JAK2, CALR, and MPL Mutation Profiles in Colombian patients with BCR-ABL Negative Myeloproliferative Neoplasms

Background: Among the chronic myeloproliferative neoplasms (MPNs) not associated with BCR-ABL mutations are polycythemia vera, primary myelofibrosis, and essential thrombocythemia. These diseases are caused by mutations in genes, such as the JAK2, MPL, and CALR genes, which participate in regulating the JAK-STAT signaling pathway. Objective: This study aimed to establish the frequencies of mutations in the JAK2, MPL, and CALR genes in a group of Colombian patients with a negative clinical diagnosis of BCR-ABL chronic myeloproliferative neoplasms. Methods: The JAK2 V617F and MPL W515K mutations and deletions or insertions in exon 9 of the CALR gene were analyzed in 52 Colombian patients with polycythemia vera, primary myelofibrosis, and essential thrombocythemia. Results: The JAK2V617F mutation was carried by 51.9% of the patients, the CALR mutation by 23%, and the MPL mutation by 3.8%; 23% were triple-negative for the mutations analyzed. In these neoplasms, 6 mutation types in CALR were identified, one of which has not been previously reported. Additionally, one patient presented a double mutation in both the CALR and JAK2 genes. Regarding the hematological results for the mutations, significant differences were found in the hemoglobin level, hematocrit level, and platelet count among the three neoplasms. Conclusion: Thus, this study demonstrates the importance of the molecular characterization of the JAK2, CALR and MPL mutations in Colombian patients (the genetic context of which remains unclear in the abovementioned neoplasms) to achieve an accurate diagnosis, a good prognosis, adequate management, and patient survival.

Antecedentes: Entre las neoplasias mieloproliferativas crónicas no asociadas con mutaciones BCR-ABL se encuentran la policitemia vera, la mielofibrosis primaria y la trombocitemia esencial. Estas enfermedades están causadas por mutaciones en genes, como los genes JAK2, MPL y CALR, que participan en la regulación de la vía de señalización JAK-STAT. Objetivo: Establecer las frecuencias de mutaciones en los genes JAK2, MPL y CALR en un grupo de pacientes colombianos con diagnóstico clínico negativo de NMP BCR-ABL. Metodos: Se analizaron las mutaciones y deleciones o inserciones JAK2 V617F y MPL W515K en el exón 9 del gen CALR en 52 pacientes colombianos con policitemia vera, mielofibrosis primaria y trombocitemia esencial. Resultados: La mutación JAK2V617F la portaban el 51.9% de los pacientes, la mutación CALR el 23.0% y la mutación MPL el 3.8%; El 23.0% fueron triple negativos para las mutaciones analizadas. En estas neoplasias se identificaron seis tipos de mutación en CALR, uno de los cuales no ha sido reportado previamente. Además, un paciente presentó una doble mutación tanto en el gen CALR como en el JAK2. En cuanto a los resultados hematológicos para las mutaciones, se encontraron diferencias significativas en el nivel de hemoglobina, el nivel de hematocrito y el recuento de plaquetas entre las tres neoplasias. Conclusiones: Así, este estudio demuestra la importancia de la caracterización molecular de las mutaciones JAK2, CALR y MPL en pacientes colombianos (cuyo contexto genético aún no está claro en las neoplasias antes mencionadas) para lograr un diagnóstico certero, un buen pronóstico, un manejo adecuado y una mejoría del paciente. supervivencia.

Oclusión intestinal por policitemia vera en una anciana / Intestinal occlusion due to polycythemia vera in an old woman

Se describe el caso clínico de una paciente de 67 años de edad con varias comorbilidades, entre ellas la policitemia vera, quien acudió al Cuerpo de Guardia del Hospital Clinicoquirúrgico Universitario Dr. Ambrosio Grillo Portuondo de Santiago de Cuba por presentar síntomas y signos de un síndrome de abdomen agudo oclusivo. Se indicó intervención quirúrgica de urgencia, que permitió confirmar el diagnóstico presuntivo de afección vascular mesentérica de tipo trombótica. La inmediatez del tratamiento quirúrgico, la reversibilidad del daño vascular sin necesidad de procedimiento de resección intestinal y la administración efectiva de anticoagulantes permitieron una evolución favorable y sin complicaciones.

The case report of a 67 years patient with several comorbidities is described, among them polycythemia vera, who went to the emergency room of Ambrosio Grillo Portuondo University Clinical Surgical Hospital in Santiago de Cuba due to symptoms and signs of a syndrome of occlusive acute abdomen. An emergency surgical intervention was indicated, that confirmed the presumptive diagnosis of mesenteric vascular thrombosis. The immediacy of the surgical treatment, the reversibility of the vascular damage without necessity of intestinal resection procedure and the effective use of anticoagulants allowed a favorable clinical course without complications.

Análisis causal integrado en la radiosinoviortesis y el tratamiento mielosupresor de la policitemia vera / Integrated causal analysis in radiosynoviorthesis and the myelosupressor treatment of polycythemia vera

Introducción: Con la matriz de riesgo se identifican las medidas de control relevantes. El análisis de modos y efectos de fallo posterga definir la efectividad de las medidas correctivas. El uso de uno solo de estos métodos limita el alcance al evaluar los riesgos y la toma de decisiones. Objetivos: Determinar la contribución individual de las causas básicas de fallo en el riesgo radiológico de la radiosinoviortesis y el tratamiento mielosupresor de la policitemia vera, a partir del modelo de la matriz y los reportes. Métodos: Se adaptó el análisis de la gestión de la calidad en radioterapia a las prácticas en estudio y la selección individual de las causas básicas más contribuyentes al riesgo radiológico. La base internacional de incidentes aportó las causas que completaron el listado de las derivadas de la aplicación del principio de Pareto. Resultados: Los subprocesos más contribuyentes al riesgo fueron, por orden de importancia, la administración del radiofármaco, su preparación y la prescripción clínica. Para estos se identificaron las etapas, modos de fallo y sus causas más importantes. Existieron causas que contribuyeron a varios modos de fallo. El incumplimiento de procedimientos, protocolos o prácticas, la falta de entrenamiento del personal y la fatiga del personal son las causas de los riesgos identificados. Conclusiones: Se caracterizó la efectividad de las medidas correctivas de las causas más contribuyentes, las que se adicionan a las derivadas de la matriz, en el plan de mejora en la radiosinoviortesis y el tratamiento mielosupresor de la policitemia vera en Cuba(AU)

Introduction: The risk matrix identifies the relevant control measures. Failure modes and effects analysis postpones defining the effectiveness of corrective measures. Using just one of these methods limits the scope when assessing risks and making decisions. Objectives: To determine the individual contribution of the basic causes of failure in the radiological risk of radiosynoviorthesis and the myelosupressor treatment of polycythemia vera, based on the matrix model and the reports. Methods: The analysis of quality management in radiotherapy was adapted to the practices under study and the individual selection of the basic causes most contributing to radiological risk. The international incident base provided the causes that completed the list of those derived from the application of the Pareto principle. Results: The sub-processes that contributed the most to risk were, in order of importance, the administration of the radiopharmaceutical, its preparation and the clinical prescription. For these, the most important, stages, failure modes and their causes were identified. There were causes that contributed to various failure modes. Non-compliance with procedures, protocols or practices, lack of staff training and staff fatigue are the causes of the identified risks. Conclusions: The effectiveness of the corrective measures of the most contributing causes, which are added to those derived from the matrix, was characterized in the improvement plan in radiosynoviorthesis and myelosupressor treatment of polycythemia vera in Cuba(AU)

Calidad de vida en pacientes con neoplasias mieloproliferativas crónicas Filadélfia negativas / Quality of life in patients with Philadelphia negative chronic myeloproliferative neoplasms

Resumen Introducción: la carga sintomática de pacientes con neoplasias mieloproliferativas crónicas Filadélfia negativas (NMC-PhN) afecta la calidad de vida (CV). Existen escalas para evaluar la magnitud de los síntomas, una de ellas, MPN-SAF-10. En nuestra región existe escasa información sobre CV de pacientes con NMC-PhN. Objetivos: estimar el puntaje de calidad de vida con la escala MPN-SAF-10 en pacientes con NMC-PhN atendidos en el Hospital de San José (Bogotá, Colombia) y explorar asociaciones entre el tiempo de tratamiento, carga de complicaciones y el efecto en la CV. Material y métodos: estudio de corte transversal analítico para evaluar CV basada en carga sintomática de pacientes con NMC-PhN del Hospital de San José (Bogotá, Colombia). Se realizó análisis descriptivo y estratificado de calidad de vida, tratamiento citorreductor y de diferentes complicaciones, así como pruebas de asociación de los puntajes de riesgo de cada enfermedad con sus respectivos puntajes de CV. Resultados: en 64 pacientes la escala MPN-SAF-10 documentó medianas de puntajes globales de CV de 3 (RIC 1-6), MPN-SAF-10 de 20 (RIC 8-32). Un 49% de los pacientes tuvo algún grado de alteración (30% moderada y 19% severa), sin diferencias entre las tres enfermedades. Los puntajes de CV no variaron entre las NMC-PhN. El tratamiento y duración del mismo no se correlacionaron con la escala de MPN-SAF-10 (hidroxiúrea r: - 0.27; ruxolitinib r: 0.12). Conclusiones: en pacientes con NMC-PhN, la evaluación de CV con la escala MPN-SAF-10 evidencia algún grado de afectación a pesar del tratamiento; ésta es útil para objetivar dicha afectación y debe implementarse en la práctica clínica. (Acta Med Colomb 2019; 44: 82-90).

Abstract Introduction: the symptomatic burden of patients with Philadelphia negative chronic myelopro liferative neoplasms (NMC-PhN) affects the quality of life (QL). There are scales to evaluate the magnitude of the symptoms; one of them, MPN-SAF-10. In our region there is scarce information on QL of patients with NMC-PhN. Objectives: To estimate the quality of life score with the MPN-SAF-10 scale in patients with NMC-PhN treated at Hospital de San José (Bogotá, Colombia) and to explore associations between treatment time, complication load and the effect on the QL. Material and methods: Analytical cross-sectional study to evaluate QL based on symptomatic load of patients with NMC-PhN from Hospital de San José (Bogotá, Colombia). A descriptive and stratified analysis of quality of life, cytoreductive treatment and different complications was carried out, as well as association tests of the risk scores of each disease with their respective QL scores. Results: in 64 patients the MPN-SAF-10 scale documented medians of global QL scores of 3 (RIC 1-6), MPN-SAF-10 of 20 (RIC 8-32). 49% of the patients had some degree of alteration (30% moderate and 19% severe), without differences between the three diseases. The QL scores did not vary between the NMC-PhN. The treatment and its duration did not correlate with the MPN-SAF-10 scale (Hydroxyurea r: - 0.27, Ruxolitinib r: 0.12). Conclusions: in patients with NMC-PhN, the evaluation of QL with the MPN-SAF-10 scale shows some degree of affectation despite the treatment; this is useful to objectify this affectation and should be implemented in clinical practice. (Acta Med Colomb 2019; 44: 82-90).

Evaluación del riesgo radiológico en la radiosinoviortesis y el tratamiento mielosupresor de la policitemia vera / Radiological risk assessment in radiosynoviorthesis and the myelosupressor treatment of polycythemia vera

Introducción: La aplicación del método de la matriz de riesgo para la evaluación del riesgo radiológico en la medicina permite identificar de manera proactiva debilidades en las etapas del proceso y hacer un plan de acciones de mejora para la seguridad y calidad. Objetivo: Evaluar los riesgos radiológicos de la radiosinoviortesis y el tratamiento mielosupresor con Fósforo-32 de la policitemia vera. Método: Se utilizó el método de matriz de riesgo y se realizó el análisis y tratamiento de los riesgos radiológicos por medio del código cubano SECURE-MR-FMEA 3.0. Resultados: El 17 por ciento del riesgo alto se eliminó con las medidas adicionales adoptadas; predominaron las consecuencias medias para los trabajadores y el público, 30 por ciento y el 14 por ciento, respectivamente. Las defensas más importantes fueron: levantamiento radiológico inicial de las áreas del departamento; revisión independiente del proyecto con las regulaciones de seguridad aplicables; inspección de trabajos de construcción civil y montaje de equipos antes de iniciar la operación del departamento; capacitación de los médicos nucleares en los tratamientos; existencia de protocolos de tratamiento; análisis de lecciones aprendidas de incidentes radiológicos; levantamiento radiológico periódico de las áreas del servicio y procedimiento de emergencia para reducir la dosis en órganos críticos en caso de administración errónea de radiofármacos. Se creó una base de datos de incidentes utilizada como referencia para el modelo utilizado. El factor humano fue la causa mayor de los sucesos radiológicos analizados (88 por ciento). Conclusiones: Estos resultados facilitan la toma de decisiones para el mejor desempeño de la radiosinoviortesis y el tratamiento de la policitemia vera con Fósforo-32 en Cuba. Se sugiere elaborar el plan de mejora de la seguridad con especial atención a las operaciones de administración del radiofármaco en ambos casos.(AU)

Introduction: The application of risk matrix for ionizing radiation medicine allow identify in proactive way the weakness of the process' step, which implies in the design of safety and quality improvement plan for this. Method: Risk matrix method applied for radiosynoviorthesis and the myelosupressor treatment with Phosphorus-32 of polycythemia vera. The Cuban code SECURE-MR-FMEA 3.0 is used. Results: It was eliminated the 17 percent of the high risk with additional measures, and the medium consequences for workers and public are 30 percent and 14 percent, respectively. The most important identified safety measures were the initial radiological monitoring from different nuclear medicine department areas; the project revision based on the applicable safety regulations; a survey of civil construction works and equipment assembly before work began; training of nuclear medicine doctors in related aspects of nuclear medicine treatments; existence of treatment protocols; the analysis of learned lessons from radiological incidents; the periodical radiological monitoring from different services areas and the emergency procedure for the cases of mistake in the radiopharmaceuticals administration. Human factor was the major cause in analyzed radiological events (88 percent). Conclusions: These results facilitate taking decisions for the best performance of radiosynoviorthesis and the myelosupressor treatment with Phosphorus-32 of polycythemia vera in Cuba. It is recommended to elaborate the safety improvement plan from these and focussing in the radiopharmaceutical administration operations in both cases.(AU)

Policitemia vera: Presentación clínica, diagnóstico y nuevos abordajes teraPéuticos / Polycythemia Vera: clinical presentation, diagnosis and new therapeutic approaches

Introducción: los desórdenes mieloproliferativos como la Policitemia vera (PV) pertenecientes al grupo clásico filadelfia negativo, son un área de la hematología que requiere un acercamiento de mayor profundidad, de modo que sea posible ofrecer un abordaje clínico, diagnóstico y terapéutico de carácter amplio, pertinente y actualizado.Así será factible ofrecer alternativas a individuos que no responden a un tratamiento convencional. Objetivo: recoger los elementos clínicos característicos o de mayor importancia de la Policitemia vera y realizar una contextualización sobre las opciones terapéuticas existentes o disponibles y las nuevas alternativas en desarrollo, desde diferentes disciplinas médicas básicas como la biología molecular y el área de la inmunología. Materiales y métodos: se realizó durante el segundo semestre de 2017 y el primer trimestre de 2018 una revisión exhaustiva de material bibliográfico existente sobre la Policitemia vera, su fisiopatología, enfoque terapéutico actual y las nuevas alternativas médicas disponibles para su tratamiento, todo lo anterior en la base de datos de la Universidad Pontificia Bolivariana, utilizando motores de búsqueda como lo son PubMed, Clinical Key, SciELO y Science Direct. Conclusión: es de vital importancia el estudio y la comprensión de la fisiopatología de la Policitemia vera para llegar, en un futuro, a la instauración de nuevas alternativas terapéuticas para los pacientes que la padecen y no responden a terapias tradicionales, pues aún no existe cura para esta condición hematológica y actualmente su enfoque terapéutico se centra principalmente, en controlar, mitigar y prevenir las complicaciones asociadas a la misma..(AU)

Introduction: myeloproliferative disorders such as Polycythemia vera (PV) belonging to the classic Philadelphian negative group, are an area of internal medicine and hematology that requires a closer look, in order to offer a clinical, diagnostic and therapeutic approach of a broad, pertinent and updated nature. Thus it would be feasibleto offer alternatives to individuals who do not respond or do not have an indication to apply a conventional treatment. Objective: to collect the characteristic or most important clinical elements of the Polycythemia Vera and to contextualize the existing or available therapeutic options and the new alternatives in development, from different basic medical disciplines such as molecular biology and the area of immunology. Materials and methods: an exhaustive review of existing bibliographic material on Polycythemia Vera, its physiopathology, current therapeutic approach and the new medical alternatives available for its treatment, was carried out during the second semester of 2017 and the first quarter of 2018. This was made under the license of Universidad Pontificia Bolivarina database, using search engines such as PubMed, Clinical Key, SciELO and Science Direct. Conclusion: the study and understanding of the pathophysiology of Polycythemia Vera is of vital importance to reach the establishment of new therapeutic alternatives for patients who suffer it and do not respond to traditional therapies, as there is still no cure for this hematological condition and currently, its therapeutic approach is mainly focused on controlling, mitigating and preventing complications associated with it..(AU)

Trombosis espleno-portal no cirrótica, no tumoral y policitemia vera: una asociación poco frecuente / Non-cirrhotic Splenic-portal Thrombosis, non-tumoral Polycitemia Vera: an Infrequent Association

La policitemia vera se incluye dentro del grupo de las neoplasias mieloproliferativas crónicas. Tiene una incidencia inferior a 2,5 de cada 100 000 personas. Las formas trombóticas de presentación representan solo entre el 10-15 % de casos. La trombosis del eje espleno-portal no asociada a cirrosis o neoplasias tiene una prevalencia inferior a 5 por cada 10000 habitantes, entre el 17-53 % se asocian a algún tipo de síndrome mieloproliferativo primario. Se presenta el caso de una paciente de 70 años de edad que acudió debido a dolor abdominal de 15 días de evolución. El ultrasonido abdominal mostró en el hígado un marcado aumento de la ecogenicidad hacia las paredes de las estructuras vasculares, compatible con extensas áreas de trombosis del eje espleno-portal, corroborado luego por tomografía por contraste. La biopsia de médula ósea concluyó una hiperplasia de las tres series, la determinación de la mutación JAK2V617F resultó positiva. La baja incidencia de la policitemia vera y la forma inusual de mostrarse como una trombosis del sistema espleno-portal motivó a la presentación de este caso.

Polycitemia vera is included in the group chronic mieloproliferative neoplasias. It has an incidence below 2.5 every 100 000 people. The thrombotic forms represent only between 10.15 % of the cases. Splenic-portal thrombosis not associated to cirrhosis or neoplasias have an incidence below 5 every 10000 inhabitants, between 17-53 % are associated to any type of primary mieloproliferative syndrome. A case of a 70 year old patient who came to the doctor complainig of an abdominal pain of 15 day duration. Abdominal ultrasound showed a markedly ecogenic liver towards vascular structures, compatible with extensive thrombotic areas of the splenic-portal axis, corroborated later by contrast tomography. Bone morrow biopsy concluded a three series hyperplasia, the determination of JAK2V617F mutation was positive. The low incidence of polycitemia vera and its unusual way of presenting as thromobosis of splenic-portal system motivated the presentation of this case.

Perfil dos pacientes com Neoplasia Mieloproliferativa Cromossomo Philadelfia Negativo na Unidade de Alta Complexidade do Hospital São José em Criciúma/SC no período de 2008 a 2015 / Profile of patients with Philadelfia Negative Myeloproliferative neoplasm in São José Hospital's High Complexity Oncologic Unit in Criciúma/SC in the 2008 to 2015 period

O presente artigo tem como objetivo conhecer o perfil dos pacientes portadores de Neoplasias Mieloproliferativas Crônicas (NMPC) cromossomo Philadelfia (Ph) negativo clássicas que compreendem as entidades Policitemia Vera (PV), Trombocitose Essencial (TE) e Mielofibrose Primária (MP) na Unidade de Alta Complexidade Oncológica no período de 2008 a 2015. Trata-se de um estudo observacional, descritivo, retrospectivo e de abordagem quantitativa em que foram avaliados 77 prontuários de pacientes com diagnóstico de Policitemia Vera, Trombocitose Essencial e Mielofibrose Primária. Os resultados demonstraram que 54,5% (n=42) tinham diagnóstico de Trombocitose Essencial, 27,3% (n=21) de Policitemia Vera e 18,2% (n=14) de Mielofibrose Primária. A idade média ao diagnóstico girou em torno da sexta e sétima década de vida. As principais alterações laboratoriais encontradas na Policitemia Vera e na Mielofibrose Primária foram a hemoglobina, a qual tem como média 16,05(±2,89) e 9,98(±3,31) respectivamente, e o hematócrito com média de 51,48(±8,69) e 30,70 (±10,14) nesta ordem; já na Trombocitose Essencial as plaquetas foram a principal alteração, com média de 1.728.000(±447136,4). Em relação aos eventos tromboembólicos, 28,6% dos pacientes com PV, 21,4% com TE e 14,3% com MI apresentaram algum tipo de evento (IAM, TVP ou AVC).A mutação JAK2 foi positiva principalmente em portadores de Policitemia Vera, 76,2% (n=16). Dos pacientes portadores de Policitemia Vera 85,7% (n=18), 95,2% (n=40) de Trombocitose Essencial e 57,1% (n=8) de MP permanecem vivos e em tratamento. Concluise que o sexo feminino foi o mais acometido, a idade média ao diagnóstico foi entre a sexta e sétima década de vida, sendo a Trombocitose Essencial a doença mais incidente.

The present article aims to know the profile of patients with classic Philadelphia-negative Chronic Myeloproliferative Neoplasms (CMPNs) who comprehend the entities Polycythemia Vera (PV), Essential Thrombocytosis (ET) and Primary Myelofibrosis (PM) at the High Complexity Oncology Unit between 2008 and 2015. This is an observational, descriptive, retrospective and of quantitative approach study in which 77 diagnosed with Polycythemia Vera, Essential Thrombocytosis and Primary Myelofibrosis patients' charts were analyzed. Results demonstrated that 54,5% (n=42) were diagnosed with Essential Thrombocytosis, 27,3% (n=21) with Polycythemia Vera and 18,2% (n=14) with Primay Myelofibrosis. The mean age at diagnosis was around the sixth and seventh decade of life. The main laboratorial alterations found in Polycythemia Vera and Primary Myelofibrosis were hemoglobin, which has mean 16,05(±2,89) and 9,98(±3,31), respectively, and hematocrit, with mean 51,48(±8,69) and 30,70 (±10,14), in that order; in Essential Thrombocytosis, platelets were the main alteration, with mean 1.728.000(±447136,4). The frequency of thrombotic event was 64,3%, most of which had the diagnosis of Essential Thrombocytosis. The JAK2 mutation was positive mainly on patients with Polycythemia Vera, 76,2% (n=16). 85,7% (n=18) Polycythemia Vera, 95,2% (n=40) Essential Thrombocytosis and 57,1% (n=8) Primary Myelofibrosis patients remain alive and on treatment. It was concluded that females were the most affected, that the mean age at diagnosis was between the sixth and seventh decade of life and that Essential Thrombocytosis was the most incident disease.

Descripción de las caracteristicas clínicas de las neoplasias mieloproliferativas crónicas (NMPC). Primer informe del registro colombiano de NMPC / Description of the clinical characteristics of chronic myeloproliferative neoplasms (MPNs). First report of the colombian registry of MPNs

Resumen Introducción y objetivos: las neoplasias mieloproliferativas crónicas (NMPC) son relativamente raras, con incidencias que varían entre 0.47-1.03/100 000 habitantes. Se presenta el primer informe del trabajo del registro colombiano de NMPC, cuyo objetivo es describir las características clínicas de estos pacientes en nuestro país. Material y métodos: estudio descriptivo observacional, multicéntrico, retrospectivo y prospectivo en ocho centros del país, de abril de 2013 a diciembre de 2014. Las variables cualitativas se presentan con frecuencias absolutas y relativas; y las cuantitativas se resumen en medidas de tendencia central y dispersión. Resultados: once centros fueron aprobados, ocho ingresaron pacientes. En los primeros 179 casos reportados, 50% eran hombres, la edad promedio al diagnóstico 58.7 años (rango 19-92). Noventa y tres muestran trombocitemia esencial (TE); 55, policitemia vera (PV); y 31, mielofibrosis (MF). El 41% tenía esplenomegalia al diagnóstico; el 20% tuvo complicaciones trombóticas; y 12.85%, sangrado. Sólo en 57.5% se realizó JAK; de ellos, en 53.5% fue positivo, en especial sólo 60% de las PV. El 8% de los casos no tenía estudio de médula ósea, el 29.3% tiene algún grado de fibrosis. El hallazgo más frecuente fue hiperplasia megacariocítica en 59.78%. Más de 50% de pacientes estaban sintomáticos al diagnóstico. Sólo el 11% no recibió tratamiento farmacológico; los más frecuentes fueron hidroxiurea en 149 casos y ASA en 79. Con promedio de seguimiento de 52.6 meses; el 97.21% de los pacientes están vivos. Conclusiones: los hallazgos sugieren que algunas características de las NMPC podrían ser diferentes a lo reportado en otras series, lo que valida la importancia del esfuerzo de recoger información local.

Abstract Introduction and objectives: chronic MPNs are relatively rare, with incidences varying between 0.47-1.03 / 100 000 inhabitants. The first report of the work of the Colombian registry of chronic MPNs, whose objective is to describe the clinical characteristics of these patients in our country, is presented. Materials and methods: descriptive observational, multicenter, retrospective and prospective study in eight centers of the country, from April 2013 to December 2014. Qualitative variables are presented with absolute and relative frequencies, and the quantitative ones are summarized in measures of central tendency and dispersion. Results: eleven centers were approved; 8 admitted patients. In the first 179 cases reported, 50% were men; the average age at diagnosis was 58.7 years (range 19-92). Ninety-three present essential thrombocythemia (ET); 55, polycythemia vera (PV); and 31, myelofibrosis (MF). 41% had splenomegaly at diagnosis; 20% had thrombotic complications, and 12.85%, bleeding. JAK was performed in only 57.5%. Of them, in 53.5% was positive, especially in only 60% of the PV. 8% of the cases had no bone marrow study; 29.3% had some degree of fibrosis. The most frequent finding was megakaryocytic hyperplasia in 59.78%. More than 50% of patients were symptomatic at diagnosis. Only 11% did not receive pharmacological treatment, being the most frequent hydroxyurea in 149 cases and ASA in 79, with an average follow-up of 52.6 months. 97.21% of patients are alive. Conclusions: the findings suggest that some characteristics of chronic MPNs could be different from those reported in other series, which validates the importance of the effort to collect local information.

Policitemia vera y trombofilia / Polycythemia vera and thrombophilia

La policitemia vera es un síndrome mieloproliferativo crónico resultado de la proliferación anormal de la célula madre pluripotente, que da lugar a una hematopoyesis clonal con predominio de hiperplasia eritroide sobre el resto de las líneas hematopoyéticas. Como en otros síndromes mieloproliferativos, se observan complicaciones trombóticas y hemorrágicas, que son causa de morbimortalidad en este grupo de pacientes. La asociación de policitemia vera y estados trombofílicos no es frecuente y cuando aparece aumenta la tendencia a la formación de trombos. Por otro lado, las trombofilias son un grupo heterogéneo de condiciones asociadas a un mayor riesgo de aparición de trombosis arteriales y venosas en las que existen un grupo de factores de riesgo. En este trabajo se presenta un paciente masculino de 50 años con el diagnóstico de policitemia vera de 12 años de evolución, que ha llevado tratamiento con hidroxiurea e interferón alfa recombinante. Durante los dos últimos años comenzó a presentar cuadros de hemorragias recurrentes en ambos miembros inferiores y superiores y además presentó una trombosis venosa profunda por lo que se le realizaron estudios de hemostasia y se detectó una disminución significativa de la actividad de las proteínas C y S, asociación descrita de forma infrecuente, concomitante con alteraciones de la función plaquetaria. Con la presentación de este caso se demuestra la importancia de pesquisar la presencia de estados trombofílicos asociados a procesos hematológicos malignos...

Polycythemia vera is a chronic myeloproliferative syndrome resulting from abnormal proliferation of the pluripotent stem cell, giving rise to a clonal hematopoiesis, with predominant erythroid hyperplasia over other hematopoietic lines. In this as in other myeloproliferative syndromes thrombotic and hemorrhagic complications are observed, which are cause of morbidity and mortality in this group of patients. The association of polycythemia vera and thrombophilic states is infrequent and when it appears tendency of thrombus formation is increased. Furthermore, thrombophilias are a heterogeneous group of conditions associated to an increased risk of arterial and venous thrombosis where a group of risk factors exists. We present a 50 year-old male patient with a diagnosis of polycythemia vera 12 years ago, who has been treated with hydroxyurea and recombinant alpha interferon. During the last two years he started suffering recurrent bleeding episodes in both upper and lower limbs also presenting a deep vein thrombosis. Hemostasis studies were performed and a significant reduction in the activity of proteins C and S were detected, which association is infrequently described, concomitant with alterations of platelet function. This case demonstrates the importance of searching for the presence of thrombophilic states associated to hematological malignancies...

Características clínicas y paraclínicas de las neoplasias mieloproliferativas crónicas cromosoma Filadelfia negativas / Clinical and paraclinical characteristics of chronic myeloproliferative neoplasms Philadelphia chromosome negative

Objetivo: describir las características clínicas y paraclínicas de los pacientes con neoplasias mieloproliferativas crónicas cromosoma Filadelfia negativa valorados en la consulta externa de hematología del Hospital de San José desde enero de 2005 hasta mayo de 2010. Material y métodos: estudio de serie de casos en el que se incluyeron los pacientes diagnosticados con neoplasias mieloproliferativas crónicas cromosoma Filadelfia negativas. Resultados: un total de 34 pacientes con neoplasias mieloproliferativas (NM) cromosomas Filadelfia negativas fueron identificados. El principal diagnóstico encontrado fue de trombocitemia esencial en 17 pacientes (50%), policitemia Vera Rubra en seis pacientes (17.6%), neoplasia mieloproliferativa asociadas a eosinofilia en seis pacientes (17.6%), mielofibrosis primaria en tres pacientes (8.8%) Y neoplasias mieloproliferativas no clasificables en dos pacientes (5.8%). La mediana de edad fue de 63.5 años (RIQ: 51 a 74) y 21 pacientes (61.7%) correspondían al sexo femenino. Dos pacientes del número total progresaron a mielofibrosis (5.8%), ningún paciente desarrolló leucemia aguda. Veintisiete pacientes (79.4%) recibieron hidroxiurea como manejo farmacológico principal. Catorce pacientes presentaron complicaciones (41.1%), de los cuales cinco fueron episodios trombóticos (14.7%), tres episodios hemorrágicos (8.8%), tres pacientes presentaron hipertensión pulmonar (8.8%) y un paciente desarrolló vértigo (2.9%). Finalmente el tiempo desde el diagnóstico hasta la aparición de complicaciones fue de 19.55 meses (RIQ: 8-50.23) Conclusiones: las neoplasias mieloproliferativas crónicas cromosoma Filadelfia negativas son patologías muy raras, el mayor número se agrupan en trombocitemia esencial, policitemia Vera y neoplasias asociadas a eosinofilia. La principal opción terapéutica es la hidroxiurea con una baja toxicidad. No es posible analizar la presencia de las mutaciones tirosina-kinasas (JAK2 V617F, PGDFRA, ...

Objective: describe features clinics and patients with chronic myeloproliferative neoplasm chromosome Philadelphia negative valued at the Hospital San Jose hematology outpatient from January 2005 until May 2010. Materials and methods: Studio series case included patients diagnosed with chronic myeloproliferative neoplasm chromosome Philadelphia negative. Results: A total of 34 chronic myeloproliferative neoplasm chromosome Philadelphia negative patients were identified. The main found diagnosis was Essential Thrombocythemia in 17 patients (50%), Polycythemia Rubra Vera in six patients (17.6%), chronic myeloproliferative neoplasm associated with eosinophilia in six patients (17.6%), myelofibrosis primary in three patients (8.8%) and chronic myeloproliferative neoplasm not classifiable in two patients (5.8%). The median age was 63.5 years (R: 51-74) and 21 patients (61.7%) were female. Two patients in the total number progressed Myelofibrosis (5.8%), no patient acute leukemia development. Twenty-seven patients (79.4%) received Hydroxyurea as main pharmacological management. Fourteen patients presented complications (41.1%), of which fve were thrombotic episodes (14.7%), three bleeding episodes (8.8%), three patients had pulmonary hypertension (8.8%) and one patient developed Vertigo (2.9%). Finally the time since diagnosis until the occurrence of complications was 19.55 months (R: 8-50.23). Conclusión: neoplasm Mieloproliferativas Chronicles are very rare pathologies, as many are grouped into essential Thrombocythemia, Polycythemia Vera and neoplasms associated with Eosinophilia. The main therapeutic option is with a low toxicity Hydroxyurea. It is not possible to analyze the presence of mutations tyrosine kinases (JAK2 V617F PGDFRA PDGFRB, FGFR1) because they are tools of recent entry to the diagnostic arsenal and whose impact as a prognostic factor or therapeutic is in studio. Thrombotic venous events are frequently found in these patients. ...

Hemorragia digestiva alta como complicación de un síndrome de Budd-Chiari: reporte de un caso / High digestive hemorrhage resulting from a Budd-Chiari syndrome complication: case report

INTRODUCCIÓN: El Síndrome de Budd-Chiari es una obstrucción del drenaje venoso hepático. Las principales etiologías son los síndromes mieloproliferativos y anti-fosfolípido. La clínica que predomina deriva insuficiencia hepática crónica igual que sus complicaciones. El diagnóstico es mediante imágenes o biopsia hepática. El tratamiento va a depender de la causa y tiene una supervivencia de 75 por ciento a diez años. PRESENTACIÓN DEL CASO Mujer de 26 años con antecedentes de Policitemia Vera, Síndrome de Budd-Chiari y aborto espontáneo secundario a trombosis placentaria, consulta en Servicio de Urgencia del Hospital San Juan de Dios de San Fernando por vómitos rojizos asociados a melena. A su ingreso se plantearon los siguientes diagnósticos: hemorragia digestiva alta, anemia severa, anasarca, síndrome de Budd-Chiari, Policitemia Vera e insuficiencia hepática crónica; además de Child-Pugh C. La paciente se hospitaliza en Unidad de Cuidados Intermedios con tratamiento en base a suero fisiológico, transfusiones sanguíneas, omeprazol, vitamina K y furosemida. Endoscopia digestiva alta revela signos de hipertensión portal y várices esofágicas medianas con signo rojo presente. Luego de ocho días de hospitalización cede la hemorragia digestiva y se decide dar el alta, con control en siete días. DISCUSIÓN: El sangrado gastrointestinal es una complicación que alcanza un 10 por ciento a 15 por ciento en pacientes con síndrome de Budd-Chiari, y puede ocurrir en los que están recibiendo terapia anticoagulante, así como en aquellos con hipertensión portal secundaria a insuficiencia hepática crónica.

INTRODUCTION: Budd-Chiari syndrome is an obstruction of hepatic venous drainage. The main causes are myeloproliferative and anti-phospholipid syndromes. The predominant clinical results are from chronic liver failure as well as its complications. Diagnosis is by imaging or liver biopsy. Treatment will depend on the cause and have a survival of 75 percent at ten years. CASE REPORT: A 26 year old woman with history of polycythemia vera, Budd-Chiari syndrome and spontaneous abortion secondary to placental thrombosis, consulted in the Emergency Service in Hospital San Juan de Dios of San Fernando because of red vomits associated with melena. On admission were raised the following diagnoses: Upper gastrointestinal tract hemorrhage, severe anemia, anasarca, Budd Chiari Syndrome, Polycythemia Vera and Chronic Liver failure; Child-Pugh C. The patient was hospitalized on intermediate care unit with treatment based on physiological saline, blood transfusions, omeprazole, vitamin K and furosemide. Upper gastrointestinal endoscopy revealed signs of portal hypertension and esophageal medium varices with red sign. After eight days hospitalized, gastrointestinal bleeding stops, the patient is discharged and control is decided in seven more days. DISCUSSION: Gastrointestinal bleeding is a complication that achieves 10 percent to 15 percent in patients with Budd-Chiari syndrome, and can occur in the ones who are receiving anticoagulant therapy, as well in those with portal hypertension secondary to chronic liver failure.

Efeitos colaterais cutâneos após uso prolongado de hidroxiuréia na Policitemia Vera / Cutaneous effects after prolongaded use of hydroxyurea in Polycythemia Vera

A hidroxiureia é um derivado hidroxilado da ureia utilizado em diversas desordens hematológicas. Inúmeras alterações cutâneas, porém raras, são relatadas após seu uso prolongado. A patogênese das mesmas não está bem esclarecida, porém, sugere-se que a droga tenha uma ação tóxica direta sobre a pele. Descrevemos um homem de 75 anos, branco, com diagnóstico de Policitemia Vera que, ao longo de 11 anos de tratamento com hidroxiureia, evoluiu com várias lesões cutâneas: hiperpigmentação da pele, lesões atróficas em antebraços, melanoníquia longitudinal das 20 unhas, úlcera em antebraço direito, xerose cutânea, ictiose em pernas e carcinoma espinocelular no pavilhão auricular direito. Até o momento, os relatos na literatura descrevem pouca diversidade de lesões nos pacientes acometidos.

Hydroxyurea is an hydroxylated urea derivative used in many myeloproliferative disorders. Many, but unusual cutaneous disorders are related after its prolonged use. Their pathogenesis is not clear, but it is suggested that there is direct toxicity of the drug on the skin. We described a white, 75-year old man with diagnosis of Polycythemia Vera that in 11 years of treatment developed many cutaneous lesions: skin hyperpigmentation, atrophic lesions on forearms, longitudinal melanonychia of 20 nails, right forearm ulcer, cutaneous xerosis, ichthyosis and auricular spinocellular carcinoma. At this moment, the literature reports describe little diversity of lesions in affected patients.

Policitemia Vera. Experiencias en el diagnóstico y tratamiento en el Instituto de Hematología e Inmunología / Polycythemia vera: Experiences in diagnosis and treatment in the Institute of Hematology and Immunology

La policitemia Vera se encuentra entre las neoplasias mieloides según la clasificación más reciente de la Organización Mundial de la Salud (OMS). Sus criterios diagnósticos han tenido variaciones en los últimos años y en este trabajo se realiza un análisis de estos criterios, así como de la respuesta a los tratamientos empleados en 349 pacientes atendidos en el Instituto de Hematología e Inmunología en los últimos 40 años. Se sugiere, dada su factibilidad y eficacia, continuar utilizando por el momento la clasificación OMS del 2001, y de acuerdo con la experiencia acumulada, se propone el tratamiento con medicamentos de primera y segunda líneas según la edad y las características clínicas de cada enfermo

The Polycythemia vera is located among the myeloid neoplasms according to the more recent classification of the HWO. Its diagnostic criteria have underwent variations in past years and in present paper authors made an analysis of such criteria, as well as of the response to treatments applied in 349 patients seen in the Institute of Hematology and Immunology during the past 40 years. Due to feasibility and effectiveness, for the moment, is has been suggested to carry on with the use of the classification of WHO of 2001, and according to the experience gained, it is proposed the treatment with first and second line drugs by age and the clinical features of each patient

Deregulated expression of A1, Bcl-2, Bcl-xL, and Mcl-1 antiapoptotic proteins and Bid, Bad, and Bax proapoptotic genes in polycythemia vera patients

Apoptosis deregulation might have a role in the pathophysiology of polycythemia vera (PV). This study evaluated Bcl-2 molecule expression in CD34+ cells and leukocytes in 12 PV patients. Gene expression was investigated by real time PCR using SybrGreen Quantitect kit and protein expression was evaluated by western-blotting. JAK2 V617F mutation was detected according to Baxter et al (2005). CD34+ cells from PV patients presented higher levels of A1 and Mcl-1 expression (median: 22.6 and 5.2, respectively) in comparison with controls (0.9 and 0.5, p=0.004 and p=0.020); while Bcl-2 and Bcl-xL expression decreased in PV patients (0.18 and 1.19) compared with controls (1.39 and 2.01, p=0.006 and p=0.020). CD34+ cells in PV patients showed an elevated Bid expression (14.4) in comparison with healthy subjects (1.0; p=0.002). Patients' leukocytes showed an A1 augmentation (7.41, p=0.001) and a reduced expression of Bax (0.19; p=0.040) and Bad (0.2; p=0.030). There was no correlation between JAK2 V617F allele burden and molecular expression. PV patients showed alterations in Bcl-2 members' expression, which may interfere with control of apoptotic machinery and contribute to disease pathogenesis.

A desregulação da apoptose parece participar da fisiopatologia da policitemia vera (PV). Este estudo avaliou a expressão das moléculas da família Bcl-2 em células hematopoéticas CD34 + e leucócitos de 12 pacientes com PV. Foram realizados: a quantificação da expressão gênica por PCR em tempo real utilizando kit Sybrgreen Quantitect, avaliação da expressão de proteínas por western-blot e detecção da mutação JAK2 V617F segundo Baxter et al. (2005). Células CD34 + dos pacientes com PV apresentaram maior expressão de A1 e Mcl-1 (mediana: 22,6 e 5,2, respectivamente) em comparação com controles (0,9 e 0,5, p = 0,004 e p = 0,020) e expressão de Bcl-2 e Bcl-xL diminuída nestes pacientes (0,18 e 1,19) em relação aos controles (1,39 e 2,01, p = 0,006 e p = 0,020). Células CD34 + dos pacientes com PV mostraram expressão elevada de bid (14,4) em comparação aos controles (1,0; p = 0,002). Leucócitos dos pacientes mostraram aumento de A1 (7,41, p = 0,001) e expressão reduzida do Bax (0,19; p = 0,04) e Bad (0,2; p = 0,030). Não houve correlação entre percentagem de alelos JAK2 V617F mutados e expressão molecular. Pacientes com PV apresentaram alterações na expressão de moléculas Bcl-2 que podem interferir no controle da apoptose e contribuir para a patogênese da doença.

Neoplasias mieloproliferativas: revisão dos critérios diagnósticos e dos aspectos clínicos / Myeloproliferative neoplasms: a review of diagnostic criteria and clinical aspects

As síndromes mieloproliferativas crônicas, atualmente denominadas neoplasias mieloproliferativas (NMP), de acordo com a 4ª. edição da classificação da Organização Mundial da Saúde (OMS), são doenças clonais de célula-tronco hematopoética, nas quais há a proliferação aumentada de uma ou mais das séries mieloides (granulocítica, eritrocítica, megacariocítica ou mastocítica) com maturação eficaz. A progressão de todas é caracterizada por fibrose medular ou transformação leucêmica. Pela classificação da OMS, as NMP incluem: leucemia mieloide crônica (LMC), policitemia vera (PV), mielofibrose idiopática crônica (MF), trombocitemia essencial (TE), leucemia neutrofílica crônica (LNC), leucemia eosinofílica crônica não especificada(LEC), mastocitose (M) e neoplasia mieloproliferativa inclassificável (NMI). É interessante notar que tanto a LMC (BCR/ABL1) como PV, MF e TE (JAK2 V617F e éxon 12, MPLW515L/K) e M (KITD816V) tiveram suas bases moleculares desvendadas e apresentam em comum a ativação constitutiva de tirosino-quinase graças às mutações adquiridas pela célula-tronco hematopoética. A mutação JAK2 V617F é observada em mais de 90 por cento dos casos de PV, mas também em cerca de 50 por cento-60 por cento das MF e TE, levando ao questionamento de como uma única lesão molecular desencadeia três manifestações clínicas diversas. Já há evidências de que eventos genéticos e epigenéticos adicionais contribuem para a patogênese, tais como MPLW515L e MPLW515K. No presente manuscrito são apresentados os aspectos clínicos, a fisiopatologia e os critérios diagnósticos das diferentes NMP.

Chronic myeloproliferative disorders, currently called myeloproliferative neoplasms (MPN), according to the 4th edition of the World Health Organization (WHO) classification are clonal diseases of hematopoietic stem cells, in which there is increased proliferation of the myeloid series (granulocytic, erythrocytic, megakaryocytic series or mast cells) with effective maturation. The progression of all is characterized by marrow fibrosis or leukemic transformation. According to the WHO classification, the MPNs include: chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), idiopathic myelofibrosis (IM), chronic neutrophilic leukemia (CNL), chronic eosinophilic leukemia not otherwise categorized (CEL-NC), mastocytosis (M) and myeloproliferative neoplasm unclassifiable (MPNU). It is worth noting that the molecular basis of CML (BCR/ABL1), as well as PV,ET, IM (JAK2V617F and exon 12, MPL W515L/K) and M (KITD816V) have been identified and have, in common, constitutive activation of tyrosine kinase due to acquired hematopoietic stem cell defects. The JAK2V617F mutation is observed in around 90 percent of PV cases and in around 50-60 percent of IM and ET leading to the question why a single molecular lesion induces three different clinical manifestations. There is already evidence that additional genetic and epigenetic events contribute to the pathogenesis, including MPL W515L/K mutation. Some clinical aspects, the pathophysiology and diagnostic criteria of MPNs are presented in this paper.

Síndrome de Sweet associada à policitemia vera / Sweet’s syndrome associated withpolycythemiavera

A síndrome de Sweet pode estar associada a malignidades hematológicas, principalmente, à leucemia mieloide aguda, porém existem poucos relatos demonstrando a associação com a policitemia vera. Relata-se o caso de doente do sexo masculino, de 65 anos, portador de policitemia vera,que evoluiu com aparecimento de síndrome de Sweet na sua forma paraneoplásica.

Sweet’s syndrome may be associated with hematological malignancies, particularly with acute myelogenous leukemia, but there are few reports of its association with polycythemiavera. We describethe case of a 65-year-old male patient, diagnosed with polycythemiavera, which developedinto paraneoplastic Sweet's syndrome.

Diagnosis and treatment of polycythemia vera: Brazilian experience from a single institution

CONTEXT AND OBJECTIVE: Polycythemia vera (PV) is a chronic myeloproliferative disorder characterized by predominant proliferation of erythroid precursors. Few data are available concerning Brazilian patients with this condition. The aim of this study was to describe clinical and demographic characteristics of PV patients at diagnosis and analyze their long-term outcomes. DESIGN AND SETTING: Retrospective study at the Division of Hematology, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo. METHODS: All consecutive patients with PV diagnosed according to World Health Organization criteria were eligible for this study. Clinical and demographic characteristics, thrombotic events, transformation to acute leukemia, myelofibrosis and survival were evaluated. RESULTS: Sixty-six patients were evaluated. Thirty-six (54.5 percent) were females, with a median age at diagnosis of 61 years. At diagnosis, the median hemoglobin concentration was 18.8 mg/dl and the median platelet count was 593,000/mm³. Fifty-eight patients (88.0 percent) were treated with hydroxyurea with or without phlebotomy. During a median follow-up of 77 months, 22 patients (33.3 percent) had new thrombotic events, mainly of arterial type. The overall incidence of leukemia and myelofibrosis was 0.42 percent per patient-year and 1.06 percent per patient-year, respectively. Median overall survival was not reached and the seven-year survival rate was 77.8 percent. CONCLUSION: The PV patients described here had long survival and arterial thrombotic events were the most important and common complication among this population.

CONTEXTO E OBJETIVO: A policitemia vera (PV) é uma doença mieloproliferativa crônica, caracterizada pela proliferação de precursores hematopoéticos, principalmente da série eritróide. Poucos dados são disponíveis sobre pacientes brasileiros portadores desta doença. O objetivo do presente estudo é analisar as características de pacientes portadores de PV ao diagnóstico e a sua evolução clínica a longo prazo. TIPO DE ESTUDO E LOCAL: Estudo retrospectivo unicêntrico, realizado no Serviço de Hematologia da Faculdade de Medicina da Universidade de São Paulo. MÉTODOS: Foram elegíveis para este estudo os pacientes com PV diagnosticados de acordo com os critérios estabelecidos pela Organização Mundial da Saúde. Foram avaliadas as características demográficas e clínicas ao diagnóstico, as complicações trombóticas, a transformação para leucemia aguda e mielofibrose e a sobrevida. RESULTADOS: Foram avaliados 66 pacientes; 36 (54,5 por cento) eram do sexo feminino, com uma mediana de idade ao diagnóstico de 61 anos. As medianas da concentração de hemoglobina e da plaquetometria ao diagnóstico foram de 18,8 mg/dl e 593.000/mm³, respectivamente. 58 (88,0 por cento) foram tratados com hidroxiuréia associada ou não à flebotomia. Em uma mediana de acompanhamento de 77 meses, 22 (33,3 por cento) pacientes apresentaram eventos trombóticos, predominantemente arteriais. A incidência de leucemia e mielofibrose foi de 0,42/100 pacientes-ano e 1,06/100 pacientes-ano, respectivamente. A mediana de sobrevida global não foi atingida, a taxa de sobrevida em sete anos foi de 77,8 por cento. CONCLUSÃO: Os portadores de PV em nosso serviço apresentaram longa sobrevida. Os eventos trombóticos arteriais foram a principal complicação da população estudada.