| 1. |
- Irestorm, Elin, et al.
(författare)
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Auditory hypersensitivity and attention in survivors of paediatric brain tumours
- 2020
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Konferensbidrag (refereegranskat)abstract
- Objective: Both auditory and visual hypersensitivity are clinical features of mental fatigue after acquired brain damage or in neurological disorders. Both types of hypersensitivity are also associated with attention deficits, especially in neurodevelopmental syndromes. The aim of this study was to examine auditory and visual hypersensitivity, and associations to attention, in a group of children and adolescents treated for paediatric brain tumours (PBTs).Participants and Methods: Included in the study were 34 survivors of PBTs, 8–18 years of age (M: 13.6, SD: 3.0). Eighteen participants were female and 16 were male. Mean time since diagnosis was 4.2 years (SD: 2.2). Auditory and visual hypersensitivity were assessed using two items from the questionnaire Mental Fatigue Scale (MFS), scored on a 7-point Likert scale from 0 – 3. Scores above 1 indicate hypersensitivity. Attention was assessed using Conners Continuous Performance Test 3 (detectability, commissions, variability), and T-scores above 60 were considered impaired. Spearman correlations were conducted between the performance-based and self-report measures.Results: Results from the MFS revealed that 53% of the survivors experienced auditory and 18% visual hypersensitivity as a sequela. Regarding attention, elevated scores were more common for detectability (18%) and variability (21%) than commissions (8%). Visual hypersensitivity was not significantly associated with any of the attention measures, whereas auditory hypersensitivity was significantly associated with detectability (r=.42, p=0.013) and variability (r=.57, p<0.001).Conclusions: These results suggest that auditory hypersensitivity is common after treatment for PBT, and that it is associated with decreased attention. This relationship should be taken into consideration when assessing survivors of PBTs.
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| 2. |
- Irestorm, Elin, et al.
(författare)
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Cognitive fatigue in relation to depressive symptoms after treatment for childhood cancer
- 2020
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Ingår i: BMC Psychology. - : Springer Science and Business Media LLC. - 2050-7283. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Cognitive fatigue after childhood cancer is frequently overlooked despite guidelines recommending follow-up, and might be mistaken for depression due to overlapping symptoms. Our objectives were: 1) to examine ratings of fatigue in survivors of paediatric brain tumours (BT) and acute lymphoblastic leukaemia (ALL) compared to healthy controls, 2) to examine the relationship between symptoms of depression and cognitive fatigue, and 3) to evaluate parent-child concordance in ratings of cognitive fatigue. Methods: Survivors of BT (n = 30), survivors of ALL (n = 30), and healthy controls (n = 60) aged 8-18 years completed the Pediatric Quality of Life Multidimensional Fatigue Scale and the Beck Youth Inventories. Associations between cognitive fatigue, diagnosis and depression were assessed with general linear modelling. Group differences were analysed using the Kruskal-Wallis test. Parent-child concordance was investigated with internal consistency reliability. Results: Cognitive fatigue was prevalent in 70% of survivors of BT survivors and in 30% of survivors of ALL. Diagnosis was the main predictor of cognitive fatigue (p <.001, ηp2 = 0.178), followed by depression (p =.010, ηp2 = 0.080). Survivors of BT reported significantly more fatigue than healthy controls on all fatigue subscales. While they also expressed more symptoms of depression, we found no evidence for an interaction effect. Parent-child concordance was moderate to good among survivors, but poor for controls. Conclusions: Survivors of BT and ALL suffer from cognitive fatigue, with survivors of BT expressing more problems. Cognitive fatigue and depression should be assessed in survivors of childhood cancer using both self-rated and proxy-rated measures, and appropriate interventions offered. © 2020 The Author(s).
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| 3. |
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| 4. |
- Bleeker, Gitta, et al.
(författare)
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MIBG scans in patients with stage 4 neuroblastoma reveal two metastatic patterns, one is associated with MYCN amplification and in MYCN-amplified tumours correlates with a better prognosis
- 2015
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Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer Science and Business Media LLC. - 1619-7070 .- 1619-7089. ; 42:2, s. 222-230
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Tidskriftsartikel (refereegranskat)abstract
- Purpose The aim of this study was to find clinically relevant MIBG-avid metastatic patterns in patients with newly diagnosed stage 4 neuroblastoma. Methods Diagnostic I-123-MIBG scans from 249 patients (123 from a European and 126 from the COG cohort) were assessed for metastatic spread in 14 body segments and the form of the lesions: "focal" (clear margins distinguishable from adjacent background) or "diffuse" (indistinct margins, dispersed throughout the body segment). The total numbers of diffuse and focal lesions were recorded. Patients were then categorized as having lesions exclusively focal, lesions more focal than diffuse, lesions more diffuse than focal, or lesions exclusively diffuse. Results Diffuse lesions affected a median of seven body segments and focal lesions a median of two body segments (P<0.001, both cohorts). Patients with a focal pattern had a median of 2 affected body segments and those with a diffuse pattern a median of 11 affected body segments (P<0.001, both cohorts). Thus, two MIBG-avid metastatic patterns emerged: "limited-focal" and "extensive-diffuse". The median numbers of affected body segments in MYCN-amplified (MNA) tumours were 5 (European cohort) and 4 (COG cohort) compared to 9 and 11, respectively, in single-copy MYCN (MYCNsc) tumours (P<0.001). Patients with exclusively focal metastases were more likely to have a MNA tumour (60 % and 70 %, respectively) than patients with the other types of metastases (23 % and 28 %, respectively; P<0.001). In a multivariate Cox regression analysis, focal metastases were associated with a better event-free and overall survival than the other types of metastases in patients with MNA tumours in the COG cohort (P<0.01). Conclusion Two metastatic patterns were found: a " limited and focal" pattern found mainly in patients with MNA neuroblastoma that correlated with prognosis, and an " extensive and diffuse" pattern found mainly in patients with MYCNsc neuroblastoma.
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| 5. |
- Braekeveldt, Noémie, et al.
(författare)
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Neuroblastoma patient-derived orthotopic xenografts reflect the microenvironmental hallmarks of aggressive patient tumours
- 2016
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Ingår i: Cancer Letters. - : Elsevier BV. - 1872-7980 .- 0304-3835. ; 375:2, s. 384-389
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Tidskriftsartikel (refereegranskat)abstract
- Treatment of high-risk childhood neuroblastoma is a clinical challenge hampered by a lack of reliable neuroblastoma mouse models for preclinical drug testing. We have previously established invasive and metastasising patient-derived orthotopic xenografts (PDXs) from high-risk neuroblastomas that retained the genotypes and phenotypes of patient tumours. Given the important role of the tumour microenvironment in tumour progression, metastasis, and treatment responses, here we analysed the tumour microenvironment of five neuroblastoma PDXs in detail. The PDXs resembled their parent tumours and retained important stromal hallmarks of aggressive lesions including rich blood and lymphatic vascularisation, pericyte coverage, high numbers of cancer-associated fibroblasts, tumour-associated macrophages, and extracellular matrix components. Patient-derived tumour endothelial cells occasionally formed blood vessels in PDXs; however, tumour stroma was, overall, of murine origin. Lymphoid cells and lymphatic endothelial cells were found in athymic nude mice but not in NSG mice; thus, the choice of mouse strain dictates tumour microenvironmental components. The murine tumour microenvironment of orthotopic neuroblastoma PDXs reflects important hallmarks of aggressive and metastatic clinical neuroblastomas. Neuroblastoma PDXs are clinically relevant models for preclinical drug testing.
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| 6. |
- Braekeveldt, Noémie, et al.
(författare)
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Neuroblastoma Patient-Derived Orthotopic Xenografts Retain Metastatic Patterns and Geno- and Phenotypes of Patient Tumours.
- 2015
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 136:5, s. 252-261
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Tidskriftsartikel (refereegranskat)abstract
- Neuroblastoma is a childhood tumour with heterogeneous characteristics and children with metastatic disease often have a poor outcome. Here we describe the establishment of neuroblastoma patient-derived xenografts (PDXs) by orthotopic implantation of viably cryopreserved or fresh tumour explants of patients with high risk neuroblastoma into immunodeficient mice. In vivo tumour growth was monitored by magnetic resonance imaging and fluorodeoxyglucose - positron emission tomography. Neuroblastoma PDXs retained the undifferentiated histology and proliferative capacity of their corresponding patient tumours. The PDXs expressed neuroblastoma markers NCAM, chromogranin A, synaptophysin and tyrosine hydroxylase. Whole genome genotyping array analyses demonstrated that PDXs retained patient-specific chromosomal aberrations such as MYCN amplification, deletion of 1p, and gain of chromosome 17q. Thus, neuroblastoma PDXs recapitulate the hallmarks of high-risk neuroblastoma in patients. PDX-derived cells were cultured in serum-free medium where they formed free-floating neurospheres, expressed neuroblastoma gene markers MYCN, CHGA, TH, SYP and NPY, and retained tumour-initiating and metastatic capacity in vivo. PDXs showed much higher degree of infiltrative growth and distant metastasis as compared to neuroblastoma SK-N-BE(2)c cell line-derived orthotopic tumours. Importantly, the PDXs presented with bone marrow involvement, a clinical feature of aggressive neuroblastoma. Thus, neuroblastoma PDXs serve as clinically relevant models for studying and targeting high-risk metastatic neuroblastoma. © 2014 Wiley Periodicals, Inc.
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| 7. |
- Braekeveldt, Noémie, et al.
(författare)
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Patient-derived xenograft models reveal intratumor heterogeneity and temporal stability in neuroblastoma
- 2018
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Ingår i: Cancer Research. - 0008-5472. ; 78:20, s. 5958-5969
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Tidskriftsartikel (refereegranskat)abstract
- Patient-derived xenografts (PDX) and the Avatar, a single PDX mirroring an individual patient, are emerging tools in preclinical cancer research. However, the consequences of intratumor heterogeneity for PDX modeling of biomarkers, target identification, and treatment decisions remain underexplored. In this study, we undertook serial passaging and comprehensive molecular analysis of neuroblastoma orthotopic PDXs, which revealed strong intrinsic genetic, transcriptional, and phenotypic stability for more than 2 years. The PDXs showed preserved neuroblastoma-associated gene signatures that correlated with poor clinical outcome in a large cohort of patients with neuroblastoma. Furthermore, we captured spatial intratumor heterogeneity using ten PDXs from a single high-risk patient tumor. We observed diverse growth rates, transcriptional, proteomic, and phosphoproteomic profiles. PDX-derived transcriptional profiles were associated with diverse clinical characteristics in patients with high-risk neuroblastoma. These data suggest that high-risk neuroblastoma contains elements of both temporal stability and spatial intratumor heterogeneity, the latter of which complicates clinical translation of personalized PDX-Avatar studies into preclinical cancer research.
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| 8. |
- Broberg, Olof, et al.
(författare)
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Characterization of Cardiac, Vascular, and Metabolic Changes in Young Childhood Cancer Survivors
- 2021
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Ingår i: Frontiers in Pediatrics. - : Frontiers Media SA. - 2296-2360. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Background: Childhood cancer survivors (CCS) are at an increased risk for cardiovascular diseases (CVD). It was the primary aim of this study to determine different measures of cardiac, carotid, lipid, and apolipoprotein status in young adult CCS and in healthy controls. Methods: Cardiac and common carotid artery (CCA) structure and function were measured by ultrasonography. Lipids and apolipoproteins were measured in the blood. Peripheral arterial endothelial vasomotor function was assessed by measuring digital reactive hyperemia index (PAT-RHI) using the Endo-PAT 2000. Results: Fifty-three CCS (20-30 years, 35 men) and 53 sex-matched controls were studied. The CCS cohort was divided by the median dose of anthracyclines into a low anthracycline dose (LAD) group (50-197 mg/m2, n = 26) and a high anthracycline dose (HAD) group (200-486 mg/m2, n = 27). Carotid distensibility index (DI) and endothelial function determined by PAT-RHI were both lower in the CCS groups compared with controls (p < 0.05 and p = 0.02). There was no difference in carotid intima media thickness. Atherogenic apolipoprotein-B (Apo-B) and the ratio between Apo-B and Apoliprotein-A1 (Apo-A1) were higher in the HAD group compared with controls (p < 0.01). Apo-B/Apo-A1-ratio was over reference limit in 29.6% of the HAD group, in 15.4% of LAD group, and in 7.5% of controls (p = 0.03). Measured lipid markers (low density lipoprotein and total cholesterol and triglycerides) were higher in both CCS groups compared with controls (p < 0.05). Systolic and diastolic function were measurably decreased in the HAD group, as evidenced by lower EF (p < 0.001) and lower é-wave (p < 0.005) compared with controls. CCA DI correlated with Apo-B/Apo-A1-ratio and Apo-A1. Follow-up time after treatment correlated with decreased left ventricular ejection fraction (p = 0.001). Conclusion: Young asymptomatic CCS exhibit cardiac, vascular, lipid, and apolipoprotein changes that could account for increased risk for CVD later in life. These findings emphasize the importance of cardiometabolic monitoring even in young CCS.
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| 9. |
- Broberg, Olof, et al.
(författare)
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Childhood Cancer Survivors Have Impaired Strain-Derived Myocardial Contractile Reserve by Dobutamine Stress Echocardiography
- 2023
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Ingår i: Journal of Clinical Medicine. - 2077-0383. ; 12:8, s. 1-14
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Tidskriftsartikel (refereegranskat)abstract
- Abnormal left ventricular contractile reserve (LVCR) is associated with adverse cardiac outcomes in different patient cohorts and might be useful in the detection of cardiomyopathy in childhood cancer survivors (CCS) after cardiotoxic treatment. The aim of this study was to evaluate LVCR by dobutamine stress echocardiography (DSE) combined with measures of myocardial strain in CCS previously treated with anthracyclines (AC). Fifty-three CCS (age 25.34 ± 2.44 years, 35 male) and 53 healthy controls (age 24.40 ± 2.40 years, 32 male) were included. Subjects were examined with echocardiography at rest, at low-dose (5 micrograms/kg/min), and at high-dose (40 micrograms/kg/min) dobutamine infusion. Left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS), strain rate (GSR), and early diastolic strain rate (GEDSR) at different DSE phases were used as measures of LVCR. The mean follow-up time among CCS was 15.8 ± 5.8 years. GLS, GSR, and LVEF were lower at rest in CCS compared to controls (p ≤ 0.03). LVEF was within the normal range in CCS. ΔGLS, ΔGSR, and ΔGEDSR but not ΔLVEF were lower in CCS compared to controls after both low- (p ≤ 0.048) and high-dose dobutamine infusion (p ≤ 0.023). We conclude that strain measures during low-dose DSE detect impaired myocardial contractile reserve in young CCS treated with AC at 15-year follow-up. Thus, DSE may help identify asymptomatic CCS at risk for heart failure and allows for tailored follow-up accordingly.
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| 10. |
- Broberg, Olof, et al.
(författare)
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Circulating leptin is associated with adverse vascular changes in young adult survivors of childhood cancer
- 2024
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Ingår i: Cardiology in the Young. - 1047-9511 .- 1467-1107.
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Proteomics may help discover novel biomarkers and underlying mechanisms for cardiovascular disease. This could be useful for childhood cancer survivors as they show an increased risk of cardiovascular disease. The aim of this study was to investigate circulating cardiovascular proteins in young adult survivors of childhood cancer and their relationship to previously reported subclinical cardiovascular disease.METHODS: Ninety-two cardiovascular proteins were measured in 57 childhood cancer survivors and in 52 controls. For proteins that were significantly different between childhood cancer survivors and controls, we performed correlations between protein levels and measures of peripheral arterial stiffness (carotid distensibility and stiffness index, and augmentation index) and endothelial dysfunction (reactive hyperemia index).RESULTS: Leptin was significantly higher in childhood cancer survivors compared to controls (normalized protein expression units: childhood cancer survivors 6.4 (1.5) versus 5.1 (1.7), p < 0.0000001) after taking multiple tests into account. Kidney injury molecule-1, MER proto-oncogene tyrosine kinase, selectin P ligand, decorin, alpha-1-microglobulin/bikunin precursor protein, and pentraxin 3 showed a trend towards group differences (p < 0.05). Among childhood cancer survivors, leptin was associated with anthracycline treatment after adjustment for age, sex, and body mass index (p < 0.0001). Higher leptin correlated with lower carotid distensibility after adjustment for age, sex, body mass index, and treatments with radiotherapy and anthracyclines (p = 0.005).CONCLUSION: This proteomics approach identified that leptin is higher in young asymptomatic adult survivors of childhood cancer than in healthy controls and is associated with adverse vascular changes. This could indicate a role for leptin in driving the cardiovascular disease burden in this population.
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