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1.
Lancet Oncol ; 25(5): 668-682, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38552658

RESUMO

BACKGROUND: Constitutional mismatch repair deficiency (CMMRD) syndrome is a rare and aggressive cancer predisposition syndrome. Because a scarcity of data on this condition contributes to management challenges and poor outcomes, we aimed to describe the clinical spectrum, cancer biology, and impact of genetics on patient survival in CMMRD. METHODS: In this cohort study, we collected cross-sectional and longitudinal data on all patients with CMMRD, with no age limits, registered with the International Replication Repair Deficiency Consortium (IRRDC) across more than 50 countries. Clinical data were extracted from the IRRDC database, medical records, and physician-completed case record forms. The primary objective was to describe the clinical features, cancer spectrum, and biology of the condition. Secondary objectives included estimations of cancer incidence and of the impact of the specific mismatch-repair gene and genotype on cancer onset and survival, including after cancer surveillance and immunotherapy interventions. FINDINGS: We analysed data from 201 patients (103 males, 98 females) enrolled between June 5, 2007 and Sept 9, 2022. Median age at diagnosis of CMMRD or a related cancer was 8·9 years (IQR 5·9-12·6), and median follow-up from diagnosis was 7·2 years (3·6-14·8). Endogamy among minorities and closed communities contributed to high homozygosity within countries with low consanguinity. Frequent dermatological manifestations (117 [93%] of 126 patients with complete data) led to a clinical overlap with neurofibromatosis type 1 (35 [28%] of 126). 339 cancers were reported in 194 (97%) of 201 patients. The cumulative cancer incidence by age 18 years was 90% (95% CI 80-99). Median time between cancer diagnoses for patients with more than one cancer was 1·9 years (IQR 0·8-3·9). Neoplasms developed in 15 organs and included early-onset adult cancers. CNS tumours were the most frequent (173 [51%] cancers), followed by gastrointestinal (75 [22%]), haematological (61 [18%]), and other cancer types (30 [9%]). Patients with CNS tumours had the poorest overall survival rates (39% [95% CI 30-52] at 10 years from diagnosis; log-rank p<0·0001 across four cancer types), followed by those with haematological cancers (67% [55-82]), gastrointestinal cancers (89% [81-97]), and other solid tumours (96% [88-100]). All cancers showed high mutation and microsatellite indel burdens, and pathognomonic mutational signatures. MLH1 or MSH2 variants caused earlier cancer onset than PMS2 or MSH6 variants, and inferior survival (overall survival at age 15 years 63% [95% CI 55-73] for PMS2, 49% [35-68] for MSH6, 19% [6-66] for MLH1, and 0% for MSH2; p<0·0001). Frameshift or truncating variants within the same gene caused earlier cancers and inferior outcomes compared with missense variants (p<0·0001). The greater deleterious effects of MLH1 and MSH2 variants as compared with PMS2 and MSH6 variants persisted despite overall improvements in survival after surveillance or immune checkpoint inhibitor interventions. INTERPRETATION: The very high cancer burden and unique genomic landscape of CMMRD highlight the benefit of comprehensive assays in timely diagnosis and precision approaches toward surveillance and immunotherapy. These data will guide the clinical management of children and patients who survive into adulthood with CMMRD. FUNDING: The Canadian Institutes for Health Research, Stand Up to Cancer, Children's Oncology Group National Cancer Institute Community Oncology Research Program, Canadian Cancer Society, Brain Canada, The V Foundation for Cancer Research, BioCanRx, Harry and Agnieszka Hall, Meagan's Walk, BRAINchild Canada, The LivWise Foundation, St Baldrick Foundation, Hold'em for Life, and Garron Family Cancer Center.


Assuntos
Proteínas de Ligação a DNA , Síndromes Neoplásicas Hereditárias , Humanos , Masculino , Feminino , Criança , Pré-Escolar , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/terapia , Estudos Transversais , Adolescente , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/epidemiologia , Reparo de Erro de Pareamento de DNA , Estudos Longitudinais , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Neoplasias Colorretais/mortalidade , Incidência , Proteína 2 Homóloga a MutS/genética , Proteína 1 Homóloga a MutL/genética , Adulto , Adulto Jovem , Mutação
2.
Acta Neuropathol ; 144(4): 747-765, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35945463

RESUMO

Gliomas arising in the setting of neurofibromatosis type 1 (NF1) are heterogeneous, occurring from childhood through adulthood, can be histologically low-grade or high-grade, and follow an indolent or aggressive clinical course. Comprehensive profiling of genetic alterations beyond NF1 inactivation and epigenetic classification of these tumors remain limited. Through next-generation sequencing, copy number analysis, and DNA methylation profiling of gliomas from 47 NF1 patients, we identified 2 molecular subgroups of NF1-associated gliomas. The first harbored biallelic NF1 inactivation only, occurred primarily during childhood, followed a more indolent clinical course, and had a unique epigenetic signature for which we propose the terminology "pilocytic astrocytoma, arising in the setting of NF1". The second subgroup harbored additional oncogenic alterations including CDKN2A homozygous deletion and ATRX mutation, occurred primarily during adulthood, followed a more aggressive clinical course, and was epigenetically diverse, with most tumors aligning with either high-grade astrocytoma with piloid features or various subclasses of IDH-wildtype glioblastoma. Several patients were treated with small molecule MEK inhibitors that resulted in stable disease or tumor regression when used as a single agent, but only in the context of those tumors with NF1 inactivation lacking additional oncogenic alterations. Together, these findings highlight recurrently altered pathways in NF1-associated gliomas and help inform targeted therapeutic strategies for this patient population.


Assuntos
Astrocitoma , Neoplasias Encefálicas , Glioma , Neurofibromatose 1 , Adulto , Astrocitoma/genética , Neoplasias Encefálicas/genética , Glioma/genética , Glioma/patologia , Homozigoto , Humanos , Neurofibromatose 1/complicações , Neurofibromatose 1/genética , Deleção de Sequência
3.
Pediatr Neurosurg ; 56(5): 482-491, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34320494

RESUMO

INTRODUCTION: Tumor-associated intracranial aneurysms are rare and not well understood. CASE PRESENTATION: We describe a 4-year-old female with multiple intracranial aneurysms intimately associated with a suprasellar germ cell tumor (GCT). We provide the clinical history, medical, and surgical treatment course, as well as a comprehensive and concise synthesis of the literature on tumor-associated aneurysms. DISCUSSION: We discuss mechanisms for aneurysm formation with relevance to the current case, including cellular and paracrine signaling pertinent to suprasellar GCTs and possible molecular pathways involved. We review the complex multidisciplinary treatment required for complex tumor and cerebrovascular interactions.


Assuntos
Aneurisma Intracraniano , Neoplasias Embrionárias de Células Germinativas , Neoplasias Hipofisárias , Pré-Escolar , Feminino , Humanos , Aneurisma Intracraniano/diagnóstico por imagem , Aneurisma Intracraniano/etiologia , Aneurisma Intracraniano/cirurgia , Neoplasias Embrionárias de Células Germinativas/diagnóstico por imagem , Neoplasias Embrionárias de Células Germinativas/cirurgia
4.
Pediatr Blood Cancer ; 67(3): e28119, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31850678

RESUMO

BACKGROUND: Effective treatment for pediatric embryonal brain tumors includes dose-intensive multiagent chemotherapy (DIMAC) followed by high-dose chemotherapy with stem cell rescue (HDCSCR). Use of repeated cycles of DIMAC including high-dose methotrexate (HDMTX) without HDCSCR has not been described. PROCEDURE: We retrospectively reviewed the responses/toxicities in 13 patients (aged 2-155 months, median 22 months) with central nervous system (CNS) tumors (atypical teratoid rhabdoid tumors, CNS embryonal tumors not otherwise specified, pineoblastoma, embryonal tumor with multilayered rosettes, and CNS sarcoma) treated over a 12-year period with repeated cycles of HDMTX followed by etoposide, cisplatin, cyclophosphamide, and vincristine. RESULTS: Six patients (46.2%) had disseminated disease at presentation and five (38.5%) had gross total resection. A total of 64 courses of therapy were administered with a median of five courses per patient.  Eight patients (61.5%) received radiation therapy (one at relapse). By completion of therapy, 11 patients (84.6%) achieved a response (six complete, five partial).  Six of the 13 patients (46.2%) remain alive with a median follow-up of 48 months (6-146).  Acute toxicities included fever/neutropenia (70.3%), bacteremia (15.6%), and grade 3 mucositis (18.8%).  Long-term complications included learning disability, seizure disorder, and brain necrosis, without treatment-related deaths. CONCLUSIONS: DIMAC with HDMTX without HDCSCR may be an effective treatment option for selected patients with embryonal or high-grade CNS tumors.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/patologia , Criança , Pré-Escolar , Cisplatino/administração & dosagem , Ciclofosfamida/administração & dosagem , Relação Dose-Resposta a Droga , Etoposídeo/administração & dosagem , Feminino , Seguimentos , Humanos , Lactente , Masculino , Gradação de Tumores , Estudos Retrospectivos , Taxa de Sobrevida , Vincristina/administração & dosagem
5.
Pediatr Blood Cancer ; 64(12)2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28696020

RESUMO

Anaplastic oligodendroglioma (AO) is rare in children. Treatment typically consists of varying combinations of surgery, chemotherapy, and radiotherapy. We present a pediatric case of frontal lobe AO with periventricular subcallosal extension and local leptomeningeal involvement. The isocitrate dehydrogenase (IDH) wild-type tumor was MGMT methylated and contained an ATRX mutation, BRAF alteration, and 1p/19q co-deletion; a combination of alterations mostly encountered in pediatric oligodendrogliomas. The patient underwent a near total resection and had a complete, durable response to temozolomide alone, suggesting that conservative management without radiation may be appropriate in some cases. We review the literature of this uncommon subtype of glioma in children.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Dacarbazina/análogos & derivados , Oligodendroglioma/tratamento farmacológico , Neoplasias Encefálicas/genética , Criança , Dacarbazina/uso terapêutico , Humanos , Isocitrato Desidrogenase/genética , Masculino , Oligodendroglioma/genética , Temozolomida
6.
Nat Commun ; 15(1): 477, 2024 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-38216572

RESUMO

Schwann cell tumors are the most common cancers of the peripheral nervous system and can arise in patients with neurofibromatosis type-1 (NF-1) or neurofibromatosis type-2 (NF-2). Functional interactions between NF1 and NF2 and broader mechanisms underlying malignant transformation of the Schwann lineage are unclear. Here we integrate bulk and single-cell genomics, biochemistry, and pharmacology across human samples, cell lines, and mouse allografts to identify cellular de-differentiation mechanisms driving malignant transformation and treatment resistance. We find DNA methylation groups of Schwann cell tumors can be distinguished by differentiation programs that correlate with response to the MEK inhibitor selumetinib. Functional genomic screening in NF1-mutant tumor cells reveals NF2 loss and PAK activation underlie selumetinib resistance, and we find that concurrent MEK and PAK inhibition is effective in vivo. These data support a de-differentiation paradigm underlying malignant transformation and treatment resistance of Schwann cell tumors and elucidate a functional link between NF1 and NF2.


Assuntos
Neurilemoma , Neurofibromatoses , Neurofibromatose 1 , Neurofibromatose 2 , Animais , Humanos , Camundongos , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Neurilemoma/genética , Neurilemoma/patologia , Neurofibromatoses/metabolismo , Neurofibromatoses/patologia , Neurofibromatose 1/genética , Neurofibromatose 1/metabolismo , Neurofibromatose 2/genética , Neurofibromatose 2/patologia , Células de Schwann/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética
7.
Pediatr Blood Cancer ; 60(4): 669-75, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23042746

RESUMO

BACKGROUND: The present study investigated the relationship between cardiorespiratory fitness and executive functioning in pediatric brain tumor survivors who received cranial radiation. This population is known to show executive dysfunction and lower rates of aerobic exercise compared to peers. PROCEDURE: Nine adolescent survivors of pediatric posterior fossa tumor completed an n-back working memory task during a functional MRI scan, as well as cardiorespiratory fitness testing on a cycle ergometer. RESULTS: Neuroimaging findings indicated typical activation patterns associated with working memory, mainly in the frontal-parietal network. Higher cardiorespiratory fitness was related to better performance on a behavioral measure of working memory and more efficient neural functioning. CONCLUSIONS: This study provides preliminary evidence that cardiorespiratory fitness may be related to executive functioning, particularly working memory, in pediatric brain tumor survivors. Descriptions of the brain regions recruited for working memory by pediatric brain tumor survivors may be used to inform future interventions or indicators of treatment efficacy.


Assuntos
Irradiação Craniana/efeitos adversos , Neoplasias Infratentoriais/radioterapia , Memória de Curto Prazo/fisiologia , Aptidão Física/fisiologia , Sobreviventes , Adolescente , Criança , Teste de Esforço , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Transtornos da Memória/epidemiologia , Transtornos da Memória/etiologia
8.
J Pediatr Hematol Oncol ; 35(3): e123-6, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23425999

RESUMO

Prognosis for children with glioblastoma is unacceptably poor. Modest improvements in progression-free survival were seen in adults with glioblastoma by combining temozolomide and bevacizumab with conformal radiation. We retrospectively reviewed 3 cases of glioblastoma in children treated using upfront bevacizumab and temozolomide during radiation, followed by 12 cycles of maintenance therapy. All patients completed therapy with minimal toxicity and no delays in treatment. Two patients remain disease free at 38 and 49 months from diagnosis. One patient recurred 14 months off therapy and currently receives salvage therapy 48 months from diagnosis. These results support further investigation of this regimen.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/terapia , Quimiorradioterapia , Glioblastoma/terapia , Adolescente , Anticorpos Monoclonais Humanizados/administração & dosagem , Bevacizumab , Neoplasias Encefálicas/patologia , Criança , Dacarbazina/administração & dosagem , Dacarbazina/análogos & derivados , Feminino , Glioblastoma/patologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Prognóstico , Estudos Retrospectivos , Temozolomida
9.
Neuro Oncol ; 25(11): 2074-2086, 2023 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-37318058

RESUMO

BACKGROUND: The objective of this study was to determine the safety, tolerability, and distribution of MTX110 (aqueous panobinostat) delivered by convection-enhanced delivery (CED) in patients with newly diagnosed diffuse intrinsic pontine glioma (DIPG) who completed focal radiation therapy (RT). METHODS: Patients with DIPG (2-21 years) were enrolled after RT. CED of MTX110 combined with gadoteridol was completed across 7 dose levels (DL) (30-90 µM; volumes ranging from 3 mL to 2 consecutive doses of 6 mL). An accelerated dose escalation design was used. Distribution of infusate was monitored with real-time MR imaging. Repeat CED was performed every 4-8 weeks. Quality-of-life (QoL) assessments were obtained at baseline, every 3 months on therapy, and end of therapy. RESULTS: Between May 2018 and March 2020, 7 patients who received a total of 48 CED infusions, were enrolled (median age 8 years, range 5-21). Three patients experienced dose-limited toxicities. Four grade 3 treatment-related adverse events were observed. Most toxicities were transient new or worsening neurologic function. Median overall survival (OS) was 26.1 months (95% confidence interval: 14.8-not reached). Progression-free survival was 4-14 months (median, 7). Cumulative percentage of tumor coverage for combined CED infusions per patient ranged from 35.6% to 81.0%. Increased CED infusions were negatively associated with self-reported QoL assessments. CONCLUSION: Repeat CED of MTX110 with real-time imaging with gadoteridol is tolerable for patients with DIPG. Median OS of 26.1 months compares favorably with historical data for children with DIPG. The results support further investigation of this strategy in a larger cohort.


Assuntos
Antineoplásicos , Neoplasias do Tronco Encefálico , Glioma Pontino Intrínseco Difuso , Glioma , Humanos , Criança , Pré-Escolar , Adolescente , Adulto Jovem , Adulto , Panobinostat/uso terapêutico , Antineoplásicos/uso terapêutico , Glioma Pontino Intrínseco Difuso/tratamento farmacológico , Neoplasias do Tronco Encefálico/patologia , Qualidade de Vida , Convecção , Glioma/patologia , Inibidores de Histona Desacetilases/uso terapêutico
10.
Neuro Oncol ; 25(12): 2221-2236, 2023 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-37436963

RESUMO

BACKGROUND: Schwannomas are common peripheral nerve sheath tumors that can cause severe morbidity given their stereotypic intracranial and paraspinal locations. Similar to many solid tumors, schwannomas and other nerve sheath tumors are primarily thought to arise due to aberrant hyperactivation of the RAS growth factor signaling pathway. Here, we sought to further define the molecular pathogenesis of schwannomas. METHODS: We performed comprehensive genomic profiling on a cohort of 96 human schwannomas, as well as DNA methylation profiling on a subset. Functional studies including RNA sequencing, chromatin immunoprecipitation-DNA sequencing, electrophoretic mobility shift assay, and luciferase reporter assays were performed in a fetal glial cell model following transduction with wildtype and tumor-derived mutant isoforms of SOX10. RESULTS: We identified that nearly one-third of sporadic schwannomas lack alterations in known nerve sheath tumor genes and instead harbor novel recurrent in-frame insertion/deletion mutations in SOX10, which encodes a transcription factor responsible for controlling Schwann cell differentiation and myelination. SOX10 indel mutations were highly enriched in schwannomas arising from nonvestibular cranial nerves (eg facial, trigeminal, vagus) and were absent from vestibular nerve schwannomas driven by NF2 mutation. Functional studies revealed these SOX10 indel mutations have retained DNA binding capacity but impaired transactivation of glial differentiation and myelination gene programs. CONCLUSIONS: We thus speculate that SOX10 indel mutations drive a unique subtype of schwannomas by impeding proper differentiation of immature Schwann cells.


Assuntos
Neoplasias de Bainha Neural , Neurilemoma , Neuroma Acústico , Humanos , Mutação INDEL , Ativação Transcricional , Neurilemoma/genética , Neurilemoma/patologia , Neuroma Acústico/patologia , Mutação , Fatores de Transcrição SOXE/genética , Fatores de Transcrição SOXE/metabolismo
11.
J Pediatr Hematol Oncol ; 34(6): e222-7, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22810754

RESUMO

Advances in medical therapies have greatly improved survivorship rates in children diagnosed with brain tumor; as a result, morbidities associated with survivorship have become increasingly important to identify and address. In general, pediatric posterior fossa tumor survivors tend to be less physically active than peers. This may be related to late effects of diagnosis and treatment, including cardiovascular, endocrine, psychological, and neurocognitive difficulties. Exercise has been shown to be effective in improving physical functioning, mood, and even cognitive functioning. Consequently, the benefits of physical exercise need to be explored and incorporated into the daily lives of pediatric posterior fossa tumor survivors. The primary aim of the present study was to establish the feasibility and safety of cardiorespiratory fitness testing in pediatric posterior fossa tumor survivors who had received cranial radiation therapy. In addition, comparing our cohort with previously published data, we found that pediatric posterior fossa tumor survivors tended to be less fit than children with pulmonary disease and healthy controls and approximately as fit as children with chronic heart disease and survivors of other types of childhood cancer. The importance of cardiorespiratory fitness in pediatric posterior fossa tumor survivors is discussed along with implications for future directions.


Assuntos
Neoplasias Encefálicas/patologia , Fenômenos Fisiológicos Cardiovasculares , Exercício Físico/fisiologia , Neoplasias Infratentoriais/patologia , Aptidão Física/fisiologia , Fenômenos Fisiológicos Respiratórios , Sobreviventes , Adolescente , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/radioterapia , Criança , Estudos de Coortes , Estudos de Viabilidade , Feminino , Humanos , Neoplasias Infratentoriais/mortalidade , Neoplasias Infratentoriais/radioterapia , Masculino
12.
Cancer Discov ; 11(5): 1176-1191, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33355208

RESUMO

Although replication repair deficiency, either by mismatch repair deficiency (MMRD) and/or loss of DNA polymerase proofreading, can cause hypermutation in cancer, microsatellite instability (MSI) is considered a hallmark of MMRD alone. By genome-wide analysis of tumors with germline and somatic deficiencies in replication repair, we reveal a novel association between loss of polymerase proofreading and MSI, especially when both components are lost. Analysis of indels in microsatellites (MS-indels) identified five distinct signatures (MS-sigs). MMRD MS-sigs are dominated by multibase losses, whereas mutant-polymerase MS-sigs contain primarily single-base gains. MS deletions in MMRD tumors depend on the original size of the MS and converge to a preferred length, providing mechanistic insight. Finally, we demonstrate that MS-sigs can be a powerful clinical tool for managing individuals with germline MMRD and replication repair-deficient cancers, as they can detect the replication repair deficiency in normal cells and predict their response to immunotherapy. SIGNIFICANCE: Exome- and genome-wide MSI analysis reveals novel signatures that are uniquely attributed to mismatch repair and DNA polymerase. This provides new mechanistic insight into MS maintenance and can be applied clinically for diagnosis of replication repair deficiency and immunotherapy response prediction.This article is highlighted in the In This Issue feature, p. 995.


Assuntos
Transformação Celular Neoplásica , Reparo de Erro de Pareamento de DNA , DNA Polimerase Dirigida por DNA , Regulação Neoplásica da Expressão Gênica , Instabilidade de Microssatélites , Neoplasias/genética , Humanos , Sequenciamento do Exoma
13.
Pediatr Blood Cancer ; 55(6): 1227-30, 2010 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-20882580

RESUMO

We report two cases of primary CNS lymphoma (PCNSL) treated with high-dose methotrexate. Though standard adult treatment of PCNSL incorporates whole-brain radiotherapy, the literature suggests it may be possible to delay or avoid radiotherapy and the associated increased risk of neurologic sequelae in pediatric patients. Studies in adults indicate methotrexate therapy can be effective against PCNSL and has advantages over the current standard of treatment. Both patients have no evidence of disease 9 and 7 years after treatment, suggesting high-dose methotrexate may lead to disease control in pediatric patients with PCNSL while avoiding the effects of radiotherapy.


Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Linfoma de Células B/tratamento farmacológico , Linfoma Anaplásico de Células Grandes/tratamento farmacológico , Metotrexato/uso terapêutico , Adolescente , Neoplasias do Sistema Nervoso Central/imunologia , Neoplasias do Sistema Nervoso Central/patologia , Relação Dose-Resposta a Droga , Feminino , Humanos , Imunocompetência , Lactente , Linfoma de Células B/imunologia , Linfoma de Células B/patologia , Linfoma Anaplásico de Células Grandes/imunologia , Linfoma Anaplásico de Células Grandes/patologia , Masculino , Resultado do Tratamento
14.
Mol Ther ; 17(7): 1125-35, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19367259

RESUMO

Despite improving survival rates for children with cancer, a subset of patients exist with disease resistant to traditional therapies such as surgery, chemotherapy, and radiation. These patients require newer, targeted treatments used alone or in combination with more traditional approaches. Oncolytic herpes simplex virus (HSV) is one of these newer therapies that offer promise for several difficult to treat pediatric malignancies. The potential benefit of HSV therapy in pediatric solid tumors including brain tumors, neuroblastomas, and sarcomas is reviewed along with the many challenges that need to be addressed prior to moving oncolytic HSV therapy from the laboratory to the beside in the pediatric population.


Assuntos
Terapia Viral Oncolítica/métodos , Simplexvirus , Neoplasias Encefálicas/terapia , Humanos , Neuroblastoma/terapia , Sarcoma/terapia
15.
Neuro Oncol ; 22(10): 1527-1535, 2020 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-32236425

RESUMO

BACKGROUND: Activation of the mammalian target of rapamycin (mTOR) pathway is observed in neurofibromatosis type 1 (NF1) associated low-grade gliomas (LGGs), but agents that inhibit this pathway, including mTOR inhibitors, have not been studied in this population. We evaluate the efficacy of the orally administered mTOR inhibitor everolimus for radiographically progressive NF1-associated pediatric LGGs. METHODS: Children with radiologic-progressive, NF1-associated LGG and prior treatment with a carboplatin-containing chemotherapy were prospectively enrolled on this phase II clinical trial to receive daily everolimus. Whole blood was analyzed for everolimus and markers of phosphatidylinositol-3 kinase (PI3K)/mTOR pathway inhibition. Serial MRIs were obtained during treatment. The primary endpoint was progression-free survival at 48 weeks. RESULTS: Twenty-three participants (median age, 9.4 y; range, 3.2-21.6 y) were enrolled. All participants were initially evaluable for response; 1 patient was removed from study after development of a malignant peripheral nerve sheath tumor. Fifteen of 22 participants (68%) demonstrated a response, defined as either shrinkage (1 complete response, 2 partial response) or arrest of tumor growth (12 stable disease). Of these, 10/15 remained free of progression (median follow-up, 33 mo). All remaining 22 participants were alive at completion of therapy. Treatment was well tolerated; no patient discontinued therapy due to toxicity. Pharmacokinetic parameters and pre-dose concentrations showed substantial between-subject variability. PI3K/mTOR pathway inhibition markers demonstrating blood mononuclear cell mTOR pathway inactivation was achieved in most participants. CONCLUSION: Individuals with recurrent/progressive NF1-associated LGG demonstrate significant disease stability/shrinkage during treatment with oral everolimus with a well-tolerated toxicity profile. Everolimus is well suited for future consideration as upfront or combination therapy in this patient population.


Assuntos
Antineoplásicos , Glioma , Neurofibromatose 1 , Antineoplásicos/uso terapêutico , Criança , Everolimo/uso terapêutico , Glioma/diagnóstico por imagem , Glioma/tratamento farmacológico , Humanos , Neurofibromatose 1/tratamento farmacológico , Sirolimo/uso terapêutico , Serina-Treonina Quinases TOR
16.
J Clin Oncol ; 38(11): 1175-1185, 2020 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-32105509

RESUMO

PURPOSE: Atypical teratoid/rhabdoid tumor (AT/RT) is an aggressive, early-childhood brain tumor without standard effective treatment. To our knowledge, we conducted the first AT/RT-specific cooperative group trial, ACNS0333, to examine the efficacy and safety of intensive postoperative chemotherapy and focal radiation to treat AT/RT. PATIENTS AND METHODS: Patients from birth to 22 years of age with AT/RT were eligible. After surgery, they received 2 courses of multiagent chemotherapy, followed by 3 courses of high-dose chemotherapy with peripheral blood stem cell rescue and involved-field radiation therapy. Timing of radiation was based on patient age and disease location and extent. Central testing of tumor and blood for SMARCB1 status was mandated. Tumor molecular subclassification was performed retrospectively. The primary analysis was event-free survival (EFS) for patients < 36 months of age compared with a cooperative groups' historical cohort. Although accrual was based on the therapeutic question, potential prognostic factors, including age, tumor location, M stage, surgical resection, order of therapy, germline status, and molecular subtype, were explored. RESULTS: Of 65 evaluable patients, 54 were < 36 months of age. ACNS0333 therapy significantly reduced the risk of EFS events in patients < 36 months of age compared with the historical cohort (P < .0005; hazard rate, 0.43; 95% CI, 0.28 to 0.66). Four-year EFS and overall survival for the entire cohort were 37% (95% CI, 25% to 49%) and 43% (95% CI, 31% to 55%), respectively. Timing of radiation did not affect survival, and 91% of relapses occurred by 2 years from enrollment. Treatment-related deaths occurred in 4 patients. CONCLUSION: The ACNS0333 regimen dramatically improved survival compared with historical therapies for patients with AT/RT. Clinical characteristics and molecular subgrouping suggest prognostic differences. ACNS0333 results lay a foundation on which to build future studies and incorporate testing of new therapeutic agents.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Radioterapia Conformacional/métodos , Tumor Rabdoide/terapia , Teratoma/terapia , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Criança , Pré-Escolar , Terapia Combinada , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Prognóstico , Tumor Rabdoide/genética , Tumor Rabdoide/mortalidade , Proteína SMARCB1/genética , Teratoma/genética , Teratoma/mortalidade , Adulto Jovem
17.
Hum Gene Ther Clin Dev ; 28(1): 7-16, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28319448

RESUMO

Primary central nervous system tumors are the most common solid neoplasm of childhood and the leading cause of cancer-related death in pediatric patients. Survival rates for children with malignant supratentorial brain tumors are poor despite aggressive treatment with combinations of surgery, radiation, and chemotherapy, and survivors often suffer from damaging lifelong sequelae from current therapies. Novel innovative treatments are greatly needed. One promising new approach is the use of a genetically engineered, conditionally replicating herpes simplex virus (HSV) that has shown tumor-specific tropism and potential efficacy in the treatment of malignant brain tumors. G207 is a genetically engineered HSV-1 lacking genes essential for replication in normal brain cells. Safety has been established in preclinical investigations involving intracranial inoculation in the highly HSV-sensitive owl monkey (Aotus nancymai), and in three adult phase 1 trials in recurrent/progressive high-grade gliomas. No dose-limiting toxicities were seen in the adult studies and a maximum tolerated dose was not reached. Approximately half of the 35 treated adults had radiographic or neuropathologic evidence of response at a minimum of one time point. Preclinical studies in pediatric brain tumor models indicate that a variety of pediatric tumor types are highly sensitive to killing by G207. This clinical protocol outlines a first in human children study of intratumoral inoculation of an oncolytic virus via catheters placed directly into recurrent or progressive supratentorial malignant tumors.


Assuntos
Vetores Genéticos/administração & dosagem , Herpesvirus Humano 1/genética , Terapia Viral Oncolítica , Projetos de Pesquisa , Neoplasias Supratentoriais/genética , Neoplasias Supratentoriais/radioterapia , Adolescente , Adulto , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/virologia , Criança , Pré-Escolar , Feminino , Terapia Genética , Humanos , Masculino , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/radioterapia , Recidiva Local de Neoplasia/virologia , Vírus Oncolíticos/genética , Segurança , Neoplasias Supratentoriais/virologia
19.
Neuro Oncol ; 6(2): 127-33, 2004 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15134627

RESUMO

Treatment strategies for CNS germinoma are currently evolving. Current approaches include reducing the volume and dose of radiation by adding pre-irradiation chemotherapy. Very accurate staging is necessary with such an approach to prevent failures. Eight consecutive patients with pineal germinoma at one institution underwent endoscopic surgery for tumor biopsy, direct visualization of the third ventricular region, and third ventriculostomy for those with hydrocephalus. All patients were treated with 4 cycles of chemotherapy. Conformal field radiation therapy followed, with the dose to the tumor bed dependent on the response to chemotherapy. Patients who had MRI, endoscopic, or cerebrospinal fluid evidence of multicentric or disseminated disease also received craniospinal radiation. Six patients had diabetes insipidus (DI) at presentation. All 6 had tumor studding the floor of the third ventricle on endoscopic visualization, while only 4 of those patients had MRI evidence of disease in that region. All patients have completed therapy and are alive, with no evidence of disease at median follow-up of 31.5 months from diagnosis. Direct endoscopic visualization of the third ventricular region may be more sensitive than MRI for evaluating the presence of suprasellar disease and appears to add important information. This parameter should be added to the staging evaluation when feasible. In this series, the presence of DI was 100% predictive of suprasellar disease, even when the MRI was negative for involvement of that region. Patients should be evaluated for DI as part of the initial staging, and if it is present, the patients should be treated for suprasellar disease regardless of MRI findings.


Assuntos
Diabetes Insípido/patologia , Germinoma/patologia , Neuroendoscopia/métodos , Pinealoma/patologia , Adolescente , Adulto , Criança , Diabetes Insípido/cirurgia , Feminino , Germinoma/radioterapia , Germinoma/cirurgia , Humanos , Masculino , Estadiamento de Neoplasias , Neuroendoscopia/estatística & dados numéricos , Pinealoma/radioterapia , Pinealoma/cirurgia
20.
J Neurosurg ; 100(5 Suppl Pediatrics): 430-6, 2004 May.
Artigo em Inglês | MEDLINE | ID: mdl-15287450

RESUMO

OBJECT: Intracranial germinomas commonly occur in the pineal region, the floor of the third ventricle (hypothalamus), or both, and they are often associated with diabetes insipidus (DI). The authors conducted a study to correlate preoperative DI with the endoscopic and magnetic resonance (MR) imaging evidence of tumor on the third ventricle floor. METHODS: The authors reviewed hospital records, office charts, and MR imaging studies obtained in patients in whom a biopsy sampling procedure was performed with or without endoscopic third ventriculostomy (ETV) at Children's Hospital, Birmingham, Alabama between May 1998 and July 2002. Ten patients with the pathological diagnosis of pure germinoma were identified. Preoperative MR imaging findings and presenting symptoms were correlated with intraoperative neuroendoscopic findings. Seven patients presented with symptomatic hydrocephalus and underwent concomitant ETV. Six patients presented with DI and MR imaging evidence of involvement of the third ventricle floor. Two patients presented with DI and no initial MR imaging evidence of neoplastic involvement of the third ventricle floor; in both there was endoscopic evidence of neoplastic involvement of the floor of the third ventricle. In two children without DI, neither MR imaging nor endoscopic evidence of involvement of the third ventricle floor was observed. CONCLUSIONS: In the authors' experience with intracranial germinoma, endoscopic tumor biopsy sampling, and ETV provide an effective, safe, and minimally invasive means of obtaining diagnostic tissue and treating any concomitant hydrocephalus. The authors found that preoperative DI is an absolute predictor of neoplastic involvement of the hypothalamus regardless of MR imaging findings. Therefore, in the setting of DI and intracranial germinoma without neuroimaging evidence of hypothalamic involvement, germinomatous involvement of the hypothalamus should be assumed present, if not confirmed endoscopically at the time of biopsy sampling or third ventriculostomy, when devising adjuvant treatment plans for such patients.


Assuntos
Neoplasias Encefálicas/cirurgia , Diabetes Insípido/complicações , Germinoma/cirurgia , Neuroendoscopia , Glândula Pineal , Pinealoma/cirurgia , Adolescente , Adulto , Biópsia , Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/patologia , Criança , Pré-Escolar , Germinoma/complicações , Germinoma/patologia , Humanos , Hidrocefalia/etiologia , Hidrocefalia/cirurgia , Imageamento por Ressonância Magnética , Masculino , Pinealoma/complicações , Pinealoma/patologia , Estudos Retrospectivos , Terceiro Ventrículo/patologia
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