Philadelphia-like acute lymphoblastic leukemia: Characterization in a pediatric cohort in a referral center in Colombia.

BACKGROUND: Philadelphia-like (Ph-like) acute lymphoblastic leukemia (ALL) is a subtype of pediatric leukemia with high risk factors and poor outcome. There are few reports of its prevalence in Latin America. AIM: This study evaluated the frequency and clinical and biological characteristics of Ph-like ALL in a pediatric cancer center in Colombia. METHODS: The Ph-like genetic profile was analyzed by a low-density array (LDA). Samples from patients with Ph-like ALL were analyzed by fluorescent in situ hybridization for cytokine receptor like factor 2 (CRLF2) and ABL proto-oncogene 1, non-receptor tyrosine kinase (ABL1) rearrangements. Copy number variations were assessed by multiplex ligation probe amplification. RESULTS: Data from 121 patients were analyzed. Fifteen patients (12.4%) had Ph-like ALL, and these patients had significantly higher leukocyte counts at diagnosis and higher levels of minimal residual disease on days 15 and 33 of induction than patients without the Ph-like subtype. There were no significant differences in sex, age, or response to prednisone at day 8 between the two groups. CRLF2 rearrangements were identified in eight patients, and ABL1 rearrangements were identified in two patients. Other genetic alterations alone or in combination were identified in 77% of patients, including deletions in cyclin dependent kinase inhibitor 2 A/B (46.2%), IKAROS family zinc finger 1 (38.3%), and paired box 5 (30.8%). CONCLUSIONS: Ph-like ALL had a 12.4% prevalence in our cohort of patients with pediatric ALL. The identification of this group of patients has importance for risk stratification and future targeted therapy.

Cost of Patients With Hemophilia A and High-Titer Inhibitors in Colombia.

BACKGROUND: In Colombia, hemophilia is considered a high-cost disease, and hemophilia A with high-titer inhibitors may be responsible for a significant economic pressure on the Colombian health system. OBJECTIVES: To estimate the direct cost of care for patients with hemophilia A with high-titer inhibitors in Colombia, from the perspective of the health system. METHODS: A cost-of-illness study was carried out using standard case methodology, which was designed based on literature review and validation by expert consensus. Scenarios were established for adults and children, including cases of prophylaxis, immune tolerance induction, bleeding, and surgery. The frequencies were taken from the official report for Colombia, issued by the High-Cost Account 2017 (reported 2018). The prices were obtained from the list of regulated medicines in the country. The cost estimate is presented with a range of values by weight (between 10 kg and 90 kg). RESULTS: The total estimated cost per year for Colombia was US $44 905 252 (between US $32 260 497 and US $58 202 393). The average cost per year calculated for a patient was US $498 947 (between US $358 450 and US $646 693). A total of 99.8% of the estimated cost was directly related to the cost of the coagulation factors and bypassing agents. CONCLUSIONS: Hemophilia A with high-titer inhibitors is a disease that generates significant pressure on the Colombian health system, mainly linked to the cost of factors and bypassing agents.

Estudio molecular de la inversión de los intrones 1 y 22 del factor VIII de la coagulación en niños con hemofilia A severa utilizando técnica de PCR de larga distancia / Molecular study in children with hemophilia A in Colombia: analysis of Intron 1 and 22 inversion using long-distance PCR technique

Resumen Introducción. La hemofilia A es una enfermedad recesiva ligada al cromosoma X, con una incidencia de 1 en 5 000 a 10 000 varones y es el trastorno hemostático congénito más frecuente en varones. En pacientes con fenotipo severo, las inversiones de los intrones 22 y 1 son las mutaciones más comunes con una prevalencia del 45% a 50% y del 1% al 5% de los pacientes, respectivamente. Objetivo. Determinar la frecuencia de la inversión de los intrones 1 y 22 del gen del factor VIII de la coagulación en menores de 18 años con hemofilia A severa en Bogotá D.C. Materiales y métodos. Estudio descriptivo y transversal. La identificación de la inversión de los intrones 1 y 22 del gen del factor VIII se realizó mediante técnicas de reacción en cadena de polimerasa de larga distancia. Resultados. Se estudiaron 30 pacientes y se encontró inversión del intrón 22 en 12 pacientes (40%) e inversión 1 en 3 pacientes, cifras similares a las observadas en otros estudios. Conclusiones. Se encontraron las inversiones de los intrones 1 y 22 en la mitad de los pacientes evaluados. Los resultados son reproducibles, por lo que constituyen una herramienta útil para la identificación de las dos mutaciones más frecuentes en hemofilia A severa.

Abstract Introduction: Hemophilia A is an X-linked recessive disease with an incidence of 1 in 5 000 to 10 000 males. It is the most common congenital hemostatic disorder in men. The inversion of introns 1 and 22 in patients with a severe phenotype is considered the most frequent abnormality, with a prevalence of 1 to 5% and 45 to 50%, respectively. Objective: To determine the frequency of introns 1 and 22 inversions in factor VIII gene in children under 18 years with severe hemophilia A in Bogotá. Materials and methods: This is a non-experimental, descriptive, transverse study. The inversions of introns 1 and 22 for factor VIII gene were identified using long-distance polymerase chain reaction techniques in pediatric patients with severe Hemophilia A treated in different centers of Bogotá, Colombia. Results: Thirty patients were analyzed. Inversion of intron 22 was found in 12 patients (40%), while inversion of intron 1 was observed in 3 patients. These findings are similar to other studies. Conclusions: Inversions of intron 22 and 1 were found in half of this group of patients. These results are reproducible and useful to identify the two most frequent mutations in severe hemophilia A patients.

Intensive chemotherapy in children with acute lymphoblastic leukemia. Interim analysis in a referral center in Colombia / Quimioterapia intensiva en niños con leucemia linfoblástica aguda. Análisis ínterin en un centro de referencia en Colombia

Abstract Background: Acute lymphoblastic leukemia is the most common cancer in children. In developed countries, overall survival rates are around 80%, while in developing countries, survival rate is much lower due to high rates of relapse, and abandonment and complications arising from the disease treatment. Objectives: To assess induction mortality, relapse and treatment abandonment. To describe the most frequent side effects of chemotherapy. To evaluate survival rates of patients and compare the findings found in this study with the existing literature. Material and methods: A retrospective cohort study was conducted on patients aged 1 to 18 with acute lymphoblastic leukemia, who received treatment under the BFM ALL IC 2009 protocol at Fundación Hospital La Misericordia (HOMI), from November 2012 to December 2014. Results: 119 patients were included. Death occurred in two cases during induction (1.67%) and in nine (7.7%) due to treatment, all of them caused by infection/sepsis and in complete remission. Six patients abandoned treatment (5%), while seven relapses occurred (5.9%). All patients experienced some type of side effect related to chemotherapy, the most frequent being febrile neutropenia (41.2%) and grade 3-4 infections (15.8%). Overall survival and event-free survival rates were 79.9% and 73.3%, respectively. Conclusions: Evaluating complications of treatment and death allows adopting measures and strategies to reduce such complications.

Resumen Introducción. La leucemia linfoblástica aguda es el cáncer más frecuente en los niños. La sobrevida en países desarrollados está alrededor de 80%, mientras que en países de bajos ingresos la tasa de supervivencia es menor debido a altas cifras de recaída, abandono de tratamiento y complicaciones relacionadas con el tratamiento. Objetivos. Hacer una evaluación de muerte en inducción relacionada con el tratamiento, las recaídas y los abandonos de tratamiento; describir las reacciones adversas más observadas relacionadas con medicamentos de quimioterapia; evaluar la sobrevida, y comparar los hallazgos con publicaciones previas. Materiales y métodos. Estudio de cohorte retrospectivo. Se incluyeron pacientes con edades entre 1 y 18 años, con diagnóstico de leucemia linfoblástica aguda tratada entre noviembre de 2012 y diciembre de 2014 en la Fundación Hospital La Misericordia de Bogotá (HOMI) y a quienes se les había aplicado tratamiento con el protocolo BFM ALL IC 2009. Resultados. Se incluyeron 119 pacientes. Se presentaron dos (1.67%) muertes en inducción y nueve (7.7%) relacionadas con tratamiento -todas por infección/sepsis y en remisión completa-, seis abandonos (5%) y siete recaídas (5.9%). Todos los pacientes presentaron algún tipo de reacción adversa relacionada con medicamentos de quimioterapia, las más frecuentes fueron neutropenia febril (41.2%) e infecciones grado 3-4 (15.8%). Las sobrevidas global y libre de evento fueron de 79.9% y 73.3%, respectivamente. Conclusiones. La evaluación de los efectos deletéreos del tratamiento y muerte durante tratamiento permiten tomar medidas para disminuir estas complicaciones.

Profilaxis con CCPa en pacientes con hemofilia A con inhibidores de alta respuesta Una estrategia alternativa al estándar de tratamiento / Prophylaxis with activated prothrombin complex concentrate in patients with hemophilia A with high response inhibitors An alternative approach to standard treatment

Introducción: la complicación más grave de los pacientes con hemofilia es el desarrollo de anticuerpos inhibidores; hasta un 30% de los pacientes con hemofilia A severa los desarrollan. Para erradicarlos, la inducción de tolerancia inmune es el tratamiento de elección; cuando persisten, los tratamientos profilácticos con agentes de puente como el concentrado de complejo de protrombina activado CCPa (FEIBA®) o rFVIIa (Novoseven®) ofrecen una alternativa terapéutica para reducir lossangrados y la artropatía hemofílica. Para evaluar la eficacia de profilaxis con CCPa se compararon los sangrados antes y después de recibir profilaxis (11-12 meses) en ocho pacientes hemofílicos con inhibidores de alta respuesta. Material y métodos: se realizó un estudio multicéntrico, se incluyeron niños y adultos con diagnóstico de hemofilia A, con título de inhibidores altos, de cuatro centros de atención en dos ciudades. Se excluyeron pacientes con hemofilia adquirida. Resultados: seis pacientes tenían hemofilia A severa y dos moderada; 7/8 pacientes tenían artropatía hemofílica. La media de edad fue 19 años (rango 7-38) y la del título de inhibidor 80 UB (rango 15-1178). La dosis de CCPa fluctuó entre 40 y 75 U/kg, dos a tres veces por semana. Las tasas anuales de sangrado global y de hemartrosis previas a profilaxis fueron (8/año y 3.1/año)y después de profilaxis durante un periodo de 11-12 meses fueron (1.08/año y 1/año); se encontró una reducción de 86 y 68% respectivamente. No hubo eventos de trombosis. El cumplimiento del esquema de tratamiento con CCPa fue mayor a 80%. Conclusiones: este es el primer reporte de casos en Colombia sobre el uso de CCPa en pacientes hemofílicos con inhibidores del factor VIII de alta respuesta. Persisten interrogantes sobre la duración o ajustes al esquema de tratamiento. (Acta Med Colomb 2015; 40:288-293).

The most serious complication of hemophilia patients is the development of inhibitory antibodies; up to 30% of patients with severe hemophilia A develop them. To eradicate these antibodies, induction of immune tolerance is the treatment of choice; when they persist, prophylactic treatment with bridge agents as activated prothrombin complex concentrate aPCC (FEIBA®) or rFVIIa (Novoseven®) offer a therapeutic alternative for reducing bleeding and hemophilic arthropathy. To evaluate the efficacy of prophylaxis with aPCC, bleeds were compared before and after receiving prophylaxis (11-12 months) in 8 hemophilia patients with high response inhibitors. Material and methods: a multicenter study was conducted in children and adults with a diagnosis of hemophilia A with high titer inhibitors in 4 attention centers in two cities. Patients with acquired haemophilia were excluded. Results: six patients had severe hemophilia A and 2 moderate; 7/8 patients had hemophilic arthropathy. The mean age was 19 years (range 7-38) and mean inhibitor titer was 80 UB (range 151178). aPCC dose ranged from 40-75 U / kg, 2-3 times a week. The overall annual rates of bleeding and hemarthrosis pre-prophylaxis were (8 / year and 3.1 / yr) and after prophylaxis during a period of 11- 12 months were (1.08 / year and 1 / year); a reduction of 86% and 68% respectively was found. There were no thrombotic events. Compliance scheme of aPCC treatment was higher than 80%. Conclusions: this is the first case report in Colombia on the use of aPCC in haemophilia patients with high responding inhibitors to factor VIII. Questions remain about the length or adjustments to the treatment schedule. (Acta Med Colomb 2015; 40:88-293).

Convergencia de los grupos armadosorganizados al margen de la ley en laminería aurífera aluvial en la subregióndel Bajo Cauca antioqueño / Convergence of illegal organized armed groups in alluvial goldmining at the Department of Antioquia’s Bajo Cauca subregion / A convergência dos grupos armados organizados à margem dalei na mineração aurífera aluvial na sub-região do Baixo Caucaem Antioquia (Colômbia)

Se tuvo como propósito describir la minería aurífera aluvialy la convergencia de los grupos armados organizados almargen de la ley en la subregión del Bajo Cauca antioqueño.Los resultados obtenidos se centran en identificar el marcoteórico, proponer un concepto y describir los rasgos característicosde esta actividad desde la perspectiva criminal. Loanterior se logró a partir de una aproximación conceptual yla representación fáctica de la información obtenida, a travésde la revisión teórica, la consulta bibliográfica y el trabajode campo, en el que se aplicaron diferentes técnicas de recolección,como la entrevista semiestructurada, el grupo focaly la observación no participante. El precedente para comenzarla indagación se centró en la ausencia de un concepto que delimitelos tipos de minería y la confusión que existe al colocar atodos los mineros ilegales, informales y criminales dentro unamisma categoría. Además, se busca suscitar una reflexión críticarespecto a los posibles riesgos y amenazas que genera laconvergencia de estos grupos en los tipos de minería, con elcontrol social y territorial, el poder, la coacción y la institucionalizaciónde actividades económicas criminales.

The purpose of this article was to describe alluvial goldmining and the convergence of the organized illegal armedgroups in the Department of Antioquia’s Bajo Caucasubregion. The results obtained are focused on identifyingthe theoretical framework, suggesting a concept, and describingthe characteristic features of this activity from thecriminal perspective. This was achieved on the basis of aconceptual approach and the factual representation ofthe information obtained through theoretical review, bibliographicconsultation and field work in which differentgathering techniques such as semistructured interviews, focusgroups and non-participant observation were applied.The precedent for starting the inquiry was focused on theabsence of a concept serving to delimit mining types andthe confusion created by placing all illegal miners, either informalor criminal, within the same category. In addition, itis intended to raise a critical reflection with respect to thepotential risks and threats that the convergence of thesegroups in these types of mining can create with social andterritorial control, power and coercive power, and the institutionalizationof criminal economic activities.

O propósito era descrever a mineração aurífera aluvial e aconvergência dos grupos armados organizados à margem dalei na sub-região do Baixo Cauca em Antioquia (Colômbia).Os resultados obtidos focam-se em identificar o marco teórico,propor um conceito e descrever as características destaatividade desde a perspetiva criminal. Esses resultados foramobtidos de uma aproximação conceptual e a representaçãofática das informações obtidas, através da revisão teórica, aconsulta bibliográfica e o trabalho de campo. Utilizaram-setécnicas diferentes de colheita, como a entrevista semiestruturada,o grupo focal e a observação não participante.O precedente para começar a investigação foi centrado naausência de um conceito que limitasse os tipos de mineraçãoe da confusão que existe ao colocar a todos o mineiros ilegais,informais e criminosos dentro de uma mesma categoria.Além, procura-se provocar uma reflexão crítica com respeitoaos riscos e às ameaças possíveis que a convergência destesgrupos gera nos tipos de minaração, com o controle social eterritorial, o poder, do coação e a institucionalização de atividadeseconômicas criminosas.

Correlación de la t(9;22), t(12;21) e hiperdiploidía de ADN con el inmunofenotipo y la tasa de proliferación de células B neoplásicas en niños con leucemia linfoblástica aguda de precursores / Correlation of the t(9;22), t(12;21), and DNA hyperdiploid content with immunophenotype and proliferative rate of leukemic B-cells of pediatric patients with B-cell acute lymphoblastic leukemia

Introducción. Del 60 al 80 % de los pacientes con leucemia linfoblástica aguda de precursores B presentan alteraciones genéticas que influyen en el pronóstico de la enfermedad y en la biología del tumor. Objetivo. Analizar distintas alteraciones genéticas en leucemia linfoblástica aguda de precursores B en niños, y su relación con el inmunofenotipo y con la tasa de proliferación, en comparación con precursores B normales. Materiales y métodos. En 44 pacientes se evaluó, por citometría de flujo, el inmunofenotipo, el contenido de ADN y la proliferación, y por RT-PCR, las traslocaciones t(9;22), t(12;21), t(4;11) y t(1;19). Mediante un análisis jerarquizado de conglomerados se identificaron los patrones inmunofenotípicos de expresión asociados a las traslocaciones, tomando como referencia precursores B normales. Resultados. La cuantificación del ADN mostró que el 21 % de los casos de leucemia linfoblástica aguda de precursores B eran hiperdiploides de índice alto y, el 47,7 %, hiperdiploides de índice bajo. La presencia de hiperdiploidía se asoció con mayor proliferación tumoral y con inmunofenotipos aberrantes, que incluyeron expresión anormal de CD10, TdT, CD38 y CD45 y un mayor tamaño de los linfoblastos. La presencia de t(9;22) y t(12;21) discrimina células normales de células tumorales con aberraciones en la expresión de CD19, CD20, CD13, CD33, CD38, CD34 y CD45. Conclusiones. El perfil de aberraciones fenotípicas detectado en conjunto con anormalidades en la proliferación tumoral, se asocia de forma significativa con hiperdiploidiía de ADN y discrimina de forma clara linfoblastos con t(9;22) y t(12;21) de los precursores B normales. La identificación de estos parámetros será de gran utilidad como herramienta para la clasificación y seguimiento de los pacientes.

Introduction: Between 60 and 80% of patients with B-cell acute lymphoblastic leukemia show genetic abnormalities which influence the prognosis of the disease and the biology of the tumor. Objective: To analyze different genetic abnormalities in acute B lymphoblastic leukemia in children, its relationship with the immunophenotype and the proliferative rate compared with normal B cell precursors. Materials and methods: We assessed immunophenotype, DNA content and proliferative rate in 44 samples by flow cytometry, and translocations t(9;22), t(12;21), t(4;11), and t(1;19) by RT-PCR. Using a hierarchical cluster analysis, we identified some immunophenotypic patterns associated to genetic abnormalities when compared with normal B cell precursors. Results: DNA quantification showed that 21% of the cases had high hyperdiploidy and 47.7% has low hyperdiploidy. The presence of hyperdiploidy was associated with increased tumor proliferation and aberrant immunophenotypes, including abnormal expression of CD10, TdT, CD38, and CD45 and an increased size of the lymphoblasts. The presence of t(9;22) and t(12;21) discriminates normal cells from tumor cells with aberrant immunophenotype in the expression of CD19, CD22, CD13, CD33, CD38, CD34, and CD45. Conclusions: The aberrant immunophenotype profile detected in neoplastic cells along with abnormalities in the proliferative rate were significantly associated with DNA hyperdiploidy and clearly distinguished lymphoblasts with t(9;22) and t(12;21) from normal B cell precursors. The identification of these parameters is useful as a tool for classification and monitoring of these patients.

[Correlation of the t(9;22), t(12;21), and DNA hyperdiploid content with immunophenotype and proliferative rate of leukemic B-cells of pediatric patients with B-cell acute lymphoblastic leukemia]. / Correlación de la t(9;22), t(12;21) e hiperdiploidía de ADN con el inmunofenotipo y la tasa de proliferación de células B neoplásicas en niños con leucemia linfoblástica aguda de precursores.

INTRODUCTION: Between 60 and 80% of patients with B-cell acute lymphoblastic leukemia show genetic abnormalities which influence the prognosis of the disease and the biology of the tumor. OBJECTIVE: To analyze different genetic abnormalities in acute B lymphoblastic leukemia in children, its relationship with the immunophenotype and the proliferative rate compared with normal B cell precursors. MATERIALS AND METHODS: We assessed immunophenotype, DNA content and proliferative rate in 44 samples by flow cytometry, and translocations t(9;22), t(12;21), t(4;11), and t(1;19) by RT-PCR. Using a hierarchical cluster analysis, we identified some immunophenotypic patterns associated to genetic abnormalities when compared with normal B cell precursors. RESULTS: DNA quantification showed that 21% of the cases had high hyperdiploidy and 47.7% has low hyperdiploidy. The presence of hyperdiploidy was associated with increased tumor proliferation and aberrant immunophenotypes, including abnormal expression of CD10, TdT, CD38, and CD45 and an increased size of the lymphoblasts. The presence of t(9;22) and t(12;21) discriminates normal cells from tumor cells with aberrant immunophenotype in the expression of CD19, CD22, CD13, CD33, CD38, CD34, and CD45. CONCLUSIONS: The aberrant immunophenotype profile detected in neoplastic cells along with abnormalities in the proliferative rate were significantly associated with DNA hyperdiploidy and clearly distinguished lymphoblasts with t(9;22) and t(12;21) from normal B cell precursors. The identification of these parameters is useful as a tool for classification and monitoring of these patients.

Genetics and congenital malformations: interpretations, attitudes and practices in suburban communities and the shamans of ecuador.

OBJECTIVES: The purpose of the present article was to evaluate how shamans and the suburban communities of Quito interpret the terminology used in genetics. METHODS: One hundred people living in 5 suburban districts of Quito were surveyed as well as 19 shamans of the Salasaca community. RESULTS: The results show that members of both groups are little informed about genetics. As knowledge about genetics is correlated to educational level, which is very poor in both groups, knowledge and understanding of genetics are either very basic or nonexistent. As for the medical practices in treating genetic alterations, the surveys show that while in very severe cases scientific medicine is sought, in most cases explanations and a cure are given by shamanic medicine. CONCLUSION: There is limited knowledge of genetics and its terminology in the study population. Shamanic and marginal health practices seem to remain prevalent in these communities due to their low costs, the personal attention the individuals receive, and the holistic point of view employed. It is important that the community councils, the medical doctors and the shamans work together to set up community programs on medical education, particularly on genetics.