5 years DKMS Chile: approach, results and impact of the first unrelated stem cell donor center in Chile.

Introduction: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is performed worldwide to treat blood cancer and other life-threatening blood disorders. As successful transplantation requires an HLA-compatible donor, unrelated donor centers and registries have been established worldwide to identify donors for patients without a family match. Ethnic minorities are underrepresented in large donor registries. Matching probabilities are higher when donors and patients share the same ethnic background, making it desirable to increase the diversity of the global donor pool by recruiting donors in new regions. Here, we report the establishment and the first 5 years of operation of the first unrelated stem cell donor center in Chile, a high-income country in South America with a population of over 19 million. Methods: We used online and in-person donor recruitment practices through patient appeals and donor drives in companies, universities, the armed forces, and public services. After confirmatory typing donors were subjected to medical work-up and cleared for donation. Results: We recruited almost 170,000 donors in 5 years. There were 1,488 requests received for confirmatory typing and donor availability checks, of which 333 resulted in medical work-up, leading to 194 stem cell collections. Products were shipped to Chile (48.5%) and abroad. Even when the COVID-19 pandemic challenged our activities, the number of donors recruited and shipped stem cell products remained steady. In Chile there was an almost 8-fold increase in unrelated donor transplantation activity from 16 procedures in 2016-2018 to 124 procedures in 2019-2021, mainly for pediatric patients following the center's establishment. We estimate that 49.6% of Chilean patients would find at least one matched unrelated donor in the global DKMS donor pool. Discussion: Establishing a DKMS donor center in Chile has significantly increased donor availability for Chilean patients and contributed to an increase of unrelated donor stem cell transplant activity.

Uso de nivolumab en pacientes con recaída postrasplante alogénico de progenitores hematopoyéticos en enfermedad de Hodgkin: reporte de dos casos clínicos / Treatment of Hodgkin disease relapse after allogeneic transplantation with nivolumab. Report of two cases

Hodgkin's Lymphoma has a very good prognosis. In the unusually refractory patients allogeneic transplantation offers a chance of cure. The so-called checkpoint inhibitors, such as Nivolumab can play a relevant role in this type of patients. Their side effects and usefulness after allogeneic transplantation are under investigation. Relapse after allogeneic transplantation has an extremely poor prognosis. We report two patients with refractory Hodgkin's lymphoma who relapsed after an allogeneic transplant and who were successfully treated with Nivolumab.

[Treatment of Hodgkin disease relapse after allogeneic transplantation with nivolumab. Report of two cases]. / Uso de nivolumab en pacientes con recaída postrasplante alogénico de progenitores hematopoyéticos en enfermedad de Hodgkin: reporte de dos casos clínicos.

Hodgkin's Lymphoma has a very good prognosis. In the unusually refractory patients allogeneic transplantation offers a chance of cure. The so-called checkpoint inhibitors, such as Nivolumab can play a relevant role in this type of patients. Their side effects and usefulness after allogeneic transplantation are under investigation. Relapse after allogeneic transplantation has an extremely poor prognosis. We report two patients with refractory Hodgkin's lymphoma who relapsed after an allogeneic transplant and who were successfully treated with Nivolumab.

L-arginina: suplemento nutricional sin beneficios demostrados en patologías del embarazo / L-arginine supplementation in patients with disorders of pregnancy

Objetivo: análisis crítico de estudios clínicos randomizados para determinar si el suplemento con L-arginina mejora el resultado perinatal en pacientes embarazadas en riesgo o que presenten patologías como parto prematuro, síndrome hipertensivo del embarazo o restricción de crecimiento fetal intrauterino. Métodos: se realizó una búsqueda bibliográfica en base de datos Pubmed, Tripdatabase y una multibúsqueda en el Sistema de Bibliotecas de la Pontificia Universidad Católica de Chile con posterior análisis crítico de los estudios seleccionados. Resultados: se seleccionaron 14 estudios clínicos randomizados; 4 de ellos corresponden a estudios de L-arginina en hipertensión gestacional, 5 estudios de L-arginina en preeclampsia, 1 estudio de L-arginina en parto prematuro, 1 estudio de L-arginina en hipertensión crónica y 4 estudios de L-arginina en restricción de crecimiento intrauterino. Solo dos de los estudios son de buena calidad metodológica, pero uno de ellos estudia un resultado intermedio y no clínicamente relevante. El resultado más promisorio muestra que el uso de L-arginina asociada a vitaminas antioxidantes reduce significativamente la incidencia de preeclampsia en mujeres de riesgo (antecedente personal o familiar de preeclampsia). Conclusiones: no se ha demostrado la efectividad de la suplementación antenatal con L-arginina para mejorar el resultado perinatal en embarazadas en riesgo o que presentan patologías como parto prematuro, síndrome hipertensivo del embarazo o restricción de crecimiento fetal. Se requieren estudios de buen diseño que permitan conclusiones definitivas.

Objective: critical analysis of randomized clinical trials to determine whether supplementation with L-arginine improves perinatal outcome in pregnant patients at risk or presenting conditions such as preterm labor, hypertensive disorders or intrauterine fetal growth restriction. Methods: we performed a literature search in Pubmed, Tripdatabase and multisearch in the Library System of the Pontifical Catholic University of Chile to further critical analysis of selected studies. Results: We selected 14 randomized trials, 4 of them are for studies of L-arginine in gestational hypertension, 5 studies of L-arginine in preeclampsia, one study of L-arginine in preterm labor, one study of L-arginine in chronic hypertension and 4 studies of L-arginine in intrauterine growth restriction. Only two of the studies were of good methodological quality, but one these studies analyzes an intermediate result that is not clinically relevant. The most promising result shows that the use of L-arginine associated with antioxidant vitamins significantly reduced the incidence of preeclampsia in women at risk (personal or family history of preeclampsia). Conclusions: is not shown the effectiveness of antenatal supplementation with L-arginine to improve perinatal outcome in pregnant women at risk or with pathological conditions such as premature labor, hypertensive disorders and fetal growth restriction. More studies of good design are needed to allow definitive conclusions.

El trasplante intracoronario de células mononucleares de médula ósea se asocia a mejoría la función ventricular izquierda, en pacientes con cardiopatía dilatada de diferente etiología: Proyecto INNOVA Chile N°205-4350 / Autologous bone marrow cell transplantation improves ejection fraction in patients with dilated cardiomyopathy of diverse etiologies: Proyecto innova chile n° 205-4350

Introducción: Estudios recientes indican que el trasplante intracoronario de células mononucleares de médula ósea (BMCs) autólogas, mejoran la fracción de eyección (FEVI) y otros marcadores clínicos en pacientes con insuficiencia cardíaca (IC). Objetivo: Evaluar la seguridad y eficacia de la administración intracoronaria de BMCs autólogas, en pacientes con insuficiencia cardíaca (IC) en fase dilatada, de diferente etiología y en óptimas condiciones de tratamiento médico. Método: De 23 pacientes consecutivos que cumplieron con los criterios de inclusión, 12 fueron asignados a trasplante intracoronario de BMCs autólogas, recibiendo una dosis media de 8.19+/-4.43 x 10(6) células CD34+ (Grupo trasplantado). Los pacientes restantes sólo recibieron terapia estándar (Grupo control). Todos los pacientes fueron evaluados mediante Electrocardiograma, Ecocardiografía, Holter ECG, RMN Cardíaca, Test de esfuerzo, Potenciales Ventriculares Tardíos, Variabilidad de Frecuencia Cardíaca y evaluación clínica a los 0, 3, 6 y 12 meses. La capacidad funcional (CF) fue evaluada clínicamente y por cuestionarios de calidad de vida. Elanálisis estadístico fue realizado mediante Test Anova, y test de Bonferroni. Resultados: El grupo trasplantado presentó un aumento significativo de la FEVI a los 6 meses (26.75+/-4.85 vs 37.82+/-6.97 por ciento, p=0.001) mejoría que se mantuvo a los 12 meses (26.75+/-4.85 vs 37.27+/-7.51 por ciento, p=0.002). Hubo una mejora significativa de la CF en el grupo trasplantado a los 6 y 12 meses (p<0.001). No hubo cambios significativos en los volúmenes de ventrículo izquierdo, así como en las restantes variables estudiadas. En el grupo control no observamos cambios de estas variables. No hubo complicaciones en relación al trasplante de BMCs. Conclusión: En pacientes con IC severa y baja FEVI, el trasplante intracoronario de células BMCs au-tólogas, se asoció a una mejoría significativa de la FEVI y la CF, a los 6 y 12 meses. Adicionalmente, no observamos ...

Background: Recent studies indicate that intra-coronary delivery of autologous bone marrow mono-nuclear cells (BMCs) improves the ejection fraction (LVEF) and other clinical markers in patients with heart failure (HF). Aim: To evaluate the safety and efficacy of intraco-ronary delivery of autologous BMCs in patients with HF in dilated phase under optimal medical treatment. Method: Of 23 consecutive patients who met the inclusion criteria, 12 were assigned to autologous BMCs intracoronary transplantation, receiving a mean dose of 8.19+/-4.43 x 106 CD34+ cells (BMCs group). The remaining patients received only standard therapy (control group). All patients were evaluated by Electrocardiogram, Echocardiography, Holter Monitoring, Cardiac Magnetic Resonance Imaging, Stress Testing, Ventricular Late potetials, Heart Rate Variability, and regular clinical examination at baseline and at follow-up (3, 6 and 12 months). Repeated measures ANOVA and Bonferroni testing were used for statistic analysis. Results: The BMCs group presented a significant increase in EF at sixth months (26.75+/-4.85 vs. 37.82+/-6.97 per cent, p=0.001) and 12 months post-transplant (26.75+/-4.85 vs. 37.27+/-7.51 per cent, p=0.002). There was a significant improvement in functional (NYHA) in the transplanted group at 6 and 12 months (p<0.001). There were no significant changes concerning left ventricular volumes, heart rate variability and exercise stress testing. We observed no improvement of these variables in the control group. There were no complications related to the BMCs transplant. Conclusions: Intracoronary infusion of auto-logous BMCs, in addition to standard therapy, was associated with significant improvement of left ventricular function at 12 months in patients with HF. We observed no complications relative to the procedure.

[Fibrolamellar liver carcinoma: report of two cases and review of the literature]. / Carcinoma hepatocelular variedad fibrolamelar metastásico en menores de 20 años: Reporte de 2 casos tratados con intención curativa y revisión de la literatura.

Fibrolamellar hepatocellular carcinoma (FLC) is a rare histologic variant of hepatocellular carcinoma that appears most commonly in teenagers and young adults. The diagnosis is often made incidentally and surgical resection is the only curative treatment. Here we report two cases of incidental FLC involving a 19 year-old male, initially diagnosed with screening abdominal ultrasound, and a 14 year-old female that presented with abdominal pain. Diagnostic workup consisted of abdominal PET/CT and MR1 Imaging studies and tissue diagnosis was confirmed with percutaneous liver biopsy. Both patients were treated with radical liver resection/tumor excision. However, tumor recurrence was observed in both during short-term follow-up. The male patient was treated successfully with surgical treatment however the female patient succumbed top regression of disease.

Carcinoma hepatocelular variedad fibrolamelar metastásico en menores de 20 años: Reporte de 2 casos tratados con intención curativa y revisión de la literatura / Fibrolamellar liver carcinoma: Report of two cases

Fibrolamellar hepatocellular carcinoma (FLC) is a rare histologic variant of hepatocellular carcinoma that appears most commonly in teenagers and young adults. The diagnosis is often made incidentally and surgical resection is the only curative treatment. Here we report two cases of incidental FLC involving a 19 year-old male, initially diagnosed with screening abdominal ultrasound, and a 14 year-old female that presented with abdominal pain. Diagnostic workup consisted of abdominal PET/CT and MRI Imaging studies and tissue diagnosis was confirmed with percutaneous liver biopsy. Both patients were treated with radical liver resection/tumor excision. However, tumor recurrence was observed in both during short-term follow-up. The male patient was treated successfully with surgical treatment however the female patient succumbed top regression of disease.

Prior chemotherapy and allograft CD34+ dose impact donor engraftment following nonmyeloablative allogeneic stem cell transplantation in patients with solid tumors.

Significant engraftment variability occurs among patients following nonmyeloablative hematopoietic cell transplantation. We analyzed the impact of multiple factors on donor myeloid and T-cell engraftment in 36 patients with metastatic tumors undergoing cyclophosphamide/fludarabine-based conditioning. Higher CD34(+) doses facilitated donor myeloid engraftment, while prior chemotherapy exposure facilitated both donor myeloid and T-cell engraftment. At day 30, median donor T-cell and myeloid chimerism was 98% and 76%, respectively, in those patients with prior chemotherapy versus 88% (P =.008) and 26% (P <.0001) in chemotherapy-naive patients. Donor myeloid chimerism at day 45 was predicted by prior chemotherapy exposure and the log(10) of the CD34(+) dose (adjusted coefficient of determination [R(2)] =.47; P <.0001), while chemotherapy alone impacted donor T-cell engraftment. Patients with prior chemotherapy were more likely to develop acute grades II to IV graft-versus-host disease (GVHD; 8/18) compared with chemotherapy-naive patients (2/18; P =.031). Thus, tailoring the intensity of nonmyeloablative conditioning based on prior chemotherapy exposure is an important consideration in trial design.

In vitro and in vivo evidence of PNH cell sensitivity to immune attack after nonmyeloablative allogeneic hematopoietic cell transplantation.

It has been proposed that paroxysmal nocturnal hemoglobinuria (PNH) cells may proliferate through their intrinsic resistance to immune attack. To evaluate this hypothesis, we examined the impact of alloimmune pressure on PNH and normal cells in the clinical setting of nonmyeloablative allogeneic hematopoietic cell transplantation (HCT). Five patients with severe PNH underwent HCT from an HLA-matched family donor after conditioning with cyclophosphamide and fludarabine. PNH neutrophils (CD15(+)/CD66b(-)/CD16(-)) were detected in all patients at engraftment, but they subsequently declined to undetectable levels in all cases by 4 months after transplantation. To test for differences in susceptibility to immune pressure, minor histocompatibility antigen (mHa)-specific T-cell lines or clones were targeted against glycosylphosphatidylinositol (GPI)-negative and GPI-positive monocyte and B-cell fractions purified by flow cytometry sorting. Equivalent amounts of interferon-gamma (IFN-gamma) were secreted following coculture with GPI-negative and GPI-positive targets. Furthermore, mHa-specific T-cell lines and CD8(+) T-cell clones showed similar cytotoxicity against both GPI-positive and GPI-negative B cells. Presently, all 5 patients survive without evidence of PNH 5 to 39 months after transplantation. These in vitro and in vivo studies show PNH cells can be immunologically eradicated following nonmyeloablative HCT. Relative to normal cells, no evidence for a decreased sensitivity of PNH cells to T-cell-mediated immunity was observed.

Nonmyeloablative stem cell transplantation as immunotherapy for kidney cancer and other metastatic solid tumors.

Over the past few decades, great strides have been made to advance the field of allogeneic hematopoietic stem cell transplantation. The donor immune mediated graft-vs-tumor effect that follows the procedure is now widely accepted as the most effective form cancer immunotherapy available for patients with a variety of advanced hematological malignancies. Recognition that a transplanted immune system could cure patients with treatment refractory leukemia led to the development of ;low-intensity' conditioning regimens, which have improved the safety of the procedure and broadened the application of allogeneic immunotherapy to a growing list of neoplastic diseases. Here we discuss the investigational use of allogeneic transplantation as immunotherapy for patients with metastatic, treatment-refractory solid tumors.

Absence of donor-derived keratinocyte stem cells in skin tissues cultured from patients after mobilized peripheral blood hematopoietic stem cell transplantation.

OBJECTIVE: Recent studies suggest that primitive bone marrow-derived cells contribute to regeneration of many tissues, including muscle, endothelium, myocardium, neural tissues, liver, and skin. Conversely, primitive cells resident in muscle and other tissues have been reported to reconstitute hematopoiesis. We investigated the contribution of cells with a primitive hematopoietic phenotype to human epidermal skin formation in recipients of allogeneic mobilized peripheral blood hematopoietic stem cell (HSC) transplantation. PATIENTS AND METHODS: Our study population included female patients who had received granulocyte colony-stimulating factor mobilized peripheral blood HSC transplants from male donors for a variety of benign and malignant hematologic disorders at least 6 months before study entry, with a history of skin graft-vs-host disease. Epidermal skin cells (keratinocytes) obtained from punch biopsies of the skin were cultured under conditions specific for growth and expansion of homogenous populations of keratinocytes from keratinocyte stem cells. After multiple passages, DNA was extracted from cultured cells and evaluated by two different polymerase chain reaction (PCR) method for detection of Y chromosome specific sequences. RESULTS: Neither sensitive PCR-based technique revealed the presence of male donor-derived keratinocyte stem cells in keratinocytes cultured from skin biopsies of female allogeneic transplantation recipients. CONCLUSIONS: We could not confirm the contribution of donor mobilized peripheral blood hematopoietic stem cells to keratinocyte stem cell populations after HSC transplantation. These results cannot explain the presence of donor-derived cells with keratinocyte phenotypic markers in tissue sections of HSC transplant recipients.