RESUMO
Most children who may benefit from stem cell transplantation lack a matched related donor. Alternative donor transplantations with an unrelated donor (URD) or a partially matched related donor (PMRD) carry an increased risk of graft-versus-host-disease (GVHD) and mortality compared with matched related donor transplantations. We hypothesized that a strategy of partial CD3+/CD19+ depletion for URD or PMRD peripheral stem cell transplantation (PSCT) would attenuate the risks of GVHD and mortality. We enrolled 84 pediatric patients with hematologic malignancies at the Children's Hospital of Philadelphia and the Children's Hospital of Wisconsin between April 2005 and February 2015. Two patients (2.4%) experienced primary graft failure. Relapse occurred in 23 patients (27.4%; cumulative incidence 26.3%), and 17 patients (20.2%) experienced nonrelapse mortality (NRM). Grade III-IV acute GVHD was observed in 18 patients (21.4%), and chronic GVHD was observed and graded as limited in 24 patients (35.3%) and extensive in 8 (11.7%). Three-year overall survival (OS) was 61.8% (95% confidence interval [CI], 50.2% to 71.4%) and event-free survival (EFS) was 52.0% (95% CI, 40.3% to 62.4%). Age ≥15 years was associated with decreased OS (P= .05) and EFS (P= .05). Relapse was more common in children in second complete remission (P = .03). Partially CD3+-depleted alternative donor PSCT NRM, OS, and EFS compare favorably with previously published studies of T cell-replete PSCT. Historically, T cell-replete PSCT has been associated with a higher incidence of extensive chronic GVHD compared with limited chronic GVHD, which may explain the comparatively low relapse and NRM rates in our study cohort despite similar overall rates of chronic GVHD. Partial T cell depletion may expand donor options for children with malignant transplantation indications lacking a matched related donor by mitigating, but not eliminating, chronic GVHD.
Assuntos
Doença Enxerto-Hospedeiro , Neoplasias Hematológicas , Transplante de Células-Tronco Hematopoéticas , Transplante de Células-Tronco de Sangue Periférico , Adolescente , Criança , Neoplasias Hematológicas/terapia , Humanos , Recidiva Local de Neoplasia , Taxa de Sobrevida , Condicionamento Pré-Transplante , Doadores não RelacionadosRESUMO
Studies in human immunodeficiency virus (HIV)-infected individuals suggest excess weight gain with integrase inhibitor-based antiretroviral therapy. The HIV Prevention Trials Network Study 077 evaluated changes in weight and fasting metabolic parameters in HIV-uninfected individuals randomized to cabotegravir or a placebo. No differences between arms were found for change in weight or fasting metabolic parameters overall or for subgroups.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV , Piridonas , Aumento de Peso , HIV , Infecções por HIV/tratamento farmacológico , HumanosRESUMO
BACKGROUND: Donor lymphocyte infusion (DLI) is often used to treat leukemic relapse after hematopoietic cell transplantation (HCT). However, the relationship between outcomes and distinct DLI cellular composition has not been previously reported. Additionally, there are limited published data on efficacy in pediatrics. We evaluated whether DLI cellular content and development of graft-versus-host disease (GVHD) impacted disease and influenced overall survival (OS) in children receiving DLI for recurrent leukemia. METHODS: We performed an Institutional Review Board-approved, retrospective study investigating all consecutive DLIs given to patients at the Children's Hospital of Wisconsin between 1980 and 2018. Analyses were conducted using Mann-Whitney, Fisher exact, and chi-square tests. RESULTS: Thirty patients ≤20 years old with hematologic malignancies (myeloid [AML/MDS/CML/JMML], n = 23; lymphoid [ALL], n = 7) received DLI to treat post-transplant relapse. We found no significant difference in OS or development of GVHD based on CD3, CD4, CD8, CD56, or CD19 DLI cellular composition. With a median follow-up of 0.69 (range, 0.04-16.61) years, OS at five years was 32% ± 9%. The lymphoid group had a five-year survival rate at 71% ± 17% compared with the myeloid group at 22% ± 9%, although not statistically significant (P = 0.11). The development of GVHD did not affect OS (P = 0.62). CONCLUSION: Here, we report a single-center, long-term experience of pediatric DLIs. Surprisingly, many children with ALL were able to achieve durable remissions. Although cellular composition did not have a significant effect on GVHD or OS in our small study, engineering DLI products to maximize specific effector cell populations could be one strategy to improve efficacy.
Assuntos
Transfusão de Linfócitos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Terapia de Salvação , Adolescente , Criança , Feminino , Seguimentos , Efeito Enxerto vs Leucemia , Transplante de Células-Tronco Hematopoéticas , Humanos , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Masculino , Síndromes Mielodisplásicas/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Recidiva , Estudos Retrospectivos , Risco , Taxa de Sobrevida , Adulto JovemRESUMO
Hematopoietic cell transplantation (HCT) is effective in the treatment of inherited marrow failure disorders and other nonmalignant diseases. Conventional myeloablative conditioning regimens have been associated with high transplant-related mortality, particularly in patients with comorbid conditions. Here we report on 14 patients with marrow failure disorders (Shwachman-Diamond syndrome, n = 3; Diamond Blackfan anemia, n = 4; GATA2 deficiency, n = 2; paroxysmal nocturnal hemoglobinuria, n = 4; and an undefined marrow failure disorder, n = 1) who underwent HCT on a prospective, phase II, multicenter clinical trial. Patients were given HLA-matched related (n = 2) or unrelated (n = 12) grafts after conditioning with treosulfan (42 g/m2), fludarabine (150 mg/m2), ± thymoglobulin (n = 11; 6 mg/kg). All patients engrafted. At a median follow-up of 3 years, 13 patients are alive with complete correction of their underlying disease. These results indicate that the combination of treosulfan, fludarabine, and thymoglobulin is effective at establishing donor engraftment with a low toxicity profile and excellent disease-free survival in patients with marrow failure disorders.
Assuntos
Doenças da Medula Óssea/terapia , Bussulfano/análogos & derivados , Transplante de Células-Tronco Hematopoéticas/métodos , Condicionamento Pré-Transplante/métodos , Adolescente , Soro Antilinfocitário/uso terapêutico , Bussulfano/uso terapêutico , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Sobrevivência de Enxerto , Humanos , Lactente , Masculino , Transplante Homólogo , Resultado do Tratamento , Vidarabina/análogos & derivados , Vidarabina/uso terapêutico , Adulto JovemRESUMO
Survivors of hematopoietic cell transplantation (HCT) are at risk of subsequent solid tumors, including central nervous system (CNS) tumors. The risk of CNS tumors after HCT in pediatric HCT recipients is not known. We evaluated the incidence and risk factors for CNS tumors in pediatric recipients of allogeneic HCT reported to the Center for International Blood and Marrow Transplant Research between 1976 and 2008. A case control design was used. There were no CNS tumors in the nonmalignant cohort (n = 4543) or in those undergoing HCT for solid tumors (n = 26). There were 59 CNS tumors in 8720 patients transplanted for hematologic malignancies. In comparison with the general population, pediatric HCT recipients with hematologic malignancies had a 33 times higher than expected rate of CNS tumors (95% confidence interval, 22.98 to 45.77; P < .0001). The cumulative incidence of subsequent CNS tumors was 1.29% (95% confidence interval .87 to 1.87) at 20 years after HCT. Significant risk factors in the entire cohort were having an unrelated donor (HR, 3.35; P = .0002) and CNS disease before HCT for both acute lymphoblastic leukemia (HR, 8.21; P = .0003) and acute myeloid leukemia (HR, 6.21; P = .0174). Analysis of the matched cohort showed having an unrelated donor transplant (HR, 4.79; P = .0037), CNS disease before HCT (HR, 7.67; P = .0064), and radiotherapy exposure before conditioning (HR, 3.7; P = .0234) to be significant risk factors. Chronic graft-versus-host disease was associated with a lower risk (HR, .29; P = .0143). Survivors of HCT for nonmalignant diseases did not show an increased incidence of CNS tumors, whereas survivors of hematologic malignancies have a markedly increased incidence of CNS tumors that warrants lifelong surveillance.
Assuntos
Neoplasias do Sistema Nervoso Central/mortalidade , Neoplasias Hematológicas , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Segunda Neoplasia Primária/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras , Doadores não Relacionados , Adolescente , Adulto , Aloenxertos , Criança , Pré-Escolar , Feminino , Neoplasias Hematológicas/mortalidade , Neoplasias Hematológicas/terapia , Humanos , Incidência , Lactente , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapiaRESUMO
Alternative graft sources (umbilical cord blood [UCB], matched unrelated donors [MUD], or mismatched unrelated donors [MMUD]) enable patients without a matched sibling donor to receive potentially curative hematopoietic cell transplantation (HCT). Retrospective studies demonstrate comparable outcomes among different graft sources. However, the risk and types of infections have not been compared among graft sources. Such information may influence the choice of a particular graft source. We compared the incidence of bacterial, viral, and fungal infections in 1781 adults with acute leukemia who received alternative donor HCT (UCB, n= 568; MUD, n = 930; MMUD, n = 283) between 2008 and 2011. The incidences of bacterial infection at 1 year were 72%, 59%, and 65% (P < .0001) for UCB, MUD, and MMUD, respectively. Incidences of viral infection at 1 year were 68%, 45%, and 53% (P < .0001) for UCB, MUD, and MMUD, respectively. In multivariable analysis, bacterial, fungal, and viral infections were more common after either UCB or MMUD than after MUD (P < .0001). Bacterial and viral but not fungal infections were more common after UCB than MMUD (P = .0009 and <.0001, respectively). The presence of viral infection was not associated with an increased mortality. Overall survival (OS) was comparable among UCB and MMUD patients with Karnofsky performance status (KPS) ≥ 90% but was inferior for UCB for patients with KPS < 90%. Bacterial and fungal infections were associated with poorer OS. Future strategies focusing on infection prevention and treatment are indicated to improve HCT outcomes.
Assuntos
Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Infecções/etiologia , Leucemia/complicações , Leucemia/terapia , Doença Aguda , Adolescente , Adulto , Idoso , Transplante de Células-Tronco de Sangue do Cordão Umbilical/efeitos adversos , Transplante de Células-Tronco de Sangue do Cordão Umbilical/mortalidade , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco Hematopoéticas/mortalidade , Histocompatibilidade , Humanos , Incidência , Infecções/mortalidade , Leucemia/mortalidade , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Análise de Sobrevida , Doadores não Relacionados , Adulto JovemRESUMO
BACKGROUND AIMS: Removing DMSO post-thaw results in: reduced infusion reactions, improved recovery and stability of viable CD34+ cells. Validated methods use 5%-8.3% Dextran 40 with 2.5%-4.2% HSA for this purpose. Recent shortages of clinical grade Dextran require identification of suitable alternatives. METHODS: PBPC were used to compare a standard 2X wash medium of 5 parts 10% Dextran 40 in saline (DEX) with 1 part 25% HSA (8.3% DEX/ 4.2% HSA) with Hydroxyethyl Starch (HES)-based solutions. Cells in replicate bags were diluted with an equal volume of wash solution, equilibrated 5 minutes, the bag filled with wash medium, pelleted and the supernatant expressed. Bags were restored to the frozen volume in wash medium and tested by single platform flow cytometry and CFU. Total viability, viable TNC, MNC, and CD34+ cell recovery, and CD34+ cell viability were compared immediately post-thaw and after 90 minutes. RESULTS: 5.2% HES/4.2% HSA did not differ from our standard in CD34 recovery or viability. Due to concerns that high concentrations of HES could affect renal function we tested 0.6% HES/2.5% HSA resulting in significantly poorer CD34 recovery and viability. Results improved using 2.4% HES/4.2% HSA and when 0.6% HES/4.2%HSA was used no significant differences were seen. CFU assays confirmed no differences between the standard dextran arm and HES at 2.4% or 0.6% so long as HSA was at 4.2%. CONCLUSIONS: We conclude that HES from 0.6% to 5.2% with 4.2% HSA is a suitable substitute for Dextran 40 as a reconstitution/washing medium for PBPC products.
Assuntos
Criopreservação/métodos , Dextranos/farmacologia , Células-Tronco Hematopoéticas/citologia , Derivados de Hidroxietil Amido/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Ensaio de Unidades Formadoras de Colônias , Meios de Cultura , Congelamento , Humanos , MasculinoRESUMO
Propensity for developing coronary heart disease (CHD) is linked with Framingham-defined cardiovascular risk factors and elevated inflammatory biomarkers. Cardiovascular risk and inflammatory biomarkers were evaluated in ARIES, a Phase IIIb/IV clinical trial in which 515 antiretroviral-naive HIV-infected subjects initially received abacavir/lamivudine + atazanavir/ritonavir for 36 weeks. Subjects who were virologically suppressed by week 30 were randomized 1:1 at week 36 to either maintain or discontinue ritonavir for an additional 108 weeks. Framingham 10-year CHD risk scores (FRS) and risk category of <6% or ≥6%, lipoprotein-associated phospholipase A(2) (Lp-PLA(2)), interleukin-6 (IL-6), and high-sensitivity C-reactive protein (hsCRP) were assessed at baseline, week 84, and week 144. Biomarkers were stratified by FRS category. When ritonavir-boosted/nonboosted treatment groups were combined, median hsCRP did not change significantly between baseline (1.6 mg/liter) and week 144 (1.4 mg/liter) in subjects with FRS <6% (p=0.535) or with FRS ≥6% (1.9 mg/liter vs. 2.0 mg/liter, respectively; p=0.102). Median IL-6 was similar for subjects with FRS <6% (p=0.267) at baseline (1.6 pg/ml) and week 144 (1.4 pg/ml) and for FRS ≥6% (2.0 pg/ml vs. 2.2 pg/ml, respectively; p=0.099). Median Lp-PLA(2) decreased significantly (p<0.001) between baseline (197 nmol/min/ml) and week 144 (168 nmol/min/ml) in subjects with FRS <6% and with FRS ≥6% (238 nmol/min/ml vs. 175 nmol/min/ml, respectively; p<0.001). In conclusion, in antiretroviral-naive subjects treated with abacavir-based therapy for 144 weeks, median inflammatory biomarker levels for hsCRP and IL-6 generally remained stable with no significant difference between baseline and week 144 for subjects with either FRS <6% or FRS ≥6%. Lp-PLA(2) median values declined significantly over 144 weeks for subjects in either FRS stratum.
Assuntos
Doença das Coronárias/epidemiologia , Didesoxinucleosídeos/administração & dosagem , Infecções por HIV/tratamento farmacológico , Inflamação/patologia , Lamivudina/administração & dosagem , Lipídeos/sangue , Oligopeptídeos/administração & dosagem , Piridinas/administração & dosagem , Ritonavir/administração & dosagem , 1-Alquil-2-acetilglicerofosfocolina Esterase/sangue , Adulto , Idoso , Fármacos Anti-HIV/administração & dosagem , Sulfato de Atazanavir , Biomarcadores/sangue , Proteína C-Reativa/análise , Combinação de Medicamentos , Feminino , Infecções por HIV/patologia , Humanos , Interleucina-6/sangue , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Medição de Risco , Resultado do Tratamento , Adulto JovemRESUMO
There have been no studies on patient outcome after allogeneic hematopoietic cell transplantation (HCT) in patients with X-linked inhibitor of apoptosis (XIAP) deficiency. To estimate the success of HCT, we conducted an international survey of transplantation outcomes. Data were reported for 19 patients. Seven patients received busulfan-containing myeloablative conditioning (MAC) regimens. Eleven patients underwent reduced intensity conditioning (RIC) regimens predominantly consisting of alemtuzumab, fludarabine, and melphalan. One patient received an intermediate-intensity regimen. Survival was poor in the MAC group, with only 1 patient surviving (14%). Most deaths were from transplantation-related toxicities, including venoocclusive disease and pulmonary hemorrhage. Of the 11 patients who received RIC, 6 are currently surviving at a median of 570 days after HCT (55%). Preparative regimen and HLH activity affected outcomes, and of RIC patients reported to be in remission from HLH, survival is 86% (P = .03). We conclude that MAC regimens should not be used for patients with XIAP deficiency. It is possible that the loss of XIAP and its antiapoptotic functions contributes to the high incidence of toxicities observed with MAC regimens. RIC regimens should be pursued with caution and, if possible, efforts should be made to ensure HLH remission before HCT in these patients.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Doenças Genéticas Ligadas ao Cromossomo X/terapia , Transplante de Células-Tronco Hematopoéticas/métodos , Transtornos Linfoproliferativos/terapia , Condicionamento Pré-Transplante/métodos , Adolescente , Criança , Pré-Escolar , Terapia Combinada , Europa (Continente) , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/mortalidade , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Hemorragia/etiologia , Hepatopatia Veno-Oclusiva/etiologia , Humanos , Lactente , Japão , Pulmão/irrigação sanguínea , Transtornos Linfoproliferativos/genética , Transtornos Linfoproliferativos/mortalidade , Mutação , Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , Indução de Remissão , Estudos Retrospectivos , Análise de Sobrevida , Taxa de Sobrevida , Transplante Homólogo , Estados Unidos , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/genética , Adulto JovemRESUMO
BACKGROUND: Coccidioidomycosis is usually a self-limited infection in immunocompentent people. In immunocompentent human beings second infections due to Coccidioides are very rare, indicating that recovery from infection results in protective immunity. In experimental animals, immunization with several different proteins or attenuated mutants protects against a virulent challenge. To explore what mechanisms are responsible for protective immunity, we investigated the course of Coccidioides infection in the gp91phox knock out mouse that has a defect in the oxidative burst that results in chronic granulomatous disease. RESULTS: We found that the gp91phox knock out mice were somewhat more resistant to intraperitoneal infection and equally as resistant to low dose intranasal infection, but slightly more susceptible to high dose intranasal infection compared to control mice. The gp91phox knock out mice made a more robust inflammatory response to infection than controls, as measured by histology and production of inflammatory cytokines. The gp91phox knock out mice were as protected by immunization with the recombinant Coccidioides protein Ag2/PRA as the controls were against either intraperitoneal or intranasal infection. Coccidioides immitis arthroconidia and spherules were significantly more resistant to H2O2 treatment in vitro than Aspergillus fumigatus spores. CONCLUSION: These data suggest that oxidative burst may not be required for protective immunity to coccidioidomycois.
Assuntos
Coccidioides/imunologia , Coccidioidomicose/imunologia , Espécies Reativas de Oxigênio/imunologia , Espécies Reativas de Oxigênio/metabolismo , Animais , Coccidioidomicose/mortalidade , Coccidioidomicose/patologia , Contagem de Colônia Microbiana , Modelos Animais de Doenças , Feminino , Histocitoquímica , Pulmão/microbiologia , Pulmão/patologia , Masculino , Glicoproteínas de Membrana/deficiência , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia , NADPH Oxidase 2 , NADPH Oxidases/deficiência , Análise de SobrevidaRESUMO
PURPOSE: We report a male child who presented at 15 months with perianal abscesses and proctitis, progressing to transmural pancolitis with colocutaneous fistulae, consistent with a Crohn disease-like illness. The age and severity of the presentation suggested an underlying immune defect; however, despite comprehensive clinical evaluation, we were unable to arrive at a definitive diagnosis, thereby restricting clinical management. METHODS: We sought to identify the causative mutation(s) through exome sequencing to provide the necessary additional information required for clinical management. RESULTS: After sequencing, we identified 16,124 variants. Subsequent analysis identified a novel, hemizygous missense mutation in the X-linked inhibitor of apoptosis gene, substituting a tyrosine for a highly conserved and functionally important cysteine. X-linked inhibitor of apoptosis was not previously associated with Crohn disease but has a central role in the proinflammatory response and bacterial sensing through the NOD signaling pathway. The mutation was confirmed by Sanger sequencing in a licensed clinical laboratory. Functional assays demonstrated an increased susceptibility to activation-induced cell death and defective responsiveness to NOD2 ligands, consistent with loss of normal X-linked inhibitor of apoptosis protein function in apoptosis and NOD2 signaling. CONCLUSIONS: Based on this medical history, genetic and functional data, the child was diagnosed as having an X-linked inhibitor of apoptosis deficiency. Based on this finding, an allogeneic hematopoietic progenitor cell transplant was performed to prevent the development of life-threatening hemophagocytic lymphohistiocytosis, in concordance with the recommended treatment for X-linked inhibitor of apoptosis deficiency. At >42 days posttransplant, the child was able to eat and drink, and there has been no recurrence of gastrointestinal disease, suggesting this mutation also drove the gastrointestinal disease. This report describes the identification of a novel cause of inflammatory bowel disease. Equally importantly, it demonstrates the power of exome sequencing to render a molecular diagnosis in an individual patient in the setting of a novel disease, after all standard diagnoses were exhausted, and illustrates how this technology can be used in a clinical setting.
Assuntos
Doenças Inflamatórias Intestinais/diagnóstico , Doenças Inflamatórias Intestinais/genética , Análise de Sequência de DNA , Sequência de Aminoácidos , Éxons , Transplante de Células-Tronco Hematopoéticas , Humanos , Lactente , Doenças Inflamatórias Intestinais/terapia , Masculino , Dados de Sequência Molecular , Mutação , Alinhamento de Sequência , Resultado do Tratamento , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/genéticaRESUMO
We describe long-term disease-free survival (DFS) after unrelated donor bone marrow transplantation (BMT) for myelodysplastic syndrome (MDS) in 118 patients aged ≤18 years. Forty-six patients had refractory cytopenia (RC), 55 refractory anemia with excess blasts (RAEB), and 17 refractory anemia with excess blasts in transformation (RAEB-t). Transplant-related mortality was higher after mismatched BMT (relative risk [RR] 3.29, P = .002). Disease recurrence was more likely with advanced stages of MDS at the time of BMT: RAEB (RR 6.50, P = .01) or RAEB-t (RR 11.00, P = .004). Treatment failure (recurrent disease or death from any cause; inverse of DFS) occurred in 68 patients. Treatment failure was higher after mismatched BMT (RR 2.79, P = .001) and in those with RAEB-t (RR 2.38, P = .02). Secondary MDS or chemotherapy prior to BMT was not associated with recurrence or treatment failure. Similarly, cytogenetic abnormalities were not associated with transplant outcomes. Eight-year DFS for patients with RC after matched and mismatched unrelated donor BMT was 65% and 40%, respectively. Corresponding DFS for patients with RAEB and RAEB-t was 48% and 28%, respectively. When a matched adult unrelated donor is available, BMT should be offered as first-line therapy, and children with RC can be expected to have the best outcome.
Assuntos
Transplante de Medula Óssea/métodos , Síndromes Mielodisplásicas/terapia , Adolescente , Antineoplásicos/administração & dosagem , Plaquetas/citologia , Transplante de Medula Óssea/efeitos adversos , Transplante de Medula Óssea/imunologia , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/fisiopatologia , Antígenos HLA/imunologia , Humanos , Masculino , Síndromes Mielodisplásicas/imunologia , Síndromes Mielodisplásicas/mortalidade , Síndromes Mielodisplásicas/fisiopatologia , Neutrófilos/citologia , Recidiva , Doadores de Tecidos , Transplante Homólogo , Falha de TratamentoRESUMO
Many of the 51 serotypes of adenovirus have been associated with clinically relevant infection. Adenovirus can disseminate rapidly in patients with a compromised immune system, such as that which occurs secondary to haematopoietic progenitor-cell transplantation. The higher rate of infection in recipients of T cell-depleted grafts and in those undergoing T cell-targeted treatment during graft versus host disease demonstrates the importance of a T-cell response in preventing disseminated infection. Studies have shown that the memory response to adenovirus is directed primarily to the hexon protein and is dominated by CD4+ T cells, probably due to the ability of the virus to block its presentation on HLA class I antigens. We have developed an approach to expand adenovirus-specific T cells using a pool of overlapping pentadecapeptides derived from selected conserved regions of hexon. We characterized responses to identify the peptides that are recognized, the responding T-cell subsets and their HLA restriction. Of eight lines that were characterized extensively, seven included both CD4+ and CD8+ T cells and each recognized between two and eight unique peptide sequences. By focusing the response on the conserved sequences of hexon, the cell lines are likely to recognize most of the serotypes responsible for clinically relevant disease. The 15 aa peptides used to prime the responses are more likely than whole virus or longer peptides to expand the less frequent CD8+ memory subset. Lines prepared by using our method may be more effective in adoptive immunotherapy protocols designed to prevent or treat disseminated adenovirus infections in high-risk patients.
Assuntos
Adenovírus Humanos/imunologia , Proteínas do Capsídeo/imunologia , Linfócitos T Citotóxicos/imunologia , Infecções por Adenoviridae/terapia , Transferência Adotiva , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Humanos , Hospedeiro Imunocomprometido , Oligopeptídeos/imunologiaRESUMO
BACKGROUND: Cutaneous eruptions commonly occur in children receiving chemotherapy, and the clinical situation often demands immediate diagnosis and initiation of treatment. Several patterns of cutaneous eruptions to chemotherapy have been reported; however, the nomenclature used to describe these entities has been derived from the histologic findings. The morphologic characteristics, distribution, and natural history of these reactions have not been well established. OBSERVATIONS: We report the clinical features of 16 pediatric patients with a distinctive chemotherapy-induced eruption. The eruption is most prominent in or limited to intertriginous regions and areas of occlusion. We were not able to identify any single chemotherapeutic agent or even a group of agents in the same pharmacologic family that seemed to be associated with this reaction. The eruption did not appear to be related to sex, age, ethnicity, underlying malignancy, or genetic disease. CONCLUSIONS: Recognition of this distinct clinical pattern can help rule out more serious entities, avoid a biopsy, and reassure the physician and patient of the benign and self-resolving clinical course. This entity may be observed with many chemotherapeutic agents and underlying diseases, but most often with high-dose chemotherapy protocols.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Toxidermias/etiologia , Intertrigo/induzido quimicamente , Abdome , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Braço , Axila , Criança , Pré-Escolar , Feminino , Virilha , Neoplasias Cardíacas/tratamento farmacológico , Hemangiossarcoma/tratamento farmacológico , Humanos , Lactente , Masculino , Neuroblastoma/tratamento farmacológico , Estudos Retrospectivos , TóraxRESUMO
The field of allogeneic transplantation has made vast improvements since its inception in 1968. Improvements in supportive care have greatly improved survival. Delayed immune reconstitution, graft versus host disease, and relapse of disease still pose great obstacles. This article has highlighted novel strategies for using cellular therapy in conjunction with hematopoietic cell transplantation (HCT) that potentially may lead to improved clinical outcomes for patients undergoing HCT in the future.
Assuntos
Transplante de Células-Tronco Hematopoéticas/tendências , Transfusão de Leucócitos , Pediatria/tendências , Infecções por Vírus de DNA/prevenção & controle , Infecções por Vírus de DNA/terapia , Doença Enxerto-Hospedeiro/diagnóstico , Efeito Enxerto vs Leucemia , Humanos , Imunoterapia , Neoplasias/terapia , Linfócitos T/imunologia , Viroses/imunologia , Viroses/terapiaRESUMO
Peripheral blood progenitor cells (PBPCs) are now widely used as a source of progenitor cells for allogeneic transplantation. Recombinant human granulocyte colony-stimulating factor is used to mobilize PBPCs for collection by leukapheresis. Although side effects of mobilization are generally benign, adverse effects have been reported. The authors present a case of spontaneous splenic rupture, without splenomegaly, in a parental donor undergoing PBPC mobilization, review the literature regarding this adverse event, and explore issues regarding donor safety.
Assuntos
Mobilização de Células-Tronco Hematopoéticas/efeitos adversos , Ruptura Esplênica/etiologia , Doadores de Tecidos , Adulto , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Humanos , Masculino , Pais , Transplante de Células-Tronco de Sangue Periférico , Baço/irrigação sanguínea , Baço/patologiaAssuntos
Anticorpos Monoclonais/uso terapêutico , Anticorpos Antineoplásicos/uso terapêutico , Antineoplásicos/uso terapêutico , Leucemia Linfoide/tratamento farmacológico , Leucemia de Células T/tratamento farmacológico , Alemtuzumab , Anticorpos Monoclonais Humanizados , Feminino , Citometria de Fluxo , Humanos , Imunofenotipagem , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
Malignant infantile osteopetrosis (MIOP), a rare genetic disorder of the osteoclast, is fatal without hematopoietic stem cell transplantation. Primary pulmonary hypertension (PPH), a rare progressive disorder of the pulmonary circulation, is predominantly fatal in the absence of successful therapy. A clinical association between these two disorders has not been recognized and a pathophysiologic link between osteoclast function and pulmonary vascular pressure as a rationale for such an association is not readily apparent. Here, we report five infants with MIOP, without cardiac abnormalities, who were found to have PPH after undergoing stem cell transplantation. We suggest that PPH may be linked to a specific variant of MIOP and recognizing the potential for pulmonary hypertension in children with MIOP may lead to a more rapid diagnosis and life-saving intervention.
Assuntos
Hipertensão Pulmonar/complicações , Osteopetrose/complicações , Anti-Hipertensivos/uso terapêutico , Feminino , Humanos , Hipertensão Pulmonar/patologia , Hipertensão Pulmonar/terapia , Lactente , Masculino , Osteopetrose/patologia , Osteopetrose/terapia , Transplante de Células-Tronco , Resultado do TratamentoRESUMO
A major risk faced by bone-marrow and solid organ transplant patients is the development of post-transplant lymphoproliferative disease or post-transplant lymphoma (PTLD). In pediatric transplantation, PTLD onset is often associated with a rapid rise in Epstein-Barr virus (EBV) load in peripheral blood mononuclear cells (PBMC). We have analyzed EBV viral loads in PBMC over time using real-time quantitative PCR in 56 patients, 19 of which have been followed for more than 1 year. In nine patients; eight bone marrow (BMT) and one kidney transplant, PTLD was associated with a rapid rise in viral load, exceeding 1 x 10(5) EBV genomes/microg of PBMC-derived DNA. Four of these patients exceeded 1 x 10(6) EBV genomes/microg PBMC DNA. All patients with viral loads exceeding 1 x 10(5) EBV genomes/microg PBMC DNA were clearly at high risk for transplant-associated mortality, with only six of nine surviving. Importantly, only one of these deaths was directly attributable to EBV. A second elevated state of EBV load, defined as exceeding 2 x 10(4) EBV genomes/microg PBMC, was seen in a total of 12 BMT, kidney, heart, and liver transplant patients. These patients did not appear to be at immediate lethal risk for PTLD and one EBV-attributable death was found in this group as well. Thirty-four transplant patients whose EBV viral load oscillated from undetectable to 10 000 EBV genomes/microg PBMC DNA are reported as well. The threshold for normal EBV viral load based on our combined experience with viral load analysis is defined as 1 x 10(4) EBV genomes/microg PBMC DNA. The ability to rapidly analyze EBV load allows rapid changes in viral load, such as those that occur with PTLD onset, and the impact of anti-CD20 antibody therapy to be rapidly detected.