| 1. |
- Jakola, Asgeir Store, et al.
(författare)
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Disulfiram repurposing combined with nutritional copper supplement as add-on to chemotherapy in recurrent glioblastoma (DIRECT) : Study protocol for a randomized controlled trial
- 2018
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Ingår i: F1000 Research. - : F1000Research. - 2046-1402. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Background: Disulfiram (DSF) is a well-tolerated, inexpensive, generic drug that has been in use to treat alcoholism since the 1950s. There is now independent preclinical data that supports DSF as an anticancer agent, and experimental data suggest that copper may increase its anti-neoplastic properties. There is also some clinical evidence that DSF is a promising anticancer agent in extracranial cancers. In glioblastoma, DSF induced O 6-methylguanine methyltransferase (MGMT) inhibition may increase response to alkylating chemotherapy. A recent phase I study demonstrated the safety of DSF in glioblastoma patients when DSF was administered at doses below 500 mg/day together with chemotherapy. We plan to assess the effects of DSF combined with nutritional copper supplement (DSF-Cu) as an adjuvant to alkylating chemotherapy in glioblastoma treatment.Methods: In an academic, industry independent, multicenter, open label randomized controlled phase II/III trial with parallel group design (1:1) we will assess the efficacy and safety of DSF-Cu in glioblastoma treatment. The study will include 142 patients at the time of first recurrence of glioblastoma where salvage therapy with alkylating chemotherapy is planned. Patients will be randomized to treatment with or without DSF-Cu. Primary end-point is survival at 6 months. Secondary end-points are overall survival, progression free survival, quality of life, contrast enhancing tumor volume and safety.Discussion: There is a need to improve the treatment of recurrent glioblastoma. Results from this randomized controlled trial with DSF-Cu in glioblastoma will serve as preliminary evidence of the future role of DSF-Cu in glioblastoma treatment and a basis for design and power estimations of future studies. In this publication we provide rationale for our choices and discuss methodological issues.Trial registration: The study underwent registration in EudraCT 2016-000167-16 (Date: 30.03.2016,) and Clinicaltrials.gov NCT02678975 (Date: 31.01.2016) before initiating the study.
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| 2. |
- Werlenius, Katja, et al.
(författare)
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Effect of Disulfiram and Copper Plus Chemotherapy vs Chemotherapy Alone on Survival in Patients With Recurrent Glioblastoma: A Randomized Clinical Trial.
- 2023
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Ingår i: JAMA network open. - : American Medical Association (AMA). - 2574-3805. ; 6:3
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Tidskriftsartikel (refereegranskat)abstract
- Disulfiram has demonstrated broad antitumoral effect in several preclinical studies. One of the proposed indications is for the treatment of glioblastoma.To evaluate the efficacy and safety of disulfiram and copper as add-on to alkylating chemotherapy in patients with recurrent glioblastoma.This was a multicenter, open-label, randomized phase II/III clinical trial with parallel group design. Patients were recruited at 7 study sites in Sweden and 2 sites in Norway between January 2017 and November 2020. Eligible patients were 18 years or older, had a first recurrence of glioblastoma, and indication for treatment with alkylating chemotherapy. Patients were followed up until death or a maximum of 24 months. The date of final follow-up was January 15, 2021. Data analysis was performed from February to September 2022.Patients were randomized 1:1 to receive either standard-of-care (SOC) alkylating chemotherapy alone, or SOC with the addition of disulfiram (400 mg daily) and copper (2.5 mg daily).The primary end point was survival at 6 months. Secondary end points included overall survival, progression-free survival, adverse events, and patient-reported quality of life.Among the 88 patients randomized to either SOC (n=45) or SOC plus disulfiram and copper (n=43), 63 (72%) were male; the mean (SD) age was 55.4 (11.5) years. There was no significant difference between the study groups (SOC vs SOC plus disulfiram and copper) in 6 months survival (62% [26 of 42] vs 44% [19 of 43]; P=.10). Median overall survival was 8.2 months (95% CI, 5.4-10.2 months) with SOC and 5.5 months (95% CI, 3.9-9.3 months) with SOC plus disulfiram and copper, and median progression-free survival was 2.6 months (95% CI, 2.4-4.6 months) vs 2.3 months (95% CI, 1.7-2.6 months), respectively. More patients in the SOC plus disulfiram and copper group had adverse events grade 3 or higher (34% [14 of 41] vs 11% [5 of 44]; P=.02) and serious adverse events (41% [17 of 41] vs 16% [7 of 44]; P=.02), and 10 patients (24%) discontinued disulfiram treatment because of adverse effects.This randomized clinical trial found that among patients with recurrent glioblastoma, the addition of disulfiram and copper to chemotherapy, compared with chemotherapy alone, resulted in significantly increased toxic effects, but no significant difference in survival. These findings suggest that disulfiram and copper is without benefit in patients with recurrent glioblastoma.ClinicalTrials.gov Identifier: NCT02678975; EUDRACT Identifier: 2016-000167-16.
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| 3. |
- Bartek, Jiri, et al.
(författare)
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The role of angiotensin converting enzyme inhibitor in patients with chronic subdural hematoma: a Scandinavian population-based multicenter study.
- 2018
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Ingår i: World neurosurgery. - : Elsevier BV. - 1878-8769 .- 1878-8750. ; 113
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Tidskriftsartikel (refereegranskat)abstract
- To investigate the role of angiotensin converting enzyme (ACE) inhibitors in recurrence of chronic subdural hematoma (cSDH) after burr-hole surgery.A retrospective review was conducted in a Scandinavian multicenter population-based cohort of 1252 adult cSDH patients operated with burr-hole surgery between January 1, 2005 and December 31, 2010. The risk of cSDH recurrence was assessed in users of ACE inhibitors, users of angiotensin II receptor blockers (ARB) and those without ACE inhibitor treatment (no ACE inhibitor group) using univariable and multivariable regression analyses.There were 98 users (7.8%) of ACE inhibitors, and 63 users (5%) of ARBs only. The recurrence rate in the ACE inhibitor group was 16.3% (n=16), compared to 13.3% (n=153) in the no ACE inhibitor group (p=0.39) and 14.3% (n=9) in the ARB group (p=0.73). When comparing groups, age (p=0.01), Charlson comorbidity Index (p=0.01), the use of platelet inhibitors (p=0.001) and use of anticoagulants (p=0.01) differed between the ACE inhibitor and the no ACE inhibitor group. Only age differed (p=0.03) between the ACE inhibitor and ARB groups. In the analyses adjusted for differences in baseline characteristics, ACE inhibitor treatment did not influence risk for recurrence (OR 1.2, 95 % CI 0.7-2.2 p=0.46).Use of ACE inhibitors was not associated with risk of recurrence following burrhole surgery for cSDH in this population based study..
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| 4. |
- Bartek jr, Jiri, et al.
(författare)
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Standardized reporting of adverse events after microvascular decompression of cranial nerves; a population-based single-institution consecutive series.
- 2016
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Ingår i: Acta Neurochirurgica. - : Springer Science and Business Media LLC. - 0001-6268 .- 0942-0940. ; 158:9, s. 1775-1781
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Tidskriftsartikel (refereegranskat)abstract
- Objective To investigate frequencies of adverse events occurring within 30 days after microvascular decompression (MVD) surgery using a standardized report form of adverse events. Methods We conducted a retrospective review of 98 adult patients (≥16 years) treated with MVD between 1 January 1994 and 1 June 2013. Adverse events occurring within 30 days were classified according to the Landriel Ibanez classification for neurosurgical complications: grade I represents any non-life threatening complication treated without invasive procedures; grade II is complications requiring invasive management; grade III is life-threatening adverse events requiring treatment in an intensive care unit (ICU); grade IV is death as a result of complications. We sought to compare our results with reports from the literature. RESULTS: Patients' median age was 61 years (range 26-83), and 64 (65 %) were females. Indications for MVD were trigeminal neuralgia (n=77, 79 %), glossopharyngeal neuralgia (n=4, 4 %), hemifacial spasm (n=16, 16 %) and combined trigeminal neuralgia and hemifacial spasm (n=1, 1 %). The overall 30-day complication rate was 20 %, with 14 % grade I complications, 5 % grade II complications and 1 % grade III complications. The comparison with the literature was hampered by the diverse and unsystematic way of reporting complications. CONCLUSION: We provide a standardized report of postoperative complications in a consecutive patient series undergoing MVD. Due to the heterogeneous and non-standardized reporting of complications in the literature, it is difficult to know if our 20 % complication rate is low or high. Standardized reporting is a necessity for meaningful and more valid comparisons across studies. The safety of MVD, a fairly standardized neurosurgical procedure, is well suited for comparisons across centers provided that complications are reported in a standardized manner
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| 5. |
- Bø, Hans Kristian, et al.
(författare)
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Intra-rater variability in low-grade glioma segmentation.
- 2017
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Ingår i: Journal of neuro-oncology. - : Springer Science and Business Media LLC. - 1573-7373 .- 0167-594X. ; 131:2, s. 393-402
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Tidskriftsartikel (refereegranskat)abstract
- Assessment of size and growth are key radiological factors in low-grade gliomas (LGGs), both for prognostication and treatment evaluation, but the reliability of LGG-segmentation is scarcely studied. With a diffuse and invasive growth pattern, usually without contrast enhancement, these tumors can be difficult to delineate. The aim of this study was to investigate the intra-observer variability in LGG-segmentation for a radiologist without prior segmentation experience. Pre-operative 3D FLAIR images of 23 LGGs were segmented three times in the software 3D Slicer. Tumor volumes were calculated, together with the absolute and relative difference between the segmentations. To quantify the intra-rater variability, we used the Jaccard coefficient comparing both two (J2) and three (J3) segmentations as well as the Hausdorff Distance (HD). The variability measured with J2 improved significantly between the two last segmentations compared to the two first, going from 0.87 to 0.90 (p=0.04). Between the last two segmentations, larger tumors showed a tendency towards smaller relative volume difference (p=0.07), while tumors with well-defined borders had significantly less variability measured with both J2 (p=0.04) and HD (p<0.01). We found no significant relationship between variability and histological sub-types or Apparent Diffusion Coefficients (ADC). We found that the intra-rater variability can be considerable in serial LGG-segmentation, but the variability seems to decrease with experience and higher grade of border conspicuity. Our findings highlight that some criteria defining tumor borders and progression in 3D volumetric segmentation is needed, if moving from 2D to 3D assessment of size and growth of LGGs.
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| 6. |
- Bø, Hans Kristian, et al.
(författare)
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Intraoperative 3D ultrasound-guided resection of diffuse low-grade gliomas: radiological and clinical results.
- 2020
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Ingår i: Journal of neurosurgery. - 1933-0693. ; 132:2, s. 518-529
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVEExtent of resection (EOR) and residual tumor volume are linked to prognosis in low-grade glioma (LGG) and there are various methods for facilitating safe maximal resection in such patients. In this prospective study the authors assess radiological and clinical results in consecutive patients with LGG treated with 3D ultrasound (US)-guided resection under general anesthesia.METHODSConsecutive LGGs undergoing primary surgery guided with 3D US between 2008 and 2015 were included. All LGGs were classified according to the WHO 2016 classification system. Pre- and postoperative volumetric assessments were performed, and volumetric results were linked to overall and malignant-free survival. Pre- and postoperative health-related quality of life (HRQoL) was evaluated.RESULTSForty-seven consecutive patients were included. Twenty LGGs (43%) were isocitrate dehydrogenase (IDH)-mutated, 7 (14%) were IDH wild-type, 19 (40%) had both IDH mutation and 1p/19q codeletion, and 1 had IDH mutation and inconclusive 1p/19q status. Median resection grade was 93.4%, with gross-total resection achieved in 14 patients (30%). An additional 24 patients (51%) had small tumor remnants < 10 ml. A more conspicuous tumor border (p = 0.02) and lower University of California San Francisco prognostic score (p = 0.01) were associated with less remnant tumor tissue, and overall survival was significantly better with remnants < 10 ml (p = 0.03). HRQoL was maintained or improved in 86% of patients at 1 month. In both cases with severe permanent deficits, relevant ischemia was present on diffusion-weighted postoperative MRI.CONCLUSIONSThree-dimensional US-guided LGG resections under general anesthesia are safe and HRQoL is preserved in most patients. Effectiveness in terms of EOR appears to be consistent with published studies using other advanced neurosurgical tools. Avoiding intraoperative vascular injury is a key factor for achieving good functional outcome.
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| 7. |
- Corell, Alba, et al.
(författare)
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Stemness and clinical features in relation to the subventricular zone in diffuse lower-grade glioma : an exploratory study
- 2022
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Ingår i: Neuro-Oncology Advances. - : Oxford University Press. - 2632-2498. ; 4:1
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Tidskriftsartikel (refereegranskat)abstract
- Background The subventricular zone (SVZ) of the human brain is a site of adult stem cell proliferation and a microenvironment for neural stem cells (NSCs). It has been suggested that NSCs in the SVZ are potential cells of origin containing driver mutations of glioblastoma, but their role in the origin of diffuse lower-grade gliomas (dLGGs) is not much studied. Methods We included 188 patients >= 18 years with IDH-mutated dLGG (WHO grades 2-3) histologically diagnosed between 2007 and 2020. Tissue microarrays of tumor samples for patients between 2007 and 2016 were used for immunodetection of Nestin, SOX2, SOX9, KLF4, NANOG, CD133 cMYC, and Ki67. DNA methylation profile was used for stemness index (mDNAsi). Tumor contact with the SVZ was assessed and the distance was computed. Results Overall, 70.2% of the dLGG had SVZ contact. Tumors with SVZ contact were larger (102.4 vs 30.9 mL, P < .01), the patients were older (44.3 vs 40.4 years, P = .04) and more often had symptoms related to increased intracranial pressure (31.8% vs 7.1%, P < .01). The expression of SOX2, SOX9, Nestin, and Ki67 showed intersample variability, but no difference was found between tumors with or without SVZ contact, nor with the actual distance to the SVZ. mDNAsi was similar between groups (P = .42). Conclusions We found no statistical relationship between proximity with the SVZ and mDNAsi or expression of SOX2, SOX9, Nestin, and Ki67 in IDH-mutated dLGG. Our data suggest that the potential impact of SVZ on IDH-mutated dLGG is probably not associated with a more stemness-like tumor profile.
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| 8. |
- Drewes, Christina, et al.
(författare)
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Perioperative and postoperative quality of life in glioma patients - A longitudinal cohort study.
- 2018
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Ingår i: World neurosurgery. - : Elsevier BV. - 1878-8769 .- 1878-8750. ; 117
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Tidskriftsartikel (refereegranskat)abstract
- Few studies assess patient-reported quality of life (QoL) in glioma patients undergoing surgery, and even fewer provide longitudinal data. Accordingly, there is little knowledge about the changes of QoL over time in glioma patients. We sought to explore peri- and postoperative development of generic QoL during the first six months after primary glioma surgery.136 adult patients undergoing primary surgery for high-grade (HGG) or low-grade (LGG) glioma were prospectively included in this explorative, longitudinal study. Patient-reported QoL was measured with the generic tool EQ-5D 3L preoperatively and at 1 and 6 months after surgery.At group level, there was no difference in EQ-5D index values in patients with HGG compared to patients with LGG at baseline or at 1 month. At 6 months, EQ-5D index values in HGG patients had deteriorated significantly (p<0.001), but remained stable in LGG patients. Individual level QoL development was more diverse. American Society of Anesthesiology class ≥3, resection grades other than gross total resection (GTR) and HGG were identified as independent predictors for negative development of QoLbetween 1 and 6 months after surgery.At group level, development of generic QoL between baseline and 1 and 6 months postoperatively seems to follow the natural disease trajectories of LGG and HGG, with deterioration in HGG patients at 6 months. Individual development of QoL is heterogeneous. HGG, resection grades other than GTR and preoperative comorbidity are predictors of postoperative QoL-impairment.
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| 9. |
- Drewes, Christina, et al.
(författare)
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Quality of life in patients with intracranial tumors: does tumor laterality matter?
- 2016
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Ingår i: Journal of Neurosurgery. - 0022-3085. ; 125:6, s. 1400-1407
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE Traditionally, the dominant (usually left) cerebral hemisphere is regarded as the more important one, and everyday clinical decisions are influenced by this view. However, reported results on the impact of lesion laterality are inconsistent in the scarce literature on quality of life (QOL) in patients with brain tumors. The authors aimed to study which cerebral hemisphere is the most important to patients with intracranial tumors with respect to health-related QOL (HRQOL). METHODS Two hundred forty-eight patients with unilateral, unifocal gliomas or meningiomas scheduled for primary surgery were included in this prospective cohort study. Generic HRQOL was measured using the EQ-5D-3L questionnaire preoperatively and after 4-6 weeks. Cross-sectional and longitudinal analyses of data were performed. RESULTS Tumor volumes were significantly larger in right-sided tumors at diagnosis, and language or speech problems were more common in left-sided lesions. Otherwise, no differences existed in baseline data. The median EQ-5D-3L index was 0.73 (range -0.24 to 1.00) in patients with right-sided tumors and 0.76 (range -0.48 to 1.00) in patients with left-sided tumors (p = 0.709). Due to the difference in tumor volumes at baseline, histopathology and tumor volumes were matched in 198 patients. EQ-5D-3L index scores in this 1:1 matched analysis were 0.74 (range -0.7 to 1.00) for patients with right-sided and 0.76 (range -0.48 to 1.00) for left-sided lesions (p = 0.342). In the analysis of longitudinal data, no association was found between tumor laterality and postoperative EQ-5D-3L index scores (p = 0.957) or clinically significant change in HRQOL following surgery (p = 0.793). CONCLUSIONS In an overall patient-reported QOL perspective, tumor laterality does not appear to be of significant importance for generic HRQOL in patients with intracranial tumors. This may imply that right-sided cerebral functions are underestimated by clinicians.
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| 10. |
- Fyllingen, Even Hovig, et al.
(författare)
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Does Risk of Brain Cancer Increase with Intracranial Volume? A Population-Based Case-Control Study.
- 2018
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Ingår i: Neuro-oncology. - : Oxford University Press (OUP). - 1523-5866 .- 1522-8517. ; 20:9, s. 1225-1230
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Tidskriftsartikel (refereegranskat)abstract
- Glioma is the most common primary brain tumor and is believed to arise from glial stem cells. Despite large efforts there are limited established risk factors. It has been suggested that tissue with more stem cells may exhibit higher risk of cancer due to chance alone. Assuming a positive correlation between the number of stem cell divisions in an organ and size of the same organ, we hypothesized that variation in intracranial volume, as a proxy for brain size may be linked to risk of high-grade glioma.Intracranial volume was calculated from pre-treatment 3D T1-weighted MRI brain scans from 124 patients with high-grade glioma and 995 general population based controls. Binomial logistic regression analyses were performed to ascertain the effect of intracranial volume and sex on the likelihood that participants have high-grade glioma.An increase in intracranial volume of 100 mL was associated with an odds ratio (OR) of high-grade glioma of 1.69 (95 % CI 1.44 to 1.98; P < 0.001). After adjusting for intracranial volume, female sex emerged as a risk factor for high-grade glioma (OR for male sex = 0.56, 95 % CI 0.33 to 0.93; P = 0.026).Intracranial volume is strongly associated with risk of high-grade glioma. After correcting for intracranial volume, risk of high-grade glioma was higher in women. The development of glioma is correlated to brain size and may to a large extent be a stochastic event related to the number of cells at risk.
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