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BACKGROUND: The authors analyzed the incidence and types of second malignant neoplasms (SMNs) in patients treated for medulloblastoma. METHODS: The authors compared the incidence of SMNs after radiotherapy (RT) for medulloblastoma in patients treated in 1973-2014 with the incidence in the general population with the multiple primary-standardized incidence ratio function of Surveillance, Epidemiology, and End Results 9. Observed-to-expected incidence (O/E) ratios and 95% confidence intervals (CIs) were reported for the entire cohort and by disease site according to age at diagnosis, treatment era, and receipt of chemotherapy. P values < .05 were considered statistically significant. RESULTS: Of the 1294 patients with medulloblastoma who received RT, 68 developed 75 SMNs. The O/E ratio for SMNs among all patients was 4.49 (95% CI, 3.53-5.62; P < .05). The site at highest risk was the central nervous system (CNS; O/E, 40.62; 95% CI, 25.46-61.51), which was followed by the endocrine system (O/E, 15.95; 95% CI, 9.12-25.91), bone (O/E, 14.45; 95% CI, 1.75-52.21), soft tissues (O/E, 9.01; 95% CI, 1.09-32.56), the digestive system (O/E, 5.03; 95% CI, 2.51-9.00), and the lymphatic/hematopoietic system (O/E, 3.37; 95% CI, 1.35-6.94). The O/E ratio was higher for patients given chemotherapy and RT (O/E, 5.52; 95% CI, 3.75-7.83) than for those given RT only (O/E, 3.96; 95% CI, 2.88-5.32). CONCLUSIONS: Patients with medulloblastoma are at elevated risk for SMNs in comparison with the general population. Variations in O/E for SMNs by organ systems were found for treatment modality, age at diagnosis, and time of diagnosis. The most common site, the CNS, was involved more often in younger patients and those given chemotherapy with RT.
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Neoplasias Cerebelosas , Meduloblastoma , Neoplasias Primarias Secundarias , Neoplasias Cerebelosas/complicaciones , Neoplasias Cerebelosas/epidemiología , Neoplasias Cerebelosas/radioterapia , Humanos , Incidencia , Meduloblastoma/complicaciones , Meduloblastoma/epidemiología , Meduloblastoma/radioterapia , Neoplasias Primarias Secundarias/epidemiología , Neoplasias Primarias Secundarias/etiología , Neoplasias Primarias Secundarias/patología , Factores de RiesgoRESUMEN
PURPOSE: To assess the safety and efficacy of concurrent carboplatin during craniospinal irradiation (CSI) in high-risk/metastatic medulloblastoma defined as either residual tumor >1.5 cm2 or leptomeningeal metastases. METHODS: This single-arm combined prospective (2005-2011) and retrospective (2011-2019) study was undertaken at a tertiary care cancer center in India. Following surgery, patients with newly diagnosed high-risk/metastatic medulloblastoma received concurrent carboplatin (35 mg/m2 ) for 15 days (day 1 to day 15) during CSI plus posterior fossa/tumor bed boost, followed by six cycles of standard adjuvant chemotherapy. RESULTS: All 97 patients completed their planned course of radiotherapy without interruptions, except for two (2.1%) patients who had brief gaps due to treatment-related toxicity. Grade 3-4 anemia, neutropenia, thrombocytopenia, and febrile neutropenia were seen in four (4.1%), 41 (42.2%) 21 (21.6%), and 18 (18.6%) patients, necessitating packed cell transfusion, granulocyte colony-stimulating factor, and platelet support in five (5.1%), 41 (42.2%), and five (5.1%) patients, respectively, during the concurrent phase. Following myelorecovery, 92 (94.9%) patients completed the planned six cycles of standard adjuvant systemic chemotherapy. There were no treatment-related deaths during the concurrent chemo-radiotherapy phase, while three (3.1%) toxic deaths were ascribed to adjuvant chemotherapy-related complications. At a median follow-up of 82 months, the 5-year Kaplan-Meier estimates of progression-free survival and overall survival were 60.2% and 62.1%, respectively. On univariate analysis, leptomeningeal metastases (M0/M1 vs. M2/M3) and histological subtype (large cell/anaplastic vs. others) emerged as significant prognostic factors for survival. CONCLUSION: Addition of concurrent carboplatin to RT as radiosensitizing chemotherapy is a simple and effective way of treatment intensification in high-risk/metastatic medulloblastoma.
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Antineoplásicos/administración & dosificación , Carboplatino/administración & dosificación , Neoplasias Cerebelosas/terapia , Quimioradioterapia/métodos , Meduloblastoma/terapia , Adolescente , Quimioterapia Adyuvante/métodos , Niño , Irradiación Craneoespinal/métodos , Femenino , Humanos , MasculinoRESUMEN
INTRODUCTION: In the last decade, a number of genomic and pharmacological studies have demonstrated the importance of epigenetic dysregulation in medulloblastoma initiation and progression. High throughput approaches including gene expression array, next-generation sequencing (NGS), and methylation profiling have now clearly identified at least four molecular subgroups within medulloblastoma, each with distinct clinical and prognostic characteristics. These studies have clearly shown that despite the overall paucity of mutations, clinically relevant events do occur within the cellular epigenetic machinery. Thus, this review aims to provide an overview of our current understanding of the spectrum of epi-oncogenetic perturbations in medulloblastoma. METHODS: Comprehensive review of epigenetic profiles of different subgroups of medulloblastoma in the context of molecular features. Epigenetic regulation is mediated mainly by DNA methylation, histone modifications and microRNAs (miRNA). Importantly, epigenetic mis-events are reversible and have immense therapeutic potential. CONCLUSION: The widespread epigenetic alterations present in these tumors has generated intense interest in their use as therapeutic targets. We provide an assessment of the progress that has been made towards the development of molecular subtypes-targeted therapies and the current status of clinical trials that have leveraged these recent advances.
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Neoplasias Cerebelosas , Meduloblastoma , MicroARNs , Neoplasias Cerebelosas/genética , Neoplasias Cerebelosas/terapia , Metilación de ADN , Epigénesis Genética , Humanos , Meduloblastoma/genética , Meduloblastoma/terapia , MicroARNs/genéticaRESUMEN
BACKGROUND: As treatment modalities for medulloblastoma have developed and overall survival (OS) has improved, there are relatively limited data on the impact of long-term effects such as risk of second primary tumors (SPT). To address the knowledge gap, we analyzed factors associated with the risk of SPT and OS by treatment modality for medulloblastoma. METHODS: We queried the Surveillance, Epidemiology, and End Results (SEER)-18 database for patients diagnosed with medulloblastoma in 1973-2014. Patients were then grouped by age, gender, race, geographic region, histology, adjuvant treatment (no radiation [RT] and no chemotherapy [CT], RT and CT, RT alone, or CT alone), era of diagnosis (1973-1994 or 1995-2014), and survival time. Cumulative incidence, factors associated with SPT and OS were analyzed. RESULTS: Of 2271 patients, 146 developed SPT, of which 42 were benign. The incidence of SPT was 3.1% and 4.9% at 10 and 15 years, respectively. The incidence of SPT was 3.1% with RT + CT versus 3.7% with RT alone at 10 years. The most common site for an SPT was the central nervous system. Female gender (P = 0.01) and longer OS of ≥21 years (P < 0.01) were associated with higher risk of SPT. RT + CT led to better OS than RT only (66.1% and 61.4% vs 55.6% and 49.7% at 10 and 15 years) (P < 0.01). CONCLUSIONS: Medulloblastoma patients have a relatively low risk of SPT at 10 years with treatment. Use of RT + CT led to better OS with no statistical difference in SPT compared with the RT alone.
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Neoplasias Cerebelosas , Bases de Datos Factuales , Meduloblastoma , Neoplasias Primarias Secundarias , Adolescente , Adulto , Neoplasias Cerebelosas/diagnóstico , Neoplasias Cerebelosas/mortalidad , Neoplasias Cerebelosas/terapia , Niño , Preescolar , Supervivencia sin Enfermedad , Femenino , Humanos , Incidencia , Lactante , Recién Nacido , Masculino , Meduloblastoma/diagnóstico , Meduloblastoma/mortalidad , Meduloblastoma/terapia , Neoplasias Primarias Secundarias/diagnóstico , Neoplasias Primarias Secundarias/mortalidad , Estudios Retrospectivos , Factores de Riesgo , Tasa de SupervivenciaRESUMEN
There was a typo in author Andrew Wahba's name in the initial online publication. The original article has been corrected.
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PURPOSE: Medulloblastoma (MB) is the most common malignant brain tumor in children. Recent studies have shown the ability of natural killer (NK) cells to lyse MB cell lines in vitro, but in vivo successes remain elusive and the efficacy and fate of NK cells in vivo remain unknown. METHODS: To address these questions, we injected MB cells into the cerebellum of immunodeficient mice and examined tumor growth at various days after tumor establishment via bioluminescence imaging. NK cells were labeled with a fluorine-19 (19F) MRI probe and subsequently injected either intratumorally or contralaterally to the tumor in the cerebellum and effect on tumor growth was monitored. RESULTS: The 19F probe efficiently labeled the NK cells and exhibited little cytotoxicity. Fluorine-19 MRI confirmed the successful and accurate delivery of the labeled NK cells to the cerebellum of the mice. Administration of 19F-labeled NK cells suppressed MB growth, with the same efficacy as unlabeled cells. Immunohistochemistry confirmed the presence of NK cells within the tumor, which was associated with induction of apoptosis in tumor cells. NK cell migration to the tumor from a distal location as well as activation of apoptosis was also demonstrated by immunohstochemistry. CONCLUSIONS: Our results show that NK cells present a novel opportunity for new strategies in MB treatment. Further, 19F-labeled NK cells can suppress MB growth while enabling 19F MRI to provide imaging feedback that can facilitate study and optimization of therapeutic paradigms.
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Neoplasias Cerebelosas/prevención & control , Monitoreo de Drogas/métodos , Radioisótopos de Flúor/uso terapéutico , Células Asesinas Naturales/trasplante , Imagen por Resonancia Magnética/métodos , Meduloblastoma/prevención & control , Animales , Apoptosis , Proliferación Celular , Neoplasias Cerebelosas/inmunología , Neoplasias Cerebelosas/patología , Humanos , Meduloblastoma/inmunología , Meduloblastoma/patología , Ratones , Ratones Endogámicos NOD , Ratones SCID , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: H3 K27M-mutant diffuse midline glioma is a fatal malignancy with no proven medical therapies. The entity predominantly occurs in children and young adults. ONC201 is a small molecule selective antagonist of dopamine receptor D2/3 (DRD2/3) with an exceptional safety profile. Following up on a durable response in the first H3 K27M-mutant diffuse midline glioma patient who received ONC201 (NCT02525692), an expanded access program was initiated. METHODS: Patients with H3 K27M-mutant gliomas who received at least prior radiation were eligible. Patients with leptomeningeal spread were excluded. All patients received open-label ONC201 orally once every week. Safety, radiographic assessments, and overall survival were regularly assessed at least every 8 weeks by investigators. As of August 2018, a total of 18 patients with H3 K27M-mutant diffuse midline glioma or DIPG were enrolled to single patient expanded access ONC201 protocols. Among the 18 patients: seven adult (> 20 years old) and seven pediatric (< 20 years old) patients initiated ONC201 with recurrent disease and four pediatric patients initiated ONC201 following radiation, but prior to disease recurrence. FINDINGS: Among the 14 patients with recurrent disease prior to initiation of ONC201, median progression-free survival is 14 weeks and median overall survival is 17 weeks. Three adults among the 14 recurrent patients remain on treatment progression-free with a median follow up of 49.6 (range 41-76.1) weeks. Among the 4 pediatric patients who initiated adjuvant ONC201 following radiation, two DIPG patients remain progression-free for at least 53 and 81 weeks. Radiographic regressions, including a complete response, were reported by investigators in a subset of patients with thalamic and pontine gliomas, along with improvements in disease-associated neurological symptoms. INTERPRETATION: The clinical outcomes and radiographic responses in these patients provide the preliminary, and initial clinical proof-of-concept for targeting H3 K27M-mutant diffuse midline glioma with ONC201, regardless of age or location, providing rationale for robust clinical testing of the agent.
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Antineoplásicos/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Glioma/tratamiento farmacológico , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico , Histonas/genética , Mutación , Receptores de Dopamina D2/química , Adolescente , Adulto , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Niño , Preescolar , Femenino , Estudios de Seguimiento , Glioma/genética , Glioma/patología , Humanos , Imidazoles , Masculino , Pronóstico , Piridinas , Pirimidinas , Tasa de Supervivencia , Adulto JovenRESUMEN
Nearly 20 years ago, the concept of targeting the proteasome for cancer therapy began gaining momentum. This concept was driven by increased understanding of the biology/structure and function of the 26S proteasome, insight into the role of the proteasome in transformed cells, and the synthesis of pharmacological inhibitors with clinically favorable features. Subsequent in vitro, in vivo, and clinical testing culminated in the FDA approval of three proteasome inhibitors-bortezomib, carfilzomib, and ixazomib -for specific hematological malignancies. However, despite in vitro and in vivo studies pointing towards efficacy in solid tumors, clinical responses broadly have been evasive. For brain tumors, a malignancy in dire need of new approaches both in adult and pediatric patients, this has also been the case. Elucidation of proteasome-dependent processes in specific types of brain tumors, the evolution of newer proteasome targeting strategies, and the use of proteasome inhibitors in combination strategies will clarify how these agents can be leveraged more effectively to treat central nervous system malignancies. Since brain tumors represent a heterogeneous subset of solid tumors, and in particular, pediatric brain tumors possess distinct biology from adult brain tumors, tailoring of proteasome inhibitor-based strategies to specific subtypes of these tumors will be critical for advancing care for affected patients, and will be discussed in this review.
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Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , Inhibidores de Proteasoma/farmacología , Ubiquitina/metabolismo , Adulto , Animales , Niño , Glioma/tratamiento farmacológico , Glioma/metabolismo , Humanos , Redes y Vías Metabólicas/efectos de los fármacos , Inhibidores de Proteasoma/uso terapéuticoRESUMEN
BACKGROUND: Ganglioglioma (GG) is a rare mixed glial-neuronal neoplasm accounting for 0.5-5% of all pediatric central nervous system (CNS) tumors. Rarity of this tumor has precluded defining robust treatment guidelines. This retrospective study evaluates the prognostic factors and outcomes of this rare neoplasm. PATIENTS AND METHODS: Retrospective analysis of 55 patients with GG was conducted to describe clinical findings, and outcomes. Kaplan-Meier survival and Cox-regression analyses were performed to assess the overall survival (OS) and progression-free survival (PFS). RESULTS: The mean age at diagnosis was 11.8 years (range 1-21 years) with a median follow-up period of 9.5 years. 53 patients (92.7%) had low grade GG and 2 patients had anaplastic GG. 25 patients had tumor progression, whose median PFS was 12 years. Six patients with low grade GG progressed to a higher grade, with median survival of 9.1 month after transformation. The 5 and 10 year PFS were 65 and 57%, respectively. The 5 and 10 year OS was 96 and 86% respectively. 8 of the 19 (42%) samples tested demonstrated positivity for the BRAF V600E mutation. Multivariate Cox regression analyses showed location and extent of resection were significant factors for PFS and presence of metastatsis attained significance for OS. CONCLUSION: This is the one of the largest retrospective study of pediatric GG. Identifying clinical variables, which could stratify these tumors into low- and high-risk groups might help to profile a risk-based therapeutic strategy. Collaborative multiinstitutional prospective studies are warranted to delineate treatment consensus and investigate prognostic factors.
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Neoplasias Encefálicas/terapia , Ganglioglioma/terapia , Recurrencia Local de Neoplasia/terapia , Adolescente , Adulto , Neoplasias Encefálicas/patología , Niño , Preescolar , Terapia Combinada , Femenino , Estudios de Seguimiento , Ganglioglioma/patología , Humanos , Lactante , Masculino , Recurrencia Local de Neoplasia/patología , Pronóstico , Estudios Retrospectivos , Literatura de Revisión como Asunto , Tasa de Supervivencia , Adulto JovenRESUMEN
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.
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Neoplasias Cerebelosas/genética , Neoplasias Cerebelosas/terapia , Meduloblastoma/genética , Meduloblastoma/terapia , Adolescente , Adulto , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Neoplasias Cerebelosas/metabolismo , Neoplasias Cerebelosas/patología , Niño , Preescolar , Femenino , Humanos , Neoplasias Infratentoriales/genética , Neoplasias Infratentoriales/metabolismo , Neoplasias Infratentoriales/patología , Neoplasias Infratentoriales/terapia , Masculino , Meduloblastoma/metabolismo , Meduloblastoma/patología , Persona de Mediana Edad , Medicina de Precisión , Adulto JovenRESUMEN
Children with neurofibromatosis type 1 (NF1) are predisposed to develop central nervous system neoplasms, the most common of which are low-grade gliomas (LGGs). The absence of human NF1 associated LGG-derived cell lines, coupled with an inability to generate patient-derived xenograft models, represents barriers to profile molecularly targeted therapies for these tumors. Thus, genetically engineered mouse models have been identified to evaluate the interplay between Nf1-deficient tumor cells and nonneoplastic stromal cells to evaluate potential therapies for these neoplasms. Future treatments might also consider targeting the nonneoplastic cells in NF1-LGGs to reduce tumor growth and neurologic morbidity in affected children.
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Glioma , Neoplasias Experimentales , Neurofibromatosis 1 , Neurofibromina 1/deficiencia , Neoplasias del Nervio Óptico , Adolescente , Animales , Línea Celular Tumoral , Niño , Preescolar , Femenino , Glioma/genética , Glioma/metabolismo , Glioma/patología , Glioma/terapia , Humanos , Lactante , Recién Nacido , Masculino , Ratones , Neoplasias Experimentales/genética , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patología , Neoplasias Experimentales/terapia , Neurofibromatosis 1/genética , Neurofibromatosis 1/metabolismo , Neurofibromatosis 1/patología , Neurofibromatosis 1/terapia , Neoplasias del Nervio Óptico/genética , Neoplasias del Nervio Óptico/metabolismo , Neoplasias del Nervio Óptico/patología , Neoplasias del Nervio Óptico/terapia , Ensayos Antitumor por Modelo de Xenoinjerto/métodosRESUMEN
Advances in genomic, transcriptomic and epigenomic profiling now identifies pediatric ependymoma as a defined biological entity. Molecular interrogation has segregated these tumors into distinct biological subtypes based on anatomical location, age and clinical outcome, which now defines the need to tailor therapy even for histologically similar tumors. These findings now provide reasons for a paradigm shift in therapy, which should profile future clinical trials focused on targeted therapeutic strategies and risk-based treatment. The need to diagnose and differentiate the aggressive variants, which include the posterior fossa group A and the supratentorial RELA fusion subtypes, is imperative to escalate therapy and improve survival.
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Ependimoma/terapia , Animales , Ensayos Clínicos como Asunto , Terapia Combinada , Manejo de la Enfermedad , Ependimoma/diagnóstico , Ependimoma/etiología , Ependimoma/mortalidad , Humanos , Resultado del TratamientoRESUMEN
PURPOSE: Nuclear medicine studies have previously been utilized to assess for blockage of cerebrospinal fluid (CSF) flow prior to intraventricular chemotherapy infusions. To assess CSF flow without nuclear medicine studies, we obtained cine phase-contrast MRI sequences that assess CSF flow from the fourth ventricle down to the sacrum. METHODS: In three clinical trials, 18 patients with recurrent malignant posterior fossa tumors underwent implantation of a ventricular access device (VAD) into the fourth ventricle, either with or without simultaneous tumor resection. Prior to infusing therapeutic agents into the VAD, cine MRI phase-contrast CSF flow sequences of the brain and total spine were performed. Velocity encoding (VENC) of 5 and 10 cm/s was used to confirm CSF flow from the fourth ventricular outlets to the cervical, thoracic, and lumbar spine. Qualitative CSF flow was characterized by neuroradiologists as present or absent. RESULTS: All 18 patients demonstrated CSF flow from the outlets of the fourth ventricle down to the sacrum with no evidence of obstruction. One of these patients, after disease progression, subsequently showed obstruction of CSF flow. No patient required a nuclear medicine study to assess CSF flow prior to initiation of infusions. Fourteen patients have received infusions to date, and none has had neurological toxicity. CONCLUSIONS: CSF flow including the fourth ventricle and the total spine can be assessed noninvasively with phase-contrast MRI sequences. Advantages over nuclear medicine studies include avoiding both an invasive procedure and radiation exposure.
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Antineoplásicos/administración & dosificación , Líquido Cefalorraquídeo/diagnóstico por imagen , Cuarto Ventrículo/diagnóstico por imagen , Neoplasias Infratentoriales/diagnóstico por imagen , Infusiones Intraventriculares , Imagen por Resonancia Magnética/métodos , Adolescente , Niño , Preescolar , Medios de Contraste , Estudios de Evaluación como Asunto , Femenino , Cuarto Ventrículo/efectos de los fármacos , Humanos , Lactante , Neoplasias Infratentoriales/tratamiento farmacológico , Masculino , Adulto JovenRESUMEN
BACKGROUND: The treatment for childhood intracranial ependymoma includes maximal surgical resection followed by involved-field radiotherapy, commonly in the form of intensity-modulated radiation therapy (IMRT). Proton-beam radiation therapy (PRT) is used at some centers in an effort to decrease long-term toxicity. Although protons have the theoretical advantage of a minimal exit dose to the surrounding uninvolved brain tissue, it is unknown whether they have the same efficacy as photons in preventing local recurrence. METHODS: A retrospective review of medical records from September 2000 to April 2013 was performed. Seventy-nine children with newly diagnosed localized intracranial ependymomas treated with either IMRT (n = 38) or PRT (n = 41) were identified, and progression-free survival (PFS) was analyzed with Kaplan-Meier and Cox multivariate analyses. RESULTS: The median age at diagnosis was 3.7 years for all patients (range, 0.4-18.7 years). There were 54 patients with infratentorial tumors (68% of the total population). Patients treated with PRT were younger (median age, 2.5 vs 5.7 years; P = .001) and had a shorter median follow-up (2.6 vs 4.9 years; P < .0001). Gross total resection (GTR) was achieved in 67 patients (85%) and was more frequent in the PRT group versus the IMRT group (93% vs 76%; P = .043). The 3-year PFS rates were 60% and 82% with IMRT and PRT, respectively (P = .031). CONCLUSIONS: Children with localized ependymomas treated with PRT have a 3-year PFS rate comparable to that of children treated with IMRT. This analysis suggests that local control is not compromised by the use of PRT. The data also support GTR as the only prognostic factor for PFS. Cancer 2017;123:2570-78. © 2017 American Cancer Society.
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Neoplasias Encefálicas/radioterapia , Ependimoma/radioterapia , Procedimientos Neuroquirúrgicos , Terapia de Protones/métodos , Radioterapia de Intensidad Modulada/métodos , Adolescente , Niño , Preescolar , Supervivencia sin Enfermedad , Femenino , Humanos , Lactante , Masculino , Radioterapia Adyuvante , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
There is a paucity of literature reporting the outcome of intracranial sarcomas (IS) in children, adolescents, and young adults (CAYA). A multimodal therapeutic approach is commonly used, with no well-established treatment consensus. We conducted a retrospective review of CAYA with IS, treated at our institution, to determine their clinical findings, treatments, and outcomes. Immunohistochemistry (PDGFRA and EGFR) and DNA sequencing were performed on 5 tumor samples. A literature review of IS was also conducted. We reviewed 13 patients (median age, 7 years) with a primary diagnosis of IS between 1990 and 2015. Diagnoses included unclassified sarcoma (n = 9), chondrosarcoma (n = 2), and rhabdomyosarcoma (n = 2). Five patients underwent upfront gross total resection (GTR) of the tumor. The 5-drug regimen (vincristine, doxorubicin, cyclophosphamide, etoposide, and ifosfamide) was the most common treatment used. Nine patients died due to progression or recurrence (n = 8) or secondary malignancy (n = 1). The median follow-up period of the 4 surviving patients was 1.69 years (range 1.44-5.17 years). The 5-year progression-free survival and overall survival rates were 21 and 44 %, respectively. BRAF, TP53, KRAS, KIT, ERBB2, MET, RET, ATM, and EGFR mutations were detected in 4 of the 5 tissue samples. All 5 samples were immunopositive for PDGFRA, and only 2 were positive for EGFR. IS remain a therapeutic challenge due to high progression and recurrence rates. Collaborative multi-institutional studies are warranted to delineate a treatment consensus and investigate tumor biology to improve the disease outcome.
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Biomarcadores de Tumor/metabolismo , Neoplasias Encefálicas/patología , Recurrencia Local de Neoplasia/patología , Neoplasias de los Tejidos Blandos/patología , Adolescente , Adulto , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/terapia , Niño , Preescolar , Terapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Técnicas para Inmunoenzimas , Lactante , Recién Nacido , Masculino , Recurrencia Local de Neoplasia/metabolismo , Recurrencia Local de Neoplasia/terapia , Estadificación de Neoplasias , Pronóstico , Neoplasias de los Tejidos Blandos/metabolismo , Neoplasias de los Tejidos Blandos/terapia , Tasa de Supervivencia , Adulto JovenRESUMEN
Currently medulloblastoma is treated with a uniform therapeutic approach based on histopathology and clinico-radiological risk stratification, resulting in unpredictable treatment failure and relapses. Improved understanding of the biological, molecular and genetic make-up of these tumors now clearly identifies it as a compendium of four distinct subtypes (WNT, SHH, group 3 and 4). Advances in utilization of the genomic and epigenomic machinery have now delineated genetic aberrations and epigenetic perturbations in each subgroup as potential druggable targets. This has resulted in endeavors to profile targeted therapy. The challenge and future of medulloblastoma therapeutics will be to keep pace with the evolving novel biological insights and translating them into optimal targeted treatment regimens.
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Proteínas Hedgehog/genética , Meduloblastoma/tratamiento farmacológico , Meduloblastoma/genética , Proteínas Wnt/genética , Epigenómica , Proteínas Hedgehog/antagonistas & inhibidores , Humanos , Meduloblastoma/clasificación , Meduloblastoma/patología , Terapia Molecular Dirigida , Proteínas Wnt/antagonistas & inhibidoresRESUMEN
We hypothesize that chemotherapy can be safely administered directly into the fourth ventricle to treat recurrent malignant brain tumors in children. For the first time in humans, methotrexate was infused into the fourth ventricle in children with recurrent, malignant brain tumors. A catheter was surgically placed into the fourth ventricle and attached to a ventricular access device. Cerebrospinal fluid (CSF) flow was confirmed by CINE MRI postoperatively. Each cycle consisted of 4 consecutive daily methotrexate infusions (2 milligrams). Disease response was monitored with serial MRI scans and CSF cytologic analysis. Trough CSF methotrexate levels were sampled. Five patients (3 with medulloblastoma and 2 with ependymoma) received 18, 18, 12, 9, and 3 cycles, respectively. There were no serious adverse events or new neurological deficits attributed to methotrexate. Two additional enrolled patients were withdrawn prior to planned infusions due to rapid disease progression. Median serum methotrexate level 4 h after infusion was 0.04 µmol/L. Range was 0.02-0.13 µmol/L. Median trough CSF methotrexate level 24 h after infusion was 3.18 µmol/L (range 0.53-212.36 µmol/L). All three patients with medulloblastoma had partial response or stable disease until one patient had progressive disease after cycle 18. Both patients with ependymoma had progressive disease after 9 and 3 cycles, respectively. Low-dose methotrexate can be infused into the fourth ventricle without causing neurological toxicity. Some patients with recurrent medulloblastoma experience a beneficial anti-tumor effect both within the fourth ventricle and at distant sites.
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Antineoplásicos/administración & dosificación , Neoplasias del Ventrículo Cerebral/tratamiento farmacológico , Ependimoma/tratamiento farmacológico , Meduloblastoma/tratamiento farmacológico , Metotrexato/administración & dosificación , Tumor Rabdoide/tratamiento farmacológico , Adolescente , Niño , Preescolar , Femenino , Cuarto Ventrículo/efectos de los fármacos , Humanos , Imagen por Resonancia Magnética , Masculino , Recurrencia Local de Neoplasia , Proyectos Piloto , Médula Espinal/patología , Adulto JovenRESUMEN
BACKGROUND: Choroid plexus carcinoma (CPC) is a rare aggressive intracranial neoplasm with a predilection for young children and a historically poor outcome. Currently, no defined optimal therapeutic strategy exists. The Head Start (HS) regimens have included irradiation-avoiding strategies in young children with malignant brain tumors using high dose chemotherapy to improve survival and minimize neurocognitive sequelae. PROCEDURE: Three sequential HS studies have been conducted from 1991 to 2009. HS treatment strategy has consisted of maximal surgical resection followed by five cycles of intensive induction followed by consolidation myeloablative chemotherapy with autologous hematopoietic stem cell rescue (AuHCR). Irradiation was given following recovery from consolidation based on the patient's age and evidence of residual disease. RESULTS: Twelve children with CPC (median age of 19.5 months) have been treated with HS regimens. Ten patients had >95% resection. Three patients had disseminated disease at diagnosis. Ten patients completed consolidation of whom five are alive, irradiation and disease free at 29, 43, 61, 66 and 89 months from diagnosis. Seven patients experienced tumor recurrence/progression at a median time of 13 months (range 2-43 months). Five patients received irradiation, one for residual disease and four upon progression or recurrence, of whom one is alive at 61 months. The 3- and 5-year progression-free survivals are 58% and 38% and overall survivals 83% and 62% respectively. Late deaths from disease beyond 5 years were also noted. CONCLUSION: Head Start strategies may produce long-term remission in young children with newly diagnosed CPC with avoidance of cranial irradiation.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Encefálicas/terapia , Carcinoma/terapia , Neoplasias del Plexo Coroideo/terapia , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/patología , Carboplatino/administración & dosificación , Carcinoma/mortalidad , Carcinoma/patología , Quimioradioterapia , Preescolar , Neoplasias del Plexo Coroideo/mortalidad , Neoplasias del Plexo Coroideo/patología , Cisplatino/administración & dosificación , Irradiación Craneana , Ciclofosfamida/administración & dosificación , Etopósido/administración & dosificación , Femenino , Estudios de Seguimiento , Humanos , Lactante , Recién Nacido , Agencias Internacionales , Masculino , Estadificación de Neoplasias , Pronóstico , Estudios Prospectivos , Tasa de Supervivencia , Vincristina/administración & dosificaciónRESUMEN
Low-grade gliomas are the commonest brain tumor in children comprising heterogeneous pathological entities. Though the overall prognosis is good, unresectable, and recurrent or progressive tumors in eloquent areas of the brain remain major therapeutic challenge even with advances in chemotherapeutic strategies. With the evolving surge of molecular data, improved understanding of the biology of these tumors is now perceivable that could provide insights into novel therapies. We hope the new era will enable us to profile comprehensive histopathological/molecular classification and prognostic molecular markers in these tumors and guide us to tailor optimal targeted therapy.
Asunto(s)
Neoplasias Encefálicas/patología , Glioma/patología , Biomarcadores de Tumor , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Niño , Glioma/genética , Glioma/terapia , Humanos , PronósticoRESUMEN
Currently, the treatment of childhood medulloblastoma (MB) is tailored to risk groups defined by clinical parameters. Growing evidence of tumoral heterogeneity is apparent as response remains varied and unpredictable based on current treatment strategies, indicating the lack of understanding of the elusive biology that drives oncogenesis of these tumors. Advances in genomic technologies are revealing newer insights into the molecular pathogenesis of MB. Utilization of the genomic machinery has enabled the definition of new molecular markers and signaling pathways, resulting in a paradigm shift in the classification of childhood MB. Recent focus into the postgenomic era has revealed varied perturbations in the epigenetic machinery in these subtypes as likely predictive biomarkers and potential therapeutic targets. Ahead lies the task and challenge in the ability to comprehensively evaluate all these data, which could provide clues to profile the next-generation clinical trials combining conventional with molecularly targeted novel therapies.