Outcomes for children with recurrent/refractory atypical teratoid rhabdoid tumor: A single-institution study with molecular correlation.

BACKGROUND: Survival data for recurrent pediatric atypical teratoid rhabdoid tumor (ATRT) and its association to molecular groups are extremely limited. METHODS: Single-institution retrospective study of 64 children less than 21 years old with recurrent or treatment-refractory (progressive disease [PD]) ATRT treated at St. Jude Hospital from January 2000 to December 2020. Demographic, clinicopathologic, treatment, molecular grouping (SHH, TYR, and MYC) and germline data were collected. Progression-free survival (PFS2: time from PD to subsequent first progression) and overall survival (OSpostPD: time from PD to death/last follow-up) were estimated by Kaplan-Meier analysis. RESULTS: Median age at and time from initial diagnosis to PD were 2.1 years (range: 0.5-17.9 years) and 5.4 months (range: 0.5-125.6 months), respectively. Only five of 64 children (7.8%) are alive at median follow-up of 10.9 (range: 4.2-18.1) years from PD. The 2/5-year PFS2 and OSpostPD were 3.1% (±1.8%)/1.6% (±1.1%) and 20.3% (±4.8%)/7.3% (±3.5%), respectively. Children with TYR group (n = 10) had a better OSpostPD compared to those with MYC (n = 11) (2-year survival estimates: 60.0% ± 14.3% vs. 18.2% ± 9.5%; p = .019), or those with SHH (n = 21; 4.8% ± 3.3%; p = .014). In univariate analyses, OSpostPD was better with older age at diagnosis (p = .037), female gender (p = .008), and metastatic site of PD compared to local or combined sites of PD (p < .001). Two-year OSpostPD for patients receiving any salvage therapy (n = 39) post PD was 33.3% ± 7.3%. CONCLUSIONS: Children with recurrent/refractory ATRT have dismal outcomes. Older age at diagnosis, female gender, TYR group, and metastatic site of PD were associated with relatively longer survival in our study.

How modern treatments have modified the role of surgery in pediatric low-grade glioma.

Low-grade gliomas are the most common brain tumor of childhood, and complete resection offers a high likelihood of cure. However, in many instances, tumors may not be surgically accessible without substantial morbidity, particularly in regard to gliomas arising from the optic or hypothalamic regions, as well as the brainstem. When gross total resection is not feasible, alternative treatment strategies must be considered. While conventional chemotherapy and radiation therapy have long been the backbone of adjuvant therapy for low-grade glioma, emerging techniques and technologies are rapidly changing the landscape of care for patients with this disease. This article seeks to review the current and emerging modalities of treatment for pediatric low-grade glioma.

Epigenetics to clinicopathological features: a bibliometric analysis of H3 G34-mutant diffuse hemispheric glioma literature.

PURPOSE: Pediatric-type diffuse high-grade gliomas are the leading cause of cancer-related morbidity and mortality in children. More than 30% of diffuse hemispheric gliomas (DHG) in adolescents harbor histone H3 G34 mutations and are recognized by the World Health Organization as a distinct tumor entity. By reporting bibliometric characteristics of the most cited publications on H3 G34-mutant DHG (H3 G34 DHG), we provide an overview of emerging literature and speculate where future research efforts may lead. METHODS: One hundred fourteen publications discussing H3 G34 DHG were identified, categorized as basic science (BSc), clinical (CL), or review (R), and ranked by citation number. Various bibliometric parameters were summarized, and a comparison between article types was performed. RESULTS: Articles within this study represent principal investigators from 15 countries and were published across 63 journals between 2012 and 2024, with 36.84% of articles originating in the United States. Overall median values were as follows: citation count, 20 (range, 0-2591), number of authors, 9 (range, 2-78), and year of publication, 2020 (range, 2012-2024). Among the top ten most cited articles, BSc articles accounted for all ten reports. Compared to CL and R articles, BSc articles were published in journals with higher impact factors. CONCLUSION: We establish variability in bibliometric parameters for the most cited publications on H3 G34 DHG. Our findings demonstrate a paucity of high-impact and highly cited CL reports and acknowledge an unmet need to intersect basic mechanism with clinical data to inform novel therapeutic approaches.

Trends in pediatric CNS tumors in Armenia: a multicenter retrospective study.

PURPOSE: 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 1st January 1995 to 31st 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.

Proton therapy and limited surgery for paediatric and adolescent patients with craniopharyngioma (RT2CR): a single-arm, phase 2 study.

BACKGROUND: Compared with photon therapy, proton therapy reduces exposure of normal brain tissue in patients with craniopharyngioma, which might reduce cognitive deficits associated with radiotherapy. Because there are known physical differences between the two methods of radiotherapy, we aimed to estimate progression-free survival and overall survival distributions for paediatric and adolescent patients with craniopharyngioma treated with limited surgery and proton therapy, while monitoring for excessive CNS toxicity. METHODS: In this single-arm, phase 2 study, patients with craniopharyngioma at St Jude Children's Research Hospital (Memphis TN, USA) and University of Florida Health Proton Therapy Institute (Jacksonville, FL, USA) were recruited. Patients were eligible if they were aged 0-21 years at the time of enrolment and had not been treated with previous radiotherapeutic or intracystic therapies. Eligible patients were treated using passively scattered proton beams, 54 Gy (relative biological effect), and a 0·5 cm clinical target volume margin. Surgical treatment was individualised before proton therapy and included no surgery, single procedures with catheter and Ommaya reservoir placement through a burr hole or craniotomy, endoscopic resection, trans-sphenoidal resection, craniotomy, or multiple procedure types. After completing treatment, patients were evaluated clinically and by neuroimaging for tumour progression and evidence of necrosis, vasculopathy, permanent neurological deficits, vision loss, and endocrinopathy. Neurocognitive tests were administered at baseline and once a year for 5 years. Outcomes were compared with a historical cohort treated with surgery and photon therapy. The coprimary endpoints were progression-free survival and overall survival. Progression was defined as an increase in tumour dimensions on successive imaging evaluations more than 2 years after treatment. Survival and safety were also assessed in all patients who received photon therapy and limited surgery. This study is registered with ClinicalTrials.gov, NCT01419067. FINDINGS: Between Aug 22, 2011, and Jan 19, 2016, 94 patients were enrolled and treated with surgery and proton therapy, of whom 49 (52%) were female, 45 (48%) were male, 62 (66%) were White, 16 (17%) were Black, two (2%) were Asian, and 14 (15%) were other races, and median age was 9·39 years (IQR 6·39-13·38) at the time of radiotherapy. As of data cutoff (Feb 2, 2022), median follow-up was 7·52 years (IQR 6·28-8·53) for patients who did not have progression and 7·62 years (IQR 6·48-8·54) for the full cohort of 94 patients. 3-year progression-free survival was 96·8% (95% CI 90·4-99·0; p=0·89), with progression occurring in three of 94 patients. No deaths occurred at 3 years, such that overall survival was 100%. At 5 years, necrosis had occurred in two (2%) of 94 patients, severe vasculopathy in four (4%), and permanent neurological conditions in three (3%); decline in vision from normal to abnormal occurred in four (7%) of 54 patients with normal vision at baseline. The most common grade 3-4 adverse events were headache (six [6%] of 94 patients), seizure (five [5%]), and vascular disorders (six [6%]). No deaths occurred as of data cutoff. INTERPRETATION: Proton therapy did not improve survival outcomes in paediatric and adolescent patients with craniopharyngioma compared with a historical cohort, and severe complication rates were similar. However, cognitive outcomes with proton therapy were improved over photon therapy. Children and adolescents treated for craniopharyngioma using limited surgery and post-operative proton therapy have a high rate of tumour control and low rate of severe complications. The outcomes achieved with this treatment represent a new benchmark to which other regimens can be compared. FUNDING: American Lebanese Syrian Associated Charities, American Cancer Society, the US National Cancer Institute, and Research to Prevent Blindness.

Shifting Strategies in the Treatment of Pediatric Craniopharyngioma.

PURPOSE OF REVIEW: Craniopharyngiomas represent one of the most challenging diseases to treat. Despite their benign histology, and after many decades of surgical experience and technological advancements, there is still no clear consensus regarding the most effective management for this tumor. Due to their location and aggressive local characteristics, purely surgical approaches all too often result in unacceptable morbidity. RECENT FINDINGS: Partial resection combined with radiation therapy results in similar control rates when compared to aggressive surgery, while also minimalizing the neuro-endocrinological morbidity. In this manuscript, we describe the historical progression of the shifting strategies in the management of pediatric craniopharyngioma. Time has also altered our expectations for outcomes, evolving from purely morbidity and mortality to simple Glasgow Outcomes Scales, now to formal neuro-psychometric and quality of life data.

The Greatest Healthcare Disparity: Addressing Inequities in the Treatment of Childhood Central Nervous System Tumors in Low- and Middle-Income Countries.

The antithesis between childhood cancer survival rates in low- and middle-income countries (LMIC) and high-income countries (HIC) represents one of healthcare's most significant disparities. In HICs, the 5-year survival rate for children with cancer, including most brain tumors, exceeds 80%. Unfortunately, children in LMICs experience far worse outcomes with 5-year survival rates as low as 20%. To address inequities in the treatment of childhood cancer and disease burden globally, the World Health Organization (WHO) launched the Global Initiative for Childhood Cancer. Within this initiative, pediatric low-grade glioma (LGG) represents a unique opportunity for the neurosurgical community to directly contribute to a paradigm shift in the survival outcomes of children in LMICs, as many of these tumors can be managed with surgical resection alone. In this chapter, we discuss the burden of pediatric LGG and outline actions the neurosurgical community might consider to improve survival for children with LGG in LMICs.

Review and update on pediatric ependymoma.

Since our last Special Annual Issue dedicated to the topic of ependymoma in 2009, critical advancements have been made in the understanding of this disease which is largely confined to childhood. In the era of molecular profiling, the prior classification of ependymoma based on histology has become largely irrelevant, with multiple new subtypes of this disease now being described in the newest 2021 WHO CNS Tumor Classification System. Despite our advancements in understanding the underlying biology of these tumors, the mainstays of treatment-gross total surgical resection followed by confocal radiation therapy-have continued to yield the best treatment results across multiple studies and centers. Here, we provide an update on our understanding of the advancements made in tumor biology, surgical, and oncologic management of this disease. As we move into an era of more personalized medicine, it is critical to reflect on our historical understanding of different disease entities, to better understand the future directions of our treatments.

Molecular classification and outcome of children with rare CNS embryonal tumors: results from St. Jude Children's Research Hospital including the multi-center SJYC07 and SJMB03 clinical trials.

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.

Radiotherapy alone for pediatric patients with craniopharyngioma.

PURPOSE: Radiotherapy alone, without tumor-directed surgery, may be appropriate for selected patients with craniopharyngioma reducing the risks associated with neurosurgery. Understanding outcomes for patients with craniopharyngioma treated with radiotherapy alone will further refine patient selection and treatment options. METHODS: Since 2002, 13 children, adolescents and young adults, with craniopharyngioma were treated with radiotherapy alone and followed for disease control and functional outcomes at a single institution. The median age at treatment was 13 years (range, 3-21 years). All patients received 54 Gy/54 Gy(RBE) in 30 fractions. Five patients were treated with intensity-modulated photon therapy, four with passively scattered proton therapy, and four with intensity-modulated proton therapy. RESULTS: With a median follow-up of 5 years (range 3 months-14 years), all patients were alive. One experienced tumor progression 8.5 years after treatment. No significant changes in vision, hearing or neurologic function attributed to radiotherapy. Hormone deficiencies and body mass index were within the expected range at baseline and 5 years after treatment. There was no evidence of cognitive decline based on assessment of IQ, memory and attention. Unexpected complications included single cases of out-of-field malignancy, white matter changes, large vessel narrowing, and pontine capillary telangiectasia. Six patients had sphenoid bone abnormalities on follow-up imaging attributed to radiotherapy. CONCLUSION: Radiotherapy alone is an important treatment option to consider when radical resection is contraindicated, or surgical intervention is not required to alleviate symptoms. Disease control and functional outcomes are excellent after radiation therapy alone in appropriately selected patients.

Pre-operative embolization for staged treatment of infantile choroid plexus papilloma.

Choroid plexus papillomas (CPPs) are benign but rare neuroepithelial neoplasms of the choroid plexus that represent the non-malignant form of a spectrum of tumors of the choroid plexus. The vast majority of CPPs present in children under 5 years of age. Some CPPs are diagnosed prenatally, but many of them reach a large size before diagnosis. CPPs typically present with signs and symptoms of hydrocephalus. Treatment of these tumors has traditionally been with surgical resection. Large CPPs in young children present a challenge due to risk of high blood loss during resection. Here, the authors describe the case of a 3-month-old presenting with hydrocephalus and a large CPP of the third ventricle that was managed with a staged strategy of embolization followed by a delayed resection, allowing the tumor to involute prior to surgery.

Creation of a successful multidisciplinary course in pediatric neuro-oncology with a systematic approach to curriculum development.

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.

Utility of Epilepsy Surgery in Survivors of Childhood Cancer.

Resection of an epileptogenic focus improves seizure control in patients with drug-resistant epilepsy. There is little data available on usefulness of epilepsy surgery in childhood cancer survivors with drug-resistant epilepsy. To learn about seizure outcome after epilepsy surgery in childhood cancer survivors, we retrospectively reviewed charts of 42 children who were referred to an epilepsy center for surgical evaluation. Sixteen children (38%) were offered epilepsy surgery and 10 consented. Seizure outcome was classified based on International League Against Epilepsy outcome scale. All 10 children were having multiple seizures a month on therapeutic doses of three antiepilepsy drugs (AEDs). At a median follow-up of 5.6 years after epilepsy surgery, three children had class 1 outcome (no seizures), four had class 3 outcome (1-3 seizure days/year), and three had class 4 outcome (≥ 50% reduction in seizure frequency). One child was off AEDs, seven were on a single AED, and two were on three AEDs at their last follow-up. Epilepsy surgery had low morbidity and improved seizure control in childhood cancer survivors with drug-resistant epilepsy. Childhood cancer survivors with drug-resistant epilepsy should be referred to an epilepsy center for a higher level of care.

MRI-based diagnosis and treatment of pediatric brain tumors: is tissue sample always needed?

Traditional management of newly diagnosed pediatric brain tumors (PBTs) consists of cranial imaging, typically magnetic resonance imaging (MRI), and is frequently followed by tissue diagnosis, through either surgical biopsy or tumor resection. Therapy regimes are typically dependent on histological diagnosis. To date, many treatment regimens are based on molecular biology. The scope of this article is to discuss the role of diagnosis and further treatment of PBTs based solely on MRI features, in light of the latest treatment protocols. Typical MRI findings and indications for surgical biopsy of these lesions are described.

Patient-derived orthotopic xenografts of pediatric brain tumors: a St. Jude resource.

Pediatric brain tumors are the leading cause of cancer-related death in children. Patient-derived orthotopic xenografts (PDOX) of childhood brain tumors have recently emerged as a biologically faithful vehicle for testing novel and more effective therapies. Herein, we provide the histopathological and molecular analysis of 37 novel PDOX models generated from pediatric brain tumor patients treated at St. Jude Children's Research Hospital. Using a combination of histopathology, whole-genome and whole-exome sequencing, RNA-sequencing, and DNA methylation arrays, we demonstrate the overall fidelity and inter-tumoral molecular heterogeneity of pediatric brain tumor PDOX models. These models represent frequent as well as rare childhood brain tumor entities, including medulloblastoma, ependymoma, atypical teratoid rhabdoid tumor, and embryonal tumor with multi-layer rosettes. PDOX models will be valuable platforms for evaluating novel therapies and conducting pre-clinical trials to accelerate progress in the treatment of brain tumors in children. All described PDOX models and associated datasets can be explored using an interactive web-based portal and will be made freely available to the research community upon request.

Risk-adapted therapy and biological heterogeneity in pineoblastoma: integrated clinico-pathological analysis from the prospective, multi-center SJMB03 and SJYC07 trials.

Pineoblastoma is a rare embryonal tumor of childhood that is conventionally treated with high-dose craniospinal irradiation (CSI). Multi-dimensional molecular evaluation of pineoblastoma and associated intertumoral heterogeneity is lacking. Herein, we report outcomes and molecular features of children with pineoblastoma from two multi-center, risk-adapted trials (SJMB03 for patients ≥ 3 years; SJYC07 for patients < 3 years) complemented by a non-protocol institutional cohort. The clinical cohort consisted of 58 patients with histologically diagnosed pineoblastoma (SJMB03 = 30, SJYC07 = 12, non-protocol = 16, including 12 managed with SJMB03-like therapy). The SJMB03 protocol comprised risk-adapted CSI (average-risk = 23.4 Gy, high-risk = 36 Gy) with radiation boost to the primary site and adjuvant chemotherapy. The SJYC07 protocol consisted of induction chemotherapy, consolidation with focal radiation (intermediate-risk) or chemotherapy (high-risk), and metronomic maintenance therapy. The molecular cohort comprised 43 pineal parenchymal tumors profiled by DNA methylation array (n = 43), whole-exome sequencing (n = 26), and RNA-sequencing (n = 16). Respective 5-year progression-free survival rates for patients with average-risk or high-risk disease on SJMB03 or SJMB03-like therapy were 100% and 56.5 ± 10.3% (P = 0.007); respective 2-year progression-free survival rates for those with intermediate-risk or high-risk disease on SJYC07 were 14.3 ± 13.2% and 0% (P = 0.375). Of patients with average-risk disease treated with SJMB03/SJMB03-like therapy, 17/18 survived without progression. DNA-methylation analysis revealed four clinically relevant pineoblastoma subgroups: PB-A, PB-B, PB-B-like, and PB-FOXR2. Pineoblastoma subgroups differed in age at diagnosis, propensity for metastasis, cytogenetics, and clinical outcomes. Alterations in the miRNA-processing pathway genes DICER1, DROSHA, and DGCR8 were recurrent and mutually exclusive in PB-B and PB-B-like subgroups; PB-FOXR2 samples universally overexpressed the FOXR2 proto-oncogene. Our findings suggest superior outcome amongst older children with average-risk pineoblastoma treated with reduced-dose CSI. The identification of biologically and clinically distinct pineoblastoma subgroups warrants consideration of future molecularly-driven treatment protocols for this rare pediatric brain tumor entity.

Correction to: Risk-adapted therapy and biological heterogeneity in pineoblastoma: integrated clinico-pathological analysis from the prospective, multi-center SJMB03 and SJYC07 trials.

The original version of this article unfortunately contained a typesetting error in Fig 3c. The corrected Fig. 3 is given in the following page.

Treatment-related calvarial lesions in pediatric brain tumor survivors.

BACKGROUND: Despite improved survival, many pediatric brain tumor survivors receiving radiation therapy (RT) experience late effects. PROCEDURE: To study calvarial lesions in this population, we retrospectively reviewed records of patients undergoing neurosurgical evaluation for calvarial bone lesions detected in posttreatment follow-up imaging at St. Jude Children's Research Hospital. Primary tumor diagnosis, treatment, imaging, surgical intervention, and histopathology from patients with radiographic evidence of lesions followed for ≥2 years post-RT were studied. RESULTS: For 17 patients with 18 index lesions, median time to lesion manifestation was 2.34 years. Medulloblastoma patients developed lesions at a shorter interval from RT than ependymoma patients (P = .05). Twelve of 14 lesions requiring surgery were benign fibro-osseous or sclerotic. Two malignant lesions distinct from the primary tumor had genetic predisposition to malignancy. CONCLUSION: Most calvarial lesions arising post-RT are benign and fibro-osseous. Serial imaging is recommended, and high index of suspicion for malignant lesions is warranted for patients genetically predisposed to cancer.

C11orf95-RELA fusions drive oncogenic NF-κB signalling in ependymoma.

Members of the nuclear factor-κB (NF-κB) family of transcriptional regulators are central mediators of the cellular inflammatory response. Although constitutive NF-κB signalling is present in most human tumours, mutations in pathway members are rare, complicating efforts to understand and block aberrant NF-κB activity in cancer. Here we show that more than two-thirds of supratentorial ependymomas contain oncogenic fusions between RELA, the principal effector of canonical NF-κB signalling, and an uncharacterized gene, C11orf95. In each case, C11orf95-RELA fusions resulted from chromothripsis involving chromosome 11q13.1. C11orf95-RELA fusion proteins translocated spontaneously to the nucleus to activate NF-κB target genes, and rapidly transformed neural stem cells--the cell of origin of ependymoma--to form these tumours in mice. Our data identify a highly recurrent genetic alteration of RELA in human cancer, and the C11orf95-RELA fusion protein as a potential therapeutic target in supratentorial ependymoma.

The overshadowed scientific endeavours of Berengario Da Carpi, a renaissance physician and the Forerunner of neurosurgery: a historical vignette.

Jacopo Berengario da Carpi was Renaissance-era physician, surgeon, and anatomy lecturer who transformed medieval anatomy and surgery-which were, at the time, dominated mostly by religious dogma-into a modern science based on direct observation, experience, and cadaveric dissection. He was an accomplished and innovative neuroanatomist and educator, a prolific researcher and publisher, and a successful practicing surgeon who treated the head injuries of many renowned patients of that period. He published a landmark commentary on skull fractures that was the first printed book in history devoted to head injuries, which became a model of new medical understanding. Nonetheless, Berengario's achievements in anatomy, medicine, neuroanatomy, and what would later become neurotraumatology and neurosurgery, would have been more widely known had his work and research not been surpassed by Andreas Vesalius and Ambroise Paré, both of whom advanced anatomic and medical knowledge even further. In this historical vignette, we discuss the political conditions of sixteenth Century Italy and pay a homage to Berengario da Carpi, emphasizing his work in establishing neuroanatomy as a field of medicine that became a precursor to modern neuroscience. We also describe the improvements he made in neurotraumatology technique and instrumentation, and his explanations of skull fractures and other brain injuries outlined in ground-breaking clinical books he published. Finally, we try to elucidate possible reasons why his scientific and professional achievements-despite of their enormous impact-were overshadowed by the achievements of his more famous immediate successors.