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.

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

Background: Relapsed 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). Methods: This 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. Results: Twenty-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. Conclusions: This 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.

DIPG Harbors Alterations Targetable by MEK Inhibitors, with Acquired Resistance Mechanisms Overcome by Combinatorial Inhibition.

The survival of children with diffuse intrinsic pontine glioma (DIPG) remains dismal, with new treatments desperately needed. In a prospective biopsy-stratified clinical trial, we combined detailed molecular profiling and drug screening in newly established patient-derived models in vitro and in vivo. We identified in vitro sensitivity to MEK inhibitors in DIPGs harboring MAPK pathway alterations, but treatment of patient-derived xenograft models and a patient at relapse failed to elicit a significant response. We generated trametinib-resistant clones in a BRAFG469V model through continuous drug exposure and identified acquired mutations in MEK1/2 with sustained pathway upregulation. These cells showed hallmarks of mesenchymal transition and expression signatures overlapping with inherently trametinib-insensitive patient-derived cells, predicting sensitivity to dasatinib. Combined trametinib and dasatinib showed highly synergistic effects in vitro and on ex vivo brain slices. We highlight the MAPK pathway as a therapeutic target in DIPG and show the importance of parallel resistance modeling and combinatorial treatments for meaningful clinical translation. SIGNIFICANCE: We report alterations in the MAPK pathway in DIPGs to confer initial sensitivity to targeted MEK inhibition. We further identify for the first time the mechanism of resistance to single-agent targeted therapy in these tumors and suggest a novel combinatorial treatment strategy to overcome it in the clinic. This article is highlighted in the In This Issue feature, p. 587.

ALK-positive histiocytosis: a new clinicopathologic spectrum highlighting neurologic involvement and responses to ALK inhibition.

ALK-positive histiocytosis is a rare subtype of histiocytic neoplasm first described in 2008 in 3 infants with multisystemic disease involving the liver and hematopoietic system. This entity has subsequently been documented in case reports and series to occupy a wider clinicopathologic spectrum with recurrent KIF5B-ALK fusions. The full clinicopathologic and molecular spectra of ALK-positive histiocytosis remain, however, poorly characterized. Here, we describe the largest study of ALK-positive histiocytosis to date, with detailed clinicopathologic data of 39 cases, including 37 cases with confirmed ALK rearrangements. The clinical spectrum comprised distinct clinical phenotypic groups: infants with multisystemic disease with liver and hematopoietic involvement, as originally described (Group 1A: 6/39), other patients with multisystemic disease (Group 1B: 10/39), and patients with single-system disease (Group 2: 23/39). Nineteen patients of the entire cohort (49%) had neurologic involvement (7 and 12 from Groups 1B and 2, respectively). Histology included classic xanthogranuloma features in almost one-third of cases, whereas the majority displayed a more densely cellular, monomorphic appearance without lipidized histiocytes but sometimes more spindled or epithelioid morphology. Neoplastic histiocytes were positive for macrophage markers and often conferred strong expression of phosphorylated extracellular signal-regulated kinase, confirming MAPK pathway activation. KIF5B-ALK fusions were detected in 27 patients, whereas CLTC-ALK, TPM3-ALK, TFG-ALK, EML4-ALK, and DCTN1-ALK fusions were identified in single cases. Robust and durable responses were observed in 11/11 patients treated with ALK inhibition, 10 with neurologic involvement. This study presents the existing clinicopathologic and molecular landscape of ALK-positive histiocytosis and provides guidance for the clinical management of this emerging histiocytic entity.

The role of sex genotype in paediatric CNS tumour incidence and survival.

PURPOSE: Evidence exists, in CNS germinomas and medulloblastomas (MB), that patient sex significantly influences incidence and outcome. The role of sex genotype in other paediatric CNS tumours remains unclear. This study sought to examine the role of sex genotype in CNS tumour incidence and overall survival (OS). METHODS: Age-adjusted incidence and OS rates were collected from the Surveillance Epidemiology and End Result (SEER) registry between 2000 and 2011 for common paediatric (<=19 years) CNS tumours: pilocytic astrocytoma (PA), anaplastic astrocytoma, glioblastoma (GBM), medulloblastoma, supratentorial CNS embryonal tumour, ependymoma, and germinoma. All patients with histologically confirmed, ICD-03 coded, first tumours, were included. Kaplan-Meier and Cox regression analyses were used to calculate hazard ratios (HR). RESULTS: The total cases are as follows: males=3018 and females=2276. Highest incidence was seen in PA (n=2103). GBM displayed the worst OS, whilst PA displayed the best. Higher incidence was observed in males for all tumours, except PA. Females with ependymoma had significantly better OS compared to males, whereas males with germinomas had better OS compared to females. Females <1 year with AA had better OS than males. Increasing age significantly improved male and female survival in ependymoma and medulloblastoma. CONCLUSION: Interrogating population-based registries such as SEER minimises bias and provides credible data. Observed differences in incidence and OS between the sexes for different paediatric CNS tumours provide useful prognostic information for clinicians. Sex genotype was a significant independent prognostic factor in ependymomas and germinomas. Further investigation of possible epigenetic and hormonal differences may provide sex-specific vulnerabilities that may be exploitable for targeted therapy.

Childhood cancer in high resource settings.

Treatment of childhood cancer in High income countries (HIC) has been a success story of the 20th century with data demonstrating ever increasing survival. Some countries (for example, the UK) have national and regional registries providing high quality data, whilst in other countries the lack of population based data makes comparison impossible. In middle and low income countries (MIC and LIC) the incidence of childhood cancer appears to be lower than in HIC, almost certainly due to the lack of diagnosing and reporting of cases. There may be poor understanding and recognition of symptoms, presentation to traditional healers, poor access to healthcare facilities in rural areas and lack of diagnostic testing. Once on treatment, abandonment of further care can be multifactorial in underlying cause but subsequent relapse and death may add to suspicion of "western" medicine. Additionally, the presenting symptoms of childhood cancer can mimic common infectious diseases such as malaria so that cases remain undiagnosed. By reflecting on some common examples of childhood cancer it can be helpful to identify the points on the pathway to diagnosis and treatment which demonstrate the differences between HIC and MIC/LIC. Some interventions, such as funding for travel to treatment centres, accommodation and treatment, can make the difference between some treatment and no treatment. Highlighting these opportunities for change will improve outcomes in childhood cancer and raise standards of care for paediatrics in general. We have described the pathway to diagnosis and management of childhood cancers in HIC and presented the pathways for common malignancies in HIC and comparators for MIC/LIC to encourage supportive dialogue to improve measures to widen global access to diagnosis and management for children with these conditions. A longer term goal would be to support registries for population-based data collection as part of wider understanding of cancer on a global scale.

Management of severe pulmonary Langerhans cell histiocytosis in children.

Patients with pulmonary Langerhans cell histiocytosis (LCH) typically have a benign course but may have extensive cystic lung disease with rare life-threatening complications including multiple and recurrent pneumothoraces and respiratory failure. We report seven severely affected pediatric patients treated with chemotherapy, aggressive chest tube management, and pleurodesis of whom five survived. Patients with extraordinary amounts of pulmonary cystic disease and multiple pneumothoraces due to LCH can have remarkable, curative outcomes with early recognition, optimal LCH-directed therapy, and supportive care.

Neurocognitive, academic and functional outcomes in survivors of infant ependymoma (UKCCSG CNS 9204).

PURPOSE: This is the first UK multi-centre case-controlled study with follow-up in excess of 10 years to report the neurocognitive, academic and psychological outcomes of individuals diagnosed with a brain tumour in early childhood. Children enrolled into the UKCCSG CNS 9204 trial, diagnosed with intracranial ependymoma when aged ≤ 36 months old, who received a primary chemotherapy strategy to defer or avoid radiotherapy, were recruited. METHODS: Outcomes of those who relapsed and subsequently received radiotherapy (n = 13) were compared to those enrolled who did not relapse (n = 16), age-matched controls-diagnosed with solid non-central nervous system (SN-CNS; n = 15) tumours or low-grade posterior fossa pilocytic astrocytoma (PFPA; n = 15), and normative data. Analyses compared nine neurocognitive outcomes as primary measures with quality of survival as secondary measures. RESULTS: Relapsed ependymoma participants performed significantly worse than their non-relapsed counterparts on measures of Full Scale IQ, Perceptual Reasoning, Word Reading and Numerical Operations. The relapsed ependymoma group performed significantly worse than SN-CNS controls on all primary measures, whereas non-relapsing participants only differed significantly from SN-CNS controls on measures of Processing Speed and General Memory. Relapsed ependymoma participants fared worse than all groups on measures of quality of survival. CONCLUSIONS: The relapsed irradiated ependymoma group demonstrated the most significantly impaired neurocognitive outcomes at long-term follow-up. Non-relapsing participants demonstrated better outcomes than those who relapsed. Results tentatively suggest avoiding radiotherapy helped preserve neurocognitive and learning outcomes of individuals diagnosed with ependymoma when aged ≤ 36 months old. Prospective neurocognitive surveillance is required. Recommendations for clinical and research practice are provided.

Visual outcomes after chemotherapy for optic pathway glioma in children with and without neurofibromatosis type 1: results of the International Society of Paediatric Oncology (SIOP) Low-Grade Glioma 2004 trial UK cohort.

AIMS: To report visual acuity (VA) outcomes following chemotherapy for optic pathway glioma (OPG) in children with or without neurofibromatosis type-1 (NF1) and to analyse associated risk factors. METHODS: A prospective, multicentre, cohort study involving 155 children treated between September 2004 and December 2012. Initial and final VA was used for per-eye and per-subject analysis. Correlation tests were performed to determine whether initial VA predicted final VA. Logistic regression was used to determine whether age and tumour location were associated risk factors. RESULTS: 90 children had complete ophthalmological data. At initiation of chemotherapy, 26% and 49% of eyes with NF1-OPG and sporadic OPG, respectively, had VA of ≥0.7 log of the minimum angle of resolution (logMAR). At final visit, per eye, 49% had ≤0.2, 23% had 0.30-0.60 and 28% had VA≥0.70 logMAR in the NF1-OPG group. In the sporadic OPG group, per eye, 32% had ≤0.2, 11% had VA 0.30-0.60 and 57% had ≥0.70 logMAR. Children with sporadic OPG, per eye, were significantly less likely to have VA outcomes ≤0.60 logMAR compared with children with NF1-OPG (OR=0.30; 95% CI 0.16 to 0.56; P<0.0001). Per subject, VA improved in 24%, remained stable in 35% and worsened in 41% of children with NF1-OPG and improved in 18%, remained stable in 43% and worsened in 39% of children with sporadic OPG. CONCLUSIONS: Children with and without NF1 demonstrated the same rate of VA improvement, stabilisation or worsening; however, children with sporadic OPG had a poorer VA outcome. Better initial VA, older age, absence of postchiasm tumour and presence of NF1 were associated with improved or stable VA outcomes.

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.

A European randomised controlled trial of the addition of etoposide to standard vincristine and carboplatin induction as part of an 18-month treatment programme for childhood (≤16 years) low grade glioma - A final report.

BACKGROUND: The use of chemotherapy to manage newly diagnosed low grade glioma (LGG) was first introduced in the 1980s. One randomised trial has studied two- versus four-drug regimens with a duration of 12 months of treatment after resection. METHODS: Within the European comprehensive treatment strategy for childhood LGG, the International Society of Paediatric Oncology-Low Grade Glioma (SIOP LGG) Committee launched a randomised trial involving 118 institutions and 11 countries to investigate the addition of etoposide (100 mg/m2, days 1, 2 & 3) to a four-course induction of vincristine (1.5 mg/m2 × 10 wkly) and carboplatin (550 mg/m2 q 3 weekly) as part of 18-month continuing treatment programme. Patients were recruited after imaging diagnosis, resection or biopsy with progressive disease/symptoms. Some 497 newly diagnosed patients (M/F 231/266; median age 4.26 years (interquartile range (IQR) 2.02-7.06)) were randomised to receive vincristine carboplatin (VC) (n = 249) or VC plus etoposide (VCE) during induction (n = 248), stratified by age and tumour site. FINDINGS: No differences between the two arms were found in term of survival and radiological response. Response and non-progression rates at 24 weeks for VC and VCE, were 46% versus 41%, and 93% versus 91% respectively; 5-year Progression-Free Survival (PFS) and Overall Survival (OS) were 46% (StDev 3.5) versus 45% (StDev 3.5) and 89% (StDev 2.1) versus 89% (StDev 2.1) respectively. Age and diencephalic syndrome are adverse clinical risk factors for PFS and OS. 5-year OS for patients in early progression at week 24 were 46% (StDev 13.8) and 49% (StDev 16.5) in the two arms, respectively. INTERPRETATION: The addition of etoposide to VC did not improve PFS or OS. High non-progression rates at 24 weeks justify retaining VC as standard first-line therapy. Infants with diencephalic syndrome and early progression need new treatments to be tested. Future trials should use neurological/visual and toxicity outcomes and be designed to discriminate between the impact on disease outcomes of 'duration of therapy' and 'age at stopping therapy'.

Oncolytic Herpes Simplex Virus Inhibits Pediatric Brain Tumor Migration and Invasion.

Pediatric high-grade glioma (pHGG) and diffuse intrinsic pontine glioma (DIPG) are invasive tumors with poor survival. Oncolytic virotherapy, initially devised as a direct cytotoxic treatment, is now also known to act via immune-mediated mechanisms. Here we investigate a previously unreported mechanism of action: the inhibition of migration and invasion in pediatric brain tumors. We evaluated the effect of oncolytic herpes simplex virus 1716 (HSV1716) on the migration and invasion of pHGG and DIPG both in vitro using 2D (scratch assay, live cell imaging) and 3D (spheroid invasion in collagen) assays and in vivo using an orthotopic xenograft model of DIPG invasion. HSV1716 inhibited migration and invasion in pHGG and DIPG cell lines. pHGG cells demonstrated reduced velocity and changed morphology in the presence of virus. HSV1716 altered pHGG cytoskeletal dynamics by stabilizing microtubules, inhibiting glycogen synthase kinase-3, and preventing localized clustering of adenomatous polyposis coli (APC) to the leading edge of cells. HSV1716 treatment also reduced tumor infiltration in a mouse orthotopic xenograft DIPG model. Our results demonstrate that HSV1716 targets the migration and invasion of pHGG and DIPG and indicates the potential of an oncolytic virus (OV) to be used as a novel anti-invasive treatment strategy for pediatric brain tumors.

Biallelic TRIP13 mutations predispose to Wilms tumor and chromosome missegregation.

Through exome sequencing, we identified six individuals with biallelic loss-of-function mutations in TRIP13. All six developed Wilms tumor. Constitutional mosaic aneuploidies, microcephaly, developmental delay and seizures, which are features of mosaic variegated aneuploidy (MVA) syndrome, were more variably present. Through functional studies, we show that TRIP13-mutant patient cells have no detectable TRIP13 and have substantial impairment of the spindle assembly checkpoint (SAC), leading to a high rate of chromosome missegregation. Accurate segregation, as well as SAC proficiency, is rescued by restoring TRIP13 function. Individuals with biallelic TRIP13 or BUB1B mutations have a high risk of embryonal tumors, and here we show that their cells display severe SAC impairment. MVA due to biallelic CEP57 mutations, or of unknown cause, is not associated with embryonal tumors and cells from these individuals show minimal SAC deficiency. These data provide insights into the complex relationships between aneuploidy and carcinogenesis.

TPMT, COMT and ACYP2 genetic variants in paediatric cancer patients with cisplatin-induced ototoxicity.

OBJECTIVES: Cisplatin ototoxicity affects 42-88% of treated children. Catechol-O-methyltransferase (COMT), thiopurine methyltransferase (TPMT) and AYCP2 genetic variants have been associated with ototoxicity, but the findings have been contradictory. The aims of the study were as follows: (a) to investigate these associations in a carefully phenotyped cohort of UK children and (b) to perform a systematic review and meta-analysis. METHODS: We recruited 149 children from seven UK centres using a retrospective cohort study design. All participants were clinically phenotyped carefully. Genotyping was performed for one ACYP2 (rs1872328), three TPMT (rs12201199, rs1142345 and rs1800460) and two COMT (rs4646316 and rs9332377) variants. RESULTS: For CTCAE grading, hearing loss was present in 91/120 (75.8%; worst ear) and 79/120 (65.8%; better ear). Using Chang grading, hearing loss was diagnosed in 85/119 (71.4%; worst ear) versus 75/119 (63.0%; better ear). No TPMT or COMT single-nucleotide polymorphisms (SNPs) were associated with ototoxicity. ACYP2 SNP rs1872328 was associated with ototoxicity (P=0.027; worst ear). Meta-analysis of our data with that reported in previous studies showed the pooled odds ratio (OR) to be statistically significant for both the COMT SNP rs4646316 (OR: 1.50; 95% confidence interval: 1.15-1.95) and the ACYP2 SNP rs1872328 (OR: 5.91; 95% confidence interval: 1.51-23.16). CONCLUSION: We showed an association between the ACYP2 polymorphism and cisplatin-induced ototoxicity, but not with the TPMT and COMT. A meta-analysis was statistically significant for both the COMT rs4646316 and the ACYP2 rs1872328 SNPs. Grading the hearing of children with asymmetric hearing loss requires additional clarification.

Access to principal treatment centres and survival rates for children and young people with cancer in Yorkshire, UK.

BACKGROUND: Principal Treatment Centres (PTC) were established to provide age-appropriate care as well as clinical expertise for children and young people with cancer. However, little is known about the effects of specialist treatment centres on survival outcomes especially for teenagers and young adults. This population-based study aimed to describe access to PTC and the associated trends in survival for 0-24 year olds accounting for stage of disease at presentation and treatment. METHODS: Patients diagnosed from 1998-2009 aged 0-24 years were extracted from the Yorkshire Specialist Register of Cancer in Children and Young People, including information on all treating hospitals, followed-up until 31st December 2014. The six commonest cancer types were included: leukaemia (n = 684), lymphoma (n = 558), CNS tumours (n = 547), germ cell tumours (n = 364), soft tissue sarcomas (n = 171) and bone tumours (n = 163). Treatment was categorised into three groups: 'all', 'some' or 'no' treatment received at a PTC. Treatment at PTC was examined by diagnostic group and patient characteristics. Overall survival was modelled using Cox regression adjusting for case-mix including stage, treatment and other socio-demographic and clinical characteristics. RESULTS: Overall 72% of patients received all their treatment at PTC whilst 13% had no treatment at PTC. This differed by diagnostic group and age at diagnosis. Leukaemia patients who received no treatment at PTC had an increased risk of death which was partially explained by differences in patient case-mix (adjusted Hazard Ratio (HR) = 1.73 (95%CI 0.98-3.04)). Soft tissue sarcoma patients who had some or no treatment at PTC had better survival outcomes, which remained after adjustment for patient case-mix (adjusted HR = 0.48 (95%CI 0.23-0.99)). There were no significant differences in outcomes for other diagnostic groups (lymphoma, CNS tumours, bone tumours and germ cell tumours). For leukaemia patients survival outcomes for low risk patients receiving no treatment at PTC were similar to high risk patients who received all treatment at PTC, implying a benefit for care at the PTC. CONCLUSION: This study demonstrates that for leukaemia patients receiving treatment at a PTC is associated with improved survival that may compensate for a poorer prognosis presentation. However, further information on risk factors is needed for all diagnostic groups in order to fully account for differences in patient case-mix.

Aminoaciduria in the prediction of ifosfamide-induced tubulopathy after childhood cancer: a feasibility study.

BACKGROUND: Ifosfamide, an alkylating agent used widely in the treatment of childhood malignancy, can cause many side effects including a proximal tubulopathy. Studies suggest that aminoaciduria is seen most commonly of all the biochemical abnormalities of ifosfamide-induced tubulopathy. A recent systematic review has found a paucity of data regarding the value of early markers indicating clinically significant tubulopathy. We undertook a pilot study to determine the feasibility of examining whether patients can be risk-stratified on the basis of aminoaciduria for the development of future significant ifosfamide-induced tubulopathy, to allow the evolution of appropriate follow-up strategies. We also aimed to define accrual rates, costs and clinical demands for a future larger study. METHODS: This observational study recruited 21 patients from the Leeds Paediatric Oncology service. The medical notes of each patient were reviewed for demographic and clinical data. Simultaneous samples of blood and urine were obtained. RESULTS: The investigations in the feasibility study were acceptable to patients and were minimally demanding on both clinical and laboratory staff. Financially, the cost per patient was minimal. This study was not powered to detect significant associations with TmP/GFR (ratio of renal tubular maximum reabsorption rate of phosphate to glomerular filtration rate), growth and electrolyte supplementation. However, all patients with minimal aminoaciduria (≤2 elevated urinary amino acids) had normal TmP/GFR and no need for electrolyte supplementation. CONCLUSIONS: This pilot study has shown that a larger study is feasible and may provide clinically useful data to change current practice. This should aim to establish whether the number of abnormal amino acids or the degree of abnormality is most significant in predicting clinically significant proximal tubulopathy.

The UK Experience of a Treatment Strategy for Pediatric Metastatic Medulloblastoma Comprising Intensive Induction Chemotherapy, Hyperfractionated Accelerated Radiotherapy and Response Directed High Dose Myeloablative Chemotherapy or Maintenance Chemotherapy (Milan Strategy).

BACKGROUND: Historically, the 5-year overall survival (OS) for metastatic medulloblastoma (MMB) was less than 40%. The strategy of post-operative induction chemotherapy (IC) followed by hyperfractionated accelerated radiotherapy (HART) and response directed high dose chemotherapy (HDC) was reported in a single center study to improve 5-year OS to 73%. We report outcomes of this strategy in UK. METHODS: Questionnaires were sent to all 20 UK pediatric oncology primary treatment centers to collect retrospective data on delivered treatment, toxicity and survival with this strategy in children aged 3-19 years with MMB. RESULTS: Between February 2009 and October 2011, 34 patients fulfilled the entry criteria of the original study. The median age was 7 years (range 3-15). Median interval from surgery to HART was 109 versus 85 days in the original series. The incidence of grade 3 or 4 hematological toxicities with IC and HDC was 83-100%. All 16 patients who achieved complete response by the end of the regimen remain in remission but only three of 18 patients with lesser responses are still alive (P < 0.0001). With a median follow-up of 45 months for survivors, the estimated 3-year OS is 56% (95% CI 38, 71). This result is outside the 95% CI of the original study results and encompasses the historical survival result of 40%. CONCLUSION: Within the limits of statistical significance, we did not replicate the improved survival results reported in the original series. The reasons include differences in patient sub-groups and protocol administration. International randomized phase III studies are needed.