RESUMEN
Primary graft failure (PGF) and multi-lineage cytopenia (MLC) increase the risk of nonrelapse mortality in allogeneic hematopoietic cell transplants (HCT). We evaluated the impact of post-transplant cyclophosphamide (PTCy) and splenomegaly on PGF and MLC for hematological malignancies. This study included patients with PTCy (N=84) and conventional graft-vs.-host disease prophylaxis (N=199). The occurrence of splenomegaly varied widely, ranging from 17.1â¯% (acute myeloid leukemia) to 66.7â¯% (myeloproliferative neoplasms). Ten patients (N=8 in the PTCy and N=2 in the non- PTCy) developed PGF, and 44 patients developed MLC (both N=22). PTCy and severe splenomegaly (≥20â¯cm) were risk factors for PGF (odds ratio (OR): 10.40, p<0.01 and 6.74, p=0.01 respectively). Moreover, severe splenomegaly was a risk factor for PGF in PTCy patients (OR: 10.20, p=0.01). PTCy (hazard ratio (HR) 2.09, p=0.02), moderate (≥15, <20â¯cm, HR 4.36, p<0.01), and severe splenomegaly (HR 3.04, p=0.01) were independent risk factors for MLC. However, in subgroup analysis in PTCy patients, only mild splenomegaly (≥12, <15â¯cm, HR 4.62, p=0.01) was a risk factor for MLC. We recommend all patients be screened for splenomegaly before HCT, and PTCy is cautioned in those with splenomegaly.
Asunto(s)
Ciclofosfamida , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Esplenomegalia , Humanos , Ciclofosfamida/efectos adversos , Ciclofosfamida/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Esplenomegalia/etiología , Femenino , Masculino , Persona de Mediana Edad , Adulto , Enfermedad Injerto contra Huésped/etiología , Adolescente , Adulto Joven , Anciano , Rechazo de Injerto/etiología , Trasplante Homólogo/efectos adversos , Factores de Riesgo , Estudios Retrospectivos , Inmunosupresores/efectos adversos , Inmunosupresores/uso terapéutico , Neoplasias Hematológicas/terapia , Niño , CitopeniaRESUMEN
Chimerism analysis is used to evaluate patients after allogeneic hematopoietic stem cell transplant (allo-HSCT) for engraftment and minimal measurable residual disease (MRD) monitoring. A combination of short-tandem repeat (STR) and quantitative polymerase chain reaction (qPCR) was required to achieve both sensitivity and accuracy in the patients with various chimerism statuses. In this study, an insertion/deletion-based multiplex chimerism assay by next generation sequencing (NGS) was evaluated using 5 simulated unrelated donor-recipient combinations from 10 volunteers. Median number of informative markers detected was 8 (range = 5 - 11). The limit of quantitation (LoQ) was determined to be 0.1 % recipient. Assay sample number/batch was 10-20 and total assay time was 19-31 h (manual labor = 2.1 h). Additionally, 50 peripheral blood samples from 5 allo-HSCT recipients (related: N = 4; unrelated: N = 1) were tested by NGS and STR/qPCR. Median number of informative markers detected was 7 (range = 4 - 12). Results from both assays demonstrated a strong correlation (Y = 0.9875X + 0.333; R2 = 0.9852), no significant assay bias (difference mean - 0.08), and 100 % concordant detection of percent recipient increase ≥ 0.1 % (indicator of increased relapse risk). NGS-based chimerism assay can support all allo-HSCT for engraftment and MRD monitoring and simplify clinical laboratory workflow compared to STR/qPCR.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Secuenciación de Nucleótidos de Alto Rendimiento , Repeticiones de Microsatélite , Humanos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Repeticiones de Microsatélite/genética , Quimerismo , Trasplante Homólogo , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , Quimera por Trasplante/genética , Neoplasia Residual/diagnóstico , Neoplasia Residual/genética , Sensibilidad y Especificidad , Reproducibilidad de los ResultadosRESUMEN
Chimerism testing supports the study of engraftment and measurable residual disease (MRD) in patients after allogeneic hematopoietic stem cell transplant. In chimerism MRD, relapse can be predicted by increasing mixed chimerism (IMC), recipient increase ≥0.1% in peripheral blood, and proliferating recipient cells as a surrogate of tumor activity. Conventionally, the combination of short-tandem repeat (STR) and quantitative PCR (qPCR) was needed to ensure assay sensitivity and accuracy in all chimerism status. We evaluated the use of next-generation sequencing (NGS) as an alternate technique. The median numbers of informative markers in unrelated/related cases were 124/82 (NGS; from 202 single-nucleotide polymorphism), 5/3 (qPCR), and 17/10 (STR). Assay sensitivity was 0.22% (NGS), 0.1% (qPCR), and 1% (STR). NGS batch (4 to 48 samples) required 19.60 to 24.80 hours and 1.52 to 2.42 hours of hands-on time (comparable to STR/qPCR). NGS assay cost/sample was $91 to $151, similar to qPCR ($99) but higher than STR ($27). Using 56 serial DNAs from six post-transplant patients monitored by the qPCR/STR, the correlation with NGS was strong for percentage recipient (y = 1.102x + 0.010; R2 = 0.968) and percentage recipient change (y = 0.892x + 0.041; R2 = 0.945). NGS identified all 17 IMC events detected by qPCR (100% sensitivity). The NGS chimerism provides sufficient sensitivity, accuracy, and economical/logistical feasibility in supporting engraftment and MRD monitoring.
Asunto(s)
Quimerismo , Trasplante de Células Madre Hematopoyéticas , Humanos , Recurrencia Local de Neoplasia , Repeticiones de Microsatélite , Neoplasia Residual/diagnóstico , Neoplasia Residual/genética , Reacción en Cadena de la Polimerasa/métodos , Secuenciación de Nucleótidos de Alto RendimientoRESUMEN
Allogeneic hematopoietic stem cell transplantation (alloSCT) is, in many clinical settings, the only curative treatment for acute myeloid leukemia (AML). The clinical benefit of alloSCT greatly relies on the graft-versus-leukemia (GVL) effect. However, AML relapse remains the top cause of posttransplant death; this highlights the urgent need to enhance GVL. Studies of human GVL have been hindered by the lack of optimal clinically relevant models. In this article, we report, the successful establishment of a novel (to our knowledge) humanized GVL model system by transplanting clinically paired donor PBMCs and patient AML into MHC class I/II knockout NSG mice. We observed significantly reduced leukemia growth in humanized mice compared with mice that received AML alone, demonstrating a functional GVL effect. Using this model system, we studied human GVL responses against human AML cells in vivo and discovered that AML induced T cell depletion, likely because of increased T cell apoptosis. In addition, AML caused T cell exhaustion manifested by upregulation of inhibitory receptors, increased expression of exhaustion-related transcription factors, and decreased T cell function. Importantly, combined blockade of human T cell-inhibitory pathways effectively reduced leukemia burden and reinvigorated CD8 T cell function in this model system. These data, generated in a highly clinically relevant humanized GVL model, not only demonstrate AML-induced inhibition of alloreactive T cells but also identify promising therapeutic strategies targeting T cell depletion and exhaustion for overcoming GVL failure and treating AML relapse after alloSCT.
RESUMEN
HLA-C*07:985:01:02Q differs from HLA-C*07:985:01 by one nucleotide substitution at the Intron 1 splicing acceptor site.
Asunto(s)
Antígenos HLA-C , Empalme del ARN , Humanos , Antígenos HLA-C/genética , Alelos , Secuencia de Bases , Mutación , IntronesRESUMEN
Full donor T-cell chimerism (FDTCC) after allogeneic stem cell transplant (allo-SCT) has been associated with improved outcomes in hematologic malignancy. We studied if donor human leukocyte antigen (HLA) mismatch improves achievement of FDTCC because mismatched HLA promotes donor T-cell proliferation where recipient T-cells had been impaired by previous treatment. Patients (N = 138) received allo-SCT with reduced-intensity conditioning (RIC) from 39 HLA mismatched donors (16 unrelated; 23 haploidentical) with post-transplant cyclophosphamide (PTCy) or 99 matched donors (21 siblings; 78 unrelated) with PTCy (N = 18) or non-PTCy (N = 81). Achievement of FDTCC by day 100 was higher with HLA mismatched donors than matched donors (82.1% vs. 27.3%, p < 00,001), which was further improved with 200 cGy total body irradiation (87.9%) or lymphoid (versus myeloid) malignancy (93.8%). Since all mismatched transplants used PTCy, FDTCC was higher with PTCy than non-PTCy (68.4% vs. 25.7%, p < 0.00001), but not in the matched transplant with PTCy (38.9%), negating PTCy as the primary driver. Lymphocyte recovery was delayed with PTCy than without (median on day + 30: 100 vs. 630/µL, p < 0.0001). The benefit of FDTCC was not translated into survival outcomes, especially in myeloid malignancies, possibly due to the insufficient graft-versus-tumor effects from the delayed lymphocyte recovery. Further studies are necessary to improve lymphocyte count recovery in PTCy transplants.
Asunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Humanos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Quimerismo , Enfermedad Injerto contra Huésped/etiología , Linfocitos T , Ciclofosfamida/uso terapéutico , Trasplante de Células Madre/efectos adversos , Antígenos HLA , Acondicionamiento Pretrasplante/efectos adversos , Donante no Emparentado , Estudios RetrospectivosAsunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Humanos , Quimerismo , Irradiación Corporal Total , Linfocitos T , Ciclofosfamida , Acondicionamiento Pretrasplante , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/prevención & controlRESUMEN
The prognosis for acute myeloid leukemia (AML) relapse post allogeneic hematopoietic stem cell transplantation (alloSCT) is dismal. Novel effective treatment is urgently needed. Clinical benefit of alloSCT greatly relies on the graft-versus-leukemia (GVL) effect. The mechanisms that mediate immune escape of leukemia (thus causing GVL failure) remain poorly understood. Studies of human GVL have been hindered by the lack of optimal clinically relevant models. Here, using our large, longitudinal clinical tissue bank that include AML cells and G-CSF mobilized donor hematopoietic stem cells (HSCs), we successfully established a novel GVL model in humanized mice. Donor HSCs were injected into immune-deficient NOD-Cg-Prkdcscid IL2rgtm1Wjl /SzJ (NSG) mice to build humanized mice. Immune reconstitution in these mice recapitulated some clinical scenario in the patient who received the corresponding HSCs. Allogeneic but HLA partially matched patient-derived AML cells were successfully engrafted in these humanized mice. Importantly, we observed a significantly reduced (yet incomplete elimination of) leukemia growth in humanized mice compared with that in control NSG mice, demonstrating a functional (but defective) GVL effect. Thus, for the first time, we established a novel humanized mouse model that can be used for studying human GVL responses against human AML cells in vivo. This novel clinically relevant model provides a valuable platform for investigating the mechanisms of human GVL and development of effective leukemia treatments.
Asunto(s)
Modelos Animales de Enfermedad , Efecto Injerto vs Leucemia/inmunología , Trasplante de Células Madre Hematopoyéticas/métodos , Células Madre Hematopoyéticas/citología , Leucemia Mieloide Aguda/terapia , Animales , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Humanos , Leucemia Mieloide Aguda/inmunología , Ratones , Ratones Endogámicos NOD , Ratones SCID , Trasplante HomólogoRESUMEN
BACKGROUND: There is a scarcity of long-term data on steroid-free immunosuppression using alemtuzumab in pediatric kidney transplantation (KTx). This study examines long-term outcomes with alemtuzumab without steroid maintenance therapy in pediatric KTx. METHODS: From July 2005 to June 2015, 71 pediatric KTx recipients received alemtuzumab without steroid maintenance. They were followed from 4.1 to 14.1 years post KTx. RESULTS: Patient survival: One child expired with a functioning graft from post-transplant lymphoproliferative disorder (PTLD). Patient survival was 98.6%. Graft survival: Eighteen grafts were lost (16 from chronic rejection). Graft survival at 5 and 10 years was 92.3% and 61.3%, respectively. Rejection: Twenty-three (32.4%) patients were free from T-cell-mediated rejection (TCMR), 16 (22.5%) had >3 episodes. Sixteen (22.5%) were treated for antibody-mediated rejection (AMR). Infection: Twenty-three children developed Epstein-Barr virus (EBV), 5 developed cytomegalovirus (CMV), and 20 developed BK virus infection. Four (5.6%) developed PTLD. Twenty-two (31.0%) required treatment for neutropenia. Growth parameters: Mean height and weight increased by 0.56 and 0.69 SDS (standard deviation score), respectively. Body mass index increased by 5.1 kg/m2 at 10 years. Less than 40% required antihypertensive medications at all-time points. CONCLUSION: Alemtuzumab, without corticosteroid maintenance, offers 98.6% patient survival at 14 years with five and 10-year graft survival of 92.3% and 61.3%, respectively. TCMR and AMR requiring treatment were 67.4% and 22.5%, respectively. CMV, EBV, and BK viremia rates were 7.0%, 32.4%, and 28.2%, respectively. Thirty-one percent were treated for neutropenia; 5.6% developed PTLD. There were improvements in growth parameters and blood pressure.
Asunto(s)
Alemtuzumab/uso terapéutico , Terapia de Inmunosupresión/métodos , Trasplante de Riñón , Adolescente , Niño , Preescolar , Infecciones por Citomegalovirus/etiología , Infecciones por Virus de Epstein-Barr/etiología , Femenino , Rechazo de Injerto , Humanos , Inmunosupresores/administración & dosificación , Lactante , Trastornos Linfoproliferativos/etiología , Masculino , Ácido Micofenólico/administración & dosificación , Tacrolimus/administración & dosificaciónRESUMEN
The immunopathogenesis of multisystem inflammatory syndrome (MIS-C) in children that may follow exposure to SARS-CoV-2 is incompletely understood. Here, we studied SARS-CoV-2-specific T cells in MIS-C, Kawasaki disease (KD), and SARS-CoV-2 convalescent controls using peptide pools derived from SARS-CoV-2 spike or nonspike proteins, and common cold coronaviruses (CCC). Coordinated CD4+ and CD8+ SARS-CoV-2-specific T cells were detected in five MIS-C subjects with cross-reactivity to CCC. CD4+ and CD8+ T-cell responses alone were documented in three and one subjects, respectively. T-cell specificities in MIS-C did not correlate with disease severity and were similar to SARS-CoV-2 convalescent controls. T-cell memory and cross-reactivity to CCC in MIS-C and SARS-CoV-2 convalescent controls were also similar. The chemokine receptor CCR6, but not CCR9, was highly expressed on SARS-CoV-2-specific CD4+ but not on CD8+ T cells. Only two of 10 KD subjects showed a T-cell response to CCC. Enumeration of myeloid APCs revealed low cell precursors in MIS-C subjects compared to KD. In summary, children with MIS-C mount a normal T-cell response to SARS-CoV-2 with no apparent relationship to antecedent CCC exposure. Low numbers of tolerogenic myeloid DCs may impair their anti-inflammatory response.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , COVID-19/complicaciones , Inmunidad Celular , Memoria Inmunológica , Síndrome Mucocutáneo Linfonodular , SARS-CoV-2/inmunología , Síndrome de Respuesta Inflamatoria Sistémica/inmunología , Adolescente , COVID-19/inmunología , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Síndrome Mucocutáneo Linfonodular/complicaciones , Síndrome Mucocutáneo Linfonodular/inmunologíaRESUMEN
DQA1*03:03:01:16Q differs from DQA1*03:03:01:01 by one nucleotide at the Intron 3 splicing acceptor site.
Asunto(s)
Sitios de Empalme de ARN , Alelos , Cadenas alfa de HLA-DQ , Humanos , Intrones/genética , Mutación , Sitios de Empalme de ARN/genéticaRESUMEN
Chimerism testing by short tandem repeats (STRs) is used to monitor engraftment after allogeneic hematopoietic stem cell transplantation (HSCT). Generally, STR alleles are stable and transferred from parent to child or from donor to recipient. However, 3 cases did not follow this norm. Additional work-up with help from forensic literature solved these mysteries. In case 1, the patient received HSCT from his son. The son shared STR alleles in 22/23 loci except Penta E, which was explained by repeat expansion in the son. In case 2, the patient had been in remission for 14 years after HSCT for lymphoma and developed repeat expansion in CSF1PO in granulocytes. In case 3, a pre-HSCT patient demonstrated 3 alleles, with 2 peaks taller than the third, in the FGA locus (chromosome 4). A combination of a triallelic variant and leukemia-associated trisomy 4 explained the finding. STR number variants are rare and clinically inconsequential but can overlap malignancy-associated, clinically significant changes.
Asunto(s)
Genética Forense , Marcadores Genéticos , Pruebas Genéticas , Repeticiones de Microsatélite , Quimera por Trasplante/genética , Anciano , Alelos , Reglas de Decisión Clínica , Genética Forense/métodos , Antígenos HLA/genética , Trasplante de Células Madre Hematopoyéticas , Humanos , Masculino , Persona de Mediana Edad , Trasplante HomólogoRESUMEN
A non-sense mutation in either DPA1*01:03:01:02 or DPA1*01:03:01:05/01:03:01:15 results in the novel allele, HLA-DPA1*01:35N.
Asunto(s)
Cadenas alfa de HLA-DP , Población Blanca , Alelos , Cadenas alfa de HLA-DP/genética , Humanos , Masculino , Pennsylvania , Estados Unidos , Población Blanca/genéticaRESUMEN
Kawasaki disease (KD) is a pediatric vasculitis caused by an unknown trigger in genetically susceptible children. The incidence varies widely across genetically diverse populations. Several associations with HLA Class I alleles have been reported in single cohort studies. Using a genetic approach, from the nine single nucleotide variants (SNVs) associated with KD susceptibility in children of European descent, we identified SNVs near the HLA-C (rs6906846) and HLA-B genes (rs2254556) whose association was replicated in a Japanese descent cohort (rs6906846 pâ¯=â¯0.01, rs2254556 pâ¯=â¯0.005). The risk allele (A at rs6906846) was also associated with HLA-C*07:02 and HLA-C*04:01 in both US multi-ethnic and Japanese cohorts and HLA-C*12:02 only in the Japanese cohort. The risk A-allele was associated with eight non-conservative amino acid substitutions (amino acid positions); Asp or Ser (9), Arg (14), Ala (49), Ala (73), Ala (90), Arg (97), Phe or Ser (99), and Phe or Ser (116) in the HLA-C peptide binding groove that binds peptides for presentation to cytotoxic T cells (CTL). This raises the possibility of increased affinity to a "KD peptide" that contributes to the vasculitis of KD in genetically susceptible children.
Asunto(s)
Sustitución de Aminoácidos/genética , Sitios de Unión/genética , Predisposición Genética a la Enfermedad , Antígenos HLA-C/genética , Síndrome Mucocutáneo Linfonodular/genética , Polimorfismo de Nucleótido Simple/genética , Unión Proteica/genética , Alelos , Secuencia de Aminoácidos/genética , Presentación de Antígeno/genética , Estudios de Cohortes , Frecuencia de los Genes/genética , Genotipo , Antígenos HLA-C/química , Prueba de Histocompatibilidad , Humanos , Japón , Péptidos/genética , Dominios Proteicos/genética , Linfocitos T Citotóxicos/inmunologíaRESUMEN
Chimerism testing is used to monitor engraftment and risk of relapse after allogeneic hematopoietic stem cell transplantation for hematologic malignancies. Although short tandem repeat (STR) method is widely used among clinical laboratories, quantitative PCR (qPCR) provides better sensitivity (0.1%) than STR (1% to 5%) but is less accurate than STR for patients in mixed chimerism. qPCR chimerism allows evaluation of residual recipient cells as a surrogate of measurable residual disease. To achieve higher sensitivity and accuracy, we applied qPCR or STR based on patient chimerism status (recipient alleles <5% or ≥5%, respectively). Of the 230 patients tested by STR in a 1-year period, excluding 10 deceased patients, 30 qPCR markers were genotyped and 167 patients converted to qPCR chimerism (76%), including eight patients undergoing multiple-donor transplantation. STR was continued on 53 patients (24%) for the following reasons: mixed chimerism (n = 23), lack of donor or pretransplantation DNA (n = 22), and insufficient qPCR informative markers [8 of 60 patients with related donors (13.3%)]. qPCR detected residual recipient chimerism in 85.5% of patients with complete chimerism by STR (<5% recipient). Selecting STR or qPCR testing based on each patient's chimerism status facilitates sensitive and accurate chimerism testing in clinical settings. In addition, we discuss clinical relevance of chimerism testing for measurable residual disease detection in various hematologic malignancies.
Asunto(s)
Quimerismo , Neoplasias Hematológicas/diagnóstico , Trasplante de Células Madre Hematopoyéticas , Repeticiones de Microsatélite , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , Adolescente , Adulto , Anciano , Alelos , Niño , Preescolar , Familia , Femenino , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/patología , Neoplasias Hematológicas/terapia , Humanos , Lactante , Masculino , Persona de Mediana Edad , Neoplasia Residual , Recurrencia , Estudios Retrospectivos , Trasplante Homólogo , Donante no EmparentadoRESUMEN
Acute myeloid leukemia (AML) is a devastating blood cancer with poor prognosis. Immunotherapy targeting inhibitory pathways to unleash the antileukemia T-cell response is a promising strategy for the treatment of leukemia, but we must first understand the underlying molecular mechanisms. Eomesodermin (Eomes) and T-bet are both T-box transcription factors that regulate CD8+ T-cell responses in a context-specific manner. Here, we examined the role of these transcription factors in CD8+ T-cell immunity in AML patients. We report that the frequency of Eomes+T-betlow CD8+ T cells increased in newly diagnosed AML. This cell subset produced fewer cytokines and displayed reduced killing capacity, whereas depletion of Eomes by siRNA reversed these functional defects. Furthermore, Eomes bound the promoter of T-cell immunoglobulin and ITIM domain (TIGIT) and positively regulated the expression of this inhibitory receptor on patient-derived T cells. A high frequency of Eomes+T-betlow CD8+ T cells was associated with poor response to induction chemotherapy and shorter overall survival in AML patients. These findings have significant clinical implications as they not only identify a predictive and prognostic biomarker for AML, but they also provide an important target for effective leukemia therapeutics. SIGNIFICANCE: These findings reveal that a high frequency of Eomes+T-betlow CD8+ T cells predicts poor clinical outcome in AML and that targeting Eomes may provide a therapeutic benefit against AML.
Asunto(s)
Linfocitos T CD8-positivos/metabolismo , Leucemia Mieloide Aguda/patología , Proteínas de Dominio T Box/metabolismo , Linfocitos T CD8-positivos/inmunología , Estudios de Cohortes , Humanos , Quimioterapia de Inducción , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/inmunología , Pronóstico , Regiones Promotoras Genéticas , Receptores Inmunológicos/genética , Receptores Inmunológicos/metabolismo , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
Kidney transplant from donors with hepatitis C virus (HCV) antibody has been limited to HCV viremic recipients only, due to concern of the HCV transmission. However, the new antiviral medications provide an opportunity to expand the utilization of these donors. To study the risk of HCV transmission in kidney transplantation, we used discarded donor kidneys and determined HCV RNA levels by quantitative real-time PCR in bilateral (right and left) kidney biopsies and plasma from 14 HCV antibody-positive donors (sensitivity: 15 international unit (IU)/mL plasma; 1.8 IU/50 nL kidney). In three NAT-negative donors, HCV RNA was negative in plasma and kidney. In all 11 NAT-positive donors, HCV RNA was positive in plasma (range: 5807-19 134 177 IU/mL) but negative in six kidneys from four donors with plasma HCV RNA <1.5 million IU/µL. HCV RNA correlated between right and left kidneys (P = 0.75) and between kidney and plasma (r = 0.86). When normalized by volume, HCV RNA median (range) was 49 (0-957) IU/50 nL plasma and 1.0 (0-103) IU/50 nL kidney, significantly lower in kidney (P = 0.005) than in plasma (14-fold). Plasma HCV RNA can be used to predict the kidney HCV load. Future studies are needed if plasma/kidney HCV levels can be used to stratify donors for transmission risk and recipients for post-transplant management in extended utilization of HCV antibody-positive donors.
Asunto(s)
Hepacivirus/genética , Anticuerpos contra la Hepatitis C/sangre , Hepatitis C/diagnóstico , Riñón/metabolismo , ARN Viral/genética , Donantes de Tejidos/provisión & distribución , Recolección de Tejidos y Órganos/estadística & datos numéricos , Hepatitis C/genética , Hepatitis C/transmisión , Humanos , Riñón/virologíaRESUMEN
BACKGROUND/AIMS: Typical approach for increasing apheresis platelet collections is to recruit new donors. Here, we investigated the effectiveness of an alternative strategy: optimizing donor scheduling, prior to recruitment, at a hospital-based blood donor center. METHODS: Analysis of collections, during the 89 consecutive months since opening of donor center, was performed. Linear regression and segmented time-series analyses were performed to calculate growth rates of collections and to test for statistical differences, respectively. RESULTS: Pre-intervention donor scheduling capacity was 39/month. In the absence of active donor recruitment, during the first 29 months, the number of collections rose gradually to 24/month (growth-rate of 0.70/month). However, between month-30 and -55, collections exhibited a plateau at 25.6 ± 3.0 (growth-rate of -0.09/month) (p<0.0001). This plateau-phase coincided with donor schedule approaching saturation (65.6 ± 7.6% schedule booked). Scheduling capacity was increased by following two interventions: adding an apheresis instrument (month-56) and adding two more collection days/week (month-72). Consequently, the scheduling capacity increased to 130/month. Post-interventions, apheresis platelet collections between month-56 and -81 exhibited a spontaneous renewed growth at a rate of 0.62/month (p<0.0001), in absence of active donor recruitment. Active donor recruitment in month-82 and -86, when the donor schedule had been optimized to accommodate further growth, resulted in a dramatic but transient surge in collections. CONCLUSION: Apheresis platelet collections plateau at nearly 2/3rd of the scheduling capacity. Optimizing the scheduling capacity prior to active donor recruitment is an effective strategy to increase platelet collections at a hospital-based donor center.
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Donantes de Sangre/estadística & datos numéricos , Admisión y Programación de Personal , Plaquetoferesis/estadística & datos numéricos , HumanosRESUMEN
Approximately 30-40% of patients with acute myeloid leukemia (AML) experience induction failures. In these patients who do not achieve remission with two cycles of standard induction therapies, the probability of achieving remission with subsequent inductions is very limited. Hematopoietic stem cell transplantation (HSCT) is the only curative option for these patients, but high relapse rate and transplant-related mortality often preclude them to proceed to transplant. Thus, AML not in remission at time of HSCT remains a huge unmet need in current HSCT practice, particularly if the patient does not have an HLA-matched donor identified by the time of two induction failures. We used clofarabine cytoreduction immediately followed by fludarabine (Flu) and busulfan (Bu) × 3 with total-body irradiation (TBI) conditioning (Flu/Bu3/TBI) for haploidentical peripheral blood stem cell transplant with post-transplant cyclophosphamide for two cases of refractory AML with a very high tumor burden at transplant and achieved complete remission by day + 30 in both cases.