Current assessment and management of measurable residual disease in patients with acute lymphoblastic leukemia in the setting of CAR-T-cell therapy / 中华医学杂志(英文版)

Chimeric antigen receptor (CAR)-modified T-cell therapy has achieved remarkable success in the treatment of acute lymphoblastic leukemia (ALL). Measurable/minimal residual disease (MRD) monitoring plays a significant role in the prognostication and management of patients undergoing CAR-T-cell therapy. Common MRD detection methods include flow cytometry (FCM), polymerase chain reaction (PCR), and next-generation sequencing (NGS), and each method has advantages and limitations. It has been well documented that MRD positivity predicts a poor prognosis and even disease relapse. Thus, how to perform prognostic evaluations, stratify risk based on MRD status, and apply MRD monitoring to guide individual therapeutic decisions have important implications in clinical practice. This review assesses the common and novel MRD assessment methods. In addition, we emphasize the critical role of MRD as a prognostic biomarker and summarize the latest studies regarding MRD-directed combination therapy with CAR-T-cell therapy and allogeneic hematopoietic stem cell transplantation (allo-HSCT), as well as other therapeutic strategies to improve treatment effect. Furthermore, this review discusses current challenges and strategies for MRD detection in the setting of disease relapse after targeted therapy.

Research Progress of Allogeneic Hematopoietic Stem Sell Trans-plantation in the Treatment of Adult Hemophagocytic Lympho-histiocytosis --Review / 中国实验血液学杂志

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory clinical syndrome of uncontrolled immune response which results in hypercytokinemia due to underlying primary or secondary immune defect. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only cure therapy for primary HLH and recurrent/refractory hemophagocytic lymphohistiocytosis. Compared with children HLH, adult HLH is a much more heterogeneous syndrome requiring a more individualized protocol depending on the underlying trigger, disease severity and genetic background. At present, there remain controversies in various aspects including indications of haematopoietic cell transplantation (HCT), conditioning regimen, efficacy and prognosis. This article will review the recent advances of allo-HSCT in the treatment of adult HLH based on the above issues.

The Clinical Efficacy of Haploidentical Hematopoietic Stem Cell Transplantation by Using Parental Donors in Patients with Thalassemia / 中国实验血液学杂志

OBJECTIVE@#To analyze the clinical efficacy of haploidentical hematopoietic stem cell transplantation (haplo-HSCT) by using parental donors on thalassemia patients.@*METHODS@#The 13 thalassemia patients treated by haplo-HSCT using parental donors in our hospital from July 1, 2016, to July 1, 2020 were retrospectively reviewed. Hematopoiesis reconstitution, the incidence of GVHD, infections and the long-term survival of the patients were analyzed.@*RESULTS@#Twelve of the 13 patients were successfully implanted, the success rate of implantation was 92.3%. The median time of neutrophil and platelet engraftment was 12.5 days (range, 9-22 days) and 21 days (range,12-34 days), respectively. One patient achieved primary graft failure. Three (25%) patients developed to acute GVHD (aGVHD) and achieved complete remission after treatment. Chronic GVHD developed in three (25%) patients, one of them was extensive and under treatment, while one patient developed to severe bacterial infection (7.7%). CMV viremia was diagnosed in two patients (15.4%). There were no patients developed to CMV disease. Three (23.1%) patients achieved EB viremia after transplantation, one of them developed to EBV-related lymphocytic proliferative disease, while there were no patients showed invasive fungal infection. At the last follow-up, all patients survived, twelve of them were free from transfusion dependency. There were no transplant-related deaths. Projected overall and thalassemia-free survival at three years was 100% and 92.3%, respectively.@*CONCLUSION@#The transplant protocol of haplo-HSCT by using parental donors in patients with thalassemia has reliable source of donors, high incidence of successful implantation and low incidence of GVHD, which can be used as an effective way to increase the source of donors in children with thalassemia.

Evaluación pretrasplante en otorrinolaringología / Pretransplant evaluation in otolaryngology

Resumen Los pacientes trasplantados presentan mayor vulnerabilidad a complicaciones infecciosas, no solo debido al uso de drogas inmunosupresoras, sino que también, a las enfermedades subyacentes que presentan y a la falla de órganos primarios. A pesar de que las infecciones otorrinolaringológicas no son frecuentes en estos pacientes, es importante establecer un adecuado estudio y tratamiento de ellas. A través del siguiente artículo se aportan directrices en el estudio pretrasplante desde un enfoque otorrinolaringológico, generando recomendaciones de acuerdo a la patología del paciente y el órgano a trasplantar. Si bien, las recomendaciones se realizan según evaluación rinosinusal, otológica y faringoamigdalina, una adecuada anamnesis y examen físico son los pilares de la evaluación pretrasplante en otorrinolaringología, reservándose el estudio con imágenes para aquellos pacientes con alteraciones sospechosas.

Abstract Transplanted patients have higher frequency of infectious complications, not only due to the use of immunosuppressive drugs, but also the underlying diseases that present and the failure of primary organs. Although ear, nose and throat (ENT) infections are not frequent in these patients, it is important to establish an adequate study and treatment of them. Through the following article, guidelines are provided in the pretransplant study from an ENT approach, generating recommendations according to the pathology of the patient and the organ to be transplanted. Although, the recommendations are made according to rhinosinusal, otological and pharyngotonsiline evaluation, adequate anamnesis and physical examination are the pillars of the pretransplant evaluation in otolaryngology, reserving the study with images for patients with suspicious alterations.

Estudio pre-trasplante hepático: ¿qué buscar y cómo hacerlo? Si algo es positivo: ¿qué hacemos? / Liver transplant pre-study: what to search for and how to do it? what shall we do in case of positive findings?

The process of evaluation of candidate patients for liver transplantation should include the risk of infectious diseases in order to prevent the drop out of the waiting list due to infections or the occurrence of these in the post-transplant period. Cirrhotic patients in the pre-transplant stage are very ill and usually have severe infections. The most common is spontaneous bacterial peritonitis, but they can also present urinary infections and pneumonias. Mortality due to infectious causes has been reported up to 40% in patients on the transplant waiting list. The transplanted patients may have a poor immune response to vaccination, so the optimal immunization period is pre-transplant. In the post-transplant period, Gram-negative bacterial infections are one of the main complications. Invasive fungal infections and cytomegalovirus can also have a high impact on morbidity and mortality. Transplanted patients may also have mycobacterial infections in relation to a latent tuberculosis infection. In the following article we present the pre-transplant evaluations, vaccination schemes and antimicrobial prophylaxis that are used in liver transplantation.

El proceso de evaluación de pacientes candidatos para trasplante hepático debe incluir el riesgo de enfermedades infecciosas a fin de prevenir la salida de la lista por infecciones o la ocurrencia de éstas en el período post-trasplante. Los pacientes cirróticos en la etapa pre-trasplante están muy enfermos y suelen presentar infecciones graves. La más común es la peritonitis bacteriana espontánea, pero también pueden presentar infecciones urinarias y neumonías. La mortalidad por causa infecciosa se ha reportado hasta en 40% en pacientes en lista de espera de trasplante. Los pacientes trasplantados pueden tener una pobre respuesta inmune a la vacunación, por lo que el momento óptimo de inmunización es en el período pretrasplante. En el período post-trasplante las infecciones bacterianas por Gram negativos son una de las principales complicaciones. Las infecciones por hongos invasores y el citomegalovirus también pueden tener un alto impacto en morbilidad y mortalidad. Los pacientes trasplantados también pueden presentar infecciones por micobacterias en relación a una infección latente por tuberculosis. En el siguiente artículo se presentan las evaluaciones pre-trasplante, esquemas de vacunación y profilaxis antimicrobiana que se utilizan en trasplante hepático.

Cardiovascular risk and use of conicity index in patients submitted to autologous hematopoietic stem cell transplantation / Risco cardiovascular e uso do índice de conicidade em pacientes submetidos ao transplante autólogo de células-tronco hematopoiéticas

ABSTRACT Objective To analyze the prevalence of overweight and the use of conicity index for cardiovascular risk assessment in individuals submitted to autologous hematopoietic stem cell transplantation. Methods The sample comprised 91 patients of both sexes, who underwent autologous hematopoietic stem cell transplantation from September 2008 to December 2013, aged 18 years or over. To determine the nutritional profile, we collected anthropometric data on weight, height, waist circumference upon hospital admission. The body mass index and the conicity index were calculated. Results A total of 91 patients diagnosed with multiple myeloma, Hodgkin's lymphoma, non-Hodgkin's lymphoma and other conditions were evaluated. The mean age was 43.5 (14.2) years, 63.7% were male. We verified that according to the body mass index, 63.7% were overweight and, according to waist circumference, 74.7% had a higher risk for cardiovascular diseases. According to the calculation of the conicity index, 92.3% of patients presented increased cardiovascular risk. Patients with multiple myeloma had a higher conicity index when compared to other patients (p<0.01). Conclusion This study revealed a high prevalence of overweight and cardiovascular risk. It should be noted that the conicity index was a good method to evaluate cardiovascular risk and that new studies using this index should be performed.

RESUMO Objetivo Analisar a prevalência de excesso de peso e a utilização do índice de conicidade para a avaliação do risco cardiovascular em indivíduos submetidos ao transplante autólogo de células-tronco hematopoiéticas. Métodos A amostra foi composta por 91 pacientes, de ambos os sexos, submetidos ao transplante autólogo de células-tronco hematopoiéticas, de setembro de 2008 a dezembro de 2013, com idade igual ou superior a 18 anos. Para traçar o perfil nutricional, foram coletados dados antropométricos, como peso, altura e circunferência da cintura, na admissão hospitalar. Calcularam-se o índice de massa corporal e o índice de conicidade. Resultados Foram avaliados 91 pacientes, diagnosticados com mieloma múltiplo, linfoma de Hodgkin, linfoma não Hodgkin e outras patologias. A média de idade foi de 43,5 (14,2) anos, e 63,7% eram do sexo masculino. Verificou-se que, de acordo com o índice de massa corporal, 63,7% apresentavam excesso de peso e, segundo a circunferência da cintura, 74,7% possuíam maior risco para doenças cardiovasculares. De acordo com o cálculo do índice de conicidade, constatou-se que 92,3% dos pacientes apresentavam risco cardiovascular aumentado. Os pacientes com mieloma múltiplo apresentaram índice de conicidade mais elevado, se comparado aos outros pacientes (p<0,01). Conclusão Este estudo revelou alta prevalência de excesso de peso e de risco cardiovascular. Salienta-se que o índice de conicidade se mostrou um bom método para avaliação do risco cardiovascular e que novos estudos utilizando este índice devem ser realizados.

Neurological outcomes after hematopoietic stem cell transplantation for cerebral X-linked adrenoleukodystrophy, late onset metachromatic leukodystrophy and Hurler syndrome / Desfechos neurológicos após transplante de células tronco hematopoiéticas na adrenoleucodistrofia ligada ao X, forma cerebral, na leucodistrofia metacromática de início tardio e na síndrome de Hurler

ABSTRACT Hematopoietic stem cell transplantation (HSCT) is the only available treatment for the neurological involvement of disorders such as late-onset metachromatic leukodystrophy (MLD), mucopolysaccharidosis type I-Hurler (MPS-IH), and X-linked cerebral adrenoleukodystrophy (CALD). Objective To describe survival and neurological outcomes after HSCT for these disorders. Methods Seven CALD, 2 MLD and 2 MPS-IH patients underwent HSCT between 2007 and 2014. Neurological examinations, magnetic resonance imaging, molecular and biochemical studies were obtained at baseline and repeated when appropriated. Results Favorable outcomes were obtained with 4/5 related and 3/6 unrelated donors. Two patients died from procedure-related complications. Nine transplanted patients were alive after a median of 3.7 years: neurological stabilization was obtained in 5/6 CALD, 1/2 MLD, and one MPS-IH patient. Brain lesions of the MPS-IH patient were reduced four years after HSCT. Conclusion Good outcomes were obtained when HSCT was performed before adulthood, early in the clinical course, and/or from a related donor.

RESUMO O transplante de células tronco hematopoiéticas (TCTH) é o único tratamento disponível para o envolvimento neurológico de doenças como a leucodistrofia metacromática (MLD), a mucopolissacaridose tipo I-Hurler (MPS-IH) e a adrenoleucodistrofia (CALD). Objetivos Descrever a sobrevida e os desfechos neurológicos após o TCTH nessas doenças. Métodos Sete pacientes CALD, 2 MLD e 2 MPS-IH realizaram TCTH entre 2007 e 2014. Avaliações neurológicas, ressonância nuclear magnética e estudos bioquímicos e moleculares foram feitos no baseline e repetidos quando apropriado. Resultados Desfechos favoráveis foram obtidos em 4/5 TCTH de doadores relacionados e em 3/6 não relacionados. Dois pacientes faleceram de complicações do procedimento. Nove transplantados sobreviveram após uma mediana de 3,7 anos: estabilização neurológica foi obtida em 5/6 CALD, ½ MLD e em um caso MPS-IH. As lesões encefálicas de um caso MPS-IH reduziram-se quatro anos após o TCTH. Conclusão Bons desfechos foram obtidos quando o TCTH foi feito antes da vida adulta, cedo no curso clínico e/ou a partir de um doador relacionado.

Allogenic bone narrow transplantation in sickle-cell diseases / Transplante alogênico de medula óssea em doenças falciformes

SUMMARY Sickle-cell diseases are the most common inherited hemoglobinopathies worldwide. Improvement in survival has been seen in the last decades with the introduction of careful screening and prevention of complications and the introduction of hydroxyurea. Stem-cell transplantation is currently the only curative option for these patients and has been indicated for patients with neurological events, repeated vaso-occlusive crisis, any organ damage or presence of red blood cell antibodies. Related bone-marrow or cord-blood transplant has shown an overall survival of more than 90% with a disease-free survival of 90% in 1,000 patients transplanted in the last decades. The use of unrelated donors unfortunately has not shown the same good results, but better typing methods and improved support may improve the outcome with this source of stem cells in the future. In Brazil, only recently stem cell transplant from related donors has been included in the procedures performed in the public health system. The use of related bone marrow or cord blood and a myeloablative conditioning regimen are considered standard of care for patients with sickle-cell diseases. Transplants with non-myeloablative regimens, unrelated donors or haploidentical donors should be performed only in controlled clinical trials.

RESUMO As doenças falciformes são as hemoglobinopatias mais frequentes mundialmente. Nas últimas décadas vivenciamos melhora na sobrevida de portadores destas patologias com a introdução de medidas preventivas e o uso precoce da hidroxiurea. O transplante de medula óssea alogênico (alo TMO) é a única opção terapêutica curativa para as hemoglobinopatias. O mesmo tem sido indicado para pacientes com complicações neurológicas, crises vasoclusivas repetidas, alguma lesão orgânica e alosensibilizados. O uso de doadores relacionados de medula óssea ou cordão umbilical mostrou em 1000 procedimentos realizados sobrevida global de 95% e sobrevida livre de ventos de 90%. O uso de doadores não aparentados não mostrou resultados tão expressivos, mas no futuro métodos melhores de tipagem de HLA e de medidas de suporte podem melhorar estes resultados. No Brasil apenas recentemente o alo TMO foi incluído no âmbito do sistema único de saúde (SUS) como opção terapêutica para portadores de doenças falciformes. O uso de doadores aparentados de MO ou de SCU com regime mieloablativo é considerado hoje tratamento estabelecido, sendo que o uso de doadores alternativos não aparentados ou haploidenticos e o uso de transplante com regime não mieloablativo deve ser considerado apenas em estudos clínicos.

Hodgkin's Lymphoma - evaluation of patients submitted to Autologous transplantation of hematopoietic cells in the Hematology Service of the Hospital Walter Cantídio - Fortaleza, Brazil / Linfoma de Hodgkin - avaliação dos pacientes submetidos a transplante autólogo de células hematopoéticas no Serviço de Hematologia do HUWC

SUMMARY The Autologous HSCT is an important alternative for refractory or recurrent HL patients in terms of survival and improved quality of life. This study analyzes the results of autologous BMT performed in HL patients in the Transplant Unit of the HUWC/ HEMOCE (Fortaleza - CE, Brazil). Fifty-two transplanted patients were studied from January 2009 to October 2015, among them, 30 men and 22 women, mean age of 28.2 years. All of them received GCS-F during the mobilization, in some cases associated with Vinorelbine or Plerixafor, with CD34 collection averaging 4.8 CD34/kg. The conditioning was performed with BEAC, NEAM or BEAM and the grafting with an average of 10 days. The evaluation on D + 100 showed: CR - 42 (82.7%), PR - 08 (13.5%) and 02 (3.8%) deaths, three and six days after cell infusion. After the D+100, 08 patients in CR showed HL recurrence from 06 to 36 months; 03 died and 05 are being treated with brentuximab; among the 08 patients in PR, 01 died due to HL activity, 04 months after BMT and 07 patients are undergoing treatment. The final evaluation of HL transplant patients showed an OS of 88.5% and a DFS of 61.5% in 6 years, with OS of the chemosensitive patients of 81% and of the chemoresistant ones, of 72.6%. It is possible to conclude that the Autologous HSCT has shown to be an excellent rescue therapy regarding tolerance, as well as the overall survival.

RESUMO O TCTH autólogo é uma importante alternativa para os pacientes de LH refratários ou recidivados, em termos de sobrevida e melhora da qualidade de vida. O presente trabalho analisa os resultados do TMO autólogo realizado em pacientes de LH na Unidade de Transplante do SH do HUWC/HEMOCE. Foram estudados 52 pacientes submetidos ao TMO de janeiro de 2009 a outubro de 2015, sendo 30 homens e 22 mulheres, média de idade de 28,2 anos. Todos receberam GCS-F na mobilização, em alguns casos associados a Vinorelbine ou a Plerixafor e coleta de CD34 com média de 4,8CD34/kilo. O condicionamento foi realizado com BEAC, NEAM ou BEAM e a enxertia com média de 10 dias. A avaliação no D+100 mostrou: RC – 42 (82,7%), RP – 08 (13,5%) e 02 (3,8%) óbitos ocorridos 3 e 6 dias após a infusão das células. Após o D+100, 08 pacientes em RC apresentaram recidiva do LH entre 6 e 36 meses; 3 foram a óbito e 5 estão em tratamento com brentuximabe; os 8 pacientes em RP, 1 faleceu por atividade do LH, 4 meses após o TMO e 7 estão em tratamento. A avaliação final dos pacientes de LH transplantados mostrou uma SG de 88,5% e SLD de 61,5% em 6 anos, SG dos pacientes quimiossensiveis de 81% e dos quimioresistentes de 72,6%. É possível concluir que o TCTH Autólogo se coloca como excelente terapia de resgate em relação à tolerância, bem como na sobrevida global.

Ajuste de intensidad para el trasplante hematopoyético alogénico en leucemia aguda / Intensity adjustment of hematopoietic alogeneic transplantation in acute leukemia

Background: The intensity of conditioning chemotherapy and radiotherapy in hematopoietic stem cell transplantation (HSCT) varies according to several factors including the patient’s age, pre-existing conditions and performance status. Myeloablative conditioning (MA) increases transplant related mortality and reduces survival in older patients. Reduced intensity conditioning (RIC) is a good option for these patients. Aim: To report our experience with HSCT in patients of different ages with acute leukemia. Material and Methods: Retrospective analysis of 115 allogeneic HSCT performed in patients with acute myeloid or lymphoblastic leukemia. Results: We analyzed the cohort of patients in groups according to age at transplantation: younger than 40 years (n = 74), 41 to 50 years (n = 25) and older than 51 years of age (n = 16). Overall survival (OS), Disease free survival (DFS) and relapse at five years were similar in both groups of patients younger than 50 years (OS 40 and 44% respectively, DFS 38 and 42% respectively and relapse 40% and 34% respectively, p = NS). Patients over 51 years had a five years OS of 12%. However when we analyzed those patients by date and conditioning we found that patients who were treated with MA regimens in the first decade of the transplant program (before 2000) had lower OS compared to those treated after 2000 with RIC (five years OS 49% and 12% respectively, p < 0.01). No significant differences in terms of OS, recurrence or incidence of graft-versus-host disease were found when comparing groups under 40 years, between 41 and 50 years and older than 51 years treated only with RIC. Conclusions: RIC provides the possibility of HSCT in older patients with rates comparable to those obtained in younger patients successfully treated with MA conditioning.

Evaluación de dispositivo de asistencia ventricular cardiológico (DAV) / Evaluation of cardiological ventricular assist device (VAD)

INTRODUCCIÓN: Antecedentes: La insuficiencia es una anomalia de la estrutura o la función cardiacas que hace que el corazón no pueda suministrar oxígenio a una frecuencia acorde con las necesidades de los tejidos normales de llenado. Se define clinciamente como un síndrome con síntomas (disnea, edema de miembros inferiores, fatiga...) y signos tipicos (presión venosa yugular elevada, crepitantes pulmonares, latido apical desplazado...) consecuencia de la alteración estructural o de la función cardiacas. Aspectos Generales: La insuficiencia cardiaca es una enfermedad progresiva y letal, aún con tratamiento adecuado. Así, una vez establecido el diagnp´óstico de insuficiência cardiaca, la tasa de mortalidad es del 50% a los 4 años y el 40% de los pacientes ingresados por insuficiencia cardiaca fallece o reingresa durante el primer año. En situación de insuficiencia cardiaca grave refractaria, el pronóstico, con tratamiento médico, es aún peor, con una supervivencia al año menor de 25%, comparable al de las neoplasias más agresivas. Tecnología Sanitaria de Interés: Los dispositivos de asistencia ventricular (DAV) son aquellos capaces de generar flujo circulatorio para sustituir parcial o totalmente la función del corazón en situaciones agudas o crónicas de fracaso cardiaco severo que no responde a otros tratamientos. Los DAV pueden proporcionar apoyo hemodinámico al ventrículo izquierdo, al derecho o a ambos, e incluso pueden sustituir completamente sus funciones. METODOLOGÍA: Estrategia de Búsqueda: Se realizó una búsqueda de la literatura con respecto a la eficacia y seguridad del uso de los Dispositivos de Asistencia Ventricular (DAV) en las bases de datos MEDLINE y TRIPDATABASE. Se hizo una búsqueda en www.clinicaltrials.gov, para poder identificar ensayos aún en elaboración o que no hayan sido publicados. Adicionalmente, se hizo una búsqueda dentro de la información generada por grupos que realizan revisiones sistemáticas, evaluación de tecnologías sanitarias y guías de práctica clínica, tales como The Cochrane Library y The National Institute for Health and Care Excellence (NICE). RESULTADOS: Se realizó la búsqueda bibliográfico y de evidencia científica para el sustento del uso de los DAV en pacientes candidato a trasplante. Se presenta la evidencia disponible en guías de práctica clínica, Evaluación de Tecnologías sanitarias, revisiones sistemáticas y ensayos clínicos. CONCLUSIONES: En la presente evaluación de tecnología sanitaria se evidencia la eficacia y seguridad del uso de los Dispositivos de Asistencia Ventricular (DAV) como puente al trasplante cardiaco. Se demuestra la alta tasa de supervivencia que tienen los pacientes con insuficiencia cardiaca terminal, a los cuales se le indicó el uso de un Dispositivio de Asistencia Ventricular como puente al tranplante cardiaco. Se evidencia la recuperación de la funcionalidad cardiaca y la calidad de vida de los pacientes con severidad progresiva a la insuficiencia cardiaca. Los estudios corroboran adicionalmente, que el uso del Dispositivo de Asistencia Ventricular están siendo utilizados para otras indicaciones, como los pacientes inotrópicos dependientes, los pacientes con riesgo de mortalidad al año y los que tienen falla de otros órganos.

Preparation of infertile male rabbits by local electron beam irradiation for intratesticular transplantation of autologous bone marrow stem cells

PURPOSE: To explore an efficient and safe protocol for the preparation of infertile male rabbits from which bone marrow stem cells (BMSCs) could be isolated and cultured. METHODS: Autologous BMSCs could be used for intratesticular transplantation and male infertility research. For this model, various doses (e.g., 6, 8, 10, or 12 Gy) of electron beam irradiation from a linear accelerator were locally applied to the scrotum of 5-month-old male New Zealand white rabbits. The effects of irradiation were compared between treatment groups, and with age-matched normal controls. Both morphology and hollow ratios of seminiferous tubules (HRST) were examined two, four, six, eight and 12-weeks post-irradiation. RESULTS: The seminiferous epithelium showed varying degrees of damage in all treatment groups compared with unirradiated controls, yet Sertoli and Leydig cells appeared unaffected. A dose-dependent response in spermatogenesis was also observed. BMSCs that were isolated and cultured from rabbits of the normal control group and the 12 Gy treatment group were compared with respect to morphology and growth. Starting at 6 weeks, HRST of the 12 Gy-treatment group were stable, and were the highest among all the groups. BMSCs from rabbits treated with 12 Gy also exhibited similar growth as the control group. CONCLUSION: Local dose of 12 Gy to the testes of 5-month-old male New Zealand rabbits is a protocol with which to obtain autologous bone marrow stem cells.

Primeros diez trasplantes autólogos de progenitores hematopoyéticos en adultos, en el servicio público de salud en Chile / First ten hematopoietic stem cell transplants performed in the adult public health service in Chile

Background: Hematopoietic stem cell transplantation (HSCT) is an effective therapy for hematological diseases such as lymphoma and multiple myeloma. In 2004, the Cancer Unit of the Ministry of Health incorporated the HSCT to the National Cancer Program in Adults. Until 2008 we purchased services to private institutions while implementing the national center for HSCT of adults in the Hospital del Salvador. Aim: To report the first ten HSCT conducted in this center. Material and Methods: All cases were approved by a national commission for adult HSCT. The entire process was carried out based on evidence-based protocols. Results: Six patients with Hodgkin lymphoma, three with multiple myeloma and one with a diffuse large B cell lymphoma were transplanted. Age range was 19 to 48 years and five patients were male. An average of 2.2 aphereses per patient was required. The CD 34 stem cell collection was 5.06 x 10(6) x Kg. The conditioning regimes were BEAM (carmus-tine, etoposide, cytosine arabinoside, melphalan) and melphalan 200 according to the underlying disease. Seventy percent of the patients developed mild to moderate mucositis and 50% had febrile neutropenia, with good response to treatment. In two cases there was an association with influenza. The engraftment of neutrophils and platelets was achieved on day +10 and +11 respectively. At follow-up until day +100, there was no morbidity or mortality. Conclusions: These results confirm the quality standard that this intervention has achieved in our institution. The Chilean National Center for HSCT on Adults should be established as a public core care, teaching and research facility.

Inmunosupresión en donantes renales: Expresión de citoquinas proinflamatorias / Immunosuppression in kidney donors with rapamycin and tacrolimus: Proinflammatory cytokine expression

La lesión por isquemia y reperfusión (IRI) es uno de los principales problemas en el trasplante. Nuestro objetivo fue evaluar el efecto del pre - acondicionamiento al donante con rapamicina y tacrolimus para prevenir la lesión por IRI. Las ratas Wistar donantes, 12 horas antes de la nefrectomía, recibieron fármacos inmunosupresores. La muestra se dividió en cuatro grupos experimentales: un grupo con intervención simulada (sham), un grupo control sin tratamiento, otro tratado con rapamicina (2 mg/kg) y el restante tratado con tacrolimus (0.3 mg/kg). Se retiró el riñón izquierdo y después de tres horas de isquemia fría, se lo trasplantó. Veinticuatro horas después, el órgano trasplantado se recuperó para el análisis histológico y la evaluación de la expresión de citoquinas. El tratamiento de pre-acondicionamiento con rapamicina o con tacrolimus redujo significativamente el nitrógeno ureico en sangre y los niveles de creatinina en comparación con el control (BUN: p < 0.001; creatinina: p < 0.001). La necrosis tubular aguda fue significativamente menor en las ratas donantes tratadas con inmunosupresores en comparación con el grupo control (p < 0.001). Finalmente, las citoquinas inflamatorias, como TNF-α, IL-6 y rIL-21, mostraron niveles más bajos en el injerto de los animales que recibieron tratamiento. Este estudio experimental exploratorio muestra que el pre-acondicionamiento en donantes con rapamicina y tacrolimus en dos grupos distintos mejora los resultados clínicos y anatomopatológicos en receptores, con una reducción in situ de citoquinas pro-inflamatorias relacionadas con la diferenciación Th17, y de este modo crea un ambiente favorable para la diferenciación de células T regulatorias (Tregs).

The ischemia-reperfusion injury (IRI) remains a major problem in transplantation. The objective of this study was to evaluate the effects of preconditioning a donor group with rapamycin and another donor group with tacrolimus to prevent IRI. Twelve hours before nephrectomy, donor Wistar rats received immunosuppressive drugs. The sample was divided into four experimental groups: a sham group, an untreated control group, a group treated with rapamycin (2 mg/kg) and a group treated with tacrolimus (0.3 mg/kg). Left kidneys were removed and, after three hours of cold ischemia, grafts were transplanted. Twenty-four hours later, the transplanted organs were recovered for histological analysis and evaluation of cytokine expression. The pre-conditioning treatment with rapamycin or tacrolimus significantly reduced donor blood urea nitrogen and creatinine levels compared with control group (BUN: p < 0.001 vs. control and creatinine: p < 0.001 vs. control). Acute tubular necrosis was significantly lower in donors treated with immunosuppressant drugs compared with the control group (p < 0.001). Finally, inflammatory cytokines such as TNF-α, IL-6 and rIL-21 showed lower levels in the graft of pre-treated animals. This exploratory experimental study shows that preconditioning donors with rapamycin and tacrolimus in different groups improves clinical outcome and pathology in recipients and reduces in situ pro-inflammatory cytokines associated with Th17 differentiation, creating a favorable environment for the differentiation of regulatory T cells (Tregs).

Modelo experimental ex vivo com bloco pulmonar dividido / Ex vivo experimental model: split lung block technique

Modelos de recondicionamento pulmonar ex vivo têm sido avaliados desde sua proposição. Quando são utilizados pulmões humanos descartados para transplante, a grande variabilidade entre os casos pode limitar o desenvolvimento de alguns estudos. No intuito de reduzir esse problema, desenvolvemos uma técnica de separação do bloco pulmonar em direito e esquerdo com posterior reconexão, permitindo que um lado sirva de caso e o outro de controle.

Since they were first established, ex vivo models of lung reconditioning have been evaluated extensively. When rejected donor lungs are used, the great variability among the cases can hinder the progress of such studies. In order to avoid this problem, we developed a technique that consists of separating the lung block into right and left blocks and subsequently reconnecting those two blocks. This technique allows us to have one study lung and one control lung.

Autologous blood stem cell transplantation for Hodgkin and non-Hodgkin lymphoma: Complications and outcome.

Background. We analysed data on patients of Hodgkin and non-Hodgkin lymphoma treated with high dose chemotherapy followed by autologous stem cell transplantation to determine the toxicity, pattern of infections and long term outcome. Methods. There were 34 male and 10 female patients (median age 35 years, range 15–67 years). Before transplantation, 31 patients (70.5%) had chemosensitive disease and 13 (29.5%) had chemoresistant disease. Granulocyte-colony stimulating factor mobilized peripheral blood stem cells were used as the source of stem cells. The patients received high dose chemotherapy using CBV (cyclophosphamide, BCNU and VP- 16 [etoposide] n=38), BEAM (BCNU, etoposide, cytosine arabinoside and melphalan, n=3), cytosine arabinoside, etoposide and melphalan (n=2) and melphalan alone (n=1). Prophylaxis with antifungal drugs (fluconazole/itraconazole) and acyclovir was used. Results. Following transplant, 32 patients (72.7%) responded; complete response was achieved in 25 patients (56.8%) and partial response in 7 (15.9%). The rate of complete response was higher for patients with pre-transplant chemosensitive disease (23/31 [74.2%] v. 2/13 [15.4%], p<0.001). Gastrointestinal toxicity, and renal and liver dysfunctions were major non-haematological toxicities; 3 patients (7%) died of regimen-related toxicity. Infections (predominantly Gram-negative) accounted for 2 deaths (4.5%) seen before day 30. At a median follow up of 79 months (range 14–168 months), median overall and event-free survival were 78 months and 28 months, respectively. Estimated mean (SE) overall and event-free survival at 60 months were 54.34% (0.07) and 34.3% (9.88), respectively. Conclusion. Patients with pre-transplant chemosensitive disease and those who achieved complete response following transplant had a significantly better chance of survival.

Cytomegalovirus Ventriculoencephalitis after Unrelated Double Cord Blood Stem Cell Transplantation with an Alemtuzumab-containing Preparative Regimen for Philadelphia-positive Acute Lymphoblastic Leukemia

Despite the prophylaxis and preemptive strategies using potent antiviral agents, cytomegalovirus (CMV) remains a major infectious cause of morbidity and mortality in allogeneic stem cell transplantation (SCT) recipients. Delayed immune reconstitution after SCT, such as cord blood and T-cell depleted SCT with the use of alemtuzumab, has been associated with an increased frequency of CMV disease as well as CMV reactivation. CMV disease involving central nervous system is an unusual presentation in the setting of SCT. We report a case of CMV ventriculoencephalitis after unrelated double cord blood SCT with an alemtuzumab-containing preparative regimen for Philadelphia-positive acute lymphoblastic leukemia.

A retrospective compariso of cyclophosphamide plus antithymocyte globulin with cyclophosphamide plus busulfan as the conditioning regimen for severe aplastic anemia

Allogeneic hematopoietic stem cell transplantation (AHSCT) is the treatment of choice for young patients with severe aplastic anemia (SAA). The association of antithymocyte globulin (ATG) and cyclophosphamide (CY) is the most frequently used conditioning regimen for this disease. We performed this retrospective study in order to compare the outcomes of HLA-matched sibling donor AHSCT in 41 patients with SAA receiving cyclophosphamide plus ATG (ATG-CY, N = 17) or cyclophosphamide plus busulfan (BU-CY, N = 24). The substitution of BU for ATG was motivated by the high cost of ATG. There were no differences in the clinical features between the two groups, including age, gender, cytomegalovirus status, ABO match, interval between diagnosis and transplant, and number of total nucleated cells infused. No differences were observed in the time to neutrophil and platelet engraftment, or in the risk of veno-occlusive disease and hemorrhage. However, there was a higher risk of mucositis in the BU-CY group (71 vs 24 percent, P = 0.004). There were no differences in the incidence of neutrophil and platelet engraftment, acute and chronic graft-versus-host disease, and transplant-related mortality. There was a higher incidence of late rejection in the ATG-CY group (41 vs 4 percent, P = 0.009). Although the ATG-CY group had a longer follow-up (101 months) than the BU-CY group (67 months, P = 0.04), overall survival was similar between the groups (69 vs 58 percent, respectively, P = 0.32). We conclude that the association BU-CY is a feasible option to the conventional ATG-CY regimen in this population.

Medicamentos utilizados em transplante de medula óssea: um estudo sobre combinações dos antimicrobianos potencialmente interativos / Drugs used in bone marrow transplantation: a study about combinations of antimicrobial potentially interactives / Medicamentos utilizados en casos de trasplante de médula ósea: un estudio sobre combinaciones antimicrobianas potencialmente interactivas

O objetivo do estudo foi caracterizar o perfil dos medicamentos e identificar combinações decorrentes da co-administração de antimicrobianos potencialmente interativos e outros agentes. 70 prescrições médicas de pacientes submetidos a transplante de medula óssea (TMO), todos internados no Instituto do Coração, São Paulo, Brasil, foram analisadas. Os medicamentos foram classificados de acordo com o sistema Alfa, e o potencial de interação e as características farmacológicas foram listados a partir da literatura. Na analise dos dados utilizou-se estatística descritiva. Verificou-se que 72,7 por cento dos medicamentos apresentaram potencial interativo, destacando-se os precipitadores (79,2 por cento) e o fluconazol (85,7 por cento) como o antimicrobiano mais envolvido nas combinações, associado ao omeprazol em 40 por cento da amostra. Nos pacientes de TMO, a co-administração de medicamentos potencialmente interativos foi freqüente, condição que, associada à polifarmácia e ao aprazamento simultâneo de horários na administração desses agentes, poderia predispor o paciente a eventos indesejados, afetando, deste modo, a segurança da terapia.

The study aimed at characterizing the profile of the drugs and identify combinations between potentially interactive anti-microbial drugs used in patients who underwent bone marrow transplantation (BMT). The analysis covered 70 prescription medications for BMT patients hospitalized at Instituto do Coração, São Paulo, Brazil. Medications were classified according to the Alpha system, listing their interactive potential and pharmacological characteristics according to literature. Data were analyzed through descriptive statistics. Results showed that 72.7 percent of drugs presented an interactive potential, with precipitators (79.2 percent) and fluconazole (85.7 percent), high-lighted as the most involved anti-microbial in the combinations, associated to omeprazole in 40 percent of the samples. BMT patients were frequently administered combinations of potentially interactive drugs. This condition, when associated with simultaneous schedules, could predispose patients to undesirable events, thus affecting the security of the therapy.

El objetivo del estudio fue determinar el perfil de medicamentos e identificar combinaciones por administración conjunta de antimicrobianos potencialmente interactivos y otros agentes. Fueron analizadas 70 prescripciones médicas de pacientes sometidos a trasplante de médula ósea (TMO), todos internados en el Instituto del Corazón, São Paulo, Brasil. Los medicamentos fueron clasificados según el sistema Alfa. El potencial de interacción y las características farmacológicas fueron establecidas según la bibliografía. El análisis de datos a través de estadística descriptiva. El 72,7 por ciento de los medicamentos mostró potencial interactivo, destacándose los precipitadores (79,2 por ciento) y como antimicrobiano más utilizado en las combinaciones el fluconazol (85,7 por ciento), siendo asociado al omeprazol en 40 por ciento de la muestra. La combinación de medicamentos potencialmente interactivos fue frecuente en estos pacientes, condición que asociada a la polifarmacia y a la distribución simultánea de horarios en su administración podría predisponer al paciente a efectos adversos, afectando la seguridad en el tratamiento.

Allogeneic Stem Cell Transplantation for Patients with Advanced Hematological Malignancies: Comparison of Fludarabine-based Reduced Intensity Conditioning versus Myeloablative Conditioning

We compared the outcomes of allogeneic hematopoietic stem cell transplantation using reduced intensity and myeloablative conditioning for the treatment of patients with advanced hematological malignancies. A total of 75 adult patients received transplants from human leukocyte antigen-matched donors, coupled with either reduced intensity (n=40; fludarabine/melphalan, 28; fludarabine/cyclophosphamide, 12) or myeloablative conditioning (n=35, busufan/cyclophosphamide). The patients receiving reduced intensity conditioning were elderly, or exhibited contraindications for myeloablative conditioning. Neutrophil and platelet engraftment occurred more rapidly in the reduced intensity group (median, 9 days vs. 18 days in the myeloablative group, p or =grade II) occurred at comparable frequencies in both groups, while the incidence of hepatic veno-occlusive disease was lower in the reduced intensity group (3% vs. 20% in the myeloablative group, p=0.02). The overall 1-yr survival rates of the reduced intensity and myeloablative group patients were 44% and 15%, respectively (p=0.16). The results of present study indicate that patients with advanced hematological malignancies, even the elderly and those with major organ dysfunctions, might benefit from reduced intensity transplantation.