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1.
J Neurooncol ; 145(1): 177-184, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31522324

RESUMO

INTRODUCTION: Diffuse intrinsic pontine glioma (DIPG) is a rare clinically, neuro-radiologically, and molecularly defined malignancy of the brainstem with a median overall survival of approximately 11 months. Our aim is to evaluate the current tendency for its treatment in Europe in order to develop (inter)national consensus guidelines. METHODS: Healthcare professionals specialized in DIPG were asked to fill in an online survey with questions regarding usual treatment strategies at diagnosis and at disease progression in their countries and/or their centers, respectively. RESULTS: Seventy-four healthcare professionals responded to the survey, of which 87.8% were pediatric oncologists. Only 13.5% of the respondents biopsy all of their patients, 41.9% biopsy their patients infrequently. More than half of the respondents (54.1%) treated their patients with radiotherapy only at diagnosis, whereas 44.6% preferred radiotherapy combined with chemotherapy. When the disease progresses, treatment strategies became even more diverse, and the tendency for no treatment increased from 1.4% at diagnosis to 77.0% after second progression. 36.5% of the healthcare professionals treat children younger than 3 years differently than older children at diagnosis. This percentage decreased, when the disease progresses. Most of the participants (51.4%) included less than 25% of their patients in clinical trials. CONCLUSION: This survey demonstrates a large heterogeneity of treatment regimens, especially at disease progression. We emphasize the need for international consensus guidelines for the treatment of DIPG, possible by more collaborative clinical trials.

2.
Pediatr Blood Cancer ; 65(1)2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28792659

RESUMO

BACKGROUND: Diffuse intrinsic pontine gliomas (DIPGs) have a dismal prognosis. Previously, diagnosis was based on a typical clinical presentation and magnetic resonance imaging findings. After the start of the era of biopsies, DIPGs bearing H3 K27 mutations have been reclassified into a novel entity, diffuse midline glioma, based on the presence of this molecular alteration. However, it is not well established how clinically diagnosed DIPG overlap with H3 K27-mutated diffuse midline gliomas, and whether rare long-term survivors also belong to this group. METHODS: We studied tumor samples obtained at diagnosis or upon autopsy from 23 children, including two long-term survivors. Based on clinical, radiological, and histological findings, all tumors were previously diagnosed as DIPGs. All samples were analyzed for genetic alterations by next-generation sequencing (NGS) and for protein expression by immunohistochemistry (IHC). RESULTS: H3 K27 was mutated in NGS or IHC in 20 patients, excluding both long-term survivors. One of these long-term survivors harbored a mutation in IDH1, formerly considered to be an alteration absent in pediatric diffuse brainstem gliomas. Other altered genes in NGS included TP53 (10 patients), MET and PDGFRA (3 patients each), VEGFR and SMARCA4 (2 patients each), and PPARγ, PTEN and EGFR in 1 patient, respectively. IHC revealed cMYC expression in 15 of 24 (63%) of all samples, exclusively in the biopsies. CONCLUSIONS: Eighty-seven percent of the tumors formerly diagnosed as DIPGs could be reclassified as H3 K27-mutated diffuse midline gliomas. Both long-term survivors lacked this alteration. Contrary to former conceptions, IDH1 mutations may occur also in pediatric brainstem gliomas.


Assuntos
Regulação Neoplásica da Expressão Gênica , Glioma , Sequenciamento de Nucleotídeos em Larga Escala , Proteínas de Neoplasias , Proteínas do Tecido Nervoso , Adolescente , Biópsia , Neoplasias do Tronco Encefálico/genética , Neoplasias do Tronco Encefálico/metabolismo , Neoplasias do Tronco Encefálico/patologia , Criança , Pré-Escolar , Feminino , Glioma/genética , Glioma/metabolismo , Glioma/patologia , Humanos , Masculino , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/genética
3.
J Neurooncol ; 132(2): 255-266, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28110411

RESUMO

Diffuse intrinsic pontine glioma (DIPG) is a rare and deadly childhood malignancy. After 40 years of mostly single-center, often non-randomized trials with variable patient inclusions, there has been no improvement in survival. It is therefore time for international collaboration in DIPG research, to provide new hope for children, parents and medical professionals fighting DIPG. In a first step towards collaboration, in 2011, a network of biologists and clinicians working in the field of DIPG was established within the European Society for Paediatric Oncology (SIOPE) Brain Tumour Group: the SIOPE DIPG Network. By bringing together biomedical professionals and parents as patient representatives, several collaborative DIPG-related projects have been realized. With help from experts in the fields of information technology, and legal advisors, an international, web-based comprehensive database was developed, The SIOPE DIPG Registry and Imaging Repository, to centrally collect data of DIPG patients. As for April 2016, clinical data as well as MR-scans of 694 patients have been entered into the SIOPE DIPG Registry/Imaging Repository. The median progression free survival is 6.0 months (95% Confidence Interval (CI) 5.6-6.4 months) and the median overall survival is 11.0 months (95% CI 10.5-11.5 months). At two and five years post-diagnosis, 10 and 2% of patients are alive, respectively. The establishment of the SIOPE DIPG Network and SIOPE DIPG Registry means a paradigm shift towards collaborative research into DIPG. This is seen as an essential first step towards understanding the disease, improving care and (ultimately) cure for children with DIPG.


Assuntos
Neoplasias do Tronco Encefálico/diagnóstico por imagem , Glioma/diagnóstico por imagem , Serviços de Informação , Cooperação Internacional , Imagem por Ressonância Magnética , Sistema de Registros , Criança , Pré-Escolar , Europa (Continente) , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Ponte/diagnóstico por imagem , Adulto Jovem
4.
Acta Paediatr ; 105(8): 946-51, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26801815

RESUMO

AIM: Children with refractory or high-risk malignancies frequently suffer from poor quality of life during palliative care. This study explored the effect of metronomic drug administration on survival and quality of life in paediatric patients with various refractory or high-risk tumours. METHODS: We treated 17 patients with a maintenance therapy that consisted of metronomic thalidomide, etoposide and celecoxib. The endpoints of the study were overall and progression-free survival, changes in the Karnofsky-Lansky scores from baseline to the end of the study therapy and radiological responses. RESULTS: The median overall survival after the start of the study therapy was 6.2 months (range 2.0-57.7), and the six-, 12- and 24-month survival rates were 59%, 18% and 18%, respectively. The median progression-free survival was 3.2 months (range 0.3-17.8). The Karnofsky-Lansky scores increased significantly during the study therapy (p = 0.02), with 35% of the patients having a transient improvement in their clinical status. Radiologically, one partial response and two disease stabilisations were encountered. Grade III-V adverse events occurred in 76% of the patients. CONCLUSION: Metronomic therapy may increase the quality of life during palliative care for childhood cancer, but requires careful patient selection to minimise the risk of serious adverse events.


Assuntos
Neoplasias/tratamento farmacológico , Cuidados Paliativos , Seleção de Pacientes , Qualidade de Vida , Administração Metronômica , Criança , Feminino , Humanos , Avaliação de Estado de Karnofsky , Masculino , Neoplasias/mortalidade , Estudos Prospectivos
5.
Anticancer Res ; 25(4): 2873-8, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-16080540

RESUMO

BACKGROUND: Estramustine is an anti-mitotic cytostatic drug that also enhances the effect of radiotherapy. The mechanism of radiosensitization is not thoroughly known. Since both radiotherapy and estramustine induce apoptosis in prostate cancer cells, we conducted an experiment to show whether radiosensitization is mediated by apoptosis. MATERIALS AND METHODS: DU-145 human prostate cancer cells were xenografted to nude mice and treated with estramustine for 2 weeks and external radiation for 3 to 6 days (18 to 36 Gy). Tumor regression was measured mechanically and the rate of apoptosis defined by the amount of low molecular weight DNA fragmentation. Follow-up time was 1 to 18 days. RESULTS: The tumor size regressed in the group of mice receiving both radiotherapy and estramustine. Four weeks after the treatment, apoptosis was accentuated in the tumors treated with estramustine or radiation but not with their combination. CONCLUSION: Estramustine potentiates radiotherapy, but not by enhancing radiation-induced apoptosis.


Assuntos
Estramustina/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/radioterapia , Radiossensibilizantes/farmacologia , Animais , Antineoplásicos Hormonais/efeitos adversos , Antineoplásicos Hormonais/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Linhagem Celular Tumoral , Terapia Combinada , Fragmentação do DNA/efeitos dos fármacos , Fragmentação do DNA/efeitos da radiação , Estramustina/efeitos adversos , Humanos , Masculino , Camundongos , Camundongos Nus , Neoplasias da Próstata/patologia , Radiossensibilizantes/efeitos adversos , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Am J Pathol ; 166(3): 773-81, 2005 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-15743789

RESUMO

Early apoptosis-inducing events are potentially important targets for preventing germ cell loss caused by external stress. The sphingolipid sphingosine-1-phosphate (S1P) is an important regulator of stress-induced apoptosis. It affects the cell as an intracellular signaling molecule or as a ligand to its cell membrane-bound S1P(1-5) receptors. We previously demonstrated that S1P inhibits stress-induced male germ cell death in vitro and in vivo. Here, we further define the mechanisms of S1P-mediated inhibition of male germ cell death. Using immunohistochemistry, we detected expression of the S1P(1) and S1P(2) receptors in the somatic Sertoli cells of the human testis. In a culture of human seminiferous tubules, S1P inhibited germ cell apoptosis, suppressed both nuclear factor kappaB (NF-kappaB) DNA-binding activity and expression of phosphorylated Akt, but did not affect activator protein-1 (AP-1) DNA-binding activity. Dihydro-S1P, which binds to and activates S1P receptors but has no direct intracellular effect, suppressed neither apoptosis nor NF-kappaB activity. These results suggest that S1P inhibits male germ cell apoptosis independently of its receptors, possibly by inhibiting the transcription factor NF-kappaB and Akt phosphorylation.


Assuntos
Apoptose , Células Germinativas/patologia , Lisofosfolipídeos/fisiologia , NF-kappa B/metabolismo , Esfingosina/análogos & derivados , Esfingosina/fisiologia , Testículo/metabolismo , Idoso , Southern Blotting , Western Blotting , Morte Celular , Núcleo Celular/metabolismo , Citoplasma/metabolismo , DNA/metabolismo , Fragmentação do DNA , Ativação Enzimática , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Células Germinativas/metabolismo , Humanos , Proteínas I-kappa B/metabolismo , Imuno-Histoquímica , Ligantes , Lisofosfolipídeos/metabolismo , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Inibidor de NF-kappaB alfa , Fosforilação , Ligação Proteica , Túbulos Seminíferos/metabolismo , Transdução de Sinais , Esfingosina/metabolismo , Fatores de Tempo , Fator de Transcrição AP-1/metabolismo
7.
Fertil Steril ; 82 Suppl 3: 1077-85, 2004 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-15474077

RESUMO

OBJECTIVE: To investigate the effects of T, dihydrotestosterone (DHT), and 17beta-estradiol on human ovarian stromal tissue survival in culture and to identify steroids capable of inhibiting cell death in vitro. DESIGN: Prospective study. SETTING: Academic research setting. PATIENT(S): Thirty women, aged 18-38 years, undergoing gynecological operations for benign conditions and eight women, aged 27-36 years, undergoing IVF because of tubal obstruction or male factor infertility. INTERVENTION(S): Cultured tissue was exposed to T, DHT, 17beta-estradiol, or the anti-androgen casodex. MAIN OUTCOME MEASURE(S): Immunohistochemistry for androgen receptor (AR), Southern blot analysis of DNA fragmentation, histology, and in situ end labeling of apoptotic DNA. RESULT(S): Androgen receptors were detected in the ovarian stroma and granulosa cells of the primordial follicles, although they were more clearly seen in primary follicles and more advanced-stage follicles. Testosterone only marginally suppressed ovarian tissue apoptosis in vitro. DHT was more effective than T, whereas 17beta-estradiol had no notable effect on the viability of the tissue. The effects of androgens on the ovarian tissue may be mediated through ARs, since blocking the receptors with an AR antagonist reversed the suppressive effect of DHT. CONCLUSION(S): DHT may be useful for enhancing human ovarian tissue survival in vitro.


Assuntos
Di-Hidrotestosterona/farmacologia , Estradiol/farmacologia , Ovário/efeitos dos fármacos , Ovário/fisiologia , Testosterona/farmacologia , Adulto , Antagonistas de Androgênios/farmacologia , Antagonistas de Receptores de Andrógenos , Anilidas/farmacologia , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Técnicas de Cultura , Feminino , Células da Granulosa/efeitos dos fármacos , Células da Granulosa/fisiologia , Humanos , Nitrilos , Ovário/metabolismo , Estudos Prospectivos , Receptores Androgênicos/metabolismo , Sobrevivência de Tecidos/efeitos dos fármacos , Compostos de Tosil
8.
Mol Hum Reprod ; 10(10): 743-53, 2004 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-15299089

RESUMO

Apoptosis limits germ cell number in the testis, and its dysregulation is associated with male infertility. Here, we evaluated the role of the transcription factor activator protein 1 (AP-1) in male germ cell apoptosis in a culture of human seminiferous tubules. AP-1 DNA-binding activity increased in cultured tubules within 2.5 h, which was earlier than the onset of apoptosis as detected by caspase 3 activation and apoptotic DNA fragmentation. The c-Jun, c-Fos and JunD proteins were detected in the Sertoli cell nuclei, whereas apoptosis occurred in the germ cells. Follicle-stimulating hormone (FSH), whose receptors are expressed in the Sertoli cells, inhibited germ cell apoptosis and concomitantly suppressed AP-1 DNA-binding activity, but had no effect on nuclear factor kappaB (NF-kappaB) activation. These results suggest that AP-1 transcription factors are involved in the Sertoli cell-mediated control of germ cell apoptosis, and that inhibition of germ cell apoptosis by FSH appears to involve suppression of AP-1 activation.


Assuntos
Apoptose , Células Germinativas/fisiologia , Fator de Transcrição AP-1/metabolismo , Idoso , Idoso de 80 Anos ou mais , Animais , Caspase 3 , Caspases/metabolismo , Células Cultivadas , Fragmentação do DNA , Ativação Enzimática , Inibidores Enzimáticos/metabolismo , Hormônio Foliculoestimulante/metabolismo , Células Germinativas/citologia , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas c-fos/metabolismo , Proteínas Proto-Oncogênicas c-jun/metabolismo , Receptores Androgênicos/metabolismo , Túbulos Seminíferos/citologia , Túbulos Seminíferos/metabolismo
9.
J Clin Endocrinol Metab ; 88(11): 5572-9, 2003 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-14602806

RESUMO

It has been suggested that apoptosis is controlled by two intracellular sphingolipids, ceramide and sphingosine-1-phosphate (S1P), which are widely distributed in mammalian tissues. In the ovary, S1P was found to effectively block apoptosis caused by cancer therapies. Its role in male germ cell death, however, was unknown. In this study, we investigated the effects of ceramide and S1P on human male germ cell apoptosis. Germ cell death was induced by incubation of segments of seminiferous tubules in vitro. During apoptosis, ceramide levels increased rapidly before appearance of caspase 3 activation and DNA laddering, suggesting a role for ceramide in the induction of germ cell death. Ceramide appeared to regulate an early step of apoptosis because n-acetyl-L-cysteine and blockade of mitochondrial respiration inhibited apoptosis but had no effect on ceramide levels. Moreover, fumonisin B1 (ceramide synthetase inhibitor) did not significantly affect testicular apoptosis. Therefore, elevated ceramide levels are likely to result from breakdown of sphingomyelin rather than from de novo synthesis. Finally, we found that S1P at 1 and 10 micromol/liter suppressed germ cell apoptosis by 30% (P < 0.001). Taken together, sphingolipids appear to play a role in male germ cell apoptosis and can partly be inhibited by S1P.


Assuntos
Apoptose/efeitos dos fármacos , Lisofosfolipídeos , Espermatócitos/citologia , Esfingosina/análogos & derivados , Esfingosina/farmacologia , Respiração Celular/efeitos dos fármacos , Respiração Celular/fisiologia , Células Cultivadas , Ceramidas/metabolismo , Inibidores Enzimáticos/farmacologia , Fumonisinas/farmacologia , Humanos , Técnicas In Vitro , Masculino , Mitocôndrias/metabolismo , Oxirredutases/antagonistas & inibidores , Cianeto de Potássio/farmacologia , Túbulos Seminíferos/citologia , Espermatócitos/efeitos dos fármacos , Esfingomielina Fosfodiesterase/metabolismo
11.
Am J Pathol ; 160(1): 205-18, 2002 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-11786414

RESUMO

Apoptotic cell death plays an important role in limiting testicular germ cell population during spermatogenesis and its dysregulation has been shown to be associated with male infertility. The growing evidence on the role of the transcription factor nuclear factor (NF)-kappa B in controlling apoptosis prompted us to investigate NF-kappa B activity in the normal human testis and its role in testis tissue undergoing excessive apoptosis in vitro. In electrophoretic mobility shift assays, low-level constitutive NF-kappa B DNA-binding activity was found and, by immunostaining of the RelA and p50 NF-kappa B subunits, was localized to Sertoli cell nuclei. During in vitro-induced testicular apoptosis, the Sertoli cell nuclear NF-kappa B levels and whole seminiferous tubule NF-kappa B DNA-binding activity increased previous detection of germ cells undergoing apoptosis. The anti-inflammatory drug sulfasalazine effectively suppressed stress-induced NF-kappa B DNA binding and NF-kappa B-mediated I kappa B alpha gene expression. Importantly, concomitantly with inhibiting NF-kappa B, sulfasalazine blocked germ cell apoptosis. These results suggest that during testicular stress Sertoli cell NF-kappa B proteins exert proapoptotic effects on germ cells, which raises the possibility that pharmacological inhibition of NF-kappa B could be a therapeutic target in transient stress situations involving excessive germ cell death.


Assuntos
Apoptose/fisiologia , NF-kappa B/fisiologia , Neoplasias Testiculares/fisiopatologia , Idoso , Apoptose/efeitos dos fármacos , Núcleo Celular/metabolismo , DNA/metabolismo , Proteína Ligante Fas , Humanos , Técnicas In Vitro , Masculino , Glicoproteínas de Membrana/metabolismo , Pessoa de Meia-Idade , NF-kappa B/antagonistas & inibidores , Células de Sertoli/fisiologia , Espermatozoides/fisiologia , Sulfassalazina/farmacologia , Testículo/metabolismo
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