| 1. |
- AHLSTEDT, JONATAN, et al.
(författare)
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Effect of Blockade of Indoleamine 2, 3-dioxygenase in Conjunction with Single Fraction Irradiation in Rat Glioma
- 2015
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Ingår i: Jacobs journal of radiation oncology. - 2376-9424. ; 2:3
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Tidskriftsartikel (refereegranskat)abstract
- Glioblastoma (GBM), or WHO Astrocytoma grade IV, is the most common primary brain tumour in adults. GBM is shown to escape host immune surveillance through many paths, of which expression of indoleamine 2,3-dioxygenase (IDO), leading to induction and accumulation of regulatory T-cells in the tumour microenvironment, has been shown to be of importance. 1-Methyl tryptophan (1-MT) is an inhibitor of IDO that has been shown to have a positive effect on survival in experimental models of GBM. In this study, we evaluate the effect of combined single-fraction irradiation of 8 Gy with 1-MT treatment in Fischer rats carrying the RG2 glioma model. We also investigate expression of IDO in the RG2 model before and after irradiation. Thirty-three Fischer 344 rats received intracranial inoculations of RG2 tumour cells, and were treated with either intraperito-neal 1-MT, 8 Gy single-fraction radiotherapy, or a combination of the two. Survival in the combined treatment group (29 days ± 0.75) was significantly better than controls (20 ± 0.99, p=0.015) and radiation only (17 ± 2.75, p=0.014). Survival was also better with combined treatment compared to 1-MT only but the difference was non-significant (18 ± 0.28, p=0.215).Our results add to the growing base of evidence suggesting 1-methyl-tryptophan is an attractive candidate for clinical investi-gation in patients carrying highly malignant astrocytoma, especially in combination with radiation treatment, even in singular fraction settings.
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| 2. |
- Ahlstedt, Jonatan, et al.
(författare)
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Evaluating vacquinol-1 in rats carrying glioblastoma models RG2 and NS1
- 2018
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 9:9, s. 8391-8399
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Tidskriftsartikel (refereegranskat)abstract
- Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor, and available experimental and routine therapies result in limited survival benefits. A vulnerability of GBM cells to catastrophic vacuolization and cell death, a process termed methuosis, induced by Vacquinol-1 (VQ-1) has been described earlier. In the present study, we investigate the efficacy of VQ-1 treatment in two syngeneic rat GBM models, RG2 and NS1. VQ-1 treatment affected growth of both RG2 and NS1 cells in vitro. Intracranially, significant reduction in RG2 tumor size was observed, although no effect was seen on overall survival. No survival advantage or effect on tumor size was seen in animals carrying the NS1 models compared to untreated controls. Furthermore, immunological staining of FOXP3, CD4 and CD8 showed no marked difference in immune cell infiltrate in tumor environment following treatment. Taken together, a survival advantage of VQ-1 treatment alone could not be demonstrated here, even though some effect upon tumor size was seen. Staining for immune cell markers did not indicate that VQ-1 either reduced or increased host anti-tumor immune response.
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| 3. |
- Ahlstedt, Jonatan, et al.
(författare)
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Growth pattern of experimental glioblastoma
- 2020
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Ingår i: Histology and Histopathology. - 1699-5848. ; 35:8, s. 871-886
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Tidskriftsartikel (refereegranskat)abstract
- Glioblastoma multiforme (GBM) is an aggressive primary brain malignancy with a very poor prognosis. Researchers employ animal models to develop potential therapies. It is important that these models have clinical relevance. This means that old models, propagated for decades in cultures, should be questioned. Parameters to be evaluated include whether animals are immune competent or not, the infiltrative growth pattern of the tumor, tumor volume resulting in symptoms and growth rate.We here describe the growth pattern of an experimental glioblastoma model in detail with GFP positive glioblastoma cells in fully immune competent animalsand study tumor growth rate and tumor mass as a function of time from inoculation.We were able to correlate findings made with classical immunohistochemistry and MR findings. The tumor growth rate was fitted by a Gompertz function. The model predicted the time until onset of symptoms for 5000 inoculated cells to 18.7±0.4 days, and the tumor mass at days 10 and 14, which are commonly used as the start of treatment in therapeutic studies, were 5.97±0.62 mg and 29.1±3.0 mg, respectively.We want to raise the question regarding the clinical relevance of the outline of glioblastoma experiments, where treatment is ofteninitiated at a very early stage. The approach presented here could potentially be modified to gain information also from other tumor models.
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| 4. |
- Ahlstedt, Jonatan, et al.
(författare)
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Increased effect of two-fraction radiotherapy in conjunction with IDO1 inhibition in experimental glioblastoma
- 2020
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 15:5
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Tidskriftsartikel (refereegranskat)abstract
- Objectives The aim of the study was to investigate therapeutic efficacy of single-or two-fraction radiotherapy in conjunction with IDO1-inhibition in a syngeneic rat glioblastoma model. IDO is known to cause immunosuppression through breakdown of tryptophan in the tumor microenvironment. Methods Gene expression analyses of IDO in glioblastoma were performed with data from publicly available datasets. Fractionation studies were done on animals to evaluate tumor size, immune cell infiltration of tumors and serum profile on day 18 after tumor inoculation. Survival analyses were done with animals carrying intracranial glioblastomas comparing twofraction radiotherapy+IDO1-inhibition to controls. IDO inhibition was achieved by administration of 1-methyl tryptophan (1-MT), and radiotherapy (RT) was delivered in doses of 8Gy. Results The expression of IDO1 was increased on gene level in glioblastoma stem cells. Tumor size was significantly reduced in animals treated with 1-MT+RTx 2 (both long and short intervals, i.e. 7 and 4 days between the treatments) as compared to control animals, animals treated with only 1-MT or animals treated with 1-MT+RTx1. Serum levels of IL-1A were significantly altered in all treated animals as compared to control animals. Survival was significantly increased in the animals treated with 1-MT+RTx2 (7-day interval) compared to control animals. Conclusions Addition of two-fraction RT to IDO1 inhibition with 1-MT significantly reduced tumor size in animals with glioblastoma. Survival was significantly increased in animals treated with twofractioned RT+1-MT as compared to untreated controls increased significantly. Advances in knowledge The currently used combination of only two fractions of radiotherapy and immune therapy is a promising area of research, increasing efficacy compared to single fraction irradiation, while potentially lowering radiation side effects compared to radiation in current clinical practice.
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| 5. |
- Bartek, Jiri, Jr., et al.
(författare)
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Scandinavian Multicenter Acute Subdural Hematoma (SMASH) Study : Study Protocol for a Multinational Population-Based Consecutive Cohort
- 2019
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Ingår i: Neurosurgery. - : Ovid Technologies (Wolters Kluwer Health). - 0148-396X .- 1524-4040. ; 84:3, s. 799-803
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUNDTraumatic acute subdural hematomas (ASDHs) are associated with high rate of morbidity and mortality, especially in elderly individuals. However, recent reports indicate that the morbidity and mortality rates might have improved.OBJECTIVETo evaluate postoperative (30-d) mortality in younger vs elderly (70 yr) patients with ASDH. Comparing younger and elderly patients, the secondary objectives are morbidity patterns of care and 6 mo outcome according to Glasgow outcome scale (GOS). Finally, in patients with traumatic ASDH, we aim to provide prognostic variables.METHODS This is a large-scale population-based Scandinavian study including all neurosurgical departments in Denmark and Sweden. All adult (18 yr) patients surgically treated between 2010 and 2014 for a traumatic ASDH in Denmark and Sweden will be included. Identification at clinicaltrials.gov is NCT03284190.EXPECTED OUTCOMESWe expect to provide data on potential differences between younger vs elderly patients in terms of mortality and morbidity. We hypothesize that elderly patients selected for surgery have a similar pattern of care as compared with younger patients. We will provide functional outcome in terms of GOS at 6 mo in younger vs elderly patients undergoing ASDH evacuation. Finally, clinical useful prognostic factors for favorable (GOS 4-5) vs unfavorable (GOS 1-3) will be identified.DISCUSSION An improved understanding of the clinical outcome, treatment and resource allocation, clinical course, and the prognostic factors of traumatic ASDH will allow neurosurgeons to make better treatment decisions.
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| 6. |
- Bartek, Jiri, Jr, et al.
(författare)
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Neurokirurgin alltjämt kärnan i behandlingen av hjärntumörer : [Neurosurgery still pivotal in the diagnostics and treatment of brain tumor patients]
- 2023
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Ingår i: Läkartidningen. - : Läkartidningen Förlag AB. - 0023-7205 .- 1652-7518. ; 120
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Tidskriftsartikel (refereegranskat)abstract
- Behandling av hjärntumörer görs i samverkan mellan flera medicinska discipliner: neurokirurgi, onkologi, neurologi, neuropatologi, neuroradiologi och rehabiliteringsmedicin.Symtom som talar för förhöjt intrakraniellt tryck, såsom kraftig huvudvärk, illamående, kräkningar och papillödem, bör leda till snabb utredning och kontakt med neurokirurg. Förbättrad preoperativ kartläggning av tumören samt angränsande anatomiska och funktionella hjärnområden tillsammans med avancerad mikrokirurgisk teknik, intraoperativ monitorering och visualisering samt nya minimalinvasiva tekniker gör operationer säkrare, och det är i dag möjligt att utföra ingrepp som tidigare ansågs omöjliga eller alltför riskabla.
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| 7. |
- Bartek, Jiri, et al.
(författare)
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Neurosurgery still pivotal in the diagnostics and treatment of brain tumor patients
- 2023
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Ingår i: Läkartidningen. - 0023-7205. ; 120
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Treatment of adult patients with brain tumors is a multi-disciplinary effort involving several medical disciplines: neurosurgery, oncology, neurology, neuropathology, neuroradiology, and rehabilitation medicine. While the brain tumor field has gone through vast diagnostical changes during the last decade, the hopes of similar achievements in the systemic treatment of these patients with new methods have so far not been fulfilled. As such, neurosurgery still has a pivotal role in the diagnostics and treatment of brain tumor patients. Improved preoperative evaluation of the tumor and adjacent anatomical and functional brain areas, together with advanced microsurgical techniques, intraoperative mapping and monitoring, as well as new minimally invasive techniques, makes brain tumor surgery safer. Indeed, it is now possible to safely operate patients previously considered to have too unfavorable risk-benefit ratio. This article aims at presenting an overview of current neurosurgical treatments of brain tumors.
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| 8. |
- Ceberg, Crister, et al.
(författare)
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Photon activation therapy of RG2 glioma carrying Fischer rats using stable thallium and monochromatic synchrotron radiation.
- 2012
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Ingår i: Physics in Medicine and Biology. - : IOP Publishing. - 1361-6560 .- 0031-9155. ; 57:24, s. 8377-8391
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Tidskriftsartikel (refereegranskat)abstract
- 75 RG2 glioma-carrying Fischer rats were treated by photon activation therapy (PAT) with monochromatic synchrotron radiation and stable thallium. Three groups were treated with thallium in combination with radiation at different energy; immediately below and above the thallium K-edge, and at 50 keV. Three control groups were given irradiation only, thallium only, or no treatment at all. For animals receiving thallium in combination with radiation to 15 Gy at 50 keV, the median survival time was 30 days, which was 67% longer than for the untreated controls (p = 0.0020) and 36% longer than for the group treated with radiation alone (not significant). Treatment with thallium and radiation at the higher energy levels were not effective at the given absorbed dose and thallium concentration. In the groups treated at 50 keV and above the K-edge, several animals exhibited extensive and sometimes contra-lateral edema, neuronal death and frank tissue necrosis. No such marked changes were seen in the other groups. The results were discussed with reference to Monte Carlo calculated electron energy spectra and dose enhancement factors.
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| 9. |
- Cederberg, David, et al.
(författare)
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Extreme intracranial pressure elevation > 90 mmHg in an awake patient with primary CNS lymphoma—case report
- 2020
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Ingår i: Acta Neurochirurgica. - : Springer Science and Business Media LLC. - 0001-6268 .- 0942-0940. ; 162:8, s. 1819-1823
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Tidskriftsartikel (refereegranskat)abstract
- We describe a patient with primary CNS lymphomas, awake despite an extreme ICP elevation. A 48-year-old woman presented with headache since 1 month, and bilateral papillary edema was observed. Magnetic resonance imaging revealed diffuse infiltration around the petrous bone. Following external ventricular drainage (EVD) placement, ICP levels of > 90 mmHg were recorded while the patient was fully awake. Cytology revealed an aggressive primary CNS lymphoma. Cerebrospinal fluid (CSF) drainage at high opening pressure levels was required. We conclude that extreme ICP elevations, treatable by CSF drainage, can be observed without a reduced level of consciousness.
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| 10. |
- Chakwizira, Arthur, et al.
(författare)
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Mathematical modelling of the synergistic combination of radiotherapy and indoleamine-2,3-dioxygenase (IDO) inhibitory immunotherapy against glioblastoma
- 2018
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Ingår i: British Journal of Radiology. - : British Institute of Radiology. - 0007-1285 .- 1748-880X. ; 91:1087
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Recent research has shown that combining radiotherapy and immunotherapy can counteract the ability of cancer to evade and suppress the native immune system. To optimise the synergy of the combined therapies, factors such as radiation dose and fractionation must be considered, alongside numerous parameters resulting from the complexity of cancer-immune system interactions. It is instructive to use mathematical models to tackle this problem. Methods: In this work, we adapted a model primarily to describe the synergistic effect between single-fraction radiotherapy and immunotherapy (1-methyl tryptophan) observed in previous experiments with glioblastoma-carrying rats. We also showed how the model can be used to generate hypotheses on the outcome of other treatment fractionation schemes. Results: The model successfully reproduced the results of the experiments. Moreover, it provided support for the hypothesis that, for a given biologically effective dose, the efficacy of the combination therapy and the synergy between the two therapies are favoured by the administration of radiotherapy in a hypofractionated regime. Furthermore, for a double-fraction irradiation regimen, the synergy is favoured by a short time interval between the treatment fractions. Conclusion: It was concluded that the model could be fitted to reproduce the experimental data well within its uncertainties. It was also demonstrated that the fitted model can be used to form hypotheses to be validated by further pre-clinical experiments. Advances in knowledge: The results of this work support the hypothesis that the synergetic action of combined radiotherapy and immunotherapy is favoured by using a hypofractionated radiation treatment regimen, given over a short time interval.
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