An Unusual Case of Immune Complex-Mediated Membranoproliferative Glomerulonephritis as Renal Manifestation of Idiopathic Hypereosinophilic Syndrome: A Case Report and Literature Review.

BACKGROUND: Idiopathic hypereosinophilic syndrome (IHES) is a disorder characterized by abnormal and persistent peripheral blood hypereosinophilia (eosinophil count ≥ 1.5 × 109/L and ≥10% eosinophils) with duration ≥ 6 months, associated organ damage, and/or dysfunction attributable to tissue eosinophilic infiltrate of unknown cause. IHES affects different organs such as the heart, lungs, nervous system, and skin, with renal involvement being rare in this condition. CASE PRESENTATION: We present a case of a young patient with IHES and immune complex-mediated membranoproliferative glomerulonephritis with nephrotic syndrome, as a rare renal manifestation. We discuss the clinical, analytical, and histopathologic renal and hematologic features, comparing them with other reported cases in the literature.

Inmunología en el trasplante alogénico de progenitores hematopoyrticos / Inmunology in allogeneic hematopoietic stem cell transplantation

El uso del trasplante alogénico de progenitores hematopoyéticos (TAPH) para el tratamiento de enfermedades oncohematológicas, degenerativas y auto inmunes y para inmunodeficiencias primarias se ha incrementado significativamente en años recientes, debido a los adelantos en el conocimiento y modificación de los mecanismos inmunes inmersos en el TAPH. El desarrollo de la inmunología en TAPH fue impulsado principalmente por el descubrimiento del complejo mayor de histocompatibilidad (CMH), en 1967. Esto llevó a la identificación de donante y receptor totalmente compatible; lo que ha mejorado notablemente los resultados en supervivencia libre de enfermedad y en supervivencia global. Adicionalmente, el rol de los diferentes componentes celulares y humorales en relación a la enfermedad injerto contra huésped (EICH) e injerto contra enfermedad (ICE) han sido identificados; estos incluyen anticuerpos, células presentadoras de antígenos, subpoblaciones linfocitarias T, moléculas en la superficie de células inmunes, mecanismos de señalización, citocinas y otras; tanto en el donante como en el receptor. El desarrollo de nuevos fármacos, que inhiben con gran eficiencia y baja toxicidad a los diferentes componentes que interactúan e inducen la EICH, ha sido de gran utilidad para mejorar los resultados globales en TAPH. De igual forma, se han desarrollado recientemente estrategias que incluyen diferentes fuentes celulares de progenitores hematopoyéticos como sangre de cordón umbilical, células mesenquimales y tejidos fetal es; así como selección de poblaciones específicas. Otro avance son los regímenes pretrasplante con menores toxicidades -denominados condicionamientos de intensidad reducida (CIR)-, que han modificado la elegibilidad etaria y las condiciones clínicas de los pacientes candidatos a TAPH.

Use of hematopoietic progenitor allogeneic transplant (HPAT) for oncohematologic, degenerative, autoimmune and primary immunodeficiency diseases has increased significantly in recent years due to advances in knowledge and modification of the immune mechanisms involved in HPAT. The development of immunology in HPAT has been mainly driven by the discovery of the Major Histocompatibility Complex (MHC) in 1967, leading to the identification of the donor and receptor ful/ support, which have greatly improved the results in disease-free survival and overal/ survival. Additionally, the role of different cel/ular and humoral components in relation to the graft versus host disease (GVHD) and graft versus disease (GVD) ha ve been identified and these include antibodies, antigen presenting cel/s, T lymphocyte subpopulations (T regulators, T helpers, T -cytotoxic) molecules on the surface of immune cel/s, signaling mechanisms, and other cytokines, both the donor and recipient. The development of new drugs and combinations of these have been very useful to improve the overal/ performance in HPAT, since inhibit with high efficiency and low toxicity of the different components that interact and induce GVHD. Similar/y, strategies have recently be en developed which include different sources of hematopoietic stem cel/ and cord blood, mesenchymal cel/s and fetal tissues, and selection of specific populations or vent. Have also been developed with lower toxicities pretransplant regimens cal/ed reduced intensity constraints (RIC), which have changed the eligibility age and clínical conditions of the candidates for HPAT patients.

Células mesenquimales estromales / Mesenchymal stromal cells

Las células mesenquimales estromales (MSC, por sus siglas en inglés) son una población celular que ha sido adecuadamente caracterizada biológicamente en años recientes. Es una población celular con propiedades especiales en el medio de cultivos y con una específica expresión de marcadores celulares en estudios de citometría de flujo. Su presencia en médula ósea es muy baja y desde el punto de vista ultraestructural presenta vimentina, la cual interviene mucho en las modificaciones morfológicas de estas células en cultivos. Adicionalmente las MSC tienen en su membrana citoplasmática una amplia variedad de receptores de citocinas que hace suponer la diversidad de subpoblaciones dentro de las MSC. Hay muchas fuentes de MSC donde destaca la médula ósea, células progenitoras fetales (amnios, sangre de cordón umbilical, placenta y otros), y tejido graso. Al parecer la expresión de genes de pluripotencialidad en células progenitoras fetales hace que las MSC de sangre de cordón umbilical tengan mayor capacidad de replicación in Vitro. Las propiedades paracrino e inmunomoludora de las MSC han sido ampliamente estudiadas en modelos experimentales; que han permitido explorar la utilidad clínica de las MSC en estudios de fase I a III en una variedad de enfermedades donde destaca la enfermedad injerto contra huésped e infarto de miocardio. La potencialidad clínica de MSC debe ser adecuada y metodológicamente estudiada en ensayos clínicos.

Mesenchymal stromal cells (MSC) are a population cell that had been recently biologically characterized. It is a population cell with special properties in culture media and with a specific cell markers expression by flow cytometry. Its presences on bone marrow is pretty low and from the ultraestructural point of view present vimentin, which interacts on cells morphological modifications on cultures. MSC presents a chemokines receptor repertoire on their membrane cells that make feasible subpopulations diversity among MSC. There are many MSC source as: bone marrow, fetal stem cells (amniotic membrane, umbilical cord blood, placenta and others), and adipose tissue. It looks that the pluripotential genes expression on fetal stem cell makes that umbilical cord blood MSC had a mayor proliferation capacity in vitro. The paracrine and immunomodulatory MSC capacities had been extensively studied on experimental models; those had led to explore the MS utility on the clinic by means of phase I to III triáis on a variety of diseases as: graft versus host disease and myocardial infarction. The clinical potency of MSC must be accuracy and methodologically studied on clinical trials.

The CD271 expression could be alone for establisher phenotypic marker in Bone Marrow derived mesenchymal stem cells.

Mesenchymal stem cells (MSCs) are of great interest for their potential use in cellular therapies. To define the population more precisely, diverse surface markers have been used. We propose here to use CD271 as the sole marker for MSCs in fresh bone marrow. We compared CD271+ populations to the presence or absence of five defined markers for MSCs: CD90+, CD105+, CD45-, CD34- and CD79. The correlations between markers were evaluated and analyzed with a Pearson's correlation test. We found that the average percentage of cells expressing the combination of markers CD90+, CD105+, CD45-, CD34- and CD79- was 0.54%, and that the average percentage average of CD271+ cells was 0.53%. The results were significant (p<0.05). The exclusive use of CD271 as a marker for MSCs from fresh samples of bone marrow appears to be highly selective. Using CD271 as the sole identification marker for MSCs could reduce costs and accelerate the process of identifying MSCs for the field of cellular therapy.

Biología y aplicación de las células madre de la médula ósea / Biology and application of stem cells from bone marrow

En los últimos años el interés por las células madre (CM) ha crecido debido a su potencial terapéutico en enfermedades crónico degenerativas como las cardiopatías isquémicas, la insuficiencia arterial periférica, la diabetes mellitus, la enfermedad de Parkinson, cirrosis hepática, etc. Las células más estudiadas y más utilizadas actualmente a nivel clínico son Cm de la Médula Osea (CMMO), debido a la ausencia de problemas éticos y de complicaciones con respecto a las CM embrionarias, y a su relativa fácil obtención y aislamiento, frente a otras CM adultas. La utilización experimental de estas CMMO en diferentes modelos animales de enfermedades humanas crónico-degenerativas, ha demostrado no sólo la transdifereneciación de estas CM en células del tejido u órgano lesionado, si no también, la mejoría estructural y funcional de dichos órganos luego del implante de CMMO. Esto ha servido de base para el inicio de los estudios clínicos, los cuales están demostrando buenos resultados tras el implante de CMMO en el tratamiento de diferentes patologías crónico-degenerativas, especialmente las enfermedades cardiacas isquémicas. Los resultados son muy promisorios y la expectativa es grande con respecto a la capacidad terapéutica de estas células. Los próximos años permitirán demostrar el verdadero alcance del implante de las CMMO en el tratamiento de las enfermedades arriba mencionadas y en otras.

Some years ago, there had been an increased interest on stem cells because of its therapeutic potential in chronic degenerative diseases as ischemic cardiopathy, peripheral artery insufficiency, diabetes mellitus, ParkinsonÆs disease, liver cirrosis, etc. the most studied and used stem cell source is the home marrow due of the absence of ethical problems and complications comparing with embryonic stem cells; also because its relative easiest collection and isolation comparing with other adults stem cell sources. The experimental used on animal models of chronic and degenerative human diseases had shown not only transdifferentiation to tissue specific cells or damage tissue cell, also, the structural and functional improvement of those organs after bone narrow stem cell (BMSC) implant. This had lead clinical trials that have been showing good outcomes after BMSC implant on different chronic degenerative diseases mainly ischemic heart diseases. The outcomes are very encouraging and the therapeutic potential of these cells had a high demonstrate the truly capacity of BMSC implant on the treatment of diseases mentioned above and other.

Alemtuzumab for the treatment of steroid-refractory acute graft-versus-host disease.

The treatment of steroid-refractory acute graft-versus-host disease (aGVHD) remains a clinical challenge, for which no standard therapy exists. Alemtuzumab is a humanized anti-CD52 monoclonal antibody (mAb) that has been successfully used as part of conditioning regimens for hematopoietic stem cell transplantation (HSCT) to prevent GVHD. The purpose of this study was to evaluate the safety and efficacy of alemtuzumab in treating steroid-refractory aGVHD (>or=grade II) following HSCT. Eighteen patients received subcutaneous alemtuzumab 10 mg daily on 5 consecutive days. Response was assessed at day 28 following initiation of alemtuzumab. Eight patients had grade II aGVHD, 8 had grade III, and 2 had grade IV. The main organ involved was the liver in 4 patients, gastrointestinal (GI) tract in 5, skin in 3, skin and liver in 3, and skin and GI tract in 3. Fifteen patients (83%) responded to alemtuzumab, including 6 (33%) with complete response. All 3 unresponsive patients died of GVHD. Ten of 15 responders are alive at median follow-up of 11 months (range: 3-24). Infections occurred in 14 patients, including cytomegalovirus (CMV) reactivation in 11. Grade 3 neutropenia and thrombocytopenia occurred in 6 and 4 patients, respectively. Alemtuzumab was well tolerated, and induces promising response rates in steroid-refractory aGVHD.

Células T regulatorias en cáncer: ¿Cómo las neoplasias malignas tornan anérgica nuestra inmunidad? / Regulatory T cells in cancer: How malignancies become anergic our immunity?

Las células T reguladoras (Treg) constituyen una subpoblación de células T implicadas en el mantenimiento de la tolerancia a antígenos propios. Treg expresa CD25 , Foxp3 y CTLA-4, induciendo inhibición de la actividad de la célula T directamente o mediada por citocinas inhibitorias como el Factor Transformante Beta o la interleucina 10. Su repercusión no sólo es a nivel del microambiente tumoral sino a nivel sistémico. En tumores sólidos y algunos tumores hematológicos está documentado su valor pronóstico desfavorable asociado generalmente al estadio de la enfermedad. Las células IDO+ y las células mieloides supresoras (CMS) producen inmunosupresión en parte por inducción de actividad Treg. La depleción de Treg por anticuerpos monoclonales y/o drogas selectivas constituye en una estrategia terapéutica prometedora la cual mejora la erradicación tumoral en modelos animales. Además la eliminación y/o inactivación funcionalde Treg podrían potenciar la actividadde vacunas antitumorales. Esta revisión muestra el rol fundamental de Treg en cáncer y las nuevas posibilidades terapéuticas mediante su manipulación.

Long-term follow-up of allogeneic hematopoietic stem-cell transplantation with reduced-intensity conditioning for patients with chronic myeloid leukemia.

Allogeneic hematopoietic stem-cell transplantation (HSCT) remains an effective strategy for inducing durable remission in chronic myeloid leukemia (CML). Reduced-intensity conditioning (RIC) regimens extend HSCT to older patients and those with comorbidities who would otherwise not be suitable candidates for HSCT. The long-term efficacy of this approach is not established. We evaluated outcomes of 64 CML patients with advanced-phase disease (80% beyond first chronic phase), not eligible for myeloablative preparative regimens due to older age or comorbid conditions, who were treated with fludarabine-based RIC regimens. Donor type was matched related (n =30), 1 antigen-mismatched related (n =4), or matched unrelated (n =30). With median follow-up of 7 years, overall survival (OS) and progression-free survival (PFS) were 33% and 20%, respectively, at 5 years. Incidence of treatment-related mortality (TRM) was 33%, 39%, and 48% at 100 days, and 2 and 5 years after HSCT, respectively. In multivariate analysis, only disease stage at time of HSCT was significantly predictive for both OS and PFS. RIC HSCT provides adequate disease control in chronic-phase CML patients, but alternative treatment strategies need to be explored in patients with advanced disease. TRM rates are acceptable in this high-risk population but increase over time.

Allogeneic hematopoietic stem cell transplantation for the treatment of high-risk acute myelogenous leukemia and myelodysplastic syndrome using reduced-intensity conditioning with fludarabine and melphalan.

Reduced-intensity conditioning has extended the use of allogeneic hematopoietic stem cell transplantation (HSCT) to patients otherwise not eligible for this treatment due to older age or frailty. One hundred twelve acute myelogenous leukemia/myelodysplastic syndromes patients received fludarabine and melphalan (FM) conditioning with allogeneic HSCT. Most patients (73%) were not in remission. Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus and mini-methotrexate. Median age was 55 years (range, 22-74). Donors were related (53%) and unrelated (47%). Median follow-up of surviving patients (n = 43) was 29.4 months (range, 13.1-87.7). The complete remission (CR) rate was 82%. Estimates of 2-year survival were 66%, 40%, and 23% for patients in CR, with active disease without and with circulating blasts at HSCT, respectively. In multivariate analysis, survival was negatively influenced by active disease at HSCT and development of grade II-IV acute GVHD. Presence of circulating blasts at HSCT negatively influenced freedom from disease progression. Incidence of nonrelapse mortality (NRM) was significantly higher for patients with active disease, but was not influenced by patient age. Patients in CR had a day-100 and 2-year NRM of 0% and 20%, respectively. Use of unrelated donors increased the risk of NRM only among patients with active disease. FM and HSCT elicited long-term disease control in a significant fraction of this high-risk cohort.

Advances in the therapy of chronic idiopathic myelofibrosis.

The molecular basis of chronic idiopathic myelofibrosis (CIMF) has remained elusive, thus hampering the development of effective targeted therapies. However, significant progress regarding the molecular mechanisms involved in the pathogenes is of this disease has been made in recent years that will likely provide ample opportunity for the investigation of novel therapeutic approaches. At the fore front of these advances is the discovery that 35%-55% of patients with CIMF harbor mutations in the Janus kinase 2 tyrosine kinase gene. Until very recently, the management of patients with CIMF involved the use of supportive measures, including growth factors, transfusions, or interferon, and the administration of cyto-reductive agents, such as hydroxyurea and anagrelide. However, several trials have demonstrated the efficacy of antiangiogenic agents alone or in combination with corticosteroids. In addition, the use of reduced-intensity conditioning allogeneic stem cell transplantation has resulted in prolonged survival and lower transplant-related mortality.

Incidencia de enfermedad tromboembólica en neoplasias malignas en cuatro hospitales de Lima / Thromboembolic incedence in malignant neoplasias four hospitals of Lima

Objetivo: Conocer la incidencia de la relación entre neoplasias y enfermedad tromboembólica en nuestro medio. Material y Métodos: Se estudió a 200 pacientes portadores de neoplasia maligna, diagnóstico histopatológico y/o citológico, con riesgo moderado/alto para enfermedad tromboembólica. Ciento ochenta y nueve pacientes completaron el estudio. Once pacientes no concluyeron el estudio por fallecimiento o por abandono. Resultados: De los 189 pacientes que completaron el estudio, 50 pacientes tuvieron neoplasias hematológicas, 44, de aparato digestivo, 35, prostática, 23, ginecológicas, 16, de pulmón, 5, de sistema nervioso y 16, de otras localizaciones. A todos se les realizó la prueba de marcador plasmático dímero D (Dimer Test) para trombosis venosa, se halló 158 resultados positivos y 42 negativos. De los 158 resultados positivos, 46 (24,3 por ciento del total) presentaron diagnóstico por imágenes compatibles con trombosis venosa profunda (TVP) presentaron diagnóstico por imágenes compatibles con trombosis venosa profunda (TVP). De ellos, la asociación más frecuente fue en neoplasias de aparato digestivo (14), de próstata (12), de aparato ginecológico (7) y de tipo hematológico (7). Nueve de estos pacientes presentaron en el transcurso de la investigación, evidencia clínica y gammagráfica de embolia pulmonar. Veinticinco pacientes tuvieron diagnóstico de insuficiencia venosa, 87 calificaron en la ecografía como normal y 11 pacientes no tuvieron estudios por imágenes. El mayor porcentaje de TVP lo presentaron los pacientes con neoplasia del sistema nervioso con 40 por ciento (2/5), le siguieron 34 por ciento (12/35) de pacientes con neoplasia de próstata, 32 por ciento (14/44) de neoplasias del aparato digestivo, 30 por ciento (7/23) de neoplasias ginecológicas, 14 por ciento (7/50) de hematológicas y 13 por ciento (2/16) de neoplasias pulmonares. El grupo de edad mayor de 60 años mostró la mayor cantidad de casos de enfermedad tromboembólica...