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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).)

Because of the low mutational burden and consequently, fewer potential neoantigens, children with acute myeloid leukemia (AML) are thought to have a T cell-depleted or 'cold' tumor microenvironment and may have a low likelihood of response to T cell-directed immunotherapies. Understanding the composition, phenotype, and spatial organization of T cells and other microenvironmental populations in the pediatric AML bone marrow (BM) is essential for informing future immunotherapeutic trials about targetable immune-evasion mechanisms specific to pediatric AML. Here, we conducted a multidimensional analysis of the tumor immune microenvironment in pediatric AML and non-leukemic controls. We demonstrated that nearly one-third of pediatric AML cases has an immune-infiltrated BM, which is characterized by a decreased ratio of M2- to M1-like macrophages. Furthermore, we detected the presence of large T cell networks, both with and without colocalizing B cells, in the BM and dissected the cellular composition of T- and B cell-rich aggregates using spatial transcriptomics. These analyses revealed that these aggregates are hotspots of CD8 + T cells, memory B cells, plasma cells and/or plasmablasts, and M1-like macrophages. Collectively, our study provides a multidimensional characterization of the BM immune microenvironment in pediatric AML and indicates starting points for further investigations into immunomodulatory mechanisms in this devastating disease., (© 2024. The Author(s).)

Background: Due to the relatively advanced age and high mortality rate of patients with high-grade chondrosarcoma (CS), it is important to holistically assess patient- and tumor characteristics in multidisciplinary team and shared decision-making with regard to treatment options. While current prognostic models include multiple tumor and treatment characteristics, the only patient characteristics that are commonly included are age and gender. Based on clinical experience, we believe that factors related to patient preoperative systemic health status such as the American Society of Anesthesiologists (ASA) score may be equally important prognostic factors for overall survival (OS). Methods: A retrospective nationwide cohort study was identified from four specialized bone sarcoma centers in The Netherlands. Patients with a primary CS grade II, III, and dedifferentiated CS were eligible. Prognostic factors including age at presentation, gender, ASA score, CVD, tobacco use, BMI, histological tumor grade, tumor size, pathological fracture, presentation after unplanned excision, type of surgery and surgical margin were evaluated. The outcome measure was OS at the time of surgery. The Kaplan-Meier methodology was employed to estimate OS; a log-rank test was used to assess the difference in survival. To study the impact of prognostic factors on OS, a multivariate Cox proportional hazard regression model was estimated. Results: In total, 249 patients were eligible for this study, and 89 were deceased at the end of follow-up. In multivariate analysis, histological grade (HR 2.247, 95% CI 1.334-3.783), ASA score III (HR 2.615, 95% CI 1.145-5.976, vs. ASA I), and age per year (HR: 1.025, 95% CI 1.004-1.045) were negatively associated with OS. No association was found between tobacco use, BMI, gender or cardiovascular disease and OS in this cohort. Pathological fracture and tumor size were only associated with OS in univariate analysis. Conclusions: This multicenter study is the first on sarcomas to include ASA in a prognostic model. Results show that ASA score as a proxy for patients' systemic health status should be included when providing a prognosis for patients with a high-grade primary CS, besides the conventional risk factors such as tumor grade and age. Specifically, severe systemic disease (ASA score III) is a strong negative predictor. Conversely, we found no difference in OS between ASA scores I and II. These findings aid multidisciplinary team and shared decision-making with regard to these complex sarcoma patients that often require life-changing surgeries. Level of Evidence: Prognostic level III. See the instructions for authors for the complete description of levels of evidence.

Background: Taurolidine-citrate(-heparin) lock solutions (TCHL) are suggested as a promising and safe method for the prevention of central-line-associated bloodstream infections (CLABSI)., Aim: To investigate the efficacy of TCHL for the prevention of CLABSI in paediatric oncology patients., Methods: An assessor-blinded randomized controlled trial at the Princess Máxima Centre for paediatric oncology, the Netherlands, was performed from 2020 to 2023. Paediatric oncology patients receiving a tunnelled central venous access device (CVAD) were eligible. A total of 462 patients were required to compare the TCHL to the heparin-only lock (HL). Patients were followed-up for the first 90 days after CVAD insertion. The primary outcome was the incidence of the first CLABSI from CVAD insertion until the end of follow-up. Intention-to-treat and per-protocol analyses were performed., Findings: In total, 232 were randomized in the HL and 231 in the TCHL group. A total of 47 CLABSIs were observed. The intention-to-treat analysis showed that a CLABSI was observed in 26 (11.2%) of the HL group patients versus 21 (9.1%) of the TCHL group patients; incidence rate ratio (IRR) of 0.81 (95% confidence interval (CI): 0.46-1.45) in favour of the TCHL group. The per-protocol analysis showed that a CLABSI was observed in 10 (7.9%) of the HL group patients versus 6 (4.8%) of the TCHL group patients; IRR of 0.59 (95% CI: 0.21-1.62) in favour of the TCHL group. Adverse events were more common in the TCHL group but rarely reported., Conclusion: No difference was detected between the TCHL and HL in the incidence of CLABSI in paediatric oncology patients., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Our aim is to investigate the association of treatment with survival in patients with diffuse intrinsic pontine glioma (DIPG) by examining 6 historical treatment paths., Methods: We retrospectively analyzed data from 409 patients with radiologically centrally reviewed DIPG, sourced from the German Society of Pediatric Oncology and Hematology HIT-HGG trial database and the SIOPE-DIPG/DMG Registry. Survival outcomes were estimated using the Kaplan-Meier method, and univariable and multivariable Cox proportional hazard models were estimated to study treatment effects., Results: The median overall survival (OS) from diagnosis was 11.2 months (95% confidence interval [CI], 10.5-11.9). Patients who by choice received no frontline treatment had an OS of 3.0 months (95% CI, 2.0-4.0), while those treated with radiation therapy (RT) alone had a median OS of 10.4 months (95% CI, 9.1-11.8). Those receiving RT combined with chemotherapy had the longest median OS of 11.7 months (95% CI, 10.8-12.6). The median post-progression survival (PPS) was 4.1 months (95% CI, 3.5-4.7). Patients who relapsed and did not receive treatment had a PPS of 2.2 months (95% CI, 1.8-2.6), while those treated with chemotherapy alone had a PPS of 4.4 months (95% CI, 3.7-5.0), and those who underwent reirradiation, with or without chemotherapy, had the longest survival after relapse of 6.6 months (95% CI, 5.3-8.0). Treatment differences remained significant in multivariable analysis adjusted for age and symptom duration in both diagnosis and relapse setting., Conclusions: This study shows increased survival outcomes associated with radiation and chemotherapy treatment or a combination thereof, at diagnosis and relapse, in a historical DIPG cohort., Competing Interests: None declared., (© The Author(s) 2024. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Background and Purpose:  Developmental dysplasia (DDH) and Legg-Calvé-Perthes disease (LCPD) are common indications for total hip arthroplasty (THA) at a young age, and may be associated with increased revision risk. We aimed to investigate the 10-year cumulative aseptic cup revision and overall revision risk of THA, and investigated whether these are increased compared with THA for primary osteoarthritis (OA) in patients below 55 years., Methods:  All THAs (2007-2019) in patients under the age of 55 for the indications OA, DDH, and LCPD were extracted from the Dutch Arthroplasty register. The 10-year cumulative incidences of aseptic cup failure and overall revision were assessed for the 3 groups, with death as a competing risk. Cox regression analysis was used., Results:  24,263 THAs were identified: 20,645 (85%) for OA, 3,032 (13%) for DDH, and 586 (2%) for LCPD. The 10-year cumulative revision risk for aseptic cup failure was 3.4% (95% confidence interval [CI] 3.0-3.8) for OA, 3.4% (CI 2.4-3.4) for DDH, and 1.7% (CI 0.2-3.1) for LCPD. The 10-year cumulative overall revision risk was 6.0% (CI 5.6-6.5) for OA, 6.0% (CI 4.9-7.2) for DDH, and 5.1% (2.7-7.5) for LCPD. The multivariable Cox regression analysis for aseptic cup failure yielded hazard ratios of 0.7 (0.5-1.2) for DDH, and 0.8 (0.3-2.1) for LCPD compared with OA. No statistically significant differences for overall revision were found., Conclusion:  THA performed for DDH or LCDP in patients under the age of 55 was not associated with a statistically significant increased risk of aseptic cup revision or overall revision, compared with THA performed for primary OA in the same age group.

Since the mid-1980s, there has been little progress in improving survival of patients diagnosed with osteosarcoma. Survival prediction models play a key role in clinical decision-making, guiding healthcare professionals in tailoring treatment strategies based on individual patient risks. The increasing interest of the medical community in using machine learning (ML) for predicting survival has sparked an ongoing debate on the value of ML techniques versus more traditional statistical modelling (SM) approaches. This study investigates the use of SM versus ML methods in predicting overall survival (OS) using osteosarcoma data from the EURAMOS-1 clinical trial (NCT00134030). The well-established Cox proportional hazard model is compared to the extended Cox model that includes time-varying effects, and to the ML methods random survival forests and survival neural networks. The impact of eight variables on OS predictions is explored. Results are compared on different model performance metrics, variable importance, and patient-specific predictions. The article provides comprehensive insights to aid healthcare researchers in evaluating diverse survival prediction models for low-dimensional clinical data.

Introduction: Treating older adults with chemotherapy remains a challenge, given their under-representation in clinical trials and the lack of robust treatment guidelines for this population. Moreover, older patients, especially those with frailty, have an increased risk of developing chemotherapy-related toxicity, resulting in a decreased quality of life (QoL), increased hospitalisations and high healthcare costs. Phase II trials have suggested that upfront dose reduction of chemotherapy can reduce toxicity rates while maintaining efficacy, leading to fewer treatment discontinuations and an improved QoL. The DOSAGE aims to show that upfront dose-reduced chemotherapy in older patients with metastatic colorectal cancer is non-inferior to full-dose treatment in terms of progression-free survival (PFS), with adaption of the treatment plan (monotherapy or doublet chemotherapy) based on expected risk of treatment toxicity., Methods and Analysis: The DOSAGE study is an investigator-initiated phase III, open-label, non-inferiority, randomised controlled trial in patients aged≥70 years with metastatic colorectal cancer eligible for palliative chemotherapy. Based on toxicity risk, assessed using the Geriatric 8 (G8) tool, patients will be stratified to either doublet chemotherapy (fluoropyrimidine with oxaliplatin) or fluoropyrimidine monotherapy. Patients classified as low risk will be randomised between a fluoropyrimidine plus oxaliplatin in either full-dose or with an upfront dose reduction of 25%. Patients classified as high risk will be randomised between fluoropyrimidine monotherapy in either full-dose or with an upfront dose reduction. In the dose-reduced arm, dose escalation after two cycles is allowed. The primary outcome is PFS. Secondary endpoints include grade≥3 toxicity, QoL, physical functioning, number of treatment cycles, dose reductions, hospital admissions, overall survival, cumulative received dosage and cost-effectiveness. Considering a median PFS of 8 months and non-inferiority margin of 8 weeks, we shall include 587 patients. The study will be enrolled in 36 Dutch Hospitals, with enrolment scheduled to start in July 2024. This study will provide new evidence regarding the effect of dose-reduced chemotherapy on survival and treatment outcomes, as well as the use of the G8 to choose between doublet chemotherapy or monotherapy. Results will contribute to a more individualised approach in older patients with metastatic colorectal cancer, potentially leading to improved QoL while maintaining survival benefits., Ethics and Dissemination: This trial has received ethical approval by the ethical committee Leiden Den Haag Delft (P24.018) and will be approved by the Institutional Ethical Committee of the participating institutions. The results will be disseminated in peer-reviewed scientific journals., Trial Registration Number: NCT06275958., Competing Interests: Competing interests: MS reports serving on advisory boards of Bristol-Myers Squibb, Eli Lilly & Company and AstraZeneca outside the submitted work. The other authors declare that they have no competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Update: This article was updated on July 17, 2024 because of a previous error, which was discovered after the preliminary version of the article was posted online. The byline that had read "Richard E. Evenhuis, MD 1 , Michiel A.J. van de Sande, MD, PhD 1,2 , Marta Fiocco, PhD 2,3,4 , Demien Broekhuis, MD 1 , Michaël P.A. Bus, MD, PhD 1 , and the LUMiC® Study Group*" now reads "Richard E. Evenhuis, MD 1 , Michiel A.J. van de Sande, MD, PhD 1,2 , Marta Fiocco, PhD 2,3,4 , Edwin F. Dierselhuis, MD, PhD 5 , Demien Broekhuis, MD 1 , Michaël P.A. Bus, MD, PhD 1 , and the LUMiC® Study Group*". The Department of Orthopaedic Surgery, Radboudumc, Nijmegen, The Netherlands, has been added as the affiliation for Edwin F. Dierselhuis, MD, PhD., Background: We previously reported promising early results for periacetabular tumor reconstructions using the LUMiC prosthesis. The current study evaluates mid-term complications, revision rates, cumulative incidence of implant revision, and risk factors for complications in a multicenter cohort., Methods: We assessed patients in whom a tumor defect after type P1b+2, P2, P2+3, or P1b+2+3 internal hemipelvectomy was reconstructed with a LUMiC prosthesis during the period of 2008 to 2022. Complications were reported according to the Henderson classification. Competing risks models were used to estimate the cumulative incidence of implant revision for mechanical and nonmechanical reasons, and reoperations for any complication. Cox models were used to study the effect of risk factors on dislocation and infection., Results: One hundred and sixty-six patients (median follow-up, 4.2 years [interquartile range, 2.6 to 7.6 years]) were included. A total of 114 (69%) were treated for a primary malignant tumor, 46 (28%) for metastatic carcinoma, 5 (3%) for a benign aggressive lesion, and 1 (1%) for another reason. One hundred and sixty-five reoperations were performed in 82 (49%) of the patients; 104 (63%) of the reoperations were within 6 months. Thirty-two (19%) of 166 implants were revised: 13 (8%) for mechanical reasons, mainly dislocation (n = 5, 3%), and 19 (11%) for nonmechanical reasons, mainly periprosthetic joint infection (PJI) (n = 15, 9%). The cumulative incidences of revision for mechanical reasons and PJI (Henderson 1 to 4) at 2, 5, and 10 years were 11% (95% confidence interval [CI], 7% to 17%), 18% (12% to 25%), and 24% (16% to 33%), respectively. Previous surgery at the same site was associated with an increased dislocation risk (cause-specific hazard ratio [HR CS ], 3.0 [95% CI, 1.5 to 6.4]; p < 0.01), and resections involving the P3 region were associated with an increased infection risk (HR CS , 2.5 [95% CI, 1.4 to 4.7]; p < 0.01)., Conclusions: Despite a substantial reoperation risk, the LUMiC prosthesis demonstrated its durability in the mid-term, with a low mechanical revision rate and most patients retaining their primary implant. Most complications occur in the first postoperative months. Patients with previous surgery at the same site had an increased dislocation risk and might benefit from more conservative rehabilitation and aftercare. Measures should be aimed at reducing the PJI risk, especially in resections involving the P3 region., Level of Evidence: Therapeutic Level IV . See Instructions for Authors for a complete description of levels of evidence., Competing Interests: Disclosure: This investigator-initiated study was funded by an unconditional research grant from Implantcast GmbH, Buxtehude, Germany, the manufacturer of the implant studied in this investigation. The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article ( http://links.lww.com/JBJS/H997 )., (Copyright © 2024 The Authors. Published by The Journal of Bone and Joint Surgery, Incorporated.)

Recent trials show 5-year survival rates >95% for ETV6::RUNX1 Acute Lymphoblastic Leukemia (ALL). Since treatment has many side effects, an overview of cumulative drug doses and intensities between eight international trials is presented to characterize therapy needed for cure. A meta-analysis was performed as a comprehensive summary of survival outcomes at 5 and 10 years. For drug dose comparison in non-high risk trial arms, risk group distribution was applied to split the trials into two groups: trial group A with ~70% (range: 63.5-75%) of patients in low risk (LR) (CCLSG ALL2004, CoALL 07-03, NOPHO ALL2008, UKALL2003) and trial group B with ~45% (range: 38.7-52.7%) in LR (AIEOP-BFM ALL 2000, ALL-IC BFM ALL 2002, DCOG ALL10, JACLS ALL-02). Meta-analysis did not show evidence of heterogeneity between studies in trial group A LR and medium risk (MR) despite differences in treatment intensity. Statistical heterogeneity was present in trial group B LR and MR. Trials using higher cumulative dose and intensity of asparaginase and pulses of glucocorticoids and vincristine showed better 5-year event-free survival but similar overall survival. Based on similar outcomes between trials despite differences in therapy intensity, future trials should investigate, to what extent de-escalation is feasible for ETV6::RUNX1 ALL., (© 2024. The Author(s).)

Background: The authors developed a pain monitoring app offering educational information, and real-time health care professional feedback on clinically significant pain (>4 numeric rating scale [NRS]-11) for children with cancer to reduce pain at home., Methods: This monocenter, nonblinded randomized controlled trial enrolled Dutch children (0-18 years old) receiving cancer treatment (≥3 months after diagnosis, ≥2 months treatment remaining). Children were randomly assigned to use the app or receive usual care (two parallel groups). We assessed whether use of the app yielded less clinically significant pain (aim 1) and whether it affected pain severity, duration, interference, pain management strategies, and parental emotional well-being (aim 2). The app was also evaluated by families (aim 3)., Results: A total of 94 children were randomized to use the app (15 drop-outs), and 90 were to receive care as usual (11 drop-outs). The app group (n = 79, mean age: 7.5 [5.1] years, 48% girls, 63% hemato-oncology diagnosis) reported significantly less clinically significant pain compared to usual care (n = 79, mean age: 7.5 [5.4] years, 52% girls, 65% hemato-oncology diagnosis) (odds ratio [OR], 0.38; 95% confidence interval [CI], 0.198-0.734]) (aim 1), as well as significantly lower pain severity (β = -0.27; 95% CI, -0.407 to -0.142). No differences were found for duration, interference, or management strategies. Parents in the app group reported significantly less distress compared to usual care (β = -0.84; 95% CI, -1.61 to -0.03]) (aim 2). Families generally evaluated the app positively (aim 3)., Conclusions: Use of the app resulted in less clinically significant pain at home. The exact working mechanisms of the app should be further elucidated., (© 2023 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Current prediction models for patients with ostosarcoma are restricted to predictions from a single, static point in time, such as diagnosis or surgery. These approaches discard information which becomes available during follow-up and may have an impact on patient's prognosis. This study aims at developing a dynamic prediction model providing 5-year overall survival (OS) predictions from different time points during follow-up. The developed model considers relevant baseline prognostic factors, accounting for where appropriate time-varying effects and time-varying intermediate events such as local recurrence (LR) and new metastatic disease (NM). A landmarking approach is applied to 1965 patients with high-grade resectable osteosarcoma from the EURAMOS-1 trial (NCT00143030). Results show that LR and NM negatively affected 5-year OS (HRs: 2.634, 95% CI 1.845-3.761; 8.558, 95% CI 7.367-9.942, respectively). Baseline factors with strong prognostic value (HRs > 2) included poor histological response (≥10% viable tumor), axial tumor location, and the presence of lung metastases. The effect of poor versus good histological response changed over time, becoming non-significant from 3.25 years post-surgery onwards. This time-varying effect, as well as the strong impact of disease-related time-varying variables, show the importance of including updated information collected during follow-up in the model to provide more accurate survival predictions.

Background: Estimation of the SARS-CoV-2 incubation time distribution is hampered by incomplete data about infection. We discuss two biases that may result from incorrect handling of such data. Notified cases may recall recent exposures more precisely (differential recall). This creates bias if the analysis is restricted to observations with well-defined exposures, as longer incubation times are more likely to be excluded. Another bias occurred in the initial estimates based on data concerning travellers from Wuhan. Only individuals who developed symptoms after their departure were included, leading to under-representation of cases with shorter incubation times (left truncation). This issue was not addressed in the analyses performed in the literature., Methods: We performed simulations and provide a literature review to investigate the amount of bias in estimated percentiles of the SARS-CoV-2 incubation time distribution., Results: Depending on the rate of differential recall, restricting the analysis to a subset of narrow exposure windows resulted in underestimation in the median and even more in the 95th percentile. Failing to account for left truncation led to an overestimation of multiple days in both the median and the 95th percentile., Conclusion: We examined two overlooked sources of bias concerning exposure information that the researcher engaged in incubation time estimation needs to be aware of., (© 2024. The Author(s).)

Purpose: Percutaneous hepatic perfusion with melphalan (M-PHP) is a minimally invasive therapy with proven efficacy in patients with uveal melanoma (UM) liver metastases. M-PHP is associated with a short hospital admission time and limited systemic side effects. In this study, we assessed quality of life (QoL) in UM patients treated with M-PHP., Materials and Methods: A prospective, single-center study including 24 patients treated with M-PHP for UM metastases to the liver. QoL questionnaires were collected at baseline, on day 2/3 after M-PHP, and on day 7 and day 21 after M-PHP, according to study protocol. The results were scored according to EORTC-QLQ C30 global health status (GHS), functional scales, and symptom scales. The difference in scores at baseline and subsequent time points was analyzed with the Wilcoxon signed-rank test and multiple testing Bonferroni correction. Adverse events (AE) were registered up to 30 days after M-PHP according to CTCAE v5.0., Results: Twenty-four patients (14 males; median age 63.0 years) completed 96 questionnaires. Most scores on all scales declined on day 2/3 after M-PHP. On day 21 after M-PHP, 12 out of 15 scores returned to baseline, including median GHS scores. Three variables were significantly worse on day 21 compared to baseline: fatigue (6-33; p = 0.002), physical functioning (100 vs 86.7; p = 0.003), and role functioning (100 vs 66.7; p = 0.001). Grade 3/4 AEs consisted mainly of hematological complications, such as leukopenia and thrombopenia., Conclusion: M-PHP causes fatigue and a decline in physical and role functioning in the 1st weeks after treatment, but GHS returns to baseline levels within 21 days. LEVEL OF EVIDENCE 3: Cohort study., (© 2024. The Author(s).)

Background: The decreased perfusion of osteosarcoma in dynamic contrast-enhanced (DCE) MRI, reflecting a good histological response to neoadjuvant chemotherapy, has been described., Purpose: In this study, we aim to explore the potential of the relative wash-in rate as a prognostic factor for event-free survival (EFS)., Methods: Skeletal high-grade osteosarcoma patients, treated in two tertiary referral centers between 2005 and 2022, were retrospectively included. The relative wash-in rate (rWIR) was determined with DCE-MRI before, after, or during the second cycle of chemotherapy (pre-resection). A previously determined cut-off was used to categorize patients, where rWIR < 2.3 was considered poor and rWIR ≥ 2.3 a good radiological response. EFS was defined as the time from resection to the first event: local recurrence, new metastases, or tumor-related death. EFS was estimated using Kaplan-Meier's methodology. Multivariate Cox proportional hazard model was used to estimate the effect of histological response and rWIR on EFS, adjusted for traditional prognostic factors., Results: Eighty-two patients (median age: 17 years; IQR: 14-28) were included. The median follow-up duration was 11.8 years (95% CI: 11.0-12.7). During follow-up, 33 events occurred. Poor histological response was not significantly associated with EFS (HR: 1.8; 95% CI: 0.9-3.8), whereas a poor radiological response was associated with a worse EFS (HR: 2.4; 95% CI: 1.1-5.0). In a subpopulation without initial metastases, the binary assessment of rWIR approached statistical significance (HR: 2.3; 95% CI: 1.0-5.2), whereas its continuous evaluation demonstrated a significant association between higher rWIR and improved EFS (HR: 0.7; 95% CI: 0.5-0.9), underlining the effect of response to chemotherapy. The 2- and 5-year EFS for patients with a rWIR ≥ 2.3 were 85% and 75% versus 55% and 50% for patients with a rWIR < 2.3., Conclusion: The predicted poor chemo response with MRI (rWIR < 2.3) is associated with shorter EFS even when adjusted for known clinical covariates and shows similar results to histological response evaluation. rWIR is a potential tool for future response-based individualized healthcare in osteosarcoma patients before surgical resection.

Purpose: The primary objective of this randomized study was to determine whether a continuous dosing schedule (without the asparaginase-free interval) would result in less hypersensitivity reactions to PEGasparaginase (PEGasp) compared with the standard noncontinuous dosing schedule., Methods: Eight hundred eighteen patients (age 1-18 years) with ALL were enrolled in the Dutch Childhood Oncology Group-ALL11 protocol and received PEGasp. Three hundred twelve patients stratified in the medium-risk arm were randomly assigned to receive 14 individualized PEGasp doses once every two weeks in either a noncontinuous or continuous schedule after the first three doses in induction (EudraCT: 2012-000067-25). Hypersensitivity reactions were defined as allergies, allergic-like reactions, and silent inactivation. Secondary end points were other asparaginase-related toxicities, asparaginase activity and antibody levels, and outcome., Results: During induction, 27 of 818 patients (3.3%) experienced hypersensitivity reactions. After random assignment, 4 of 155 (2.6%) in the continuous treatment arm versus 17 of 157 (10.8%) patients in the noncontinuous treatment arm had hypersensitivity reactions ( P < .01), of which two (1.3%) versus 13 (8.3%) were inactivating reactions ( P < .01). The occurrence of inactivating hypersensitivity reactions was seven times lower in the continuous arm (odds ratio, 0.15 [0.032-0.653]). In addition, antibody levels were significantly lower in the continuous arm ( P < .01). With exception of a lower incidence of increased amylase in the continuous arm, there were no significant differences in total number of asparaginase-associated toxicities between arms. However, the timing of the toxicities was associated with the timing of the asparaginase administrations. No difference in 5-year cumulative incidence of relapse, death, or disease-free survival was found between both treatment arms., Conclusion: A continuous dosing schedule of PEGasp is an effective approach to prevent antibody formation and inactivating hypersensitivity reactions. The continuous PEGasp schedule did not increase toxicity and did not affect the efficacy of the therapy.

Context: During treatment, children with acute lymphoblastic leukemia (ALL) receive high doses dexamethasone, which induce acute side effects., Objective: To determine the influence of a 5-day dexamethasone course on changes in leptin, fat mass, BMI, hunger, sleep, and fatigue and to explore associations between these changes., Methods: Pediatric ALL patients were included during maintenance treatment. Data were collected before (T1) and after (T2) a 5-day dexamethasone course (6 mg/m2/day). At both time points, BMI, fat mass (bioelectrical impedance analysis), and leptin were assessed, as well as parent-reported questionnaires regarding hunger, fatigue, and sleep problems. Changes between T1 and T2 were assessed using paired tests. Correlation coefficients were calculated to assess associations between these changes (Delta scores: T2-T1). Univariable regression models were estimated to study associations between covariates and elevated leptin., Results: We included 105 children, with median age 5.4 years (range, 3.0-18.8). Leptin and fat mass, as well as hunger scores, fatigue, and sleep deteriorated after 5 days of dexamethasone (P < .001), in contrast to BMI (P = .12). No correlations between delta leptin and delta fat mass, BMI, hunger, fatigue, or sleep were found. Elevated leptin on T1 was associated with older age (odds ratio [OR] 1.51; 95% CI, 1.28-1.77), higher fat mass (OR 1.19; 95% CI, 1.07-1.33), and earlier maintenance week (OR 0.96; 95% CI, 0.92-0.99)., Conclusion: Five days of high-dose dexamethasone treatment led to direct and significant changes in leptin, hunger scores, and fat mass. Since children with ALL are at increased risk for metabolic adverse events, understanding underlying mechanisms is important, and a dexamethasone-induced state of acute leptin resistance might play a role., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Smell and taste changes are bothersome treatment symptoms interfering with food intake. It remains unclear how and when children with cancer experience such changes during chemotherapy, and if the symptoms resolve after treatment. In this longitudinal study, we measured smell and taste function of 94 childhood cancer patients treated for hematological, solid, or brain malignancies. Smell and taste function were assessed using commercial Sniffin' Sticks and Taste Strips, respectively. For both tests, normative values were used to identify the presence of smell and taste abnormalities. Self-reported chemosensory and appetite changes were assessed using a questionnaire. 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). We found that smell and taste scores did not change during active treatment (T0-2). However, approximately 20% of the patients suffered from decreased taste function according to normative values, particularly children with lymphoma or solid tumors. Changes in smell were predominantly characterized as increased rather than decreased. Self-reported changes were much more common than objectively measured, with smell changes ranging from 26 to 53% and taste changes up to 80% during treatment. After active treatment, odor threshold scores decreased in children with ALL during maintenance phase, whereas total taste scores increased in all children at T3. In summary, objectively measured smell and taste function remained stable during active treatment, while at the individual level a fairly large number of children suffered from chemosensory distortions which comprised either increased or decreased sensitivity. Individual dietary advice and coping strategies are warranted to prevent detrimental effects on food intake in children with cancer., Competing Interests: Declaration of competing interest The work of Mirjam van den Brink and Remco C. Havermans is supported by the Dutch Province of Limburg. The funding organization had no role in the design and conduct of the study; collection, management, analysis and interpretation of the data; preparation, review or approval of the manuscript or decision to submit the manuscript for publication. The remaining authors have no financial disclosures or conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: To assess the presence of upper extremity pain after stroke over time and the course of its intensity in patients with persistent pain., Materials and Methods: Patients with stroke completed a question on the presence of upper extremity pain (yes/no) and rated its intensity with a visual analogue scale (0-10) at 3, 18, and 30 months after starting multidisciplinary rehabilitation. The presence of upper extremity pain and its intensity over time were analysed with Generalized Estimating Equations models and Linear Mixed Models, respectively., Results: 678 patients were included. The proportions of patients reporting upper extremity pain were 41.8, 36.0, and 32.7% at 3, 18, and 30 months, respectively, with the decline in proportions reaching statistical significance (odds ratio 0.82, 95% confidence interval 0.74-0.92, p  < 0.001). At all time points, in those reporting pain the median intensity was 5.0 (interquartile ranges (IQR) 4.0-7.0 at 3 and 3.0-6.0 at 18 and 30 months). In the 73 patients with persistent pain, there was no significant change in intensity over time., Conclusions: The proportion of patients reporting upper extremity pain after stroke was considerable, despite a significant decrease in 2.5 years. In patients reporting persistent pain, the intensity did not change over time.IMPLICATIONS FOR REHABILITATIONAbout one-third of patients with stroke reported upper extremity pain at 30 months after starting rehabilitation.In patients with stroke who reported persistent upper extremity pain, there was no significant change in pain intensity over time.There is room for improvement of diagnosis and treatment of upper extremity pain in patients with stroke.