| 1. |
- Blomstrand, Malin, 1974
(författare)
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Characterizing and modulating the effects of ionizing radiation to the juvenile hippocampus
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Survival rates after childhood cancer treatment have improved, leading to a growing population of survivors. Radiotherapy is an important tool for curing cancer in the brain. Unfortunately, radiotherapy is associated with late side effects e.g. of cognitive impairment. The mechanisms underlying radiation-induced cognitive dysfunctions are not fully understood but involve changes in the neurogenic niche of the hippocampus. The aim of this thesis was to characterize and modulate the effects of ionizing radiation to the hippocampus of the juvenile brain, with the future goal of ameliorating cognitive deficit of childhood cancer survivors following radiation for intracranial disease. We investigated the effects of low-dose radiation of the brain in infancy. A total of 3,860 boys were treated with radiation for cutaneous hemangiomas before the age of 18 months. Of these, 3,030 were analyzed for military test scores at the age of 18 years and 2,559 for the highest obtained educational level. We also characterized and compared the radiation-induced reactions in the hippocampus of the juvenile and adult rat brain, as well as evaluated the modulating effect of amifostine, WR-1065 and N-acetylcysteine during cranial irradiation of the juvenile rat brain. This was done in a rat model. Further, we tried to modulate the dose to the hippocampus in medulloblastoma patients by the use of modern radiotherapy techniques. Different radiation prescription scenarios, by means of computer-based treatment, were used to evaluate the possibilities of sparing the hippocampus from radiation and to assess their potential benefits regarding cognitive outcome. We did not find any effect on the highest obtained education when we investigated the risk of cognitive dysfunctions after exposure to low doses of cranial radiation in infancy. There was no decrease in logical, technical or spatial test scores after radiation doses up to the highest dose category (median 680 mGy). Verbal test scores displayed a very small but statistically significant trend for decreasing scores with increasing doses to the hippocampus. We concluded that the juvenile brain, from a clinical perspective, was not sensitive to doses overlapping the range used for diagnostic purposes, contrasting with earlier findings. For therapeutic doses of radiation in rodents, we found that the radiation reaction in the hippocampus differed in the juvenile brain compared to the adult brain in terms of density of resident microglia, number of activated microglia, levels of apoptosis, specific cytokines/chemokines and growth factors. In rodents, we did not find any protection by amifostine, WR-1065 or N-acetylcystein using tolerable doses during cranial radiation. However, in children we could conclude that sparing the hippocampus from radiation during cranial radiotherapy is feasible by the use of modern treatment techniques. We found that the greatest potential for hippocampal sparing was offered by intensity-modulated proton therapy. Interestingly, we also found that the use of different techniques influenced the dose to the hippocampus to a higher extent, than the use of smaller treatment volumes for the tumor boost. Further, we estimated that a hippocampal sparing strategy could ameliorate the cognitive impairment seen after cranial radiotherapy.
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| 2. |
- Blomstrand, Malin, 1974, et al.
(författare)
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Different reactions to irradiation in the juvenile and adult hippocampus
- 2014
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Ingår i: International Journal of Radiation Biology. - : Informa UK Limited. - 0955-3002 .- 1362-3095. ; 90:9, s. 807-815
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Cranial radiotherapy is an important tool in the cure of primary brain tumors. Unfortunately, it is associated with late-appearing toxicity to the normal brain tissue, including cognitive impairment, particularly in children. The underlying mechanisms are not fully understood but involve changes in hippocampal neurogenesis. Recent studies report essentially different responses in the juvenile and the adult brain after irradiation, but this has never been verified in a comparative study. Materials and methods: We subjected juvenile (9-day-old) and adult (6-month-old) male rats to a single dose of 6 Gray (Gy) whole brain irradiation and euthanized them 6 hours, 7 days or 4 weeks later. Hippocampal lysates were analyzed for caspase-3 activity (apoptosis) and the expression of cytokines, chemokines and growth factors. Four weeks after irradiation, the number of microglia (expressing ionized calcium-binding adapter molecule 1, Iba-1), activated microglia (expressing cluster of differentiation 68 [CD68]), bromodeoxyuridine (BrdU) incorporation and granule cell layer (GCL) volume were assessed. Results: The major findings were (i) higher baseline BrdU incorporation (cell proliferation) in juvenile than in adult controls, which explains the increased susceptibility to irradiation and higher level of acute cell death (caspase activity) in juvenile rats, leading to impaired growth and subsequently a smaller dentate gyrus volume 4 weeks after irradiation, (ii) more activated (CD68-positive) microglia in adult compared to juvenile rats, regardless of irradiation, and (iii) differently expressed cytokines and chemokines after cranial irradiation in the juvenile compared to the adult rat hippocampus, indicating a more pro-inflammatory response in adult brains. Conclusion: We found essentially diverse irradiation reactions in the juvenile compared to the adult hippocampus, indicating different mechanisms involved in degeneration and regeneration after injury. Strategies to ameliorate the cognitive deficits after cranial radiotherapy should therefore likely be adapted to the developmental level of the brain.
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| 3. |
- Blomstrand, Malin, 1974, et al.
(författare)
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No clinically relevant effect on cognitive outcomes after low-dose radiation to the infant brain: A population-based cohort study in Sweden
- 2014
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Ingår i: Acta Oncologica. - : Informa UK Limited. - 0284-186X .- 1651-226X. ; 53:9, s. 1143-1150
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Tidskriftsartikel (refereegranskat)abstract
- While the detrimental effects of cranial radiotherapy on the developing brain are well known, the effects on cognitive performance of low doses of ionizing radiation is less studied. We performed a population-based cohort study to determine whether low doses of ionizing radiation to the brain in infancy affects cognitive function later in life. Further we hypothesized that the dose to the hippocampus predicts cognitive late side effects better than the anterior or the posterior brain doses. Material and methods. During 1950 - 1960 3860 boys were treated with radiation in Sweden for cutaneous hemangiomas before the age of 18 months. Of these, 3030 were analyzed for military test scores at the age of 18 years and 2559 for the highest obtained educational level. Results. Logical, spatial and technical test scores were not affected by increasing irradiation doses. The verbal test scores displayed a significant trend for decreasing scores with increasing doses to the hippocampus (p = 0.005). However, the absolute mean difference between the zero dose and the highest dose category (median 680 mGy) was very small, only 0.64 stanine points, and the significance was dependent on the highest dose category, containing few subjects. The educational level was not affected by brain irradiation. Overall, the hippocampal dose was a better predictor of late cognitive side effects than the doses to the anterior or the posterior brain. In conclusion, there was no decrease in logical, spatial and technical verbal or global test scores after ionizing radiation doses up to 250 mGy, but a subtle decrease in verbal test scores if the highest dose category was included (median 680 mGy). However, the clinical relevance of this decline in the highest dose group is questionable, since we could not find any effect on the highest obtained educational level.
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| 4. |
- Brodin, N Patrik, et al.
(författare)
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Hippocampal sparing radiotherapy for pediatric medulloblastoma: impact of treatment margins and treatment technique.
- 2014
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Ingår i: Neuro-oncology. - : Oxford University Press (OUP). - 1523-5866 .- 1522-8517. ; 16:4, s. 594-602
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundWe investigated how varying the treatment margin and applying hippocampal sparing and proton therapy impact the risk of neurocognitive impairment in pediatric medulloblastoma patients compared with current standard 3D conformal radiotherapy.MethodsWe included 17 pediatric medulloblastoma patients to represent the variability in tumor location relative to the hippocampal region. Treatment plans were generated using 3D conformal radiotherapy, hippocampal sparing intensity-modulated radiotherapy, and spot-scanned proton therapy, using 3 different treatment margins for the conformal tumor boost. Neurocognitive impairment risk was estimated based on dose-response models from pediatric CNS malignancy survivors and compared among different margins and treatment techniques.ResultsMean hippocampal dose and corresponding risk of cognitive impairment were decreased with decreasing treatment margins (P < .05). The largest risk reduction, however, was seen when applying hippocampal sparing proton therapy-the estimated risk of impaired task efficiency (95% confidence interval) was 92% (66%-98%), 81% (51%-95%), and 50% (30%-70%) for 3D conformal radiotherapy, intensity-modulated radiotherapy, and proton therapy, respectively, for the smallest boost margin and 98% (78%-100%), 90% (60%-98%), and 70% (39%-90%) if boosting the whole posterior fossa. Also, the distance between the closest point of the planning target volume and the center of the hippocampus can be used to predict mean hippocampal dose for a given treatment technique.ConclusionsWe estimate a considerable clinical benefit of hippocampal sparing radiotherapy. In choosing treatment margins, the tradeoff between margin size and risk of neurocognitive impairment quantified here should be considered.
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| 5. |
- Embring, A., et al.
(författare)
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Re-irradiation in Paediatric Tumours of the Central Nervous System: National Guidelines from the Swedish Workgroup of Paediatric Radiotherapy
- 2023
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Ingår i: Clinical Oncology. - : Elsevier. - 0936-6555 .- 1433-2981. ; 35:9, s. 571-575
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Tidskriftsartikel (refereegranskat)abstract
- There is a lack of clinical protocols for re-irradiation in paediatric central nervous system (CNS) tumours. To fill this void, the Swedish Workgroup of Paediatric Radiotherapy (SBRTG) compiled national guidelines on re-irradiation in paediatric CNS tumours (diffuse intrinsic pontine glioma, ependymoma, germinoma and medulloblastoma). These have been in clinical practice since 2019 in all paediatric radiotherapy centres in Sweden. Since the implementation, the guidelines have been complemented with a yearly review on clinical outcome and toxicities in all paediatric patients treated according to the guidelines. This article presents the Swedish national guidelines on re-irradiation in paediatric CNS tumours. & COPY; 2023 Published by Elsevier Ltd on behalf of The Royal College of Radiologists.
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| 6. |
- Heggebo, L. C., et al.
(författare)
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Investigating survival, quality of life and cognition in PROton versus photon therapy for IDH-mutated diffuse grade 2 and 3 GLIOmas (PRO-GLIO): a randomised controlled trial in Norway and Sweden
- 2023
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Ingår i: Bmj Open. - : BMJ. - 2044-6055. ; 13:3
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Tidskriftsartikel (refereegranskat)abstract
- IntroductionThe use of proton therapy increases globally despite a lack of randomised controlled trials demonstrating its efficacy and safety. Proton therapy enables sparing of non-neoplastic tissue from radiation. This is principally beneficial and holds promise of reduced long-term side effects. However, the sparing of seemingly non-cancerous tissue is not necessarily positive for isocitrate dehydrogenase (IDH)-mutated diffuse gliomas grade 2-3, which have a diffuse growth pattern. With their relatively good prognosis, yet incurable nature, therapy needs to be delicately balanced to achieve a maximal survival benefit combined with an optimised quality of life.Methods and analysisPRO-GLIO (PROton versus photon therapy in IDH-mutated diffuse grade 2 and 3 GLIOmas) is an open-label, multicentre, randomised phase III non-inferiority study. 224 patients aged 18-65 years with IDH-mutated diffuse gliomas grade 2-3 from Norway and Sweden will be randomised 1:1 to radiotherapy delivered with protons (experimental arm) or photons (standard arm). First intervention-free survival at 2 years is the primary endpoint. Key secondary endpoints are fatigue and cognitive impairment, both at 2 years. Additional secondary outcomes include several survival measures, health-related quality of life parameters and health economy endpoints.Ethics and disseminationTo implement proton therapy as part of standard of care for patients with IDH-mutated diffuse gliomas grade 2-3, it should be deemed safe. With its randomised controlled design testing proton versus photon therapy, PRO-GLIO will provide important information for this patient population concerning safety, cognition, fatigue and other quality of life parameters. As proton therapy is considerably more costly than its photon counterpart, cost-effectiveness will also be evaluated. PRO-GLIO is approved by ethical committees in Norway (Regional Committee for Medical & Health Research Ethics) and Sweden (The Swedish Ethical Review Authority) and patient inclusion has commenced. Trial results will be published in international peer-reviewed journals, relevant conferences, national and international meetings and expert forums.Trial registration numberClinicalTrials.gov Registry (NCT05190172).
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| 7. |
- Martinsson, Ulla, et al.
(författare)
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Complications after proton radiotherapy in children, focusing on severe late complications. A complete Swedish cohort 2008-2019
- 2023
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Ingår i: ACTA ONCOLOGICA. - : Taylor & Francis. - 0284-186X .- 1651-226X. ; 62:10, s. 1348-1356
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Tidskriftsartikel (refereegranskat)abstract
- Background: Proton radiotherapy (RT) is an attractive tool to deliver local therapy with minimal dose to uninvolved tissue, however, not suitable for all patients. The aim was to explore complications, especially severe late complications (grades 3-4), following proton RT delivered to a complete Swedish cohort of paediatric patients aged <18 years treated 2008-2019.Material and Methods: Data was downloaded from a national registry. Complications with a possible causation with RT are reported. Proton treatments until July 2015 was performed with a fixed horizontal 172 MeV beam (The Svedberg Laboratory (TSL), Uppsala) in a sitting position and thereafter with gantry-based pencil-beam scanning technique (Skandion Clinic, Uppsala) in a supine position.Results: 219 courses of proton RT (77 at TSL and 142 at Skandion) were delivered to 212 patients (mean age 9.2 years) with various tumour types (CNS tumours 58%, sarcomas 26%, germ cell tumours 7%). Twenty-five patients had severe acute complications (skin, mucous membrane, pharynx/oesophagus, larynx, upper gastrointestinal canal, lower gastrointestinal canal, eyes, ears). Fifteen patients had severe late complications; with increased proportion over time: 4% at 1-year follow-up (FU), 5% at 3-year, 11% at 5-year. Organs affected were skin (1 patient), subcutaneous tissue (4), salivary glands (1), upper GI (1), bone (7), joints (2), CNS (2), PNS (1), eyes (1) and ears (5). Twenty-one of the 28 patients with 10-year FU had at least one late complication grades 1-4 and fourteen of them had more than one (2-5 each).Conclusion: The most important result of our study is the relatively low proportion of severe late complications, comparable with other proton studies on various tumours. Furthermore, the numbers of late complications are lower than our own data set on a mixed population of photon and proton treated paediatric patients, assuring the safety of using proton therapy also in the clinical practice.
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| 8. |
- Rydén, Isabelle, et al.
(författare)
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Neuropsychological functioning in childhood cancer survivors following cranial radiotherapy - results from a long-term follow-up clinic
- 2022
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Ingår i: Neurocase. - : Informa UK Limited. - 1355-4794 .- 1465-3656. ; 28:2, s. 163-172
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Tidskriftsartikel (refereegranskat)abstract
- Treatment of malignant childhood posterior fossa tumors (CPFT) often includes surgical resection and craniospinal radiotherapy (CSI). Nasopharyngeal tumors in childhood (CNPHT) are often treated with surgery and radiotherapy (RT), leading to incidental brain irradiation. RT to the developing brain is associated with risks for cognitive impairments. We studied cognitive functioning, health-related quality of life (HRQOL), fatigue, and psychological distress, in adult survivors of CPFT and CNPHT, representing two groups, which had received high and low radiation dose-exposure to the brain, respectively. Cognitive tests were used to compare CPFT (n = 12) and CNPHT (n = 7) survivors to matched healthy controls (n = 28). HRQOL data was compared to the general population (GP) (n = 1415-1459). Average follow-up was 23 (CPFT) and 19 years (CNPHT). CPFT survivors had significant deficits in all cognitive domains. CNPHT survivors showed results below the control group but differed statistically only on one executive test. HRQOL-ratings indicated that both groups had similar self-reported cognitive problems. CPFT survivors reported more emotional problems and fatigue. Anxiety was seen in both CPFT and CNPHT survivors. This study confirmed long-term cognitive sequelae after RT in adult survivors of CPFT,and possible RT-induced cognitive deficits in adult CNPHT survivors.
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| 9. |
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| 10. |
- Vecchio, Tomás Gomez, et al.
(författare)
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Global health status and fatigue score in isocitrate dehydrogenase-mutant diffuse glioma grades 2 and 3: A longitudinal population-based study from surgery to 12-month follow-up
- 2024
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Ingår i: NEURO-ONCOLOGY PRACTICE. - 2054-2577 .- 2054-2585.
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Tidskriftsartikel (refereegranskat)abstract
- Background. At the group level, health-related quality of life (HRQoL) in patients with IDH-mutant diffuse glioma grades 2 and 3 seems to remain stable over time. However, clinical experience indicates that there are patients with unfavorable outcomes on key HRQoL subdomains. The aim of this longitudinal population-based study, following patients over a period of 12 months from surgery, was to describe individual-level data on global health status and fatigue score and explore possible predictors of deterioration. Methods. All patients undergoing surgery for presumed glioma grades 2 or 3 at the Sahlgrenska University Hospital during 2017-2022, were screened for the study. Patients were invited to complete the European Organization of Research and Treatment of Cancer core questionnaires and brain module at baseline, 3 and 12 months postoperatively. Data is reported with respect to minimal clinical important difference (MCID). Results. We included 51 patients with IDH-mutant diffuse glioma grades 2 or 3. There was no difference in group-level data of either global health status or fatigue score from baseline to the 12-month follow-up (P-value > .05). Unfavorable individual changes (beyond MCID) in global health status and fatigue score were observed in 12 and in 17 patients, respectively (23.5% and 33.3%). A lower proportion of proton radiotherapy was found in patients with unfavorable changes in fatigue (10/15, 66.7%) compared to all other patients undergoing radiotherapy (22/23, 95.7%, P-value .03). Conclusions. Deterioration beyond MCID was seen in approximately one-third of patients. Changes in global health status could not be predicted, but changes in fatigue may be influenced by tumor-targeted and symptomatic treatment.
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