Primary central nervous system germ cell tumors in Central America and the Caribbean Region: an AHOPCA 20-year experience.

Background: Primary central nervous system germ cell tumors (GCT) are rare neoplasms in pediatrics. Treatment depends on the histological subtype and extent of the disease. Overall survival (OS) is above 90% for germinomas and 70%-80% for nongerminomatous GCT (NGGCT) in high-income countries (HIC) while data are usually lacking for patients in Low-Middle Income country (LMIC). Objective: This study aims to describe the experience of treating patients with CNS GCT in four of eight countries, members of the Asociación de Hemato-Oncología Pediátrica de Centro América (AHOPCA), and determine their 5-year OS. Design/methods: We conducted a retrospective chart review of patients treated for CNS GCT. Epidemiological and clinical characteristics, histology, treatment modalities, and outcomes were analyzed. Results: From 2001 to 2021, 48 patients were included: 22 from Guatemala, 18 from Nicaragua, three from the Dominican Republic, and five from El Salvador. Thirty-one (64.6%) were boys; the median age at diagnosis was 10.2 years (range: 1 to 17 years). Presenting symptoms were headaches (n = 24, 50%), visual disturbances (n = 17, 35.4%), vomiting (n = 12, 25%), nausea (n = 8, 16.7%), and diabetes insipidus (n = 7, 14.6%). Two patients with NGGCT presented with precocious puberty. Biopsy or tumor resection was performed in 38 cases (79.2%): 23 (88.4%) germinomas, 11 (78.6%) NGGCT, and four (50%) CNS GCT. Eight patients were diagnosed and treated based on CSF tumor marker elevation; four germinomas (BHCG 11.32-29.41 mUI/mL) and four NGGCT (BHCG 84.43-201.97 mUI/mL or positive AFP > 10 UI/mL). Tumor locations included suprasellar (n = 17, 35.4%), pineal (n = 13, 27.1%), thalamus/basal ganglia (n = 5, 10.4%), other (n = 12, 25%), and one bifocal. Four (8.3%) had metastatic disease, and six had positive CSF; staging data were incomplete in 25 patients (52%). Patients were treated with varied chemotherapy and radiotherapy modalities. Nine patients had incomplete data regarding treatment. Five-year OS was 65% (68% for germinoma, 50.6% for NGGCT, and 85.7% for unclassified GCT). Conclusions: Germinoma was the most common histology, and there was a male predominance. More than half of patients had incomplete staging data and treatment was variable across the region. OS is lower compared to HIC. Standardized treatment protocols will aid in adequate staging and treatment planning, prevent complications, and improve survival.

Marrow-ablative consolidation chemotherapy and molecular targeted therapy delivered in a risk-adapted manner for newly diagnosed children with choroid plexus carcinoma: A work in progress.

Choroid plexus carcinomas (CPC) are early childhood cancers characterized by loss of TP53 function and poor survival. We are analyzing data on TP53 status, survival, and second cancers from the largest cohort of CPC receiving chemotherapy followed by consolidation with marrow-ablative chemotherapy (HDCx). Additionally, we discuss the rationale for targeted therapies for CPC patients. Currently, 8 of the 13 with Li-Fraumeni Syndrome-associated CPC were treated and continued CPC-free, indicating that HDCx improves CPC-free survival in young children with TP53-mutated CPC. These data justify the inclusion of HDCx in the planned prospective international trial for children with TP53-mutated CPC.

Impact of treatment and clinical characteristics on the survival of children with medulloblastoma in Mexico.

Introduction: Data on medulloblastoma outcomes and experiences in low- and middle-income countries, especially in Latin America, is limited. This study examines challenges in Mexico's healthcare system, focusing on assessing outcomes for children with medulloblastoma in a tertiary care setting. Methods: A retrospective analysis was conducted, involving 284 patients treated at 21 pediatric oncology centers in Mexico. Results: High-risk patients exhibited markedly lower event-free survival than standard-risk patients (43.5% vs. 78.3%, p<0.001). Influential factors on survival included anaplastic subtype (HR 2.4, p=0.003), metastatic disease (HR 1.9, p=0.001); residual tumor >1.5cm², and lower radiotherapy doses significantly impacted event-free survival (EFS) and overall survival (OS). Platinum-based chemotherapy showed better results compared to the ICE protocol in terms of OS and EFS, which was associated with higher toxicity. Patients under 3 years old displayed notably lower OS and EFS compared to older children (36.1% vs. 55.9%, p=0.01).

[Design and implementation of a transdisciplinary care model for patients with hereditary angioedema, in a Colombian health institution]. / Diseño e implementación de un modelo de atención transdisciplinaria para pacientes con angioedema hereditario, en una institución de salud colombiana.

OBJECTIVE: Describe the design and implementation of a transdisciplinary care model for patients with hereditary angioedema in Colombia. METHODS: Descriptive longitudinal observational study. 140 patients with hereditary angioedema were included in a transdisciplinary care model for one year. Seizure rates, hospitalizations, emergency room visits, quality of life, and pharmacological adherence were measured. RESULTS: The model was associated with reductions of 76% in seizures, 66% in hospitalizations, and 87% in emergency room visits. Pharmacological adherence increased 19% and was complete after four months. The quality of life increased significantly. CONCLUSIONS: Hereditary angioedema is an orphan disease that requires a comprehensive approach for effective care.

OBJETIVO: Describir el diseño e implementación de un modelo transdisciplinario de atención para pacientes con angioedema hereditario en Colombia. MÉTODOS: Estudio observacional longitudinal descriptivo. 140 pacientes con angioedema hereditario fueron incluidos en un modelo de atención transdisciplinario por un año. Se midieron tasas de crisis, hospitalizaciones, visitas a urgencias, calidad de vida y adherencia farmacológica. RESULTADOS: El modelo se asoció con reducciones del 76% en crisis, 66% en hospitalizaciones y 87% en visitas a urgencias. La adherencia farmacológica aumentó 19% y fue completa después de cuatro meses. La calidad de vida aumentó significativamente. CONCLUSIÓN: El angioedema hereditario es una enfermedad solitaria que requiere un abordaje integral para la atención eficaz.

Alta proporción de macrodisco en pacientes de dos centros oftalmológicos en el occidente de Honduras / High proportion of macrodisc in patients from two ophthalmological centers in western Honduras

Antecedentes: Cuando el nervio óptico presenta una superficie mayor a 2.5 mm2 , y sin patologías asociadas, se trata de un macrodisco, cuya excavación es proporcional al tamaño aumentado del mismo. Con base en la distribución bajo la curva de Gauss, se define como "macrodisco" cuando está por encima de 2 desviaciones estándar arriba de la media. Se espera que solo el 2.3% de la población exceda estos límites. Objetivo: Determinar el tamaño promedio del disco óptico y proporción de macrodisco en la población sin glaucoma ni patologías retinianas que acude a dos clínicas oftalmológicas del occidente de Honduras, en el periodo de julio 2021 hasta julio 2022. Métodos: Estudio retrospectivo descriptivo. Se midieron los parámetros morfométricos del disco óptico mediante Tomografía de Coherencia Óptica ZEISS Cirrus HD Model 4000. Se definió macrodisco como: área del disco óptico >2.5 mm 2 y área del disco más 2 o más desviaciones estándar arriba de la media. Resultados: La proporción de macrodisco fue de 31% tomando en cuenta la definición de área de disco >2.5 mm2 , y 3% considerando la definición con base a la distribución bajo la curva de Gauss (>3.17mm2 ). Se obtuvo un promedio de área de disco óptico de 2.28±0.45 mm 2 , ratio copa/disco (C/D) de 0.59±0.13, ratio C/D vertical de 0.56±0.13, área de anillo neuroretiniano de 1.37±0.22 mm 2 , espesor de Capa de Fibras Nerviosas Retinianas (CFNR) de 97.4±10.664µm. Discusión: El área de disco promedio obtenido es mayor que los caucásicos, similar a lo reportado en los hispánicos, y menor que afrodescendientes y asiáticos...(AU)

The frequency of complications in a cohort of patients diagnosed with hemophilia A and hemophilia B receiving prophylactic treatment in Colombia: A retrospective noninterventional study.

INTRODUCTION: Hemophilia A and B are disorders associated with the deficit of coagulation factors VIII and IX. OBJECTIVE: Was to determine the incidence of complications in a cohort of patients diagnosed with moderate and severe hemophilia A or B under treatment in a specialized institution. METHODS: A retrospective study of a cohort of patients with replacement therapy for hemophilia A or B, evaluating treatment and complications between January/2012 and July/2019. Sociodemographic, clinical and disease management-related variables were extracted from the medical records. Time to inhibitor development and rate associated with bleeding and hospitalizations were evaluated. RESULTS: A total of 159 male patients were identified with hemophilia A (n = 140; 88.1%) and B (n = 19; 11.9%) with a mean follow-up of 5.9±2.3 years. The mean age was 23.6±16.1 years, hemophilia was reported as severe in 125 patients in hemophilia A (89.3%) and 13 patients in hemophilia B (68.4%). Primary prophylaxis was registered in 17.0% of patients, 44.7% secondary, and 38.3% tertiary, with recombinant factors (n = 84; 52.8%) followed by plasma derived factors (n = 75; 47.2%). The incidence of inhibitor development was 0.3 per 100 patients/year, with mean time to event of 509 days. The incidence of bleeding was 192 per 100 patients/year, especially at the joint (n = 99; 62.3%) and muscle (n = 25; 15.7%) level. The incidence of hospitalization was 3.7 per 100 patients/year. CONCLUSIONS: The most common complication was joint bleeding which was expected in this type of patients. Low proportion of patients developed factor inhibitors during the follow up.

Adsorption of chloroquine, propranolol, and metformin in aqueous solutions using magnetic graphene oxide nanocomposite.

The work proposes the application of a nanocomposite formed by graphene oxide and magnetite to remove chloroquine, propranolol, and metformin from water. Tests related to adsorption kinetics, equilibrium isotherms and adsorbent reuse were studied, and optimization parameters related to the initial pH of the solution and the adsorbent dosage were defined. For all pharmaceuticals, adsorption tests indicated that removal efficiency was independent of initial pH at adsorbent dosages of 0.4 g L-1 for chloroquine, 1.2 g L-1 for propranolol, and 1.6 g L-1 for metformin. Adsorption equilibrium was reached within the first few minutes, and the pseudo-second-order model represented the experimental data well. While the equilibrium data fit the Sips isotherm model at 298 K, the predicted maximum adsorption capacities for chloroquine, propranolol, and metformin were 44.01, 16.82, and 12.23 mg g-1, respectively. The magnetic nanocomposite can be reused for three consecutive cycles of adsorption-desorption for all pharmaceuticals, being a promising alternative for the removal of different classes of pharmaceuticals in water.

Infantile metastatic ependymoma with a novel molecular profile and favorable outcome to intensive chemotherapy without irradiation: Case-based review.

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.

Clinical, Pathological, and Molecular Characteristics of Diffuse Spinal Cord Gliomas.

Diffuse spinal cord gliomas (SCGs) are rare tumors associated with a high morbidity and mortality that affect both pediatric and adult populations. In this retrospective study, we sought to characterize the clinical, pathological, and molecular features of diffuse SCG in 22 patients with histological and molecular analyses. The median age of our cohort was 23.64 years (range 1-82) and the overall median survival was 397 days. K27M mutation was significantly more prevalent in males compared to females. Gross total resection and chemotherapy were associated with improved survival, compared to biopsy and no chemotherapy. While there was no association between tumor grade, K27M status (p = 0.366) or radiation (p = 0.772), and survival, males showed a trend toward shorter survival. K27M mutant tumors showed increased chromosomal instability and a distinct DNA methylation signature.

Factors influencing outcomes of older children with medulloblastoma over 15 years in Peru, a resource-limited setting.

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.

Epidemiological characteristics and survival outcomes of children with medulloblastoma treated at the National Cancer Institute (INCA) in Rio de Janeiro, Brazil.

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.

Prognostic factors for patients with relapsed central nervous system nongerminomatous germ cell tumors.

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.

Desafíos de la terapia ocupacional en salud mental: reflexiones desde una experiencia de docencia / Desafios da terapia ocupacional em saúde mental: reflexões a partir de uma experiência docente / Challenges for occupational therapy in mental health: an approach from the teaching experience

Resumen Reflexionar la terapia ocupacional en salud mental desde la práctica docente, con enfoque cualitativo y crítico permite identificar desafíos profesionales en los contextos habituales de las personas y colectivos. Priorizar el contexto clínico para la atención ha condicionado la integralidad y continuidad de los procesos. La terapia ocupacional en salud mental debe transitar además por los contextos habituales, en los que las personas participan en ocupaciones. Este artículo presenta las reflexiones hechas, en torno a los desafíos de la terapia ocupacional en la atención integral en salud mental, desde la práctica docente. Dichas reflexiones parten del uso de técnicas cualitativas de análisis empleadas por las docentes del área psicosocial entre 2013 y 2020, entre las cuales se incluye la revisión y el análisis documental del marco normativo y conceptual, diarios de campo, documentos de sistematización de experiencias, observación participante y espacios académicos de discusión. Se observa que la terapia ocupacional en salud mental en Colombia, se ha estructurado principalmente en contextos clínicos, con enfoque resolutivo que frecuentemente da respuesta a necesidades individuales relacionadas con sintomatología asociada a los trastornos prevalentes; esta institucionalización de las prácticas limita la continuidad de los procesos. Es necesario realizar una aproximación a reflexiones que se vienen dando, en las que se reconoce al terapeuta ocupacional como el profesional que promueve el análisis, la interacción entre sistemas, contextos, personas, poblaciones y ocupaciones; perspectiva que permitiría responder a planteamientos actuales de política; de atención integral e inclusión social. La profesión debe contemplar el abordaje de necesidades ocupacionales subjetivas en los contextos habituales, redimensionando el uso de la ocupación como herramienta para la autonomía e inclusión social.

Resumo Refletir a terapia ocupacional em saúde mental desde a prática docente, com enfoque qualitativo e crítico, permite identificar desafios profissionais nos contextos habituais das pessoas e coletivos. Priorizar o contexto clínico para o atendimento condicionou a integralidade e continuidade dos processos. A terapia ocupacional em saúde mental deve transitar também pelos contextos habituais, nos quais as pessoas participam de ocupações. Este artigo aborda reflexões desde a prática docente sobre os desafios da terapia ocupacional na atenção integral em saúde mental. Essas reflexões são baseadas no uso de técnicas de análise qualitativa utilizadas por docentes da área psicossocial, entre 2013 e 2020, entre os quais se inclui a revisão e análise documental do marco normativo e conceitual, diários de campo, documentos de sistematização de experiências, observação participante em espaços acadêmicos de discussão. Observa-se que a terapia ocupacional em saúde mental na Colômbia tem sido estruturada principalmente em contextos clínicos, com enfoque resolutivo. Frequentemente dá resposta a necessidades individuais relacionadas com a sintomatologia associada aos transtornos prevalentes; esta institucionalização das práticas limita a continuidade dos processos. É necessário realizar uma aproximação a reflexões que vêm se dando, nas quais se reconhece o terapeuta ocupacional como o profissional que promove a análise, a interação entre sistemas, contextos, pessoas, populações e ocupações; perspectiva que permitiria responder a abordagens atuais de política de atenção integral e inclusão social. A profissão deve contemplar a abordagem de necessidades ocupacionais subjetivas nos contextos habituais, redimensionando o uso da ocupação como ferramenta para a autonomia e inclusão social.

Abstract Reflecting on occupational therapy in mental health from an academic practice while utilizing a critical qualitative approach allows one to identify professional challenges in the daily live contexts of individuals and groups. Prioritizing the clinical context to care has conditioned integral and continuous processes. Occupational therapy in mental health must also transit the daily contexts in which people participate in occupations. This article reflects on occupational therapy challenges in mental health care from academic practice. These reflections are based on the use of qualitative analysis techniques used by two educators in the psychosocial area between 2013 and 2020, among which are included the documentary revision and analysis of the normative and conceptual framework, field journal, documents of systematization of experiences, participant observation and academic spaces for discussion. It allows us to observe that occupational therapy in mental health in Colombia has been structured mainly in clinical contexts, with a resolutive approach. It frequently responds to individual needs related to symptoms associated with prevalent disorders; this institutionalization of the practices limits the continuity of the processes. It is necessary to recognize the current reflections in which occupational therapists are valued professionals who promote the analysis and interaction between systems, contexts, people, populations, and occupations. This dynamic would allow responding to current policy approaches, comprehensive care, and social inclusion. The profession must contemplate subjective occupational needs in daily life contexts, making use of occupation as a tool for autonomy and social inclusion.

Comprensiones de lo comunitario en Terapia Ocupacional: aproximaciones desde la Revista Ocupación Humana, 1996- 2021 / Understandings of community in Occupational Therapy: approaches from the perspective of the Revista Ocupación Humana, 1996 to 2021 / Entendimentos do comunitário na Terapia Ocupacional: abordagens a partir da Revista Ocupación Humana, 1996-2021

Este artículo identifica y analiza el camino recorrido en las maneras de concebir lo comunitario en las publicaciones de la Revista Ocupación Humana, entre los años 1996 y 2021. Como metodología, se realizó una revisión documental de los artículos publicados en esta revista y disponibles en línea, guiada por la presencia de las palabras comunidad, comunitario y participación comunitaria, en español, en los títulos, resúmenes y palabras clave. El corpus documental quedó conformado por 13 artículos. De la revisión documental emergieron dos formas de entender lo comunitario: la primera, como un grupo poblacional a intervenir, y la segunda, en clave relacional. Este artículo aporta a la comprensión de lo comunitario en Terapia Ocupacional y contribuye a los análisis situados y críticos locales.

This article identifies and analyzes how 'community' has been conceived in the publications of the Revista Ocupación Humana between 1996 and 2021. The employed methodology consisted of a documentary review of digital publications guided by the terms community, communitarian, and community participation, in Spanish. These were identified in the titles, abstracts, and keywords. The documentary corpus was made up of 13 articles. As a result of the documentary review, two ways of understanding the community emerged: the first linked to an understanding of 'community' as a population group to intervene, and the second of 'community' as a relational form. This article contributes to the understanding of the community in occupational therapy and local situated and critical analyses.

Este artigo identifica e analisa o caminho percorrido nas formas de conceber o comunitário nas publicações da Revista Ocupación Humana, entre os anos de 1996 e 2021. Como metodologia, foi realizada uma revisão documental dos artigos publicados nesta revista e disponíveis online. A exploração foi orientada pela presença das palavras "comunidade", "comunitário" e "participação da comunidade" nos títulos, resumos e palavras-chave. O corpus documental ficou composto em 13 artigos. Duas formas de compreensão do comunitário emergiram desta revisão: a primeira é entendida como um grupo populacional para intervenção, e a segunda, como uma chave relacional. Este artigo contribui para a compreensão do comunitário em Terapia Ocupacional e também para as análises situadas e as críticas locais.

Clinically aggressive pediatric spinal ependymoma with novel MYC amplification demonstrates molecular and histopathologic similarity to newly described MYCN-amplified spinal ependymomas.

Primary spinal cord tumors contribute to ≤ 10% of central nervous system tumors in individuals of pediatric or adolescent age. Among intramedullary tumors, spinal ependymomas make up ~ 30% of this rare tumor population. A twelve-year-old male presented with an intradural, extramedullary mass occupying the dorsal spinal canal from C6 through T2. Gross total resection and histopathology revealed a World Health Organization (WHO) grade 2 ependymoma. He recurred eleven months later with extension from C2 through T1-T2. Subtotal resection was achieved followed by focal proton beam irradiation and chemotherapy. Histopathology was consistent with WHO grade 3 ependymoma. Molecular profiling of the primary and recurrent tumors revealed a novel amplification of the MYC (8q24) gene, which was confirmed by fluorescence in situ hybridization studies. Although MYC amplification in spinal ependymoma is exceedingly rare, a newly described classification of spinal ependymoma harboring MYCN (2p24) amplification (SP-MYCN) has been defined by DNA methylation-array based profiling. These individuals typically present with a malignant progression and dismal outcomes, contrary to the universally excellent survival outcomes seen in other spinal ependymomas. DNA methylation array-based classification confidently classified this tumor as SP-MYCN ependymoma. Notably, among the cohort of 52 tumors comprising the SP-MYCN methylation class, none harbor MYC amplification, highlighting the rarity of this genomic amplification in spinal ependymoma. A literature review comparing our individual to reported SP-MYCN tumors (n = 26) revealed similarities in clinical, histopathologic, and molecular features. Thus, we provide evidence from a single case to support the inclusion of MYC amplified spinal ependymoma within the molecular subgroup of SP-MYCN.

Discovery of clinically relevant fusions in pediatric cancer.

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.

Follow-up evaluation of a web-based pediatric brain tumor board in Latin America.

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.

Molecular classification of a complex structural rearrangement of the RB1 locus in an infant with sporadic, isolated, intracranial, sellar region retinoblastoma.

Retinoblastoma is a childhood cancer of the retina involving germline or somatic alterations of the RB Transcriptional Corepressor 1 gene, RB1. Rare cases of sellar-suprasellar region retinoblastoma without evidence of ocular or pineal tumors have been described. A nine-month-old male presented with a sellar-suprasellar region mass. Histopathology showed an embryonal tumor with focal Flexner-Wintersteiner-like rosettes and loss of retinoblastoma protein (RB1) expression by immunohistochemistry. DNA array-based methylation profiling confidently classified the tumor as pineoblastoma group A/intracranial retinoblastoma. The patient was subsequently enrolled on an institutional translational cancer research protocol and underwent comprehensive molecular profiling, including paired tumor/normal exome and genome sequencing and RNA-sequencing of the tumor. Additionally, Pacific Biosciences (PacBio) Single Molecule Real Time (SMRT) sequencing was performed from comparator normal and disease-involved tissue to resolve complex structural variations. RNA-sequencing revealed multiple fusions clustered within 13q14.1-q21.3, including a novel in-frame fusion of RB1-SIAH3 predicted to prematurely truncate the RB1 protein. SMRT sequencing revealed a complex structural rearrangement spanning 13q14.11-q31.3, including two somatic structural variants within intron 17 of RB1. These events corresponded to the RB1-SIAH3 fusion and a novel RB1 rearrangement expected to correlate with the complete absence of RB1 protein expression. Comprehensive molecular analysis, including DNA array-based methylation profiling and sequencing-based methodologies, were critical for classification and understanding the complex mechanism of RB1 inactivation in this diagnostically challenging tumor.

Oncolytic HSV-1 G207 Immunovirotherapy for Pediatric High-Grade Gliomas.

BACKGROUND: Outcomes in children and adolescents with recurrent or progressive high-grade glioma are poor, with a historical median overall survival of 5.6 months. Pediatric high-grade gliomas are largely immunologically silent or "cold," with few tumor-infiltrating lymphocytes. Preclinically, pediatric brain tumors are highly sensitive to oncolytic virotherapy with genetically engineered herpes simplex virus type 1 (HSV-1) G207, which lacks genes essential for replication in normal brain tissue. METHODS: We conducted a phase 1 trial of G207, which used a 3+3 design with four dose cohorts of children and adolescents with biopsy-confirmed recurrent or progressive supratentorial brain tumors. Patients underwent stereotactic placement of up to four intratumoral catheters. The following day, they received G207 (107 or 108 plaque-forming units) by controlled-rate infusion over a period of 6 hours. Cohorts 3 and 4 received radiation (5 Gy) to the gross tumor volume within 24 hours after G207 administration. Viral shedding from saliva, conjunctiva, and blood was assessed by culture and polymerase-chain-reaction assay. Matched pre- and post-treatment tissue samples were examined for tumor-infiltrating lymphocytes by immunohistologic analysis. RESULTS: Twelve patients 7 to 18 years of age with high-grade glioma received G207. No dose-limiting toxic effects or serious adverse events were attributed to G207 by the investigators. Twenty grade 1 adverse events were possibly related to G207. No virus shedding was detected. Radiographic, neuropathological, or clinical responses were seen in 11 patients. The median overall survival was 12.2 months (95% confidence interval, 8.0 to 16.4); as of June 5, 2020, a total of 4 of 11 patients were still alive 18 months after G207 treatment. G207 markedly increased the number of tumor-infiltrating lymphocytes. CONCLUSIONS: Intratumoral G207 alone and with radiation had an acceptable adverse-event profile with evidence of responses in patients with recurrent or progressive pediatric high-grade glioma. G207 converted immunologically "cold" tumors to "hot." (Supported by the Food and Drug Administration and others; ClinicalTrials.gov number, NCT02457845.).