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Survivors of paediatric intracranial tumours are at increased risk of psychosocial, neuro-developmental, and functional impairment. This study aimed to evaluate long-term health-related quality-of-life (HRQOL) outcomes in patients with benign paediatric brain tumours treated curatively with surgical resection alone.This was a cross-sectional study of patients with benign paediatric intracranial tumours managed with surgery alone between 2000 and 2015. Eligible patients with a minimum of 5-years follow-up after surgery were identified. Validated health-related quality of life (HRQOL) questionnaires were administered: SF-36, QLQ-BN20, QLQ-C30 and PedsQL™.Twenty-three patients participated (median age at surgery 13 years; range 1-18; 12 male). The most common diagnosis was pilocytic astrocytoma (n = 15). Median time from surgery to participation was 11 years(range 6-19). Fourteen patients achieved A-level qualifications and two obtained an undergraduate degree. Twelve patients were employed, eight were studying and three were unemployed or volunteering. HRQOL outcomes demonstrated significant limitation from social functioning (p = 0.03) and cognitive functioning (p = 0.023) compared to the general population. Patients also experienced higher rates of loss of appetite (p = 0.009) and nausea and vomiting (p = 0.031). Ten patients were under transitional teenager and young-adult (TYA) clinic follow-up. TYA patients achieved higher levels of education (p = 0.014), were more likely to hold a driver's license (p = 0.041) compared to patients not followed-up through these services.Childhood brain-tumour survivors have a greater risk of developing psychological, neuro-cognitive and physical impairment. Early comprehensive assessment, specialist healthcare and TYA services are vital to support these patients.

Objective: Investigate the performance of qualitative review (QR) for assessing dynamic susceptibility contrast (DSC-) MRI data quality in paediatric normal brain and develop an automated alternative to QR. Methods: 1027 signal–time courses were assessed by Reviewer 1 using QR. 243 were additionally assessed by Reviewer 2 and % disagreements and Cohen’s κ (κ) were calculated. The signal drop-to-noise ratio (SDNR), root mean square error (RMSE), full width half maximum (FWHM) and percentage signal recovery (PSR) were calculated for the 1027 signal–time courses. Data quality thresholds for each measure were determined using QR results. The measures and QR results trained machine learning classifiers. Sensitivity, specificity, precision, classification error and area under the curve from a receiver operating characteristic curve were calculated for each threshold and classifier. Results: Comparing reviewers gave 7% disagreements and κ = 0.83. Data quality thresholds of: 7.6 for SDNR; 0.019 for RMSE; 3 s and 19 s for FWHM; and 42.9 and 130.4% for PSR were produced. SDNR gave the best sensitivity, specificity, precision, classification error and area under the curve values of 0.86, 0.86, 0.93, 14.2% and 0.83. Random forest was the best machine learning classifier, giving sensitivity, specificity, precision, classification error and area under the curve of 0.94, 0.83, 0.93, 9.3% and 0.89. Conclusion: The reviewers showed good agreement. Machine learning classifiers trained on signal–time course measures and QR can assess quality. Combining multiple measures reduces misclassification. Advances in knowledge: A new automated quality control method was developed, which trained machine learning classifiers using QR results.

The introduction of molecular methods into the diagnostics of central nervous system (CNS) tumours and the subsequent deciphering of their molecular heterogeneity has resulted in a significant impact on paediatric neurooncology. Particularly in the field of rare embryonal and sarcomatous CNS tumours, novel tumour types have been delineated and introduced in the recent 5th edition of the WHO classification of CNS tumours. The rarity and novelty of these tumour types result in diagnostic and therapeutic challenges. Apart from distinct histopathological and molecular features, these tumour types exhibit characteristic clinical properties and require different therapeutic approaches for optimal patient management. However, based on the limited availability of clinical data, current therapeutic recommendations have to be based on data from small, predominantly retrospective patient cohorts. Within this article, we provide guidance for diagnostic work-up and clinical management of rare CNS embryonal tumours (‘embryonal tumour with multi-layered rosettes’, ETMR; ‘CNS neuroblastoma, FOXR2-activated’, CNS NB-FOXR2; ‘CNS tumour with BCOR-ITD, CNS BCOR-ITD) and rare CNS sarcomatous tumours (‘primary intracranial sarcoma, DICER1-mutant’, CNS DICER1; ‘CIC-rearranged sarcoma’, CNS CIC). By emphasizing the significant consequences on patient management in paediatric CNS tumours, we want to encourage wide implementation of comprehensive molecular diagnostics and stress the importance for joint international efforts to further collect and study these rare tumour types.

Surgery for posterior fossa tumours (PFTs) in children is associated with bulbar palsy and swallowing difficulties although this risk is not well defined in the literature and issues contributing to dysphagia following surgery are not fully understood.This study aims to study the eating, drinking and swallowing function of children following PFT resection in a specialist paediatric neurosurgery centre. This included the frequency and duration of dysphagia, the risk of aspiration and the link between tumour type and dysphagia.This is a retrospective review of children undergoing surgery for PFT between 2014 and 2019. Information was obtained from the patients' hospital and speech and language therapy (SLT) notes, oncology database and clinical letters. The International Dysphagia Diet Standardisation Initiative (IDDSI) Framework was used to describe food and fluid modifications.Seventy children had surgery to resect a posterior fossa tumour at Alder Hey from 2014 to 2019. Thirty-one children were included in the study following referral to SLT. Videofluoroscopy (VF) was undertaken at our institution in 68% (21/31) of cases. Fifty-two percent (11/21) of children aspirated or were considered at risk, and 55% (6/11) of those who aspirated showed silent aspiration. After 3 months, 43% (13/30) still required modified food and/or fluid textures, with this proportion reducing as time progressed. By tumour type, VF was performed in 5/7 medulloblastoma patients with 3/5 showing aspiration and 3/3 silently aspirating; in 8/9 patients with ependymoma with 4/8 patients aspirating with 2/4 showing silent aspiration; and 6/12 glioma patients with 4/6 aspirating with 1/4 showing silent aspiration.Swallowing difficulties, including silent aspiration, are an important complication of PFT resection. A proportion of children will need ongoing food and/or fluid modification. Further study into dysphagia following PFT resection is indicated.

We have identified USP31 as a microtubule and centrosome associated deubiquitylase, depletion of which leads to an increase in individual cell mass and defective proliferation. We have examined its dynamics and impact during mitosis. GFP-USP31 associates with the mitotic and central spindles, its levels are increased 2-3-fold in prometaphase compared to asynchronous cells and it is dynamically phosphorylated in a CDK1 dependent manner. We find that USP31 depleted cells display altered spindle morphology and chromosomal segregation errors, whilst stable expression of a catalytically inactive form of USP31 leads to polyploidy. At prometaphase, levels of multiple CPC components are destabilised, most prominently INCENP. Under anaphase conditions, depletion of USP31 impairs the translocation of both endogenous and ectopically expressed INCENP to the spindle mid-zone, whilst expression of catalytically inactive USP31 results in multiple ectopic cleavage furrows. In summary, our data indicate a multifaceted regulatory role for USP31 during mitosis, with a profound impact on chromosomal passenger complex abundance, dynamics and function.

Core Outcome Sets (COS) define minimum outcomes to be measured and reported in clinical effectiveness trials for a particular health condition/health area. Despite recognition as critical to clinical research design for other health areas, none have been developed for neuro-oncology. COS development projects should carefully consider: scope (how the COS should be used), stakeholders involved in development (including patients as both research partners and participants), and consensus methodologies used (typically a Delphi survey and consensus meeting), as well as dissemination plans. Developing COS for neuro-oncology is potentially challenging due to extensive tumor subclassification (including molecular stratification), different symptoms related to anatomical tumor location, and variation in treatment options. Development of a COS specific to tumor subtype, in a specific location, for a particular intervention may be too narrow and would be unlikely to be used. Equally, a COS that is applicable across a wider area of neuro-oncology may be too broad and therefore lack specificity. This review describes why and how a COS may be developed, and discusses challenges for their development, specific to neuro-oncology. The COS under development are briefly described, including: adult glioma, incidental/untreated meningioma, meningioma requiring intervention, and adverse events from surgical intervention for pediatric brain tumors.

Purpose: Childhood cancer is rare, and treatment is frequently associated with long-term morbidity. Disparities in survival and long-term side effects encourage the establishment of networks to increase access to complex organ-conservative strategies, such as brachytherapy. We report our experience of an international cooperation model in childhood cancers. Methods and Materials: We examined the outcome of all children referred to our center from national or international networks to be treated according to a multimodal organ-conservative approach, including brachytherapy. Results: We identified 305 patients whose median age at diagnosis was 2.2 years (range, 1.4 months to 17.2 years). Among these patients, 99 (32.4%) were treated between 2015 and 2020; 172 (56.4%) were referred from national centers; and 133 (43.6%) were international patients from 31 countries (mainly Europe). Also, 263 patients were referred for primary treatment and 42 patients were referred for salvage treatment. Genitourinary tumors were the most frequent sites, with 56.4% bladder/prostate rhabdomyosarcoma and 28.5% gynecologic tumors. In addition to brachytherapy, local treatment consisted of partial tumor resection in 207 patients (67.9%), and 39 patients (13%) had additional external radiation therapy. Median follow-up was 58 months (range, 1 month to 48 years), 93 months for national patients, and 37 months for international patients (P < .0001). Five-year local control, disease-free survival, and overall survival rates were 90.8% (95% confidence interval [CI], 87.3%-94.4%), 84.4% (95% CI, 80.1%-89.0%), and 93.3% (95% CI, 90.1%-96.5%), respectively. Patients referred for salvage treatment had poorer disease-free survival (P < .01). Implementation of image guided pulse-dose-rate brachytherapy was associated with better local control among patients with rhabdomyosarcoma referred for primary treatment (hazard ratio, 9.72; 95% CI, 1.24-71.0). At last follow-up, 16.7% patients had long-term severe treatment-related complications, and 2 patients (0.7%) had developed second malignancy. Conclusions: This retrospective series shows the feasibility of a multinational referral network for brachytherapy allowing high patient numbers in rare pediatric cancers. High local control probability and acceptable late severe complication probability could be achieved despite very challenging situations. This cooperation model could serve as a basis for generating international reference networks for high-tech radiation such as brachytherapy to increase treatment care opportunities and cure probability.

Attitudes to surgery for paediatric thalamic tumours have evolved due to improved preoperative imaging modalities and the advent of intraoperative MRI (iMRI) as well as enhanced understanding of tumour biology. We review the developments in our local practice over the last three decades with particular attention to the impact of iMRI. We identified all paediatric patients from a prospectively maintained neuro-oncology database who received surgery for a thalamic tumour (n = 30). All children were treated in a single UK tertiary paediatric neurosurgery centre between January 1991 and June 2020. Twenty patients underwent surgical resection, the remainder (10) undergoing biopsy only. Pre-operative surgical intent (biopsy versus debulking, near-total resection, or complete resection) as well as the use of iMRI were prospectively recorded. Complications recorded in clinical documentation between postoperative days 0 and 30 were retrospectively graded using a modified version of the Clavien Dindo scale. The extent of resection with respect to the pre-determined surgical aim was also recorded. Data on patient survival and disease progression status were obtained retrospectively. In our series, there were 42 procedures (25 craniotomies, 17 biopsies) performed on 30 patients (17 male, with a median age of 8 at surgery). Of the 25 surgical resections performed, complete resection was achieved in 9 (36%), near-total resection in 10 (40%), and limited debulking in 6 (24%). The predetermined surgical aim was achieved or exceeded in 91.3% of cases. The proportion of craniotomies for which substantial resection was achieved, increased from 37.5 to 94.2% with use of iMRI (p = 0.014). Surgical morbidity was not associated with greater extent of surgical resection. High-grade histology is identified as the only independent significant factor influencing overall survival as calculated by Cox proportional hazards model (p = 0.006). We note a significant change in the rate and extent of attempted resection of paediatric thalamic tumours that has developed over the last 3 decades. Use of iMRI is associated with a significant increase in substantial tumour resection surgeries. This is not associated with any significant level of surgical morbidity. Improvements in pre- and intra-operative imaging alongside better understanding of tumour biology facilitate patient selection and a surgically more aggressive approach in selected cases whilst maintaining safety and avoiding operative morbidity.

SummaryMedulloblastoma is currently sub-classified into distinct DNA methylation subgroups/subtypes with particular clinico-molecular features. Using RNA-seq in large well annotated cohorts of medulloblastoma we show that transcriptionally Group3 and Group4 medulloblastomas exist not as discrete types but as intermediates on a bipolar continuum between archetypal Group3 and Group4 entities. Continuum position is prognostic, reflects propensity for specific DNA copy-number changes, key switches in isoform/enhancer usage and RNA-editing. Examining scRNA-seq profiles we show intra-tumoral transcriptional heterogeneity along the continuum is limited in a subtype-dependent manner. By integrating with a human scRNA-seq reference atlas we show this continuum is mirrored by an equivalent continuum of transcriptional cell types in early fetal cerebellar development. We identify unique developmental niches for all four major subgroups and link each to a common developmental antecedent. Our findings show a transcriptional continuum arising from oncogenic disruption of highly specific fetal cerebellar cell types, linked to almost every aspect of Group3/Group4 molecular biology and clinico-pathology.

Background Bevacizumab is increasingly used in children with pediatric low-grade glioma (PLGG) despite limited evidence. A nationwide UK service evaluation was conducted to provide larger cohort “real life” safety and efficacy data including functional visual outcomes. Methods Children receiving bevacizumab-based treatments (BBT) for PLGG (2009–2020) from 11 centers were included. Standardized neuro-radiological (RANO-LGG) and visual (logMAR visual acuity) criteria were used to assess clinical–radiological correlation, survival outcomes and multivariate prognostic analysis. Results Eighty-eight children with PLGG received BBT either as 3rd line with irinotecan (85%) or alongside 1st/2nd line chemotherapies (15%). Toxicity was limited and minimal. Partial response (PR, 40%), stable disease (SD, 49%), and progressive disease (PD, 11%) were seen during BBT. However, 65% progressed at 8 months (median) from BBT cessation, leading to a radiology-based 3 yr-progression-free survival (PFS) of 29%. Diencephalic syndrome (P = .03) was associated with adverse PFS. Pre-existing visual morbidity included unilateral (25%) or bilateral (11%) blindness. Improvement (29%) or stabilization (49%) of visual acuity was achieved, more often in patients’ best eyes. Vision deteriorated during BBT in 14 (22%), with 3-year visual-PFS of 53%; more often in patients’ worst eyes. A superior visual outcome (P = .023) was seen in neurofibromatosis type 1-associated optic pathway glioma (OPG). Concordance between visual and radiological responses was 36%; optimized to 48% using only best eye responses. Conclusions BBTs provide effective short-term PLGG control and delay further progression, with a better sustained visual (best > worst eye) than radiological response. Further research could optimize the role of BBT toward a potentially sight-saving strategy in OPG.

The antitumour effects of OTX015, a first-in-class BET inhibitor (BETi), were investigated as a single agent or in combination with ionizing radiation (IR) in preclinical in vitro models of rhabdomyosarcoma (RMS), the most common childhood soft tissue sarcoma. Herein, we demonstrated the upregulation of BET Bromodomain gene expression in RMS tumour biopsies and cell lines compared to normal skeletal muscle. In vitro experiments showed that OTX015 significantly reduced RMS cell proliferation by altering cell cycle modulators and apoptotic related proteins due to the accumulation of DNA breaks that cells are unable to repair. Interestingly, OTX015 also impaired migration capacity and tumour-sphere architecture by downregulating pro-stemness genes and was able to potentiate ionizing radiation effects by reducing the expression of different drivers of tumour dissemination and resistance mechanisms, including the GNL3 gene, that we correlated for the first time with the RMS phenotype. In conclusion, our research sheds further light on the molecular events of OTX015 action against RMS cells and indicates this novel BETi as an effective option to improve therapeutic strategies and overcome the development of resistant cancer cells in patients with RMS.

Cerebellar mutism syndrome (CMS) is a severe neurological complication of posterior fossa tumour surgery in children, and postoperative speech impairment (POSI) is the main component. Left-handedness was previously suggested as a strong risk factor for POSI. The aim of this study was to investigate the relationship between handedness and the risk of POSI.We prospectively included children (aged 18 years) undergoing surgery for posterior fossa tumours in 26 European centres. Handedness was assessed pre-operatively and postoperative speech status was categorised as either POSI (mutism or reduced speech) or habitual speech, based on the postoperative clinical assessment. Logistic regression was used in the risk factor analysis of POSI as a dichotomous outcome.Of the 500 children included, 37 (7%) were excluded from the present analysis due to enrolment at a reoperation; another 213 (43%) due to missing data about surgery (n = 37) and/or handedness (n = 146) and/or postoperative speech status (n = 53). Out of the remaining 250 (50%) patients, 20 (8%) were left-handed and 230 (92%) were right-handed. POSI was observed equally frequently regardless of handedness (5/20 [25%] in left-handed, 61/230 [27%] in right-handed, OR: 1.08 [95% CI: 0.40-3.44], p = 0.882), also when adjusted for tumour histology, location and age.We found no difference in the risk of POSI associated with handedness. Our data do not support the hypothesis that handedness should be of clinical relevance in the risk assessment of CMS.

Background Less than 5% of medulloblastoma (MB) patients survive following failure of contemporary radiation-based therapies. Understanding the molecular drivers of medulloblastoma relapse (rMB) will be essential to improve outcomes. Initial genome-wide investigations have suggested significant genetic divergence of the relapsed disease. Methods We undertook large-scale integrated characterization of the molecular features of rMB—molecular subgroup, novel subtypes, copy number variation (CNV), and driver gene mutation. 119 rMBs were assessed in comparison with their paired diagnostic samples (n = 107), alongside an independent reference cohort sampled at diagnosis (n = 282). rMB events were investigated for association with outcome post-relapse in clinically annotated patients (n = 54). Results Significant genetic evolution occurred over disease-course; 40% of putative rMB drivers emerged at relapse and differed significantly between molecular subgroups. Non-infant MBSHH displayed significantly more chromosomal CNVs at relapse (TP53 mutation-associated). Relapsed MBGroup4 demonstrated the greatest genetic divergence, enriched for targetable (eg, CDK amplifications) and novel (eg, USH2A mutations) events. Importantly, many hallmark features of MB were stable over time; novel subtypes (>90% of tumors) and established genetic drivers (eg, SHH/WNT/P53 mutations; 60% of rMB events) were maintained from diagnosis. Critically, acquired and maintained rMB events converged on targetable pathways which were significantly enriched at relapse (eg, DNA damage signaling) and specific events (eg, 3p loss) predicted survival post-relapse. Conclusions rMB is characterised by the emergence of novel events and pathways, in concert with selective maintenance of established genetic drivers. Together, these define the actionable genetic landscape of rMB and provide a basis for improved clinical management and development of stratified therapeutics, across disease-course.

MRS can provide high accuracy in the diagnosis of childhood brain tumours when combined with machine learning. A feature selection method such as principal component analysis is commonly used to reduce the dimensionality of metabolite profiles prior to classification. However, an alternative approach of identifying the optimal set of metabolites has not been fully evaluated, possibly due to the challenges of defining this for a multi‐class problem. This study aims to investigate metabolite selection from in vivo MRS for childhood brain tumour classification. Multi‐site 1.5 T and 3 T cohorts of patients with a brain tumour and histological diagnosis of ependymoma, medulloblastoma and pilocytic astrocytoma were retrospectively evaluated. Dimensionality reduction was undertaken by selecting metabolite concentrations through multi‐class receiver operating characteristics and compared with principal component analysis. Classification accuracy was determined through leave‐one‐out and k‐fold cross‐validation. Metabolites identified as crucial in tumour classification include myo‐inositol (P < 0.05, AUC = 0 . 81 ± 0 . 01 ), total lipids and macromolecules at 0.9 ppm (P < 0.05, AUC = 0 . 78 ± 0 . 01 ) and total creatine (P < 0.05, AUC = 0 . 77 ± 0 . 01 ) for the 1.5 T cohort, and glycine (P < 0.05, AUC = 0 . 79 ± 0 . 01 ), total N‐acetylaspartate (P < 0.05, AUC = 0 . 79 ± 0 . 01 ) and total choline (P < 0.05, AUC = 0 . 75 ± 0 . 01 ) for the 3 T cohort. Compared with the principal components, the selected metabolites were able to provide significantly improved discrimination between the tumours through most classifiers (P < 0.05). The highest balanced classification accuracy determined through leave‐one‐out cross‐validation was 85% for 1.5 T 1H‐MRS through support vector machine and 75% for 3 T 1H‐MRS through linear discriminant analysis after oversampling the minority. The study suggests that a group of crucial metabolites helps to achieve better discrimination between childhood brain tumours.

Aims Application of advanced molecular pathology in rare tumours is hindered by low sample numbers, access to specialised expertise/technologies and tissue/assay QC and rapid reporting requirements. We assessed the feasibility of co‐ordinated real‐time centralised pathology review (CPR), encompassing molecular diagnostics and contemporary genomics (RNA‐seq/DNA methylation‐array). Methods This nationwide trial in medulloblastoma (, Application of advanced molecular pathology in rare tumours is hindered by low sample numbers, access to specialised expertise/technologies, and tissue/assay QC and rapid reporting requirements. We undertook a UK‐wide trial in medulloblastoma (

Ovarian neoplasms in children are rare heterogeneous lesions with variable biological behaviour and outcome. We herein report a 25-year experience from a UK specialist centre managing paediatric ovarian tumours. All female patients requiring operation for ovarian tumours were identified during the study period 1990–2018. Patient demographics, clinical presentation, and management are highlighted. Eighty-eight females with 101 ovarian tumours including cases with synchronous and metachronous neoplasms were documented. Mean age at diagnosis was 11.8 years. Tumours were equally distributed in left and right ovary(s). Bilateral disease occurred in 11 (10.8%) patients. Eighty-six (85%) neoplasms were benign and 15 (15%) malignant requiring in addition to surgery chemotherapy and/or radiation. There were no significant difference(s) observed in maximum tumour diameter in benign vs malignant lesions. Only half of malignant tumours had positive tumour markers. Fifteen patients (15%) had ovarian lesions that were metastatic at primary presentation including a rare case of disseminated peritoneal gliomatosis. Surgical management included salpingo-oopherectomy n = 21 (21%), ovary excision n = 33 (33%), ‘ovary sparing’ tumourectomy n = 34 (34%), and cyto-reductive extirpation in 2 cases (2%). Lymphadenectomy was performed in 9 patients (9%) together with peritoneal fluid cytology in 18 cases (18%) who had abdominal ascites. Omentectomy was required in 14 patients (14%), multiple peritoneal biopsy(s)—in 11 cases (11%) and biopsy of other suspicious involved organs notably bowel, gut mesentery and contralateral ovary in 7 (7%) further patients. Recurrent and metachronous lesions occurred in 10 (10%) cases in those with teratoma (n = 9) and adenocarcinoma(s) (n = 1). Overall patient survival was 97% with only 3 deaths—mucinous cystadenocarcinoma (n = 1), desmoplastic small round cell tumour of ovarian origin (n = 1), and a small cell carcinoma of ovary with hypercalcaemia (n = 1). Findings from this study show an excellent survival (97%) for paediatric ovarian neoplasms. Rare malignant neoplasms though do carry a poor prognosis. In the modern era of care, all efforts should be made to preserve future hormonal health and fertility with ‘ovarian sparing’ operation(s) where appropriate.

AIMS Survivors of paediatric intracranial malignancies are at increased risk of psychosocial, neuro-developmental and functional impairment, important measures of patients’ well-being. This study aimed to evaluate long-term quality of life outcomes (QOL) in patients with benign paediatric brain tumours treated curatively with surgical resection alone. METHOD Cross-sectional cohort study of benign paediatric intracranial tumours managed with surgery alone between 2000-2015. Validated QOL questionnaires were administered: SF-36, QLQ-BN20, QLQ-C30 and PedsQLTM. RESULTS Twenty-three patients participated (median age at surgery 13 years; range 1-18), twelve were male. The most common diagnosis was pilocytic astrocytoma (n=15). Median time from surgery to participation was 11 years (range 6-19). Fourteen patients achieved A-level qualifications and two obtained an undergraduate degree. Twelve patients were employed, eight were studying and three were unemployed or volunteering. Twelve patients were currently driving. QOL outcomes demonstrated significant limitation from social functioning (p=0.03) and cognitive functioning (p=0.023) compared to the general population norms. Patients also experienced increased loss of appetite (p=0.009) and symptoms of nausea and vomiting (p=0.031). Ten patients were under transitional teenager and young-adult (TYA) clinic follow-up. TYA patients achieved higher levels of education (p=0.014), were more likely to hold a driver’s license (p=0.041) and had improved physical functioning (p=0.005) compared to patients not transitioned through these services. CONCLUSION Childhood brain-tumour survivors are particularly vulnerable and at greater risk of developing psychological, neuro-cognitive, socialisation and physical development challenges. Early identification, comprehensive assessment and specialist TYA cancer healthcare input are vital to support these patients and improve their quality of life.

BACKGROUND: Brain tumours are associated with high morbidity both from the tumour and the medical and surgical interventions used to treat them. Post operative morbidity reporting following surgery for paediatric brain tumours is poor due to the lack of a common language when reporting harms. One solution is to develop a core adverse outcome set to stipulate the minimum post operative harms that should be reported. The COMBAT (Core post operative morbidity set for paediatric brain tumours) Project will develop a core adverse outcome set that can be applied to post operative paediatric brain tumour patients to harmonise how harms are measured and reported, enabling comparison between different trials, studies and clinical services. We aim to generate interest in the COMBAT Project and invite collaboration with healthcare professionals and researchers experienced in paediatric neuro oncology surgery. METHODS AND ANALYSIS : A systematic review will identify harms reported in post operative paediatric brain tumour patients and how they are measured. We will engage with national and international stakeholders including healthcare professionals, researchers, patients and their carers. Qualitative interviews with patients and carers will identify any important harms not extracted in the systematic review. A Delphi survey will be created from the harms identified. An international consensus meeting will be held to finalise the core adverse outcomes set. The final core adverse outcome set will be published and disseminated to encourage uptake. DISCUSSION: There is a clear need for a common language to harmonise measurement and reporting of harms following surgery for paediatric brain tumour patients. The core adverse outcome set will be developed with collaboration with key stakeholder groups to ensure it is representative. It will be used to standardise surgical morbidity outcome measurement and reporting in trials, studies and clinical practice and will inform future research in this field.

ObjectiveTo evaluate a new protocol of risk stratification and early discharge for children with febrile neutropenia (FN).DesignProspective service evaluation from 17 April 2020 to 16 April 2021.Setting13 specialist centres in the UK.Patients405 children presenting with FN.InterventionAll children received intravenous antibiotics at presentation. Risk stratification was determined using the Australian-UK-Swiss (AUS) rule and eligibility for homecare assessed using criteria including disease, chemotherapy, presenting features and social factors. Those eligible for homecare could be discharged on oral antibiotics after a period of observation proportional to their risk group.Main outcome measuresMedian duration of admission and of intravenous antibiotics, and percentage of patients with positive blood cultures, significant infection, readmission within 7 days of initial presentation, intensive care unit (ICU) admission, death from infection and death from other causes.Results13 centres contributed 729 initial presentations of 405 patients. AUS rule scores were positively correlated with positive blood cultures, significant infection, ICU admission and death. 20% of children were eligible for homecare with oral antibiotics, of which 55% were low risk (AUS 0–1). 46% low-risk homecare eligible patients were discharged by 24 hours vs 2% homecare ineligible. Homecare readmission rates were 14% overall and 16% for low-risk cases (similar to a meta-analysis of previous studies). No child eligible for homecare was admitted to ICU or died.ConclusionsUse of the AUS rule and homecare criteria allow for safe early outpatient management of children with FN.

BACKGROUND Paediatric brain tumour survivors may have treatment toxicity associated with signal change on follow-up MRI. Quantitative MRI texture features can potentially be used as surrogates of the underlying tissue changes following radiation therapy. MATERIAL AND METHODS Longitudinal retrospective study in 51 paediatric primary brain tumours treated with photon (N=30) and proton (N=21) radiotherapy (RT). T2 MRI scans at baseline and multiple time point from the date of surgery to 2 years following radiotherapy were selected for the textural analysis. Scans were bias corrected, registered with the CT dose maps and with baseline scan for each patient using 3Dslicer. Regions of interest (ROI) of fixed diameter were drawn in 11 predetermined non-tumoral regions of brain including in peri-tumoural region (PTV). ROIs were placed in homogenous white/grey matter. Radiation dose was calculated in each of these 11 ROIs and texture features were extracted using pyradiomics. Data were analysed using machine learning and statistical analysis. General linear multivariate model was used to corelate primary texture features over period of 24 months and radiation dose, time, effect of dose*time together at each ROI separately. RESULTS There were Brainstem 4, Cerebellar19, Hemispheric cerebral 7 and Supratentorial midline 10 tumours. Median age at diagnosis was 8.26 years (range: 0–20). Median RT treatment dose was 28.52Gy (0-60Gy). Multivariate analysis shows significant corelation (p < 0.001) between radiation dose and longitudinal primary texture features in all 11ROIs. Time showed corelation with feature values only in 3 ROIs and dose* time showed corelation in 5ROIs. Primary (statistical) feature values showing consistent correlation with dose in all 11 ROIs over 24 months are total energy, 10%, 90%, energy, entropy, mean, median, and minimum. CONCLUSION Radiomic texture analysis is a promising modality to understand dose related textural changes in the normal part of brain in paediatric brain tumour patients treated with radiation therapy. Radiomic changes need to be related to neurological outcomes in future research.

The effectiveness of exercise and physical therapy for children with ataxia is poorly understood. The aim of this systematic review was to critically evaluate the range, scope and methodological quality of studies investigating the effectiveness of exercise and physical therapy interventions for children with ataxia. The following databases were searched: AMED, CENTRAL, CDSR, CINAHL, ClinicalTrials.gov, EMBASE, Ovid MEDLINE, PEDro and Web of Science. No limits were placed on language, type of study or year of publication. Two reviewers independently determined whether the studies met the inclusion criteria, extracted all relevant outcomes, and conducted methodological quality assessments. A total of 1988 studies were identified, and 124 full texts were screened. Twenty studies were included in the review. A total of 40 children (aged 5–18 years) with ataxia as a primary impairment participated in the included studies. Data were able to be extracted from eleven studies with a total of 21 children (aged 5–18 years), with a range of cerebellar pathology. The studies reported promising results but were of low methodological quality (no RCTs), used small sample sizes and were heterogeneous in terms of interventions, participants and outcomes. No firm conclusions can be made about the effectiveness of exercise and physical therapy for children with ataxia. There is a need for further high-quality child-centred research. Electronic supplementary material The online version of this article (10.1007/s12311-019-01063-z) contains supplementary material, which is available to authorized users.

Paediatric cerebellar pilocytic astrocytomas (PA) (WHO grade 1) are amongst the most common of childhood brain tumours and are generally amenable to resection, with surgery alone being curative in the majority of cases. There is, however, a lack of consensus regarding the frequency and duration of post-treatment MRI surveillance for these tumours. This is important, as follow-up imaging is a significant use of resources and often associated with patient and family anxiety. We have assessed the utility of MRI surveillance in the detection of cerebellar PA recurrence at our regional paediatric neurosurgical centre. The tumour register at Alder Hey Children’s Hospital was searched to identify all patients diagnosed between 2007 and 2017, with a confirmed histopathological diagnosis of cerebellar PA. Patient demographics, surgical outcome, number of MRI scans and length of follow-up were recorded for each patient. Forty patients met the inclusion criteria. The mean age at diagnosis was 7.8 years (range 2 to 17 years). Complete surgical resection (CR), confirmed by post-operative MRI, was achieved in 36 of the 40 patients, including all 31 cases from 2009 and later for which intraoperative MRI (iMRI) was utilised. There was one case of recurrence after CR (at 2.2 years) out of the 36 cases, whereas all 4 patients with initial partial resections had progressive growth of their tumours and required second surgical interventions. This series confirms the very low likelihood of recurrence for completely resected cerebellar PAs and suggests that in such cases the duration and frequency of surveillance imaging could be limited to a maximum of 2.5 to 3 years of follow-up imaging. This report also indicates improved complete resection rates over time, probably associated with technical advances including the routine in-house use of iMRI in 2009.

BACKGROUND: Brain tumours are the most common solid tumours in childhood. Half of these tumours occur in the posterior fossa, where surgical removal is complicated by the risk of cerebellar mutism syndrome, of which postoperative speech impairment (POSI) is a cardinal symptom, in up to 25% of patients. The surgical approach to midline tumours, mostly undertaken by transvermian or telovelar routes, has been proposed to influence the risk of POSI. We aimed to investigate the risk of developing POSI, the time course of its resolution, and its association with surgical approach and other clinical factors. METHODS: In this observational prospective multicentre cohort study, we included children (aged

Ovarian neoplasms in children are rare heterogeneous lesions with variable biological behaviour and outcome. We herein report a 25-year experience from a UK specialist centre managing paediatric ovarian tumours.All female patients requiring operation for ovarian tumours were identified during the study period 1990-2018. Patient demographics, clinical presentation, and management are highlighted.Eighty-eight females with 101 ovarian tumours including cases with synchronous and metachronous neoplasms were documented. Mean age at diagnosis was 11.8 years. Tumours were equally distributed in left and right ovary(s). Bilateral disease occurred in 11 (10.8%) patients. Eighty-six (85%) neoplasms were benign and 15 (15%) malignant requiring in addition to surgery chemotherapy and/or radiation. There were no significant difference(s) observed in maximum tumour diameter in benign vs malignant lesions. Only half of malignant tumours had positive tumour markers. Fifteen patients (15%) had ovarian lesions that were metastatic at primary presentation including a rare case of disseminated peritoneal gliomatosis. Surgical management included salpingo-oopherectomy n = 21 (21%), ovary excision n = 33 (33%), 'ovary sparing' tumourectomy n = 34 (34%), and cyto-reductive extirpation in 2 cases (2%). Lymphadenectomy was performed in 9 patients (9%) together with peritoneal fluid cytology in 18 cases (18%) who had abdominal ascites. Omentectomy was required in 14 patients (14%), multiple peritoneal biopsy(s)-in 11 cases (11%) and biopsy of other suspicious involved organs notably bowel, gut mesentery and contralateral ovary in 7 (7%) further patients. Recurrent and metachronous lesions occurred in 10 (10%) cases in those with teratoma (n = 9) and adenocarcinoma(s) (n = 1). Overall patient survival was 97% with only 3 deaths-mucinous cystadenocarcinoma (n = 1), desmoplastic small round cell tumour of ovarian origin (n = 1), and a small cell carcinoma of ovary with hypercalcaemia (n = 1).Findings from this study show an excellent survival (97%) for paediatric ovarian neoplasms. Rare malignant neoplasms though do carry a poor prognosis. In the modern era of care, all efforts should be made to preserve future hormonal health and fertility with 'ovarian sparing' operation(s) where appropriate.

Aims\ud \ud Biomarker‐driven therapies have not been developed for infant medulloblastoma (iMB). We sought to robustly sub‐classify iMB, and proffer strategies for personalized, risk‐adapted therapies.\ud \ud \ud \ud Methods\ud \ud We characterized the iMB molecular landscape, including second‐generation subtyping, and the associated retrospective clinical experience, using large independent discovery/validation cohorts (n = 387).\ud \ud \ud \ud Results\ud \ud iMBGrp3 (42%) and iMBSHH (40%) subgroups predominated. iMBGrp3 harboured second‐generation subtypes II/III/IV. Subtype II strongly associated with large‐cell/anaplastic pathology (LCA; 23%) and MYC amplification (19%), defining a very‐high‐risk group (0% 10yr overall survival (OS)), which progressed rapidly on all therapies; novel approaches are urgently required. Subtype VII (predominant within iMBGrp4) and subtype IV tumours were standard risk (80% OS) using upfront CSI‐based therapies; randomized‐controlled trials of upfront radiation‐sparing and/or second‐line radiotherapy should be considered. Seventy‐five per cent of iMBSHH showed DN/MBEN histopathology in discovery and validation cohorts (P < 0.0001); central pathology review determined diagnosis of histological variants to WHO standards. In multivariable models, non‐DN/MBEN pathology was associated significantly with worse outcomes within iMBSHH. iMBSHH harboured two distinct subtypes (iMBSHH‐I/II). Within the discriminated favourable‐risk iMBSHH DN/MBEN patient group, iMBSHH‐II had significantly better progression‐free survival than iMBSHH‐I, offering opportunities for risk‐adapted stratification of upfront therapies. Both iMBSHH‐I and iMBSHH‐II showed notable rescue rates (56% combined post‐relapse survival), further supporting delay of irradiation. Survival models and risk factors described were reproducible in independent cohorts, strongly supporting their further investigation and development.\ud \ud \ud \ud Conclusions\ud \ud Investigations of large, retrospective cohorts have enabled the comprehensive and robust characterization of molecular heterogeneity within iMB. Novel subtypes are clinically significant and subgroup‐dependent survival models highlight opportunities for biomarker‐directed therapies.

Background Only few data are available on treatment-associated behavior of distinct rare CNS embryonal tumor entities previously treated as “CNS-primitive neuroectodermal tumors” (CNS-PNET). Respective data on specific entities, including CNS neuroblastoma, FOXR2 activated (CNS NB-FOXR2), and embryonal tumors with multilayered rosettes (ETMR) are needed for development of differentiated treatment strategies. Methods Within this retrospective, international study, tumor samples of clinically well-annotated patients with the original diagnosis of CNS-PNET were analyzed using DNA methylation arrays (n = 307). Additional cases (n = 66) with DNA methylation pattern of CNS NB-FOXR2 were included irrespective of initial histological diagnosis. Pooled clinical data (n = 292) were descriptively analyzed. Results DNA methylation profiling of “CNS-PNET” classified 58 (19%) cases as ETMR, 57 (19%) as high-grade glioma (HGG), 36 (12%) as CNS NB-FOXR2, and 89(29%) cases were classified into 18 other entities. Sixty-seven (22%) cases did not show DNA methylation patterns similar to established CNS tumor reference classes. Best treatment results were achieved for CNS NB-FOXR2 patients (5-year PFS: 63% ± 7%, OS: 85% ± 5%, n = 63), with 35/42 progression-free survivors after upfront craniospinal irradiation (CSI) and chemotherapy. The worst outcome was seen for ETMR and HGG patients with 5-year PFS of 18% ± 6% and 22% ± 7%, and 5-year OS of 24% ± 6% and 25% ± 7%, respectively. Conclusion The historically reported poor outcome of CNS-PNET patients becomes highly variable when tumors are molecularly classified based on DNA methylation profiling. Patients with CNS NB-FOXR2 responded well to current treatments and a standard-risk CSI-based regimen may be prospectively evaluated. The poor outcome of ETMR across applied treatment strategies substantiates the necessity for evaluation of novel treatments.

INTRODUCTION: Bevacizumab/Irinotecan is currently 3rd-line treatment in the UK for progressive Paediatric Low-Grade Glioma (PLGG) based on limited evidence. A nationwide service evaluation was conducted to review its safety and efficacy amongst a larger cohort. METHODS: Data from children with PLGG receiving Bevacizumab-based Treatments (BBT) from 11 UK Centres (2009-2020) were reviewed. Radiological and visual outcomes were based on standardized measurements. Clinical-radiological correlation was investigated. Time to progression from BBT stop, progression free-survival (PFS) curves and multivariate analysis of prognostic factors (p 0.05) were performed. RESULTS: 88 children with PLGG (88% OPG, 24% NF1) had BBT for radiological (43%), visual (20%) or combined (27%) progression, after 40 months (median) from diagnosis. Amongst OPG cases, visual acuity (VA) per eye (better/worse) before BBT was logMAR 0.0-0.3 (23/7) 0.3 - 1.0 (27/20), > 1.0 (14/18) and LP/NLP (8/27), with 19/8 children respectively blind (LP/NLP) in one or both eyes. Bevacizumab 10 mg/kg every 14 days (median 24 doses) was given as 3rd line+ with Irinotecan (85%) or alongside 1st/2nd line chemo (15%) leading to remarkable radiological (88%) and visual (74%) responses (stable or improved) within 3-6 months, with limited toxicity. 12% progressed on treatment, and 8% died unrelated to BBT. After initial response 65% progressed at a median of 8 months (4 - 23) after BBT, resulting in 3-year-all-causes-PFS of 16% and 3-yr-visual-PFS of 45% from start of BBT. Visual concordance with MRI was poor (36%) but increases (47%) when better-eye determines visual outcome. Lack of NF1 and diencephalic syndrome (DS) at presentation were independent negative prognostic factors for PFS. CONCLUSIONS: A remarkable but transient effect of BBT has been confirmed. Visual > radiological responses can be sustained after BBT. Variations in current BBT strategies justifies further research, including the potential upfront use alongside conventional first-line chemotherapy as sight-saving strategy.

Background Numerous factors have been identified as carrying prognostic value in neuroblastoma (NB) and therefore incorporated in risk stratification of disease. Here, we investigate the association of anatomical site of NB with molecular biology and clinical outcomes. Methods A total of 117 patients with NB were studied over a 30-year period. Tumour location was confirmed with computed tomography/magnetic resonance imaging. Data on molecular biology were obtained as testing became available. Chi-squared, Fisher's exact test and Kaplan-Meier log-rank tests were used for statistical analysis. Results Tumour originated in the thoracic region (thoracic NB, TNB) in 15 patients (13%), adrenal gland (adrenal NB, ANB) in 88 patients (75%) and abdominal/paravertebral chain (paravertebral NB, PVNB) in 14 patients (12%). Overall survival (OS) for ANB was significantly lower (38%; P = 0.015). ANB cases were more frequently diagnosed at stage IV (69%; P = 0.001). MYCN amplification was noted in 33% of ANB cases and associated with lower OS (17% versus 62% MYCN non-amplified ANB; P = 0.01). The vast majority of TNB and PVNB were non-MYCN amplified (100% and 86%, respectively) and carried better prognosis (OS 86% and 83%, respectively). Forty-two percent of ANB cases were diploid and had lower OS (20% versus 71% hyperdiploid ANB; P = 0.079). TNB and PVNB were found to be mostly hyperdiploid (86% and 100%, respectively) with better OS (83% and 33%, respectively). Segmental chromosomal alterations had prognostic significance in those with PVNB (P = 0.03). Conclusion TNB tumours have better outcomes than adrenal tumours. This may be due to varied factors reported here including non-metastatic disease at presentation, non-amplification of the MYCN oncogene and overall favourable molecular biology characteristics.

Purpose To report the course of ataxia in children up to 2 years post-operatively, following surgical resection of a posterior fossa tumour (PFT). Methods Thirty-five children, (median age 9 years, range 4–15) having resection of PFT, were assessed using the Scale for the Assessment and Rating of Ataxia (SARA), Brief Ataxia Rating Scale (BARS) and the mobility domain of the Paediatric Evaluation of Disability Index (PEDI-m) at initial post-operative period (baseline), 3 months, 1 year and 2 years post-operatively. Results Baseline median scores of the SARA and BARS were 8.5 (range 0–35.5), and 7 (0–25) respectively. Ataxia improved at 3 months (median SARA and BARS reduction 3.5 and 4, respectively). Additional gradual improvements in SARA were recorded at 1 (median reduction 2) and 2 years post-operatively (median reduction 0.5). Median baseline PEDI-m was 54.75 (range 15.2–100) with improvement at 3 months (median increase 36.95) and small improvement at 1 year (median increase 2.5) and 2 years (median increase 5.8). Children with medulloblastoma and midline tumours (median baseline SARA 10 and 11, respectively) demonstrated more severe ataxia than children with low-grade gliomas and unilateral tumours (median baseline SARA 7.5 and 6.5, respectively). Conclusion The largest improvement in ataxia scores and functional mobility scores is demonstrated within the first 3 months post-operatively, but ongoing gradual improvement is observed at 2 years. Children with medulloblastoma and midline tumour demonstrated higher ataxia scores long term.

Intraoperative MRI (ioMRI) is a valuable tool aiding paediatric brain tumour resection. There is no published evidence comparing the effectiveness of the final intraoperative MRI and early post-operative (24–72 h) MRI as baseline scans following brain tumour resection. We aimed to evaluate whether the final ioMRI scan could serve as the post-operative baseline scan after paediatric brain tumour resections. This prospective study compared the final ioMRI scan with the immediate post-operative MRI scan performed 24–72 h post-surgery. We included 20 patients aged 6.6–21 years undergoing brain tumour resection using ioMRI and were suitable for MRI scan without general anaesthesia. The scans were independently evaluated by experienced local and external paediatric neuroradiologists. Identical sequences in the final ioMRI and the 24–72-h MRI were compared to assess the extent of resection, imaging characteristics of residual tumour, the surgical field, extent of surgically induced contrast enhancement, and diffusion abnormalities. In 20 patients undergoing intraoperative and early post-operative MRI, there was no difference between ioMRI and 24–72-h post-op scans in identifying residual tumour. Surgically induced contrast enhancement was similar in both groups. There were more abnormalities on diffusion imaging and a greater degree of oedema around the surgical cavity on the 24–72-h scan. The final 3-T ioMRI scan may be used as a baseline post-operative scan provided standard imaging guidelines are followed and is evaluated jointly by the operating neurosurgeon and neuroradiologist. Advantages of final ioMRI as a baseline scan are identified.

Summary Background Disease relapse occurs in around 30% of children with medulloblastoma, and is almost universally fatal. We aimed to establish whether the clinical and molecular characteristics of the disease at diagnosis are associated with the nature of relapse and subsequent disease course, and whether these associations could inform clinical management. Methods In this multicentre cohort study we comprehensively surveyed the clinical features of medulloblastoma relapse (time to relapse, pattern of relapse, time from relapse to death, and overall outcome) in centrally reviewed patients who relapsed following standard upfront therapies, from 16 UK Children's Cancer and Leukaemia Group institutions and four collaborating centres. We compared these relapse-associated features with clinical and molecular features at diagnosis, including established and recently described molecular features, prognostic factors, and treatment at diagnosis and relapse. Findings 247 patients (175 [71%] boys and 72 [29%] girls) with medulloblastoma relapse (median year of diagnosis 2000 [IQR 1995–2006]) were included in this study. 17 patients were later excluded from further analyses because they did not meet the age and treatment criteria for inclusion. Patients who received upfront craniospinal irradiation (irradiated group; 178 [72%] patients) had a more prolonged time to relapse compared with patients who did not receive upfront craniospinal irradiation (non-irradiated group; 52 [21%] patients; p

Background Relative cerebral blood volume (rCBV) measured using dynamic susceptibility-contrast MRI can differentiate between low- and high-grade pediatric brain tumors. Multicenter studies are required for translation into clinical practice. Objective We compared leakage-corrected dynamic susceptibility-contrast MRI perfusion parameters acquired at multiple centers in low- and high-grade pediatric brain tumors. Materials and methods Eighty-five pediatric patients underwent pre-treatment dynamic susceptibility-contrast MRI scans at four centers. MRI protocols were variable. We analyzed data using the Boxerman leakage-correction method producing pixel-by-pixel estimates of leakage-uncorrected (rCBVuncorr) and corrected (rCBVcorr) relative cerebral blood volume, and the leakage parameter, K2. Histological diagnoses were obtained. Tumors were classified by high-grade tumor. We compared whole-tumor median perfusion parameters between low- and high-grade tumors and across tumor types. Results Forty tumors were classified as low grade, 45 as high grade. Mean whole-tumor median rCBVuncorr was higher in high-grade tumors than low-grade tumors (mean ± standard deviation [SD] = 2.37±2.61 vs. –0.14±5.55; PP=0.010), remaining higher in high-grade tumors than low grade-tumors. Low-grade tumors, particularly pilocytic astrocytomas, showed T1-dominant leakage effects; high-grade tumors showed T2*-dominance (mean K2=0.017±0.049 vs. 0.002±0.017). Parameters varied with tumor type but not center. Median rCBVuncorr was higher (mean = 1.49 vs. 0.49; P=0.015) and K2 lower (mean = 0.005 vs. 0.016; P=0.013) in children who received a pre-bolus of contrast agent compared to those who did not. Leakage correction removed the difference. Conclusion Dynamic susceptibility-contrast MRI acquired at multiple centers helped distinguish between children’s brain tumors. Relative cerebral blood volume was significantly higher in high-grade compared to low-grade tumors and differed among common tumor types. Vessel leakage correction is required to provide accurate rCBV, particularly in low-grade enhancing tumors.

OBJECTIVE Complications in pediatric neurooncology surgery are seldom and inconsistently reported. This study quantifies surgical morbidity after pediatric brain tumor surgery from the last decade in a single center, using existing morbidity and outcome measures. METHODS The authors identified all pediatric patients undergoing surgery for an intracranial tumor in a single tertiary pediatric neurosurgery center between January 2008 and December 2018. Complications between postoperative days 0 and 30 that had been recorded prospectively were graded using appropriate existing morbidity scales, i.e., the Clavien-Dindo (CD), Landriel, and Drake scales. The result of surgery with respect to the predetermined surgical aim was also recorded. RESULTS There were 477 cases (364 craniotomies and 113 biopsies) performed on 335 patients (188 males, median age 9 years). The overall 30-day mortality rate was 1.26% (n = 6), and no deaths were a direct result of surgical complication. Morbidity on the CD scale was 0 in 55.14%, 1 in 10.69%, 2 in 18.66%, 3A in 1.47%, 3B in 11.74%, and 4 in 1.05% of cases. Morbidity using the Drake classification was observed in 139 cases (29.14%). Neurological deficit that remained at 30 days was noted in 8.39%; 78% of the returns to the operative theater were for CSF diversion. CONCLUSIONS To the authors’ knowledge, this is the largest series presenting outcomes and morbidity from pediatric brain tumor surgery. The mortality rate and morbidity on the Drake classification were comparable to those of published series. An improved tool to quantify morbidity from pediatric neurooncology surgery is necessary.

Glioblastoma, a grade IV astrocytoma, has a poor survival rate in part due to ineffective treatment options available. These tumours are heterogeneous with areas of low oxygen levels, termed hypoxic regions. Many intra-cellular signalling pathways, including DNA repair, can be altered by hypoxia. Since DNA damage induction and subsequent activation of DNA repair mechanisms is the cornerstone of glioblastoma treatment, alterations to DNA repair mechanisms could have a direct influence on treatment success. Our aim was to elucidate the impact of chronic hypoxia on DNA repair gene expression in a range of glioblastoma cell lines. We adopted a NanoString transcriptomic approach to examine the expression of 180 DNA repair related genes in four classical glioblastoma cell lines (U87-MG, U251-MG, D566-MG, T98G) exposed to 5 days of normoxia (21% O2), moderate (1% O2) or severe (0.1% O2) hypoxia. We observed altered gene expression in several DNA repair pathways including homologous recombination repair, non-homologous end-joining and mismatch repair, with hypoxia primarily resulting in downregulation of gene expression. The extend of gene expression changes was function of the hypoxic severity. Some, but not all, of these downregulations were directly under the control of HIF activity. For example, the downregulation of LIG4, a key component of non-homologous end-joining, was reversed upon inhibition of the hypoxia inducible factor (HIF). In contrast, the downregulation of the mismatch repair gene, PMS2, was not affected by HIF inhibition. This suggests that numerous molecular mechanisms lead to hypoxia-induced reprogramming of the transcriptional landscape of DNA repair. Whilst the global impact of hypoxia on DNA repair gene expression is likely to lead to genomic instability, tumorigenesis and reduced sensitivity to anti-cancer treatment, treatment re-sensitizing might require additional approaches to a simple HIF inhibition.

Surgery is the main treatment option for patients with aneurysmal bone cyst (ABC). We report our experience of using denosumab as an alternative treatment in a child with a multiply recurrent and unresectable tibial ABC. The efficacy and safety of denosumab in the paediatric population, and in the treatment of ABC, are still to be fully evaluated. We describe a 13-year-old boy with an extensive and aggressive ABC involving the proximal tibia, which had recurred following multiple previous surgeries. The patient had ongoing severe pain, was unable to weight-bear, and was at significant risk of pathological fracture. En bloc resection and embolization were not deemed viable, and a decision to use denosumab was made. He received 17 doses of subcutaneous denosumab (70 mg/m2) over a 27-month period, at increasing dose intervals. His symptoms significantly improved, and bony consolidation was observed within six months of treatment. He was able to walk without protection and fully weight-bear without any pain by 18 months. With an increase to a six-month dosing interval, the patient presented with a severe, symptomatic rebound hypercalcaemia requiring bisphosphonate therapy. This reoccurred on two further occasions. This case adds to the evidence that denosumab is effective in the treatment of ABC in paediatric patients, but there is a risk of rebound hypercalcaemia. Therefore, patient awareness and biochemical monitoring for rebound hypercalcaemia are essential.

Purpose PARP inhibitors (PARPi) are used in a wide range of human solid tumours but a limited evidence is reported in rhabdomyosarcoma (RMS), the most frequent childhood soft-tissue sarcoma. The cellular and molecular effects of Olaparib, a specific PARP1/2 inhibitor, and AZD2461, a newly synthesized PARP1/2/3 inhibitor, were assessed in alveolar and embryonal RMS cells both as single-agent and in combination with ionizing radiation (IR). Methods Cell viability was monitored by trypan blue exclusion dye assays. Cell cycle progression and apoptosis were measured by flow cytometry, and alterations of specific molecular markers were investigated by, Real Time PCR, Western blotting and immunofluorescence experiments. Irradiations were carried out at a dose rate of 2 Gy (190 UM/min) or 4 Gy (380 UM/min). Radiosensitivity was assessed by using clonogenic assays. Results Olaparib and AZD2461 dose-dependently reduced growth of both RH30 and RD cells by arresting growth at G2/M phase and by modulating the expression, activation and subcellular localization of specific cell cycle regulators. Downregulation of phospho-AKT levels and accumulation of γH2AX, a specific marker of DNA damage, were significantly and persistently induced by Olaparib and AZD2461 exposure, this leading to apoptosis-related cell death. Both PARPi significantly enhanced the effects of IR by accumulating DNA damage, increasing G2 arrest and drastically reducing the clonogenic capacity of RMS-cotreated cells. Conclusions This study suggests that the combined exposure to PARPi and IR might display a role in the treatment of RMS tumours compared with single-agent exposure, since stronger cytotoxic effects are induced, and compensatory survival mechanisms are prevented. Electronic supplementary material The online version of this article (10.1007/s00432-018-2774-6) contains supplementary material, which is available to authorized users.