Survival rates and prognostic predictors of high grade brain stem gliomas in childhood : a systematic review and meta-analysis

Diagnosis of a pediatric high grade brain stem glioma is devastating with dismal outcomes. This systematic review and meta-analysis was undertaken to determine the survival rates and assess potential prognostic factors including selected interventions. Studies included involved pediatric participants with high grade brain stem gliomas diagnosed by magnetic resonance imaging or biopsy reporting overall survival rates. Meta-analysis was undertaken using a binomial random effects model. Sixty-five studies (2336 participants) were included. Meta-analysis showed 1 year overall survival (OS) of 41% (95% confidence interval (CI) 38-44%, I-sq 52%, 2083 participants), 2 year OS of 15.3% (95% confidence interval 12-20%, I-sq 73.1%, 1329 participants) and 3 year OS of 7.3% (95% confidence interval 5.2-10%, I-sq 26%, 584 participants). Meta-analyses of median overall survival results was not possible due to the lack of reported measures of variance. Subgroup analysis comparing date of study, classification of tumor, use of temozolomide, non-standard interventions or phase 1/2 versus other studies demonstrated no difference in survival outcomes. There was insufficient data to undertake subgroup meta-analysis of patient age, duration of symptoms, K27M histone mutations and AVCR1 mutations. Survival outcomes of high grade brain stem gliomas have remained very poor, and do not clearly vary according to classification, phase of study or use of different therapeutic interventions. Future studies should harmonize outcome and prognostic variable reporting to enable accurate meta-analysis and better exploration of prognosis

Multiple Effects of Prefrontal Lesions on Task-Switching

This study examined the performance of 41 patients with focal prefrontal cortical lesions and 38 healthy controls on a task-switching procedure. Three different conditions were evaluated: single tasks without switches and two switching tasks with the currently relevant task signalled either 1500 ms (Long Cue) or 200 ms (Short Cue) before the stimulus. Patients with Superior Medial lesions showed both a general slowing of reaction time (RT) and a significantly increased switch cost as measured by RT. No other prefrontal group showed this increased reaction time switch cost. Increased error rates in the switching conditions, on the other hand, were observed in patients with Inferior Medial lesions and, to a lesser extent, ones with Superior Medial lesions. Patients with left dorsolateral lesions (9/46v) showed slower learning of the task as indicated by a high error rate early on. Several different processes are involved in task-switching and these are selectively disrupted by lesions to specific areas of the frontal lobes

Space-time clustering of childhood central nervous system tumours in Yorkshire, UK

<p>Abstract</p> <p>Background</p> <p>We specifically tested the aetiological hypothesis that a factor influencing geographical or temporal heterogeneity of childhood central nervous system (CNS) tumour incidence was related to exposure to a transient environmental agent.</p> <p>Methods</p> <p>Information was extracted on individuals aged 0-14 years, diagnosed with a CNS tumour between the 1st January 1974 and 31st December 2006 from the Yorkshire Specialist Register of Cancer in Children and Young People. Ordnance Survey eight-digit grid references were allocated to each case with respect to addresses at the time of birth and the time of diagnosis, locating each address to within 0.1 km. The following diagnostic groups were specified <it>a priori </it>for analysis: ependymoma; astrocytoma; primitive neuroectodermal tumours (PNETs); other gliomas; total CNS tumours. We applied the <it>K</it>-function method for testing global space-time clustering using fixed geographical distance thresholds. Tests were repeated using variable nearest neighbour (NN) thresholds.</p> <p>Results</p> <p>There was statistically significant global space-time clustering for PNETs only, based on time and place of diagnosis (<it>P </it>= 0.03 and 0.01 using the fixed geographical distance and the variable NN threshold versions of the <it>K</it>-function method respectively).</p> <p>Conclusions</p> <p>There was some evidence for a transient environmental component to the aetiology of PNETs. However, a possible role for chance cannot be excluded.</p

Clinical features and survival among children with retinoblastoma in Uganda

AIMS: To characterise the clinical features, treatment and outcome of children diagnosed with retinoblastoma in Uganda. METHODS: The study comprised a 6-year nationwide enrolment with follow-up. RESULTS: In total, 282 cases were enrolled, 26% (72) were bilateral; 6% were lost to follow-up. Almost all diagnoses in the first affected eye were International Classification of Retinoblastoma group E or worse. Histology was available for 92%; of those, 45%, had extraocular tumour at diagnosis. Enucleation of the first eye was done for 271; 94 received radiotherapy to the socket and in the last 2 years, 70 children received chemotherapy. At close of study, 139 children had died. Survival, as determined in a proportional hazards model adjusted for age, sex, laterality and treatment era (pre or post introduction of chemotherapy), varied by extent of the tumour (p<0.001); children with only intraocular involvement were 80% less likely to die (HR=0.21, 95% CI 0.12 to 0.35) compared with children with extraocular involvement. CONCLUSIONS: Diagnostic delay results in relatively high mortality among children with retinoblastoma in Uganda. There is an urgent need for more effective treatment modalities, particularly chemotherapy, and nationwide efforts to encourage earlier access to medical care

Clinical features and survival among children with retinoblastoma in Uganda

AIMS: To characterise the clinical features, treatment and outcome of children diagnosed with retinoblastoma in Uganda. METHODS: The study comprised a 6-year nationwide enrolment with follow-up. RESULTS: In total, 282 cases were enrolled, 26% (72) were bilateral; 6% were lost to follow-up. Almost all diagnoses in the first affected eye were International Classification of Retinoblastoma group E or worse. Histology was available for 92%; of those, 45%, had extraocular tumour at diagnosis. Enucleation of the first eye was done for 271; 94 received radiotherapy to the socket and in the last 2 years, 70 children received chemotherapy. At close of study, 139 children had died. Survival, as determined in a proportional hazards model adjusted for age, sex, laterality and treatment era (pre or post introduction of chemotherapy), varied by extent of the tumour (p<0.001); children with only intraocular involvement were 80% less likely to die (HR=0.21, 95% CI 0.12 to 0.35) compared with children with extraocular involvement. CONCLUSIONS: Diagnostic delay results in relatively high mortality among children with retinoblastoma in Uganda. There is an urgent need for more effective treatment modalities, particularly chemotherapy, and nationwide efforts to encourage earlier access to medical care

Improving survival of retinoblastoma in Uganda

BACKGROUND: Diagnostic delay results in relatively high mortality among children with retinoblastoma in Uganda, where treatment was limited to surgery and, for some, radiotherapy. In order to improve outcomes, a simple programme of neoadjuvant and adjuvant chemotherapy was introduced. Here we report survival before and after this change to medical practice. METHODS: Affordable standard off-patent chemotherapy agents were administered by trained paramedical staff to groups of patients at the same time. Survival before and after the introduction of chemotherapy was monitored. Between 2006 and 2013 a total of 270 patients with retinoblastoma were included, 181 treated prior to chemotherapy and 89 after (beginning in 2009). We had 94% follow-up and 249 had histological verification of diagnosis. RESULTS: Using a proportional hazards model adjusted for age, sex and laterality, children treated after chemotherapy was introduced had a 37% lower risk of dying (HR 0.63, 95% CI 0.41 to 0.99) compared with children treated before. Prior to the introduction of chemotherapy only 15% of children who survived bilateral disease retained vision after treatment compared with 71% after chemotherapy. CONCLUSIONS: The introduction of chemotherapy proved safe and cost-effective in non-specialist hands and was associated with significant improvements in survival and, among bilateral cases, in preserving vision

Phase II study of intravenous etoposide in patients with relapsed ependymoma (CNS 2001 04)

BackgroundRelapsed ependymoma has a dismal prognosis, and the role of chemotherapy at relapse remains unclear. This study prospectively evaluated the efficacy of intensive intravenous (IV) etoposide in patients less than 21 years of age with relapsed intracranial ependymoma (NCT00278252).MethodsThis was a single-arm, open-label, phase II trial using Gehan’s two-stage design. Patients received IV etoposide 100 mg/m2 on days 1-3, 8-10, and 15-17 of each 28-day cycle, up to maximum of 6 cycles. Primary outcome was radiological response after 3 cycles. Pharmacokinetic analysis was performed in 10 patients.ResultsTwenty-five patients were enrolled and included in the intention-to-treat (ITT) analysis. Three patients were excluded in per-protocol (PP) analysis. After 3 cycles of etoposide, 5 patients (ITT 20%/PP 23%) had a complete response (CR), partial response (PR), or objective response (OR). Nine patients (ITT 36%/PP 41%,) had a best overall response of CR, PR, or OR. 1-year PFS was 24% in ITT and 23% in PP populations. 1-year OS was 56% and 59%, 5-year OS was 20% and 18%, respectively, in ITT and PP populations. Toxicity was predominantly hematological, with 20/25 patients experiencing a grade 3 or higher hematological adverse event.ConclusionsThis study confirms the activity of IV etoposide against relapsed ependymoma, however, this is modest, not sustained, and similar to that with oral etoposide, albeit with increased toxicity. These results confirm the dismal prognosis of this disease, provide a rationale to include etoposide within drug combinations, and highlight the need to develop novel treatments for recurrent ependymoma

A nationwide evaluation of bevacizumab-based treatments in pediatric low-grade glioma in the UK: safety, efficacy, visual morbidity, and outcomes

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

Population mixing for leukaemia, lymphoma and CNS tumours in teenagers and young adults in England, 1996-2005

Background: Little aetiological epidemiological research has been undertaken for major cancers occurring in teenagers and young adults (TYA). Population mixing, as a possible proxy for infectious exposure, has been well researched for childhood malignancies. We aimed to investigate effects of population mixing in this older age group using an English national cancer dataset.Methods: Cases of leukaemia, lymphoma and central nervous system (CNS) tumours amongst 15-24 year olds in England (diagnosed 1996-2005) were included in the study. Data were obtained by ward of diagnosis and linked to 1991 census variables including population mixing (Shannon index); data on person-weighted population density and deprivation (Townsend score) were also used and considered as explanatory variables. Associations between TYA cancer incidence and census variables were investigated using negative binomial regression, and results presented as incidence rate ratios (IRR) with 95% confidence intervals (CI).Results: A total of 6251 cases of leukaemia (21%), lymphoma (49%) and CNS tumours (30%) were analysed. Higher levels of population mixing were associated with a significant decrease in the incidence of CNS tumours (IRR = 0.83, 95% CI = 0.75-0.91), accounted for by astrocytomas and 'other CNS tumours'; however, there was no association with leukaemia or lymphoma. Incidence of CNS tumours and lymphoma was 3% lower in more deprived areas (IRR = 0.97, 95% CI = 0.96-0.99 and IRR = 0.97, 95% CI =0.96-0.98 respectively). Population density was not associated with the incidence of leukaemia, lymphoma or CNS tumours.Conclusions: Our results suggest a possible role for environmental risk factors with population correlates in the aetiology of CNS tumours amongst TYAs. Unlike studies of childhood cancer, associations between population mixing and the incidence of leukaemia and lymphoma were not observed