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Retinoblastoma (RB) is the most common primary intraocular cancer of childhood. Over the last few decades, a variety of techniques and treatment modalities emerged that improved the survival and ocular salvage rate of patients with RB. We investigated the relative survival trends of patients with RB from 2000 to 2018 by using the Surveillance, Epidemiology, and End Results (SEER) database.Retrospective database review.We extracted data from SEER 18 from 2000 to 2018. All patients with clinically diagnosed RB during the study period were included. We utilized SEER*Stat 8.3.9 and JPSurv software to estimate relative 5- and 10-year survival rates and trends and generated descriptive analyses with IBM SPSS.Patient survival rates at 5- and 10-year after RB diagnosis.RB was diagnosed in 1479 patients within the SEER 18 Program during our study period. The cohort comprised 776 (52.5%) males, 615 (41.6%) non-Hispanic whites, 487(32.9%) Hispanics, 1030 (69.6%) patients with unilateral disease, and 1087 (73.5%) patients with localized disease. Relative survival trends at 5- and 10-year significantly declined over the study periods (-0.42%, and -0.50% annually, respectively) but the decline was not significant in unilateral and bilateral RB cases separately.Five- and ten-year relative survival trends declined from 2000 to 2018 and were significantly decreasing. Further studies that include more patients are needed to identify the factors contributing to reduced survival of patients with RB over time.

Childhood central nervous system (CNS) tumors have longer delays in diagnosis than do other pediatric malignancies because health care providers (HCPs) lack awareness about clinical presentation of these tumors. To evaluate the knowledge gap among HCPs, we conducted a global cross-sectional survey. The survey consisted of a set of CNS tumor knowledge questions focused on symptoms, signs, and imaging indications. The survey was disseminated to HCPs via email (November 2018-March 2020). Participants had to complete a pre-test survey, attend an education seminar on CNS tumors, and complete a post-test survey. The knowledge gap was evaluated using pre-test and post-test scores. We received 889 pre-test and 392 post-test responses. Most respondents were from Asia (73.1% of pre-test responses; 87.5% of post-test responses). The median pre-test score was 40.0% (range: 13.1-92.9%). A high percentage of correct answers were given in post-test responses (median score: 77.1%, range: 14.9-98.2%). In the pre-test, 18.7% of participants accurately responded that Cushing's triad was a less common symptom, and 15.0% recognized that children aged 10 years are at risk of late diagnosis. Surprisingly, 21.9% falsely reported that patients with malignancy experienced the longest pre-diagnostic symptom interval, and 54.5% of respondents wrongly selected medulloblastoma as the most common CNS tumor. Overall, pediatricians demonstrated a greater knowledge gap on both surveys than did other specialties. Conclusion: Pre- and post-test surveys revealed significant knowledge gaps in childhood CNS tumors among HCPs. Thus, raising professional awareness on clinical presentations of CNS tumors through educational strategies is important to address this knowledge deficit. What is Known: • Diagnostic delay in childhood central nervous system (CNS) tumors continues to be a significant problem that negatively impacts the quality of life and treatment sequelae. • Lack of medical education on CNS tumors is a contributing factor to this problem. What is New: • Most health care providers do not realize that low-grade tumors are the most common neoplasm in children. • Health care providers fail to recognize that teenagers and adolescents are a vulnerable age group for diagnostic delays, with the longest pre-diagnostic symptom interval.

Methylation profiling has radically transformed our understanding of tumors previously called central nervous system primitive neuro-ectodermal tumors (CNS-PNET). While this marks a momentous step toward defining key differences, reclassification has thrown treatment into disarray. To shed light on response to therapy and guide clinical decision-making, we report outcomes and molecular features of children with CNS-PNETs from two multi-center risk-adapted studies (SJMB03 for patients ≥ 3 years; SJYC07 for patients 3 years) complemented by a non-protocol institutional cohort. Seventy patients who had a histological diagnosis of CNS-PNET or CNS embryonal tumor from one of the new categories that has supplanted CNS-PNET were included. This cohort was molecularly characterized by DNA methylation profiling (n = 70), whole-exome sequencing (n = 53), RNA sequencing (n = 20), and germline sequencing (n = 28). Clinical characteristics were detailed, and treatment was divided into craniospinal irradiation (CSI)-containing (SJMB03 and SJMB03-like) and CSI-sparing therapy (SJYC07 and SJYC07-like). When the cohort was analyzed in its entirety, no differences were observed in the 5-year survival rates even when CSI-containing therapy was compared to CSI-sparing therapy. However, when analyzed by DNA methylation molecular grouping, significant survival differences were observed, and treatment particulars provided suggestions of therapeutic response. Patients with CNS neuroblastoma with FOXR2 activation (CNS-NB-FOXR2) had a 5-year event-free survival (EFS)/overall survival (OS) of 66.7% ± 19.2%/83.3% ± 15.2%, and CIC rearranged sarcoma (CNS-SARC-CIC) had a 5-year EFS/OS both of 57.1% ± 18.7% with most receiving regimens that contained radiation (focal or CSI) and multidrug chemotherapy. Patients with high-grade neuroepithelial tumor with BCOR alteration (HGNET-BCOR) had abysmal responses to upfront chemotherapy-only regimens (5-year EFS = 0%), but survival extended with salvage radiation after progression [5-year OS = 53.6% ± 20.1%]. Patients with embryonal tumor with multilayered rosettes (ETMR) or high-grade glioma/glioblastoma multiforme (HGG/GBM) did not respond favorably to any modality (5-year EFS/OS = 10.7 ± 5.8%/17.9 ± 7.2%, and 10% ± 9.0%/10% ± 9.0%, respectively). As an accompaniment, we have assembled this data onto an interactive website to allow users to probe and query the cases. By reporting on a carefully matched clinical and molecular cohort, we provide the needed insight for future clinical management.

Background: Central nervous system (CNS) tumors are the most common solid malignancies in children worldwide, including in Armenia. The current study aims to analyze epidemiological data, treatment, and outcomes of children and young adults (≤25 years) with CNS tumors in Armenia during the last 26 years. Methods: We collected data from pediatric and young adult patients treated in selected sites in Armenia from 1 January 1995 to 31 December 2020. Incidence by sex, age at diagnosis, time from first complaints to diagnosis, histopathology results, treatment strategies, complications, and overall survival (OS) rates were calculated. Results: The multicenter data analysis revealed 149 patients with diagnosed primary CNS tumors over 26 years. Among them, 84 (56.4%) were male. The median age at diagnosis was 7 years (range, 3 months to 25 years), and the median time from the first complaints to diagnosis was 2 months (range, 1 week to 70 months). Medulloblastomas and other embryonal tumors (47), low-grade gliomas (32), and high-grade gliomas (22) were the most commonly diagnosed malignancies. Ependymomas, craniopharyngiomas, germ cell tumors, and other malignancies were observed in 22 patients. For 26 patients, no histopathological or radiological diagnosis was available. Follow-up information was available for 98 (65.8%) patients. The 5-year OS rate for the whole study group was 67.7%. Conclusion: Consistent with international data, embryonal tumors, and gliomas were the most commonly diagnosed CNS malignancies in Armenia. Multimodal treatment was often not available in Armenia during the study period, especially for early cases.

Supplementary Figures S1 to S5

Purpose:Report relevance of molecular groups to clinicopathologic features, germline SMARCB1/SMARCA4 alterations (GLA), and survival of children with atypical teratoid rhabdoid tumor (ATRT) treated in two multi-institutional clinical trials.Materials and Methods:Seventy-four participants with newly diagnosed ATRT were treated in two trials: infants (SJYC07: age < 3 years; n = 52) and children (SJMB03: age 3–21 years; n = 22), using surgery, conventional chemotherapy (infants), or dose-dense chemotherapy with autologous stem cell rescue (children), and age- and risk-adapted radiotherapy [focal (infants) and craniospinal (CSI; children)]. Molecular groups ATRT-MYC (MYC), ATRT-SHH (SHH), and ATRT-TYR (TYR) were determined from tumor DNA methylation profiles.Results:Twenty-four participants (32%) were alive at time of analysis at a median follow-up of 8.4 years (range, 3.1–14.1 years). Methylation profiling classified 64 ATRTs as TYR (n = 21), SHH (n = 30), and MYC (n = 13), SHH group being associated with metastatic disease. Among infants, TYR group had the best overall survival (OS; P = 0.02). However, outcomes did not differ by molecular groups among infants with nonmetastatic (M0) disease. Children with M0 disease and 2 residual tumor had a 5-year progression-free survival (PFS) of 72.7 ± 12.7% and OS of 81.8 ± 11%. Infants with M0 disease had a 5-year PFS of 39.1 ± 11.5% and OS of 51.8 ± 12%. Those with metastases fared poorly [5-year OS 25 ± 12.5% (children) and 0% (infants)]. SMARCB1 GLAs were not associated with PFS.Conclusions:Among infants, those with ATRT-TYR had the best OS. ATRT-SHH was associated with metastases and consequently with inferior outcomes. Children with nonmetastatic ATRT benefit from postoperative CSI and adjuvant chemotherapy.

Germline methodology

Patients with childhood brain tumors are at risk of endocrine disorders. The prevalence of endocrine disorders varies across the world but is unknown in Malaysia. This study's objectives were to determine the prevalence of endocrine disorders among children with brain tumors in Malaysia and to identify endocrinopathy-associated risk factors. We retrospectively reviewed the clinical data of pediatric patients with brain tumors diagnosed and treated at the University Malaya Medical Center from 1 January 2001 to 31 December 2015, with a follow-up period until the age of 18 years old or at least 3 years from the initial diagnosis. A total of 106 patients were included; 71 patients (66%) were screened for endocrine disorders, and 61% of these had endocrine disorders at a median follow-up of 4 years. Hypothyroidism, short stature, and adrenocortical insufficiency were present in one-third of the patients, followed by central diabetes insipidus (21%), growth hormone deficiency (10%), delayed puberty (9%), and precocious puberty (4%). Radiation therapy and surgical intervention were risk factors for endocrine disorders, but hydrocephalus, supratentorial tumors, and malignant tumors were not. Most endocrinopathies developed within the first 2 years of brain tumor diagnosis. Therefore, standard endocrine-monitoring guidelines aiming for early diagnosis and therapy are essential.

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.

Retinoblastoma is the most common intraocular childhood cancer and is typically diagnosed in young children. With increasing number of survivors and improved medical outcomes, long-term psychosocial impacts need to be explored. Thus, the current study sought to assess functioning in school-aged survivors of retinoblastoma.Sixty-nine survivors of retinoblastoma underwent a one-time evaluation of psychosocial functioning. Survivors (MOn the whole, both survivors and caregivers indicated QoL and behavioral and emotional health within the typical range of functioning. Survivors reported better physical QoL compared to both parent report and a national healthy comparison sample, whereas caregivers reported that survivors experienced lower social, school, and physical QoL than a healthy comparison. Regarding behavioral and emotional health, survivors indicated more anxiety than a nationally representative sample. Parents of female survivors endorsed lower adaptive scores than parents of male survivors.Results indicated that survivors of retinoblastoma reported QoL and behavioral and emotional health within normal limits, although parents appear to perceive greater impairment across several assessed domains. Understanding both survivor and parent reports remains important for this population. Future research should explore psychosocial functioning of these survivors as they transition to adolescence and early adulthood, given the increased independence and behavioral and emotional concerns during these developmental periods.

To assess the frequency of torticollis as a presenting symptom of pediatric CNS tumors and its impact on pre-diagnostic symptom intervals (PSIs) and patient outcomes. We performed a systematic review of studies reporting torticollis in children with various CNS tumors. We searched PubMed for studies published from January 1972 to March 2021 in English. Case reports were included in the analysis if the following criteria were met (1) torticollis was the presenting symptom secondary to a CNS tumor (2) children18 years of age, (3) underwent imaging intervention and (4) outcome data provided. Of 1,365 relevant articles, 45 were eligible for analysis according to our inclusion criteria representing 95 patients. Two independent investigators extracted the data, and a third investigator arbitrated discrepancies. We found that 38.9% of CNS tumors exhibited torticollis as the only presenting symptom. PSI lengths ranged from 0 to 4 years (median, 5 months) for low-grade tumors, and patient age and PSI length were inversely associated. Of patients with low-grade tumors, 23.8% received physiotherapy, in contrast with 0% of patients with high-grade tumors. PSI length also increased for patients who received rehabilitation, and 39.3% and 7.1% of patients with high-grade and low-grade tumors, respectively, died of their disease. Patients with low-grade tumors and torticollis as a primary presenting symptom were more likely to have a prolonged PSI. Therefore, CNS tumors should be considered in the differential diagnosis of acquired torticollis in children.

Iraq's health care system has gradually declined after several decades of wars, terrorism, and UN economic sanctions. The Oncology Unit at Children's Welfare Teaching Hospital (CWTH) in Baghdad was lacking basic facilities and support. To address this shortcoming, a humanitarian and educational partnership was established between CWTH and Sapienza University of Rome (SUR).We investigated the outcomes of 80 online and 16 onsite educational sessions and 142 teleconsultation sessions from 2006 to 2014. We also determined the outcomes of pathology reviews by SUR of 1216 tissue specimens submitted by CWTH from 2007 until 2019 for second opinions. The primary outcomes were discordance, concordance, and changes among clinical diagnoses and pathology review findings. The measures included the frequency of teleconsultation and tele-education sessions, the topics discussed in these sessions, and the number of pathology samples requiring second opinions.A total of 500 cases were discussed via teleconsultations during the study period. The median patient age was 7 years (range, 24 days to 16·4 years), and the cases comprised 79 benign tumors, 299 leukemias, 120 lymphomas, and 97 solid tumors. The teleconsultation sessions yielded 27 diagnostic changes, 123 confirmed diagnoses, and 13 equivocal impacts. The pathology reviews by SUR were concordant for 996 (81·9%) cases, discordant for 186 (15·3%), and inconclusive for 34 (2·8%). The major cause of discordance was inadequate immunohistochemical staining. The percentage of discordance markedly decreased over time (from 40% to 10%). The cause of the improvement is multifactorial: training of two CWTH pathologists at SUR, better immunohistochemical staining, and the ongoing clinical and pathologic telemedicine activities. The partnership yielded 12 publications, six posters, and three oral presentations by CWTH investigators.The exchange of knowledge and expertise across continental boundaries meaningfully improved the diagnoses and management of pediatric cancer at CWTH.

Background Unresectable hypothalamic/optic pathway pilocytic astrocytoma (PA) often progresses despite multiple therapies. Identifying clinical and molecular characteristics of progressive tumors may aid in prognostication and treatment. Methods We collected 72 unresectable, non-neurofibromatosis type 1-associated hypothalamic/optic pathway PA to identify clinical and biologic factors associated with tumor progression. Tumors that progressed after therapy, metastasized, or resulted in death were categorized into Cohort B; those that did not meet these criteria were categorized into Cohort A. DNA methylation and transcriptome analyses were performed on treatment-naïve tumors, and the findings were validated by immunohistochemistry (IHC). Results The median follow-up of the entire cohort was 12.3 years. Cohort B was associated with male sex (M:F = 2.6:1), younger age at diagnosis (median 3.2 years vs 6.7 years, P = .005), and high incidence of KIAA1549-BRAF fusion (81.5% vs 38.5%, P = .0032). Cohort B demonstrated decreased CpG methylation and increased RNA expression in mitochondrial genes and genes downstream of E2F and NKX2.3. Transcriptome analysis identified transcription factor TBX3 and protein kinase PIM1 as common downstream targets of E2F and NKX2.3. IHC confirmed increased expression of TBX3 and PIM1 in Cohort B tumors. Gene enrichment analysis identified enrichment of MYC targets and MAPK, PI3K/AKT/mTOR, and p53 pathways, as well as pathways related to mitochondrial function. Conclusions We identified risk factors associated with progressive PA. Our results support the model in which the p53-PIM1-MYC axis and TBX3 act alongside MAPK and PI3K/AKT/mTOR pathways to promote tumor progression, highlighting potential new targets for combination therapy and refining disease prognostication.

PURPOSE: To describe clinical data, rehabilitation services, and outcomes of children with handedness switching as their presenting symptom before low-grade glioma (LGG) diagnosis. METHODS: A retrospective chart review was performed for five patients (four female and four white) with LGG and confirmed handedness switching before LGG diagnosis. RESULTS: All children were less than 8 years at diagnosis, and two patients were less than 3 years. All children were initially right-handed and experienced loss of motor function, ranging from weakness to paresis, in their dominant hand. The median time from switching handedness to diagnosis was 1 month (range: 0.75–60 months). Rehabilitation was offered for three patients, and motor function deficits in the initial dominant hand were resolved in two of the total cohort. At long-term follow-up, hand dominance returned to the initial hand in three patients. CONCLUSIONS: Handedness switching should be acknowledged as a potential sign of LGG in children, and early long-term rehabilitation services should be offered for these children.

Purpose: Report relevance of molecular groups to clinicopathologic features, germline SMARCB1/SMARCA4 alterations (GLA), and survival of children with atypical teratoid rhabdoid tumor (ATRT) treated in two multi-institutional clinical trials. Materials and Methods: Seventy-four participants with newly diagnosed ATRT were treated in two trials: infants (SJYC07: age < 3 years; n = 52) and children (SJMB03: age 3–21 years; n = 22), using surgery, conventional chemotherapy (infants), or dose-dense chemotherapy with autologous stem cell rescue (children), and age- and risk-adapted radiotherapy [focal (infants) and craniospinal (CSI; children)]. Molecular groups ATRT-MYC (MYC), ATRT-SHH (SHH), and ATRT-TYR (TYR) were determined from tumor DNA methylation profiles. Results: Twenty-four participants (32%) were alive at time of analysis at a median follow-up of 8.4 years (range, 3.1–14.1 years). Methylation profiling classified 64 ATRTs as TYR (n = 21), SHH (n = 30), and MYC (n = 13), SHH group being associated with metastatic disease. Among infants, TYR group had the best overall survival (OS; P = 0.02). However, outcomes did not differ by molecular groups among infants with nonmetastatic (M0) disease. Children with M0 disease and Conclusions: Among infants, those with ATRT-TYR had the best OS. ATRT-SHH was associated with metastases and consequently with inferior outcomes. Children with nonmetastatic ATRT benefit from postoperative CSI and adjuvant chemotherapy.

Multidisciplinary team meetings (MDTMs) are essential in the clinical management of pediatric central nervous system (CNS) tumors. Evaluations of the impact of MDTMs on childhood CNS tumors and clinicians’ perspectives on their effectiveness are scarce. We retrospectively reviewed the clinical data of pediatric patients (aged

Objective To evaluate the efficacy of integrating telemedicine-based twinning partnership and centralized care for Retinoblastoma (RB) on survival and eye salvage. Design A cohort of 478 RB patients from 2003 to 2019 treated at tertiary referral cancer center (King Hussein Cancer Centre, KHCC). Participants 478 RB patients who were treated at KHCC after implementing a telemedicine-based program with St. Jude Children’s Research Hospital. Methods We reviewed the outcomes of RB patients who were treated at King Hussein Cancer Centre (KHCC) after implementing a telemedicine-based eye salvage program with St. Jude Children’s Research Hospital, and we compared that with outcomes for RB patients who were treated before implementing a telemedicine-based RB service at KHCC. Main Outcome Measures We analyzed patient demographics, clinical characteristics, treatments received, consultation type and duration, and long-term patient outcomes before and after implementing the twinning program. Results Over 17 years, 813 eyes from 478 children with RB were treated at KHCC, 335(70%) patients had bilateral disease, and family history of RB was positive in 6(4%) of unilateral cases, and in 66(20%) of bilateral cases. After the twinning program was established in 2003, the mortality rate decreased from 38% to 5%(P Conclusions Centralization of care at a single center in developing countries can achieve patient outcomes comparable with those of developed countries via twinning and telemedicine. This benefit can extend to a large region because two thirds of patients treated at KHCC were non-Jordanians.

BACKGROUND The St Jude Global Academy Neuro-Oncology Training Seminar (NOTS) is a hybrid course in pediatric neuro-oncology specifically designed for physicians from low-income and middle-income countries. METHODS The curriculum for the course was created by conducting a targeted needs assessment that evaluated 11 domains of care for children with central nervous system (CNS) tumors. The targeted needs assessment was completed by 24 institutions across the world, and the data were used to define 5 core elements included in the 2 components of the NOTS: a 9-week online course and a 7-day in-person workshop. Participant acquisition of knowledge and changes in clinical behavior were evaluated as measures of success. RESULTS Teams from 8 institutions located in 8 countries enrolled in the online course, and it was successfully completed by 36 participants representing 6 specialties. On the basis of their performance in the online course, 20 participants from 7 institutions took part in the on-site workshop. The participants exhibited improved knowledge in core elements of treating children with CNS tumors, including barriers of care, possible solutions, and steps for project implementation (P < .0001). All participants expressed a belief that they acquired new concepts and knowledge, leading to changes in their clinical practice. Those present at the workshop created an international multidisciplinary group focused on treating CNS tumors in low-income and middle-income countries. CONCLUSIONS By using a hybrid online and in-person approach, the authors successfully created a multidisciplinary course focused on pediatric CNS tumors for resource-limited settings. Their experience supports this strategy as a feasible mechanism for driving further global collaborations.

Retinoblastoma (RB) tumors having high-risk histopathologic features (HRFs) have an increased risk of metastasis and disease relapse. However, RB has not been studied widely in Pakistan. Therefore, we evaluated the association of clinical, histopathologic, and radiological findings with HRFs in patients with RB who were treated at the Indus HealthHospital Network in Karachi, Pakistan.We enrolled treatment-naïve patients with RB who received upfront enucleation from September 2017 to February 2021. We evaluated enucleated eyes with the Intraocular Classification of Retinoblastoma system and classified HRFs as invasion of the anterior chamber, including the iris and ciliary body, or massive invasion of the choroid, sclera, or optic nerve (postlaminar and/or up to the transection line).Of 117 patients with RB treated at our institution during the study period, 54 received upfront enucleation. Unilateral disease was present in 92.6% of cases. The most frequent disease signs and symptoms included the presence of vitreous seeds (30.6%) and leukocoria (100%), respectively. The most frequent HRFs and radiological findings comprised massive choroidal invasion (15.1%) and anterior chamber enhancement (66.7%), respectively. The majority (62.9%) of patients did not exhibit any HRFs. Female sex, pseudohypopyon, iris neovascularization, buphthalmos, and glaucoma had significant predictive ability for HRF occurrence.Pseudohypopyon, iris neovascularization, buphthalmos, and glaucoma are important clinical factors that should be taken into consideration before the management of RB. Early recognition of high-risk histopathological and radiological features is essential for appropriate treatment of RB.

Central nervous system (CNS) tumors represent the most deadly cancer in pediatric age group. In China, thousands of children are diagnosed with CNS tumors every year. Despite the improving socioeconomic status and availability of medical expertise within the country, unique challenges remain for the delivery of pediatric neuro‐oncology service. In this review, we discuss the existing hurdles for improving the outcome of children with CNS tumors in China. Need for precise disease burden estimation, lack of intra‐ and inter‐hospital collaborative networks, high probability of treatment abandonment, along with financial toxicities from treatment represent the key challenges that Chinese healthcare providers encounter. The tremendous opportunities for advancing the status of pediatric neuro‐oncology care in and beyond the country are explored.

Background Management of unresectable pediatric low-grade glioma and glioneuronal tumor (LGG/LGGNT) is controversial. There are no validated prognostic features to guide use of radiation therapy (RT). Our study aimed to identify negative prognostic features in patients treated with RT using clinicopathologic and molecular data and validate these findings in an external dataset. Methods Children with non-metastatic, biopsy-proven unresectable LGG/LGGNT treated with RT at a single institution between 1997 and 2017 were identified. Recursive partitioning analysis (RPA) was used to stratify patients into low- and high-risk prognostic groups based on overall survival (OS). CNS9702 data were used for validation. Results One hundred and fifty patients met inclusion criteria. Median follow-up was 11.4 years. RPA yielded low- and high-risk groups with 10-year OS of 95.6% versus 76.4% (95% CI: 88.7%–98.4% vs 59.3%–87.1%, P = 0.003), respectively. These risk groups were validated using CNS9702 dataset (n = 48) (4-year OS: low-risk vs high-risk: 100% vs 64%, P < 0.001). High-risk tumors included diffuse astrocytoma or location within thalamus/midbrain. Low-risk tumors included pilocytic astrocytoma/ganglioglioma located outside of the thalamus/midbrain. In the subgroup with known BRAF status (n = 49), risk stratification remained prognostic independently of BRAF alteration (V600E or fusion). Within the high-risk group, delayed RT, defined as RT after at least one line of chemotherapy, was associated with a further decrement in overall survival (P = 0.021). Conclusion A high-risk subgroup of patients, defined by diffuse astrocytoma histology or midbrain/thalamus tumor location, have suboptimal long-term survival and might benefit from timely use of RT. These results require validation.

PURPOSE: Most pediatric spinal tumors are low-grade gliomas (LGGs). Characterization of these tumors has been difficult given their heterogeneity and rare incidence. The objective was to characterize such tumors diagnosed at our institution. METHODS: Spinal tumors diagnosed in our pediatric patients between 1984 and 2014 were reviewed retrospectively. Demographics, presentation, pathology, imaging, management, and sequelae were examined. RESULTS: Forty patients had spinal LGG tumors, 24 (62%) of which were pilocytic astrocytomas. The most common initial presentations were pain (n=15), partial extremity paralysis (n=13), and ataxia (n=11), with the diagnosis frequently delayed by months (median=5.9 months, range=4 days-6.2 years). Twenty-nine patients had some tumor resection, and 8 required adjuvant therapy with chemotherapy (n=4) or radiation (n=4) post-resection. Ten other patients received only biopsy for histologic diagnosis, who were treated with chemotherapy (n=4) or radiation (n=5) post biopsy. Tumor progression was noted in 16 patients (2 after gross-total resection; 10, partial resection; and 4, biopsy). During the evaluation period, 3 patients died secondary to tumor progression. BRAF status could have shortened progression-free survival: patients with BRAFV600E mutations (n=3) all experienced progression within 10 months. Long-term sequelae of the disease/treatment were mostly residual neurologic deficits (paresthesia, paralysis), chemotherapy-induced hearing loss, and scoliosis. CONCLUSIONS: Spinal LGG is a rare entity with significant long-term effects. Although surgery is the most common initial treatment option, more in-depth analysis of molecular biomarkers may improve stratification and prognostication.

Unresectable hypothalamic/optic pathway pilocytic astrocytoma (PA) can be challenging to manage due to repeated progressions despite multiple lines of therapy. To identify clinical and biologic factors associated with tumor progression, we retrospectively identified 72 unresectable non-NF1-associated hypothalamic/optic pathway PA. Tumors were classified as high-risk (50%) if they progressed after three or more lines of chemotherapy/targeted therapy, progressed after radiation, developed metastatic disease, or died of disease. DNA methylation profiling and transcriptome analysis (RNA sequencing) were performed on treatment-naïve tumors with available tissue (n=40), and the findings were validated by immunohistochemistry (IHC) on additional tumor tissue. The median follow-up of the entire cohort was 12.3 years. High-risk tumors were associated with male sex (M:F = 2.6:1), younger age at diagnosis (median 3.2 years vs. 6.7 years, P = 0.005), and high incidence of KIAA1549-BRAF fusion (81.5% vs. 38.5%, P = 0.0032). High-risk tumors demonstrated decreased CpG methylation and increased RNA expression in many mitochondrial genes and genes downstream of E2F and NKX2.3 transcription factors. Transcriptome analysis identified transcription factor TBX3 and proto-oncogene serine/threonine protein kinase PIM1 as common downstream targets of both E2F and NKX2.3 and potential drivers of tumor progression. IHC confirmed increased expression of TBX3 and PIM1 in high-risk tumors. PIM1 is known to increase the stability and transcriptional activity of MYC, and gene enrichment analysis identified enrichment of MYC targets. Signaling pathways known to be implicated in PA, such as MAPK and PI3K/AKT/mTOR, were also enriched, in addition to pathways related to mitochondrial biogenesis and oxidative phosphorylation. Our results support the model in which the p53-PIM1-MYC axis and TBX3 act alongside MAPK and PI3K/AKT/mTOR pathways to promote tumor progression, highlighting potential new targets for combination therapy and refining disease prognosis.

Hospital wait time (WT) influences healthcare quality and patient satisfaction. Long WTs are distressful for patients and considered substandard healthcare delivery. Pediatric hematology/oncology patients with complex medical conditions frequently need multiple appointments in a day, making their scheduling very challenging. Here, we report a quality improvement (QI) project aimed to decrease the percentage of patients waiting30 minutes before room placement in the neuro-oncology clinic.We measured WT from when the patient reported to the clinic (or, for those arriving early, from scheduled appointment) to when the patient got an exam room. We collected data by random sampling and collected baseline data over the initial 4 weeks; generated process mapping and Pareto charts to identify reasons for delayed patient placement in rooms; and used iterative Plan-Do-Study-Act (PDSA) cycles to test interventions. We used Run charts and Shewhart charts for data analysis.Our baseline data analyses showed provider and room availability as critical reasons for delayed room placement (38.4% and 30%, respectively). We also completed related PDSA improvement cycles. The median percent of patients waiting30 minutes decreased from 21% to 13%. The median average waiting time decreased from 21 to 11 minutes.Using structured QI methodology, we decreased the percent of patients waiting30 minutes before room placement and overall WTs. We developed a strategy for continuous improvement and future interventions. Furthermore, our results suggest that QI projects, which account for the complexity of hospital systems, can improve patient flow throughout the hospital.

The presentation of psychiatric symptoms in pediatric low-grade brain tumors is challenging because this can delay proper diagnosis and treatment. We performed a systematic review of psychiatric presenting symptoms of low-grade brain tumors in pediatric patients. We searched the PubMed and Web of Science databases of studies published in English from 1977 until 2019 reporting patients aged ≤21 years at the time of tumor diagnosis who exhibited psychiatric/behavioral symptoms before diagnosis of low-grade glioma (LGG), pilocytic astrocytoma (PA), or craniopharyngioma (CP). Our systematic search strategy coupled each tumor type with patient age and presenting symptoms by using different variations of the search terms "childhood" and "psychiatric symptoms" or "behavioral symptoms." We identified six unique articles that met our inclusion criteria in the LGG search, 27 in the PA search, and 32 in the CP search. Six patients were included in the LGG articles (age range, 3-16 years), 75 in the PA articles (age range, 0.5-21 years), and 87 in the CP articles (age range, 0.67-21 years). The most common presenting symptoms included eating disorders (n = 64) and behavioral changes (n = 49). Our findings demonstrate the need to establish clear criteria for neuroimaging indications for pediatric patients exhibiting eating disorders.

Pediatric high-grade glioma (pHGG) is a major contributor to cancer-related death in children. In vitro and in vivo disease models reflecting the intimate connection between developmental context and pathogenesis of pHGG are essential to advance understanding and identify therapeutic vulnerabilities. Here we report establishment of 21 patient-derived pHGG orthotopic xenograft (PDOX) models and eight matched cell lines from diverse groups of pHGG. These models recapitulate histopathology, DNA methylation signatures, mutations and gene expression patterns of the patient tumors from which they were derived, and include rare subgroups not well-represented by existing models. We deploy 16 new and existing cell lines for high-throughput screening (HTS). In vitro HTS results predict variable in vivo response to PI3K/mTOR and MEK pathway inhibitors. These unique new models and an online interactive data portal for exploration of associated detailed molecular characterization and HTS chemical sensitivity data provide a rich resource for pediatric brain tumor research., Patient-derived xenografts provide a resource for basic and translational cancer research. Here, the authors generate multiple pediatric high-grade glioma xenografts, use omics technologies to show that they are representative of primary tumours and use them to assess therapeutic response.

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.