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Table S3. Variants detected by NGS targeted re-sequencing

Table S1. Details for NGS amplicons

Table S2. Details of Exons covered Table S4. Details of antibodies/ streptavidin used Table S5. Summary of longitudinal progenitor LSC quantitation by FACS Table S6. Overview of toxicities Figure S1. Progenitor LSC FACS gating strategy Figure S2. Kaplan-Meier plot for duration of response Figure S3. Forest plot of sub group analysis in overall response rate and overall survival.

Purpose: Azacitidine (AZA) is a novel therapeutic option in older patients with acute myeloid leukemia (AML), but its rational utilization is compromised by the fact that neither the determinants of clinical response nor its mechanism of action are defined. Co-administration of histone deacetylase inhibitors, such as vorinostat (VOR), is reported to improve the clinical activity of AZA, but this has not been prospectively studied in patients with AML.Experimental Design: We compared outcomes in 259 adults with AML (n = 217) and MDS (n = 42) randomized to receive either AZA monotherapy (75 mg/m2 × 7 days every 28 days) or AZA combined with VOR 300 mg twice a day on days 3 to 9 orally. Next-generation sequencing was performed in 250 patients on 41 genes commonly mutated in AML. Serial immunophenotyping of progenitor cells was performed in 47 patients.Results: Co-administration of VOR did not increase the overall response rate (P = 0.84) or overall survival (OS; P = 0.32). Specifically, no benefit was identified in either de novo or relapsed AML. Mutations in the genes CDKN2A (P = 0.0001), IDH1 (P = 0.004), and TP53 (P = 0.003) were associated with reduced OS. Lymphoid multipotential progenitor populations were greatly expanded at diagnosis and although reduced in size in responding patients remained detectable throughout treatment.Conclusions: This study demonstrates no benefit of concurrent administration of VOR with AZA but identifies a mutational signature predictive of outcome after AZA-based therapy. The correlation between heterozygous loss of function CDKN2A mutations and decreased OS implicates induction of cell-cycle arrest as a mechanism by which AZA exerts its clinical activity. Clin Cancer Res; 23(21); 6430–40. ©2017 AACR.

PURPOSE A dose-adjusted etoposide, doxorubicin, and cyclophosphamide with vincristine and prednisone plus rituximab (DA-EPOCH-R) regimen has been shown to deliver excellent survival for adults with primary mediastinal large B-cell lymphoma (PMLBL) without the use of radiotherapy. No international prospective evaluation of this regimen has previously been reported in children and adolescents. PATIENTS AND METHODS We conducted an international single-arm phase II trial involving patients younger than age 18 years with PMLBL who were to receive six courses of DA-EPOCH-R. The primary end point was event-free survival (EFS). Overall survival and toxicity were also assessed. This trial was registered (ClinicalTrials.gov identifier: NCT01516567 ). RESULTS Analyses were based on 46 patients. The median age was 15.4 years (interquartile range: 14-16 years). The median follow-up was 59.0 months (interquartile range: 52.6-69.2 months). Fourteen events were observed (eight relapses or progressions (including three parenchymal CNS relapses), four residual lymphoma, and two second malignancies). The 4-year EFS was 69.6% (95% CI, 55.2 to 80.9), which did not differ from the rate observed historically ( P = .59). Seven deaths occurred (six disease-related and one second malignancy). The overall survival was 84.8% (95% CI, 71.8 to 92.4). Twenty-two patients (48%) reached dose levels ≥ 4. Nonhematologic adverse events grade ≥ 3 or cardiac adverse events grade ≥ 2 occurred in 47 of 276 (17%) courses and 30 of 46 patients (65%). CONCLUSION DA-EPOCH-R did not improve the EFS compared with a historical control in this first prospective multisite international study of children and adolescents with PMLBL. Further studies are required to determine the optimum therapy for children and adolescents with this lymphoma.

Internationally, a single standard chemotherapy treatment for Ewing sarcoma is not defined. Because different chemotherapy regimens were standard in Europe and the USA for newly diagnosed Ewing sarcoma, and in the absence of novel agents to investigate, we aimed to compare these two strategies.EURO EWING 2012 was a European investigator-initiated, open-label, randomised, controlled phase 3 trial done in 10 countries. We included patients aged 2-49 years, with any histologically and genetically confirmed Ewing sarcoma of bone or soft tissue, or Ewing-like sarcomas. The eligibility criteria originally excluded patients with extrapulmonary metastatic disease, but this was amended in the protocol (version 3.0) in September, 2016. Patients were randomly assigned (1:1) to either the European regimen of vincristine, ifosfamide, doxorubicin, and etoposide induction, and consolidation using vincristine, actinomycin D, with ifosfamide or cyclophosphamide, or busulfan and melphalan (group 1); or the US regimen of vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide induction, plus ifosfamide and etoposide, and consolidation using vincristine and cyclophosphamide, or vincristine, actinomycin D, and ifosfamide, with busulfan and melphalan (group 2). All drugs were administered intravenously. The primary outcome measure was event-free survival. We used a Bayesian approach for the design, analysis, and interpretation of the results. Patients who received at least one dose of study treatment were considered in the safety analysis. The trial was registered with EudraCT, 2012-002107-17, and ISRCTN, 54540667.Between March 21, 2014, and May 1, 2019, 640 patients were entered into EE2012, 320 (50%) randomly allocated to each group. Median follow-up of surviving patients was 47 months (range 0-84). Event-free survival at 3 years was 61% with group 1 and 67% with group 2 (adjusted hazard ratio [HR] 0·71 [95% credible interval 0·55-0·92 in favour of group 1). The probability that the true HR was less than 1·0 was greater than 0·99. Febrile neutropenia as a grade 3-5 treatment toxicity occurred in 234 (74%) patients in group 1 and in 183 (58%) patients in group 2. More patients in group 1 (n=205 [64%]) required at least one platelet transfusion compared with those in group 2 (n=138 [43%]). Conversely, more patients required blood transfusions in group 2 (n=286 [89%]) than in group 1 (n=277 [87%]).Dose-intensive chemotherapy with vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide is more effective, less toxic, and shorter in duration for all stages of newly diagnosed Ewing sarcoma than vincristine, ifosfamide, doxorubicin, and etoposide induction and should now be the standard of care for Ewing sarcoma.The European Union's Seventh Framework Programme for Research, Technological Development, and Demonstration; The National Coordinating Centre in France, Centre Léon Bérard; SFCE; Ligue contre le cancer; Cancer Research UK.

Background The risk of cutaneous squamous cell carcinoma (cSCC) is significantly increased in organ transplant recipients (OTRs). Clearance of actinic keratoses (AKs) is generally regarded as a surrogate biomarker for cSCC prevention. OTR-cSCC chemoprevention with topical AK treatments has not been investigated in randomized controlled trials (RCTs), although there is evidence that 5% 5-fluorouracil (5-FU) may be chemoprotective in immunocompetent patients. Objectives To assess the feasibility, activity and evaluation outcomes relevant to the design of a future phase III RCT of topical cSCC chemoprevention in OTRs. Methods OTRs with 10 or more AKs in predefined areas were randomized 1 : 1 : 1 to topical 5-FU, 5% imiquimod (IMIQ) or sunscreen (sun-protective factor 30+) in a phase II, open-label RCT over 15 months. Feasibility outcomes included proportions of eligible OTRs randomized, completing treatment and willing to be re-treated. AK activity [AK clearance, new AK development, patient-centred outcomes (toxicity, health-related quality of life, HRQoL)] and evaluation methodology (clinical vs. photographic) were assessed. Results Forty OTRs with 903 AKs were randomized. All feasibility outcomes were met (56% of eligible OTRs were randomized; 89% completed treatment; 81% were willing to be re-treated). AK activity analyses found 5-FU and IMIQ were superior to sunscreen for AK clearance and prevention of new AKs. 5-FU was more effective than IMIQ in AK clearance and prevention in exploratory analyses. Although toxicity was greater with 5-FU, HRQoL outcomes were similar. Conclusions Trials of topical AK treatments in OTRs for cSCC chemoprevention are feasible and AK activity results support further investigation of 5-FU-based treatments in future phase III trials. What is already known about this topic? Cutaneous squamous cell carcinoma (cSCC) is significantly more common in immunocompromised individuals including organ transplant recipients (OTRs) compared with immunocompetent populations. cSCC chemoprevention activity of sunscreen and 5-fluorouracil-based (5-FU) actinic keratosis (AK) treatments has been demonstrated in randomized controlled trials (RCTs) in immunocompetent populations but not in OTRs. AKs are cSCC precursors and their clearance and prevention are generally regarded as surrogate endpoint biomarkers for potential cSCC chemoprevention activity. What does this study add? SPOT (SCC Prevention in OTRs using Topical treatments) has confirmed that RCTs of OTR-cSCC chemoprevention with topical AK treatments are feasible. It also suggests that topical 5-FU may be superior to 5% imiquimod and sunscreen in AK clearance and prevention. Together with recent evidence from several RCTs in the general population, these data provide a compelling rationale for further studies of intervention with 5-FU-based topical chemoprevention approaches in OTR-cSCC prevention.

Consensus criteria; Early phase; Neuroblastoma Criteris de consens; Fase inicial; Neuroblastoma Criterios de consenso; Fase inicial; Neuroblastoma Background International standardized criteria for eligibility, evaluable disease sites, and disease response assessment in patients with refractory, progressive, or relapsed high-risk neuroblastoma enrolled in early-phase clinical trials are lacking. Methods A National Cancer Institute–sponsored Clinical Trials Planning Meeting was convened to develop an international consensus to refine the tumor site eligibility criteria and evaluation of disease response for early-phase clinical trials in children with high-risk neuroblastoma. Results Standardized data collection of patient and disease characteristics (including specified genomic data), eligibility criteria, a definition of evaluable disease, and response evaluations for primary and metastatic sites of disease were developed. Eligibility included two distinct patient groups: progressive disease and refractory disease. The refractory disease group was subdivided into responding persistent disease and stable persistent disease to better capture the clinical heterogeneity of refractory neuroblastoma. Requirements for defining disease evaluable for a response assessment were provided; they included requirements for biopsy to confirm viable neuroblastoma and/or ganglioneuroblastoma in those patients with soft tissue or bone disease not avid for iodine-123 meta-iodobenzylguanidine. Standardized evaluations for response components and time intervals for response evaluations were established. Conclusions The use of international consensus eligibility, evaluability, and response criteria for early-phase clinical studies will facilitate the collection of comparable data across international trials and promote more rapid identification of effective treatment regimens for high-risk neuroblastoma. National Cancer Institute Pediatric and Adolescent Solid Tumor Steering Committee; Alex's Lemonade Stand Foundation for Childhood Cancer; Ben Towne Foundation; EVAN Foundation; Cancer Research UK Institute of Cancer Research, Grant/Award Number C347/A15403; National Institute for Health Research Research Methods Programme/Institute of Cancer Research Biomedical Research Centre.

PURPOSE Reduced-intensity conditioning (RIC) regimens have extended the curative potential of allogeneic stem-cell transplantation to older adults with high-risk acute myeloid leukemia (AML) and myelodysplasia (MDS) but are associated with a high risk of disease relapse. Strategies to reduce recurrence are urgently required. Registry data have demonstrated improved outcomes using a sequential transplant regimen, fludarabine/amsacrine/cytarabine-busulphan (FLAMSA-Bu), but the impact of this intensified conditioning regimen has not been studied in randomized trials. PATIENTS AND METHODS Two hundred forty-four patients (median age, 59 years) with high-risk AML (n = 164) or MDS (n = 80) were randomly assigned 1:1 to a fludarabine-based RIC regimen or FLAMSA-Bu. Pretransplant measurable residual disease (MRD) was monitored by flow cytometry (MFC-MRD) and correlated with outcome. RESULTS There was no difference in 2-year overall survival (hazard ratio 1.05 [85% CI, 0.80 to 1.38] P = .81) or cumulative incidence of relapse (CIR) (hazard ratio 0.94 [95%CI, 0.60 to 1.46] P = .81) between the control and FLAMSA-Bu arms. Detectable pretransplant MFC-MRD was associated with an increased CIR (2-year CIR 41.0% v 20.0%, P = .01) in the overall trial cohort with a comparable prognostic impact when measured by an unsupervised analysis approach. There was no evidence of interaction between MRD status and conditioning regimen intensity for relapse or survival. Acquisition of full donor T-cell chimerism at 3 months abrogated the adverse impact of pretransplant MRD on CIR and overall survival. CONCLUSION The intensified RIC conditioning regimen, FLAMSA-Bu, did not improve outcomes in adults transplanted for high-risk AML or MDS regardless of pretransplant MRD status. Our data instead support the exploration of interventions with the ability to accelerate acquisition of full donor T-cell chimerism as a tractable strategy to improve outcomes in patients allografted for AML.

The objective of this phase IIa, open-label, single-centre, single-arm, two-stage clinical trial was to evaluate the safety and activity of 177-lutetium DOTATATE (LuDO) molecular radiotherapy in neuroblastoma. Children with relapsed or refractory metastatic high-risk neuroblastoma were treated with up to four courses of LuDO. The administered activity was 75 to 100 MBq kg−1 per course, spaced at 8- to 12-week intervals. Outcomes were assessed by the International Neuroblastoma Response Criteria (primary outcome), progression-free survival (PFS), and overall survival (OS). The trial recruited 21 patients; eight received the planned four courses. There was dose-limiting haematologic toxicity in one case, but no other significant haematologic or renal toxicities. None of 14 evaluable patients had an objective response at 1 month after completion of treatment (Wilson 90% CI 0.0, 0.16; and 95% CI is 0.0, 0.22). The trial did not therefore proceed to the second stage. The median PFS was 2.96 months (95% CI 1.71, 7.66), and the median OS was 13.0 months (95% CI 2.99, 21.52). In the absence of any objective responses, the use of LuDO as a single agent at the dose schedule used in this study is not recommended for the treatment of neuroblastoma. There are several reasons why this treatment schedule may not have resulted in objective responses, and as other studies do show benefit, the treatment should not be regarded as being of no value. Further trials designed to overcome this schedule’s limitations are required. ISRCTN98918118; URL: https://www.isrctn.com/search?q=98918118

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.

10039 Background: Children with relapsed and refractory neuroblastoma (RR-NBL) have poor outcomes. Early identification of children at greatest risk of relapse could mean timelier modifications of treatment to improve outcomes. High levels of adrenergic neuroblastoma mRNAs in blood of children with stage M neuroblastoma receiving frontline treatment predict poor outcome (Viprey PMID: 24590653). Since these markers have not been thoroughly studied in the RR-NBL population, we have prospectively evaluated the prognostic potential of the adrenergic neuroblastoma mRNAs paired-like homeobox 2B (PHOX2B ) and tyrosine hydroxylase (TH) in blood from children with RR-NBL treated in the BEACON-Neuroblastoma trial (NCT02308527). Methods: Blood samples collected at baseline from 88 children were analysed by reverse transcriptase polymerase chain reaction (RTqPCR) for PHOX2B and TH mRNAs. The prognostic power of these mRNAs was evaluated using Kaplan-Meier survival curves and Cox proportional hazards regression. Progression-free (PFS) and overall survival (OS) were calculated from the date that the blood sample was taken at screening to the date of an event; progression, disease recurrence, death or censored alive at the last clinical evaluation. Results: Of the children in this cohort, 58 (66%) had relapsed and 30 (34%) had refractory disease. Twenty-three (26%) had MYC-N amplified tumours. TH and PHOX2B mRNAs were detected in 55% and 60% of blood samples respectively; the correlation coefficient between TH and PHOX2B was 0.75. Higher levels of TH, PHOX2B mRNAs or both combined were associated with reduced PFS and OS (Table). For TH, median PFS for children with TH levels below the median was 12 months (95%CI, 4.6–13 months) versus 5.5 months (95%CI, 1.8–9.4 months) for those children with TH levels above the median. For PHOX2B, median PFS for children with PHOX2B levels below the median was 11.5 months (95%CI, 7.6–34 months), compared to 5.7 months (95%CI, 1.8–10.5 months) where levels were above the median. Conclusions: TH and PHOX2B mRNAs in blood collected at baseline identify children with refractory or relapsed neuroblastoma at greatest risk of progression or death. In the RR-NBL setting, this simple blood test could be used to stratify treatment strategies. Clinical trial information: NCT02308527. [Table: see text]

Childhood liver cancers hepatoblastoma (HB) and hepatocellular carcinoma (HCC) are rare diseases but with a rising incidence. HEMNOS (Hepatocellular malignant neoplasm, not otherwise specified) is a recent entity with histopathological features of HB and HCC. Current chemotherapy treatments are effective to shrink tumor before surgery, nonetheless can cause severe lifelong adverse effects and are not effective for patients with aggressive and metastatic HB or HCC (~20% die due to the disease). The HB and HCC diagnosis is key to assign therapeutic regimens in the ongoing Pediatric Hepatic International Tumor Trial (PHITT); however, differential diagnosis for some patients is challenging due to the lack of specific biomarkers. Nowadays, there is an urgent need to identify diagnostic and prognostic biomarkers to improve the clinical management of childhood liver cancer. Herein, we aimed to uncover the proteomic profiles of different types of childhood liver cancer and identify new biomarkers for improving tumor diagnosis and early detection of the most aggressive cases. For this, 99 frozen tissue samples from 71 patients (mean age: 54.5 months, 60.6% boys, 40.9% metastasis, 23.7% deaths) including 70 primary tumors (57 HB, 8 HCC and 5 HEM-NOS), 22 non-tumors and 7 metastases were analyzed by label free mass spectrometry analysis. A total of 5,417 proteins were sequenced in the different samples. Through supervised analysis, we identified a total of 1302 differential expressed proteins in tumors as compared to non-tumor livers (FC +2 and FDR 2) was defined for HB, HCC and HEM-NOS, respectively. Hierarchical unsupervised clustering and principal component analysis showed two main cluster of tumors: one including HB and HEM-NOS and another one with a mixture of HB, HEM-NOS and HCC. Interestingly, this second cluster was associated with clinical and molecular features of aggressive tumors such as multifocality (p = 0.029), Epigenetic Epi-CB subclass (p = 0.006), high-risk Molecular Risk Stratification (p = 0.009) and poor survival (log rank test=0.012). A total of 2082 proteins were found to be differently expressed between the two prognostic clusters (FC +2 and FDR < 0.01); the GEO enrichment analysis revealed that these proteins were significantly enriched in post-transcriptional gene silencing and RNA splicing mechanisms (FDR 6 and FDR < 10−14). In conclusion, we identified a list of potential diagnostic and prognostic protein biomarkers that after a validation in large patient cohort, could be used to improve the clinical management of childhood liver cancer. Citation Format: Álvaro Del Río-Álvarez, Juan Carrillo-Reixach, Laura Royo, Montse Domingo-Sàbat, Mikel Azkargorta, Roland Kapler, Stefano Cairo, Christian Vokuhl, Ronald de Krijger, Rita Alaggio, Marta Garrido, Gabriela Guillen, Constantino Sábado, Laura Guerra, Francisco Hernandez, Maria Elena Mateos, Manuel López-Satamaría, Barbara Torres, Maria Pilar Abad, Bajčiová Viera, Piotr Czauderna, Marie Annick Buendia, Felix Elortza, Keith Wheatley, Bruce Morland, Carolina Armengol. Proteomic profiling of childhood liver cancer: identification of novel diagnostic and prognostic biomarkers [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr PO011.

Background: The main pediatric liver tumors are hepatoblastoma (HB) and, to a lesser extent, pediatric hepatocellular carcinoma (HCC). HB appears at an early age (8 years) or adolescents and it is usually associated to underlying metabolic diseases. HEM-NOS (Hepatocellular malignant neoplasm, not otherwise specified) is a recent entity with histopathological features of HB and HCC. Due to the rarity of the disease ( Citation Format: Juan Carrillo-Reixach, Álvaro del Río-Álvarez, Laura Royo, Montserrat Domingo-Sàbat, Rita Alaggio, Ronald de Krijger, Christian Vokuhl, Marta Garrido, Laura Guerra, Constantino Sábado, Francisco Hernández, Manuel López-Santamaría, Viera Bajčiová, Rudolf Maibach, Margaret Childs, Piotr Czauderna, Keith Wheatley, Roland Kappler, Stefano Cairo, Bruce Morland, Margarita Sala, Maria Rosa Sarrias, Carolina Armengol. Molecular characterization of pediatric hepatocellular carcinoma: genomic, methylomic and transcriptomic analysis [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr PO010.

PURPOSE The VIT-0910 trial was conducted to evaluate efficacy and safety of the vincristine-irinotecan combination with and without temozolomide (VIT and VI, respectively) in relapsed or refractory rhabdomyosarcoma (RMS). METHODS In this randomized European phase II trial, patients age 0.5-50 years received 21-day cycles combining vincristine (1.5 mg/m2 once a day on day 1 and day 8) and irinotecan (50 mg/m2 once a day from day 1 to day 5) with and without temozolomide (125 mg/m2 once a day from day 1 to day 5 and 150 mg/m2 once a day from cycle 2), until progression or unacceptable toxicity. The primary end point was objective response rate after two cycles. Secondary end points included best response, progression-free survival, overall survival, and adverse events. A Simon 2-stage design was initially planned to separately analyze 40 patients/arm. After amendment, the trial sample size was increased to 120 and a comparison between arms, adjusted for confounding factors, was added to the statistical plan (ClinicalTrials.gov, NCT01355445 ). RESULTS Overall, 120 patients (60 per arm) were recruited in 37 European centers. The median age was 11 years (range, 0.75-45); 89% of patients had a relapsed RMS. The objective response rate was 44% (24 of 55 evaluable patients) for VIT versus 31% (18 of 58) for VI (adjusted odds ratio, 0.50; 95% CI, 0.22 to 1.12; P = .09). The VIT arm achieved significantly better overall survival (adjusted hazard ratio, 0.55; 95% CI, 0.35 to 0.84; P = .006) compared with VI, with consistent progression-free survival results (adj-hazard ratio, 0.68; 95% CI, 0.46 to 1.01; P = .059). Overall, patients experienced adverse events ≥ grade 3 more frequently with VIT than VI (98% v 78%, respectively; P = .009), including a significant excess of hematologic toxicity (81% v 61%; P = .025). CONCLUSION The addition of temozolomide to VI improved chemotherapy efficacy for patients with relapsed RMS, with manageable increase in toxicity. VIT is considered the new standard treatment in these patients in the European paediatric Soft Tissue Sarcoma Group and will be the control arm in the next randomized trial.

Intelligibility of speech is a key outcome in speech and language therapy (SLT) and research. SLT students frequently participate as raters of intelligibility but we lack information about whether they rate intelligibility in the same way as the general public. This paper aims to determine if there is a difference in the intelligibility ratings made by SLT students (trained in speech related topics) compared to individuals from the general public (untrained). The SLT students were in year 2 of a BSc programme or the first 6 months of a MSc programme. We recorded 10 speakers with Parkinson’s disease (PD) related speech reading aloud the words and sentences from the Assessment of Intelligibility of Dysarthric Speech. These speech recordings were rated for intelligibility by ‘trained’ raters and ‘untrained’ raters. The effort required to understand the speech was also reported. There were no significant differences in the measures of intelligibility from the trained and untrained raters for words or sentences after adjusting for speaker by including them as a covariate in the model. There was a slight increase in effort reported by the untrained raters for the sentences. This difference in reported effort was not evident with the words. SLT students can be recruited alongside individuals from the general public as naïve raters for evaluating intelligibility in people with speech disorders.

LBA2 Background: 5-year survival of RR-ES is about 15%. rEECur, the first randomized controlled trial in this setting, is defining standard care, balancing efficacy and toxicity. Methods: Patients aged 4-50 with RR-ES were randomly assigned to topotecan and cyclophosphamide (TC), irinotecan and temolozomide (IT), gemcitabine and docetaxel (GD), or high-dose ifosfamide (IFOS). Primary outcome was event-free survival (EFS) for the phase III comparison. Secondary outcomes included overall survival (OS), toxicity, and quality of life (QoL). A probability-based Bayesian approach was used with multiple pairwise comparisons. At the first and second interim assessments, patients allocated to GD and IT, respectively, had worse objective response (OR) and EFS than the other arms, halting recruitment to both. The final intent-to-treat assessment of the original four arms was a phase III evaluation of TC and IFOS. Results: 451 patients recruited between 18/12/14 and 31/08/21, were randomly assigned to TC (163 patients), IT (127 patients), GD (72 patients), and IFOS (83 patients). Median age was 19 years (range 4-49). Patients had: refractory disease (18%), first recurrence (66%), > first recurrence (17%). Initial disease site was bone in 70%. Sites of progression were: primary site only (15%), pleuropulmonary metastases only (34%), and other metastatic (51%). Baseline renal function was similar in both. Median follow-up (reverse Kaplan-Meier method) was 40 months. For the phase III comparison between TC and IFOS (both, 73 patients), median EFS was 3.7 months (95% CI, 2.1-6.2) for TC and 5.7 months (95% CI, 3.8-7.0) for IFOS. Median OS was 10.4 months (95% CI, 7.5-15.5) for TC and 16.8 months (95% CI, 11.1-25.8) for IFOS. Given the observed data, the posterior probability that EFS and OS were better after IFOS than after TC (ie Pr [true hazard ratio < 1 | data]) was 95% for both. A greater survival difference was observed for patients aged under 14 than those aged ≥ 14 for EFS and OS. Subgroup analyses favored IFOS for all minimization factors. The main grade 3/4 adverse events (% patients with an event) for TC (left-hand values) compared with IFOS were: febrile neutropenia (26% vs. 25%), infections (8% vs. 14%), vomiting (1% vs. 1%), nausea (0% vs. 3%), diarrhea (1% vs. 1%), encephalopathy (0% vs. 7%), and renal toxicity (0% vs. 8%). Descriptive statistics of quality of life scores appeared to favor the IFOS arm over the TC arm in children but not in adults. Conclusions: The first randomized trial in RR-ES has shown that high-dose ifosfamide is more effective in prolonging survival than TC, having previously beaten GD and IT, and should be considered as a control arm in future randomized phase II/III studies in RR-ES if combination with IFOS is logical. rEECur is the first study to provide comparative toxicity and survival data for the four most commonly used chemotherapy regimens in RR-ES. Clinical trial information: ISRCTN36453794.

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.

BACKGROUND The PD MED study reported small but persistent benefits in patient-rated mobility scores and quality of life from initiating therapy with levodopa compared with levodopa-sparing therapies in early Parkinson's disease (PD). OBJECTIVES The objective was to estimate the cost-effectiveness of levodopa-sparing therapy (dopamine agonists or monoamine oxidase type B inhibitors compared with levodopa alone. METHODS PD MED is a pragmatic, open-label randomized, controlled trial in which patients newly diagnosed with PD were randomly assigned between levodopa-sparing therapy (dopamine agonists or monoamine oxidase type B inhibitors ) and levodopa alone. Mean quality-adjusted life-years and costs were calculated for each participant. Differences in mean quality-adjusted life-years and costs between levodopa and levodopa-sparing therapies and between dopamine agonists and monoamine oxidase type B inhibitors were estimated using linear regression. RESULTS Over a mean observation period of 4 years, levodopa was associated with significantly higher quality-adjusted life-years (difference, 0.18; 95% CI, 0.05-0.30; P

Background FMS-like tyrosine kinase 3 (FLT3) is the most frequent mutation in AML. With two FLT3 inhibitors recently approved by the FDA (midostaurin and gilteritinib), there is a need to evaluate these targeted agents. Purpose To assess the clinical effectiveness of FLT3 inhibitors in AML patients. Methods Standard systematic review methods were utilised. Searches were conducted to July 2020 for completed and in-progress randomised controlled trials of FLT3 inhibitors in AML. A fixed-effect meta-analysis was undertaken. Results Eight completed trials involving 2656 patients and assessing five different FLT3 inhibitors (sorafenib, lestaurtinib, midostaurin, gilteritinib and quizartinib) were included. The pooled results were as follows (FLT3 inhibitor/control): overall survival hazard ratio (HR) = 0.83 (95% confidence interval [CI] 0.75 to 0.92, p = 0.0005), event-free survival HR = 0.85 (95% CI 0.77 to 0.94, p = 0.002), relapse-free survival HR = 0.76 (95% CI 0.64 to 0.90, p = 0.001), complete remission relative risk (RR) = 1.11 (95% CI 1.00 to 1.22. p = 0.05) and 60-day mortality RR = 1.04 (95% CI 0.77 to 1.40, p = 0.79). Relative risk of grade 3 and above vascular, dermatological, respiratory and hepatobiliary adverse events were found to be statistically significantly higher in the FLT3 inhibitor group compared to control, but the actual numbers of events were relatively small. Nineteen ongoing trials are still in progress, only one of which specifically targets older patients with AML. Conclusions There is evidence to support the use of FLT3 inhibitors in patients with AML, but more data is needed to verify the optimum use of the drugs regarding type of inhibitor, disease stage and patient characteristics, not only in relation to disease control, but adverse events and quality of life. There are a large number of ongoing trials; therefore, the results of this review are not a fait accompli; thus, is it recommended that the review be updated in a couple of years’ time. Given the challenges in extracting the complete data set required to assess clinical effectiveness, it is highly recommended that ongoing and future trials improve transparency and consistency of reporting of all trial outcomes, particularly disease control and adverse events, to enable a global clinical effectiveness assessment. Systematic review registration PROSPERO CRD42017055581

Content: Warm antibody autoimmune hemolytic anemia (wAIHA) is a rare disorder that can have serious complications. In this disorder, autoantibodies bind to antigens on red blood cells leading to phagocytosis and destruction of the cells. This is mediated by Fcg receptors on macrophages through a spleen tyrosine kinase (SYK)-dependent pathway. Fostamatinib is a potent, oral SYK inhibitor approved for the treatment of chronic immune thrombocytopenia. Fostamatinib prevents platelet destruction by inhibition of platelet phagocytosis mediated through Fcg receptor and SYK in macrophages. Fostamatinib was evaluated for wAIHA in an open-label, multicenter, phase 2 study (NCT02612558). This study demonstrated markedly improved hemoglobin levels in 11 of 25 patients (44%) after fostamatinib treatment. Adverse events (AEs) were consistent with the safety database (>4000 patients across multiple diseases). Based on this phase 2 study, a randomized, double-blind, placebo-controlled, global phase 3 study (NCT03764618) was initiated in wAIHA patients to investigate the safety and efficacy of fostamatinib. The phase 3 study began enrolling patients at 103 sites in 22 countries (North America, Europe and Australia) in 2020 with a goal of enrolling approximately 90 patients. This is the first phase 3 study to evaluate a SYK inhibitor for the treatment of wAIHA. Inclusion criteria include: age ?18;documented diagnosis of primary or secondary wAIHA;failure of ?1 prior wAIHA treatment;haptoglobin below normal or total bilirubin above normal or lactate dehydrogenase above normal;and baseline hemoglobin ?9 g/dl or, if hemoglobin >9 g/dl and 1.5 x normal. Randomization of eligible patients will be 1:1 to fostamatinib or placebo for 24 weeks. Randomized patients will be stratified by concomitant steroid use and baseline anemia severity. Fostamatinib is started at 100 mg BID and increased to 150 mg BID at Week 4, if tolerated. The dose may be reduced for AEs. Patients may continue selected concurrent wAIHA therapies (maximum of 2) throughout the study. A steroid taper will be allowed in patients with a hemoglobin response. Rescue therapy will also be allowed. Patients who complete the study can rollover to an open-label extension. Efficacy endpoints will include hemoglobin response, ( ?10 g/dl with a ?2 g/dl increase from baseline without rescue therapy);duration of hemoglobin response;and the need for rescue therapy. Safety endpoints will be the recording of AEs. Patients will be evaluated in the clinic at two-week intervals. Using the Cochran Mantel Haenszel test at a two-sided significance level of 0.05, to detect a difference in response between the active and placebo groups with 80% power would require 90 subjects randomized 1:1. The response rate will be compared between groups using a chi-square test adjusted for randomization stratification factors. As of 11 January 2021, 62 sites are open to screening (subject to local COVID-19 regulations), and 64 patients have been randomized.

[Background] Although there have been multiple randomised trials in newly diagnosed Ewing sarcoma family of tumours (ESFT) and these have been conducted over many years and involved many international cooperative groups, the outcomes for all stages of disease have plateaued. Internationally, the standard treatment of ESFT is not defined, and there is a need to add new agents other than conventional chemotherapy to improve outcomes. This trial will compare two different induction/consolidation chemotherapy regimens: (1) vincristine, ifosfamide, doxorubicin and etoposide (VIDE) induction and vincristine, actinomycin D, ifosfamide or cyclophosphamide, or busulfan and mephalan (VAI/VAC/BuMel) consolidation and (2) vincristine, doxorubicin, cyclophosphamide, ifosfamide and etoposide (VDC/IE) induction and ifosfamide and etoposide, vincristine and cyclophosphamide, vincristine, actinomycin D and ifosfamide, or busulfan and mephalan (IE/VC/VAI/BuMel) consolidation (randomisation 1, or R1). A second randomisation (R2) will determine whether the addition of zoledronic acid to consolidation chemotherapy, as assigned at R1, is associated with improved clinical outcome., [Methods] EURO EWING 2012 is an international, multicentre, phase III, open-label randomised controlled trial. There are two randomisations: R1 and R2. Patients are randomly assigned at two different time points: at entry to the trial (R1) and following local control therapy (R2). The primary outcome measure is event-free survival. The secondary outcome measures include overall survival, adverse events and toxicity, histological response of the primary tumour, response of the primary tumour, regional lymph nodes or metastases (or both), and achievement of local control at the end of treatment., [Discussion] This study will establish which is the “standard regimen” of chemotherapy, taking into account both clinical outcomes and toxicity. This will form the chemotherapy backbone for future interventional studies where we may want to add new targeted agents. It will also determine the role of zoledronic acid in conjunction with the separate EE2008 trial. Any trial in ESFT needs to take into account the rarity of the tumour and consider that international cooperation is needed to provide answers in a timely manner., [Trial registration] Registered with EudraCT number 2012-002107-17 on 26 February 2012. Registered with ISRCTN number 92192408 on 4 November 2013., This project has received funding from the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement n°602856. The NCC in France, CLB, receives additional funding from SFCE and Ligue contre le cancer. The coordinating sponsor (the University of Birmingham, Birmingham, UK) is funded by Cancer Research UK (grant award reference C5952/A14745).

Purpose: Azacitidine (AZA) is a novel therapeutic option in older patients with acute myeloid leukemia (AML), but its rational utilization is compromised by the fact that neither the determinants of clinical response nor its mechanism of action are defined. Co-administration of histone deacetylase inhibitors, such as vorinostat (VOR), is reported to improve the clinical activity of AZA, but this has not been prospectively studied in patients with AML. Experimental Design: We compared outcomes in 259 adults with AML (n = 217) and MDS (n = 42) randomized to receive either AZA monotherapy (75 mg/m2 × 7 days every 28 days) or AZA combined with VOR 300 mg twice a day on days 3 to 9 orally. Next-generation sequencing was performed in 250 patients on 41 genes commonly mutated in AML. Serial immunophenotyping of progenitor cells was performed in 47 patients. Results: Co-administration of VOR did not increase the overall response rate (P = 0.84) or overall survival (OS; P = 0.32). Specifically, no benefit was identified in either de novo or relapsed AML. Mutations in the genes CDKN2A (P = 0.0001), IDH1 (P = 0.004), and TP53 (P = 0.003) were associated with reduced OS. Lymphoid multipotential progenitor populations were greatly expanded at diagnosis and although reduced in size in responding patients remained detectable throughout treatment. Conclusions: This study demonstrates no benefit of concurrent administration of VOR with AZA but identifies a mutational signature predictive of outcome after AZA-based therapy. The correlation between heterozygous loss of function CDKN2A mutations and decreased OS implicates induction of cell-cycle arrest as a mechanism by which AZA exerts its clinical activity. Clin Cancer Res; 23(21); 6430–40. ©2017 AACR.

Neuroblastoma may be treated with molecular radiotherapy, 131I meta-Iodobenzylguanidine and 177Lu Lutetium DOTATATE, directed at distinct molecular targets: Noradrenaline Transporter Molecule (NAT) and Somatostatin Receptor (SSTR2), respectively. This study used immunohistochemistry to evaluate target expression in archival neuroblastoma tissue, to determine whether it might facilitate clinical use of molecular radiotherapy. Tissue bank samples of formalin fixed paraffin embedded neuroblastoma tissue from patients for whom clinical outcome data were available were sectioned and stained with haematoxylin and eosin, and monoclonal antibodies directed against NAT and SSTR2. Sections were examined blinded to clinical information and scored for the percentage and intensity of tumour cells stained. These data were analysed in conjunction with clinical data. Tissue from 75 patients was examined. Target expression scores varied widely between patients: NAT median 45%, inter-quartile range 25% - 65%; and SSTR2 median 55%, interquartile range 30% – 80%; and in some cases heterogeneity of expression between different parts of a tumour was observed. A weak positive correlation was observed between the expression scores of the different targets: correlation coefficient = 0.23, p = 0.05. MYCN amplified tumours had lower SSTR2 scores: mean difference 23% confidence interval 8% - 39%, p

Disease relapse is the major cause of treatment failure after allogeneic stem cell transplantation (allo-SCT) in acute myeloid leukemia (AML). To identify AML-associated genes prognostic of AML relapse post–allo-SCT, we resequenced 35 genes in 113 adults at diagnosis, 49 of whom relapsed. Two hundred sixty-two mutations were detected in 102/113 (90%) patients. An increased risk of relapse was observed in patients with mutations in WT1 (P = .018), DNMT3A (P = .045), FLT3 ITD (P = .071), and TP53 (P = .06), whereas mutations in IDH1 were associated with a reduced risk of disease relapse (P = .018). In 29 patients, we additionally compared mutational profiles in bone marrow at diagnosis and relapse to study changes in clonal structure at relapse. In 13/29 patients, mutational profiles altered at relapse. In 9 patients, mutations present at relapse were not detected at diagnosis. In 15 patients, additional available pre–allo-SCT samples demonstrated that mutations identified posttransplant but not at diagnosis were detectable immediately prior to transplant in 2 of 15 patients. Taken together, these observations, if confirmed in larger studies, have the potential to inform the design of novel strategies to reduce posttransplant relapse highlighting the potential importance of post–allo-SCT interventions with a broad antitumor specificity in contrast to targeted therapies based on mutational profile at diagnosis.

Summary Background The INTERVAL trial showed that, over a 2-year period, inter-donation intervals for whole blood donation can be safely reduced to meet blood shortages. We extended the INTERVAL trial for a further 2 years to evaluate the longer-term risks and benefits of varying inter-donation intervals, and to compare routine versus more intensive reminders to help donors keep appointments. Methods The INTERVAL trial was a parallel group, pragmatic, randomised trial that recruited blood donors aged 18 years or older from 25 static donor centres of NHS Blood and Transplant across England, UK. Here we report on the prespecified analyses after 4 years of follow-up. Participants were whole blood donors who agreed to continue trial participation on their originally allocated inter-donation intervals (men: 12, 10, and 8 weeks; women: 16, 14, and 12 weeks). They were further block-randomised (1:1) to routine versus more intensive reminders using computer-generated random sequences. The prespecified primary outcome was units of blood collected per year analysed in the intention-to-treat population. Secondary outcomes related to safety were quality of life, self-reported symptoms potentially related to donation, haemoglobin and ferritin concentrations, and deferrals because of low haemoglobin and other factors. This trial is registered with ISRCTN, number ISRCTN24760606, and has completed. Findings Between Oct 19, 2014, and May 3, 2016, 20 757 of the 38 035 invited blood donors (10 843 [58%] men, 9914 [51%] women) participated in the extension study. 10 378 (50%) were randomly assigned to routine reminders and 10 379 (50%) were randomly assigned to more intensive reminders. Median follow-up was 1·1 years (IQR 0·7–1·3). Compared with routine reminders, more intensive reminders increased blood collection by a mean of 0·11 units per year (95% CI 0·04–0·17; p=0·0003) in men and 0·06 units per year (0·01–0·11; p=0·0094) in women. During the extension study, each week shorter inter-donation interval increased blood collection by a mean of 0·23 units per year (0·21–0·25) in men and 0·14 units per year (0·12–0·15) in women (both p0.0001 for tests of linear trend by inter-donation intervals) other than a higher reported frequency of doctor-diagnosed low iron concentrations and prescription of iron supplements in men (p

Abstract Background Despite multiple randomised trials in newly diagnosed Ewing sarcoma family of tumours (ESFT), over many years, and involving many international co-operative groups, the outcomes for all stages of disease have plateaued. Internationally, the standard treatment of ESFT is not defined, and there is a need to add new agents other than conventional chemotherapy to improve outcomes. This trial will compare two different induction/consolidation chemotherapy regimens vincristine, ifosfamide, doxorubicin and etoposide (VIDE) induction and vincristine, actinomycin D, ifosfamide or cyclophosphamide, or Busulfan and Mephalan (VAI/VAC/BuMel) consolidation compared with vincristine, doxorubicin, cyclophosphamide, ifosfamide and etoposide (VDC/IE) induction and ifosfamide and etoposide, vincristine and cyclophosphamide, vincristine, actinomycin D and ifosfamide, or Busulfan and Mephalan (IE/VC/VAI/ BuMel) consolidation- randomisation 1 (R1). A second randomisation (R2) will determine whether the addition of zoledronic acid to consolidation chemotherapy, as assigned at R1, is associated with improved clinical outcome. Methods EURO EWING 2012 is an international, multicentre, phase III, open-label randomised controlled trial. There are two randomisations: R1 and R2. Patients are randomised at two different time points, at entry to the trial (R1) and following local control therapy (R2). The primary outcome measure is event-free survival. The secondary outcome measures include overall survival, adverse events and toxicity, histological response of the primary tumour, response of the primary tumour, regional lymph nodes and/or metastases, and achievement of local control at the end of treatment. Discussion This study will establish which is the "standard regimen" of chemotherapy, taking into account both clinical outcomes and toxicity. This will form the chemotherapy backbone for future interventional studies where we may want to add new targeted agents. It will also determine the role of zoledronic acid, in conjunction with the separate EE2008 trial. Any trial in ESFT needs to take into account the rarity of the tumour and that international co-operation is needed to provide answers in a timely manner. Trial registration Registered with EudraCT number 2012-002107-17 on 26th February 2012. Registered with ISRCTN number 54540667 on 4th November 2013.

Background:\ud The ASTRAL trial showed no difference in clinical outcomes between medical therapy and revascularization for atherosclerotic renal vascular disease (ARVD). Here we report a sub-study using echocardiography to assess differences in cardiac structure and function at 12 months.\ud \ud Methods:\ud ASTRAL patients from 7 participating centres underwent echocardiography at baseline and 12 months after randomisation. Changes in left ventricular ejection fraction (LVEF), left ventricular mass (LVM), left atrial diameter (LAD), aortic root diameter (AoRD), E:A, and E deceleration time (EDT) were compared between study arms. Analyses were performed using t-tests and multivariate linear regression.\ud \ud Results:\ud Ninety two patients were included (50 medical versus 42 revascularization). There was no difference between arms in any baseline echocardiographic parameter. Comparisons of longitudinal changes in echocardiographic measurements were: δLVEF medical 0.8 ± 8.7% versus revascularization − 2.8 ± 6.8% (p = 0.05), δLVM − 2.9 ± 33 versus − 1.7 ± 39 g (p = 0.9), δLAD 0.1 ± 0.4 versus 0.01 ± 0.5 cm (p = 0.3), δAoRD 0.002 ± 0.3 versus 0.06 ± 0.3 cm (p = 0.4), δE:A − 0.0005 ± 0.6 versus 0.03 ± 0.7 (p = 0.8), δEDT − 1.1 ± 55.5 versus − 9.0 ± 70.2 ms (p = 0.6). In multivariate models, there were no differences between treatment groups for any parameter at 12 months. Likewise, change in blood pressure did not differ between arms (mean δsystolic blood pressure medical 0 mmHg [range − 56 to + 54], revascularization − 3 mmHg [− 61 to + 59], p = 0.60).\ud \ud Conclusions:\ud This sub-study did not show any significant differences in cardiac structure and function accompanying renal revascularization in ASTRAL. Limitations include the small sample size, the relative insensitivity of echocardiography, and the fact that a large proportion of ASTRAL patient population had only modest renal artery stenosis as described in the main study.

Objective To determine whether extending initial prednisolone treatment from eight to 16 weeks in children with idiopathic steroid sensitive nephrotic syndrome improves the pattern of disease relapse. Design Double blind, parallel group, phase III randomised placebo controlled trial, including a cost effectiveness analysis. Setting 125 UK National Health Service district general hospitals and tertiary paediatric nephrology centres. Participants 237 children aged 1-14 years with a first episode of steroid sensitive nephrotic syndrome. Interventions Children were randomised to receive an extended 16 week course of prednisolone (total dose 3150 mg/m 2 ) or a standard eight week course of prednisolone (total dose 2240 mg/m 2 ). The drug was supplied as 5 mg tablets alongside matching placebo so that participants in both groups received the same number of tablets at any time point in the study. A minimisation algorithm ensured balanced treatment allocation by ethnicity (South Asian, white, or other) and age (5 years or less, 6 years or more). Main outcome measures The primary outcome measure was time to first relapse over a minimum follow-up of 24 months. Secondary outcome measures were relapse rate, incidence of frequently relapsing nephrotic syndrome and steroid dependent nephrotic syndrome, use of alternative immunosuppressive treatment, rates of adverse events, behavioural change using the Achenbach child behaviour checklist, quality adjusted life years, and cost effectiveness from a healthcare perspective. Analysis was by intention to treat. Results No significant difference was found in time to first relapse (hazard ratio 0.87, 95% confidence interval 0.65 to 1.17, log rank P=0.28) or in the incidence of frequently relapsing nephrotic syndrome (extended course 60/114 (53%) v standard course 55/109 (50%), P=0.75), steroid dependent nephrotic syndrome (48/114 (42%) v 48/109 (44%), P=0.77), or requirement for alternative immunosuppressive treatment (62/114 (54%) v 61/109 (56%), P=0.81). Total prednisolone dose after completion of the trial drug was 6674 mg for the extended course versus 5475 mg for the standard course (P=0.07). There were no statistically significant differences in serious adverse event rates (extended course 19/114 (17%) v standard course 27/109 (25%), P=0.13) or adverse event rates, with the exception of behaviour, which was poorer in the standard course group. Scores on the Achenbach child behaviour checklist did not, however, differ. Extended course treatment was associated with a mean increase in generic quality of life (0.0162 additional quality adjusted life years, 95% confidence interval −0.005 to 0.037) and cost savings (difference −£1673 ($2160; €1930), 95% confidence interval −£3455 to £109). Conclusions Clinical outcomes did not improve when the initial course of prednisolone treatment was extended from eight to 16 weeks in UK children with steroid sensitive nephrotic syndrome. However, evidence was found of a short term health economic benefit through reduced resource use and increased quality of life. Trial registration ISRCTN16645249; EudraCT 2010-022489-29.

BackgroundThe optimal corticosteroid regimen for treating the presenting episode of steroid-sensitive nephrotic syndrome (SSNS) remains uncertain. Most UK centres use an 8-week regimen, despite previous systematic reviews indicating that longer regimens reduce the risk of relapse and frequently relapsing nephrotic syndrome (FRNS).ObjectivesThe primary objective was to determine whether or not an extended 16-week course of prednisolone increases the time to first relapse. The secondary objectives were to compare the relapse rate, FRNS and steroid-dependent nephrotic syndrome (SDNS) rates, requirement for alternative immunosuppressive agents and corticosteroid-related adverse events (AEs), including adverse behaviour and costs.DesignRandomised double-blind parallel-group placebo-controlled trial, including a cost-effectiveness analysis.SettingOne hundred and twenty-five UK paediatric departments.ParticipantsTwo hundred and thirty-seven children presenting with a first episode of SSNS. Participants aged between 1 and 15 years were randomised (1 : 1) according to a minimisation algorithm to ensure balance of ethnicity (South Asian, white or other) and age (≤ 5 or ≥ 6 years).InterventionsThe control group (n = 118) received standard course (SC) prednisolone therapy: 60 mg/m2/day of prednisolone in weeks 1–4, 40 mg/m2of prednisolone on alternate days in weeks 5–8 and matching placebo on alternate days in weeks 9–18 (total 2240 mg/m2). The intervention group (n = 119) received extended course (EC) prednisolone therapy: 60 mg/m2/day of prednisolone in weeks 1–4; started at 60 mg/m2of prednisolone on alternate days in weeks 5–16, tapering by 10 mg/m2every 2 weeks (total 3150 mg/m2).Main outcome measuresThe primary outcome measure was time to first relapse [Albustix®(Siemens Healthcare Limited, Frimley, UK)-positive proteinuria +++ or greater for 3 consecutive days or the presence of generalised oedema plus +++ proteinuria]. The secondary outcome measures were relapse rate, incidence of FRNS and SDNS, other immunosuppressive therapy use, rates of serious adverse events (SAEs) and AEs and the incidence of behavioural change [using Achenbach Child Behaviour Checklist (ACBC)]. A comprehensive cost-effectiveness analysis was performed. The analysis was by intention to treat. Participants were followed for a minimum of 24 months.ResultsThere was no significant difference in time to first relapse between the SC and EC groups (hazard ratio 0.87, 95% confidence interval 0.65 to 1.17; log-rankp = 0.3). There were also no differences in the incidence of FRNS (SC 50% vs. EC 53%;p = 0.7), SDNS (44% vs. 42%;p = 0.8) or requirement for other immunosuppressive therapy (56% vs. 54%;p = 0.8). The total prednisolone dose received following completion of study medication was 5475 mg vs. 6674 mg (p = 0.07). SAE rates were not significantly different (25% vs. 17%;p = 0.1) and neither were AEs, except poor behaviour (yes/no), which was less frequent with EC treatment. There were no differences in ACBC scores. EC therapy was associated with a mean increase in generic health benefit [0.0162 additional quality-adjusted life-years (QALYs)] and cost savings (£4369 vs. £2696).LimitationsStudy drug formulation may have prevented some younger children who were unable to swallow whole or crushed tablets from participating.ConclusionsThis trial has not shown any clinical benefit for EC prednisolone therapy in UK children. The cost-effectiveness analysis suggested that EC therapy may be cheaper, with the possibility of a small QALY benefit.Future workStudies investigating EC versus SC therapy in younger children and further cost-effectiveness analyses are warranted.Trial registrationCurrent Controlled Trials ISRCTN16645249 and EudraCT 2010-022489-29.FundingThis project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 23, No. 26. See the NIHR Journals Library website for further project information.

We previously reported the safety and efficacy of low dose BaP [Bezafibrate (Bez) and Medroxyprogesterone acetate (MPA)] in 20 acute myeloid leukaemia (AML) patients for whom chemotherapy was not an option. This study provided evidence that BaP had anti-AML activity and improved haemopoiesis; absence of haematological toxicity allowed continuous daily administration. Similarly a previous trial in endemic Burkitt lymphoma demonstrated anti-B cell lymphoma activity of low and high dose BaP again in the absence of toxicity.We conducted a study to further evaluate the safety and activity of high dose BaP therapy in adults with AML (and high risk Myelodysplastic Syndromes (MDS)), chronic lymphocytic leukaemia (CLL) or B-cell Non-Hodgkin Lymphoma (BHNL). Eighteen patients were recruited to the study over 20 months, 16 AML/MDS, 1 CLL, and 1 BNHL. Although MPA was well tolerated throughout the study, only 2 patients were able to tolerate Bez treatment for their whole trial duration, indicating that Bez escalation is not feasible in the setting of adult AML/MDS. Thus there has been no obvious benefit in improved haemopoiesis or overt anti-leukaemia activity from the attempts to escalate BaP dose over previous published studies. Since current therapeutic options in MDS are restricted it may be now of value to continue to evaluate low dose BaP based approaches in low risk MDS rather than AML/high risk MDS. Furthermore, screening of low dose BaP against libraries of other already available dugs may identify an addition to BaP that augments the anti-neoplastic efficacy without significant toxicity. Keywords: Clinical trials, Myeloid leukaemia, Lymphoid malignancies, Therapy, Bezafibrate, Progesterone

PURPOSE The R2Pulm trial was conducted to evaluate the effect of busulfan-melphalan high-dose chemotherapy with autologous stem-cell rescue (BuMel) without whole-lung irradiation (WLI) on event-free survival (main end point) and overall survival, compared with standard chemotherapy with WLI in Ewing sarcoma (ES) presenting with pulmonary and/or pleural metastases. METHODS From 2000 to 2015, we enrolled patients younger than 50 years of age with newly diagnosed ES and with only pulmonary or pleural metastases. Patients received chemotherapy with six courses of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) and one course of vincristine, dactinomycin, and ifosfamide (VAI) before either BuMel or seven courses of VAI and WLI (VAI plus WLI) by randomized assignment. The analysis was conducted as intention to treat. The estimates of the hazard ratio (HR), 95% CI, and P value were corrected for the three previous interim analyses by the inverse normal method. RESULTS Of 543 potentially eligible patients, 287 were randomly assigned to VAI plus WLI (n = 143) or BuMel (n = 144). Selected patients requiring radiotherapy to an axial primary site were excluded from randomization to avoid excess organ toxicity from interaction between radiotherapy and busulfan. Median follow-up was 8.1 years. We did not observe any significant difference in survival outcomes between treatment groups. Event-free survival was 50.6% versus 56.6% at 3 years and 43.1% versus 52.9% at 8 years, for VAI plus WLI and BuMel patients, respectively, resulting in an HR of 0.79 (95% CI, 0.56 to 1.10; P = .16). For overall survival, the HR was 1.00 (95% CI, 0.70 to 1.44; P = .99). Four patients died as a result of BuMel-related toxicity, and none died after VAI plus WLI. Significantly more patients in the BuMel arm experienced severe acute toxicities than in the VAI plus WLI arm. CONCLUSION In ES with pulmonary or pleural metastases, there is no clear benefit from BuMel compared with conventional VAI plus WLI.

ObjectiveTo determine the likely rate of patient randomisation and to facilitate sample size calculation for a full-scale phase III trial of varicella zoster immunoglobulin (VZIG) and aciclovir as postexposure prophylaxis against chickenpox in children with cancer.DesignMulticentre pilot randomised controlled trial of VZIG and oral aciclovir.SettingEngland, UK.PatientsChildren under 16 years of age with a diagnosis of cancer: currently or within 6 months of receiving cancer treatment and with negative varicella zoster virus (VZV) serostatus at diagnosis or within the last 3 months.InterventionsStudy participants who have a significant VZV exposure were randomised to receive PEP in the form of VZIG or aciclovir after the exposure.Main outcome measuresNumber of patients registered and randomised within 12 months of the trial opening to recruitment and incidence of breakthrough varicella.ResultsThe study opened in six sites over a 13-month period. 482 patients were screened for eligibility, 32 patients were registered and 3 patients were randomised following VZV exposure. All three were randomised to receive aciclovir and there were no cases of breakthrough varicella.ConclusionsGiven the limited recruitment to the PEPtalk2 pilot, it is unlikely that the necessary sample size would be achievable using this strategy in a full-scale trial. The study identified factors that could be used to modify the design of a definitive trial but other options for defining the best means to protect such children against VZV should be explored.Trial registration numberISRCTN48257441, EudraCT number: 2013-001332-22, sponsor: University of Birmingham.

Background Surgery is the only curative treatment for primary cutaneous melanoma, therefore it is important to determine excision margins that minimise risk of local recurrence, distant recurrence and death. Methods MEDLINE, EMBASE and Cochrane CENTRAL were searched from 2009 to 2015. Inclusion criteria were: population/setting – patients with primary melanoma; comparison – narrow versus wide margins; outcomes – overall survival, melanoma-specific survival, recurrence-free survival, and loco-regional recurrence; design – randomized controlled trials (RCTs). Results were pooled using meta-analysis and data explored using likelihood Bayesian probability plots. Results Six RCTs with 4233 patients were included. Narrow margins were defined as 1 or 2cm of clinically normal skin around the melanoma; wide margins as 3, 4 or 5cm. Hazard ratios (HR) were as follows (HR>1 indicates wide margin better): overall survival 1.09 (95% CI 0.98–1.22; p =0.1); melanoma-specific survival 1.17 (CI 1.03–1.34; p =0.02); recurrence-free survival 1.08 (CI 0.97–1.20; p =0.2); loco-regional recurrence 1.10 (CI 0.96–1.26; p =0.2), with no evidence of heterogeneity between trials for any end point or within subgroup analyses. There was an 94% probability that overall survival was worse with a narrow margin and a 43% probability that it was more than 10% worse in proportional terms (i.e. HR>1.1). Probabilities that narrow margins were worse were 99%, 92% and 92% for melanoma-specific survival, recurrence-free survival and loco-regional recurrence respectively. Conclusions Contrary to recommendations in several national guidelines that narrow margins are safe, this systematic review and meta-analysis provides evidence that a narrow margin may lead to a worse outcome than a wide margin.

11500 Background: In 2010, different chemotherapy regimens were standard in Europe and the USA for newly diagnosed ES. In the absence of novel agents to investigate, comparison of these two strategies was considered worthwhile. Methods: Newly diagnosed localised or metastatic ES patients aged 5-50 were eligible. Patients were randomized to receive either the European regimen (Arm A) of VIDE (vincristine [V], ifosfamide [I], doxorubicin [D] and etoposide [E]) induction and VAI or VAC (V, actinomycin D and I or cyclophosphamide [C]) consolidation or the USA regimen (Arm B) of compressed VDC/IE induction and IE/VC consolidation. The primary outcome measure was event-free survival (EFS); secondary outcomes included overall survival (OS) and toxicity. The design was Bayesian with interpretation based on posterior probabilities (with non-informative priors) – i.e. probability that true hazard ratio (HR) < 1.0 given the data [Pr(HR200 ml); country (37% UK, 31% France, 32% other). Median follow-up was 1.7 years. The HRs (95% CrI) were 0.70 (0.51, 0.95) for EFS and 0.64 (0.42, 0.96) for OS in favour of Arm B, with posterior probabilities of 98% for both that Arm B was better. Subgroup analyses showed no evidence that this benefit differed depending the baseline features, with no HT being close to significance (table). There were no major differences in acute toxicity: 68% of patients in Arm A experienced serious adverse events and 67% in Arm B. Conclusions: VDC/IE chemotherapy is superior to VIDE for both EFS and OS, with no excess toxicity. This benefit is consistent across all baseline stratification parameters. Clinical trial information: ISRCTN92192408 . [Table: see text]