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Objective: Children with suprasellar brain damage are at risk of hypothalamic dysfunction (HD). HD may lead to decreased resting energy expenditure (REE). Decreased REE, however, is not present in all children with HD. Our aim was to assess which children suspect for HD have low REE, and its association with clinical severity of HD or radiological hypothalamic damage. Patients and methods: A retrospective cohort study was performed. Measured REE (mREE) of children at risk of HD was compared to predicted REE (pREE). Low REE was defined as mREE

IMPORTANCE:There are concerns about increased mortality in patients with metal-on-metal bearings in total hip arthroplasty (THA). OBJECTIVE:To determine the mortality and the morbidity in patients with metal-on-metal articulations (MOM THA) compared to patients with non-metal-on-metal articulations (non-MOM THA) after primary total hip arthroplasty. DATA SOURCES:Search of PubMed, MEDLINE, EMBASE, Web of Science, Cochrane, CINAHL, AcademicSearchPremier, ScienceDirect, Wiley and clinical trial registers through March 2015, augmented by a hand search of references from the included articles. No language restrictions were applied. STUDY SELECTION:Two reviewers screened and identified randomised controlled trials and observational studies of primary total hip arthroplasty comparing MOM THA with non-MOM THA. DATA EXTRACTION AND SYNTHESIS:Two reviewers independently extracted study data and assessed risk of bias. Risk differences (RD) were calculated with random effect models. Meta-regression was used to explore modifying factors. MAIN OUTCOMES AND MEASURES:Difference in mortality and difference in morbidity expressed as revisions and medical complications between patients with MOM THA and non-MOM THA. RESULTS:Forty-seven studies were included, comprising 4,000 THA in randomised trials and over 500,000 THA in observational studies. For mortality, random effects analysis revealed a higher pooled RD of 0.7%, 95%, confidence interval (CI) [0.0%, 2.3%], I-square 42%; the heterogeneity was explained by differences in follow-up. When restricted to studies with long term follow-up (i.e. 10 years or more), the RD for mortality was 8.5%, 95%, CI [5.8%, 11.2%]; number needed to treat was 12. Further subgroup analyses and meta-regression random effects models revealed no evidence for other moderator variables (study level covariates, e.g. resurfacing vs. non-resurfacing MOM) than follow-up duration. The quality of the evidence presented in this meta-analysis was characterized as moderate according to the CLEAR-NPT (for non-pharmacological trials) and Cochrane risk of bias Table. CONCLUSIONS AND RELEVANCE:Meta-analysis suggests there may be an increased long-term risk of mortality and revision surgery for patients with MOM THA compared to patients with non-MOM THA. REGISTRATION:PROSPERO 2014:CRD42014007417.

Abstract  The notion of conceivability has traditionally been regarded as crucial to an account of modal knowledge. Despite its importance to modal epistemology, there is no received explication of conceivability. In recent discussions, some have attempted to explicate the notion in terms of epistemic possibility. There are, however, two notions of epistemic possibility, a more familiar one and a novel one. I argue that these two notions are independent of one another. Both are irrelevant to an account of modal knowledge on the predominant view of modal reality. Only the novel notion is relevant and apt on the competing view of modal reality; but this latter view is problematic in light of compelling counterexamples. Insufficient care regarding the independent notions of epistemic possibility can lead to two problems: a gross problem of conflation and a more subtle problem of obscuring a crucial fact of modal epistemology. Either problem needlessly hampers efforts to develop an adequate account of modal knowledge. I conclude that the familiar notion of epistemic possibility (and the very term ‘epistemic possibility’) should be eschewed in the context of modal epistemology. [ABSTRACT FROM AUTHOR]

We describe a new multivariate gamma distribution and discuss its implication in a Poisson-correlated gamma-frailty model. This model is introduced to account for between-subjects correlation occurring in longitudinal count data. For likelihood-based inference involving distributions in which high-dimensional dependencies are present, it may be useful to approximate likelihoods based on the univariate or bivariate marginal distributions. The merit of composite likelihood is to reduce the computational complexity of the full likelihood. A 2-stage composite-likelihood procedure is developed for estimating the model parameters. The suggested method is applied to a meta-analysis study for survival curves. [ABSTRACT FROM AUTHOR]

Abstract Background After High-Dose Methotrexate (HD-MTX), folinic acid rescue therapy (Leucovorin) is administered to reduce side effects in pediatric acute lymphoblastic leukemia (ALL) patients. Leucovorin and MTX are structural analogues, possibly competing for cellular transport and intracellular metabolism. We hypothesize that Leucovorin accumulates during consecutive courses, which might result in a lower MTX uptake. Methods We prospectively measured red blood cell (RBC) folate and MTX levels during four HD-MTX and Leucovorin courses in 43 patients treated according the DCOG ALL-11 protocol with 2-weekly HD-MTX (5 g/m2/dose) and Leucovorin (15 mg/m2/dose) using LC-MS/MS. We estimated a linear mixed model to assess the relationship between these variables over time. Results Both RBC MTX-PG and folate levels increased significantly during protocol M. MTX-PG2–5 levels increased most substantially after the first two HD-MTX courses (until median 113.0 nmol/L, IQR 76.8–165.2) after which levels plateaued during the 3d and 4th course (until median 141.3 nmol/L, IQR 100.2–190.2). In parallel, folate levels increased most substantially after the first two HD-MTX courses (until median 401.6 nmol/L, IQR 163.3–594.2) after which levels plateaued during the 3d and 4th course (until median 411.5 nmol/L, IQR 240.3–665.6). The ratio folate/MTX-PG decreased significantly over time, which was mostly due to the relatively higher increase (delta) of MTX-PG. Conclusion These results suggest that the increase in RBC folate levels does not seem to have a large effect on RBC MTX levels. Future studies, assessing competition of Leucovorin and MTX on other cellular mechanisms which might negatively affect treatment efficacy, are necessary.

Abstract Accurate survival estimations in Ewing sarcoma are necessary to develop risk- and response adaptive treatment strategies allowing for early decision-making. We aim to develop an easy-to-use survival estimation tool from diagnosis and surgery. A retrospective study of 1314 Ewing sarcoma patients was performed. Associations between prognostic variables at diagnosis/surgery and overall survival (OS), were investigated using Kaplan-Meier and multivariate Cox models. Predictive accuracy was evaluated by cross-validation and Harrell C-statistics. Median follow-up was 7.9 years (95%CI 7.6–8.3). Independent prognostic factors at diagnosis were age, volume, primary tumor localization and disease extent. 5 risk categories (A-E) were identified with 5-year OS of 88% (86–94), 69% (64–74), 57% (50–64), 51% (42–60) and 28% (22–34) respectively. Harrell C-statistic was 0.70. Independent prognostic factors from surgery were age, volume, disease extent and histological response. In categories A-B, 5y OS increased to 92% (87–97) and 79% (71–87) respectively for 100% necrosis and decreased to 76% (67–85) and 62% (55–69) respectively for

Autologous hematopoietic stem cell transplantation is used to restore bone marrow function after high-dose chemotherapy. For apheresis, granulocyte colony-stimulating factor (G-CSF) is standard of care, but obtaining sufficient stem cells can be challenging. Other mobilization agents include plerixafor and PEGylated G-CSF (PEG-G-CSF). While efficacy of these is established in adults, limited data for their use in pediatric patients are available. Here, we compare Good versus Poor Mobilizers and study success of different mobilization regimens in regard to CD34 + cell-collection, -quality, -phenotype and hematologic reconstitution in pediatric patients. In this multi-center retrospective study, we analyzed data of 278 patients with solid tumors and lymphoma, mobilized with either G-CSF ( n = 224), PEG-G-CSF ( n = 34), or G-CSF/PEG-G-CSF with additional plerixafor ( n = 20). In Poor Mobilizers (13.7% of all patients), addition of plerixafor to G-CSF augmented CD34 + cell collection, without adverse effects on hematologic reconstitution and CD34 + cell quality. PEG-G-CSF-aided mobilization was successful as first-line treatment in two-thirds of patients and did not impair hematological reconstitution, compared to G-CSF-only. Within the Poor Mobilizer group, G-CSF+plerixafor increased primitive (CD45RA - CD38 - CD90 + CD49f + ) and CXCR4-expressing CD34 + cells in apheresis products compared to G-CSF-only, without exceeding levels of Good Mobilizers. No plerixafor-related increase in tumor cells was observed in apheresis products. In conclusion, our comprehensive study supports the use of plerixafor and furthermore demonstrates the potential of patient-friendly PEG-G-CSF for mobilization of pediatric patients.

Aims: Over time, the locking mechanism of Modular Universal Tumour and Revision System (MUTARS) knee arthroplasties changed from polyethylene (PE) to polyether-ether-ketone Optima (PEEK) and metal-on-metal (MoM) in an attempt to reduce the risk of mechanical failure. In this study, we aimed to assess the cumulative incidence of locking mechanism revision for symptomatic instability by type of material, and assess potential associated risk factors., Methods: The MUTARS Orthopaedic Registry Europe was used for a retrospective review of 316 patients (54% male (n = 170), median age 44 years (IQR 23 to 61)) who underwent a MUTARS knee arthroplasty for oncological indications between December 1995 and January 2023. The minimum follow-up was 12 months, and the median follow-up was 7.9 years (IQR 3.3 to 13.0). A competing risk model was used to estimate the cumulative incidence of first locking mechanism revision with death and revision for any other reason as competing events. Possible risk factors were assessed employing a univariate cause-specific hazards regression model., Results: Symptomatic instability of the hinge or locking mechanism due to wear (n = 20) or breakage (n = 14) occurred in 34 patients (11%): 9% of PE (n = 4/45), 20% of PEEK (n = 9/44), and 9% of MoM locking mechanisms (n = 21/227). The cumulative incidences of revision for instability due to wear or locking mechanism breakage at two, five, and ten years were 0%, 5% (95% CI 1 to 15), and 5% (95% CI 1 to 15) for PE, 5% (95% CI 1 to 14), 14% (95% CI 5 to 26), and 16% (95% CI 7 to 29) for PEEK, and 0%, 3% (95% CI 1 to 6), and 10% (95% CI 5 to 16) for MoM. With PE as the reference category, the cause-specific hazard ratio for PEEK and MoM were 3.6 (95% CI 1.1 to 11.9; p = 0.036) and 3.2 (95% CI 1.1 to 9.5; p = 0.043), respectively. Age, BMI, resection length, and extra-articular resections were not associated with the time to locking mechanism revision., Conclusion: Alterations in prosthetic materials have not decreased the revision risk for locking mechanism failure. Besides locking mechanism material, no other patient- or prosthesis-related risk factors for locking mechanism failure were identified. Improvement of the locking mechanism is warranted since revision exposes patients to the risk of serious secondary complications., Competing Interests: R. E. Evenhuis, M. P. A. Bus, J. van Nes, R. J. P. van der Wal, D. Broekhuis, and M. A. J. van de Sande report an unconditional research grant, paid to their institution, from Implantcast, related to this study. The funder (and also producer of the MUTARS knee reconstructions) was not involved with the design, conduction, or analysis of the study results. M. van de Sande also reports grants from Carbofix and advisory board expenses from Synox, AnMax,and Dicephera, all of which are unrelated to this study. S. Sellevold reports support for attending meetings and/or travel for a MUTARS meeting, unrelated to this study., (© 2025 Evenhuis et al.)

Background: Current knowledge on the microvascular anatomy of adult human menisci is based on cadaveric studies. However, considerable interindividual variation in meniscal microvascularization has been reported in recent studies with small sample sizes., Purpose: To assess the association between patient characteristics and the depth of microvascularization of the meniscus., Study Design: Descriptive laboratory study., Methods: Menisci from 174 patients who received total knee replacement between March 2021 and December 2023 were collected. A total of 174 lateral and 102 medial menisci were included. Three sections were made from each meniscus: the anterior horn, midbody, and posterior horn. Immunohistochemical staining (CD-31) was used to visualize the microvasculature. The 4 primary outcome measures were the correlation between the depth of microvascular penetration into the lateral meniscus (0%-100%) and (1) age, (2) smoking, (3) degree of osteoarthritis, and (4) history of cardiovascular disease. To account for repeated measurements within each patient, a linear mixed-effects model was estimated to study the association between microvascularization and the patient's characteristics previously introduced., Results: The depth of vascular penetration ranged from 0% to 78% into the lateral menisci and from 0% to 67% into the medial menisci. No significant correlations were found between age, smoking, degree of osteoarthritis, or history of cardiovascular disease and the degree of vascular penetration into the lateral meniscus. The linear mixed-effects model analysis, adjusted for location within the meniscus (anterior horn, midbody, or posterior horn) and meniscal side (lateral or medial), showed no significant associations between the same patient characteristics and meniscal microvascularization., Conclusion: The degree of microvascular penetration into the meniscus has a wide range among adults >50 years. However, the depth of microvascularization was not associated with age, smoking, degree of osteoarthritis, or history of cardiovascular disease., Clinical Relevance: Because no associations were found between depth of microvascular penetration into the meniscus and patient characteristics, the latter cannot be used to estimate the vascular status of a meniscal tear in clinical practice., Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: This investigator-initiated study was funded by a grant from the Haaglanden Medical Center Research Fund Bronovo. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto.

Objective: This study aims to assess the long-term safety and efficacy of adding pazopanib to neo-adjuvant radiotherapy followed by surgery in patients with high-risk non-metastatic soft tissue sarcoma of the trunk and extremities treated in the PASART-1 and PASART-2 trials, as well as to compare the PASART cohorts to a control cohort receiving standard treatment during the same time period from the Netherlands Cancer Registry (IKNL) to investigate if adding pazopanib improves Overall Survival (OS)., Methods: Updated follow-up data on disease control, survival and long-term toxicities of the PASART-trials were extracted from electronic patient records. The effect of adding pazopanib to neo-adjuvant radiotherapy on OS was investigated by comparing the combined PASART cohorts to the IKNL cohort via direct comparison and exact matching analysis., Results: PASART-trials included 34 patients, IKNL cohort included 487 patients. After a median follow-up of 75.4 months (range: 30-131 months) the 1-year, 2-year and 5-year OS in the PASART-trials were 97% (95% confidence interval [CI]: 91.5-100), 85.3% (95% CI: 74.2-98.1), 79.3% (95% CI: 66.8-94.2), respectively. Matching resulted in 23 PASART and 89 IKNL patients. Adding pazopanib did not significantly improve OS when compared to standard treatment (IKNL) in a direct comparison (hazard ratio [HR]: 0.58; 95% CI: 0.30-1.13) or matched analysis (HR: 0.70; 95% CI: 0.29-1.73). Long-term toxicities, mainly fibrosis (n = 6) and edema (n = 2), were observed in 11 PASART patients and comparable to historical controls., Interpretation: The addition of pazopanib had tolerable long-term toxicity but did not improve OS when compared to a control cohort receiving standard treatment.

Purpose: Moderate hypofractionation was adopted to reduce hospital visits during the COVID-19 pandemic aiming to maintain treatment efficacy for soft tissue sarcoma (STS) patients, shifting preoperative schedules from 25 fractions of 2 Gy to 14-15 fractions of 3 Gy. This study evaluates the clinical implications and outcomes of this schedule, focusing on wound complications, radiation toxicity, local tumour control, and distant metastases., Patients and Methods: Data was collected from patients treated between 01 and 01-2020 and 31-12-2023. Outcomes included wound complications within 120 days post-surgery, local-recurrence, distant metastases and radiation toxicity. Logistic regression was performed to identify factors associated with wound complications. The cumulative incidence of local recurrence and distant metastases were estimated with a competing risk model., Results: Sixty-six patients were analysed, with a mean age of 74 years (standard deviation (SD)± 11). Tumours were mainly localized in the lower extremities (64 %), mean size 103 mm (SD±58). Median follow-up was 29 months (range 2-50). A R0 resection margin was achieved in 77 % of the operated patients. The wound complication rate was 33 %, with moderate complications in 13 patients and severe in 6. The cumulative incidences of local recurrence and distant metastases at 2 years were 7.6 % (standard error (SE) 3.7 %) and 29 % (SE 6 %, Fig. 1) respectively. Acute grade 3 dermatitis occurred in one patient (1.5 %)and two patients experienced late grade 3 toxicity (fractures, 3.0 %). Twenty patients developed distant metastases, two diagnosed before start of the treatment. Eighteen patients died, with six deaths from distant metastases and one from the primary tumour., Conclusion: Preoperative moderate hypofractionation for STS during COVID-19 showed promising results, with no increase in postoperative wound complications and favourable local failure rates., Competing Interests: Declaration of Competing Interest No conflicts of interest to declare, (Copyright © 2025 Elsevier Ltd. All rights reserved.)

Background: Because the occurrence of metabolic syndrome (MetS) might contribute to childhood cancer survivor's excess risk of cardiovascular disease, the authors assessed the prevalence and determinants of MetS in the Dutch Childhood Cancer Survivor Study (DCCSS-LATER2) cohort., Methods: In total, 2338 adult childhood cancer survivors (CCS) were cross-sectionally assessed for the prevalence of MetS, using the Lifelines cohort (N = 132,226 adults without a history of cancer) as references. The prevalence of MetS was clinically assessed using existing classifications, as well as an alternative method using dual-energy x-ray absorptiometry fat% instead of waist circumference to define abdominal adiposity. Logistic regression models, adjusted for age and sex, were used to investigate the association between the presence of MetS and both cohorts. Demographic, lifestyle, and treatment determinants of MetS were identified through multivariable logistic regression., Results: The survivor cohort (median age, 34.7 years, median follow-up time, 27.1 years) showed increased adjusted odds ratio (aOR) for MetS (modified National Cholesterol Education Program Adult Treatment Panel III criteria), as compared to the reference cohort (aOR, 2.07; 95% confidence interval [CI], 1.85-2.32). Compared to these criteria, the alternative method identified 57 additional survivors with MetS (395 of 2070 [19.1%] vs. 452 of 1960 [23.1%], respectively). Age (odds ratio [OR], 1.07; 95% CI, 1.04-1.10, per year increase), smoking (OR, 1.46; 95% CI, 1.04-2.04), low physical activity (OR, 1.48; 95% CI, 1.05-2.09), abdominal radiotherapy (OR, 2.13; 95% CI, 1.01-4.31; >30 Gy), cranial radiotherapy (OR, 2.89; 95% CI, 1.67-4.96; 1-25 Gy; and OR, 2.44; 95% CI, 1.30-4.47; >25 Gy), total body irradiation (OR, 6.17; 95% CI, 3.20-11.76), and underlying central nervous system tumor (OR, 1.78; 95% CI, 1.21-2.60) were associated with MetS., Conclusion: The high risk of MetS in CCS, combined with several potential modifiable factors, underscores the need for timely identification and intervention strategies to mitigate the long-term cardiovascular risks in CCS., (© 2025 The Author(s). Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Infections lead to substantial morbidity during the treatment of acute lymphoblastic leukemia (ALL) in which the adaptive immune system is severely affected, leading to declining serum immunoglobulin levels. We performed a trial to investigate whether intravenous immunoglobulin (IVIG) prophylaxis in pediatric patients with ALL could prevent admissions for fever. This randomized controlled trial was a subtrial of the national Dutch multicenter ALL study. Patients aged 1-19 years with medium-risk ALL were randomized into two groups receiving either IVIG prophylaxis (0.7 g/kg IVIG given every 3 weeks, starting on day 22 after diagnosis) or well-defined standard of care (control group). Between October 2012 and March 2019, 91 (51%) patients were randomly assigned to IVIG prophylaxis and 86 (49%) to the control arm. In the IVIG prophylaxis group there were 206 admissions for fever versus 271 in the control group (P=0.011). IVIG prophylaxis was not associated with bacteremia. However, there were significantly fewer admissions for fever with negative blood cultures in the IVIG prophylaxis group than in the control group (113 vs. 200, P<0.001). The difference in number of admissions for fever was observed specifically during maintenance treatment (100 vs. 166, P<0.001) resulting in fewer courses of antibiotic treatment (78 vs. 137, P<0.001) and fewer cases of chemotherapy adaptation (72 vs. 134, P<0.001). In conclusion, in pediatric patients with medium-risk ALL, IVIG prophylaxis was associated with significantly fewer admissions for fever with negative blood cultures during maintenance treatment, resulting in fewer courses of antibiotic treatment and fewer chemotherapy adaptations.

Background: Liquid biopsies offer less burdensome sensitive disease monitoring. Bone marrow (BM) metastases, common in various cancers including neuroblastoma, is associated with poor outcomes. In pediatric high-risk neuroblastoma most patients initially respond to treatment, but in the majority the disease recurs with only 40% long-term survivors, stressing the need for more sensitive detection of disseminated disease during therapy., Methods: To validate sensitive neuroblastoma mRNA RT-qPCR BM testing, we prospectively assessed serial BM samples from 345 international high-risk neuroblastoma patients, treated in trials NB2004 (GPOH) or NBL2009 (DCOG), using PHOX2B, TH, DDC, CHRNA3, and GAP43 RT-qPCR mRNA markers and BM GD2-immunocytology. Association between BM-infiltration levels and event-free survival (EFS) and overall survival (OS) was estimated by using Cox regression models and Kaplan-Meier's methodology., Results: BM infiltration >10% by RT-qPCR at diagnosis was prognostic for survival (adjusted hazard ratio (HR) 1.82 [95%CI 1.25-2.63] and 2.04 [1.33-3.14] for EFS and OS, respectively). Any post-induction RT-qPCR positivity correlated with poor EFS and OS, with a HR of 2.10 [1.27-3.49] and 1.76 [1.01-3.08] and 5-years EFS of 26.6% [standard error 5.2%] versus 60.4% [6.7] and OS of 43.8% [5.9] versus 65.7% [6.6] for RT-qPCR-positive patients versus RT-qPCR-negative patients. In contrast, post-induction immunocytology positivity was not associated with EFS or OS (HR 1.22 [0.68-2.19] and 1.26 [0.54-2.42])., Conclusion: This study validates the association of not clearing of BM metastases by sensitive RT-qPCR detection with very poor outcome. We therefore propose implementation of RT-qPCR for minimal residual disease testing in neuroblastoma to guide therapy., Competing Interests: Declarations. Ethics approval and consent to participate: The study was approved by the Medical Research Ethics Committees of the Academic Medical Center (Amsterdam, the Netherlands; MEC07/219#08.17.0836) and the University of Cologne (Cologne, Germany). Written informed consent from parents or guardians was obtained according to the declaration of Helsinki. Consent for publication: Not applicable. Competing interests: The authors report no conflict of interest., (© 2024. The Author(s).)

Background: The 5-year prognosis of non-high-risk neuroblastomas is generally good (>90%). However, a proportion of patients show progression and succumb to their disease. We aimed to identify molecular aberrations (not incorporated in the current risk stratification) associated with overall survival (OS) and/or event-free survival (EFS) in patients diagnosed with non-high-risk neuroblastoma., Methods: We conducted a systematic search in PubMed, Embase, Cochrane and Google Scholar. Two reviewers independently and blindly screened titles/abstracts, references of protocols/reviews and full texts. Risk of bias was assessed using a customized Quality in Prognostic Studies tool. Applicability was assessed using a tool designed by the researchers. GRADE criteria were used to determine quality of evidence., Results: Sixteen studies (4718 patients) were included. A segmental chromosomal aberration (SCA) profile was associated with lower survival. 1p loss of heterozygosity (LOH) and 17q gain were associated with lower OS and EFS. 1p deletion and 2p gain were associated with lower OS, but this was not the same for EFS. 3p deletion was not associated with worse outcome. Quality of evidence was downgraded because of imprecision and publication bias and upgraded because of moderate/large effect, resulting in a moderate quality of evidence., Conclusion: The association of 1p LOH, 1p deletion, 2p gain and 17q gain with OS and EFS suggests that these SCAs may be added to the risk stratification to identify non-high-risk neuroblastomas with worse prognosis.

Background: This study aims to analyse the effects of reducing Received Dose Intensity (RDI) in chemotherapy treatment for osteosarcoma patients on their survival by using a novel approach. Previous research has highlighted discrepancies between planned and actual RDI, even among patients randomized to the same treatment regimen. To mitigate toxic side effects, treatment adjustments, such as dose reduction or delayed courses, are necessary. Toxicities are therefore risk factors for mortality and predictors of future exposure levels. Toxicity introduces post-assignment confounding when assessing the causal effect of chemotherapy RDI on survival outcomes, a topic of ongoing debate., Methods: Chemotherapy administration data from BO03 and BO06 Randomized Clinical Trials (RCTs) in ostosarcoma are employed to emulate a target trial with three RDI-based exposure strategies: 1) standard, 2) reduced, and 3) highly-reduced RDI. Investigations are conducted between subgroups of patients characterised by poor or good Histological Responses (HRe), i.e., the strongest known prognostic factor for survival in osteosarcoma. Inverse Probability of Treatment Weighting (IPTW) is first used to transform the original population into a pseudo-population which mimics the target randomized cohort. Then, a Marginal Structural Cox Model with effect modification is employed. Conditional Average Treatment Effects (CATEs) are ultimately measured as the difference between the Restricted Mean Survival Time of reduced/highly-reduced RDI strategy and the standard one. Confidence Intervals for CATEs are obtained using a novel IPTW-based bootstrap procedure., Results: Significant effect modifications based on HRe were found. Increasing RDI-reductions led to contrasting trends for poor and good responders: the higher the reduction, the better (worsen) was the survival in poor (good) reponders. Due to their intrinsic resistance to chemotherapy, poor reponders could benefit from reduced RDI, with an average gain of 10.2 and 15.4 months at 5-year for reduced and highly-reduced exposures, respectively., Conclusions: This study introduces a novel approach to (i) comprehensively address the challenges related to the analysis of chemotherapy data, (ii) mitigate the toxicity-treatment-adjustment bias, and (iii) repurpose existing RCT data for retrospective analyses extending beyond the original trials' intended scopes., Competing Interests: Declarations. Ethics approval and consent to participate: Permission to recruit patients to the MRC BO03/EORTC 80861 and MRC BO06/EORTC 80931 protocol was provided by the appropriate national and local regulatory and local committees. Link-anonymised data were used for the purposes of this study, and the use of the data was consistent with the consent taken. Because it involved retrospective review, the project was exempt from Human Subjects protection requirements by the Institutional Review Board of the European Organisation for the Research and Treatment of Cancer. Consent for publication: Not required. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background & Aims: Smell and taste changes are frequently reported bothersome treatment symptoms during treatment for childhood cancer and assumed to influence outcomes such as food intake. Since nutritional status of children with cancer is already vulnerable, any detrimental effects on food intake should be prevented. Therefore, understanding the exact relationship between chemosensory changes and dietary intake, eating behavior, and other domains such as health-related quality of life (HRQoL), is important for improving outcomes., Methods: In this longitudinal study, we followed 87 childhood cancer patients treated for hematological, solid, or brain malignancies. Smell (odor threshold and odor identification) and taste function (total taste score) were objectively investigated using commercial Sniffin' Sticks and Taste Strips respectively, and by self-report. Dietary intake was measured using a 3-day food dairy. For nutritional status, BMI expressed as standard deviation scores was derived from medical records. Eating behavior and HRQoL were assessed by the Behavioral Pediatrics Feeding Assessment Scale (BPFAS) and PedsQL 4.0 Generic Core Scales, respectively. Measurements were taken approximately 6 weeks (T0), 3 months (T1), 6 months after starting chemotherapy (T2), and 3 months after termination of chemotherapy or maintenance phase for children with acute lymphoblastic leukemia (ALL) (T3). Dietary intake, eating behavior, nutritional status, and HRQoL were modelled over time using mixed model analysis. Associations between smell and taste (objective and self-report), as well as patient characteries were studied., Results: Energy intake significantly increased during the study period, with a higher age, BMI, and total taste scores associated to this increase. Boys had higher energy intake compared to girls. Eating behavior scores significantly declined, indicating less eating problems. Age, pre-diagnosis eating behavior, self-reported smell changes, and tube feeding were associated to eating behavior. BMI significantly increased, with a higher BMI at diagnosis to be related to a higher BMI during the study period. A lower BMI was found in children receiving tube feeding and self-reported taste changes. HRQoL improved during the study period, with lower HRQoL in children receiving tube feeding and self-reported taste changes., Conclusion: Both objective and subjective measures of taste and smell influence dietary intake, eating behavior, nutritional status, and HRQoL. Individual dietary advice and coping strategies are warranted to prevent detrimental effects of chemosensory changes on food intake and clinical outcomes in children with cancer., Competing Interests: Conflict of interest The authors have declared no relevant conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Childhood cancer survivors (CCS) face an increased risk of early cardiovascular disease (CVD). In our nationwide CCS cohort, we assessed the prevalence and determinants of dyslipidemia, a well-established risk factor for accelerated atherosclerosis and CVD., Methods: Prevalence of dyslipidemia was cross-sectionally assessed in 2338 adult CCS and compared to adults with no cancer history (Lifelines, n = 132 226). Dyslipidemia was defined by multiple classifications as well as lipid abnormalities to investigate the impact on prevalence and determinants. Logistic regression models, adjusted for age, sex, and BMI, were used to assess the cohort effect on presence of dyslipidemia. Determinants of dyslipidemia were identified through multivariable logistic regression., Results: CCS (median age 34.7 year, median follow-up 27.1 year) had significantly increased odds of dyslipidemia compared to the reference cohort according to all classifications (NCEP-ATP-III, WHO, EGIR, CTCAEv.4.03). In survivors without lipid-lowering agents (n = 2007), lipid abnormalities were present in 20.6% (triglycerides > 1.7 mmol/L), 30.3% (HDL-c < 1.0/1.3 mmol/L (male/female)), 29.9% (total cholesterol > 5.2 mmol/L), 7.3% (LDL-c > 4.1 mmol/L), and 7.7% (apolipoprotein-B > 130 mg/dL). Compared to references without lipid-lowering agents (n = 126 631), survivors had increased odds of high triglycerides (aOR = 1.89, 95% CI = 1.68-2.13), low HDL-c (aOR = 2.73, 95% CI = 2.46-3.03), and high apolipoprotein-B (aOR = 1.84, 95% CI = 1.53-2.20). Sex, age, BMI, physical activity, abdominal/pelvic, cranial, and total body irradiation, alkylating agents, smoking, growth hormone deficiency, and diabetes mellitus were associated with (≥1 definition of) dyslipidemia in CCS., Conclusions: CCS is at increased risk of dyslipidemia, with various modifiable and non-modifiable determinants identified, underscoring the importance of survivor-specific risk assessment tools to control cardiovascular morbidity and mortality in this high-risk population., Competing Interests: Conflict of interest: None declared, (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Endocrinology.)

Background: Children and young adults needing surgery for a primary malignant bone tumour around the knee face a difficult, life-changing decision. A previous study showed that this population wants to be involved more in the decision-making process and that more involvement leads to less decisional stress and regret. Therefore, a well-designed and standardized decision-making process based on the principles of shared decision-making needs to be designed, implemented, and evaluated., Methods: We developed a shared decision-making (SDM) model for this patient population, including an online decision aid (DA). This model has been implemented in the standard care of patients with a primary malignant bone tumour around the knee. Following implementation, we will analyse its effect on the decision-making process and the impact on patient experiences using questionnaires and interviews. Moreover, potential areas for improvement will be identified., Discussion: Given the importance of involving patients and parents in surgical decision-making, particularly in life-changing surgery such as malignant bone tumour surgery, and given the lack of SDM models applicable for this purpose, we want to share our model with the international community, including our study protocol for evaluating and optimising the model. This study will generate valuable knowledge to facilitate the optimisation of current patient care for local treatment. The sharing of our implementation and study protocol can serve as an example for other centres interested in implementing SDM methods in an era characterized by more empowered patients and parents who desire autonomy and reliable and realistic information., (© 2024. The Author(s).)

The trajectory of hematopoietic stem cell transplantation (HSCT) is often accompanied by physically disabling complications that impair physical performance of pediatric patients. However, knowledge about when impairments in physical performance arise and the factors contributing to these impairments is limited. Therefore, we conducted a retrospective analysis of physical performance 100 days post-HSCT in patients aged 3-18 years. Additionally, we aim to elucidate the relationship between pre- and post-HSCT physical performance and to unravel the impact of intensive HSCT procedures on post-HSCT physical performance. To explore associations between physical performance outcomes post-HSCT and covariates, linear regression models were estimated. Seventy-seven patients were included with a median age of 11.8 years (interquartile range: 5.9, 14.8). Patients had lower hip flexion muscle strength and appendicular skeletal muscle mass and a slower rising from the floor time 100 days post-HSCT compared to average values of the normal population. Pre-HSCT physical performance was positively associated with physical performance post-HSCT, independent of age, the cumulative glucocorticoids dosage administered and the total duration of hospitalization during the HSCT trajectory. This explorative study highlights the potential role of prehabilitation in enhancing physical performance of pediatric HSCT patients., (© 2024. The Author(s).)