4/genética , Humanos , Células Matadoras Naturais/metabolismo , Magnésio/metabolismo , RNA Mensageiro/genéticaRESUMO
Granulocytes from patients with chronic granulomatous disease (CGD) have dysfunctional phagocyte reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase that fails to generate sufficient antimicrobial reactive oxidative species. CGD patients with severe persistent fungal or bacterial infection who do not respond to antibiotic therapy may be given apheresis-derived allogeneic granulocyte transfusions from healthy volunteers to improve clearance of intractable infections. Allogeneic granulocyte donors are not HLA matched, so patients who receive the donor granulocyte products may develop anti-HLA alloimmunity. This not only precludes future use of allogeneic granulocytes in an alloimmunized CGD recipient, but increases the risk of graft failure of those recipients who go on to need an allogeneic bone marrow transplant. Here, we provide the first demonstration of efficient functional restoration of CGD patient apheresis granulocytes by messenger RNA (mRNA) electroporation using a scalable, Good Manufacturing Practice-compliant system to restore protein expression and NADPH oxidase function. Dose-escalating clinical-scale in vivo studies in a nonhuman primate model verify the feasibility, safety, and persistence in peripheral blood of infusions of mRNA-transfected autologous granulocyte-enriched apheresis cells, supporting this novel therapeutic approach as a potential nonalloimmunizing adjunct treatment of intractable infections in CGD patients.
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Remoção de Componentes Sanguíneos , Doença Granulomatosa Crônica , Granulócitos , Doença Granulomatosa Crônica/terapia , Humanos , NADPH Oxidases/genética , RNA Mensageiro/genética , TransfecçãoRESUMO
PURPOSE: Adolescent and young adult (AYA) patients with cancer face significant challenges with regard to fatigue, reduced physical activity, and social isolation, which may negatively impact quality of life. This study investigated whether the use of digital wearable technology (Fitbits, along with synced iPads) can affect health-related quality of life (HRQOL) in AYA aged patients with cancer. MATERIALS AND METHODS: This was a prospective cohort study that offered Fitbits and iPads to all AYA patients aged 15 to 29 at an academic medical center at the time of cancer diagnosis. Patients completed the Short Form Health Survey developed by RAND (RAND-36) assessing eight dimensions of HRQOL on entering the study and at the time of their 6-month follow-up or the end of treatment, whichever occurred first. At the time of follow-up, patients also completed a questionnaire that assessed user experience, including frequency of wearable device use, enjoyment, challenges, and participation, in online communities. RESULTS: Thirty-three patients participated in the study. Most patients reported enjoying the digital technology and using the devices to track multiple aspects of their health (85%). Most also reported a subjective increase in physical activity (79%). After the intervention, participants demonstrated significant improvements across all eight dimensions of HRQOL measured by the RAND-36 (p < 0.00 to 0.01). CONCLUSION: Distributing wearable technology at the time of diagnosis may provide an avenue for improving HRQOL in adolescents and young adults with cancer.
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Neoplasias/terapia , Qualidade de Vida/psicologia , Dispositivos Eletrônicos Vestíveis/normas , Adolescente , Adulto , Feminino , Humanos , Masculino , Estudos Prospectivos , Inquéritos e Questionários , Adulto JovemRESUMO
CREB (cAMP Response Element Binding protein) is a transcription factor that is overexpressed in primary acute myeloid leukemia (AML) cells and associated with a decreased event-free survival and increased risk of relapse. We recently reported a small molecule inhibitor of CREB, XX-650-23, which inhibits CREB activity in AML cells. Structure-activity relationship analysis for chemical compounds with structures similar to XX-650-23 led to the identification of the anthelminthic drug niclosamide as a potent anti-leukemic agent that suppresses cell viability of AML cell lines and primary AML cells without a significant decrease in colony forming activity of normal bone marrow cells. Niclosamide significantly inhibited CREB function and CREB-mediated gene expression in cells, leading to apoptosis and G1/S cell cycle arrest with reduced phosphorylated CREB levels. CREB knockdown protected cells from niclosamide treatment-mediated cytotoxic effects. Furthermore, treatment with a combination of niclosamide and CREB inhibitor XX-650-23 showed an additive anti-proliferative effect, consistent with the hypothesis that niclosamide and XX-650-23 regulate the same targets or pathways to inhibit proliferation and survival of AML cells. Niclosamide significantly inhibited the progression of disease in AML patient-derived xenograft (PDX) mice, and prolonged survival of PDX mice. Niclosamide also showed synergistic effects with chemotherapy drugs to inhibit AML cell proliferation. While chemotherapy antagonized the cytotoxic potential of niclosamide, pretreatment with niclosamide sensitized cells to chemotherapeutic drugs, cytarabine, daunorubicin, and vincristine. Therefore, our results demonstrate niclosamide as a potential drug to treat AML by inducing apoptosis and cell cycle arrest through inhibition of CREB-dependent pathways in AML cells.
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Citidina Desaminase/genética , Mutação em Linhagem Germinativa , Antígenos de Histocompatibilidade Menor/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/etiologia , Deleção de Sequência , Alelos , Suscetibilidade a Doenças , Testes Genéticos , Genótipo , Humanos , Razão de ChancesRESUMO
Tobacco smoke exposure has been associated with risk of childhood acute lymphoblastic leukemia (ALL). Understanding the relationship between tobacco exposures and specific mutations may yield etiologic insights. We carried out a case-only analysis to explore whether prenatal and early-life tobacco smoke exposure influences the formation of leukemogenic genomic deletions. Somatic copy number of 8 genes frequently deleted in ALL (CDKN2A, ETV6, IKZF1, PAX5, RB1, BTG1, PAR1 region, and EBF1) was assessed in 559 pretreatment tumor samples from the California Childhood Leukemia Study. Parent and child's passive tobacco exposure was assessed using interview-assisted questionnaires as well as DNA methylation in aryl-hydrocarbon receptor repressor (AHRR), a sentinel epigenetic biomarker of exposure to maternal smoking during pregnancy. Multivariable Poisson regressions were used to test the association between the smoking exposures and total number of deletions. Deletion burden varied by subtype, with a lower frequency in high-hyperdiploid and higher frequency in ETV6-RUNX1 fusion ALL. The total number of deletions per case was positively associated with tobacco smoke exposure, in particular for maternal ever-smoking (ratio of means, RM, 1.31; 95% CI, 1.08-1.59), maternal smoking during pregnancy (RM, 1.48; 95% CI, 1.12-1.94), and during breastfeeding (RM, 2.11; 95% CI, 1.48-3.02). The magnitude of association with maternal ever-smoking was stronger in male children compared with females (Pinteraction = 0.04). The total number of deletions was also associated with DNA methylation at the AHRR epigenetic biomarker (RM, 1.32; 95% CI, 1.02-1.69). Our results suggest that prenatal and early-life tobacco smoke exposure increase the frequency of somatic deletions in children who develop ALL. Cancer Res; 77(7); 1674-83. ©2017 AACR.
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Deleção de Genes , Leucemia-Linfoma Linfoblástico de Células Precursoras/etiologia , Poluição por Fumaça de Tabaco/efeitos adversos , Adolescente , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Criança , Pré-Escolar , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Metilação de DNA , Feminino , Feto/efeitos dos fármacos , Humanos , Lactente , Masculino , Distribuição de Poisson , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Gravidez , Proteínas Proto-Oncogênicas c-ets/genética , Proteínas Repressoras/genética , Variante 6 da Proteína do Fator de Translocação ETSRESUMO
It is widely suspected, yet controversial, that infection plays an etiologic role in the development of acute lymphoblastic leukemia (ALL), the most common childhood cancer and a disease with a confirmed prenatal origin in most cases. We investigated infections at diagnosis and then assessed the timing of infection at birth in children with ALL and age, gender, and ethnicity matched controls to identify potential causal initiating infections. Comprehensive untargeted virome and bacterial analyses of pretreatment bone marrow specimens (n = 127 ALL in comparison with 38 acute myeloid leukemia cases in a comparison group) revealed prevalent cytomegalovirus (CMV) infection at diagnosis in childhood ALL, demonstrating active viral transcription in leukemia blasts as well as intact virions in serum. Screening of newborn blood samples revealed a significantly higher prevalence of in utero CMV infection in ALL cases (n = 268) than healthy controls (n = 270) (odds ratio [OR], 3.71, confidence interval [CI], 1.56-7.92, P = .0016). Risk was more pronounced in Hispanics (OR=5.90, CI=1.89-25.96) than in non-Hispanic whites (OR=2.10 CI= 0.69-7.13). This is the first study to suggest that congenital CMV infection is a risk factor for childhood ALL and is more prominent in Hispanic children. Further investigation of CMV as an etiologic agent for ALL is warranted.
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Infecções por Citomegalovirus/complicações , Triagem Neonatal/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/virologia , Exame de Medula Óssea , Estudos de Casos e Controles , Infecções por Citomegalovirus/congênito , Infecções por Citomegalovirus/etnologia , Hispânico ou Latino , Humanos , Recém-Nascido , Leucemia-Linfoma Linfoblástico de Células Precursoras/etiologia , Prevalência , População BrancaRESUMO
In contrast to most pediatric cancers, there is a growing body of literature, nationally and internationally, that has implicated the role of several environmental indoor and outdoor hazards in the etiology of childhood leukemia. For example, exposures to solvents, traffic, pesticides, and tobacco smoke have consistently demonstrated positive associations with the risk of developing childhood leukemia. Intake of vitamins and folate supplementation during the preconception period or pregnancy has been demonstrated to have a protective effect. Despite the strength of these findings, the dissemination of this knowledge to clinicians has been limited. Some children may be more vulnerable than others as documented by the high and increasing incidence of childhood leukemia in Hispanics. To protect children's health, it is prudent to establish programs to alter exposure to those factors with well-established associations with leukemia risk rather than to suspend judgment until no uncertainty remains. This is particularly true because other serious health outcomes (both negative and positive) have been associated with the same exposures. We draw from historical examples to put in perspective the arguments of association versus causation, as well as to discuss benefits versus risks of immediate and long-term preventive actions.
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Poluição do Ar/efeitos adversos , Leucemia Mieloide Aguda/prevenção & controle , Praguicidas/efeitos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/prevenção & controle , Aleitamento Materno , Criança , Exposição Ambiental/efeitos adversos , Exposição Ambiental/prevenção & controle , Feminino , Ácido Fólico/uso terapêutico , Humanos , Lactente , Leucemia Mieloide Aguda/etiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/etiologia , Gravidez , Fatores de Risco , Poluição por Fumaça de Tabaco/efeitos adversosRESUMO
Juvenile myelomonocytic leukemia (JMML) is a myeloproliferative neoplasm (MPN) of childhood with a poor prognosis. Mutations in NF1, NRAS, KRAS, PTPN11 or CBL occur in 85% of patients, yet there are currently no risk stratification algorithms capable of predicting which patients will be refractory to conventional treatment and could therefore be candidates for experimental therapies. In addition, few molecular pathways aside from the RAS-MAPK pathway have been identified that could serve as the basis for such novel therapeutic strategies. We therefore sought to genomically characterize serial samples from patients at diagnosis through relapse and transformation to acute myeloid leukemia to expand knowledge of the mutational spectrum in JMML. We identified recurrent mutations in genes involved in signal transduction, splicing, Polycomb repressive complex 2 (PRC2) and transcription. Notably, the number of somatic alterations present at diagnosis appears to be the major determinant of outcome.
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Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Leucemia Mielomonocítica Juvenil/genética , Mutação , Transdução de Sinais/genética , Doença Aguda , Criança , Pré-Escolar , Variações do Número de Cópias de DNA , Progressão da Doença , Intervalo Livre de Doença , Feminino , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Lactente , Leucemia Mieloide/diagnóstico , Leucemia Mieloide/genética , Leucemia Mielomonocítica Juvenil/diagnóstico , Masculino , PrognósticoRESUMO
BACKGROUND: Epidemiologic studies worldwide have provided substantial evidence of the contributions of environmental exposures to the development of childhood cancer, yet this knowledge has not been integrated into the routine practice of clinicians who care for children with this disease. To identify the basis of this deficit, we sought to assess the environmental history-taking behavior and perceptions of environmental health among pediatric hematologists and oncologists. PROCEDURE: A web-based survey was sent from June to October 2012 to 427 pediatric oncologists, fellows, and nurse practitioners from 20 US institutions, with an overall response rate of 45%. RESULTS: Survey responses indicated that environmental exposures are of concern to clinicians. The vast majority of respondents (88%) reported receiving questions from families about the relationship between certain environmental exposures and the cancers they regularly treat. However, a lack of comfort with these topics seems to have limited their discussions with families about the role of environmental exposures in childhood cancer pathogenesis. Although 77% of respondents suspected that some of the cases they saw had an environmental origin, their methods of taking environmental histories varied widely. Over 90% of respondents believed that more knowledge of the associations between environmental exposures and childhood cancer would be helpful in addressing these issues with patients. CONCLUSIONS: Although limited in size and representativeness of participating institutions, the results of this survey indicate a need for increased training for hematology/oncology clinicians about environmental health exposures related to cancer and prompt translation of emerging research findings in biomedical journals that clinicians read.