| 1. |
- Barlind, Anna, 1978, et al.
(författare)
-
Decreased cytogenesis in the granule cell layer of the hippocampus and impaired place learning after irradiation of the young mouse brain evaluated using the IntelliCage platform.
- 2010
-
Ingår i: Experimental brain research. - : Springer Science and Business Media LLC. - 1432-1106 .- 0014-4819. ; 201:4, s. 781-787
-
Tidskriftsartikel (refereegranskat)abstract
- Radiation therapy is used to treat malignant tumors in the brain and central nervous system involvement of leukemia and lymphomas in children. However, ionizing radiation causes a number of adverse long-term side effects in the brain, including cognitive impairment. Hippocampal neurogenesis is important for place learning and has been shown to be decreased by irradiation (IR) in rats and mice. In the present study, 10-day-old male mice received 6-Gy IR to the brain on postnatal day 10. We used BrdU labeling of the granule cell layer (GCL) of the hippocampus to evaluate cell proliferation and survival. An unbiased, automated platform for monitoring of behavior in a group housing environment (IntelliCage) was used to evaluate place learning 2 months after IR. We show that cranial IR impaired place learning and reduced BrdU labeling by 50% in the GCL. Cranial IR also reduced whole body weight gain 5%. We conclude that this experimental paradigm provides a novel and time-saving model to detect differences in place learning in mice subjected to IR. This method of detecting behavioral differences can be used for further studies of adverse effects of IR on hippocampal neurogenesis and possible new strategies to ameliorate the negative effects of IR on cognition.
|
|
| 2. |
- Barlind, Anna, 1978, et al.
(författare)
-
The growth hormone secretagogue hexarelin increases cell proliferation in neurogenic regions of the mouse hippocampus.
- 2010
-
Ingår i: Growth hormone & IGF research. - : Elsevier BV. - 1532-2238 .- 1096-6374. ; 20:1, s. 49-54
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Radiation therapy (RT) to the brain is often used in the treatment of children with different types of malignant diseases affecting the brain. However, RT in childhood may also have severe side effects including impaired brain maturation and intellectual development. For childhood cancer survivors these adverse effects of RT can cause lifelong disability and suffering. Therefore, there is an unmet need to limit late effects after RT. Precursor cells in the subgranular zone of the dentate gyrus (DG) in the hippocampus are particularly sensitive to irradiation (IR). This may be of significance as newly generated neurons in the DG are important for memory and learning. GH secretagogues (GHS) have previously been shown to promote neurogenesis and to have neuroprotective effects. In addition, several parts of the brain, including the hippocampus, have been shown to express the GHS receptor 1a (GHS-R1a). The aim of this study was to evaluate the potential effect of the GHS hexarelin on proliferation and survival of progenitor cells in the hippocampus after brain IR in a mouse model. DESIGN: In the present study, 10-day-old male mice received 6Gy cranial IR. Non-irradiated sham animals were used as controls. We treated one group of irradiated and one sham group with hexarelin (100mug/kg/day) for 28days and used immunohistochemical labeling of bromo-deoxy uridine (BrdU) and phospho-histone H3 of the granular cell layer of the DG to evaluate proliferation and cell survival after IR at postnatal day ten. RESULTS: Our results show that hexarelin significantly increased the number of BrdU-positive cells in the granule cell layer by approximately 50% compared to controls. CONCLUSION: The increased number of BrdU-positive cells in the granule cell layer suggests a partial restoration in the pool of proliferating cells by hexarelin after IR.
|
|
| 3. |
- Blomstrand, Malin, 1974, et al.
(författare)
-
Different reactions to irradiation in the juvenile and adult hippocampus
- 2014
-
Ingår i: International Journal of Radiation Biology. - : Informa UK Limited. - 0955-3002 .- 1362-3095. ; 90:9, s. 807-815
-
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.
|
|
| 4. |
- Blomstrand, Malin, 1974, et al.
(författare)
-
No clinically relevant effect on cognitive outcomes after low-dose radiation to the infant brain: A population-based cohort study in Sweden
- 2014
-
Ingår i: Acta Oncologica. - : Informa UK Limited. - 0284-186X .- 1651-226X. ; 53:9, s. 1143-1150
-
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.
|
|
| 5. |
- Brodin, N Patrik, et al.
(författare)
-
Hippocampal sparing radiotherapy for pediatric medulloblastoma: impact of treatment margins and treatment technique.
- 2014
-
Ingår i: Neuro-oncology. - : Oxford University Press (OUP). - 1523-5866 .- 1522-8517. ; 16:4, s. 594-602
-
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.
|
|
| 6. |
- Brodin, N Patrik, et al.
(författare)
-
Radiobiological risk estimates of adverse events and secondary cancer for proton and photon radiation therapy of pediatric medulloblastoma.
- 2011
-
Ingår i: Acta oncologica (Stockholm, Sweden). - 1651-226X. ; 50:6, s. 806-16
-
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.
|
|
| 7. |
- Kalm, Marie, 1981, et al.
(författare)
-
Neurochemical Evidence of Potential Neurotoxicity After Prophylactic Cranial Irradiation.
- 2014
-
Ingår i: International journal of radiation oncology, biology, physics. - : Elsevier BV. - 1879-355X .- 0360-3016. ; 89:3, s. 607-614
-
Tidskriftsartikel (refereegranskat)abstract
- Toexamine whether cerebrospinal fluid biomarkers for neuroaxonal damage, neuroglial activation, and amyloid β-related processes could characterize the neurochemical response to cranial radiation.
|
|
| 8. |
- Karlsson, Niklas, et al.
(författare)
-
Learning and activity after irradiation of the young mouse brain analyzed in adulthood using unbiased monitoring in a home cage environment.
- 2011
-
Ingår i: Radiation research. - 1938-5404. ; 175:3, s. 336-46
-
Tidskriftsartikel (refereegranskat)abstract
- Cranial radiotherapy during the treatment of pediatric malignancies may cause adverse late effects. It is important to find methods to assess the functional effects of ionizing radiation in animal models and to evaluate the possible ameliorating effects of preventive or reparative treatment strategies. We investigated the long-term effects of a single 8-Gy radiation dose to the brains of 14-day-old mice. Activity and learning were evaluated in adulthood using open field and trace fear conditioning (TFC). These established methods were compared with the novel IntelliCage platform, which enables unbiased analysis of both activity and learning over time in a home cage environment. Neither activity nor learning was changed after irradiation, as judged by the open field and TFC analyses. The IntelliCage, however, revealed both altered activity and learning impairment after irradiation. Place learning and reversal learning were both impaired in the IntelliCage 3 months after irradiation. These results indicate that activity and learning should be assessed using multiple methods and that unbiased analysis over time in a home cage environment may offer advantages in the detection of subtle radiation-induced effects on the young brain.
|
|
| 9. |
- Lannering, Birgitta, 1948, et al.
(författare)
-
Hyperfractionated Versus Conventional Radiotherapy Followed by Chemotherapy in Standard-Risk Medulloblastoma: Results From the Randomized Multicenter HIT-SIOP PNET 4 Trial.
- 2012
-
Ingår i: Journal of clinical oncology : official journal of the American Society of Clinical Oncology. - 1527-7755. ; 30:26, s. 3187-93
-
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.
|
|
| 10. |
- Zackrisson, Björn, et al.
(författare)
-
Two-year results from a Swedish study on conventional versus accelerated radiotherapy in head and neck squamous cell carcinoma - The ARTSCAN study
- 2011
-
Ingår i: Radiotherapy and Oncology. - : Elsevier. - 0167-8140 .- 1879-0887. ; 100:1, s. 41-48
-
Tidskriftsartikel (refereegranskat)abstract
- Background and purpose: Studies on accelerated fractionation (AF) in head and neck cancer have shown increased local control and survival compared with conventional fractionation (CF), while others have been non-conclusive. In 1998 a national Swedish group decided to perform a randomised controlled clinical study of AF. Materials and methods: Patients with verified squamous cell carcinoma of the oral cavity, oropharynx, larynx (except glottic T1-T2, N0) and hypopharynx were included. Patients with prior chemotherapy or surgery were excluded. Patients were randomised to either CF (2Gy/day, 5days/week for 7 weeks, total dose 68Gy) or to AF (1.1Gy+2.0Gy/day, 5days/week for 4.5weeks, total dose 68Gy). An extensive quality assurance protocol was followed throughout the study. The primary end point was loco-regional tumour control (LRC) at two years after treatment. RESULTS: The study was closed in 2006 when 750 patients had been randomised. Eighty-three percent of the patients had stages III-IV disease. Forty eight percent had oropharyngeal, 21% laryngeal, 17% hypopharyngeal and 14% oral cancers. There were no significant differences regarding overall survival (OS) or LRC between the two regimens. The OS at two years was 68% for AF and 67% for CF. The corresponding figures for LRC were 71% and 67%, respectively. There was a trend towards improved LRC for oral cancers treated (p=0.07) and for large tumours (T3-T4) (p=0.07) treated with AF. The AF group had significantly worse acute reactions, while there was no significant increase in late effects. Conclusion: Overall the AF regimen did not prove to be more efficacious than CF. However, the trend towards improved results in AF for oral cancers needs to be further investigated.
|
|
