RESUMEN

This study explores the impact of a simulated radiological dispersal device (RDD) event in an urban area on young adults around 20 years old. The RDD releases radioactive Cs-137 (7.0E+3 Ci), a common industrial sterilization source. The study aims to demonstrate that combining computational codes and epidemiological models can produce valuable data to guide initial actions when confronting a hostile radioactive environment. The HotSpot Health Physics and RESRAD-RDD codes were used in the simulation to evaluate the event's initial phase. The codes were executed together, and the HotSpot output data was input into RESRAD-RDD. Based on simulated radiation dose levels, estimated doses were incorporated into radioepidemiological models proposed by the Committee on Biological Effects of Ionizing Radiation (BEIR V or VII report). Despite limitations, data transfer between the models revealed no discontinuities or antagonisms. Radiation doses were simulated under three exposure conditions and two atmospheric release modes (day or night), suggesting that atmospheric conditions, sex, and exposure routine can strongly influence the perception of radiation impacts. This combination of methods can increase situational awareness and help with decision-making and developing coping strategies.

Asunto(s)

Monitoreo de Radiación , Liberación de Radiactividad Peligrosa , Adulto Joven , Humanos , Adulto , Radioisótopos de Cesio , Monitoreo de Radiación/métodos , Concienciación , Dosis de Radiación

RESUMEN

The impact of space radiation and microgravity on DNA damage responses has been discussed controversially, largely due to the variety of model systems engaged. Here, we performed side-by-side analyses of human hematopoietic stem/progenitor cells (HSPC) and peripheral blood lymphocytes (PBL) cultivated in a 2D clinostat to simulate microgravity before, during and after photon and particle irradiation. We demonstrate that simulated microgravity (SMG) accelerates the early phase of non-homologous end joining (NHEJ)-mediated repair of simple, X-ray-induced DNA double-strand breaks (DSBs) in PBL, while repair kinetics in HSPC remained unaltered. Repair acceleration was lost with increasing LET of ion exposures, which increases the complexity of DSBs, precluding NHEJ and requiring end resection for successful repair. Such cell-type specific effect of SMG on DSB repair was dependent on the NF-кB pathway pre-activated in PBL but not HSPC. Already under unperturbed growth conditions HSPC and PBL suffered from SMG-induced replication stress associated with accumulation of single-stranded DNA and DSBs, respectively. We conclude that in PBL, SMG-induced DSBs promote repair of radiation-induced damage in an adaptive-like response. HSPC feature SMG-induced single-stranded DNA and FANCD2 foci, i.e., markers of persistent replication stress and senescence that may contribute to a premature decline of the immune system in space.

Asunto(s)

Reparación del ADN , Sistema Hematopoyético , Humanos , ADN de Cadena Simple , Roturas del ADN de Doble Cadena , Reparación del ADN por Unión de Extremidades , Daño del ADN

RESUMEN

The role of allogeneic hematopoietic stem cell transplantation (HCT) in the treatment of acute myelogenous leukemia (AML) in children is reviewed and critically evaluated in this evidence-based review. Specific criteria were used for searching the published literature, grading the quality and strength of evidence, and assigning the strength of treatment recommendations. Genomic characterization and response to therapy have been critical in the risk stratification of pediatric AML. Although some children are cured with chemotherapy alone, allogeneic HCT offers a survival benefit in selected patients with certain unfavorable risk features and is the standard of care for children who relapse following initial treatment with chemotherapy. Important aspects of HCT include recipient characteristics, donor source, and preparative regimen. The goals of HCT are to reduce incidence of relapse, enhance graft-versus-leukemia (GVL) effects, and minimize graft-versus-host disease. Relapse following HCT remains a significant cause of treatment failure, and interventions pre- and post-HCT, especially those that may augment GVL, are an important focus of ongoing investigations.

Asunto(s)

Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Síndromes Mielodisplásicos , Niño , Humanos , Recurrencia , Acondicionamiento Pretrasplante , Trasplante Homólogo , Estados Unidos

RESUMEN

Recent studies suggest that every year worldwide about a million patients might be exposed to doses of the order of 100 mGy of low-LET radiation, due to recurrent application of radioimaging procedures. This paper presents a synthesis of recent epidemiological evidence on radiation-related cancer risks from low-LET radiation doses of this magnitude. Evidence from pooled analyses and meta-analyses also involving epidemiological studies that, individually, do not find statistically significant radiation-related cancer risks is reviewed, and evidence from additional and more recent epidemiological studies of radiation exposures indicating excess cancer risks is also summarized. Cohorts discussed in the present paper include Japanese atomic bomb survivors, nuclear workers, patients exposed for medical purposes, and populations exposed environmentally to natural background radiation or radioactive contamination. Taken together, the overall evidence summarized here is based on studies including several million individuals, many of them followed-up for more than half a century. In summary, substantial evidence was found from epidemiological studies of exposed groups of humans that ionizing radiation causes cancer at acute and protracted doses above 100 mGy, and growing evidence for doses below 100 mGy. The significant radiation-related solid cancer risks observed at doses of several 100 mGy of protracted exposures (observed, for example, among nuclear workers) demonstrate that doses accumulated over many years at low dose rates do cause stochastic health effects. On this basis, it can be concluded that doses of the order of 100 mGy from recurrent application of medical imaging procedures involving ionizing radiation are of concern, from the viewpoint of radiological protection.

Asunto(s)

Neoplasias Inducidas por Radiación , Protección Radiológica , Radiación Ionizante , Humanos , Neoplasias Inducidas por Radiación/epidemiología

RESUMEN

OBJECTIVE: To assess leukemia risks among children with Down syndrome in a large, contemporary cohort. STUDY DESIGN: Retrospective cohort study including 3 905 399 children born 1996-2016 in 7 US healthcare systems or Ontario, Canada, and followed from birth to cancer diagnosis, death, age 15 years, disenrollment, or December 30, 2016. Down syndrome was identified using International Classification of Diseases, Ninth and Tenth Revisions, diagnosis codes. Cancer diagnoses were identified through linkages to tumor registries. Incidence and hazard ratios (HRs) of leukemia were estimated for children with Down syndrome and other children adjusting for health system, child's age at diagnosis, birth year, and sex. RESULTS: Leukemia was diagnosed in 124 of 4401 children with Down syndrome and 1941 of 3 900 998 other children. In children with Down syndrome, the cumulative incidence of acute myeloid leukemia (AML) was 1405/100 000 (95% CI 1076-1806) at age 4 years and unchanged at age 14 years. The cumulative incidence of acute lymphoid leukemia in children with Down syndrome was 1059/100 000 (95% CI 755-1451) at age 4 and 1714/100 000 (95% CI 1264-2276) at age 14 years. Children with Down syndrome had a greater risk of AML before age 5 years than other children (HR 399, 95% CI 281-566). Largest HRs were for megakaryoblastic leukemia before age 5 years (HR 1500, 95% CI 555-4070). Children with Down syndrome had a greater risk of acute lymphoid leukemia than other children regardless of age (<5 years: HR 28, 95% CI 20-40, ≥5 years HR 21, 95% CI 12-38). CONCLUSIONS: Down syndrome remains a strong risk factor for childhood leukemia, and associations with AML are stronger than previously reported.

Asunto(s)

Síndrome de Down/epidemiología , Leucemia Megacarioblástica Aguda/epidemiología , Adolescente , Estudios de Casos y Controles , Niño , Preescolar , Estudios de Cohortes , Femenino , Humanos , Incidencia , Lactante , Recién Nacido , Masculino , Ontario/epidemiología , Sistema de Registros , Medición de Riesgo , Estados Unidos/epidemiología

RESUMEN

The role of hematopoietic cell transplantation (HCT) in the management of newly diagnosed adult acute myeloid leukemia (AML) is reviewed and critically evaluated in this evidence-based review. An AML expert panel, consisting of both transplant and nontransplant experts, was invited to develop clinically relevant frequently asked questions covering disease- and HCT-related topics. A systematic literature review was conducted to generate core recommendations that were graded based on the quality and strength of underlying evidence based on the standardized criteria established by the American Society of Transplantation and Cellular Therapy Steering Committee for evidence-based reviews. Allogeneic HCT offers a survival benefit in patients with intermediate- and high-risk AML and is currently a part of standard clinical care. We recommend the preferential use of myeloablative conditioning in eligible patients. A haploidentical related donor marrow graft is preferred over a cord blood unit in the absence of a fully HLA-matched donor. The evolving role of allogeneic HCT in the context of measurable residual disease monitoring and recent therapeutic advances in AML with regards to maintenance therapy after HCT are also discussed.

Asunto(s)

Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Adulto , Humanos , Leucemia Mieloide Aguda/terapia , Acondicionamiento Pretrasplante , Trasplante Homólogo , Estados Unidos

RESUMEN

Angiogenesis process contributes to the pathogenesis of B-cell chronic lymphocytic leukemia (B-CLL) being the levels of VEGFA and bFGF higher in patients than in healthy controls. Our aim was to evaluate the implication of angiogenesis factors genetic variants in the predisposition to B-CLL and their association with clinical factors and survival. We performed a population-based case-control study in 224 Spanish B-CLL patients and 476 healthy randomly selected controls to evaluate susceptibility to developing B-CLL. Six polymorphisms were evaluated: rs1109324, rs1547651, rs3025039 (+936 C>T), rs833052 of the VEGFA gene, rs1449683 (c.233C>T) of the bFGF gene and (-710 C>T) of the VEGFR1 gene. The association between clinical parameters and patient outcome was analyzed. Carriers of the CT/TT variants of rs3025039 showed a significant protective effect against developing B-CLL. The CT/TT variants of rs1449683 show a tendency towards the development of the disease and the same variants associated significantly with higher genetic risk and with reduced disease free survival. Moreover, the association persisted in the early-stage disease subgroup. Our study provides evidence of the protective effect of the T/- rs3025039 VEGFA variant against B-CLL development and the association of CT/TT variants of the rs1449683 bFGF gene with genetic risk and an adverse survival.

Asunto(s)

Factores de Crecimiento de Fibroblastos/genética , Predisposición Genética a la Enfermedad , Leucemia Linfocítica Crónica de Células B/genética , Factor A de Crecimiento Endotelial Vascular/genética , Receptor 1 de Factores de Crecimiento Endotelial Vascular/genética , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Asociación Genética , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética

RESUMEN

A biologically motivated dynamical model of the radiogenic leukemia risk assessment (Smirnova, 2015, 2017; Smirnova and Cucinotta, 2018) is applied to the study of the effects of dose rate N and dose D on the excess relative risk ERR for non-CLL leukemia among continuously irradiated humans. In the study, the dose rate N of continuous irradiation is varied from 3×10-6 to 0.576 Sv/day and the dose D is varied from zero to 2.2 Sv. In the considered range of doses D, the developed model reproduces the linear dependence of ERR on D for the low dose rates N. For higher N, the dependence of ERR on D remains linear for low doses D and becomes nonlinear for higher D, that agrees with empirical observations. In turn, for the considered values of D, the developed model reproduces the practical independence of the ratio ERR/D on N at low N, the inverse dependence of the ratio ERR/D on N at higher N, and the direct dependence of the ratio ERR/D on N at more high N, that also conforms to empirical observations. Additionally, the modeling values of ERR obtained for the scenarios of continuous irradiation corresponding to those for the nuclear industry workers, Chernobyl cleanup workers, and patients treated with radiotherapy, practically, coincide with the respective empirical data. All these modeling findings, along with those obtained in our previous works, demonstrate the predictive power of the developed model and its capability of estimating, on quantitative level, the excess relative risk for non-CLL leukemia among humans exposed to continuous irradiation in wide ranges of doses and dose rates.

Asunto(s)

Accidente Nuclear de Chernóbil , Leucemia Inducida por Radiación/epidemiología , Modelos Biológicos , Exposición Profesional/efectos adversos , Humanos , Dosis de Radiación , Medición de Riesgo , Factores de Riesgo

RESUMEN

Acute myeloid leukemia (AML) induction traditionally includes seven days of cytarabine and three days of an anthracycline (7 + 3). Because of evidence of increased efficacy of cladribine combined with this regimen, we conducted a retrospective analysis of 107 AML patients treated with idarubicin, cytarabine and cladribine (IAC) at our institution. Complete remission (CR) occurred in 71%, with overall response of 79%. One-year survival overall was 59%, with 47% (27/57) among patients ≥60 years old and 72% (36/50) in those <60 (Relative Risk [RR] 1.9, 95% CI 1.2-3.2). Median overall survival was 17.3 months in all patients and Cox proportional hazard ratio (HR) for death was 2.2 (95% CI 1.3-3.6) for age ≥60 years compared to <60 years. One year survival was 100% among favorable NCCN risk patients versus 64% in intermediate-risk and 35% in poor-risk patients (p < 0.001). HR for death in intermediate- risk (4.2, 95% CI 1.5-12) and poor-risk (8.4, 95% CI 3.0-24) compared to favorable risk AML was higher than that associated with age ≥60 years (HR 2.2). We conclude that IAC is an effective AML induction regimen, NCCN leukemia risk predicts survival better than age in our population, and high intensity regimens can be justified in selected older patients.

Asunto(s)

Factores de Edad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Cladribina/uso terapéutico , Citarabina/uso terapéutico , Idarrubicina/uso terapéutico , Quimioterapia de Inducción , Leucemia Mieloide Aguda/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Cladribina/administración & dosificación , Citarabina/administración & dosificación , Femenino , Humanos , Idarrubicina/administración & dosificación , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Inducción de Remisión , Estudios Retrospectivos , Riesgo , Análisis de Supervivencia , Resultado del Tratamiento , Adulto Joven

RESUMEN

A recently developed biologically motivated dynamical model of the assessment of the excess relative risk (ERR) for radiogenic leukemia among acutely/continuously irradiated humans (Smirnova, 2015, 2017) is applied to estimate the ERR for radiogenic leukemia among astronauts engaged in long-term interplanetary space missions. Numerous scenarios of space radiation exposure during space missions are used in the modeling studies. The dependence of the ERR for leukemia among astronauts on several mission parameters including the dose equivalent rates of galactic cosmic rays (GCR) and large solar particle events (SPEs), the number of large SPEs, the time interval between SPEs, mission duration, the degree of astronaut's additional shielding during SPEs, the degree of their additional 12-hour's daily shielding, as well as the total mission dose equivalent, is examined. The results of the estimation of ERR for radiogenic leukemia among astronauts, which are obtained in the framework of the developed dynamical model for various scenarios of space radiation exposure, are compared with the corresponding results, computed by the commonly used linear model. It is revealed that the developed dynamical model along with the linear model can be applied to estimate ERR for radiogenic leukemia among astronauts engaged in long-term interplanetary space missions in the range of applicability of the latter. In turn, the developed dynamical model is capable of predicting the ERR for leukemia among astronauts for the irradiation regimes beyond the applicability range of the linear model in emergency cases. As a supplement to the estimations of cancer incidence and death (REIC and REID) (Cucinotta et al., 2013, 2017), the developed dynamical model for the assessment of the ERR for leukemia can be employed on the pre-mission design phase for, e.g., the optimization of the regimes of astronaut's additional shielding in the course of interplanetary space missions. The developed model can also be used on the phase of the real-time responses during the space mission to make the decisions on the operational application of appropriate countermeasures to minimize the risks of occurrences of leukemia, especially, for emergency cases.

Asunto(s)

Astronautas , Radiación Cósmica/efectos adversos , Leucemia/epidemiología , Neoplasias Inducidas por Radiación/epidemiología , Traumatismos por Radiación/etiología , Vuelo Espacial , Humanos , Leucemia/etiología , Neoplasias Inducidas por Radiación/etiología , Dosis de Radiación , Medición de Riesgo

RESUMEN

AIM: To analyze the efficiency and reproducibility of the ALL-2009 protocol within the Russian prospective multicenter study based on different principles of cytostatic effects (non-intensive, but continuous cytotoxic treatment and a small number of allogeneic hematopoietic stem cells). SUBJECTS AND METHODS: The ALL-2009 (NCT01193933) study conducted in April 2009 to December 2016 included 194 patients (95 males and 99 females) aged 15 to 55 years (median age 28 years) with Ph-negative B-cell acute lymphoblastic leukemia (ALL). There was early pre-B-cell ALL in 54 patients, common ALL in 101, pre-B ALL in 39, initial leukocytosis in 9.4·109/l (0.4-899.0), lactate dehydrogenase in 901 IU (31-13 059), an initial central nervous system lesion in 17 (8.7%), mediastinal injury in 3 (1.5%), and splenomegaly in 111 (57.2%). The results of standard cytogenetic analysis are known in 113 (60.4%) patients. Normal karyotypes were detected in 49 (54.5%) out of the patients; t(4;11) in 9 (5.4%), t(1;19) in 2 (1.2%), and other karyotypic abnormalities in 53 (46.9%). Thirteen (7.8%) patients underwent allogeneic hematopoietic stem cell transplantation in first complete remission (CR); their proportion did not differ in the federal and regional centers. RESULTS: The frequency of CR achievement was the same in the federal and regional centers and generally amounted to 87.5%. Early (8.8%) and CR (9.6%) mortality rates remained high despite the low aggressiveness of cytotoxic action, necessitating the improvement of auxiliary treatment. The five-year overall survival (OS) rates vary considerably in the federal and regional centers (72.6 and 43.8%), the relapse-free survival (RFS) (70.2 and 53.4%) and recurrence risk (23.1 and 36.5%) are comparable. This suggests that the non-intensive, but continuous exposure principle built in the ALL-2009 protocol makes it possible to reproduce the envisaged treatment program and to achieve satisfactory results. CONCLUSION: The ALL-2009 protocol allows both the federal and regional centers to obtain the long-term results comparable with those of current foreign studies: OS (54.2%), RFS (56.5%); and relapse risk (35.4%). Multivariate analysis has identified age (over 30 years), initial leukocytosis (30·109/l and more) and t(4;11) among the main clinical prognostic factors. Gene mutation detection evaluated in a small number of patients (8/36) is not a poor prognostic sign. There is a need for further investigations with centralized evaluation of the mutation status of leukemic cells and the clearance of minimal residual disease.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Prolinfocítica Tipo Células B , Inducción de Remisión/métodos , Enfermedad Aguda , Adulto , Femenino , Humanos , Quimioterapia de Inducción/métodos , Quimioterapia de Inducción/estadística & datos numéricos , Leucemia Prolinfocítica Tipo Células B/diagnóstico , Leucemia Prolinfocítica Tipo Células B/epidemiología , Leucemia Prolinfocítica Tipo Células B/terapia , Masculino , Pronóstico , Estudios Prospectivos , Reproducibilidad de los Resultados , Federación de Rusia/epidemiología , Prevención Secundaria/métodos , Prevención Secundaria/estadística & datos numéricos , Análisis de Supervivencia

RESUMEN

BACKGROUND: Chronic myeloid leukemia (CML) is associated to the BCR-ABL1 oncogene and can successfully be treated with tyrosine kinase inhibitors (TKIs). However, it remains still under investigation which molecular factors may influence CML risk or varying responses to TKIs. The aim of this study was to assess the role of Glutathione-S-transferases (GSTs) genetic polymorphisms in CML susceptibility and TKI clinical outcome. MATERIALS: Deletion polymorphisms in GSTM1 and GSTT1 genes and the single nucleotide polymorphism in GSTP1 c.319A>G (rs1695; p.105Ile>Val) were genotyped by PCR methods in 141 CML treated patients and 141 sex- and age-matched healthy individuals. RESULTS: Individual analysis of each GST gene showed no association with CML risk. A trend toward significance (p=0.07) for a recessive model was found for GSTP1 (OR: 2.04; CI: 0.94-4.4). However, the combined analysis showed that GSTM1-null/GSTP1-GG as well as GSTT1-null/GSTP1-GG were associated with CML development (p=0.03; OR: 3.54 CI: 1.2-14.57; p=0.05; OR: 12.65; CI: 1.17-21.5). The relationship with treatment outcome showed that the presence of GSTM1 gene was significantly linked with an inferior rate of major molecular response (p=0.048) and poor event free-survival (EFS) (p=0.02). Furthermore, a group of patients with GSTP1-GG genotype were significantly associated with reduced EFS comparing to those carrying other GSTP1 genotypes (p=0.049). GSTP1-GG genotypes had short time to treatment failure in a group of patients unresponsive to TKIs comparing to other GSTP1 genotypes (p=0.03). CONCLUSIONS: This study highlights the significance of GSTM1 and GSTP1 polymorphisms on CML susceptibility and response to TKIs in the Argentinean population.

Asunto(s)

Gutatión-S-Transferasa pi/genética , Glutatión Transferasa/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Polimorfismo Genético , Factores de Riesgo , Resultado del Tratamiento , Adulto Joven

RESUMEN

The 5,10-methylenetetrahydrofolate reductase (MTHFR) and thymidylate synthase (TS) are critical enzymes in folate metabolism. Previous studies have reported conflicting results on the associations between MTHFR/TS polymorphisms and adult leukemia risk, which may due to the lack of information on folate intake. We investigated the risks of adult leukemia with genetic polymorphisms of folate metabolic enzymes (MTHFR C677T, A1298C, and TS) and evaluated if the associations varied by dietary folate intake from a multicenter case-control study conducted in Chinese. This study comprised 442 incident adult leukemia cases and 442 outpatient controls, individually matched to cases by gender, birth quinquennium, and study site. Genotypes were determined by a polymerase chain reaction (PCR) or PCR-based restriction fragment length polymorphism assay. Dietary folate intake was assessed by face-to-face interviews using a validated food-frequency questionnaire. The MTHFR 677TT genotype conferred a significant higher risk of leukemia in males than in females and exhibited an increased risk of acute myeloid leukemia (AML) but a decreased risk of acute lymphoblastic leukemia (ALL). The MTHFR 1298AC genotype appeared to decrease the risks of leukemia in both genders, in AML and ALL. Stratified analysis by dietary folate intake showed the increased risks of leukemia with the MTHFR 677TT and TS 2R3R/2R2R genotypes were only significant in individuals with low folate intake. A significant interaction between TS polymorphism and dietary folate intake was observed (P = 0.03). This study suggests that dietary folate intake and gender may modify the associations between MTHFR/TS polymorphisms and adult leukemia risk.

Asunto(s)

Ácido Fólico/metabolismo , Leucemia/genética , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Polimorfismo de Nucleótido Simple , Timidilato Sintasa/genética , Enfermedad Aguda , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Dieta , Femenino , Ácido Fólico/farmacocinética , Frecuencia de los Genes , Predisposición Genética a la Enfermedad/genética , Genotipo , Humanos , Leucemia/metabolismo , Leucemia Mieloide/genética , Leucemia Mieloide/metabolismo , Masculino , Persona de Mediana Edad , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Factores de Riesgo , Factores Sexuales , Encuestas y Cuestionarios , Adulto Joven

RESUMEN

BACKGROUND AND AIM: Despite recent major advances in leukemia research, the etiopathogenesis of childhood leukemias remains far elusive. Individual predisposing factors, including polymorphisms in detoxification enzymes, have been implicated in the molecular pathogenesis and heterogeneity of the disease. Genetic polymorphisms of glutathione S-transferases (GSTs) that alter enzyme activity could be an additional factor that increases the risk of acute leukemia, but data are lacking in Argentina. We assessed the association of GST polymorphisms and the susceptibility to childhood leukemia in Argentina by conducting an exploratory case-control study and correlated patients' genotype to clinical and biological features. METHODS: Deletion polymorphisms in GSTM1 and GSTT1 genes and the single nucleotide polymorphism in GSTP1 c.313A>G (rs1695; p.105Ile>Val) were genotyped by PCR-RFLP in 36 patients and 133 healthy individuals. RESULTS: GSTM1-null genotype was associated with a lower risk of developing acute leukemia (P = 0.013; OR: 0.31; CI: 0.12-0.80), while GSTP1-GG variants displayed an increased risk (P = 0.01; OR: 3.9; CI: 1.85-8.2). However, no differences were found for GSTT1 gene. Conclusion These preliminary results, to be validated in a larger population from Argentina, suggest that the development of pediatric leukemia may be differentially influenced by polymorphic variants in GST genes.

Asunto(s)

Gutatión-S-Transferasa pi/genética , Glutatión Transferasa/genética , Leucemia Mieloide Aguda/genética , Polimorfismo Genético , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adolescente , Argentina , Estudios de Casos y Controles , Niño , Preescolar , Femenino , Expresión Génica , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/patología , Masculino , Mutación , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Factores de Riesgo

RESUMEN

BACKGROUND: Acute lymphoblastic leukemia (ALL) is the most common malignancy in children, though the etiology of the leukemia is poorly understood, both genetic and environmental factors appear to be involved. Previous studies investigating the association between MDR1 C3435T polymorphisms and risk of children with ALL reported controversial results. METHODS: We performed a comprehensive meta-analysis to clarify the effect of MDR1 C3435T polymorphisms on risk of childhood ALL. The strength of the association was measured by odds ratio (OR) with 95% confidence interval (CI). RESULTS: Nine studies were finally included, involving a total of 1462 cases and 1522 controls. There was no association between MDR1 C3435T polymorphism and children ALL risk in all of four models in overall populations (CT vs. CC: OR=0.86, 95% CI=0.65-1.15, P=0.310; TT vs. CC: OR=1.50, 95% CI=0.96-2.35, P=0.076; TT/CT vs. CC: OR=1.12, 95% CI=0.95-1.33, P=0.166; TT vs. CC/CT: OR=1.58, 95% CI=0.97-2.56, P=0.067). Subgroup analysis by race suggested that this association existed in Asians under the under the homozygote model and recessive model (TT vs. CC: OR=2.45, 95% CI=1.24-4.86, P=0.010; TT vs. CT/CC: OR=2.65, 95% CI=1.22-5.75, P=0.014). CONCLUSIONS: This meta-analysis suggests there was no association between MDR1 C3435T polymorphism and children ALL risk in overall populations, but significant association with an increased risk in Asians.

Asunto(s)

Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Niño , Etnicidad/genética , Heterogeneidad Genética , Humanos , Modelos Genéticos , Oportunidad Relativa , Sesgo de Publicación , Factores de Riesgo

RESUMEN

CONTEXT: The exact role of the different transcript variants of BCR-ABL in the pathogenesis of chronic myeloid leukemia (CML) and their impact on prognosis is yet to be definitely enumerated. AIMS: In this study, we have tried to correlate the presenting features, risk scores and treatment response with the BCR-ABL variants detected in our patients. SETTINGS AND DESIGN: A cross-sectional unicentric hospital-based study on 80 patients diagnosed to have CML by bone marrow cytogenetics and confirmed by reverse transcriptase-polymerase chain reaction (RT-PCR). MATERIALS AND METHODS: RT-PCR for BCR-ABL was performed on consecutive patients with CML attending the CML clinic from January 2010 to December 2010. The medical charts of these patients were analyzed after a follow-up of 18 months in a retrospective manner. STATISTICAL ANALYSIS: Box plot and histogram was used to see the distribution of variables. t-test was performed to enumerate the difference between risk scores in two populations of patients carrying two different BCR-ABL transcript variants. RESULTS: Nearly 56.25% of patients had b3a2 (e14a2) while 41.25% of patients showed b2a2 (e13a2) transcripts. The rest 2.5% (two patients) expressed the rare e19b2 variant. Patients with b2a2 presented with higher Sokal, Hasford and European Treatment and Outcomes Study score than their b3a2 counterpart. Different parameters such as the platelet count, leukocyte count, hemoglobin and splenomegaly showed a minor difference between the groups. More patients in the b2a2 group achieved complete hematologic response at 3 months, but it was not significant. CONCLUSIONS: Patients with b2a2 variant CML tend to present with higher risk score, but do not behave in a vastly different manner than their b3a2 counterparts.