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1.
Klin Padiatr ; 227(3): 108-15, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25985445

RESUMO

Curative therapies for Ewing sarcoma have been developed within cooperative groups. Consecutive clinical trials have systematically assessed the impact and timing of local therapy and the activity of cytotoxic drugs and their combinations. They have led to an increase of long-term disease-free survival to around 70% in patients with localized disease. Translational research in ES remains an area in which interdisciplinary and international cooperation is essential for future progress. This article reviews current state-of-the art therapy, with a focus on trials performed in Europe, and summarizes novel strategies to further advance both the cure rates and quality of survival.


Assuntos
Neoplasias Ósseas/terapia , Comportamento Cooperativo , Comunicação Interdisciplinar , Sarcoma de Ewing/terapia , Neoplasias de Tecidos Moles/terapia , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Ósseas/mortalidade , Criança , Ensaios Clínicos como Assunto , Terapia Combinada , Progressão da Doença , Humanos , Terapia Neoadjuvante , Osteotomia , Radioterapia Adjuvante , Sarcoma de Ewing/mortalidade , Neoplasias de Tecidos Moles/mortalidade , Taxa de Sobrevida
2.
Pediatr Blood Cancer ; 60(10): 1574-81, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23737479

RESUMO

In Germany and Austria, more than 90% of pediatric cancer patients are enrolled into nationwide disease-specific first-line clinical trials or interim registries. Essential components are a pediatric cancer registry and centralized reference laboratories, imaging review, and tumor board assistance. The five-year overall survival rate in countries where such infrastructures are established has improved from <20% before 1950 to >80% since 1995. Today, treatment intensity is tailored to the individual patient's risk to provide the highest chances of survival while minimizing deleterious late effects. Multicenter clinical trials are internationalized and serve as platforms for further improvements by novel drugs and biologicals.


Assuntos
Neoplasias , Sistema de Registros , Adolescente , Áustria/epidemiologia , Criança , Pré-Escolar , Ensaios Clínicos como Assunto/história , Ensaios Clínicos como Assunto/métodos , Intervalo Livre de Doença , Feminino , Alemanha/epidemiologia , História do Século XX , História do Século XXI , Humanos , Lactente , Masculino , Estudos Multicêntricos como Assunto/história , Estudos Multicêntricos como Assunto/métodos , Neoplasias/diagnóstico , Neoplasias/mortalidade , Neoplasias/terapia , Taxa de Sobrevida
3.
Klin Padiatr ; 225 Suppl 1: S16-29, 2013 May.
Artigo em Alemão | MEDLINE | ID: mdl-23700050

RESUMO

During the last 6 years 73 previously untreated children and adolescents with acute lymphoblastic leukemia were enrolled on a non-randomized therapy protocol. In this longitudinal study the specific accent was put on the intensified induction treatment of 8 weeks' duration which was thought to achieve a higher remission quality. In this phase 8 effective drugs were applied up to the patient's tolerance limits; in addition prophylactic irradiation to the central nervous system was given in two modifications. After 4 weeks all patients were in complete remission. During the first 4 months 6 children died due to complications for which therapy must be at least partially responsible. 17 out of 67 patients relapsed between 4 and 59 months after diagnosis, which corresponds to a remission rate according to the life table analysis of 62% (50 out of 67 patients in first remission). The majority of patients with relapse is characterized at diagnosis by a specific pattern of clinical findings. 2 therapy groups, differently treated in respect to central nervous system irradiation and duration of continuation therapy, do not at present statistically differ from each other. According to statistics 8 more children may be expected to suffer from relapse. The improved results are due to a lower incidence of bone marrow relapses; it seems that there is a direct relation between intensity of treatment during the induction phase and the occurrence of bone marrow relapses. The specific problems of the presented study take place during the induction phase, which, due to toxicity, regularly results in a number of side effects and severe complications. In order to realize the induction therapy, the use of prophylactic and supportive procedures is of utmost importance. Profound knowledge of possible side effects and complications is most essential as well as the knowledge of how to cope with these problems. It is the authors' opinion that the induction phase can only be performed in specialized institutions, because only at these places enough information may be obtained from an adequate number of patients and only there pediatric oncologists may share in the decisions and responsibilities. Only by using every kind of medical service this method of therapy may be justified at present, according to the results of this study, for the benefit of children with leukemia.

4.
Klin Padiatr ; 225 Suppl 1: S62-72, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23700060

RESUMO

Between 1981 and 2000, 6 609 children (<18 years of age) were treated in 5 consecutive trials of the Berlin-Frankfurt-Münster (BFM) study group for childhood acute lymphoblastic leukemia (ALL). Patients were treated in up to 82 centers in Germany, Austria, and Switzerland. Probability of 10-year event-free survival (survival) improved from 65% (77%) in study ALL-BFM 81-78% (85%) in ALL-BFM 95. In parallel to relapse reduction, major efforts focused on reducing acute and late toxicity through advanced risk adaptation of treatment. The major findings derived from these ALL-BFM trials were as follows: 1) preventive cranial radiotherapy could be safely reduced to 12 Gy in T-ALL and high-risk ALL patients and eliminated in non-high-risk non-T-ALL patients, if it was replaced by high-dose and intrathecal methotrexate; 2) omission of delayed reintensification severely impaired outcome of low-risk patients; 3) 6 months less maintenance therapy caused an increase in systemic relapses; 4) slow response to an initial 7-day prednisone window was identified as adverse prognostic factor; 5) condensed induction therapy resulted in a significant improvement of outcome; 6) the daunorubicin dose in induction could be safely reduced in low-risk patients; 7) intensification of consolidation/reintensification treatment led to considerable improvement of outcome in high-risk patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/história , Oncologia/história , Pediatria/história , Leucemia-Linfoma Linfoblástico de Células Precursoras/história , Ensaios Clínicos Controlados Aleatórios como Assunto/história , Asparaginase/história , Criança , Ciclofosfamida/história , Citarabina/história , Daunorrubicina/história , Europa (Continente) , Alemanha , História do Século XX , História do Século XXI , Humanos , Mercaptopurina/história , Metotrexato/história , Prednisona/história , Vincristina/história
5.
Ann Hematol ; 91(6): 949-56, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22234839

RESUMO

Allogeneic hematopoietic stem cell transplantation (HSCT) in childhood is associated with severe pulmonary complications, but the pathophysiologic mechanisms remain unclear. Our aim was to evaluate the association of total and specific IgE, eosinophil cationic protein (ECP) and eosinophilia in HSCT recipients with pulmonary complications. We prospectively measured total and specific serum IgE, eosinophils, and ECP before and 28, 100, and 180 days after HSCT. We included 30 children (age 2-17 years) undergoing HSCT. Nine patients had a history of previous atopy without being associated with pulmonary complications after HSCT until day +360. Specific IgE levels showed a decline after HSCT, associated with the absence of allergy symptoms, suggesting a reduction of atopy. Elevated total serum IgE levels occurred in seven patients on day +28 after HSCT. This elevation did not coincide with allergy symptoms. ECP showed no correlation with total allergy symptoms, eosinophilia, IgE levels, or pulmonary complications. There was a significant correlation (p = 0.0367) between ECP levels on day +28 and concurrent acute graft-versus-host disease (GvHD). Non-atopic serum ECP and IgE levels are elevated on day +28 after HSCT in children, with ECP showing a potential relation to acute GvHD.


Assuntos
Proteína Catiônica de Eosinófilo/sangue , Doença Enxerto-Hospedeiro/diagnóstico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Imunoglobulina E/sangue , Adolescente , Criança , Pré-Escolar , Pneumonia em Organização Criptogênica/sangue , Pneumonia em Organização Criptogênica/diagnóstico , Pneumonia em Organização Criptogênica/epidemiologia , Pneumonia em Organização Criptogênica/etiologia , Feminino , Doença Enxerto-Hospedeiro/sangue , Doença Enxerto-Hospedeiro/epidemiologia , Doença Enxerto-Hospedeiro/imunologia , Transplante de Células-Tronco Hematopoéticas/estatística & dados numéricos , Humanos , Hipersensibilidade Imediata/sangue , Hipersensibilidade Imediata/epidemiologia , Hipersensibilidade Imediata/imunologia , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/epidemiologia , Leucemia Mieloide Aguda/terapia , Pneumopatias/sangue , Pneumopatias/diagnóstico , Pneumopatias/epidemiologia , Pneumopatias/etiologia , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Prevalência , Transplante Homólogo
6.
Klin Padiatr ; 221(6): 351-7, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19890786

RESUMO

PURPOSE: Stem cell transplantation (SCT) can definitely cure chronic myeloid leukemia (CML), a rare disease in childhood. We prospectively evaluated the results of early SCT in pediatric CML after standardized pretreatment with hydroxyurea+/-interferon. PATIENTS AND METHODS: Between 1995 and 2004, 200 children (median age: 12.4 years) were enrolled and stratified: given the availability of an HLA-matched related donor (MRD), SCT was scheduled within 6 months and otherwise from an unrelated donor (UD) within 12 months following diagnosis. RESULTS: 176 patients underwent SCT; from MRD within median 4 months and from UD within median 11 months after diagnosis. At SCT, 158 patients were in chronic phase (CP1 or CP2), 9 patients were in accelerated phase and 9 patients were in blast crisis (BC). The conditioning regimen - total body irradiation or busulfan - exerted no different impact on overall survival (OS). Probability of OS at 5 years was 87+/-11% if grafted from a sibling (n=41), 52+/-9% from matched UD (MUD, n=71), and 45+/-16% from mismatched donors (MMD, n=55), respectively. A trend for better OS in CP1 was observed if SCT was performed within 6 months (n=49; 74+/-9%), compared to 7-12 months (n=52; 62+/-15%), and >12 months (n=43; 62+/-17%) after diagnosis, respectively (p=0.157). Probability of relapse at 5 years was 20+/-12%. Transplant-related mortality and graft-versus-host disease mainly contributed to the inferior outcome in UD and HLA-mismatched SCT. CONCLUSION: These data from the first prospective trial on CML restricted to children and adolescents might be considered for decision making when balancing the risks of SCT against the increasing use of imatinib as upfront treatment for CML.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Adolescente , Antineoplásicos/uso terapêutico , Benzamidas , Purging da Medula Óssea , Criança , Intervalo Livre de Doença , Feminino , Doença Enxerto-Hospedeiro/mortalidade , Humanos , Mesilato de Imatinib , Estimativa de Kaplan-Meier , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Masculino , Piperazinas/uso terapêutico , Estudos Prospectivos , Pirimidinas/uso terapêutico , Condicionamento Pré-Transplante/métodos , Transplante Homólogo
7.
Ann Oncol ; 19(4): 807-13, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18056650

RESUMO

BACKGROUND: The aim of this study was to evaluate feasibility and toxicity of bevacizumab (Avastin), a monoclonal antibody directed against the vascular endothelial growth factor in children and young adults. PATIENTS AND METHODS: Fifteen patients (male: n = 8; female: n = 7; median age, 14.6 years) received bevacizumab for recurrent or progressive solid tumors (carcinoma: n = 3; neuroblastoma: n = 2; astrocytoma grade III: n = 2; rhabdomyosarcoma: n = 2; nephroblastoma: n = 2; benign vascular tumors: n = 2; synovial sarcoma: n = 1; and malignant hemangiopericytoma: n = 1) on a compassionate basis. Bevacizumab was administered at 5-10 mg/kg body weight intravenously every 2-3 weeks. Most patients received chemotherapy in addition to bevacizumab. Duration of bevacizumab therapy ranged from 1.5 to 23 months. RESULTS: Bevacizumab-related side-effects were mild and included hypertonia (n = 2), proteinuria/hematuria (n = 2), epistaxis (n = 2), local erythema (n = 1), and defective wound healing and ascites (n = 1). Radiographic objective responses (partial responses) were observed in two patients with astrocytoma grade III and in one patient each with neuroblastoma and pleomorphic rhabdomyosarcoma, respectively. CONCLUSIONS: Bevacizumab seems to have a good acute safety profile and some antitumor activity in heavily pretreated children and young adults with recurrent solid tumors. Prospective clinical trials are urgently needed to further evaluate the safety and efficacy of bevacizumab in pediatric patients.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Neoplasias/tratamento farmacológico , Adolescente , Adulto , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/efeitos adversos , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Astrocitoma/tratamento farmacológico , Bevacizumab , Neoplasias Encefálicas/tratamento farmacológico , Carcinoma/tratamento farmacológico , Criança , Esquema de Medicação , Empatia , Feminino , Humanos , Neoplasias Renais/tratamento farmacológico , Masculino , Recidiva Local de Neoplasia/tratamento farmacológico , Neuroblastoma/tratamento farmacológico , Estudos Retrospectivos , Rabdomiossarcoma/tratamento farmacológico , Sarcoma/tratamento farmacológico , Tomografia Computadorizada por Raios X , Tumor de Wilms/tratamento farmacológico
8.
Leukemia ; 21(4): 642-6, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17287854

RESUMO

The t(4;11)-positive acute lymphoblastic leukemia (ALL) is a rare disease in children above the age of 1 year. We studied the clinical and biological characteristics in 32 consecutively diagnosed childhood cases (median age 10.0 years, range 1.0-17.1 years). Immunophenotyping revealed a pro-B and a pre-B stage in 24 and eight cases, respectively. IGH genes were rearranged in 84% of leukemias with a predominance of incomplete DJ(H) joints. Whereas IGK-Kde and TCRD rearrangements were rare, TCRG rearrangements were present in 50% of cases and involved mainly Vgamma11 or Vgamma9 together with a Jgamma1.3./2.3 gene segment, an unusual combination among t(4;11)-negative B-cell precursor ALL. Oligoclonality was found in about 30% as assessed by heterogeneous IGH and TCRG rearrangements. Our data are in line with transformation of a precursor cell at an early stage of B-cell development but retaining the potential to differentiate to the pre-B cell stage in vivo. Although a distinct difference between infant and older childhood cases with t(4;11) became evident, no age-related biological features were found within the childhood age group. In contrast to infants with t(4;11)-positive ALL, childhood cases had a relatively low cumulative incidence of relapse of 25% at 3.5 years with BFM-based high-risk protocols.


Assuntos
Cromossomos Humanos Par 11 , Cromossomos Humanos Par 4 , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Translocação Genética , Genes de Imunoglobulinas , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Imunofenotipagem , Lactente , Estadiamento de Neoplasias , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Receptores de Antígenos de Linfócitos T/genética
10.
Haematologica ; 92(1): e3-4, 2007 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17405740

RESUMO

Reduced intensity conditioning followed by allogeneic SCT (RIC-SCT) has recently emerged as promising new salvage option for children suffering from Langerhans cell histiocytosis (LCH) with risk organ involvement and failure to conventional therapy. We report on the posttransplant course of female toddler with high-risk LCH, who achieved complete remission after RIC-SCT, despite a posttransplant chimerism constellation, in which only the T-cell subset proved to be of donor origin in the long-term. We therefore suggest that allogeneic T-cells have played a crucial role in controlling disease activity in this patient and may exert the major curative effect after RIC-SCT for LCH.


Assuntos
Transplante de Medula Óssea , Histiocitose de Células de Langerhans/cirurgia , Subpopulações de Linfócitos T/imunologia , Condicionamento Pré-Transplante , Alemtuzumab , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Anticorpos Antineoplásicos/administração & dosagem , Anticorpos Antineoplásicos/uso terapêutico , Terapia Combinada , Quimioterapia Combinada , Etoposídeo/administração & dosagem , Etoposídeo/uso terapêutico , Feminino , Sobrevivência de Enxerto , Histiocitose de Células de Langerhans/complicações , Histiocitose de Células de Langerhans/tratamento farmacológico , Histiocitose de Células de Langerhans/imunologia , Humanos , Lactente , Transfusão de Linfócitos , Linfo-Histiocitose Hemofagocítica/etiologia , Melfalan/administração & dosagem , Melfalan/uso terapêutico , Prednisona/administração & dosagem , Prednisona/uso terapêutico , Indução de Remissão , Subpopulações de Linfócitos T/transplante , Transplante Homólogo , Vidarabina/administração & dosagem , Vidarabina/análogos & derivados , Vidarabina/uso terapêutico , Vimblastina/administração & dosagem , Vimblastina/uso terapêutico
11.
Cytotherapy ; 9(8): 755-70, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17917887

RESUMO

BACKGROUND: Cancer vaccines employing DC in their capacity as APC have been tolerated well and have shown some efficacy in clinical studies. IL-12, a cytokine critical for type 1 T-helper (Th1) lymphocyte and cytotoxic T-lymphocyte (CTL) differentiation, when released from a DC-based cancer vaccine, may support the generation of a cellular T-cell response. METHODS: We applied tumor cell lysate plus keyhole limpet hemocyanin (KLH)-loaded and 48-h lipopolysaccharide (LPS) plus IFN-gamma-stimulated fully mature DC, which do not release IL-12, subcutaneously to eight patients, and maximally 6-h stimulated semi-mature (sm) DC, which are potent producers of IL-12, subcutaneously (n=6) or intranodally (n=8) as a cancer vaccine to patients suffering from advanced solid pediatric malignancies. RESULTS: No serious adverse events were observed following application of IL-12-releasing smDC. Following immunization the majority of patients responded positively to KLH in a delayed-type hypersensitivity (DTH) test. In addition, three of six intranodally treated patients responded to the tumor Ag in the DTH test. DISCUSSION: We conclude that treatment with a DC-based cancer vaccine enabled to release the immune regulatory cytokine IL-12 is safe and feasible and has the potential to induce a cellular immune response in pediatric cancer patients.


Assuntos
Antígenos de Neoplasias/imunologia , Vacinas Anticâncer , Células Dendríticas/imunologia , Neoplasias/imunologia , Neoplasias/terapia , Vacinação , Adolescente , Adulto , Apresentação de Antígeno , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/uso terapêutico , Diferenciação Celular , Criança , Células Dendríticas/transplante , Feminino , Hemocianinas/imunologia , Humanos , Imunoterapia Adotiva , Injeções Intralinfáticas , Injeções Subcutâneas , Interferon gama/imunologia , Interleucina-12/imunologia , Interleucina-12/metabolismo , Lipopolissacarídeos/imunologia , Ativação Linfocitária , Masculino , Neoplasias/mortalidade , Resultado do Tratamento
12.
Leukemia ; 20(1): 9-17, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16281070

RESUMO

The International Acute Lymphoblastic Leukemia Working Group, the so-called 'Ponte di Legno Workshop' has led to substantial progress in international collaboration in leukemia research. On April 27-28, 2005, the 8th Meeting was held in Vienna, Austria, to continue the discussions about special common treatment elements in randomized clinical trials, ethical and clinical aspects of therapy. Furthermore, collaborative projects of clinical relevance with special emphasis on rare genetic subtypes of Childhood ALL were established. The following report summarizes the achievements and aspects of possible future cooperation.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Áustria , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco
13.
Leukemia ; 20(2): 187-92, 2006 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-16341042

RESUMO

A multicentric phase 2 study was conducted to determine the efficiency and the tolerance of imatinib mesylate in children with chronic myelogenous leukemia (CML) in advanced phase of the disease, in relapse after stem cell transplantation, or in case of failure to an interferon alpha-based regimen. In all, 30 children from eight European countries were enrolled. In 18 children assessable for hematologic response, imatinib mesylate induced complete hematologic response in eight (80%) of the 10 patients included in chronic phase and in six (75%) of eight enrolled in advanced phase of the disease with acceptable toxicity. In 27 patients assessable for cytogenetic response, imatinib mesylate induced disappearance of Philadelphia chromosome-positive bone marrow cells in 12 (60%) of 20 children included in chronic phase and in two (29%) of seven included in advanced phase. A reduction of the bcr-abl/abl ratio to less than 10(-4) was achieved in 11 (50%) of the children included in chronic phase. Estimated 12-month overall survival rate was 95% (95% CI, 87-100%) for the patients included in chronic phase and 75% (95%CI, 45-100%) for those enrolled in advanced phase. Imatinib mesylate is well tolerated and molecular remission can be achieved in children with CML.


Assuntos
Antineoplásicos/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Piperazinas/uso terapêutico , Pirimidinas/uso terapêutico , Transplante de Células-Tronco , Adolescente , Benzamidas , Criança , Pré-Escolar , Doença Crônica , Esquema de Medicação , Europa (Continente) , Feminino , Seguimentos , Humanos , Mesilato de Imatinib , Lactente , Masculino , Recidiva , Indução de Remissão , Taxa de Sobrevida , Resultado do Tratamento
14.
Bone Marrow Transplant ; 38(2): 119-26, 2006 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16820782

RESUMO

The results of a 5-year longitudinal prospective study about the health-related quality of life (HRQL) of pediatric patients receiving allogeneic bone marrow or stem cell transplantation (BMT) are described. The patients' HRQL was assessed twice before, and five times after BMT, the end point being 1 year after BMT. For the measurement of HRQL, standardized questionnaires were completed by patients, parents and physicians. The final sample consisted of 68 patients aged 4-18 years, of which 19 were lost in the course of the study owing to relapse, transplant rejection and/or death. The worst HRQL was seen shortly after transplant and HRQL thereafter improved steadily, although the improvement was not always linear and not all patients drew benefit from this average positive evolution. Compromised emotional functioning, a high level of worry and reduced communication during the acute phase of treatment had a negative impact on HRQL 1 year after BMT. Nausea and pain during the acute phase of treatment did not have an effect on later HRQL. The interobserver agreement of HRQL reports between parents and their children was moderate to good, and generally better than child-physician and parent-physician agreement.


Assuntos
Transplante de Medula Óssea , Avaliação de Resultados em Cuidados de Saúde , Qualidade de Vida , Transplante de Células-Tronco , Adolescente , Transplante de Medula Óssea/efeitos adversos , Transplante de Medula Óssea/estatística & dados numéricos , Criança , Pré-Escolar , Feminino , Humanos , Estudos Longitudinais , Masculino , Variações Dependentes do Observador , Estudos Prospectivos , Perfil de Impacto da Doença , Transplante de Células-Tronco/efeitos adversos , Transplante de Células-Tronco/estatística & dados numéricos , Transplante Homólogo
15.
Leukemia ; 19(12): 2030-42, 2005 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16304570

RESUMO

A total of 1111 children with acute myeloblastic leukaemia (AML) were treated in four consecutive Berlin-Frankfurt-Münster (BFM) studies from 1978 to 1998. The first cooperative trial AML-BFM 78 established intensive chemotherapy with seven drugs, CNS irradiation and 2-year maintenance, achieving a long-term survival (overall survival (OS)) of 40%. Induction intensification in AML-BFM 83 resulted in significant improvement of disease-free survival (DFS). The risk of haemorrhage, especially in children with hyperleukocytosis, proved the high relevance of supportive care. In AML-BFM 87, the benefit of CNS irradiation in preventing CNS/systemic relapses was demonstrated. In AML-BFM 93, the introduction of idarubicin during first induction followed by intensification with HAM increased the 5-year EFS, DFS and OS to 50+/-2, 61+/-3 and 57+/-2%, respectively. Stem cell transplantation (SCT), as applied in high-risk patients with a matched related donor, did not significantly improve the outcome compared to chemotherapy alone. In spite of treatment intensification, the therapy-related death rate decreased from trial to trial, mainly during induction. The future aim is to reduce long-term sequelae, especially cardiotoxicity, by administration of less cardiotoxic drugs, and toxicity of SCT by risk-adapted indications. The AML-BFM studies performed in three European countries with >70 cooperating centres have significantly improved the outcome in AML children; nevertheless, increasing experience with these intensive treatment regimens is of fundamental importance to reduce fatal complications.


Assuntos
Protocolos Antineoplásicos/normas , Leucemia Mieloide Aguda/terapia , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Pré-Escolar , Irradiação Craniana , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Transplante de Células-Tronco Hematopoéticas , Hemorragia/etiologia , Humanos , Lactente , Recém-Nascido , Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/mortalidade , Masculino , Indução de Remissão/métodos , Medição de Risco , Prevenção Secundária , Resultado do Tratamento
16.
Leukemia ; 19(7): 1145-52, 2005 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15902295

RESUMO

Between 1995 and 2004, six International Childhood Acute Lymphoblastic Leukemia (ALL) Workshop have been held, and the completion of several collaborative projects has established the clinical relevance and treatment options for several specific genetic subtypes of ALL. This meeting report summarizes the data presented in the seventh meeting and the discussion.


Assuntos
Neoplasia Residual/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Antineoplásicos/uso terapêutico , Criança , Coleta de Dados , Humanos , Itália , Fatores de Risco
17.
Cancer Res ; 61(16): 5992-7, 2001 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-11507040

RESUMO

EWS encodes a ubiquitously expressed RNA binding protein with largely unknown function. In Ewing sarcoma family tumors (EFT), one allele is rearranged with an ETS gene. This is the first description of an EFT with a complete EWS deficiency in the presence of two copies of a rearranged chromosome 22 carrying an interstitial EWS-FLI1 translocation. Absence of EWS protein suggested that it is dispensable for EFT growth. By sequencing of EWS cDNA from unrelated EFTs, we excluded inactivation of EWS as a general mechanism in EFT pathogenesis. Rather, EWS was found to be uniformly expressed in two splicing variants of similar abundancy, EWSalpha and EWSbeta, which differ in a single amino acid. Three EWS negative cell lines were established, which will serve as valuable models to study normal and aberrant EWS function upon reintroduction into the tumor cells.


Assuntos
Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Ribonucleoproteínas/genética , Sarcoma de Ewing/genética , Sarcoma de Ewing/patologia , Alelos , Processamento Alternativo , Divisão Celular/genética , Divisão Celular/fisiologia , Pré-Escolar , Cromossomos Humanos Par 22/genética , Feminino , Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Rearranjo Gênico , Inativação Gênica , Ribonucleoproteínas Nucleares Heterogêneas , Humanos , Proteínas de Fusão Oncogênica/genética , Proteína Proto-Oncogênica c-fli-1 , Proteína EWS de Ligação a RNA , Ribonucleoproteínas/fisiologia , Fatores de Transcrição/genética , Translocação Genética , Células Tumorais Cultivadas
18.
Oncogene ; 5(7): 1067-70, 1990 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-1695726

RESUMO

Ewing's Sarcoma (ES), the second most frequent bone tumor in childhood and adolescence, and the probably closely related peripheral primitive neuroectodermal tumor (pPNET) share a unique cytogenetic translocation between chromosomes 11 and 22. Both of them expose high amounts of a glycoprotein on their cell surface, which can be specifically detected by the mAb HBA-71. The cDNA coding for the HBA-71 antigen was isolated by screening a cDNA expression library constructed from a pPNET-derived cell line. Nucleotide sequencing revealed the HBA-71 antigen to be the product of the pseudoautosomal gene MIC2 previously identified by the mAb 12E7 in haematopoietic cells. This antigen is a glycoprotein with a molecular weight of about 29,000 and is expressed in low amounts in most human cell lines and probably normal tissues and tumors with only a few exceptions. In T-cells the antigen is involved in cell adhesion processes. In ES- and pPNET-derived cell lines MIC2 expression is significantly enhanced. No gross changes in posttranslational modification could be observed. The high expression results in easy and specific detection of the antigen in immunocytochemical analysis of paraffin embedded tissue sections making HBA-71 a useful tool in tumor diagnosis.


Assuntos
Antígenos CD , Antígenos de Neoplasias/genética , Moléculas de Adesão Celular/genética , Glicoproteínas de Membrana/metabolismo , Sarcoma de Ewing/genética , Antígeno 12E7 , Anticorpos Monoclonais/imunologia , Western Blotting , DNA/genética , Epitopos , Expressão Gênica , Humanos , Glicoproteínas de Membrana/genética , Peso Molecular , RNA Mensageiro/genética , RNA Neoplásico/genética
19.
Oncogene ; 8(10): 2683-90, 1993 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-8378080

RESUMO

The p53 and MDM2 genes are part of a physiological pathway frequently impaired in human cancer. With the exception of tumours occasionally associated with hereditary predisposition, childhood malignancies have not been studied in detail yet. This is the first report on the analysis of p53 and MDM2 in a group of non-hereditary paediatric neoplasms referred to as the Ewing tumours (ETs). Thirty-seven primary tumours and cell lines from 19 patients were screened for the presence of p53 mutations. Only 5% of the primary tumour specimens were found to carry an alteration within this gene. However, p53 mutations were 10-fold enriched in ET cell lines, thus indicating a selective growth advantage in vitro. Strikingly, five out of nine alterations detected were missense mutations within codon 273, which were previously reported to impair only partially the normal p53 function. Two single-base substitutions occurred at codons 277 and 176, and two alterations were loss-of-function mutations. Investigation of the MDM2 gene revealed neither gene amplification in the primary tumours and cell lines nor significant overexpression in any of the cell lines. Our data therefore suggest that impairment of cellular mechanisms involving p53 is rare in a distinct group of childhood malignancies.


Assuntos
Códon/genética , Éxons/genética , Genes p53/genética , Mutação/genética , Oncogenes/genética , Sarcoma de Ewing/genética , Sequência de Bases , Humanos , Dados de Sequência Molecular , Células Tumorais Cultivadas
20.
Oncogene ; 15(18): 2225-32, 1997 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-9393981

RESUMO

The pRB cell cycle regulatory cascade is frequently perturbed in neoplasia by overexpression of a component of the pRB-phosphorylating cyclin D1/CDK4 complex or by inactivation of pRB or the CDK4 inhibitors p16 and p15. We investigated the status and expression of p16, p15, CCND1, CDK4 and RB genes in the Ewing family of tumors. P16 loss was observed in 8 of 27 tumors (30%) and in 12 of 23 (52%) tumor cell lines from unrelated patients. There were no discrepancies in the p16 status between primary tumors and the corresponding cell lines and between cell lines established from consecutive tumor samples. p15 was codeleted in most cases but p15 mRNA was absent also in cell lines retaining the gene. In addition, posttranscriptional p16 inactivation was observed in two cases. Although no evidence for CDK4 or CCND1 amplification was obtained, expression of these genes varied considerably in the cell lines in a case specific manner. In wild-type p16 cell lines, pRB expression was lost in one case. Our data indicate that, despite the absence of cytogenetically detectable 9p21 chromosomal aberrations, p16 deletions constitute the most frequent secondary molecular aberration in Ewing tumors so far. These results are discussed in the context of the stage of disease and the clinical outcome of the patients. The potential prognostic impact of these findings remains to be further evaluated.


Assuntos
Proteínas de Ciclo Celular , Deleção de Genes , Genes p16 , Proteínas Proto-Oncogênicas , Proteína do Retinoblastoma/fisiologia , Sarcoma de Ewing/genética , Sarcoma de Ewing/patologia , Proteínas Supressoras de Tumor , Ciclo Celular/fisiologia , Ciclina D1/biossíntese , Quinase 4 Dependente de Ciclina , Inibidor de Quinase Dependente de Ciclina p15 , Inibidor p16 de Quinase Dependente de Ciclina/biossíntese , Quinases Ciclina-Dependentes/biossíntese , Expressão Gênica , Genes p53 , Humanos , Mutação , Prognóstico , Proteína do Retinoblastoma/biossíntese , Proteína do Retinoblastoma/genética , Sarcoma de Ewing/metabolismo , Fatores de Transcrição/biossíntese
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