Haploidentical Hematopoietic Stem Cell Transplantation with Post-Transplantation Cyclophosphamide in Children with High-Risk Leukemia Using a Reduced-Intensity Conditioning Regimen and Peripheral Blood as the Stem Cell Source.

The use of haploidentical donor hematopoietic stem cell transplantation with post-transplantation cyclophosphamide (Haplo-PTCy) in children is increasing; however, it is still not clear which preparative regimen is best in this setting. We present the long-term results of 42 patients age <18 years with high-risk leukemia who underwent this procedure using a reduced-intensity conditioning regimen (RIC) and peripheral blood as the stem cell source. Twenty-six patients had acute lymphoblastic leukemia, 13 had acute myelogenous leukemia, 2 had juvenile myelomonocytic leukemia, and 1 had blast crisis of chronic myelogenous leukemia. One-third of the patients were in first remission, 50% were in second remission, 14% were in third remission, and 3% had refractory disease. Neutrophil recovery occurred in 100% of the 40 patients alive at day +30, and transplantation-related mortality at 1 year was 14%. The incidence of acute graft-versus-disease (GVHD) grade III-IV was 17%, and the cumulative incidence of moderate to severe chronic GVHD at 1 year was 29%. The median duration of follow-up for surviving patients was 45 months; overall survival and event-free survival at 36 months were 56% and 46%, respectively. Long-term results of this series show that the use of an RIC regimen with peripheral blood stem cells as the cell source, in children with high-risk leukemia who underwent haplo-PTCy has tolerable toxicity, universal engraftment, and good survival rates.

Convergent Signaling Pathways Regulate Parathyroid Hormone and Fibroblast Growth Factor-23 Action on NPT2A-mediated Phosphate Transport.

Parathyroid hormone (PTH) and FGF23 are the primary hormones regulating acute phosphate homeostasis. Human renal proximal tubule cells (RPTECs) were used to characterize the mechanism and signaling pathways of PTH and FGF23 on phosphate transport and the role of the PDZ protein NHERF1 in mediating PTH and FGF23 effects. RPTECs express the NPT2A phosphate transporter, αKlotho, FGFR1, FGFR3, FGFR4, and the PTH receptor. FGFR1 isoforms are formed from alternate splicing of exon 3 and of exon 8 or 9 in Ir-like loop 3. Exon 3 was absent, but mRNA containing both exons 8 and 9 is present in cytoplasm. Using an FGFR1c-specific antibody together with mass spectrometry analysis, we show that RPTECs express FGFR-ß1C. The data are consistent with regulated FGFR1 splicing involving a novel cytoplasmic mechanism. PTH and FGF23 inhibited phosphate transport in a concentration-dependent manner. At maximally effective concentrations, PTH and FGF23 equivalently decreased phosphate uptake and were not additive, suggesting a shared mechanism of action. Protein kinase A or C blockade prevented PTH but not FGF23 actions. Conversely, inhibiting SGK1, blocking FGFR dimerization, or knocking down Klotho expression disrupted FGF23 actions but did not interfere with PTH effects. C-terminal FGF23(180-251) competitively and selectively blocked FGF23 action without disrupting PTH effects. However, both PTH and FGF23-sensitive phosphate transport were abolished by NHERF1 shRNA knockdown. Extended treatment with PTH or FGF23 down-regulated NPT2A without affecting NHERF1. We conclude that FGFR1c and PTHR signaling pathways converge on NHERF1 to inhibit PTH- and FGF23-sensitive phosphate transport and down-regulate NPT2A.

Impact of diabetes mellitus on bladder uroepithelial cells.

Diabetic bladder dysfunction (DBD), a prevalent complication of diabetes mellitus (DM), is characterized by a broad spectrum of symptoms including urinary urgency, frequency, and incontinence. As DBD is commonly diagnosed late, it is important to understand the chronic impact of DM on bladder tissues. While changes in bladder smooth muscle and innervation have been reported in diabetic patients, the impact of DM on the specialized epithelial lining of the urinary bladder, the urothelium (UT), is largely unknown. Quantitative polymerase chain reaction analysis and electron microscopy were used to evaluate UT gene expression and cell morphology 3, 9, and 20 wk following streptozotocin (STZ) induction of DM in female Sprague-Dawley rats compared with age-matched control tissue. Desquamation of superficial (umbrella) cells was noted at 9 wk DM, indicating a possible breach in barrier function. One causative factor may be metabolic burden due to chronic hyperglycemia, suggested by upregulation of the polyol pathway and glucose transport genes in DM UT. While superficial UT repopulation occurred by 20 wk DM, the phenotype was different, with significant upregulation of receptors associated with UT mechanosensation (transient receptor potential vanilloid subfamily member 1; TRPV1) and UT autocrine/paracrine signaling (acetylcholine receptors AChR-M2 and -M3, purinergic receptors P2X(2) and P2X(3)). Compromised barrier function and alterations in UT mechanosensitivity and cell signaling could contribute to bladder instability, hyperactivity, and altered bladder sensation by modulating activity of afferent nerve endings, which appose the urothelium. Our results show that DM impacts urothelial homeostasis and may contribute to the underlying mechanisms of DBD.

Leucemia mieloide crónica en crisis: blástica bases moleculares y diagnóstico / Chronic myelogenous leukemia in blastic crisis: molecular basis and diagnostic

La leucemia mieloide crónica es una enfermedad con comportamiento bifásico o trifásico, 90 por ciento de los pacientes debuta en fase crónica, 50 por ciento asintomáticos al diagnóstico. Un porcentaje con enfermedad crónica desarrollan en tiempo variable una enfermedad más agresiva definida por un período intermedio y crisis blástica. Se diagnostica al encontrar más del 20 por ciento de blastos en médula ósea, 30 por ciento en sangre periférica o enfermedad extramedular. El pronóstico es pobre, al lograr respuesta completa, con una mediana de sobrevida de 3-12 meses, independiente del fenotipo. El 50 por ciento de los pacientes tendrán una mieloide, 25 por ciento linfoide y 25 por ciento fenotipo indiferenciado. Un grupo de expertos clínicos de Bogotá, Colombia, revisaron la mejor evidencia sobre diagnóstico y tratamiento. La información se obtuvo de búsquedas estructuradas y varios registros de experimentos clínicos en curso. Presentamos conclusiones y recomendaciones para la toma de decisiones basadas en la mejor evidencia.

Leucemia mieloide crónica en crisis blástica: bases moleculares y diagnóstico (Parte I) / Chronic myelogenous leukemia in blastic phase: molecular bases and diagnosis (Part I)

La leucemia mieloide crónica es una enfermedad de comportamiento bifásico o trifásico, en la que cerca del 90 porciento de los pacientes comienzan en fase crónica y el 50 porciento de ellos serán asintomáticos al momento del diagnóstico. Un porcentaje de los sujetos con enfermedad crónica desarrollan, en un periodo variable, una enfermedad más agresiva, definida por un periodo intermedio o fase acelerada y por un estado avanzado o crisis blástica (CB). La CB se diagnostica al encontrar más del 20 porciento de blastos en la médula ósea y más del 30porciento en la sangre periférica o enfermedad extramedular. En la actualidad, el pronóstico de los pacientes con CB es pobre y depende especialmente de lograr una respuesta completa, con una mediana de supervivencia entre los tres y los doce meses, independientemente del fenotipo de la enfermedad. Aproximadamente, el 50porciento de los pacientes tendrán una CB mieloide; el 25porciento, linfoide, y el 25porciento, un fenotipo indiferenciado. Un grupo de expertos conformado por hematólogos, oncólogos y epidemiólogos clínicos de Bogotá D. C., Colombia, se encargó de revisar y seleccionar la mejor evidencia sobre el diagnóstico y tratamiento de la CB. La información se obtuvo a partir de búsquedas estructuradas realizadas en MedLine, Embase, Cochrane, Biosis, Cinhal, Lilacs y varios registros de experimentos clínicos en curso. Este documento presenta las principales conclusiones y recomendaciones para mejorar los principales desenlaces de la CB, al permitir la toma de decisiones basadas en la mejor evidencia, que promoverá el uso racional de los recursos en salud.

Chronic myeloid leukemia has traditionally been characterized by a biphasic or triphasic course. 85% to 90% of patients are diagnosed in the chronic phase, which is asymptomatic in up to 50%. A varying percentage of patients in chronic phase develop a more aggressive disease, frequently passing through an intermediate or accelerated phase, and finally evolving to an acute leukemia like blastic phase (BP). BP is characterized by extramedullary disease or by the presence ofblasts more than 20% in the bone marrow or more than 30% in the peripheral blood. An expert panel of hematologists, oncologists and clinical epidemiologists of Bogota-Colombia reviewed selected literature related with BP of chronic myeloid leukemia obtained from advanced searches in Medline, Embase, Cochrane, Biosis, Cinhal, Lilacs, and from in course clinical trials databases. The following document presents the main conclusions and some recommendations to improve outcomes of BP, to assist practitioners to apply the best available evidence, and to promote an accountable use of health care resources.

Leucemia mieloide crónica en crisis blástica: perspectiva terapéutica según la evidencia (Parte II) / Chronic myelogenous leukemia in blastic phase: therapeutic perspective according to clinical evidence (Part II)

En la actualidad, el pronóstico de los pacientes con crisis blástica (CB) es pobre y depende, especialmente, de lograr una respuesta completa, con una mediana de supervivencia entre los tres y los doce meses, independientemente del fenotipo de la enfermedad. Hasta el momento, no existe un tratamiento estándar para la CB, que habitualmente manifiesta un curso similar al de las leucemias agudas quimiorresistentes; las aproximaciones más recientes han mostrado que el uso de regímenes similares a los empleados en el manejo de las leucemias agudas asociados al imatinib permiten mejorar las tasas de supervivencia global y libres de progresión de la enfermedad. No obstante, los pacientes con esta condición deberán ser considerados candidatos para estudios experimentales. A pesar de que la posibilidad de lograr respuesta completa es baja, la población que logra llegar a ella deberá consolidarse con trasplante alogénico de médula ósea. Un grupo de expertos conformado por hematólogos, oncólogos y epidemiólogos clínicos de Bogotá D. C., Colombia, se encargó de revisar y seleccionar la mejor evidencia sobre el diagnóstico y tratamiento de la CB. La información se obtuvo a partir de búsquedas estructuradas realizadas en MedLine, Embase, Cochrane, Biosis, Cinhal, Lilacs y de varios registros de experimentos clínicos en curso. Este documento presenta las principales conclusiones y algunas recomendaciones para mejorar los principales desenlaces de la CB, y permitir así la toma de decisio- nes basadas en la mejor evidencia, que promoverá el uso racional de los recursos en salud.

Chronic myelogenous leukemia traditionally has been characterized by a biphasic or triphasic course. Blastic phase overall prognosis is poor, with a median survival of 3 to 12 months. Approximately 50% of patients have a myeloid phenotype, 25% have a lymphoid phenotype, and 25% have an undifferentiated phenotype. There is currently no standard treatment for the blastic phase of chronic myeloid leukemia, which is a chemoresistant form of acute leukemia. Current approaches include using standard acute myeloid leukemia regimens associated with imatinib in an effort to induce remission, variations of these approaches with drugs that seem more active in this specific leukemia, and the direct entry of patients into studies of investigational agents. Although the likelihood of achieving remission is small, immediate bone marrow transplantation in remission should be considered because it provides the only opportunity for long-term survival at this time. An expert panel of hematologists, oncologists and clinical epidemiologists of Bogotá, D.C., Colombia reviewed selected literature related with BP of chronic myeloid leukemia obtained from advanced searches of medial literature in MedLine, Embase, Cochrane, Biosis, Cinhal, Lilacs and from several in course clinical trials databases. The following document present the principal conclusions and some recommendations to improve outcomes of BP, to assist practitioners to apply the best available research evidence to clinical decisions, and to promote responsible use of health care resources.

Predicting bacteremia at the bedside.

Our aim was to develop a clinical prediction rule for detection of bacteremia in a cohort of patients observed prospectively at a reference center in Medellín, Colombia. The significant predictors of bacteremia were an age of >or=30 years (odds ratio [OR], 2.07; 95% confidence interval [CI], 1.19-3.60), a heart rate of >or=90 beats/min (OR, 1.90; 95% CI, 1.13-3.17), a temperature of >or=37.8 degrees C (OR, 2.42; 95% CI, 1.41-4.14), a leukocyte count of >or=12,000 cells/microL (OR, 2.40; 95% CI, 1.41-4.10), use of a central venous catheter (OR, 1.89; 95% CI, 1.02-3.50), and a length of hospitalization of >or=10 days (OR, 2.02; 95% CI, 1.25-3.24). The Hosmer-Lemeshow test revealed a goodness-of-fit of 2.99 (P=.981), and the area under the receiver operating characteristics curve was 0.7186. Simple variables obtained from the clinical history of patients are associated with bloodstream infection in a reproducible fashion and should be instrumental for prioritizing the requests for blood cultures by clinicians.

Ultraestructura de la vascularización placentaria en pacientes eclámpticas

Investigar las alteraciones vasculares en placentas de pacientes eclámpticas. Estudio descriptivo, 10 embarazadas normales y 10 eclámpticas, atendidas en el Servicio de Partos, Hospital Universitario del Valle, Cali, Colombia. Se realizó estudio histológico de la placenta, utilizando microscopía de luz, microscopía electrónica de barrido y microscopía electrónica de transmisión. Hallazgo característico en las pacientes eclámpticas es la presencia de necrosis fibrinoide y el depósito de material amorfo intramural, así como la disminución o estenosis del calibre de los vasos sanguíneos por engrosamiento de la capa media. Con microscopía de transmisión se observó marcado daño en el citoplasma, con presencia de vacuolas lipídicas y alteración en las organelas principalmente en el retículo endoplásmico rugoso. Lo anterior podría contribuir a explicar el disbalance en los productos endoteliales vasomotores (aumento de tromboxano, endotelina, angiotensina y disminución de prostaciclina y óxido nítrico) que se manifiesta clínicamente como preeclampsia