Mutational Landscape of CEBPA in Mexican Pediatric Acute Myeloid Leukemia Patients: Prognostic Implications.

Background: In Mexico, the incidence of acute myeloid leukemia (AML) has increased in the last few years. Mortality is higher than in developed countries, even though the same chemotherapy protocols are used. CCAAT Enhancer Binding Protein Alpha (CEBPA) mutations are recurrent in AML, influence prognosis, and help to define treatment strategies. CEBPA mutational profiles and their clinical implications have not been evaluated in Mexican pediatric AML patients. Aim of the Study: To identify the mutational landscape of the CEBPA gene in pediatric patients with de novo AML and assess its influence on clinical features and overall survival (OS). Materials and Methods: DNA was extracted from bone marrow aspirates at diagnosis. Targeted massive parallel sequencing of CEBPA was performed in 80 patients. Results: CEBPA was mutated in 12.5% (10/80) of patients. Frameshifts at the N-terminal region were the most common mutations 57.14% (8/14). CEBPA biallelic (CEBPA BI) mutations were identified in five patients. M2 subtype was the most common in CEBPA positive patients (CEBPA POS) (p = 0.009); 50% of the CEBPA POS patients had a WBC count > 100,000 at diagnosis (p = 0.004). OS > 1 year was significantly better in CEBPA negative (CEBPA NEG) patients (p = 0.0001). CEBPA POS patients (either bi- or monoallelic) had a significantly lower OS (p = 0.002). Concurrent mutations in FLT3, CSF3R, and WT1 genes were found in CEBPA POS individuals. Their contribution to poor OS cannot be ruled out. Conclusion: CEBPA mutational profiles in Mexican pediatric AML patients and their clinical implications were evaluated for the first time. The frequency of CEBPA POS was in the range reported for pediatric AML (4.5-15%). CEBPA mutations showed a negative impact on OS as opposed to the results of other studies.

Consensus in acute myeloid leukemia in Mexico.

Acute myeloid leukemia (AML) comprises a heterogeneous group of hematopoietic cell neoplasms of myeloid lineage that arise from the clonal expansion of their precursors in the bone marrow, interfering with cell differentiation, leading to a syndrome of bone marrow failure. AML is a consequence of genetic and epigenetic changes (point mutations, gene rearrangements, deletions, amplifications, and arrangements in epigenetic changes that influence gene expression) in hematopoietic precursor cells, which create a clone of abnormal cells that are capable of proliferating but cannot differentiate into mature hematopoietic cells or undergo programmed cell death. The diagnosis requires more than 20% myeloid blasts in the bone marrow and certain cytogenic abnormalities. Treatment will depend on age, comorbidities, and cytogenetic risk among the most frequent.

La leucemia mieloide aguda (LMA) comprende un grupo heterogéneo de neoplasias de células hematopoyéticas de linaje mieloide que surgen de la expansión clonal de sus precursores en la médula ósea, interfiriendo con la diferenciación celular, lo que conlleva a un síndrome de falla medular. La LMA es una consecuencia de cambios genéticos y epigenéticos (mutaciones puntuales, rearreglos de genes, deleciones, amplificaciones y arreglos en cambios epigenéticos que influyen en la expression del gen) en las células hematopoyéticas precursoras, la cual crea una clona de células anormales que son capaces de proliferar, pero no se pueden diferenciar en células hematopoyéticas maduras ni sufrir una muerte celular programada. El diagnostic requiere más del 20% de blastos mieloides en médula ósea y ciertas anormalidades citogénicas. El tratamiento dependerá de la edad, comorbilidades, riesgo citogenético entre las más frecuentes.

Consenso de leucemia mieloide aguda en México / Mexican consensus in acute myeloid leukemia in Mexico

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Abstract Acute myeloid leukemia (AML) comprises a heterogeneous group of hematopoietic cell neoplasms of myeloid lineage that arise from the clonal expansion of their precursors in the bone marrow, interfering with cell differentiation, leading to a syndrome of bone marrow failure. AML is a consequence of genetic and epigenetic changes (point mutations, gene rearrangements, deletions, amplifications, and arrangements in epigenetic changes that influence gene expression) in hematopoietic precursor cells, which create a clone of abnormal cells that are capable of proliferating but cannot differentiate into mature hematopoietic cells or undergo programmed cell death. The diagnosis requires more than 20% myeloid blasts in the bone marrow and certain cytogenic abnormalities. Treatment will depend on age, comorbidities, and cytogenetic risk among the most frequent.

Decrease of Postchemotherapy Complications With the Use of Probiotics in Children With Acute Lymphoblastic Leukemia.

INTRODUCTION: During the administration of antineoplastic drugs, acute complications because of toxicity occur, determining their hospital readmission, visits to the emergency department, use of antimicrobials, and possibilities of presenting systemic infections, impacting on their life quality. METHODS: Through a prospective cohort, 60 children with acute lymphoblastic leukemia were followed-up for 30 days after the hospital discharge because of chemotherapy administration, those patients were previously included in a single-blinded study in which 30 (group 1) received Lactobacillus rhamnosus GG probiotic during the administration of chemotherapy. The remaining 30 patients did not receive probiotics (group 2). There were evaluated gastrointestinal symptoms, such as diarrhea, dyspepsia, abdominal distension, meteorism, constipation, nausea, and vomit, development of infections, antibiotic use, number of emergency department visits, number of hospitalizations, and sepsis diagnosis. STATISTICAL ANALYSIS: To assess the impact of the use of probiotics, the difference in proportions between both study groups was evaluated. RESULTS: Gastrointestinal manifestations (nausea, vomiting, diarrhea, constipation) occurred in 30% of patients in group 1 versus 63% of group 2 (P=0.009). Nine of 30 patients (30.0%) in group 1 went to the emergency room, versus 33.3% of group 2 (P=0.7). Antimicrobials were used in 8 subjects (26.6%) in group 1 versus 6 subjects (53.3%) in group 2 (P=0.03) suspected of an infectious disease. Four (13.3%) group 1 patients were hospitalized versus 30% of group 2 (P=0.1). Two subjects (6.6%) in group 1 had sepsis versus 7 (23.3%) in group 2 (P=0.07).Conclusions:The results indicate that the use of probiotics can be a great alternative in the improvement of gastrointestinal symptoms and the adverse effects associated with chemotherapy.

Profiling FLT3 Mutations in Mexican Acute Myeloid Leukemia Pediatric Patients: Impact on Overall Survival.

Background: Acute myeloid leukemia (AML) is the second most frequent leukemia in childhood. The FLT3 gene participates in hematopoietic stem cell proliferation. FLT3 mutations are recurrent in AML and influence prognosis. In Mexican pediatric AML patients, FLT3 mutational profile, and their clinical impact have not been evaluated. Aim of the study: This study aimed to identify the profile of FLT3 mutations in pediatric patients with de novo AML and to assess their possible influence on overall survival (OS) and other clinical features. Methods: Massive parallel target sequencing of FLT3 was performed in 80 patients. Results: FLT3 mutations [internal tandem duplication (ITD) or tyrosine kinase domain (TKD)] were identified in 24% of them. OS was significantly lower in FLT3 POS cases than in FLT3 NEG (p = 0.03). The average OS for FLT3 POS was 1.2 vs. 2.2 years in FLT3 NEG. There were no significant differences in the children's sex, age, percentage of blasts in bone marrow aspirate, or white blood cell count in peripheral blood at diagnosis between both groups. No differences were identified stratifying by the mutational load (high > 0.4) or type of mutation. The negative effect of FLT3 mutations was also observed in patients with acute promyelocytic leukemia (APL). Conclusions: FLT3 mutational profile is described in Mexican pediatric AML patients for the first time. Mutated FLT3 negatively impacts the outcome of AML patients, even considering the APL group. The clinical benefit from treatment with tyrosine kinase inhibitors in the FLT3 POS pediatric patients needs to be assessed in clinical trials. FLT3 testing may contribute to better risk stratification in our pediatric AML patients.

Probiotic Supplementation Decreases Chemotherapy-induced Gastrointestinal Side Effects in Patients With Acute Leukemia.

INTRODUCTION: In children with acute leukemia, gut microbiota is modified secondary to chemotherapy administration, leading to gastrointestinal side effects. Probiotics are microorganisms that can restore gut microbiota and may help alleviate gastrointestinal symptoms. The aim of this pilot study was to assess the effects of probiotic supplementation on chemotherapy-induced gastrointestinal side effects in children with acute leukemia (AL). METHODS: In this randomized pilot study, patients under 17 years of age diagnosed with AL who were on remission induction or remission reinduction chemotherapy were randomly assigned to receive probiotic supplementation (a concentration of 5×109 CFU per sachet was administered at a standard dose twice daily, by mouth) or no probiotic supplementation. The primary endpoint was the prevalence of gastrointestinal side effects. Vomiting, nausea, flatulence, dyspepsia, diarrhea, constipation, abdominal pain, and abdominal distention were assessed in both groups. RESULTS: Gastrointestinal side effects were less prevalent in the probiotic group, and 3 of the 8 gastrointestinal side effects (nausea, vomiting, and abdominal distension) significantly decreased in the probiotic group (P<0.05). We found for diarrhea a relative risk of 0.5 (95% confidence interval [CI], 0.2-1.2; P=0.04); for nausea an RR of 0.5 (95% CI, 0.4-0.8; P=0.04) and for vomiting an RR of 0.4 (95% CI, 0.2-0.9; P=0.04). CONCLUSIONS: Daily supplementation with Lactobacillus rhamnosus reduced chemotherapy-induced gastrointestinal side effects in children with AL.

Serum concentrations of apoptosis-associated molecules in septic children with leukemia, neutropenia and fever.

It has been shown that Fas, Fas-L, TNF and TNFR-1 display high serum concentrations in subjects with sepsis. This suggests that these are potential severity markers. However, the serum concentration of these molecules in children with leukemia and suspected sepsis has to be established before proposing their use as diagnostic biomarkers. We included children <17 years of age diagnosed with acute lymphoblastic leukemia with neutropenia and fever (NF). The subjects were divided into two groups: (1) leukemia and NF with sepsis, (2) leukemia and NF without sepsis. Determination of serum levels of TNF-α, TNFR-1, Fas and Fas-L was performed using ELISA tests, and apoptosis percentage using flow cytometry. Seventy-two subjects with ALL and NF were included in the two groups. The highest serum levels of TNF-α (35.2 ± 7.6 pg/ml) and TNF-R1 (4102 ± 2440) and the lowest levels of Fas-L (19.4 ± 7.3 pg/ml) were found in group 2: however, the difference in comparison with patients without sepsis was not statistically significant. Low levels of Fas-L and low percentage of apoptotic cells are observed in septic subjects. This pattern may reflect the presence of sepsis among subjects with NF secondary to leukemia.

Gastric wall perforation secondary to presumed aspergillosis in a pediatric patient with aplastic anemia: A case report.

Aspergillosis is an opportunistic fungal infection that may develop in immunocompromised patients with conditions such as leukemia or aplastic anemia. A rare case of stomach perforation following acute fungal gastritis in a 13-year-old female patient with aplastic anemia is reported herein. The patient had developed aplastic anemia without bone marrow fibrosis secondary to acute lymphoblastic leukemia and chemotherapy. The pathological examination revealed a large ischemic transmural perforation (9.5 × 9 cm) associated with fungal septic emboli. Fungal hyphae characteristics were compatible with those of Aspergillus spp. There are few reports identifying fungi as agents associated with gastric perforation. There is a need for early identification of the infectious agent.

Antibiotic use before chemotherapy: a risk factor for developing neutropenic colitis in children with leukemia.

BACKGROUND: It has been shown that the use of antimicrobials is a determinant that favors intestinal dysbiosis. The objective of this study is to establish the association between the previous use of antimicrobials and the development of neutropenic colitis (NC). METHODS: A case-control study was carried out with subjects diagnosed with acute lymphoblastic leukemia from 2004 to July 2013. They were identified by cross-referencing the databases from the computing area and the records from the pediatric hematology section. Cases were children with neutropenia and fever, abdominal distension and pain, diarrhea or constipation, and ultrasonography or computed tomography showing an intestinal wall thickness of ≥4 mm. Controls were children with acute lymphoblastic leukemia with neutropenia and fever, with or without gastrointestinal symptomatology, but without images of NC. RESULTS: Thirty-eight cases and 75 controls were included. The factors associated with the development of NC were severe neutropenia (odds ratio [OR], 12.4; 95% confidence interval [CI], 3-51; P=0.00001), the use of antimicrobials for >10 days, within the month previous to the appearance of NC (OR, 12.4; 95% CI, 3-51; P=0.00001), and use of doxorubicin (OR, 5.43, 95% CI, 2.1-13.8, P=0.00004). In particular, the risk of developing CN was 3.46 (95% CI, 0.88-14; P=0.04) when ceftriaxone was used. CONCLUSIONS: The use of antimicrobials during >10 days before the administration of chemotherapy is a risk factor for developing NC, along with other factors previously studied.

Utilidad de la prueba directa de Coombs en el tamiz neonatal / Usefulness of direct antiglobulin test in neonatal screening

Introducción. La ictericia es un evento clínico frecuente que se presenta en los recién nacidos; las causas más frecuentes involucradas en la enfermedad hemolítica del recién nacido (EHRN) continúan siendo la incompatibilidad al sistema ABO y la isoinmunización a RhD. La prueba directa de Coombs (PDC) permite identificar la presencia de anticuerpos antieritrocitarios del isotipo IgG, provenientes del suero materno en la superficie de los eritrocitos del feto o neonato. Objetivo: presentar los resultados y especificidad de la prueba directa de Coombs (PDC) como prueba en el tamiz neonatal. Métodos. Consecutivamente se incluyeron a recién nacidos no seleccionados. En las primeras horas de vida se determinó el grupo sanguíneo ABO/RhD y la PDC con suero poliespecífico y monoespecíficos (anti-IgG y C3b/C3d). Resultados. Se incluyeron 5 007 recién nacidos, la PDC positiva se documentó en 181 neonatos (3.6%). Los casos del grupo sanguíneo A, B o AB, mostraron mayor riesgo de tener PDC positiva que los del grupo O (razón de momios 2.3, intervalo de confianza 95% 1.7-3.1). La PDC positiva se presentó en 3.5% de los neonatos RhD positivo y en 1.9% de los RhD negativo; 72.9% de los neonatos con PDC positiva tuvieron titulaciones de 1:2, 1 ;4 y 1:8, con el 33.1, 19.9 y 19.9%, respectivamente. En los neonatos con PDC positiva se pudo establecer el isotipo anti-IgG en 117 casos (64.6%), complemento sólo en 6 casos (3.3%), la combinación de ambas en 6 casos (3.3%) y en 52 neonatos (28.8%), con PDC poliespecífico positivo, no se pudo identificar la especificidad de la reacción. Conclusión. La prevalencia elevada (3.6 %) de PDC positiva en la detección neonatal rutinaria, apoya la indicación de incorporar dicha prueba al tamiz neonatal, independientemente del grupo ABO y Rh materno. Queda por establecer su beneficio en la detección temprana de la ictericia neonatal.

Background. Neonatal jaundice is a clinical event frequently present in newborns. The causes most frequently involved in hemolytic disease of newborn (HDN) are still the incompatibilities to the ABO/Rh blood system. Direct Coombs test (or direct antiglobulin test, DAT) allows identification of the presence of red blood cell antibodies (IgG isotype) coming from the maternal serum on the surface of the fetus erythrocytes. The purpose of this study is to show the results and specificity of DAT as screening in newborn infants. Methods. We studied unselected neonates in a cross-sectional design. During the early hours of life, we determined ABO/Rh and DAT with poly- and monospecific reagents (anti-IgG and C3b/C3d). Results. We included 5 007 newborns; 181 cases (3.6%) were DAT positive. Newborns with A, B or AB blood groups showed an increased association of being DAT positive than group O (OR 2.3, 95% Cl 1.7-3.1). DAT was positive in 3.5% of RhD-positive infants and 1.9% of RhD-negative infants. In six DAT-positive cases, 117 cases (64.6%) had anti-IgG bound to red cell membrane, complement in six cases (3.3%), and 52 newborns (28.8%) were polyspecific DAT positive and monospecific DAT negative. Conclusions. The high prevalence (3.6%) of DAT-positive cases in routine neonatal detection supports the indication to incorporate DAT into neonatal screening, regardless of the mother's blood group. The benefit of early intervention in neonatal jaundice remains to be established.