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Purpose 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). Methods 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. Results 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. Conclusion 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. Level of evidence IV.

PURPOSE: To investigate the natural disease course of retinal dystrophies associated with crumbs cell polarity complex component 1 (CRB1) and identify clinical end points for future clinical trials. DESIGN: Single-center, prospective case series. METHODS: An investigator-initiated nationwide collaborative study that included 22 patients with CRB1-associated retinal dystrophies. Patients underwent ophthalmic assessment at baseline and 2 years after baseline. Clinical examination included best-corrected visual acuity (BCVA) using Early Treatment Diabetic Retinopathy Study charts, Goldmann kinetic perimetry (V4e isopter seeing retinal areas), microperimetry, full-field electroretinography, full-field stimulus threshold (FST), fundus photography, spectral-domain optical coherence tomography, and fundus autofluorescence imaging. RESULTS: Based on genetic, clinical, and electrophysiological data, patients were diagnosed with retinitis pigmentosa (19 [86%]), cone-rod dystrophy (2 [9%]), or isolated macular dystrophy (1 [5%]). Analysis of the entire cohort at 2 years showed no significant changes in BCVA (P = .069) or V4e isopter seeing retinal areas (P = .616), although signs of clinical progression were present in individual patients. Macular sensitivity measured on microperimetry revealed a significant reduction at the 2-year follow-up (P < .001). FST responses were measurable in patients with nonrecordable electroretinograms. On average, FST responses remained stable during follow-up. CONCLUSION: In CRB1-associated retinal dystrophies, visual acuity and visual field measures remain relatively stable over the course of 2 years. Microperimetry showed a significant decrease in retinal sensitivity during follow-up and may be a more sensitive progression marker. Retinal sensitivity on microperimetry may serve as a functional clinical end point in future human treatment trials for CRB1-associated retinal dystrophies.

Background Dexamethasone, a highly effective drug in treating pediatric acute lymphoblastic leukemia (ALL), can induce serious neurobehavioral side effects. These side effects are experienced by patients and parents as detrimental with respect to health related quality of life (HRQoL). Based on previous studies, it has been suggested that neurobehavioral side effects are associated to cortisol depletion of the mineralocorticoid receptor in the brain. Our previously reported randomized controlled trial, the Dexadagen study (NTR3280), suggests that physiological hydrocortisone addition during dexamethasone treatment may overcome clinically relevant neurobehavioral problems in patients who experience these problems during dexamethasone treatment. With our current study, we aim to replicate these results in a targeted larger sample before further implementing this intervention into standard of care. Methods In a national center setting, pediatric ALL patients between 3 and 18 years are enrolled in an Identification study, which identifies patients with clinically relevant dexamethasone-induced neurobehavioral side effects using the Strengths and Difficulties Questionnaire (SDQ). Contributing factors, such as genetic susceptibility, dexamethasone pharmacokinetics as well as psychosocial and family factors are studied to determine their influence in the inter-patient variability for developing dexamethasone-induced neurobehavioral side effects. Patients with clinically relevant problems (i.e. a rise of ≥ 5 points on the SDQ Total Difficulties Score after 5 days of dexamethasone) are subsequently included in a randomized double-blind placebo-controlled trial with a cross-over design. They receive two courses placebo followed by two courses hydrocortisone during dexamethasone treatment, or vice versa, each time at least 16 days without study medication in between. The primary endpoint is change in SDQ score. The secondary endpoints are sleep (measured with actigraphy and the Sleep Disturbance Scale for Children) and HRQoL (Pediatric Quality of Life Questionnaire). Discussion The results of our current study may contribute to the management of future ALL patients who experience dexamethasone-induced neuropsychological problems as it may improve HRQoL for patients who suffer most from dexamethasone-induced neurobehavioral side effects. Furthermore, by investigating multiple risk factors that could be related to inter-patient variability in developing these side effects, we might be able to identify and treat patients who are at risk earlier during treatment. Trial registration Medical Ethical Committee approval number: NL62388.078.17. Affiliation: Erasmus Medical Centre. Netherlands Trial Register: NL6507 (NTR6695). Registered 5 September 2017

Background: Patients with Down syndrome and acute lymphocytic leukaemia are at an increased risk of treatment-related mortality and relapse, which is influenced by unfavourable genetic aberrations (eg, IKZF1 deletion). We aimed to investigate the potential underlying effect of Down syndrome versus the effects of adverse cancer genetics on clinical outcome. Method: Patients (aged 1–23 years) with Down syndrome and acute lymphocytic leukaemia and matched non-Down syndrome patients with acute lymphocytic leukaemia (matched controls) from eight trials (DCOG ALL10 and ALL11, ANZCHOG ALL8, AIEOP-BFM ALL2009, UKALL2003, NOPHO ALL2008, CoALL 07-03, and CoALL 08-09) done between 2002 and 2018 across various countries (the Netherlands, the UK, Australia, Denmark, Finland, Iceland, Norway, Sweden, and Germany) were included. Participants were matched (1:3) for clinical risk factors and genetics, including IKZF1 deletion. The primary endpoint was the comparison of MRD levels (absolute MRD levels were categorised into two groups, low [cs] 4·3 [1·6–11·0]; p=0·0028), but not in the IKZF1 wild-type group (relapse at 5 years 5·8% [2·1–12·2] vs 8·1% [5·1–12·0]; HRcs 1·0 [0·5–2·1]; p=0·99). In addition to increased induction deaths (15 [6%] of 251 vs 69 [0·8%] of 8426), Down syndrome and acute lymphocytic leukaemia was associated with a higher risk of post-induction TRM compared with matched controls (TRM at 5 years 12·2% [7·0–18·9] vs 2·7% [1·3–4·9]; HRcs 5·0 [2·3–10·8]; p

Background. Standard therapy for localized soft tissue sarcoma (STS) is wide, limb-sparing resection. For intermediate- or high-grade tumors, (neo)adjuvant therapies are frequently added to the treatment plan. In this study, data from a Dutch nationwide database are used to (1) assess whether perioperative management of STS follows ESMO guidelines, (2) characterize prognostic factors for overall survival (OS), and (3) assess the association between perioperative treatment and survival. Methods. All intermediate- or high-grade, localized STS cases, who have undergone surgery and diagnosed between 2000 and 2017, were identified in the Netherlands Cancer Registry (NCR) database. Variables with demographic, treatment, and survival data were obtained. Survival curves were estimated by Kaplan–Meier’s method, and the effect of prognostic factors on OS was assessed in a multivariable Cox regression analysis. Results. A total of 4957 patients were identified. There were slightly more males (54.7%). Median age at diagnosis was 64 years, and 53.6% of the tumors were located in the extremities. Radiotherapy (RT) was administered to 2481 (50.1%) patients, and 252 (5.1%) patients were treated with perioperative systemic chemotherapy. The total use of perioperative RT did not significantly change in the last 20 years, but the timing followed clinical guidelines: preoperative RT increased significantly (2000–2008: 3.7%, 2009–2017: 22.3%; p < 0.001 ), whereas the use of postoperative RT diminished (2000–2008: 45.9%, 2009–2017: 26.1%; p < 0.001 ). The use of perioperative chemotherapy slightly decreased (2000–2008: 5.9%, 2009–2017: 4.4%; p = 0.015). 5-year OS was 59.6% (95% CI: 58.2–61.0). Sex, age, year of diagnosis, tumor location, tumor size, histological grade, depth, histological subtype, surgical margins, and the use of perioperative RT were identified as independent predictors for OS. Conclusion. Preoperative RT is gradually replacing postoperative RT for localized STS in the Netherlands. The use of perioperative chemotherapy is rare and has slightly decreased in recent years. Identified baseline characteristics and treatment factors predicting OS may aid in future treatment decisions.

Background Our aim is to show whether the sentinel node procedure (SNP) is recommendable for pediatric patients with extremity rhabdomyosarcoma (RMS). Lymph node metastases are an important prognostic factor in pediatric patients with extremity RMS. Accurate nodal staging is necessary to treat the patient accordingly. An alternative to the current recommended lymph node sampling is the sentinel node procedure (SNP). Methods A systematic review was performed summarizing all published cases of SNP in addition to 13 cases from our hospital and 8 cases from two other hospitals that have not been published before. Results For all patients (n = 55), at least one SLN was identified, but the SNP technique used was not uniform. The SNP changed the nodal classification of eight patients (17.0%) and had a false-negative rate of 10.5%. Conclusions The SNP is recommendable for pediatric patients with extremity RMS. It can change lymph node status and can be used to sample patients in a more targeted way than nodal sampling alone. Therefore, we recommend use of the SNP in addition to clinical and radiological nodal assessment for pediatric patients with extremity RMS.

The incidence of central venous catheter (CVC)-related bloodstream infections is high in patients requiring a long-term CVC. Therefore, infection prevention is of the utmost importance. The aim of this study was to provide an updated overview of randomized controlled trials (RCTs) comparing the efficacy of taurolidine containing lock solutions (TL) to other lock solutions for the prevention of CVC-related bloodstream infections in all patient populations. On 15th February 2021, PubMed, Embase and The Cochrane Library were searched for RCTs comparing the efficacy of TLs for the prevention of CVC-related bloodstream infections with other lock solutions. Exclusion criteria were non-RCTs, studies describing

Purpose Chemotherapy can affect smell and taste function. This has never been investigated in childhood cancer patients during chemotherapy. The objective of this study was to determine whether psychophysical smell and taste tests are suitable for children with cancer. Taste and smell function, fungiform papillae density, and eating behavior were measured before (T1) and after (T2) a cycle of chemotherapy and compared with healthy controls. Methods Thirty-one childhood cancer patients treated for a hematological, solid, or brain malignancy (median age 12 years, 16 girls), and 24 healthy controls (median age: 11 years, 10 girls) participated. Smell function was measured using Sniffin’ Sticks, including a threshold, discrimination, and identification test. Taste Strips were used to determine recognition thresholds for sweet, sour, salty, and bitter taste. Papillae density was investigated by counting the fungiform papillae of the anterior tongue. Eating behavior was assessed using the Behavioral Pediatrics Feeding Assessment Scale (BPFAS). Results Smell and taste function could be investigated in more than 90% of the patients, while fungiform papillae density could be determined in 61% of the patients. A significant difference in smell threshold was found between patients and controls (p = 0.001), showing lower thresholds in patients. In patients, sweet taste (p p = 0.028), and total taste function (p = 0.004) were significantly different after a cycle of chemotherapy, with higher scores at T2. Conclusion The assessment of smell, taste, and fungiform papillae density is feasible in children with cancer. Results of the current study suggest that smell and taste sensitivity increased in children with cancer.

Background and purpose: Patients with advanced cancer may develop painful bone metastases, potentially resulting in pathological fractures. Adequate fracture risk assessment is of key importance to prevent fracturing and maintain mobility. This study aims to validate the clinical reliability of axial cortical involvement with a 30 mm threshold on conventional radiographs to assess fracture risk in femoral bone metastases.Materials and methods: All patients with bone metastases who received radiotherapy for pain included in two multicentre prospective studies were selected. Conventional radiographs obtained at a maximum of two months prior to radiotherapy were collected. Three experts independently measured lesions and scored radiographic characteristics. Sensitivity, specificity, positive (PPV) and negative predictive value (NPV) were calculated.Results: Hundred patients were included with a median follow-up of 23.0 months (95%CI: 10.6-35.5). Two fractures occurred in lesions with axial cortical involvement = 30 mm. Sensitivity, specificity, PPV and NPV of axial cortical involvement for predicting femoral fractures were 86%, 50%, 20% and 96%, respectively. Patients with lesions >= 30 mm had a 5.3 times higher fracture risk than patients with smaller lesions.Conclusion: Our validation study confirmed the use of 30 mm axial cortical involvement to assess fracture risk in femoral bone metastases. Until a more accurate and practically feasible method has been developed, this clinical parameter remains an easy method to assess femoral fracture risk to aid patients and clinicians to choose the optimal individual treatment modality. (C) 2019 Elsevier B.V. All rights reserved.

[Purpose] The effect of high-dose imatinib (800 mg/day) on survival in the adjuvant treatment of patients with resected KIT exon 9–mutated gastrointestinal stromal tumors (GIST) is not established. Here, the association of dose and other clinicopathologic variables with survival was evaluated in a large multi-institutional European cohort., [Experimental Design] Data from 185 patients were retrospectively collected in 23 European GIST reference centers. Propensity score matching (PSM) and inverse-probability of treatment weighting (IPTW) were used to account for confounders. Univariate and multivariate unweighted and weighted Cox proportional hazard regression models were estimated for relapse-free survival (RFS), modified-RFS (mRFS) and imatinib failure-free survival (IFFS). Univariate Cox models were estimated for overall survival., [Results] Of the 185 patients, 131 (70.8%) received a starting dose of 400 mg/d and the remaining 54 (29.2%) a dose of 800 mg/d. Baseline characteristics were partially unbalanced, suggesting a potential selection bias. PSM and IPTW analyses showed no advantage of imatinib 800 mg/d. In the weighted multivariate Cox models, high-dose imatinib was not associated with the survival outcomes [RFS: hazard ratio (HR), 1.24; 95% confidence interval (CI), 0.79–1.94; mRFS: HR, 1.69; 95% CI, 0.92–3.10; IFFS: HR, 1.35; 95% CI, 0.79–2.28]. The variables consistently associated with worse survival outcomes were high mitotic index and nongastric tumor location., [Conclusions] In this retrospective series of patients with KIT exon 9–mutated GIST treated with adjuvant imatinib, a daily dose of 800 mg versus 400 mg did not show better results in terms of survival outcomes. Prospective evaluation of the more appropriate adjuvant treatment in this setting is warranted.

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.

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.

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.

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: 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/).

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.

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.

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.

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.

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).

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

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.

Background The diagnostic workup of ovarian tumors in children and adolescents is challenging because preserving fertility, in addition to oncological safety, is of particular importance in this population. Therefore, a thorough preoperative assessment of ovarian tumors is required. Objective To investigate the diagnostic value of MR imaging in differentiating benign from malignant ovarian tumors in children and adolescents. Materials and methods We conducted a retrospective study of all children and adolescents age Results We included 30 girls who underwent MR imaging for an ovarian tumor. Signs indicative for malignancy were tumors with a diameter ≥8 cm, with areas of contrast enhancement, irregular margins, extracapsular tumor growth, and ascites. All benign and malignant ovarian tumors were correctly identified by the radiologists. Conclusion The diagnostic utility of MR imaging in classifying ovarian tumors in children and adolescents as benign or malignant is promising and might aid in defining the indication for ovarian-sparing versus non-ovarian-sparing surgery. We recommend evaluating these tumors with MR imaging prior to deciding on surgical treatment.

This cohort study examines the competing risks of death and kidney failure in an aging population with or without age-related comorbid conditions., Key Points Question Does the risk of kidney failure vary with age in adults with severe chronic kidney disease (CKD)? Findings In this population-based cohort study of approximately 4 million people, the incidence of severe CKD increased sharply with older age. In 30 801 adults who developed stage IV CKD, on average, death was 3 times more likely to occur than kidney failure, 6 times more likely among those aged 75 to 84 years, and 25 times more likely among those aged 85 years or older. Meaning The findings of this study suggest that the increasing burden of severe CKD that accompanies population aging may not translate into increased demand for treatment of kidney failure in older adults., Importance With population aging, the burden of many age-related chronic conditions, including kidney failure, is increasing globally. Objective To investigate the risks of kidney failure and death in adults with incident stage IV chronic kidney disease (CKD). Design, Setting, and Participants This population-based cohort study obtained data recorded between July 30, 2002, and March 31, 2014, from the linked laboratory and administrative data set of Alberta Health in Alberta, Canada. All adults of the province of Alberta with stage IV CKD (estimated glomerular filtration rate [eGFR] of 15-30 mL/min/1.73 m2) were eligible for inclusion. Included individuals were followed up from study entry until the date of kidney failure, death, or censoring, whichever occurred first. Observations were censored at the date of emigration from the province, the study end date (March 31, 2017), or at 10 years after study entry. Data analyses were performed from January 2020 to June 2020. Main Outcomes and Measures The primary outcome was kidney failure, defined as the earlier of either renal replacement (dialysis or kidney transplant) initiation or severe kidney impairment (eGFR

Background and aims Sacrococcygeal teratoma (SCT) is a rare extragonadal germ cell tumour mostly diagnosed during infancy and early childhood. Neonatal SCTs are mostly mature, but can also contain immature and/or malignant components. Recurrence of an SCT alters prognosis, especially when it is malignant, of which its mechanism is not yet fully understood. This study is a review and meta-analysis of the literature on malignant recurrences after an initially mature SCT. Methods A literature search was performed to identify studies describing children with SCT and presenting specific information on histology of the initial tumour as well as the recurrence. Random effect models for mature recurrence and malignant recurrence after an initially mature SCT were employed to pool study-specific percentages in order to estimate an overall percentage and its associated 95 % confidence intervals (CI). Inverse variance method, which gives more weight to larger studies, was used to pool outcomes for the different studies. Results A total of 22 articles, comprising 1516 patients with SCT, were included in the meta-analysis. The pooled proportions of mature and malignant recurrences after mature SCT were 3 % (95 % CI 1–4 %) and 5% (95 % CI 3–6 %), respectively. Fifty-seven (56 %) of a total of 102 recurrences after resection of an initially mature SCT were malignant, mostly yolk sac tumour (YST). Many recurrences occurred within 1–6 years, however some occurred as long as 20 years after initial diagnosis. Conclusions A substantial number of recurrences of mature SCT present as a malignant tumour. Overlooking malignant components on initial pathological evaluation and the progression of mature SCT cells to malignant cells may play a role. Treatment of mature SCTs with resection alone requires thorough follow-up of at least 6 years. Future research is needed to determine whether SCTs with malignant microfoci should be treated or followed-up differently from mature or immature SCTs. In addition, the value of serum biomarkers in follow-up after SCT needs to be further evaluated.

Introduction This study aimed to compare the engagement in moderate- and vigorous-intensity PA in axSpA patients with and without current physical therapy (PT). Methods In this cross-sectional study, a survey, including current PT treatment (yes/no) and PA, using the ‘Short QUestionnaire to ASsess Health-enhancing PA’ (SQUASH), was sent to 458 axSpA patients from three Dutch hospitals. From the SQUASH, the proportions meeting aerobic PA recommendations (≥ 150 min/week moderate-, ≥ 75 min/week vigorous-intensity PA or equivalent combination; yes/no) were calculated. To investigate the association between PT treatment and meeting the PA recommendations, odds ratios (OR) with 95% confidence intervals (95% CI) were estimated using logistic regression models, adjusting for sex, age, health status and hospital. Results The questionnaire was completed by 200 patients, of whom 68%, 50% and 82% met the moderate-, vigorous- or combined-intensity PA recommendations, respectively. Ninety-nine patients (50%) had PT treatment, and those patients were more likely to meet the moderate- (OR 2.09 [95% CI 1.09–3.99]) or combined-intensity (OR 3.35 [95% CI 1.38–8.13]) PA recommendations, but not the vigorous-intensity PA recommendation (OR 1.53 [95% CI 0.80–2.93]). Aerobic exercise was executed in 19% of individual PT programs. Conclusion AxSpA patients with PT were more likely to meet the moderate- and combined-intensity PA recommendations, whereas there was no difference in meeting the vigorous-intensity PA recommendation. Irrespective of having PT treatment, recommendations for vigorous-intensity PA are met by only half of the patients. Implementation should thus focus on aerobic PA in patients without PT and on vigorous-intensity PA in PT programs.

Background: Low lumbar skeletal muscle mass and density have been associated with adverse outcomes in different populations with colorectal cancer (CRC). We aimed to determine whether skeletal muscle mass, density, and physical performance are associated with postoperative complications and overall survival (OS) in older CRC patients.Methods: We analysed consecutive patients (>= 70 years) undergoing elective surgery for non-metastatic CRC (stage I-III). Lumbar skeletal muscle mass and muscle density were measured using abdominal CT-images obtained prior to surgery. Low skeletal muscle mass and low muscle density were defined using commonly used thresholds and by gender-specific quartiles (Q). The preoperative use of a mobility aid served as a marker for physical performance. Cox regression proportional hazard models were used to investigate the association between the independent variables and OS.Results: 174 Patients were included (mean age 78.0), with median follow-up 2.6 years. 36 Patients (21%) used a mobility aid preoperatively. Low muscle density (Q1 vs Q4) and not muscle mass was associated with worse postoperative outcomes, including severe complications (p < 0.05). Use of a mobility aid was associated with more complications, including severe complications (39% vs 17%, p = 0.004) and OS (HR 2.65, CI 1.29-5.44, p = 0.01). However, patients with mobility aid use and low skeletal muscle mass had worse OS (HR 5.68, p = 0.003).Conclusion: Low skeletal muscle density and not muscle mass was associated with more complications after colorectal surgery in older patients. Physical performance has the strongest association for poor surgical outcomes and should be investigated when measuring skeletal muscle mass and density. (C) 2019 Elsevier Ltd, BASO similar to The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.

About 33% patients with osteoarthritis undergoing total hip/knee arthroplasty are not satisfied with the outcome, warranting the need to improve patient selection. Handgrip strength (HGS) has been suggested as a proxy for overall muscle strength and may be associated with post-arthroplasty function. This study aims to assess the association of pre-operative HGS with change in hip/knee function and quality of life in patients with arthroplasty. 226 hip (THA) and 246 knee (TKA) arthroplasty patients were included in this prospective cohort study. Pre-operative HGS was assessed by means of a dynamometer and the HOOS/KOOS and SF-36 questionnaires were collected before arthroplasty and 1 year thereafter. The association of HGS with score change on each sub-domain of the included questionnaires was assessed by linear regression models, adjusting for sex, body mass index and baseline score. Mean pre-operative HGS was 26 kg for patients undergoing THA and 24 kg for those undergoing TKA. HGS was positively associated with an increased improvement score on “function in sport and recreation”-domain in hip (β = 0.68, P = 0.005) and knee (β = 0.52, P = 0.049) and “symptoms”-domain in hip (β = 0.56, P = 0.001). For patients with THA, HGS was associated with the “quality of life” domain (β = 0.33, P = 0.033). In patients with TKA, HGS was associated with the physical component score (β = 0.31, P = 0.001). All statistically significant effects were positive, indicating that with greater pre-operative HGS, an increased gain in 1-year post-surgery score was observed. HGS can be used as a tool to inform patients with OA who are future candidates for a prosthesis about the possible improvements of certain aspects of life after arthroplasty.

Background Tinnitus is a serious late effect of childhood cancer treatment. The aim of this study was to determine the occurrence and risk factors for tinnitus in a national cohort of childhood cancer survivors (CCS). Methods Data were collected within the national Dutch Childhood Oncology Group - Long-Term Effects after Childhood Cancer (DCOG-LATER) cohort by a self-reported health questionnaire among 5327 Dutch CCS treated between 1963 and 2002. Siblings (N = 1663) were invited to complete the same questionnaire. Relevant patient characteristics and treatment factors were obtained from the Dutch LATER database. The occurrence of tinnitus in survivors was compared to siblings. To study the effect of risk factors, multivariate logistic regression models were estimated. Results In total, 2948 CCS and 1055 siblings completed the tinnitus item. Tinnitus was reported in 9.5% of survivors and in 3.7% of siblings (odds ratio [OR] 3.0, 95% confidence interval [CI] 2.9–3.1). Risk factors associated with tinnitus in CCS were total cumulative dose cisplatin ≥400 mg/m2 (OR 2.4, 95% CI 1.4–4.0), age at diagnosis (≥10 years: OR 2.1, 95% CI 1.6–2.8), cranial irradiation/total body irradiation (TBI; OR 1.9, 95% CI 1.5–2.5), and neuro/ear, nose, throat (ENT) surgery (OR 1.8, 95% CI 1.1–2.9). Fifty-one percent of CCS with tinnitus had received treatment with either cisplatin, cranial irradiation/TBI, and/or neuro/ENT surgery. Conclusions Tinnitus in CCS was present nearly 3 times more often than in siblings. Awareness in CCS previously treated with cisplatin, cranial irradiation/TBI, and/or neuro/ENT surgery is warranted. As only half of affected CCS had a history of these treatments, it seems that other factors might be associated with tinnitus occurrence in this population.

Supplemental Digital Content is available in the text, Genomic alterations in relapsed B-cell precursor acute lymphoblastic leukemia (BCP-ALL) may provide insight into the role of specific genomic events in relapse development. Along this line, comparisons between the spectrum of alterations in relapses that arise in different upfront treatment protocols may provide valuable information on the association between the tumor genome, protocol components and outcome. Here, we performed a comprehensive characterization of relapsed BCP-ALL cases that developed in the context of 3 completed Dutch upfront studies, ALL8, ALL9, and ALL10. In total, 123 pediatric BCP-ALL relapses and 77 paired samples from primary diagnosis were analyzed for alterations in 22 recurrently affected genes. We found pronounced differences in relapse alterations between the 3 studies. Specifically, CREBBP mutations were observed predominantly in relapses after treatment with ALL8 and ALL10 which, in the latter group, were all detected in medium risk-treated patients. IKZF1 alterations were enriched 2.2-fold (p = 0.01) and 2.9-fold (p

Context Patients with craniopharyngioma suffer from obesity and impaired bone health. Little is known about longitudinal changes in body composition and bone mineral density (BMD). Objective To describe body composition and BMD (change). Design Retrospective longitudinal study. Setting Two Dutch/Swedish referral centers. Patients Patients with craniopharyngioma (n = 112) with a dual X-ray absorptiometry (DXA) scan available (2 DXA scans, n = 86; median Δtime 10.0 years; range 0.4-23.3) at age ≥ 18 years (58 [52%] male, 50 [45%] childhood onset). Main outcome measures Longitudinal changes of body composition and BMD, and associated factors of ΔZ-score (sex and age standardized). Results BMI (from 28.8 ± 4.9 to 31.2 ± 5.1 kg/m2, P Conclusions Z-scores of BMI, fat percentage, and FMI remained stable in patients with craniopharyngioma over time, while Z-scores of FFMI and BMD increased. Higher glucocorticoid dose and radiotherapy were associated with BMD loss and GHRT with increase.

Background: The surprise question (SQ), “Would I be surprised if this patient died within one year?”, is a simple instrument to identify patients with palliative care needs. The SQ-performance has ...

Currently, patients with extremity soft tissue sarcoma (eSTS) who have undergone curative resection are followed up by a heuristic approach, not covering individual patient risks. The aim of this study was to develop two flexible parametric competing risk regression models (FPCRRMs) for local recurrence (LR) and distant metastasis (DM), aiming at providing guidance on how to individually follow-up patients. Three thousand sixteen patients (1931 test, 1085 validation cohort) with high-grade eSTS were included in this retrospective, multicenter study. Histology (9 categories), grading (time-varying covariate), gender, age, tumor size, margins, (neo)adjuvant radiotherapy (RTX), and neoadjuvant chemotherapy (CTX) were used in the FPCRRMs and performance tested with Harrell-C-index. Median follow-up was 50 months (interquartile range: 23.3&ndash, 95 months). Two hundred forty-two (12.5%) and 603 (31.2%) of test cohort patients developed LR and DM. Factors significantly associated with LR were gender, size, histology, neo- and adjuvant RTX, and margins. Parameters associated with DM were margins, grading, gender, size, histology, and neoadjuvant RTX. C-statistics was computed for internal (C-index for LR: 0.705, for DM: 0.723) and external cohort (C-index for LR: 0.683, for DM: 0.772). Depending on clinical, pathological, and patient-related parameters, LR- and DM-risks vary. With the present model, implemented in the updated Personalised Sarcoma Care (PERSARC)-app, more individualized prediction of LR/DM-risks is made possible.

Introduction: Prognosis of neuroblastoma patients is very diverse, indicating the need for more accurate prognostic parameters. The excretion of catecholamine metabolites by most neuroblastomas is used for diagnostic purposes, but their correlation with prognosis has hardly been investigated. Therefore, we performed an in-depth analysis of a panel of elevated urinary catecholamine metabolites at diagnosis and their correlation with prognosis. Patients and methods: Retrospective study of eight urinary catecholamine metabolites in a test (n = 96) and validation (n = 205) cohort of patients with neuroblastoma (all stages) at diagnosis. Results: Multivariate analyses, including risk factors such as stage and MYCN amplification, revealed that 3-methoxytyramine (3MT) was an independent risk factor for event-free survival (EFS) and overall survival (OS). Furthermore, only 3MT appeared to be an independent risk factor for both EFS and OS in high-risk patients, which was independent of modern high-risk therapy and immunotherapy. Among high-risk patients, those with elevated 3MT and older than 18 months had an extremely poor prognosis compared to patients with non-elevated 3MT and younger than 18 months (5-year EFS of 14.3% +/- 4% and 66.7% +/- 18%, respectively, p = 0.001; 5-year OS of 21.8% +/- 5% and 87.5% +/- 12%, respectively, p

Background: Substantial variation in the use of (neo) adjuvant treatment in patients with gastric cancer exists. The aim of this study was to identify underlying (organizational and process) factors associated with the use of perioperative therapy. Patients and methods: Patients with resectable gastric cancer who underwent surgery between 2012 and 2014 were selected from the Dutch Upper gastrointestinal Cancer Audit (DUCA). The proportion of perioperatively treated patients was defined per hospital. Five hospitals with the lowest percentage (LP group) and 5 hospitals with the highest percentage (HP group) of perioperative therapy were identified. In the selected hospitals additional information was obtained from patients' medical records using a structured list with predefined variables. Results: In total, 429 patients (231 in LP group, 198 in HP group) from 9 different hospitals were included. Perioperative therapy was given in 16.0% of patients in the LP group compared to 40.4% in the HP group. In the LP group, patients were enrolled in a clinical trial less frequently (10.8% versus 26.8%, P = 3 upper GI specialists prior to treatment decision was positively associated with initiating perioperative therapy (OR 2.08, 95% CI 1.19-3.66). Conclusion: Results of this study confirm considerable hospital variation in the use of perioperative therapy in patients with gastric cancer. Besides known casemix factors, use of perioperative therapy was associated with the level of involvement of multidisciplinary care. (C) 2017 Elsevier Ltd, BASO similar to The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved

Introduction KMT2A-rearranged (KMT2A-r) acute myeloid leukemia (AML) is a heterogeneous genetic subgroup with a frequency of about 25% in children with AML. At the 62 nd ASH annual meeting last year, we reported on the differences in outcome of various KMT2A subgroups based on translocation partner and the significance of minimal residual disease (MRD) status during and after induction as a follow-up study of Balgobind et al., Blood 2009. The impact of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first complete remission (CR1) and the presence of additional cytogenetic aberrations (ACAs) on prognosis have not yet been described for our cohort. Methods Data on allo-HSCT in CR1 and the presence of ACAs of 1256 KMT2A-r de novo pediatric AML patients from 15 AML study groups affiliated with the I-BFM Study Group, diagnosed between 2005 and 2016, were retrospectively collected and studied. Karyotypes were reviewed and classified by two of the authors (RW&CH). Based on translocation partners, patients were classified to the KMT2A high-risk subgroup (6q27, 10p11.2, 10p12, 4q21, and 19p13.3) or non-high-risk subgroup (9p22, 19p13, 19p13.1, 1q21, Xq24, 17q21, 1p32, and 17q12). These two categories have been used to estimate a Cox model. Patients with unknown translocation partners were excluded from these analyses (n=126). Flow cytometry MRD levels at the end of induction course 1 (EOI1) and 2 (EOI2) Results Of 1256 pediatric patients with KMT2A-r AML, data on HSCT in CR1 and ACAs were available for 1186 (94.4%) and 1204 patients (95.9%), respectively; 211 (17.8%) patients received HSCT in CR1 and ACAs were present in 601 (49.9%) patients. Compared with the KMT2A non-high-risk subgroup, patients in the KMT2A high-risk subgroup underwent HSCT in CR1 more often (23.8% vs 15.0%; P < .001). ACAs were borderline significantly more common in the KMT2A high-risk subgroup (54.1% vs 46.4%; P = .015). Univariate analysis of the probability of DFS (Table 1) showed that the KMT2A high-risk subgroup (HR 2.1; 95% CI, 1.7-2.5), age ≥10 years (HR 1.4; 95% CI, 1.2-1.7), and MRD ≥0.1 at EOI1 (HR 1.5; 95% CI, 1.1-1.9) were associated with DFS. HSCT in CR1 was a borderline significant prognostic factor (HR 0.7; 95% CI, 0.6-0.9). In a multivariate analysis for DFS (n=515) (Table 1), the KMT2A high-risk subgroup (HR 2.0; 95% CI, 1.6-2.6), MRD ≥0.1 at EOI1 (HR 1.7; 95% CI, 1.2-2.3), and HSCT in CR1 (HR 0.6; 95% CI, 0.4-0.9) were associated with DFS. Univariate analysis of the probability of OS (Table 1) showed that the KMT2A high-risk subgroup (HR 1.8; 95% CI, 1.5-2.2), age ≥10 years (HR 1.6; 95% CI 1.3-2.0), WBC ≥100 x10 9/L (HR 1.4; 95% CI, 1.1-1.7), the presence of ACAs (HR 1.4; 95% CI, 1.2-1.7), and MRD ≥0.1 at EOI1 (HR 2.1; 95% CI, 1.6-2.7) were associated with OS. HSCT in CR1 was not associated with OS. The effect of HSCT in CR1 was not significantly different between the KMT2A high-risk and non-high-risk subgroups. In a multivariate analysis for OS (n=557) (Table 1), the KMT2A high-risk subgroup (HR 1.9; 95% CI, 1.4-2.5), age ≥10 years (HR 1.5; 95% CI, 1.1-1.9), the presence of ACAs (HR 1.6; 95% CI, 1.2-2.1), and MRD positivity at EOI1 (HR 1.9; 95% CI, 1.4-2.5) were associated with OS. Conclusions In this cohort of KMT2A-r pediatric AML patients, the presence of ACAs at diagnosis was independently associated with inferior OS, but not with DFS. This may be due to the exclusion of refractory patients in DFS analysis, who were significantly more common in the group of patients with ACAs. Analysis has yet to be performed to distinguish karyotype complexity. In addition, allo-HSCT in CR1 was an independent predictor of improved DFS, but was not a prognostic factor for OS. Figure 1 Figure 1. Disclosures Abrahamsson: wedish Children´s Cancer Foundation. Research grants and 50% senior research position for clinical research on pediatric leukemia: Research Funding. Locatelli: Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Miltenyi: Speakers Bureau; Medac: Speakers Bureau; Jazz Pharamceutical: Speakers Bureau; Takeda: Speakers Bureau.