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2.
World Neurosurg ; 132: 57, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31479784

RESUMO

Radiation-induced telangiectasia of the central nervous system has been described predominantly in children, with up to 20% of patients affected after 3-41 years of radiotherapy.1,2 We present the case of a 45-year-old male with a pontine pilocytic astrocytoma treated with standard-dose radiation for 6 weeks in 1993. He developed a 3-cm multicystic, hemorrhagic brainstem lesion but was asymptomatic. The lesion caused severe brainstem mass effect, compatible with cavernous malformation or capillary telangiectasia.3 It has been reported that cavernomas and capillary telangiectasias share a similar pathologic process.4,5 The patient was surgically treated with a supracerebellar infratentorial approach to diagnose the hemorrhagic component of the lesion and ensure there was no transformation of the pilocytic astrocytoma (Video 1). He was placed in a gravity-dependent supine position with the head flexed and turned to allow for natural relaxation of the cerebellum via gravity-a technique we previously described.6 Surgical treatment proceeded with a left suboccipital craniotomy to decompress the cyst and facilitate removal of the intraaxial lesion. We took care to avoid injuring the fourth and fifth cranial nerves and branches of the superior cerebellar artery. No further lesional tissue was seen in the resection cavity. Interestingly, the final pathologic diagnosis indicated a mix of both pilocytic astrocytoma and radiation-induced capillary telangiectasia. From the surgeon's perspective, capillary telangiectasias appear similar to cavernous malformations on gross inspection, so pathologic confirmation is essential. Postoperative imaging demonstrated total resection of the lesion. The patient was discharged on postoperative day 3 with no neurologic deficit.


Assuntos
Astrocitoma/radioterapia , Neoplasias do Tronco Encefálico/radioterapia , Malformações Vasculares do Sistema Nervoso Central/cirurgia , Ponte/cirurgia , Lesões por Radiação/cirurgia , Astrocitoma/patologia , Neoplasias do Tronco Encefálico/patologia , Malformações Vasculares do Sistema Nervoso Central/etiologia , Malformações Vasculares do Sistema Nervoso Central/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Ponte/patologia , Lesões por Radiação/etiologia , Lesões por Radiação/patologia , Radioterapia/efeitos adversos
3.
World Neurosurg ; 129: 200-201, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31426252

RESUMO

Only few case reports of intradural extramedullary-located cavernous angiomas are available. This report describes an extra-axial hemorrhagic lesion located on the lateral surface of the medulla oblongata at the foramen magnum. Follow-up magnetic resonance imaing clearly demonstrated growth of the lesion, probably due to repetitive intralesional hemorrhaging. Initially, a right vertebral artery aneurysm or an arteriovenous malformation was suspected. Digital subtraction angiography excluded these differential diagnoses, although doubt remained concerning the possibility of a thrombosed aneurysm. Preoperatively, the lesion did not had the typical macroscopical aspect of a cavernoma and appeared rather as an expansive encapsulated multicystic vascular lesion. Nevertheless, pathologic analysis confirmed the diagnosis of a cavernous hemangioma. Complete microsurgical resection was obtained without neurologic impairment.


Assuntos
Neoplasias do Tronco Encefálico/cirurgia , Hemangioma Cavernoso do Sistema Nervoso Central/cirurgia , Bulbo/cirurgia , Neoplasias do Tronco Encefálico/patologia , Feminino , Forame Magno/patologia , Forame Magno/cirurgia , Hemangioma Cavernoso do Sistema Nervoso Central/patologia , Humanos , Bulbo/patologia , Pessoa de Meia-Idade
4.
Nat Commun ; 10(1): 3790, 2019 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-31439867

RESUMO

Pediatric high-grade gliomas are among the deadliest of childhood cancers due to limited knowledge of early driving events in their gliomagenesis and the lack of effective therapies available. In this study, we investigate the oncogenic role of PPM1D, a protein phosphatase often found truncated in pediatric gliomas such as DIPG, and uncover a synthetic lethal interaction between PPM1D mutations and nicotinamide phosphoribosyltransferase (NAMPT) inhibition. Specifically, we show that mutant PPM1D drives hypermethylation of CpG islands throughout the genome and promotes epigenetic silencing of nicotinic acid phosphoribosyltransferase (NAPRT), a key gene involved in NAD biosynthesis. Notably, PPM1D mutant cells are shown to be sensitive to NAMPT inhibitors in vitro and in vivo, within both engineered isogenic astrocytes and primary patient-derived model systems, suggesting the possible application of NAMPT inhibitors for the treatment of pediatric gliomas. Overall, our results reveal a promising approach for the targeting of PPM1D mutant tumors, and define a critical link between oncogenic driver mutations and NAD metabolism, which can be exploited for tumor-specific cell killing.


Assuntos
Antineoplásicos/farmacologia , Neoplasias do Tronco Encefálico/genética , Nicotinamida Fosforribosiltransferase/genética , Proteína Fosfatase 2C/genética , Animais , Antineoplásicos/uso terapêutico , Neoplasias do Tronco Encefálico/tratamento farmacológico , Neoplasias do Tronco Encefálico/patologia , Linhagem Celular Tumoral , Criança , Citocinas/antagonistas & inibidores , Metilação de DNA , /patologia , Repressão Epigenética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Nicotinamida Fosforribosiltransferase/antagonistas & inibidores , Nicotinamida Fosforribosiltransferase/metabolismo , Ponte/citologia , Ponte/patologia , Cultura Primária de Células , Proteína Fosfatase 2C/metabolismo , Mutações Sintéticas Letais , Ensaios Antitumorais Modelo de Xenoenxerto
5.
World Neurosurg ; 130: 400-404, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31326640

RESUMO

BACKGROUND: Intracranial solitary fibrous tumor (SFT) is a rare occurrence and involvement of the fourth ventricle rarely reported. Because of its rarity, some characteristics of intracranial SFT seem to still remain uncertain. CASE DESCRIPTION: This study describes a very rare case of intracranial SFT in a 55-year-old woman who presented with gait disturbance and numbness in bilateral upper limbs from 3 months before visiting the hospital. Head magnetic resonance imaging scan revealed a homogeneously enhancing mass lesion located primarily in the fourth ventricle extending into the spinal canal and left foramen of Luschka, with a maximum diameter of 60 mm. Notably, this tumor presented spontaneous partial regression during waiting planned surgery without therapy, including chemotherapy and radiotherapy. This patient underwent a midline suboccipital craniotomy and resection of the tumor. Interestingly, there was no attachment to the dura mater of the posterior cranial fossa and the lesion was only attached to the dorsal part of the medulla oblongata. CONCLUSIONS: Although the location of the SFT in the fourth ventricle is rare, SFT should be considered as 1 of the differential diagnosis of fourth ventricle tumors. In addition, this case indicates that SFT in the fourth ventricle may regress on occasion spontaneously without a precisely known cause for this spontaneous partial regression.


Assuntos
Neoplasias do Tronco Encefálico/patologia , Bulbo/patologia , Tumores Fibrosos Solitários/patologia , Neoplasias do Tronco Encefálico/cirurgia , Craniotomia/métodos , Feminino , Humanos , Imagem por Ressonância Magnética , Bulbo/cirurgia , Pessoa de Meia-Idade , Neoplasia Residual/cirurgia , Doenças Raras , Remissão Espontânea , Tumores Fibrosos Solitários/cirurgia
6.
Oncogene ; 38(38): 6479-6490, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31324890

RESUMO

Diffuse intrinsic pontine glioma (or DIPG) are pediatric high-grade gliomas associated with a dismal prognosis. They harbor specific substitution in histone H3 at position K27 that induces major epigenetic dysregulations. Most clinical trials failed so far to increase survival, and radiotherapy remains the most efficient treatment, despite only transient tumor control. We conducted the first lentiviral shRNA dropout screen in newly diagnosed DIPG to generate a cancer-lethal signature as a basis for the development of specific treatments with increased efficacy and reduced side effects compared to existing anticancer therapies. The analysis uncovered 41 DIPG essential genes among the 672 genes of human kinases tested, for which several distinct interfering RNAs impaired cell expansion of three different DIPG stem-cell cultures without deleterious effect on two control neural stem cells. Among them, PLK1, AURKB, CHEK1, EGFR, and GSK3A were previously identified by similar approach in adult GBM indicating common dependencies of these cancer cells and pediatric gliomas. As expected, we observed an enrichment of genes involved in proliferation and cell death processes with a significant number of candidates belonging to PTEN/PI3K/AKT and EGFR pathways already under scrutiny in clinical trials in this disease. We highlighted VRK3, a gene involved especially in cell cycle regulation, DNA repair, and neuronal differentiation, as a non-oncogenic addiction in DIPG. Its repression totally blocked DIPG cell growth in the four cellular models evaluated, and induced cell death in H3.3-K27M cells specifically but not in H3.1-K27M cells, supporting VRK3 as an interesting and promising target in DIPG.


Assuntos
Neoplasias do Tronco Encefálico/genética , Fosfotransferases/genética , Proteínas Serina-Treonina Quinases/fisiologia , RNA Interferente Pequeno/fisiologia , Análise de Sequência de RNA/métodos , Neoplasias do Tronco Encefálico/diagnóstico , Neoplasias do Tronco Encefálico/patologia , Sobrevivência Celular/genética , Células Cultivadas , /patologia , Genes Essenciais , Células HEK293 , Humanos , Fosfatidilinositol 3-Quinases/análise , Fosfatidilinositol 3-Quinases/genética , Fosfotransferases/análise , Prognóstico , Proteínas Serina-Treonina Quinases/análise , Proteínas Serina-Treonina Quinases/genética , RNA Interferente Pequeno/análise
7.
Pediatr Blood Cancer ; 66(9): e27881, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31207154

RESUMO

BACKGROUND: There are very few studies about the role of repeat irradiation (RT2) for children with recurrent supratentorial high-grade glioma (HGG). It was the aim of this study to assess the effectiveness and safety of RT2 in this population. PROCEDURE: This was a retrospective cohort study of 40 children age 18 years and under with recurrent supratentorial HGG who had received at least one course of RT. In-field reirradiation volumes included focal or whole brain RT, with doses ranging from 30 to 54 Gy. The primary endpoint was overall survival (OS) from the first day of RT2. RESULTS: Fourteen patients underwent RT2. The median survival of these patients was 6.5 months. Patients with ≥12 months elapsed time between RT1 and RT2 experienced longer OS than patients who had < 12 months (P = 0.009). There was no difference in OS between patients with or without germline mutations (e.g., Lynch, Li-Fraumeni, or constitutional mismatch-repair deficiency, P = 0.20). Ten patients received RT2 that overlapped with RT1 volumes for locally recurrent disease. Of this group, 80% experienced clinical benefit from in-field RT2, defined as clinical/radiologic response or stable disease. Ninety-three percent completed the prescribed course of RT2, with one patient developing grade 3 radiation necrosis four months after RT2. When compared with 26 patients who were not offered reirradiation, those selected for RT2 had improved median survival from the time of first disease progression (9.4 vs 3.8 months, P = 0.005). CONCLUSIONS: Reirradiation for children with recurrent supratentorial HGG is a safe, effective treatment that provides short-term disease control.


Assuntos
Neoplasias do Tronco Encefálico/mortalidade , Neoplasias do Tronco Encefálico/radioterapia , Glioma/mortalidade , Glioma/radioterapia , Reirradiação , Adolescente , Neoplasias do Tronco Encefálico/genética , Neoplasias do Tronco Encefálico/patologia , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Seguimentos , Glioma/genética , Glioma/patologia , Humanos , Masculino , Estudos Retrospectivos , Taxa de Sobrevida
8.
World Neurosurg ; 128: 230-233, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31082554

RESUMO

BACKGROUND: Pilocytic astrocytoma is a benign glial tumor typically presenting in children. It is rare for adults to present with pilocytic astrocytoma and even less likely to manifest with multiple foci of lesions especially in nonoptic or hypothalamic locations. CASE DESCRIPTION: Our patient was a 37-year old man presenting with varied cranial neuropathies, cerebellar dysfunction, and long tract signs, with imaging demonstrating 3 discrete ill-defined contrast-enhancing lesions affecting the cerebellar peduncles, brainstem, and cervicomedullary junction. Neuronavigation-guided biopsy confirmed World Health Organization grade 1 pilocytic astrocytoma; the patient was treated with radiotherapy. CONCLUSIONS: To our knowledge, we believe this is the first reported case with multifocal infratentorial pilocytic astrocytoma on presentation in an adult patient in the absence of a prior history of associated risk factors such as neurofibromatosis 1 or chemoradiotherapeutic intervention.


Assuntos
Astrocitoma/diagnóstico por imagem , Neoplasias Infratentoriais/diagnóstico por imagem , Neoplasias Primárias Múltiplas/diagnóstico por imagem , Adulto , Astrocitoma/patologia , Astrocitoma/radioterapia , Neoplasias do Tronco Encefálico/diagnóstico por imagem , Neoplasias do Tronco Encefálico/patologia , Neoplasias do Tronco Encefálico/radioterapia , Neoplasias Cerebelares/diagnóstico por imagem , Neoplasias Cerebelares/patologia , Neoplasias Cerebelares/radioterapia , Humanos , Biópsia Guiada por Imagem , Neoplasias Infratentoriais/patologia , Neoplasias Infratentoriais/radioterapia , Imagem por Ressonância Magnética , Masculino , Neoplasias Primárias Múltiplas/patologia , Neoplasias Primárias Múltiplas/radioterapia , Neuronavegação , Radioterapia
9.
Nat Commun ; 10(1): 2235, 2019 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-31138805

RESUMO

Pediatric high-grade glioma (pHGG) and diffuse intrinsic pontine gliomas (DIPGs) are aggressive pediatric brain tumors in desperate need of a curative treatment. Oncolytic virotherapy is emerging as a solid therapeutic approach. Delta-24-RGD is a replication competent adenovirus engineered to replicate in tumor cells with an aberrant RB pathway. This virus has proven to be safe and effective in adult gliomas. Here we report that the administration of Delta-24-RGD is safe in mice and results in a significant increase in survival in immunodeficient and immunocompetent models of pHGG and DIPGs. Our results show that the Delta-24-RGD antiglioma effect is mediated by the oncolytic effect and the immune response elicited against the tumor. Altogether, our data highlight the potential of this virus as treatment for patients with these tumors. Of clinical significance, these data have led to the start of a phase I/II clinical trial at our institution for newly diagnosed DIPG (NCT03178032).


Assuntos
Adenoviridae , Neoplasias do Tronco Encefálico/terapia , Glioma/terapia , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos , Animais , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , Neoplasias do Tronco Encefálico/patologia , Linhagem Celular Tumoral , Sobrevivência Celular , Simulação por Computador , Modelos Animais de Doenças , Glioma/patologia , Humanos , Técnicas In Vitro , Camundongos , Gradação de Tumores , Ensaios Antitumorais Modelo de Xenoenxerto
10.
BMJ Case Rep ; 12(4)2019 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-30996066

RESUMO

Brainstem gliomas are rare tumours in adults, accounting for only 1%-2% of all intracranial gliomas. They are recognised as a heterogeneous group, in which most are malignant tumours. Brainstem gliomas are classified into four major groups according to the growth pattern on imaging, namely diffuse, focal, exophytic and cervicomedullary. Such a classification system is also useful for surgical decision making. The exophytic variant is extremely rare having anecdoctal reports in the literature. We report the case of an adult patient affected by an exophytic glioblastoma of the pons, which was submitted to subtotal resection followed by radiation therapy and chemotherapy with a longer overall survival. To the best of our knowledge, this is the seventh adult patient reported of an exophytic brainstem glioblastoma.


Assuntos
Neoplasias do Tronco Encefálico/patologia , Tronco Encefálico/patologia , Doenças dos Nervos Cranianos/diagnóstico por imagem , Glioblastoma/diagnóstico por imagem , Neuroimagem , Ponte/patologia , Tronco Encefálico/diagnóstico por imagem , Neoplasias do Tronco Encefálico/diagnóstico por imagem , Neoplasias do Tronco Encefálico/terapia , Quimiorradioterapia , Doenças dos Nervos Cranianos/etiologia , Doenças dos Nervos Cranianos/fisiopatologia , Evolução Fatal , Glioblastoma/patologia , Glioblastoma/terapia , Humanos , Hidrocefalia/fisiopatologia , Hemorragias Intracranianas/fisiopatologia , Masculino , Pessoa de Meia-Idade , Procedimentos Neurocirúrgicos/métodos , Ponte/diagnóstico por imagem , Fatores de Tempo
11.
Pediatr Hematol Oncol ; 36(2): 103-112, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30978130

RESUMO

Objectives: Diffusion-weighted magnetic resonance imaging (DW-MRI) offers potential to monitor response and predict survival in high-grade gliomas (HGG) and diffuse intrinsic pontine gliomas (DIPG). We hypothesized that post-radiotherapy DW-MRI may provide prognostic imaging biomarkers in children and young adults with these tumors. Methods: Patients aged ≤21 years diagnosed between 2005 and 2012 were eligible. The tumor median apparent diffusion coefficient (ADC) and its 5th percentile (C5-ADC) were determined at the first post-radiotherapy scan and at the time of radiological progression. DW-MRI parameters were correlated with survival endpoints, temozolomide use and pseudoprogression, when it occurred. Results: Out of 40 patients (20 HGG, 20 DIPG), 23 had evaluable DW-MRI post-radiotherapy and 25 at radiological progression. There were 6 episodes of pseudoprogression. Hazard ratios (95%CI) for progression-free survival were 0.998 (0.993-1.003) for median ADC and 1.003 (0.996-1.010) for C5-ADC. Hazard ratios (95%CI) for overall survival were 1.0009 (0.996-1.006) for median ADC and 0.998 (0.992-1.004) for C5-ADC. Post-radiotherapy median and C5-ADC values were not significantly different between patients treated with radiotherapy alone versus radiotherapy/temozolomide. The median and C5-ADC values were not significantly different at the time of pseudoprogression compared to those at tumor progression. Conclusions: Post-radiotherapy median ADC and C5-ADC were not prognostic, nor able to differentiate radiosensitization with temozolomide or occurrence of pseudoprogression in this cohort of HGG and DIPG patients. Further exploration of alternative DW parameters, study timepoints or data modeling may contribute to the development of prognostic/predictive imaging biomarkers for children and young adults with HGG or DIPG.


Assuntos
Neoplasias Encefálicas/radioterapia , Imagem de Difusão por Ressonância Magnética , Glioma/radioterapia , Substância Branca/patologia , Adolescente , Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Neoplasias do Tronco Encefálico/tratamento farmacológico , Neoplasias do Tronco Encefálico/mortalidade , Neoplasias do Tronco Encefálico/patologia , Neoplasias do Tronco Encefálico/radioterapia , Criança , Pré-Escolar , Terapia Combinada , Difusão , Progressão da Doença , Feminino , Glioma/tratamento farmacológico , Glioma/mortalidade , Glioma/patologia , Humanos , Masculino , Prognóstico , Modelos de Riscos Proporcionais , Temozolomida/uso terapêutico , Adulto Jovem
12.
Pediatr Neurosurg ; 54(3): 151-164, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30947221

RESUMO

BACKGROUND/AIMS: Large population-based studies are needed to assess the epidemiology and survival risk factors associated with pediatric brainstem gliomas. This retrospective study explores factors that may influence survival in this population. METHODS: Utilizing the SEER database, the authors retrospectively assessed survival in histologically confirmed brainstem gliomas in patients aged 17 and younger. Survival was described with Kaplan-Meyer curves and multivariate regression analysis. RESULTS: This analysis of 180 cases showed that age (hazard ratio [HR] 1.04, 95% CI 0.96-1.14, p = 0.34), non-white race (HR 1.00, 95% CI 0.35-2.85 p > 0.99), distant or invasive extension of the tumor (HR 0.4, 95% CI 0.08-2.53, p = 0.37), and radiation therapy (HR 1.27, 95% CI 0.52-3.11, p = 0.61) were not associated with decreased survival. High-grade tumor status (HR 8.64, 95% CI 3.49-21.41, p < 0.001) was associated with decreased survival. Partial resection (HR 0.11, 95% CI 0.04-0.30, p < 0.001) and gross-total resection (HR 0.03, 95% CI 0.01-0.14, p < 0.001) were associated with improved survival. CONCLUSIONS: High-grade brainstem gliomas have a worse prognosis. Early diagnosis and surgery appear to be associated with improved survival, while the role of radiation is unclear.


Assuntos
Astrocitoma/mortalidade , Neoplasias do Tronco Encefálico/mortalidade , Tronco Encefálico/cirurgia , Glioma/mortalidade , Programa de SEER , Análise de Sobrevida , Astrocitoma/patologia , Astrocitoma/cirurgia , Neoplasias do Tronco Encefálico/patologia , Neoplasias do Tronco Encefálico/cirurgia , Criança , Bases de Dados Factuais , Feminino , Glioma/patologia , Glioma/cirurgia , Humanos , Masculino , Pediatria , Estudos Retrospectivos
13.
Intern Med ; 58(6): 849-854, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30880301

RESUMO

Primary central nervous system lymphoma (PCNSL) and chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) can share clinical features and may be indistinguishable, even after brain biopsy. We encountered a case of Epstein-Barr virus-positive (EBV+) PCNSL recurrence in a patient with clinical features of CLIPPERS, and repeat brain biopsy was required to reach the correct diagnosis. Four years after the initial diagnosis and treatment of PCNSL, "peppering" punctate enhanced lesions with transient steroid responsiveness were detected during brain magnetic resonance imaging (MRI). A second brain biopsy supported a diagnosis of CLIPPERS, while a third biopsy confirmed the diagnosis of recurrent PCNSL.


Assuntos
Neoplasias do Tronco Encefálico/tratamento farmacológico , Neoplasias do Tronco Encefálico/genética , Neoplasias do Sistema Nervoso Central/genética , Herpesvirus Humano 4/genética , Inflamação/genética , Linfoma/genética , Metilprednisolona/uso terapêutico , Adulto , Antineoplásicos/uso terapêutico , Neoplasias do Tronco Encefálico/patologia , Neoplasias do Sistema Nervoso Central/patologia , Doença Crônica , Herpesvirus Humano 4/patogenicidade , Humanos , Inflamação/patologia , Linfócitos/efeitos dos fármacos , Linfócitos/patologia , Linfoma/patologia , Masculino , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Resultado do Tratamento
14.
Zhonghua Bing Li Xue Za Zhi ; 48(3): 192-198, 2019 Mar 08.
Artigo em Chinês | MEDLINE | ID: mdl-30831644

RESUMO

Objective: To analyze the clinicopathological characteristics and prognosis of diffuse midline glioma (DMG) with H3K27M mutation. Methods: Thirty cases of DMG were collected in Guangdong Sanjiu Brain Hospital from October 2016 to May 2018. The patients' clinicopathological data including age, tumor site and histological grade, treatment and follow-up data were collected and analyzed. Results: There were 21 males and 9 females, with a mean age of 26 years (range 5-53 years). Fourteen tumors were located in thalamus, 12 in brainstem (one involved both thalamus and brainstem), and one each in hypothalamus, fourth ventricle, and sellar region, respectively. Two cases presented as diffuse intracranial lesions. Three cases (10.0%) were of WHO grade Ⅰ, 10 cases (33.3%) were grade Ⅱ, eight cases (26.7%) were grade Ⅲ, and nine cases (30.0%) were grade Ⅳ.All patients with gradeⅠ tumors were older than 20 years. Histologically, all were pilocytic astrocytoma-like. Immunohistochemical staining demonstrated that all tumors were IDH1 negative. Twenty-eight tumors showed diffuse expression of H3K27M, and two showed focal expression. Twenty-one tumors(100.0%, 21/21) showed absent expression of H3K27me3. Sixteen tumors (57.1%, 16/28) showed strongly positive expression of p53, and ATRX was negative in eight tumors (38.1%, 8/21). The Ki-67 proliferation index ranged from 5% to 40%. Eight cases (including two cases of H3K27M expression of individual cells) showed K27M mutation in H3F3A gene. Intracranial and spinal cord dissemination occurred in six cases (20.0%, 6/30). Median progression-free survival (PFS) was 9.5 months and median overall survival (OS) was 34 months. Mean PFS was 11.2 months and mean OS was 24.3 months. Compared with adults (>20 years old), children/adolescents (no more than 20 years old) had significantly shorter median OS (8 months vs. 34 months, P=0.013). There was no significant difference in PFS and OS between DMGs located in the brain stem/thalamus and other sites within midline (P>0.05). There was no significant difference in PFS and OS between WHO grade ⅠDMGs and WHO grade Ⅱ-Ⅳ DMGs (P>0.05). Conclusions: DMGs occur more commonly in children and adolescents with male predominance. DMGs present with WHO Ⅰ-Ⅳ tumors morphologically, and pilocytic astrocytoma-like lesions with WHO Ⅰ are more common in adults. Expression of H3K27M but not H3K27me3 is helpful for diagnosis of DMG. The prognosis of children/adolescents is significantly worse than that of adults, whereas histological grade and tumor location do not affect prognosis.


Assuntos
Neoplasias Encefálicas/enzimologia , Glioma/enzimologia , Histona Desmetilases com o Domínio Jumonji/genética , Mutação , Adolescente , Adulto , Fatores Etários , Astrocitoma/química , Astrocitoma/enzimologia , Astrocitoma/mortalidade , Astrocitoma/patologia , Neoplasias Encefálicas/química , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Neoplasias do Tronco Encefálico/química , Neoplasias do Tronco Encefálico/enzimologia , Neoplasias do Tronco Encefálico/patologia , Criança , Pré-Escolar , Feminino , Glioma/química , Glioma/mortalidade , Glioma/patologia , Histonas/genética , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Tálamo , Adulto Jovem
15.
Nat Commun ; 10(1): 1023, 2019 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-30833574

RESUMO

Diffuse intrinsic pontine glioma (DIPG) is an incurable pediatric brain tumor, with approximately 25% of DIPGs harboring activating ACVR1 mutations that commonly co-associate with H3.1K27M mutations. Here we show that in vitro expression of ACVR1 R206H with and without H3.1K27M upregulates mesenchymal markers and activates Stat3 signaling. In vivo expression of ACVR1 R206H or G328V with H3.1K27M and p53 deletion induces glioma-like lesions but is not sufficient for full gliomagenesis. However, in combination with PDGFA signaling, ACVR1 R206H and H3.1K27M significantly decrease survival and increase tumor incidence. Treatment of ACVR1 R206H mutant DIPGs with exogenous Noggin or the ACVR1 inhibitor LDN212854 significantly prolongs survival, with human ACVR1 mutant DIPG cell lines also being sensitive to LDN212854 treatment. Together, our results demonstrate that ACVR1 R206H and H3.1K27M promote tumor initiation, accelerate gliomagenesis, promote a mesenchymal profile partly due to Stat3 activation, and identify LDN212854 as a promising compound to treat DIPG.


Assuntos
Receptores de Ativinas Tipo I/metabolismo , Astrocitoma/metabolismo , Neoplasias do Tronco Encefálico/metabolismo , Genoma Humano/genética , Glioma/metabolismo , Histonas/metabolismo , Receptores de Ativinas Tipo I/genética , Animais , Astrocitoma/tratamento farmacológico , Astrocitoma/genética , Astrocitoma/patologia , Neoplasias do Tronco Encefálico/tratamento farmacológico , Neoplasias do Tronco Encefálico/genética , Neoplasias do Tronco Encefálico/patologia , Proteínas de Transporte/farmacologia , Linhagem Celular Tumoral/efeitos dos fármacos , Proliferação de Células , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/genética , Glioma/tratamento farmacológico , Glioma/genética , Glioma/patologia , Histonas/genética , Humanos , Camundongos , Mutação , Fator de Crescimento Derivado de Plaquetas/metabolismo , Pirazóis/farmacologia , Pirimidinas/farmacologia , Quinolinas/farmacologia , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais
16.
J Neurooncol ; 143(1): 49-56, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30852713

RESUMO

INTRODUCTION: Diffuse intrinsic pontine glioma (DIPG) is a high fatality pediatric brain cancer without effective treatment. The field of electrotherapeutics offers new potential for other forms of glioma but the efficacy of this strategy has not been reported for DIPG. This pilot study evaluated the susceptibility of patient-derived DIPG cells to low intensity electric fields delivered using a developing technology called intratumoral modulation therapy (IMT). METHODS: DIPG cells from autopsy specimens were treated with a custom-designed, in vitro IMT system. Computer-generated electric field simulation was performed to quantify IMT amplitude and distribution using continuous, low intensity, intermediate frequency stimulation parameters. Treatment groups included sham, IMT, temozolomide (TMZ) chemotherapy and radiation therapy (RT). The impact of single and multi-modality therapy was compared using spectrophotometric and flow cytometry viability analyses. RESULTS: DIPG cells exhibited robust, consistent susceptibility to IMT fields that significantly reduced cell viability compared to untreated control levels. The ratio of viable:non-viable DIPG cells transformed from ~ 6:1 in sham-treated to ~ 1.5:1 in IMT-treated conditions. The impact of IMT was similar to that of dual modality TMZ-RT therapy and the addition of IMT to this treatment combination dramatically reduced DIPG cell viability to ~ 20% of control values. CONCLUSIONS: This proof-of-concept study provides a novel demonstration of marked DIPG cell susceptibility to low intensity electric fields delivered using IMT. The potent impact as a monotherapy and when integrated into multi-modality treatment platforms justifies further investigations into the potential of IMT as a critically needed biomedical innovation for DIPG.


Assuntos
Neoplasias do Tronco Encefálico/terapia , Terapia por Estimulação Elétrica , Glioma/terapia , Antineoplásicos Alquilantes/farmacologia , Neoplasias do Tronco Encefálico/patologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Criança , Pré-Escolar , Terapia Combinada , Campos Eletromagnéticos , Glioma/patologia , Humanos , Projetos Piloto , Ponte , Cultura Primária de Células , Estudo de Prova de Conceito , Radioterapia , Temozolomida/farmacologia
17.
Neurosci Bull ; 35(2): 216-224, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30607770

RESUMO

Diffuse intrinsic pontine glioma (DIPG) is the main cause of brain tumor-related death among children. Until now, there is still a lack of effective therapy with prolonged overall survival for this disease. A typical strategy for preclinical cancer research is to find out the molecular differences between tumor tissue and para-tumor normal tissue, in order to identify potential therapeutic targets. Unfortunately, it is impossible to obtain normal tissue for DIPG because of the vital functions of the pons. Here we report the human fetal hindbrain-derived neural progenitor cells (pontine progenitor cells, PPCs) as normal control cells for DIPG. The PPCs not only harbored similar cell biological and molecular signatures as DIPG glioma stem cells, but also had the potential to be immortalized by the DIPG-specific mutation H3K27M in vitro. These findings provide researchers with a candidate normal control and a potential medicine carrier for preclinical research on DIPG.


Assuntos
Neoplasias do Tronco Encefálico/metabolismo , Glioma/metabolismo , Células-Tronco Neurais/metabolismo , Ponte/metabolismo , Animais , Neoplasias do Tronco Encefálico/genética , Neoplasias do Tronco Encefálico/patologia , Linhagem Celular Tumoral , Senescência Celular , Feminino , Glioma/genética , Glioma/patologia , Histonas/genética , Humanos , Camundongos Endogâmicos NOD , Camundongos SCID , Transplante de Neoplasias , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/patologia , Ponte/embriologia , Ponte/patologia , Cultura Primária de Células
18.
Int J Radiat Oncol Biol Phys ; 104(1): 144-148, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30610915

RESUMO

PURPOSE: To identify an optimal dose for reirradiation (reRT) of diffuse intrinsic pontine glioma. METHODS AND MATERIALS: ReRT dose levels were selected using an adaptive utility-based dose-finding method. The coprimary endpoints were toxicity (mild, moderate, high, or severe) and efficacy, evaluated 1 month after reRT. Efficacy was defined as improvements in imaging, clinical status, and quality of life. Secondary endpoints were progression-free and overall survival. Utility of each dose level was calculated based on a combined toxicity/efficacy score, ranging from 0 for (severe toxicity, no efficacy) to 100 for (mild toxicity, all 3 efficacy improvements). RESULTS: Twelve patients completed reRT at 3 dose levels: 24 Gy in 12 fractions (6 patients), 26.4 Gy in 12 fractions (4 patients), and 30.8 Gy in 14 fractions (2 patients). One patient treated at dose level 3 developed a grade 3 acute toxicity. Five of the 6 patients receiving 24 Gy demonstrated improvement in 2 of 3 efficacy domains, and the sixth demonstrated improvement in all efficacy domains. Of 4 patients receiving 26.4 Gy, 1 demonstrated no improvement, and 1 patient each demonstrated improvement in 1, 2, and 3 efficacy domains. Of 2 patients receiving 30.8 Gy, 1 demonstrated improvement in 3 efficacy domains, and 1 did not complete the quality of life and was not assessed. Mean utilities were 88 for dose level 1, 76 for dose level 2, and 25 for dose level 3. For all patients, the median overall survival was 19.5 months from initial diagnosis (95% confidence interval, 15.6-21.1 months), and the median progression-free survival was 4.5 months from the start of reRT (95% confidence interval, 2.7-6.2 months). CONCLUSIONS: ReRT can safely be delivered for progressive diffuse intrinsic pontine glioma. Clinical improvement was seen in almost all patients. Utility analysis suggests that a regimen of 24 Gy in 12 fractions is preferred.


Assuntos
Neoplasias do Tronco Encefálico/radioterapia , Glioma/radioterapia , Reirradiação/métodos , Adolescente , Adulto , Neoplasias do Tronco Encefálico/mortalidade , Neoplasias do Tronco Encefálico/patologia , Criança , Pré-Escolar , Fracionamento da Dose de Radiação , Feminino , Glioma/mortalidade , Glioma/patologia , Humanos , Masculino , Intervalo Livre de Progressão , Estudos Prospectivos , Qualidade de Vida , Lesões por Radiação/etiologia , Reirradiação/efeitos adversos , Resultado do Tratamento , Adulto Jovem
19.
Pediatr Blood Cancer ; 66(3): e27561, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30484948

RESUMO

BACKGROUND: The mean overall survival rate of children with diffuse intrinsic pontine glioma (DIPG) is 9-11 months, with current standard treatment with fractionated radiotherapy and adjuvant chemotherapy. So far, novel therapeutic strategies have not yet resulted in significantly better survival. The main source of energy for glioblastoma cells is glucose. Therefore, metabolic alterations induced by the use of the extremely carbohydrate-restricted ketogenic diet (KD) as adjuvant therapy are subject of interest in cancer research. PROCEDURE: This study explores the safety and feasibility of the KD in children with recurrent DIPG and no remaining treatment options. Safety was defined as the number of adverse effects. Feasibility was defined as the number of patients who were able to use the KD for three months. Coping of patients and parents was measured with questionnaires. RESULTS: Three of 14 children referred to our hospital between 2010 and 2015 were included. Two patients completed the study, and one died before the end of the study. Hospitalizations were needed for placing a nasogastric tube (n = 1) and epileptic seizures (n = 1). Adverse effects related to the diet were mild and transient. Parents were highly motivated during the study. CONCLUSION: Use of KD is safe and feasible, but the effect on survival has to be proven in a larger cohort of children who start the KD earlier after diagnosis, preferably as adjuvant therapy to fractionated radiotherapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Tronco Encefálico/terapia , Quimiorradioterapia , Dieta Cetogênica/métodos , Glioma/terapia , Recidiva Local de Neoplasia/dietoterapia , Radioterapia , Adolescente , Neoplasias do Tronco Encefálico/complicações , Neoplasias do Tronco Encefálico/patologia , Quimioterapia Adjuvante , Criança , Pré-Escolar , Estudos de Viabilidade , Seguimentos , Glioma/complicações , Glioma/patologia , Humanos , Incidência , Masculino , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/epidemiologia , Países Baixos/epidemiologia , Prognóstico , Estudos Prospectivos , Segurança , Taxa de Sobrevida
20.
J Robot Surg ; 13(4): 575-579, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30523502

RESUMO

Tumours located within the brainstem comprise approximately a tenth of all paediatric brain tumours. Surgical biopsy of these tumours is technically challenging and has historically been associated with considerable risk. To this end, robot-assisted surgery theoretically allows for increased accuracy and precision. In this study we report our experience using the Neuromate robot (Renishaw, Gloucestershire, UK) to perform robot-assisted stereotactic biopsy in children with tumours located within the brainstem. An uncontrolled prospective cohort study was performed (phase II) according to the IDEAL model for safe surgical innovation. All cases were recorded on a prospectively maintained database. The database was searched over a 2-year period between the 1st December 2015 and the 31st November 2017 to identify all children with brainstem tumours that underwent robot-assisted stereotactic brain biopsy. When accessible, the post-operative MRI scans and pre-operative plans were compared to assess the target point localisation error (TPLE). Adverse events were recorded prospectively according to whether they resulted in increased hospital stay, caused neurological injury, or lead to death. In all, 11 consecutive children were identified with brain tumours located within the brainstem. In 10/11 cases specimens were diagnostic; in the remaining case a further biopsy was successful. The most frequent pathology was DIPG (7/15). Seven patients underwent an early post-operative volumetric MRI; the calculated median TPLE was 2.7 mm (range 0.5-4.2 mm). There were no surgical complications noted. Robot-assisted stereotactic biopsy in children appears to be feasible and safe. Research databases and comparative studies are warranted to further assess the technique.


Assuntos
Biópsia/métodos , Neoplasias do Tronco Encefálico/patologia , Tronco Encefálico/parasitologia , Procedimentos Cirúrgicos Robóticos/métodos , Técnicas Estereotáxicas , Adolescente , Tronco Encefálico/diagnóstico por imagem , Tronco Encefálico/cirurgia , Neoplasias do Tronco Encefálico/diagnóstico por imagem , Neoplasias do Tronco Encefálico/cirurgia , Criança , Pré-Escolar , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Neuroimagem/métodos , Estudos Prospectivos , Tomografia Computadorizada por Raios X
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