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PURPOSE: To describe the clinical and imaging features of a sellar-suprasellar pineoblastoma RB1 subgroup without pineal or retinal involvement. CASE REPORT: An 11-month-old girl presented to the emergency department with fever, rhinorrhea, vomiting, altered level of consciousness, and one seizure. Head CT and brain MRI demonstrated a large lobulated mass with calcifications and heterogeneous enhancement in the suprasellar region causing mass effect to the ventricular system and hydrocephalus. Histology revealed a CNS embryonal tumor not otherwise specified (NOS) with small round nuclei with mitotic activity and necrosis. DNA methylation analysis classified the tumor in the pineoblastoma RB1 subgroup. CONCLUSION: Pineoblastoma RB1 subgroup should be considered in the differential diagnosis of large sellar-suprasellar masses with calcifications and heterogeneous enhancement in children younger than 18 months even in cases of absent pineal or retinal involvement. Molecular analysis with DNA methylation profiling is critical for diagnosis and management.
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Neoplasias Encefálicas , Neoplasias del Sistema Nervioso Central , Glándula Pineal , Pinealoma , Neoplasias de la Retina , Femenino , Humanos , Lactante , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/genética , Neoplasias del Sistema Nervioso Central/patología , Glándula Pineal/diagnóstico por imagen , Pinealoma/diagnóstico por imagen , Pinealoma/genética , Neoplasias de la Retina/diagnóstico por imagen , Neoplasias de la Retina/patología , Proteínas de Unión a Retinoblastoma , Ubiquitina-Proteína LigasasRESUMEN
The embryonal central nervous system (CNS) tumor with PLAGL1 (pleomorphic adenoma gene-like) amplification is a novel type of pediatric neoplasm with a distinct methylation profile, described for the first time in 2022. It may be located anywhere in the neuroaxis and, as its name implies, it is driven by the amplification and overexpression of one of the PLAG family genes. Although the associated clinical, immunohistopathological, and molecular characteristics are well characterized in the seminal report of this entity, data on the radiological features is still lacking. Here, we present a case report of a 4-year-old girl with a biopsy-proven PLAGL1-amplified brainstem tumor and provide a detailed description of the corresponding conventional neuroimaging characteristics, aiming to better delineate this entity and to increase the awareness of this pathology in the radiological community.
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Factores de Transcripción , Humanos , Femenino , Preescolar , Factores de Transcripción/genética , Proteínas Supresoras de Tumor/genética , Neoplasias de Células Germinales y Embrionarias/diagnóstico por imagen , Neoplasias de Células Germinales y Embrionarias/genética , Neoplasias de Células Germinales y Embrionarias/patología , Imagen por Resonancia Magnética , Amplificación de Genes , Neoplasias del Tronco Encefálico/genética , Neoplasias del Tronco Encefálico/diagnóstico por imagen , Neoplasias del Tronco Encefálico/patología , Proteínas de Ciclo CelularRESUMEN
Objective: Basic and translational research in pediatric cancer are essential to improve patient care. To critically assess the developments achieved in these areas in Latin America, we systematically reviewed information published between 2013 and 2023. Methods: Studies of basic and translational research performed by investigators in Latin America evaluating pediatric malignant solid and central nervous system tumors were retrieved from PubMed. Original articles published in English between 2013 and 2023 were included. Collaborations among Latin American authors or among Latin American authors working with researchers from other continents were also included. Studies were excluded if they focused only on adults or on basic research in tumor biology not specifically related to the tumor types analyzed in this review. Results: A total of 550 articles were retrieved, but after removal of duplicates, 514 articles were included in the analysis, the majority of which were authored by researchers affiliated with institutions in Argentina, Brazil and Mexico. These countries also had the highest number of collaborations on original articles published with authors from Europe and North America. Argentina had the highest number of collaborations on original publications, with coauthors from Brazil and Uruguay. The median impact factor of the 244 journals in which articles were published was 3.5. The most commonly studied tumors were osteosarcomas, neuroblastomas and medulloblastomas; the most commonly studied areas were molecular analysis, tumor cell biology and biomarkers. Conclusions: In Latin America, research in pediatric oncology is on the agenda, despite a notable disparity in publication rates and frequency of collaboration between countries. There is a need to strengthen scientific collaboration within Latin America and with countries from other continents to promote research and to develop novel treatment strategies that reflect the local needs of children in Latin America who have solid tumors and brain cancer.
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PURPOSE: Central nervous system high-grade neuroepithelial tumor with MN1 alteration (CNS-HGNET-MN1) is a rare entity defined by its DNA methylation pattern and pathologically considered to be high-grade with mixed patterns, stromal hyalinization, and with astrocytic differentiation. Our aim was to present six pediatric cases to contribute to the characterization of this group of tumors. MATERIAL AND METHODS: Six female patients aged 4 to 12 years with CNS tumors with MN1 alteration identified using genome-wide methylation arrays and/or RT-PCR were included. Clinicopathological, morphological, immunohistochemical, and molecular findings were analyzed. RESULTS: Tumor location was the parietal lobe in four and the intramedullary spinal cord in two. Two were morphologically diagnosed as ependymomas, one as gliofibroma, one as a HGNET-MN1 altered and the other two were difficult to classify. All were well-defined tumors, with a cystic component in three. Only two tumors had extensive stromal hyalinization, three had pseudopapillary formations, and four had other patterns. Multinucleated, clear, and rhabdoid cells were present. Necrosis and histiocyte clusters were also observed. Proliferative index was >10 in four. GFAP, EMA, CK, and SYN were variable, while Olig2 staining was mostly positive. Four of six patients with supratentorial tumors and complete resections were alive and tumor free after 2 to 10 years of follow-up. The two cases with medullary involvement and incomplete resections were alive and undergoing treatment 2 years after surgery. CONCLUSION: Neuroepithelial-MN1 tumors are challenging and suspicion requires molecular confirmation. Our pediatric data contribute to the knowledge for accurate diagnosis. Although further studies with a larger number of cases should be conducted in order to draw more robust conclusions regarding clinico-pathological features, here we present valuable pediatric data to increase the knowledge that may lead to the accurate management of this group of tumors.
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Neoplasias Encefálicas , Neoplasias del Sistema Nervioso Central , Neoplasias Neuroepiteliales , Neoplasias Supratentoriales , Niño , Humanos , Femenino , Neoplasias Encefálicas/patología , Neoplasias del Sistema Nervioso Central/patología , Neoplasias Neuroepiteliales/genética , Médula Espinal/patología , Transactivadores , Proteínas Supresoras de Tumor/genéticaRESUMEN
INTRODUCTION: Ventriculo-peritoneal shunt (VPS) related ascites is a rare complication of pediatric low grade gliomas (pLGG). Physiopathology of this complication is not fully understood and there is paucity of data regarding the molecular profile of pLGG gliomas complicating with ascites and the optimal management of this unusual event. METHODS: International multi-institutional retrospective analysis of patients diagnosed with BRAF altered pLGG and ascites arising as a complication of VPS. Demographics, tumor characteristics, therapeutic approaches and outcomes were recorded. RESULTS: Nineteen patients were identified. Median age at diagnosis was 14 months (R: 2-144). Most patients (17; 89.4%) presented with lesions involving the optic pathway. Mean tumor standard volume was 34.8 cm2 (R: 12.5-85.4). Pilocytic Astrocytoma was the most frequent histological diagnosis (14;7 3.7%). Eight (42.1%) tumors harbored BRAF V600-E mutation and seven (36.8%) KIAA1549 fusion. The onset of ascites was documented at a median time of 5 months following VPS insertion. Four (21%) patients were managed with paracentesis only, 7(36.8%) required both paracentesis and shunt diversion, 7(36.8%) required only a shunt diversion and 1 (5.2%) patient was managed conservatively. Chemotherapy regimen was changed in 10 patients following ascites. Eight patients received targeted therapy (4 dabrafenib/4 trametinib) and 5 were radiated. There were eleven survivors with a median OS of 69 months (R: 3-144). CONCLUSIONS: Ascites is an early feature in the clinical course of young patients with midline BRAF altered pLGG, with high mortality rate observed in our cohort. The hypothesis of ascites as an adverse prognostic factor in pLGG warrants further prospective research.
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Neoplasias Encefálicas , Glioma , Ascitis/etiología , Neoplasias Encefálicas/complicaciones , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Niño , Glioma/genética , Humanos , Estudios Retrospectivos , Derivación Ventriculoperitoneal/efectos adversosRESUMEN
Therapeutic strategies avoiding craniospinal irradiation were developed for young children with medulloblastoma to improve survival while protecting the neurocognitive outcomes of these vulnerable patients. These strategies most commonly rely on high-dose chemotherapy with stem cell rescue or conventional chemotherapy combined with intraventricular chemotherapy or conventional chemotherapy with adjuvant focal irradiation. Over the past decade, our growing understanding of the molecular landscape of medulloblastoma has transformed how we risk stratify and allocate treatment in this young age group. We present the results of the most recent approaches and clinical trials for medulloblastoma of early childhood, according to the different molecular subgroups. Overall, young children with sonic hedgehog medulloblastoma treated with intensive adjuvant chemotherapy achieve excellent survival and can safely be spared from radiotherapy. For patients with group 3 and 4 medulloblastomas, the interplay between molecular alterations and treatment intensity still needs to be further delineated. While recent clinical trials point toward more encouraging survival figure for a sizeable number of them, patients identified with very high-risk feature desperately needs innovative therapies.
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Neoplasias Cerebelosas , Meduloblastoma , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Cerebelosas/tratamiento farmacológico , Quimioterapia Adyuvante , Niño , Preescolar , Terapia Combinada , Proteínas Hedgehog , Humanos , Meduloblastoma/radioterapia , Radioterapia AdyuvanteRESUMEN
Medulloblastoma has a reduced incidence in Down syndrome (DS). This protective characteristic has not been clarified yet. Here, we report the second case of SHH medulloblastoma and DS documented in the literature. A complete surgery was performed followed by reduced craniospinal irradiation dose and adjuvant chemotherapy. No evidence of tumor recurrence was observed. The overall survival was 9.1 years. No family history or physical stigma of other hereditary predisposition syndrome was found. In the elucidation of this extremely rare association, future case reports play an important role in defining the spectrum of brain tumors and their peculiar features in DS.
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Neoplasias Cerebelosas , Irradiación Craneoespinal , Síndrome de Down , Meduloblastoma , Neoplasias Cerebelosas/tratamiento farmacológico , Síndrome de Down/complicaciones , Humanos , Meduloblastoma/patología , Recurrencia Local de NeoplasiaRESUMEN
BACKGROUND: Many studies have demonstrated in the last years that once medulloblastoma has recurred, the probability of regaining tumor control is poor despite salvage therapy. Although re-irradiation has an emerging role in other relapsed brain tumors, there is a lack of strong data on re-irradiation for medulloblastoma. METHODS: This is a retrospective cohort study of patients aged 18 years or under, treated at least by a second course of external beam for recurrence medulloblastoma at Garrahan Hospital between 2009 and 2020. Twenty-four patients met eligibility criteria for inclusion. All patients received upfront radiotherapy as part of the curative-intent first radiotherapy, either craniospinal irradiation (CSI) followed by posterior fossa boost in 20 patients or focal posterior fossa radiation in 4 infants. The second course of radiation consisted of CSI in 15 and focal in 9. The 3-year post first failure OS (50% vs. 0%; p = 0.0010) was significantly better for children who received re-CSI compared to children who received focal re-irradiation. Similarly, the 3-year post-re-RT PFS (31% vs. 0%; p = 0.0005) and OS (25% vs. 0%; p = 0.0003) was significantly improved for patients who received re-CSI compared to patients who received focal re-irradiation. No symptomatic intratumoral haemorrhagic events or symptomatic radionecrosis were observed. Survivors fell within mild to moderate intellectual disability range, with a median IQ at last assessment of 58 (range 43-69). CONCLUSIONS: Re-irradiation with CSI is a safe and effective treatment for children with relapsed medulloblastoma; improves disease control and survival compared with focal re-irradiation. However this approach carries a high neurocognitive cost.
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Neoplasias Cerebelosas , Irradiación Craneoespinal , Meduloblastoma , Reirradiación , Neoplasias Encefálicas , Neoplasias Cerebelosas/radioterapia , Niño , Estudios de Seguimiento , Humanos , Lactante , Meduloblastoma/radioterapia , Recurrencia Local de Neoplasia/radioterapia , Dosificación Radioterapéutica , Estudios RetrospectivosRESUMEN
BACKGROUND: Intracranial germ cell tumor (iGCT) represents a rare and heterogeneous group, with variable incidence and diverse treatment strategies. Although multiagent chemotherapy with reduced radiotherapy strategy has been applied by several cooperative groups in North America and Western Europe, there is a paucity of data to understand if this combined regimen is suitable in low-middle income countries (LMIC). METHODS: We evaluate the outcome in a cohort of iGCT treated by SIOP-CNS-GCT-96 strategy at hospital J.P Garrahan in Argentina over the last 20 years. Radiation field and dose included focal radiotherapy (FRT) before 2009 or focal radiotherapy plus whole ventricular radiotherapy (WVRT) after 2009 for localized germinoma and FRT or FRT plus WVRT or CSI for non germinomatous germ cell tumors (NGGCT) RESULTS: Sixty iGCT were identified; 39 germinoma and 21 NGGCT. Median follow-up was 6.57 years (range 0.13-20.5). 5-year PFS and OS were 83.5% (95% CI [165.53-223.2]) and 88.7% (95% CI [169.84-223.2]) for the germinoma group, while for the NGGCT group were 75% (95% CI [133.27-219.96]) and 64.2% (95% CI [107.38-201.81]) respectively. The localized germinoma group showed poor results between 2000 and 2009 with 5-year PFS and OS of 69 and 75% respectively, and an excellent outcome between 2010 and 2019 with a 5-years PFS and OS of 92.8 and 100%. A univariable analysis identified this difference in survival as related to the field of radiotherapy, specifically whole ventricular radiotherapy. FRT increased the risk of recurrence in localized germinoma, involving not only ventricular relapses; but spinal cord and disseminated disease as well. There were no relapses of localized NGGCT after FRT and FRT plus WVRT. CONCLUSION: Herein we demonstrate that intensive chemotherapy followed by FRT plus WVRT for germinoma is a feasible and effective strategy, warranting further study in the developing world.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias Encefálicas/terapia , Neoplasias de Células Germinales y Embrionarias/terapia , Radioterapia/métodos , Adolescente , Argentina , Quimioterapia Adyuvante/métodos , Niño , Irradiación Craneana/métodos , Femenino , Humanos , Masculino , Terapia Neoadyuvante/métodos , Estudios RetrospectivosRESUMEN
Diffuse intrinsic pontine glioma (DIPG) is characterized by a short history of brainstem symptoms and well-known magnetic resonance imaging features with a fatal outcome. However, we report three unusual cases of brainstem tumors with an initial indolent and protracted course, which subsequently developed the classical imaging and clinical features of DIPG. Our findings support this notion that K27M is an early event in development and suggest that the emergence of additional events resulted in rapid progression after a long period of latency. Identification of such markers of aggressive behavior in the context of an indolent course is needed for better characterization and treatment management.
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Neoplasias del Tronco Encefálico/patología , Glioma Pontino Intrínseco Difuso/patología , Histonas/genética , Mutación , Neoplasias del Tronco Encefálico/genética , Neoplasias del Tronco Encefálico/terapia , Niño , Preescolar , Glioma Pontino Intrínseco Difuso/genética , Glioma Pontino Intrínseco Difuso/terapia , Femenino , Humanos , Lactante , Masculino , PronósticoRESUMEN
Seventeen children at six institutions with neurofibromatosis type 2 (NF2)-related vestibular schwannomas received bevacizumab. Eight of the 13 patients with initial hearing loss (61%) showed objective hearing improvement within six months of treatment. No patients showed hearing deterioration during therapy; however, only two patients showed objective radiological response. Seven of eight patients had tumor progression or worsening hearing loss upon cessation of treatment. Bevacizumab was well tolerated with no patients discontinuing therapy. Bevacizumab appears to postpone hearing loss in childhood NF2-associated vestibular schwannomas, but responses are not durable, suggesting that either longer maintenance therapy or new strategies are required.
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Bevacizumab/administración & dosificación , Neurofibromina 2/metabolismo , Neuroma Acústico/tratamiento farmacológico , Neuroma Acústico/metabolismo , Adolescente , Niño , Femenino , Humanos , Masculino , Neuroma Acústico/patología , Neuroma Acústico/fisiopatologíaRESUMEN
Central nervous system high-grade neuroepithelial tumor with MN1 alteration (CNS HGNET-MN1) is a rare recently described entity. Fourteen CNS HGNET-MN1 patients were identified using genome-wide methylation arrays/RT-PCR across seven institutions. All patients had surgery (gross total resection: 10; subtotal resection: four) as initial management followed by observation alone in three patients, followed by radiotherapy in eight patients (focal: five; craniospinal: two; CyberKnife: one) and systemic chemotherapy in three patients. Seven patients relapsed; five local and two metastatic, despite adjuvant radiotherapy, of which three died. Treatment of CNS HGNET-MN1 remains a major treatment challenge despite aggressive surgical resections and upfront radiotherapy, warranting new approaches to this rare malignancy.
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Neoplasias del Sistema Nervioso Central/patología , Mutación , Neoplasias Neuroepiteliales/patología , Transactivadores/genética , Proteínas Supresoras de Tumor/genética , Adolescente , Adulto , Neoplasias del Sistema Nervioso Central/genética , Neoplasias del Sistema Nervioso Central/terapia , Niño , Preescolar , Terapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Masculino , Neoplasias Neuroepiteliales/genética , Neoplasias Neuroepiteliales/terapia , Pronóstico , Estudios Retrospectivos , Adulto JovenAsunto(s)
COVID-19 , Neoplasias , Resiliencia Psicológica , COVID-19/epidemiología , Niño , Humanos , Oncología Médica , Neoplasias/epidemiología , Neoplasias/terapia , Pandemias , SARS-CoV-2RESUMEN
We report a retrospective review of patients with retinoblastoma and anterior segment invasion (ASI) as risk factors for extraocular relapse. Only those with ASI combined with postlaminar optic nerve invasion and/or scleral invasion received adjuvant chemotherapy and those with tumor at the resection margin received orbital radiotherapy. Those with only uveal invasion did not receive adjuvant therapy. Of 479 evaluable patients, 67 patients had pathologically confirmed ASI, including 52 with anterior chamber invasion and 47 with iris or ciliary body invasion. ASI occurred with other pathology risk factors (25 had concomitant posterior uveal invasion, 36 had postlaminar optic nerve invasion, 11 with cut-end invasion, and 25 with scleral invasion). The 5-year disease-free survival (pDFS) was 0.9 (95% CI, 0.8-0.95) for children with ASI with no significant differences among children with other pathology risk factors with and without ASI. ASI was not significantly associated with extraocular relapse in multivariate analysis. There were no significant differences in pDFS for patients with anterior chamber invasion and those with iris-ciliary body invasion (pDFS 0.89 [95% CI, 0.65-0.96] vs. 0.93 [95% CI, 0.61-0.98]). To conclude, ASI was seen with other pathology risk factors and it did not add a significant risk for extraocular relapse.
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Segmento Anterior del Ojo/patología , Neoplasias de la Retina/epidemiología , Neoplasias de la Retina/patología , Retinoblastoma/epidemiología , Retinoblastoma/patología , Quimioterapia Adyuvante , Niño , Cuerpo Ciliar/patología , Humanos , Lactante , Iris/patología , Invasividad Neoplásica , Nervio Óptico/patología , Recurrencia , Neoplasias de la Retina/tratamiento farmacológico , Retinoblastoma/tratamiento farmacológico , Estudios Retrospectivos , Factores de Riesgo , Esclerótica/patologíaRESUMEN
PURPOSE: Infant and young childhood medulloblastoma (iMB) is usually treated without craniospinal irradiation (CSI) to avoid neurocognitive late effects. Unfortunately, many children relapse. The purpose of this study was to assess salvage strategies and prognostic features of patients with iMB who relapse after CSI-sparing therapy. METHODS: We assembled a large international cohort of 380 patients with relapsed iMB, age younger than 6 years, and initially treated without CSI. Univariable and multivariable Cox models of postrelapse survival (PRS) were conducted for those treated with curative intent using propensity score analyses to account for confounding factors. RESULTS: The 3-year PRS, for 294 patients treated with curative intent, was 52.4% (95% CI, 46.4 to 58.3) with a median time to relapse from diagnosis of 11 months. Molecular subgrouping was available for 150 patients treated with curative intent, and 3-year PRS for sonic hedgehog (SHH), group 4, and group 3 were 60%, 84%, and 18% (P = .0187), respectively. In multivariable analysis, localized relapse (P = .0073), SHH molecular subgroup (P = .0103), CSI use after relapse (P = .0161), and age ≥ 36 months at initial diagnosis (P = .0494) were associated with improved survival. Most patients (73%) received salvage CSI, and although salvage chemotherapy was not significant in multivariable analysis, its use might be beneficial for a subset of children receiving salvage CSI < 35 Gy (P = .007). CONCLUSION: A substantial proportion of patients with relapsed iMB are salvaged after initial CSI-sparing approaches. Patients with SHH subgroup, localized relapse, older age at initial diagnosis, and those receiving salvage CSI show improved PRS. Future prospective studies should investigate optimal CSI doses and the role of salvage chemotherapy in this population.
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Neoplasias Encefálicas , Neoplasias Cerebelosas , Irradiación Craneoespinal , Meduloblastoma , Niño , Humanos , Lactante , Preescolar , Meduloblastoma/radioterapia , Estudios de Cohortes , Estudios Prospectivos , Irradiación Craneoespinal/efectos adversos , Proteínas Hedgehog , Recurrencia Local de Neoplasia , Neoplasias Encefálicas/terapia , Enfermedad Crónica , Neoplasias Cerebelosas/radioterapiaRESUMEN
The BRAFV600E point mutation plays a key role in the tumorigenesis of many gliomas. Inhibiting its product is part of the innovative therapies emerging in recent years. Knowing the role of these treatments is essential. The aim of this experience was to describe the clinical-radiological response of pediatric BRAFV600E mutated gliomas treated with BRAF inhibitors. To this end, a descriptive and retrospective study was performed in patients under 16 years of age with BRAFV600E gliomas, who received vemurafenib or dabrafenib at Hospital Garrahan. Thirteen patients treated in the last 7 years were included: 9 were low-grade and 4 high-grade gliomas. The median age at diagnosis was 8.6 years (0.89-14.04) and at start of targeted therapy was 11.62 years (3.64-15.42). All patients had previously a surgical procedure, and 12/13 had received another therapy prior BRAF inhibition: 11 chemotherapy (in one case, up to 4 different protocols) and 4 radiotherapy. Under targeted therapy, tumour response was obtained in 10 patients (size reduction equal to or greater than 25%), and best response was observed in the first 6 months of treatment in 7 children. Four patients progressed under treatment (all high-grade gliomas) and 2 progressed shortly after stopping the inhibitor (both low-grade gliomas). Five patients had grade 3-4 toxicity, with subsequent full recovery. A good and sustained clinical-radiological response, with acceptable tolerance, is described in patients with BRAFV600E mutated low-grade gliomas treated with BRAFV600E inhibitors. In contrast, the response in patients with high-grade gliomas was intermediate and of short duration, with early tumour progression.
La mutación puntual V600E del gen BRAF juega un papel fundamental en la tumorigénesis de muchos gliomas. La inhibición de su producto forma parte de terapias innovadoras emergentes en los últimos años. Conocer el rol de estos tratamientos resulta imprescindible. El objetivo del trabajo fue describir la respuesta clínico-radiológica en niños con gliomas BRAFV600E mutado tratados con inhibidores BRAF. Para ello se realizó un estudio descriptivo y retrospectivo en pacientes menores de 16 años con gliomas BRAFV600E mutado que recibieron vemurafenib o dabrafenib en el Hospital Garrahan. Trece pacientes tratados en los últimos 7 años fueron incluidos: 9 gliomas de bajo grado y 4 de alto grado. La mediana de edad al diagnóstico fue 8.6 años (0.89-14.04) y del comienzo del inhibidor 11.62 años (3.64-15.42). Inicialmente, todos habían realizado tratamiento quirúrgico, y 12/13 recibieron previamente otra terapia: 11 quimioterapia (eventualmente hasta 4 líneas distintas) y 4 radioterapia. Con la terapia dirigida, 10 pacientes tuvieron una disminución tumoral mayor o igual al 25%, quedando evidenciada en 7 niños la mejor respuesta dentro de los 6 meses del inicio. Hubo 4 progresados intratratamiento (todos alto grado), y 2 progresados prontamente luego de suspender el inhibidor (ambos bajo grado). Cinco presentaron efectos adversos grado 3-4, con recuperación ad-integrum. Se describe una buena y sostenida respuesta clínico-radiológica, con tolerancia aceptable, en pacientes con gliomas de bajo grado BRAFV600E mutado tratados con inhibidores BRAFV600E. En contraste, la respuesta en pacientes con gliomas de alto grado fue intermedia y de poca duración, con progresión tumoral precoz.
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Glioma , Proteínas Proto-Oncogénicas B-raf , Niño , Glioma/tratamiento farmacológico , Glioma/genética , Hospitales , Humanos , Mutación , Proto-Oncogenes Mas , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Proteínas Proto-Oncogénicas B-raf/genética , Estudios RetrospectivosRESUMEN
BACKGROUND: Within PF-EPN-A, 1q gain is a marker of poor prognosis, however, it is unclear if within PF-EPN-A additional cytogenetic events exist which can refine risk stratification. METHODS: Five independent non-overlapping cohorts of PF-EPN-A were analyzed applying genome-wide methylation arrays for chromosomal and clinical variables predictive of survival. RESULTS: Across all cohorts, 663 PF-EPN-A were identified. The most common broad copy number event was 1q gain (18.9%), followed by 6q loss (8.6%), 9p gain (6.5%), and 22q loss (6.8%). Within 1q gain tumors, there was significant enrichment for 6q loss (17.7%), 10q loss (16.9%), and 16q loss (15.3%). The 5-year progression-free survival (PFS) was strikingly worse in those patients with 6q loss, with a 5-year PFS of 50% (95% CI 45%-55%) for balanced tumors, compared with 32% (95% CI 24%-44%) for 1q gain only, 7.3% (95% CI 2.0%-27%) for 6q loss only and 0 for both 1q gain and 6q loss (P = 1.65 × 10-13). After accounting for treatment, 6q loss remained the most significant independent predictor of survival in PF-EPN-A but is not in PF-EPN-B. Distant relapses were more common in 1q gain irrespective of 6q loss. RNA sequencing comparing 6q loss to 6q balanced PF-EPN-A suggests that 6q loss forms a biologically distinct group. CONCLUSIONS: We have identified an ultra high-risk PF-EPN-A ependymoma subgroup, which can be reliably ascertained using cytogenetic markers in routine clinical use. A change in treatment paradigm is urgently needed for this particular subset of PF-EPN-A where novel therapies should be prioritized for upfront therapy.
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Ependimoma , Aberraciones Cromosómicas , Cromosomas , Ependimoma/genética , Humanos , Análisis por Micromatrices , Supervivencia sin ProgresiónRESUMEN
BACKGROUND: Infant medulloblastoma represents an enormous challenge in neuro-oncology, due to their simultaneous high-risk of recurrence and high risk of severe neurodevelopmental sequelae with craniospinal irradiation. Currently infant medulloblastoma are treated with intensified protocols, either comprising intraventricular methotrexate or autologous transplant, both of which carry significant morbidity and are not feasible in the majority of the world. We sought to evaluate the molecular predictors of outcome in a cohort of infants homogeneously treated with induction chemotherapy, focal radiation and maintenance chemotherapy. METHODS: In a retrospective analysis, 29 young children treated with a craniospinal irradiation sparing strategy from Hospital Garrahan in Buenos Aires were profiled using Illumina HumanMethylationEPIC arrays, and correlated with survival. RESULTS: Twenty-nine children (range, 0.3-4.6 y) were identified, comprising 17 sonic hedgehog (SHH), 10 Group 3/4, and 2 non-medulloblastomas. Progression-free survival (PFS) across the entire cohort was 0.704 (95% CI: 0.551-0.899). Analysis by t-distributed stochastic neighbor embedding revealed 3 predominant groups, SHHß, SHHγ, and Group 3. Survival by subtype was highly prognostic with SHHγ having an excellent 5-year PFS of 100% (95% CI: 0.633-1) and SHHß having a PFS of 0.56 (95% CI: 0.42-1). Group 3 had a PFS of 0.50 (95% CI: 0.25-1). Assessment of neurocognitive outcome was performed in 11 patients; the majority of survivors fell within the low average to mild intellectual disability, with a median IQ of 73.5. CONCLUSIONS: We report a globally feasible and effective strategy avoiding craniospinal radiation in the treatment of infant medulloblastoma, including a robust molecular correlation along with neurocognitive outcomes.
Asunto(s)
Neoplasias Cerebelosas , Meduloblastoma , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Argentina , Neoplasias Cerebelosas/tratamiento farmacológico , Preescolar , Irradiación Craneana , Femenino , Proteínas Hedgehog/genética , Humanos , Lactante , Masculino , Meduloblastoma/tratamiento farmacológico , Estudios RetrospectivosRESUMEN
BACKGROUND: Radiation necrosis is a frequent complication occurring after the treatment of pediatric brain tumors; however, treatment options remain a challenge. Bevacizumab is an anti-VEGF monoclonal antibody that has been shown in small adult cohorts to confer a benefit, specifically a reduction in steroid usage, but its use in children has not been well described. METHODS: We describe our experience with bevacizumab use for symptomatic radiation necrosis at 5 institutions including patients treated after both initial irradiation and reirradiation. RESULTS: We identified 26 patients treated with bevacizumab for symptomatic radiation necrosis, with a wide range of underlying diagnoses. The average age at diagnosis of radiation necrosis was 10.7 years, with a median time between the last dose of radiation and the presentation of radiation necrosis of 3.8 months (range, 0.6-110 months). Overall, we observed that 13 of 26 patients (50%) had an objective clinical improvement, with only 1 patient suffering from significant hypertension. Radiological improvement, defined as reduced T2/fluid-attenuated inversion recovery signal and mass effect, was observed in 50% of patients; however, this did not completely overlap with clinical response. Both early and late radiation necrosis responded equally well to bevacizumab therapy. Overall, bevacizumab was very well tolerated, permitting a reduction of corticosteroid dose and/or duration in the majority of patients. CONCLUSIONS: Bevacizumab appears to be effective and well-tolerated in children as treatment for symptomatic radiation necrosis and warrants more robust study in the context of controlled clinical trials.
RESUMEN
PURPOSE: Children with pediatric gliomas harboring a BRAF V600E mutation have poor outcomes with current chemoradiotherapy strategies. Our aim was to study the role of targeted BRAF inhibition in these tumors. PATIENTS AND METHODS: We collected clinical, imaging, molecular, and outcome information from patients with BRAF V600E-mutated glioma treated with BRAF inhibition across 29 centers from multiple countries. RESULTS: Sixty-seven patients were treated with BRAF inhibition (pediatric low-grade gliomas [PLGGs], n = 56; pediatric high-grade gliomas [PHGGs], n = 11) for up to 5.6 years. Objective responses were observed in 80% of PLGGs, compared with 28% observed with conventional chemotherapy (P < .001). These responses were rapid (median, 4 months) and sustained in 86% of tumors up to 5 years while receiving therapy. After discontinuation of BRAF inhibition, 76.5% (13 of 17) of patients with PLGG experienced rapid progression (median, 2.3 months). However, upon rechallenge with BRAF inhibition, 90% achieved an objective response. Poor prognostic factors in conventional therapies, such as concomitant homozygous deletion of CDKN2A, were not associated with lack of response to BRAF inhibition. In contrast, only 36% of those with PHGG responded to BRAF inhibition, with all but one tumor progressing within 18 months. In PLGG, responses translated to 3-year progression-free survival of 49.6% (95% CI, 35.3% to 69.5%) versus 29.8% (95% CI, 20% to 44.4%) for BRAF inhibition versus chemotherapy, respectively (P = .02). CONCLUSION: Use of BRAF inhibition results in robust and durable responses in BRAF V600E-mutated PLGG. Prospective studies are required to determine long-term survival and functional outcomes with BRAF inhibitor therapy in childhood gliomas.