Noise suppression of proton magnetic resonance spectroscopy improves paediatric brain tumour classification.

Proton magnetic resonance spectroscopy (1H-MRS) is increasingly used for clinical brain tumour diagnosis, but suffers from limited spectral quality. This retrospective and comparative study aims at improving paediatric brain tumour classification by performing noise suppression on clinical 1H-MRS. Eighty-three/forty-two children with either an ependymoma (ages 4.6 ± 5.3/9.3 ± 5.4), a medulloblastoma (ages 6.9 ± 3.5/6.5 ± 4.4), or a pilocytic astrocytoma (8.0 ± 3.6/6.3 ± 5.0), recruited from four centres across England, were scanned with 1.5T/3T short-echo-time point-resolved spectroscopy. The acquired raw 1H-MRS was quantified by using Totally Automatic Robust Quantitation in NMR (TARQUIN), assessed by experienced spectroscopists, and processed with adaptive wavelet noise suppression (AWNS). Metabolite concentrations were extracted as features, selected based on multiclass receiver operating characteristics, and finally used for identifying brain tumour types with supervised machine learning. The minority class was oversampled through the synthetic minority oversampling technique for comparison purposes. Post-noise-suppression 1H-MRS showed significantly elevated signal-to-noise ratios (P < .05, Wilcoxon signed-rank test), stable full width at half-maximum (P > .05, Wilcoxon signed-rank test), and significantly higher classification accuracy (P < .05, Wilcoxon signed-rank test). Specifically, the cross-validated overall and balanced classification accuracies can be improved from 81% to 88% overall and 76% to 86% balanced for the 1.5T cohort, whilst for the 3T cohort they can be improved from 62% to 76% overall and 46% to 56%, by applying Naïve Bayes on the oversampled 1H-MRS. The study shows that fitting-based signal-to-noise ratios of clinical 1H-MRS can be significantly improved by using AWNS with insignificantly altered line width, and the post-noise-suppression 1H-MRS may have better diagnostic performance for paediatric brain tumours.

Characterisation of paediatric brain tumours by their MRS metabolite profiles.

1H-magnetic resonance spectroscopy (MRS) has the potential to improve the noninvasive diagnostic accuracy for paediatric brain tumours. However, studies analysing large, comprehensive, multicentre datasets are lacking, hindering translation to widespread clinical practice. Single-voxel MRS (point-resolved single-voxel spectroscopy sequence, 1.5 T: echo time [TE] 23-37 ms/135-144 ms, repetition time [TR] 1500 ms; 3 T: TE 37-41 ms/135-144 ms, TR 2000 ms) was performed from 2003 to 2012 during routine magnetic resonance imaging for a suspected brain tumour on 340 children from five hospitals with 464 spectra being available for analysis and 281 meeting quality control. Mean spectra were generated for 13 tumour types. Mann-Whitney U-tests and Kruskal-Wallis tests were used to compare mean metabolite concentrations. Receiver operator characteristic curves were used to determine the potential for individual metabolites to discriminate between specific tumour types. Principal component analysis followed by linear discriminant analysis was used to construct a classifier to discriminate the three main central nervous system tumour types in paediatrics. Mean concentrations of metabolites were shown to differ significantly between tumour types. Large variability existed across each tumour type, but individual metabolites were able to aid discrimination between some tumour types of importance. Complete metabolite profiles were found to be strongly characteristic of tumour type and, when combined with the machine learning methods, demonstrated a diagnostic accuracy of 93% for distinguishing between the three main tumour groups (medulloblastoma, pilocytic astrocytoma and ependymoma). The accuracy of this approach was similar even when data of marginal quality were included, greatly reducing the proportion of MRS excluded for poor quality. Children's brain tumours are strongly characterised by MRS metabolite profiles readily acquired during routine clinical practice, and this information can be used to support noninvasive diagnosis. This study provides both key evidence and an important resource for the future use of MRS in the diagnosis of children's brain tumours.

The effectiveness and safety of proton beam radiation therapy in children and young adults with Central Nervous System (CNS) tumours: a systematic review.

BACKGROUND: Central nervous system (CNS) tumours account for around 25% of childhood neoplasms. With multi-modal therapy, 5-year survival is at around 75% in the UK. Conventional photon radiotherapy has made significant contributions to survival, but can be associated with long-term side effects. Proton beam radiotherapy (PBT) reduces the volume of irradiated tissue outside the tumour target volume which may potentially reduce toxicity. Our aim was to assess the effectiveness and safety of PBT and make recommendations for future research for this evolving treatment. METHODS: A systematic review assessing the effects of PBT for treating CNS tumours in children/young adults was undertaken using methods recommended by Cochrane and reported using PRISMA guidelines. Any study design was included where clinical and toxicity outcomes were reported. Searches were to May 2021, with a narrative synthesis employed. RESULTS: Thirty-one case series studies involving 1731 patients from 10 PBT centres were included. Eleven studies involved children with medulloblastoma / primitive neuroectodermal tumours (n = 712), five ependymoma (n = 398), four atypical teratoid/rhabdoid tumour (n = 72), six craniopharyngioma (n = 272), three low-grade gliomas (n = 233), one germ cell tumours (n = 22) and one pineoblastoma (n = 22). Clinical outcomes were the most frequently reported with overall survival values ranging from 100 to 28% depending on the tumour type. Endocrine outcomes were the most frequently reported toxicity outcomes with quality of life the least reported. CONCLUSIONS: This review highlights areas of uncertainty in this research area. A well-defined, well-funded research agenda is needed to best maximise the potential of PBT. SYSTEMATIC REVIEW REGISTRATION: PROSPERO-CRD42016036802.

Long-term cisplatin nephrotoxicity after childhood cancer: a systematic review and meta-analysis.

BACKGROUND: Cisplatin is a chemotherapeutic drug commonly used in the treatment of many childhood solid malignancies. It is known to cause long-term nephrotoxicity, most commonly manifesting as reduced glomerular filtration rate and hypomagnesaemia. Existing literature regarding the epidemiology of long-term nephrotoxicity in childhood cancer describes large variation in prevalence and risk factors. OBJECTIVES: This study is to evaluate the prevalence of, and risk factors for, long-term cisplatin nephrotoxicity after treatment for childhood cancer. STUDY ELIGIBILITY CRITERIA: Studies were eligible for inclusion if they: (i) evaluated participants treated with cisplatin who were diagnosed with cancer < 18 years of age; (ii) investigated any author-defined measure of nephrotoxicity; and (iii) performed this evaluation 3 or more months after cisplatin cessation. Studies whose scope was broader than this were included if appropriate subgroup analysis was performed. RESULTS: Prevalence of reduced glomerular filtration rate (GFR) ranged between 5.9 and 48.1%. Pooled prevalence of reduced GFR using studies with a modern consensus threshold of 90 ml/min/1.73 m2 was 29% (95% CI 0.0-58%). Prevalence of hypomagnesaemia ranged between 8.0 and 71.4%. Pooled prevalence of hypomagnesaemia was 37% (95% CI 22-51%). Substantial heterogeneity was present, with I2 statistics of 94% and 73% for reduced GFR and hypomagnesaemia respectively. All large, long-term follow-up studies described increased risk of reduced GFR with increasing cumulative cisplatin dose. Included studies varied as to whether cisplatin was a risk factor for proteinuria, and whether age was a risk factor for cisplatin nephrotoxicity. LIMITATIONS: A wide range of study methodologies were noted which impeded analysis. No studies yielded data from developing health-care settings. No non-English studies were included, further limiting generalisability. CONCLUSIONS: Both of the most common manifestations of long-term cisplatin nephrotoxicity have a prevalence of approximately a third, with increasing cumulative dose conferring increased risk of nephrotoxicity. Further work is needed to characterise the relationship between reduced GFR and hypomagnesaemia, investigate other risk factors and understand the interindividual variation in susceptibility to nephrotoxicity.

Proceedings of the first global meeting of the Posterior Fossa Society: state of the art in cerebellar mutism syndrome.

PURPOSE: The Posterior Fossa Society, an international multidisciplinary group, hosted its first global meeting designed to share the current state of the evidence across the multidisciplinary elements of pediatric post-operative cerebellar mutism syndrome (pCMS). The agenda included keynote talks from world-leading speakers, compelling abstract presentations and engaging discussions led by members of the PFS special interest groups. METHODS: This paper is a synopsis of the first global meeting, a 3-day program held in Liverpool, England, UK, in September 2022. RESULTS: Topics included nosology, patient and family experience, cerebellar modulation of cognition, and cerebellar cognitive affective syndrome. In addition, updates from large-scale studies were shared as well as abstracts across neuroradiology, neurosurgery, diagnosis/scoring, ataxia, and rehabilitation. CONCLUSIONS: Based on data-driven evidence and discussions, each special interest group created research priorities to target before the second global meeting, in the spring of 2024.

Long term quality of life outcomes following surgical resection alone for benign paediatric intracranial tumours.

PURPOSE: 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. METHODOLOGY: 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™. RESULTS: 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. CONCLUSIONS: 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.

Prevalence of dysphagia following posterior fossa tumour resection in children: the Alder Hey experience.

BACKGROUND: 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. AIMS: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Metabolite selection for machine learning in childhood brain tumour classification.

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 1 H-MRS through support vector machine and 75% for 3 T 1 H-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.

Left-handedness should not be overrated as a risk factor for postoperative speech impairment in children after posterior fossa tumour surgery: a prospective European multicentre study.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Dynamic susceptibility-contrast magnetic resonance imaging with contrast agent leakage correction aids in predicting grade in pediatric brain tumours: a multicenter study.

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; P<0.01). Average median rCBV increased following leakage correction (2.54±1.63 vs. 1.68±1.36; P=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.

Advanced molecular pathology for rare tumours: A national feasibility study and model for centralised medulloblastoma diagnostics.

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 (<80 UK diagnoses/year) introduced a national reference centre (NRC) and assessed its performance and reporting to World Health Organisation standards. Paired frozen/formalin-fixed, paraffin-embedded tumour material were co-submitted from 135 patients (16 referral centres). RESULTS: Complete CPR diagnostics were successful for 88% (120/135). Inadequate sampling was the most common cause of failure; biomaterials were typically suitable for methylation-array (129/135, 94%), but frozen tissues commonly fell below RNA-seq QC requirements (53/135, 39%). Late reporting was most often due to delayed submission. CPR assigned or altered histological variant (vs local diagnosis) for 40/135 tumours (30%). Benchmarking/QC of specific biomarker assays impacted test results; fluorescent in-situ hybridisation most accurately identified high-risk MYC/MYCN amplification (20/135, 15%), while combined methods (CTNNB1/chr6 status, methylation-array subgrouping) best defined favourable-risk WNT tumours (14/135; 10%). Engagement of a specialist pathologist panel was essential for consensus assessment of histological variants and immunohistochemistry. Overall, CPR altered clinical risk-status for 29% of patients. CONCLUSION: National real-time CPR is feasible, delivering robust diagnostics to WHO criteria and assignment of clinical risk-status, significantly altering clinical management. Recommendations and experience from our study are applicable to advanced molecular diagnostics systems, both local and centralised, across rare tumour types, enabling their application in biomarker-driven routine diagnostics and clinical/research studies.

Comparison of intraoperative and post-operative 3-T MRI performed at 24-72 h following brain tumour resection in children.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Evolution of surgical attitudes to paediatric thalamic tumours: the alder hey experience.

PURPOSE: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.

Surgical management and outcomes of paediatric ovarian tumours-a 25-year UK single centre experience.

BACKGROUND: 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. METHODS: All female patients requiring operation for ovarian tumours were identified during the study period 1990-2018. Patient demographics, clinical presentation, and management are highlighted. RESULTS: 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). CONCLUSIONS: 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.

Posterior Fossa Society Consensus Meeting 2018: a synopsis.

PURPOSE: The Posterior Fossa Society (PFS) was founded 4 years ago to systematically gather and exchange information on the post-operative (CMS) and cerebellar cognitive affective syndrome (CCAS). With its consensus meetings, the PFS orchestrates research studies in the field of cerebellar injury and progresses the knowledge of post-operative pediatric cerebellar mutism syndrome (CMS). In this article, we captured the 3-day program of presentations, group discussions, interactive workshops, and dialogue, highlighting the key topic areas of CMS and its research advances. METHODS: This synopsis is based on the third consensus meeting which was held in Reykjavik, Iceland, in August 2018. RESULTS: Three working groups have been defined to drive the future research priorities on post-surgical CMS: (i) refining definition and symptoms scoring of CMS; (ii) understanding the pathogenesis and enhancing risk-stratification strategies; and (iii) developing rehabilitation approaches and protocols. CONCLUSIONS: The third consensus meeting highlighted a unanimous desire for data-driven information to advance the knowledge and guide future research efforts. The PFS constitutes an established and expanding network of multi-disciplinary expertise that can facilitate the development of collaborative studies and produce official guidelines on the topic.

The use of neo adjuvant single-agent vinblastine for tumour shrinkage in a highly vascular paediatric low-grade glioma.

Vinblastine has shown activity as second line treatment in Low Grade Glioma (LGG) in children as well as anti-angiogenic activity in vitro.A 5 year old girl presented with 6 week history of headaches. MRI demonstrated a right temporo-parietal mass with abnormal pathological vasculature including aneurysmal vessels. Biopsy showed a pilocytic astrocytoma. Due to increased risk from surgery, first line treatment with vinblastine was given.Over 10 months, progressive reduction of tumour vascularity was demonstrated. The tumour was then surgically removed after 14 months of therapy.To our knowledge, this is the first report in which vinblastine has been successfully used in LGG to obtain tumour shrinkage prior to total tumor resection in a high vascularized LGG.

Decrease of Nibrin expression in chronic hypoxia is associated with hypoxia-induced chemoresistance in some brain tumour cells.

BACKGROUND: Solid tumours are less oxygenated than normal tissues. This is called tumour hypoxia and leads to resistance to radiotherapy and chemotherapy. The molecular mechanisms underlying such resistance have been investigated in a range of tumour types, including the adult brain tumours glioblastoma, yet little is known for paediatric brain tumours. Medulloblastoma (MB) is the most common malignant brain tumour in children. We aimed to elucidate the impact of hypoxia on the sensitivity of MB cells to chemo- and radiotherapy. METHODS: We used two MB cell line (D283-MED and MEB-Med8A) and a widely used glioblastoma cell line (U87MG) for comparison. We applied a range of molecular and cellular techniques to measure cell survival, cell cycle progression, protein expression and DNA damage combined with a transcriptomic micro-array approach in D283-MED cells, for global gene expression analysis in acute and chronic hypoxic conditions. RESULTS: In D283-MED and U87MG, chronic hypoxia (5 days), but not acute hypoxia (24 h) induced resistance to chemotherapy and X-ray irradiation. This acquired resistance upon chronic hypoxia was present but less pronounced in MEB-Med8A cells. Using transcriptomic analysis in D283-MED cells, we found a large transcriptional remodelling upon long term hypoxia, in particular the expression of a number of genes involved in detection and repair of double strand breaks (DSB) was altered. The levels of Nibrin (NBN) and MRE11, members of the MRN complex (MRE11/Rad50/NBN) responsible for DSB recognition, were significantly down-regulated. This was associated with a reduction of Ataxia Telangiectasia Mutated (ATM) activation by etoposide, indicating a profound dampening of the DNA damage signalling in hypoxic conditions. As a consequence, p53 activation by etoposide was reduced, and cell survival enhanced. Whilst U87MG shared the same dampened p53 activity, upon chemotherapeutic drug treatment in chronic hypoxic conditions, these cells used a different mechanism, independent of the DNA damage pathway. CONCLUSION: Together our results demonstrate a new mechanism explaining hypoxia-induced resistance involving the alteration of the response to DSB in D283-MED cells, but also highlight the cell type to cell type diversity and the necessity to take into account the differing tumour genetic make-up when considering re-sensitisation therapeutic protocols.

Exercise and Physical Therapy Interventions for Children with Ataxia: A Systematic Review.

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.

The utility of routine surveillance screening with magnetic resonance imaging to detect tumor recurrence/progression in children with high-grade central nervous system tumors: a systematic review.

BACKGROUND: Surveillance magnetic resonance imaging (MRI) is routinely used to detect recurrence in children with high-grade central nervous system (CNS) tumors, although no consensus has been reached regarding its effectiveness and whether earlier detection is associated with improved patient outcomes. This review aimed to evaluate this practice and any associated benefits and harms. METHODS: Systematic searches for relevant studies were undertaken in a number of databases, including MEDLINE and EMBASE, from 1985 to August 2018. Study selection and data extraction was undertaken independently by two reviewers. Due to heterogeneity between studies, no pooling of data was undertaken. Reporting followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: No comparative studies were identified. Three retrospective observational studies involving 306 patients were reviewed. All had high risk of bias by virtue of study design. Two studies reported outcomes by symptomatic status-both recurrence rates and overall survival for asymptomatic patients were comparable with those for clinically symptomatic patients. No quality-of-life outcomes were reported. CONCLUSION: There is a paucity of evidence to guide clinical practice as to the effectiveness of MRI surveillance in pediatric patients with high-grade CNS tumors. These studies do not clearly demonstrate benefit or harm for the practice. With more research needed, there is a role for researchers to build into future trials data collection on surveillance imaging to give more information for the assessment of imaging frequency and duration in asymptomatic patients. This is an important question not only to clinicians and patients and their families but also from a health service resource perspective.