Search

Wilms' tumour (WT) is the commonest renal tumour of childhood and its treatment is regarded as one of the success stories of paediatric oncology with over 90% cure rate. Most patients present with localized unilateral tumours. Histology and stage are important prognostic factors, and children with stage IV and diffuse anaplasia have poorer outcomes. Whilst there are differences in the treatment approaches around the world, outcomes are excellent for most subgroups of Wilms' tumour. The European Societe Internationale d'Oncologie Pediatrique (SIOP) recommends pre-operative chemotherapy to children over 6 months whilst the North American Children's Oncology Group offers primary nephrectomy and uses biomarkers for treatment stratification. Overall, 15% patients experience a relapse and their management depends on the initial treatment they had received. The focus of research is to decrease long term side effects, reduce treatment for selected subgroups, and improve our understanding of prognostic biomarkers to help tailor treatments. This article provides an overview for paediatricians giving an update on the important recent advances.

Objectives. Neuroblastoma is the most common extracranial tumour in children, and prognosis for refractory and relapsed disease is still poor. Early Phase clinical trials play a pivotal role in the development of novel drugs. Ensuring adequate recruitment is crucial. The primary aim was to determine the rate of participation trials for children with refractory/relapsed neuroblastoma in two of the largest Drug Development European institutions. Methods. Data from patients diagnosed with refractory/relapsed neuroblastoma between January 2012 and December 2018 at the two institutions were collected and analysed. Results. Overall, 48 patients were included. A total of 31 (65%) refractory/relapsed cases were enrolled in early Phase trials. The main reasons for not participating in clinical trials included: not fulfilling eligibility criteria prior to consent (12/17, 70%) and screening failure (2/17, 12%). Median time on trial was 4.3 months (range 0.6-13.4). Most common cause for trial discontinuation was disease progression (67.7%). Median overall survival was longer in refractory (28 months, 95% CI, 20.9-40.2) than in relapsed patients (14 months, 95% CI, 8.1-20.1)) [p=0,034]. Conclusions. Although two thirds of children with refractory/relapsed neuroblastoma were enrolled in early Phase trials, recruitment rates can still be improved. The main cause for not participating on trials was not fulfilling eligibility criteria prior to consent, mainly due to performance status and short life expectancy. This study highlights the hurdles to access to innovative therapies for children with relapsed/refractory neuroblastomas and identifies key areas of development to improve recruitment to early phase trials.

10002 Background: The BEACON phase II trial (NCT02308527) addressed a number of questions in children with relapsed/refractory high-risk neuroblastoma (RR-HRNB). Here we report the chemo-immunotherapy randomisation, assessing if anti-GD2 (dB) demonstrates activity when added to chemotherapy. Methods: Patients aged 1-21 years with RR-HRNB with adequate organ function and performance status were randomised in a 1:2 ratio to receive chemotherapy alone or with dB, given concurrently as a 7 day continuous infusion (10 mg/m2/24hr). As the trial had a factorial design, some patients were also randomised between chemotherapy regimens (temozolomide (T) versus Temozolomide-Topotecan (TTo); this randomisation closed soon after the dB randomisation opened and all patients subsequently received TTo chemotherapy. Cross-over to dB with topotecan and cyclophosphamide was allowed for patients randomised to chemotherapy alone who experienced disease progression. The primary outcome measure was best response (complete or partial) at any point during the first 6 courses of treatment, by RECIST or International Neuroblastoma Response Criteria for patients with measurable and evaluable disease respectively. Progression free and overall survival (PFS & OS) and safety were secondary outcomes. The success criterion for proceeding to a Phase 3 trial was a one-sided p-value (1p) less than 0.23 for Objective Response Rate (ORR). Results: From Aug 2019 to Feb 2021, 65 patients were randomised to chemotherapy alone (3 T, 19 TTo) or with dB (6 dBT, 37 dBTTo). Median age was 4 years; 48 and 17 had measurable and evaluable disease respectively; 29 and 36 had refractory and relapsed disease respectively; 19 had MYCN amplification. Baseline characteristics were balanced between arms. Response was assessable in all patients. The ORR was 18% with chemotherapy alone and 35% for patients receiving chemotherapy with dB (risk ratio 1.66, 80% confidence interval (CI) 0.9 to 3.06, 1p = 0.19). 1-year PFS was 27% for chemotherapy alone, and 57% for those receiving chemotherapy +dB (HR 0.63, 95% CI 0.32 to 1.25, p = 0.19). Twelve patients in the chemotherapy only arm crossed over to receive dB at progression. OS did not differ between the arms: HR = 0.99, 95% CI 0.42 to 2.36, p = 0.99. Nine (41%) patients receiving chemotherapy alone and 13 (30%) receiving chemotherapy plus dB had grade ≥3 toxicities (CTCAE v4.0). Neurotoxicities were more common in patients receiving dB compared to chemotherapy alone (Grade 1-2: 67.4% vs 13.6%, Grade 3: 9.3 vs 0%). Other toxicities were similar with and without dB. Conclusions: The Phase 2 success criterion for ORR was met and PFS is also encouraging. The addition of dB to temozolomide-based chemotherapy shows promising activity in patients with RR-HR-NB. Clinical trial information: NCT02308527.

High grade gliomas (HGG) have a dismal prognosis with survival rates of 15-35%. Approximately 10-12% of pediatric HGG occur in young children and their molecular biology and clinical outcomes differ from those arising at older ages. We report on four children aged5 years newly diagnosed with non-brainstem HGG between 2011 and 2018 who were treated with surgery and BBSFOP chemotherapy. Two died of tumor progression. The other two are still alive without radiotherapy at 3.8 and 3.9 years from diagnosis: one of whom remains disease-free off treatment; and the other one, whose tumor harbored a KCTD16:NTRK2 fusion, went on to receive larotrectinib. Additionally we review the general management, outcomes and latest updates in molecular biology and targeted therapies for young children with HGG. Infant gliomas can be stratified in molecular subgroups with clinically actionable oncogenic drivers. Chemotherapy-based strategies can avoid or delay the need for radiotherapy in young children with HGG. Harnessing the potential of NTRK, ALK, ROS1 and MET inhibitors offers the opportunity to optimize the therapeutic armamentarium to improve current outcomes for these children.

Paediatric high grade glioma and diffuse midline glioma (including DIPG) are comprised of multiple biological and clinical subgroups, the majority of which urgently require novel therapies. Patient-derivedin vitroprimary cell cultures represent potentially useful tools for mechanistic and preclinical investigation based upon their retention of key features of tumour subgroups under experimental conditions amenable to high-throughput approaches. We present 17 novel primary cultures derived from patients in London, Dublin and Belfast, and together with cultures established or shared from Barcelona, Brisbane, Rome and Stanford, assembled a panel of 52 models under 2D (laminin matrix) and/or 3D (neurospheres) conditions, fully credentialed by phenotypic and molecular comparison to the original tumour sample (methylation BeadArray, panel/exome sequencing, RNAseq). In screening a subset of these against a panel of ~400 approved chemotherapeutics and small molecules, we identified specific dependencies associated with tumour subgroups and/or specific molecular markers. These includedMYCN-amplified cells and ATM/DNA-PK inhibitors, and DIPGs withPPM1Dactivating truncating mutations and inhibitors of MDM2 or PARP1. Specific mutations inPDGFRAwere found to confer sensitivity to a range of RTK inhibitors, though not all such mutations conferred sensitivity to targeted agents. Notably, dual PDGFRA/FGFR and downstream pathway MEK inhibitors showed profound effects against both PDGFRA-sensitising mutant and FGFR1-dependent non-brainstem pHGG and DIPG. In total, 85% cells were found to have at least one drug screening hit in short term assays linked to the underlying biology of the patient’s tumour, providing a rational approach for individualised clinical translation.

Background Hepatic sinusoidal obstruction syndrome (SOS) is a serious complication of autologous stem cell transplant (ASCT) in children with historically high mortality rates. Defibrotide has shown proven benefit in its treatment and may have a modest role in prevention. We report our experience with SOS in children undergoing autologous transplant. Methods Case records of 82 consecutive patients undergoing ASCT following high-dose chemotherapy between 2010 and 2017 were reviewed. Defibrotide was used for treatment of all with SOS and prophylactically in patients receiving busulfan-based conditioning until 2014. Results Fourteen of the 82 children (17%) were diagnosed with SOS. The incidence was higher in those receiving busulfan-based conditioning (13/42 vs 1/40, P = 0.008). Mean (±SD) time to diagnosis of SOS was 19 (±5.6) days following stem cell rescue. Bilirubin levels and ultrasound were normal in 7/14 and 3/14 patients. Coagulopathy was noted in 10/14; one child developed multiorgan involvement. Nine children had mild SOS, whereas two and three had moderate and severe SOS, respectively. Intensive care was required for four of five non-mild cases. Patients with SOS had significantly delayed platelet recovery, higher transfusion requirement, and longer hospital stay. Unavailability of defibrotide prophylaxis for 17/42 receiving busulfan did not change the incidence of SOS (7/25 with defibrotide vs 6 /17 without defibrotide, P = 0.74). There was no significant difference in the severity of SOS between these groups. Conclusion Hepatic SOS was more commonly seen in children receiving busulfan-based conditioning. Stopping the use of prophylactic defibrotide did not increase incidence or severity of SOS. Overall outcome was excellent with supportive care and timely treatment with defibrotide.

The failure to develop effective therapies for paediatric glioblastoma (pGBM) and diffuse intrinsic pontine glioma (DIPG) is in part due to their intrinsic heterogeneity. We aimed to quantitatively map assess the extent to which this was present in these tumours through subclonal genomic analyses, and to determine whether distinct tumour subpopulations may interact to promote tumorigenesis by generating novel subclonal patient-derived models in vitro and in vivo. Analysis of 142 sequenced cases revealed multiple tumour subclones, spatially and temporally co-existing in a stable manner as observed by multiple sampling strategies. We isolated genotypically and phenotypically distinct subpopulations which we propose co-operate to enhance tumorigenicity and resistance to therapy. Inactivating mutations in the H4K20 histone methyltransferase KMT5B (SUV420H1), present in

Introduction Desmoplastic small round cell tumours are rare, aggressive neoplastic tumours with a predisposition to affect the intra-abdominal cavity. Hyperthermic intraperitoneal chemotherapy (HIPEC) is a mode of delivering concentrated, heated chemotherapy directly into the abdominal cavity. This has been used previously in adult patients and we describe the first UK case of HIPEC for a desmoplastic small round cell tumour in a child. Case summary An 8 year old girl (AB) was diagnosed with desmoplastic small round cell tumours after presenting with a ten day history of constipation and abdominal discomfort. Initial assessment revealed a large palpable abdominal mass. An ultrasound demonstrated a large heterogenous mass with central cystic necrosis. Two additional lesions were noted within the liver in addition to a 22 mm omental deposit. Bone marrow aspirates and biopsies confirmed the diagnosis. AB had eleven rounds of chemotherapy in total with the most recent cycle completing in April 2018. A follow-up MRI showed a residual pelvic tumour of 3.1cm indenting the superior wall of the bladder. After MDT discussion the decision was made to proceed with macroscopic resection of tumours followed by cisplatin HIPEC. Intraoperatively, lesions were noted in the following sites: omentum; pouch of Douglas; left ovary and fimbrae; jejunum and diaphragm. After resection was completed, cisplatin heated to 41 degrees C was washed over the peritoneum. This was tolerated with noradrenaline used to optimise haemodynamics. Postoperatively she was admitted to PICU for monitoring and observation. During PICU admission AB remained clinically stable. Active interventions included GCSF, thoracic epidural and PCA for analgesia, electrolyte optimisation and hyperhydration. AB was ready for discharge from PICU after 4 days. Conclusion We described the first case of HIPEC being used in paediatrics in the UK. This technique has been well tolerated and could be considered in other cases of intra-abdominal neoplasia with metastases.

We describe our experience in managing nine children and adolescents with rhabdomyosarcoma (RMS) and peritoneal involvement. The radiological pattern of peritoneal involvement was diverse from only ascites to solid peritoneal mass/omental caking. Treatment included systemic chemotherapy in all, surgery in three, and radiotherapy in eight. Two patients with presumed nonmalignant ascites, no solid peritoneal metastasis, nonalveolar histology, near-complete resection of residual disease, and radiotherapy survived long term. One patient has just completed treatment, and the remaining six relapsed/progressed at the time of reporting. Five of six patients died after a median of 5 (3-7) months from relapse despite second-line chemotherapy.

We retrospectively reviewed a paediatric intensive care unit database that supports a tertiary oncology service to explore safety and outcome of tracheostomy in oncology patients over a 12-year period and reviewed literature. A total of 895 patients were admitted with a haematological or a solid tumour malignancy of which 222 were ventilated. Six of 222 (2.7%) ventilated children were tracheostomised. Four of six children tracheostomised for ventilatory support received intensive chemotherapy complicated by neutropenia and thrombocytopenia. There was no significant tracheostomy-related complication. Tracheostomy improved patient comfort, reduced sedative requirement, and may have helped recovery. Tracheostomy should be considered early in selected children with haemato-oncological diagnoses requiring prolonged ventilation.

Background: For children with cancer, the clinical integration of precision medicine to enable predictive biomarkerebased therapeutic stratification is urgently needed. Methods: We have developed a hybrid-capture next-generation sequencing (NGS) panel, specifically designed to detect genetic alterations in paediatric solid tumours, which gives reliable results from as little as 50 ng of DNA extracted from formalin-fixed paraffin-embedded (FFPE) tissue. In this study, we offered an NGS panel, with clinical reporting via a molecular tumour board for children with solid tumours. Furthermore, for a cohort of 12 patients, we used a circulating tumour DNA (ctDNA)especific panel to sequence ctDNA from matched plasma samples and compared plasma and tumour findings. Results: A total of 255 samples were submitted from 223 patients for the NGS panel. Using FFPE tissue, 82% of all submitted samples passed quality control for clinical reporting. At least one genetic alteration was detected in 70% of sequenced samples. The overall detection rate of clinically actionable alterations, defined by modified OncoKB criteria, for all sequenced samples was 51%. A total of 8 patients were sequenced at different stages of treatment. In 6 of these, there were differences in the genetic alterations detected between time points. Sequencing of matched ctDNA in a cohort of extracranial paediatric solid tumours also identified a high detection rate of somatic alterations in plasma. Conclusion: We demonstrate that tailored clinical molecular profiling of both tumour DNA and plasma-derived ctDNA is feasible for children with solid tumours. Furthermore, we show that a targeted NGS panelebased approach can identify actionable genetic alterations in a high proportion of patients., This work was supported by Christopher’s Smile, the National Institute of Health Research (NIHR) Royal Marsden Biomedical Research Centre (BRC), Children With Cancer UK (CWC UK) Cancer Research UK (CRUK), Abbie’s Fund, the Rosetree Trust and the KiCa Fund, managed by the King Baudouin Foundation. Roche provided support for Panel development. T.S.J. is funded by The Brain Tumour Charity, CWC UK, GOSH Children’s Charity (GOSH CC), CRUK, the Olivia Hodson Cancer Fund and the NIHR GOSH BRC. J.A. and D.H. are funded by the GOSH CC and NIHR GOSH BRC. L.V.M. is funded by the Oak Foundation. The authors thank all participants and the CCLG Tissue Bank for access to samples and contributing CCLG Centres, including members of the ECMC Paediatric network. The CCLG Tissue Bank is funded by Cancer Research UK and CCLG

Objectives: Diffusion-weighted magnetic resonance imaging (DW-MRI) offers potential to monitor response and predict survival in high-grade gliomas (HGG) and diffuse intrinsic pontine gliomas (DIPG). We hypothesized that post-radiotherapy DW-MRI may provide prognostic imaging biomarkers in children and young adults with these tumors. Methods: Patients aged ≤21 years diagnosed between 2005 and 2012 were eligible. The tumor median apparent diffusion coefficient (ADC) and its 5th percentile (C5-ADC) were determined at the first post-radiotherapy scan and at the time of radiological progression. DW-MRI parameters were correlated with survival endpoints, temozolomide use and pseudoprogression, when it occurred. Results: Out of 40 patients (20 HGG, 20 DIPG), 23 had evaluable DW-MRI post-radiotherapy and 25 at radiological progression. There were 6 episodes of pseudoprogression. Hazard ratios (95%CI) for progression-free survival were 0.998 (0.993–1.003) for median ADC and 1.003 (0.996–1.010) for C5-ADC. Hazard ratios (95%CI) for overall survival were 1.0009 (0.996–1.006) for median ADC and 0.998 (0.992–1.004) for C5-ADC. Post-radiotherapy median and C5-ADC values were not significantly different between patients treated with radiotherapy alone versus radiotherapy/temozolomide. The median and C5-ADC values were not significantly different at the time of pseudoprogression compared to those at tumor progression. Conclusions: Post-radiotherapy median ADC and C5-ADC were not prognostic, nor able to differentiate radiosensitization with temozolomide or occurrence of pseudoprogression in this cohort of HGG and DIPG patients. Further exploration of alternative DW parameters, study timepoints or data modeling may contribute to the development of prognostic/predictive imaging biomarkers for children and young adults with HGG or DIPG.

10501 Background: BEACON is a randomized phase 2 trial assessing whether inhibiting angiogenesis with bevacizumab adds to the activity of chemotherapy and evaluating chemotherapy regimens for children with RR-HRNB. Methods: Patients with RR-HRNB were eligible. There were randomizations (rand), in a 3x2 factorial design, to: T, IT or topotecan (To)-T, +/- B. Toxicity and response were reported in 2019 (ASCO, ESMO). Survival outcomes – progression-free (PFS) and overall (OS) – for the I and B rands are reported here (To rand is still open). The B rand used a relaxed alpha (1-sided p=0.2) for PFS as its phase 2 success criterion; the I rand was Bayesian. Cox model hazard ratios (HR)

Background The European Neuroblastoma Study Group 5 (ENSG5) trial showed that time-intensive "rapid" induction chemotherapy (COJEC) was superior to "standard" 3-weekly chemotherapy for children with high-risk metastatic neuroblastoma. Long-term outcomes of the ENSG5 trial were analysed. Procedure Patients with metastatic neuroblastoma aged ≥12 months were randomly assigned to "standard" or "rapid" induction, receiving the same chemotherapy drugs and doses. Event-free survival (EFS) and overall survival (OS) were analysed and prognostic factors evaluated. Amongst patients surviving >5 years, a population of children with persistent metastatic disease after the end of treatment was identified and described. Results Ten-year EFS was 18.2% (95% confidence interval: 12.2-25.2) for the "standard" arm and 26.8% (19.5-34.7) for the "rapid" arm (hazard ratio [HR] 0.85, P = 0.28). Ten-year OS for the "standard" arm was 19.7% (13.4-26.8) and 28.3% (20.8-36.2) for the "rapid arm" (HR 0.83, P = 0.19). There was a trend for worse EFS and OS for patients having MYCN amplification (HR 1.37 and 1.40, respectively) and those with partial and mixed response to induction (HR 1.69 and 1.75 for EFS and 1.66 and 2.00 for OS, respectively). Among 69 patients who survived >5 years, six had persistent metastatic disease after the end of treatment. Conclusion The benefit of the "rapid" induction regimen seems to be maintained in the long term, although the small number of survivors could justify the lack of statistical significance. MYCN amplification and poor metastatic response to induction could be associated with worse outcomes. A small group of patients with persistent metastatic disease that survived long term has been described.

BACKGROUND. Molecular alterations: point mutations, amplifications and deletions give cells the ability to bypass therapeutic approaches. Molecular profiling facilitates access to personalised strategies to treat patients harbouring such alterations. METHODS. A Next Generation Sequencing (NGS) panel comprising 78 genes (version1) or 92 genes (version2) has been piloted in the UK since March 2016, using formalin-fixed paraffin embedded tissue of children and young adults with solid tumours, including central nervous system (CNS) tumours. RESULTS. Of 156 cases profiled, patients with primary CNS tumours constituted the largest subset (59 patients; 38%). Main diagnoses included high grade astrocytoma (22 patients; 37%), ependymoma (8 patients; 14%) and medulloblastoma (8 patients 14%). In 66% of sequenced samples the panel detected at least one genetic alteration and a total of 54 distinct genetic alterations were uncovered; most frequently in TP53 (16; 14%), H3F3A (8; 7%) and ATRX (7; 6%). In 2 cases (3%), identification of therapeutic targets (BRAF mutations) led to treatment with a combination of BRAF and MEK inhibitors via compassionate access programmes in young adults who had exhausted standard treatment options and were beyond the age eligibility cut-off for enrolment in the ongoing paediatric BRAF/MEK inhibitor studies. CONCLUSIONS. Molecular profiling is increasingly being integrated into standard of care for patients with CNS tumours. However, the finding of truly actionable mutations with available targeted therapies remains limited in clinical practice. More efficient approaches to implement personalised medicine strategies for CNS tumour patients are still needed as is currently illustrated by initiatives such as ESMART (NCT02813135).

BACKGROUND: Bithalamic gliomas (BG) are rare brain tumours typically with a dismal prognosis, irrespective of histological grading. Limited information is available on survival outcomes for children and adolescents with BG. METHODS: Review of patients aged ≤18 years with clinico-radiological diagnosis of BG between 1995-2017 at our institution. Clinical, radiological, histological and outcome data were collected. Log-rank test was used for survival analyses. RESULTS: Sixteen eligible patients were identified (male-female ratio 1:1). Median age was 9.1 years (range, 0.9-17.9). Twelve (75%) patients had hydrocephalus at initial presentation. Fourteen (88%) underwent surgery (debulking: 1; biopsy: 13). Histology was consistent with low grade glioma (LGG; n=6), high grade glioma (HGG; n=6) or inconclusive (n=2). Methylation profiling was available in 5 cases: K27M-mutant (n=2) and histone 3 wild-type (n=3). One patient died prior to initiation of treatment from intratumoural haemorrhage. Thirteen (81%) patients received radiotherapy: alone (n=2), combined with temozolomide (n=8) or followed by other chemotherapy regimens (n=3). Two patients who were not irradiated received vincristine/carboplatin. Median progression-free (PFS) and overall survival (OS) for the whole cohort were 8.3 months (95%CI, 2.3-14.3) and 13.8 months (95%CI, 10.5-17.1), respectively. There was no difference in median PFS or OS between patients diagnosed as LGG or HGG (p=0.769 and p=0.512, respectively). CONCLUSIONS: Our data is consistent with prior reports showing poor survival of patients with BG, regardless of histological grade. Novel approaches based on the underlying biology of these tumours are desperately needed for this subset of patients.

BACKGROUND: Before this study started, the standard postoperative chemotherapy regimen for stage II-III Wilms' tumour pretreated with chemotherapy was to include doxorubicin. However, avoidance of doxorubicin-related cardiotoxicity effects is important to improve long-term outcomes for childhood cancers that have excellent prognosis. We aimed to assess whether doxorubicin can be omitted safely from chemotherapy for stage II-III, histological intermediate-risk Wilms' tumour when a newly defined high-risk blastemal subtype was excluded from randomisation.METHODS: For this international, multicentre, open-label, non-inferiority, phase 3, randomised SIOP WT 2001 trial, we recruited children aged 6 months to 18 years at the time of diagnosis of a primary renal tumour from 251 hospitals in 26 countries who had received 4 weeks of preoperative chemotherapy with vincristine and actinomycin D. Children with stage II-III intermediate-risk Wilms' tumours assessed after delayed nephrectomy were randomly assigned (1:1) by a minimisation technique to receive vincristine 1·5 mg/m(2) at weeks 1-8, 11, 12, 14, 15, 17, 18, 20, 21, 23, 24, 26, and 27, plus actinomycin D 45 μg/kg every 3 weeks from week 2, either with five doses of doxorubicin 50 mg/m(2) given every 6 weeks from week 2 (standard treatment) or without doxorubicin (experimental treatment). The primary endpoint was non-inferiority of event-free survival at 2 years, analysed by intention to treat and a margin of 10%. Assessment of safety and adverse events included systematic monitoring of hepatic toxicity and cardiotoxicity. This trial is registered with EudraCT, number 2007-004591-39, and is closed to new participants.FINDINGS: Between Nov 1, 2001, and Dec 16, 2009, we recruited 583 patients, 341 with stage II and 242 with stage III tumours, and randomly assigned 291 children to treatment including doxorubicin, and 292 children to treatment excluding doxorubicin. Median follow-up was 60·8 months (IQR 40·8-79·8). 2 year event-free survival was 92·6% (95% CI 89·6-95·7) for treatment including doxorubicin and 88·2% (84·5-92·1) for treatment excluding doxorubicin, a difference of 4·4% (95% CI 0·4-9·3) that did not exceed the predefined 10% margin. 5 year overall survival was 96·5% (94·3-98·8) for treatment including doxorubicin and 95·8% (93·3-98·4) for treatment excluding doxorubicin. Four children died from a treatment-related toxic effect; one (INTERPRETATION: Doxorubicin does not need to be included in treatment of stage II-III intermediate risk Wilms' tumour when the histological response to preoperative chemotherapy is incorporated into the risk stratification.FUNDING: See Acknowledgments for funders.

Paediatric high grade glioma and diffuse midline glioma (including DIPG) are comprised of multiple biological and clinical subgroups, the majority of which urgently require novel therapies. Patient-derived in vitro primary cell cultures represent potentially useful tools for mechanistic and preclinical investigation based upon their retention of key features of tumour subgroups under experimental conditions amenable to high-throughput approaches. We established 21 novel primary cultures derived from patients in London, Dublin and Rome, and together with cultures shared from Barcelona, Brisbane and Stanford we assembled a panel of 42 models under 2D (laminin matrix) and/or 3D (neurospheres) conditions, fully credentialed by phenotypic and molecular comparison to the original tumour sample (methylation BeadArray, panel/exome sequencing, RNAseq). Screening against a panel of ~400 approved chemotherapeutics and small molecules, we identified specific dependencies associated with tumour subgroups and/or specific molecular markers. Examples included cells with sensitizing (HSJD-GBM-001, PDGFRA_A385ins; HSJD-DIPG-008, PDGFRA_D846N) or resistance (HSJD-GBM-002, PDGFRA_D842Y) mutations to a range of PDGFRA inhibitors, and individual models showing profound sensitivity to multiple FGFR (QCTB-R006) or EGFR (HSJD-DIPG-012) inhibitors. H3.3G34R cells were differentially sensitive to agents targeting the proteasome, whilst H3.3 K27M cells were responsive to crizotinib. MAPK-dysregulated PXA-like cultures differentially responded to inhibitors of upstream signalling via PKC and CK2. In total, 85% cells were found to have at least one drug screening hit in short term assays linked to the underlying biology of the patient’s tumour, providing a rational approach for individualised clinical translation.

Background BEACON-Neuroblastoma is a randomized phase II trial to assess the activity of backbone chemotherapy regimens for children with RR-HRNB and to determine if inhibiting angiogenesis with bevacizumab adds to the activity of this chemotherapy. Methods Patients aged 1-21 years with RR-HRNB with adequate organ function and performance status were randomized in a factorial design to: temozolomide (T) versus irinotecan-temozolomide (IT) or topotecan-temozolomide (TTo), with or without bevacizumab (Bev). The Bev randomization (Bev versus no-Bev) had two parts: Part 1 had a 2-stage Minimax Jung design with overall response (OR) as primary endpoint. Part 1 success criterion was ≥4 more responses in Bev arm compared to no-Bev. Protocol was amended to incorporate Part 2 (40 additional patients), including progression-free survival (PFS) as co-primary endpoint. OR was defined as complete or partial response (CR, PR) by RECIST (INRC for patients without measurable disease). OR and toxicity data for the Bev randomization is reported. Results For Part 1 (n=106), 17 of 52 pts on Bev had responses [33%] and 8 of 54 pts on no-Bev had responses [15%]. The trial success criterion for the primary endpoint of ORR was met. Including Part 2 (total n=154), 21 of 77 patients on Bev (7CR, 14PR) and 13 of 77 patients on no-Bev (1CR, 12PR) had responses. Response data was not available for 6 patients; 13 patients not assessable for response (discontinued before first assessment) were considered to be non-responders. OR rate [with 90% CI] was 27% [18-35%] for patients on Bev and 17% [10-24%] for patients on no-Bev. In subgroup analysis, there was no interaction between T, IT and TTo and treatment with/without Bev (heterogeneity test, p=0.8). 86% Bev and 58% no-Bev patients had grade ≥3 toxicities as per CTCAE v4.0; the most common grade ≥3 toxicities associated with Bev were platelet count decrease and anemia. Conclusions Bev reached the Phase II success criterion for OR within Part 1 of the trial when added to temozolomide-based chemotherapy in RR-HRNB. The toxicity profile for Bev is acceptable. Longer follow-up is needed before assessing whether it impacts PFS or overall survival. Clinical trial identification NCT02308527; EudraCT: 2012-000072-42. Legal entity responsible for the study University of Birmingham. Funding Roche. Disclosure L. Moreno: Honoraria (self), Travel / Accommodation / Expenses: Celgene; Honoraria (self), Advisory / Consultancy: Novartis; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Roche; Advisory / Consultancy: Bayer; Advisory / Consultancy, Travel / Accommodation / Expenses: Amgen; Advisory / Consultancy, Travel / Accommodation / Expenses: Mundipharma; Licensing / Royalties, I am member of Siopen Executive Committee, Siopen receives royalties for the sales of dinutuximab beta: Eusa Pharma. D. Valteau-Couanet: Advisory / Consultancy, Travel / Accommodation / Expenses, Licensing / Royalties, Member of Siopen Executive Committee, SIOPEN receives royalties for the sales of dinutuximab beta: Eusa Pharma; Research grant / Funding (institution): Ophelia; Travel / Accommodation / Expenses: Jazz Pharma. K. Nysom: Advisory / Consultancy: Bayer. N. Gerber: Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): Loxo; Research grant / Funding (institution): Novartis. R. Ladenstein: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses, Licensing / Royalties, Royalties to the institution for dinutuximab beta: Apeiron; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses, Licensing / Royalties, Royalties to the institution for dinutuximab beta: Eusa Pharma; Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim. A.D. Pearson: Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy: Genentech. All other authors have declared no conflicts of interest.

10001 Background: BEACON-Neuroblastoma is a randomized Phase II trial to assess the activity of backbone chemotherapy regimens for children with RR-HRNB and to determine if inhibiting angiogenesis with bevacizumab adds to the activity of this chemotherapy. Methods: Patients aged 1-21 years with RR-HRNB with adequate organ function and performance status were randomized in a 2x2 factorial design to: temozolomide (T) versus irinotecan-temozolomide (IT), with or without bevacizumab. Here we report the results of the irinotecan randomization (T vs. IT), which had a probability-based Bayesian design. Primary endpoint was best overall response (complete or partial) during the first 6 courses, by RECIST for measurable disease patients and International Neuroblastoma Response Criteria for evaluable disease patients for which overall response rate (ORR) was calculated. Results: From 2013 to 2018, 61 patients were randomized to treatment with T and 60 to IT. Median age was 5.8 years. 85 and 36 had measurable and evaluable disease respectively; 55 and 66 had refractory and relapsed disease; 22 had MYCN amplification. Baseline characteristics were balanced between the arms. Response data was not yet available for 2 patients on T. Response was not assessable for 17 patients (did not have treatment or stopped early) who were considered non-responders. The ORR was 24% for T and 17% for IT (risk ratio (RR) = 0.70, 95% credible interval 0.32 to 1.44). The probability that the RR for ORR was >1.0 was 17%, meaning that IT did not show greater activity than T. There was no interaction between treatment with/without bevacizumab (heterogeneity test, p=0.7). 27 (44%) T and 35 (58%) IT patients had grade ≥3 toxicities as per CTCAE v4.0. Diarrhea occurred in no patients on T and 7 (12%) on IT; hematological toxicities included anemia (6 T, 4 IT), neutropenia (14 T, 22 IT) and thrombocytopenia (14 T, 11 IT). Conclusions: Irinotecan does not improve the response rate when added to temozolomide in RR-HRNB, but does increase diarrhea. Longer follow-up is needed before assessing whether it impacts progression-free or overall survival. Number of responses by treatment arm. Clinical trial information: NCT02308527. [Table: see text]

Background Therapy for high-risk neuroblastoma is intensive and multimodal, and significant long-term adverse effects have been described. The aim of this study was to identify the nature and severity of late complications of metastatic neuroblastoma survivors included in the ENSG5 clinical trial. Procedure The trial protocol included induction chemotherapy (randomized Standard OPEC/OJEC vs. Rapid COJEC), surgery of primary tumor and high-dose melphalan with stem cell rescue. Two hundred and sixty-two children were randomized, 69 survived >5 years, and 57 were analyzed. Data were obtained from the ENSG5 trial database and verified with questionnaires sent to participating centers. Results Median follow-up was 12.9 (6.916.5) years. No differences were found in late toxicities between treatment arms. Twenty-eight children (49.1%) developed hearing loss. Nine patients (15.8%) developed glomerular filtration rate

ObjectiveIodine-131-labelled meta-iodobenzylguanidine (I-131-mIBG) therapy is an established treatment modality for relapsed/refractory neuroblastoma, most frequently administered according to fixed or weight-based criteria. We evaluate response and toxicity following a dosimetry-based, individualized approach.Materials and methodsA review of 44 treatments in 25 patients treated with I-131-mIBG therapy was performed. Patients received I-131-mIBG therapy following relapse (n=9), in refractory disease (n=12), or with surgically unresectable disease despite conventional treatment (n=4). Treatment schedule (including mIBG dose and number of administrations) was individualized according to the clinical status of the patient and dosimetry data from either a tracer study or previous administrations. Three-dimensional tumour dosimetry was also performed for eight patients.ResultsThe mean administered activity was 110897222MBq and the mean whole-body dose for a single administration was 1.79 +/- 0.57Gy. Tumour-absorbed doses varied considerably (3.70 +/- 3.37mGy/MBq). CTCAE grade 3/4 neutropenia was documented following 82% treatments and grade 3/4 thrombocytopenia following 71% treatments. Further acute toxicity was found in 49% of patients. All acute toxicities resolved with appropriate therapy. The overall response rate was 58% (complete or partial response), with a further 29% of patients having stable disease.ConclusionA highly personalized approach combining patient-specific dosimetry and clinical judgement enables delivery of high activities that can be tolerated by patients, particularly with stem cell support. We report excellent response rates and acceptable toxicity following individualized I-131-mIBG therapy. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

Background Radiotherapy remains a widely accepted postoperative treatment modality for unresectable or recurrent low-grade glioma (LGG). However, there is increasing evidence to suggest that chemotherapy can delay and may obviate the need for radiotherapy in progressive/recurrent LGG. The majority of the published experience is in children with hypothalamic/optic chiasmatic lesions and little information is available regarding its use in LGG of the brainstem. Procedure We describe clinical characteristics and course of children with LGG of the brainstem who received carboplatin-based chemotherapy in two institutions over 10 years (1996–2006). This was a retrospective review of consecutively treated children with LGG of the brainstem (midbrain, pons, medulla, and upper cervical cord). Vincristine and carboplatin were first-line chemotherapy regimen used in all patients. Results In this series, there were 16 children (9 males) with median age at diagnosis of 4.2 years (range 0.5–8). Eight children were treated at diagnosis while the remaining eight received chemotherapy after either radiological progression or clinical deterioration. After a median follow-up of 57 months (range 20–136) from initiation of chemotherapy all children are alive and 11 remain progression free (1 complete response, 8 with partial response + minor response, and 2 stable diseases). Conclusions The efficacy of this chemotherapy regimen in this series supports its role in children with progressive unresectable LGG of brainstem. Pediatr Blood Cancer. 2010;55:471–477. © 2010 Wiley-Liss, Inc.

Pseudoprogression (PsP) is a treatment-related phenomenon which hinders response interpretation. Its prevalence and clinical impact have not been evaluated in children/adolescents. We assessed the characteristics, risk factors and prognosis of PsP in children/adolescents and young-adults diagnosed with non-brainstem high grade gliomas (HGG) and diffuse intrinsic pontine gliomas (DIPG). Patients aged 1-21 years diagnosed with HGG or DIPG between 1995 and 2012 who had completed radiotherapy were eligible. PsP was assessed according to study-specific criteria and correlated with first-line treatment, molecular biomarkers and survival. Ninety-one patients (47 HGG, 44 DIPG) were evaluable. Median age: 10 years (range, 2-20). Eleven episodes of PsP were observed in 10 patients (4 HGG, 6 DIPG). Rates of PsP: 8.5 % (HGG); 13.6 % (DIPG). Two episodes of PsP were based on clinical findings alone; nine episodes had concurrent radiological changes: increased size of lesions (n = 5), new focal enhancement (n = 4). Temozolomide, MGMT methylation or H3F3A mutations were not found to be associated with increased occurrence of PsP. For HGG, 1-year progression-free survival (PFS) was 41.9 % no-PsP versus 100 % PsP (p = 0.041); differences in 1-year overall survival (OS) were not significant. For DIPG, differences in 1-year PFS and OS were not statistically significant. Hazard ratio (95 %CI) of PsP for OS was 0.551 (0.168-1.803; p = 0.325) in HGG; and 0.308 (0.107-0.882; p = 0.028) in DIPG. PsP occurred in both pediatric HGG and DIPG patients at a comparable rate to adult HGG. PsP was associated with improved 1-yr PFS in HGG patients. PsP had a protective effect upon OS in DIPG patients.

Children with high-risk neuroblastoma who fail to achieve adequate metastatic response after induction chemotherapy have dismal outcome and new therapeutic strategies are needed. However, timing of introduction of novel agents still remains under discussion. Given an increase in number of phase I-II studies of molecularly targeted drugs in neuroblastoma, it is crucial to determine, as early as possible, which patients may be suitable candidates for new therapeutic strategies. This single-center retrospective analysis of patients with high-risk neuroblastoma showed that the addition of conventional chemotherapy improved the quality of metastatic response only for the group of patients with partial response. It is therefore proposed to develop stratification criteria for those patients very unlikely to benefit from a plethora of additional lines of treatment, but might benefit from introduction of novel agents.

Evaluation of P-31 high-resolution magic angle spinning of intact tissue samples The first detailed evaluation is presented of high-resolution P-31 MRS using magic angle spinning (MAS) of intact tissue samples and comparison with the conventional method of studying tissue extracts. The main motivation is that MAS leaves the sample intact at the end of the study for histopathological evaluation. While MAS of tissue samples has previously been demonstrated for H-1 MRS P-31 MRS is better suited to study of the phospholipid metabolites of importance in cancer. Samples of rhabdomyosarcoma and RIF-1 experimental tumours were maintained at 4 degrees C, spun at 3 kHz and measured in 28-min acquisitions at 11.7 and 14T. Metabolite stability was evaluated using four sequential 28-min acquisitions. High-resolution MRS was performed on extracts of the same tissue samples. P-31 HR-MAS yielded well-resolved high-resolution spectra, showing peaks from phosphoethanolamine (PE), phosphocholine (PC), inorganic phosphate, glycerophosphoethanolamine and glycerophosphocholine, with linewidths in the range 3-20 Hz. In tumour samples there was no significant change in peak areas over a 2-h period, while peaks sensitive to pH (inorganic phosphate, PE and PC) showed a small change in chemical shift, corresponding to a change of 0.13 +/- 0.06 pH units. Tissue metabolite concentrations showed good agreement with concentrations measured from extracts of the same pieces of tissue. For calculation of metabolite concentrations, the measurement of a reference compound in a separate measurement is more robust than using the signal from a reference compound in the rotor with the sample. Compared with performing tissue extracts, use of MAS of intact tissue samples requires less preparation, is quicker and permits the same sample to be used for subsequent histopathology. The methodology has particular application in studying phospholipid metabolism in cancer and in monitoring tumour response to treatment, where concentrations of phospholipid-related metabolites are found to alter following response to a wide range of anti-cancer therapies. Copyright (C) 2006 John Wiley & Sons, Ltd.

Early phase trials are crucial in developing new therapies for poor prognosis childhood malignancies. Outcomes and toxicities of children treated on phase I/II trials at the Royal Marsden, one of the largest pediatric oncology early phase trial units in Europe, were examined to provide a baseline dataset and generate hypotheses. All patients recruited over a 10-year period to December 2011 were included. Variables including baseline characteristics, time on study, survival, toxicities, and admissions were collected. Seventy-two patients were recruited to 21 trials (5 phase I, 16 phase II; overall 12 involved molecularly targeted agents). Median age at consent was 12.4 years. Dose-limiting toxicities were rare in phase I trial participants (2 of 15 evaluable patients, 13%); the most common reason for leaving trials was disease progression (76%), rather than drug toxicity (1.7%). Median time on trial was 1.3 months (phase I patients) and 3.3 months (phase II). Early phase trials in children are safe and unexpected toxic side effects are infrequent. Patients and their families are willing to travel to access novel therapies, although the overall prognosis for these individuals is poor. Continued expansion of the portfolio is needed ultimately to improve the outcomes for those with resistant disease.

From 1984 to 1996, 31 consecutive children without sibling donors, aged 5-19 years (median 8) with acute lymphoblastic leukaemia (ALL) in second complete remission (CR), received unpurged autologous bone marrow transplantation (ABMT) after melphalan and single fraction total body irradiation (TBI). ABMT was performed using fresh unmanipulated marrow harvested after standard reinduction and consolidation therapy 2-11 months (median 5) after relapse. With a median survival of 2.9 years the probability of survival for all patients in continuing second CR was 45.1% (95% CI, 24%-62%) after 5 years. Regimen-related and non-leukaemia mortality was 7% (95% CI, 2%-26%). The longest time to second relapse from ABMT was 3.1 years. Pituitary and gonadal dysfunction requiring hormonal replacement therapy occurred in the majority of long-term survivors. Twelve patients developed cataracts. ABMT with melphalan/single fraction TBI has proved an effective anti-leukaemia treatment with low regimen-related mortality but significant long-term morbidity. The current approach of allogeneic BMT from an unrelated donor when no sibling donor is available, following conditioning with cyclophosphamide/ fractionated TBI has resulted in a reduced relapse rate and improved short-term overall survival in the treatment of relapsed childhood ALL. However, long-term results are awaited.

Life-threatening toxicity is often a contraindication for cytotoxic treatment. Many childhood malignancies have good outcomes with appropriate aggressive chemotherapy. It is not easy to decide whether to subject a child with a good prognostic tumor to a drug that has previously caused significant toxicity. One such situation is documented in this report.

Summary Background: In the past, the results of the treatment of nonHodgkin's lymphomas (NHL) in Indian children have been poor, due to inadequate chemotherapy and poor supportive care. In an attempt to overcome these problems, we conducted a clinical trial in Bombay with a new protocol, MCP842. Patients and methods: Seventy-four previously untreated patients < 25 years were entered on study at the Tata Memorial Hospital, Bombay. Patients with lymphoblastic lymphoma (LL) (38) without bone marrow involvement and all patients with small noncleaved cell lymphoma (SNCL) (18) and large cell lymphoma (LCL) (18) were eligible. Treatment consisted of alternating cycles of two regimens, A and B. Patients with St. Jude stages I and II received six cycles, and those with stages III or IV received eight cycles. A cycles included cyclophosphamide, adriamycin, vincristine and ara-C, and B cycles, etoposide, vincristine, methotrexate, ifosfamide and mesna. Results: Complete response was achieved in 67 (91%) of patients. Event free survival (EFS) for all patients was 58%; 68% for patients with SNCL and LCL combined, and 48% for patients with LL. There was no significant difference in EFS by histology (LL versus non-LL), or stage. There were nine (12%) toxic deaths, two during induction and seven in patients in remission; six occurred in patients with LL. Conclusions: These results are better than past results in Bombay. Unlike earlier CCG protocols, in which the outcome between patients with LL and non-LL differed, this was not so in MCP842. Even patients with extensive LL without bone marrow disease received only eight cycles of therapy, suggesting that short duration therapy is curative in as many as half of such patients - an important observation in a country with limited resources.

Wilms tumor (WT) with diffuse anaplasia has an unfavorable prognosis and is often (>70%) associated with mutations in the TP53 gene. Although most WTs are unilateral, 5–10% are bilateral, and they are almost always present with nephrogenic rests. The latter are considered a precursor of WT. Two cases of bilateral WTs with nephroblastomatosis, in which anaplastic changes were detected over a period of time, were analyzed using clinical, radiological, histopathological, and molecular-genetic data. TP53 was analyzed by direct sequencing of its full coding sequence and intron-exon boundaries in 11 fragments. DNA was extracted from paraffin-embedded or frozen specimens. High-resolution genomic copy number profiling was carried out by UCL Genomics on the Affymetrix Human Mapping 250K Nsp or Genome-Wide Human SNP Array 6.0 platform. Both cases demonstrated a strong association between the appearance of anaplastic clones and TP53 mutations. Synchronous ganglioneuroma was diagnosed in one case. Our cases are unique as they represent a long disease history and demonstrate the difficulties in managing rare cases of bilateral WT with anaplasia. These cases also emphasize the practical importance of modern molecular-genetic techniques and their clinical application. Moreover, they highlight the issue of the adequate sampling needed in order to gather comprehensive, efficient, and sufficient information about genetic events in a single tumor.

A total of 42 adults with acute lymphoblastic leukemia were treated with an aggressive induction/consolidation chemotherapy (MCP-841) between June 1986 and December 1991. 32 patients (76.19%) achieved complete remission at the end of induction. There were 9 induction deaths, 6 of them due to infection. All patients received cranial irradiation in the dose of 20 Gy and intrathecal methotrexate for CNS prophylaxis. Twelve patients relapsed, 10 in the bone marrow, one case had isolated CNS relapse and the other relapsed in the bone marrow and CNS. The actuarial overall survival of all patients at the end of 5 years was 41.94%. Patient characteristics including age, sex, FAB morphology, phenotype, WBC count, platelet count and LDH did not influence survival significantly.

BACKGROUND: Constitutional DICER1 mutations were recently reported to cause familial pleuropulmonary blastoma (PPB). AIM: To investigate the contribution and phenotypic spectrum of constitutional and somatic DICER1 mutations to cancer. METHODS AND RESULTS: The authors sequenced DICER1 in constitutional DNA from 823 unrelated patients with a variety of tumours and in 781 cancer cell lines. Constitutional DICER1 mutations were identified in 19 families including 11/14 with PPB, 2/3 with cystic nephroma, 4/7 with ovarian Sertoli-Leydig-type tumours, 1/243 with Wilms tumour (this patient also had a Sertoli-Leydig tumour), 1/1 with intraocular medulloepithelioma (this patient also had PPB), 1/86 with medulloblastoma/infratentorial primitive neuroectodermal tumour, and 1/172 with germ cell tumour. The inheritance was investigated in 17 families. DICER1 mutations were identified in 25 relatives: 17 were unaffected, one mother had ovarian Sertoli-Leydig tumour, one half-sibling had cystic nephroma, and six relatives had non-toxic thyroid cysts/goitre. Analysis of eight tumours from DICER1 mutation-positive patients showed universal retention of the wild-type allele. DICER1 truncating mutations were identified in 4/781 cancer cell lines; all were in microsatellite unstable lines and therefore unlikely to be driver mutations. CONCLUSION: Constitutional DICER1 haploinsufficiency predisposes to a broad range of tumours, making a substantial contribution to PPB, cystic nephroma and ovarian Sertoli-Leydig tumours, but a smaller contribution to other tumours. Most mutation carriers are unaffected, indicating that tumour risk is modest. The authors define the clinical contexts in which DICER1 mutation testing should be considered, the associated tumour risks, and the implications for at-risk individuals. They have termed this condition 'DICER1 syndrome'. ACCESSION NUMBERS: The cDNA Genbank accession number for the DICER1 sequence reported in this paper is NM_030621.2.

The purpose of the present paper was to report cases of avascular necrosis of bone (AVNB) arising as a complication of chemotherapy for acute lymphoblastic leukemia (ALL). X-rays and 99mtechnicium-MDP bone scans were performed on patients with symptoms of bone pain, whereby five patients out of 850 patients were detected to have avascular necrosis of the femoral head. All had received aggressive chemotherapy with steroids. Two patients were still on therapy for the primary disease. In these patients further chemotherapy was continued without steroids. The median period from diagnosis of ALL to development of AVNB was 29 months. Three patients underwent corrective surgical procedures. To conclude, the data suggest that patients receiving combination chemotherapy, especially those with high cumulative doses, run a risk of developing AVNB. Awareness of this complication is important in order to have an early diagnosis so as to limit disability.

The purpose of this retrospective study was to investigate the pattern of recurrence in paediatric malignant gliomas.We reviewed the notes, diagnostic imaging and treatment charts of 30 consecutive paediatric patients (age less than 18 years at diagnosis, range 0.5-17 years) presenting with a malignant glioma presenting to the paediatric oncology unit at the Royal Marsden Hospital over a 10-year period. The imaging at the time of first relapse was compared with the initial diagnostic scans to define a relapse as local, marginal or distant.Median follow-up was 13 months (range 1-99 months). Twenty-four of 30 patients (80%) showed evidence of progression with a median time to progression of 8.5 months (range 3-64 months). Thirteen out of 24 patients developed local or marginal recurrences while 11/24 patients recurred at distant sites as site of first relapse (46%).Our series suggests that the pattern of relapses in paediatric malignant gliomas could be different from that reported in adult studies as we observed a significant incidence of distant relapses. Larger prospective series need to be conducted to investigate the clinico-biological characteristics of the population at high risk for leptomeningeal dissemination.

Haemopoietic progenitor cell transplantation in patients with previous history of invasive fungal infection The aim of this retrospective study conducted between H. U. Marques de Valdecilla (Spain) and the Royal Marsden NHS Trust (UK) was to analyse the outcome of patients who underwent haemopoietic progenitor cell transplantation (HPCT) after a previous history of Invasive fungal infections (IFI). This study includes 27 patients (15 autologous, 12 allogeneic). The diagnosis of IFI was microbiologically proven in 21 cases and only radiologically in six. Pre-HPCT treatment included intravenous antifungals in all and surgical excision in eight cases. All patients received post-HPCT antifungal prophylaxis. Median time from diagnosis of IFI to HPCT was 131 days. At median follow-up of 193 days, three patients (two allogeneic, one autologous) had relapse of IFI resulting in death in all cases. One of them had received TBI and two were receiving treatment for graft versus host disease. Each patient was receiving a different form of prophylaxis. Overall, seven patients are alive and disease-free. Ten patients died from disease progression and 10 from transplant-related toxicity, including IFI. In our experience, the risk of post-HPCT reactivation of a previous IFI is low (11%), so IFI should not be an absolute contraindication for HPCT. The combination of aggressive antifungal treatment for IFI and antifungal prophylaxis throughout HPCT reduces the probability of reactivation.

The role of autologous stem cell transplantation in adult patients with acute myeloid leukaemia (AML) in first remission is unclear, yet it has become standard treatment for myeloma and this paper explores whether the source of transplanted stem cells may explain this paradox. In total, 57 patients from the Royal Marsden Hospital who received an unpurged bone marrow transplant (ABMT) were matched with 114 patients from the EBMT registry who had undergone peripheral blood stem cell transplantation (PBSCT). Patients were matched for karyotype, FAB type, remission-autograft interval and age. In the PBSCT group, haematopoietic recovery was significantly faster and nonrelapse mortality at 4 years was significantly lower (13 vs 1%, P=0.04). The relapse rate and overall survival at 4 years (20 vs 31% and 77 vs 63%) were also better with PBSCT, although the differences were not statistically significant. Autografting should be reassessed in a randomised trial for first remission AML patients using peripheral blood as a source of stem cells rather than bone marrow.

This brief review considers to what extent Magnetic Resonance Spectroscopy (MRS) can play a role in monitoring early tumour response with examples of preclinical studies and selected clinical studies in tumours of children and young adults. An early non-invasive indicator of tumour response to therapy would provide useful information regarding the effectiveness of therapy. This might be a relevant prognostic factor in new patients and in phase II studies could facilitate recommendations at an early stage as to whether to continue treatment. This review suggests that several markers and ratios are emerging as potential prognostic markers, but larger prospective studies are needed before translating this into clinical practice.

Neuroblastoma in a known case of congenital adrenal hyperplasia has rarely been reported. The management of such a patient in the background of hormonal imbalance can be very challenging. In this report, we share our experience in managing such a child and discuss the clinical dilemma.

The purpose of this study was to analyze the outcome of patients who completed therapy for acute lymphoblastic leukemia (ALL) and to study the role of an aggressive induction regimen in preventing post therapy relapses. Four hundred and twenty-two patients with ALL who completed therapy during the period 1975-1991 were followed. Two hundred and sixty patients received the aggressive MCP 841 protocol and 162 patients received various other less aggressive treatment regimens. Patients were followed with periodic examination and complete blood counts. The incidence of post therapy relapse was 27% in the less aggressive protocols and 15% in the MCP 841 protocol (p = 0.001). An higher percentage of relapses was seen in males (p = 0.05) and 89% relapses occurred within two years of stopping therapy. The relapse rate after 5 years of cessation of therapy was 0.59%. In conclusion, aggressive induction therapy is the most crucial factor in predicting relapses following cessation of therapy in ALL patients. However, relapses are unlikely to occur five years post therapy.