Diana S. Osorio

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.

PURPOSE: Pediatric neuro-oncology resources are mostly unknown in Chile. We report the human and material resources available in Chilean hospitals providing pediatric neuro-oncology services. METHODS: A cross-sectional survey was distributed to 17 hospitals providing pediatric neuro-oncology services (Programa Infantil Nacional de Drogas Antineoplásicas [PINDA] hospitals, 11; private, 6). RESULTS: Response rate was 71% (PINDA, 8; private, 4). Pediatric neuro-oncology services were mainly provided within general hospitals (67%). Registries for pediatric CNS tumors and chemotherapy-related toxicities were available in 100% and 67% of hospitals, respectively. CNS tumors were treated by pediatric oncologists in 92% of hospitals; none were formally trained in neuro-oncology. The most used treatment protocols were the national PINDA protocols. All WHO essential medicines for childhood cancer were available in more than 80% of the hospitals except for gemcitabine, oxaliplatin, paclitaxel, and procarbazine. The median number of pediatric neurosurgeons per hospital was two (range, 2-6). General neuroradiologists were available in 83% of the centers. Pathology specimens were sent to neuropathologists (58%), adult pathologists (25%), and pediatric pathologists (17%). Intensity-modulated radiotherapy, conformal radiotherapy, and cobalt radiotherapy were used by 67%, 58%, and 42% of hospitals, respectively. Only one private hospital performed autologous hematopoietic cell transplant for children with CNS tumors. CONCLUSION: A wide range of up-to-date treatment modalities are available for children with CNS tumors. Our survey highlights future directions to improve the pediatric neuro-oncology services available in Chile such as the expansion of multidisciplinary clinics, palliative care services, long-term cancer survivorship programs, dedicated clinical research support teams, establishing standardized mechanism for sending pathologic specimen for second opinion to international specialized centers, and establishing specialized neuro-oncology training program.

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.

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.

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.

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.

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.

Background The dismal outcome in children with high-grade brainstem gliomas (BSG) accentuates the need for effective therapeutic strategies. We investigated the role of intensive, including marrow-ablative, chemotherapy regimens in the treatment of young children with newly-diagnosed high-grade BSG. Methods Between 1991-and-2002, 15 eligible children less than 10 years of age with a diagnosis of high-grade BSG were treated on “Head-Start” I and II protocols (HSI and HSII). Treatment included Induction with 4–5 cycles of one of three intensive chemotherapy regimens followed by Consolidation with one cycle of marrow-ablative chemotherapy (thiotepa, carboplatin and etoposide) with autologous hematopoietic cell rescue (AHCR). Irradiation was required for children over 6 years of age or for those with residual tumor at the end of Consolidation. Results We had two long-term survivors who were found retrospectively to harbor low-grade glial tumors and thus were not included in the survival analysis. Of the remaining 13 patients, the 1-year event-free (EFS) and overall (OS) survival for these children were 31% (95% CI 9–55%) and 38% (95% CI 14–63%), respectively. Median EFS and OS were 6.6 (95% CI 2.7, 12.7) and 8.7 months (95% CI 6.9, 20.9), respectively. Eight patients developed progressive disease during study treatment (seven during Induction and one at the end of Consolidation). Ten children received focal irradiation, five for residual tumor (three following Induction and two following Consolidation) and five due to disease progression. Conclusions Children with high-grade BSG did not benefit from this intensive chemotherapy strategy administered prior to irradiation.

The incidence of hepatotoxicity has never been reported for intensive induction chemotherapy regimens for young children with primary malignant CNS tumors. We report our comprehensive review of available data on patients enrolled on the Head Start II trial 1997-2003. Retrospective chart review of patients enrolled on Head Start II (n=90); Patients with non-metastatic disease other than ATRT as the primary diagnosis (n=49) received Induction without HD-MTX. The rest received HD-MTX (age-based; 400mg/Kg or 12mg/m2); Peak serum ALT, AST and bilirubin were recorded for each cycle, as well as cycle days on which the peak levels were recorded. Additionally, all grade III/IV toxicities, including clinical sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) were documented. Forty-one patients received 156 Induction cycles including HD-MTX; 53 patients received 237 Induction cycles without HD-MTX. Among patients in whom test results were available, grades III/IV elevations in ALT, AST and bilirubin were recorded in 5%, 7% and 10% of HD-MTX containing cycles respectively, whereas in 3%, 0.5% and 1% of Induction cycles without HD-MTX. Timing of mean peak elevations of ALT, AST and bilirubin did not differ among patients receiving or not receiving HD-MTX Induction cycles. There were no documented reports of grades III/IV SOS/VOD. There were no permanent or severe hepatotoxicities reported during Induction chemotherapy; however, peak transaminases were higher for patients receiving HD-MTX. These data provide a baseline from which to evaluate hepatotoxicity and incidence of SOS/VOD in the current Head Start 4 trial in which all patients received HD-MTX during Induction.

Primary CNS embryonal carcinoma confers a poor prognosis despite conventional chemotherapy and radiotherapy. We report upon a novel treatment approach to CNS embryonal carcinoma using intensive, including marrow-ablative, chemotherapy followed by maintenance therapy with brentuximab-vedotin without irradiation. Brentuximab-vedotin is an anti-CD30 antibody conjugated to an anti-tubulin synthetic analog. Retrospective review of two patients’ medical records treated since 2015 at Nationwide Children’s Hospital. We report upon the management of two patients with suprasellar pure, CD30-positive embryonal carcinoma. A 17-years-old female with Down syndrome compounded by autism and a 9-years-old male with documented cognitive dysfunction received two cycles of carboplatin/etoposide interspersed with one cycle of cyclophosphamide/etoposide for induction, followed by three cycles of marrow-ablative thiotepa/carboplatin with autologous hematopoietic cell rescue. The first patient achieved complete radiographic and tumor marker response to induction and marrow-ablative chemotherapy, and has completed six cycles of intravenous brentuximab-vedotin, continuing now disease-free 28 months since diagnosis without adverse effects. The second patient had a complete serum and cerebrospinal fluid tumor marker response and a dramatic radiographic response with a small residual abnormality at the end of marrow-ablative chemotherapy that was found at surgery to be composed of predominately reactive changes. Currently, the patient has received the first of six proposed cycles of intravenous brentuximab-vedotin. Intensive, including marrow-ablative chemotherapy followed by maintenance with an anti-CD30 antibody-drug conjugate may provide selective and safe alternative to radiotherapy in the management of patients with CNS embryonal carcinoma especially for patients at high risk of developing irradiation-related complications.