Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 68
Filtrar
5.
Sci Rep ; 12(1): 10671, 2022 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-35739280

RESUMO

As the second most common pediatric bone and soft tissue tumor, Ewing sarcoma (ES) is an aggressive disease with a pathognomonic chromosomal translocation t(11;22) resulting in expression of EWS-FLI1, an "undruggable" fusion protein acting as transcriptional modulator. EWS-FLI1 rewires the protein expression in cancer cells by activating and repressing a multitude of genes. The role and contribution of most repressed genes remains unknown to date. To address this, we established a CRISPR activation system in clonal SKNMC cell lines and interrogated a custom focused library covering 871 genes repressed by EWS-FLI1. Among the hits several members of the TGFß pathway were identified, where PEG10 emerged as prime candidate due to its strong antiproliferative effect. Mechanistic investigations revealed that PEG10 overexpression caused cellular dropout via induction of cell death. Furthermore, non-canonical TGFß pathways such as RAF/MEK/ERK, MKK/JNK, MKK/P38, known to lead to apoptosis or autophagy, were highly activated upon PEG10 overexpression. Our study sheds new light onto the contribution of TGFß signalling pathway repression to ES tumorigenesis and suggest that its re-activation might constitute a novel therapeutic strategy.


Assuntos
Proteínas Reguladoras de Apoptose , Proteínas de Ligação a DNA , Tumores Neuroectodérmicos Primitivos Periféricos , Proteínas de Ligação a RNA , Sarcoma de Ewing , Proteínas Reguladoras de Apoptose/genética , Linhagem Celular Tumoral , Criança , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Proteínas de Ligação a DNA/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Proteína Proto-Oncogênica c-fli-1/genética , Proteína Proto-Oncogênica c-fli-1/metabolismo , Proteína EWS de Ligação a RNA/genética , Proteína EWS de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genética , Sarcoma de Ewing/patologia , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo
6.
Neoplasia ; 27: 100784, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35366465

RESUMO

Oncogenic transcription factors lacking enzymatic activity or targetable binding pockets are typically considered "undruggable". An example is provided by the EWS-FLI1 oncoprotein, whose continuous expression and activity as transcription factor are critically required for Ewing sarcoma tumor formation, maintenance, and proliferation. Because neither upstream nor downstream targets have so far disabled its oncogenic potential, we performed a high-throughput drug screen (HTS), enriched for FDA-approved drugs, coupled to a Global Protein Stability (GPS) approach to identify novel compounds capable to destabilize EWS-FLI1 protein by enhancing its degradation through the ubiquitin-proteasome system. The protein stability screen revealed the dual histone deacetylase (HDAC) and phosphatidylinositol-3-kinase (PI3K) inhibitor called fimepinostat (CUDC-907) as top candidate to modulate EWS-FLI1 stability. Fimepinostat strongly reduced EWS-FLI1 protein abundance, reduced viability of several Ewing sarcoma cell lines and PDX-derived primary cells and delayed tumor growth in a xenograft mouse model, whereas it did not significantly affect healthy cells. Mechanistically, we demonstrated that EWS-FLI1 protein levels were mainly regulated by fimepinostat's HDAC activity. Our study demonstrates that HTS combined to GPS is a reliable approach to identify drug candidates able to modulate stability of EWS-FLI1 and lays new ground for the development of novel therapeutic strategies aimed to reduce Ewing sarcoma tumor progression.


Assuntos
Sarcoma de Ewing , Animais , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Humanos , Camundongos , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Proteína Proto-Oncogênica c-fli-1/genética , Proteína Proto-Oncogênica c-fli-1/metabolismo , Proteína EWS de Ligação a RNA/genética , Proteína EWS de Ligação a RNA/metabolismo , Sarcoma de Ewing/tratamento farmacológico , Sarcoma de Ewing/patologia
7.
Cancer Immunol Immunother ; 71(6): 1371-1392, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34668039

RESUMO

Endemic Burkitt lymphoma (eBL) is an aggressive B cell cancer characterized by an IgH/c-myc translocation and the harboring of Epstein-Barr virus (EBV). Evidence accumulates that CD4 + T cells might contribute to eBL pathogenesis. Here, we investigate the presence of CD4 + T cells in primary eBL tissue and their potential dichotomous impact on an EBV-infected pre-eBL cell model using ex vivo material and in vitro co-cultures. In addition, we establish a novel method to study the effect of IgH/c-myc translocation in primary B cells by employing a CRISPR/Cas9 knock-in approach to introduce and tag de novo translocation. We unprecedently document that CD4 + T cells are present in primary eBL tumor tissue. Furthermore, we demonstrate that CD4 + T cells on the one hand suppress eBL development by killing pre-eBL cells lacking IgH/c-myc translocation in vitro and on the other hand indirectly promote eBL development by inducing crucial EBV Latency III to Latency I switching in pre-eBL cells. Finally, we show that while the mere presence of an IgH/c-myc translocation does not suffice to escape CD4 + T-cell-mediated killing in vitro, the CD4 + T-cell-mediated suppression of EBV's Latency III program in vivo may allow cells harboring an IgH/c-myc translocation and additional mutations to evade immune control and proliferate by means of deregulated c-myc activity, resulting in neoplasia. Thus, our study highlights the dichotomous effects of CD4 + T cells and the mechanisms involved in eBL pathogenesis, suggests mechanisms of their impact on eBL progression, and provides a novel in vitro model for further investigation of IgH/c-myc translocation.


Assuntos
Linfoma de Burkitt , Infecções por Vírus Epstein-Barr , Linfócitos B/metabolismo , Linfoma de Burkitt/genética , Sobrevivência Celular , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/genética , Herpesvirus Humano 4 , Humanos
8.
Nat Commun ; 11(1): 4629, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32934208

RESUMO

Cancer therapy is currently shifting from broadly used cytotoxic drugs to patient-specific precision therapies. Druggable driver oncogenes, identified by molecular analyses, are present in only a subset of patients. Functional profiling of primary tumor cells could circumvent these limitations, but suitable platforms are unavailable for most cancer entities. Here, we describe an in vitro drug profiling platform for rhabdomyosarcoma (RMS), using a living biobank composed of twenty RMS patient-derived xenografts (PDX) for high-throughput drug testing. Optimized in vitro conditions preserve phenotypic and molecular characteristics of primary PDX cells and are compatible with propagation of cells directly isolated from patient tumors. Besides a heterogeneous spectrum of responses of largely patient-specific vulnerabilities, profiling with a large drug library reveals a strong sensitivity towards AKT inhibitors in a subgroup of RMS. Overall, our study highlights the feasibility of in vitro drug profiling of primary RMS for patient-specific treatment selection in a co-clinical setting.


Assuntos
Antineoplásicos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Rabdomiossarcoma/metabolismo , Animais , Bancos de Espécimes Biológicos , Perfilação da Expressão Gênica , Humanos , Fenótipo , Inibidores de Proteínas Quinases , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Rabdomiossarcoma/tratamento farmacológico , Rabdomiossarcoma/genética , Células Tumorais Cultivadas/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Sci Rep ; 9(1): 951, 2019 01 30.
Artigo em Inglês | MEDLINE | ID: mdl-30700749

RESUMO

Ewing sarcoma is the second most common pediatric bone and soft tissue tumor presenting with an aggressive behavior and prevalence to metastasize. The diagnostic translocation t(22;11)(q24;12) leads to expression of the chimeric oncoprotein EWS-FLI1 which is uniquely expressed in all tumor cells and maintains their survival. Constant EWS-FLI1 protein turnover is regulated by the ubiquitin proteasome system. Here, we now identified ubiquitin specific protease 19 (USP19) as a regulator of EWS-FLI1 stability using an siRNA based screening approach. Depletion of USP19 resulted in diminished EWS-FLI1 protein levels and, vice versa, upregulation of active USP19 stabilized the fusion protein. Importantly, stabilization appears to be specific for the fusion protein as it could not be observed neither for EWSR1 nor for FLI1 wild type proteins even though USP19 binds to the N-terminal EWS region to regulate deubiquitination of both EWS-FLI1 and EWSR1. Further, stable shUSP19 depletion resulted in decreased cell growth and diminished colony forming capacity in vitro, and significantly delayed tumor growth in vivo. Our findings not only provide novel insights into the importance of the N-terminal EWSR1 domain for regulation of fusion protein stability, but also indicate that inhibition of deubiquitinating enzyme(s) might constitute a novel therapeutic strategy in treatment of Ewing sarcoma.


Assuntos
Endopeptidases/metabolismo , Proteínas de Fusão Oncogênica/metabolismo , Proteína Proto-Oncogênica c-fli-1/metabolismo , Proteína EWS de Ligação a RNA/metabolismo , Sarcoma de Ewing/metabolismo , Sarcoma de Ewing/patologia , Ubiquitinação , Animais , Proliferação de Células , Humanos , Camundongos , Modelos Biológicos , Proteínas de Fusão Oncogênica/química , Domínios Proteicos , Estabilidade Proteica , Proteína Proto-Oncogênica c-fli-1/química , RNA Interferente Pequeno/metabolismo , Proteína EWS de Ligação a RNA/química
10.
J Biol Chem ; 291(52): 26922-26933, 2016 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-27875302

RESUMO

E-26 transformation-specific (ETS) proteins are transcription factors directing gene expression through their conserved DNA binding domain. They are implicated as truncated forms or interchromosomal rearrangements in a variety of tumors including Ewing sarcoma, a pediatric tumor of the bone. Tumor cells express the chimeric oncoprotein EWS-FLI1 from a specific t(22;11)(q24;12) translocation. EWS-FLI1 harbors a strong transactivation domain from EWSR1 and the DNA-binding ETS domain of FLI1 in the C-terminal part of the protein. Although Ewing cells are crucially dependent on continuous expression of EWS-FLI1, its regulation of turnover has not been characterized in detail. Here, we identify the EWS-FLI1 protein as a substrate of the ubiquitin-proteasome system with a characteristic polyubiquitination pattern. Using a global protein stability approach, we determined the half-life of EWS-FLI1 to lie between 2 and 4 h, whereas full-length EWSR1 and FLI1 were more stable. By mass spectrometry, we identified two ubiquitin acceptor lysine residues of which only mutation of Lys-380 in the ETS domain of the FLI1 part abolished EWS-FLI1 ubiquitination and stabilized the protein posttranslationally. Expression of this highly stable mutant protein in Ewing cells while simultaneously depleting the endogenous wild type protein differentially modulates two subgroups of target genes to be either EWS-FLI1 protein-dependent or turnover-dependent. The majority of target genes are in an unaltered state and cannot be further activated. Our study provides novel insights into EWS-FLI1 turnover, a critical pathway in Ewing sarcoma pathogenesis, and lays new ground to develop novel therapeutic strategies in Ewing sarcoma.


Assuntos
Neoplasias Ósseas/metabolismo , Regulação Neoplásica da Expressão Gênica , Lisina/metabolismo , Proteínas Mutantes/metabolismo , Proteínas de Fusão Oncogênica/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteína Proto-Oncogênica c-fli-1/metabolismo , Proteína EWS de Ligação a RNA/metabolismo , Sarcoma de Ewing/metabolismo , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Células HEK293 , Humanos , Lisina/genética , Proteínas Mutantes/genética , Mutação/genética , Proteínas de Fusão Oncogênica/genética , Regiões Promotoras Genéticas , Proteólise , Proteína Proto-Oncogênica c-fli-1/genética , Proteína EWS de Ligação a RNA/genética , Sarcoma de Ewing/genética , Sarcoma de Ewing/patologia , Ubiquitinação
11.
Oncotarget ; 7(2): 1451-63, 2016 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-26623725

RESUMO

Ewing sarcomas (ES) are highly malignant bone or soft tissue tumors. Genetically, ES are defined by balanced chromosomal EWS/ETS translocations, which give rise to chimeric proteins (EWS-ETS) that generate an oncogenic transcriptional program associated with altered epigenetic marks throughout the genome. By use of an inhibitor (JQ1) blocking BET bromodomain binding proteins (BRDs) we strikingly observed a strong down-regulation of the predominant EWS-ETS protein EWS-FLI1 in a dose dependent manner. This was further enhanced by co-treatment with an inhibitor of the PI3K pathway. Microarray analysis further revealed JQ1 treatment to block a typical ES associated expression program. The effect on this expression program was mimicked by RNA interference with BRD3 or BRD4 expression, indicating that the EWS-FLI1 mediated expression profile is at least in part mediated via such epigenetic readers. Consequently, contact dependent and independent proliferation of different ES lines was strongly inhibited. Mechanistically, treatment of ES resulted in a partial arrest of the cell cycle as well as induction of apoptosis. Tumor development was suppressed dose dependently in a xeno-transplant model in immune deficient mice, overall indicating that ES may be susceptible to treatment with epigenetic inhibitors blocking BET bromodomain activity and the associated pathognomonic EWS-ETS transcriptional program.


Assuntos
Antineoplásicos/farmacologia , Azepinas/farmacologia , Neoplasias Ósseas/tratamento farmacológico , Proteínas Nucleares/antagonistas & inibidores , Proteínas de Fusão Oncogênica/metabolismo , Proteína Proto-Oncogênica c-fli-1/metabolismo , Proteína EWS de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/antagonistas & inibidores , Sarcoma de Ewing/tratamento farmacológico , Fatores de Transcrição/antagonistas & inibidores , Transcrição Gênica/efeitos dos fármacos , Triazóis/farmacologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Ciclo Celular/efeitos dos fármacos , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Regulação para Baixo , Epigênese Genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Terapia de Alvo Molecular , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas de Fusão Oncogênica/genética , Fosfatidilinositol 3-Quinase/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/farmacologia , Proteína Proto-Oncogênica c-fli-1/genética , Interferência de RNA , Proteína EWS de Ligação a RNA/genética , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Sarcoma de Ewing/genética , Sarcoma de Ewing/metabolismo , Sarcoma de Ewing/patologia , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Transfecção , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Pediatr Blood Cancer ; 63(10): 1731-6, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-26701148

RESUMO

BACKGROUND: Parameningeal rhabdomyosarcomas (PM-RMSs) represent approximately 25% of all rhabdomyosarcoma (RMS) cases. These tumors are associated with early recurrence and poor prognosis. This study assessed the clinical outcome and late toxicity of pencil beam scanning (PBS) proton therapy (PT) in the treatment of children with PM-RMS. PROCEDURES: Thirty-nine children with PM-RMS received neoadjuvant chemotherapy followed by PBS-PT at the Paul Scherrer Institute, with concomitant chemotherapy. The median age was 5.8 years (range, 1.2-16.1). Due to young age, 25 patients (64%) required general anesthesia during PT. The median time from the start of chemotherapy to PT was 13 weeks (range, 3-23 weeks). Median prescription dose was 54 Gy (relative biologic effectiveness, RBE). RESULTS: With a mean follow-up of 41 months (range, 9-106 months), 10 patients failed. The actuarial 5-year progression-free survival (PFS) was 72% (95% CI, 67-94%) and the 5-year overall survival was 73% (95% CI, 69-96%). On univariate analysis, a delay in the initiation of PT (>13 weeks) was a significant detrimental factor for PFS. Three (8%) patients presented with grade 3 radiation-induced toxicity. The estimated actuarial 5-year toxicity ≥grade 3 free survival was 95% (95% CI, 94-96%). CONCLUSIONS: Our data contribute to the growing body of evidence demonstrating the safety and effectiveness of PT for pediatric patients with PM-RMS. These preliminary results are encouraging and in line with other combined proton-photon and photons series; observed toxicity was acceptable.


Assuntos
Terapia com Prótons/métodos , Rabdomiossarcoma Embrionário/radioterapia , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Planejamento da Radioterapia Assistida por Computador , Eficiência Biológica Relativa , Rabdomiossarcoma Embrionário/mortalidade , Falha de Tratamento
13.
Oncotarget ; 6(30): 28895-910, 2015 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-26336820

RESUMO

Ewing sarcoma (ES) is the second most frequent bone cancer in childhood and is characterized by the presence of the balanced translocation t(11;22)(q24;q12) in more than 85% of cases, generating a dysregulated transcription factor EWS/FLI1. This fusion protein is an essential oncogenic component of ES development which is necessary for tumor cell maintenance and represents an attractive therapeutic target. To search for modulators of EWS/FLI1 activity we screened a library of 153 targeted compounds and identified inhibitors of the PI3K pathway to directly modulate EWS/FLI1 transcription. Surprisingly, treatment of four different ES cell lines with BEZ235 resulted in down regulation of EWS/FLI1 mRNA and protein by ~50% with subsequent modulation of target gene expression. Analysis of the EWS/FLI1 promoter region (-2239/+67) using various deletion constructs identified two 14 bp minimal elements as being important for EWS/FLI1 transcription. We identified SP1 as modulator of EWS/FLI1 gene expression and demonstrated direct binding to one of these regions in the EWS/FLI1 promoter by EMSA and ChIP experiments. These results provide the first insights on the transcriptional regulation of EWS/FLI1, an area that has not been investigated so far, and offer an additional molecular explanation for the known sensitivity of ES cell lines to PI3K inhibition.


Assuntos
Neoplasias Ósseas/enzimologia , Regulação Neoplásica da Expressão Gênica , Proteínas de Fusão Oncogênica/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Proteína Proto-Oncogênica c-fli-1/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteína EWS de Ligação a RNA/metabolismo , Sarcoma de Ewing/enzimologia , Transdução de Sinais , Fator de Transcrição Sp1/metabolismo , Transcrição Gênica , Antineoplásicos/farmacologia , Sítios de Ligação , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Imidazóis/farmacologia , Proteínas de Fusão Oncogênica/genética , Fosfatidilinositol 3-Quinase/genética , Inibidores de Fosfoinositídeo-3 Quinase , Regiões Promotoras Genéticas , Ligação Proteica , Inibidores de Proteínas Quinases/farmacologia , Proteína Proto-Oncogênica c-fli-1/genética , Quinolinas/farmacologia , Interferência de RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteína EWS de Ligação a RNA/genética , Sarcoma de Ewing/tratamento farmacológico , Sarcoma de Ewing/genética , Sarcoma de Ewing/patologia , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição Sp1/genética , Transcrição Gênica/efeitos dos fármacos , Transfecção
14.
PLoS One ; 9(7): e101696, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25020130

RESUMO

BACKGROUND: In children and adolescents with fever in neutropenia (FN) during chemotherapy for cancer, hemoglobin ≥90 g/L at presentation with FN had been associated with adverse events (AE). This analysis explored three hypothetical pathophysiological mechanisms potentially explaining this counterintuitive finding, and further analyzed the statistical association between hemoglobin and AE. METHODS: Two of 8 centers, reporting on 311 of 421 FN episodes in 138 of 215 patients participated in this retrospective analysis based on prospectively collected data from three databases (SPOG 2003 FN, transfusion and hematology laboratories). Associations with AE were analyzed using mixed logistic regression. RESULTS: Hemoglobin was ≥90 g/L in 141 (45%) of 311 FN episodes, specifically in 59/103 (57%) episodes with AE, and in 82/208 (39%) without (OR, 2.3; 99%CI, 1.1-4.9; P = 0.004). In FN with AE, hemoglobin was bimodally distributed with a dip around 85 g/L. There were no significant interactions for center, age and sex. In multivariate mixed logistic regression, AE was significantly and independently associated with leukopenia (leukocytes <0.3 G/L; OR, 3.3; 99%CI, 1.1-99; P = 0.004), dehydration (hemoglobinPresentation/hemoglobin8-72 hours ≥1.10 in untransfused patients; OR, 3.5; 99%CI, 1.1-11.4; P = 0.006) and non-moderate anemia (difference from 85 g/L; 1.6 per 10 g/L; 1.0-2.6; P = 0.005), but not with recent transfusion of packed red blood cells (pRBC), very recent transfusion of pRBC or platelets, or with hemoglobin ≥90 g/L as such. CONCLUSIONS: Non-moderate anemia and dehydration were significantly and relevantly associated with the risk of AE in children with cancer and FN. These results need validation in prospective cohorts before clinical implementation.


Assuntos
Antineoplásicos/efeitos adversos , Febre/etiologia , Hemoglobinas/análise , Neoplasias/tratamento farmacológico , Neutropenia/etiologia , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Modelos Logísticos , Masculino , Neoplasias/complicações , Estudos Retrospectivos , Risco
15.
Support Care Cancer ; 22(2): 339-49, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24081625

RESUMO

PURPOSE: We aimed to (1) describe the utilization of mental health-care in survivors and siblings, the association with severity of distress, and visits to other professionals in distressed survivors not utilizing mental health-care; and (2) identify factors associated with utilization of mental health-care in distressed survivors. METHODS: Within the Swiss Childhood Cancer Survivor Study, we sent postal questionnaires to all participants aged <16 years at diagnosis (1976-2003), who survived ≥5 years after diagnosis and were aged ≥16 years at study. Survivors and siblings could indicate if they utilized mental health-care in the past year. Psychological distress was assessed with the Brief Symptom Inventory-18 (BSI-18). Participants with scores T ≥ 57 on two of three scales or the Global Severity Index were considered distressed. RESULTS: We included 1,602 survivors and 703 siblings. Overall, 160 (10 %) and 53 (8 %), utilized mental health-care and 203 (14 %) and 127 (14 %) were considered distressed. Among these, 69 (34 %) survivors and 20 (24 %) siblings had utilized mental health-care. Participants with higher distress were more likely to utilize mental health-care. Distressed survivors not utilizing mental health-care were more likely to see a medical specialist than nondistressed. In the multivariable regression, factors associated with utilizing mental health-care were higher psychological distress and reporting late effects. CONCLUSIONS: Our results underline the importance of developing interventional programs and implementing psychological screening in follow-up of survivors. It is also important to systematically address siblings' needs. In follow-up, patients at risk should be informed about existing possibilities or advised to visit mental health professionals.


Assuntos
Serviços de Saúde Mental/estatística & dados numéricos , Neoplasias/psicologia , Sobreviventes/psicologia , Adolescente , Feminino , Humanos , Masculino , Transtornos Mentais/epidemiologia , Transtornos Mentais/etiologia , Saúde Mental , Pessoa de Meia-Idade , Neoplasias/epidemiologia , Irmãos , Estresse Psicológico/epidemiologia , Estresse Psicológico/etiologia , Inquéritos e Questionários , Suíça/epidemiologia
16.
Ann Surg ; 259(6): 1166-72, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24045440

RESUMO

OBJECTIVE: To analyze the clinical course, treatment, complications, outcome, and quality of life (QOL) in patients with perineal/perianal rhabdomyosarcoma (PRMS) treated within the CWS-86, -91, -96, and -2002P trials. BACKGROUND: Although multiple international study trials exist for the treatment of rhabdomyosarcoma, only very limited information is given on treatment, outcome, and QOL in PRMS. METHODS: A total of 35 patients suffering from PRMS were treated with neoadjuvant chemotherapy. Local therapy with radiation and/or surgery was performed, followed by adjuvant chemotherapy. Functional long-term follow-up was evaluated by a gastrointestinal/QOL survey. RESULTS: Thirty-two patients were evaluated (exclusion n = 3). Eight patients had embryonal histology, and 24 patients had alveolar histology. The median age was 108 months (median follow-up: 5.8 years). The 5-year overall survival was 47% (95% confidence interval: 29-64). Sixteen IRS (Intergroup Rhabdomyosarcoma Study) III and IV patients had locoregional lymph node involvement at diagnosis. Seven patients were treated with chemotherapy/surgery alone [5-year event-free survival (EFS): 85.7%]. Eleven patients received only radiochemotherapy (5-year EFS: 27.3%). Combined radiochemotherapy/surgery was used in 12 patients (5-year EFS: 63.6%). Two patients were treated only with chemotherapy and they died. Patients with embryonal histology had a significantly better 5-year EFS (87.5%) than patients with alveolar histology (39.1%; P = 0.013). Some patients reported symptoms of fecal incontinence. The median Wexner fecal incontinence score was 9 (possible range: 0-20), and the median QOL score was 90.5 (applicable range: 0-144). CONCLUSIONS: The outcome of these patients remains unsatisfactory. Prognostic factors for a favorable outcome are tumor size of smaller than 5 cm, negative locoregional lymph nodes, age less than 10 years, low IRS group, and embryonal histology. Fecal incontinence seems to be a problem.


Assuntos
Neoplasias Pélvicas/terapia , Qualidade de Vida , Rabdomiossarcoma/terapia , Canal Anal , Criança , Pré-Escolar , Terapia Combinada , Intervalo Livre de Doença , Feminino , Seguimentos , Alemanha/epidemiologia , Humanos , Masculino , Neoplasias Pélvicas/mortalidade , Períneo , Estudos Retrospectivos , Rabdomiossarcoma/mortalidade , Inquéritos e Questionários , Taxa de Sobrevida/tendências , Suíça/epidemiologia , Fatores de Tempo , Resultado do Tratamento
17.
Pediatr Blood Cancer ; 60(5): 799-805, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23193083

RESUMO

BACKGROUND: The definition of fever, and thus fever and neutropenia (FN), varies between different pediatric oncology centers. Higher temperature limit should reduce FN rates, but may increase rates of FN with complications by delaying therapy. This study determined if different fever definitions are associated with different FN rates. PROCEDURE: Two pediatric oncology centers had used three fever definitions in 2004-2011: ear temperature ≥38.5 °C persisting ≥2 hours (low definition); axillary temperature ≥38.5 °C ≥ 2 hours or ≥39.0 °C once (middle); and ear temperature ≥39.0 °C once (high). Clinical information was retrospectively extracted from charts. FN rates were compared using mixed Poisson regression. RESULTS: In 521 pediatric patients with cancer, 783 FN were recorded during 6,009 months cumulative chemotherapy exposure time (501 years; rate, 0.13/month [95% CI, 0.12-0.14]), 124 of them with bacteremia (16%; 0.021/month [0.017-0.025]). In univariate analysis, the high versus low fever definition was associated with a lower FN rate (0.10/month [0.08-0.11] vs. 0.15/month [0.13-0.16]; rate ratio, 0.66 [0.45-0.97]; P = 0.036), the middle definition was intermediate (0.13/month [0.11-0.15]). This difference was not confirmed in multivariate analysis (rate ratio, 0.94 [0.67-1.33]; P = 0.74). The high versus low definition was not associated with an increased rate of FN with bacteremia (multivariate rate ratio, 1.39 [0.53-3.62]; P = 0.50). CONCLUSION: A higher fever definition was not associated with a lower FN rate, nor with an increased rate of FN with bacteremia. These may be false negative findings due to methodological limitations. These questions, with their potential impact on health-related quality of life, and on costs, need to be assessed in prospective studies.


Assuntos
Febre/diagnóstico , Neoplasias/tratamento farmacológico , Neutropenia/diagnóstico , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bacteriemia/diagnóstico , Bacteriemia/tratamento farmacológico , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Febre/complicações , Febre/etiologia , Humanos , Lactente , Recém-Nascido , Masculino , Análise Multivariada , Neutropenia/complicações , Qualidade de Vida , Estudos Retrospectivos
18.
J Pediatric Infect Dis Soc ; 2(2): 155-61, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26619462

RESUMO

BACKGROUND: It is unknown whether serum concentrations of mannan-binding lectin (MBL) and MBL-associated serine protease-2 (MASP-2) influence the risk of adverse events (AEs) in children with cancer presenting with fever in neutropenia (FN). METHODS: Pediatric patients with cancer presenting with FN after non-myeloablative chemotherapy were observed in a prospective multicenter study. Mannan-binding lectin and MASP-2 were measured using commercially available enzyme-linked immunosorbent assay in serum taken at cancer diagnosis. Multiple FN episodes per patient were allowed. Associations of MBL and MASP-2 with AE in general, with bacteremia, and with serious medical complications (SMC) during FN were analyzed using mixed logistic regression. RESULTS: Of 278 FN episodes, AE was reported in 84 (30%), bacteremia was reported in 42 (15%), and SMC was reported in 16 (5.8%). Median MBL was 2152 ng/mL (range, 7-10 060). It was very low (<100) in 11 (9%) patients, low (100-999) in 36 (29%) patients, and normal (≥1000) in 79 (63%) patients. Median MASP-2 was 410 ng/mL (range, 68-2771). It was low (<200) in 18 (14%) patients and normal in the remaining 108 (86%) patients. Mannan-binding lectin and MASP-2 were not significantly associated with AE or bacteremia. Normal versus low MBL was independently associated with a significantly higher risk of SMC (multivariate odds ratio, 12.8; 95% confidence interval, 1.01-163; P = .050). CONCLUSIONS: Mannan-binding lectin and MASP-2 serum concentrations were not found to predict the risk to develop AEs or bacteremia during FN. Normal MBL was associated with an increased risk of SMC during FN. This finding, in line with earlier studies, does not support the concept of MBL supplementation in MBL-deficient children with cancer presenting with FN.

20.
PLoS One ; 7(5): e38015, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22662262

RESUMO

BACKGROUND: Relapses occur in about 20% of children with acute lymphoblastic leukemia (ALL). Approximately one-third of these children can be cured. Their risk for late effects is high because of intensified treatment, but their health-related quality of life (HRQOL) was largely unmeasured. Our aim was to compare HRQOL of ALL survivors with the general population, and of relapsed with non-relapsed ALL survivors. METHODOLOGY/PRINCIPAL FINDINGS: As part of the Swiss Childhood Cancer Survivor Study (SCCSS) we sent a questionnaire to all ALL survivors in Switzerland who had been diagnosed between 1976-2003 at age <16 years, survived ≥5 years, and were currently aged ≥16 years. HRQOL was assessed with the Short Form-36 (SF-36), which measures four aspects of physical health and four aspects of mental health. A score of 50 corresponded to the mean of a healthy reference population. We analyzed data from 457 ALL survivors (response: 79%). Sixty-one survivors had suffered a relapse. Compared to the general population, ALL survivors reported similar or higher HRQOL scores on all scales. Survivors with a relapse scored lower in general health perceptions (51.6) compared to those without (55.8;p=0.005), but after adjusting for self-reported late effects, this difference disappeared. CONCLUSION/SIGNIFICANCE: Compared to population norms, ALL survivors reported good HRQOL, even after a relapse. However, relapsed ALL survivors reported poorer general health than non-relapsed. Therefore, we encourage specialists to screen for poor general health in survivors after a relapse and, when appropriate, specifically seek and treat underlying late effects. This will help to improve patients' HRQOL.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras/psicologia , Qualidade de Vida , Sobreviventes/psicologia , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Recidiva , Inquéritos e Questionários , Suíça
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...