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Non-surgical therapy has proved to be effective in chronic diffuse sclerosing osteomyelitis (DSO) of the mandible in children. Therefore we aimed to investigate the effect of non-surgical therapy in adult DSO patients. We included consecutive patients with DSO who received non-surgical therapy in our center. They all received occlusal splint therapy, counselling about the disease, and/or physiotherapy by a specialised team. The use of analgesics, preferably nonsteroidal anti-inflammatory drugs, was advised for symptomatic control during periods of exacerbation. Sixteen patients (11/5 female/male) aged 39.9 ± 15.0 years with DSO of the mandible were included. The mean duration of symptoms was 39.7 ± 26.3 months before referral to our center. Patients were treated with a broad range of treatments before referral. All patients underwent non-surgical treatment. In 12 patients this led to remission. Four patients still had complaints after 12 months of non-surgical therapy and started with intravenous bisphosphonate therapy. In our center, DSO of the mandible was successfully treated with non-surgical therapy, despite a long duration before referral and extensive pre-treatment. Considering this high success rate, we recommend this non-surgical approach as the first treatment option for DSO of the mandible. In case of persistence, alternative treatments such as bisphosphonates should be explored.

Background and purpose - The Taperloc Complete hip is the successor of the Taperloc hip, aiming to increase range of motion and optimizing femoral fit with intermediate stem sizes. We evaluated whether these design changes affect fixation, and this RSA study compares 2-year migration. Patients and methods - In this prospective, multi-arm study, 100 patients were randomized to cementless total hip arthroplasty (THA) with Taperloc Complete full profile (TCFP), Taperloc Complete reduced distal (TCRD), Taperloc full profile (TFP), or Taperloc reduced distal (TRD). Migration was measured with model-based RSA postoperatively, and after 3, 12, and 24 months. Results - Results based on mixed-model analysis on 2-year postoperative RSA data from 74 patients showed similar subsidence (mm) in the first 3 months (mean [95% CI] TCFP 0.44 [0.20-0.69], TCRD 0.91 [0.40-1.42], TFP 0.71 [0.22-1.19], TRD 1.25 [0.58-1.91]) and stabilization afterwards. The TCFP showed statistically significantly less retroversion (°) at 2-year postoperatively compared with TFP and TCRD (mean [95% CI] TCFP: -0.13 [-0.64 to 0.38], TCRD: 0.84 [0.35-1.33], TFP: 0.56 [0.12-1.00], TRD: 0.37 [-0.35 to 1.09]). Interpretation - As expected in successful cementless THA, RSA shows stabilization after initial subsidence. Based on these results the Taperloc Complete stem is expected to have similar long-term fixation to the Taperloc stems. The reduced distal groups have larger, but statistically non-significant, initial migration compared with the TCFP group, which could be due to implantation in Dorr B, C femur types. It may be important to consider the femur shape for choosing a full profile or reduced distal stem to minimize migration.

There is a lack of understanding whether plasma levels of anticancer drugs (such as pazopanib) correlate with intra-tumoral levels and whether the plasma compartment is the best surrogate for pharmacokinetic and pharmacodynamic evaluation. Therefore, we aimed to quantify pazopanib concentrations in tumor tissue, to assess the correlation between tumor concentrations and plasma concentrations and between tumor concentrations and efficacy. In this clinical trial, non-metastatic STS patients were treated with neo-adjuvant concurrent radiotherapy and pazopanib. Plasma samples and tumor biopsies were collected, and pazopanib concentrations were measured using liquid chromatography-tandem mass spectrometry. Twenty-four evaluable patients were included. The median pazopanib tumor concentration was 19.2 µg/g (range 0.149–200 µg/g). A modest correlation was found between tumor concentrations and plasma levels of pazopanib (ρ = 0.41, p = 0.049). No correlation was found between tumor concentrations and percentage of viable tumor cells (p &gt, 0.05), however, a trend towards less viable tumor cells in patients with high pazopanib concentrations in tumor tissue was observed in a categorical analysis. Possible explanations for the lack of correlation might be heterogeneity of the tumors and timing of the biopsy procedure.

Purpose: To evaluate the ipsilateral breast tumor recurrence (IBTR) after 2 accelerated partial breast irradiation (APBI) techniques (intraoperative electron radiation therapy [IOERT] and external beam APBI [EB-APBI]) in patients with early-stage breast cancer.Methods and Materials: Between 2011 and 2016, women >= 60 years of age with breast carcinoma or Ductal Carcinoma In Situ (DCIS) of

BACKGROUND Uncontrolled seizures on antiepileptic drug (AED) monotherapy are common in glioma patients and about a third of patients need an add-on AED. The aim of this study was to determine whether levetiracetam combined with valproic acid (LEV+VPA), a commonly prescribed duotherapy, was more effective than other duotherapy combinations, which included either LEV or VPA, in glioma patients. METHODS In this multicenter observational cohort study, data of patients with a diffuse grade 2-4 glioma and having uncontrolled seizures on their first-line monotherapy LEV or VPA, was retrospectively analyzed. Primary outcome was treatment failure (i.e. replacement by or addition of a new AED, or withdrawal of an AED) for any reason. Secondary outcomes included: 1) treatment failure due to uncontrolled seizures; and 2) treatment failure due to adverse effects. Time to treatment failure was estimated with multivariable Cox proportional hazard models, from moment of AED duotherapy treatment initiation. The maximum duration of follow-up was 36 months. RESULTS A total of 355 patients received AED duotherapy after they showed treatment failure due to uncontrolled seizures on monotherapy. LEV+VPA was prescribed in 66% (236/355) and other AED duotherapy combinations including LEV or VPA in 34% (119/355) of patients. Patients using other duotherapy versus LEV+VPA had higher risk of treatment failure for any reason (cause-specific hazard ratio [csHR]=1.50 [95%CI=1.07-2.12], p=0.020), due to uncontrolled seizures (csHR=1.73 [95%CI=1.10-2.73], p=0.018), but not due to adverse effects (csHR=0.88 [95%CI=0.47-1.67]), p=0.703). CONCLUSIONS This observational cohort study showed that LEV+VPA has better efficacy than other AED combinations with either LEV or VPA, but toxicity was similar in the two groups.

Context Craniopharyngioma is a sellar tumor associated with high rates of pituitary deficiencies (~98%) and hypothalamic obesity (~50%). Objective To determine the efficacy regarding long-term weight loss after bariatric surgery in obese craniopharyngioma patients with hypothalamic dysfunction. Design Retrospective case control study. Setting Multicenter international study. Patients and participants Obese craniopharyngioma patients (N = 16; of which 12 women) with a history of bariatric surgery [12 Roux-en-Y gastric bypass, 4 sleeve gastrectomy; median age of 21 years (range 15-52), median follow-up 5.2 years (range 2.0-11.3)] and age/sex/surgery/BMI-matched obese controls (N = 155). Main outcome measures Weight loss and obesity-related comorbidities up to 5 years after bariatric surgery were compared and changes in hormonal replacement therapy evaluated. Results Mean weight loss at 5-year follow-up was 22.0% (95% CI 16.1, 27.8) in patients versus 29.5% (28.0, 30.9) in controls (P = 0.02), which was less after Roux-en-Y gastric bypass (22.7% [16.9, 28.5] vs. 32.0% [30.4, 33.6]; P = 0.003) but at a similar level after sleeve gastrectomy (21.7% [–1.8, 45.2] vs. 21.8% [18.2, 25.5]; P = 0.96). No major changes in endocrine replacement therapy were observed after surgery. One patient died (unknown cause). One patient had long-term absorptive problems. Conclusions Obese patients with craniopharyngioma had a substantial mean weight loss of 22% at 5-year follow-up after bariatric surgery, independent of type of bariatric surgery procedure. Weight loss was lower than in obese controls after Roux-en-Y gastric bypass. Bariatric surgery appears effective and relatively safe in the treatment of obese craniopharyngioma patients.

BACKGROUND Some children with central nervous system (CNS) and solid tumors are at risk to develop ototoxicity during treatment. Up to now, several risk factors have been identified that may contribute to ototoxicity, such as platinum derivates, cranial irradiation, and brain surgery. Comedication, like antibiotics and diuretics, is known to enhance ototoxicity, but their independent influence has not been investigated in childhood cancer patients. Recommendations for hearing loss screening are missing or vary highly across treatment protocols. Additionally, adherence to existing screening guidelines is not always optimal. Currently, knowledge is lacking on the prevalence of ototoxicity. OBJECTIVE The aim of the Study on Prevalence and Determinants of Ototoxicity During Treatment of Childhood Cancer (SOUND) is to determine the feasibility of audiological testing and to determine the prevalence and determinants of ototoxicity during treatment for childhood cancer in a national cohort of patients with solid and CNS tumors. METHODS The SOUND study is a prospective cohort study in the national childhood cancer center in the Netherlands. The study aims to include all children aged 0 to 19 years with a newly diagnosed CNS or solid tumor. Part of these patients will get audiological examination as part of their standard of care (stratum 1). Patients in which audiological examination is not the standard of care will be invited for inclusion in stratum 2. Age-dependent audiological assessments will be pursued before the start of treatment and within 3 months after the end of treatment. Apart from hearing loss, we will investigate the feasibility to screen patients for tinnitus and vertigo prevalence after cancer treatment. This study will also determine the independent contribution of antibiotics and diuretics on ototoxicity. RESULTS This study was approved by the Medical Research Ethics Committee Utrecht (Identifier 20-417/M). Currently, we are in the process of recruitment for this study. CONCLUSIONS The SOUND study will raise awareness about the presence of ototoxicity during the treatment of children with CNS or solid tumors. It will give insight into the prevalence and independent clinical and cotreatment-related determinants of ototoxicity. This is important for the identification of future high-risk patients. Thereby, the study will provide a basis for the selection of patients who will benefit from innovative otoprotective intervention trials during childhood cancer treatment that are currently being prepared. CLINICALTRIAL Netherlands Trial Register NL8881; https://www.trialregister.nl/trial/8881 INTERNATIONAL REGISTERED REPORT DERR1-10.2196/34297

Purpose: Survival of children with rhabdomyosarcoma that suffer from recurrent or progressive disease is poor. Identifying these patients upfront remains challenging, indicating a need for improvement of risk stratification. Detection of tumor-derived mRNA in bone marrow (BM) and peripheral blood (PB) using reverse-transcriptase qPCR (RT-qPCR) is a more sensitive method to detect disseminated disease. We identified a panel of genes to optimize risk stratification by RT-qPCR. Experimental Design: Candidate genes were selected using gene expression data from rhabdomyosarcoma and healthy hematologic tissues, and a multiplexed RT-qPCR was developed. Significance of molecular disease was determined in a cohort of 99 Dutch patients with rhabdomyosarcoma (72 localized and 27 metastasized) treated according to the European pediatric Soft tissue sarcoma Study Group (EpSSG) RMS2005 protocol. Results: We identified the following 11 rhabdomyosarcoma markers: ZIC1, ACTC1, MEGF10, PDLIM3, SNAI2, CDH11, TMEM47, MYOD1, MYOG, and PAX3/7-FOXO1. RT-qPCR was performed for this 11-marker panel on BM and PB samples from the patient cohort. Five-year event-free survival (EFS) was 35.5% [95% confidence interval (CI), 17.5%–53.5%] for the 33/99 RNA-positive patients, versus 88.0% (95% CI, 78.9%–97.2%) for the 66/99 RNA-negative patients (P < 0.0001). Five-year overall survival (OS) was 54.8% (95% CI, 36.2%–73.4%) and 93.7% (95% CI, 86.6%–100.0%), respectively (P < 0.0001). RNA panel positivity was negatively associated with EFS (Hazard Ratio = 9.52; 95% CI, 3.23–28.02), whereas the RMS2005 risk group stratification was not, in the multivariate Cox regression model. Conclusions: This study shows a strong association between PCR-based detection of disseminated disease at diagnosis with clinical outcome in pediatric patients with rhabdomyosarcoma, also compared with conventional risk stratification. This warrants further validation in prospective trials as additional technique for risk stratification.

Background: Computed tomography (CT) is often used to investigate muscle and fat mass in adult patients with cancer. However, this method has rarely been used in the pediatric cancer population. The present retrospective study aimed to investigate changes in body composition using CT during treatment in children with neuroblastoma.Procedure: CT images of 29 patients with high-risk neuroblastoma were retrospectively analyzed at diagnosis and longitudinally during treatment. The cross-sectional area of skeletal muscle, intermuscular adipose tissue (IMAT), visceral adipose tissue (VAT), and subcutaneous adipose tissue (SAT) and skeletal muscle density at the level of the third lumbar vertebra were examined. To correct for height, cross-sectional areas were divided by height in meters squared. A linear mixed model was estimated to investigate changes in body composition over time.Results: A small increase in skeletal muscle (p =.029), skeletal muscle density (p =.002), and IMAT (p Conclusions: CT scans obtained during standard care provide insight into the direction and timing of changes in skeletal muscle and different types of adipose tissue in childhood cancer patients. Future research is needed regarding the consequences of the rapid increase of VAT and SAT early during treatment.

Willem van Zwet made deep and influential contributions to probability and statistics, which we review in this paper. Bickel and Götze collaborated with him on his major contributions to higher order asymptotics of nonlinear statistics and on resampling and the bootstrap. We relate this work to his remarkable development of the properties of the Hoeffding expansion for symmetric statistics as well as Fourier analytic tools. Fiocco and De Gunst were his students. We describe how in their theses and subsequent papers with him they developed statistical inference in two subtle stochastic models, the contact process and cell population development under a plausible regime. We also touch on his solutions of intriguing problems not related directly to his main interests.

Purpose A prior phase I study showed that the neo-adjuvant combination of pazopanib and radiotherapy was well tolerated, and induced promising pathological responses in soft-tissue sarcoma patients. Results of the subsequent prospective, multicenter phase II, PASART-2 trial are presented here, further investigating the efficacy and safety of this combination. Patients and methods Patients with high-risk, localized soft-tissue sarcoma received neo-adjuvant radiotherapy, 50 Gy in 25 fractions (PASART-2A) or with a subsequent dose de-escalation to 36 Gy in 18 fractions (PASART-2B). This was combined with 800 mg once daily pazopanib, which started one week before radiotherapy and finished simultaneously. After an interval of 4-8 weeks, surgical resection was performed. The primary endpoint was the rate of pathological complete responses (pCR), defined as ≤5% viable cells. Results 25 patients were registered in the study, 21 in PASART-2A and 4 in PASART-2B. After central pathology review, the combination treatment led to a pCR in 5 patients (20%). 17 patients (68%) experienced grade 3+ toxicities during neo-adjuvant treatment, of which the most common were alanine aminotransferase (ALT) elevation, aspartate aminotransferase (AST) elevation, and hypertension, all asymptomatic. Grade 3+ acute post-operative toxicities occurred in 5 patients (20%), of which the most common was wound infection. All patients completed the full radiotherapy regimen and underwent surgery. Pazopanib was discontinued before completion in 9 patients (36%), due to elevated ALT and/or AST, and shortly interrupted in 2 patients (8%), due to hypertension. Conclusion Apart from asymptomatic hepatotoxicity, the study regimen was well tolerated. Although the pre-specified efficacy endpoint (30% pCR) was not met, a more than doubling of historical pCR rates after neo-adjuvant radiotherapy alone was observed, which warrants further investigation.

BACKGROUND During treatment for pediatric acute lymphoblastic leukemia (ALL), children receive high doses of dexamethasone for its apoptotic effect on leukemia cells; however, muscle atrophy is a well-known serious side effect. Muscle atrophy (loss of muscle mass) accompanied by a decreased muscle strength may lead to a generalized impaired skeletal muscle state called sarcopenia. Loss of muscle mass is also an indicator of physical frailty, which is defined as a state of increased vulnerability that is characterized by co-occurrence of low muscle mass, muscle weakness, fatigue, slow walking speed, and low physical activity. Both sarcopenia and physical frailty are related to an increased risk of infections, hospitalizations, and decreased survival in children with chronic diseases. OBJECTIVE This study aims to (1) estimate the occurrence of sarcopenia and physical frailty in children during ALL maintenance therapy, (2) evaluate the effect of administering dexamethasone, and (3) explore determinants associated with these outcomes. METHODS This prospective study is being pursued within the framework of the DexaDays-2 study: a randomized controlled trial on neurobehavioral side effects in pediatric patients with ALL. A total of 105 children (3-18 years) undergoing ALL maintenance treatment at the Princess Máxima Center for Pediatric Oncology are included in this study. Sarcopenia/frailty assessments are performed before and just after a 5-day dexamethasone course. A subset of 50 children participating in the DexaDays-2 trial because of severe dexamethasone-induced neurobehavioral problems were assessed at 3 additional timepoints. The sarcopenia/frailty assessment consists of bioimpedance analysis (skeletal muscle mass [SMM]), handheld dynamometry (handgrip strength), Pediatric Quality of Life Inventory Multidimensional Fatigue Scale (fatigue), Timed Up and Go Test (TUG; walking speed), and physical activity questionnaires. To evaluate potential change in sarcopenia/frailty components after a 5-day dexamethasone administration, a paired Student t test or Mann-Whitney U test will be used. Because of the presence of repeated measurements, generalized linear mixed models will be used to estimate the effect of dexamethasone on sarcopenia and frailty outcomes. Multivariable regression models will be estimated to investigate associations between the assessment scores and patient and treatment-related factors. RESULTS Patient accrual started in 2018 and was finalized in spring 2021. From autumn 2021 onward final data analyses will be performed. CONCLUSIONS This first study combining parameters of sarcopenia and physical frailty is of importance because these conditions can seriously complicate continuation of ALL therapy, independence in physical functioning, reaching motor milestones, and participating in daily life activities. The results will provide knowledge about these complications, the association between dexamethasone treatment and muscle loss and other components of frailty, and therefore insights into the severity of this side effect. By exploring potential determinants that may be associated with sarcopenia and physical frailty, we may be able to identify children at risk at an earlier stage and provide timely interventions. INTERNATIONAL REGISTERED REPORT DERR1-10.2196/33517

BACKGROUND Optimal treatment with antiepileptic drugs (AEDs) is an important part of care for brain tumor patients with epileptic seizures. Lamotrigine and lacosamide are both examples of frequently used non-enzyme inducing AEDs with limited to no drug-drug interactions, reducing the risk of unfavorable side effects. This study aimed to compare the effectiveness of lamotrigine versus lacosamide. MATERIAL AND METHODS In this multicenter study we retrospectively analyzed data of patients with diffuse grade 2–4 glioma with epileptic seizures. All patients received either lamotrigine or lacosamide during the course of their disease after treatment failure of first-line monotherapy with levetiracetam or valproic acid. Primary outcome was the cumulative incidence of treatment failure, from initiation of lamotrigine or lacosamide, with death as competing event, for which a competing risk model was used. Secondary outcomes were uncontrolled seizures after AED initiation and level of toxicity. RESULTS We included a total of 139 patients of whom 61 (44%) used lamotrigine and 78 (56%) used lacosamide. At 12 months, there was no statistically significant difference in the cumulative incidence of treatment failure for any reason between lamotrigine and lacosamide: 38% (95%CI: 26–51%) versus 30% (95%CI: 20–41%), respectively. The adjusted hazard ratio for treatment failure of lacosamide compared to lamotrigine was 0.84 (95%CI: 0.46–1.56). The cumulative incidences of treatment failure due to uncontrolled seizures (18% versus 11%) and due to adverse events (17% versus 19%) did not differ significantly between lamotrigine and lacosamide. CONCLUSION Lamotrigine and lacosamide show similar effectiveness in diffuse glioma patients with epilepsy.

Background: In 2002, the European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group reported well-established values for conducting phase II trials for soft-tissue sarcomas. An update is provided for leiomyosarcoma (LMS). Materials and methods: Clinical trials with advanced or metastatic LMS were identified via literature review in PubMed (published 2003-2018, >10 adult LMS patients). End-points were 3-and 6-month progression-free survival rates (PFSR-3m and PFSR-6m). When estimates could not be derived from publications, data requests were sent out. Treatments were classified as recommended (R-T) or non-recommended (NR-T) according to the ESMO 2018 guidelines. A random effects meta-analysis was used to pool trial-specific estimates for first-line (1L) or pre-treated (2L+) patients separately. The ESMO Magnitude of Clinical Benefit Scale was used to guide the treatment effect to target in future trials. Results: From 47 studies identified, we obtained information on 7 1L and 16 2L+ trials for 1500 LMS patients. Overall, in 1L, PFSR-3m and PFSR-6m were 74% (95% confidence interval [CI] 64-82%) and 58% (95% CI 50-66%), respectively. For 2L+, PFSR-3m was 48% (95% CI 41-54%), and PFSR-6m was 28% (95% CI 22-34%). No difference was observed between R-T and NR-T for first or later lines. Under the alternative that the true benefit amounts to a hazard ratio of 0.65, a PFSR-6m >70% can be considered to suggest drug activity in 1L. For 2L+, a PFSR-3m >62% or PFSR-6m >44% would suggest drug activity. Specific results are also provided for uterine LMS. Conclusions: This work provides a new benchmark for designing phase II studies for advanced or metastatic LMS. (c) 2021 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

High-risk neuroblastoma accounts for 4% of newly diagnosed pediatric malignancies, but for 9-10% of pediatric cancer mortality. To reduce the number of (late) recurrences and subsequently improve survival, anti-GD2 monoclonal antibody based immunotherapy has been added to the maintenance phase of treatment. The first randomized study (ANBL0032) was ground breaking, showing a 20% improved event free survival. Subsequently immunotherapy was included in all international high-risk treatment regimens. Randomization will never be repeated. In this article we present additional data from our retrospective cohort to corroborate the ANBL0032 study. Our cohort contains 84 Dutch high-risk neuroblastoma patients. They were treated with GPOH or POG induction, followed by immunotherapy according to original ANBL0032 protocol (immunotherapy group) or single-agent isotretinoin (historical control group). In the complete cohort, 5 year OS was 64 +/- 7% and 49 +/- 8% for the immunotherapy group and the control group, respectively (p = 0.16). Five year EFS was 57 +/- 7% and 41 +/- 8%, respectively (p = 0.16). In the subgroup of patients +/- 18 months, 5-yr OS was 63 +/- 8% and 39 +/- 9, respectively (p = 0.04) and EFS 54 +/- 8% and 29 +/- 8%, respectively (p = 0.05). Our five year data suggest a role for the immunotherapy in preventing late events, especially in patients >= 18 months old.Background: Anti-GD2 based immunotherapy has improved overall (OS) and event free survival (EFS) for high-risk neuroblastoma (HR-NBL) patients. Here, we evaluate the longterm efficacy of anti-GD2 immunotherapy in combination with isotretinoin, GM-CSF, and IL-2. Methods: Dutch HR-NBL patients treated with immunotherapy according to the COG-ANBL0032 protocol (n = 47) were included and compared to historical controls (n = 37) treated with singleagent isotretinoin maintenance therapy. Survival time was calculated from start of the maintenance therapy.Results: The study and control group were similar concerning baseline characteristics. In the complete cohort, 5 year OS was 64 +/- 7% and 49 +/- 8% for the immunotherapy group and the control group, respectively (p = 0.16). Five year EFS was 57 +/- 7% and 41 +/- 8%, respectively (p = 0.16). In the subgroup of patients >= 18 months, 5-yr OS was 63 +/- 8% and 39 +/- 9, respectively (p = 0.04) and EFS 54 +/- 8% and 29 +/- 8%, respectively (p = 0.05). Landmark analysis for EFS with landmark point at 6 months after start of maintenance suggests a larger effect on the prevention of late than early events.Conclusions: This study is the first to confirm the results of the COG-ANBL0032 study in a cohort treated with a different induction regimen. Anti-GD2 immunotherapy prevents late events, most significantly in patients older than 18 months of age at diagnosis.

BACKGROUND About 10% of glioma patients with epilepsy need antiseizure medication (ASM) tripletherapy due to refractory epilepsy. This study aimed to determine whether levetiracetam combined with valproic acid and clobazam (LEV+VPA+CLB), a commonly prescribed tripletherapy, has favorable effectiveness compared to other tripletherapy combinations in glioma patients. METHODS In this multicenter retrospective observational cohort study, the primary outcome was to estimate the cumulative incidence of treatment failure for any reason, from initiation of ASM tripletherapy. Secondary outcomes included cumulative incidences of: 1) treatment failure due to uncontrolled seizures; 2) treatment failure due to adverse effects; and 3) recurrent seizure. Maximum duration of follow-up was 36 months. RESULTS Out of n=1435 patients in the original cohort, n=90 patients received ASM tripletherapy after second-line ASM treatment failure due to uncontrolled seizures. LEV+VPA+CLB was prescribed to 48% (43/90) and other ASM tripletherapy to 52% (47/90) patients. The cumulative incidence of treatment failure for any reason of LEV+VPA+CLB did not significantly differ from other tripletherapy (12 months: 47% [95%CI, 31-62%] versus 42% [95%CI, 27-56%], p=0.892). No statistical significant differences for treatment failure due to uncontrolled seizures (12 months: 12% [95%CI, 4-25%] versus 18% [95%CI, 8-30%], p=0.445), due to adverse effects (12 months: 22% [95%CI, 11-36%] versus 15% [95%CI, 7-27%], p=0.446), or recurrent seizure (1 month: 65% [95%CI, 48-78%] versus 63% [95%CI, 47-75%], p=0.911) were found. CONCLUSIONS LEV+VPA+CLB showed equivalent effectiveness compared to other ASM tripletherapy combinations in glioma patients.

About 30% of glioma patients need an add-on antiepileptic drug (AED) due to uncontrolled seizures on AED monotherapy. This study aimed to determine whether levetiracetam combined with valproic acid (LEV+VPA), a commonly prescribed duotherapy, is more effective than other duotherapy combinations including either LEV or VPA in glioma patients.In this multicenter retrospective observational cohort study, treatment failure (i.e. replacement by, addition of, or withdrawal of an AED) for any reason was the primary outcome. Secondary outcomes included: 1) treatment failure due to uncontrolled seizures; and 2) treatment failure due to adverse effects. Time to treatment failure was estimated from moment of AED duotherapy initiation. Multivariable cause-specific cox proportional hazard models were estimated to study the association between risk factors and treatment failure. The maximum duration of follow-up was 36 months.A total of 1435 patients were treated with first-line monotherapy LEV or VPA, of which 355 patients received AED duotherapy after they had treatment failure due to uncontrolled seizures on monotherapy. LEV+VPA was prescribed in 66% (236/355) and other AED duotherapy combinations including LEV or VPA in 34% (119/355) of patients. Patients using other duotherapy versus LEV+VPA had higher risk of treatment failure for any reason (cause-specific adjusted hazard ratio [aHR]=1.50 [95%CI=1.07-2.12], p=0.020), due to uncontrolled seizures (cause-specific aHR=1.73 [95%CI=1.10-2.73], p=0.018), but not due to adverse effects (cause-specific aHR=0.88 [95%CI=0.47-1.67]), p=0.703).This observational cohort study suggests that LEV+VPA has better efficacy than other AED combinations. Similar toxicities were experienced in the two groups.This study provides Class III evidence that for glioma patients with uncontrolled seizures on AED monotherapy, LEV+VPA has better efficacy than other AED combinations.

Background Histopathological classification of Wilms tumors determines treatment regimen. Machine learning has been shown to contribute to histopathological classification in various malignancies but requires large numbers of manually annotated images and thus specific pathological knowledge. This study aimed to assess whether trained, inexperienced observers could contribute to reliable annotation of Wilms tumor components for classification performed by machine learning. Methods Four inexperienced observers (medical students) were trained in histopathology of normal kidneys and Wilms tumors by an experienced observer (pediatric pathologist). Twenty randomly selected scanned Wilms tumor-slides (from n = 1472 slides) were annotated, and annotations were independently classified by both the inexperienced observers and two experienced pediatric pathologists. Agreement between the six observers and for each tissue element was measured using kappa statistics (κ). Results Pairwise interobserver agreement between all inexperienced and experienced observers was high (range: 0.845–0.950). The interobserver variability for the different histological elements, including all vital tumor components and therapy-related effects, showed high values for all κ-coefficients (> 0.827). Conclusions Inexperienced observers can be trained to recognize specific histopathological tumor and tissue elements with high interobserver agreement with experienced observers. Nevertheless, supervision by experienced pathologists remains necessary. Results of this study can be used to facilitate more rapid progress for supervised machine learning-based algorithm development in pediatric pathology and beyond.

Purpose Optimal treatment with antiepileptic drugs (AEDs) is an important part of care for brain tumor patients with epileptic seizures. Lamotrigine and lacosamide are both examples of frequently used non-enzyme inducing AEDs with limited to no drug-drug interactions, reducing the risk of unfavorable side effects. This study aimed to compare the effectiveness of lamotrigine versus lacosamide. Methods In this multicenter study we retrospectively analyzed data of patients with diffuse grade 2–4 glioma with epileptic seizures. All patients received either lamotrigine or lacosamide during the course of their disease after treatment failure of first-line monotherapy with levetiracetam or valproic acid. Primary outcome was the cumulative incidence of treatment failure, from initiation of lamotrigine or lacosamide, with death as competing event, for which a competing risk model was used. Secondary outcomes were uncontrolled seizures after AED initiation and level of toxicity. Results We included a total of 139 patients of whom 61 (44%) used lamotrigine and 78 (56%) used lacosamide. At 12 months, there was no statistically significant difference in the cumulative incidence of treatment failure for any reason between lamotrigine and lacosamide: 38% (95%CI 26–51%) versus 30% (95%CI 20–41%), respectively. The adjusted hazard ratio for treatment failure of lacosamide compared to lamotrigine was 0.84 (95%CI 0.46–1.56). The cumulative incidences of treatment failure due to uncontrolled seizures (18% versus 11%) and due to adverse events (17% versus 19%) did not differ significantly between lamotrigine and lacosamide. Conclusion Lamotrigine and lacosamide show similar effectiveness in diffuse glioma patients with epilepsy.

Background and AimsIn our current healthcare situation, burden on healthcare services is increasing, with higher costs and increased utilization. Structured population health management has been developed as an approach to balance quality with increasing costs. This approach identifies sub-populations with comparable health risks, to tailor interventions for those that will benefit the most. Worldwide, the use of routine healthcare data extracted from electronic health registries for risk stratification approaches is increasing. Different risk stratification tools are used on different levels of the healthcare continuum. In this systematic literature review, we aimed to explore which tools are used in primary healthcare settings and assess their performance.MethodsWe performed a systematic literature review of studies applying risk stratification tools with health outcomes in primary care populations. Studies in Organisation for Economic Co-operation and Development countries published in English-language journals were included. Search engines were utilized with keywords, for example, “primary care,” “risk stratification,” and “model.” Risk stratification tools were compared based on different measures: area under the curve (AUC) and C-statistics for dichotomous outcomes and R2 for continuous outcomes.ResultsThe search provided 4718 articles. Specific election criteria such as primary care populations, generic health utilization outcomes, and routinely collected data sources identified 61 articles, reporting on 31 different models. The three most frequently applied models were the Adjusted Clinical Groups (ACG, n = 23), the Charlson Comorbidity Index (CCI, n = 19), and the Hierarchical Condition Categories (HCC, n = 7). Most AUC and C-statistic values were above 0.7, with ACG showing slightly improved scores compared with the CCI and HCC (typically between 0.6 and 0.7).ConclusionBased on statistical performance, the validity of the ACG was the highest, followed by the CCI and the HCC. The ACG also appeared to be the most flexible, with the use of different international coding systems and measuring a wider variety of health outcomes.

Simple Summary Germ cell tumours are a heterogeneous group of neoplasms and are predominantly midline tumours occurring from birth to late adulthood. Suboptimal outcomes remain for several groups of patients, including adolescents, and patients with extragonadal tumours, high tumour markers at diagnosis or platinum-resistant disease. The aim of our systematic review was to explore survival rates internationally over the past two decades in order to better define future practice and treatment strategies and also to define specific subgroups with inferior outcomes. The results of our systematic review describe the heterogeneous nature of germ cell tumours in different anatomical locations, impacting on stage at presentation, treatment modalities used and survival data. Despite this heterogeneity, subpopulations can be defined which have an inferior survival and where future research and more individualised treatment would help to improve survival. Abstract Objective: This systematic review and meta-analysis was performed to explore overall survival (OS) and event free survival (EFS) rates internationally over the past two decades and to define specific subgroups with inferior outcomes which may demand different treatment strategies. Methods: The search focused on malignant extracranial germ cell tumours (GCTs) in the paediatric population. The initial database search identified 12,556 articles; 32 articles were finally included in this review, comprising a total of 5095 patients. Results: The studies were heterogeneous, varying from single institution reports to large prospective trials. Older studies, describing eras where non-platinum-based chemotherapy regimens were used, showed clearly worse outcomes. Survival for stage I–II gonadal disease is excellent. On the other hand, patients with an initial alpha-fetoprotein (AFP) > 10,000 ng/mL or kU/L, age > 11 years and stage IV disease confer a survival disadvantage. For testicular disease in particular, lymphovascular invasion and certain histopathological subtypes, such as embryonal carcinoma (EC) and mixed malignant GCTs, survival is poorer. Survival data for sacrococcygeal and mediastinal GCTs show a heterogeneous distribution across studies in this review, independent of year of publication. Patients > 12 years presenting with a mediastinal GCT pose a subpopulation which fares worse than GCTs in other locations or age groups. This is independent of AFP levels, stage of disease or treatment protocol, and these patients may demand a different treatment strategy. Conclusions: This review describes the heterogeneous nature of GCTs in different anatomical locations, impacting on stage at presentation, treatment modalities used and survival data. Despite this heterogeneity, in line with the current developmental biology-based classification system, subpopulations can be defined which have an inferior EFS and OS and where future research and more individualised treatment would help to improve survival.

Summary Childhood cancer survivors (CCS) are at increased risk to develop metabolic syndrome (MetS), diabetes, and cardiovascular disease. Common criteria underestimate adiposity and possibly underdiagnose MetS, particularly after abdominal radiotherapy. A systematic literature review and meta‐analysis on the diagnostic and predictive value of nine newer MetS related biomarkers (adiponectin, leptin, uric acid, hsCRP, TNF‐alpha, IL‐1, IL‐6, apolipoprotein B (apoB), and lipoprotein(a) [lp(a)]) in survivors and adult non‐cancer survivors was performed by searching PubMed and Embase. Evidence was summarized with GRADE after risk of bias evaluation (QUADAS‐2/QUIPS). Eligible studies on promising biomarkers were pooled. We identified 175 general population and five CCS studies. In the general population, valuable predictive biomarkers are uric acid, adiponectin, hsCRP and apoB (high level of evidence), and leptin (moderate level of evidence). Valuable diagnostic biomarkers are hsCRP, adiponectin, uric acid, and leptin (low, low, moderate, and high level of evidence, respectively). Meta‐analysis showed OR for hyperuricemia of 2.94 (age‐/sex‐adjusted), OR per unit uric acid increase of 1.086 (unadjusted), and AUC for hsCRP of 0.71 (unadjusted). Uric acid, adiponectin, hsCRP, leptin, and apoB can be alternative biomarkers in the screening setting for MetS in survivors, to enhance early identification of those at high risk of subsequent complications.

Context Fibrous dysplasia/McCune-Albright syndrome (FD/MAS) is a rare bone disorder commonly treated with bisphosphonates, but clinical and biochemical responses may be incomplete. Objective To evaluate the efficacy and tolerability of the receptor activator of nuclear factor-κB ligand inhibitor denosumab in the treatment of patients with FD/MAS refractory to bisphosphonate therapy. Design Case series. Setting Academic center of expertise for rare bone diseases. Patients Data were collected from 12 consecutive patients with FD/MAS with persistent pain and increased biochemical markers of bone turnover (BTMs) after long-term treatment with bisphosphonates (median, 8.8 years) and were treated with subcutaneous denosumab 60 mg at 3- or 6-month intervals with a follow-up for at least 12 months. Main outcome(s) Sustained reduction of BTMs and bone pain. Results A 60 mg dose of denosumab once every 3 months, but not once every 6 months, induced a sustained reduction of BTMs. After a median treatment period of 15.5 months (range, 12 to 19) serum alkaline phosphatase activity and propeptide of type 1 procollagen levels were respectively reduced from 212 ± 39.4 IU/L to 79 ± 6.0 IU/L (P = 0.004) and from 346.2 ± 111.1 ng/mL to 55.7 ± 16.6 ng/mL (P = 0.023) and normalized in 70% and 75% of patients, respectively. Although not quantitavely measured, 10 patients reported a reduction in bone pain of whom 6 reported complete elimination of pain. Treatment with denosumab was well tolerated. Conclusion Our results indicate that 60 mg of denosumab every 3 months is a promising, well-tolerated treatment of most patients with FD/MAS refractory to bisphosphonate therapy. These results together with those of previously published case reports provide the necessary background for the design of a larger, controlled study.

AIMS: For violinists, the shoulder rest is an ergonomic adaptation to reduce musculoskeletal load. In this study, we aimed to evaluate how the height of the shoulder rest affects the violin fixation force and electromyographic (EMG) activity of the superficial neck and shoulder muscles. METHODS: In professional violinists, four different shoulder rest heights during five playing conditions were evaluated. Outcome variables included the jaw-shoulder violin fixation force and bilateral surface EMG of the upper trapezius (mTP), sternocleidomastoid (mSCM), and left anterior part of the left deltoid muscle (mDTA). Playing comfort was subjectively rated on a visual analogic scale (VAS). Linear regression models were estimated to investigate the influence of the shoulder rest height on muscle activity and violin fixation force as well as the muscle activity of the five evaluated muscles on violin fixation force. RESULTS: 20 professional violinists (4 males, 16 females, mean age 29.4 yrs) participated in this study. The shoulder rest condition had a significant effect on playing comfort (p

Purpose: Targeted radiotherapy with 131iodine-meta-iodobenzylguanidine (131I-MIBG) is effective for neuroblastoma (NBL), although optimal scheduling during high-risk (HR) treatment is being investigated. We aimed to evaluate the feasibility of stem cell apheresis and study hematologic reconstitution after autologous stem cell transplantation (ASCT) in patients with HR-NBL treated with upfront 131I-MIBG-therapy. Experimental Design: In two prospective multicenter cohort studies, newly diagnosed patients with HR-NBL were treated with two courses of 131I-MIBG-therapy, followed by an HR-induction protocol. Hematopoietic stem and progenitor cell (e.g., CD34+ cell) harvest yield, required number of apheresis sessions, and time to neutrophil (>0.5 × 109/L) and platelet (>20 × 109/L) reconstitution after ASCT were analyzed and compared with “chemotherapy-only”–treated patients. Moreover, harvested CD34+ cells were functionally (viability and clonogenic capacity) and phenotypically (CD33, CD41, and CD62L) tested before cryopreservation (n = 44) and/or after thawing (n = 19). Results: Thirty-eight patients (47%) were treated with 131I-MIBG-therapy, 43 (53%) only with chemotherapy. Median cumulative 131I-MIBG dose/kg was 0.81 GBq (22.1 mCi). Median CD34+ cell harvest yield and apheresis days were comparable in both groups. Post ASCT, neutrophil recovery was similar (11 days vs. 10 days), whereas platelet recovery was delayed in 131I-MIBG- compared with chemotherapy-only–treated patients (29 days vs. 15 days, P = 0.037). Testing of harvested CD34+ cells revealed a reduced post-thaw viability in the 131I-MIBG-group. Moreover, the viable CD34+ population contained fewer cells expressing CD62L (L-selectin), a marker associated with rapid platelet recovery. Conclusions: Harvesting of CD34+ cells is feasible after 131I-MIBG. Platelet recovery after ASCT was delayed in 131I-MIBG-treated patients, possibly due to reinfusion of less viable and CD62L-expressing CD34+ cells, but without clinical complications. We provide evidence that peripheral stem cell apheresis is feasible after upfront 131I-MIBG-therapy in newly diagnosed patients with NBL. However, as the harvest of 131I-MIBG-treated patients contained lower viable CD34+ cell counts after thawing and platelet recovery after reinfusion was delayed, administration of 131I-MIBG after apheresis is preferred.

Background: Obesity is an increasing problem worldwide that can influence perioperative and postoperative outcomes. However, the relationship between obesity and treatment-related perioperative and short-term postoperative morbidity after colorectal resections is still subject to debate. Study: Patients were selected from the DCRA, a population-based audit including 83 hospitals performing colorectal cancer (CRC) surgery. Data regarding primary resections between 2009 and 2016 were eligible for analyses. Patients were subdivided into six categories: underweight, normal weight, overweight and obesity class I, II and III. Results: Of 71,084 patients, 17.7% with colon and 16.4% with rectal cancer were categorized as obese. Significant differences were found for the 30-day overall postoperative complication rate (p < 0.001), prolonged hospitalization (p < 0.001) and readmission rate (colon cancer p < 0.005; rectal cancer p < 0.002) in obese CRC patients. Multivariate analysis identified BMI ≥30 kg/m2 as independent predictor of a complicated postoperative course in CRC patients. Furthermore, obesity-related comorbidities were associated with higher postoperative morbidity, prolonged hospitalization and a higher readmission rate. No significant differences in performance were observed in postoperative outcomes of morbidly obese CRC patients between hospitals performing bariatric surgery and hospitals that did not. Conclusion: The real-life data analysed in this study reflect daily practice in the Netherlands and identify obesity as a significant risk factor in CRC patients. Obesity-related comorbidities were associated with higher postoperative morbidity, prolonged hospitalization and a higher readmission rate in obese CRC patients. No differences were observed between hospitals performing bariatric surgery and hospitals that did not.

PurposeCure rate models accounting for cured and uncured patients, provide additional insights into long and short term survival. We aim to better understand the prognostic value of histologic response and chemotherapy intensification on cure fraction and progression-free survival (PFS) for the uncured patients.MethodsA logistic model is assumed for the effect of histologic response and intensified chemotherapy on the cure status, while a Cox regression model is estimated only for the uncured patients on PFS. The mixture cure model is used to simultaneously study these two effects.ResultsHistologic response is a strong prognostic factor for the cure status (OR: 3.00 [1.75-5.17]), but it has no clear effect on PFS for the uncured patients (HR: 0.78 [0.53-1.16]). The cure fractions are 55% [46%-63%] and 29% [22%-35%] among patients with good histologic response (GR) and poor responders (PR) respectively. The intensified regimen was associated with higher cure fraction among PR (OR: 1.90 [0.93 – 3.89]), with no evidence of effect for GR (OR: 0.78 [0.38 – 1.59]).ConclusionsAccounting for cured patients is valuable in distinguishing the covariate effects on cure and PFS. Estimating cure chances based on these prognostic factors is relevant for counseling patients and can affect treatment decisions.

Purpose: Optimal treatment with antiepileptic drugs (AEDs) is an important part of care for brain tumor patients with epileptic seizures. Lamotrigine and lacosamide are both examples of frequently used non-enzyme inducing AEDs with limited to no drug-drug interactions, reducing the risk of unfavorable side effects. This study aimed to compare the effectiveness of lamotrigine versus lacosamide.Methods: In this multicenter study we retrospectively analyzed data of patients with diffuse grade 2-4 glioma with epileptic seizures. All patients received either lamotrigine or lacosamide during the course of their disease after treatment failure of first-line monotherapy with levetiracetam or valproic acid. Primary outcome was the cumulative incidence of treatment failure, from initiation of lamotrigine or lacosamide, with death as competing event, for which a competing risk model was used. Secondary outcomes were uncontrolled seizures after AED initiation and level of toxicity.Results: We included a total of 139 patients of whom 61 (44%) used lamotrigine and 78 (56%) used lacosamide. At 12 months, there was no statistically significant difference in the cumulative incidence of treatment failure for any reason between lamotrigine and lacosamide: 38% (95%CI: 26-51%) versus 30% (95%CI: 20-41%), respectively. The adjusted hazard ratio for treatment failure of lacosamide compared to lamotrigine was 0.84 (95%CI: 0.46-1.56). The cumulative incidences of treatment failure due to uncontrolled seizures (18% versus 11%) and due to adverse events (17% versus 19%) did not differ significantly between lamotrigine and lacosamide. Conclusion: Lamotrigine and lacosamide show similar effectiveness in diffuse glioma patients with epilepsy.

This population-based validation study compares the prediction of kidney failure from models that do and do not account for the competing risk of death in adults with severe chronic kidney disease., Key Points Question Does accounting for the competing risk of death make a difference when predicting kidney failure in adults with stage 4 chronic kidney disease? Findings In this external prognostic study with 14 619 people in the development cohort and 2295 in the validation cohort, models that did and did not account for the competing risk of death provided comparable 2-year predictions of kidney failure. Differences in model predictions emerged after 2 years and increased with longer prediction times, especially among participants aged 65 years or older and those with more comorbidity. Meaning These findings suggest that accounting for the competing risk of death when making predictions about kidney failure becomes increasingly important with longer follow-up time, older age, and the presence of more comorbidities., Importance Kidney failure risk prediction has implications for disease management, including advance care planning in adults with severe (ie, estimated glomerular filtration rate [eGFR] category 4, [G4]) chronic kidney disease (G4-CKD). Existing prediction tools do not account for the competing risk of death. Objective To compare predictions of kidney failure (defined as estimated glomerular filtration rate [eGFR]

PURPOSE Childhood brain tumor survivors (CBTS) are at risk for developing obesity, which negatively influences cardiometabolic health. The prevalence of obesity in CBTS may have been overestimated in previous cohorts because of inclusion of children with craniopharyngioma. On the contrary, the degree of weight gain may have been underestimated because of exclusion of CBTS who experienced weight gain, but were neither overweight nor obese. Weight gain may be an indicator of underlying hypothalamic-pituitary (HP) dysfunction. We aimed to study prevalence of and risk factors for significant weight gain, overweight, or obesity, and its association with HP dysfunction in a national cohort of noncraniopharyngioma and nonpituitary CBTS. METHODS Prevalence of and risk factors for significant weight gain (body mass index [BMI] change ≥ +2.0 standard deviation score [SDS]), overweight, or obesity at follow-up, and its association with HP dysfunction were studied in a nationwide cohort of CBTS, diagnosed in a 10-year period (2002-2012), excluding all craniopharyngioma and pituitary tumors. RESULTS Of 661 CBTS, with a median age at follow-up of 7.3 years, 33.1% had significant weight gain, overweight, or obesity. Of the CBTS between 4 and 20 years of age, 28.7% were overweight or obese, compared with 13.2% of the general population between 4 and 20 years of age. BMI SDS at diagnosis, diagnosis of low-grade glioma, diabetes insipidus, and central precocious puberty were associated with weight gain, overweight, or obesity. The prevalence of HP dysfunction was higher in overweight and obese CTBS compared with normal-weight CBTS. CONCLUSION Overweight, obesity, and significant weight gain are prevalent in CBTS. An increase in BMI during follow-up may be a reflection of HP dysfunction, necessitating more intense endocrine surveillance.

Objective: This study aimed at estimating the cumulative incidence of antiepileptic drug (AED) treatment failure of first-line monotherapy levetiracetam vs valproic acid in glioma patients with epilepsy. Methods: In this retrospective observational study, a competing risks model was used to estimate the cumulative incidence of treatment failure, from AED treatment initiation, for the two AEDs with death as a competing event. Patients were matched on baseline covariates potentially related to treatment assignment and outcomes of interest according to the nearest neighbor propensity score matching technique. Maximum duration of follow-up was 36 months. Results: In total, 776 patients using levetiracetam and 659 using valproic acid were identified. Matching resulted in two equal groups of 429 patients, with similar covariate distribution. The cumulative incidence of treatment failure for any reason was significantly lower for levetiracetam compared to valproic acid (12 months: 33% [95% confidence interval (CI) 29%–38%] vs 50% [95% CI 45%–55%]; P

Background Within the Dutch health care system the focus is shifting from a disease oriented approach to a more population based approach. Since every inhabitant in the Netherlands is registered with one general practice, this offers a unique possibility to perform Population Health Management analyses based on general practitioners’ (GP) registries. The Johns Hopkins Adjusted Clinical Groups (ACG) System is an internationally used method for predictive population analyses. The model categorizes individuals based on their complete health profile, taking into account age, gender, diagnoses and medication. However, the ACG system was developed with non-Dutch data. Consequently, for wider implementation in Dutch general practice, the system needs to be validated in the Dutch healthcare setting. In this paper we show the results of the first use of the ACG system on Dutch GP data. The aim of this study is to explore how well the ACG system can distinguish between different levels of GP healthcare utilization. Methods To reach our aim, two variables of the ACG System, the Aggregated Diagnosis Groups (ADG) and the mutually exclusive ACG categories were explored. The population for this pilot analysis consisted of 23,618 persons listed with five participating general practices within one region in the Netherlands. ACG analyses were performed based on historical Electronic Health Records data from 2014 consisting of primary care diagnoses and pharmaceutical data. Logistic regression models were estimated and AUC’s were calculated to explore the diagnostic value of the models including ACGs and ADGs separately with GP healthcare utilization as the dependent variable. The dependent variable was categorized using four different cut-off points: zero, one, two and three visits per year. Results The ACG and ADG models performed as well as models using International Classification of Primary Care chapters, regarding the association with GP utilization. AUC values were between 0.79 and 0.85. These models performed better than the base model (age and gender only) which showed AUC values between 0.64 and 0.71. Conclusion The results of this study show that the ACG system is a useful tool to stratify Dutch primary care populations with GP healthcare utilization as the outcome variable.

Introduction: Excellent long-term survival has been reported for both the Taperloc and the Mallory-Head cementless stems. However, little is known about the migration behaviour of these stems which have different design rationales. The purpose of this randomised clinical trial was to compare the migration and clinical outcomes of these stems during 5 years of follow-up. Methods: 42 consecutive hips in 38 patients scheduled to receive cementless THA were randomised to either a Taperloc or a Mallory-Head stem. Evaluation took place preoperatively and postoperatively on the second day, at 6, 12, 26, and 52 weeks, and annually thereafter. Primary outcome was stem migration measured using roentgen stereophotogrammetric analysis (RSA) and secondary outcomes were the Harris Hip Score (HHS) and 36-Item Short-Form Health Survey (SF-36). No patients were lost to follow-up; in 1 patient the THA was removed due to deep infection 3 months postoperatively. In 6 hips migration measurements were not possible due to insufficient marker configuration. Results: Throughout the follow-up period of 5 years, 3-dimensional migration was comparable between the Taperloc and the Mallory-Head stems ( p-values > 0.05). However, at the 5-year follow-up point the retroversion of the Mallory-Head stem was 0.9° more than the Taperloc stem ( p = 0.04). Initial subsidence and retroversion were respectively as large as 6.8 mm and 3.6° for the Taperloc stem and 5 mm and 3.6° for the Mallory-Head stem. After the first postoperative year, both implants had stabilised. The mean increment of HHS, as well as the SF-36 scores during the 5-year follow-up, were comparable between the 2 stems. Conclusions: The excellent long-term survival of both designs was confirmed in this study showing comparable initial migration with subsequent stabilisation. However, the Taperloc design with a flat, wedged geometry showed better rotational stability.

The purpose of this study was to assess whether the vascularisation of the meniscus could be visualised intra-operatively using near-infrared fluorescence (NIRF) imaging with indocyanine green (ICG) in patients undergoing total knee arthroplasty (TKA).The anterior horn (i.e., Cooper classification: zones C and D) of the meniscus that was least affected (i.e., least degenerative) was removed during TKA surgery in ten patients to obtain a cross section of the inside of the meniscus. Thereafter, 10 mg of ICG was injected intravenously, and vascularisation of the cross section of the meniscus was assessed using the Quest spectrum NIRF camera system. We calculated the percentage of patients in whom vascularisation was observed intra-operatively using NIRF imaging compared to immunohistochemistry.Meniscal vascularisation using NIRF imaging was observed in six out of eight (75%) patients in whom vascularisation was demonstrated with immunohistochemistry. The median extent of vascularisation was 13% (interquartile range (IQR) 3-28%) using NIRF imaging and 15% (IQR 11-23%) using immunohistochemistry.This study shows the potential of NIRF imaging to visualise vascularisation of the meniscus, as vascularisation was observed in six out of eight patients with histologically proven meniscal vascularisation.IV.

ObjectivesThis study aims at exploring and quantifying multiple types of adverse events (AEs) experienced by patients during cancer treatment. A novel longitudinal score to evaluate the Multiple Overall Toxicity (MOTox) burden is proposed. The MOTox approach investigates the personalised evolution of high overall toxicity (high-MOTox) during the treatment.DesignRetrospective analysis of the MRC-BO06/EORTC-80931 randomised controlled trial for osteosarcoma.SettingInternational multicentre population-based study.ParticipantsA total of 377 patients with resectable high-grade osteosarcoma, who completed treatment within 180 days after randomisation without abnormal dosages (+25% higher than planned).InterventionsPatients were randomised to six cycles of conventional versus dose-intense regimens of doxorubicin and cisplatin. Non-haematological toxicity data were collected prospectively and graded according to the Common Terminology Criteria for Adverse Events (CTCAE).Main outcome measuresThe MOTox score described the overall toxicity burden in terms of multiple toxic AEs, maximum-severity episode and cycle time-dimension. Evolution of high-MOTox was assessed through multivariable models, that investigated the impact of personalised characteristics (eg, achieved chemotherapy dose, previous AEs or biochemical factors) cycle-by-cycle.ResultsA cycle-by-cycle analysis identifies different evolutions of MOTox levels during treatment, detecting differences in patients’ health. Mean MOTox values and percentages of patients with high-MOTox decreased cycle-by-cycle from 2.626 to 1.953 and from 57.8% to 36.6%, respectively. High-MOTox conditions during previous cycles were prognostic risk factors for a new occurrence (ORs range from 1.522 to 4.439), showing that patient’s history of toxicities played an important role in the evolution of overall toxicity burden during therapy. Conventional regimen may be preferred to dose-intense in terms of AEs at cycles 2–3 (pConclusionsThe novel longitudinal method developed can be applied to any cancer studies with CTCAE-graded toxicity data. After validation in other studies, the MOTox approach may lead to improvements in healthcare assessment and treatment planning.Trial registration numberISRCTN86294690; Post-results.

Background Potential late effects of treatment for childhood cancer include adiposity, insulin resistance, dyslipidemia, and hypertension. These risk factors cluster together as metabolic syndrome and increase the risk for development of diabetes mellitus and cardio- and cerebrovascular disease. Knowledge on risk factors, timely diagnosis, and preventive strategies is of importance to prevent cardio- and cerebrovascular complications and improve quality of life. Currently, no national cohort studies on the prevalence and determinants of metabolic syndrome in childhood cancer survivors, including biomarkers and genetic predisposition, are available. Objective The objectives of the Dutch LATER METS study are to assess 1) the prevalence and risk factors of metabolic syndrome and its separate components, and 2) the potential diagnostic and predictive value of additional biomarkers for surveillance of metabolic syndrome in the national cohort of adult long-term survivors of childhood cancer. Methods This is a cross-sectional study based on recruitment of all survivors treated in the Netherlands between 1963 and 2002. Metabolic syndrome will be classified according to the definitions of the third Adult Treatment Panel Report of the National Cholesterol Education Program as well as the Joint Interim Statement and compared to reference data. Dual-energy x-ray absorptiometry scans were performed to assess body composition in more detail. The effect of patient characteristics, previous treatment, and genetic variation on the risk of metabolic syndrome will be assessed. The diagnostic and predictive value of novel biomarkers will be tested. Results Patient accrual started in 2016 and lasted until April 2020. A total of 2380 survivors from 7 pediatric oncology hospitals have participated. From July 2020, biomarker testing, single nucleotide polymorphism analysis, and data analysis will be performed. Conclusions The Dutch LATER METS study will provide knowledge on clinical and genetic determinants of metabolic syndrome and the diagnostic value of biomarkers in childhood cancer survivors. The results of this study will be used to optimize surveillance guidelines for metabolic syndrome in survivors based on enhanced risk stratification and screening strategies. This will improve diagnosis of metabolic syndrome and prevent complications. International Registered Report Identifier (IRRID) DERR1-10.2196/21256

IntroductionHospitalised paediatric oncology patients are at risk to develop acute complications. Early identification of clinical deterioration enabling adequate escalation of care remains challenging. Various Paediatric Early Warning Systems (PEWSs) have been evaluated, also in paediatric oncology patients but mostly in retrospective or case–control study designs. This study protocol encompasses the first prospective cohort with the aim of evaluating the predictive performance of a modified Bedside PEWS score for non-elective paediatric intensive care unit (PICU) admission or cardiopulmonary resuscitation in hospitalised paediatric oncology patients.Methods and analysisA prospective cohort study will be conducted at the 80-bed Dutch paediatric oncology hospital, where all national paediatric oncology care has been centralised, directly connected to a shared 22-bed PICU. All patients between 1 February 2019 and 1 February 2021 admitted to the inpatient nursing wards, aged 0–18 years, with an International Classification of Diseases for Oncology (ICD-O) diagnosis of paediatric malignancy will be eligible. A Cox proportional hazard regression model will be used to estimate the association between the modified Bedside PEWS and time to non-elective PICU transfer or cardiopulmonary arrest. Predictive performance (discrimination and calibration) will be assessed internally using resampling validation. To account for multiple occurrences of the event of interest within each patient, the unit of study is a single uninterrupted ward admission (a clinical episode).Ethics and disseminationThe study protocol has been approved by the institutional ethical review board of our hospital (MEC protocol number 16-572/C). We adapted our enrolment procedure to General Data Protection Regulation compliance. Results will be disseminated at scientific conferences, regional educational sessions and publication in peer-reviewed journals.Trial registration numberNetherlands Trial Registry (NL8957).

Background. Studies focusing on prediction models are widespread in medicine. There is a trend in applying machine learning (ML) by medical researchers and clinicians. Over the years, multiple ML algorithms have been adapted to censored data. However, the choice of methodology should be motivated by the real-life data and their complexity. Here, the predictive performance of ML techniques is compared with statistical models in a simple clinical setting (small/moderate sample size and small number of predictors) with Monte-Carlo simulations. Methods. Synthetic data (250 or 1000 patients) were generated that closely resembled 5 prognostic factors preselected based on a European Osteosarcoma Intergroup study (MRC BO06/EORTC 80931). Comparison was performed between 2 partial logistic artificial neural networks (PLANNs) and Cox models for 20, 40, 61, and 80% censoring. Survival times were generated from a log-normal distribution. Models were contrasted in terms of the C-index, Brier score at 0-5 years, integrated Brier score (IBS) at 5 years, and miscalibration at 2 and 5 years (usually neglected). The endpoint of interest was overall survival. Results. PLANNs original/extended were tuned based on the IBS at 5 years and the C-index, achieving a slightly better performance with the IBS. Comparison with Cox models showed that PLANNs can reach similar predictive performance on simulated data for most scenarios with respect to the C-index, Brier score, or IBS. However, Cox models were frequently less miscalibrated. Performance was robust in scenario data where censored patients were removed before 2 years or curtailing at 5 years was performed (on training data). Conclusion. Survival neural networks reached a comparable predictive performance with Cox models but were generally less well calibrated. All in all, researchers should be aware of burdensome aspects of ML techniques such as data preprocessing, tuning of hyperparameters, and computational intensity that render them disadvantageous against conventional regression models in a simple clinical setting.

PURPOSE: To investigate the natural history of RHO-associated retinitis pigmentosa (RP). METHODS: A multicenter, medical chart review of 100 patients with autosomal dominant RHO-associated RP. RESULTS: Based on visual fields, time-to-event analysis revealed median ages of 52 and 79 years to reach low vision (central visual field

Background: Down syndrome (DS) patients with acute lymphoblastic leukemia (ALL) are at a higher risk of treatment-related mortality and of relapse, which is influenced by a higher incidence of unfavorable genetic aberrations, such as IKZF1 deletion. We aimed to investigate the potential underlying effect of DS versus the impact of adverse cancer genetics on clinical outcome. Method: The association between DS and minimal residual disease (MRD) and clinical outcome was evaluated in a cohort of 136 DS ALL and 407 non-DS ALL pediatric patients matched for clinical risk factors and genetics, including IKZF1 deletion. Findings: The percentage of patients in the higher MRD category (≥1E-4) at the end of induction treatment did not significantly differ between DS ALL (38%) and matched non-DS ALL (39%; p=0·88). DS ALL was associated with a higher relapse risk compared with matched non-DS ALL in the IKZF1 -deleted group (cause-specific hazard ratio [HRcs], 4·3; 95% confidence interval [CI], 1·6 to 11, p=0·003), but not in the IKZF1 -wildtype group (HRcs, 1·0; 95% CI, 0·48 to 2·1; p=0·99). Our matched cohort confirmed that in addition to more induction deaths (6% versus 0·8%), DS ALL was associated with a higher risk of post-induction treatment-related mortality (HRcs, 5·0; 95% CI, 2·3 to 11; p

Simple Summary Age is one of many prognostic factors for overall survival in patients with skeletal osteosarcoma. This retrospective study provides an overview of survival in patients with high-grade osteosarcoma in different age groups. It shows prognostic variables for survival and local control among the overall cohort. In this study, in which 402 patients with skeletal high-grade osteosarcoma were included, poor survival was associated with increasing age. Age groups, tumor size, poor histopathological response, distant metastasis at presentation, and local recurrence were independent prognostic factors associated to overall survival and event-free survival. Differences in outcome among different age groups can be partially explained by patient characteristics and treatment characteristics. Abstract Age is a known prognostic factor for many sarcoma subtypes, however in the literature there are limited data on the different risk profiles of different age groups for osteosarcoma survival. This study aims to provide an overview of survival in patients with high-grade osteosarcoma in different age groups and prognostic variables for survival and local control among the entire cohort. In this single center retrospective cohort study, 402 patients with skeletal high-grade osteosarcoma were diagnosed and treated with curative intent between 1978 and 2017 at the Leiden University Medical Center (LUMC). Prognostic factors for survival were analyzed using a Cox proportional hazard model. In this study poor overall survival (OS) and event-free survival (EFS) were associated with increasing age. Age groups, tumor size, poor histopathological response, distant metastasis (DM) at presentation and local recurrence (LR) were important independent prognostic factors influencing OS and EFS. Differences in outcome among different age groups can be partially explained by patient and treatment characteristics.

Background: ABL-class fusion genes other than BCR–ABL1 have been identified in approximately 3% of children with newly diagnosed acute lymphocytic leukaemia, and studies suggest that leukaemic cells carrying ABL-class fusions can be targeted successfully by tyrosine-kinase inhibitors. We aimed to establish the baseline characteristics and outcomes of paediatric patients with ABL-class fusion B-cell acute lymphocytic leukaemia in the pre-tyrosine-kinase inhibitor era. Methods: This multicentre, retrospective, cohort study included paediatric patients (aged 1–18 years) with newly diagnosed ABL-class fusion (ABL1 fusion-positive, ABL2 fusion-positive, CSF1R fusion-positive, and PDGFRB fusion-positive) B-cell acute lymphocytic leukaemia enrolled in clinical trials of multidrug chemotherapy done between Oct 3, 2000, and Aug 28, 2018, in which tyrosine-kinase inhibitors had not been given as a first-line treatment. Patients from 14 European, North American, and Asia-Pacific study groups of the Ponte di Legno group were included. No patients were excluded, and patients were followed up by individual study groups. Through the Ponte di Legno group, we collected data on the baseline characteristics of patients, including IKZF1, PAX5, and CDKN2A/B deletion status, and whether haematopoietic stem cell transplantation (HSCT) had been done, as well as treatment outcomes, including complete remission, no response, relapse, early death, and treatment-related mortality, response to prednisone, and minimal residual disease (MRD) at end of induction therapy. 5-year event-free survival and 5-year overall survival were estimated by use of Kaplan-Meier methods, and the 5-year cumulative incidence of relapse was calculated by use of a competing risk model. Findings: We identified 122 paediatric patients with newly diagnosed ABL-class fusion B-cell acute lymphocytic leukaemia (77 from European study groups, 25 from North American study groups, and 20 from Asia-Pacific study groups). 64 (52%) of 122 patients were PDGFRB fusion-positive, 40 (33%) were ABL1 fusion-positive, ten (8%) were CSF1R fusion-positive, and eight (7%) were ABL2 fusion-positive. In all 122 patients, 5-year event-free survival was 59·1% (95% CI 50·5–69·1), 5-year overall survival was 76·1% (68·6–84·5), and the 5-year cumulative incidence of relapse was 31·0% (95% CI 22·4–40·1). MRD at the end of induction therapy was high (≥10−2 cells) in 61 (66%) of 93 patients, and most prevalent in patients with ABL2 fusions (six [86%] of 7 patients) and PDGFRB fusion-positive B-cell acute lymphocytic leukaemia (43 [88%] of 49 patients). MRD at the end of induction therapy of 10−2 cells or more was predictive of an unfavourable outcome (hazard ratio of event-free survival in patients with a MRD of ≥10−2 vs those with a MRD of

Purpose: No studies extensively compared the young adults (YA, 18-39 years), middle-aged (40-69 years), and elderly (≥70 years) population with primary high-grade extremity soft tissue sarcoma (eSTS). This study aimed to determine whether the known effect of age on overall survival (OS) and disease progression can be explained by differences in tumour characteristics and treatment protocol among the YA, middle-aged and elderly population in patients with primary high-grade eSTS treated with curative intent. Methods: In this retrospective multicentre study, inclusion criteria were patients with primary high-grade eSTS of 18 years and older, surgically treated with curative intent between 2000 and 2016. Cox proportional hazard models and a multistate model were used to determine the association of age on OS and disease progression. Results: A total of 6260 patients were included in this study. YA presented more often after 'whoops'-surgery or for reresection due to residual disease, and with more deep-seated tumours. Elderly patients presented more often with grade III and larger (≥10 cm) tumours. After adjustment for the imbalance in tumour and treatment characteristics the hazard ratio for OS of the middle-aged population is 1.47 (95% confidence interval [CI]: 1.23-1.76) and 3.13 (95% CI: 2.59-3.78) in the elderly population, compared with YA. Discussion: The effect of age on OS could only partially be explained by the imbalance in the tumour characteristics and treatment variables. The threefold higher risk of elderly could, at least partially, be explained by a higher other-cause mortality. The results might also be explained by a different tumour behaviour or suboptimal treatment in elderly compared with the younger population. Keywords: Adolescents and young adults; Elderly; Extremities; Metastasis; Middle-aged; Recurrence; Soft tissue sarcoma; Survival.