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The Parker Solar Probe's discovery that magnetic switchbacks and velocity spikes in the young solar wind are abundant has prompted intensive research into their origin(s) and formation mechanism(s) in the solar atmosphere. Recent studies, based on in situ measurements and numerical simulations, argue that velocity spikes are produced through interchange magnetic reconnection. Our work studies the relationship between interplanetary velocity spikes and coronal brightenings induced by changes in the photospheric magnetic field. Our analysis focuses on the characteristic periodicities of velocity spikes detected by the Proton Alpha Sensor on the Solar Orbiter during its fifth perihelion pass. Throughout the time period analyzed here, we estimate their origin along the boundary of a coronal hole. Around the boundary region, we identify periodic variations in coronal brightening activity observed by the Atmospheric Imaging Assembly onboard the Solar Dynamics Observatory. The spectral characteristics of the time series of in situ velocity spikes, remote coronal brightenings, and remote photospheric magnetic flux exhibit correspondence in their periodicities. Therefore, we suggest that the localized small-scale magnetic flux within coronal holes fuels a magnetic reconnection process that can be observed as slight brightness augmentations and outward fluctuations or jets. These dynamic elements may act as mediators, bonding magnetic reconnection with the genesis of velocity spikes and magnetic switchbacks.

Abstract Mercury’s magnetosphere is known to involve fundamental processes releasing particles and energy like at Earth due to the solar wind interaction. The resulting cycle is however much faster and involves acceleration, transport, loss, and recycling of plasma. Direct experimental evidence for the roles of electrons during this cycle is however missing. Here we show that in-situ plasma observations obtained during BepiColombo’s first Mercury flyby reveal a compressed magnetosphere hosts of quasi-periodic fluctuations, including the original observation of dynamic phenomena in the post-midnight, southern magnetosphere. The energy-time dispersed electron enhancements support the occurrence of substorm-related, multiple, impulsive injections of electrons that ultimately precipitate onto its surface and induce X-ray fluorescence. These observations reveal that electron injections and subsequent energy-dependent drift now observed throughout Solar System is a universal mechanism that generates aurorae despite the differences in structure and dynamics of the planetary magnetospheres.

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Summary: Background: Pharmacological synergisms are an attractive anticancer strategy. However, with more than 5000 approved-drugs and compounds in clinical development, identifying synergistic treatments represents a major challenge. Methods: High-throughput screening was combined with target deconvolution and functional genomics to reveal targetable vulnerabilities in glioblastoma. The role of the top gene hit was investigated by RNA interference, transcriptomics and immunohistochemistry in glioblastoma patient samples. Drug combination screen using a custom-made library of 88 compounds in association with six inhibitors of the identified glioblastoma vulnerabilities was performed to unveil pharmacological synergisms. Glioblastoma 3D spheroid, organotypic ex vivo and syngeneic orthotopic mouse models were used to validate synergistic treatments. Findings: Nine targetable vulnerabilities were identified in glioblastoma and the top gene hit RRM1 was validated as an independent prognostic factor. The associations of CHK1/MEK and AURKA/BET inhibitors were identified as the most potent amongst 528 tested pairwise drug combinations and their efficacy was validated in 3D spheroid models. The high synergism of AURKA/BET dual inhibition was confirmed in ex vivo and in vivo glioblastoma models, without detectable toxicity. Interpretation: Our work provides strong pre-clinical evidence of the efficacy of AURKA/BET inhibitor combination in glioblastoma and opens new therapeutic avenues for this unmet medical need. Besides, we established the proof-of-concept of a stepwise approach aiming at exploiting drug poly-pharmacology to unveil druggable cancer vulnerabilities and to fast-track the identification of synergistic combinations against refractory cancers. Funding: This study was funded by institutional grants and charities.

BackgroundThe survival rates for pediatric patients with relapsed and refractory tumors are poor. Successful treatment strategies are currently lacking and there remains an unmet need for novel therapies for these patients. We report here the results of a phase 1 study of talimogene laherparepvec (T-VEC) and explore the safety of this oncolytic immunotherapy for the treatment of pediatric patients with advanced non–central nervous system tumors.MethodsT-VEC was delivered by intralesional injection at 106 plaque-forming units (PFU)/ml on the first day, followed by 108 PFU/ml on the first day of week 4 and every 2 weeks thereafter. The primary objective was to evaluate the safety and tolerability as assessed by the incidence of dose-limiting toxicities (DLTs). Secondary objectives included efficacy indicated by response and survival per modified immune-related response criteria simulating the Response Evaluation Criteria in Solid Tumors (irRC-RECIST).ResultsFifteen patients were enrolled into two cohorts based on age: cohort A1 (n = 13) 12 to ≤21 years old (soft-tissue sarcoma, n = 7; bone sarcoma, n = 3; neuroblastoma, n = 1; nasopharyngeal carcinoma, n = 1; and melanoma, n = 1) and cohort B1 (n = 2) 2 to

Background: Cancer therapies targeting actionable molecular alterations (AMA) have developed, but the clinical routine impact of high-throughput molecular profiling remains unclear. We present a monocentric experience of molecular profiling based on liquid biopsy in patients with cancer. Methods: Patients included had solid cancer and underwent cfDNA genomic profiling with FoudationOne Liquid CDx (F1LCDx) test, analyzing 324 genes. Primary endpoint was to describe patients with an AMA for whom clinical decisions were impacted by F1LCDx test results. Results: 191 patients were included, mostly with lung cancer (46%). An AMA was found in 52%. The most common molecular alterations were: TP53 (52%), KRAS (14%) and DNMT3 (11%). The most common AMA were: CHEK2 (10%), PIK3CA (9%), ATM (7%). There was no difference in progression-free survival (2.66 months vs. 3.81 months, p = 0.17), overall survival (5.3 months vs. 7.1 months, p = 0.64), or PFS2/PFS1 ratio ≥ 1.3 (20% vs. 24%, p = 0.72) between patients receiving a molecularly matched therapy (MMT) or a non-MMT, respectively. Patients with a MMT had an overall response rate of 19% and a disease control of 32%. Conclusions: Routine cfDNA molecular profiling is feasible and can lead to the access of targeted therapies. However, no notable benefit in patient’s outcomes was shown in this unselected pan-cancer study.

Ho-Bouldoires, Sollier, Zamfirov and Broders-Bondon et al. show that high frequency pulsatile mechanical stresses maintain the physiological level of mice colon stem cells through the mechanosensitive Ret kinase and that Ret activation is elevated in human colon cancer tissue. They go on to show that the maintenance of such stimulation in the form of tumour growth pressure results in mechanically-induced hyperproliferation and tumorigenic transformation of stem cells, which can be prevented by Ret kinase inhibition.

The discovery of a myriad of exoplanets in the past decades has revolutionized the understanding of our place in the Universe. How different are exoplants and do some of them harbor life, just like Earth? To do so, their parent stars must drive a stellar wind and carve what we call astrospheres into the surrounding interstellar medium. Astrospheres are ubiquitous in our immediate neighborhood and show similar structure to our heliosphere. Voyager 1 and 2, Ulysses, Cassini, and IBEX have shown that the interaction between interstellar medium and solar wind is much more complex and involved than previously believed. This stellar-interstellar interaction is key to understand astrospheres and the shielding they provide to the planetary systems they harbor. This article summarizes a whitepaper that was submitted to NASA’s 2023/2024 decadal survey which is being conducted by the US National Academies. It is based in parts on a proposal submitted to the European Space Agency (ESA) in response to its 2021 call for medium-class mission proposals. The whitepaper and this article propose to study the interaction described above in situ at the heliospheric boundaries and to explore the very local interstellar medium beyond. Furthermore, they highlight possible European contributions to a NASA-led Interstellar Probe (ISP).

Abstract We present initial results of low‐energy ion observations from BepiColombo's first Mercury flyby. Unprecedentedly high time resolution measurements of low energy ions at Mercury by BepiColombo Mio reveal rapid (a few seconds) and large (1–2 orders of magnitude) fluctuations of ion flux around the magnetopause and within the magnetosphere. Around the magnetic equator in the pre‐midnight magnetotail, Mio observed plasma sheet ions consistent with previous observations. In the midnight magnetotail near the closest approach, Mio observed the co‐existence of high‐energy (∼keV/q) and low‐energy (

Summary: Background: Medulloblastoma is the most frequent brain malignancy of childhood. The current multimodal treatment comes at the expense of serious and often long-lasting side effects. Drug repurposing is a strategy to fast-track anti-cancer therapy with low toxicity. Here, we showed the ability of β-blockers to potentiate radiotherapy in medulloblastoma with bad prognosis. Methods: Medulloblastoma cell lines, patient-derived xenograft cells, 3D spheroids and an innovative cerebellar organotypic model were used to identify synergistic interactions between β-blockers and ionising radiations. Gene expression profiles of β-adrenergic receptors were analysed in medulloblastoma samples from 240 patients. Signaling pathways were explored by RT-qPCR, RNA interference, western blotting and RNA sequencing. Medulloblastoma cell bioenergetics were evaluated by measuring the oxygen consumption rate, the extracellular acidification rate and superoxide production. Findings: Low concentrations of β-blockers significantly potentiated clinically relevant radiation protocols. Although patient biopsies showed detectable expression of β-adrenergic receptors, the ability of the repurposed drugs to potentiate ionising radiations did not result from the inhibition of the canonical signaling pathway. We highlighted that the efficacy of the combinatorial treatment relied on a metabolic catastrophe that deprives medulloblastoma cells of their adaptive bioenergetics capacities. This led to an overproduction of superoxide radicals and ultimately to an increase in ionising radiations-mediated DNA damages. Interpretation: These data provide the evidence of the efficacy of β-blockers as potentiators of radiotherapy in medulloblastoma, which may help improve the treatment and quality of life of children with high-risk brain tumours. Funding: This study was funded by institutional grants and charities.

(1) Background: Children and young adults with cancer are poorly represented in COVID-19 vaccination studies, and long-term protection conferred by vaccination is not known. (2) Objectives: 1. To determine the adverse effects associated with BNT162B2 vaccination in children and young adults with cancer. 2. To assess its efficacy in stimulating immunological response and in preventing severe COVID-19 disease. (3) Methods: Retrospective single-center study evaluating patients aged 8 to 22 years, with cancer, who underwent vaccination from January 2021 to June 2022. ELISA serologies and serum neutralization were collected monthly from the first injection. Serologies below 26 were considered negative, while those above 264 BAU/mL were considered positive and indicative of protection. Antibodies titers were considered positive above 20. Data on adverse events and infections were collected. (4) Results: 38 patients were included (M/F = 1.7, median age 16 years), of whom 63% had a localized tumor and 76% were undergoing treatment at the time of the first vaccination. Two or three vaccine injections were administered in 90% of patients. Adverse events were mainly systemic and not severe, except for seven grade 3 toxicities. Four cancer-related deaths were reported. Median serology was negative the month following the first vaccination and became protective during the third month. At 3 and 12 months, median serology was 1778 and 6437 BAU/mL, respectively. Serum neutralization was positive in 97% of the patients. COVID-19 infection occurred despite vaccination in 18%; all were mild forms. (5) Conclusions: In children and young adults with cancer, vaccination was well tolerated and conferred effective serum neutralization. COVID-19 infections were mild, and vaccine seroconversion persisted after 12 months in most patients. The value of additional vaccination should be further established.

Preclinical data support the activity of celecoxib and fluvastatin in high-grade (HGG) and low-grade gliomas (LGG). A phase I trial (NCT02115074) was designed to evaluate the safety of this combination in children with refractory/relapsed HGG and LGG using four dose levels of fluvastatin with a fixed daily dose of celecoxib. A Continual Reassessment Method was used for fluvastatin dose escalation. Dose-limiting toxicities (DLT) were determined on the first treatment cycle. Twenty patients were included. Ten LGG and ten HGG patients received a median of 3.5 treatment cycles. Two DLTs were reported: one grade 3 maculopapular rash (4 mg/kg dose level) and one grade 4 increase of Creatine Phospho-Kinase (6 mg/kg dose level). We identified the dose of 6 mg/kg/day as the recommended phase II dose (RP2D) of fluvastatin with celecoxib. Four patients with LGG continued treatment beyond 12 cycles because of stable disease, including one patient who received 23 treatment cycles. In children with refractory/relapsed glioma, the RP2D of fluvastatin with celecoxib is 6 mg/kg/day. The long-term stable diseases observed in LGG suggest a possible role of the combination in a maintenance setting, given its good tolerance and low cost for children living in low- and middle-income countries.

Background: Relapses in pediatric high-risk brain tumors remain unmet medical needs. Over the last 15 years, metronomic chemotherapy has gradually emerged as an alternative therapeutic approach. Patients and Methods: This is a national retrospective study of patients with relapsing pediatric brain tumors treated according to the MEMMAT or MEMMAT-like regimen from 2010 to 2022. Treatment consisted of daily oral thalidomide, fenofibrate, and celecoxib, and alternating 21-day cycles of metronomic etoposide and cyclophosphamide associated with bevacizumab and intraventricular chemotherapy. Results: Forty-one patients were included. The most frequent malignancies were medulloblastoma (22) and ATRT (8). Overall, the best responses were CR in eight patients (20%), PR in three patients (7%), and SD in three patients (7%), for a clinical benefit rate of 34%. The median overall survival was 26 months (IC95% = 12.4–42.7), and median EFS was 9.7 months (IC95% = 6.0–18.6). The most frequent grade ¾ toxicities were hematological. Dose had to be adjusted in 27% of the cases. There was no statistical difference in outcome between full or modified MEMMAT. The best setting seems to be when MEMMAT is used as a maintenance and at first relapse. Conclusions: The metronomic MEMMAT combination can lead to sustained control of relapsed high-risk pediatric brain tumors.

Abstract Background Despite its cardiotoxicity doxorubicin is widely used for the treatment of paediatric malignancies. Current treatment regimens appear to be suboptimal as treatment strategies vary and do not follow a clear pharmacological rationale. Standardisation of dosing strategies in particular for infants and younger children is required but is hampered by scarcely defined exposure-response relationships. The aim is to provide a rational dosing concept allowing for a reduction of variability in systemic therapy intensity and subsequently unforeseen side effects. Methods Doxorubicin plasma concentrations in paediatric cancer patients were simulated for different treatment schedules using a population pharmacokinetic model which considers age-dependent differences in doxorubicin clearance. Overall drug exposure and peak concentrations were assessed. Simulation results were used to support a three round Delphi consensus procedure with the aim to clarify the pharmacological goals of doxorubicin dosing in young children. A group of 28 experts representing paediatric trial groups and clinical centres were invited to participate in this process. Results Pharmacokinetic simulations illustrated the substantial differences in therapy intensity associated with current dosing strategies. Consensus among the panel members was obtained on a standardised a priori dose adaptation that individualises doxorubicin doses based on age and body surface area targeting uniform drug exposure across children treated with the same protocol. Further, a reduction of peak concentrations in very young children by prolonged infusion was recommended. Conclusions An approach to standardise current dose modification schemes in young children is proposed. The consented concept takes individual pharmacokinetic characteristics into account and involves adaptation of both the dose and the infusion duration potentially improving the safety of doxorubicin administration.

This work introduces a new measurement methodology for enhancing gas detection by tuning the magnitude and polarity of back-gate voltage of a field-effect transistor (FET)-based sensor. The aim is to simultaneously strengthen the sensor response and accelerate the sensor recovery. In addition, this methodology can consume less energy compared with conventional measurements by direct current bias. To illustrate the benefits of the proposed methodology, we fabricated and characterized a polypyrrole/graphene (PPy/G) FET sensor for ammonia (NH3) detection. Our experiment, simulation and calculation results demonstrated that the redox reaction between the NH3 molecules and the PPy/G sensitive layer could be controlled by altering the polarity and the magnitude of the back-gate voltage. This proof-of-principle measurement methodology, which solves the inherent contradiction between high response and slow recovery of the chemiresistive sensor, could be extended to detect other gases, so as to improve global gas measurement systems. It opens up a new route for FET-based gas sensors in practical applications.

PURPOSE: Low- and middle-income countries (LMICs) experience the burden of 80% of new childhood cancer cases worldwide, with cure rates as low as 10% in some countries. Metronomics combines frequent administrations of low-dose chemotherapy with drug repurposing, which consists of using already-approved drugs for new medical applications. With wide availability, limited costs, and little infrastructure needs, metronomics can be part of constraint-adapted regimens in these resource-limited settings—with the understanding that metronomics shall not be a substitute for standard treatments when available and doable. Our study aims to describe the experience, practices, opinions, and needs in metronomics of physicians working in LMICs. METHODS: An online questionnaire was sent to more than 1,200 physicians in pediatric oncology networks in LMICs. Items included the type of center, physician’s demographics, experience in pediatric oncology, and experience with current knowledge of metronomics. Opinions and perspectives were explored using multiple-answer and open questions. RESULTS: Of physicians, 17% responded. Of respondents, 54.9% declared that they had already used a metronomic regimen. The most frequently cited repositioned drugs were celecoxib (44%) followed by propranolol and valproic acid (17%). Respondents highlighted the advantages of outpatient use (20%) and expected low toxicity (24%). In considering the drawbacks of metronomics, 47% of responses highlighted the lack of scientific evidence or guidelines, 33% the availability or affordability of drugs, and 18% the problem of acceptance or compliance. Of physicians, 79% believed that use of metronomics will spread in LMICs in the near future and 98% of them were willing to participate in international metronomic protocols or registries. CONCLUSION: Metronomics is already used in LMICs and is a potential answer to unmet needs in pediatric oncology. There is room for improvement in the availability of drugs and a necessity to develop collaborative protocols and research to generate level A evidence.

Precision oncology requires tumor molecular profiling to identify actionable targets. Tumor biopsies are considered as the gold standard, but their indications are limited by the burden of procedures in children. Blood-derived liquid biopsy (LB) is a potential alternative that is not yet documented in real-world settings, especially in pediatric oncology. We performed a retrospective analysis of children and teenagers with a relapsing or refractory disease, upon whom LB was performed using the Foundation One® liquid CDx from 1 January 2020 to 31 December 2021 in a single center. Forty-five patients (27 boys) were included, with a median age of 9 years of age (range: 1.5–17 years old). Underlying malignancies were neuroblastoma (12 patients), bone sarcoma (12), soft tissue sarcoma (9), brain tumors (7), and miscellaneous tumors (5). Forty-three patients had metastatic disease. Six patients had more than one biopsy because of a failure in first LB. Median time to obtain results was 13 days. Overall, analysis was successful for 33/45 patients. Eight patients did not present any molecular abnormalities. Molecular alterations were identified in 25 samples with a mean of 2.1 alterations per sample. The most common alterations concerned TP53 (7 pts), EWS-FLI1 (5), ALK (3), MYC (3), and CREBBP (2). TMB was low in all cases. Six patients received treatment based on the results from LB analysis and all were treated off-trial. Three additional patients were included in early phase clinical trials. Mean duration of treatment was 85 days, with one patient with stable disease after eight months. Molecular profiling using Foundation One® Liquid CDx was feasible in pediatric patients with high-risk solid tumors and lead to identification of targetable mutations in a subset of patients.

Medulloblastoma patients receive adapted therapies stratified according to their risk-profile. Favourable, standard, and high disease-risk groups are each defined by the status of clinical and pathological risk factors, alongside an evolving repertoire of diagnostic and prognostic biomarkers. Medulloblastoma clinical trials in Europe are coordinated by the International Society for Paediatric Oncology (SIOP-Europe) brain tumour group. Favourable and standard-risk patients are eligible for the SIOP-PNET5-MB clinical trial protocol. In contrast, therapies for high-risk disease worldwide have, to date, encompassed a range of different treatment philosophies, with no clear consensus on approach. Higher radiotherapy doses are typically deployed, delivered either conventionally or in hyper-fractionated/accelerated regimens. Similarly, both standard and high-dose chemotherapies were assessed. However, trials to date in high-risk medulloblastoma have commonly been institutional or national, based on modest cohort sizes, and have not evaluated the relative performance of different strategies in a randomised fashion. We describe the concepts and design of the SIOP-E high-risk medulloblastoma clinical trial (SIOP-HR-MB), the first international biomarker-driven, randomised, clinical trial for high-risk medulloblastoma. SIOP-HR-MB is programmed to recruit >800 patients in 16 countries across Europe; its primary objectives are to assess the relative efficacies of the alternative established regimens. The HR-MB patient population is molecularly and clinically defined, and upfront assessments incorporate a standardised central review of molecular pathology, radiology, and radiotherapy quality assurance. Secondary objectives include the assessment of (i) novel therapies within an upfront ‘window’ and (ii) therapy-associated neuropsychology, toxicity, and late effects, alongside (iii) the collection of materials for comprehensive integrated studies of biological determinants within the SIOP-HR-MB cohort.

MASER (Measurements, Analysis, and Simulation of Emission in the Radio range) is a comprehensive infrastructure dedicated to time-dependent low frequency radio astronomy (up to about 50 MHz). The main radio sources observed in this spectral range are the Sun, the magnetized planets (Earth, Jupiter, Saturn), and our Galaxy, which are observed either from ground or space. Ground observatories can capture high resolution data streams with a high sensitivity. Conversely, space-borne instruments can observe below the ionospheric cut-off (at about 10 MHz) and can be placed closer to the studied object. Several tools have been developed in the last decade for sharing space physics data. Data visualization tools developed by various institutes are available to share, display and analyse space physics time series and spectrograms. The MASER team has selected a sub-set of those tools and applied them to low frequency radio astronomy. MASER also includes a Python software library for reading raw data from agency archives.

Despite recent advances in deciphering cancer drug resistance mechanisms, relapse is a widely observed phenomenon in advanced cancers, mainly due to intratumor clonal heterogeneity. How tumor clones progress and impact each other remains elusive. In this study, we developed 2D and 3D non-small cell lung cancer co-culture systems and defined a phenomenological mathematical model to better understand clone dynamics. Our results demonstrated that the drug-sensitive clones inhibit the proliferation of the drug-resistant ones under untreated conditions. Model predictions and their experimental in vitro and in vivo validations indicated that a metronomic schedule leads to a better regulation of tumor cell heterogeneity over time than a maximum-tolerated dose schedule, while achieving control of tumor progression. We finally showed that drug-sensitive and -resistant clones exhibited different metabolic statuses that could be involved in controlling the intratumor heterogeneity dynamics. Our data suggested that the glycolytic activity of drug-sensitive clones could play a major role in inhibiting the drug-resistant clone proliferation. Altogether, these computational and experimental approaches provide foundations for using metronomic therapy to control drug-sensitive and -resistant clone balance and highlight the potential of targeting cell metabolism to manage intratumor heterogeneity.

Abstract Background There is a great need for high quality clinical research for children. The European Pediatric Regulation aimed to improve the quality of clinical trials in order to increase the availability of treatments for children. The main purpose of this study was to assess the evolution of both the number and the quality of pediatric trial protocols that were submitted to a French Institutional Review Board (IRB00009118) before and after the initiation of the EU Pediatric Regulation. Methods All protocols submitted to the IRB00009118 between 2003 and 2014 and conducting research on subjects under eighteen years of age were eligible. The quality of randomized clinical trials was assessed according to the guidelines developed by the Enhancing the QUAlity and Transparency Of health Research (EQUATOR) Network and ranked using the Jadad score. Results Out of 622 protocols submitted to the Institutional Review Board (IRB), 21% (133/622) included children. Among these 133 pediatric protocols, the number of submitted pediatric protocols doubled between the two studied periods. From 2003 to 2008, 47 protocols including 21 institutionally sponsored were submitted to the IRB and from 2009 until 2014, 86 protocols including 48 institutionally sponsored were submitted. No significant trend was observed on the quality of RCTs. The overall median score of RCTs on the Jadad scale was high (3.5), 70.0% of protocols had a Jadad score ≥ 3, and 30.0% had a score

This research assessed the geospatial supply of cellulosic feedstocks for potential mill sites in Kansas (KS), with procurement zones extending to Arkansas (AR), Iowa (IA), Missouri (MO), Oklahoma (OK), and Nebraska (NE). A web-based modeling system, the Kansas Biomass Supply Assessment Tool, was developed to identify least-cost sourcing areas for logging residues and upland hardwood roundwood biomass feedstocks. Geospatial boundaries were used according to the 5-digit zip code tabulation area (ZCTA). This higher level of resolution advanced the understanding of the geospatial economics of modeling the supply chain for cellulosic feedstocks. The analyses were conducted for six sub-regions (Chanute, Effingham, El Dorado, Manhattan, Ottawa, and Pratt) within Kansas that were identified by the US Forest Service as suitable for forest habitat. Atchison County of Effingham region had the least marginal costs for upland hardwood roundwood, ranging from $92.59 to $108.68 per dry metric ton, with an available annual supply of approximately 72 thousand dry metric tons. The least favorable was the El Dorado region, where the marginal costs ranged from $97.32 to $108.05 per dry metric ton, with an annual supply of approximately 4.4 thousand dry metric tons.

Background: to evaluate the safety and efficacy of a physical activity program (PAP) in children and adolescents with cancer. Methods: children and adolescents with cancer were randomly assigned in a 1:1 ratio to the six-month PAP (intervention group) or to the control group. The first evaluation was performed at the end of the PAP (T0 + 6 mo). At T0 + 6 mo, both groups received the six-month PAP with a second evaluation at T0 + 12 mo. The primary outcome was the evolution of exercise capacity measured using the six-minute walk test (6 MWT) at T0 + 6 mo. Secondary outcomes included PAP safety and changes in other physical functions, self-esteem, and quality-of-life parameters. Results: The trial involved 80 children and adolescents (age range 5.0–18.4 years), of whom 41 were assigned to the interventional group and 39 to the control group. Underlying malignancies were leukemia (39%) and a broad range of solid tumors (61%). No adverse events occurred. At T0 + 6 mo, the evolution of the 6 MWT distance (±SEM) was improved in the intervention group vs. the control group (86 ± 12 m vs. 32 ± 6 m, p < 0.001). Several other physical parameters were significantly improved in the intervention group. Global self-esteem and parent-reported quality-of-life were significantly increased in the intervention group. Analysis at T0 + 12 mo showed persistence of the benefits in the intervention group on exercise capacity evolution (115 ± 18 m vs. 49 ± 11 m, p = 0.004) and on most physical and QoL parameters. Conclusion: In children and adolescents with cancer, a physical activity program is safe, improves exercise capacity, and may have physical and psychological benefits.

Data regarding coronavirus disease 2019 (COVID-19) description are still limited in pediatric oncology. The French society of pediatric oncology (SFCE) initiated a study to better describe COVID-19 in patients followed in French pediatric oncology and hematology wards. All patients diagnosed with COVID-19 and followed in a SFCE center were enrolled. Data from medical records were analyzed for all patients enrolled up to the end of May 2020. Data were available for 37 patients. Thirty-one were children under 18 years of age. Nineteen patients were female. Seventeen patients had a solid tumor, 16 had a hematological malignancy and four recently underwent hematopoietic stem cell transplantation (HSCT) for non-oncological conditions. Twenty-eight patients presented symptoms, most often with fever, cough, rhinorrhea and asthenia. Ground-glass opacities were the most frequent radiological finding with abnormalities mostly bilateral and peripherally distributed. Twenty-four patients received chemotherapy a month prior to COVID-19 diagnosis. Most patients did not require hospitalization. Three patients required oxygen at the time of diagnosis. In total, five patients were admitted in an intensive care unit because of COVID-19 and one died from the disease. Children and young adults treated for a cancer and/or with a HSCT may be at risk for severe COVID-19 and should be closely monitored.

Hypoxic environment is a prognostic factor linked in pediatric cancers to a worse outcome, favoring tumor progression and resistance to treatments. The activation of mechanistic Target Of Rapamycin (mTor)/hypoxia inducible factor (HIF)-1 pathway can be targeted by rapamycin and irinotecan, respectively. Therefore, we designed a phase I trial associating both drugs in pediatric refractory/relapsing solid tumors. Patients were enrolled according to a 3 + 3 escalation design with ten levels, aiming to determine the MTD (maximum tolerated dose) of rapamycin plus irinotecan. Rapamycin was administered orally once daily in a 28-day cycle (1 to 2.5 mg/m2/day), associating biweekly intravenous irinotecan (125 to 240 mg/m2/dose). Toxicities, pharmacokinetics, efficacy analyses, and pharmacodynamics were evaluated. Forty-two patients, aged from 2 to 18 years, were included. No MTD was reached. Adverse events were mild to moderate. Only rapamycin doses of 1.5 mg/m2/day reached over time clinically active plasma concentrations. Tumor responses and prolonged stable disease were associated with a mean irinotecan area under the curve of more than 400 min.mg/L. Fourteen out of 31 (45.1%) patients had a non-progressive disease at 8 weeks. Most of them were sarcomas and brain tumors. For the phase II trial, we can then propose biweekly 125 mg/m2 irinotecan dose with a pharmacokinetic (PK) follow-up and a rapamycin dose of 1.5 mg/m2/day, reaching a blood concentration above 10 g/L.

Developing precision medicine is a major trend in clinical oncology. The main adverse effects of ifosfamide, actinomycin D and vincristine (IVA) treatment for rhabdomyosarcoma are haematological toxicities such as neutropenia or thrombocytopenia. The severity of these effects vary among patients but their dynamic profiles are similar. A non-empirical adjustment of the chemotherapy dose to avoid severe toxicities could help secure the treatment administration. Twenty-four patients with rhabdomyosarcoma treated with IVA chemotherapy courses were selected. Before and during each cycle, routine multiple blood cell counts were performed allowing for a dynamic study of the haematological toxicities. We developed a machine learning analysis using a gradient boosting regression technique to forecast the ifosfamide induced haematological toxicities as a function of neutrophils and platelets initial levels and the initial ifosfamide dose. To validate models’ accuracy, predicted and observed neutrophils and platelets levels were compared. The model was able to reproduce the dynamic profiles of the haematological toxicities. Among all cycles, the mean absolute errors between predicted and observed neutrophils and platelets levels were 1.0 and 72.8 G/L, respectively. Adjusting a patient’s ifosfamide dose based upon the predicted haematological toxicity levels at the end of a treatment cycle could enable tailored treatment.

Background: Metronomic chemotherapy (MC) is defined as the frequent administration of chemotherapy at doses below the maximal tolerated dose and with no prolonged drug-free break. MC has shown its efficacy in adult tumor types such as breast and ovarian cancer and has to some extent been studied in pediatrics.Objective: To assess the anti-tumor activity and toxicity of a four-drug metronomic regimen in relapsing/refractory pediatric brain tumors (BT) with progression-free survival (PFS) after two cycles as primary endpoint.Methods: Patients ≥4 to 25 years of age were included with progressing BT. Treatment consisted of an 8-week cycle of celecoxib, vinblastine, and cyclophosphamide alternating with methotrexate. Kepner and Chang two-steps model was used with 10 patients in the first stage. If stabilization was observed in ≥2 patients, 8 additional patients were recruited. Assessment was according WHO criteria with central radiology review.Results: Twenty-nine patients (27 evaluable) were included in two groups: ependymoma (group 1, N = 8), and miscellaneous BT (group 2): 3 medulloblastoma (MB), 5 high grade glioma (HGG), 11 low grade glioma (LGG), 2 other BT. After first stage, recruitment for ependymoma was closed [one patient had stable disease (SD) for 4 months]. Cohort 2 was opened for second stage since 1 HGG and 3 LGG patients had SD after two cycles. Recruitment was limited to LGG for the second stage and 2 partial responses (PR), 6 SD and 2 progressive disease (PD) were observed after two cycles. Of these patients with LGG, median age was 10 years, nine patients received vinblastine previously. Median number of cycles was 6.8 (range: 1–12). Treatment was interrupted in five patients for grade 3/4 toxicity.Conclusion: This regimen is active in patients with LGG, even if patients had previously received vinblastine. Toxicity is acceptable.Trial Registration: This study was registered under clinicaltrials.gov – NCT01285817; EUDRACT nr: 2010-021792-81.

An abundant, low-cost, and high-quality supply of lignocellulosic feedstock is necessary to realize the large-scale implementation of biomass conversion technologies capable of producing renewable fuels, chemicals, and products. Barriers to this goal include the variability in the chemical and physical properties of available biomass, and the seasonal and geographic availability of biomass. Blending several different types of biomass to produce consistent feedstocks offers a solution to these problems and allows for control over the specifications of the feedstocks. For thermochemical conversion processes, attributes of interest include carbon content, total ash, specific inorganics, density, particle size, and moisture content. In this work, a series of switchgrass and pine residues blends with varying physical and chemical properties were evaluated. Physical and chemical properties of the pure and blended materials were measured, including compositional analysis, elemental analysis, compressibility, flowability, density, and particle size distribution. To screen blends for thermochemical conversion behavior, the analytical technique, pyrolysis gas chromatography mass spectrometry (Py-GC/MS), was used to analyze the vapor-phase pyrolysis products of the various switchgrass/pine residues blends. The py-GC/MS findings were validated by investigating the bio-oils produced from the selected blends using a lab-scale fluidized-bed pyrolysis reactor system. Results indicate that the physical properties of blended materials are proportional to the blend ratio of pure feedstocks. In addition, pyrolysis of pine residues resulted in bio-oils with higher carbon content and lower oxygen content, while switchgrass derived pyrolysis products contained relatively greater amount of anhydrosugars and organic acids. The distribution of the pyrolysis vapors and isolated bio-oils appear to be a simple linear combination of the two feedstocks. The concentration of alkali and alkaline earth metals (Ca, K, Mg, and Na) in the blended feedstocks were confirmed to be a critical parameter due to their negative effects on the bio-oil yield. This work demonstrates that blending different sources of biomass can be an effective strategy to produce a consistent feedstock for thermochemical conversion.

Atypical teratoid rhabdoid tumor (ATRT) is a rare and highly aggressive embryonal tumor of the central nervous system with a dismal prognosis and no definitive guidelines for treatment, especially at relapse or in case of refractory disease. Metronomic chemotherapy (MC) has emerged as a new treatment option in solid malignancies, with lower toxicity and is frequently combined with drug repositioning. We report a case of ATRT in an 8-year-old boy who progressed during multimodal therapy including surgical resection, chemotherapy and radiotherapy. He was treated with MC involving continuous oral celecoxib with alternating metronomic etoposide and cyclophosphamide, in combination with biweekly bevacizumab and monthly intrathecal liposomal cytarabine. To date, he remains clinically and symptomatically disease-free with a follow-up of 10 months. The treatment was well-tolerated. Metronomics represent a possible alternative regimen for children with recurrent or progressive ATRT.

The effect of membrane deflection has been investigated for thermal flow sensors. Catastrophic membrane breakage is a common occurrence in membrane based thermal flow sensors due to thermal expansion and internal stresses. This work analyses three sensors comprising a tungsten heater embedded in buried oxide membrane with a silicon nitride passivation layer, the use of back etching creates a cavity underneath to reduce the thermal conduction. The investigation is done using interferometry to measure the membrane shape at room and operating temperature for three membranes of different sizes. As expected, the deflection increases with temperature up to 15 µm at operating temperature and with the reduction of membrane size the deflection is reduced to a minimum of 3 µm for the smallest membrane. The lower deflection measured in devices with a smaller cavity can be related to a reduced internal stress, improving the long term stability.

BackgroundAnimals' ability for cross-modal recognition has recently received much interest. Captive or domestic animals seem able to perceive cues of human attention and appear to have a multisensory perception of humans.Methodology/principal findingsHere, we used a task where horses have to remain immobile under a vocal order to test whether they are sensitive to the attentional state of the experimenter, but also whether they behave and respond differently to the familiar order when tested by a familiar or an unknown person. Horses' response varied according to the person's attentional state when the order was given by an unknown person: obedience levels were higher when the person giving the order was looking at the horse than when he was not attentive. More interesting is the finding that whatever the condition, horses monitored much more and for longer times the unknown person, as if they were surprised to hear the familiar order given by an unknown voice.Conclusion/significanceThese results suggest that recognition of humans may lie in a global, integrated, multisensory representation of specific individuals, that includes visual and vocal identity, but also expectations on the individual's behaviour in a familiar situation.

Abstract Background The distinction between primary and secondary ovarian tumors may be challenging for pathologists. The purpose of the present work was to develop genomic and transcriptomic tools to further refine the pathological diagnosis of ovarian tumors after a previous history of breast cancer. Methods Sixteen paired breast-ovary tumors from patients with a former diagnosis of breast cancer were collected. The genomic profiles of paired tumors were analyzed using the Affymetrix GeneChip® Mapping 50 K Xba Array or Genome-Wide Human SNP Array 6.0 (for one pair), and the data were normalized with ITALICS (ITerative and Alternative normaLIzation and Copy number calling for affymetrix Snp arrays) algorithm or Partek Genomic Suite, respectively. The transcriptome of paired samples was analyzed using Affymetrix GeneChip® Human Genome U133 Plus 2.0 Arrays, and the data were normalized with gc-Robust Multi-array Average (gcRMA) algorithm. A hierarchical clustering of these samples was performed, combined with a dataset of well-identified primary and secondary ovarian tumors. Results In 12 of the 16 paired tumors analyzed, the comparison of genomic profiles confirmed the pathological diagnosis of primary ovarian tumor (n = 5) or metastasis of breast cancer (n = 7). Among four cases with uncertain pathological diagnosis, genomic profiles were clearly distinct between the ovarian and breast tumors in two pairs, thus indicating primary ovarian carcinomas, and showed common patterns in the two others, indicating metastases from breast cancer. In all pairs, the result of the transcriptomic analysis was concordant with that of the genomic analysis. Conclusions In patients with ovarian carcinoma and a previous history of breast cancer, SNP array analysis can be used to distinguish primary and secondary ovarian tumors. Transcriptomic analysis may be used when primary breast tissue specimen is not available.