Clinical utility of vinblastine therapeutic drug monitoring for the treatment of infantile myofibroma patients:A case series

Infantile myofibroma is a rare, benign tumour of infancy typically managed surgically. In a minority of cases, more aggressive disease is seen and chemotherapy with vinblastine and methotrexate may be used, although evidence for this is limited. Chemotherapy dosing in infants is challenging, and vinblastine disposition in infants is unknown. We describe the use of vinblastine therapeutic drug monitoring in four cases of infantile myofibroma. Marked inter- and intrapatient variability was observed, highlighting the poorly understood pharmacokinetics of vinblastine in children, the challenges inherent in treating neonates, and the role of adaptive dosing in optimising drug exposure in challenging situations.</p

Parents' responses to prognostic disclosure at diagnosis of a child with a high-risk brain tumor:Analysis of clinician-parent interactions and implications for clinical practice

BackgroundPrevious studies have found that parents of children with cancer desire more prognostic information than is often given even when prognosis is poor. We explored in audio‐recorded consultations the kinds of information they seek.MethodsEthnographic study including observation and audio recording of consultations at diagnosis. Consultations were transcribed and analyzed using an interactionist perspective including tools drawn from conversation and discourse analysis.ResultsEnrolled 21 parents and 12 clinicians in 13 cases of children diagnosed with a high‐risk brain tumor (HRBT) over 20 months at a tertiary pediatric oncology center. Clinicians presented prognostic information in all cases. Through their questions, parents revealed what further information they desired. Clinicians made clear that no one could be absolutely certain what the future held for an individual child. Explicit communication about prognosis did not satisfy parents’ desire for information about their own child. Parents tried to personalize prognostic information and to apply it to their own situation. Parents moved beyond prognostic information presented and drew conclusions, which could change over time. Parents who were present in the same consultations could form different views of their child's prognosis.ConclusionPopulation level prognostic information left parents uncertain about their child's future. The need parents revealed was not for more such information but rather how to use the information given and how to apply it to their child in the face of such uncertainty. Further research is needed on how best to help parents deal with uncertainty and make prognostic information actionable

Comment on: "Tumour-agnostic drugs in paediatric cancers", Chisholm et al., BJC 2020.

Funder: NIHR Great Ormond Street Hospital Biomedical Research Centre NIHR Academic Clinical fellowshipFunder: Wellcome Trust (Wellcome); doi: https://doi.org/10.13039/10000444

Recurrent intragenic rearrangements of EGFR and BRAF in soft tissue tumors of infants.

Soft tissue tumors of infancy encompass an overlapping spectrum of diseases that pose unique diagnostic and clinical challenges. We studied genomes and transcriptomes of cryptogenic congenital mesoblastic nephroma (CMN), and extended our findings to five anatomically or histologically related soft tissue tumors: infantile fibrosarcoma (IFS), nephroblastomatosis, Wilms tumor, malignant rhabdoid tumor, and clear cell sarcoma of the kidney. A key finding is recurrent mutation of EGFR in CMN by internal tandem duplication of the kinase domain, thus delineating CMN from other childhood renal tumors. Furthermore, we identify BRAF intragenic rearrangements in CMN and IFS. Collectively these findings reveal novel diagnostic markers and therapeutic strategies and highlight a prominent role of isolated intragenic rearrangements as drivers of infant tumors

A nationwide evaluation of bevacizumab-based treatments in pediatric low-grade glioma in the UK: safety, efficacy, visual morbidity, and outcomes

BACKGROUND: Bevacizumab is increasingly used in children with pediatric low-grade glioma (PLGG) despite limited evidence. A nationwide UK service evaluation was conducted to provide larger cohort "real life" safety and efficacy data including functional visual outcomes. METHODS: Children receiving bevacizumab-based treatments (BBT) for PLGG (2009-2020) from 11 centers were included. Standardized neuro-radiological (RANO-LGG) and visual (logMAR visual acuity) criteria were used to assess clinical-radiological correlation, survival outcomes and multivariate prognostic analysis. RESULTS: Eighty-eight children with PLGG received BBT either as 3rd line with irinotecan (85%) or alongside 1st/2nd line chemotherapies (15%). Toxicity was limited and minimal. Partial response (PR, 40%), stable disease (SD, 49%), and progressive disease (PD, 11%) were seen during BBT. However, 65% progressed at 8 months (median) from BBT cessation, leading to a radiology-based 3 yr-progression-free survival (PFS) of 29%. Diencephalic syndrome (P = .03) was associated with adverse PFS. Pre-existing visual morbidity included unilateral (25%) or bilateral (11%) blindness. Improvement (29%) or stabilization (49%) of visual acuity was achieved, more often in patients' best eyes. Vision deteriorated during BBT in 14 (22%), with 3-year visual-PFS of 53%; more often in patients' worst eyes. A superior visual outcome (P = .023) was seen in neurofibromatosis type 1-associated optic pathway glioma (OPG). Concordance between visual and radiological responses was 36%; optimized to 48% using only best eye responses. CONCLUSIONS: BBTs provide effective short-term PLGG control and delay further progression, with a better sustained visual (best > worst eye) than radiological response. Further research could optimize the role of BBT toward a potentially sight-saving strategy in OPG

Effects of frozen soil on soil temperature, spring infiltration, and runoff: results from the PILPS 2(d) experiment at Valdai, Russia

Permission to place copies of these works on this server has been provided by the American Meteorological Society (AMS). The AMS does not guarantee that the copies provided here are accurate copies of the published work. © Copyright 2003 American Meteorological Society (AMS). Permission to use figures, tables, and brief excerpts from this work in scientific and educational works is hereby granted provided that the source is acknowledged. Any use of material in this work that is determined to be “fair use” under Section 107 of the U.S. Copyright Act or that satisfies the conditions specified in Section 108 of the U.S. Copyright Act (17 USC §108, as revised by P.L. 94-553) does not require the AMS’s permission. Republication, systematic reproduction, posting in electronic form on servers, or other uses of this material, except as exempted by the above statement, requires written permission or a license from the AMS. Additional details are provided in the AMS Copyright Policy, available on the AMS Web site located at (http://www.ametsoc.org/AMS) or from the AMS at 617-227-2425 or [email protected] Project for Intercomparison of Land-Surface Parameterization Schemes phase 2(d) experiment at Valdai, Russia, offers a unique opportunity to evaluate land surface schemes, especially snow and frozen soil parameterizations. Here, the ability of the 21 schemes that participated in the experiment to correctly simulate the thermal and hydrological properties of the soil on several different timescales was examined. Using observed vertical profiles of soil temperature and soil moisture, the impact of frozen soil schemes in the land surface models on the soil temperature and soil moisture simulations was evaluated. It was found that when soil-water freezing is explicitly included in a model, it improves the simulation of soil temperature and its variability at seasonal and interannual scales. Although change of thermal conductivity of the soil also affects soil temperature simulation, this effect is rather weak. The impact of frozen soil on soil moisture is inconclusive in this experiment due to the particular climate at Valdai, where the top 1 m of soil is very close to saturation during winter and the range for soil moisture changes at the time of snowmelt is very limited. The results also imply that inclusion of explicit snow processes in the models would contribute to substantially improved simulations. More sophisticated snow models based on snow physics tend to produce better snow simulations, especially of snow ablation. Hysteresis of snow-cover fraction as a function of snow depth is observed at the catchment but not in any of the models

Effects of Frozen Soil on Soil Temperature, Spring Infiltration, and Runoff: Results from the PILPS 2(d) Experiment at Valdai, Russia

The Project for Intercomparison of Land-Surface Parameterization Schemes phase 2(d) experiment at Valdai, Russia, offers a unique opportunity to evaluate land surface schemes, especially snow and frozen soil parameterizations. Here, the ability of the 21 schemes that participated in the experiment to correctly simulate the thermal and hydrological properties of the soil on several different timescales was examined. Using observed vertical profiles of soil temperature and soil moisture, the impact of frozen soil schemes in the land surface models on the soil temperature and soil moisture simulations was evaluated. It was found that when soil-water freezing is explicitly included in a model, it improves the simulation of soil temperature and its variability at seasonal and interannual scales. Although change of thermal conductivity of the soil also affects soil temperature simulation, this effect is rather weak. The impact of frozen soil on soil moisture is inconclusive in this experiment due to the particular climate at Valdai, where the top 1 m of soil is very close to saturation during winter and the range for soil moisture changes at the time of snowmelt is very limited. The results also imply that inclusion of explicit snow processes in the models would contribute to substantially improved simulations. More sophisticated snow models based on snow physics tend to produce better snow simulations, especially of snow ablation. Hysteresis of snow-cover fraction as a function of snow depth is observed at the catchment but not in any of the models

The representation of snow in land surface schemes: results from PILPS 2(d)

Permission to place copies of these works on this server has been provided by the American Meteorological Society (AMS). The AMS does not guarantee that the copies provided here are accurate copies of the published work. © Copyright 2001 American Meteorological Society (AMS). Permission to use figures, tables, and brief excerpts from this work in scientific and educational works is hereby granted provided that the source is acknowledged. Any use of material in this work that is determined to be “fair use” under Section 107 of the U.S. Copyright Act or that satisfies the conditions specified in Section 108 of the U.S. Copyright Act (17 USC §108, as revised by P.L. 94-553) does not require the AMS’s permission. Republication, systematic reproduction, posting in electronic form on servers, or other uses of this material, except as exempted by the above statement, requires written permission or a license from the AMS. Additional details are provided in the AMS Copyright Policy, available on the AMS Web site located at (http://www.ametsoc.org/AMS) or from the AMS at 617-227-2425 or [email protected] land surface schemes (LSSs) performed simulations forced by 18 yr of observed meteorological data from a grassland catchment at Valdai, Russia, as part of the Project for the Intercomparison of Land-Surface Parameterization Schemes (PILPS) Phase 2(d). In this paper the authors examine the simulation of snow. In comparison with observations, the models are able to capture the broad features of the snow regime on both an intra- and interannual basis. However, weaknesses in the simulations exist, and early season ablation events are a significant source of model scatter. Over the 18-yr simulation, systematic differences between the models’ snow simulations are evident and reveal specific aspects of snow model parameterization and design as being responsible. Vapor exchange at the snow surface varies widely among the models, ranging from a large net loss to a small net source for the snow season. Snow albedo, fractional snow cover, and their interplay have a large effect on energy available for ablation, with differences among models most evident at low snow depths. The incorporation of the snowpack within an LSS structure affects the method by which snow accesses, as well as utilizes, available energy for ablation. The sensitivity of some models to longwave radiation, the dominant winter radiative flux, is partly due to a stability-induced feedback and the differing abilities of models to exchange turbulent energy with the atmosphere. Results presented in this paper suggest where weaknesses in macroscale snow modeling lie and where both theoretical and observational work should be focused to address these weaknesses

Ophthalmologic adverse events in childhood head and neck rhabdomyosarcoma survivors treated according to four different local treatment strategies

Introduction: Ophthalmological adverse events (OAEs) are known to frequently occur following local treatment for pediatric head and neck rhabdomyosarcoma (HNRMS). The exact nature of these OAEs and the burden they put on survivors is less well described. Moreover, it is suspected there might be differences in the prevalence and nature of OAEs depending on local treatment strategy applied: external beam radiation therapy with photons, external beam radiation therapy with protons, macroscopically radical surgery combined with brachytherapy, or microscopically radical surgery combined with external beam radiation therapy. Methods: We cross-sectionally assessed 98 HNRMS survivors with long (median 9 years) follow-up time, according to a predefined list of OAEs based on the Common Terminology Criteria for Adverse Events system. We added information from chart reviews on the nature and management of all OAEs scored grade ≥1. We describe the prevalence of OAEs for the different tumor sites and treatment strategies separately. Results: OAEs occurred following treatment of all HNRMS sites. The most frequently observed OAEs are eyelid abnormalities, dry eyes, and cataracts. Sixty-two percent of survivors had several different OAEs simultaneously. In 27 % of survivors additional (surgical) treatment of OAEs was required during follow-up. The patterns observed suggest a possible relationship between OAE type and treatment strategy. Conclusion: OAEs in HNRMS survivors confer a high burden of chronic toxicity. The simultaneous occurrence of multiple OAEs in individual survivors present a particularly challenging clinical scenario and demand specific expertise. We propose a standardized screening scheme to detect possible OAEs in asymptomatic survivors based on primary tumor localization

Facial deformation following treatment for pediatric head and neck rhabdomyosarcoma; the difference between treatment modalities. Results of a trans-Atlantic, multicenter cross-sectional cohort study

Background: The four different local therapy strategies used for head and neck rhabdomyosarcoma (HNRMS) include proton therapy (PT), photon therapy (RT), surgery with radiotherapy (Paris-method), and surgery with brachytherapy (AMORE). Local control and survival is comparable; however, the impact of these different treatments on facial deformation is still poorly understood. This study aims to quantify facial deformation and investigates the differences in facial deformation between treatment modalities. Methods: Across four European and North American institutions, HNRMS survivors treated between 1990 and 2017, more than 2 years post treatment, had a 3D photograph taken. Using dense surface modeling, we computed facial signatures for each survivor to show facial deformation relative to 35 age–sex–ethnicity-matched controls. Additionally, we computed individual facial asymmetry. Findings: A total of 173 HNRMS survivors were included, survivors showed significantly reduced facial growth (p <.001) compared to healthy controls. Partitioned by tumor site, there was reduced facial growth in survivors with nonparameningeal primaries (p =.002), and parameningeal primaries (p ≤.001), but not for orbital primaries (p =.080) All patients were significantly more asymmetric than healthy controls, independent of treatment modality (p ≤.001). There was significantly more facial deformation in orbital patients when comparing RT to AMORE (p =.046). In survivors with a parameningeal tumor, there was significantly less facial deformation in PT when compared to RT (p =.009) and Paris-method (p =.007). Interpretation: When selecting optimal treatment, musculoskeletal facial outcomes are an expected difference between treatment options. These anticipated differences are currently based on clinicians’ bias, expertise, and experience. These data supplement clinician judgment with an objective analysis highlighting the impact of patient age and tumor site between existing treatment options