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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

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.

Purpose: Patients with hematological malignancies (HM) have more unpredictable disease trajectories compared to patients with advanced solid tumors (STs) and miss opportunities for a palliative care approach. They often undergo intensive disease-directed treatments until the end of life with frequent emergency department (ED) visits and in-hospital deaths. Insight into end-of-life trajectories and quality of end-of-life care can support arranging appropriate care according to patients’ wishes. Method: Mortality follow-back study to compare of end-of-life trajectories of HM and ST patients who died Results: We included 78 HM patients and 420 ST patients, with a median age of 63 years; 35% had Eastern Cooperative Oncology Group performance status 3-4. At the ED, common symptoms were dyspnea (22%), pain (18%), and fever (11%). After ED visit, 91% of HM patients versus 76% of ST patients were hospitalized ( P = .001). Median survival was 17 days (95% confidence interval [CI]: 15-19): 15 days in HM patients (95% CI: 10-20) versus 18 days in ST patients (95% CI: 15-21), P = .028. Compared to ST patients, HM patients more often died in hospital (68% vs 30%, P < .0001) and in the ICU or ED (30% vs 3%, P < .0001). Conclusion: Because end-of-life care is more aggressive in HM patients compared to ST patients, a proactive integrated care approach with early start of palliative care alongside curative care is warranted. Timely discussions with patients and family about advance care planning and end-of-life choices can avoid inappropriate care at the end of life.

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.

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

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.

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.

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

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. 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: 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.

Sentinel node procedures (SNP) are performed with the use of tracer-agents, mainly radio-colloid and/or blue dye. Fluorescent agents have emerged as a new tracer-agent to identify the SLN intra-operatively with near-infrared imaging. Our aim is to compare the detection rate of fluorescent agents to current "golden standards" (blue dye and/or radio-colloid) for the SNP by means of a systematic review and meta-analysis without any restrictions based on tumor type.A systematic search in PubMed, Embase and The Cochrane Library was performed. Articles that compared the detection rates of fluorescent agents with radio-colloid and/or blue dye were included. Meta-analyses were performed for breast, gynecological and dermatological cancer using a random effects model.In total 6195 articles were screened which resulted in a final inclusion of 55 articles. All studies used indocyanine green (ICG) as fluorescent agent. Meta-analyses comparing ICG with blue dye showed a significant and clinically relevant difference in detection rate in favor of ICG, for both breast, dermatological and gynecological cancer. Meta-analyses comparing ICG with radio-colloid did not show any significant differences, with the exception of ICG versus radio-colloid + blue dye for the bilateral SLN detection in gynecological cancer.Near-infrared fluorescence imaging using ICG provides a higher detection rate compared to blue dye for the SNP in a range of different tumor types. SLN detection rates of ICG are comparable to radiocolloid. Due to their complementary characteristics in terms of spatial resolution and transdermal sensitivity, we suggest to use a combination of both ICG and a radio-colloid. (C) 2020 The Authors. Published by Elsevier Ltd.

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

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

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 and purpose - Little is known about the long-term migration pattern of cementless stems in total hip arthroplasty (THA). Furthermore, the role of bioactive coatings in fixation, and thus migration, remains uncertain. Hydroxyapatite (HA) is the most commonly used bioactive coating. However, delamination of the coating might induce loosening. Alternatively, fluorapatite (FA) has proved to be more thermostable than HA, thereby potentially increasing longevity. We assessed the long-term migration of cementless stems with different coatings using radiostereometric analysis (RSA), thereby establishing a reference for acceptable migration.Patients and methods - 61 THAs in 53 patients were randomized to receive either a HA, FA, or uncoated Mallory-Head Porous stem during the years 1992 to 1994. Primary outcome was stem migration measured using RSA and secondary outcome was the Harris Hip Score (HHS). Evaluation took place preoperatively and postoperatively on the second day, at 6, 12, 25 and 52 weeks, and annually thereafter. At the 25-year follow-up, 12 patients (17 THAs) had died and 1 patient (1 THA) was lost to follow-up. Due to the high number of missing second-day postoperative RSA radiographs, the 1-year postoperative RSA radiograph was used as baseline for the comparative analyses.Results - Mean follow-up was 17 years (SD 6.6). All stems showed initial rapid migration with median subsidence of 0.2 mm (-0.1 to 0.6) and median retroversion of 0.9 degrees (-3.2 to 2) at 12 months, followed by stable migration reaching a plateau phase. No stem was revised, albeit 1 stem showed continuous subsidence up to 1.5 mm. Comparing the different coatings, we could not find a statistically significant difference in overall 25-year migration (p-values > 0.05). Median subsidence at 15-year follow-up was for HA -0.1 mm (-0.4 to 0.2), for FA 0 mm (-0.1 to 0.2), and for uncoated stems 0.2 mm (-0.1 to 0.5). Median internal rotation at 15-year follow-up was for HA not available, for FA 1.1 degrees (-0.5 to 2.6), and for uncoated stems 0 degrees (-0.5 to 0.4). HHS were also comparable (p-values > 0.05), with at 15-year follow-up for HA 85 points (41-99), for FA 76 points (61-90), and for uncoated stems 79 points (74-90).Interpretation - The long-term migration pattern of cementless stems using different bioactive coatings has not previously been described. No beneficial effect, or side effect at long-term follow-up of bioactive coatings, was found. The provided migration data can be used in future research to establish thresholds for acceptable migration patterns cementless stem designs.

Background: Pain is a common symptom in childhood cancer. Since children spend more time at home, families are increasingly responsible for pain management. This study aimed at assessing pain at home. Procedure: In this longitudinal observational study (April 2016-January 2017), pain severity and prevalence, analgesic use, and pain interference with daily life (Brief Pain Inventory Short Form) were assessed for 4 consecutive days around the time of multiple chemotherapy appointments. Descriptive statistics (frequencies and percentages) were used to report pain severity (with clinically significant pain defined as: score ≥ 4 on “worst pain” or “average pain in the last 24 h”), pain prevalence, and analgesic use. Mixed models were estimated to assess whether patient characteristics were associated with pain severity, and whether pain severity was associated with interference with daily life. Results: Seventy-three children (50.7% male) participated (1-18 years). A majority (N = 57, 78%) experienced clinically significant pain at least once, and 30% reported clinically significant pain at least half the time. In 33.6% of scores ≥ 4, no medication was used. We found an association between pain severity and interference with daily life: the higher the pain, the bigger the interference (estimated regression coefficient = 1.01 [95% CI 0.98-1.13]). Conclusions: The majority of children experienced clinically significant pain at home, and families frequently indicated no medication use. A stronger focus on education and coaching of families seems essential, as well as routine screening for pain in the home setting.

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 Although less frequent than in adults, taste loss also occurs in childhood. “Taste Strips” are frequently used for diagnosing taste dysfunction; however, normative values are lacking for children. In this study, we will create normative values for the “Taste Strips” in children. Methods This cross-sectional study included 609 children aged 6–15 years. “Taste Strips” were used to determine sweet, sour, salty, and bitter taste scores by a non-forced procedure. The 10th percentile was used to distinguish normal taste function from a reduced sense of taste. Multivariable generalized linear models (GLM) were estimated to study the effect of age (group), sex, and 6‐n‐propylthiouracil (PROP) status on taste function. Results Taste function changed with age, allowing for a distinction of three age groups: (I) 6–7 years, (II) 8–9 years, and (III) 10–15 years. Normative values were created for the age groups and boys and girls separately. Additionally, GLM showed a significant effect of (1) age (group) on sweet, salty, bitter, and total taste scores; (2) sex on sweet, sour, and total taste scores; and (3) PROP status on total taste scores. Conclusions This study provided normative values for the “Taste Strips” in children, highlighting age- and sex-related differences. Impact Taste dysfunction can be harmful and impacts quality of life, a topic that became increasingly important since the COVID-19 pandemic. Although taste dysfunction is thought to be rare in childhood, the detrimental impact of such dysfunction might be large, as children’s eating habits are strongly influenced by input from the chemical senses. Measuring taste function may elucidate the relationship between taste dysfunction and disease, fostering the development of more appropriate supportive strategies. However, adequate tools are lacking for children. Normative values of the “Taste Strips” are now available for children, which bolster the clinical utility of this test.

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 ...

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

Patients with nonmetastatic esophageal cancer not suitable for surgery can be treated with definitive chemoradiotherapy with curative intent. The purpose of this retrospective study is to evaluate the clinical outcomes of definitive chemoradiotherapy using carboplatin and paclitaxel. Medical records were reviewed of patients treated for nonmetastatic squamous cell or adenocarcinoma of the esophagus between January 2009 and December 2013 in two collaborating institutes. Treatment consisted of external beam radiotherapy (28 fractions of 1.8 Gy) and 6 weekly courses of carboplatin (AUC = 2) and paclitaxel (50 mg/m2). Data on survival, progression, toxicity, and effect on dysphagia were recorded. Sixty-six patients were included. Median overall survival (OS) was 13.1 months (95% CI 4.7-21.5 months) and a 2-year OS was 30% (95% CI 18%-42%). At 2 years, 26% of patients developed local progression (95% CI 15%-37%) and 49% developed distant metastases (95% CI 36%-64%). Acute toxicity grade ≥3 was observed in 47% of patients. Late adverse events grade ≥3 were seen in 20%, mostly esophageal stenoses. Of patients with available data 3 months after treatment, 70% had relief of dysphagia. Definitive chemoradiotherapy led to a median OS of 13 months. Toxicity was common, mostly due to hematological toxicity. Given the relatively short median survival, an adequate selection of patients for this intensive treatment is required.

Permanent alopecia after haematopoietic stem cell transplantation (HSCT) is distressing and few studies have investigated this late effect. The aim of the study was to assess the percentage of patients with alopecia and investigate risk factors for alopecia. Patients who underwent allogeneic HSCT before age 19 years, from January 1990 to January 2013, who were at least 2 years after transplant and in follow-up in our clinic were included. Alopecia was defined as clinically apparent decreased hair density. Possible risk factors considered for alopecia after HSCT included: gender, age, diagnosis, donor type, conditioning regimen: cranial irradiation (TBI/cranial radiotherapy) and/or chemotherapy, which chemotherapeutic agents were used and acute/chronic GvHD. The percentage of permanent alopecia in our cohort was 15.6% (41/263 patients). All patients had diffuse alopecia except for one with alopecia totalis. In multivariate analysis, a conditioning regimen with busulphan and busulphan plus fludarabine (odds ratio (OR) 5.7 (confidence interval (CI): 2.5-12.7) and OR 7.4 (CI: 3.3-16.2), respectively, was the main risk factor and associated with alopecia independent of acute/chronic GvHD. Neither TBI nor other alkylating chemotherapy, including treosulfan, was associated with alopecia. In conclusion, permanent alopecia after HSCT is associated with busulphan and GvHD and occurs in 16% of patients.

INTRODUCTION: Neuroblastoma (NBL) accounts for 10% of the paediatric malignancies and is responsible for 15% of the paediatric cancer-related deaths. Vanillylmandelic acid (VMA) and homovanillic acid (HVA) are most commonly analysed in urine of NBL patients. However, their diagnostic sensitivity is suboptimal (82%). Therefore, we performed in-depth analysis of the diagnostic sensitivity of a panel of urinary catecholamine metabolites.PATIENTS AND METHODS: Retrospective study of a panel of 8 urinary catecholamine metabolites (VMA, HVA, 3-methoxytyramine [3MT], dopamine, epinephrine, metanephrine, norepinephrine and normetanephrine [NMN]) from 301 NBL patients at diagnosis. Special attention was given to subgroups, metaiodobenzylguanidine (MIBG) non-avid tumours and VMA/HVA negative patients.RESULTS: Elevated catecholamine metabolites, especially 3MT, correlated with nine out of 12 NBL characteristics such as stage, age, MYCN amplification, loss of heterozygosity for 1p and bone-marrow invasion. The combination of the classical markers VMA and HVA had a diagnostic sensitivity of 84%. NMN was the most sensitive single diagnostic metabolite with overall sensitivity of 89%. When all 8 metabolites were combined, a diagnostic sensitivity of 95% was achieved. Among the VMA and HVA negative patients, were also 29% with stage 4 disease, which usually had elevation of other catecholamine metabolites (93%). Diagnostic sensitivity for patients with MIBG non-avid tumour was improved from 33% (VMA and/or HVA) to 89% by measuring the panel.CONCLUSIONS: Our study demonstrates that analysis of a urinary catecholamine metabolite panel, comprising 8 metabolites, ensures the highest sensitivity to diagnose NBL patients.

Background Modular endoprostheses are commonly used to reconstruct defects of the distal femur and proximal tibia after bone tumor resection. Because limb salvage surgery for bone sarcomas is relatively new, becoming more frequently used since the 1980s, studies focusing on the long-term results of such prostheses in treatment of primary tumors are scarce. Questions/purposes (1) What proportion of patients experience a mechanical complication with the MUTARS® modular endoprosthesis when used for tumor reconstruction around the knee, and what factors may be associated with mechanical failure? (2) What are the nonmechanical complications? (3) What are the implant failure rates at 5, 10, and 15 years? (4) How often is limb salvage achieved using this prosthesis? Methods Between 1995 and 2010, endoprostheses were the preferred method of reconstruction after resection of the knee in adolescents and adults in our centers. During that period, we performed 114 MUTARS® knee replacements in 105 patients; no other endoprosthetic systems were used. Four patients (four of 105 [4%]) were lost to followup, leaving 110 reconstructions in 101 patients for review. The reverse Kaplan-Meier method was used to calculate median followup, which was equal to 8.9 years (95% confidence interval [CI], 8.0–9.7). Mean age at surgery was 36 years (range, 13–82 years). Predominant diagnoses were osteosarcoma (n = 56 [55%]), leiomyosarcoma of bone (n = 10 [10%]), and chondrosarcoma (n = 9 [9%]). In the early period of our study, we routinely used uncemented uncoated implants for primary reconstructions. Later, hydroxyapatite (HA)-coated implants were the standard. Eighty-nine reconstructions (89 of 110 [81%]) were distal femoral replacements (78 uncemented [78 of 89 {88%}, 42 of which were HA-coated [42 of 78 {54%}]) and 21 (21 of 110 [19%]) were proximal tibial replacements. In 26 reconstructions (26 of 110 [24%]), the reconstruction was performed for a failed previous reconstruction. We used a competing risk model to estimate the cumulative incidence of implant failure. Results Complications of soft tissue or instability occurred in seven reconstructions (seven of 110 [6%]). With the numbers we had, for uncemented distal femoral replacements, we could not detect a difference in loosening between revision (five of 17 [29%]) and primary reconstructions (eight of 61 [13%]) (hazard ratio [HR], 1.72; 95% CI, 0.55–5.38; p = 0.354). Hydroxyapatite-coated uncemented implants had a lower risk of loosening (two of 42 [5%]) than uncoated uncemented implants (11 of 36 [31%]) (HR, 0.23; 95% CI, 0.05–1.06; p = 0.060). Structural complications occurred in 15 reconstructions (15 of 110 [14%]). Infections occurred in 14 reconstructions (14 of 110 [13%]). Ten patients had a local recurrence (10 of 101 [10%]). With failure for mechanical reasons as the endpoint, the cumulative incidences of implant failure at 5, 10, and 15 years were 16.9% (95% CI, 9.6–24.2), 20.7% (95% CI, 12.5–28.8%), and 37.9% (95% CI, 16.1–59.7), respectively. We were able to salvage some of the failures so that at followup, 90 patients (90 of 101 [89%]) had a MUTARS® in situ. Conclusions Although no system has yet proved ideal to restore normal function and demonstrate long-term retention of the implant, MUTARS® modular endoprostheses represent a reliable long-term option for knee replacement after tumor resection, which seems to be comparable to other modular implants available to surgeons. Although the number of patients is relatively small, we could demonstrate that with this prosthesis, an uncemented HA-coated implant is useful in achieving durable fixation. Level of Evidence Level IV, therapeutic study.

Reconstruction of periacetabular defects after pelvic tumor resection ranks among the most challenging procedures in orthopaedic oncology, and reconstructive techniques are generally associated with dissatisfying mechanical and nonmechanical complication rates. In an attempt to reduce the risk of dislocation, aseptic loosening, and infection, we introduced the LUMiC(A (R)) prosthesis (implantcast, Buxtehude, Germany) in 2008. The LUMiC(A (R)) prosthesis is a modular device, built of a separate stem (hydroxyapatite-coated uncemented or cemented) and acetabular cup. The stem and cup are available in different sizes (the latter of which is also available with silver coating for infection prevention) and are equipped with sawteeth at the junction to allow for rotational adjustment of cup position after implantation of the stem. Whether this implant indeed is durable at short-term followup has not been evaluated.(1) What proportion of patients experience mechanical complications and what are the associated risk factors of periacetabular reconstruction with the LUMiC(A (R)) after pelvic tumor resection? (2) What proportion of patients experience nonmechanical complications and what are the associated risk factors of periacetabular reconstruction with the LUMiC(A (R)) after pelvic tumor resection? (3) What is the cumulative incidence of implant failure at 2 and 5 years and what are the mechanisms of reconstruction failure? (4) What is the functional outcome as assessed by Musculoskeletal Tumor Society (MSTS) score at final followup?We performed a retrospective chart review of every patient in whom a LUMiC(A (R)) prosthesis was used to reconstruct a periacetabular defect after internal hemipelvectomy for a pelvic tumor from July 2008 to June 2014 in eight centers of orthopaedic oncology with a minimum followup of 24 months. Forty-seven patients (26 men [55%]) with a mean age of 50 years (range, 12-78 years) were included. At review, 32 patients (68%) were alive. The reverse Kaplan-Meier method was used to calculate median followup, which was equal to 3.9 years (95% confidence interval [CI], 3.4-4.3). During the period under study, our general indications for using this implant were reconstruction of periacetabular defects after pelvic tumor resections in which the medial ilium adjacent to the sacroiliac joint was preserved; alternative treatments included hip transposition and saddle or custom-made prostheses in some of the contributing centers; these were generally used when the medial ilium was involved in the tumorous process or if the LUMiC(A (R)) was not yet available in the specific country at that time. Conventional chondrosarcoma was the predominant diagnosis (n = 22 [47%]); five patients (11%) had osseous metastases of a distant carcinoma and three (6%) had multiple myeloma. Uncemented fixation (n = 43 [91%]) was preferred. Dual-mobility cups (n = 24 [51%]) were mainly used in case of a higher presumed risk of dislocation in the early period of our study; later, dual-mobility cups became the standard for the majority of the reconstructions. Silver-coated acetabular cups were used in 29 reconstructions (62%); because only the largest cup size was available with silver coating, its use depended on the cup size that was chosen. We used a competing risk model to estimate the cumulative incidence of implant failure.Six patients (13%) had a single dislocation; four (9%) had recurrent dislocations. The risk of dislocation was lower in reconstructions with a dual-mobility cup (one of 24 [4%]) than in those without (nine of 23 [39%]) (hazard ratio, 0.11; 95% CI, 0.01-0.89; p = 0.038). Three patients (6%; one with a preceding structural allograft reconstruction, one with poor initial fixation as a result of an intraoperative fracture, and one with a cemented stem) had loosening and underwent revision. Infections occurred in 13 reconstructions (28%). Median duration of surgery was 6.5 hours (range, 4.0-13.6 hours) for patients with an infection and 5.3 hours (range, 2.8-9.9 hours) for those without (p = 0.060); blood loss was 2.3 L (range, 0.8-8.2 L) for patients with an infection and 1.5 L (range, 0.4-3.8 L) for those without (p = 0.039). The cumulative incidences of implant failure at 2 and 5 years were 2.1% (95% CI, 0-6.3) and 17.3% (95% CI, 0.7-33.9) for mechanical reasons and 6.4% (95% CI, 0-13.4) and 9.2% (95% CI, 0.5-17.9) for infection, respectively. Reasons for reconstruction failure were instability (n = 1 [2%]), loosening (n = 3 [6%]), and infection (n = 4 [9%]). Mean MSTS functional outcome score at followup was 70% (range, 33%-93%).At short-term followup, the LUMiC(A (R)) prosthesis demonstrated a low frequency of mechanical complications and failure when used to reconstruct the acetabulum in patients who underwent major pelvic tumor resections, and we believe this is a useful reconstruction for periacetabular resections for tumor or failed prior reconstructions. Still, infection and dislocation are relatively common after these complex reconstructions. Dual-mobility articulation in our experience is associated with a lower risk of dislocation. Future, larger studies will need to further control for factors such as dual-mobility articulation and silver coating. We will continue to follow our patients over the longer term to ascertain the role of this implant in this setting.Level IV, therapeutic study.

Purpose To assess whether delayed radiological hip screening at five months (versus ultrasound at 3 months) results in a higher incidence of persistent developmental dysplasia of the hip (DDH) at 18 months. Methods We analyzed 3536 screened neonates (2009–2013) at age two to three weeks. In the case of risk factors for DDH, 460 infants were assigned to a pelvic radiograph at five months between 2009 and 2010 and 651 infants were assigned to an ultrasound at three months (2011–2013). In the case of DDH, appropriate treatment was started and radiological follow-up occurred at eight, ten, 12, and 18 months. We compared incidence and severity of persistent DDH at 18 months. Analysis was performed using linear regression. Results Both groups were comparable for risk factors (breech, gender, twins, family history). Eighty-nine patients (2.5%) showed DDH (n = 43 (group 1), n = 46 (group 2)). At 18 months, ten patients showed persistent DDH (n = 8 (group 1), n = 2 (group 2) (7.7% vs. 0.3% respectively)). The mean acetabular index (AI) at 18 months in group 1 (left hip) is 22.4° (95% CI 20.6–24.3°) vs. group 2 at 22.3° (95% CI 21.2–23.4°) (p = 0.098). The mean AI in group 1 (right hip) is 21.9° (95% CI 18.9–24.9°) vs. 21.2° (95% CI 20.5–22.0°) in group 2 (p = 0.293). Adjusted for risk factors, there is no difference in incidence of persistent DDH between both groups after 18 months (OR 0.519; 0.07, 3.845). Discussion This study revealed no significant difference in incidence or severity of persistent DDH at 18 months between the two screening groups. These results suggest justification for delayed screening to prevent overtreatment of immature hips. Conclusion In clinically stable hips, delayed ultrasound between three and five months is regarded as safe and could prevent for overtreatment of mild dysplastic hips.

Background Adjuvant bisphosphonates are associated with improved breast cancer survival in postmenopausal patients. Addition of zoledronic acid (ZA) to neoadjuvant chemotherapy did not improve pathological complete response in the phase III NEOZOTAC trial. Here we report the results of the secondary endpoints, disease-free survival, (DFS) and overall survival (OS). Patients and methods Patients with HER2-negative, stage II/III breast cancer were randomized to receive the standard 6 cycles of neoadjuvant TAC (docetaxel/doxorubicin/cyclophosphamide) chemotherapy with or without 4 mg intravenous (IV) ZA administered within 24 h of chemotherapy. This was repeated every 21 days for 6 cycles. Cox regression models were used to evaluate the effect of ZA and covariates on DFS and OS. Regression models were used to examine the association between insulin, glucose, insulin growth factor-1 (IGF-1) levels, and IGF-1 receptor (IGF-1R) expression with survival outcomes. Results Two hundred forty-six women were eligible for inclusion. After a median follow-up of 6.4 years, OS for all patients was significantly worse for those who received ZA (HR 0.468, 95% CI 0.226–0.967, P = 0.040). DFS was not significantly different between the treatment arms (HR 0.656, 95% CI 0.371–1.160, P = 0.147). In a subgroup analysis of postmenopausal women, no significant difference in DFS or OS was found for those who received ZA compared with the control group (HR 0.464, 95% CI 0.176–1.222, P = 0.120; HR 0.539, 95% CI 0.228–1.273, P = 0.159, respectively). The subgroup analysis of premenopausal patients was not significantly different for DFS and OS ((HR 0.798, 95% CI 0.369–1.725, P = 0.565; HR 0.456, 95% CI 0.156–1.336, P = 0.152, respectively). Baseline IGF-1R expression was not significantly associated with DFS or OS. In a predefined additional study, lower serum levels of insulin were associated with improved DFS (HR 1.025, 95% CI 1.005–1.045, P = 0.014). Conclusions Our results suggest that ZA in combination with neoadjuvant chemotherapy was associated with a worse OS in breast cancer (both pre- and postmenopausal patients). However, in a subgroup analysis of postmenopausal patients, ZA treatment was not associated with DFS or OS. Also, DFS was not significantly different between both groups. IGF-1R expression in tumor tissue before and after neoadjuvant treatment did not predict survival. Trial registration ClinicalTrials.gov, NCT01099436, April 2010.

Purpose: To investigate the safety and toxicity of percutaneous hepatic perfusion with melphalan (M-PHP) with the Delcath Systems’ second-generation (GEN 2) filter and compare the outcomes with historical data from studies using the first-generation filter. Materials and Methods: A prospective, single-arm, single-center phase II study was carried out including 35 patients with unresectable, histologically confirmed liver metastases from ocular melanoma between February 2014 and June 2017. Main exclusion criteria were extrahepatic disease and age > 75 years. M-PHP was performed with melphalan 3 mg/kg (maximum dose 220 mg). Safety and toxicity were assessed according to the Common Terminology Criteria for Adverse Events version 4.03. Results: A total of 67 M-PHPs were performed in 35 patients (median 2 procedures). Although hematologic grade 3/4 events were seen in the majority of patients (thrombocytopenia 54.5%, leukopenia 75.6%, neutropenia 66.7%, anemia (only grade 3) 18.1%), these were all well manageable or self-limiting. Of the non-hematologic grade 3 events (n = 14), febrile neutropenia (n = 3), pulmonary emboli (n = 2) and post-procedural hemorrhage (n = 2) were most common. A case of sepsis with bacterial pharyngitis was the only non-hematologic grade 4 event. Prior therapy for liver metastases was found to be a predictor of late grade 3/4 neutropenia with an odds ratio of 5.5 (95% CI 1.4–21.7). Conclusions: M-PHP using the GEN 2 filter has an acceptable safety and toxicity profile, and seems to reduce hematologic toxicity when compared to M-PHP with a first-generation filter. Prior therapy of liver metastases is a possible predictive factor in developing grade 3/4 hematologic toxicity.

Purpose Patients with advanced cancer commonly visit the emergency department (ED) during the last 3 months of life. Identification of these patients and their palliative care needs help initiating appropriate care according to patients' wishes. Our objective was to provide insight into ED visits of advanced cancer patients at the end of life. Methods Adult palliative patients with solid tumours who died < 3 months after their ED visit were included (2011-2014). Patients, ED visits, and follow-up were described. Factors associated with approaching death were assessed using Cox proportional hazards models. Results Four hundred twenty patients were included, 54.5% was male, median age 63 years. A total of 54.6% was on systemic anti-cancer treatments and 10.5% received home care >= 1 per day. ED visits were initiated by patients and family in 34.0% and 51.9% occurred during out-of-office hours. Dyspnoea (21.0%) or pain (18.6%) were most reported symptoms. Before the ED visit, limitations on life-sustaining treatments were discussed in 33.8%, during or after the ED visit in 70.7%. Median stay at the ED was 3:29 h (range 00:12-18:01 h), and 319 (76.0%) were hospitalized. Median survival was 18 days (IQ range 7-41). One hundred four (24.8%) died within 7 days after the ED visit, of which 71.2% in-hospital. Factors associated with approaching death were lung cancer, neurologic deterioration, dyspnoea, hypercalcemia, and jaundice. Conclusion ED visits of advanced cancer patients often lead to hospitalization and in-hospital deaths. Timely recognition of patients with limited life expectancies and urgent palliative care needs, and awareness among ED staff of the potential of ED-initiated palliative care may improve the end-of-life trajectory of these patients.

BackgroundMethotrexate (MTX) is an important anti-folate agent in pediatric acute lymphoblastic leukemia (ALL) treatment. Folinic acid rescue therapy (Leucovorin) is administered after MTX to reduce toxicity. Previous studies hypothesized that Leucovorin could `rescue' both normal healthy cells and leukemic blasts from cell death. We assessed whether Leucovorin is able to restore red blood cell folate levels after MTX.MethodsWe prospectively determined erythrocyte folate levels (5-methyltetrahydrofolate (THF) and non-methyl THF) and serum folate levels in 67 children with ALL before start (T0) and after stop (T1) of HD-MTX and Leucovorin courses.ResultsErythrocyte folate levels increased between T0 and T1 (mean +/- SD: 416.7 +/- 145.5 nmol/L and 641.2 +/- 196.3 nmol/L respectively, p T genotype.ConclusionIntracellular folate levels accumulate after HD-MTX and Leucovorin therapy in children with ALL, suggesting that Leucovorin restores the intracellular folate pool. Future studies are necessary to assess concomitant lower uptake of MTX.

Single-port laparoscopy (SPL) is a relatively new technique, used in various procedures. There is limited knowledge about the cost effectiveness and the learning curve of this technique. The primary aim of this study was to compare hospital costs between SPL and conventional laparoscopic resections (CLR) for colorectal cancer; the secondary aim was to identify a learning curve of SPL. All elective colorectal cancer SPL and CLR performed in a major teaching hospital between 2011 and 2012 that were registered in the Dutch Surgical Colorectal Audit were included (n = 267). The economic evaluation was conducted from a hospital perspective, and costs were calculated using time-driven activity-based costing methodology up to 90 days after discharge. When looking at SPL only, the introduction year (2011) was compared to the next year (2012). SPL (n = 78) was associated with lower mortality, lower reintervention rates, and more complications as compared to CLR (n = 189); however, none of these differences were statistically significant. A significant shorter operating time was seen in the SPL. Total costs were higher for SPL group as compared to CLR; however, this difference was not statistically significant. For the SPL group, most clinical outcomes improved between 2011 and 2012; moreover, total hospital costs for SPL in 2012 became comparable to CLR. No significant differences in financial outcomes between SPL and CLR were identified. After the introduction period, SPL showed similar results as compared to CLR. Conclusions are based on a small single-port group and the conclusions of this manuscript should be an impetus for further research.

AimsThe widely used and well-proven Palacos R (a.k.a. Refobacin Palacos R) bone cement is no longer commercially available and was superseded by Refobacin bone cement R and Palacos R + G in 2005. However, the performance of these newly introduced bone cements have not been tested in a phased evidence-based manner, including roentgen stereophotogrammetric analysis (RSA).Patients and MethodsIn this blinded, randomised, clinical RSA study, the migration of the Stanmore femoral component was compared between Refobacin bone cement R and Palacos R + G in 62 consecutive total hip arthroplasties. The primary outcome measure was femoral component migration measured using RSA and secondary outcomes were Harris hip score (HHS), Hip disability and Osteoarthritis Outcome Score (HOOS), EuroQol 5D (EQ-5D) and Short Form 36 (SF-36).ResultsFemoral component migration was comparable between Refobacin bone cement R and Palacos R + G during the two-year follow-up period with an estimated mean difference of 0.06 mm of subsidence (p = 0.56) and 0.08° of retroversion (p = 0.82). Five hips (three Refobacin bone cement R and two Palacos R + G) showed non-stabilising, continuous migration; the femoral cement mantle in these hips, was mean 0.7 mm thicker (p = 0.02) and there were more radiolucencies at the bone-cement interface (p = 0.004) in comparison to hips showing stabilising migration. Post-operative HHS was comparable throughout the follow-up period (p = 0.62). HOOS, EQ5D, and SF-36 scores were also comparable (p-values > 0.05) at the two-year follow-up point.ConclusionRefobacin bone cement R and Palacos R + G show comparable component migration and clinical outcome during the first two post-operative years. Hips showing continuous migration are at risk for early failure. However, this seems to be unrelated to cement type, but rather to cementing technique. Cite this article: Bone Joint J 2016;98-B:1333–41.

Study Design.A retrospective cohort study.Objective.The aim of this study was to assess and compare the predictive accuracy of six models designed to estimate survival of patients suffering from spinal bone metastases Just (SBMs).Summary of Background Data.On the basis of the estimated survival of patients with SBM, extent of treatment can be adjusted. To aid clinicians in the difficult task of assessing probability of survival, prognostic scoring systems have been developed by Tomita, Tokuhashi, Van der Linden, Bauer, Rades, and Bollen.Methods.All patients who were treated for SBM between 2000 and 2010 were included in this international, multicenter, retrospective study (n=1379). Medical records were reviewed for all items needed to use the scoring systems. Survival time was calculated as the difference between start of treatment for SBM and date of death. Survival curves were estimated using the Kaplan-Meier method and accuracy was assessed with the c-statistic. Survival rates of the worst prognostic groups were evaluated at 4 months.Results.Median follow-up was 6.7 years [95% confidence interval (95% CI) 5.6-7.7] with a minimum of 2.3 years and a maximum of 12.3 years. The overall median survival was 5.1 months (95% CI 4.6-5.6). The most common primary tumors were breast (n=388, 28%), lung (n=318, 23%), and prostate cancer (n=259, 19%). The Tokuhashi, Bauer, Tomita, and Van der Linden models performed similar with a c-statistic of 0.64 to 0.66 and a 4-month accuracy of 62% to 65%. The Rades model (c-statistic 0.44) and Bollen model (c-statistic 0.70) had a 4-month accuracy of 69% and 75%, respectively.Conclusion.The Bollen model performs better than the other models. However, improvements are still warranted to increase the accuracy.Level of Evidence: 3

Background and purpose — There is no consensus on the impact of radiographic severity of hip and knee osteoarthritis (OA) on the clinical outcome of total hip arthroplasty (THA) and total knee arthroplasty (TKA). We assessed whether preoperative radiographic severity of OA is related to improvements in functioning, pain, and health-related quality of life (HRQoL) 1 year after THA or TKA. Patients and methods — This prospective cohort study included 302 THA patients and 271 TKA patients with hip or knee OA. In the THA patients, preoperatively 26% had mild OA and 74% had severe OA; in the TKA patients, preoperatively 27% had mild OA and 73% had severe OA. Radiographic severity was determined according to the Kellgren and Lawrence (KL) classification. Clinical assessments preoperatively and 1 year postoperatively included: sociodemographic characteristics and patient-reported outcomes (PROMs): Oxford hip/knee score, hip/knee injury and osteoarthritis outcome score (HOOS/KOOS), SF36, and EQ5D. Change scores of PROMs were compared with mild OA (KL 0–2) and severe OA (KL 3–4) using a multivariate linear regression model. Results — Adjusted for sex, age, preoperative scores, BMI, and Charnley score, radiographic severity of OA in THA was associated with improvement in HOOS “Activities of daily living”, “Pain”, and “Symptoms”, and SF36 physical component summary (“PCS”) scale. In TKA, we found no such associations. Interpretation — The decrease in pain and improvement in function in THA patients, but not in TKA patients, was positively associated with the preoperative radiographic severity of OA.

Introduction The clinical importance of the detection of neuroblastoma messenger RNA (mRNA) in bone marrow (BM) of localised neuroblastoma patients at diagnosis remains unclear. In this prospective multicentre study, BM samples of a large cohort, were studied using real-time quantitative polymerase chain reaction (qPCR). Methods BM samples at diagnosis from 160 patients with localised neuroblastoma were prospectively collected at Dutch and German centres between 2009 and 2013. qPCR was performed using five neuroblastoma specific markers. The association with other biological factors and the prognostic impact of BM positivity and clinical response was assessed. Results In 58 out of 160 patients neuroblastoma mRNA was detected in BM. In 47 of the 58 positive samples only one marker was found positive. BM positivity was significantly associated with MYCN amplification (p = 0.02) and deletion of chromosome 1p (p = 0.04). In total 31 patients had an event, of which only five patients had progression to stage IV. BM positivity was not associated with an unfavourable outcome. However, the detection of more than one marker was associated with an unfavourable outcome (systemic or local relapse) (event free survival 48% versus 85%; p = 0.03) in the whole cohort and in the observation group. Conclusions BM positivity was associated with unfavourable biological factors and might represent more aggressive tumours. Patients with qPCR positive BM should not be upstaged, because of very few systemic events in the cohort. However, for patients with more than one marker positive a more careful follow-up is advisable. These results need to be verified in a very large cohort of localised patients.

Background Actual and impending pathologic fractures of the femur are commonly treated with intramedullary nails because they provide immediate stabilization with a minimally invasive procedure and enable direct weightbearing. However, complications and revision surgery are prevalent, and despite common use, there is limited evidence identifying those factors that are associated with complications.Questions/purposes Among patients treated with intramedullary nailing for femoral metastases, we asked the following questions: (1) What is the cumulative incidence of local complications? (2) What is the cumulative incidence of implant breakage and what factors are associated with implant breakage? (3) What is the cumulative incidence of revision surgery and what factors are associated with revision surgery?Methods Between January 2000 and December 2015, 245 patients in five centers were treated with intramedullary nails for actual and impending pathologic fractures of the femur caused by bone metastases. During that period, the general indications for intramedullary nailing of femoral metastases were impending fractures of the trochanter region and shaft and actual fractures of the trochanter region if sufficient bone stock remained; nails were used for lesions of the femoral shaft if they were large or if multiple lesions were present. Of those treated with intramedullary nails, 51% (117) were actual fractures and 49% (111) were impending fractures. A total of 60% (128) of this group were women; the mean age was 65 years (range, 29-93 years). After radiologic followup (at 4-8 weeks) with the orthopaedic surgeon, because of the palliative nature of these treatments, subsequent in-person followup was performed by the primary care provider on an as-needed basis (that is, as desired by the patient, without any scheduled visits with the orthopaedic surgeon) throughout each patient's remaining lifetime. However, there was close collaboration between the primary care providers and the orthopaedic team such that orthopaedic complications would be reported. A total of 67% (142 of 212) of the patients died before 1 year, and followup ranged from 0.1 to 175 months (mean, 14.4 months). Competing risk models were used to estimate the cumulative incidence of local complications (including persisting pain, tumor progression, and implant breakage), implant breakage separately, and revision surgery (defined as any reoperation involving the implant other than debridement with implant retention for infection). A cause-specific multivariate Cox regression model was used to estimate the association of factors (fracture type/preoperative radiotherapy and fracture type/use of cement) with implant breakage and revision, respectively.Results Local complications occurred in 12% (28 of 228) of the patients and 6-month cumulative incidence was 8% (95% confidence interval [CI], 4.7-11.9). Implant breakage occurred in 8% (18 of 228) of the patients and 6-month cumulative incidence was 4%(95% CI, 1.4-6.5). Independent factors associated with increased risk of implant breakage were an actual (as opposed to impending) fracture (cause-specific hazard ratio [HR_cs], 3.61; 95% CI, 1.23-10.53, p = 0.019) and previous radiotherapy (HR_cs, 2.97; 95% CI, 1.13-7.82, p = 0.027). Revisions occurred in 5% (12 of 228) of the patients and 6-month cumulative incidence was 2.2% (95% CI, 0.3-4.1). The presence of an actual fracture was independently associated with a higher risk of revision (HR_cs, 4.17; 95% CI, 0.08-0.82, p = 0.022), and use of cement was independently associated with a lower risk of revision (HR_cs, 0.25; 95% CI, 1.20-14.53, p = 0.025).Conclusions The cumulative incidence of local complications, implant breakage, and revisions is low, mostly as a result of the short survival of patients. Based on these results, surgeons should consider use of cement in patients with intramedullary nails with actual fractures and closer followup of patients after actual fractures and preoperative radiotherapy. Future, prospective studies should further analyze the effects of adjuvant therapies and surgery-related factors on the risk of implant breakage and revisions.

IntroductionMetastasectomy is hypothesised to improve OS in metastatic STS, but evidence in favour of this approach derives from non-controlled single-arm cohorts affected by selection bias. The objective was to quantify the effect of metastasectomy vs. non-surgical management on overall survival (OS) in patients with metachronous metastases from extremity- and trunk soft tissue sarcoma (STS).Materials and methodsFrom a population of 1578 STS patients, 135 patients who underwent surgery for localised STS at two European centres between 1998 and 2015 and developed metachronous STS metastases were included. Propensity score analyses with inverse-probability-of-treatment-weights (IPTW) and landmark analyses were performed to control for selection and immortal time bias, respectively.ResultsOS was significantly longer in the 68 patients undergoing metastasectomy than in the 67 patients who were treated non-invasively for their metastasis (10-year OS: 23% vs. 4%; hazard ratio (HR) = 0.34, 95% CI: 0.22–0.53, p ConclusionIn this observational bi-centre study, metastasectomy was associated with prolonged survival in patients with metachronous STS metastases. In the absence of randomized studies, our results indicate that metastasectomy should be considered as an important treatment option for metachronous STS metastases.

Targeted radiotherapy withIn two prospective multicenter cohort studies, newly diagnosed patients with HR-NBL were treated with two courses ofThirty-eight patients (47%) were treated withHarvesting of CD34

Organ transplant recipients (OTRs) have a 100‐fold increased risk of cutaneous squamous cell carcinoma (cSCC). We prospectively evaluated the association between β genus human papillomaviruses (βPV) and keratinocyte carcinoma in OTRs. Two OTR cohorts without cSCC were assembled: cohort 1 was transplanted in 2003‐2006 (n = 274) and cohort 2 was transplanted in 1986‐2002 (n = 352). Participants were followed until death or cessation of follow‐up in 2016. βPV infection was assessed in eyebrow hair by using polymerase chain reaction–based methods. βPV IgG seroresponses were determined with multiplex serology. A competing risk model with delayed entry was used to estimate cumulative incidence of histologically proven cSCC and the effect of βPV by using a multivariable Cox regression model. Results are reported as adjusted hazard ratios (HRs). OTRs with 5 or more different βPV types in eyebrow hair had 1.7 times the risk of cSCC vs OTRs with 0 to 4 different types (HR 1.7, 95% confidence interval 1.1‐2.6). A similar risk was seen with high βPV loads (HR 1.8, 95% confidence interval 1.2‐2.8). No significant associations were seen between serum antibodies and cSCC or between βPV and basal cell carcinoma. The diversity and load of βPV types in eyebrow hair are associated with cSCC risk in OTRs, providing evidence that βPV is associated with cSCC carcinogenesis and may present a target for future preventive strategies., In two cohorts of organ transplant recipients, those with five and more different beta‐genus human papillomavirus types and high virus loads in eyebrow hairs subsequently develop significantly more cutaneous squamous cell carcinomas than others, suggesting that these virus types may increase the risk of cutaneous squamous cell carcinoma in these patients.