Jf Liu

A multivariate analysis of factors determining tumor progression in childhood low-grade glioma: a population-based cohort study (CCLG CNS9702)

The purpose of this study was to identify risk factors for the progression of low-grade glioma in children from a large population-based cohort. Patient and tumor details of a national cohort of children with low-grade glioma, recruited into an international multidisciplinary clinical strategy, were subjected to univariate and multivariate analyses of progression-free survival and overall survival. From the cohort of 798 patients, 639 patients were eligible, with a median age 6.71 years (0.26-16.75 years); 49% were males; 15.9% had neurofibromatosis type 1, 63.7% pilocytic astrocytoma, 5.9% fibrillary astrocytoma, 4.2% mixed neuronal-glial tumors, and 3.6% others; 21.1% were diagnosed clinically. Anatomically implicated were 31.6% cerebellum, 24.6% chiasma/hypothalamus, 16.0% cerebral hemispheres, 9.9% brain stem, 6.1% other supratentorial midline structures, 5.9% optic nerve only, 4.5% spinal cord, and 1.4% others. The 5-year overall survival and progression-free survival in the whole cohort were 94.6% and 69.4%, respectively. There was a significant association between age and site (P < .001) and extent of tumor resection and site (P < .001). Multivariate analysis identified young age, fibrillary astrocytoma, and extent of surgical resection as significant independent risk factors for progression. Hypothalamic/chiasmatic tumors demonstrated the most sustained tendency to progress. In conclusion, the influence of age and anatomical site upon the risk of tumor progression suggests that these factors strongly influence tumor behavior for the majority of pilocytic tumors. Age <1 year and 1-5 years, fibrillary histology, completeness of resection, and chiasmatic location are candidates for stratification in future studies.

A new clinical guideline from the Royal College of Paediatrics and Child Health with a national awareness campaign accelerates brain tumor diagnosis in UK children—“HeadSmart: Be Brain Tumour Aware”

BACKGROUNDnA national survey in 2006 identified that UK referral practice for pediatric CNS tumors ranked poorly in international comparisons, which led to new National Health Service (NHS) Evidence accredited referral guidelines published in 2008 by the Royal College of Paediatrics and Child Health and a campaign to raise awareness of early features of CNS tumors and the need for timely imaging.nnnMETHODSnThe HeadSmart: Be Brain Tumour Aware campaign was launched in June 2011 across the UK as a quality improvement strategy directed at reducing the total diagnostic interval (TDI) from a pre-campaign (2006) median of 14 (mean, 35.4) weeks to a target of 5 weeks in order to equal the best reported internationally. Professional and public awareness was measured by questionnaire surveys. TDI was collected by clinical champions in 18 regional childrens cancer centers and the public campaign was coordinated by a national charity, working with a network of community champions.nnnRESULTSnThe guidelines and campaign raised awareness among pediatricians and were associated with reduction in TDI to a median of 6.7 (mean, 21.3) weeks by May 2013. This change in referral practice was most pronounced in the time from first medical contact to CNS imaging, for which the median was reduced from 3.3 to 1.4 weeks between January 2011 and May 2013 (P = .009).nnnCONCLUSIONnThis strategy to accelerate brain tumor diagnosis by the NHS using a public and professional awareness campaign is a world first in pediatric cancer and is being emulated internationally and acknowledged by a series of NHS and charity awards for excellence.

Development of a pre-operative scoring system for predicting risk of post-operative paediatric cerebellar mutism syndrome

Abstract Background: Despite previous identification of pre-operative clinical and radiological predictors of post-operative paediatric cerebellar mutism syndrome (CMS), a unifying pre-operative risk stratification model for use during surgical consent is currently lacking. The aim of the project is to develop a simple imaging-based pre-operative risk scoring scheme to stratify patients in terms of post-operative CMS risk. Methods: Pre-operative radiological features were recorded for a retrospectively assembled cohort of 89 posterior fossa tumour patients from two major UK treatment centers (age 2–23yrs; gender 28u2009M, 61u2009F; diagnosis: 38 pilocytic astrocytoma, 32 medulloblastoma, 12 ependymoma, 1 high grade glioma, 1 pilomyxoid astrocytoma, 1 atypical teratoid rhabdoid tumour, 1 hemangioma, 1 neurilemmoma, 2 oligodendroglioma). Twenty-six (29%) developed post-operative CMS. Based upon results from univariate analysis and C4.5 decision tree, stepwise logistic regression was used to develop the optimal model and generate risk scores. Results: Univariate analysis identified five significant risk factors and C4.5 decision tree analysis identified six predictors. Variables included in the final model are MRI primary location, bilateral middle cerebellar peduncle involvement (invasion and/or compression), dentate nucleus invasion and age at imaging >12.4 years. This model has an accuracy of 88.8% (79/89). Using risk score cut-off of 203 and 238, respectively, allowed discrimination into low (38/89, predicted CMS probability <3%), intermediate (17/89, predicted CMS probability 3–52%) and high-risk (34/89, predicted CMS probability ≥52%). Conclusions: A risk stratification model for post-operative paediatric CMS could flag patients at increased or reduced risk pre-operatively which may influence strategies for surgical treatment of cerebellar tumours. Following future testing and prospective validation, this risk scoring scheme will be proposed for use during the surgical consenting process.

G392(P) A Regional paediatric neuro-oncology cohort study of seizure characteristics and their management: a proposal for service evaluation criteria

Aims To describe the presentation of epileptic seizures, the tumour-related risk factors, seizure treatments used and the timing of withdrawal of anti-epileptic drugs (AEDs). Methods Retrospective case note review of 120 newly diagnosed brain tumour patients referred between 01/2010 and 12/2014 to the regional paediatric cancer service was carried out to determine patient, tumour, seizure characteristics and their treatment and outcomes. Statistical analyses using Fischer Test, Mann-Whitney U test and logistic regression test of association between variables were performed. Results Two patients with tuberous sclerosis and associated seizures and 1 patient lost to follow up, were excluded. 67/117 (57.3%) were male, median age at tumour presentation was 8.1 years (IQR 25°–75°: 3.6–12.7). Anatomical distribution was posterior fossa 36%, cerebral hemisphere 28%, supratentorial midline 24%, spinal cord 5%, metastatic 7%. Most common histological types include pilocytic astrocytoma 15%, visual pathway glioma 8%, other low grade astrocytoma 11%; high grade glioma 10%, medulloblastoma 11%. With a median follow up of 33 months (IQR 25°–75°: 24–56), there were 35 patients (29%) with seizures. Logistic regression analysis identified cerebral hemisphere localization as risk factor for seizures (OR: 7.07 IC 95% 2.89–17.3). In particular, neither age at diagnosis nor tumour type were associated with seizure risk, although 6/8 patients with glioneuronal tumours developed seizures. With a median follow up of 24 months (IQR25°-75°: 15–48) 37% were seizure free (SF) off AEDs, 43% were SF on AEDs and 20% experienced continuing seizures. One patient was untreated, seizures resolved. 12 patients withdrew AEDs, median duration of AED therapy before withdrawal was 11 months (IQR25°–75° 5–14 months), and the median follow up after withdrawal was 15 months (IQR25°–75° 5–34 months). 4 children had seizure relapse after further acute events (2 had acute hydrocephalus, 1 had sepsis, 1 had ventriculitis after shunt revision). Conclusions Epileptic seizures affect about 1/3rd of children presenting with brain tumours, most commonly in cortically-located tumours. The low risk of recurrent seizures after treatment justifies early withdrawal of AED after stabilisation of seizures. A 3 month seizure free interval prior to AED withdrawal is proposed as a service evaluation target for future studies. Acknowledgement: on behalf of the East Midlands Children and Young People’s Integrated Cancer Service (EMCYPICS) and University of Nottingham Children’s Brain Tumour Research Centre (www.cbtrc.org)

G14 A consensus survey on risk-based selection criteria for the next SIOP trial of ‘sight-saving therapy’ for children with NF1-associated optic pathway glioma (NF1-OPG)

Aims The natural history of children with NF1-OPG is unpredictable, indications for therapy to save vision, using patient, imaging and visual factors have not been studied in Europe. In the previous SIOP-E NF1-OPG multi-disciplinary workshop, consensus on imaging and visual classification was achieved, including a schematic for recording patient, visual and imaging details. This survey was setup to collect opinions on selecting NF1-associated OPG patients for observation, treatment and randomisation, and assess the feasibility of a randomised trial from an external multidisciplinary group. Methods Eight SIOP-LGG2004 centres contributed 83 NF1-OPG cases with complete imaging, visual and clinical datasets. From these, 10 cases were selected to display a range of ages on presentation and tumour locations in accordance with the PLAN classification (Figure 1).1 Abstract G14 Figure 1 PLAN classificatioin1, visual acuity and age at diagnosis of the ten patients selected for the survey The survey targets all medical professionals involved in the multi-disciplinary team making management decisions for NF1-OPG patients. The questionnaire consists of 32 questions to collect data on (1) management decision of 10 representative cases and reasoning, (2) information about the participant and (3) feedback on the questionnaire. This questionnaire was pre-tested among SIOP-E NF1-OPG workshop participants in late 2014 then revised in 2015. Results Sixty-two medical professionals took part in the survey and allocated 4 cases for treatment and 2 cases for observation with consensus (>70% agreement). Respondents did not reach consensus on the management decision of 4 patients (Table 1); 20–43% of the respondents voted for randomisation for the four patients.Abstract G14 Table 1 Survey results from 62 medical professionals involved in the multi-disciplinary team making management decisions for the ten NF1-OPG patients Conclusions The SIOP-E NF1-OPG group will invite more medical professionals to express their opinion on using patient, imaging and visual factors to select patients for sight-saving therapy. The results will assist the group in planning the next SIOP-LGG trial. Subgroups that did not reach consensus on treatment decision may be eligible for randomisation. Reference Taylor T, Jaspan T, Milano G, et al. Radiological classification of optic pathway gliomas: experience of a modified functional classification system. The British Journal of Radiology 2008;81(970):761–6

G362(P) Recommendations from the revision of the RCPCH pathways to diagnosis: The diagnosis of brain tumours guideline

Aims The RCPCH guideline entitled Pathways to Diagnosis: The Diagnosis of Brain Tumours was published in 2008 and later accredited by NHS (NICE) Evidence. The HeadSmart: Be Brain tumour aware campaign was launched in 2011 to amplify the guidance and has successfully halved the total diagnostic interval in the UK. We are conducting a systematic review and meta-analysis in order to update the guideline using current published evidence. Methods Medline, Pubmed and Embase databases were searched without language restriction from January 2005–August 2015. Key words were “brain tumour (s)”, “brain tumour (s)”, “brain neoplasm (s)”, “diagnosis”, “signs (s)”, “symptom (s)”, “presentation (s)”. All references were restricted to “all child”. All papers containing data of brain tumour presentation, diagnosis or presenting signs and symptoms were included. A standard data extraction form was used to record the numbers of children with each symptom/sign. Some studies were detailed on individual symptoms (headache, vomiting, papilloedema) whilst others recorded complexes (eg intracranial pressure). If a symptom/sign was not recorded, it was assumed not to have occurred in that population. Results 20,068 papers were identified by the search terms. We reviewed 664 papers in full of which 71 met the inclusion criteria describing the signs and symptoms in 3818 children. A total of 152 symptoms were identified of which 80% presented with signs and symptoms of raised intracranial pressure (including headache and vomiting). Visual symptoms (16%), ataxia (11%), CN palsies (10%) and seizures (9%) together with raised ICP made up the top 5 presenting signs/symptoms. HeadSmart data shows that children with midline supratentorial tumours and adolescents have the longest total diagnostic intervals. Subgroup analyses of tumour location, children under the age of 2, and young people is ongoing. Where no substantial clinical research evidence is identified, a formal consensus method will be used to formulate recommendations. Conclusions Our HeadSmart data has given us valuable guidance as to which subgroups to focus this analysis on. The presentation will summarise the new recommendations which will help us meet the government target of all cancer diagnoses within 4 weeks. The revised draft guideline will be discussed at the conference.

G12 Development and clinical acceptability of a pre-operative risk stratification tool of cerebellar mutism syndrome in children with posterior fossa tumour

Aims Despite identification of numerous pre-operative cerebellar mutism syndrome (CMS) clinical and radiological predictors, a unifying pre-operative risk stratification model for use during surgical consent is currently lacking. The aims of the project are (1) to develop a simple, easy to implemented risk scoring scheme to flag patients at higher risk of post-operative CMS; and (2) to assess its clinical acceptability amongst medical professionals. Methods The combined cohort consists of 89 patients from two major treatment centres (age: 2–23yrs, gender 28M,61F, MRI pathology estimate 36 medulloblastoma, 40 pilocytic astrocytoma, 12 ependymoma, 1 non-committal); 26 (29%) of whom developed post-operative CMS. Post-operative CMS status was ascertained from clinical notes and pre-operative MRI scans, blinded to CMS status, underwent structured evaluation for 21 tightly-defined candidate imaging risk markers based on prior literature. All variables were first screened based upon results from univariate analysis and C4.5 decision tree. Stepwise logistic regression was then used to develop the optimal model, and multiple logistic regression coefficients for the predictors were converted into risk scores. Results Univariate analysis identified five significant risks and C4.5 decision tree identified six predictors. The final model (Table 1) has an accuracy of 88.8% (79/89), with a sensitivity of 96.2% (25/26) and specificity of 85.7% (54/63). Using risk score cut-offs 203 and 238 permit discrimination into low (38/89, predicted probability < 3%), intermediate (17/89, predicted probability 3–52%) and high-risk (34/89, predicted probability ≥ 52%), respectively (Figure 1). Three illustrative cases from these categories will be used to collect clinicians’ opinion on surgical treatment decision and the acceptability of using this risk stratification for decision making and surgical consenting process. A web-based voting app will be used.Abstract G12 Table 1 Variables in the risk prediction model and risk scoreAbstract G12 Figure 1 Predicted post-operative CMS probability by risk score Conclusions A risk stratification model for post-operative CMS could flag patients at increased risk pre-operatively and may influence strategies for surgical treatment of cerebellar tumours. Following future testing and prospective validation, this risk scoring scheme may be utilised during the surgical consenting process.

P01 A Service Evaluation of Implementation of RCPCH Brain Pathways Clinical Guideline Linked to HeadSmart – Be Brain Tumour Aware (HeadSmart). A Health Foundation, Closing the Gap Project

Aims To evaluate the impact of the HeadSmart Campaign upon symptom interval (SI) for newly diagnosed childhood brain tumours at UK Children’s Cancer and Leukaemia Group (CCLG) treatment centres. Introduction HeadSmart’s national awareness campaign (www.headsmart.org.uk) aims to disseminate the RCPCH endorsed Brain Pathways Guideline for referral and imaging of patients with symptoms suggestive of brain tumour. Methods The SI experienced by children newly diagnosed with brain tumours was determined from January 2011 to December 2012 by HeadSmart Clinical Champions at 18 CCLG treatment centres reporting to an online database as part of a service evaluation under Caldicott guardian permission. Results Data from 353 children (median 6.7 yr, range 0.02–17.71) is available. The median SI is 7.57 weeks (mean 21.8, range 0 to 435 weeks). The median symptom onset to consultation with a healthcare professional interval is 2.3 weeks (mean 12.9, range 0 to 433 weeks), and the median consultation to diagnosis interval is 2.7 weeks (mean 9.0, range 0 to 156 weeks). Imaging that identified the tumour took place as an outpatient in 28.3%, an inpatient in 43.3% and from the emergency department in 19.5%. 3.1% of children were referred via a “two week wait” cancer referral. The most frequent symptoms and signs at symptom onset were headache (46%), vomiting (41%), abnormal coordination (12%), abnormal gait (12%), lethargy (12%); and at diagnosis were vomiting (53%), headache (48%), abnormal coordination (26%), abnormal gait (23%), lethargy (21%), and papilloedema (21%). The medium SI prior to campaign launch was 9.3 weeks, and after launch 6.9 weeks (p = 0.043); mean SI during the same period was 22.9 and 21.0 weeks. The median consultation to diagnosis interval was 3 weeks prior to launch; post launch it was 2.3 weeks during the first 6 months, and reduced to 1.0 week between the 7th – 18th month of the campaign (p = 0.026). Changes in mean during the same period did not show a reduction trend; mean SI 15.2, 10.3, 13.3 weeks, respectively. Conclusions Analysis of the SI experienced by UK children before and after the HeadSmart launch suggests that the SI and the consultation to diagnosis interval have reduced. Further data is required to determine whether this reduction is sustained.