RESUMEN
BACKGROUND: As balance training seems to be a promising training method to improve physical limitations of the lower limbs, this study aims to evaluate feasibility, subjective benefits and preliminary effects on physical abilities of balance training in pediatric cancer patients. PATIENTS: 11 pediatric cancer patients (5-21 years) undergoing acute medical treatment were included in the study. METHOD: Participants took part in a 4-week balance training intervention. 3 trainings/week were conducted either supervised or self-administered. Subjective benefits were evaluated using a questionnaire, effects on selected physical abilities were assessed using functional-motor assessments. RESULTS: Participants completed 71.21+37.34% of balance training sessions, no adverse events occurred. Participants were satisfied with the intervention and described various subjective benefits. Significant improvements were found in functional strength of the lower limbs as well as positive trends in balance. DISCUSSION: Balance training seems feasible with pediatric cancer patients undergoing acute medical treatment potentially improving functions of the lower limbs relevant for daily physical activity. CONCLUSION: Balance training can be a valuable conjunct to general exercise programs in pediatric oncology. HINTERGRUND: Da ein Gleichgewichtstraining eine vielversprechende Trainingsmethode zur Verbesserung körperlicher Beeinträchtigungen der unteren Extremitäten darstellt, untersucht die vorliegende Studie die Machbarkeit, subjektive und erste objektive Effekte eines Gleichgewichtstrainings auf körperliche Fähigkeiten bei onkologisch erkrankten Kindern. PATIENTEN: 11 Kinder und Jugendliche (5-21 Jahre) während der akutmedizinischen Behandlung einer onkologischen Erkrankung wurden in die Studie eingeschlossen. METHODIK: Die Patient*innen nahmen an einem 4-wöchigen Gleichgewichtstraining teil. 3 Trainingseinheiten/Woche wurden entweder supervidiert oder selbstständig umgesetzt. Subjektive Effekte wurden mit einem Fragebogen und die Effekte auf ausgewählte körperliche Fähigkeiten mittels funktionell-motorischer Testungen evaluiert. ERGEBNISSE: Die Teilnehmer*innen absolvierten 71.21+37.34% der Trainingseinheiten und es traten keine trainingsbedingten Zwischenfälle auf. Die Kinder waren zufrieden mit der Intervention und beschrieben verschiedene subjektive Effekte. Positive Veränderungen zeigten sich im Bereich der funktionellen Kraft der unteren Extremitäten und des Gleichgewichts. DISKUSSION: Ein Gleichgewichtstraining während der akutmedizinischen Behandlung in der Kinderonkologie scheint machbar und zeigt potenziell positive Effekte auf relevante Funktionen der unteren Extremitäten. SCHLUSSFOLGERUNG: Ein Gleichgewichtstraining kann eine wertvolle Ergänzung allgemeiner Bewegungsprogramme in der pädiatrischen Onkologie darstellen.
RESUMEN
BACKGROUND: Although severe COVID-19 in children is rare, those with certain pre-existing health conditions are more prone to severe disease. Monoclonal antibodies (mAbs) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are potent antiviral agents that reduce adverse clinical outcomes in adults, but are commonly not approved for use in pediatric patients. METHODS: We retrospectively evaluated mAb treatment in children <12 years of age or <40kg with SARS-CoV-2 infection between January 1, 2021, and March 7, 2022, in 12 tertiary care centers in 3 European countries. RESULTS: We received data from 53 patients from Austria, Denmark and Germany. Median age was 5.4 years [0-13.8, interquartile range (IQR) = 6.2], and median body weight was 20 kg (3-50.1, IQR = 13). The most frequent SARS-CoV-2 variant in this study, if known, was Omicron, followed by Delta and Alpha. Pre-existing conditions included immunodeficiency, malignancy, hematologic disease, cardiac disease, chronic lung disease, chronic liver disease, kidney disease and diabetes. Forty-two patients received sotrovimab (79%), 9 casirivimab/imdevimab (17%) and 2 bamlanivimab (4%). All but 1 patient survived. Median duration of hospital stay was 3 days (0-56, IQR = 6). Seven patients required treatment in an intensive care unit, and 5 required high-flow nasal cannula treatment. Potential side effects included neutropenia (6/53, 11%), lymphopenia (3/53, 6%), nausea or vomiting (2/53, 4%), rise of alanine transaminase (1/53, 2%) and hypotonia (1/53, 2%). CONCLUSIONS: MAb treatment was well tolerated by children in this cohort.
Asunto(s)
COVID-19 , Leucopenia , Adulto , Humanos , Niño , Lactante , Preescolar , Estudios Retrospectivos , SARS-CoV-2 , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Neutralizantes , Anticuerpos Antivirales , Enfermedad CrónicaRESUMEN
Although allogeneic hematopoietic stem-cell transplantation (HSCT) provides high cure rates for children with high-risk acute lymphoblastic leukaemia (ALL), relapses remain the main cause of treatment failure. Whereas donor killer cell immunoglobulin-like receptor (KIR) genotype was shown to impact on relapse incidence in adult myeloid leukaemia similar studies in paediatric ALL are largely missing. Effect of donor KIR genotype on transplant outcome was evaluated in 317 children receiving a first myeloablative HSCT from an HLA-matched unrelated donor or sibling within the prospective ALL-SCT-BFM-2003 trial. Analysis of donor KIR gene polymorphism revealed that centromeric presence and telomeric absence of KIR B haplotypes was associated with reduced relapse risk. A centromeric/telomeric KIR score (ct-KIR score) integrating these observations correlated with relapse risk (hazard ratio (HR) 0.58; P = 0.002) while it had no impact on graft-versus-host disease or non-relapse mortality. In multivariable analyses ct-KIR score was associated with reduced relapse risk (HR 0.58; P = 0.003) and a trend towards improved event-free survival (HR 0.76; P = 0.059). This effect proved independent of MRD level prior to HSCT. Our data suggest that in children with ALL undergoing HSCT after myeloablative conditioning, donor selection based on KIR genotyping holds promise to improve clinical outcome by decreasing relapse risk and prolonged event-free survival.
Asunto(s)
Selección de Donante , Haplotipos , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Polimorfismo Genético , Leucemia-Linfoma Linfoblástico de Células Precursoras , Receptores KIR/genética , Telómero/genética , Acondicionamiento Pretrasplante , Adolescente , Adulto , Niño , Preescolar , Supervivencia sin Enfermedad , Femenino , Humanos , Lactante , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/terapia , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Tasa de SupervivenciaRESUMEN
Here, we report the case of severe adenoviremia in a 7-year-old boy with highly-resistant, acute leukemia. A combined approach of αßTCR-CD19-depleted stem cell transplantation, enabling immunosuppression-free post-transplant care, and early transfer of adenovirus-specific donor T cells during aplasia resulted in rapid and complete clearance of the treatment-refractory adenoviremia.
Asunto(s)
Infecciones por Adenovirus Humanos/terapia , Trasplante de Células Madre Hematopoyéticas , Linfocitos T/trasplante , Linfocitos T/virología , Viremia/terapia , Infecciones por Adenovirus Humanos/etiología , Antígenos CD19 , Niño , Terapia Combinada , Resultado Fatal , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/virologíaRESUMEN
PIK3R1 (phosphoinositide-3-kinase, regulatory subunit 1) gain-of-function has recently been described in patients with recurrent sinopulmonary infections, chronic CMV-/EBV-infections, lymphoproliferation, and hypogammaglobulinemia. Here we report a 15-year-old boy with treatment refractory CMV lymphadenitis, severe combined immunodeficiency, microcephaly and a severe developmental defect of Th17 cells. To avoid poor outcome, hematopoietic stem cell transplantation (HSCT) was performed. Subsequently, whole exome sequencing revealed a de novo heterozygous G-to-C mutation (chr5: 5:67,589,663: G>C) at the splice donor site of the PIK3R1 gene. Our data suggest that PIK3R1 gain-of-function leads to developmental defects in helper and regulatory T-cell subsets, the latter expanding the immunological features of PIK3R1 gain-of-function. T-cell subsets play a critical role in the regulation of immune response against infectious agents and of autoimmunity and thus may be particularly accountable for the clinical phenotype of affected patients.
Asunto(s)
Infecciones por Citomegalovirus , Linfadenitis , Microcefalia , Fosfatidilinositol 3-Quinasas , Infecciones del Sistema Respiratorio , Adolescente , Fosfatidilinositol 3-Quinasa Clase Ia , Infecciones por Citomegalovirus/complicaciones , Infecciones por Citomegalovirus/genética , Infecciones por Citomegalovirus/inmunología , Humanos , Linfadenitis/complicaciones , Linfadenitis/genética , Linfadenitis/inmunología , Masculino , Microcefalia/complicaciones , Microcefalia/genética , Senos Paranasales/fisiopatología , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/inmunología , Recurrencia , Infecciones del Sistema Respiratorio/complicaciones , Infecciones del Sistema Respiratorio/genética , Células Th17/inmunologíaRESUMEN
Children with B cell malignancies refractory to standard therapy are known to have a poor prognosis and very limited treatment options. Here, we report on the treatment and follow-up of ten patients diagnosed with relapsed or refractory mature B-cell Non Hodgkin Lymphoma (B-NHL), Burkitt leukaemia (B-AL) or pre B-acute lymphoblastic leukaemia (pre B-ALL). All children were treated with FBTA05 (now designated Lymphomun), an anti-CD3 x anti-CD20 trifunctional bispecific antibody (trAb) in compassionate use. Within individual treatment schedules, Lymphomun was applied (a) after allogeneic stem cell transplantation (allo-SCT, n = 6) to induce sustained long-term remission, or (b) stand alone prior to subsequent chemotherapy to eradicate residual disease before allo-SCT (n = 4). Nine of ten children displayed a clinical response: three stable diseases (SD), one partial remission (PR) and five induced or sustained complete remissions (CR). Five of these nine responders died during follow-up. The other patients still maintain CR with a current overall survival of 874-1424 days (median: 1150 days). In conclusion, despite the dismal clinical prognosis of children refractory to standard therapy, immunotherapy with Lymphomun resulted in a favourable clinical outcome in this cohort of refractory paediatric patients.
Asunto(s)
Anticuerpos Biespecíficos/administración & dosificación , Linfoma de Burkitt/terapia , Inmunoterapia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Trasplante de Células Madre , Adolescente , Aloinjertos , Anticuerpos Biespecíficos/efectos adversos , Linfoma de Burkitt/mortalidad , Linfoma de Burkitt/patología , Niño , Preescolar , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidad , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patología , Tasa de SupervivenciaAsunto(s)
Antivirales/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/métodos , Síndrome de Job/cirugía , Infecciones por Polyomavirus/tratamiento farmacológico , Infecciones Tumorales por Virus/tratamiento farmacológico , Viremia/tratamiento farmacológico , Adolescente , Antígenos CD19/inmunología , Virus BK , Femenino , Factores de Intercambio de Guanina Nucleótido/genética , Humanos , Inmunoglobulina G/uso terapéutico , Síndrome de Job/complicaciones , Síndrome de Job/genética , Depleción Linfocítica , Infecciones por Polyomavirus/complicaciones , Receptores de Antígenos de Linfocitos T alfa-beta/inmunología , Linfocitos T/inmunología , Infecciones Tumorales por Virus/complicaciones , Turquía , Viremia/complicacionesRESUMEN
We report for the first time the impact of neoadjuvant oral low-dose chemotherapy consisting of oral trofosfamide, idarubicin, and etoposide (O-TIE) in the case of alveolar rhabdomyosarcoma (RMS) in the lower jaw of an 18-year-old woman at 27 weeks of gestation, without fetal complications and a highly efficient anti-tumor response. Our study suggests the possible application of O-TIE treatment in a neoadjuvant setting during pregnancy and recommends a schedule that can be considered for the treatment of patients with high-risk sarcomas who cannot be treated with intensive chemotherapy for various reasons.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Complicaciones Neoplásicas del Embarazo/tratamiento farmacológico , Rabdomiosarcoma Alveolar/tratamiento farmacológico , Administración Oral , Adolescente , Ciclofosfamida/administración & dosificación , Ciclofosfamida/análogos & derivados , Relación Dosis-Respuesta a Droga , Etopósido/administración & dosificación , Femenino , Humanos , Idarrubicina/administración & dosificación , Embarazo , PronósticoRESUMEN
For effective immunotherapy, maintaining the frequency and cytotoxic potential of effector cells is critical. In this context costimulation via the CD70/CD27 pathway has been proven essential. CD70 has been reported to be expressed to varying degrees on malignant B cells. However, in B cell precursor acute lymphoblastic leukemia, the most common childhood malignancy, the role of CD70 in stimulation of antileukemic T cell responses has so far not been delineated. Herein we demonstrate that in B cell precursor acute lymphoblastic leukemia expression of CD70 is low but can be induced upon blast activation via CD40. Both CD70 and CD80/CD86 up-regulated on CD40-stimulated blasts contribute to primary stimulation of T cell proliferation and cytokine production in an additive manner. These two signals also cooperate in the prevention of T cell anergy. In contrast to blockade of CD70 during the effector phase, inhibition of CD70-mediated costimulation during generation of antileukemic T cells prevents effector cell proliferation and reduces their cytotoxic capacity. Modulation of the CD70/CD27 pathway may thus represent a novel therapeutic approach for augmenting magnitude and quality of the antileukemic response in B cell precursor acute lymphoblastic leukemia.
Asunto(s)
Ligando CD27/fisiología , Activación de Linfocitos/inmunología , Leucemia-Linfoma Linfoblástico de Células Precursoras B/inmunología , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Transducción de Señal/inmunología , Linfocitos T Citotóxicos/inmunología , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/fisiología , Subgrupos de Linfocitos B/inmunología , Subgrupos de Linfocitos B/patología , Ligando CD27/biosíntesis , Ligando CD27/genética , Diferenciación Celular/inmunología , Proliferación Celular , Técnicas de Cocultivo , Pruebas Inmunológicas de Citotoxicidad , Humanos , Prueba de Cultivo Mixto de Linfocitos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Células Madre/inmunología , Células Madre/patología , Linfocitos T Citotóxicos/metabolismo , Células Tumorales Cultivadas , Regulación hacia Arriba/inmunologíaRESUMEN
BACKGROUND AND OBJECTIVES: Impaired apoptosis, mediated by members of the inhibitor of apoptosis proteins (IAP) family such as survivin, is thought to contribute to leukemic cell survival. In contrast to low expression of survivin in normal differentiated adult tissues, very high levels of survivin have been described in a number of different tumors. Overexpression of survivin was found to correlate with poor prognosis in a variety of cancers including hematologic malignancies. To date, however, there is no information available on the prognostic role of survivin in pediatric precursor B-cell acute lymphocytic leukemia (BCP-ALL), the most frequent malignancy in childhood. DESIGN AND METHODS: In a retrospective study including 66 pediatric patients we analyzed the impact of survivin protein levels on outcome in BCP-ALL. RESULTS: Survivin overexpression, with an up to ten-fold increase of the normal level, was detected in 65% of the leukemic samples in contrast to negligible expression in non-malignant hematopoietic cells. Despite considerable variety of expression levels in ALL cells, there was no association of survivin levels with established risk factors. However, patients suffering relapse of disease or death had significantly higher survivin expression than those with a favorable outcome. Overexpression of survivin is a significant prognostic marker for 3 year relapse free, event-free and overall survival, again independent of the established prognostic factors in ALL, such as age and leukocyte count at diagnosis as assessed in multivariate analysis. INTERPRETATION AND CONCLUSIONS: Overexpression of survivin in BCP-ALL identifies patients with a high risk of early relapse. Upon confirmation in a prospective analysis, survivin expression may, in the future, serve to further refine treatment stratification with intensification of therapy in those patients prone to relapse.
Asunto(s)
Proteínas Inhibidoras de la Apoptosis/análisis , Proteínas Asociadas a Microtúbulos/análisis , Proteínas de Neoplasias/análisis , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Adolescente , Apoptosis , Médula Ósea/patología , Niño , Preescolar , Estudios de Cohortes , Supervivencia sin Enfermedad , Femenino , Regulación Leucémica de la Expresión Génica , Humanos , Lactante , Proteínas Inhibidoras de la Apoptosis/fisiología , Estimación de Kaplan-Meier , Masculino , Proteínas Asociadas a Microtúbulos/fisiología , Proteínas de Neoplasias/fisiología , Células Madre Neoplásicas/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidad , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patología , Pronóstico , Estudios Retrospectivos , Estadísticas no Paramétricas , Análisis de Supervivencia , Survivin , Resultado del TratamientoRESUMEN
Previous studies on apoptosis defects in acute lymphoblastic leukemia (ALL) have focused on chemotherapy-induced, primarily mitochondrial death pathways. Yet, immunologic surveillance mechanisms including sensitization to apoptotic signals mediated via the death receptor CD95 might contribute to leukemic control. Here, we show that primary B-cell precursor ALL cells from children escape from receptor-dependent cell death in 2 ways: Resting ALL blasts are protected from receptor-mediated apoptosis due to the absence of CD95 surface expression. However, even though CD40 ligation results in up-regulation of CD95, ALL blasts, unlike normal B cells, remain resistant to apoptosis. We show that this apoptosis resistance involves the selective up-regulation of the short isoforms of the caspase-8 inhibitor c-FLIP acting directly at the CD95 receptor level. Treatment with cycloheximide during CD40 activation prevents up-regulation of those c-FLIP isoforms and sensitizes ALL cells toward CD95-mediated apoptosis. We therefore propose that induction of the short c-FLIP isoforms inhibits the onset of CD95-induced apoptosis in primary CD40-stimulated ALL cells despite high CD95 expression.