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Rhabdoid tumor predisposition syndrome (RTPS) is a rare disorder associated with malignant rhabdoid tumor of the kidney (RTK), atypical teratoid rhabdoid tumor (ATRT), and/or other extracranial, extrarenal rhabdoid tumors (EERT), and these pediatric malignancies are difficult to treat. Presently, most of the information regarding clinical manifestations, treatment, and outcomes of rhabdoid tumors comes from large data registries and case series. Our current understanding of treatments for patients with rhabdoid tumors may inform how we approach patients with RTPS. In this manuscript, we review the genetic and clinical features of RTPS and, using known registry data and clinical reports, review associated tumor types ATRT, RTK, and EERT, closing with potential new approaches to treatment. We propose collaborative international efforts to study the use of SMARC (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin)-targeting agents, high-dose consolidative therapy, and age-based irradiation of disease sites in RTPS.
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Ependymal tumors are the third most common brain tumor under 14 years old. Even though metastatic disease is a rare event, it affects mostly young children and carries an adverse prognosis. The factors associated with dissemination and the best treatment approach have not yet been established and there is limited published data on how to manage metastatic disease, especially in patients under 3 years of age. We provide a review of the literature on clinical characteristics and radiation-sparing treatments for metastatic ependymoma in children under 3 years of age treated. The majority (73%) of the identified cases were above 12 months old and had the PF as the primary site at diagnosis. Chemotherapy-based approaches, in different regimens, were used with radiation reserved for progression or relapse. The prognosis varied among the studies, with an average of 50%-58% overall survival. This study also describes the case of a 7-month-old boy with metastatic posterior fossa (PF) ependymoma, for whom we identified a novel SPECC1L-RAF1 gene fusion using a patient-centric comprehensive molecular profiling protocol. The patient was successfully treated with intensive induction chemotherapy followed by high-dose chemotherapy and autologous hematopoietic progenitor cell rescue (AuHSCR). Currently, the patient is in continuous remission 5 years after his diagnosis, without radiation therapy. The understanding of the available therapeutic approaches may assist physicians in their management of such patients. This report also opens the perspective of newly identified molecular alterations in metastatic ependymomas that might drive more chemo-sensitive tumors.
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Neoplasias Encefálicas , Ependimoma , Trasplante de Células Madre Hematopoyéticas , Niño , Masculino , Humanos , Preescolar , Lactante , Adolescente , Recurrencia Local de Neoplasia , Ependimoma/tratamiento farmacológico , Ependimoma/genética , Ependimoma/radioterapia , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/diagnósticoRESUMEN
OBJECTIVE: To describe disease outcomes including overall survival and relapse patterns by subgroup in young pediatric patients treated for medulloblastoma with a radiation-sparing approach. METHODS: Retrospective analysis of clinical outcomes includes treatment, relapse, and salvage therapy and late effects in children treated for medulloblastoma with a radiation-sparing approach at British Columbia Children's Hospital (BCCH) between 2000 and 2020. RESULTS: There were 30 patients (median age 2.8 years, 60% male) treated for medulloblastoma with a radiation-sparing approach at BCCH. Subgroups included Sonic Hedgehog (SHH) (n = 14), group 3 (n = 7), group 4 (n = 6), and indeterminate status (n = 3). Three- and 5-year event-free survival (EFS) were 49.0% (30.2-65.4%) and 42.0% (24.2-58.9%) and overall survival (OS) 66.0% (95% CI 46.0-80.1%) and 62.5% (95% CI 42.5 and 77.2%), respectively, with a median follow-up of 9.5 years. Relapse occurred in 12/25 patients following a complete response, of whom six (group 4: n = 4; group 3: n = 1; unknown: n = 1) were successfully salvaged with craniospinal axis (CSA) RT and remain alive at a median follow-up of 7 years. Disease/treatment-related morbidity included endocrinopathies (n = 8), hearing loss n = 16), and neurocognitive abnormalities (n = 9). CONCLUSIONS: This radiation sparing treatment approach for young patients with medulloblastoma resulted in a durable cure in most patients with SHH subgroup medulloblastoma. In those patients with groups 3 and 4 medulloblastoma, relapse rates were high; however, most group 4 patients were salvaged with RT.
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Neoplasias Cerebelosas , Meduloblastoma , Niño , Humanos , Masculino , Preescolar , Femenino , Estudios Retrospectivos , Proteínas Hedgehog , Meduloblastoma/tratamiento farmacológico , Neoplasias Cerebelosas/tratamiento farmacológico , RecurrenciaRESUMEN
BACKGROUND: Medulloblastoma (MB),the most common malignant brain tumor of childhood has survival outcomes exceeding 80% for standard-risk and 60% for high-risk patients in high-income countries (HICs). These results have not been replicated in low- and middle-income countries (LMICs), where 80% of children with cancer live. METHODS: This is a retrospective review of 114 children aged 3-18 years diagnosed with MB from 1997 to 2016 at National Cancer Institute (INCA). Sociodemographic, clinical, and treatment data were extracted from the medical records and summarized descriptively. Overall survival (OS) and progression-free survival (PFS) were calculated using the Kaplan-Meier method. RESULTS: The male-to-female ratio was 1.32 and the median age at diagnosis was 8.2 years. Headache (83%) and nausea/vomiting (78%) were the most common presenting symptoms. Five-year OS was 59.1% and PFS was 58.4%. The OS for standard-risk and high-risk patients was 69% and 53%, respectively. The median time to diagnosis interval was 50.5 days and the median time from surgery to radiation therapy initiation was 50.4 days. Patients who lived >40 km from INCA fared better (OS = 68.2% vs. 51.1%, p = .032). Almost 20% of families lived below the Brazilian minimum wage. Forty-five patients (35%) had metastatic disease at admission. Gross total resection was achieved in 57% of the patitents. CONCLUSIONS: Although there are considerable barriers to deliver effective MB treatment in countries like Brazil, the OS seen in the present study demonstrates that good outcomes are not only feasible but can and should be increased with appropriate interventions.
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Neoplasias Cerebelosas , Meduloblastoma , Brasil/epidemiología , Neoplasias Cerebelosas/epidemiología , Neoplasias Cerebelosas/terapia , Niño , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Meduloblastoma/epidemiología , Meduloblastoma/terapia , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
We aimed toidentify prognostic factors that may help better understand the behavior of relapsed central nervous system nongerminomatous germ cell tumors. We identified nine studies, including 101 patients; 33 patients (33%) were alive 12 months post-initial relapse. Sixty percent of patients with serum/cerebrospinal fluid (CSF) alpha-fetoprotein (AFP) level ≤25 ng/mL at initial diagnosis were survivors compared with 28% among patients with serum/CSF AFP level >25 ng/mL (P = 0.01). Seventy-one percent of patients who achieved complete response/continued complete response (CR/CCR) by the end of therapy at relapse were survivors compared with 7% among patients who had less than CR/CCR (P < 0.0001). Forty-eight percent of patients who received marrow-ablative chemotherapy followed by autologous hematopoietic cell rescue (HDCx/AuHCR) following relapse were survivors compared with 12% among patients who did not receive HDCx/AuHCR (P = 0.0001). Local relapse site, gross total surgical resection, and radiotherapy at relapse were not associated with improved outcomes.
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Neoplasias del Sistema Nervioso Central , Neoplasias de Células Germinales y Embrionarias , Protocolos de Quimioterapia Combinada Antineoplásica , Sistema Nervioso Central , Neoplasias del Sistema Nervioso Central/terapia , Terapia Combinada , Humanos , Recurrencia Local de Neoplasia/terapia , Neoplasias de Células Germinales y Embrionarias/terapia , Pronóstico , Neoplasias Testiculares , alfa-FetoproteínasRESUMEN
BACKGROUND: Medulloblastoma is the most common malignant brain tumor in children. While survival has improved in high-income countries (HIC), the outcomes for patients in low-to-middle-income countries (LMIC) are unclear. Therefore, we sought to determine the survival of children with medulloblastoma at the Instituto Nacional de Enfermedades Neoplasicas (INEN) between 1997 and 2013 in Peru. METHODS: Between 1997 and 2013, data from 103 children older than 3 years with medulloblastoma were analyzed. Fourteen patients were excluded. The patients were split into two distinct cohorts, 1997-2008 and 2009-2013, corresponding with chemotherapy regimen changes. Event-free (EFS) and overall survival (OS) were calculated using the Kaplan-Meier method, whereas prognostic factors were determined by univariate analysis (log-rank test). RESULTS: Eighty-nine patients were included; median age was 8.1 years (range: 3-13.9 years). The 5-year OS was 62% (95% CI: 53%-74%), while EFS was 57% (95% CI: 48%-69%). The variables adversely affecting survival were anaplastic histology (compared to desmoplastic; OS: HR = 3.4, p = .03), metastasis (OS: HR = 3.5, p = .01; EFS: HR = 4.3, p = .004), delay in radiation therapy of 31-60 days (compared to ≤30 days; EFS: HR = 2.1, p = .04), and treatment 2009-2013 cohort (OS: HR = 2.2, p = .02; EFS: HR = 2.0, p = .03). CONCLUSIONS: Outcomes for medulloblastoma at INEN were low compared with HIC. Anaplastic subtype, metastasis at diagnosis, delay in radiation therapy, and treatment in the period 2009-2013 negatively affected the outcomes in our study. Multidisciplinary teamwork, timely delivery of treatment, and partnerships with loco-regional groups and colleagues in HIC is likely beneficial.
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Neoplasias Encefálicas , Neoplasias Cerebelosas , Meduloblastoma , Adolescente , Neoplasias Cerebelosas/patología , Niño , Preescolar , Supervivencia sin Enfermedad , Humanos , Meduloblastoma/patología , Perú/epidemiología , Pronóstico , Factores de RiesgoRESUMEN
Wnt-activated medulloblastoma (MB) confers an excellent prognosis. However, specific treatment strategies for patients with relapsed Wnt-MB are unknown. We report two patients with recurrent beta-catenin nucleopositive Wnt-MB successfully treated by incorporating marrow-ablative chemotherapy and autologous hematopoietic progenitor cell rescue (HDCx/AuHPCR). We also present a review of the literature for previously reported cases of relapsed Wnt-MB. We propose that patients with recurrent Wnt-MB may be treated using a multi-disciplinary approach that includes HDCx/AuHPCR with or without re-irradiation.
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Neoplasias Encefálicas , Neoplasias Cerebelosas , Meduloblastoma , Médula Ósea , Neoplasias Encefálicas/terapia , Neoplasias Cerebelosas/diagnóstico por imagen , Neoplasias Cerebelosas/terapia , Células Madre Hematopoyéticas , Humanos , Meduloblastoma/diagnóstico por imagen , Meduloblastoma/terapiaRESUMEN
BACKGROUND: Pediatric cancers typically have a distinct genomic landscape when compared to adult cancers and frequently carry somatic gene fusion events that alter gene expression and drive tumorigenesis. Sensitive and specific detection of gene fusions through the analysis of next-generation-based RNA sequencing (RNA-Seq) data is computationally challenging and may be confounded by low tumor cellularity or underlying genomic complexity. Furthermore, numerous computational tools are available to identify fusions from supporting RNA-Seq reads, yet each algorithm demonstrates unique variability in sensitivity and precision, and no clearly superior approach currently exists. To overcome these challenges, we have developed an ensemble fusion calling approach to increase the accuracy of identifying fusions. RESULTS: Our Ensemble Fusion (EnFusion) approach utilizes seven fusion calling algorithms: Arriba, CICERO, FusionMap, FusionCatcher, JAFFA, MapSplice, and STAR-Fusion, which are packaged as a fully automated pipeline using Docker and Amazon Web Services (AWS) serverless technology. This method uses paired end RNA-Seq sequence reads as input, and the output from each algorithm is examined to identify fusions detected by a consensus of at least three algorithms. These consensus fusion results are filtered by comparison to an internal database to remove likely artifactual fusions occurring at high frequencies in our internal cohort, while a "known fusion list" prevents failure to report known pathogenic events. We have employed the EnFusion pipeline on RNA-Seq data from 229 patients with pediatric cancer or blood disorders studied under an IRB-approved protocol. The samples consist of 138 central nervous system tumors, 73 solid tumors, and 18 hematologic malignancies or disorders. The combination of an ensemble fusion-calling pipeline and a knowledge-based filtering strategy identified 67 clinically relevant fusions among our cohort (diagnostic yield of 29.3%), including RBPMS-MET, BCAN-NTRK1, and TRIM22-BRAF fusions. Following clinical confirmation and reporting in the patient's medical record, both known and novel fusions provided medically meaningful information. CONCLUSIONS: The EnFusion pipeline offers a streamlined approach to discover fusions in cancer, at higher levels of sensitivity and accuracy than single algorithm methods. Furthermore, this method accurately identifies driver fusions in pediatric cancer, providing clinical impact by contributing evidence to diagnosis and, when appropriate, indicating targeted therapies.
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Genoma , Neoplasias , Niño , Genómica , Humanos , Neoplasias/genética , Análisis de Secuencia de ADN , Análisis de Secuencia de ARNRESUMEN
BACKGROUND: Pediatric cancer cure rates differ among high-income countries (HIC) and upper middle-income countries (UMIC). We have compared individual capacities of two major referral pediatric centers from a HIC and an UMIC caring for children with central nervous system (CNS) cancer. METHODS: A quantitative needs assessment questionnaire and key informant interviews, distributed in March of 2017, were used to evaluate the treatment of children with CNS cancer at Grupo de Apoio ao Adolescente e à Criança com Câncer (GRAACC) children's cancer center in São Paulo, Brazil and Nationwide Children's Hospital (NCH) in Columbus, Ohio, United States of America (USA). RESULTS: Both hospitals had 24-hour pediatric oncology, nursing and intensivist coverage. Supportive care available at both institutions included social workers, psychologists, child life specialists, and physical/occupational/speech therapists. Differences included two part-time neuroradiologists and one pathologist specializing in neuropathology at IOP/GRAACC/UNIFESP, whereas eight full-time neuroradiologists and two neuropathologists at NCH/OSU. There were four pediatric neurosurgeons on staff at each hospital; however, there were only 2 operative days per week at IOP/GRAACC/UNIFESP, compared with 7 days at NCH/OSU. Additionally, time to initiation of radiation therapy at IOP/GRAACC/UNIFESP extended 2-4 weeks compared with less than 1 week at NCH/OSU. CONCLUSIONS: Center-specific differences in resources exist in highly specialized hospitals caring for children with CNS cancer in HIC and UMIC. This quantitative needs assessment may facilitate the development of targeted strategies for effective interventions to improve on the management of children with CNS cancers.
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Neoplasias del Sistema Nervioso Central/mortalidad , Neoplasias del Sistema Nervioso Central/terapia , Fuerza Laboral en Salud/estadística & datos numéricos , Evaluación de Necesidades , Calidad de la Atención de Salud/estadística & datos numéricos , Factores Socioeconómicos , Brasil , Sistema Nervioso Central/patología , Niño , Humanos , Renta/estadística & datos numéricos , Meduloblastoma/mortalidad , Meduloblastoma/terapia , Calidad de Vida , Encuestas y Cuestionarios , Tasa de Supervivencia , Resultado del Tratamiento , Estados UnidosRESUMEN
BACKGROUND: Central nervous system (CNS) tumors are the second most common malignancy of childhood, and published data on venous thromboembolism (VTE) rate and risk factors for these patients are outdated or incomplete. Here, we determine the cumulative incidence and risk factors for VTE in this population. PROCEDURE: VTE diagnosis and associated clinical risk factors were abstracted and analyzed for two cohorts of children (0-21 years) diagnosed with CNS tumors between January 1, 2010 to September 30, 2018. The first study was a retrospective single institution cohort study. The initial observations were confirmed across multiple pediatric hospitals using the Pediatric Health Information System (PHIS) administrative database. RESULTS: The single-institution cohort included 338 patients aged 3 days to 20.9 years (median age, 8.6 years); VTE developed in eight (2.4%) patients. The PHIS cohort included 17 634 patients aged from 0 to 21.9 years (median: 9.5 years); VTE developed in 354 (2.0%) patients. Univariate analysis for the single-institution cohort identified central venous catheter (CVC) placement as a risk factor for VTE (odds ratio [OR] 8.40, 95% confidence interval [CI] 1.43-49.41, P = .0186). Multivariable analysis of the PHIS dataset identified CVC placement (OR 1.97, 95% CI 1.57-2.46; P < .0001), obesity (OR 2.96, 95% CI 1.21-7.26; P = .0177), and more than one hospital admission (OR 3.54, 95% CI 2.69-4.64; P < .0001) as significant predictors of VTE. VTE diagnosis was not associated with increased mortality in either cohort. CONCLUSIONS: The VTE rate in children with CNS tumors is low (2%). CVC placement was identified as a modifiable risk factor in both cohorts.
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Neoplasias del Sistema Nervioso Central/complicaciones , Bases de Datos Factuales/estadística & datos numéricos , Hospitalización/estadística & datos numéricos , Tromboembolia Venosa/patología , Adolescente , Adulto , Niño , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Lactante , Recién Nacido , Masculino , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Tromboembolia Venosa/etiología , Adulto JovenRESUMEN
BACKGROUND: Since 2013, pediatric oncologists from Central and South America discuss neuro-oncology cases with experts from North America and Europe in a web-based "Latin American Tumor Board" (LATB). Here, we evaluate the feasibility of recommendations rendered by the Board. METHODS: An electronic questionnaire was distributed to physicians who had received recommendations between October 2017 and October 2018. Physicians were asked regarding the feasibility of each recommendation given during the LATB discussion. Baseline case characteristics of all presented cases were obtained from anonymized minutes. RESULTS: Of the 142 patients discussed, data on 103 patients from 15 countries were available, corresponding to 283 recommendations. Physicians followed 60% of diagnostic procedural recommendations and 69% of therapeutic recommendations. The most difficult recommendations to follow were genetic and molecular testing, pathology review, chemotherapy, surgery, and molecular targeted therapies. Histological diagnoses changed in eight of 18 cases in which a pathology review was undertaken. Fifty-four percent of the recommendations that could not be implemented were considered not feasible in the specific context of the patient, while 31% were not implemented due to a decision of the medical staff or the parents (15% not specified). However, 96% of respondents considered the recommendations useful. CONCLUSION: Recommendations were frequently perceived as useful, and were applicable in the participating institutions. Nevertheless, limitations in availability of diagnostic procedures and treatment modalities affected the feasibility of some recommendations. Tele-oncology tumor boards offer physicians from low- and middle-income countries access to real-time, high-level subspecialist expertise and provide a valuable platform for worldwide information exchange.
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Neoplasias Encefálicas , Oncología Médica , Telecomunicaciones , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/terapia , Niño , Estudios de Seguimiento , Humanos , Internet , América Latina , Oncología Médica/métodosRESUMEN
PURPOSE: Children with brain tumors experience cognitive late effects, often related to cranial radiation. We sought to determine differential effects of surgery and chemotherapy on brain structure and neuropsychological outcomes in children who did not receive cranial radiation therapy (CRT). METHODS: Twenty-eight children with a history of posterior fossa tumor (17 treated with surgery, 11 treated with surgery and chemotherapy) underwent neuroimaging and neuropsychological assessment a mean of 4.5 years (surgery group) to 9 years (surgery + chemotherapy group) posttreatment, along with 18 healthy sibling controls. Psychometric measures assessed IQ, language, executive functions, processing speed, memory, and social-emotional functioning. Group differences and correlations between diffusion tensor imaging findings and psychometric scores were examined. RESULTS: The z-score mapping demonstrated fractional anisotropy (FA) values were ≥2 standard deviations lower in white matter tracts, prefrontal cortex gray matter, hippocampus, thalamus, basal ganglia, and pons between patient groups, indicating microstructural damage associated with chemotherapy. Patients scored lower than controls on visuoconstructional reasoning and memory (P ≤ .02). Lower FA in the uncinate fasciculus (R = -0.82 to -0.91) and higher FA in the thalamus (R = 0.73-0.91) associated with higher IQ scores, and higher FA in the thalamus associated with higher scores on spatial working memory (R = 0.82). CONCLUSIONS: Posterior fossa brain tumor treatment with surgery and chemotherapy affects brain microstructure and neuropsychological functioning years into survivorship, with spatial processes the most vulnerable. Biomarkers indicating cellular changes in the thalamus, hippocampus, pons, prefrontal cortex, and white matter tracts associate with lower psychometric scores.
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Antineoplásicos/uso terapéutico , Lesiones Encefálicas/patología , Neoplasias Encefálicas/terapia , Neoplasias Infratentoriales/terapia , Síndromes de Neurotoxicidad/patología , Síndromes de Neurotoxicidad/psicología , Adolescente , Anisotropía , Neoplasias Encefálicas/psicología , Niño , Estudios Transversales , Femenino , Hipocampo/fisiología , Humanos , Neoplasias Infratentoriales/psicología , Masculino , Pruebas Neuropsicológicas , Puente/fisiología , Corteza Prefrontal/fisiología , Psicometría , Tálamo/fisiología , Sustancia Blanca/fisiologíaRESUMEN
BACKGROUND: Central nervous system (CNS) germinomas are treatment-sensitive tumors with excellent survival outcomes. Current treatment strategies combine chemotherapy with radiotherapy (RT) in order to reduce the field and dose of RT. Germinomas originating in the basal ganglia/thalamus (BGTGs) have proven challenging to treat given their rarity and poorly defined imaging characteristics. Craniospinal (CSI), whole brain (WBI), whole ventricle (WVI), and focal RT have all been utilized; however, the best treatment strategy remains unclear. METHODS: Retrospective multi-institutional analysis has been conducted across 18 institutions in four countries. RESULTS: For 43 cases of nonmetastatic BGTGs, the 5- and 10-year event-free survivals (EFS) were 85.8% and 81.0%, respectively, while the 5- and 10-year overall survivals (OS) were 100% and 95.5%, respectively (one patient fatality from unrelated cause). Median RT doses were as follows: CSI: 2250 cGy/cGy(RBE) (1980-2400); WBI: 2340 cGy/cGy(RBE) (1800-3000); WVI: 2340 cGy/cGy(RBE) (1800-2550); focal: 3600 cGy (3060-5400). Thirty-eight patients (90.5%) received chemotherapy. There was no statistically significant difference in the EFS based on initial field extent (p = .84). Nevertheless, no relapses were reported in patients who received CSI or WBI. Chemotherapy alone had significantly inferior EFS compared to combined therapy (p = .0092), but patients were salvageable with RT. CONCLUSION: Patients with BGTGs have excellent outcomes and RT proved to be an integral component of the treatment plan. This group of patients should be included in future prospective clinical trials and the best RT field should be investigated further.
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Neoplasias Encefálicas , Neoplasias del Sistema Nervioso Central , Germinoma , Ganglios Basales/patología , Neoplasias Encefálicas/radioterapia , Germinoma/radioterapia , Humanos , Recurrencia Local de Neoplasia , Dosificación Radioterapéutica , Estudios Retrospectivos , Tálamo/diagnóstico por imagenRESUMEN
Gliosarcoma is rare among pediatric patients and among individuals with Neurofibromatosis Type 1 (NF1). Here we compare 2 pediatric gliosarcoma patients, one of whom has NF1. We performed whole-exome sequencing, methylation, and copy number analysis on tumor and blood for both patients. Whole-exome sequencing showed higher mutational burden in the tumor of the patient without NF1. Copy number analysis showed differences in chromosomal losses/gains between the tumors. Neither tumor showed O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation. The NF1 patient survived without progression while the other expired. This is the first reported case of gliosarcoma in a child with NF1.
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Metilasas de Modificación del ADN/genética , Enzimas Reparadoras del ADN/genética , Secuenciación del Exoma/métodos , Exoma , Gliosarcoma/patología , Mutación , Neurofibromatosis 1/patología , Proteínas Supresoras de Tumor/genética , Niño , Femenino , Gliosarcoma/complicaciones , Gliosarcoma/genética , Humanos , Masculino , Neurofibromatosis 1/complicaciones , Neurofibromatosis 1/genética , Pronóstico , Regiones Promotoras GenéticasRESUMEN
BACKGROUND: We report the outcomes of patients with pineoblastoma and trilateral retinoblastoma syndrome enrolled on the Head Start (HS) I-III trials. METHODS: Twenty-three children were enrolled prospectively between 1991 and 2009. Treatment included maximal surgical resection followed by five cycles of intensive chemotherapy and consolidation with marrow-ablative chemotherapy and autologous hematopoietic cell rescue (HDCx/AuHCR). Irradiation following consolidation was reserved for children over six years of age or those with residual tumor at the end of induction. RESULTS: Median age was 3.12 years (range, 0.44-5.72). Three patients withdrew from the study treatment and two patients experienced chemotherapy-related death. Eight patients experienced progressive disease (PD) during induction chemotherapy and did not proceed to HDCx/AuHCR. Ten patients received HDCx/AuHCR; eight experienced PD post-consolidation. Seven patients received craniospinal irradiation (CSI) with a median dose of 20.7 Gy (range, 18-36 Gy) with boost(s) (median dose 27 Gy; range, 18-36 Gy); three received CSI as adjuvant therapy (two post-HDCx/AuHCR) and four upon progression/recurrence. The five-year progression-free survival (PFS) and overall survival (OS) were 9.7% (95% confidence intervals [CI]: 2.6%-36.0%) and 13% (95% CI: 4.5%-37.5%), respectively. Only three patients survived beyond five years. Favorable OS prognostic factors were CSI (hazard ratio [HR] = 0.30 [0.11-0.86], P = 0.025) and HDCx/AuHCR (HR = 0.40 [0.16-0.99], P = 0.047). CONCLUSIONS: Within the HS I-III trials, CSI and HDCx/AuHCR were statistically associated with improved survival. The high PD rate during later induction cycles and following consolidation chemotherapy warrants consideration of fewer induction cycles prior to consolidation and the potential intensification of consolidation with multiple cycles of marrow-ablative chemotherapy and irradiation.
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Neoplasias Encefálicas/terapia , Glándula Pineal/patología , Pinealoma/terapia , Neoplasias Encefálicas/patología , Niño , Preescolar , Terapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Lactante , Masculino , Pinealoma/patología , Pronóstico , Estudios Prospectivos , Tasa de SupervivenciaRESUMEN
PURPOSE: Germ cell tumors (GCT) in the central nervous system (CNS) are rare tumors that occur with highest frequency in males, Asian populations, and children less than age 20 years. Due to the rarity of these tumors, their patterns of incidence are not well-described. The aim of this study is to provide the most up-to-date data on incidence and survival patterns for CNS GCT by sex, race, and age at diagnosis. METHODS: The Central Brain Tumor Registry of the United States (CBTRUS) is the largest aggregation of population-based incidence data on primary brain and other CNS tumors in the United States, containing incidence data from 51 central cancer registries and representing 100% of the US population. The current study used the CBTRUS analytic file to examine incidence (IR) of CNS GCT from 2006 to 2015, as well as registry data from the Surveillance, Epidemiology, and End Results (SEER) program to examine survival. RESULTS: Males had greater IR than females in all CNS GCT histologies examined. Asian and Pacific Islanders had a significantly greater IR of CNS GCT than the other race categories. We confirmed that CNS GCT IR was greatest for those age 10-14 years and male. Overall survival rates were high for malignant CNS GCT, germinoma, mixed GCT, and malignant teratoma. CONCLUSIONS: There is significant variation in CNS GCT incidence by sex, race, and age at diagnosis. Ascertaining accurate incidence and survival rates of CNS GCT provides vital information usable in real time for clinicians, public health planners, patients, and their families.
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Neoplasias del Sistema Nervioso Central/epidemiología , Neoplasias del Sistema Nervioso Central/mortalidad , Neoplasias de Células Germinales y Embrionarias/epidemiología , Neoplasias de Células Germinales y Embrionarias/mortalidad , Sistema de Registros/estadística & datos numéricos , Adolescente , Adulto , Factores de Edad , Neoplasias del Sistema Nervioso Central/patología , Niño , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Neoplasias de Células Germinales y Embrionarias/patología , Pronóstico , Tasa de Supervivencia , Factores de Tiempo , Estados Unidos/epidemiología , Adulto JovenRESUMEN
Multimodal strategies have significantly improved the outcomes for patients with central nervous system nongerminomatous germ cell tumors. Two large cooperative group studies have recently reported much improved outcomes compared with historical series. However, a substantial proportion of patients still attain inadequate responses to initial chemotherapy prior to irradiation, with adverse impact upon survival; optimal induction chemotherapy regimens and radiotherapy strategies are as yet unidentified. Outcomes for patients with relapsed disease remain poor. There is an obvious need to incorporate molecular studies within prospective clinical trials that will likely lead to the incorporation of targeted, more effective future treatment strategies.
Asunto(s)
Neoplasias del Sistema Nervioso Central/terapia , Neoplasias de Células Germinales y Embrionarias/terapia , Neoplasias Testiculares/terapia , Terapia Combinada , Manejo de la Enfermedad , Humanos , PronósticoRESUMEN
BACKGROUND: Germ cell tumors (GCT) arising from non-midline structures (basal ganglia, thalamus, and posterior fossa) are rare. Although patients with midline (pineal and suprasellar) germinoma have excellent survival with chemotherapy and whole ventricular irradiation (WVI), germinoma in non-midline locations have traditionally been treated with craniospinal irradiation (CSI) or whole brain irradiation (WBI) to achieve similar outcomes. However, CSI and WBI are associated with significant long-term neuropsychological sequelae. METHODS: We describe the clinical and neuropsychological outcomes of patients with non-midline germinoma treated at the Children's Hospital Los Angeles between 1990 and 2015. RESULTS: Nine patients had basal ganglia/thalamic germinoma and one patient had a cerebellar primary. Eight patients received chemotherapy followed by reduced dose/volume irradiation, whereas two patients received chemotherapy alone as upfront therapy. One patient in the chemotherapy alone group relapsed after 4.3 years and was salvaged with CSI plus boost. The overall survival for the entire cohort was 100% at a median follow-up of 8.5 years. Neuropsychological data were available for six patients at a median of five months (baseline) and 4.2 years (follow-up) post-diagnosis. At four-year follow-up, data available revealed intact overall cognitive ability, verbal memory, and executive functioning, but persistent deficits in fine motor function. Comparison of baseline to follow-up suggests a downward trend in working memory, planning/problem-solving, verbal memory, and visuospatial integration. CONCLUSION: Chemotherapy followed by reduced dose/volume of irradiation is an effective strategy resulting in long-term survival in patients with non-midline germinoma. Neuropsychological data suggest relatively minimal morbidity over time.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias del Sistema Nervioso Central/terapia , Quimioradioterapia/efectos adversos , Irradiación Craneana/efectos adversos , Germinoma/terapia , Enfermedades del Sistema Nervioso/patología , Adolescente , Adulto , Neoplasias del Sistema Nervioso Central/patología , Niño , Preescolar , Femenino , Estudios de Seguimiento , Germinoma/patología , Humanos , Masculino , Enfermedades del Sistema Nervioso/etiología , Enfermedades del Sistema Nervioso/psicología , Pruebas Neuropsicológicas , Pronóstico , Dosificación Radioterapéutica , Estudios Retrospectivos , Adulto JovenRESUMEN
PURPOSE: The Latin American Brain Tumor Board (LATB) is a weekly teleconference connecting pediatric neuro-oncologists from referral centers in high-income countries with pediatric subspecialists from 20 Latin American countries since 2013. This survey explored the participants' experience utilizing this resource. METHODS: A cross-sectional electronic questionnaire was distributed to 159 participants through email and Cure4Kids. RESULTS: Ninety-five respondents (60%) from all the participating countries completed the survey. Sixty-one reported frequent-attendance (≥ 1 per month), 23 reported infrequent-attendance (< 1 per month), and 11 never participated. The most frequently reported attendance-barriers were the subspecialist's workload (64%), the timing of the teleconference (38%), and Internet connectivity problems (29%). Subspecialist's workload was more frequently reported as a barrier compared with other barriers, in both the frequent- and infrequent-attendance groups (p < 0.05), with the exception of the timing of the meeting in the infrequent-attendance group. More than 80% of attendees found the frequency and duration of the teleconference were sufficient. Utilizing Spanish as the primary language was reported to enhance the recommendations by 93% of the attendees. Moreover, 84% reported that the recommendations (almost) always fit the local circumstances. Furthermore, 99% of attendees found the teleconference provided a continuing medical education opportunity. Finally, 96% of attendees (almost) always found that the provided recommendations helped to improve the outcomes/quality of life of the patients. CONCLUSIONS: The LATB teleconference provided a valuable tool for the management of pediatric brain tumors in Latin America as it provided a feasible and easy to access continued medical education opportunity for the participants.
Asunto(s)
Neoplasias Encefálicas , Oncología Médica/métodos , Neurología/métodos , Pediatría/métodos , Consulta Remota/métodos , Telecomunicaciones , Estudios Transversales , Humanos , Internet , América Latina , Oncología Médica/educación , Neurología/educación , Pediatría/educación , Encuestas y CuestionariosRESUMEN
Single agent studies targeting the tumor microenvironment in central nervous system (CNS) tumors have largely been disappointing. Combination therapies targeting various pathways and cell types may be a more effective strategy. In this phase I study, we evaluated the combination of dasatinib, lenalidomide, and temozolomide in children with relapsed or refractory primary CNS tumors. Patients 1-21 years old with relapsed or refractory CNS tumors were eligible. Starting doses of dasatinib and lenalidomide were 65 mg/m2/dose twice daily and 55 mg/m2 once daily, respectively, while temozolomide was constant at 75 mg/m2 daily. The study followed a 3 + 3 phase I design, with a 4-week dose-limiting toxicity (DLT) evaluation period. Serial peripheral blood lymphocyte subsets were evaluated in consenting patients. Fifteen patients were enrolled and thirteen were DLT-evaluable. DLTs occurred in 5 patients, including somnolence and confusion (1 patient), hypokalemia (1 patient) and thrombocytopenia (3 patients). The maximum tolerated dose for the combination was dasatinib 65 mg/m2 twice daily, lenalidomide 40 mg/m2 daily, and temozolomide 75 mg/m2 daily, for 21 days followed by 7 days rest in repeating 28-day cycles. Transient increases in natural killer effector cells and cytotoxic T-cells were seen after 1 week of treatment. One out of six response-evaluable patients showed a partial response. The combination was feasible and relatively well tolerated in this heavily pre-treated population. The most common toxicities were hematologic. Preliminary evidence of clinical benefit was seen.