TGF-ß/SMAD Pathway Is Modulated by miR-26b-5p: Another Piece in the Puzzle of Chronic Lymphocytic Leukemia Progression.

Clinical and molecular heterogeneity are hallmarks of chronic lymphocytic leukemia (CLL), a neoplasm characterized by accumulation of mature and clonal long-lived CD5 + B-lymphocytes. Mutational status of the IgHV gene of leukemic clones is a powerful prognostic tool in CLL, and it is well established that unmutated CLLs (U-CLLs) have worse evolution than mutated cases. Nevertheless, progression and treatment requirement of patients can evolve independently from the mutational status. Microenvironment signaling or epigenetic changes partially explain this different behavior. Thus, we think that detailed characterization of the miRNAs landscape from patients with different clinical evolution could facilitate the understanding of this heterogeneity. Since miRNAs are key players in leukemia pathogenesis and evolution, we aim to better characterize different CLL behaviors by comparing the miRNome of clinically progressive U-CLLs vs. stable U-CLLs. Our data show up-regulation of miR-26b-5p, miR-106b-5p, and miR-142-5p in progressive cases and indicate a key role for miR-26b-5p during CLL progression. Specifically, up-regulation of miR-26b-5p in CLL cells blocks TGF-ß/SMAD pathway by down-modulation of SMAD-4, resulting in lower expression of p21-Cip1 kinase inhibitor and higher expression of c-Myc oncogene. This work describes a new molecular mechanism linking CLL progression with TGF-ß modulation and proposes an alternative strategy to explore in CLL therapy.

Enfermedad Tromboembólica Venosa en el período grávido puerperal. Diagnóstico, tratamiento y profilaxis / Venous Thromboembolic Disease in the puerperal gravid period. Diagnosis, treatment and prophylaxis / Doença tromboembólica venosa no período gravídico puerperal. Diagnóstico, tratamento e profilaxia

Resumen: El embarazo y puerperio son situaciones asociadas fisiológicamente con un marcado aumento del riesgo de enfermedad tromboembólica venosa. El riesgo se estima entre 7 a 10 veces superior que en mujeres de igual edad y 15-35 veces superior que la población control, durante el puerperio y hasta la sexta semana post-parto. Los factores de riesgo son distintos durante el período prenatal y post-parto. Los métodos diagnósticos incluyen radiografía, angio-tomografía de tórax y centellograma pulmonar ventilación-perfusión, ecodoppler venoso y venografía por resonancia nuclear magnética. El tratamiento supone un desafío que va desde la elección de la droga anticoagulante, los cambios en la farmacocinética durante el embarazo, entre otros. Se presentan algoritmos diagnósticos y terapéuticos.

Abstract: Pregnancy and the puerperium are physiologically associated with a markedly increased risk of venous thromboembolic disease. The risk is estimated between 7 to 10 times higher than in women of the same age and 15-35 times higher than the control population, during the puerperium and up to the sixth week postpartum. Risk factors are different during the prenatal and postpartum period. Diagnostic methods include radiography, chest angio-tomography and ventilation-perfusion lung scintigraphy, venous Doppler ultrasound, and magnetic resonance venography. Treatment involves a challenge that ranges from the choice of anticoagulant drug, changes in pharmacokinetics during pregnancy, among others. Diagnostic and therapeutic algorithms are presented.

Resumo: A gravidez e o puerpério estão fisiologicamente associados a um risco acentuadamente aumentado de doença tromboembólica venosa. O risco é estimado entre 7 a 10 vezes maior do que em mulheres da mesma idade e 15 a 35 vezes maior do que na população controle, durante o puerpério e até a sexta semana pós-parto. Os fatores de risco são diferentes durante o período pré-natal e pós-parto. Os métodos de diagnóstico incluem radiografia, angiotomografia de tórax e cintilografia pulmonar de ventilação-perfusão, ultrassom Doppler venoso e venografia por ressonância magnética nuclear. O tratamento envolve um desafio que vai desde a escolha do anticoagulante, mudanças na farmacocinética durante a gravidez, entre outros. Algoritmos diagnósticos e terapêuticos são apresentados.

Absolute monocyte count as a prognostic parameter in diffuse large B cell lymphoma / Recuento absoluto de monocitos como parámetro pronóstico en linfoma difuso de células B grandes

ABSTRACT Background Prognosis of patients with Diffuse Large B Cell Lymphoma (DLBCL) is highly variable, and despite the use of modern immunochemotherapy regimens, almost 50% of patients will eventually relapse. Standard risk models, like the International Prognostic Index or the Revised International Prognostic Index (R_IPI) incorporate patient and tumor characteristics but do not consider variables related to host adaptive immunity which have been shown to be of significant prognostic value in non-Hodgkin lymphomas. Aim To analyze the prognostic significance of the absolute monocyte count at diagnosis in diffuse large-B-cell lymphoma in a retrospective setting. Material and Methods We reviewed data of 171 patients with DLBCL treated with Rituximab-based immunochemotherapy at two reference public Hospitals in Montevideo-Uruguay. The outcome measures were overall and relapse free survival. Results The absolute monocyte count, analyzed as a dichotomized variable predicted progression-free and overall survival in low risk patients according to the R-IPI score. Worse outcomes were observed in those with high monocyte count al diagnosis. Conclusions Absolute monocyte count could help in the identification of high-risk patients otherwise expected to have a good prognosis according to traditional scores.

Antecedentes El pronóstico de pacientes con Linfoma Difuso de Células B Grandes (DLBCL) es muy variable y el 50% de los pacientes recae a pesar de uso de regímenes actualizados de inmuno-quimioterapia. Los modelos pronósticos clásicos como el International Prognostic Index o el Revised International Prognostic Index (R_IPI) incorporan características del paciente o del tumor pero no incorporan variables asociadas a la inmunidad adaptativa que tienen valor en linfomas no Hodgkin. Objetivo Analizar retrospectivamente el valor pronóstico del recuento absoluto de monocitos al momento del diagnóstico en pacientes con DLBCL. Material y Métodos Se revisó información de 171 pacientes con DLBCL tratados con inmuno-quimioterapia basada en rituximab en dos centros de referencia públicos de Montevideo, Uruguay. Las variables de resultado fueron la sobrevida global y libre de recaída. Resultados El recuento absoluto de monocitos, tratado como una variable dicotómica, predijo la sobrevida libre de recaída en pacientes de bajo riesgo, de acuerdo al puntaje R-IPI. El pronóstico fue peor en pacientes con altos recuentos al momento del diagnóstico. Conclusiones El recuento absoluto de monocitos puede identificar pacientes de alto riesgo, clasificados como de bajo riesgo por los puntajes tradicionales.

Absolute monocyte count as a prognostic parameter in diffuse large B cell lymphoma.

Background Prognosis of patients with Diffuse Large B Cell Lymphoma (DLBCL) is highly variable, and despite the use of modern immunochemotherapy regimens, almost 50% of patients will eventually relapse. Standard risk models, like the International Prognostic Index or the Revised International Prognostic Index (R_IPI) incorporate patient and tumor characteristics but do not consider variables related to host adaptive immunity which have been shown to be of significant prognostic value in non-Hodgkin lymphomas. Aim To analyze the prognostic significance of the absolute monocyte count at diagnosis in diffuse large-B-cell lymphoma in a retrospective setting. Material and Methods We reviewed data of 171 patients with DLBCL treated with Rituximab-based immunochemotherapy at two reference public Hospitals in Montevideo-Uruguay. The outcome measures were overall and relapse free survival. Results The absolute monocyte count, analyzed as a dichotomized variable predicted progression-free and overall survival in low risk patients according to the R-IPI score. Worse outcomes were observed in those with high monocyte count al diagnosis. Conclusions Absolute monocyte count could help in the identification of high-risk patients otherwise expected to have a good prognosis according to traditional scores.

[Magnetic resonance as initial screening diagnosis of secondary involvement of central nervous system in NHL diffuse large B cell lymphoma] / Resonancia magnética como screening inicial de diagnóstico de compromiso secundario del sistema nervioso central en LNH difuso de grandes Células B.

Background: Background: Central Nervous System (CNS) relapse in Diffuse Large B-cell Lymphoma occurs mostly 6-8 months after disease onset. This has led to propose that CNS infiltration is an early event in the evolution of the disease. We intend to evaluate the role of magnetic resonance imaging (MR) at diagnosis to detect early SNC compromise. Methods: Prospective longitudinal cohort's study in DGCB patients treated at Hospital de Clínicas between 2013 and 2015. Skull MRI was performed in all patients at diagnosis and lumbar puncture was done according to predefined risk factors. Results: 35 patients were analyzed. Median age: 68 years (24-85 years). Stage III-IV: 62%, 57% good prognosis according to RIPI score and 43% poor prognosis. MRI was performed in all patients, with no pathological findings in any of them. Twenty-one patients fullfilled criteria for cerebrospinal fluid study. Twenty-two patients were studied and received intrathecal methotrexate prophylaxis. Meningeal relapse was observed in a single patient who had negative studies at diagnosis and had received complete prophylaxis at the end of the 6 R-CHOP series. Conclusions: Only one of the 35 patients relapsed in the CNS. This patient had a noral MRI and CSF study at diagnosis and had received prophylaxis with intrathecal chemotherapy. This results lead us to believe that the value of MRI to detect early infiltration in asymptomatic patients at diagnosis is low.

Antecedentes: la recaída en el Sistema Nervioso Central (SNC) del Linfoma No Hodgkin Difuso de Grandes Células B ocurre más frecuentemente 6-8 meses del debut de la enfermedad. Esto ha levado a plantear que la infiltración en SNC es un evento temprano en esta enfermedad. Nos proponemos evaluar el valor de la realización de estudio imagenológico por Resonancia Magnética (RM) al debut para detectar compromiso precoz. Materiales y métodos: Estudio longitudinal prospectivo de cohortes en LNH DGCB tratados en el Hospital de Clínicas entre 2013 y 2015. A todos los pacientes se les realizó RM de cráneo al debut y estudio de líquido cefaloraquídeo (LCR) según factores de riesgo predefinidos. Resultados: Se analizaron 35 pacientes. Mediana de edad: 68 años (24-85 años). Estadío III-IV: 62%; 57% presentaron buen pronóstico según score RIPI al debut y 43% mal pronóstico. Se realizó RM a todos los pacientes, no habiéndose encontrado hallazgos patológicos en ninguno de ellos. Veintitres pacientes tuvieron criterio de estudio del LCR de los cuales veintidós se estudiaron y recibieron profilaxis con metotrexate intratecal. Se observó recaída meníngea en una única paciente con estudios negativos al debut y profilaxis completa al mes de finalizadas las 6 series de R-CHOP. Conclusiones: De 35 pacientes uno sólo recayó en el SNC; el mismo había recibido profilaxis con quimioterapia intratecal y presentó una RM normal al debut de su enfermedad. Los resultados nos conducen a pensar que el valor de la RM para detectar precozmente infiltración en pacientes asintomáticos al debut es bajo.

LPL protein in Chronic Lymphocytic Leukaemia have different origins in Mutated and Unmutated patients. Advances for a new prognostic marker in CLL.

Lipoprotein lipase (LPL) mRNA expression in chronic lymphocytic leukaemia (CLL) is associated with an unmutated immunoglobulin profile and poor clinical outcome. We evaluated the subcellular localization of LPL protein in CLL cells that did or did not express LPL mRNA. Our results show that LPL protein is differently located in CLL cells depending on whether it is incorporated from the extracellular medium in mutated CLL or generated de novo by leukaemic cells of unmutated patients. The specific quantification of endogenous LPL protein correlates with mRNA expression levels and mutational IGHV status, suggesting LPL protein as a possible reliable prognostic marker in CLL.

S100-A9 protein in exosomes from chronic lymphocytic leukemia cells promotes NF-κB activity during disease progression.

Chronic lymphocytic leukemia (CLL) is an incurable disease characterized by accumulation of clonal B lymphocytes, resulting from a complex balance between cell proliferation and apoptotic death. Continuous crosstalk between cancer cells and local/distant host environment is required for effective tumor growth. Among the main actors of this dynamic interplay between tumoral cells and their microenvironment are the nano-sized vesicles called exosomes. Emerging evidence indicates that secretion, composition, and functional capacity of exosomes are altered as tumors progress to an aggressive phenotype. In CLL, no data exist exploring the specific changes in the proteomic profile of plasma-derived exosomes from patients during disease evolution. We hereby report for the first time different proteomic profiles of plasma exosomes, both between indolent and progressive CLLs as well as within the individual patients at the onset of disease and during its progression. Next, we focus on the changes of the exosome protein cargoes, which are found exclusively in patients with progressive CLL after disease progression. The alterations in the proteomic cargoes underline different networks specific for leukemia progression related to inflammation, oxidative stress, and NF-κB and phosphatidylinositol 3-kinase/AKT pathway activation. Finally, our results suggest a preponderant role for the protein S100-A9 as an activator of the NFκB pathway during CLL progression and suggest that the leukemic clone can generate an autoactivation loop through S100-A9 expression, NF-κB activation, and exosome secretion. Collectively, our data propose a new pathway for NF-κB activation in CLL and highlight the importance of exosomes as extracellular mediators promoting tumor progression in CLL.

[Cytarabine and skin reactions in acute myeloid leukemia]. / Citarabina y reacciones cutáneas en leucemia aguda mieloide.

Cytarabine is an antimetabolite used in the treatment of acute myeloid leukemia (AML). It has many adverse effects as: myelosuppression, toxic reactions involving central nervous system, liver, gastrointestinal tract, eyes or skin. Dermatologic toxicity is often described as rare; nevertheless there are differences in the reported frequency. We performed a retrospective study including all AML treated with chemotherapy that involved cytarabine between 1st July of 2006 and 1st July of 2012; 46 patients were included with a median age of 55 years. The overall incidence of skin reactions was 39% (n = 18). Sex, age, history of atopy, history of drug reactions, or dose of cytarabine used, were not associated with them. Skin reactions were observed from 2 to 8 days after treatment started. Considering injury degree: 27.8% had grade 1, 38.9% grade 2 and 33.3% grade 3. We did not find any injury grade 4 or death associated with skin toxicity. As for the type of injury: 55.6% presented macules, 22.2% papules and 22.2% erythema. Lesions distribution was diffuse in 52% of patients, acral in 39.3%, and at flexural level in 8.7%. Adverse cutaneous reactions secondary to the administration of cytarabine are frequent in our service and include some cases with severe involvement. Although these reactions usually resolve spontaneously, they determine an increased risk of infection and a compromise of the patient quality of life.

Citarabina y reacciones cutáneas en leucemia aguda mieloide / Cytarabine and skin reactions in acute myeloid leukemia

La citarabina es un antimetabolito utilizado en el tratamiento de las leucemias agudas mieloides (LAM). Esta droga presenta numerosos efectos adversos (mielosupresión, toxicidad en sistema nervioso central, hepática, gastrointestinal, ocular y cutánea). La toxicidad dermatológica es habitualmente descrita como rara, sin embargo existen diferencias en la incidencia comunicada. Se realizó un estudio retrospectivo donde se incluyeron todas las LAM tratadas con quimioterapia que incluía citarabina, entre el 1º de julio 2006 y el 1° de julio 2012. Se incluyeron 46 pacientes con una mediana de edad de 55 años. La incidencia global de reacciones cutáneas fue de 39% (n = 18). La presencia de lesiones cutáneas no se asoció con sexo, edad, antecedentes de atopía, de reacciones medicamentosas, tipo de LAM ni dosis de citarabina utilizada. Las lesiones se observaron entre 2 a 8 días de iniciado el tratamiento. En cuanto al grado lesional, 27.8% presentaron grado 1, 38.9% grado 2 y 33.3% grado 3. No existieron lesiones grado 4 ni muerte vinculada a toxicidad cutánea. En cuanto al tipo de lesiones, 55.6% se presentaban con máculas, 22.2% con pápulas y 22.2% con eritema. Con respecto a la distribución de las lesiones, 52% de los pacientes presentaron una distribución difusa, 39.3% acral y 8.7% a nivel flexural. Las reacciones adversas cutáneas con la administración de citarabina son frecuentes en nuestro medio, en algunos casos con afectación grave. Si bien suelen resolverse espontáneamente, pueden determinar mayor riesgo de infección, así como comprometer la calidad de vida.

Cytarabine is an antimetabolite used in the treatment of acute myeloid leukemia (AML). It has many adverse effects as: myelosuppression, toxic reactions involving central nervous system, liver, gastrointestinal tract, eyes or skin. Dermatologic toxicity is often described as rare; nevertheless there are differences in the reported frequency. We performed a retrospective study including all AML treated with chemotherapy that involved cytarabine between 1st July of 2006 and 1st July of 2012; 46 patients were included with a median age of 55 years. The overall incidence of skin reactions was 39% (n = 18). Sex, age, history of atopy, history of drug reactions, or dose of cytarabine used, were not associated with them. Skin reactions were observed from 2 to 8 days after treatment started. Considering injury degree: 27.8% had grade 1, 38.9% grade 2 and 33.3% grade 3. We did not find any injury grade 4 or death associated with skin toxicity. As for the type of injury: 55.6% presented macules, 22.2% papules and 22.2% erythema. Lesions distribution was diffuse in 52% of patients, acral in 39.3%, and at flexural level in 8.7%. Adverse cutaneous reactions secondary to the administration of cytarabine are frequent in our service and include some cases with severe involvement. Although these reactions usually resolve spontaneously, they determine an increased risk of infection and a compromise of the patient quality of life.

Citarabina y reacciones cutáneas en leucemia aguda mieloide / Cytarabine and skin reactions in acute myeloid leukemia

La citarabina es un antimetabolito utilizado en el tratamiento de las leucemias agudas mieloides (LAM). Esta droga presenta numerosos efectos adversos (mielosupresión, toxicidad en sistema nervioso central, hepática, gastrointestinal, ocular y cutánea). La toxicidad dermatológica es habitualmente descrita como rara, sin embargo existen diferencias en la incidencia comunicada. Se realizó un estudio retrospectivo donde se incluyeron todas las LAM tratadas con quimioterapia que incluía citarabina, entre el 1º de julio 2006 y el 1° de julio 2012. Se incluyeron 46 pacientes con una mediana de edad de 55 años. La incidencia global de reacciones cutáneas fue de 39% (n = 18). La presencia de lesiones cutáneas no se asoció con sexo, edad, antecedentes de atopía, de reacciones medicamentosas, tipo de LAM ni dosis de citarabina utilizada. Las lesiones se observaron entre 2 a 8 días de iniciado el tratamiento. En cuanto al grado lesional, 27.8% presentaron grado 1, 38.9% grado 2 y 33.3% grado 3. No existieron lesiones grado 4 ni muerte vinculada a toxicidad cutánea. En cuanto al tipo de lesiones, 55.6% se presentaban con máculas, 22.2% con pápulas y 22.2% con eritema. Con respecto a la distribución de las lesiones, 52% de los pacientes presentaron una distribución difusa, 39.3% acral y 8.7% a nivel flexural. Las reacciones adversas cutáneas con la administración de citarabina son frecuentes en nuestro medio, en algunos casos con afectación grave. Si bien suelen resolverse espontáneamente, pueden determinar mayor riesgo de infección, así como comprometer la calidad de vida.(AU)

Cytarabine is an antimetabolite used in the treatment of acute myeloid leukemia (AML). It has many adverse effects as: myelosuppression, toxic reactions involving central nervous system, liver, gastrointestinal tract, eyes or skin. Dermatologic toxicity is often described as rare; nevertheless there are differences in the reported frequency. We performed a retrospective study including all AML treated with chemotherapy that involved cytarabine between 1st July of 2006 and 1st July of 2012; 46 patients were included with a median age of 55 years. The overall incidence of skin reactions was 39% (n = 18). Sex, age, history of atopy, history of drug reactions, or dose of cytarabine used, were not associated with them. Skin reactions were observed from 2 to 8 days after treatment started. Considering injury degree: 27.8% had grade 1, 38.9% grade 2 and 33.3% grade 3. We did not find any injury grade 4 or death associated with skin toxicity. As for the type of injury: 55.6% presented macules, 22.2% papules and 22.2% erythema. Lesions distribution was diffuse in 52% of patients, acral in 39.3%, and at flexural level in 8.7%. Adverse cutaneous reactions secondary to the administration of cytarabine are frequent in our service and include some cases with severe involvement. Although these reactions usually resolve spontaneously, they determine an increased risk of infection and a compromise of the patient quality of life.(AU)

Citarabina y reacciones cutáneas en leucemia aguda mieloide. / [Cytarabine and skin reactions in acute myeloid leukemia].

Cytarabine is an antimetabolite used in the treatment of acute myeloid leukemia (AML). It has many adverse effects as: myelosuppression, toxic reactions involving central nervous system, liver, gastrointestinal tract, eyes or skin. Dermatologic toxicity is often described as rare; nevertheless there are differences in the reported frequency. We performed a retrospective study including all AML treated with chemotherapy that involved cytarabine between 1st July of 2006 and 1st July of 2012; 46 patients were included with a median age of 55 years. The overall incidence of skin reactions was 39

(n = 18). Sex, age, history of atopy, history of drug reactions, or dose of cytarabine used, were not associated with them. Skin reactions were observed from 2 to 8 days after treatment started. Considering injury degree: 27.8

had grade 1, 38.9

grade 2 and 33.3

grade 3. We did not find any injury grade 4 or death associated with skin toxicity. As for the type of injury: 55.6

presented macules, 22.2

papules and 22.2

erythema. Lesions distribution was diffuse in 52

of patients, acral in 39.3

, and at flexural level in 8.7

. Adverse cutaneous reactions secondary to the administration of cytarabine are frequent in our service and include some cases with severe involvement. Although these reactions usually resolve spontaneously, they determine an increased risk of infection and a compromise of the patient quality of life.