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Importance: The combination of ifosfamide and etoposide (IE) is commonly used to treat relapsed or refractory osteosarcoma; however, second-line treatment recommendations vary across guidelines., Objective: To evaluate whether the addition of lenvatinib to IE (LEN-IE) improves outcomes in children and young adults with relapsed or refractory osteosarcoma., Design, Setting, and Participants: The OLIE phase II, open-label, randomized clinical trial was conducted globally across Europe, Asia and the Pacific, and North America. From March 22, 2020, through November 11, 2021, the trial enrolled patients aged 2 to 25 years with high-grade osteosarcoma, measurable or evaluable disease per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1), and 1 to 2 prior lines of systemic treatment. The data analyses were performed between March 22, 2020 (first patient in) and June 22, 2022 (data cutoff for the primary analysis), and September 29, 2023 (end of study final database lock)., Interventions: The OLIE trial assessed the efficacy and safety of lenvatinib (14 mg/m2 taken orally once daily) combined with up to 5 cycles of ifosfamide (3000 mg/m2 intravenously) and etoposide (100 mg/m2 intravenously) on days 1 to 3 of each cycle vs IE alone at the same doses. Patients randomized to IE could cross over to receive lenvatinib upon disease progression by independent imaging review., Main Outcomes and Measures: The primary end point was progression-free survival (PFS) per RECIST 1.1 by independent imaging review. The Kaplan-Meier method was used to estimate the PFS distribution, with a prespecified 1-sided significance threshold of .025 by stratified log-rank test. Secondary end points included PFS rate at 4 months and overall survival. Adverse events were summarized using descriptive statistics., Results: A total of 81 patients were enrolled (median [IQR] age, 15.0 [12.0-18.0] years; 46 males [56.8%]), with 40 in the LEN-IE arm and 41 in the IE arm. Median PFS was 6.5 months (95% CI, 5.7-8.2 months) for the LEN-IE arm and 5.5 months (95% CI, 2.9-6.5 months) for the IE arm (hazard ratio [HR], 0.54; 95% CI, 0.27-1.08; 1-sided P = .04). The rate of PFS at 4 months was 76.3% (95% CI, 59.3%-86.9%) in the LEN-IE arm and 66.0% (95% CI, 47.7%-79.2%) in the IE arm. Median overall survival was 11.9 months (95% CI, 10.1 months to not estimable) with LEN-IE and 17.4 months (95% CI, 14.2 months to not estimable) with IE (HR, 1.28; 95% CI, 0.60-2.70; 1-sided nominal P = .75). Grade 3 or higher treatment-related adverse events occurred in 35 of 39 patients (89.7%) in the LEN-IE arm and 31 of 39 patients (79.5%) in the IE arm., Conclusions and Relevance: Although LEN-IE did not meet prespecified statistical significance for improved PFS vs IE, this study demonstrates the importance of international collaboration and randomized clinical trials in patients with relapsed or refractory osteosarcoma and may inform future trial design., Trial Registration: ClinicalTrials.gov Identifier: NCT04154189.

This systematic review provides a structured overview of the measurement instruments of functional outcome used in lower extremity and pelvic bone sarcoma patients. We identified 42 unique instruments covering 18 distinct functional outcome constructs with most studies measuring constructs within the activity domain of the International Classification of Functioning, disability, and health. The MusculoSkeletal Tumor Society 1993 and 1987 score, Toronto Extremity Salvage Score, and range of motion instruments were the measurement instruments most commonly used., (© 2024 Wiley Periodicals LLC.)

Background: Adolescents (15-19 years) with sarcoma are known to have significantly worse survival than children (0-14 years). One possible reason may be that the adolescent sarcomas exhibit specific biological characteristics resulting in differences in clinical presentation and treatment resistance behaviors. The BIOSCA project aims to further explore these age-related differences in survival accounting for molecular tumor characteristic in children and adolescents with sarcoma., Methods: A retrospective national population-based observational study with documented somatic genetic analyses was conducted between 2011 and 2016 of all patients aged from 0 to 17 years with a diagnosis of sarcoma using the National Registry of Childhood Cancers Database., Results: A total of 1637 children (0-9years: 40%), preadolescents (10-14years: 35%) and adolescents (15-17 years: 25%) with a diagnosis of bone (N = 845) or soft-tissue (N = 792) sarcoma were included. Adolescents had significantly worse outcome for undifferentiated small round cell sarcoma (USRCS), alveolar rhabdomyosarcoma (ARMS), and epithelioid sarcoma. Five-year overall survivals were worse among CIC-rearranged USRCS cases (47% [95%CI:21-69]) as compared to other USRCS, and PAX3::FOXO1 ARMS patients (44% [95%CI:32-55]) as compared to other ARMS. Adjusting for stage and genomic-profiling status, adolescents with USRCS were 1.6-fold more likely to die than children (P = 0.05), while the difference in survival between age of ARMS patients was weaken. Indeed, the prevalence of PAX3::FOXO1 increased significantly with age., Conclusion: Age was an independent prognostic factor of outcome only in patients with USRCS, while the association between age and survival of patients with ARMS could be partly explained by differences in prevalence of PAX3::FOXO1., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The "Groupe Onco-hématologie Adolescents Jeunes Adultes" (GO-AJA) born in 2012 is a French collaborative group. It focuses on heterogeneity and unmet needs for AYA with cancer. This article highlights GO-AJA's achievements and future prospects, emphasizing its role in structuring a professional national network, improving AYAs' comprehensive care and strengthening the roles of coordinating nurses. It also covers AYA multidisciplinary tumor boards, guidelines edition, education and training. Challenges persist, including limited AYA clinical trials and territorial inequalities in care access and team resources. Future success hinges on increased medical community awareness, stakeholders investment, and European collaborations.

Introduction: Ewing sarcoma (ES), is a rare cancer affecting children, adolescents and adults. After VIDE (vincristine-ifosfamide-doxorobucin-etoposide) induction chemotherapy, Busulfan-Melphalan (BuMel) high-dose chemotherapy followed by autologous hematopoietic stem cells transplantation improved outcomes in unfavourable localized ES, but with more toxicities than conventional chemotherapy (VAI: Vincristine-dactinomycin-Ifosfamide). We evaluated whether the risk of acute toxicity associated with BuMel compared to VAI varied according to age in patients recruited in the R2Loc and R2Pulm randomised trials of the Euro-E.W.I.N.G.99 and Ewing-2008 trials., Methods: We included patients with a localized high-risk disease, or pulmonary or pleural metastasis. We analysed the risk of severe toxicity according to randomised treatment group (VAI versus BuMel) and age group (<12 years, 12-17 years, 18-24 years, ≥25 years). We evaluated the heterogeneity of treatment effects by age group using interaction terms in logistic multivariable models., Results: The analysis included 243 patients treated with VAI and 205 with BuMel. Overall, BuMel was associated with a higher risk of severe acute toxicity than VAI particularly haematological, gastrointestinal, liver, sinusoidal occlusive syndrome, and infections. Severe haematological toxicity and lower general condition were significantly more frequent in younger patients, whatever treatment. We did not observe any significant heterogeneity in terms of the excess risk of severe toxicities associated with BuMel compared to VAI according to age group., Conclusion: The excess of acute toxicity associated with BuMel compared to VAI does not vary significantly with age, suggesting the feasibility of BuMel across all age groups., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Osteosarcoma and Ewing sarcoma are bone tumors mostly diagnosed in children, adolescents, and young adults. Despite multimodal therapy, morbidity is high and survival rates remain low, especially in the metastatic disease setting. Trials investigating targeted therapies and immunotherapies have not been groundbreaking. Better understanding of biological subgroups, the role of the tumor immune microenvironment, factors that promote metastasis, and clinical biomarkers of prognosis and drug response are required to make progress. A prerequisite to achieve desired success is a thorough, systematic, and clinically linked biological analysis of patient samples, but disease rarity and tissue processing challenges such as logistics and infrastructure have contributed to a lack of relevant samples for clinical care and research. There is a need for a Europe-wide framework to be implemented for the adequate and minimal sampling, processing, storage, and analysis of patient samples. Two international panels of scientists, clinicians, and patient and parent advocates have formed the Fight Osteosarcoma Through European Research consortium and the Euro Ewing Consortium. The consortia shared their expertise and institutional practices to formulate new guidelines. We report new reference standards for adequate and minimally required sampling (time points, diagnostic samples, and liquid biopsy tubes), handling, and biobanking to enable advanced biological studies in bone sarcoma. We describe standards for analysis and annotation to drive collaboration and data harmonization with practical, legal, and ethical considerations. This position paper provides comprehensive guidelines that should become the new standards of care that will accelerate scientific progress, promote collaboration, and improve outcomes., (©2024 The Authors; Published by the American Association for Cancer Research.)

Background: Lesbian, gay, bisexual, transgender, and queer (LGBTQ) individuals with cancer have specific and unique health issues and needs. Reports persist of inequalities in the care provided for these patients, making it important to assess the attitudes and knowledge of LGBTQ needs among those who provide care., Materials and Methods: The European Society for Medical Oncology (ESMO) and the European Society for Paediatric Oncology (SIOP Europe) Adolescents and Young Adults Working Group designed this survey comprising 67 questions covering demographics, knowledge, and education of LGBTQ health needs, and attitudes regarding LGBTQ patients with cancer., Results: Among the 672 respondents, a majority do not ask about sexual orientation and gender identity during first visit (64% and 58%, respectively). Only a minority of the respondents considered themselves well informed regarding gay/lesbian and transgender patients' health (44% and 25%, respectively) and psychosocial needs (34%). There was high interest in receiving education regarding the unique health needs of LGBTQ patients (73%)., Conclusions: Survey respondents indicated a willingness to provide care to LGBTQ patients, but a lack of confidence in the knowledge of the health issues and needs of LGBTQ individuals. Lack of training provided in medical schools and postgraduate training programmes and strong interest for additional education on these issues were reported., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

For decades, it has been known that Liquid-Liquid Critical Points (LLCPs) can exist in one-component liquids, yet a comprehensive understanding of the conditions under which they arise remains elusive. To better comprehend the possible interplay between the LLCP and the crystalline phase, we conduct molecular dynamics simulations using the nonbonded family of modified-WAC (mWAC) models, which are known to exhibit a LLCP for certain parameter values. By comparing different versions of the mWAC model-those featuring a LLCP and those lacking one-we identify several key differences between the models relating to crystallization. Those models that do have a LLCP are found to have multiple stable crystalline phases, one of them being a solid-state ionic conductor similar to superionic ice. Moreover, we find that for models that do not have a LLCP, the liquid becomes a glass at a larger range of temperatures, possibly preventing the occurrence of a LLCP. Further studies are required to determine if these results are general or model-specific., (© 2024 Author(s). Published under an exclusive license by AIP Publishing.)

Multimodality reporter gene imaging combines the sensitivity, resolution and translational potential of two or more signals. The approach has not been widely adopted by the animal imaging community, mainly because its utility in this area is unproven. We developed a new complementation-based reporter gene system where the large component of split NanoLuc luciferase (LgBiT) presented on the surface of cells (TM-LgBiT) interacts with a radiotracer consisting of the high-affinity complementary HiBiT peptide labeled with a radionuclide. Radiotracer uptake could be imaged in mice using SPECT/CT and bioluminescence within two hours of implanting reporter-gene-expressing cells. Imaging data were validated by ex vivo biodistribution studies. Following the demonstration of complementation between the TM-LgBiT protein and HiBiT radiotracer, we validated the use of the technology in the highly specific in vivo multimodal imaging of cells. These findings highlight the potential of this new approach to facilitate the advancement of cell and gene therapies from bench to clinic.

Background: Previous studies have shown that neutrophil-to-lymphocyte (NLR) ratio at diagnosis and early lymphocytes recovery on doxorubicin-based chemotherapy, may impact the outcome in patients with osteosarcoma (OST). This study aimed to evaluate the prognostic value of hemogram parameters in patients with OST treated with high-dose methotrexate and etoposide/ifosfamide (M-EI) chemotherapy., Materials and Methods: We retrospectively analyzed the prognostic value of various hemogram parameters at diagnosis and during therapy in a large consecutive cohort of patients with OST included in the French OS2006 trial and treated with M-EI chemotherapy., Results: A total of 164 patients were analyzed. The median age was 14.7 years (interquartile range [IQR]: 11.7-17). Median follow-up was 5.6 years (IQR: 3.3-7.7 years). Three-year event-free survival (EFS) and overall survival (OS) were 71.5% (95% confidence interval [CI]: 64%-78%) and 86.4% (95% CI: 80%-91%), respectively. In univariate analysis, blood count parameters at diagnosis and early lymphocyte recovery at Day 14 were not found prognostic of survival outcomes. By contrast, an increase of NLR ratio at Day 1 of the first EI chemotherapy (NLR-W4) was associated with reduced OS in univariate (p = .0044) and multivariate analysis (hazards ratio [HR] = 1.3, 95% CI: 1.1-1.5; p = .002), although not with EFS. After adjustment on histological response and metastatic status, an increase of the ratio NLR-W4 of 1 was associated with an increased risk of death of 30%., Conclusions: We identified NLR-W4 as a potential early biomarker for survival in patients with OST treated with M-EI chemotherapy. Further studies are required to confirm the prognostic value of NLR and better identify immune mechanisms involved in disease surveillance., (© 2024 Wiley Periodicals LLC.)

Background : Substance use disorders present a tremendous challenge within contemporary healthcare systems. Specifically, in the domain of opioid use disorders (OUDs), several foundational elements are crucial for the efficacious management of afflicted individuals. Regrettably, the premature discontinuation of inpatient opioid withdrawal treatment is a prevalent phenomenon. This study aims to elucidate the prevalence of the premature termination of inpatient opioid withdrawal treatment among patients with comorbid ADHD. Methods : We conducted a comprehensive assessment of all participants currently undergoing inpatient opioid withdrawal treatment. Our assessment protocol included the administration of the ADHD Self-Report Scale (ADHD-SR) and the Wender Utah Rating Scale (WURS-k). Additionally, participants who met the thresholds on one or both questionnaires underwent further evaluation using the Diagnostic Interview for ADHD in Adults (DIVA-2.0). Results : The prevalence of individuals diagnosed with ADHD within the studied cohort was determined to be 29.3%. Among the subset of participants identified as ADHD-positive, a notable 54.5% prematurely ceased therapy. In contrast, among those identified as ADHD-negative, the premature discontinuation rate was substantially lower at 28.3%. Conclusions : In summary, the impact of ADHD as a comorbid condition on the efficacy of inpatient opioid withdrawal treatment has been underscored. By identifying comorbid ADHD early in the treatment process, tailored therapeutic approaches may help to maximize the effectiveness of interventions and may improve patient outcomes. This underscores the importance of proactive screening for ADHD as a psychiatric comorbidity in optimizing the management of individuals undergoing inpatient opioid withdrawal treatment.

High-grade osteosarcoma is the most common paediatric bone cancer. More than one third of patients relapse and die of osteosarcoma using current chemotherapeutic and surgical strategies. To improve outcomes in osteosarcoma, two crucial challenges need to be tackled: 1-the identification of hard-to-treat disease, ideally from diagnosis; 2- choosing the best combined or novel therapies to eradicate tumor cells which are resistant to current therapies leading to disease dissemination and metastasize as well as their favorable microenvironment. Genetic chaos, tumor complexity and heterogeneity render this task difficult. The development of new technologies like next generation sequencing has led to an improvement in osteosarcoma oncogenesis knownledge. This review summarizes recent biological and therapeutical advances in osteosarcoma, as well as the challenges that must be overcome in order to develop personalized medicine and new therapeutic strategies and ultimately improve patient survival., (Copyright © 2024. Published by Elsevier Masson SAS.)

Background: Osteosarcoma stratification relies on clinical parameters and histological response. We developed a new personalized stratification using less invasive circulating tumor DNA (ctDNA) quantification., Patients and Methods: Plasma from patients homogeneously treated in the prospective protocol OS2006, at diagnosis, before surgery and end of treatment, were sequenced using low-passage whole-genome sequencing (lpWGS) for copy number alteration detection. We developed a prediction tool including ctDNA quantification and known clinical parameters to estimate patients' individual risk of event., Results: ctDNA quantification at diagnosis (diagCPA) was evaluated for 183 patients of the protocol OS2006. diagCPA as a continuous variable was a major prognostic factor, independent of other clinical parameters, including metastatic status [diagCPA hazard ratio (HR) = 3.5, P = 0.002 and 3.51, P = 0.012, for progression-free survival (PFS) and overall survival (OS)]. At the time of surgery and until the end of treatment, diagCPA was also a major prognostic factor independent of histological response (diagCPA HR = 9.2, P < 0.001 and 11.6, P < 0.001, for PFS and OS). Therefore, the addition of diagCPA to metastatic status at diagnosis or poor histological response after surgery improved the prognostic stratification of patients with osteosarcoma. We developed the prediction tool PRONOS to generate individual risk estimations, showing great performance ctDNA quantification at the time of surgery and the end of treatment still required improvement to overcome the low sensitivity of lpWGS and to enable the follow-up of disease progression., Conclusions: The addition of ctDNA quantification to known risk factors improves the estimation of prognosis calculated by our prediction tool PRONOS. To confirm its value, an external validation in the Sarcoma 13 trial is underway., (Copyright © 2023 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Motivation: Spatial transcriptomics enables the analysis of cell crosstalk in healthy and diseased organs by capturing the transcriptomic profiles of millions of cells within their spatial contexts. However, spatial transcriptomics approaches also raise new computational challenges for the multidimensional data analysis associated with spatial coordinates., Results: In this context, we introduce a novel analytical framework called CellsFromSpace based on independent component analysis (ICA), which allows users to analyze various commercially available technologies without relying on a single-cell reference dataset. The ICA approach deployed in CellsFromSpace decomposes spatial transcriptomics data into interpretable components associated with distinct cell types or activities. ICA also enables noise or artifact reduction and subset analysis of cell types of interest through component selection. We demonstrate the flexibility and performance of CellsFromSpace using real-world samples to demonstrate ICA's ability to successfully identify spatially distributed cells as well as rare diffuse cells, and quantitatively deconvolute datasets from the Visium, Slide-seq, MERSCOPE, and CosMX technologies. Comparative analysis with a current alternative reference-free deconvolution tool also highlights CellsFromSpace's speed, scalability and accuracy in processing complex, even multisample datasets. CellsFromSpace also offers a user-friendly graphical interface enabling non-bioinformaticians to annotate and interpret components based on spatial distribution and contributor genes, and perform full downstream analysis., Availability and Implementation: CellsFromSpace (CFS) is distributed as an R package available from github at https://github.com/gustaveroussy/CFS along with tutorials, examples, and detailed documentation., Competing Interests: None declared., (© The Author(s) 2024. Published by Oxford University Press.)

Background: The REGOBONE multi-cohort study explored the efficacy and safety of regorafenib for patients with advanced bone sarcomas; this report details the Ewing sarcoma (ES) cohort., Methods: Patients with relapsed ES progressing despite prior standard therapy, were randomised (2:1) to receive regorafenib or placebo. Patients on placebo could crossover to receive regorafenib after centrally confirmed progression. The primary endpoint was the progression-free rate at 8 weeks. With one-sided α of 0.05, and 80% power, at least 14/24 progression-free patients at 8 weeks were needed for success., Results: From September 2014 to November 2019, 41 patients were accrued. 36 patients were evaluable for efficacy: 23 on regorafenib and 13 on placebo. Thirteen patients (56%; one-sided 95% CI [37.5%-[)) were progression-free at 8 weeks on regorafenib vs. 1 (7.7%; 95% CI [0.4%-[) on placebo. Median PFS was 11.4 weeks on regorafenib, and 3.9 weeks on placebo. Ten placebo patients crossed over to receive regorafenib after progression. The most common grade ≥3 regorafenib-related adverse events were pain (22%), asthenia (17%), thrombocytopenia (13%) and diarrhoea (13%)., Conclusion: Although the primary endpoint was not met statistically in this randomised cohort, there is evidence to suggest that regorafenib might modestly delay tumour progression in relapsed ES after failure of prior chemotherapy., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

DICER1-mutated rhabdomyosarcoma is a rare, emerging entity with a predilection for the gynecologic and genitourinary tracts. We report here a case of DICER1-mutated rhabdomyosarcoma of the ovary in a 14 years old girl which displayed interspersed mature teratoid glands, neuroectodermal rosettes and immature blastematous-like tubes. Morphologically the sarcomatous component predominated, corresponding to a high grade spindle cell rhabdomyosarcoma with botryoid features. Islets of cartilage were present. The sarcomatous proliferation encased the teratoid glands, forming cambium layer-like arrangements. The sarcoma cells were Myogenin and MYOD1 positive, the neuroectodermal rosettes expressed SALL4 along with cytokeratins and EMA and were negative for Inhibin; immature blastematous-like tubes were negative for SALL4 and Inhibin. Whole RNA- and targeted DNA-sequencing revealed two DICER1 mutations in exon 26: c.5113G>A: p.(Glu1705Lys) and exon 12: c.1642C>T: p.(Gln548X). The sarcomatous component harbored a complex genetic profile while the teratoid component was diploid, none of the above displayed abnormality of 12p. DICER1-mutated sarcomas display pathological features similar to embryonal rhabdomyosarcomas, botryoid type. They also display heterogeneous features combining cartilage foci, teratoid mature glands, immature blastematous-like tubes and/or neuroectodermal components. Molecular testing remains necessary to confirm the diagnosis. Further studies need to clarify the nosology of DICER1-mutated sarcomas and devise specific therapeutic strategies., (© 2023 The Authors. Genes, Chromosomes and Cancer published by Wiley Periodicals LLC.)

Background/objective: To analyze changes in recurrent/refractory osteosarcoma phase II trials over time to inform future trials in this population with poor prognosis., Methods: A systematic review of trials registered on trial registries between 01/01/2017-14/02/2022. Comparison of 98 trials identified between 2003 and 2016. Publication search/analysis for both periods, last update on 01/12/2022., Results: Between 2017 and 2022, 71 phase-II trials met our selection criteria (19 osteosarcoma-specific trials, 14 solid tumor trials with and 38 trials without an osteosarcoma-specific stratum). The trial number increased over time: 13.9 versus 7 trials/year (p = 0.06). Monotherapy remained the predominant treatment (62% vs. 62%, p = 1). Targeted therapies were increasingly evaluated (66% vs. 41%, P = 0.001). Heterogeneity persisted in the trial characteristics. The inclusion criteria were measurable disease (75%), evaluable disease (14%), and surgical remission (11%). 82% of the trials included pediatric or adolescent patients. Biomarker-driven trials accounted for 25% of the total trials. The survival endpoint use (rather than response) slightly increased (40% versus 31%), but the study H 1 /H 0 hypotheses remained heterogeneous. Single-arm designs predominated over multiarm trials (n = 7). Available efficacy data on 1361 osteosarcoma patients in 58 trials remained disappointing, even though 21% of these trials were considered positive, predominantly those evaluating multi-targeted kinase inhibitors., Conclusion: Despite observed changes in trial design and an increased number of trials investigating new therapies, high heterogeneity remained with respect to patient selection, study design, primary endpoints, and statistical hypotheses in recently registered phase II trials for osteosarcoma. Continued optimization of trial design informed by a deeper biological understanding should strengthen the development of new therapies., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [RE declares funding by the Princess Maxima foundation. KB declares honoraria for educational events for Novartis and has received honoraria for participation on advisory boards for glaxosmithkline, Bayer, NEC Oncoimmunity and Incyte. NE declares honoraria for educational events by Merck/MSD. NH declares a grant by the Swedish Childhood Cancer Fund. EP declares honoraria for participation on advisory boards for Deciphera Pharmaceutical, Eusa Pharma, SynOx Therapeutics and Daiichy Sankyo. SS declares consulting fees by Ceridwen Oncology, support for travel by Adaptimmune and has received honoraria for participation of an advisory board for glaxosmithkline. All remaining authors have declared no conflicts of interest.]., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose: This study was undertaken to describe the Adolescents and Young Adults' (AYA-aged patients') neuro-oncology care pathways at Grenoble Alpes University Hospital according to the French health recommendations. Methods: A retrospective monocentric observational study was conducted between 2020 and 2021, on patients 13-29 years of age, diagnosed from January 2013 to 2019 in our institute with a primary brain tumor, excluding meningiomas, schwannomas, and neurinomas. The detailed analysis took into account the type of care unit (adult or pediatric), whether or not a dedicated AYA support team was involved, and various pretherapeutic actions. Results: Sixty patients were included in this study. Three of the 9 key stages of the care process were completed regardless of the type of management. Management in a pediatric oncology department seems to improve multidisciplinary discussions and access to the AYA team. Collaboration with an AYA team seems to improve the recourse to pediatric advice and supportive care. Conclusions: Increased vigilance at all key steps as defined in the recommendations of the Directorate General of Healthcare Services would significantly improve the overall quality of care for this specific population. In the absence of a dedicated AYA hospitalization unit, interdisciplinary cooperation between the different professionals of the adult and pediatric services is essential, and the involvement of the AYA mobile team is a factor that favors links and exchanges and ultimately an overall improvement in patient care and life. We propose our vision of an ideal AYA neuro-oncology care pathway.

Osteosarcoma is a rare bone cancer in adolescents and young adults with a dismal prognosis because of metastatic disease and chemoresistance. Despite multiple clinical trials, no improvement in outcome has occurred in decades. There is an urgent need to better understand resistant and metastatic disease and to generate in vivo models from relapsed tumors. We developed eight new patient-derived xenograft (PDX) subcutaneous and orthotopic/paratibial models derived from patients with recurrent osteosarcoma and compared the genetic and transcriptomic landscapes of the disease progression at diagnosis and relapse with the matching PDX. Whole exome sequencing showed that driver and copy-number alterations are conserved from diagnosis to relapse, with the emergence of somatic alterations of genes mostly involved in DNA repair, cell cycle checkpoints, and chromosome organization. All PDX patients conserve most of the genetic alterations identified at relapse. At the transcriptomic level, tumor cells maintain their ossification, chondrocytic, and trans-differentiation programs during progression and implantation in PDX models, as identified at the radiological and histological levels. A more complex phenotype, like the interaction with immune cells and osteoclasts or cancer testis antigen expression, seemed conserved and was hardly identifiable by histology. Despite NSG mouse immunodeficiency, four of the PDX models partially reconstructed the vascular and immune-microenvironment observed in patients, among which the macrophagic TREM2/TYROBP axis expression, recently linked to immunosuppression. Our multimodal analysis of osteosarcoma progression and PDX models is a valuable resource to understand resistance and metastatic spread mechanisms, as well as for the exploration of novel therapeutic strategies for advanced osteosarcoma., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 da Costa, Droit, Khneisser, Gomez-Brouchet, Adam-de-Beaumais, Nolla, Signolles, Torrejon, Lombard, Loew, Ayrault, Scoazec, Geoerger, Vassal, Marchais and Gaspar.)

In Euro-EWING99-R1 randomized trial, cyclophosphamide was shown to be noninferior to ifosfamide in the consolidation of standard-risk Ewing sarcoma (SR-EWS) after a common induction with VIDE (vincristine-ifosfamide-doxorubicin-etoposide). We present the results of the late effects analysis of VAC (vincristine-dactinomycin-cyclophoshamide) vs VAI (vincristine-dactinomycin-ifosfamide) conducted in Euro-EWING99-R1 French cohort. Of 267 French randomized patients, 204 were alive and free-of-relapse at 5-years including 172 with available long-term follow-up data concerning cardiac, renal and/or gonadal functions (sex-ratio M/F = 1.3, median age at diagnosis = 14 years): 84 randomized in VAC (median cumulative doses: cyclophosphamide = 9.7 g/m 2 , ifosfamide = 59.4 g/m 2 ) and 88 in VAI (ifosfamide = 97.1 g/m 2 ). With a median follow-up of 10 years (range = 5-17), five late relapses and five second malignancies were recorded. The 10-year event-free survival among 5-year free-of-relapse survivors was similar between VAC and VAI (93% vs 95%, P = .63). We estimated the 10-year cumulative probabilities of cardiac and kidney toxicities at 4.4% (95% confidence interval [95% CI] = 1.1%-7.6%) and 34.8% (95% CI = 26.8%-42.0%), respectively. Cardiac toxicity cumulative probability was similar in both arms, whereas kidney toxicity was higher in VAI (at 10 years, 43.0% vs 25.7%, P = .02), resulting from significant difference in glomerular toxicity (31.1% vs 13.1%, P < .01). At 10 years, gonadal toxicity was observed in 27% and 28% of pubertal men and women, respectively, without significant difference between VAC and VAI. Kidney and gonadal toxicities represent major issues in Euro-EWING99-R1, with significantly higher risk of kidney toxicities with VAI, without significant gonadal toxicity reduction. These results support the need to limit cumulative doses of both alkylating agents and to use mixed regimen as in VIDE-VAC or VDC/IE (vincristine-doxorubicin-cyclophoshamide/ifosfamide-etoposide)., (© 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: CIC-rearranged sarcomas (CIC-RS) represent the most frequent subset of "Ewing-like" undifferentiated small round cell sarcomas. These tumors tend to be more aggressive than Ewing sarcomas. Moreover, treatment strategy can differ according to teams. The primary aim of this retrospective study was to describe the characteristics, treatments, and outcome for patients with CIC-RS included in the French NETSARC+ database., Methods: Pediatric and adult patients from 13 French centers with a diagnosis of CIC-RS were registered from October 2008 to March 2021. Patients and tumors characteristics were collected from the national network NETSARC+ database (http://netsarc.sarcomabcb.org). CIC-RS diagnosis was pathologically and molecularly confirmed with a central review by expert pathologists. Two groups of patients were studied: those treated as classical Ewing sarcomas (cohort EwS) and those treated as high-grade soft tissue sarcomas (cohort STS) according to ESMO and/or EpSSG guidelines. Survival was calculated using the Kaplan-Meier method and the log-rank test was used to compare survival., Results: Among 79 patients, the male/female sex ratio was 0.7 and the median age at diagnosis was 27 years (range 2-87). With a median follow-up of 37 months, 39 patients died of the disease. Median overall survival from diagnosis was 18 months, with no significant difference between both cohorts (p = 0.9). Nevertheless, when focusing on patients with metastatic disease at diagnosis (N = 21), all patients from cohort STS died of disease while some patients from cohort EwS were still alive and in complete remission., Conclusion: FSG experience confirms the aggressive clinical course of CDS patients regardless of chemotherapy regimen., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Formal language hierarchy describes levels of increasing syntactic complexity (adjacent dependencies, nonadjacent nested, nonadjacent crossed) of which the transcription into a hierarchy of cognitive complexity remains under debate. The cognitive foundations of formal language hierarchy have been contradicted by two types of evidence: First, adjacent dependencies are not easier to learn compared to nonadjacent; second, crossed nonadjacent dependencies may be easier than nested. However, studies providing these findings may have engaged confounds: Repetition monitoring strategies may have accounted for participants' high performance in nonadjacent dependencies, and linguistic experience may have accounted for the advantage of crossed dependencies. We conducted two artificial grammar learning experiments where we addressed these confounds by manipulating reliance on repetition monitoring and by testing participants inexperienced with crossed dependencies. Results showed relevant differences in learning adjacent versus nonadjacent dependencies and advantages of nested over crossed, suggesting that formal language hierarchy may indeed translate into a hierarchy of cognitive complexity. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Background: Alveolar rhabdomyosarcoma (ARMS) is an aggressive pediatric cancer and cases with fusion PAX3-FOXO1 and PAX7-FOXO1 seem to have a poor prognosis. The aim is to evaluate whether PAX-FOXO1 alterations influence clinical outcome in childhood and adolescence population with ARMS., Procedure: A population-based study was conducted between 2011 and 2016 in patients less than 17 years with a diagnosis of ARMS. Overall survival (OS) depending on fusion status with clinical factors was analyzed., Results: Out of 111 ARMS patients recorded in the French National Childhood Cancer Registry during the 2011-2016 period, 61% expressed PAX3-FOXO1, 15% expressed PAX7-FOXO1, 13% were FOXO1 fusion-positive without PAX specification, and 7% were PAX-FOXO1 negative (n = 4 missing data). Compared to patients with PAX7-FOXO1 positive ARMS, those with PAX3-FOXO1 positive tumor were significantly older (10-17 years: 57.4% vs. 29.4%), and had more often a metastatic disease (54.4% vs. 23.5%). Poorer 5-year OS for patients with PAX3-FOXO1 and PAX not specified FOXO1-positive tumor were observed (44.0% [32.0-55.4] and 35.7% [13.1-59.4], respectively). After adjustment for stage at diagnosis, patients with positive tumor for PAX3-FOXO1 were 3.6-fold more likely to die than those with positive tumor for PAX7-FOXO1., Conclusion: At the population level, PAX3-FOXO1 was associated with a significant higher risk of death compared to PAX7-FOXO1-positive and PAX-FOXO1-negative tumors, and could explain poorer 5-year OS observed in adolescence population diagnosed with ARMS. A continuous risk score derived from the combination of clinical parameters with PAX3-FOXO1 fusion status represents a robust approach to improving current risk-adapted therapy for ARMS., (© 2023 Wiley Periodicals LLC.)

Ewing sarcoma (EwS) is a rare bone and soft tissue malignancy driven by chromosomal translocations encoding chimeric transcription factors, such as EWSR1-FLI1, that bind GGAA motifs forming novel enhancers that alter nearby expression. We propose that germline microsatellite variation at the 6p25.1 EwS susceptibility locus could impact downstream gene expression and EwS biology. We performed targeted long-read sequencing of EwS blood DNA to characterize variation and genomic features important for EWSR1-FLI1 binding. We identified 50 microsatellite alleles at 6p25.1 and observed that EwS-affected individuals had longer alleles (>135 bp) with more GGAA repeats. The 6p25.1 GGAA microsatellite showed chromatin features of an EWSR1-FLI1 enhancer and regulated expression of RREB1, a transcription factor associated with RAS/MAPK signaling. RREB1 knockdown reduced proliferation and clonogenic potential and reduced expression of cell cycle and DNA replication genes. Our integrative analysis at 6p25.1 details increased binding of longer GGAA microsatellite alleles with acquired EWSR-FLI1 to promote Ewing sarcomagenesis by RREB1-mediated proliferation., Competing Interests: Declaration of interests The authors declare no competing interests., (Published by Elsevier Inc.)

Background: Cancer epidemiology is unique in adolescents and young adults (AYAs; aged 15-39 years). The European Society for Medical Oncology/European Society for Paediatric Oncology (ESMO/SIOPE) AYA Working Group aims to describe the burden of cancers in AYAs in Europe and across European Union (EU) countries., Patients and Methods: We used data available on the Global Cancer Observatory. We retrieved crude and age-standardised (World Standard Population) incidence and mortality rates. We reported about AYA cancer burden in Europe and between 28 EU member states. We described incidence and mortality for all cancers and for the 13 cancers most relevant to the AYA population., Results: Incidence and mortality varied widely between countries with the highest mortality observed in Eastern EU countries. Cancers of the female breast, thyroid and male testis were the most common cancers across countries followed by melanoma of skin and cancers of the cervix. Variations in cancer incidence rates across different populations may reflect different distribution of risk factors, variations in the implementation or uptake of screening as well as overdiagnosis. AYA cancer mortality disparities may be due to variation in early-stage diagnoses, different public education and awareness of cancer symptoms, different degrees of access or availability of treatment., Conclusions: Our results highlight the future health care needs and requirements for AYA-specialised services to ensure a homogeneous treatment across different countries as well as the urgency for preventive initiatives that can mitigate the increasing burden., Competing Interests: Disclosure DS reports receipt of honoraria for providing academic peer review for research programme from French INCa, non-financial interest for advisory role in the clinical reference group advising NHS England about cancer policy in children and young people and non-remunerated membership of the Association of Cancer Physicians of the UK, SIOP Europe Adolescent Cancer Committee; IBS reports receipt of honoraria for participation in Advisory Board from Roche, receipt of honoraria as invited speaker from AstraZeneca, Novartis, Pfizer, Roche, receipt of personal and institutional financial interest as local PI from Novartis, Roche, non-financial interest for serving as local PI in EORTC Breast Group, OncoDistinct studies and non-remunerated advisory role in the Ethical Committee Serbia, National Agency for Drug Registration Serbia, the Working Group for Oncology of the Ministry of Health Serbia; NG reports receipt of honoraria to institution for participation in Advisory Board from Y-mAbs Therapeutics, receipt of financial support to institution from Eisai for covering travel expenses and registration fees as invited speaker at international meeting for the presentation of the results from the studies as international PI, receipt of consultancy fee to institution from Ipsen, non-remunerated Co-chair of the Fostering Age inclusive Research (FAIR) trial group of ACCELERATE; non-remunerated member of the Executive Committee of EEC (Euro-Wing Consortium), non-financial interest for leadership role as Chair of the FOSTER Consortium (Fight Osteosarcoma Through European Research) and non-remunerated member of GO-AJA, SFCE, SIOP Europe; FP reports receipt of honoraria for participation in Advisory Board from Roche Diagnostics, receipt of honoraria for providing expert testimony from Ipsen, Merck and non-financial interest for leadership role as Scientific Director of the European School of Oncology; ATo reports receipt of honoraria for participation in Advisory Board from MSD, AstraZeneca, Pfizer, Eli Lilly, receipt of honoraria as invited speaker from Eli Lilly, Novartis and non-remunerated member of AIOM; KS reports receipt of honoraria for participation in Advisory Board from Bayer, Novartis, Novo Nordisk, Roche, non-financial interest for leadership role in PanCare, SPOG, SSPHO and non-remunerated member of Board of Directors of SIOP Europe; GM reports receipt of honoraria for participation in Advisory Board from BMS, Janssen, Roche, Takeda, and receipt of honoraria as invited speaker from Amgen, AstraZeneca, MSD, Novartis, Pfizer; SB reports receipt of honoraria for participation in Advisory Board from Bayer Healthcare, Boehringer Ingelheim, Eli Lilly, Hofmann La Roche, MAP-Biopharma; non-financial interest as principal investigator of the Bayer’s larotrectinib study; and non-remunerated member of the European Musculoskeletal Oncology Society (EMSOS), German Pediatric Oncology Society (GPOH); ES reports receipt of honoraria for participation in Advisory Board from AstraZeneca A.E., AstraZeneca UK Ltd., Gilead Sciences Hellas, Merck, Sharp & Dohme, Pfizer Hellas, receipt of honoraria as invited speaker from Amgen Hellas, Pfizer Hellas, receipt of honoraria for providing expert testimony from Ipsen and non-remunerated member of Board of Directors of Hellenic Oncology Research Group, Hellenic Society of Medical Oncology. All other authors have declared no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

(1) Background: Attention deficit hyperactivity disorder (ADHD) is a common comorbid condition in opioid use disorder (OUD) and is associated with a more severe course of substance use. Patients with severe OUD who have not responded to oral opioid maintenance treatment can be treated with intravenous diamorphine up to three times per day. Here, we investigated the prevalence of ADHD among patients undergoing either daily diamorphine maintenance treatment or daily oral opioid maintenance treatment. (2) Methods: We assessed all participants with the WURS-k and the ADHD-SR. The Diagnostic Interview for ADHD in Adults (DIVA) was performed with all participants who met the cut-off in the WURS-k and/or ADHD-SR. (3) Results: The overall prevalence of ADHD was 17.9%. Prevalence of ADHD among patients undergoing daily diamorphine maintenance treatment was 14.3%. Prevalence of ADHD among patients undergoing daily oral opioid maintenance treatment was 20.3%. The combined presentation of ADHD was the most prevalent condition. In urine samples of participants with comorbid ADHD, heroin was detected the most and cocaine the least frequently. (4) Conclusions: Almost one out of five patients with OUD suffered from comorbid ADHD. In 83.3%, ADHD had not been diagnosed prior to participation in this study. Thus, patients with SUD could benefit from being routinely screened for ADHD.

Background: The initial management of patients with sarcoma is a critical issue. We used the nationwide French National Cancer Institute-funded prospective sarcoma database NETSARC to report the management and oncologic outcomes in adolescents and young adults (AYAs) patients with sarcoma at the national level., Patients and Methods: NETSARC database gathers regularly monitored and updated data from patients with sarcoma. NETSARC was queried for patients (15-30 years) with sarcoma diagnosed from 2010 to 2017 for whom tumor resection had been performed. We reported management, locoregional recurrence-free survival (LRFS), progression-free survival (PFS), and overall survival (OS) in AYA treated in French reference sarcoma centers (RSC) and outside RSC (non-RSC) and conducted multivariable survival analyses adjusted for classical prognostic factors., Results: Among 3,227 patients aged 15-30 years with sarcoma diagnosed between 2010 and 2017, the study included 2,227 patients with surgery data available, among whom 1,290 AYAs had been operated in RSC, and 937 AYAs in non-RSC. Significant differences in compliance to guidelines were observed including pre-treatment biopsy (RSC: 85.9%; non-RSC 48.1%), pre-treatment imaging (RSC: 86.8%; non-RSC: 56.5%) and R0 margins (RSC 57.6%; non-RSC: 20.2%) (p < 0.001). 3y-OS rates were 81.1% (95%CI 78.3-83.6) in AYA in RSC and 82.7% (95%CI 79.4-85.5) in AYA in non-RSC, respectively. Whereas no significant differences in OS was observed in AYAs treated in RSC and in non-RSC, LRFS and PFS were improved in AYAs treated in RSC compared to AYAs treated in non-RSC (Hazard Ratios (HR): 0.58 and 0.83, respectively)., Conclusions: This study highlights the importance for AYA patients with sarcoma to be managed in national sarcoma reference centers involving multidisciplinary medical teams with paediatric and adult oncologists., (© 2023. The Author(s).)

The objective was to evaluate the sociodemographic factors associated with the level of knowledge of early puerperal women about oral health prevention in infants. This cross-sectional and analytical study evaluated 303 early puerperal women from a hospital in the Peruvian capital. A validated 18-question questionnaire was used to measure the level of knowledge. A logistic regression model was used to evaluate the influence of age, marital status, educational level, number of children, monthly income, and having a dentist as a family member. A significance of p < 0.05 was considered. A total of 46.86%, 30.36%, and 22.77% of the puerperal had poor, fair, and good knowledge, respectively. The risk of having poor knowledge was two times higher (OR = 2.43; CI: 1.26-4.70) in early postpartum women aged 18 to 25 years than in those older than 35 years. Early postpartum women with no education, primary and secondary education were 11 times (OR = 11.76; CI: 2.41-57.43), 6 times (OR = 6.61; CI: 1.72-25.45), and 5 times (OR = 5.50; CI: 1.52-19.89), respectively, more likely to have significantly poor knowledge compared to those with university education. In conclusion, only a small minority of early postpartum women had a good knowledge of oral health prevention in infants aged 0 to 2 years. Younger and less educated puerperal were at greater risk of having little knowledge on this topic. Finally, not having basic education was the main risk factor identified.

(1) Background: Attention deficit hyperactivity disorder (ADHD) is characterized by a persistent pattern of age-inappropriate levels of inattention and/or hyperactivity/impulsivity that results in functional impairment at work, education, or hobbies and affects family life, social contacts, and self-confidence. ADHD is a comorbid condition associated with a prognosis of severe substance use disorder (SUD) and the early onset of such. The aim of this meta-analysis was to obtain the best estimate of the prevalence of ADHD in SUD populations. (2) Methods: A literature research was conducted using PUBMED ® and Web of Science ® . The following search terms were used: [ADHD], [prevalence], and [substance use disorder]. RStudio ® was used for meta-analysis methods. (3) Results: In total, 31 studies were included. We estimate the prevalence of ADHD among SUD patients at 21%.

Competing Interests: The authors report no conflicts of interest.

Beginning in March 2020, to reduce COVID-19 transmission, the US President's Emergency Plan for AIDS Relief supporting voluntary medical male circumcision (VMMC) services was delayed in 15 sub-Saharan African countries. We reviewed performance indicators to compare the number of VMMCs performed in 2020 with those performed in previous years. In all countries, the annual number of VMMCs performed decreased 32.5% (from 3,898,960 in 2019 to 2,631,951 in 2020). That reduction is largely attributed to national and local COVID-19 mitigation measures instituted by ministries of health. Overall, 66.7% of the VMMC global annual target was met in 2020, compared with 102.0% in 2019. Countries were not uniformly affected; South Africa achieved only 30.7% of its annual target in 2020, but Rwanda achieved 123.0%. Continued disruption to the VMMC program may lead to reduced circumcision coverage and potentially increased HIV-susceptible populations. Strategies for modifying VMMC services provide lessons for adapting healthcare systems during a global pandemic.

Background: As a system of European Reference Networks (ERNs) emerges, the differences in quality of care for patients with rare cancers may increase at national level. We aimed to elucidate the processes and healthcare planning principles through which the reference centres (RCs) for rare cancers are embedded in national health systems., Methods: We used a multiple case-study design based on the experiences of Czechia, Finland, France, Italy, Lithuania and Spain. Using sarcoma as an example of rare cancer, 52 semi-structured interviews were conducted during on-site visits, including a multidisciplinary group of professionals, Ministry of Health professionals, patient representatives and European policymakers., Results: The comparative analysis showed substantial heterogeneity in the processes for formalizing RCs' status and in their levels of integration in the different health systems, but two models (centre-based and the network-based) can be envisaged at national level. RCs for rare cancers were legally established only in France and Spain. Expert clinicians cooperate in a structured way, using network mechanisms, in France and Italy, and these countries, plus Finland and Lithuania, had a referral system to facilitate patients' access from non-expert centres to RCs. Seven key healthcare planning principles in instituting RCs at the national level were identified., Conclusions: The conditions governing patient access to treatment centres-whether RCs or not-are decided at the national level. It is advisable to progressively align the European and national levels so that the RCs that participate in the ERNs also play a significant role at the national level., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Public Health Association.)

Background: 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., Methods: 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., Findings: 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%])., Interpretation: 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., Funding: 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., Competing Interests: Declaration of interests SS has received honoraria and consulting fees from GSK, Lilly, and Ceridwen Oncology. JM-B reports institutional grants from Adaptimmune, Amgen, AROG, Bayer, Blueprint, Bristol Myers Squibb, Celgene, Daichii-Sankyo, Deciphera, Eisai, FORMA, GSK, IMMIX Biopharma, Karyopharm, Lilly, Nektar, Novartis, Pfizer, and PharmaMar; honoraria from PharmaMar and Tecnofarma; payment for expert testimony from Bayer, Eisai, Lilly, and PharmaMar; support for attending meetings and travel from PharmaMar and Asofarma; and participation on a data safety monitoring board or advisory board for Asofarma, PharmaMar, Boheringer, Tecnofarma, Roche, and Bayer. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The eighth Paediatric Strategy Forum focused on multi-targeted kinase inhibitors (mTKIs) in osteosarcoma and Ewing sarcoma. The development of curative, innovative products in these tumours is a high priority and addresses unmet needs in children, adolescents and adults. Despite clinical and investigational use of mTKIs, efficacy in patients with bone tumours has not been definitively demonstrated. Randomised studies, currently being planned or in progress, in front-line and relapse settings will inform the further development of this class of product. It is crucial that these are rapidly initiated to generate robust data to support international collaborative efforts. The experience to date has generally indicated that the safety profile of mTKIs as monotherapy, and in combination with chemotherapy or other targeted therapy, is consistent with that of adults and that toxicity is manageable. Increasing understanding of relevant predictive biomarkers and tumour biology is absolutely critical to further develop this class of products. Biospecimen samples for correlative studies and biomarker development should be shared, and a joint academic-industry consortium created. This would result in an integrated collection of serial tumour tissues and a systematic retrospective and prospective analyses of these samples to ensure robust assessment of biologic effect of mTKIs. To support access for children to benefit from these novel therapies, clinical trials should be designed with sufficient scientific rationale to support regulatory and payer requirements. To achieve this, early dialogue between academia, industry, regulators, and patient advocates is essential. Evaluating feasibility of combination strategies and then undertaking a randomised trial in the same protocol accelerates drug development. Where possible, clinical trials and development should include children, adolescents, and adults less than 40 years. To respond to emerging science, in approximately 12 months, a multi-stakeholder group will meet and review available data to determine future directions and priorities., Competing Interests: Conflcits of interest statement The authors declare the following financial interests/ personal relationships which may be considered as potential competing interests: FB is an employee and stockholder of Ipsen Pharma. JC is an employee of Bayer Healthcare Pharmaceuticals. MC has served as an advisor for Astra-Zeneca, Bayer, BMS, Pfizer, and Servier. SGD has received consulting fees from Amgen, Bayer, and Loxo Oncology and has received travel reimbursement from Roche and Salarius. EG is an employee of Oncoheroes Biosciences. AH is an employee of Blueprint Medicines. KJ has received consulting fees from Bayer and Ipsen and honoraria fromTakeda and Foundation Medicine. JK is an employee of Allarity Therapeutics. SK is an employee of HUTCHMED International Corporation. CO is an employee of Eisai GmbH. ADJP has consulted for Lilly, Norgine and Developmental Therapeutics Consortium Limited and been an advisor for Amgen. All remaining authors have declared no conflicts of interest., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Resection of all lung metastases in patients with osteosarcoma improves survival. The increased computed tomography (CT) scan quality allows detecting smaller nodules. We aimed to evaluate the prognostic impact of those nodules that do not meet the classical criteria for lung metastases., Methods: A central radiology review (CRR) on lung CT scans performed during the treatment of patients included in OS2006 trial and treated with a high-dose methotrexate-based chemotherapy from 2007 to 2013 was realized in three centers., Results: At trial enrollment, among 77 patients, six (8%) had nodules meeting the trial's criteria for metastatic disease, 46 (60%) were classified as having localized disease, and 25 (32%) as having doubtful nodules. After CRR, 218 nodules were found at diagnosis (all in patients classified as "metastatic or doubtful" and 13 patients classified as "localized") (median two nodules per patient [1-52]). The 5-year event-free survival/overall survival (EFS/OS) of patients with at least one nodule versus no nodule were similar (67.7%/79.2% vs. 81.8%/91%). After histological analysis, two of 46 (4.3%) "localized" and eight of 25 (32.0%) "doubtful" patients were re-classified as "metastatic," whereas there was no change in patients initially "metastatic." The 5-year OS of confirmed histological metastatic versus nonmetastatic patients were different (56% vs. 92%, p < .01)., Conclusion: Central review of lung CT scan increased the detection of nodules in osteosarcoma. Patients with small lung nodules classified as doubtful had a quite similar outcome as those with a localized disease. However, patients with confirmed metastatic nodules have a poorer prognosis, even if considered as "localized" at diagnosis., (© 2022 Wiley Periodicals LLC.)

The purpose of the present study was to calculate the construct validity, internal consistency and normative data of the Phonological Verbal Fluency Test (letters F, A, S, and M), Semantic Verbal Fluency Test (Animals, Fruits and Professions categories), and Boston Naming Test (short and standard version), and to generate normative data for these tests after adjusting for age, education, and sex. A sample of 293 European Portuguese adults participated in the study. Results showed adequate construct validity and internal consistency for all of the tests and the final multiple regression models found that age and education were significantly associated with P-VFT (letters F, A, S, and M), S-VFT (Animals, Fruits and Professions categories), and BNT performance. Sex was only found to have an effect on the fruit category, with women scoring higher than men. The normative data provided in this study will contribute to improving the clinical practice of neuropsychology in Portugal.

Osteosarcoma (OS) is a pediatric malignant bone tumor that predominantly affects adolescent and young adults. It has high risk for relapse and over the last four decades no improvement of prognosis was achieved. It is therefore crucial to identify new drug candidates for OS treatment to combat drug resistance, limit relapse, and stop metastatic spread. Two acquired hallmarks of cancer cells, mitochondria-related regulated cell death (RCD) and metabolism are intimately connected. Both have been shown to be dysregulated in OS, making them attractive targets for novel treatment. Promising OS treatment strategies focus on promoting RCD by targeting key molecular actors in metabolic reprogramming. The exact interplay in OS, however, has not been systematically analyzed. We therefore review these aspects by synthesizing current knowledge in apoptosis, ferroptosis, necroptosis, pyroptosis, and autophagy in OS. Additionally, we outline an overview of mitochondrial function and metabolic profiles in different preclinical OS models. Finally, we discuss the mechanism of action of two novel molecule combinations currently investigated in active clinical trials: metformin and the combination of ADI-PEG20, Docetaxel and Gemcitabine., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lai, Naumova, Marchais, Gaspar, Geoerger and Brenner.)

This study aimed to analyze surgical procedures for head and neck Ewing sarcoma (HNES) with regard to oncological, functional, and esthetic outcomes. A blinded multidisciplinary retrospective chart review of operated French HNES patients (Euro-EWING 99 trial, 1999-2014) was performed to assess patient/tumor characteristics, treatment details, and outcomes. Primary surgery without reconstruction was undertaken in 13 patients (emergency context/misdiagnosis). However, because of contaminated surgical margins, all patients had to undergo systematic postoperative radiotherapy. Twenty-six patients underwent multidisciplinary evaluation and were scheduled to undergo postchemotherapy surgery, with 19 patients scheduled for immediate reconstruction. All cases showed R0 margins after postchemotherapy surgery of the initial tumor bed by multidisciplinary surgical teams, while n = 3/4 of local relapses (very poor prognosis) had R1a margins after surgery of the residual tumor volume following chemotherapy. Only three surgical expertise centers operated on ≥ 4 patients over the 15-year period. Thirty patients developed long-term sequelae, with increased complications following radiotherapy. Referring patients to surgical expertise centers following a suspected diagnosis, with planned postchemotherapy surgery of the initial tumor bed at these centers, might limit the need for intralesional resections, allowing radical R0 resections and thus reducing long-term sequelae as well as the risk of secondary radio-induced malignancy by limiting the need for postoperative radiotherapy., (Copyright © 2021 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.)

Transgenic mouse models have facilitated research of human diseases and validation of therapeutic approaches. Inclusion of optical reporter genes (fluorescent or bioluminescent genes) in the targeting vectors used to develop such models makes in vivo imaging of cellular and molecular events possible, from the microscale to the macroscale. In particular, transgenic mouse models expressing optical reporter genes allowed accurately distinguishing immune cell types from trafficking in vivo using intravital microscopy or whole-body optical imaging. Besides lineage tracing and trafficking of different subsets of immune cells, the ability to monitor the function of immune cells is of pivotal importance for investigating the effects of immunotherapies against cancer. Here, we introduce the reader to state-of-the-art approaches to develop transgenics, optical imaging techniques, and several notable examples of transgenic mouse models developed for immunology research by critically highlighting the models that allow the following of immune cell function., (© 2021. The Author(s).)

The outcomes of adolescents/young adults with osteosarcoma have not improved in decades. The chaotic karyotype of this rare tumor has precluded the identification of prognostic biomarkers and patient stratification. We reasoned that transcriptomic studies should overcome this genetic complexity. RNA sequencing (RNA-seq) of 79 osteosarcoma diagnostic biopsies identified stable independent components that recapitulate the tumor and microenvironment cell composition. Unsupervised classification of the independent components stratified this cohort into favorable (G1) and unfavorable (G2) prognostic tumors in terms of overall survival. Multivariate survival analysis ranked this stratification as the most influential variable. Functional characterization associated G1 tumors with innate immunity and G2 tumors with angiogenic, osteoclastic, and adipogenic activities as well as PPARγ pathway upregulation. A focused gene signature that predicted G1/G2 tumors from RNA-seq data was developed and validated within an independent cohort of 82 osteosarcomas. This signature was further validated with a custom NanoString panel in 96 additional osteosarcomas. This study thus proposes new biomarkers to detect high-risk patients and new therapeutic options for osteosarcoma., Significance: These findings indicate that the osteosarcoma microenvironment composition is a major feature to identify hard-to-treat patient tumors at diagnosis and define the biological pathways and potential actionable targets associated with these tumors., (©2022 American Association for Cancer Research.)

Background: Osteosarcomas (OTS) represent the most common primary bone cancer diagnosed in adolescents and young adults. Despite remarkable advances, there are no objective molecular or imaging markers able to predict an OTS outcome at diagnosis. Focusing on biomarkers contributing broadly to treatment resistance, we examine the interplay between the tumor-associated macrophages and intra-tumor hypoxia., Methods: Radiological and immunohistochemical (IHC) data were correlated with the outcome in a retrospective and monocentric cohort of 30 pediatric OTS. We studied hypoxic (pS6, phospho-mTor, HIF-1α and carbonic anhydrase IX (CAIX)) and macrophagic (CD68 and CD163) biomarkers., Results: The imaging analyses were based on MRI manual volumetric measures on axial post-contrast T1 weighted images, where, for each tumor, we determined the necrotic volume and its ratio to the entire tumor volume. When they were above 50 cm 3 and 20%, respectively, they correlated with a worse overall survival ( p = 0.0072 and p = 0.0136, respectively) and event-free survival ( p = 0.0059 and p = 0.0143, respectively). IHC assessments enable a significant statistical link between HIF-1α/CAIX hyper-expressions, CD68+ cells and a worse outcome, whereas activation of mTor pathway was linked to a better survival rate and CD163+ cells., Conclusions: This study evidenced the links between hypoxia and immunity in OTS, as their poor outcome may be related to a larger necrotic volume on diagnostic MRI and, in biopsies, to a specific IHC profile.

Given constrained funding for HIV, achieving global goals on VMMC scale-up requires that providers improve service delivery operations and use labor and capital inputs as efficiently as possible to produce as many quality VMMCs as feasible. The Voluntary Medical Male Circumcision Site Capacity and Productivity Assessment Tool (SCPT) is an electronic visual management tool developed to help VMMC service providers to understand and improve their site's performance. The SCPT allows VMMC providers to: 1) track the most important human resources and capital inputs to VMMC service delivery, 2) strategically plan site capacity and targets, and 3) monitor key site-level VMMC service delivery performance indicators. To illustrate a real-world application of the SCPT, we present selected data from two provinces in Mozambique-Manica and Tete, where the SCPT was piloted We looked at the data prior to the introduction of SCPT (October 2014 to August 2016), and during the period when the tool began to be utilized (September 2016 to September 2017). The tool was implemented as part of a broader VMMC site optimization strategy that VMMC implementers in Mozambique put in place to maximize programmatic impact. Routine program data for Manica and Tete from October 2014 to September 2017 showcase the turnaround of the VMMC program that accompanied the implementation of the SCPT together with the other components of the VMMC site optimizatio strategy. From October 2016, there was a dramatic increase in the number of VMMCs performed. The number of fixed service delivery sites providing VMMC services was expanded, and each fixed site extended service delivery by performing VMMCs in outreach sites. Alignment between site targets and the number of VMMCs performed improved from October 2016. Utilization rates stabilized between October 2016 and September 2017, with VMMCs performed closely tracking VMMC site capacity in most sites. The SCPT is designed to address the need for site level data for programmatic decision-making during site planning, implementation, monitoring and evaluation. Deployment of the SCPT can help VMMC providers monitor the performance of VMMC service delivery sites and improve their performance. We recommend use of the customized version of this tool and model to the need of other programs., Competing Interests: The authors have read the journal’s policy and have the following competing interests: authors MT, PS, MH and SF are employees of Avenir Health. Authors FN and FZ are employees of Jhpiego. The fact that Avenir Health and Jhpiego are private contractors does not alter our adherence to PLOS Global Public Health journal policies on sharing data and materials. There are no patents, products in development or marketed products associated with this research to declare., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Competing Interests: Disclosure SJS has received honoraria for participation in advisory board for GlaxoSmithKline (GSK); NA non-remunerated leadership and advisory roles for Sociedade Portuguesa de Cirurgia; JB has no personal financial disclosure, received research grants (institutional) from Eli Lilly, Novartis, Roche, Samsung Bioepis, Paxman Coolers Ltd, Sun Pharma and non-remunerated advisory role for Novartis, non-remunerated leadership activities for Immuno-oncology society of India, Indian Society of Medical and Paediatric Oncology, Teenage and Young Adult Cancer Foundation and Indian cooperative oncology network; SB has received honoraria for participation in advisory boards for Deciphera, Blueprint Medicines, Lilly, Novartis, Daiichi-Sankyo, Plexxikon, Roche, GSK, invited speaker fees from Pfizer and PharmaMar, institutional research grant from Novartis, institutional research as principal investigator (PI) for Daiichi-Sankyo, Roche, Deciphera, Lilly, Novartis, Blueprint Medicines, Bristol Myers Squibb (BMS), Incyte, non-remunerated activities for Federal Institute for Drugs and Medical Devices (BfArm) and founding member of German Sarcoma Foundation; RB reports non-remunerated activities as PI for IRCSS Galeazzi Orthopedic Institute and IRE-ISG Regina Elena Institute, participation at the Clinical Experience Exchange Meeting, III IDBN National Congress 2019, Italian Association of Medical Oncology (AIOM), IRE-ISG Regina Elena Institute and Lazio Association of Orthopaedic Hospital Traumatologists (ALOTO); SBi has received honoraria for participation in advisory boards from Bayer Healthcare, Boehringer Ingelheim, ClinGen, Hofmann La Roche, Ipsen, Eli Lilly and Sensorion, non-remunerated activities for Bayer and membership of the German Pediatric Oncology Society and European Musculoskeletal Oncology Society; JYB received research support from Merck Sharp & Dohme (MSD), Roche, GSK, Novartis, Bayer, PharmaMar outside the present work; SBon has received honoraria for advisory board from Nanobiotix and as invited speaker for PharmaMar, trial research grant from the Institut National du Cancer (INCa); IB has received honoraria for participation in advisory boards for Roche, Lilly, Sanofi, Pierre Fabre, Ipsen, and as invited speaker for Amgen, BMS, Novartis, Leo Pharma, AstraZeneca and Genesis, member of Board of Directors for Hellenic Society of Medical Oncology, Hellenic Society of Sarcomas and Rare Tumors, Hellenic Oncology Research Group (HORG), PI trial research support from Novartis, BMS, Regeneron, MSD, Lilly and Roche; JVMGB receives royalties from UpToDate and Wolters Kluwer, and direct research funding from TRACON pharmaceuticals; KB has received honoraria for expert testimony and advisory boards for Bayer, invited speaker fees and research grant from Eli Lilly, PI for Deciphera and Novartis; TB has received honoraria for participation in advisory boards for Bayer and Eli Lilly, invited speaker fees from PharmaMar and Novartis; EDÁ has received honoraria for participation in advisory board for Bayer, invited speaker for Lilly, PharmaMar and Roche, institutional research support from Pfizer, Roche and AstraZeneca; APDT has received honoraria for participation in advisory boards for Bayer and Roche, invited speaker for PharmaMar and Novartis; XGDM has received honoraria for participation in advisory boards for Ipsen, EUSA Pharma, BMS, Pfizer, Roche and PharmaMar, invited speaker for Lilly, Astellas Pharma, Eisai and Pfizer and institutional research grant from AstraZeneca; ME has received honoraria for participation in advisory boards for Clinigen and Bayer, consulting fees from Blueprint Medicines, institutional research funding from Novartis; AF has received honoraria for participation in advisory board for Novartis and invited speaker fees for MSD and Amgen; VF has received honoraria for participation in advisory boards and speaker fees for BMS, Novartis and MSD and speaker fees from Pierre Fabre; NG has received honoraria as invited speaker for Eisai and reports membership of the European Society for Paediatric Oncology (SIOPE), ACCELERATE, Societe Francaise de lutte contre les cancers et leucemies de l'enfant et de l'adolescent (SFCE) and Groupe Onco- hématologie Adolescents et Jeunes Adultes (GO-AJA); SG has reported institutional research for Blueprint Medicines and member of American Society of Clinical Oncology (ASCO) and AIOM; HG has reported PI research for Daiichi, Deciphera and Novartis, co-ordinating PI for Boehringer Ingelheim and AmMax Bio; FG has received honoraria for participation in advisory board for Amgen and expert testimony for Deciphera, stock ownership for Atlanthera, licensing fees from Zimmer, non-remunerated activities for 3D-Side and INCa DGOS funding and member of the board of NetSarc the French clinical reference network for soft tissue and visceral sarcomas; GG has received honoraria for participation in advisory boards for Lilly, Eisai, Merck, Bayer and GSK, invited speaker fees from PharmaMar and Novartis, institutional grants from PharmaMar, Bayer and Novartis; AG has received honoraria for participation in advisory boards for Novartis, Pfizer, Bayer, Lilly, PharmaMar, SpringWorks and Nanobiotix, invited speaker for Lilly, PharmaMar and research grant from PharmaMar; RH has received honoraria from GSK; ABH is a member of Board of Directors for EIT health UK and Ireland, received or currently receives direct research funding as a PI from Roche, performs work in clinical trials or contracted research for the Institution and Clinical Director of the Oncology and Haematology Directorate, Oxford Cancer Centre; SHN reports institutional research role as deputy PI for Eisai, non-remunerated activity for Harmonization International Bones Sarcoma Consortium (HIBISCus), membership of SIOPE, German, Swiss, Austrian Society of Paediatric Oncology and Hematology (GPOH) and German Society of Pediatrics and Adolescent Medicine (DGKJ); NH has received honoraria as expert testimony and invited speaker from PharmaMar, performs work in clinical trials or contracted research for which his/her institution received financial support from PharmaMar, Lilly, Adaptimmune Therapeutics, AROG Pharmaceuticals, Bayer, Eisai, Lixte, Karyopharm, Deciphera, GSK, Novartis, Blueprint Medicines, Nektar Therapeutics, Forma, Amgen and Daiichi-Sankyo, non-remunerated leadership roles for Grupo Español de Investigación en Sarcomas (GEIS) and SELNET, and has non-remunerated membership or affiliation with ESMO, Sociedad Española de Oncología Médica (SEOM), ASCO, Connective Tissue Oncology Society (CTOS) and European Organisation for Research and Treatment of Cancer (EORTC); PH has received honoraria for participation in advisory boards for Pfizer, Roche and GSK, invited speaker fees from PharmaMar and Lilly, clinical expert fees from Boehringer Ingelheim, institutional research funding for clinical trials from Siemens, Novartis, Blueprint Medicines and meeting sponsorship from PEKKIP Oncology, non-remunerated activities for the German Sarcoma Foundation (DSS), German Interdisciplinary Sarcoma Group (GISG) and Interdisciplinary Working Party on Sarcomas (IAWS) of the German Cancer Society (DKG), advisory role for the German Cancer Aid (DKH) Committee on Health Technology Assessment and Sarcoma Patients EuroNet (SPAEN); HJ has received honoraria for participation in advisory boards for Orion Pharma, Neutron Therapeutics and Maud Kuistila Memorial Foundation, had full time or part time employment at Orion Pharma, until 31 August 2020, stocks in Orion Pharma and Sartar Therapeutics; RLJ has received honoraria for expert testimony consultancy for Adaptimmune, Bayer, Boehringer Ingelheim, Blueprint Medicines, Clinigen, Eisai, Epizyme, Daiichi, Deciphera, Immune Design, Lilly, SpringWorks, Tracon, UpToDate, PharmaMar, advisory board for Athenex, institutional research grant from MSD; CJ has received travel grants from Ipsen and PharmaMar; LK has received honoraria for participation in advisory boards for Bayer, Novartis and Agios; BK has received honoraria for participation in advisory boards for Bayer, Blueprint Medicines, Boehringer Ingelheim, SpringWorks, GSK and PharmaMar, institutional research support from PharmaMar and SpringWorks, member of EORTC and Chair of the EORTC soft tissue and bone sarcoma group (STBSG); AK has received honoraria for participation in advisory boards for Daiichi-Sankyo and Otsuka and invited speaker fees from Novartis, Taiho and Eisai; KK has received honoraria for participation in advisory board for Bayer and expert testimony for Eli Lilly and Roche; ALC has received honoraria for participation in advisory boards for Deciphera and Lilly, invited speaker fees from PharmaMar and Bayer; EL received honoraria from SpringWorks Therapeutics for scientific advisory board participation and member of the European Reference Network GENTURIS; AL has received institutional research grants from Johnson & Johnson, Alphamed, Medacta and ImplanTec, non-remunerated activities for European Musculoskeletal Society (EMSOS), Austrian Society of Orthopaedic Surgeons (OGO) and membership of CTOS; ALP has received honoraria as invited speaker for PharmaMar, institutional research funding from the Spanish Health Ministry, reported non-remunerated activities as PI for PharmaMar, Cebiotex, Deciphera, Lilly, GSK, Daiichi, Epizyme, Advenchen Laboratories, Novartis, Karyopharm, Blueprint medicines, GEIS and other activity for EORTC; JMB has received honoraria for expert testimony for Lilly, PharmaMar, Eisai, Bayer, invited speaker fee from PharmaMar, institutional research for PharmaMar, Eisai, Novartis, Immix Biopharma, Lixte, Karyopharm, Bayer, Celgene, Pfizer, BMS, Blueprint Medicines, Deciphera, Nektar Therapeutics, Forma, Amgen, Daiichi-Sankyo, Lilly, AROG Pharmaceutcials, Adaptimmune and GSK; OM has received honoraria for participation in advisory boards for MSD, Megapharm, AstraZeneca, Takeda and Progenetics, invited speaker fees from MSD and Roche; CM has performed non-remunerated activities for International Cancer Imaging Society and EORTC STBSG; OMi has received honoraria for participation in advisory boards for Bayer, Blueprint Medicines, MSD, Pfizer, invited speaker fees from BMS, Eli Lilly, Ipsen, Roche and Servier, institutional research for Blueprint Medicines, Bayer, Epizyme and Eli-Lilly; BM has received honoraria from Clinigen as invited speaker; EP has received honoraria for participation in advisory boards for SynOx, Daiichi-Sankyo and Deciphera Pharmaceuticals and invited speaker fees from Peer View Educational; MAP has received honoraria for participation in advisory boards for Roche, invited speaker fees from Eli Lilly, Pfizer, and Novartis, expert testimony from Blueprints Medicine and institutional research grant from Novartis; SPN has received honoraria for participation in advisory board for Immunocore; PR has received honoraria for participation in advisory boards for Bayer, Clinigen, Roche, MSD, Deciphera, Mundibiopharma, PharmaMar, Blueprint Medicines, invited speaker fees from Lilly, PharmaMar, institutional research for PharmaMar, Karyopharm, SpringWorks, AROG Pharmaceuticals, Blueprint, Deciphera, Amgen, Astellas, Epizyme, Lilly, MSD, Pfizer, Novartis and Philogen, membership of German Sarcoma Foundation; PRu has received honoraria for participation in advisory boards for MSD, BMS, Pierre Fabre, Merck, Sanofi, Blueprint Medicines, invited speaker fees from MSD, BMS, Pierre Fabre, Merck, Sanofi, Novartis, institutional research funding from Pfizer, BMS and non-remunerated activities for the Polish Society of Surgical Oncology and ASCO; MS has received honoraria for travel grant from PharmaMar and writing engagement for Lilly; SS has reported a research grant from Johnson & Johnson and research funding from Roche Austria; PS has received honoraria for participation in advisory boards for Deciphera, Blueprint Medicines, Boehringer Ingelheim, Ellipses Pharma, Transgene, Exelixis, Medscape, Guided Clarity, Ysios, Modus Outcomes, Studiecentrum voor Kernenergie, Curio Science, institutional honoraria for advisory boards for Blueprint Medicines, Ellipses Pharma, Intellisphere, expert testimony for Advanced Medical/Teladoc Health, institutional research funding from CoBioRes NV, Eisai, G1 Therapeutics, Novartis and PharmaMar; SSl Chair of Centre for Personalised Cancer Treatment and Route Personalised Medicine, Dutch Science Agenda, member of supervisory board for SkylineDX and Scientific advisory committee Pan-Cancer T BV; KSH reports non-remunerated activity for CTOS as President 2020 and membership of the Scandinavian Sarcoma Group; MAJvdS has performed work in clinical trials or contracted research for which the institution received financial support from Daiichi-Sankyo, Implantcast and Carbofix; WTAvdG has received institutional honoraria for participation in advisory boards for Bayer and GSK, institutional research grants from Novartis and Lilly and consultancy work for SpringWorks; WJvH has received institutional honoraria for participation in advisory board for Belpharma, invited speaker fees from Amgen, expert testimony for Sanofi and MSD, personal travel grant from Novartis and institutional research grant from BMS; TF reported institutional research funding from the Foundation ARC and Ligue Régionale contre le Cancer, leadership role for ERN GENTURIS; PGC has received honoraria for participation in advisory board for Bayer, institutional research funding from Amgen Dompé, Advenchen, Bayer, Blueprint, Deciphera, Eli Lilly, Epizyme, Daiichi, GSK, Karyopharm, Novartis, Pfizer, PharmaMar, SpringWorks, AROG Pharmaceuticals and Eisai, non-remunerated activities for the Italian Sarcoma Group, European School of Oncology, Federation of Italian Cooperative Groups and Rare Cancers Europe; SSta has received honoraria for participation in advisory boards for Bayer, Deciphera, Eli Lilly, Daiichi, Maxivax, Novartis, invited speaker fees from GSK and PharmaMar, expert testimony fee from Bavarian Nordic and Epizyme, institutional research funding from Amgen Dompé, Advenchen, Bayer, Blueprint Medicines, Deciphera, Eli Lilly, Epizyme, Daiichi, GSK, Karyopharm, Novartis, Pfizer, PharmaMar, SpringWorks and Hutchinson MediPharma International Inc., non-remunerated activities for CTOS, Chordoma Foundation, Epithelioid Haemangioendothelioma Foundation, Desmoid Foundation, EORTC STBSG and Italian Sarcoma Group Onlus. AMF, AB, SBo, BB, AD, FF, AFer, PJ, DAK, FLG, ABM, MM, CMo, RP, AAS, CS, DS, AT, MU and RL have declared no conflicts of interests.

Context: Osteosarcoma is the most common primary solid malignancy of the bone, mainly affecting pediatric patients. The main clinical issues are chemoresistance and metastatic spread, leading to a survival rate stagnating around 60% for four decades., Purpose: Here, we investigated the effect of simvastatin as adjuvant therapy on chemotherapy., Methods: Cell viability was assessed by the MTT test, and a combination index was evaluated by an isobologram approach. Cell motility was assessed by wound-healing assay. Cell-derived xenograft models were established in mice. FFPE tumor samples were assessed by immunohistochemistry., Results: In vitro experiments indicate that simvastatin synergized the conventional chemotherapy drugs' inhibitory effect on cell viability. Functional assays reveal that simvastatin supplementation favored the anticancer mechanism of action of the tested chemotherapy drugs, such as DNA damage through intercalation or direct alkylation and disorganization of microtubules. Additionally, we show that even though simvastatin alone did not modify tumor behavior, it potentiated the inhibitory effect of doxorubicin on primary tumor growth (+50%, p < 0.05) and metastatic spread (+50%, p < 0.05). Our results provide evidence that simvastatin exerted an anti-tumor effect combined with chemotherapy in the preclinical murine model and represents valuable alternative adjuvant therapy that needs further investigation in clinical trials.

While survival rates for patients with relapsed/refractory osteosarcoma are low, kinase inhibitors have shown efficacy in its treatment. The multikinase inhibitor lenvatinib, plus ifosfamide and etoposide, showed antitumor activity in a Phase II study in patients with relapsed/refractory osteosarcoma. This Phase II randomized controlled trial (OLIE) will assess whether the combination of lenvatinib + ifosfamide + etoposide is superior to ifosfamide + etoposide alone in children, adolescents and young adults with relapsed/refractory osteosarcoma. The primary end point is progression-free survival; secondary and exploratory end points include, but are not limited to, overall survival, objective response rate, safety and tolerability, pharmacokinetic characterization of lenvatinib in the combination treatment, quality of life and quantification of baseline unresectable lesions that are converted to resectable.

Background: We report results from the phase I dose-finding and phase II expansion part of a multicenter, open-label study of single-agent lenvatinib in pediatric and young adult patients with relapsed/refractory solid tumors, including osteosarcoma and radioiodine-refractory differentiated thyroid cancer (RR-DTC) (NCT02432274)., Patients and Methods: The primary endpoint of phase I was to determine the recommended phase II dose (RP2D) of lenvatinib in children with relapsed/refractory solid malignant tumors. Phase II primary endpoints were progression-free survival rate at 4 months (PFS-4) for patients with relapsed/refractory osteosarcoma; and objective response rate/best overall response for patients with RR-DTC at the RP2D., Results: In phase I, 23 patients (median age, 12 years) were enrolled. With lenvatinib 14 mg/m 2 , three dose-limiting toxicities (hypertension, n = 2; increased alanine aminotransferase, n = 1) were reported, establishing 14 mg/m 2 as the RP2D. In phase II, 31 patients with osteosarcoma (median age, 15 years) and 1 patient with RR-DTC (age 17 years) were enrolled. For the osteosarcoma cohort, PFS-4 (binomial estimate) was 29.0% [95% confidence interval (CI) 14.2% to 48.0%; full analysis set: n = 31], PFS-4 by Kaplan-Meier estimate was 37.8% (95% CI 20.0% to 55.4%; full analysis set) and median PFS was 3.0 months (95% CI 1.8-5.4 months). The objective response rate was 6.7% (95% CI 0.8% to 22.1%). The patient with RR-DTC had a best overall response of partial response. Some 60.8% of patients in phase I and 22.6% of patients in phase II (with osteosarcoma) had treatment-related treatment-emergent adverse events of grade ≥3., Conclusions: The lenvatinib RP2D was 14 mg/m 2 . Single-agent lenvatinib showed activity in osteosarcoma; however, the null hypothesis could not be rejected. The safety profile was consistent with previous tyrosine kinase inhibitor studies. Lenvatinib is currently being investigated in osteosarcoma in combination with chemotherapy as part of a randomized, controlled trial (NCT04154189), in pediatric solid tumors in combination with everolimus (NCT03245151), and as a single agent in a basket study with enrollment ongoing (NCT04447755)., Competing Interests: Disclosure SGM: personal fees from Loxo Oncology, Bayer, and EUSA Pharma, outside the submitted work. FL: consultant or advisory role for Novartis, Amgen, Bellicum Pharmaceuticals, and Pfizer; honoraria for speaking at symposia from Amgen, Novartis, bluebird bio, Miltenyi, Bellicum Pharmaceuticals, and Jazz Pharmaceuticals. FB: consultant or advisory role for Bayer, Amgen, Roche, Sanofi, and EUSA Pharma; honoraria for speaking at symposia from Amgen and Jazz Pharmaceuticals; support for attending symposia from Takeda, EUSA Pharma, Shire, and Jazz Pharmaceuticals. CR: consultant or advisory role for Amgen, Bristol Myers Squibb (BMS), Celgene, Genentech, Novartis, Pfizer, and Roche. ACN: personal fees from Bayer and EUSA Pharma, outside of the submitted work. AL: nonfinancial support and ‘other’ from PharmaMar; grants and nonfinancial support from Takeda, during the conduct of the study. SJS: consultant or advisory role for Lilly outside the submitted work. CO: employee of Eisai Ltd. CH: employee of Eisai Inc. LD: employee of Eisai Inc. MC: advisory roles for AstraZeneca, Bayer, BMS, Eisai, Lilly, and Roche outside the submitted work. All other authors have declared no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Tyrosine kinase inhibitors have shown activity in osteosarcoma and might enhance the efficacy of chemotherapy. We aimed to determine the recommended phase 2 dose and antitumour activity of lenvatinib with etoposide plus ifosfamide in patients with refractory or relapsed osteosarcoma., Methods: This multicentre, open-label, multicohort, phase 1/2 trial was done at 17 hospitals in six countries. Eligible patients were aged 2-25 years, had relapsed or refractory osteosarcoma, measurable or evaluable disease per Response Evaluation Criteria in Solid Tumors version 1.1, Lansky play-performance score or Karnofsky performance score of 50% or higher, up to one previous VEGF or VEGF receptor-targeted therapy, and a life expectancy of at least 3 months. This study includes a combination dose-finding phase 1 part (cohort 3A) and a phase 2 combination expansion in patients with osteosarcoma (cohort 3B). Lenvatinib was administered orally at a starting dose of 11 mg/m 2 per day, capped at 24 mg per day, and etoposide (100 mg/m 2 per day) plus ifosfamide (3000 mg/m 2 per day) were administered intravenously on days 1-3 of each 21-day cycle for a maximum of five cycles. Lenvatinib monotherapy continued after these five cycles until disease progression, toxic effects, or patient choice to discontinue. The phase 1 primary endpoint was to determine the recommended phase 2 dose by evaluating dose-limiting toxicity and the phase 2 primary endpoint was progression-free survival at 4 months. Progression-free survival was measured in the full analysis set, which included all patients enrolled for efficacy outcomes; safety was assessed in all patients who received any study drug. This study is registered with ClinicalTrials.gov, NCT02432274., Findings: 30 patients were screened for enrolment into cohort 3A between May 9, 2016, and June 3, 2019, and 22 patients for enrolment into cohort 3B between Sept 13, 2018, and July 18, 2019. Eight patients from cohort 3A and two from cohort 3B were ineligible for enrolment in the study. In phase 1, dose-limiting toxicities were observed in three patients (one in the lenvatinib 11 mg/m 2 combination group and two in the 14 mg/m 2 combination group) and the recommended phase 2 dose was determined as lenvatinib 14 mg/m 2 per day (with daily dose cap of 24 mg) and etoposide 100 mg/m 2 per day plus ifosfamide 3000 mg/m 2 per day administered intravenously on days 1-3 of each 21-day cycle for a maximum of five cycles. 35 patients from phase 1 (cohort 3A; n=15) and phase 2 (cohort 3B; n=20) were treated at the recommended phase 2 dose and their results were pooled. Progression-free survival at 4 months was 51% (95% CI 34-69) in 18 of 35 patients per the binomial estimate. The most common grade 3-4 treatment-emergent adverse events were neutropenia (27 [77%] of 35), thrombocytopenia (25 [71%]), anaemia (19 [54%]), and decreased white blood cell count (19 [54%]). 26 [74%] of 35 patients had serious treatment-emergent adverse events and no treatment-related deaths occurred., Interpretation: Lenvatinib with etoposide plus ifosfamide shows promising antitumour activity with no new safety signals in patients with refractory and relapsed osteosarcoma. These findings warrant further investigation in an ongoing randomised phase 2 study (NCT04154189)., Funding: Eisai and Merck Sharp & Dohme., Competing Interests: Declaration of interests NG reports fees from Eisai for presenting the study results at a scientific congress meeting. SH-N reports institutional study and grant funding from Eisai and an unpaid leadership role as cochair of the Pediatric Cancer Data Commons. SGM reports personal fees from Bayer for an educational event and personal fees from Loxo Oncology, Bayer, and Eusa Pharma for participating on an advisory board. SJS reports personal consulting fees from GSK for participating on an advisory board. CEO, CH, and LD are employees of Eisai. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The international pediatric oncology community has a long history of research collaboration. In the United States, the 2019 launch of the Children's Cancer Data Initiative puts the focus on developing a rich and robust data ecosystem for pediatric oncology. In this spirit, we present here our experience in constructing the Pediatric Cancer Data Commons (PCDC) to highlight the significance of this effort in fighting pediatric cancer and improving outcomes and to provide essential information to those creating resources in other disease areas. The University of Chicago's PCDC team has worked with the international research community since 2015 to build data commons for children's cancers. We identified six critical features of successful data commons design and implementation: (1) establish the need for a data commons, (2) develop and deploy the technical infrastructure, (3) establish and implement governance, (4) make the data commons platform easy and intuitive for researchers, (5) socialize the data commons and create working knowledge and expertise in the research community, and (6) plan for longevity and sustainability. Data commons are critical to conducting research on large patient cohorts that will ultimately lead to improved outcomes for children with cancer. There is value in connecting high-quality clinical and phenotype data to external sources of data such as genomic, proteomics, and imaging data. Next steps for the PCDC include creating an informed and invested data-sharing culture, developing sustainable methods of data collection and sharing, standardizing genetic biomarker reporting, incorporating radiologic and molecular analysis data, and building models for electronic patient consent. The methods and processes described here can be extended to any clinical area and provide a blueprint for others wishing to develop similar resources., Competing Interests: Suzi BirzConsulting or Advisory Role: Litmus Health Stefanie Hecker-NoltingResearch Funding: Eisai Nathalie GasparConsulting or Advisory Role: Eisai, IpsenTravel, Accommodations, Expenses: Eisai Gianni BisognoConsulting or Advisory Role: Bayer, Roche, iQone healthcareTravel, Accommodations, Expenses: Jazz Pharmaceuticals Dirk ReinhardtConsulting or Advisory Role: Novartis, Bluebird Bio, Hexal, BMS, Jazz Pharmaceuticals, JanssenResearch Funding: Celgene, Roche/Genentech, Novartis, BluebirBioTravel, Accommodations, Expenses: Jazz Pharmaceuticals C. Michel ZwaanConsulting or Advisory Role: Takeda, incyte, Sanofi, Bayer, NovartisResearch Funding: Pfizer, Jazz Pharmaceuticals, Celgene, TakedaTravel, Accommodations, Expenses: Jazz Pharmaceuticals Lindsay FrazierStock and Other Ownership Interests: Decibel TherapeuticsConsulting or Advisory Role: Decibel Therapeutics Katherine JanewayHonoraria: Foundation MedicineConsulting or Advisory Role: Bayer, IpsenTravel, Accommodations, Expenses: Bayer Doug HawkinsResearch Funding: Loxo, Bristol Myers Squibb, Merck Sharp & Dohme, Bayer, Lilly, Eisai, Amgen, Incyte, Jazz Pharmaceuticals, PfizerTravel, Accommodations, Expenses: Bayer, AstraZeneca E. Anders KolbTravel, Accommodations, Expenses: Roche/Genentech Susan CohnStock and Other Ownership Interests: Merck, Stryker (I), Amgen (I), Pfizer (I), AbbVie, Amgen, Lilly, Sanofi, Accelerated Medical Diagnostics, Novo Nordisk, Gilead Sciences, United Health Group, TevaHonoraria: Y-mAbs TherapeuticsResearch Funding: United Therapeutics, Merck Andrew D. J. PearsonConsulting or Advisory Role: Lilly, Takeda, Merck, CelgeneTravel, Accommodations, Expenses: Lilly, Takeda, Merck, Celgene Samuel VolchenboumStock and Other Ownership Interests: Litmus HealthConsulting or Advisory Role: AccordantTravel, Accommodations, Expenses: Sanford HealthNo other potential conflicts of interest were reported.