39 results on '"Asklund T"'
Search Results
2. P01.151 Gender differences in glioma - findings from the Swedish National Quality Registry for Primary Brain Tumors
- Author
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Malmström, A, primary, Åkesson, L, additional, Asklund, T, additional, Kinhult, S, additional, Werlenius, K, additional, Hesselager, G, additional, Hylin, S, additional, and Henriksson, R, additional
- Published
- 2018
- Full Text
- View/download PDF
3. PV-0527: Gray-level invariant Haralick texture features
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Brynolfsson, P., primary, Löfstedt, T., additional, Asklund, T., additional, Nyholm, T., additional, and Garpebring, A., additional
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- 2018
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- View/download PDF
4. A Complete Nation-Based Registration Ensures Equal And Optimal Management Of Primary Brain Tumors Patients
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Malmström, A., Asklund, T., Kinhult, S., Sjögren, M., Hylin, S., Rosenlund, L., Bergqvist, M., Milos, P., Hesselager, Göran, Henriksson, R., Malmström, A., Asklund, T., Kinhult, S., Sjögren, M., Hylin, S., Rosenlund, L., Bergqvist, M., Milos, P., Hesselager, Göran, and Henriksson, R.
- Abstract
Supplement: 4, Meeting Abstract: P02.02
- Published
- 2016
5. P02.02 A Complete Nation-Based Registration Ensures Equal and Optimal Management of Primary Brain Tumors Patients
- Author
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Malmstrom, A., primary, Asklund, T., additional, Kinhult, S., additional, Sjögren, M., additional, Hylin, S., additional, Rosenlund, L., additional, Bergqvist, M., additional, Milos, P., additional, Hesselager, G., additional, and Henriksson, R., additional
- Published
- 2016
- Full Text
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6. PO-0958: Correlations between DCE-MRI, [18F]-FLT PET and survival in patients with high grade glioma
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Brynolfsson, P., primary, Asklund, T., additional, Gref, M., additional, Axelsson, J., additional, Riklund, K., additional, and Nyholm, T., additional
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- 2015
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7. O9.03 * BRAIN TUMORS IN SWEDEN: DATA FROM A POPULATION BASED REGISTRY 1999-2012
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Asklund, T., primary, Malmstrom, A., additional, Bergqvist, M., additional, Bjor, O., additional, and Henriksson, R., additional
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- 2014
- Full Text
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8. P15.14 * DEVELOPING PATIENT REPORTED OUTCOME MEASURES (PRO) FOR IMPLEMENTATION IN THE SWEDISH NATIONAL QUALITY REGISTER FOR PRIMARY BRAIN TUMORS
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Rosenlund, L., primary, Henriksson, R., additional, Asklund, T., additional, and Petersson, L., additional
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- 2014
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9. P16.02 * ADC TEXTURE - AN IMAGING BIOMARKER FOR HIGH GRADE GLIOMA?
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Asklund, T., primary, Birgander, R., additional, Brynolfsson, P., additional, Garpebring, A., additional, Hauksson, J., additional, Henriksson, R., additional, Karlsson, M., additional, Nilsson, D., additional, Nyholm, T., additional, and Trygg, J., additional
- Published
- 2014
- Full Text
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10. Durable stabilization of three chordoma cases by bevacizumab and erlotinib
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Asklund, T., primary, Sandström, M., additional, Shahidi, S., additional, Riklund, K., additional, and Henriksson, R., additional
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- 2014
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11. EP-1601: Accuracy of inverse treatment planning on substitute CT images derived from MR data in brain lesions
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Jonsson, J., primary, Akhtari, M., additional, Karlsson, M., additional, Johansson, A., additional, Asklund, T., additional, and Nyholm, T., additional
- Published
- 2014
- Full Text
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12. PET response and tumor stabilization under erlotinib and bevacizumab treatment of an intracranial lesion non-invasively diagnosed as likely chordoma
- Author
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Asklund, T, Danfors, Torsten, Henriksson, R, Asklund, T, Danfors, Torsten, and Henriksson, R
- Abstract
INTRODUCTION: Chordoma is a rare and a slow-growing tumor originating from the notochord and commonly localized in the skull base. Surgery and occasionally radiotherapy have emerged as the treatments of choice. In the relapsed situations available treatment options are strictly limited; however, recently molecularly targeted agents have been proposed to be of potential beneficial value. THE CASE: A 63-year-old male presenting with seizures and an extradural mass in the left brain hemisphere. An attempt to resect the tumor was followed by severe bradycardia when manipulating with the dura and therefore discontinued. It was considered too hazardous even to take a biopsy specimen. The tumor was considered radiologically and macroscopically as a chordoma. As the tumor progressed after radiotherapy, chemotherapy with erlotinib in combination with cetuximab was initiated. This treatment was interrupted due to progressive disease and toxicity. However, combination treatment with erlotinib and bevacizumab normalized the uptake of [11C]methionine PET signal and resulted in a slight tumor shrinkage on MRI. The patient is still (March 2011) free of symptoms, without cranial nerve deficits or seizures. DISCUSSION: This report shows that erlotinib and bevacizumab in combination may completely quench the transport of the essential amino acid methionine to a treatment refractory intracranial tumor bearing radiological and clinical characteristics of a chordoma. Further studies are necessary to establish this strategy as a treatment option for this indication.
- Published
- 2011
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13. NEOADJUVANT TEMOZOLOMIDE FOR GRADE III AND IV ATROCYTOMA: A RANDOMIZED PHASE II STUDY in NEURO-ONCOLOGY, vol 12, issue , pp 39-40
- Author
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Malmström, Annika, Skovgaard Poulsen, H, Stragliotto, G, Gronberg, B, Hansen, S, Asklund, T, Henriksson, R, Malmström, Annika, Skovgaard Poulsen, H, Stragliotto, G, Gronberg, B, Hansen, S, Asklund, T, and Henriksson, R
- Abstract
n/a
- Published
- 2010
14. Radiotherapy and pacemaker: 80 Gy to target close to the device may be feasible
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Kesek, M., primary, Nyholm, T., additional, and Asklund, T., additional
- Published
- 2012
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15. PET response and tumor stabilization under erlotinib and bevacizumab treatment of an intracranial lesion non-invasively diagnosed as likely chordoma
- Author
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Asklund, T., primary, Danfors, T., additional, and Henriksson, R., additional
- Published
- 2011
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16. Intratumoral retrograde microdialysis treatment of high-grade glioma with cisplatin.
- Author
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Tabatabaei P, Asklund T, Bergström P, Björn E, Johansson M, and Bergenheim AT
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- Adult, Aged, Aged, 80 and over, Antineoplastic Agents administration & dosage, Brain metabolism, Brain pathology, Brain Neoplasms pathology, Cisplatin administration & dosage, Female, Glioma pathology, Glucose metabolism, Glutamic Acid metabolism, Glycerol metabolism, Humans, Male, Middle Aged, Neoplasm Recurrence, Local metabolism, Quality of Life, Treatment Outcome, Antineoplastic Agents therapeutic use, Brain Neoplasms drug therapy, Cisplatin therapeutic use, Glioma drug therapy, Microdialysis methods
- Abstract
Purpose: This study evaluates the application of a microdialysis technique for interstitial chemotherapy using cisplatin in high-grade glioma., Method: An in vitro study demonstrated that cisplatin can be administered through retrograde microdialysis and defined the recovery for cisplatin. In a subsequent phase I study, 1-4 microdialysis catheters were implanted in tumor tissue, brain adjacent to tumor (BAT) tissue, and subcutaneous tissue in 10 patients with recurrent high-grade glioma. Cisplatin was administered continuously in daily doses between 0.3 and 3.9 mg for 4 to12 days. Microdialysis samples were continuously collected and analyzed for glucose metabolites, glutamate, glycerol, and cisplatin concentrations. Treatment tolerability was evaluated through clinical monitoring. Quality of life was assessed using the EORTC-QLQ-C30 questionnaire for up to 3 months after treatment., Results: This in vitro study showed that cisplatin could be administrated with a recovery of 41-97%, depending on flowrate, type of catheter, and cisplatin concentration. During the treatment, patients were exposed to a total dose of 1.2-36.8 mg cisplatin. The concentration of cisplatin in BAT, serum, and subcutaneous tissue was close to detection level in all but two patients. A transient neurologic deterioration due to edema was commonly observed, but no systemic side effects were recorded. After onset of treatment, concentrations of glutamate and glycerol were significantly increased in tumor tissue but not in BAT, with a peak after 3 days, and consistent for the rest of the treatment. Five of the patients survived between 153 and 492 days after treatment., Conclusion: This phase I study demonstrates that retrograde microdialysis can be used to administer cisplatin interstitially into high-grade glioma tissue. A high cytotoxicity was detected in tumor tissue, but not in the surrounding brain. Retrograde microdialysis appears to be a clinically useful method for intratumoral drug administration in high-grade glioma.
- Published
- 2020
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17. Metabolic response patterns in brain microdialysis fluids and serum during interstitial cisplatin treatment of high-grade glioma.
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Björkblom B, Jonsson P, Tabatabaei P, Bergström P, Johansson M, Asklund T, Bergenheim AT, and Antti H
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- Adult, Aged, Aged, 80 and over, Antineoplastic Agents administration & dosage, Brain metabolism, Brain pathology, Brain surgery, Brain Neoplasms metabolism, Brain Neoplasms secondary, Brain Neoplasms surgery, Cisplatin metabolism, Female, Glioma metabolism, Glioma pathology, Glioma surgery, Glucose metabolism, Humans, Lactic Acid metabolism, Male, Microdialysis methods, Middle Aged, Neoplasm Staging, Brain drug effects, Brain Neoplasms drug therapy, Cisplatin administration & dosage, Glioma drug therapy
- Abstract
Background: High-grade gliomas are associated with poor prognosis. Tumour heterogeneity and invasiveness create challenges for effective treatment and use of systemically administrated drugs. Furthermore, lack of functional predictive response-assays based on drug efficacy complicates evaluation of early treatment responses., Methods: We used microdialysis to deliver cisplatin into the tumour and to monitor levels of metabolic compounds present in the tumour and non-malignant brain tissue adjacent to tumour, before and during treatment. In parallel, we collected serum samples and used multivariate statistics to analyse the metabolic effects., Results: We found distinct metabolic patterns in the extracellular fluids from tumour compared to non-malignant brain tissue, including high concentrations of a wide range of amino acids, amino acid derivatives and reduced levels of monosaccharides and purine nucleosides. We found that locoregional cisplatin delivery had a strong metabolic effect at the tumour site, resulting in substantial release of glutamic acid, phosphate, and spermidine and a reduction of cysteine levels. In addition, patients with long-time survival displayed different treatment response patterns in both tumour and serum. Longer survival was associated with low tumour levels of lactic acid, glyceric acid, ketoses, creatinine and cysteine. Patients with longer survival displayed lower serum levels of ketohexoses, fatty acid methyl esters, glycerol-3-phosphate and alpha-tocopherol, while elevated phosphate levels were seen in both tumour and serum during treatment., Conclusion: We highlight distinct metabolic patterns associated with high-grade tumour metabolism, and responses to cytotoxic cisplatin treatment.
- Published
- 2020
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18. Gray-level invariant Haralick texture features.
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Löfstedt T, Brynolfsson P, Asklund T, Nyholm T, and Garpebring A
- Subjects
- Algorithms, Color, Density Functional Theory, Pattern Recognition, Automated, Image Processing, Computer-Assisted
- Abstract
Haralick texture features are common texture descriptors in image analysis. To compute the Haralick features, the image gray-levels are reduced, a process called quantization. The resulting features depend heavily on the quantization step, so Haralick features are not reproducible unless the same quantization is performed. The aim of this work was to develop Haralick features that are invariant to the number of quantization gray-levels. By redefining the gray-level co-occurrence matrix (GLCM) as a discretized probability density function, it becomes asymptotically invariant to the quantization. The invariant and original features were compared using logistic regression classification to separate two classes based on the texture features. Classifiers trained on the invariant features showed higher accuracies, and had similar performance when training and test images had very different quantizations. In conclusion, using the invariant Haralick features, an image pattern will give the same texture feature values independent of image quantization., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2019
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19. Postoperative neoadjuvant temozolomide before radiotherapy versus standard radiotherapy in patients 60 years or younger with anaplastic astrocytoma or glioblastoma: a randomized trial.
- Author
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Malmström A, Poulsen HS, Grønberg BH, Stragliotto G, Hansen S, Asklund T, Holmlund B, Łysiak M, Dowsett J, Kristensen BW, Söderkvist P, Rosell J, and Henriksson R
- Subjects
- Adult, Astrocytoma genetics, Brain Neoplasms genetics, DNA Modification Methylases genetics, DNA Repair Enzymes genetics, Dacarbazine therapeutic use, Female, Glioblastoma genetics, Humans, Isocitrate Dehydrogenase genetics, Kaplan-Meier Estimate, Male, Middle Aged, Multivariate Analysis, Mutation, Pilot Projects, Prognosis, Promoter Regions, Genetic, Survival Rate, Temozolomide, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Proteins genetics, X-linked Nuclear Protein genetics, Young Adult, Antineoplastic Agents, Alkylating therapeutic use, Astrocytoma therapy, Brain Neoplasms therapy, Chemoradiotherapy, Adjuvant methods, Dacarbazine analogs & derivatives, Glioblastoma therapy, Neurosurgical Procedures, Radiotherapy, Adjuvant methods
- Abstract
Introduction: A pilot study of temozolomide (TMZ) given before radiotherapy (RT) for anaplastic astrocytoma (AA) and glioblastoma (GBM) resulted in prolonged survival compared to historical controls receiving RT alone. We therefore investigated neoadjuvant TMZ (NeoTMZ) in a randomized trial. During enrollment, concomitant and adjuvant radio-chemotherapy with TMZ became standard treatment. The trial was amended to include concurrent TMZ., Patients and Methods: Patients, after surgery for GBM or AA, age ≤60 years and performance status (PS) 0-2, were randomized to either 2-3 cycles of TMZ, 200 mg/m
2 days 1-5 every 28 days, followed by RT 60 Gy in 30 fractions or RT only. Patients without progressive disease after two TMZ cycles, received the third cycle. From March 2005, TMZ 75 mg/m2 was administered daily concomitant with RT. TMZ was recommended first-line treatment at progression. Primary endpoint was overall survival and secondary safety., Results: The study closed prematurely after enrolling 144 patients, 103 with GBM and 41 with AA. Median age was 53 years (range 24-60) and 89 (62%) were male. PS was 0-1 for 133 (92%) patients, 53 (37%) had complete surgical resection and 18 (12%) biopsy. Ninety-two (64%) received TMZ concomitant with RT. Seventy-two (50%) were randomized to neoadjuvant treatment. For the overall study population survival was 20.3 months for RT and 17.7 months for NeoTMZ (p = .76), this not reaching the primary objective. For the preplanned subgroup analysis, we found that NeoTMZ AA patients had a median survival of 95.1 months compared to 35.2 months for RT (p = .022). For patients with GBM, no difference in survival was observed (p = .10). MGMT and IDH status affected outcome., Conclusions: No advantage of NeoTMZ was noted for the overall study population or subgroup of GBM, while NeoTMZ resulted in 5 years longer median survival for patients diagnosed as AA.- Published
- 2017
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20. Haralick texture features from apparent diffusion coefficient (ADC) MRI images depend on imaging and pre-processing parameters.
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Brynolfsson P, Nilsson D, Torheim T, Asklund T, Karlsson CT, Trygg J, Nyholm T, and Garpebring A
- Abstract
In recent years, texture analysis of medical images has become increasingly popular in studies investigating diagnosis, classification and treatment response assessment of cancerous disease. Despite numerous applications in oncology and medical imaging in general, there is no consensus regarding texture analysis workflow, or reporting of parameter settings crucial for replication of results. The aim of this study was to assess how sensitive Haralick texture features of apparent diffusion coefficient (ADC) MR images are to changes in five parameters related to image acquisition and pre-processing: noise, resolution, how the ADC map is constructed, the choice of quantization method, and the number of gray levels in the quantized image. We found that noise, resolution, choice of quantization method and the number of gray levels in the quantized images had a significant influence on most texture features, and that the effect size varied between different features. Different methods for constructing the ADC maps did not have an impact on any texture feature. Based on our results, we recommend using images with similar resolutions and noise levels, using one quantization method, and the same number of gray levels in all quantized images, to make meaningful comparisons of texture feature results between different subjects.
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- 2017
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21. A Retrospective Evaluation of Bevacizumab Treatment in Patients with Progressive Malignant Glioma in Northern Sweden.
- Author
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Sandström M, Laudius M, Lindqvist T, Asklund T, and Johansson M
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- Adult, Aged, Brain Neoplasms pathology, Disease Progression, Female, Glioma pathology, Humans, Male, Middle Aged, Neoplasm Grading, Neoplasm Recurrence, Local pathology, Prognosis, Retrospective Studies, Survival Rate, Sweden, Angiogenesis Inhibitors therapeutic use, Bevacizumab therapeutic use, Brain Neoplasms drug therapy, Glioma drug therapy, Neoplasm Recurrence, Local drug therapy
- Abstract
Background/aim: Overall survival for glioblastoma patients is short. Standard treatment is surgery followed by radiochemotherapy and adjuvant temozolomide. The aim of this study was to evaluate the outcome for all patients with progressive disease treated with bevacizumab-based treatment combinations in the northern region of Sweden., Patients and Methods: This was a single-center retrospective analysis after bevacizumab-based second-line treatment for malignant glioma. All patients treated with bevacizumab, between 2007 and 2011 in our Center were retrospectively evaluated., Results: Progression-free survival after the start of bevacizumab-based treatment was 20 weeks and overall survival was 31 weeks. Treatment was well tolerated, but 9% of patients (n=6) suffered from serious adverse events. In 68% of patients, a ≥25% decrease in contrast enhancement was seen at best response., Conclusion: Results from this retrospective study are comparable with earlier phase-II studies and motivate randomized trials of bevacizumab-based treatment in the second-line setting., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)
- Published
- 2017
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22. Effect of Increased Radiotoxicity on Survival of Patients with Non-small Cell Lung Cancer Treated with Curatively Intended Radiotherapy.
- Author
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Holgersson G, Bergström S, Liv P, Nilsson J, Edlund P, Blomberg C, Nyman J, Friesland S, Ekman S, Asklund T, Henriksson R, and Bergqvist M
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- Adenocarcinoma pathology, Adenocarcinoma radiotherapy, Adult, Aged, Aged, 80 and over, Carcinoma, Non-Small-Cell Lung pathology, Carcinoma, Non-Small-Cell Lung radiotherapy, Carcinoma, Squamous Cell pathology, Carcinoma, Squamous Cell radiotherapy, Esophagitis diagnosis, Esophagitis etiology, Female, Follow-Up Studies, Humans, Lung Neoplasms pathology, Lung Neoplasms radiotherapy, Male, Middle Aged, Neoplasm Staging, Prognosis, Radiation Injuries diagnosis, Radiation Injuries etiology, Radiation Pneumonitis diagnosis, Radiation Pneumonitis etiology, Retrospective Studies, Survival Rate, Adenocarcinoma mortality, Carcinoma, Non-Small-Cell Lung mortality, Carcinoma, Squamous Cell mortality, Esophagitis mortality, Lung Neoplasms mortality, Radiation Injuries mortality, Radiation Pneumonitis mortality, Radiotherapy adverse effects
- Abstract
Aim: To elucidate the impact of different forms of radiation toxicities (esophagitis, radiation pneumonitis, mucositis and hoarseness), on the survival of patients treated with curatively intended radiotherapy for non-small cell lung cancer (NSCLC)., Patients and Methods: Data were individually collected retrospectively for all patients diagnosed with NSCLC subjected to curatively intended radiotherapy (≥50 Gy) in Sweden during the time period 1990 to 2000., Results: Esophagitis was the only radiation-induced toxicity with an impact on survival (hazard ratio=0.83, p=0.016). However, in a multivariate model, with clinical- and treatment-related factors taken into consideration, the impact of esophagitis on survival was no longer statistically significant (hazard ratio=0.88, p=0.17)., Conclusion: The effect on survival seen in univariate analysis may be related to higher radiation dose and to the higher prevalence of chemotherapy in this group. The results do not suggest that the toxicities examined have any detrimental effect on overall survival., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)
- Published
- 2015
23. Brain tumors in Sweden: data from a population-based registry 1999-2012.
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Asklund T, Malmström A, Bergqvist M, Björ O, and Henriksson R
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- Activities of Daily Living, Adolescent, Adult, Age Distribution, Aged, Geography, Medical, Humans, Meningeal Neoplasms epidemiology, Meningeal Neoplasms surgery, Meningioma epidemiology, Meningioma surgery, Middle Aged, Postoperative Complications mortality, Severity of Illness Index, Survival Analysis, Sweden epidemiology, Time Factors, Time-to-Treatment, Brain Neoplasms diagnosis, Brain Neoplasms epidemiology, Brain Neoplasms radiotherapy, Brain Neoplasms surgery, Glioma diagnosis, Glioma epidemiology, Glioma radiotherapy, Glioma surgery, Registries statistics & numerical data
- Abstract
Background: The Swedish brain tumor registry has, since it was launched in 1999, provided significant amounts of data on histopathological diagnoses and on important aspects of surgical and medical management of these patients. The purpose is mainly quality control, but also as a resource for research., Methods: Three Swedish healthcare regions, constituting 40% of the Swedish population, have had an almost complete registration. The following parameters are registered: diagnosis according to SNOMED/WHO classification, symptoms, performance status, pre- and postoperative radiology, tumor size and localization, extent of surgery and occurrence of postoperative complications, postoperative treatment, such as radiotherapy and/or chemotherapy, other treatments, complications and toxicity, occurrence of reoperation/s, participation in clinical trials, multidisciplinary conferences and availability of a contact nurse., Results: Surgical radicality has been essentially constant, whereas the use of early (within 72 hours) postoperative CT and MRI has increased, especially for high-grade glioma, which is a reflection of quality of surgery. Survival of patients with high-grade glioma has increased, especially in the age group 60-69. Patients aged 18-39 years had a five-year survival of 40%. Waiting times for the pathological report has been slightly prolonged. Geographical differences do exist for some of the variables., Conclusion: Population-based registration is valuable for assessment of clinical management, which could have impact on patient care. As a result of short survival and/or the propensity to affect cognitive functions this patient group has considerable difficulties to make their voices heard in society. We therefore believe that a report like the present one can contribute to the spread of knowledge and increase the awareness for this patient group among caregivers and policy makers.
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- 2015
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24. Accuracy of inverse treatment planning on substitute CT images derived from MR data for brain lesions.
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Jonsson JH, Akhtari MM, Karlsson MG, Johansson A, Asklund T, and Nyholm T
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- Humans, Radiotherapy Dosage, Radiotherapy, Intensity-Modulated methods, Brain Neoplasms radiotherapy, Glioblastoma radiotherapy, Image Processing, Computer-Assisted methods, Magnetic Resonance Imaging methods, Radiotherapy Planning, Computer-Assisted methods, Tomography, X-Ray Computed methods
- Abstract
Background: In this pilot study we evaluated the performance of a substitute CT (s-CT) image derived from MR data of the brain, as a basis for optimization of intensity modulated rotational therapy, final dose calculation and derivation of reference images for patient positioning., Methods: S-CT images were created using a Gaussian mixture regression model on five patients previously treated with radiotherapy. Optimizations were compared using D max, D min, D median and D mean measures for the target volume and relevant risk structures. Final dose calculations were compared using gamma index with 1%/1 mm and 3%/3 mm acceptance criteria. 3D geometric evaluation was conducted using the DICE similarity coefficient for bony structures. 2D geometric comparison of digitally reconstructed radiographs (DRRs) was performed by manual delineation of relevant structures on the s-CT DRR that were transferred to the CT DRR and compared by visual inspection., Results: Differences for the target volumes in optimization comparisons were small in general, e.g. a mean difference in both D min and D max within ±0.3%. For the final dose calculation gamma evaluations, 100% of the voxels passed the 1%/1 mm criterion within the PTV. Within the entire external volume between 99.4% and 100% of the voxels passed the 3%/3 mm criterion. In the 3D geometric comparison, the DICE index varied between approximately 0.8-0.9, depending on the position in the skull. In the 2D DRR comparisons, no appreciable visual differences were found., Conclusions: Even though the present work involves a limited number of patients, the results provide a strong indication that optimization and dose calculation based on s-CT data is accurate regarding both geometry and dosimetry.
- Published
- 2015
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25. ADC texture--an imaging biomarker for high-grade glioma?
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Brynolfsson P, Nilsson D, Henriksson R, Hauksson J, Karlsson M, Garpebring A, Birgander R, Trygg J, Nyholm T, and Asklund T
- Subjects
- Adult, Age Factors, Aged, Antineoplastic Agents, Alkylating therapeutic use, Brain drug effects, Brain pathology, Brain radiation effects, Brain Neoplasms drug therapy, Brain Neoplasms radiotherapy, Chemoradiotherapy, Adjuvant, Dacarbazine analogs & derivatives, Dacarbazine therapeutic use, Disease Progression, Follow-Up Studies, Glioma drug therapy, Glioma radiotherapy, Humans, Middle Aged, Multivariate Analysis, Neoplasm Grading, Principal Component Analysis, Prognosis, Survival Analysis, Temozolomide, Treatment Outcome, Brain Neoplasms diagnosis, Brain Neoplasms pathology, Diffusion Magnetic Resonance Imaging methods, Glioma diagnosis, Glioma pathology, Image Interpretation, Computer-Assisted methods
- Abstract
Purpose: Survival for high-grade gliomas is poor, at least partly explained by intratumoral heterogeneity contributing to treatment resistance. Radiological evaluation of treatment response is in most cases limited to assessment of tumor size months after the initiation of therapy. Diffusion-weighted magnetic resonance imaging (MRI) and its estimate of the apparent diffusion coefficient (ADC) has been widely investigated, as it reflects tumor cellularity and proliferation. The aim of this study was to investigate texture analysis of ADC images in conjunction with multivariate image analysis as a means for identification of pretreatment imaging biomarkers., Methods: Twenty-three consecutive high-grade glioma patients were treated with radiotherapy (2 Gy/60 Gy) with concomitant and adjuvant temozolomide. ADC maps and T1-weighted anatomical images with and without contrast enhancement were collected prior to treatment, and (residual) tumor contrast enhancement was delineated. A gray-level co-occurrence matrix analysis was performed on the ADC maps in a cuboid encapsulating the tumor in coronal, sagittal, and transversal planes, giving a total of 60 textural descriptors for each tumor. In addition, similar examinations and analyses were performed at day 1, week 2, and week 6 into treatment. Principal component analysis (PCA) was applied to reduce dimensionality of the data, and the five largest components (scores) were used in subsequent analyses. MRI assessment three months after completion of radiochemotherapy was used for classifying tumor progression or regression., Results: The score scatter plots revealed that the first, third, and fifth components of the pretreatment examinations exhibited a pattern that strongly correlated to survival. Two groups could be identified: one with a median survival after diagnosis of 1099 days and one with 345 days, p = 0.0001., Conclusions: By combining PCA and texture analysis, ADC texture characteristics were identified, which seems to hold pretreatment prognostic information, independent of known prognostic factors such as age, stage, and surgical procedure. These findings encourage further studies with a larger patient cohort.
- Published
- 2014
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26. CT substitutes derived from MR images reconstructed with parallel imaging.
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Johansson A, Garpebring A, Asklund T, and Nyholm T
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- Adult, Aged, Algorithms, Female, Head diagnostic imaging, Head pathology, Humans, Male, Middle Aged, Time Factors, Young Adult, Magnetic Resonance Imaging methods, Tomography, X-Ray Computed methods
- Abstract
Purpose: Computed tomography (CT) substitute images can be generated from ultrashort echo time (UTE) MRI sequences with radial k-space sampling. These CT substitutes can be used as ordinary CT images for PET attenuation correction and radiotherapy dose calculations. Parallel imaging allows faster acquisition of magnetic resonance (MR) images by exploiting differences in receiver coil element sensitivities. This study investigates whether non-Cartesian parallel imaging reconstruction can be used to improve CT substitutes generated from shorter examination times., Methods: The authors used gridding as well as two non-Cartesian parallel imaging reconstruction methods, SPIRiT and CG-SENSE, to reconstruct radial UTE and gradient echo (GE) data into images of the head for 23 patients. For each patient, images were reconstructed from the full dataset and from a number of subsampled datasets. The subsampled datasets simulated shorter acquisition times by containing fewer radial k-space spokes (1000, 2000, 3000, 5000, and 10,000 spokes) than the full dataset (30,000 spokes). For each combination of patient, reconstruction method, and number of spokes, the reconstructed UTE and GE images were used to generate a CT substitute. Each CT substitute image was compared to a real CT image of the same patient., Results: The mean absolute deviation between the CT number in CT substitute and CT decreased when using SPIRiT as compared to gridding reconstruction. However, the reduction was small and the CT substitute algorithm was insensitive to moderate subsampling (≥ 5000 spokes) regardless of reconstruction method. For more severe subsampling (≤ 3000 spokes), corresponding to acquisition times less than a minute long, the CT substitute quality was deteriorated for all reconstruction methods but SPIRiT gave a reduction in the mean absolute deviation of down to 25 Hounsfield units compared to gridding., Conclusions: SPIRiT marginally improved the CT substitute quality for a given number of radial spokes as compared to gridding. However, the increased reconstruction time of non-Cartesian parallel imaging reconstruction is difficult to motivate from this improvement. Because the CT substitute algorithm was insensitive to moderate subsampling, data for a CT substitute could be collected in as little as minute and reconstructed with gridding without deteriorating the CT substitute quality.
- Published
- 2014
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27. Improved quality of computed tomography substitute derived from magnetic resonance (MR) data by incorporation of spatial information--potential application for MR-only radiotherapy and attenuation correction in positron emission tomography.
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Johansson A, Garpebring A, Karlsson M, Asklund T, and Nyholm T
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- Humans, Image Processing, Computer-Assisted, Models, Theoretical, Neoplasms radiotherapy, Pilot Projects, Prognosis, Radiotherapy Planning, Computer-Assisted, Regression Analysis, Risk Factors, Tumor Burden, Brachytherapy, Magnetic Resonance Imaging, Neoplasms diagnostic imaging, Positron-Emission Tomography, Quality Improvement, Radiotherapy, Image-Guided, Tomography, X-Ray Computed
- Abstract
Background: Estimation of computed tomography (CT) equivalent data, i.e. a substitute CT (s-CT), from magnetic resonance (MR) images is a prerequisite both for attenuation correction of positron emission tomography (PET) data acquired with a PET/MR scanner and for dose calculations in an MR-only radiotherapy workflow. It has previously been shown that it is possible to estimate Hounsfield numbers based on MR image intensities, using ultra short echo-time imaging and Gaussian mixture regression (GMR). In the present pilot study we investigate the possibility to also include spatial information in the GMR, with the aim to improve the quality of the s-CT., Material and Methods: MR and CT data for nine patients were used in the present study. For each patient, GMR models were created from the other eight patients, including either both UTE image intensities and spatial information on a voxel by voxel level, or only UTE image intensities. The models were used to create s-CT images for each respective patient., Results: The inclusion of spatial information in the GMR model improved the accuracy of the estimated s-CT. The improvement was most pronounced in smaller, complicated anatomical regions as the inner ear and post-nasal cavities., Conclusions: This pilot study shows that inclusion of spatial information in GMR models to convert MR data to CT equivalent images is feasible. The accuracy of the s-CT is improved and the spatial information could make it possible to create a general model for the conversion applicable to the whole body.
- Published
- 2013
- Full Text
- View/download PDF
28. Treatment planning of intracranial targets on MRI derived substitute CT data.
- Author
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Jonsson JH, Johansson A, Söderström K, Asklund T, and Nyholm T
- Subjects
- Aged, Female, Humans, Image Processing, Computer-Assisted, Male, Middle Aged, Radiotherapy Dosage, Brain radiation effects, Magnetic Resonance Imaging methods, Radiotherapy Planning, Computer-Assisted methods, Tomography, X-Ray Computed methods
- Abstract
Background: The use of magnetic resonance imaging (MRI) as a complement to computed tomography (CT) in the target definition procedure for radiotherapy is increasing. To eliminate systematic uncertainties due to image registration, a workflow based entirely on MRI may be preferable. In the present pilot study, we investigate dose calculation accuracy for automatically generated substitute CT (s-CT) images of the head based on MRI. We also produce digitally reconstructed radiographs (DRRs) from s-CT data to evaluate the feasibility of patient positioning based on MR images., Methods and Materials: Five patients were included in the study. The dose calculation was performed on CT, s-CT, s-CT data without inhomogeneity correction and bulk density assigned MRI images. Evaluation of the results was performed using point dose and dose volume histogram (DVH) comparisons, and gamma index evaluation., Results: The results demonstrate that the s-CT images improve the dose calculation accuracy compared to the method of non-inhomogeneity corrected dose calculations (mean improvement 2.0% points) and that it performs almost identically to the method of bulk density assignment. The s-CT based DRRs appear to be adequate for patient positioning of intra-cranial targets, although further investigation is needed on this subject., Conclusion: The s-CT method is very fast and yields data that can be used for treatment planning without sacrificing accuracy., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)
- Published
- 2013
- Full Text
- View/download PDF
29. Considerable improvement in survival for patients aged 60-84 years with high grade malignant gliomas -- data from the Swedish Brain Tumour Population-based Registry.
- Author
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Asklund T, Malmström A, Björ O, Blomquist E, and Henriksson R
- Subjects
- Aged, Aged, 80 and over, Brain Neoplasms pathology, Brain Neoplasms therapy, Female, Glioma pathology, Glioma therapy, Humans, Male, Middle Aged, Sweden epidemiology, Brain Neoplasms mortality, Glioma mortality, Registries
- Published
- 2013
- Full Text
- View/download PDF
30. Early and persisting response to vismodegib in a patient with bone metastasizing medulloblastoma.
- Author
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Asklund T, Henriksson R, Axelsson J, Bergström Å, Kasper M, Ögren M, Toftgård R, and Riklund KÅ
- Subjects
- Adult, Antineoplastic Agents therapeutic use, Bone Neoplasms diagnostic imaging, Cerebellar Neoplasms diagnostic imaging, Cerebellar Neoplasms drug therapy, Humans, Male, Medulloblastoma diagnostic imaging, Medulloblastoma drug therapy, Radionuclide Imaging, Remission Induction methods, Time Factors, Treatment Outcome, Anilides therapeutic use, Bone Neoplasms drug therapy, Bone Neoplasms secondary, Cerebellar Neoplasms pathology, Medulloblastoma secondary, Pyridines therapeutic use
- Published
- 2013
- Full Text
- View/download PDF
31. Uncertainty estimation in dynamic contrast-enhanced MRI.
- Author
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Garpebring A, Brynolfsson P, Yu J, Wirestam R, Johansson A, Asklund T, and Karlsson M
- Subjects
- Computer Simulation, Humans, Image Enhancement methods, Male, Middle Aged, Models, Statistical, Reproducibility of Results, Sensitivity and Specificity, Algorithms, Brain Neoplasms diagnosis, Brain Neoplasms metabolism, Gadolinium DTPA pharmacokinetics, Image Interpretation, Computer-Assisted methods, Magnetic Resonance Imaging methods, Models, Biological
- Abstract
Using dynamic contrast-enhanced MRI (DCE-MRI), it is possible to estimate pharmacokinetic (PK) parameters that convey information about physiological properties, e.g., in tumors. In DCE-MRI, errors propagate in a nontrivial way to the PK parameters. We propose a method based on multivariate linear error propagation to calculate uncertainty maps for the PK parameters. Uncertainties in the PK parameters were investigated for the modified Kety model. The method was evaluated with Monte Carlo simulations and exemplified with in vivo brain tumor data. PK parameter uncertainties due to noise in dynamic data were accurately estimated. Noise with standard deviation up to 15% in the baseline signal and the baseline T1 map gave estimated uncertainties in good agreement with the Monte Carlo simulations. Good agreement was also found for up to 15% errors in the arterial input function amplitude. The method was less accurate for errors in the bolus arrival time with disagreements of 23%, 32%, and 29% for K(trans) , ve , and vp , respectively, when the standard deviation of the bolus arrival time error was 5.3 s. In conclusion, the proposed method provides efficient means for calculation of uncertainty maps, and it was applicable to a wide range of sources of uncertainty., (Copyright © 2012 Wiley Periodicals, Inc.)
- Published
- 2013
- Full Text
- View/download PDF
32. Evaluation of an attenuation correction method for PET/MR imaging of the head based on substitute CT images.
- Author
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Larsson A, Johansson A, Axelsson J, Nyholm T, Asklund T, Riklund K, and Karlsson M
- Subjects
- Brain Neoplasms diagnostic imaging, Brain Neoplasms radiotherapy, Fluorodeoxyglucose F18, Glioma diagnostic imaging, Glioma radiotherapy, Humans, Magnetic Resonance Imaging instrumentation, Models, Statistical, Multimodal Imaging instrumentation, Positron-Emission Tomography instrumentation, Radiopharmaceuticals, Radiotherapy Dosage, Regression Analysis, Brain Neoplasms diagnosis, Glioma diagnosis, Image Enhancement methods, Image Processing, Computer-Assisted methods, Magnetic Resonance Imaging methods, Multimodal Imaging methods, Positron-Emission Tomography methods, Tomography, X-Ray Computed
- Abstract
Object: The aim of this study was to evaluate MR-based attenuation correction of PET emission data of the head, based on a previously described technique that calculates substitute CT (sCT) images from a set of MR images., Materials and Methods: Images from eight patients, examined with (18)F-FLT PET/CT and MRI, were included. sCT images were calculated and co-registered to the corresponding CT images, and transferred to the PET/CT scanner for reconstruction. The new reconstructions were then compared with the originals. The effect of replacing bone with soft tissue in the sCT-images was also evaluated., Results: The average relative difference between the sCT-corrected PET images and the CT-corrected PET images was 1.6% for the head and 1.9% for the brain. The average standard deviations of the relative differences within the head were relatively high, at 13.2%, primarily because of large differences in the nasal septa region. For the brain, the average standard deviation was lower, 4.1%. The global average difference in the head when replacing bone with soft tissue was 11%., Conclusion: The method presented here has a high rate of accuracy, but high-precision quantitative imaging of the nasal septa region is not possible at the moment.
- Published
- 2013
- Full Text
- View/download PDF
33. Synergistic killing of glioblastoma stem-like cells by bortezomib and HDAC inhibitors.
- Author
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Asklund T, Kvarnbrink S, Holmlund C, Wibom C, Bergenheim T, Henriksson R, and Hedman H
- Subjects
- Apoptosis drug effects, Boronic Acids administration & dosage, Bortezomib, Brain Neoplasms pathology, Cell Line, Tumor, Drug Synergism, Glioblastoma pathology, Histone Deacetylase Inhibitors administration & dosage, Humans, Hydroxamic Acids administration & dosage, Hydroxamic Acids pharmacology, Neoplastic Stem Cells pathology, Neural Stem Cells pathology, Phenylbutyrates administration & dosage, Phenylbutyrates pharmacology, Pyrazines administration & dosage, Valproic Acid administration & dosage, Valproic Acid pharmacology, Vorinostat, Antineoplastic Combined Chemotherapy Protocols pharmacology, Boronic Acids pharmacology, Brain Neoplasms drug therapy, Glioblastoma drug therapy, Histone Deacetylase Inhibitors pharmacology, Neoplastic Stem Cells drug effects, Neural Stem Cells drug effects, Pyrazines pharmacology
- Abstract
Background: The malignant brain tumour glioblastoma is a devastating disease that remains a therapeutic challenge., Materials and Methods: Effects of combinations of the US Food and Drug Administation (FDA) approved proteasome inhibitor bortezomib and the histone deacetylase (HDAC) inhibitors vorinostat, valproic acid and sodium phenylbutyrate were studied on primary glioblastoma stem cell lines and conventional glioblastoma cell lines. Cell survival, proliferation and death were analyzed by fluorometric microculture cytotoxicity assay (FMCA), propidium iodide labeling and flow cytometry, and cell cloning through limiting dilution and live-cell bright-field microscopy., Results: Bortezomib and the HDAC inhibitors showed synergistic cell killing at clinically relevant drug concentrations, while the conventional cell lines cultured in serum-containing medium were relatively resistant to the same treatments., Conclusion: These findings of synergistic glioblastoma stem cell killing by bortezomib and three different FDA-approved HDAC inhibitors confirm and expand previous observations on co-operative effects between these classes of drugs.
- Published
- 2012
34. Voxel-wise uncertainty in CT substitute derived from MRI.
- Author
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Johansson A, Karlsson M, Yu J, Asklund T, and Nyholm T
- Subjects
- Sensitivity and Specificity, Image Processing, Computer-Assisted methods, Magnetic Resonance Imaging methods, Tomography, X-Ray Computed methods, Uncertainty
- Abstract
Purpose: In an earlier work, we demonstrated that substitutes for CT images can be derived from MR images using ultrashort echo time (UTE) sequences, conventional T2 weighted sequences, and Gaussian mixture regression (GMR). In this study, we extend this work by analyzing the uncertainties associated with the GMR model and the information contributions from the individual imaging sequences., Methods: An analytical expression for the voxel-wise conditional expected absolute deviation (EAD) in substitute CT (s-CT) images was derived. The expression depends only on MR images and can thus be calculated along with each s-CT image. The uncertainty measure was evaluated by comparing the EAD to the true mean absolute prediction deviation (MAPD) between the s-CT and CT images for 14 patients. Further, the influence of the different MR images included in the GMR model on the generated s-CTs was investigated by removing one or more images and evaluating the MAPD for a spectrum of predicted radiological densities., Results: The largest EAD was predicted at air-soft tissue and bone-soft tissue interfaces. The EAD agreed with the MAPD in both these regions and in regions with lower EADs, such as the brain. Two of the MR images included in the GMR model were found to be mutually redundant for the purpose of s-CT generation., Conclusions: The presented uncertainty estimation method accurately predicts the voxel-wise MAPD in s-CT images. Also, the non-UTE sequence previously used in the model was found to be redundant., (© 2012 American Association of Physicists in Medicine.)
- Published
- 2012
- Full Text
- View/download PDF
35. [Survival in malignant gliomas has increased the last decade. Analysis of quality data].
- Author
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Asklund T, Björ O, Malmström A, Blomquist E, and Henriksson R
- Subjects
- Adult, Age Distribution, Aged, Female, Glioma diagnosis, Glioma epidemiology, Glioma therapy, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Sex Distribution, Survival Analysis, Sweden, Glioma mortality, Registries statistics & numerical data, Survival Rate trends
- Published
- 2012
36. Impact of therapy on quality of life, neurocognitive function and their correlates in glioblastoma multiforme: a review.
- Author
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Henriksson R, Asklund T, and Poulsen HS
- Subjects
- Cognition Disorders etiology, Humans, Statistics as Topic, Time Factors, Brain Neoplasms complications, Brain Neoplasms psychology, Brain Neoplasms therapy, Cognition Disorders therapy, Glioblastoma complications, Glioblastoma psychology, Glioblastoma therapy, Quality of Life
- Abstract
The maintenance of quality of life (QoL) in patients with high-grade glioma is an important endpoint during treatment, particularly in those with glioblastoma multiforme (GBM) given its dismal prognosis despite limited advances in standard therapy. It has proven difficult to identify new therapies that extend survival in patients with recurrent GBM, so one of the primary aims of new therapies is to reduce morbidity, restore or preserve neurologic functions, and the capacity to perform daily activities. Apart from temozolomide, cytotoxic chemotherapeutic agents do not appear to significantly impact response or survival, but produce toxicity that is likely to negatively impact QoL. New biological agents, such as bevacizumab, can induce a clinically meaningful proportion of durable responses among patients with recurrent GBM with an acceptable safety profile. Emerging evidence suggests that bevacizumab produces an improvement or preservation of neurocognitive function in GBM patients, suggestive of QoL improvement, in most poor-prognosis patients who would otherwise be expected to show a sudden and rapid deterioration in QoL.
- Published
- 2011
- Full Text
- View/download PDF
37. Phase-based arterial input functions in humans applied to dynamic contrast-enhanced MRI: potential usefulness and limitations.
- Author
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Garpebring A, Wirestam R, Yu J, Asklund T, and Karlsson M
- Subjects
- Aged, Algorithms, Feasibility Studies, Female, Humans, Image Interpretation, Computer-Assisted methods, Male, Middle Aged, Regression Analysis, Reproducibility of Results, Carotid Arteries physiology, Contrast Media, Magnetic Resonance Imaging methods, Models, Cardiovascular, Plasma Volume physiology
- Abstract
Object: Phase-based arterial input functions (AIFs) provide a promising alternative to standard magnitude-based AIFs, for example, because inflow effects are avoided. The usefulness of phase-based AIFs in clinical dynamic contrast-enhanced MRI (DCE-MRI) was investigated, and relevant pitfalls and sources of uncertainty were identified., Materials and Methods: AIFs were registered from eight human subjects on, in total, 21 occasions. AIF quality was evaluated by comparing AIFs from right and left internal carotid arteries and by assessing the reliability of blood plasma volume estimates., Results: Phase-based AIFs yielded an average bolus peak of 3.9 mM and a residual concentration of 0.37 mM after 3 min, (0.033 mmol/kg contrast agent injection). The average blood plasma volume was 2.7% when using the AIF peak in the estimation, but was significantly different (p < 0.0001) and less physiologically reasonable when based on the AIF tail concentration. Motion-induced phase shifts and accumulation of contrast agent in background tissue regions were identified as main sources of uncertainty., Conclusion: Phase-based AIFs are a feasible alternative to magnitude AIFs, but sources of errors exist, making quantification difficult, especially of the AIF tail. Improvement of the technique is feasible and also required for the phase-based AIF approach to reach its full potential.
- Published
- 2011
- Full Text
- View/download PDF
38. HDAC inhibition amplifies gap junction communication in neural progenitors: potential for cell-mediated enzyme prodrug therapy.
- Author
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Khan Z, Akhtar M, Asklund T, Juliusson B, Almqvist PM, and Ekström TJ
- Subjects
- Cell Communication drug effects, Cell Differentiation, Cell Line, Cell Proliferation, Connexin 43 analysis, Connexin 43 metabolism, Gap Junctions chemistry, Humans, Hydroxamic Acids pharmacology, Phenylbutyrates pharmacology, Stem Cells enzymology, Drug Delivery Systems, Enzyme Inhibitors pharmacology, Gap Junctions drug effects, Histone Deacetylase Inhibitors, Neurons enzymology, Neurons transplantation, Prodrugs administration & dosage, Stem Cell Transplantation
- Abstract
Enzyme prodrug therapy using neural progenitor cells (NPCs) as delivery vehicles has been applied in animal models of gliomas and relies on gap junction communication (GJC) between delivery and target cells. This study investigated the effects of histone deacetylase (HDAC) inhibitors on GJC for the purpose of facilitating transfer of therapeutic molecules from recombinant NPCs. We studied a novel immortalized midbrain cell line, NGC-407 of embryonic human origin having neural precursor characteristics, as a potential delivery vehicle. The expression of gap junction protein connexin 43 (Cx43) was analyzed by western blot and immunocytochemistry. While Cx43 levels were decreased in untreated differentiating NGC-407 cells, the HDAC inhibitor 4-phenylbutyrate (4-PB) increased Cx43 expression along with increased membranous deposition in both proliferating and differentiating cells. Simultaneously, Ser 279/282-phosphorylated form of Cx43 was declined in both culture conditions by 4-PB. The 4-PB effect in NGC-407 cells was verified by using HNSC.100 human neural progenitors and Trichostatin A. Improved functional GJC is of imperative importance for therapeutic strategies involving intercellular transport of low molecular-weight compounds. We show here an enhancement by 4-PB, of the functional GJC among NGC-407 cells, as well as between NGC-407 and human glioma cells, as indicated by increased fluorescent dye transfer.
- Published
- 2007
- Full Text
- View/download PDF
39. Gap junction-mediated bystander effect in primary cultures of human malignant gliomas with recombinant expression of the HSVtk gene.
- Author
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Asklund T, Appelskog IB, Ammerpohl O, Langmoen IA, Dilber MS, Aints A, Ekström TJ, and Almqvist PM
- Subjects
- Biomarkers, Tumor, Brain Neoplasms genetics, Brain Neoplasms metabolism, Cell Communication genetics, Cell Death drug effects, Cell Death genetics, Connexin 43 metabolism, Cytotoxins genetics, Cytotoxins therapeutic use, Ganciclovir therapeutic use, Gap Junctions genetics, Gap Junctions metabolism, Glioma genetics, Glioma metabolism, Glycyrrhetinic Acid pharmacology, Glycyrrhetinic Acid therapeutic use, Humans, Phosphorylation drug effects, Thymidine Kinase genetics, Thymidine Kinase therapeutic use, Tumor Cells, Cultured, Viral Proteins genetics, Viral Proteins therapeutic use, Brain Neoplasms drug therapy, Cell Communication drug effects, Cytotoxins pharmacology, Ganciclovir pharmacology, Gap Junctions drug effects, Glioma drug therapy, Thymidine Kinase pharmacology, Viral Proteins pharmacology
- Abstract
The ability of herpes simplex virus type 1 thymidine kinase (HSV-tk)-expressing cells incubated with ganciclovir (GCV) to induce cytotoxicity in neighboring HSV-tk-negative (bystander) cells has been well documented. Although it has been suggested that this bystander cell killing occurs via the transfer of phosphorylated GCV, the mechanism(s) of this bystander effect and the importance of gap junctions for the effect of prodrug/suicide gene therapy in primary human glioblastoma cells remains elusive. Surgical biopsies of malignant gliomas were used to establish explant primary cultures. Proliferating tumor cells were characterized immunohistochemically and found to express glial tumor markers including nestin, vimentin, glial fibrillary acidic protein (GFAP), S-100, and gap junction protein connexin 43 (Cx43). Western blot analysis revealed the presence of phosphorylated isoforms of Cx43 and Calcein/DiI fluorescent dye transfer showed evidence of efficient gap junction communication (GJC). In order to study the effect(s) of prodrug/suicide gene therapy in these cultures, human glioblastoma cell cultures were transfected with the HSVtk gene for transient or stable expression. Ganciclovir treatment of these cultures led to >90% of cells dead within 1 week. Eradication of cells could be inhibited by the addition of alpha-glycyrrhetinic acid (AGA), a GJC inhibitor. In parallel experiments, AGA decreased the immunodetection of phosphorylated Cx43 as analyzed by Western blot and inhibited fluorescent dye transfer. In conclusion, these observations are consistent with GJC as the mediator of the bystander effect in primary cultures of human glioblastoma cells by the transfer of phosphorylated GCV from HSVtk gene transfected cells to untransfected ones.
- Published
- 2003
- Full Text
- View/download PDF
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