| 1. |
- Björkblom, Benny, et al.
(författare)
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Metabolic response patterns in brain microdialysis fluids and serum during interstitial cisplatin treatment of high-grade glioma
- 2020
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Ingår i: British Journal of Cancer. - : Nature Publishing Group. - 0007-0920 .- 1532-1827. ; 122:2, s. 221-232
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Tidskriftsartikel (refereegranskat)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.
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| 2. |
- Tabatabaei, Pedram, et al.
(författare)
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Intratumoral retrograde microdialysis treatment of high-grade glioma with cisplatin
- 2020
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Ingår i: Acta Neurochirurgica. - : Springer. - 0001-6268 .- 0942-0940. ; 162:12, s. 3043-3053
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Tidskriftsartikel (refereegranskat)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.
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| 3. |
- Tabatabaei, Pedram, 1978-
(författare)
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Stereotactic microdialysis for metabolic assessment and experimental treatment of malignant glioma
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Glioblastoma multiforme, the most common primary brain tumor, has a dire prognosis despite multimodal treatments that include surgery and radio-chemotherapy. To improve the outcome of this destructive disease, we need to improve our understanding of its tumor biology. Furthermore, the development of new treatment strategies will improve with a better understanding of the interplay between malignant cells and their direct surrounding microenvironment.This thesis aims to increase the understanding of the processes within high-grade glioma and its microenvironment during normal conditions as well as during the distress associated with treatment. Specifically, we have investigated the metabolic response to radiotherapy (study I and II), the immunologic response to radiotherapy (study II), and the metabolic response pattern to loco-regional treatment with cisplatin (study III and IV). Using microdialysis, we collected samples from the extracellular space in both normal brain and tumor tissue during radiotherapy (study I and II) and loco-regional cisplatin treatment (study III and IV). Theses samples were analyzed for glucose metabolites, glycerol, and glutamate (study I, II, and III) and for cytokines (study II). In addition, we analyzed the global metabolism with mass spectrometry to identify and assess the response pattern of malignant glioma cells to loco-regional cisplatin treatment (study IV).In study I and II, we found that malignant glioma cells used glucose at a higher rate than normal cells and preferred glycolysis for glucose metabolism. The given radiation dose (2 Gray (Gy) daily for five days) did not significantly affect glucose metabolism, glycerol levels, or glutamate levels in tumor tissue or the microenvironment. However, in study II, we observed an induced inflammatory effect due to the given radiation dose as several of the cytokines investigated showed significantly increased levels during radiotherapy. In study IV, we observed a complex and strong metabolic response to the loco-regional cisplatin therapy. At baseline, we found a metabolic pattern corresponding well with highly proliferating tumor tissue–i.e., high levels of amino acids, their metabolites, and other metabolic end products and low levels of sugar derivatives, antioxidants, and nucleotides. During the loco-regional therapy, we observed a clearly localized cytotoxic effect within the tumor and a metabolic response pattern corresponding with cisplatin’s complex mechanism of action, affecting several metabolic pathways within the malignant cell. Glutamate and glycerol also increased in tumor tissue following loco-regional treatment, a finding that further supported the observation of local toxicity.In study III, we investigated microdialysis as a method to assess the microenvironment in high-grade glioma and as a method for drug delivery (retrograde microdialysis). All studies demonstrated the usefulness of microdialysis as a tool for in vivo real-time assessment of molecular events in malignant glioma tissue. Although the method is invasive, no complications related to the surgical procedure or assessment were noted. In study III, we also demonstrated that retrograde microdialysis is a feasible method for locally delivering clinically significant doses of drugs such as cisplatin to tumor tissue in the brain. However, in addition to having a cytotoxic effect on tumor cells, cisplatin may induce clinically significant edema.
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