RESUMO
Insights regarding the biodistribution and homing of mesenchymal stromal cells (MSCs), as well as their interaction with alloreactive T-cells are critical for understanding how MSCs can regulate graft-versus-host disease (GVHD) following allogeneic (allo) bone marrow transplantation (BMT). We developed novel assays based on 3D, microscopic, cryo-imaging of whole-mouse-sized volumes to assess the therapeutic potential of human MSCs using an established mouse GVHD model. Following infusion, we quantitatively tracked fluorescently labeled, donor-derived, T-cells and third party MSCs in BMT recipients using multispectral cryo-imaging. Specific MSC homing sites were identified in the marginal zones in the spleen and the lymph nodes, where we believe MSC immunomodulation takes place. The number of MSCs found in spleen of the allo BMT recipients was about 200% more than that observed in the syngeneic group. To more carefully define the effects MSCs had on T cell activation and expansion, we developed novel T-cell proliferation assays including secondary lymphoid organ (SLO) enlargement and Carboxyfluoescein succinimidyl ester (CFSE) dilution. As anticipated, significant SLO volume enlargement and CFSE dilution was observed in allo but not syn BMT recipients due to rapid proliferation and expansion of labeled T-cells. MSC treatment markedly attenuated CFSE dilution and volume enlargement of SLO. These assays confirm evidence of potent, in vivo, immunomodulatory properties of MSC following allo BMT. Our innovative platform includes novel methods for tracking cells of interest as well as assessing therapeutic function of MSCs during GVHD induction. Our results support the use of MSCs treatment or prevention of GVHD and illuminate the wider adoption of MSCs as a standard medicinal cell therapy.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Camundongos , Humanos , Animais , Distribuição Tecidual , Transplante de Medula Óssea , Doença Enxerto-Hospedeiro/patologia , Modelos Animais de DoençasRESUMO
BACKGROUND: During the coronavirus disease-2019 (COVID-19) pandemic, Italian hospitals faced the most daunting challenges of their recent history, and only essential therapeutic interventions were feasible. From March to April 2020, the Laboratory of Advanced Cellular Therapies (Vicenza, Italy) received requests to treat a patient with severe COVID-19 and a patient with acute graft-versus-host disease with umbilical cord-derived mesenchymal stromal cells (UC-MSCs). Access to clinics was restricted due to the risk of contagion. Transport of UC-MSCs in liquid nitrogen was unmanageable, leaving shipment in dry ice as the only option. METHODS: We assessed effects of the transition from liquid nitrogen to dry ice on cell viability; apoptosis; phenotype; proliferation; immunomodulation; and clonogenesis; and validated dry ice-based transport of UC-MSCs to clinics. RESULTS: Our results showed no differences in cell functionality related to the two storage conditions, and demonstrated the preservation of immunomodulatory and clonogenic potentials in dry ice. UC-MSCs were successfully delivered to points-of-care, enabling favourable clinical outcomes. CONCLUSIONS: This experience underscores the flexibility of a public cell factory in its adaptation of the logistics of an advanced therapy medicinal product during a public health crisis. Alternative supply chains should be evaluated for other cell products to guarantee delivery during catastrophes.
Assuntos
COVID-19/terapia , Atenção à Saúde/organização & administração , Gelo-Seco , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/citologia , Sistemas Automatizados de Assistência Junto ao Leito/organização & administração , Meios de Transporte , Doença Aguda , COVID-19/epidemiologia , COVID-19/patologia , Proliferação de Células , Sobrevivência Celular , Células Cultivadas , Transplante de Células-Tronco de Sangue do Cordão Umbilical/efeitos adversos , Atenção à Saúde/normas , Equipamentos e Provisões Hospitalares/normas , Equipamentos e Provisões Hospitalares/provisão & distribuição , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/patologia , Doença Enxerto-Hospedeiro/terapia , Humanos , Itália/epidemiologia , Administração de Materiais no Hospital/organização & administração , Administração de Materiais no Hospital/normas , Transplante de Células-Tronco Mesenquimais/métodos , Transplante de Células-Tronco Mesenquimais/normas , Células-Tronco Mesenquimais/fisiologia , Organização e Administração/normas , Pandemias , Fenótipo , Sistemas Automatizados de Assistência Junto ao Leito/normas , SARS-CoV-2/fisiologia , Índice de Gravidade de Doença , Meios de Transporte/métodos , Meios de Transporte/normasRESUMO
(1) Background: survivors of allogeneic hematopoietic cell transplantation (alloHCT) suffer from morbidity and mortality due to cardiovascular events. We hypothesized that vascular injury and pro-coagulant activity are evident in alloHCT survivors without existing alloHCT complications or relapse. (2) Methods: we enrolled consecutive adult alloHCT survivors without established cardiovascular disease and control individuals matched for traditional cardiovascular risk factors (January-December 2019). Circulating microvesicles (MVs) of different cellular origins (platelet, erythrocyte, and endothelial) were measured by a standardized flow cytometry protocol as novel markers of vascular injury and pro-coagulant activity. (3) Results: we recruited 45 survivors after a median of 2.3 (range 1.1-13.2) years from alloHCT, and 45 controls. The majority of patients suffered from acute (44%) and/or chronic (66%) graft-versus-host disease (GVHD). Although the two groups were matched for traditional cardiovascular risk factors, alloHCT survivors showed significantly increased platelet and erythrocyte MVs compared to controls. Within alloHCT survivors, erythrocyte MVs were significantly increased in patients with a previous history of thrombotic microangiopathy. Interestingly, endothelial MVs were significantly increased only in alloHCT recipients of a myeloablative conditioning. Furthermore, MVs of different origins showed a positive association with each other. (4) Conclusions: endothelial dysfunction and increased thrombotic risk are evident in alloHCT recipients long after alloHCT, independently of traditional cardiovascular risk factors. An apparent synergism of these pathophysiological processes may be strongly involved in the subsequent establishment of cardiovascular disease.
Assuntos
Fatores de Coagulação Sanguínea , Doenças Cardiovasculares/diagnóstico , Micropartículas Derivadas de Células/patologia , Endotélio Vascular/lesões , Doença Enxerto-Hospedeiro/etiologia , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Adolescente , Adulto , Sobreviventes de Câncer/estatística & dados numéricos , Doenças Cardiovasculares/etiologia , Estudos de Casos e Controles , Feminino , Doença Enxerto-Hospedeiro/patologia , Fatores de Risco de Doenças Cardíacas , Humanos , Masculino , Pessoa de Meia-Idade , Transplante Homólogo , Adulto JovemRESUMO
BACKGROUND: Skin biopsies are often used in daily practice for the diagnosis of acute (aGvHD) or chronic graft versus host disease (cGvHD). With the latest understanding in pathogenesis and new National Institute of Health (NIH) classifications for aGvHD and cGvHD, there is a need to evaluate the current prognostic value of histological grading cutaneous GvHD and its correlation to the clinical grade. METHODS: In a retrospective study with 120 skin biopsies (all taken for suspected GvHD) from 110 patients (all classified according to the NIH), biopsies were revised and graded, blinded for clinical information, for either acute of chronic features. Morphological grades were compared for concordance with the clinical grade and survival analyses were done for clinical and histological grading. RESULTS: Correlation for histologic vs. clinical grading was (very) poor for aGvHD and cGvHD (weighted κ - 0.038 and 0.0009, respectively). Patients with clinical aGvHD had worse prognosis compared to cGvHD. However, at time of biopsy neither clinical nor histological grading predicted the eventual survival for either aGvHD (p = 0.9739 and p = 0.0744, respectively) or cGvHD (p = 0.2149 and p = 0.4465, respectively). CONCLUSIONS: Confirming the diagnosis of GvHD is still a valuable reason for taking a skin biopsy, but this study shows that histologic grading of GvHD in the skin biopsy has no additional value for clinicians in current practice.
Assuntos
Doença Enxerto-Hospedeiro/patologia , Doença Aguda , Adolescente , Adulto , Idoso , Biópsia , Criança , Pré-Escolar , Doença Crônica , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Owing to the difficulty in isolating T cells from human biopsy samples, the characteristics of T cells that are infiltratinghuman acute graft-versus-host disease (GVHD) tissues remain largely uninvestigated. In the present study, TCR-ß deep sequencing of various GVHD tissue samples and concurrent peripheral blood obtained from transplant recipients was performed in combination with functional assays of tissue-infiltrating T cell clones. The T cell repertoire was more skewed in GVHD tissues than in the peripheral blood. The frequent clonotypes differed from tissue to tissue in the same patient, and the frequent clonotypes in the same tissue differed from patient to patient. Two T cell clones were successfully isolated from GVHD skin of a patient. In a cytotoxicity assay, both Tcell clones lysed patient peripheral blood mononuclear cells, but not donor-derived Epstein-Barr virus-transformed lymphoblastoid cells. Their clonotypes were identical to the most and second most frequent T cell clonotypes in the original GVHD skin and accounted for almost all of the skin-infiltrating T cells. These results suggest that human acute GVHD may result from only a few different alloreactive cytotoxic T cell clones, which differ from tissue to tissue and from patient to patient. The characterization of T cells infiltrating human GVHD tissues should be further investigated.
Assuntos
Doença Enxerto-Hospedeiro/patologia , Linfócitos T Citotóxicos/citologia , Movimento Celular , Células Clonais/citologia , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Pele/imunologia , Pele/patologia , Transplante HomólogoRESUMO
PURPOSE: Data from developing countries about incidence, prognosis and healthcare cost of cytomegalovirus (CMV) reactivation amongst patients with allogeneic hematopoietic stem cell transplantation (AHSCT) remain scarce. The purpose of the study was to describe the epidemiology, outcome and cost implications of CMV reactivation and CMV disease amongst patients with AHSCT in cancer hospital in Eastern India. MATERIALS AND METHODS: The study design was a retrospective audit of clinical records. RESULTS: Ninety-nine per cent of patients and 94% of the donors were found to be CMV seropositive. CMV reactivation rate was 43.8% amongst patients with AHSCT (n = 130 patients). CMV reactivation occurred 118 days after AHSCT (median; range: 28-943 days). Patients with any grade of graft-versus-host disease (GVHD) had higher CMV reactivation rate than patients without GVHD. Patients with CMV reactivation had more frequent GVHD than patients without CMV reactivation. Use of steroids was associated with CMV reactivation. We found no differences in overall survival of patients with or without CMV reactivation. The cost of in-house CMV-polymerase chain reaction at our centre was USD $57 (Rs. 3650), cost for intravenous ganciclovir was USD $26 (Rs. 1665) per infusion and oral valganciclovir USD $8 (Rs. 512)/900 mg tablet. The median duration of anti-CMV therapy was 14 days (interquartile range: 14-28 days) and the average cost per patient per month directed towards CMV management ranged between USD $800 and USD $1,300 (Rs. 51,238-Rs. 83,264). Three patients (2.3%) in this series had CMV disease, all of whom died. CONCLUSION: In an increasingly globalised world, where medical tourism is common, data from developing countries regarding cost and outcome of CMV infections in AHSCT patients are of relevance.
Assuntos
Antivirais/economia , Infecções por Citomegalovirus , Ganciclovir/análogos & derivados , Ganciclovir/economia , Custos de Cuidados de Saúde/estatística & dados numéricos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Adolescente , Adulto , Antivirais/uso terapêutico , Criança , Pré-Escolar , Citomegalovirus/crescimento & desenvolvimento , Infecções por Citomegalovirus/tratamento farmacológico , Infecções por Citomegalovirus/economia , Infecções por Citomegalovirus/epidemiologia , Feminino , Ganciclovir/uso terapêutico , Doença Enxerto-Hospedeiro/patologia , Humanos , Índia/epidemiologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Valganciclovir , Ativação Viral , Adulto JovemRESUMO
The China Assessment of Antifungal Therapy in Hematological Disease study, the first large-scale observational study of invasive fungal disease (IFD) in China, enrolled 1401 patients undergoing hematopoietic stem cell transplantation (HSCT) (75.2% allogeneic and 24.8% autologous) at 31 hospitals across China. The overall incidence of proven or probable IFD was 7.7% (108 of 1401); another 266 cases (19.0%) were possible IFD. After allogeneic or autologous HSCT, the incidence of proven/probable IFD was 8.9% (94 of 1053) and 4.0% (14 of 348), respectively. Some cases (14 of 108) developed during conditioning before transplantation. The cumulative incidence of proven/probable IFD increased steeply in the first month after transplantation and after 6 months, the incidence was significantly higher in allogeneic than it was in autologous transplant recipients (9.2% versus 3.5%; P = .001) and when stem cells were derived from cord blood or bone marrow and peripheral blood (P = .02 versus other sources). Independent risk factors for proven/probable IFD in allogeneic HSCT were diabetes, HLA-matched unrelated donor, prolonged severe neutropenia (absolute neutrophil count > 500/mm(3) for >14 days), and immunosuppressants (odds ratio, 2.0 to 3.4 for all). Antifungal prophylaxis was independently protective (P = .01). Previous IFD and prolonged severe neutropenia were significant independent risk factors among autologous transplantation patients (P < .01, P = .04, respectively). In total, 1175 (83.9%) patients received antifungal prophylaxis (91.6% triazoles) and 514 (36.7%) were treated in the hospital with therapeutic antifungals (89.1% triazoles; median 27 days). Empirical, pre-emptive, and targeted antifungals were used in 82.3%, 13.6%, and 4.1% of cases, respectively. Overall mortality (13.4%; 188 deaths) was markedly higher in patients with proven (5 of 16; 31.3%), probable (20 of 92; 21.7%), or possible (61 of 266; 22.9%) IFD; allogeneic (171 of 1053; 16.2%) rather than autologous (17 of 348; 4.9%) HSCT and was significantly higher in patients receiving pre-emptive (18.6%) rather than empirical (6.1%) or targeted (9.5%) antifungal therapy (P = .002). Improvements in the selection and timing of prophylactic antifungals would be welcome. Health care providers should remain alert to the increased risk of IFD and associated mortality in allogeneic HSCT recipients and the ongoing risk of IFD even after discharge from the hospital.
Assuntos
Antifúngicos/uso terapêutico , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Micoses/tratamento farmacológico , Condicionamento Pré-Transplante , Triazóis/uso terapêutico , Adolescente , Adulto , China , Doença Crônica , Feminino , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/patologia , Doença Enxerto-Hospedeiro/prevenção & controle , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/mortalidade , Neoplasias Hematológicas/patologia , Humanos , Imunossupressores/uso terapêutico , Incidência , Masculino , Micoses/etiologia , Micoses/microbiologia , Micoses/mortalidade , Agonistas Mieloablativos/uso terapêutico , Neutropenia/tratamento farmacológico , Neutropenia/etiologia , Neutropenia/microbiologia , Neutropenia/mortalidade , Prognóstico , Estudos Prospectivos , Fatores de Risco , Irmãos , Análise de Sobrevida , Transplante Autólogo , Transplante Homólogo , Resultado do Tratamento , Doadores não RelacionadosRESUMO
Poverty is correlated with negative health outcomes in pediatric primary care and subspecialties; its association with childhood hematopoietic stem cell transplantation (HSCT) patterns of care and clinical outcomes is not known. We describe family-reported financial hardship at a primary referral center in New England and explore the relationship between measures of poverty and patterns of care and clinical outcomes. Forty-five English-speaking parents of children after allogeneic HSCT in the prior 12 months completed a 1-time survey (response rate 88%). Low-income families, defined as ≤200% federal poverty level (FPL), were compared with all others. Eighteen (40%) families reported pre-HSCT incomes ≤200% FPL. Material hardship, including food, housing, or energy insecurity was reported by 17 (38%) families in the cohort. Low-income families reported disproportionate transplantation-related income losses, with 7 (39%) reporting annual income losses of >40% compared with 2 (18%) wealthier families (P = .02). In univariate analyses, 11 (61%) low-income children experienced graft-versus-host disease (GVHD) of any grade in the first 180 days after HSCT compared with 2 (7%) wealthier children (P = .004). We conclude that low income and, in particular, material hardship, are prevalent in a New England pediatric HSCT population and represent targets for improvement in quality of life. The role of poverty in mediating GVHD deserves further investigation in larger studies that can control for known risk factors and may provide a targetable source of transplantation-associated morbidity.
Assuntos
Doença Enxerto-Hospedeiro/economia , Neoplasias Hematológicas/economia , Transplante de Células-Tronco Hematopoéticas/economia , Hemoglobinúria Paroxística/economia , Pobreza , Adolescente , Anemia Aplástica , Doenças da Medula Óssea , Transtornos da Insuficiência da Medula Óssea , Criança , Pré-Escolar , Estudos Transversais , Feminino , Doença Enxerto-Hospedeiro/patologia , Doença Enxerto-Hospedeiro/psicologia , Neoplasias Hematológicas/patologia , Neoplasias Hematológicas/psicologia , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/psicologia , Hemoglobinúria Paroxística/patologia , Hemoglobinúria Paroxística/psicologia , Hemoglobinúria Paroxística/terapia , Humanos , Renda , Masculino , New England , Qualidade de Vida , Estudos Retrospectivos , Inquéritos e Questionários , Transplante HomólogoRESUMO
Reduced intensity conditioning (RIC) regimens have allowed older patients and those with comorbidities to receive hematopoietic cell transplantation (HCT). We analyzed medical costs from the beginning of conditioning to 100 days after HCT for 484 patients and up to 2 years for 311 patients who underwent a RIC HCT at two institutions from January 2008 to December 2010. Multiple linear regression was used to analyze the association between clinical variables, center effect, and costs. Patient and transplant characteristics were comparable between the sites, although differences were seen in pretransplant performance scores. Significant predictors for lower costs for the first 100 days included a diagnosis of lymphoma/myeloma and use of human leukocyte antigen-matched related donors. Grade II-IV acute graft-versus-host disease (GVHD) was associated with higher costs. The overall short-term costs between the two institutions were comparable when adjusted for clinical variables (p = .43). Late costs between 100 days and 2 years after HCT were available for one cohort (n = 311); median costs during this period were $39,000 and accounted for 39% of costs during the first 2 years. Late costs were not associated with any pretransplant variables, but were higher with extensive chronic GVHD and death. After adjustment for clinical characteristics, the overall costs of the RIC transplants were similar between the two institutions despite different management approaches (inpatient vs. outpatient conditioning) and accounting methodologies. Use of unrelated/alternative donors, transplant for diseases other than lymphoma or myeloma, and acute GVHD were predictors for higher early costs, and extensive chronic GVHD and death were associated with higher late costs.
Assuntos
Neoplasias Hematológicas/economia , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/economia , Transplante Homólogo/economia , Idoso , Medula Óssea/patologia , Intervalo Livre de Doença , Feminino , Doença Enxerto-Hospedeiro/economia , Doença Enxerto-Hospedeiro/patologia , Neoplasias Hematológicas/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Doadores de TecidosRESUMO
Thirty-day readmission (30-DR) has become an important quality-of-care measure. Allogeneic hematopoietic cell transplantation (allo-HCT) presents a medical setting with higher readmission rates. We analyzed factors affecting 30-DR and its impact on patient outcomes and on health care costs in 91 patients who underwent reduced-toxicity conditioning (RTC) allo-HCT with fludarabine and busulfan. The patient cohort was divided into 2: the readmission group (R-gp) or the no-readmission group (NR-gp). Overall, 38% (n = 35) required readmission with a median time to readmission of 14 days. In multivariate analysis, only documented infection during the index admission predicted 30-DR, P = .01. With a median follow-up of 18 months (range, 1 to 69) for surviving patients, the 2-year overall survival was 49% and 58% in the R-gp and NR-gp respectively, P = .48. The 1-year nonrelapse mortality in R-gp and NR-gp was 18% and 13% respectively, P = .43. The median post-transplantation hospital charges in the R-gp and NR-gp were $85,115 (range, $32,015 to $242,519) and $45,083 (range, $10,715 to $485,456), P = .0002. In conclusion, only documented infections during the index hospitalization influenced 30-DR after RTC allo-HCT. Although 30-DR did not adversely affect mortality or survival, it was associated with significantly increased 100-day post-transplantation hospital charges, thus supporting its role as a quality-of-care measure in allo-HCT patients.
Assuntos
Neoplasias Hematológicas/economia , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/economia , Readmissão do Paciente/economia , Condicionamento Pré-Transplante/economia , Adolescente , Adulto , Idoso , Bussulfano/uso terapêutico , Infecção Hospitalar/economia , Infecção Hospitalar/etiologia , Infecção Hospitalar/imunologia , Infecção Hospitalar/mortalidade , Feminino , Doença Enxerto-Hospedeiro/economia , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/patologia , Custos de Cuidados de Saúde , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/mortalidade , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Agonistas Mieloablativos/uso terapêutico , Análise de Sobrevida , Condicionamento Pré-Transplante/métodos , Transplante Homólogo , Resultado do Tratamento , Vidarabina/análogos & derivados , Vidarabina/uso terapêuticoRESUMO
The optimal healthcare model for follow-up of allogeneic hematopoietic stem cell transplantation (HSCT) recipients after day 100 is not clear. We previously demonstrated that longitudinal follow-up at the transplant center using a multidisciplinary approach is associated with superior survival. Recent data suggest that increased distance from the transplant center is associated with inferior survival. A dedicated long-term transplant clinic (LTTC) was established in 2006 at our center. We hypothesized that geographic distance would not be associated with inferior outcome if patients are followed in the LTTC. We studied 299 consecutive patients who underwent HSCT and established care in an LTTC. The median distance from the transplant center was 118 miles (range, 1 to 1591). The 75th percentile (170 miles) was used as the cut-off to analyze the impact of distance from the center on outcome (219 patients ≤ 75th percentile; 80 patients >75th percentile). The 2 groups were balanced for pretransplant characteristics. In multivariate analyses adjusted for donor type, Center for International Blood and Marrow Transplant Research risk, and transplant regimen intensity, distance from transplant center did not impact outcome. Our study suggests that geographic distance from the transplant center is not associated with inferior outcome when follow-up care is delivered via a dedicated LTTC incorporating well-coordinated multidisciplinary care.
Assuntos
Acessibilidade aos Serviços de Saúde/organização & administração , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas , Assistência de Longa Duração/organização & administração , Adulto , Idoso , Feminino , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/patologia , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/mortalidade , Neoplasias Hematológicas/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Análise de Sobrevida , Transplante Homólogo , Resultado do TratamentoAssuntos
Doenças do Colo/patologia , Doença Enxerto-Hospedeiro/patologia , Sigmoidoscopia/métodos , Transplante de Células-Tronco/efeitos adversos , Adulto , Doenças do Colo/tratamento farmacológico , Doenças do Colo/etiologia , Cor , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/etiologia , Humanos , Masculino , Transplante Homólogo/efeitos adversosRESUMO
Traditional methods for flow cytometry (FCM) data processing rely on subjective manual gating. Recently, several groups have developed computational methods for identifying cell populations in multidimensional FCM data. The Flow Cytometry: Critical Assessment of Population Identification Methods (FlowCAP) challenges were established to compare the performance of these methods on two tasks: (i) mammalian cell population identification, to determine whether automated algorithms can reproduce expert manual gating and (ii) sample classification, to determine whether analysis pipelines can identify characteristics that correlate with external variables (such as clinical outcome). This analysis presents the results of the first FlowCAP challenges. Several methods performed well as compared to manual gating or external variables using statistical performance measures, which suggests that automated methods have reached a sufficient level of maturity and accuracy for reliable use in FCM data analysis.
Assuntos
Biologia Computacional , Citometria de Fluxo/métodos , Processamento de Imagem Assistida por Computador , Algoritmos , Animais , Análise por Conglomerados , Interpretação Estatística de Dados , Citometria de Fluxo/normas , Citometria de Fluxo/estatística & dados numéricos , Doença Enxerto-Hospedeiro/sangue , Doença Enxerto-Hospedeiro/patologia , Humanos , Leucócitos Mononucleares/patologia , Leucócitos Mononucleares/virologia , Linfoma Difuso de Grandes Células B/sangue , Linfoma Difuso de Grandes Células B/patologia , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Software , Febre do Nilo Ocidental/sangue , Febre do Nilo Ocidental/patologia , Febre do Nilo Ocidental/virologiaRESUMO
When designing a study for allogeneic hematopoietic stem cell transplantation (HSCT), many choices must be made, including conditioning regimen, stem cell source, and graft-versus-host disease (GVHD) prevention method. For each of these, there are a growing number of options, which can be combined into a bewildering number of possible HSCT protocols. To properly interpret the results of a given strategy and compare them with others, it is essential that there be agreement on the definitions and estimation methods of HSCT endpoints. We report a survey of the recent HSCT literature that confirms the heterogeneity of endpoint definitions and estimation methods used. Unfortunately, this heterogeneity may lead to significant biases in the estimates of key endpoints, including nonrelapse mortality, relapse, GVHD, or engraftment. This can preclude adequate comparisons among studies, even though such comparisons are the major tool with which to improve HSCT outcome. In the context of our survey, we discuss some of the statistical issues that arise when dealing with HSCT endpoints and the ramifications of the choice of endpoint definition, when the endpoint occurs in the context of competing risks. Our hope is to generate discussion and motivate a search for consensus among those who perform transplantations and statisticians.
Assuntos
Determinação de Ponto Final/estatística & dados numéricos , Sobrevivência de Enxerto , Doença Enxerto-Hospedeiro/patologia , Transplante de Células-Tronco Hematopoéticas/estatística & dados numéricos , Condicionamento Pré-Transplante/métodos , Doença Enxerto-Hospedeiro/mortalidade , Humanos , Análise Multivariada , Recidiva , Análise de Sobrevida , Transplante Homólogo , Resultado do TratamentoRESUMO
The development of an adverse graft-versus-host disease (GvHD) is a major complication of stem cell transplantations, which are widely used to cure increasing number of hematologic malignancies. Patients with chronic GvHD are at risk of joint contractures secondary to sclerodermatous skin changes. Several clinical scores or serologic markers have been used to assess skin sclerosis in scleroderma patients. Evaluation of sclerotic skin changes using biometric tools remains to be challenging. The purpose of this study was to illustrate and exemplify ultrasound measurement and measurement of skin elasticity of five chronic sclerodermoid GvHD patients. There is still a substantial lack of studies using objective and non-invasive methods helpful in assessment of patients with skin involvement of GvHD. Although ultrasound is not the ideal method, it is worth emphasizing that it is still useful, non-invasive, and repeatable device in monitoring patients suffering from GvHD. It should also be added, that it seems to be advisable to repeat USG examination at an interval of 3 months after the treatment. In addition, skin echogenicity may be a more sensitive parameter than skin thickness in assessment of cGvHD patients.
Assuntos
Dermoscopia/métodos , Doença Enxerto-Hospedeiro/complicações , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Esclerodermia Localizada/diagnóstico por imagem , Ultrassonografia/métodos , Adulto , Doença Crônica , Dermoscopia/normas , Elasticidade , Feminino , Doença Enxerto-Hospedeiro/diagnóstico por imagem , Doença Enxerto-Hospedeiro/patologia , Doença de Hodgkin/terapia , Humanos , Leucemia Mieloide Aguda/terapia , Linfoma não Hodgkin/terapia , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Reprodutibilidade dos Testes , Esclerodermia Localizada/etiologia , Esclerodermia Localizada/patologia , Esclerodermia Localizada/radioterapia , Sensibilidade e Especificidade , Ultrassonografia/normas , Terapia Ultravioleta , Adulto JovemRESUMO
Graft-versus-host disease (GVHD) remains a frequently occurring and difficult-to-treat complication in human allogeneic stem cell transplantation. Murine transplantation models are often used to study and understand the complex pathogenesis of GVHD and to explore new treatment strategies. Although GVHD kinetics may differ in murine and human models, adequate models are essential for identification of the crucial factors responsible for the major pathology in GVHD. We present a detailed description of the specific histological features of a graft-versus-host-induced fibrotic response in xenogeneic RAG2(-/-)γc(-/-) mice after total body irradiation and injection with human peripheral blood mononuclear cells. We describe the full morphological features of this reaction, including a detailed analysis of the specific tissue infiltration patterns of the human peripheral blood mononuclear cells. Our data show the development of fibrosis, predominantly near blood vessels, and reveal different cell populations and specific cell migration patterns in the affected organs. The combination of immunohistochemical cell characterization and mRNA expression analysis of both human (donor)- and murine (host)-derived cytokines reveals an interaction between host tissues and donor-derived cells in an entangled cytokine profile, in which both donor- and host-derived cytokines contribute to the formation of fibrosis.
Assuntos
Vasos Sanguíneos/patologia , Doença Enxerto-Hospedeiro/patologia , Transplante de Células-Tronco Hematopoéticas , Leucócitos Mononucleares/transplante , Animais , Vasos Sanguíneos/imunologia , Movimento Celular/imunologia , Citocinas/biossíntese , Citocinas/imunologia , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/imunologia , Modelos Animais de Doenças , Feminino , Doença Enxerto-Hospedeiro/imunologia , Humanos , Imuno-Histoquímica , Subunidade gama Comum de Receptores de Interleucina/deficiência , Subunidade gama Comum de Receptores de Interleucina/genética , Subunidade gama Comum de Receptores de Interleucina/imunologia , Leucócitos Mononucleares/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Esclerose , Transplante Heterólogo , Irradiação Corporal TotalRESUMO
Eosinophils are often present in the inflammatory infiltrate of an interface dermatitis, but the diagnostic specificity of eosinophils in interface dermatitis has not been formally evaluated. We retrospectively identified 97 examples of interface dermatitis with clinically confirmed diagnoses, including lupus erythematosus (LE), lichen planus, pityriasis lichenoides (PL), graft-vs.-host disease (GVHD), dermatomyositis (DM) and drug reaction. Diagnoses were clinically confirmed by at least two dermatologists. Slides were reviewed in a blinded fashion by at least two dermatopathologists. The average eosinophil count per 10 ×200 (×20 objective) fields was lowest for PL (0.2), DM (0.3), GVHD (0.4), and LE (0.5) [defined as Group 1] and was higher for lichen planus, drug reactions, erythema multiforme (major and minor) and viral exanthems [defined as Group 2]. Distinction between Group 1 and Group 2 was maximized using an eosinophil count cutoff of 1.1. In conclusion, eosinophils are usually rare to absent in PL, DM, most forms of LE and GVHD. While final interpretation requires a composite assessment of all features, our results suggest that the presence of even a single eosinophil within nine or ten ×20 fields argues against a diagnosis of PL, DM or LE.
Assuntos
Eosinófilos/patologia , Doença Enxerto-Hospedeiro/patologia , Pitiríase Liquenoide/patologia , Pele/patologia , Dermatomiosite/patologia , Toxidermias/patologia , Feminino , Humanos , Lúpus Eritematoso Cutâneo/patologia , Masculino , Estudos RetrospectivosRESUMO
BACKGROUND: Hyperacute graft-versus-host disease (GVHD) is defined as GVHD occurring within 14 days after haematopoietic stem-cell transplantation (HSCT). AIM: To evaluate the usefulness of skin biopsy in assessing hyperacute GVHD. METHODS: We examined 19 cases of hyperacute GVHD from a total of 134 consecutive HSCT cases at Shinshu University Hospital between 1999 and 2008. RESULTS: Exanthemas were seen in all patients, which were mainly disseminated maculopapular erythemas, commonly present in acute GVHD as well. Most patients presented with a high fever, and a few had mild hepatic dysfunction and/or diarrhoea. The clinical grade of GVHD was 1-2 in all patients; there were no cases of clinical grades 3-4. The histological findings of skin biopsy were divided into three groups: (i) eight had grade 2 changes, characterized by diffuse vacuolization of basal cells, with dyskeratotic bodies; (ii) five had grade 1 changes, characterized by vacuolization of epidermal basal cells (all these cases were diagnosed as acute GVHD with grade 2 histological changes at subsequent biopsy); (iii) and six had no significant changes (these cases were also diagnosed as acute GVHD with grade 2 (four cases) or grade 1 (one case) histological changes on the second biopsy). Many of the patients developed acute and later chronic GVHD. CONCLUSION: Skin biopsy should be considered when eruption develops after HSCT even before engraftment, especially when other organ involvement is minimal. If the first skin biopsy is inconclusive, follow-up biopsy within a short time is helpful in the diagnosis of hyperacute GVHD.
Assuntos
Doença Enxerto-Hospedeiro/patologia , Doença Aguda , Adolescente , Adulto , Biópsia , Criança , Pré-Escolar , Feminino , Doença Enxerto-Hospedeiro/classificação , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
In 2005, the National Institutes of Health sponsored a Consensus Development Project on Criteria for Clinical Trials in chronic graft-versus-host (cGVHD) to achieve consensus about key elements of cGVHD research, including definitions for diagnosis, severity scoring, and response measures. To test these proposed definitions, a multicenter prospective cohort study of people with cGVHD is ongoing. This study will evaluate the performance of proposed prognostic factors, measures of disease activity, and surrogate endpoints for therapeutic response. Data are collected at 6-month intervals in a heterogeneous population of patients reflecting modern transplant techniques and posttransplantation clinical management (target enrollment 672 with cGVHD from 10 transplantation centers). This report describes the rationale, design, and methods of the cGVHD cohort study, and invites other investigators to collaborate with the Consortium to analyze data or specimens.
Assuntos
Ensaios Clínicos como Assunto/métodos , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/tratamento farmacológico , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Doença Crônica , Estudos de Coortes , Coleta de Dados , Feminino , Doença Enxerto-Hospedeiro/patologia , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Estudos Prospectivos , Resultado do Tratamento , Adulto JovemRESUMO
Although hematopoietic stem cell transplantation (HSCT) has been widely used to treat pediatric patients with beta-thalassemia major, evidence showing whether this treatment improves health-related quality of life (HRQoL) is lacking. We used child-self and parent-proxy reports to prospectively evaluate HRQoL in 28 children with beta-thalassemia from Middle Eastern countries who underwent allogeneic HSCT in Italy. The PedsQL 4.0 Generic Core Scales were administered to patients and their parents 1 month before and 3, 6, and 18 months after transplantation. Two-year overall survival, thalassemia-free survival, mortality, and rejection were 89.3%, 78.6%, 10.9% and 14.3%, respectively. The cumulative incidence of acute and chronic graft-versus-host disease (GVHD) was 36% and 18%, respectively. Physical functioning declined significantly from baseline to 3 months after HSCT (median PedsQL score, 81.3 vs 62.5; P = .02), but then increased significantly up to 18 months after HSCT (median score, 93.7; P = .04). Agreement between child-self and parent-proxy ratings was high. Chronic GVHD was the most significant factor associated with lower HRQoL scores over time (P = .02). The child-self and parent-proxy reports showed improved HRQoL in the children with beta-thalassemia after HSCT. Overall, our study provides preliminary evidence-based data to further support clinical decision making in this area.