| 1. |
- Zhu, Changlian, 1964, et al.
(författare)
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X chromosome-linked inhibitor of apoptosis protein reduces oxidative stress after cerebral irradiation or hypoxia-ischemia through up-regulation of mitochondrial antioxidants.
- 2007
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Ingår i: The European journal of neuroscience. - : Wiley. - 1460-9568 .- 0953-816X. ; 26:12, s. 3402-10
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Tidskriftsartikel (refereegranskat)abstract
- We demonstrate that X chromosome-linked inhibitor of apoptosis protein (XIAP) counteracts oxidative stress in two essentially different disease-related models of brain injury, hypoxia-ischemia and irradiation, as judged by lower expression of nitrotyrosine (5-fold) and 4-hydroxy-2-nonenal (10-fold) in XIAP-overexpressing compared with wild-type mice. XIAP overexpression induced up-regulation of at least three antioxidants residing in mitochondria, superoxide dismutase 2, thioredoxin 2 and lysine oxoglutarate reductase. Cytochrome c release from mitochondria was reduced in XIAP-overexpressing mice. Hence, in addition to blocking caspases, XIAP can regulate reactive oxygen species in the brain, at least partly through up-regulation of mitochondrial antioxidants. XIAP-induced prevention of oxidative stress was not secondary to tissue protection because although XIAP overexpression provides tissue protection after hypoxia-ischemia, it does not prevent tissue loss after irradiation. This is a previously unknown role of XIAP and may provide the basis for development of novel protective strategies for both acute and chronic neurodegenerative diseases, where oxidative stress is an integral component of the injury mechanisms involved.
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| 2. |
- Blomstrand, Malin, 1974, et al.
(författare)
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Estimated clinical benefit of protecting neurogenesis in the developing brain during radiation therapy for pediatric medulloblastoma.
- 2012
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Ingår i: Neuro-Oncology. - : Oxford University Press (OUP). - 1523-5866 .- 1522-8517. ; 14:7, s. 882-889
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Tidskriftsartikel (refereegranskat)abstract
- We sought to assess the feasibility and estimate the benefit of sparing the neurogenic niches when irradiating the brain of pediatric patients with medulloblastoma (MB) based on clinical outcome data. Pediatric MB survivors experience a high risk of neurocognitive adverse effects, often attributed to the whole-brain irradiation that is part of standard management. Neurogenesis is very sensitive to radiation, and limiting the radiation dose to the hippocampus and the subventricular zone (SVZ) may preserve neurocognitive function. Radiotherapy plans were created using 4 techniques: standard opposing fields, intensity-modulated radiotherapy (IMRT), intensity-modulated arc therapy (IMAT), and intensity-modulated proton therapy (IMPT). Mean dose to the hippocampus and SVZ (mean for both sites) could be limited to 88.3% (range, 83.6%-91.0%), 77.1% (range, 71.5%-81.3%), and 42.3% (range, 26.6%-51.2%) with IMAT, IMRT, and IMPT, respectively, while maintaining at least 95% of the prescribed dose in 95% of the whole-brain target volume. Estimated risks for developing memory impairment after a prescribed dose of 23.4 Gy were 47% (95% confidence interval [CI], 21%-69%), 44% (95% CI, 21%-65%), 41% (95% CI, 22%-60%), and 33% (95% CI, 23%-44%) with opposing fields, IMAT, IMRT, and IMPT, respectively. Neurogenic niche sparing during cranial irradiation of pediatric patients with MB is feasible and is estimated to lower the risks of long-term neurocognitive sequelae. Greatest sparing is achieved with intensity-modulated proton therapy, thus making this an attractive option to be tested in a prospective clinical trial.
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| 3. |
- 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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| 4. |
- Brodin, N Patrik, et al.
(författare)
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Radiobiological risk estimates of adverse events and secondary cancer for proton and photon radiation therapy of pediatric medulloblastoma.
- 2011
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Ingår i: Acta oncologica (Stockholm, Sweden). - 1651-226X. ; 50:6, s. 806-16
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Tidskriftsartikel (refereegranskat)abstract
- Abstract Introduction. The aim of this model study was to estimate and compare the risk of radiation-induced adverse late effects in pediatric patients with medulloblastoma (MB) treated with either three-dimensional conformal radiotherapy (3D CRT), inversely-optimized arc therapy (RapidArc(®) (RA)) or spot-scanned intensity-modulated proton therapy (IMPT). The aim was also to find dose-volume toxicity parameters relevant to children undergoing RT to be used in the inverse planning of RA and IMPT, and to use in the risk estimations. Material and methods. Treatment plans were created for all three techniques on 10 pediatric patients that have been treated with craniospinal irradiation (CSI) at our institution in 2007-2009. Plans were generated for two prescription CSI doses, 23.4 Gy and 36 Gy. Risk estimates were based on childhood cancer survivor data when available and secondary cancer (SC) risks were estimated as a function of age at exposure and attained age according to the organ-equivalent dose (OED) concept. Results. Estimates of SC risk was higher for the RA plans and differentiable from the estimates for 3D CRT at attained ages above 40 years. The risk of developing heart failure, hearing loss, hypothyroidism and xerostomia was highest for the 3D CRT plans. The risks of all adverse effects were estimated as lowest for the IMPT plans, even when including secondary neutron (SN) irradiation with high values of the neutron radiation weighting factors (WR(neutron)). Conclusions. When comparing RA and 3D CRT treatment for pediatric MB it is a matter of comparing higher SC risk against higher risks of non-cancer adverse events. Considering time until onset of the different complications is necessary to fully assess patient benefit in such a comparison. The IMPT plans, including SN dose contribution, compared favorably to the photon techniques in terms of all radiobiological risk estimates.
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| 5. |
- Fukuda, A., et al.
(författare)
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Age-dependent sensitivity of the developing brain to irradiation is correlated with the number and vulnerability of progenitor cells
- 2005
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Ingår i: J Neurochem. ; 92:3, s. 569-84
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Tidskriftsartikel (refereegranskat)abstract
- In a newly established model of unilateral, irradiation (IR)-induced injury we compared the outcome after IR to the immature and juvenile brain, using rats at postnatal days 9 or 23, respectively. We demonstrate that (i) the immature brains contained more progenitors in the subventricular zone (SVZ) and subgranular zone (SGZ) compared with the juvenile brains; (ii) cellular injury, as judged by activation of caspase 3 and p53, as well as nitrotyrosine formation, was more pronounced in the SVZ and SGZ in the immature brains 6 h after IR; (iii) the number of progenitor and immature cells in the SVZ and SGZ decreased 6 h and 7 days post-IR, corresponding to acute and subacute effects in humans, respectively, these effects were more pronounced in immature brains; (iv) myelination was impaired after IR at both ages, and much more pronounced after IR to immature brains; (v) the IR-induced changes remained significant for at least 10 weeks, corresponding to late effects in humans, and were most pronounced after IR to immature brains. It appears that IR induces both an acute loss of progenitors through apoptosis and a perturbed microenvironment incompatible with normal proliferation and differentiation, and that this is more pronounced in the immature brain.
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| 6. |
- Fukuda, Aya, et al.
(författare)
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Progenitor cell injury after irradiation to the developing brain can be modulated by mild hypothermia or hyperthermia
- 2005
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Ingår i: J Neurochem. ; 94:6, s. 1604-19
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Tidskriftsartikel (refereegranskat)abstract
- Ionizing radiation induced acute cell death in the dentate gyrus subgranular zone (SGZ) and the subventricular zone (SVZ). Hypomyelination was also observed. The effects of mild hypothermia and hyperthermia for 4 h after irradiation (IR) were studied in postnatal day 9 rats. One hemisphere was irradiated with a single dose of 8 Gy and animals were randomized to normothermia (rectal temperature 36 degrees C for 4 h), hypothermia (32 degrees C for 4 h) or hyperthermia (39 degrees C for 4 h). Cellular injury, e.g. chromatin condensation and nitrotyrosine formation, appeared to proceed faster when the body temperature was higher. Caspase-3 activation was more pronounced in the hyperthermia group and nuclear translocation of p53 was less pronounced in the hypothermia group 6 h after IR. In the SVZ the loss of nestin-positive progenitors was more pronounced (48%) and the size was smaller (45%) in the hyperthermia group 7 days post-IR. Myelination was not different after hypo- or hyperthermia. This is the first report to demonstrate that hypothermia may be beneficial and that hyperthermia may aggravate the adverse side-effects after radiation therapy to the developing brain.
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| 7. |
- Fukuda, Hirotsugu, et al.
(författare)
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Irradiation-induced progenitor cell death in the developing brain is resistant to erythropoietin treatment and caspase inhibition
- 2004
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Ingår i: Cell Death Differ. - Univ Gothenburg, Dept Physiol, Perinatal Ctr, SE-40530 Gothenburg, Sweden. Osaka Univ, Sch Med, Dept Obstet & Gynecol, Suita, Osaka 5650871, Japan. Zhengzhou Univ, Affiliated Hosp 3, Dept Pediat, Zhengzhou 450052, Peoples R China. Uppsala Univ, Dept Neurosci, SE-75123 Uppsala, Sweden. Sahlgrens Univ Hosp, Dept Radiat Phys, SE-41345 Gothenburg, Sweden. H Lundbeck & Co AS, Mol Dis Biol, DK-2500 Copenhagen, Denmark. Sahlgrens Univ Hosp, Dept Oncol, SE-41345 Gothenburg, Sweden. Queen Silvia Childrens Hosp, Dept Pediat, SE-41685 Gothenburg, Sweden. : NATURE PUBLISHING GROUP. - 1350-9047 .- 1476-5403. ; 11:11, s. 1166-78
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Tidskriftsartikel (refereegranskat)abstract
- One hemisphere of postnatal day 8 (P8) rats or P10 mice was irradiated with a single dose of 4-12 Gy, and animals were killed from 2 h to 8 weeks after irradiation (IR). In the subventricular zone (SVZ) and the granular cell layer (GCL) of the dentate gyrus, harboring neural and other progenitor cells, nitrosylation and p53 peaked 2-12 h after IR, followed by markers for active caspase-3, apoptosis-inducing factor and TUNEL (6-24 h). Ki67-positive (proliferating) cells had disappeared by 12 h and partly reappeared by 7 days post-IR. The SVZ and GCL areas decreased approximately 50% 7 days after IR. The development of white matter was hampered, resulting in 50-70% less myelin basic protein staining. Pretreatment with erythropoietin did not confer protection against IR. Caspase inhibition by overexpression of XIAP prevented caspase-9 and caspase-3 activation but not cell death, presumably because of increased caspase-independent cell death.
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| 8. |
- Kalm, Marie, 1981, et al.
(författare)
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Irradiation-induced loss of microglia in the young brain.
- 2009
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Ingår i: Journal of neuroimmunology. - : Elsevier BV. - 0165-5728. ; 206:1-2, s. 70-5
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Tidskriftsartikel (refereegranskat)abstract
- Irradiation-induced loss of neural stem and progenitor cells may contribute to cognitive deficits. Furthermore, subsequent inflammation inhibits neural progenitor cell differentiation. Here we have characterized the microglia response after a single dose of 8 Gy to the brains of postnatal day 9 or 21 rats. The number of Iba-1-positive microglia increased 6 h after IR but had decreased 7 days later, below control levels, and this decrease was more pronounced in P9 rats. Active caspase-3 and TUNEL staining revealed irradiation-induced microglia death. This age-dependent IR-induced loss of microglia likely affects both the response to IR and further brain development.
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| 9. |
- Kalm, Marie, 1981, et al.
(författare)
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Transient inflammation in neurogenic regions after irradiation of the developing brain.
- 2009
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Ingår i: Radiation research. - 0033-7587. ; 171:1, s. 66-76
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Tidskriftsartikel (refereegranskat)abstract
- Kalm, M., Fukuda, A., Fukuda, H., Ohrfelt, A., Lannering, B., Björk-Eriksson, T., Blennow, K., Márky, I. and Blomgren, K. Transient Inflammation in Neurogenic Regions after Irradiation of the Developing Brain. Radiat. Res. 171, 66-76 (2009).We characterized the inflammatory response after a single dose of 8 Gy to the brains of postnatal day 9 rats. Affymetrix gene chips revealed activation of multiple inflammatory mechanisms in the acute phase, 6 h after irradiation. In the subacute phase, 7 days after irradiation, genes related to neurogenesis and cell cycle were down-regulated, but glial fibrillary acidic protein (GFAP) was up-regulated. The concentrations of 14 different cytokines and chemokines were measured using a microsphere-based xMAPtrade mark technology. CCL2, Gro/KC and IL-1alpha were the most strongly up-regulated 6 h after irradiation. CCL2 was expressed in astrocytes and microglia in the dentate gyrus and the subventricular zone (SVZ). Hypertrophy, but not hyperplasia, of astrocytes was demonstrated 7 days after irradiation. In summary, we found transient activation of multiple inflammatory mechanisms in the acute phase (6 h) after irradiation and activation of astrocytes in the subacute phase (7 days) after irradiation. It remains to be elucidated whether these transient changes are involved in the persistent effects of radiation observed on neurogenesis and cognition in rodents.
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| 10. |
- Lannering, Birgitta, 1948, et al.
(författare)
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Hyperfractionated Versus Conventional Radiotherapy Followed by Chemotherapy in Standard-Risk Medulloblastoma: Results From the Randomized Multicenter HIT-SIOP PNET 4 Trial.
- 2012
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Ingår i: Journal of clinical oncology : official journal of the American Society of Clinical Oncology. - 1527-7755. ; 30:26, s. 3187-93
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE To compare event-free survival (EFS), overall survival (OS), pattern of relapse, and hearing loss in children with standard-risk medulloblastoma treated by postoperative hyperfractionated or conventionally fractionated radiotherapy followed by maintenance chemotherapy. PATIENTS AND METHODS In all, 340 children age 4 to 21 years from 122 European centers were postoperatively staged and randomly assigned to treatment with hyperfractionated radiotherapy (HFRT) or standard (conventional) fractionated radiotherapy (STRT) followed by a common chemotherapy regimen consisting of eight cycles of cisplatin, lomustine, and vincristine. Results After a median follow-up of 4.8 years (range, 0.1 to 8.3 years), survival rates were not significantly different between the two treatment arms: 5-year EFS was 77% ± 4% in the STRT group and 78% ± 4% in the HFRT group; corresponding 5-year OS was 87% ± 3% and 85% ± 3%, respectively. A postoperative residual tumor of more than 1.5 cm(2) was the strongest negative prognostic factor. EFS of children with all reference assessments and no large residual tumor was 82% ± 2% at 5 years. Patients with a delay of more than 7 weeks to the start of RT had a worse prognosis. Severe hearing loss was not significantly different for the two treatment arms at follow-up. CONCLUSION In this large randomized European study, which enrolled patients with standard-risk medulloblastoma from more than 100 centers, excellent survival rates were achieved in patients without a large postoperative residual tumor and without RT treatment delays. EFS and OS for HFRT was not superior to STRT, which therefore remains standard of care in this disease.
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