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1.
Pediatr Radiol ; 54(8): 1395-1398, 2024 07.
Artículo en Inglés | MEDLINE | ID: mdl-38671145

RESUMEN

Bone marrow metastases-noted in 6% of patients with rhabdomyosarcoma-have been linked to very poor outcomes. Bilateral bone marrow sampling from iliac crests has been the gold standard for bone marrow examination in rhabdomyosarcoma, but sampling errors due to patchy bone marrow involvement may limit its sensitivity. Here, we report the case of a 6-year-old boy with embryonal rhabdomyosarcoma of the skull base and multiple 2-[18F]fluoro-2-deoxy-D-glucose (2-[18F]FDG)-avid bone marrow metastases visualized by positron emission tomography and computed tomography (2-[18F]FDG PET/CT). His bone marrow aspirates were tumor-free. This case illustrates the diagnostic value of 2-[18F]FDG PET/CT in the detection of bone marrow metastases in rhabdomyosarcoma patients, which may re-shape the definition of bone marrow disease and, ultimately, alter disease staging and risk stratification.


Asunto(s)
Neoplasias de la Médula Ósea , Fluorodesoxiglucosa F18 , Tomografía Computarizada por Tomografía de Emisión de Positrones , Radiofármacos , Humanos , Masculino , Niño , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Neoplasias de la Médula Ósea/diagnóstico por imagen , Neoplasias de la Médula Ósea/patología , Rabdomiosarcoma/diagnóstico por imagen , Rabdomiosarcoma/patología
2.
Pediatr Blood Cancer ; 66(3): e27539, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30426671

RESUMEN

PURPOSE: In 2014, we published the qPET method to quantify fluorodeoxyglucose positron emission tomography (FDG-PET) responses. Analysis of the distribution of the quantified signals suggested that a clearly abnormal FDG-PET response corresponds to a visual Deauville score (vDS) of 5 and high qPET values ≥ 2. Evaluation in long-term outcome data is still pending. Therefore, we analyzed progression-free survival (PFS) by early FDG-PET response in a subset of the GPOH-HD2002 trial for pediatric Hodgkin lymphoma (PHL). PATIENTS/METHODS: Pairwise FDG-PET scans for initial staging and early response assessment after two cycles of chemotherapy were available in 93 PHL patients. vDS and qPET measurement were performed and related to PFS. RESULTS: Patients with a qPET value ≥ 2.0 or vDS of 5 had 5-year PFS rates of 44%, respectively 50%. Those with qPET values < 2.0 or vDS 1 to 4 had 5-year PFS rates of 90%, respectively 80%. The positive predictive value of FDG-PET response assessment increased from 18% (9%; 33%) using a qPET threshold of 0.95 (vDS ≤ 3) to 30% (13%; 54%) for a qPET threshold of 1.3 (vDS ≤ 4) and to 56% (23%; 85%) when the qPET threshold was ≥ 2.0 (vDS 5). The negative predictive values remained stable at ≥92% (CI: 82%; 98%). CONCLUSION: Only strongly enhanced residual FDG uptake in early response PET (vDS 5 or qPET ≥ 2, respectively) seems to be markedly prognostic in PHL when treatment according to the GPOH-HD-2002 protocol is given.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Fluorodesoxiglucosa F18/metabolismo , Enfermedad de Hodgkin/patología , Tomografía de Emisión de Positrones/métodos , Radiofármacos/metabolismo , Niño , Ensayos Clínicos como Asunto , Femenino , Estudios de Seguimiento , Enfermedad de Hodgkin/diagnóstico por imagen , Enfermedad de Hodgkin/tratamiento farmacológico , Enfermedad de Hodgkin/metabolismo , Humanos , Masculino , Pronóstico , Curva ROC , Tasa de Supervivencia
3.
Klin Padiatr ; 228(3): 105-12, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-27135270

RESUMEN

Nasopharyngeal carcinoma (NPC) is a rare malignant tumor arising from epithelial cells of the nasopharynx. Its incidence is highest in Southeast Asia. Age distribution of NPC is bimodal, with one peak in young adolescents and another in patients 55-59 years of age. EBV appears to be the primary etiologic agent in the pathogenesis, environmental factors such as nitrosamines and genetic factors are contributory. NPC is most commonly diagnosed in locally advanced stages, with lymph node metastases occurring in up to 90% of patients. About 5-10% of patients present with distant metastases. Diagnosis of NPC is made histologically, supported by an abnormal anti-EBV-VCA IgA titer and elevated plasma EBV-DNA load. Superior results in children and adolescents with advanced locoregional NPC, with overall and event-free survival rates>90%, have been achieved by neoadjuvant chemotherapy with 5-fluoruracil and cisplatin, followed by synchronous radiochemotherapy and subsequent maintenance therapy with interferon-ß as demonstrated by the 2 prospective studies GPOH-NPC-91 and -2003. Response to therapy can be assessed by PET-imaging and in patients with complete remission after neoadjuvant chemotherapy, the radiation dose to the primary tumor can be safely reduced from 59.4 to 54.4 Gy. Since the majority of long term sequalae such as xerostomia, skin and tissue fibrosis are caused by high radiation dosages, radiotherapy modalities such as intensity-modulated radiotherapy should be used to efficiently spare non-tumorous tissue. For patients with metastatic disease and relapse, survival chances are low. New treatment strategies, such as the application of EBV-specific T-lymphocytes should be considered for these patients.


Asunto(s)
Neoplasias Nasofaríngeas/diagnóstico , Adolescente , Biomarcadores de Tumor/análisis , Niño , Terapia Combinada , ADN Viral/análisis , Infecciones por Virus de Epstein-Barr/diagnóstico , Infecciones por Virus de Epstein-Barr/mortalidad , Infecciones por Virus de Epstein-Barr/patología , Infecciones por Virus de Epstein-Barr/terapia , Humanos , Ganglios Linfáticos/patología , Metástasis Linfática/patología , Imagen por Resonancia Magnética , Neoplasias Nasofaríngeas/mortalidad , Neoplasias Nasofaríngeas/patología , Neoplasias Nasofaríngeas/terapia , Nasofaringe/patología , Estadificación de Neoplasias , Tasa de Supervivencia , Adulto Joven
4.
Klin Padiatr ; 227(3): 157-65, 2015 May.
Artículo en Inglés | MEDLINE | ID: mdl-25985449

RESUMEN

Allogeneic hematopoietic stem cell transplantation (HSCT) is currently the only curative therapy for the severe hematopoietic complications associated with Fanconi anemia (FA). In Germany, it is estimated that 10-15 transplants are performed annually for FA. However, because FA is a DNA repair disorder, standard conditioning regimens confer a high risk of excessive regimen-related toxicities and mortality, and reduced intensity regimens are linked with graft failure in some FA patients. Moreover, development of graft-versus-host disease is a major contributing factor for secondary solid tumors. The relative rarity of the disorder limits HSCT experience at any single center. Consensus meetings were convened to develop a national approach for HSCT in FA. This manuscript outlines current experience and knowledge about HSCT in FA and, based on this analysis, general recommendations reached at these meetings.


Asunto(s)
Anemia de Fanconi/terapia , Trasplante de Células Madre Hematopoyéticas , Niño , Trasplante de Células Madre de Sangre del Cordón Umbilical , Anemia de Fanconi/sangre , Alemania , Supervivencia de Injerto , Enfermedad Injerto contra Huésped/prevención & control , Adhesión a Directriz , Hospitales Especializados , Humanos , Terapia de Inmunosupresión , Estudios Retrospectivos , Factores de Riesgo , Acondicionamiento Pretrasplante
5.
Transpl Infect Dis ; 16(5): 713-23, 2014 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-25200928

RESUMEN

INTRODUCTION: Cytomegalovirus (CMV) and human adenovirus (ADV) infections are causes of morbidity after stem cell transplantation. Antigen (Ag)-specific T cells are essential for the control of viral infections. However, in vivo expansion potential of T-cell subpopulations is hardly predictable in humans. Furthermore, ex vivo identification of human T cells with repopulating capacity for adoptive T-cell transfer has been difficult. METHODS: We analyzed Ag-specific T-cell populations, subdivided according to the expression of different THELPER- 1 (Th1) cytokines. Isolation by flow cytometry was based on interferon-gamma (IFN)-γ, interleukin (IL)-2, or tumor necrosis factor-alpha (TNF-α) secretion of T cells after ex vivo stimulation with the Ags hexon (for ADV) and pp65 (for CMV). Isolated T cells were expanded and examined for functional characteristics, expansion/differentiation potential, and naïve, effector memory, central memory, and late effector phenotypes. RESULTS: Isolation based on IFN-γ production provides a T-cell population with a mixture of early, central memory, and effector memory T cells, high expansion potential, and effective cytokine production. Selection of T cells with Ag-specific expression of IL-2 or TNF-α, however, results in a T-cell population with reduced proliferation and lower effector potential after expansion. CONCLUSION: We conclude that the exclusive secretion of IFN-γ in the human antiviral T-cell responses preferentially leads to higher repopulation capacities of antiviral T cells, compared to IL-2 or TNF-α secreting T-cell populations.


Asunto(s)
Linfocitos T CD8-positivos , Interferón gamma/metabolismo , Interleucina-2/metabolismo , Células TH1/inmunología , Células TH1/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Inmunidad Adaptativa , Linfocitos T CD8-positivos/química , Proteínas de la Cápside/inmunología , Diferenciación Celular , Proliferación Celular , Células Cultivadas , Humanos , Memoria Inmunológica , Interferón gamma/análisis , Interleucina-2/análisis , Selectina L/análisis , Antígenos Comunes de Leucocito/análisis , Recuento de Linfocitos , Fosfoproteínas/inmunología , Células TH1/química , Factor de Necrosis Tumoral alfa/análisis , Proteínas de la Matriz Viral/inmunología
6.
Klin Padiatr ; 226(6-7): 351-6, 2014 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-25431868

RESUMEN

BACKGROUND: High-dose chemotherapy (HDC) with autologous stem-cell rescue (ASCR) is a treatment option for pediatric patients with relapsed nephroblastoma. We present long term results of 9 patients treated between 1993 and 2013 at our center. PROCEDURE: Reinduction therapy was carried out according to GPOH and SIOP recommendations. The conditioning regimen consisted of carboplatin (1 200 mg/m²), etoposide (800 mg/m² or 40 mg/kg) and melphalan (180 mg/m²). Purging of the grafts with immunomagnetic CD34 positive selection was performed in 5 patients. RESULTS: 8 of 9 Patients (90%) are alive without evidence of disease after a median follow-up of 8.5 years. Leukocyte engraftment occurred after a median of 10 days (range 8-12). Median numbers of 667/µl CD3+, 329/µl CD4+, 369/µl CD8+T cells and 949/µl B cells were reached after 180 days. No negative impact of CD34 selection was observed. No transplantation-related death occurred. Acute toxicity comprised mucositis III°-IV° in all and veno-occlusive disease in one patient. Long term effects probably related to treatment occurred in 3/7 evaluable patients and comprised hearing impairment, reduced renal phosphate reabsorption, mild creatinine elevation and hypothyroidism (n=1, each). CONCLUSION: Thus, in our experience HDC with ASCR is an effective treatment of recurrent or refractory nephroblastoma with acceptable side effects. However, a randomized trial proving its efficiency with a high level of evidence is needed.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trasplante de Células Madre Hematopoyéticas , Neoplasias Renales/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Tumor de Wilms/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carboplatino/administración & dosificación , Carboplatino/efectos adversos , Niño , Preescolar , Terapia Combinada , Dactinomicina/administración & dosificación , Dactinomicina/efectos adversos , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Etopósido/administración & dosificación , Etopósido/efectos adversos , Femenino , Humanos , Lactante , Neoplasias Renales/diagnóstico , Neoplasias Renales/mortalidad , Neoplasias Renales/patología , Masculino , Melfalán/administración & dosificación , Melfalán/efectos adversos , Recurrencia Local de Neoplasia/diagnóstico , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/patología , Acondicionamiento Pretrasplante , Vincristina/administración & dosificación , Vincristina/efectos adversos , Tumor de Wilms/diagnóstico , Tumor de Wilms/mortalidad , Tumor de Wilms/patología
7.
Klin Padiatr ; 225(3): 164-9, 2013 May.
Artículo en Inglés | MEDLINE | ID: mdl-23700092

RESUMEN

Viral infections after allogeneic stem cell transplantation (SCT) are an important cause of morbidity and mortality as SCT can expose patients to a transient state of combined immunodeficieny. Most viral infections after SCT are caused by the endogenous reactivation of persistent pathogens such as adenovirus (ADV), cytomegalovirus (CMV), and Epstein-Barr-virus (EBV). The control of these infections will ultimately depend on the restoration of adequate T-cell immunity.


Asunto(s)
Infecciones por Adenoviridae/inmunología , Infecciones por Adenoviridae/terapia , Traslado Adoptivo , Infecciones por Citomegalovirus/inmunología , Infecciones por Citomegalovirus/terapia , Infecciones por Virus de Epstein-Barr/inmunología , Infecciones por Virus de Epstein-Barr/terapia , Trasplante de Células Madre Hematopoyéticas , Infecciones Oportunistas/inmunología , Infecciones Oportunistas/terapia , Linfocitos T/inmunología , Niño , Estudios de Seguimiento , Humanos , Resultado del Tratamiento
8.
Transpl Infect Dis ; 14(6): 555-63, 2012 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-23146063

RESUMEN

Human adenovirus (HAdV) infections are increasingly recognized as important pathogens in immunocompromised hosts, especially in patients with severely suppressed T-cell function. The 4th European Conference of Infections in Leukemia (ECIL-4) has developed evidence-based guidelines for diagnosis and management of HAdV infections. The risk for HAdV-associated disease is increased in children, and risk factors for HAdV disease are T-cell depletion, unrelated and cord blood hematopoietic stem cell transplantation, graft-versus-host disease grades III-IV, and lymphopenia. The recommended technique for monitoring of high-risk patients is quantitative polymerase chain reaction. Cidofovir is the most used antiviral therapy, although no controlled study has been performed. HAdV-specific T-cell therapy is in development.


Asunto(s)
Infecciones por Adenovirus Humanos/diagnóstico , Infecciones por Adenovirus Humanos/terapia , Leucemia/complicaciones , Guías de Práctica Clínica como Asunto , Trasplante de Células Madre/efectos adversos , Infecciones por Adenovirus Humanos/etiología , Europa (Continente) , Humanos
9.
Biol Blood Marrow Transplant ; 14(1 Suppl 1): 59-65, 2008 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-18162222

RESUMEN

Delayed immune reconstitution is 1 of the major contributions to the morbidity and mortality after haploidentical transplantation. Patients with a slow recovery of the innate and especially of the adaptive immune system are at high risk for severe and often lethal infections. The reason for delayed immune reconstitution after haploidentical transplantation include the T cell depletion (TCD) of the graft, the thymic dysfunction induced by pretransplant chemotherapies and by the conditioning regimens, and the occurrence of graft-versus-host disease (GVHD) and its treatment. The detailed analysis, understanding, and manipulation of the reconstitution of the cellular immune system will be of utmost importance to overcome the posttransplant immunodefcient status, and should result in a reduced risk of severe and overwhelming infections and hopefully also to a reduced risk of relapse through better immunological control of residual malignant cells.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas/métodos , Inmunidad Celular/fisiología , Regeneración , Niño , Haplotipos , Humanos , Células Asesinas Naturales/inmunología , Depleción Linfocítica
10.
Bone Marrow Transplant ; 39(12): 767-73, 2007 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-17438586

RESUMEN

Transplantation of HLA-mismatched stem cells may allow determination of chimerism status of single cells by differential expression of HLA molecules. Monoclonal antibodies against HLA antigens can be used to determine the HLA type of sub-populations by standard flow cytometry. Blood samples from 23 patients transplanted from HLA-mismatched family donors were monitored using HLA-specific antibodies. Suitable antibodies could be found for all donor recipient pairs by using differences in HLA Bw4 and Bw6 groups or other serological antigens. Pretransplant controls of donor and recipient were used to correct for variable fluorescence intensities of the antibodies and sub-populations. Owing to the high sensitivity, cell populations with a minimum frequency of 0.1% were detectable. Flow-cytometric analysis was confirmed by chimerism analysis of immunomagnetically isolated T cells by standard PCR technique. In addition to chimerism evaluation, HLA antibodies improved the detection of leukemic cells after transplantation with aberrant phenotype. In conclusion, flow cytometry using antibodies against HLA antigens is an interesting tool for determination of chimerism and minimal residual disease after HLA-mismatched transplantation. Information about the chimerism status is given on a single-cell level and allows fast and convenient analysis of sub-populations.


Asunto(s)
Anticuerpos Monoclonales , Citometría de Flujo/métodos , Antígenos HLA/inmunología , Neoplasia Residual/diagnóstico , Trasplante de Células Madre/efectos adversos , Quimera por Trasplante/inmunología , Femenino , Antígenos HLA/genética , Haplotipos , Prueba de Histocompatibilidad , Humanos , Masculino , Neoplasia Residual/inmunología , Sensibilidad y Especificidad , Linfocitos T/inmunología , Quimera por Trasplante/genética
11.
Clin Microbiol Infect ; 22(2): 209.e5-209.e8, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-26482270

RESUMEN

To evaluate the human herpes virus 6 (HHV-6) -specific immune response in individuals with chromosomally integrated HHV-6 (ciHHV-6), we measured HHV-6-antigen-specific cytokine responses (interferon-γ, interleukin-2, tumour necrosis factor-α) in T cells by flow cytometry in 12 and 16 individuals with and without ciHHV-6, respectively. All individuals with ciHHV-6 showed HHV-6-specific T cells with higher frequencies of HHV-6-specific CD8(+) cells (0.03-14.93, median 2.15% of CD8(+) cells) compared with non-ciHHV-6 (0.0-10.67, median 0.36%, p 0.026). The observed increased HHV-6-specific functionally active responses in individuals with ciHHV-6 clearly disprove speculations on immune tolerance in ciHHV-6 and indicate clinical and immunological implications of ciHHV-6.


Asunto(s)
Citocinas/metabolismo , Herpesvirus Humano 6/genética , Infecciones por Roseolovirus/virología , Linfocitos T/citología , Adulto , Anciano , Anciano de 80 o más Años , Cromosomas Humanos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Infecciones por Roseolovirus/genética , Infecciones por Roseolovirus/inmunología , Linfocitos T/metabolismo , Integración Viral , Adulto Joven
12.
Bone Marrow Transplant ; 36(2): 91-7, 2005 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-15908973

RESUMEN

Relapse is a major problem after allogeneic transplantation in children with acute B-lineage lymphoblastic leukemias (ALL) and lymphomas and additional therapeutic strategies are needed to increase graft versus leukemia effects without inducing graft versus host disease (GvHD). Several studies have shown the efficacy of a humanized CD20 antibody (rituximab) for treatment of CD20+ malignancies together with conventional chemotherapy but less is known about its post transplant usefulness. We studied the ability of rituximab to mediate antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) with effector cells and complement from patients who were transplanted with T-cell-depleted grafts from unrelated or mismatched related donors. Highest lytic activity (ADCC) was observed against leukemia-derived MHH4 cells and Burkitt's lymphoma-derived Raji cells in the first months after transplantation, corresponding to the high percentage of regenerating CD56+ CD16+ cells. Moreover, primary cryopreserved ALL-blasts from a pediatric patient were also efficiently lysed. Increased lysis was obtained after stimulation with interleukin-2. Combination of ADCC and CDC had additive effects. These findings encourage clinical trials on the use of rituximab for improving minimal residual disease control and relapse prevention after allogeneic high-risk transplantation in the small group of pediatric patients with CD20+ leukemias/lymphomas.


Asunto(s)
Anticuerpos Monoclonales/farmacología , Citotoxicidad Celular Dependiente de Anticuerpos/inmunología , Antineoplásicos/farmacología , Linfoma de Burkitt/inmunología , Linfoma de Células B/inmunología , Animales , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales de Origen Murino , Antineoplásicos/uso terapéutico , Linfoma de Burkitt/terapia , Niño , Preescolar , Proteínas del Sistema Complemento/inmunología , Femenino , Trasplante de Células Madre Hematopoyéticas , Humanos , Linfoma de Células B/terapia , Masculino , Ratones , Rituximab , Trasplante Homólogo
13.
Bone Marrow Transplant ; 50 Suppl 2: S6-10, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-26039210

RESUMEN

Immune recovery was retrospectively analyzed in a cohort of 41 patients with acute leukemia, myelodysplastic syndrome and nonmalignant diseases, who received αß T- and B-cell-depleted allografts from haploidentical family donors. Conditioning regimens consisted of fludarabine or clofarabine, thiotepa, melphalan and serotherapy with OKT3 or ATG-Fresenius. Graft manipulation was carried out with anti-TCRαß and anti-CD19 Abs and immunomagnetic microbeads. The γδ T cells and natural killer cells remained in the grafts. Primary engraftment occurred in 88%, acute GvHD (aGvHD) grades II and III-IV occurred in 10% and 15%, respectively. Immune recovery data were available in 26 patients and comparable after OKT3 (n=7) or ATG-F (n=19). Median time to reach >100 CD3+ cells/µL, >200 CD19+ cells/µL and >200 CD56+ cells/µL for the whole group was 13, 127 and 12.5 days, respectively. Compared with a historical control group of patients with CD34+ selected grafts, significantly higher cell numbers were found for CD3+ at days +30 and +90 (267 vs 27 and 397 vs 163 cells/µL), for CD3+4+ at day +30 (58 vs 11 cells/µL) and for CD56+ at day +14 (622 vs 27 cells/µL). The clinical impact of this accelerated immune recovery will be evaluated in an ongoing prospective multicenter trial.


Asunto(s)
Antígenos CD19 , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Depleción Linfocítica/instrumentación , Síndromes Mielodisplásicos , Leucemia-Linfoma Linfoblástico de Células Precursoras , Receptores de Antígenos de Linfocitos T alfa-beta , Recuperación de la Función/inmunología , Acondicionamiento Pretrasplante/métodos , Adolescente , Aloinjertos , Linfocitos B/inmunología , Niño , Preescolar , Femenino , Humanos , Leucemia Mieloide Aguda/inmunología , Leucemia Mieloide Aguda/terapia , Masculino , Síndromes Mielodisplásicos/inmunología , Síndromes Mielodisplásicos/terapia , Estudios Retrospectivos , Linfocitos T/inmunología , Donantes de Tejidos
14.
Bone Marrow Transplant ; 50 Suppl 2: S72-6, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-26039213

RESUMEN

Natural killer (NK) cell activity has been shown to have potential activity against Ewing's sarcoma (EWS) especially in tumors with low HLA I expression and high NKG2D expression. Two patients with metastatic relapsed and primary metastatic stage IV EWS who had received two courses of high dose chemotherapy with autologous stem cell rescue were transplanted from a haploidentical parental stem cell donor. Patients are alive in ongoing CR for 10.2 and 3.4 years now. Post transplant local second and first relapses were treated successfully in both patients. In vivo IL-2 stimulation not only increased the number and activity of effector cells in one patient but was also associated with severe GvHD. In vitro studies demonstrated high NK cell activity against K562 and relevant activity against EWS cell line A673 post transplant. NK activity was enhanced by cytokine prestimulation as well as by EWS targeting anti-GD2 Ab. Haploidentical hematopoietic stem cell transplantation (HSCT) might contribute to long-term survival by NK cell-mediated effect exerted by donor-derived NK cells. Local tumor recurrence was manageable in both high-risk patients indicating systemic immune control preventing subsequent metastasizing. The efficacy of haploidentical HSCT, cytokine application and tumor targeting antibodies for the use of Ab-dependent cellular cytotoxicity needs evaluation in clinical trials.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Células Asesinas Naturales/inmunología , Recurrencia Local de Neoplasia , Sarcoma de Ewing , Adolescente , Femenino , Estudios de Seguimiento , Humanos , Masculino , Subfamilia K de Receptores Similares a Lectina de Células NK/inmunología , Metástasis de la Neoplasia , Recurrencia Local de Neoplasia/inmunología , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/prevención & control , Estadificación de Neoplasias , Sarcoma de Ewing/inmunología , Sarcoma de Ewing/patología , Sarcoma de Ewing/prevención & control
15.
Hum Immunol ; 65(5): 423-31, 2004 May.
Artículo en Inglés | MEDLINE | ID: mdl-15172441

RESUMEN

Human cytomegalovirus (HCMV) remains a cause of serious infectious complications after allogeneic transplantation of hematopoietic stem cells, especially in recipients of T-cell-depleted grafts. Here we investigated the antiviral activity of natural killer (NK) cells from healthy donors (n = 8) as well as of mononuclear cells (MNC) from transplanted pediatric patients (n = 11) who had received CD34(+) selected (and thus T-cell-depleted) stem cells from unrelated and mismatched related donors. Allogeneic human fibroblasts infected with HCMV laboratory strain AD169 for 5 days were used as targets in a 2-h cytotoxicity assay. Downregulation of human leukocyte antigen class I and upregulation of the adhesion molecules CD54 (ICAM-1) and CD58 (LFA-3) were observed after infection. In this experimental setting, NK cells from healthy donors exerted no specific lysis. However, antibody-dependent cellular cytotoxicity (ADCC) mediated by human anti-CMV IgG (cytoglobin) as well as stimulation with low-dose interleukin-(IL)-2 or IL-15 enhanced lysis markedly. MNC from two thirds of the patients (7/11) were capable of lysing infected targets without stimulation. Here also, lytic activity was significantly increased by IL-2 or IL-15, used in combination with ADCC. In contrast, 4/11 patients exerted no lysis. The observed antiviral activity may contribute to the low incidence of CMV DNAemia (29% at day 100, detected by polymerase chain reaction) in the whole group of our patients who have been transplanted with CD34(+)-selected allografts since 1995. Furthermore, our data suggest a potential benefit of using low-dose IL-2 or IL-15, also combined with anti-CMV immunoglobulinG, for immune modulation in CMV disease.


Asunto(s)
Antígenos CD34/inmunología , Citomegalovirus/inmunología , Citotoxicidad Inmunológica/inmunología , Fibroblastos/virología , Trasplante de Células Madre Hematopoyéticas , Adolescente , Citotoxicidad Celular Dependiente de Anticuerpos/inmunología , Antígenos CD/análisis , Antígeno CD56/análisis , Antígenos CD58/metabolismo , Niño , Infecciones por Citomegalovirus/diagnóstico , Pruebas Inmunológicas de Citotoxicidad , ADN Viral/análisis , Fibroblastos/química , Fibroblastos/inmunología , Citometría de Flujo , Antígenos de Histocompatibilidad Clase I/metabolismo , Humanos , Molécula 1 de Adhesión Intercelular/metabolismo , Interleucina-15/farmacología , Interleucina-2/farmacología , Células Asesinas Naturales/efectos de los fármacos , Células Asesinas Naturales/inmunología , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/inmunología , Donantes de Tejidos , Trasplante Homólogo
17.
Bone Marrow Transplant ; 43(11): 875-81, 2009 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-19151793

RESUMEN

Relapse after allo-SCT in patients with acute leukaemia remains a major problem. A beneficial impact of alloreactive natural killer (NK) cells has been reported for myeloid malignancies, but has been questionable for B-lineage ALL. We analysed lysis of primary paediatric precursor-B-ALL blasts by 285 NK cell clones to investigate whether HLA class I expression on the blasts and phenotypic killer cell Ig-like receptor (KIR) expression on NK cells affect the lytic activity against ALL blasts. Precursor-B-ALL blasts with low HLA-I expression were lysed by a majority (79%) of NK cell clones, whereas those with high HLA-I expression showed low susceptibility to NK clones independent of their KIR expression patterns. NK cell activity against susceptible blasts was regulated by differential surface expression of the three major KIRs (CD158a, CD158b, CD158e). NK clones with none of these three KIRs or a single KIR that recognized no ligand, were not inhibited by the targets and exerted higher lysis (P = <0.0005) in comparison to NK clones expressing KIRs with a ligand on the ALL blasts. In conclusion, the quantity of HLA-I expression on precursor-B-ALL blast regulates overall NK cell susceptibility; in case of reduced HLA expression, differential surface expression of KIRs affects NK cell alloreactivity against those blasts.


Asunto(s)
Antígenos de Histocompatibilidad Clase I/genética , Células Asesinas Naturales/inmunología , Leucemia-Linfoma Linfoblástico de Células Precursoras B/inmunología , Receptores KIR/genética , Antígenos de Histocompatibilidad Clase I/inmunología , Humanos , Fenotipo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Receptores KIR/inmunología
18.
Klin Padiatr ; 218(6): 321-6, 2006.
Artículo en Inglés | MEDLINE | ID: mdl-17080334

RESUMEN

Pediatric patients with relapsed metastatic tumors have a poor prognosis and new treatment strategies are warranted. We present preliminary results of a pilot study, evaluating the feasibility and toxicity of transplantation of haploidentical T and B cell depleted grafts with high numbers of NK cells. 6 patients with relapsed metastatic neuroblastomas (n = 4), rhabdomyosarcoma (n = 1) or Ewing's sarcoma (n = 1) after previous autologous transplantation received CD3/CD19 depleted grafts from mismatched family donors with a median number of 16 x 10 (6)/kg stem cells, 167 x 10 (6)/kg Natural Killer cells and only 5.4 x 10 (4)/kg residual T cells. A melphalan-based, reduced intensity conditioning was used. Despite pretransplant chemotherapy, patients entered transplantation with significant tumor burden. Primary engraftment occurred in 6/6 patients. One patient had secondary graft failure. Hematopoietic recovery was rapid (ANC > 0.5 x 10 (9)/L: 11 days (9-12); independence from platelet substitution: 8 days (7-11)). Four patients had acute GvHD grade II, limited chronic GvHD was observed in 2 patients. No transplant-related mortality and only low toxicity occurred. Four patients died from progression, two patients are alive. Overall median survival time is 6 months (2-11) to date. Analysis of posttransplant NK cell function revealed stable cytotoxic activity against K562 targets, whereas activity against neuroblastoma targets was low. Stimulation with cytokines and use of appropriate antibodies clearly enhanced specific lysis in vitro. In summary, these preliminary results indicate the feasibility and low toxicity even in intensively pre-treated patients with neuroblastomas/sarcomas. This approach may form the basis for posttransplant immunomodulation and other therapeutic strategies. Further experience is warranted to evaluate the method.


Asunto(s)
Efecto Injerto vs Tumor , Células Asesinas Naturales/inmunología , Neuroblastoma/terapia , Trasplante de Células Madre de Sangre Periférica , Rabdomiosarcoma/terapia , Sarcoma de Ewing/terapia , Enfermedad Aguda , Adolescente , Adulto , Niño , Preescolar , Pruebas Inmunológicas de Citotoxicidad , Progresión de la Enfermedad , Estudios de Factibilidad , Estudios de Seguimiento , Haploidia , Humanos , Proyectos Piloto , Factores de Tiempo , Acondicionamiento Pretrasplante , Trasplante Homólogo , Resultado del Tratamiento
19.
Cytotherapy ; 8(5): 465-72, 2006.
Artículo en Inglés | MEDLINE | ID: mdl-17050251

RESUMEN

BACKGROUND: T- and B-cell depletion of apheresis products is an attractive alternative to standard stem cell enrichment in haplo-identical transplantation. Thorough T- and B-cell depletion is necessary for prevention of acute GvHD and T-cell depletion-associated lymphoproliferative disorders. However, the large number of non-T and -B cells in the graft requires special protocols for the determination of extremely low frequencies of residual T cells. METHODS: Apheresis products from healthy donors were T- and B-cell depleted by the CliniMACS system using CD3 and CD19 Ab reagents and the LS tubing set. The recovery of cells and degree of depletion were determined. A four-color multigating strategy was used for enumeration of residual T and B cells. RESULTS: One-hundred and three separations were performed, with a mean cell recovery of 38+/-12%, CD34 recovery of 61+/-16% and CD56 recovery of 63+/-33%. T and B cells were depleted by log 4.15+/-0.46 and log 3.64+/-0.63, respectively. Four-color multigating flow cytometry allowed the detection of single T cells. DISCUSSION: Combined T- and B-cell depletion is a feasible method for obtaining stem cell grafts with acceptable stem cell recovery, profound T- and B-cell depletion and a very high amount of NK cells and monocytes. However, analysis of residual T cells is challenging and requires special protocols.


Asunto(s)
Citometría de Flujo , Enfermedad Injerto contra Huésped/prevención & control , Células Madre Hematopoyéticas/citología , Separación Inmunomagnética , Depleción Linfocítica , Enfermedad Aguda , Linfocitos B/citología , Citometría de Flujo/métodos , Humanos , Separación Inmunomagnética/métodos , Leucaféresis/métodos , Depleción Linfocítica/métodos , Trasplante de Células Madre de Sangre Periférica/efectos adversos , Trasplante de Células Madre de Sangre Periférica/métodos , Linfocitos T/citología , Trasplante Homólogo
20.
Klin Padiatr ; 217(6): 334-8, 2005.
Artículo en Inglés | MEDLINE | ID: mdl-16307419

RESUMEN

Transplantation of hematopoietic stem cells from mismatched related donors makes a potential donor available for every child in need of stem cell transplantation. Here, we compare three different graft manipulation methods in patients with leukemias and lymphomas: positive selection of stem cells with either CD34 (n = 39) or CD133-coated magnetic microbeads (n = 14) and a new strategy which depletes T- and B-cells through the use of CD3- and CD19-coated microbeads (n = 11). Median purity of stem cells was comparable after CD34 (+)-selection and CD133 (+)-selection, whereas stem cells were only slightly enriched after CD3 (+)/CD19 (+)-depletion (97.5 %, 93.4 % and 1.02 %). Indirect depletion of T-cells by positive selection resulted in 1 x 10 (4) (median) residual CD3 (+)-cells/kg (0.7-3 x 10 (4)). Patients with CD3/CD19-depleted grafts received 3.2 x 10 (4) (median) (0.7-16 x 10 (4)) residual T-cells/kg. Those grafts also comprised NK-cells (median number: 86 x 10 (6)/kg), dendritic cells and monocytes/granulocytes. Primary engraftment of the stem cell products was comparable after CD34- and CD133-selection (85 and 72 %). In the CD3/CD19 group, 91 % had a primary engraftment. After reconditioning, all patients (64/64) were finally engrafted. Patients with CD34-selected or CD133-selected grafts had similar incidences of a GvHD II-IV (3 and 7 %), whereas a GvHD was slightly increased in patients receiving CD3/CD19-depleted cells (27 %). Reconstitution of CD3 (+) T-cells was faster in the CD3/CD19 group than in the CD34 or CD133 group. These preliminary results indicate, that CD3/CD19-selected grafts may be advantageous regarding engraftment and immunoreconstitution. Since effector cell with potential antileukemic activity are cotransfused, such grafts may be suited in particular for patients with insufficient remission.


Asunto(s)
Haploidia , Trasplante de Células Madre Hematopoyéticas/métodos , Leucemia/terapia , Linfoma/terapia , Antígeno AC133 , Adolescente , Adulto , Antígenos CD/inmunología , Antígenos CD19/inmunología , Antígenos CD34/inmunología , Complejo CD3/inmunología , Recuento de Células , Niño , Preescolar , Femenino , Glicoproteínas/inmunología , Humanos , Lactante , Leucemia/inmunología , Leucemia/mortalidad , Depleción Linfocítica , Linfoma/inmunología , Linfoma/mortalidad , Masculino , Microesferas , Péptidos/inmunología , Proyectos Piloto , Tasa de Supervivencia
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