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Our international team highlights issues with efficacy reports in several studies on DMG with the new drug ONC201.

Purpose: Hearing loss occurs in 50%-70% of children treated with cisplatin. Scientific efforts have led to the recent approval of a pediatric formula of intravenous sodium thiosulfate (STS) for otoprotection by the US Food and Drug Administration, the European Medicines Agency, and the Medicines and Health Regulatory Authority in the United Kingdom. To inform stakeholders regarding the clinical utility of STS, the current review summarizes available literature on the efficacy, pharmacokinetics (PK), and safety of systemic STS to minimize cisplatin-induced hearing loss (CIHL)., Design: A comprehensive narrative review is presented., Results: Thirty-one articles were summarized. Overall, systemic STS effectively reduces CIHL in the preclinical and controlled clinical study settings, in both adults and children with cancer. The extent of CIHL reduction depends on the timing and dosing of STS in relation to cisplatin. Both preclinical and clinical data suggest that systemic STS may affect plasma platinum levels, but studies are inconclusive. Delayed systemic administration of STS, at 6 hours after the cisplatin infusion, does not affect cisplatin-induced inhibition of tumor growth or cellular cytotoxicity in the preclinical setting, nor affect cisplatin efficacy and survival in children with localized disease in the clinical setting., Conclusion: Systemic administration of STS effectively reduces the development and degree of CIHL in both the preclinical and clinical settings. More studies are needed on the PK of STS and cisplatin drug combinations, the efficacy and safety of STS in patients with disseminated disease, and the ability of STS to prevent further deterioration of pre-established hearing loss.

The International Society of Paediatric Oncology (SIOP) launched a program to map all pediatric cancer facilities around the world. After the results in Africa were completed, the strategy for data collection for Latin America was revised to improve the accuracy and avoid duplications. In partnership with SIOP, the Sociedad Latino Americana de Oncología Pediátrica (SLAOP) approached their delegates who provided the contacts for a 10-question survey about their institutional capacities. Data were collected by email, online meetings, or telephone calls, and stored in a secure platform. All but one country participated and a high number of centers were recorded., (© 2023 Wiley Periodicals LLC.)

Aim: This phase I/expansion study assessed the safety, pharmacokinetics and preliminary antitumor activity of afatinib in paediatric patients with cancer., Methods: The dose-finding part enroled patients (2-<18 years) with recurrent/refractory tumours. Patients received 18 or 23 mg/m 2 /d afatinib orally (tablet or solution) in 28-d cycles. In the maximum tolerated dose (MTD) expansion, eligible patients (1-<18 years) had tumours fulfilling ≥2 of the following criteria in the pre-screening: EGFR amplification; HER2 amplification; EGFR membrane staining (H-score>150); HER2 membrane staining (H-score>0). The primary end-points were dose-limiting toxicities (DLTs), afatinib exposure, and objective response., Results: Of 564 patients pre-screened, 536 patients had biomarker data and 63 (12%) fulfilled ≥2 EGFR/HER2 criteria required for inclusion in the expansion part. A total of 56 patients were treated (17 in the dose-finding and 39 in the expansion part). DLTs were observed in one of six MTD-evaluable patients receiving 18 mg/m²/d and in two of five MTD-evaluable patients receiving 23 mg/m²/d; 18 mg/m²/d was defined as the MTD. There were no new safety signals. Pharmacokinetics confirmed exposure consistent with the approved dose in adults. One partial response (-81% per Response Assessment in Neuro-Oncology) was observed in a patient with a glioneuronal tumour harbouring a CLIP2::EGFR fusion; unconfirmed partial responses were observed in two patients. In total, 25% of patients experienced objective response or stable disease (95% confidence interval: 14-38)., Conclusion: Targetable EGFR/HER2 drivers are rare in paediatric cancers. Treatment with afatinib led to a durable response (>3 years) in one patient with a glioneuronal tumour with CLIP2::EGFR fusion., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Birgit Geoerger reports being paid for a consulting/advisory role by Boehringer Ingelheim, AstraZeneca, and Novartis. Lynley Marshall reports being paid for a consulting/advisory role, honoraria, and participating in a speakers’ bureau by Bayer; and a consulting/advisory role by Illumina, BMS and Tesaro, and participation in independent data monitoring committees for studies run by Eisai and Merck. Karsten Nysom reports being paid for a consulting or advisory role and honoraria by Y-mAbs and Bayer; being paid for a consulting/advisory role by EUSA Pharma and for participation in independent data monitoring committee for a study run by Lilly; and has received travel/accommodation/expenses from Bayer. Eric Bouffet reports being paid for a consulting or advisory role by Novartis, Bayer, and Roche, and has received institutional research funding grants from Roche and BMS. Isabelle Aerts reports being paid for a consulting/advisory role by AstraZeneca. Kim Van Vlerken reports being an employee of Boehringer Ingelheim and has been compensated for a leadership role on clinical trials for Boehringer Ingelheim. Eric Fu and Flavio Solca report being employees of Boehringer Ingelheim. Robert M. Lorence reports both being an employee of Boehringer Ingelheim and being paid for a consulting/advisory role by Boehringer Ingelheim. David S. Ziegler reports being paid for a consulting/advisory role by Bayer, AstraZeneca, Accendatech, Novartis, Day One, FivePhusion, Amgen, Alexion and Norgine. Guy Makin, Anne-Sophie Defachelles, Loredana Amoroso, Pierre Leblond and Paulette Barahona report no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Competing Interests: Daniel A. MorgensternHonoraria: Ology Medical Education, WebMD, PlatformQ HealthConsulting or Advisory Role: Clarity Pharmaceuticals, EUSA Pharma, Ymabs Therapeutics IncSpeakers' Bureau: Ymabs Therapeutics IncResearch Funding: Bristol Myers Squibb (Inst), AbbVie (Inst), Lilly (Inst), Bayer (Inst), Cellectar (Inst), Roche (Inst)Travel, Accommodations, Expenses: Lilly Sumedha SudhamanEmployment: Strand Life Sciences David E. KramConsulting or Advisory Role: Foundation Medicine Cynthia HawkinsConsulting or Advisory Role: BayerPatents, Royalties, Other Intellectual Property: IP for low-grade glioma and sarcoma fusion panels as well as medulloblastoma subgrouping panel Eric BouffetConsulting or Advisory Role: NovartisResearch Funding: Roche (Inst), Bristol Myers Squibb (Inst) Yoon-Jae ChoExpert Testimony: Barr and MudfordNo other potential conflicts of interest were reported.

Background: The COVID-19 pandemic has had a major impact on access to health care resources. Our objective was to estimate the impact of the COVID-19 pandemic on the incidence of childhood cancer in Canada. We also aimed to compare the proportion of patients who enrolled in clinical trials at diagnosis, presented with metastatic disease or had an early death during the first 9 months of the COVID-19 pandemic compared with previous years., Methods: We conducted an observational study that included children younger than 15 years with a new diagnosis of cancer between March 2016 and November 2020 at 1 of 17 Canadian pediatric oncology centres. Our primary outcome was the monthly age-standardized incidence rates (ASIRs) of cancers. We evaluated level and trend changes using interventional autoregressive integrated moving average models. Secondary outcomes were the proportion of patients who were enrolled in a clinical trial, who had metastatic or advanced disease and who died within 30 days. We compared the baseline and pandemic periods using rate ratios (RRs) and 95% confidence intervals (CIs)., Results: Age-standardized incidence rates during COVID-19 quarters were 157.7, 164.6, and 148.0 per million, respectively, whereas quarterly baseline ASIRs ranged between 150.3 and 175.1 per million (incidence RR 0.93 [95% CI 0.78 to 1.12] to incidence RR 1.04 [95% CI 0.87 to 1.24]). We found no statistically significant level or slope changes between the projected and observed ASIRs for all new cancers (parameter estimate [β], level 4.98, 95% CI -15.1 to 25.04, p = 0.25), or when stratified by cancer type or by geographic area. Clinical trial enrolment rate was stable or increased during the pandemic compared with baseline (RR 1.22 [95% CI 0.70 to 2.13] to RR 1.71 [95% CI 1.01 to 2.89]). There was no difference in the proportion of patients with metastatic disease (RR 0.84 [95% CI 0.55 to 1.29] to RR 1.22 [0.84 to 1.79]), or who died within 30 days (RR 0.16 [95% CI 0.01 to 3.04] to RR 1.73 [95% CI 0.38 to 15.2])., Interpretation: We did not observe a statistically significant change in the incidence of childhood cancer, or in the proportion of children enrolling in a clinical trial, presenting with metastatic disease or who died early during the first 9 months of the COVID-19 pandemic, which suggests that access to health care in pediatric oncology was not reduced substantially in Canada., Competing Interests: Competing interests: None declared., (© 2021 CMA Joule Inc. or its licensors.)

Introduction: Inalignment with the World Health Organization (WHO) Global Initiative for Childhood Cancer (GICC), the International Society of Pediatric Oncology initiated a program to map global pediatric oncology services. As survival rates in Africa are low and data are scant, this continent was mapped first to identify areas with greatest need., Methods: Beginning November 2018, an electronic survey was sent to all known stakeholders, followed by email communications and internet searches to verify data. Availability of pediatric oncologists, chemotherapy, surgical expertise, and radiotherapy was correlated with geographic region, World Bank income status, Universal Health Coverage, population < 15 and < 24 years, percentage of gross domestic product spent on healthcare, and Human Development Index (HDI)., Results: Responses were received from 48/54 African countries. All three treatment modalities were reportedly available in 9/48 countries, whereas seven countries reported no pediatric oncology services. Negative correlations were detected between provision of all three services and geographic region (P = 0.01), younger median population age (P = 0.002), low-income country status (P = 0.045), and lower HDI (P < 0.001)., Conclusion: This study provides a comprehensive overview of pediatric oncology care in Africa, emphasizing marked disparities between countries: some have highly specialized services, whereas others have no services. A long-term strategy to eliminate disparities in African pediatric cancer care should be aligned with the WHO GICC aims and facilitated by SIOP Africa., Meeting Abstracts: SIOP maps pediatric oncology services in Africa to address inequalities in childhood cancer services. Geel J, Ranasinghe N, Davidson A, Challinor J, Howard S, Wollaert S, Myezo K, Renner L, Hessissen L, Bouffet E. 51st Annual Congress of the International Society of Paediatric Oncology (SIOP), Lyon, France, October 2019. Pediatric Blood and Cancer Vol 66 S219-S219. Pediatric cancer care in Africa: SIOP Global Mapping Program report on economic and population indicators., (© 2021 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

Importance: Ototoxicity is an irreversible direct and late effect of certain childhood cancer treatments. Audiologic surveillance during therapy as part of the supportive care pathway enables early detection of hearing loss, decision-making about ongoing cancer treatment, and, when applicable, the timely use of audiologic interventions. Pediatric oncologic clinical practice and treatment trials have tended to be driven by tumor type and tumor-specific working groups. Internationally accepted standardized recommendations for monitoring hearing during treatment have not previously been agreed on., Objective: To provide standard recommendations on hearing loss monitoring during childhood cancer therapy for clinical practice., Methods: An Ototoxicity Task Force was formed under the umbrella of the International Society of Paediatric Oncology, consisting of international audiologists, otolaryngologists, and leaders in the field of relevant pediatric oncology tumor groups. Consensus meetings conducted by experts were organized, aimed at providing standardized recommendations on age-directed testing, timing, and frequency of monitoring during cancer treatment based on literature and consensus. Consensus statements were prepared by the core group, adapted following several videoconferences, and finally agreed on by the expert panel., Findings: The consensus reached was that children who receive ototoxic cancer treatment (platinum agents, cranial irradiation, and/or brain surgery) require a baseline case history, monitoring of their middle ear and inner ear function, and assessment of tinnitus at each audiologic follow-up. As a minimum, age-appropriate testing should be performed before and at the end of treatment. Ideally, audiometry with counseling before each cisplatin cycle should be considered in the context of the individual patient, specific disease, feasibility, and available resources., Conclusions and Relevance: This is an international multidisciplinary consensus report providing standardized supportive care recommendations on hearing monitoring in children undergoing potentially ototoxic cancer treatment. The recommendations are intended to improve the care of children with cancer and facilitate comparative research on the timing and development of hearing loss caused by different cancer treatment regimens.

Background: Previous studies have shown that children and adolescents with COVID-19 generally have mild disease. Children and adolescents with cancer, however, can have severe disease when infected with respiratory viruses. In this study, we aimed to understand the clinical course and outcomes of SARS-CoV-2 infection in children and adolescents with cancer., Methods: We did a cohort study with data from 131 institutions in 45 countries. We created the Global Registry of COVID-19 in Childhood Cancer to capture de-identified data pertaining to laboratory-confirmed SARS-CoV-2 infections in children and adolescents (<19 years) with cancer or having received a haematopoietic stem-cell transplantation. There were no centre-specific exclusion criteria. The registry was disseminated through professional networks through email and conferences and health-care providers were invited to submit all qualifying cases. Data for demographics, oncological diagnosis, clinical course, and cancer therapy details were collected. Primary outcomes were disease severity and modification to cancer-directed therapy. The registry remains open to data collection., Findings: Of 1520 submitted episodes, 1500 patients were included in the study between April 15, 2020, and Feb 1, 2021. 1319 patients had complete 30-day follow-up. 259 (19·9%) of 1301 patients had a severe or critical infection, and 50 (3·8%) of 1319 died with the cause attributed to COVID-19 infection. Modifications to cancer-directed therapy occurred in 609 (55·8%) of 1092 patients receiving active oncological treatment. Multivariable analysis revealed several factors associated with severe or critical illness, including World Bank low-income or lower-middle-income (odds ratio [OR] 5·8 [95% CI 3·8-8·8]; p<0·0001) and upper-middle-income (1·6 [1·2-2·2]; p=0·0024) country status; age 15-18 years (1·6 [1·1-2·2]; p=0·013); absolute lymphocyte count of 300 or less cells per mm 3 (2·5 [1·8-3·4]; p<0·0001), absolute neutrophil count of 500 or less cells per mm 3 (1·8 [1·3-2·4]; p=0·0001), and intensive treatment (1·8 [1·3-2·3]; p=0·0005). Factors associated with treatment modification included upper-middle-income country status (OR 0·5 [95% CI 0·3-0·7]; p=0·0004), primary diagnosis of other haematological malignancies (0·5 [0·3-0·8]; p=0·0088), the presence of one of more COVID-19 symptoms at the time of presentation (1·8 [1·3-2·4]; p=0·0002), and the presence of one or more comorbidities (1·6 [1·1-2·3]; p=0·020)., Interpretation: In this global cohort of children and adolescents with cancer and COVID-19, severe and critical illness occurred in one fifth of patients and deaths occurred in a higher proportion than is reported in the literature in the general paediatric population. Additionally, we found that variables associated with treatment modification were not the same as those associated with greater disease severity. These data could inform clinical practice guidelines and raise awareness globally that children and adolescents with cancer are at high-risk of developing severe COVID-19 illness., Funding: American Lebanese Syrian Associated Charities and the National Cancer Institute., Competing Interests: Declaration of interests EB participates on the data safety monitoring board or advisory board for Novartis and Bayer and reports institutional clinical trial support from Roche and Bristol Myers Squibb. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Although replication repair deficiency, either by mismatch repair deficiency (MMRD) and/or loss of DNA polymerase proofreading, can cause hypermutation in cancer, microsatellite instability (MSI) is considered a hallmark of MMRD alone. By genome-wide analysis of tumors with germline and somatic deficiencies in replication repair, we reveal a novel association between loss of polymerase proofreading and MSI, especially when both components are lost. Analysis of indels in microsatellites (MS-indels) identified five distinct signatures (MS-sigs). MMRD MS-sigs are dominated by multibase losses, whereas mutant-polymerase MS-sigs contain primarily single-base gains. MS deletions in MMRD tumors depend on the original size of the MS and converge to a preferred length, providing mechanistic insight. Finally, we demonstrate that MS-sigs can be a powerful clinical tool for managing individuals with germline MMRD and replication repair-deficient cancers, as they can detect the replication repair deficiency in normal cells and predict their response to immunotherapy. SIGNIFICANCE: Exome- and genome-wide MSI analysis reveals novel signatures that are uniquely attributed to mismatch repair and DNA polymerase. This provides new mechanistic insight into MS maintenance and can be applied clinically for diagnosis of replication repair deficiency and immunotherapy response prediction. This article is highlighted in the In This Issue feature, p. 995 ., (©2020 American Association for Cancer Research.)

POLE mutations are a major cause of hypermutant cancers, yet questions remain regarding mechanisms of tumorigenesis, genotype-phenotype correlation, and therapeutic considerations. In this study, we establish mouse models harboring cancer-associated POLE mutations P286R and S459F, which cause rapid albeit distinct time to cancer initiation in vivo , independent of their exonuclease activity. Mouse and human correlates enabled novel stratification of POLE mutations into three groups based on clinical phenotype and mutagenicity. Cancers driven by these mutations displayed striking resemblance to the human ultrahypermutation and specific signatures. Furthermore, Pole -driven cancers exhibited a continuous and stochastic mutagenesis mechanism, resulting in intertumoral and intratumoral heterogeneity. Checkpoint blockade did not prevent Pole lymphomas, but rather likely promoted lymphomagenesis as observed in humans. These observations provide insights into the carcinogenesis of POLE -driven tumors and valuable information for genetic counseling, surveillance, and immunotherapy for patients. SIGNIFICANCE: Two mouse models of polymerase exonuclease deficiency shed light on mechanisms of mutation accumulation and considerations for immunotherapy. See related commentary by Wisdom and Kirsch p. 5459 ., (©2020 American Association for Cancer Research.)

Purpose: Adequate clinical services have yet to be established in the majority of African countries, where childhood cancer survival rates vary from 8.1% to 30.3%. The aim of this review is to describe the landscape of pediatric oncology trials in Africa, identify challenges, and offer future opportunities for research collaborations., Methods: The study includes data from the International Pediatric Oncology Society (SIOP) global mapping survey, meta-research identifying trials in Africa in ClinicalTrials.gov, and a literature overview of publications on the subject of pediatric oncology clinical research supported by expert opinions on the current situation and challenges., Results: The SIOP global mapping survey received responses from 47 of 54 African countries, of which 23 have active clinical research programs. A preliminary search of ClinicalTrials.gov showed that only 105 (12.1%) of 868 African oncology studies included children and adolescents. Of these, 53 (50.5%) were interventional trials according to the registry's classification. The small number of African trials for children and adolescents included palliative care and leukemia trials. In African oncology journals and international pediatric oncology journals, < 1% of the pediatric oncology publications come from Africa. Services and research were strengthened by international collaboration. National studies focused on clinical needs, local challenges, or interventional priorities. Both the literature review and the expert opinions highlight the need to expand clinical research in Africa, despite ongoing regional instability and lack of resources., Conclusion: While a low number of pediatric clinical treatment trials are open to African children and adolescents, clinical research of high quality is being done in Africa. Several initiatives are stimulating the development of the research capacity across the continent, which should increase the publication output.

The COVID-19 pandemic is one of the most serious global challenges to delivering affordable and equitable treatment to children with cancer we have witnessed in the last few decades. This Special Report aims to summarize general principles for continuing multidisciplinary care during the SARS-CoV-2 (COVID-19) pandemic. With contributions from the leadership of the International Society for Pediatric Oncology (SIOP), Children's Oncology Group (COG), St Jude Global program, and Childhood Cancer International, we have sought to provide a framework for healthcare teams caring for children with cancer during the pandemic. We anticipate the burden will fall particularly heavily on children, their families, and cancer services in low- and middle-income countries. Therefore, we have brought together the relevant clinical leads from SIOP Europe, COG, and SIOP-PODC (Pediatric Oncology in Developing Countries) to focus on the six most curable cancers that are part of the WHO Global Initiative in Childhood Cancer. We provide some practical advice for adapting diagnostic and treatment protocols for children with cancer during the pandemic, the measures taken to contain it (e.g., extreme social distancing), and how to prepare for the anticipated recovery period., (© 2020 Wiley Periodicals, Inc.)

We estimate that there will be 13·7 million new cases of childhood cancer globally between 2020 and 2050. At current levels of health system performance (including access and referral), 6·1 million (44·9%) of these children will be undiagnosed. Between 2020 and 2050, 11·1 million children will die from cancer if no additional investments are made to improve access to health-care services or childhood cancer treatment. Of this total, 9·3 million children (84·1%) will be in low-income and lower-middle-income countries. This burden could be vastly reduced with new funding to scale up cost-effective interventions. Simultaneous comprehensive scale-up of interventions could avert 6·2 million deaths in children with cancer in this period, more than half (56·1%) of the total number of deaths otherwise projected. Taking excess mortality risk into consideration, this reduction in the number of deaths is projected to produce a gain of 318 million life-years. In addition, the global lifetime productivity gains of US$2580 billion in 2020-50 would be four times greater than the cumulative treatment costs of $594 billion, producing a net benefit of $1986 billion on the global investment: a net return of $3 for every $1 invested. In sum, the burden of childhood cancer, which has been grossly underestimated in the past, can be effectively diminished to realise massive health and economic benefits and to avert millions of needless deaths., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Purpose: The 2-part, phase I/IIa, open-label study (NCT01677741) sought to determine the safety, tolerability, pharmacokinetics, and preliminary activity of dabrafenib in pediatric patients with advanced BRAF V600-mutated cancers., Patients and Methods: This phase I dose-finding part treated patients ages 1 to <18 years with BRAF V600 mutation-positive tumors with oral dabrafenib 3 to 5.25 mg/kg/day to determine the RP2D based on safety and drug exposure target., Results: Between May 2013 and November 2014, 27 patients [12 male; median age, 9 years (range, 1-17 years)] with BRAF V600-mutant solid tumors recurrent/refractory to treatment (low- or high-grade glioma, Langerhans cell histiocytosis, neuroblastoma, or thyroid cancer) were enrolled. The median treatment duration was 75.6 weeks (range, 5.6-148.7 weeks), with 63% treated for >52 weeks and 52% undergoing treatment at data cutoff date. The most common grade 3/4 adverse events suspected to be related to study drug were maculopapular rash and arthralgia (2 patients each). No dose-limiting toxicities were observed. Pharmacokinetic analyses showed a dose-dependent increase in AUC 0-12 and achievement of adult exposure levels at the recommended phase II doses of 5.25 mg/kg/day (age <12 years) and 4.5 mg/kg/day (age ≥12 years) divided into 2 equal doses daily, not exceeding 300 mg daily., Conclusions: In this first clinical trial in pediatric patients with pretreated BRAF V600-mutant tumors, dabrafenib was well tolerated while achieving target exposure levels; the average treatment duration was >1 year with many patients still on treatment. The phase II component is also closed and will be reported separately., (©2019 American Association for Cancer Research.)

Each year ~429,000 children and adolescents aged 0 to 19 years are expected to develop cancer. Five-year survival rates exceed 80% for the 45,000 children with cancer in high-income countries (HICs) but are less than 30% for the 384,000 children in lower-middle-income countries (LMICs). Improved survival rates in HICs have been achieved through multidisciplinary care and research, with treatment regimens using mostly generic medicines and optimized risk stratification. Children's outcomes in LMICs can be improved through global collaborative partnerships that help local leaders adapt effective treatments to local resources and clinical needs, as well as address common problems such as delayed diagnosis and treatment abandonment. Together, these approaches may bring within reach the global survival target recently set by the World Health Organization: 60% survival for all children with cancer by 2030., (Copyright © 2019, American Association for the Advancement of Science.)

Combining mammalian target of rapamycin (mTOR) inhibitors and vinca alkaloids has shown therapeutic synergy in xenograft models of pediatric cancers. This phase I study assessed safety and toxicity of temsirolimus in combination with vinblastine in children., Procedure: Patients ≥ 1 and ≤ 18 years with recurrent/refractory solid or CNS tumors were eligible. Vinblastine (4 mg/m 2 ) and temsirolimus (15 mg/m 2 ) were administered i.v. weekly, with planned dose escalation of vinblastine using a rolling six phase I design. Pharmacokinetic and pharmacodynamic data were collected., Results: Seven patients with median age 12 years (range, 8-18 years) were enrolled; all were evaluable for toxicity and six for response. At dose level 1, four of six patients developed grade 3 mucositis, of which one met duration criteria for dose-limiting toxicity (DLT). Four patients required dose omissions for grade 3 or 4 hematologic toxicity, including one prolonged neutropenia DLT. A subsequent patient was enrolled on dose level -2 (temsirolimus 10 mg/m 2 , vinblastine 4 mg/m 2 ) with no protocol-related toxicity > grade 1, except grade 2 neutropenia. Two serious adverse events (SAE) occurred-an allergic reaction to temsirolimus (grade 2) and an intracranial hemorrhage in a CNS tumor patient (grade 3)-unlikely related to study therapy. Soluble VEGFR2 was reduced at cycle 1, day 36 in keeping with inhibition of angiogenesis. Four patients achieved prolonged stable disease for a median of 5.0 months (range, 3.1-8.3 months)., Conclusion: The combination of weekly temsirolimus (15 mg/m 2 ) and vinblastine (4 mg/m 2 ) exceeds the maximum tolerated dose in children, with frequent oral mucositis and hematologic toxicity., (© 2018 Wiley Periodicals, Inc.)

Pediatric radiotherapy is a critical part of pediatric oncology protocols and the quality of the radiotherapy may determine the future quality of life for long-term survivors. Multidisciplinary team decision making provides the basis for high-quality care. However, delivery of high-quality radiotherapy is dependent on resources. This article provides guidelines for delivery of good quality radiation therapy in resource-limited countries based on rational procurement and maintenance planning, protocol development, three-dimensional planning, quality assurance, and adequate staff numbers and training., (© 2017 Wiley Periodicals, Inc.)

We present an extensive assessment of mutation burden through sequencing analysis of >81,000 tumors from pediatric and adult patients, including tumors with hypermutation caused by chemotherapy, carcinogens, or germline alterations. Hypermutation was detected in tumor types not previously associated with high mutation burden. Replication repair deficiency was a major contributing factor. We uncovered new driver mutations in the replication-repair-associated DNA polymerases and a distinct impact of microsatellite instability and replication repair deficiency on the scale of mutation load. Unbiased clustering, based on mutational context, revealed clinically relevant subgroups regardless of the tumors' tissue of origin, highlighting similarities in evolutionary dynamics leading to hypermutation. Mutagens, such as UV light, were implicated in unexpected cancers, including sarcomas and lung tumors. The order of mutational signatures identified previous treatment and germline replication repair deficiency, which improved management of patients and families. These data will inform tumor classification, genetic testing, and clinical trial design., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Sonidegib (LDE225) is a potent, selective hedgehog (Hh) inhibitor of Smoothened. This study explored the safety and pharmacokinetics of sonidegib in children with relapsed/recurrent tumors followed by a phase II trial in pediatric and adult patients with relapsed medulloblastoma (MB) to assess tumor response., Methods: Pediatric patients aged ≥1 to <18 years were included according to a Bayesian design starting at 372 mg/m2 of continuous once daily oral sonidegib. Tumor samples were analyzed for Hh pathway activation using a validated 5-gene Hh signature assay. In phase II, pediatric patients were treated at the recommended phase II dose (RP2D) while adults received 800 mg daily., Results: Sixteen adult (16 MB) and 60 pediatric (39 MB, 21 other) patients with an age range of 2-17 years were enrolled. The RP2D of sonidegib in pediatric patients was established at 680 mg/m2 once daily. The phase II study was closed prematurely. The 5-gene Hh signature assay showed that the 4 complete responders (2 pediatric and 2 adult) and 1 partial responder (adult) all had Hh-activated tumors, while 5 patients with activated Hh had either stable disease (n = 3) or progressive disease (n = 2). No patient with an Hh-negative signature (n = 50) responded. The safety profile for pediatric patients was generally consistent with the one established for adult patients; however, growth plate changes were observed in prepubertal pediatric patients., Conclusions: Sonidegib was well tolerated and the RP2D in pediatric patients was 680 mg/m2 once daily. Five of the 10 MB patients with activated Hh pathway demonstrated complete or partial responses., (© The Author(s) 2017. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com)

This study addressed parental spirituality in the context of pediatric cancer with a poor prognosis. Drawing upon previous research implementing a longitudinal grounded theory design examining parental hope, 35 parents were interviewed regarding their experiences with an emergent description of the role of spirituality in parents' daily lives. Spirituality included religious beliefs and practices, notions of a higher force or cosmos, relationship with a divine being, as well as elements emerging from meaning-making and relationships. Parental expectations of spirituality remained relatively constant across data collection time points (3-9 months postdiagnosis), although limited variation occurred relative to shifting circumstance (e.g., deterioration of the child's condition). Spirituality appeared to offer: greater acceptance of parents' inability to protect their child from harm related to her/his life-threatening illness, guidance and emotion decompression, and support from one's faith community. Recommendations for integrating spiritual assessment in clinical care practice are offered.

To study the prevalence of pediatric cancer patients who have underlying inherited bone marrow failure syndrome (IBMFS), we retrospectively reviewed the medical records of newly diagnosed pediatric cancer patients at The Hospital for Sick Children from June 2009 to May 2010, focusing on clinical, laboratory, and treatment-related findings which may indicate underlying IBMFS. We found five (1.8%) patients out of 276 who had two or more findings suggestive of IBMFS. We conclude that a small fraction of patients with cancer have clinical features that indicate investigations to rule out underlying IBMFSs. A prospective study is needed to determine their prevalence., (© 2016 Wiley Periodicals, Inc.)

Background: There are identified gaps in the care provided to children with cancer based on the self-identified lack of education for health care professionals in pediatric palliative care and in the perceptions of bereaved parents who describe suboptimal care. In order to address these gaps, we will implement and evaluate a national roll-out of Education in Palliative and End-of-Life Care for Pediatrics (EPEC®-Pediatrics), using a 'Train-the-Trainer' model., Methods/design: In this study we are using a pre- post-test design and an integrated knowledge translation approach to assess the impact of the educational roll-out in four areas: 1) self-assessed knowledge of health professionals; 2) knowledge dissemination outcomes; 3) practice change outcomes; and 4) quality of palliative care. The quality of palliative care will be assessed using data from three sources: a) parent and child surveys about symptoms, quality of life and care provided; b) health record reviews of deceased patients; and c) bereaved parent surveys about end-of-life and bereavement care. After being trained in EPEC®-Pediatrics, 'Master Facilitators' will train 'Regional Teams' affiliated with 16 pediatric oncology programs in Canada. Each team will consist of three to five health professionals representing oncology, palliative care, and the community. Each team member will complete online modules and attend one of two face-to-face conferences, where they will receive training and materials to teach the EPEC®-Pediatrics curriculum to 'End-Users' in their region. Regional Teams will also choose a Tailored Implementation of Practice Standards (TIPS) Kit to guide implementation of a quality improvement project in their region; support will be provided via quarterly meetings with Co-Leads and via a listserv and webinars with other teams., Discussion: Through this study we aim to raise the level of pediatric palliative care education amongst health care professionals in Canada. Our study will be a significant step forward in evaluation of the impact of EPEC®-Pediatrics both on dissemination outcomes and on care quality at a national level. Based on the anticipated success of our project we hope to expand the EPEC®-Pediatrics roll-out to health professionals who care for children with non-oncological life-threatening conditions.

Objective: This prospective and longitudinal study was designed to further our understanding of parental hope when a child is being treated for a malignancy resistant to treatment over three time points during the first year after diagnosis using a qualitative approach to inquiry., Methods: We prospectively recruited parents of pediatric cancer patients with a poor prognosis who were treated in the Hematology/Oncology Program at a large children's hospital for this longitudinal grounded theory study. Parents were interviewed at three time points: within 3 months of the initial diagnosis, at 6 months, and at 9 months. Data collection and analysis took place concurrently using line-by-line coding. Constant comparison was used to examine relationships within and across codes and categories., Results: Two overarching categories defining hope as a positive inner source were found across time, but their frequency varied depending on how well the child was doing and disease progression: future-oriented hope and present-oriented hope. Under future-oriented hope, we identified the following: hope for a cure and treatment success, hope for the child's future, hope for a miracle, and hope for more quality time with child. Under present-oriented hope, we identified hope for day-to-day/moment-to-moment, hope for no pain and suffering, and hope for no complications., Conclusions: For parents of children with a diagnosis of cancer with a poor prognosis, hope is an internal resource that can be present and future focused. These views fluctuated over time in response to changes in the child's well-being and disease progression., (Copyright © 2013 John Wiley & Sons, Ltd.)

Background: The meaning and role of hope in parents of children with life-threatening illnesses remain relatively unstudied., Objective: The objectives of this study were to explore parental hope when a child is being treated for a malignancy resistant to treatment and to identify facilitators and barriers to maintaining hope in this context., Methods: Thirty-five parents of children with difficult-to-treat cancer were interviewed 3 months after diagnosis. Line-by-line coding of transcripts was used to establish categories and themes. Constant comparison was used to examine relationships within and across codes and categories., Results: Parental hope was related to the child's cure and future. The concept, however, oscillated between being tenacious and robust, and tenuous and elusive, depending on how the child was responding to treatment and the psychosocial context. Focusing on positive outcomes and experiences, spirituality, and social support facilitated being hopeful. Awareness of negative outcomes, information overload, physical and emotional depletion, and fear and uncertainty challenged parental hope., Conclusions: Developing a model that identifies the nature of parental hope as well as barriers and facilitators to maintaining hope shortly after childhood cancer diagnosis may assist healthcare professionals in supporting parents., Implications for Practice: Understanding parental hope may assist healthcare professionals to avoid overloading parents with too much information at once. Healthcare professionals can also ensure that social support from family, community, and the medical center is available for parents and that their physical and emotional needs are being met to ensure that they maintain hope to best care for their child with cancer.

Background: The choice between palliative chemotherapy (defined as the use of cytotoxic medications delivered intravenously for the purpose of our study) and supportive care alone is one of the most difficult decisions in pediatric oncology, yet little is known about the preferences of parents and health care professionals. We compared the strength of these preferences by considering children's quality of life and survival time as key attributes. In addition, we identified factors associated with the reported preferences., Methods: We included parents of children whose cancer had no reasonable chance of being cured and health care professionals in pediatric oncology as participants in our study. We administered separate interviews to parents and to health care professionals. Visual analogue scales were shown to respondents to illustrate the anticipated level of the child's quality of life, the expected duration of survival and the probability of cure (shown only to health care professionals). Respondents were then asked which treatment option they would favour given these baseline attributes. In addition, respondents reported what factors might affect such a decision and ranked all factors identified in order of importance. The primary measure was the desirability score for supportive care alone relative to palliative chemotherapy, as obtained using the threshold technique., Results: A total of 77 parents and 128 health care professionals participated in our study. Important factors influencing the decision between therapeutic options were child quality-of-life and survival time among both parents and health care professionals. Hope was particularly important to parents. Parents significantly favoured chemotherapy (42/77, 54.5%) compared with health care professionals (20/128, 15.6%; p < 0.0001). The opinions of the physician and child significantly influenced the parents' desire for supportive care; for health care professionals, the opinions of parents and children were significant factors influencing this decision., Interpretation: Compared with health care professionals, parents more strongly favour aggressive treatment in the palliative phase and rank hope as a more important factor for making decisions about treatment. Understanding the differences between parents and health care professionals in the relative desirability of supportive care alone may aid in communication and improve end-of-life care for children with cancer.

The importance of prognostic factors in predicting outcome in pediatric oncology is largely recognized, and most current protocols tailor treatment based on risk stratification. Further refinements of classical staging systems are ongoing, and the future of pediatric oncology is in the development of strategies based on individual tumor characteristics. This review details significant advances in our understanding of prognostic factors in the most common pediatric solid tumors and potential applications for clinical management.

The ultimate aim of our research program is to provide strategies that facilitate parental decision-making for parents of children with cancer receiving end-of-life care. As a first step to develop this program, we needed insight into parents' reactions and opinions about the research methods planned for a larger study. In particular, we needed their opinions about the general experience of making the decision between palliative cytotoxic chemotherapy and supportive care alone and the factors that parents regard as important when making this decision. In addition, we wished to know whether the methodology proposed for the future study was easy to understand and whether it might cause unnecessary emotional trauma. Finally, we asked their opinions regarding the appropriate target sample of parents to include in the future study. Qualitative data about these issues were collected using focus group methodology involving seven participants. The comments made during the focus group discussions were content-analyzed for common themes. The results from the focus group discussion led to particular modifications in the proposed design and interview strategies planned for the future larger study. We found it was extremely beneficial to include a focus group pre-phase in a study that will interview parents in a high sensitivity area.

The aim of this study was to evaluate the feasibility, toxicity and efficacy of escalating doses of subcutaneous recombinant interleukin-6 (IL-6) in children with solid tumours in relapse. Recombinant IL-6 was administered subcutaneously once daily for 14 consecutive days, with a 14 day follow-up period. The starting dose for IL-6 was 1 microgram/kg/day and was escalated in subsequent patients groups until 10 micrograms/kg. Doses were escalated every 3 patients, provided that grade III or IV organ toxicity did not occur at the preceding dose level. Twelve patients were treated, three at each dose level. No grade 3-4 major organ toxicity was observed. Flu-like symptoms and fatigue were the most common side effects. All these symptoms resolved after the end of IL-6 administration. Significant increases in acute-phase proteins (CRP [C reactive protein], fibrinogen) and ESR (Erthrocyte sedimentation rate) were observed in all patients. Stimulatory effects on thrombocytopoiesis were observed at every dose level, and were maximal at 5 micrograms/kg and 10 microgram/kg. There was no tumour response observed during IL-6 administration. Pharmacokinetic profiles performed in 3 patients are consistent with previous reports in adults. IL-6 is a promising new cytokine for paediatric oncology, in particular to increase thrombocyte counts. We recommend that further studies in children proceed at a dose of 5-10 micrograms/kg/day in a once or, better, twice daily administration.

For children with incurable life-threatening diseases, social reintegration is an illusion. Schooling for these children is both possible and desirable, but its specific objectives must be adapted. The educational career of 30 French school children with incurable cancer was followed. Data concerning the children's degree of motivation to attend school and its evolution during the course of the disease as well as the measures adopted to maintain school attendance were analysed. Sixty per cent of the children demonstrated a genuine desire to attend school until the advanced stages of their disease. Reading, mathematics and computer work were their favourite subjects, increasing physical disability and fatigue diminished their motivation over time. Refusal to attend school occurred in 40% of the children, who had either extracurricular interests or poorly controlled pain. School attendance for the terminally ill child's part of palliative care and has specific medical and educational goals. As such, its objectives are quite distinct from those of other educational reintegration projects proposed for children with cancer.

Background: School intervention programs for children and adolescents with cancer have been developed in France during the last years. Their primary objective is to improve the pschychosocial adaptation of these children to normal life through school integration. These programs are however inadequate for these children who will ultimately die from their disease and may require a specific school intervention., Material and Methods: School data from 30 children requiring palliative care were prospectively collected. School interest, its evolution and specific adaptations according to the child's status were analysed., Results: Sixty per cent of the children showed a continuous desire for school education throughout their life's end. Reading, mathematics and computer work were the most favorite topics. Physical disability and fatigue may change their request during the evolution of the disease. School refusal occurred in 40% of the children and is mainly due to other extra-academic topics, or related to uncontrolled pain., Conclusion: Objectives of life's end school are different from educational programs proposed for children with cancer. They must be part of palliative care and have to be defined as a specific entity.

The feasibility and efficacy of a once daily antibiotic regimen were assessed in children with malignant tumours. Over a 44 month period, 296 febrile episodes were treated with a regimen of once daily ceftriaxone-amikacin (and teicoplanin or vancomycin if the patient had a central line). The treatment was successful in 272 (92%) episodes without modification of the antibiotic regimen, and only one patient died of uncontrolled sepsis. A once daily antibiotic regimen is therefore feasible and worthwhile in the treatment of febrile episodes in children with cancer.

Using experimental modes with normal allogeneic bone marrow (BM) contaminated with Burkitt or neuroblastoma cell lines, and a liquid culture assay, we demonstrated that, when used in optimal conditions, the immunomagnetic depletion technique permitted a reproducible elimination of 3-4 log malignant cells. Results were very similar to those obtained with the complement lysis procedure in Burkitt lymphoma. This immunomagnetic procedure was used in 123 cases of autologous bone marrow transplantation (ABMT) in children with neuroblastoma. The analysis of the cases demonstrated, first, that the procedure induced a significant loss of mononuclear cells but was not toxic for BM precursors. Delays to engraftment observed in a few patients were probably due to the combination of pejorative factors, especially the damage caused to the micro-environment by previous heavy and prolonged chemotherapy or the double ABMT programme. Second, patients presented with profound T-cell defect with undetectable IL2 secretion up to 1 year post-graft but they all had normal NK functions from the first month post-graft, these functions exceeding normal values on the second and third months post-graft. Finally, in 20 cases, dual-immunofluorescence staining permitted the demonstration that the autograft contained malignant cells before purging that were eliminated by the immunomagnetic depletion.

From 1984 to 1987, 80 pediatric oncology patients were transferred from Algeria to the centre Léon-Bérard (Lyon, France). Diagnoses were mainly lymphomas neuroblastomas and bone tumours (75% of the total number of cases). Survival (39% at 46 months), number of hospitalization days (12,655) and cost (29,324,254 FF) were calculated. These costs were compared with the mean annual public health allocation per capita in Algeria and with the French limitations on accepting transfer of spending money for children from abroad. New directions are suggested to improve the efficiency of these transfers to optimize the use of limited resources in both countries and to increase survival of individual patients.

Massive therapy with ABMT is now an established treatment modality in paediatric oncology. The technical aspects and most treatment-related complications have been clarified and many phase II studies have shown encouraging results. In advanced neuroblastoma the poor outlook with conventional chemotherapy has stimulated extensive investigation of forms of massive therapy. Current results from several centres indicate that although the median survival is increased, long-term survival in an unselected group of stage IV patients is unlikely to exceed 30% with current regimens. In the future, management of this disease may involve the use of more intensive induction regimens to improve the quality of remission at the time of ABMT, which remains the single most important prognostic factor. Improved purging procedures involve the possible use of double massive therapy regimens and a combination of immunological and chemical treatments. In other paediatric tumours, the relative rarity and limited indications for ABMT make the evaluation of its role more difficult. Preliminary results in advanced rhabdomyosarcoma and Ewing's sarcoma are none the less encouraging and justify further investigation. The value of purging procedures remains controversial and their assessment has been hampered by the lack of sensitive clonogenic assays to detect residual tumour cells. However, neuroblastoma has provided a useful model for the investigation of physical, immunological and chemical procedures. Massive therapy is expensive, time consuming, and carries a high cost in patient morbidity and stress to the families involved. As with any new treatment, it must be adequately assessed in phase III, randomized studies. The ENSG and SIOP trials are a beginning and the future of massive therapy in the paediatric patient will, we hope, be based on a rigorous and scientific comparison with other treatment modalities.