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There are few well-established risk factors for childhood leukemias. While the frequency of childhood leukemias might be partially attributable to some diseases (accounting for a small fraction of cases) or ionizing radiation, the role of heavy metals has not been assessed. The objective of our study was to assess the potential association between levels of cadmium (Cd) and lead (PB) in soil and childhood leukemias incidence. We conducted a population-based case-control study of childhood leukaemia in Spain, covering 2897 incident cases gathered from the Spanish Registry of Childhood Tumours and including 14 Spanish Regions with a total population of 5,307,433 children (period 1996-2015). Cd and Pb bioavailable levels at every children's home address were estimated using data from the Geochemical Atlas of Spain. We used logistic regression to estimate odds ratios (ORs) and their 95% confidence intervals (95%CIs); we included as covariates: sex, rurality, employment rate and socioeconomic status. Metal levels were analysed according to two definitions: as continuous variable assuming linearity and as categorical variables to explore a potentially nonlinear association (quantiles). Increases in both Cd and Pb topsoil levels were associated with increased probability of childhood leukemias incidence. The results for the models with the continuous variables showed that a unit increase on the topsoil level was associated with an OR of 1.11 for Cd (95%CI 1.00-1.24) and an OR of 1.10 for Pb (95%CI 0.99-1.21). Our study may point towards a possible link between residential Cd and Pb topsoil levels and the probability of childhood leukemias incidence. Residing in a location with the highest concentrations of these heavy metals compared to those locations with the lowest could increase the risk around a 20%, for both Cd and Pb.

Several noise sources, such as the Johnson-Nyquist noise, affect MR images disturbing the visualization of structures and affecting the subsequent extraction of radiomic data. We evaluate the performance of 5 denoising filters (anisotropic diffusion filter (ADF), curvature flow filter (CFF), Gaussian filter (GF), non-local means filter (NLMF), and unbiased non-local means (UNLMF)), with 33 different settings, in T2-weighted MR images of phantoms (N = 112) and neuroblastoma patients (N = 25). Filters were discarded until the most optimal solutions were obtained according to 3 image quality metrics: peak signal-to-noise ratio (PSNR), edge-strength similarity-based image quality metric (ESSIM), and noise (standard deviation of the signal intensity of a region in the background area). The selected filters were ADFs and UNLMs. From them, 107 radiomics features preservation at 4 progressively added noise levels were studied. The ADF with a conductance of 1 and 2 iterations standardized the radiomic features, improving reproducibility and quality metrics.

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/m2, three dose-limiting toxicities (hypertension, n = 2; increased alanine aminotransferase, n = 1) were reported, establishing 14 mg/m2 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/m2. 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)., Highlights • The recommended phase II dose of lenvatinib in children with relapsed/refractory solid malignant tumors is 14 mg/m2. • This dose is equivalent to the recommended dose of 24 mg/day for single-agent lenvatinib in adults with DTC. • Single-agent lenvatinib showed activity of interest in children and young adults with osteosarcoma. • Based on this initial report, lenvatinib is currently being investigated in combination with chemotherapy in osteosarcoma.

Background Lenvatinib (LEN) is a multikinase inhibitor of VEGFR1–3 and other targets. We report data from phase Ib dose-finding and phase II expansion cohorts of LEN + etoposide + ifosfamide in pts with r/r osteosarcoma. Methods Pts were aged 2 to ≤ 25 years with r/r osteosarcoma and Results In the phase Ib dose-finding cohort (n = 22), pts received LEN 11 mg/m2 (n = 7) and 14 mg/m2 (n = 15) + chemo. Dose-limiting toxicities were: Grade (G) 4 thrombocytopenia (n = 1; LEN 11 mg/m2), G4 thrombocytopenia and G3 epistaxis (n = 1; LEN 14 mg/m2), G2 oral dysesthesia, G3 muscle spasm, and G2 back pain (n = 1; LEN 14 mg/m2). RPh2D was LEN 14 mg/m2 + chemo. In the expansion cohort (n = 20), the median number of LEN cycles received was 4 (range: 1–7). As reported in the database, the most frequent treatment-emergent adverse events (TEAEs) were platelet count decreased/thrombocytopenia (50%/30%), neutropenia/neutrophil count decreased (45%/25%), anemia (45%), nausea (40%), ALT increased, diarrhea, and white blood cell count decreased (30% each). Most frequent G ≥ 3 TEAEs were neutropenia/neutrophil count decreased (45%/25%), platelet count decreased/thrombocytopenia (40%/20%), white blood cell count decreased (30%), and anemia (25%). Pneumothorax was observed in the dose-finding cohort (n = 6) and expansion cohort (n = 1); 2 (dose-finding cohort) were ≥G3; and 1 was post-thoracotomy. 4 Pts (dose-finding cohort) discontinued treatment due to TEAEs. There were no treatment-related fatal serious AEs. In the dose-finding combination cohort, 12/18 evaluable pts (66.7%) achieved PFS-4. In the phase II expansion cohort, 5/8 evaluable pts (62.5%) achieved PFS-4. Conclusions The combination of RPh2D LEN (14 mg/m2) + chemo had a manageable safety profile with promising preliminary evidence of efficacy. Clinical trial identification NCT02432274. Legal entity responsible for the study Eisai Inc. Funding Eisai Inc. Disclosure A. Longhi: Non-remunerated activity/ies, non-financial support: PharmaMar, Takeda; Research grant / Funding (institution): Takeda. M. Casanova: Advisory / Consultancy, advisory role: Bayer; Advisory / Consultancy, advisory role: Lilly; Advisory / Consultancy, advisory role: Roche; Advisory / Consultancy, advisory role: Tesaro. S.S. Bielack: Travel / Accommodation / Expenses, site fees for study preparation: Eisai; Travel / Accommodation / Expenses, personal fees from Clinigen: Clinigen; Travel / Accommodation / Expenses, personal fees from Lilly: Lilly; Travel / Accommodation / Expenses, personal fees from Novartis: Novartis; Travel / Accommodation / Expenses, personal fees from Bayer: Bayer; Travel / Accommodation / Expenses, personal fees from Pfizer: Pfizer; Travel / Accommodation / Expenses, personal fees from Isofol: Isofol; Travel / Accommodation / Expenses, personal fees from Sensorion: Sensorion; Travel / Accommodation / Expenses, personal fees from Ipsen: Ipsen; Advisory / Consultancy, Institution negotiating consultancy agreement with Eisai: Eisai. S. Gallego Melcon: Travel / Accommodation / Expenses: Loxo Oncology; Advisory / Consultancy: Bayer, Eusa. All other authors have declared no conflicts of interest.

With the Directive 2011/24/EU on patients' rights in cross-border healthcare and the related delegated decisions, the European Commission defined a legal framework on how healthcare shall be organised by European Union (EU) member states (MS) where patients can move beyond the borders of their home country. Among other aspects, Article 12 of the directive is concerned with supporting MS with the development of so called European Reference Networks (ERN), dedicated to the treatment of "patients with a medical condition requiring a particular concentration of expertise in medical domains where expertise is rare". In the "European Expert Paediatric Oncology Reference Network for Diagnostics and Treatment" (ExPO-r-Net) project, the establishment of such an ERN in the domain of Paediatric Oncology is currently piloted. The present paper describes the high level use cases, the main requirements and a corresponding interoperability architecture capable to serve as the necessary IT platform to facilitate cross-border health data exchange.

Background: The EUROCARE-5 study revealed disparities in childhood cancer survival among European countries, giving rise to important initiatives across Europe to reduce the gap. Extending its representativeness through increased coverage of eastern European countries, the EUROCARE-6 study aimed to update survival progress across countries and years of diagnosis and provide new analytical perspectives on estimates of long-term survival and the cured fraction of patients with childhood cancer. Methods: In this population-based study, we analysed 135 847 children (aged 0–14 years) diagnosed during 2000–13 and followed up to the end of 2014, recruited from 80 population-based cancer registries in 31 European countries. We calculated age-adjusted 5-year survival differences by country and over time using period analysis, for all cancers combined and for major cancer types. We applied a variant of standard mixture cure models for survival data to estimate the cure fraction of patients by childhood cancer and to estimate projected 15-year survival. Findings: 5-year survival for all childhood cancer combined in Europe in 2010–14 was 81% (95% CI 81–82), showing an increase of three percentage points compared with 2004–06. Significant progress over time was observed for almost all cancers. Survival remained stable for osteosarcomas, Ewing sarcoma, Burkitt lymphoma, non-Hodgkin lymphomas, and rhabdomyoscarcomas. For all cancers combined, inequalities still persisted among European countries (with age-adjusted 5-year survival ranging from 71% [95% CI 60–79] to 87% [77–93]). The 15-year survival projection for all patients with childhood cancer diagnosed in 2010–13 was 78%. We estimated the yearly long-term mortality rate due to causes other than the diagnosed cancer to be around 2 per 1000 patients for all childhood cancer combined, but to approach zero for retinoblastoma. The cure fraction for patients with childhood cancer increased over time from 74% (95% CI 73–75) in 1998–2001 to 80% (79–81) in 2010–13. In the latter cohort, the cure fraction rate ranged from 99% (95% CI 74–100) for retinoblastoma to 60% (58–63) for CNS tumours and reached 90% (95% CI 87–93) for lymphoid leukaemia and 70% (67–73) for acute myeloid leukaemia. Interpretation: Childhood cancer survival is increasing over time in Europe but there are still some differences among countries. Regular monitoring of childhood cancer survival and estimation of the cure fraction through population-based registry data are crucial for evaluating advances in paediatric cancer care. Funding: European Commission.