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1.
Cancer Radiother ; 23(3): 179-187, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31109839

RESUMO

PURPOSE: Medulloblastoma is the most common primary malignant central nervous system tumour in children. These last decades, treatment modalities have largely evolved resulting in better survival rates. Nevertheless, long-term toxicity is a major concern in this setting. The purpose of this study was to analyse the clinical results and medical outcomes of a cohort of paediatric patients treated for medulloblastoma in Xhinhua Hospital in Shanghai. These results are compared with those from other centres reported in literature. PATIENTS AND METHODS: This was a retrospective study conducted at Xhinhua Hospital in Shanghai, China. It included 121 patients treated for medulloblastoma from 1993 to December 2013. RESULTS: Mean age at diagnosis was 6.7 years (range: 1-14.3 years). Total surgical resection was achieved in 60% of the cases. Classic medulloblastoma was found in 59% of the cases. Adjuvant radiotherapy was delivered in all cases and chemotherapy concerned 70.2% of the studied cohort. The median follow-up time of the study was 84 months (range: 24-120 months). Five- and 10 years progression-free survival rates were 83.2%, and 69.5% and 5 years and 10 years. Overall survival rates were 82.5%, and 72.5%. Patient's age significantly influenced survival: patients under 3 years old had the worse outcomes (P=0.01). T and M stages also significantly impacted survival rates: advanced stages were associated with lower rates (P=0.08 and 0.05 respectively). Finally, patients receiving temezolomide had bad outcomes when compared to the new standard protocol used in the department (P=0.03). The most commonly reported late toxicity was growth suppression in 35 patients (52.2%). Hypothyroidism requiring hormone replacement was recorded in 29% of the cases. Hearing loss, and problems including poor concentration, poor memory and learning difficulties were reported in 19% and 25% of the cases respectively. Second cancers were noted in three cases. CONCLUSION: Overall, our results are comparable to those reported in literature. Nevertheless, efforts should be made to ensure longer follow-ups and correctly assess treatment-related toxicity.


Assuntos
Neoplasias Cerebelares/terapia , Meduloblastoma/terapia , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento
2.
J Clin Neurosci ; 64: 33-35, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30905661

RESUMO

BACKGROUND: To describe an exceptional case of late recurrence of medulloblastoma after 17 years of complete remission. CASE DESCRIPTION: A 42-year-old male consulted in ER for 10-day occipital headache. He had a previous history of cerebellar medulloblastoma 17 years ago treated with gross total resection, chemotherapy and radiotherapy. During his yearly follow-up he had maintained complete remission. MRi showed a cerebellar mass suggestive of medulloblastoma recurrence vs radio-induced tumor. Craniotomy and complete resection of the tumor was performed. The anatomopathological analysis confirmed the recurrence of medulloblastoma. The patient received high dose of adjuvant chemotherapy and he maintains complete remission after 18 months. CONCLUSION: Recurrence of medulloblastoma may occur despite more than 15 years of complete remission. Because of this fact it is mandatory to continue the follow-up of these patients. Aggressive management of recurrence is recommended in absence of disease dissemination.


Assuntos
Neoplasias Cerebelares/patologia , Meduloblastoma/patologia , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Adulto , Neoplasias Cerebelares/terapia , Quimiorradioterapia Adjuvante/métodos , Quimioterapia Adjuvante/métodos , Terapia Combinada/métodos , Humanos , Masculino , Meduloblastoma/terapia , Indução de Remissão
3.
Nat Commun ; 10(1): 332, 2019 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-30659187

RESUMO

Drugs that modify the epigenome are powerful tools for treating cancer, but these drugs often have pleiotropic effects, and identifying patients who will benefit from them remains a major clinical challenge. Here we show that medulloblastomas driven by the transcription factor Gfi1 are exquisitely dependent on the enzyme lysine demethylase 1 (Kdm1a/Lsd1). We demonstrate that Lsd1 physically associates with Gfi1, and that these proteins cooperate to inhibit genes involved in neuronal commitment and differentiation. We also show that Lsd1 is essential for Gfi1-mediated transformation: Gfi1 proteins that cannot recruit Lsd1 are unable to drive tumorigenesis, and genetic ablation of Lsd1 markedly impairs tumor growth in vivo. Finally, pharmacological inhibitors of Lsd1 potently inhibit growth of Gfi1-driven tumors. These studies provide important insight into the mechanisms by which Gfi1 contributes to tumorigenesis, and identify Lsd1 inhibitors as promising therapeutic agents for Gfi1-driven medulloblastoma.


Assuntos
Carcinogênese/efeitos dos fármacos , Neoplasias Cerebelares/patologia , Proteínas de Ligação a DNA/metabolismo , Histona Desmetilases/metabolismo , Meduloblastoma/patologia , Fatores de Transcrição/metabolismo , Animais , Antibióticos Antineoplásicos/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Neoplasias Cerebelares/genética , Neoplasias Cerebelares/terapia , Proteínas de Ligação a DNA/genética , Doxorrubicina/uso terapêutico , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Histona Desmetilases/genética , Humanos , Meduloblastoma/genética , Meduloblastoma/terapia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos SCID , Células NIH 3T3 , Transplante de Neoplasias , Vírus Oncogênicos , Retroviridae , Fatores de Transcrição/genética
4.
DNA Repair (Amst) ; 74: 70-79, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30606609

RESUMO

DSBs are harmful lesions produced through endogenous metabolism or by exogenous agents such as ionizing radiation, that can trigger genomic rearrangements. We have recently shown that exposure to 2 Gy of X-rays has opposite effects on the induction of Shh-dependent MB in NHEJ- and HR-deficient Ptch1+/- mice. In the current study we provide a comprehensive link on the role of HR/NHEJ at low doses (0.042 and 0.25 Gy) from the early molecular changes through DNA damage processing, up to the late consequences of their inactivation on tumorigenesis. Our data indicate a prominent role for HR in genome stability, by preventing spontaneous and radiation-induced oncogenic damage in neural precursors of the cerebellum, the cell of origin of MB. Instead, loss of DNA-PKcs function increased DSBs and apoptosis in neural precursors of the developing cerebellum, leading to killing of tumor initiating cells, and suppression of MB tumorigenesis in DNA-PKcs-/-/Ptch1+/- mice. Pathway analysis demonstrates that DNA-PKcs genetic inactivation confers a remarkable radiation hypersensitivity, as even extremely low radiation doses may deregulate many DDR genes, also triggering p53 pathway activation and cell cycle arrest. Finally, by showing that DNA-PKcs inhibition by NU7441 radiosensitizes human MB cells, our in vitro findings suggest the inclusion of MB in the list of tumors beneficiating from the combination of radiotherapy and DNA-PKcs targeting, holding promise for clinical translation.


Assuntos
Neoplasias Cerebelares/genética , Reparo do DNA/efeitos da radiação , Meduloblastoma/genética , Neoplasias Induzidas por Radiação/genética , Receptor Patched-1/deficiência , Receptor Patched-1/metabolismo , Animais , Carcinogênese/genética , Carcinogênese/efeitos da radiação , Linhagem Celular Tumoral , Neoplasias Cerebelares/metabolismo , Neoplasias Cerebelares/patologia , Neoplasias Cerebelares/terapia , Dano ao DNA , Reparo do DNA por Junção de Extremidades/efeitos da radiação , DNA Helicases/genética , Proteína Quinase Ativada por DNA/deficiência , Proteínas de Ligação a DNA/deficiência , Relação Dose-Resposta à Radiação , Recombinação Homóloga/efeitos da radiação , Humanos , Meduloblastoma/metabolismo , Meduloblastoma/patologia , Meduloblastoma/terapia , Camundongos , Terapia de Alvo Molecular , Mutação , Neoplasias Induzidas por Radiação/metabolismo , Neoplasias Induzidas por Radiação/patologia , Neoplasias Induzidas por Radiação/terapia , Proteínas Nucleares/deficiência , Proteínas Nucleares/genética , Risco , Raios X/efeitos adversos
6.
Neurologist ; 23(6): 191-193, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30379742

RESUMO

We describe a gentleman diagnosed with a posterior fossa medulloblastoma in 1998, successfully treated with craniospinal radiation therapy (RT) and posterior fossa RT boost, followed by 12 months of adjuvant chemotherapy. Nineteen years later, at the age of 28, the patient presented with multiple cranial neuropathies and was found to have disseminated high-grade glioma with leptomeningeal dissemination. In addition to the salient features of this case, we provide a brief review of RT-induced malignancies and the need for further research regarding surveillance and prevention strategies.


Assuntos
Neoplasias Encefálicas/terapia , Irradiação Craniana/efeitos adversos , Gerenciamento Clínico , Neoplasias Induzidas por Radiação/terapia , Adulto , Neoplasias Encefálicas/diagnóstico por imagem , Transtornos de Deglutição/diagnóstico por imagem , Transtornos de Deglutição/etiologia , Disartria/diagnóstico por imagem , Disartria/etiologia , Epilepsia/diagnóstico por imagem , Epilepsia/etiologia , Humanos , Imagem por Ressonância Magnética , Masculino , Meduloblastoma/diagnóstico por imagem , Meduloblastoma/terapia
7.
World Neurosurg ; 117: 344-349, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29966776

RESUMO

BACKGROUND: Lhermitte-Duclos disease is an extremely rare pathologic entity characterized by a cerebellar mass composed of enlarged cerebellar folia containing abnormal ganglion cells. This entity usually presents in young and middle-aged adults and rarely in children. There is no study in the literature analyzing the long-term clinical course of this disease to assess the behavior primarily because of its rarity. CASE DESCRIPTION: We present our experience with a 7-year-old patient of Lhermitte-Duclos disease who was followed up for 5 years and found to have progressed to bilateral World Health Organization grade IV medulloblastoma. This case denotes the malignant potential of this rare disorder. CONCLUSIONS: LDD is seen rarely and demands a high degree of suspicion in patients presenting with cerebellar mass and/or imaging characteristics. It is prudent to keep these patients in close follow-up for early detection of malignant transformation.


Assuntos
Neoplasias Cerebelares/fisiopatologia , Síndrome do Hamartoma Múltiplo/fisiopatologia , Meduloblastoma/fisiopatologia , Neoplasias Cerebelares/diagnóstico por imagem , Neoplasias Cerebelares/patologia , Neoplasias Cerebelares/terapia , Criança , Progressão da Doença , Síndrome do Hamartoma Múltiplo/diagnóstico por imagem , Síndrome do Hamartoma Múltiplo/tratamento farmacológico , Humanos , Masculino , Meduloblastoma/diagnóstico por imagem , Meduloblastoma/patologia , Meduloblastoma/terapia
8.
J Neurooncol ; 139(3): 713-720, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29869738

RESUMO

INTRODUCTION: Medulloblastoma is an aggressive but potentially curable central nervous system tumor that remains a treatment challenge. Analysis of therapeutic targets can provide opportunities for the selection of agents. METHODS: Using multiplatform analysis, 36 medulloblastomas were extensively profiled from 2009 to 2015. Immunohistochemistry, next generation sequencing, chromogenic in situ hybridization, and fluorescence in situ hybridization were used to identify overexpressed proteins, immune checkpoint expression, mutations, tumor mutational load, and gene amplifications. RESULTS: High expression of MRP1 (89%, 8/9 tumors), TUBB3 (86%, 18/21 tumors), PTEN (85%, 28/33 tumors), TOP2A (84%, 26/31 tumors), thymidylate synthase (TS; 80%, 24/30 tumors), RRM1 (71%, 15/21 tumors), and TOP1 (63%, 19/30 tumors) were found in medulloblastoma. TOP1 was found to be enriched in metastatic tumors (90%; 9/10) relative to posterior fossa cases (50%; 10/20) (p = 0.0485, Fisher exact test), and there was a positive correlation between TOP2A and TOP1 expression (p = 0.0472). PD-1 + T cell tumor infiltration was rare, PD-L1 tumor expression was uncommon, and TML was low, indicating that immune checkpoint inhibitors as a monotherapy should not necessarily be prioritized for therapeutic consideration based on biomarker expression. Gene amplifications such as those of Her2 or EGFR were not found. Several unique mutations were identified, but their rarity indicates large-scale screening efforts would be necessary to identify sufficient patients for clinical trial inclusion. CONCLUSIONS: Therapeutics are available for several of the frequently expressed targets, providing a justification for their consideration in the setting of medulloblastoma.


Assuntos
Neoplasias Cerebelares/genética , Neoplasias Cerebelares/terapia , Meduloblastoma/genética , Meduloblastoma/terapia , Adolescente , Adulto , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias Cerebelares/metabolismo , Neoplasias Cerebelares/patologia , Criança , Pré-Escolar , Feminino , Humanos , Neoplasias Infratentoriais/genética , Neoplasias Infratentoriais/metabolismo , Neoplasias Infratentoriais/patologia , Neoplasias Infratentoriais/terapia , Masculino , Meduloblastoma/metabolismo , Meduloblastoma/patologia , Pessoa de Meia-Idade , Medicina de Precisão , Adulto Jovem
9.
World Neurosurg ; 117: 25-31, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29883827

RESUMO

BACKGROUND: Medulloblastoma is a malignant tumor of the posterior fossa and is predominantly seen in children younger than 15 years of age. This tumor is uncommon in adults, especially those older than 40 years of age, and reports of cases in patients older than 60 years of age are particularly rare. Although surgery and radiotherapy play important roles in treatment of medulloblastoma in adults, addition of chemotherapy is controversial, especially prior to radiotherapy. CASE DESCRIPTION: We present a case of a 63-year-old woman with an atypical medulloblastoma in the cerebellum and a lesion in the suprasellar area that did not appear to be a metastasis of the medulloblastoma. The patient underwent a subtotal resection of the cerebellar medulloblastoma, which was classified histologically as classic subtype and molecularly as non-Wingless/non-Sonic hedgehog subtype in World Health Organization 2016 classification. Then she underwent postoperative chemotherapy followed by radiotherapy. We administered chemotherapy to facilitate therapeutic diagnosis of the suprasellar lesion. The combination treatment resulted in the disappearance of the cerebellar medulloblastoma with treatment toxicity well tolerated. Additionally, the suprasellar lesion remains under control. CONCLUSIONS: Even in adults over 60 years of age, medulloblastoma should be included in the differential diagnosis of a cerebellar mass. Chemotherapy for adult medulloblastoma has the potential to be efficacious and tolerable.


Assuntos
Neoplasias Cerebelares/diagnóstico , Neoplasias Cerebelares/terapia , Meduloblastoma/diagnóstico , Meduloblastoma/terapia , Neoplasias Cerebelares/patologia , Terapia Combinada , Diagnóstico Diferencial , Feminino , Humanos , Meduloblastoma/patologia , Pessoa de Meia-Idade
10.
Handb Clin Neurol ; 155: 289-299, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29891066

RESUMO

The cerebellum is the most common site of presentation of central nervous system tumors in children but exceedingly rare in adults. Children often present with acute symptoms related to increased intracranial pressure, requiring urgent surgical intervention. The differential diagnosis is broad and includes a variety of benign and malignant entities. Cerebellar low-grade gliomas are the most common and benign, slow-growing tumors, for which surgical resection alone is curative. Embryonal tumors, on the other hand - most commonly medulloblastomas - are highly aggressive and treatment includes intensive postsurgical radiotherapy and chemotherapy. Driven by multiple genomewide profiling studies, the field of neuro-oncology is making great strides towards understanding how different tumors develop and embarking on a new generation of molecularly informed clinical trials.


Assuntos
Neoplasias Cerebelares/terapia , Meduloblastoma/terapia , Antineoplásicos/uso terapêutico , Neoplasias Cerebelares/diagnóstico por imagem , Neoplasias Cerebelares/epidemiologia , Humanos , Imagem por Ressonância Magnética , Meduloblastoma/diagnóstico por imagem , Meduloblastoma/epidemiologia , Radioterapia/métodos
11.
Pediatr Hematol Oncol ; 35(1): 76-89, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29652554

RESUMO

BACKGROUND: Parent-reported attention problems have been associated with social functioning in a broad sample of pediatric cancer survivors. OBJECTIVE: The present study focused on a more homogeneous sample (pediatric medulloblastoma survivors), with the novel inclusion of self-reported attention ratings. PARTICIPANTS/METHODS: Thirty-three pediatric medulloblastoma survivors, ages 7-18 years, completed a brief IQ measure and self-report of attentional and social functioning. Parents rated patients' attentional and social functioning. RESULTS: Mean attention ratings were average based on both parent- and self-report, though parent ratings were significantly discrepant from normative means. No significant demographic or treatment-related predictors of self-reported attention problems were identified, whereas female gender was associated with greater parent-reported attention problems. Canonical correlation analysis revealed a significant association between parent-reported attention difficulties and social functioning in pediatric medulloblastoma survivors, but there was no association between self-reported attention problems and measures of social functioning. CONCLUSIONS: Consistent with existing literature in broader samples of pediatric cancer survivors, the present study further affirms attention deficits as an underlying contributor to social deficits in pediatric medulloblastoma survivors while also finding little relationship between self-reports of attention and social performance. Notably, present findings provide additional support suggesting that attention functioning is a more significant contributor to social outcomes for pediatric medulloblastoma survivors than the level of cognitive ability.


Assuntos
Atenção , Neoplasias Cerebelares/psicologia , Cognição , Meduloblastoma/psicologia , Comportamento Social , Adolescente , Neoplasias Cerebelares/terapia , Criança , Feminino , Humanos , Masculino , Meduloblastoma/terapia , Autorrelato , Fatores Sexuais
12.
PLoS One ; 13(3): e0194206, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29538458

RESUMO

Medulloblastoma (MB), the tumor of the cerebellum, is the most frequent brain cancer in childhood and a major cause of pediatric mortality. Based on gene profiling, four MB subgroups have been identified, i.e., Wnt or Sonic Hedgehog (Shh) types, and subgroup 3 or 4. The Shh-type MB has been shown to arise from the cerebellar precursors of granule neurons (GCPs), where a hyperactivation of the Shh pathway leads to their neoplastic transformation. We have previously shown that the gene Tis21 (PC3/Btg2) inhibits the proliferation and promotes the differentiation and migration of GCPs. Moreover, the overexpression or the deletion of Tis21 in Patched1 heterozygous mice, a model of spontaneous Shh-type MB, highly reduces or increases, respectively, the frequency of MB. Here we tested whether Tis21 can inhibit MB allografts. Athymic nude mice were subcutaneously grafted with MB cells explanted from Patched1 heterozygous mice. MB allografts were then injected with adeno-associated viruses either carrying Tis21 (AAV-Tis21) or empty (AAV-CBA). We observed that the treatment with AAV-Tis21 significantly inhibited the growth of tumor nodules, as judged by their volume, and reduced the number of proliferating tumor cells (labeled with Ki67 or BrdU), relative to AAV-CBA-treated control mice. In parallel, AAV-Tis21 increased significantly tumor cells labeled with early and late neural differentiation markers. Overall the results suggest that Tis21-gene therapy slows down MB tumor growth through inhibition of proliferation and enhancement of neural differentiation. These results validate Tis21 as a relevant target for MB therapy.


Assuntos
Proliferação de Células , Neoplasias Cerebelares , Dependovirus , Terapia Genética , Proteínas Imediatamente Precoces , Meduloblastoma , Neoplasias Experimentais , Proteínas Supressoras de Tumor , Aloenxertos , Animais , Linhagem Celular Tumoral , Neoplasias Cerebelares/genética , Neoplasias Cerebelares/metabolismo , Neoplasias Cerebelares/patologia , Neoplasias Cerebelares/terapia , Proteínas Imediatamente Precoces/genética , Proteínas Imediatamente Precoces/metabolismo , Meduloblastoma/genética , Meduloblastoma/metabolismo , Meduloblastoma/patologia , Meduloblastoma/terapia , Camundongos , Camundongos Nus , Transplante de Neoplasias , Neoplasias Experimentais/genética , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Neoplasias Experimentais/terapia , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo
13.
Radiother Oncol ; 127(1): 96-102, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29373196

RESUMO

BACKGROUND AND PURPOSE: The optimal treatment for adults with newly diagnosed medulloblastoma (MB) has not been defined. We report a large series of cases from the Rare Cancer Network. MATERIAL AND METHODS: Thirteen institutions enrolled 206 MB patients who underwent postoperative radiotherapy (RT) between 1976 and 2014. Log-rank univariate and Cox-modeled multivariate analyses were used to analyze data collected. RESULTS: Median patient age was 29 years; follow-up was 31 months. All patients had the tumor resected; surgery was complete in 140 (68%) patients. Postoperative RT was given in 202 (98%) patients, and 94% received craniospinal irradiation (CSI) and, usually, a posterior fossa boost. Ninety-eight (48%) patients had chemotherapy, mostly cisplatin and vincristine-based. The 10-year local control, overall survival, and disease-free survival rates were 46%, 51%, and 38%, respectively. In multivariate analyses, Karnofsky Performance Status (KPS) ≥80 and CSI were significant for disease-free and overall survival (P ≤ .04 for all); receiving chemotherapy and KPS ≥80 correlated with better local-control rates. CONCLUSIONS: Patients with high KPS who received CSI had better rates of disease-free and overall survival. Chemotherapy was associated with better local control. These results may serve as a benchmark for future studies designed to improve outcomes for adults with medulloblastoma.


Assuntos
Neoplasias Cerebelares/terapia , Meduloblastoma/terapia , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Cerebelares/mortalidade , Neoplasias Cerebelares/patologia , Neoplasias Cerebelares/cirurgia , Quimiorradioterapia Adjuvante , Cisplatino/administração & dosagem , Radiação Cranioespinal , Intervalo Livre de Doença , Europa (Continente)/epidemiologia , Feminino , Humanos , Masculino , Meduloblastoma/mortalidade , Meduloblastoma/patologia , Meduloblastoma/cirurgia , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Estudos Retrospectivos , Resultado do Tratamento , Estados Unidos/epidemiologia , Vincristina/administração & dosagem , Adulto Jovem
14.
Pediatr Blood Cancer ; 65(1)2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28905508

RESUMO

BACKGROUND: The purpose of this study was to determine the feasibility and tolerability of tandem courses of high-dose thiotepa with autologous hematopoietic cell rescue (AHCR) in patients with recurrent, refractory solid tumors who were ineligible for a single course of high-dose therapy due to greater than minimal residual disease. Patients with decreased hearing or poor renal function were eligible. PROCEDURE: Thiotepa was administered intravenously at a dose of 200 mg/m2 /day (6.67 mg/kg/day) daily for 3 days followed by AHCR. A second course of thiotepa was given 4 weeks later provided blood counts recovered sufficiently without evidence of tumor progression. RESULTS: Fifty-eight patients received 96 courses. Thirty-eight (65%) patients received two courses of therapy. Twenty-seven courses (28%) were administered completely in the outpatient setting. A toxic mortality rate of 3.4% was observed. Five of 26 patients with medulloblastoma were alive at a median of 35 months, whereas 21 patients died at a median of 11.7 months. Four of five patients with central nervous system germ cell tumors (CNS GCT) were alive 68-103 months following AHCR. CONCLUSIONS: Two cycles of high-dose thiotepa with AHCR were well tolerated even in these heavily pretreated patients. This therapy may provide prolonged survival in patients with recurrent malignant brain tumors, particularly medulloblastoma and CNS GCT.


Assuntos
Neoplasias Encefálicas , Transplante de Células-Tronco Hematopoéticas , Meduloblastoma , Tiotepa/administração & dosagem , Adolescente , Adulto , Autoenxertos , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/terapia , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Masculino , Meduloblastoma/mortalidade , Meduloblastoma/terapia , Taxa de Sobrevida , Tiotepa/efeitos adversos
15.
Tumori ; 104(1): 43-50, 2018 Jan-Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28777430

RESUMO

BACKGROUND: Medulloblastoma is the most common posterior fossa tumor in children and one that easily metastasizes. The mechanisms of how the medulloblastoma develops and progresses remain to be elucidated. The present study aimed to assess the role of long noncoding colon cancer-associated transcript-1 (lncRNA CCAT1) in cell proliferation and metastasis in human medulloblastoma. METHODS: Levels of CCAT1 were measured in samples and cell lines of medulloblastoma. Cell cycle progression, cell viability assay, colony formation assay, wound-healing and Transwell assays Corning, Cambridge, MA, USA were used to investigate the viability and motility of cells. Western blot assay was used to investigate the levels of CCAT1 and other proteins. RESULTS: The initial findings indicated that CCAT1 was significantly up-regulated in clinical cancerous tissues and expressed differently in a series of medulloblastoma cell lines. CCAT1 knockdown significantly slowed cell proliferation rates and inhibited cell clonogenic potential in Daoy cells and D283 cells. Cell cycle progression was disrupted with cell proportions in the G0/G1 phase decreased and the proportion in the S phase and G2/M phases increased, in Daoy cells and D283 cells. Concordantly, medulloblastoma tumor cell growth rates were found to be impaired in xenotransplanted mice. After CCAT1 knockdown, cell wound recovery ability was significantly inhibited. Furthermore, the phosphorylated levels of MAPK, ERK and MEK, but not their total levels decreased after the down-regulation of CCAT1 in Daoy and D283 cells. CONCLUSIONS: Our results suggested that the lncRNA CCAT1 promotes cell proliferation and metastasis in human medulloblastoma by possibly regulating the MAPK pathway.


Assuntos
Proliferação de Células/genética , Neoplasias Cerebelares/genética , Regulação Neoplásica da Expressão Gênica , Sistema de Sinalização das MAP Quinases/genética , Meduloblastoma/genética , RNA Longo não Codificante/genética , Animais , Linhagem Celular Tumoral , Neoplasias Cerebelares/patologia , Neoplasias Cerebelares/terapia , Humanos , Meduloblastoma/patologia , Meduloblastoma/terapia , Camundongos Nus , Metástase Neoplásica , Interferência de RNA , Terapêutica com RNAi/métodos , Carga Tumoral/genética , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
16.
Curr Neuropharmacol ; 16(7): 1045-1058, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29189165

RESUMO

BACKGROUND: Medulloblastoma is the most common malignant brain tumor in children, currently treated uniformly based on histopathology and clinico-radiological risk stratification leading to unpredictable relapses and therapeutic failures. Identification of molecular subgroups have thrown light on the reasons for these and now reveals clues to profile molecularly based personalized therapy against these tumors. METHODS: Research and online contents were evaluated for pediatric medulloblastoma which included latest information on the molecular subgroups and their clinical relevance and update on efforts to translate them into clinics. RESULTS: Scientific endeavors over the last decade have clearly identified four molecular variants (WNT, SHH, Group 3, and Group 4) and their demographic, genomic, and epigenetic profile. Latest revelations include significant heterogeneity within these subgroups and 12 different subtypes of MB are now identified with disparate outcomes and biology. These findings have important implications for stratification and profiling future clinical trials against these formidable tumors. CONCLUSION: With the continued outpouring of genomic/epigenomic data of these molecular subgroups and evolution of further subtypes in each subgroup, the challenge lies in comprehensive evaluation of these informations. Current and future endeavors are now needed to profile personalized therapy for each child based on the molecular risk stratification of medulloblastoma, with a hope to improve survival outcome and reduce relapses.


Assuntos
Neoplasias Encefálicas/terapia , Meduloblastoma/terapia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Criança , Humanos , Meduloblastoma/genética , Meduloblastoma/metabolismo
17.
Strahlenther Onkol ; 194(3): 225-234, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29147840

RESUMO

PURPOSE: Adult medulloblastoma is a rare disease treated according to the current pediatric treatment guidelines. This retrospective analysis investigated the clinical outcomes and prognostic factors of adult medulloblastoma patients, who received multimodal therapy at our institution. METHODS: Treatment charts of all patients over the age of 15 years of age with de novo medulloblastoma, who had been treated at our institution between 2001 and 2014, were retrospectively analyzed. Patients' demographic parameters, initial symptoms, treatment modalities, toxicities, and survival outcomes were investigated. RESULTS: In all, 21 patients with a median age of 30.2 years were identified. The most frequent histologies were desmoplastic and classic, and the most common molecular subtype was sonic hedgehog (SHH). After tumor resection, all patients received craniospinal irradiation (median dose 35.2 Gy) and a boost to the posterior fossa (median dose 19.8 Gy). Simultaneous chemotherapy with vincristine was given to 20 patients and sequential chemotherapy to 15 patients. The most common side effects were hematological toxicities. Median overall survival (OS) has not been reached after a median follow-up of 92 months. Estimated 5­ and 10-year OS was 89 and 80%, respectively. Estimated 5­ and 10-year progression-free survival (PFS) was 89 and 81%, respectively. In univariate analysis, a shorter interval between tumor resection and end of irradiation was significantly associated with improved OS and PFS, anaplastic histology with worse OS and PFS. CONCLUSIONS: The combined modality treatment showed a good outcome in adults with medulloblastoma. Treatment time was revealed to be prognostic and should be kept as short as possible.


Assuntos
Neoplasias Cerebelares/terapia , Terapia Combinada , Meduloblastoma/terapia , Adolescente , Adulto , Neoplasias Cerebelares/mortalidade , Neoplasias Cerebelares/patologia , Quimiorradioterapia Adjuvante , Radiação Cranioespinal , Craniotomia , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Meduloblastoma/mortalidade , Meduloblastoma/patologia , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto Jovem
18.
Rio de Janeiro; s.n; 2018. 91 f p. il.
Tese em Português | LILACS | ID: biblio-904966

RESUMO

Com o objetivo de contribuir para a tomada de decisão do processo de gestão de tecnologias no âmbito do SUS, foi desenvolvida neste trabalho, uma avaliação de custo efetividade que compare o uso do dexrazoxano em diferentes populações e o uso do acelerador de prótons com o de fótons para tratar crianças com meduloblastoma. O horizonte temporal de toda a vida do paciente e a perspectiva de análise do SUS, foram usados em ambos os estudos. Uma análise de impacto orçamentário para cada tecnologia também foi construída. Após uma busca na literatura, foi desenvolvido um modelo de Markov capaz de comparar o uso do dexrazoxano em 6 perfis de pacientes com risco de desenvolver cardiotoxicidade. Usar o medicamento nas crianças menores de 5 anos de idade se mostrou a alternativa mais custo-efetiva (ICER de R$6.156,96), seguido de usar em todos os pacientes (ICER de R$ 58.968,7). Caso o preço diminua a um valor menor que R$250,00 por frasco, a alternativa de usar em todas as crianças se torna a mais custo-efetiva. O impacto orçamentário ao final de 5 anos foi de R$30.622.404,81 para uso apenas nas crianças menores de 5 anos. Usar a tecnologia em todas as crianças, produziria um impacto incremental de R$ 94.352.898,77. Para avaliar o custo-efetividade do acelerador de prótons, foi desenvolvido um modelo de microssimulação comparando cenários de vida útil dos equipamentos e número de pacientes tratados. Como cenário base foi adotado os parâmetros de 50 pacientes com vida útil dos equipamentos de 20 anos. Para esse cenário, o ganho em QALY foi de 2,71 e o ICER médio de R$171.012,51/QALY. Para o limiar de disposição a pagar de 1 PIB percapita foi observado que a incorporação da tecnologia seria custo-efetiva, se fosse tratar a partir de 150 pacientes. A vida útil dos equipamentos e as outras variáveis tiveram participação limitada ao serem variadas na análise de sensibilidade, sem alterar significativamente as respostas do modelo. Ao final de 20 anos, o impacto orçamentário foi de R$ 345.598.440,91. O estudo recomenda a incorporação do dexrazoxano para crianças menores de 5 anos e não recomenda a incorporação do acelerador de prótons no tratamento do meduloblastoma em crianças


Assuntos
Humanos , Criança , Criança , Análise Custo-Benefício/economia , Dexrazoxano/uso terapêutico , Efetividade , Avaliação em Saúde/economia , Meduloblastoma/terapia , Aceleradores de Partículas , Avaliação da Tecnologia Biomédica/economia
19.
Trends Pharmacol Sci ; 38(12): 1061-1084, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29061299

RESUMO

Medulloblastoma (MB) is the most common childhood brain tumor, which occurs in the posterior fossa. MB tumors are highly heterogeneous and have diverse genetic make-ups, with differential microRNA (miRNA) expression profiles and variable prognoses. MB can be classified into four subgroups, each with different origins, pathogenesis, and potential therapeutic targets. miRNA and small-molecule targeted therapies have emerged as a potential new therapeutic paradigm in MB treatment. However, the development of chemoresistance due to surviving cancer stem cells and dysregulation of miRNAs remains a challenge. Combination therapies using multiple drugs and miRNAs could be effective approaches. In this review we discuss various MB subtypes, barriers, and novel therapeutic options which may be less toxic than current standard treatments.


Assuntos
Neoplasias Cerebelares/terapia , Meduloblastoma/terapia , Animais , Criança , Terapia Combinada , Modelos Animais de Doenças , Humanos
20.
CNS Oncol ; 6(4): 287-290, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28984140

RESUMO

Spinal cord involvement (SCI) is a rare feature of posterior reversible encephalopathy syndrome (PRES), especially in children. SCI is generally symptomatic, and may have a different outcome compared with encephalic localization of PRES. We reported about two cases of SCI in pediatric patients with PRES, after multimodal anticancer therapies, including radiotherapy, chemotherapy and targeted agents.


Assuntos
Síndrome da Leucoencefalopatia Posterior/patologia , Medula Espinal/patologia , Adolescente , Neoplasias Cerebelares/terapia , Criança , Feminino , Humanos , Masculino , Meduloblastoma/terapia
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