RESUMEN
BACKGROUND: Patients with steroid-refractory acute graft-versus-host disease (aGvHD) not tolerating/responding to ruxolitinib (RR-aGvHD) have a dismal prognosis. METHODS: We retrospectively assessed real-world outcomes of RR-aGvHD treated with the random-donor allogeneic MSC preparation MSC-FFM, available via Hospital Exemption in Germany. MSC-FFM is provided as frozen cell dispersion for administration as i.v. infusion immediately after thawing, at a recommended dose of 1-2 million MSCs/kg body weight in 4 once-weekly doses. 156 patients, 33 thereof children, received MSC-FFM; 5% had Grade II, 40% had Grade III, and 54% had Grade IV aGvHD. Median (range) number of prior therapies was 4 (1-10) in adults and 7 (2-11) in children. RESULTS: The safety profile of MSC-FFM was consistent with previous reports for MSC therapies in general and MSC-FFM specifically. The overall response rate at Day 28 was 46% (95% confidence interval [CI] 36-55%) in adults and 64% (45-80%) in children; most responses were durable. Probability of overall survival at 6, 12 and 24 months was 47% (38-56%), 35% (27-44%) and 30% (22-39%) for adults, and 59% (40-74%), 42% (24-58%) and 35% (19-53%) for children, respectively (whole cohort: median OS 5.8 months). CONCLUSION: A recent real-world analysis of outcomes for 64 adult RR-aGvHD patients not treated with MSCs reports survival of 20%, 16% and 10% beyond 6, 12 and 24 months, respectively (median 28 days). Our data thus suggest effectiveness of MSC-FFM in RR-aGvHD.
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Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Niño , Adulto , Humanos , Trasplante de Células Madre Mesenquimatosas/efectos adversos , Estudios Retrospectivos , Enfermedad Aguda , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Enfermedad Injerto contra Huésped/tratamiento farmacológicoRESUMEN
Viral infections cause life-threatening disease in immunocompromised patients and especially following transplantation. T cell receptor (TCR) engineering redirects specificity and can bring significant progress to emerging adoptive T cell transfer (ACT) approaches. T cell epitopes are well described, although knowledge is limited on which TCRs mediate protective immunity. In this study, refractory adenovirus (AdV) infection after hematopoietic stem cell transplantation (HSCT) was treated with ACT of highly purified Hexon5-specific T cells using peptide major histocompatibility complex (pMHC)-Streptamers against the immunodominant human leukocyte antigen (HLA)-A∗0101-restricted peptide LTDLGQNLLY. AdV was successfully controlled through this oligoclonal ACT. Novel protective TCRs were isolated ex vivo and preclinically engineered into the TCR locus of allogeneic third-party primary T cells by CRISPR-Cas9-mediated orthotopic TCR replacement. Both TCR knockout and targeted integration of the new TCR in one single engineering step led to physiological expression of the transgenic TCR. Reprogrammed TCR-edited T cells showed strong virus-specific functionality such as cytokine release, effector marker upregulation, and proliferation capacity, as well as cytotoxicity against LTDLGQNLLY-presenting and AdV-infected targets. In conclusion, ex vivo isolated TCRs with clinical proven protection through ACT could be redirected into T cells from naive third-party donors. This approach ensures that transgenic TCRs are protective with potential off-the-shelf use and widened applicability of ACT to various refractory emerging viral infections.
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Receptores de Antígenos de Linfocitos T , Virosis , Traslado Adoptivo , Humanos , Inmunoterapia Adoptiva , Receptores de Antígenos de Linfocitos T/genética , Linfocitos TRESUMEN
OBJECTIVES: Hematopoietic stem cell transplantation (HSCT) or intensive chemotherapy for the treatment of malignant diseases is a highly distressing experience. The affected person's resilience is crucial to coping with this challenging experience. Experience with resilience-enhancing interventions in children and young adults during cancer therapy is scarce. The major objective of this work was developing and evaluating an effective psycho-oncological mental training that complements the standard psychosocial care. METHODS: In this prospective, randomized single-center study, a total of 30 patients (12 to 22 years of age) who underwent HSCT or high-dose chemotherapy received either the standard psychosocial care (control group [CG]) or additionally underwent a novel and specifically developed resilience-enhancing 14-session mental training (therapy group [TG]). The patients were observed over an 8-month period and were screened for distress, thyroid, and immune function parameters, as well as generalized anxiety, affect, and sports orientation. RESULTS: Patients of the TG showed significantly greater improvements in all assessed mental aspects, including anxiety, affect, competitiveness, win orientation, goal orientation, self-optimization, self-blocking, and loss of focus, as well as cortisol levels within 8 months, as opposed to patients of the CG (effect size range ξ: 0.74-1.00). SIGNIFICANCE OF RESULTS: Patients who underwent the mental training displayed less anxiety, better affect, and improved mental performance with less self-blocking. This resulted in improved goal orientation, competitiveness, self-optimization, and focus when compared to the CG patients. However, larger prospective trials are necessary to substantiate these findings.
RESUMEN
BACKGROUND: Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative option for children with both malignant and nonmalignant diseases. T-cell depletion techniques may result in reduced transplant-related mortality compared with unmanipulated grafts due to a lower incidence of GvHD. METHODS: Immune recovery and outcome were analyzed in a cohort of 23 patients with malignant and nonmalignant diseases who received CD3+TCRαß+ T- and B-cell-depleted allografts from matched donors after reduced-intensity or myeloablative conditioning. The median number of CD34+, CD3+TCRαß+, and CD19+B-cells infused was 12.7 × 106 /kg, 16.8 × 103 /kg, and 96 × 103 /kg bodyweight. RESULTS: With a median follow-up of 36 (range 1-73) months, overall survival and disease-free survival at 3 years were 65.2% and 60.8%. Eight patients died, six due to the underlying disease and two of extended visceral cGvHD. Immune reconstitution, disease-free, and overall survivals were similar compared with a historical cohort of 23 patients transplanted with matched unmanipulated bone marrow. A significant lower rate of higher grade (III-IV) aGvHD was observed in the manipulated HSCT group (8.7% vs. 26%; p = 0.001), whereas the incidence of cGvHD was equal. CONCLUSIONS: Our data suggest that this graft manipulation strategy could be a safe and effective alternative to conventional HSCT techniques in matched donors.
Asunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Antígenos CD19 , Niño , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Depleción Linfocítica , Receptores de Antígenos de Linfocitos T alfa-beta , Acondicionamiento Pretrasplante/métodosRESUMEN
OBJECTIVE: Pediatric patients with relapsed or refractory acute lymphoblastic leukemia have a poor prognosis. We here assess the response rates, adverse events, and long-term follow-up of pediatric patients with relapsed/refractory acute lymphoblastic leukemia receiving blinatumomab. METHODS: Retrospective analysis of a single-center experience with blinatumomab in 38 patients over a period of 10 years. RESULTS: The median age at onset of therapy was 10 years (1-21 years). Seventy-one percent of patients had undergone at least one hematopoietic stem cell transplantation (HSCT) prior to treatment with blinatumomab. We observed a response to blinatumomab in 13/38 patients (34%). The predominant side effect was febrile reactions, nearly half of the patients developed a cytokine release syndrome. Eight events of neurotoxicity were registered over the 78 cycles (15%). To date, nine patients (24%) are alive and in complete molecular remission. All survivors underwent haploidentical HSCT after treatment with blinatumomab. CONCLUSIONS: Despite heavy pretreatment of most of our patients, severe adverse events were rare and response rates encouraging. Blinatumomab is a valuable bridging salvage therapy for relapsed or refractory patients to a second or even third HSCT.
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Anticuerpos Biespecíficos/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamiento farmacológico , Adolescente , Anticuerpos Biespecíficos/administración & dosificación , Anticuerpos Biespecíficos/efectos adversos , Antineoplásicos Inmunológicos/administración & dosificación , Antineoplásicos Inmunológicos/efectos adversos , Niño , Preescolar , Terapia Combinada , Manejo de la Enfermedad , Resistencia a Antineoplásicos , Femenino , Humanos , Lactante , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/etiología , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidad , Pronóstico , Recurrencia , Retratamiento , Estudios Retrospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
Arsenic trioxide (ATO) has become an established component of treatment protocols for acute promyelocytic leukemia (APL) with excellent efficacy and no relevant sustained toxicity. Part of its action has been attributed to the inhibition of Hedgehog signaling (Hh) which enables a possible therapeutic approach as many pediatric tumor entities have been associated with increased Hh activity. We retrospectively analyzed 31 patients with refractory and relapsed pediatric cancer who were treated with ATO at the University Children's Hospital of Tuebingen. Additionally a literature review on the clinical and preclinical use of ATO in pediatric cancer treatment was performed.ATO alone as well as combinations with other drugs have proven effective in vitro and in mouse models of various pediatric malignancies. However, only few data on the clinical use of ATO in pediatric patients besides APL exist. In our patient sample, ATO was overall well tolerated in the treatment of various pediatric cancers, even in combination with other cytostatic drugs. Due to distinct tumor entities, differently progressed disease stages and varying co-medication, no clear statement can be made regarding the efficacy of ATO treatment. However, patients with proven Hh activation in molecular tumor profiling surpassed all other patients, who received ATO in an experimental treatment setting, in terms of survival. As molecular profiling of tumors increases and enhanced Hh activity can be detected at an early stage, ATO might expand its clinical use to other pediatric malignancies beyond APL depending on further clinical studies.
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Antineoplásicos/uso terapéutico , Trióxido de Arsénico/uso terapéutico , Neoplasias Hematológicas/tratamiento farmacológico , Leucemia Promielocítica Aguda/tratamiento farmacológico , Adolescente , Adulto , Antineoplásicos/efectos adversos , Trióxido de Arsénico/efectos adversos , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Adulto JovenRESUMEN
BACKGROUND: Chemotherapy-induced nausea and vomiting (CINV) belong among the most burdensome side effects in hemato-oncology. Mostly, a combination of ondansetron and dexamethasone is used as antiemetic prophylaxis in pediatric patients undergoing emetogenic chemotherapy. However, dexamethasone is prohibited in different pediatric chemotherapy protocols. Currently, data on the use of ondansetron with the new antiemetic agent fosaprepitant without dexamethasone is not available for pediatric patients. METHODS: In this non-interventional observation study, 79 pediatric patients with a median age of 8.0 years (range 0.5-17.9 years) who received a CINV prophylaxis regimen with either fosaprepitant (4 mg/kg; maximum 150 mg) and ondansetron (as 24-h continuous infusion) (n = 40; fosaprepitant group/FG) or ondansetron only (n = 39; control group/CG) during moderately or highly emetogenic chemotherapy were analyzed. The groups were analyzed and compared for frequency of vomiting, administered doses of on-demand antiemetic dimenhydrinate and adverse events during the acute (0-24 h after chemotherapy administration) and delayed (> 24 h-120 h) CINV phases. RESULTS: A total of 112 and 116 chemotherapy blocks were analyzed in the fosaprepitant and the control group, respectively. The emetogenic potential of the administered chemotherapy did not significantly differ (p = 0.8812) between the two cohorts. In the acute CINV phase, the percentage of patients experiencing vomiting (n = 26 patients) and the vomiting events were significantly higher (p = 0.0005 and p < 0.0001, respectively) in the CG (n = 26 patients (66.7%); 88 events) compared with the FG (n = 10 patients (25.0%); 37 events). In the delayed CINV phase, the percentage of patients experiencing vomiting and the vomiting events were also significantly higher (p = 0.0017 and p < 0.0001, respectively) in the CG (n = 31 patients (79.5%); 164 events) compared with the FG (n = 17 patients (42.5%); 103 events). Additionally, significantly more dimenhydrinate doses were administered in the CG compared with the FG patients (n = 322/n = 198; p < 0.0001). The occurrence of adverse events did not significantly differ between the two groups (p > 0.05). CONCLUSION: Fosaprepitant (4.0 mg/kg) in addition to ondansetron, without application of dexamethasone, was well tolerated, safe, effective and superior to ondansetron only as CINV prophylaxis in pediatric patients during moderately and highly emetogenic chemotherapy.
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Antieméticos/uso terapéutico , Antineoplásicos/efectos adversos , Morfolinas/uso terapéutico , Náusea/prevención & control , Neoplasias/tratamiento farmacológico , Vómitos/prevención & control , Adolescente , Antieméticos/efectos adversos , Antineoplásicos/administración & dosificación , Estudios de Casos y Controles , Niño , Preescolar , Estudios de Factibilidad , Femenino , Humanos , Lactante , Masculino , Morfolinas/efectos adversos , Náusea/inducido químicamente , Neoplasias/patología , Ondansetrón/efectos adversos , Ondansetrón/uso terapéutico , Seguridad del Paciente , Resultado del Tratamiento , Vómitos/inducido químicamenteRESUMEN
BACKGROUND: Invasive mold disease (IMD) is a severe infectious complication in immunocompromised patients. The outcome of central nervous system (CNS) IMD is poor, but contemporary data, in particular in the pediatric setting, are lacking. PROCEDURE: For this retrospective multicenter analysis, pediatric patients < 18 years with proven or probable CNS IMD receiving chemotherapy or undergoing allogeneic HSCT were reported by the local investigator. CNS IMD had to be diagnosed between 2007 and 2016. Proven CNS IMD was defined as compatible CNS imaging or macroscopic autopsy findings in conjunction with a positive microscopic or microbiological result in the brain tissue or cerebrospinal fluid. Probable CNS IMD was defined as compatible CNS imaging findings in combination with proven or probable IMD at a site outside the CNS. RESULTS AND CONCLUSIONS: A total of 29 patients (median age, 14 years; 14 allogeneic HSCT recipients) were diagnosed with proven (n = 12) or probable (n = 17) CNS IMD. Aspergillus spp. was the most common fungal pathogen. All but one patient had IMD sites outside the CNS and eight patients (27.6%) were neurologically asymptomatic at diagnosis of CNS IMD. Forty-nine percent of the patients survived CNS IMD; however, 46.7% of the survivors suffered from severe long-term neurological sequelae. Our data suggest that (1) outcome of CNS IMD has improved in children as compared with previous series, (2) half of surviving patients suffer from severe neurological sequelae, and (3) imaging of the CNS should be performed in all children with IMD irrespective of neurological symptoms.
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Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Enfermedades del Sistema Nervioso Central/terapia , Neoplasias Hematológicas/terapia , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Infecciones Fúngicas Invasoras/epidemiología , Adolescente , Enfermedades del Sistema Nervioso Central/patología , Niño , Preescolar , Terapia Combinada , Femenino , Estudios de Seguimiento , Alemania/epidemiología , Neoplasias Hematológicas/patología , Humanos , Incidencia , Lactante , Infecciones Fúngicas Invasoras/etiología , Infecciones Fúngicas Invasoras/microbiología , Masculino , Pronóstico , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
Poor graft function (PGF) is a severe complication of haematopoietic stem cell transplantation (HSCT) and administration of donor stem cell boosts (SCBs) represents a therapeutic option. We report 50 paediatric patients with PGF who received 61 boosts with CD34+ selected peripheral blood stem cells (PBSC) after transplantation from matched unrelated (n = 25) or mismatched related (n = 25) donors. Within 8 weeks, a significant increase in median neutrophil counts (0·6 vs. 1·516 × 109 /l, P < 0·05) and a decrease in red blood cell and platelet transfusion requirement (median frequencies 1 and 7 vs. 0, P < 0·0001 and <0·001), were observed, and 78·8% of patients resolved one or two of their cytopenias. 36·5% had a complete haematological response. Median lymphocyte counts for CD3+ , CD3+ CD4+ , CD19+ and CD56+ increased 8·3-, 14·2-, 22.- and 1·6-fold. The rate of de novo acute graft-versus-host disease (GvHD) grade I-III was only 6% and resolved completely. No GvHD grade IV or chronic GvHD occurred. Patients who responded to SCB displayed a trend toward better overall survival (OS) (P = 0·07). Thus, administration of CD34+ selected SCBs from alternative donors is safe and effective. Further studies are warranted to clarify the impact on immune reconstitution and survival.
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Supervivencia de Injerto , Trasplante de Células Madre Hematopoyéticas , Células Madre Hematopoyéticas , Adolescente , Adulto , Antígenos CD34/metabolismo , Linaje de la Célula , Niño , Preescolar , Estudios de Cohortes , Femenino , Enfermedad Injerto contra Huésped/etiología , Hematopoyesis , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodos , Células Madre Hematopoyéticas/metabolismo , Humanos , Lactante , Masculino , Pronóstico , Retratamiento , Estudios Retrospectivos , Quimera por Trasplante , Acondicionamiento Pretrasplante , Trasplante Homólogo , Resultado del Tratamiento , Adulto JovenRESUMEN
Relapsed/refractory B-precursor acute lymphoblastic leukemia (pre-B ALL) remains a major therapeutic challenge. Chimeric antigen receptor (CAR) T cells are promising treatment options. Central memory T cells (Tcm) and stem cell-like memory T cells (Tscm) are known to promote sustained proliferation and persistence after T-cell therapy, constituting essential preconditions for treatment efficacy. Therefore, we set up a protocol for anti-CD19 CAR T-cell generation aiming at high Tcm/Tscm numbers. 100 ml peripheral blood from pediatric pre-B ALL patients was processed including CD4+/CD8+-separation, T-cell activation with modified anti-CD3/-CD28 reagents and transduction with a 4-1BB-based second generation CAR lentiviral vector. The process was performed on a closed, automated device requiring additional manual/open steps under clean room conditions. The clinical situation of these critically ill and refractory patients with leukemia leads to inconsistent cellular compositions at start of the procedure including high blast counts and low T-cell numbers with exhausted phenotype. Nevertheless, a robust T-cell product was achieved (mean CD4+ = 50%, CD8+ = 39%, transduction = 27%, Tcm = 50%, Tscm = 46%). Strong proliferative potential (up to > 100-fold), specific cytotoxicity and low expression of co-inhibitory molecules were documented. CAR T cells significantly released TH1 cytokines IFN-γ, TNF-α and IL-2 upon target-recognition. In conclusion, partly automated GMP-generation of CAR T cells from critically small blood samples was feasible with a new stimulation protocol that leads to high functionality and expansion potential, balanced CD4/CD8 ratios and a conversion to a Tcm/Tscm phenotype.
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Antígenos CD19/metabolismo , Linfocitos T CD4-Positivos/trasplante , Linfocitos T CD8-positivos/trasplante , Memoria Inmunológica/inmunología , Leucemia-Linfoma Linfoblástico de Células Precursoras/inmunología , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Receptores de Antígenos de Linfocitos T/inmunología , Células Madre/inmunología , Adolescente , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Citocinas/metabolismo , Citotoxicidad Inmunológica , Femenino , Humanos , Inmunoterapia Adoptiva , Activación de Linfocitos , Fenotipo , PronósticoRESUMEN
Invasive fungal infections are one of the major complications in pediatric patients during prolonged neutropenia after chemotherapy. Evaluation of the efficacy and safety of the triazole posaconazole in these patients is missing. This multicenter survey analyzed trough concentrations of 33 pediatric patients with a median age of 8 years during 108 neutropenic episodes who received prophylactic posaconazole oral suspension. A total of 172 posaconazole trough levels were determined to median 438 ng/ml (range 111-2011 ng/ml; mean 468 ± 244 ng/ml). Age and gender had no influence on posaconazole plasma levels. Posaconazole was not discontinued due to adverse events in any of the patients. Only hepatic parameters significantly increased beyond the upper normal limit to median values of ALT of 87 U/l (P < .0001), and AST of 67 U/l (P < .0001). One patient with a median posaconazole trough concentration of 306 ng/ml experienced an invasive fungal infection. In conclusion, posaconazole was effective, safe and feasible in 33 pediatric patients with neutropenia ≥5 days after chemotherapy. Median posaconazole plasma concentrations were approximately 1.6-fold lower than the recommended plasma level of 700 ng/ml. Larger patient cohorts are needed to evaluate these findings.
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Antifúngicos/farmacocinética , Quimioprevención/métodos , Micosis/prevención & control , Neutropenia/complicaciones , Plasma/química , Triazoles/farmacocinética , Adolescente , Factores de Edad , Antifúngicos/administración & dosificación , Antifúngicos/efectos adversos , Niño , Preescolar , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Estudios Retrospectivos , Factores Sexuales , Triazoles/administración & dosificación , Triazoles/efectos adversosRESUMEN
Diagnosis of adverse events following hematopoietic stem cell transplantation (HSCT) is mainly assigned to clinical symptoms or biopsies and thus rather unspecific and/or invasive. Studies indicate a distinct role of serum ferritin in HSCT and its correlation with adverse events such as graft-versus-host disease (GvHD), veno-occlusive disease (VOD), or infections. However, published data on the relevance of ferritin as a prognostic marker for post-transplant adverse events is rare, especially in pediatric patients. The present study analyzes ferritin plasma concentrations of 138 pediatric patients after HSCT between 2007 and 2010 including the control group (n = 21). Given the initial results regarding ferritin as a significant predictor for acute graft rejection after allogeneic HSCT in 9 of the 138 pediatric patients, serum ferritin of all pediatric patients (n = 27) who experienced graft rejection between 2007 and 2014 was analyzed. In addition, laboratory parameters including C-reactive protein (CRP), lactate dehydrogenase (LDH), fibrinogen, and D-dimer as possible differentiation markers for graft rejection were determined. In 24 (88.9 %) of the 27 pediatric patients with graft rejection, a significant increase of ferritin levels was observed 1 to 7 days prior to (P < 0.0001) and at the time of graft rejection (P < 0.0001). Moreover, there was an increase of D-dimer, CRP, LDH, and fibrinogen 1-7 days before graft rejection. Ferritin increased significantly at time of VOD (P = 0.0067), at time of intestinal (P < 0.0001) and skin GvHD (P < 0.0001), and at time of sepsis (P = 0.0005) and bacteremia (P = 0.0029). Ferritin might serve as a readily available identification marker for differentiation and identification of adverse events after HSCT in combination with other laboratory markers.
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Ferritinas/sangre , Rechazo de Injerto/sangre , Rechazo de Injerto/diagnóstico , Neoplasias Hematológicas/sangre , Neoplasias Hematológicas/terapia , Trasplante de Células Madre Hematopoyéticas/tendencias , Adolescente , Biomarcadores/sangre , Niño , Preescolar , Femenino , Rechazo de Injerto/etiología , Neoplasias Hematológicas/diagnóstico , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Lactante , Masculino , Estudios Retrospectivos , Acondicionamiento Pretrasplante/efectos adversos , Acondicionamiento Pretrasplante/tendencias , Trasplante Homólogo/efectos adversos , Trasplante Homólogo/tendenciasRESUMEN
Posaconazole has been proven to be effective for antifungal prophylaxis in adults after hematopoietic stem cell transplantation (HSCT). Due to low gastrointestinal resorption of posaconazole suspension, bioavailability is impaired. Fatty food improves the uptake of posaconazole, but insufficient data on the pharmacokinetics of posaconazole in pediatric patients are available so far. The single-center analysis investigated 161 posaconazole serum concentrations in 27 pediatric patients after HSCT receiving 12 mg·kg BW(-1)·d(-1) posaconazole suspension depending on age, gender, and intestinal graft-versus-host (iGvHD) disease, and the influence of posaconazole on cyclosporine A plasma concentrations. To improve the uptake of posaconazole, one patient cohort received higher fat nutrition with the drug administration. A comparison of the regular nutrition and higher-fat nutrition groups revealed the following values: 31 (27.4%) versus 8 (16.7%) < 500 ng/ml; 12 (10.6%) versus 7 (14.6%) 500-700 ng/ml; 8 (7.1%) versus 6 (12.5%) 700-1000 ng/ml; 51 (45.1%) versus 21 (43.8%) 1000-2000 ng/ml; and 11 (9.7%) versus 6 (12.5%) > 2000 ng/ml. The mean posaconazole concentrations in patients with regular nutrition was 1123 ± 811 ng/ml and with higher-fat nutrition was 1191 ± 673 ng/ml. Posaconazole levels in patients with iGvHD were significantly lower (P = 0.0003) than in patients without GvHD. The majority of samples showed a sufficient posaconazole concentration above 700 ng/ml. Posaconazole levels were slightly higher in patients with higher-fat nutrition and significantly lower in patients with iGvHD. Cyclosporine A levels were not significantly higher during posaconazole administration.
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Antifúngicos/farmacocinética , Quimioprevención/métodos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Micosis/prevención & control , Plasma/química , Trasplante Homólogo/efectos adversos , Triazoles/farmacocinética , Adolescente , Antifúngicos/administración & dosificación , Niño , Preescolar , Dieta/métodos , Femenino , Humanos , Masculino , Triazoles/administración & dosificaciónRESUMEN
BACKGROUND: Veno-occlusive disease, Graft-versus-Host disease, invasive or localized bacterial, viral and fungal infections are known as adverse events after hematopoietic stem cell transplantation representing the major cause for morbidity and mortality. Detection and differentiation of these adverse events are based on clinical symptoms and routine measurements of laboratory parameters. METHODS: To identify the role of cytokines as a possible complication-marker for adverse events, 61 consecutive pediatric patients with a median age of 7.0 years who underwent hematopoietic stem cell transplantation were enrolled in this single-center retrospective study. Interleukin-1 beta (IL-1ß), soluble interleukin-2 receptor (sIL-2R), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-10 (IL-10) and tumor necrosis factor-α serum (TNF-α) levels were regularly assessed after transplantation and during transplantation related adverse events. RESULTS: Veno-occlusive disease was accompanied by a significant increase in levels of IL-6, IL-8 and TNF-α.Graft-versus-Host disease was associated with a significant increase of IL-10, sIL-2R, IL-6 and TNF-α, depending on the respective stage or grade. Cytokine IL-6 enabled a significant differentiation between sepsis and fungemia, sepsis and viremia, and sepsis and bacteremia. Moreover, cytokine IL-8 enabled a significant differentiation between sepsis and viremia, sepsis and bacteremia, and bacteremia and viremia whereas IL-10 made a distinction between sepsis and viremia possible. CONCLUSION: The data demonstrate that proinflammatory cytokines might be putative indicators for early detection and differentiation of post-transplant adverse events and may allow prompt and adequate clinical intervention. Prospective clinical trials are needed to evaluate these findings.
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Biomarcadores/sangre , Citocinas/sangre , Trasplante de Células Madre Hematopoyéticas , Complicaciones Posoperatorias/sangre , Enfermedad Aguda , Adolescente , Adulto , Niño , Preescolar , Femenino , Enfermedad Injerto contra Huésped/etiología , Humanos , Lactante , Masculino , Micosis/etiología , Estudios Retrospectivos , Sepsis/etiología , Enfermedades Vasculares/etiología , Virosis/etiología , Adulto JovenRESUMEN
Human leukocyte antigen DR surface expression in "classical" CD14++CD16- (M1), "intermediate" CD14++CD16+ (M2), and "non-classical" CD14+CD16++ (M3) monocytes reflects the activation state of these cells. The full spectrum of monocyte and its function is still unknown. The present pilot study describes the monocyte subpopulations and their human leukocyte antigen DR expression during the post-transplant period as well as during transplant-related adverse events of 30 pediatric patients and young adults with hemato-oncological malignancies and immunodeficiency disorders in comparison to healthy children and young adults. A significant change of the human leukocyte antigen DR expression in all three monocyte subpopulations during the period after bone marrow transplantation depending on the time after transplantation and adverse events could be recognized. Prior to and during sepsis or bacterial infection, a significant decrease in human leukocyte antigen DR expression occurred. A significant increase on CD14++CD16- monocytes could be observed during graft-versus-host disease. The alterations of human leukocyte antigen DR expression on the monocyte subpopulations during adverse events after hematopoietic stem cell transplantation may be a sign of changes in the capacity of these subpopulations. Moreover, human leukocyte antigen DR expression in monocyte subpopulations may be used to monitor treatment responses in these entities.
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Antígenos HLA-DR/metabolismo , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Monocitos/metabolismo , Adolescente , Adulto , Femenino , Citometría de Flujo , Enfermedad Injerto contra Huésped/metabolismo , Enfermedad Injerto contra Huésped/terapia , Humanos , Receptores de Lipopolisacáridos/metabolismo , Masculino , Sepsis/metabolismo , Sepsis/terapia , Adulto JovenRESUMEN
The human leukocyte antigen DR surface expression on CD14+ monocytes reflects the degree to which these cells have been activated. Given the central role monocytes and macrophages play in the immune system, a decreased human leukocyte antigen DR expression on CD14+ monocytes results in a hallmark of altered immune status during systemic inflammatory response syndrome. We hypothesize that human leukocyte antigen DR expression might be similarly altered after hematopoietic stem cell transplantation and during post-transplant complications. Using flow cytometry, this study investigates the human leukocyte antigen DR surface expression of CD14+ monocytes in 30 pediatric and young adult patients up to 1 year after hematopoietic stem cell transplantation. Normal values were derived from a control group of healthy children, adolescents, and young adults. Human leukocyte antigen DR expression decreased significantly prior and during bacterial infection or sepsis. By contrast, human leukocyte antigen DR expression levels were elevated before and at the time of viremia. Human leukocyte antigen DR expression was also elevated during acute graft-versus-host disease. In contrast, the expression was reduced when patients had hepatic veno-occlusive disease. A significant decrease of human leukocyte antigen DR expression was associated with a relapse of the underlying disease and before death. Human leukocyte antigen DR expression on CD14+ monocytes appears to be a promising parameter that might allow identification of patients at risk after hematopoietic stem cell transplantation.
Asunto(s)
Antígenos HLA-DR/inmunología , Trasplante de Células Madre Hematopoyéticas/métodos , Receptores de Lipopolisacáridos/inmunología , Monocitos/inmunología , Adolescente , Adulto , Niño , Preescolar , Femenino , Citometría de Flujo , Enfermedad Injerto contra Huésped/diagnóstico , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/inmunología , Factor Estimulante de Colonias de Granulocitos/inmunología , Factor Estimulante de Colonias de Granulocitos/farmacología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Lactante , Receptores de Lipopolisacáridos/efectos de los fármacos , Receptores de Lipopolisacáridos/metabolismo , Masculino , Monocitos/metabolismo , Proyectos Piloto , Estudios Prospectivos , Sepsis/diagnóstico , Sepsis/etiología , Sepsis/inmunología , Enfermedades Vasculares/diagnóstico , Enfermedades Vasculares/etiología , Enfermedades Vasculares/inmunología , Virosis/diagnóstico , Virosis/etiología , Virosis/inmunología , Adulto JovenRESUMEN
BACKGROUND: Congenital grouped skin lesions are alarming signs of a variety of threatening diagnoses of quite different origin. The present case report shows an impressive clinical pattern of a neonate and illustrates the difficulty in differential diagnosis of mixed connective tissue disease and neonatal lupus erythematosus in newborns. This reported case is to our knowledge the first description of an unrecognized mixed connective tissue disease in the mother with an unusual clinical manifestation in the newborn, comprising skin lesions, neurological damage and non-typical antibody constellation. CASE PRESENTATION: We report on a Caucasian female neonate from a perinatally asymptomatic mother, who presented with grouped facial pustular-like skin lesions, followed by focal clonic seizures caused by multiple ischemic brain lesions. Herpes simplex virus infection was excluded and both the mother and her infant had the antibody pattern of systemic lupus erythematosus and neonatal lupus erythematosus, respectively. However, clinical signs in the mother showed overlapping features of mixed connective tissue disease. CONCLUSION: This case report emphasizes congenital Lupus erythematosus and mixed connective tissue disease as important differential diagnoses of grouped skin lesions in addition to Herpes simplex virus-infection. The coexistence of different criteria for mixed connective tissue disease makes it difficult to allocate precisely maternal and congenital infantile disease.
Asunto(s)
Isquemia Encefálica/patología , Epilepsia Parcial Motora/etiología , Dermatosis Facial/diagnóstico , Lupus Eritematoso Sistémico/diagnóstico , Enfermedad Mixta del Tejido Conjuntivo/diagnóstico , Anticuerpos Antinucleares/sangre , Autoanticuerpos/sangre , Diagnóstico Diferencial , Femenino , Herpes Simple/diagnóstico , Humanos , Recién Nacido , Lupus Eritematoso Sistémico/congénito , Lupus Eritematoso Sistémico/inmunología , Imagen por Resonancia Magnética , Deficiencia de Proteína C/complicaciones , Ribonucleoproteínas Nucleares Pequeñas/inmunología , Proteínas Nucleares snRNP/inmunologíaRESUMEN
The etiology of pediatric acute lymphatic leukemia (ALL) is still unclear. Whole-metagenome shotgun sequencing of bone marrow samples in patients with treatment-naïve ALL (n=6) was performed for untargeted investigation of bacterial and viral DNA. The control group consisted of healthy children (n=4) and children with non-oncologic diseases (n=2) undergoing bone marrow sampling. Peripheral blood of all participants was investigated at the same time. After bioinformatical elimination of potential contaminants by comparison with the employed controls, no significant amounts of microbial or viral DNA were identified.
Asunto(s)
ADN Viral , Metagenoma , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Niño , Masculino , Femenino , Preescolar , ADN Viral/genética , ADN Bacteriano/genética , Metagenómica/métodos , Médula Ósea , Adolescente , Bacterias/genética , Bacterias/aislamiento & purificación , Bacterias/clasificación , Análisis de Secuencia de ADNRESUMEN
OBJECTIVES: To evaluate the long-term effectiveness and safety of autologous haematopoiesis stem cell transplantation (AHSCT) for severe, refractory autoimmune diseases in paediatric patients. METHODS: A single-centre study of consecutive children and adolescents with refractory autoimmune diseases undergoing AHSCT was performed. Demographics, clinical, laboratory features, pre-AHSCT medications, disease activity and functional status were captured. The primary outcome was progression-free survival, secondary outcomes included overall survival, disease-specific treatment responses, disease activity at the last follow-up and AHSCT safety. RESULTS: The study included seven patients: two systemic sclerosis, one pansclerotic morphoea, one eosinophilic fasciitis, one juvenile dermatomyositis and two patients with systemic juvenile idiopathic arthritis; four women, three men median age at AHSCT of 10 years (7-19), median follow-up post-AHSCT of 17 years. Median progression-free survival and overall survival was 4.2 years (95% CI: 0.98 to 8.3) and 17 years (95% CI: 11.8 to 22.1), respectively. Progression-free survival rates at 1 and 2 years post-AHSCT were 100% and 77%, respectively. All children survived. All patients are in clinical remission, only four require ongoing immunotherapy. SAFETY: Three experienced infections, including HHV6, Candida and Ralstonia sepsis; one developed a systemic inflammatory response syndrome; two new onset secondary autoimmune diseases including autoimmune haemolytic anaemia, Graves' disease and one was found to have a breast fibroadenoma. Treatment toxicity: one cyclophosphamide-associated transient renal failure and pericardial effusion, one patient with amenorrhoea/infertility. CONCLUSIONS: AHSCT was an effective and safe approach for children and adolescents with treatment-refractory autoimmune diseases. The indication and timing of transplantation requires a careful consideration and a multidisciplinary approach.