| 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. |
- Merchut-Maya, Joanna Maria, et al.
(författare)
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Human cytomegalovirus hijacks host stress response fueling replication stress and genome instability
- 2022
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Ingår i: Cell Death and Differentiation. - : Springer Science and Business Media LLC. - 1350-9047 .- 1476-5403. ; 29:8, s. 1639-1653
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Tidskriftsartikel (refereegranskat)abstract
- Viral infections enhance cancer risk and threaten host genome integrity. Although human cytomegalovirus (HCMV) proteins have been detected in a wide spectrum of human malignancies and HCMV infections have been implicated in tumorigenesis, the underlying mechanisms remain poorly understood. Here, we employed a range of experimental approaches, including single-molecule DNA fiber analysis, and showed that infection by any of the four commonly used HCMV strains: AD169, Towne, TB40E or VR1814 induced replication stress (RS), as documented by host-cell replication fork asymmetry and formation of 53BP1 foci. The HCMV-evoked RS triggered an ensuing host DNA damage response (DDR) and chromosomal instability in both permissive and non-permissive human cells, the latter being particularly relevant in the context of tumorigenesis, as such cells can survive and proliferate after HCMV infection. The viral major immediate early enhancer and promoter (MIEP) that controls expression of the viral genes IE72 (IE-1) and IE86 (IE-2), contains transcription-factor binding sites shared by promoters of cellular stress-response genes. We found that DNA damaging insults, including those relevant for cancer therapy, enhanced IE72/86 expression. Thus, MIEP has been evolutionary shaped to exploit host DDR. Ectopically expressed IE72 and IE86 also induced RS and increased genomic instability. Of clinical relevance, we show that undergoing standard-of-care genotoxic radio-chemotherapy in patients with HCMV-positive glioblastomas correlated with elevated HCMV protein markers after tumor recurrence. Collectively, these results are consistent with our proposed concept of HCMV hijacking transcription-factor binding sites shared with host stress-response genes. We present a model to explain the potential oncomodulatory effects of HCMV infections through enhanced replication stress, subverted DNA damage response and induced genomic instability.
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| 3. |
- Jakobsson, Johan, et al.
(författare)
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Long-Term Functional Outcome and Quality of Life After Surgical Evacuation of Spontaneous Supratentorial Intracerebral Hemorrhage: Results from a Swedish Nationwide Cohort
- 2022
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Ingår i: World Neurosurgery. - : Elsevier BV. - 1878-8750 .- 1878-8769. ; 70
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To investigate long-term survival, neurologic outcome, and quality of life in patients with spontaneous supratentorial intracerebral hemorrhage (ICH) treated with craniotomy and hematoma evacuation. Methods: A nationwide multicenter retrospective analysis of 341 patients who underwent craniotomy and evacuation of supratentorial ICH between January 1, 2011, and December 31, 2015, was performed. Baseline characteristics associated with 6-month mortality and long-term mortality were investigated. Survivors received a questionnaire about their state of health from which EuroQol 5D (EQ-5D) and modified Rankin scale (mRS) were obtained. Predictors of mortality, unfavorable outcome, and life quality were analyzed. Results: The mean follow-up time was 55.2 months. Predictors of 6-month mortality in multiple regression analysis were age ≥75 years, previous myocardial infarction, lower level of consciousness, and mechanical ventilation. Predictors of long-term mortality were higher age and mechanical ventilation. At follow-up, 49.5% of survivors had a favorable neurologic outcome (mRS ≤3). Predictors of an unfavorable functional outcome were higher age and ICH volume ≥50 mL. The mean EQ-5D health index was 0.719, and the mean EQ-5D visual analog scale score was 53.9. In multiple regression, only a higher mRS score was significantly associated with worse life quality. Conclusions: Knowledge about survival, functional outcome, and life quality as well as their predictors in this specific patient group is previously primarily described in short-term follow-up. This multicenter study provides novel information in the long-term perspective, which is important for improved surgical decision-making and prognostication.
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| 4. |
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| 5. |
- Rydén, Isabelle, et al.
(författare)
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Return to work following diagnosis of low-grade glioma: A nationwide matched cohort study.
- 2020
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Ingår i: Neurology. - : Lippincott Williams & Wilkins. - 1526-632X .- 0028-3878. ; 95:7
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Tidskriftsartikel (refereegranskat)abstract
- Return-to-work (RTW) following diagnosis of infiltrative low-grade gliomas (LGG) is unknown.Swedish patients with histopathological verified WHO grade II diffuse glioma diagnosed between 2005-2015 were included. Data were acquired from several Swedish registries. A total of 381 patients aged 18-60 were eligible. A matched control population (n=1900) was acquired. Individual data on sick leave, compensations, comorbidity and treatments assigned were assessed. Predictors were explored using multivariable logistic regression.One year before surgery/index date, 88 % of cases were working compared to 91 % of controls. The proportion of controls working remained constant, while patients had a rapid increase in sick leave approximately six months prior to surgery. After one and two years respectively, 52 % and 63 % of the patients were working. Predictors for no-RTW after one year were previous sick leave (OR 0.92, 95 % CI 0.88-0.96, p <0.001), older age (OR 0.96, 95 % CI 0.94-0.99, p=0.005) and lower functional level (OR 0.64 95% CI, 0.45-0.91 p=0.01). Patients receiving adjuvant treatment were less likely to RTW within the first year. At two years, biopsy (as opposed to resection), female sex and comorbidity were also unfavorable, while age and adjuvant treatment were no longer significant.Approximately half of the patients RTW within the first year. Lower functional status, previous sick leave, older age and adjuvant treatment were risk factors for no-RTW at one year after surgery. Female sex, comorbidity and biopsy only were also unfavorable for RTW at two years.
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| 6. |
- Munkvold, Bodil Karoline Ravn, et al.
(författare)
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Variations in the management of diffuse low-grade gliomas : A Scandinavian multicenter study
- 2021
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Ingår i: Neuro-Oncology Practice. - : Oxford University Press. - 2054-2577 .- 2054-2585. ; 8:6, s. 706-717
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Tidskriftsartikel (refereegranskat)abstract
- Background. Early extensive surgery is a cornerstone in treatment of diffuse low-grade gliomas (DLGGs), and an additional survival benefit has been demonstrated from early radiochemotherapy in selected "high-risk" patients. Still, there are a number of controversies related to DLGG management. The objective of this multicenter population-based cohort study was to explore potential variations in diagnostic work-up and treatment between treating centers in 2 Scandinavian countries with similar public health care systems.Methods. Patients screened for inclusion underwent primary surgery of a histopathologically verified diffuse WHO grade II glioma in the time period 2012 through 2017. Clinical and radiological data were collected from medical records and locally conducted research projects, whereupon differences between countries and inter-hospital variations were explored.Results. A total of 642 patients were included (male:female ratio 1:4), and annual age-standardized incidence rates were 0.9 and 0.8 per 100 000 in Norway and Sweden, respectively. Considerable inter-hospital variations were observed in preoperative work-up, tumor diagnostics, surgical strategies, techniques for intraoperative guidance, as well as choice and timing of adjuvant therapy.Conclusions. Despite geographical population-based case selection, similar health care organizations, and existing guidelines, there were considerable variations in DLGG management. While some can be attributed to differences in clinical implementation of current scientific knowledge, some of the observed inter-hospital variations reflect controversies related to diagnostics and treatment. Quantification of these disparities renders possible identification of treatment patterns associated with better or worse outcomes and may thus represent a step toward more uniform evidence-based care.
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| 7. |
- Thurin, Erik, et al.
(författare)
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Depression and ability to work after vestibular schwannoma surgery : a nationwide registry-based matched cohort study on antidepressants, sedatives, and sick leave
- 2021
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Ingår i: Acta Neurochirurgica. - : Springer Nature. - 0001-6268 .- 0942-0940. ; 163:8, s. 2225-2235
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundIn patients with vestibular schwannomas (VS), tumor control is often achieved, and life expectancy is relatively good. The main risks of surgical treatment are hearing loss and facial nerve function. The occurrence of mood and sleeping disorders in relation to surgery is an important aspect of health that has rarely been studied. Similarly, only limited data exist on the rate of sick leave for patients with VS. In this nationwide registry-based study, we define the use of antidepressants and sedatives and the sick leave pattern before and after VS surgery.MethodsAdult patients with histopathologically verified VS were identified in the Swedish Brain Tumor Registry (SBTR) and clinical data were linked to relevant national registries after assigning five matched controls to each patient. We studied patterns of dispensed antidepressants and sedative drugs as well as patterns of sick leave compared to respective controls at 2 years before and 2 years following surgery.ResultsWe identified 333 patients and 1662 matched controls. The rate of antidepressant use was similar between patients and controls 2 years before surgery (6.0% vs 6.3%) and 2 years after surgery (10.1% vs 7.5%). The rate of sedative use was also similar 2 years before surgery (3.9% vs 4.3%) and 2 years after surgery (4.8% vs 5.3%). The rate of sick leave was similar at baseline between patients and controls, but at 2 years after surgery, 75% of patients vs 88% of controls (p < 0.01) had no registered sick leave. Long-term sick leave after surgery was predicted by use of sedatives (OR 0.60, 95% CI 0.38–0.94, p = 0.03), more preoperative sick leave (OR 0.91, 95% CI 0.89–0.93, p < 0.001), and new-onset neurological deficits after surgery (OR 0.42, 95% CI 0.24–0.76, p = 0.004).ConclusionThis nationwide study shows no significant differences in the use of antidepressants and sedatives between patients and controls, while the rate of postoperative sick leave was higher in patients than in controls after VS surgery. Our findings underpin the importance of avoiding surgical sequelae and facilitating return to normal professional life.
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| 8. |
- Vecchio, Tomás Gomez, et al.
(författare)
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Lower-Grade Gliomas: An Epidemiological Voxel-Based Analysis of Location and Proximity to Eloquent Regions.
- 2021
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Ingår i: Frontiers in oncology. - : Frontiers Media SA. - 2234-943X. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Glioma is the most common intra-axial tumor, and its location relative to critical areas of the brain is important for treatment decision-making. Studies often report tumor location based on anatomical taxonomy alone since the estimation of eloquent regions requires considerable knowledge of functional neuroanatomy and is, to some degree, a subjective measure. An unbiased and reproducible method to determine tumor location and eloquence is desirable, both for clinical use and for research purposes.To report on a voxel-based method for assessing anatomical distribution and proximity to eloquent regions in diffuse lower-grade gliomas (World Health Organization grades 2 and 3).A multi-institutional population-based dataset of adult patients (≥18 years) histologically diagnosed with lower-grade glioma was analyzed. Tumor segmentations were registered to a standardized space where two anatomical atlases were used to perform a voxel-based comparison of the proximity of segmentations to brain regions of traditional clinical interest.Exploring the differences between patients with oligodendrogliomas, isocitrate dehydrogenase (IDH) mutated astrocytomas, and patients with IDH wild-type astrocytomas, we found that the latter were older, more often had lower Karnofsky performance status, and that these tumors were more often found in the proximity of eloquent regions. Eloquent regions are found slightly more frequently in the proximity of IDH-mutated astrocytomas compared to oligodendrogliomas. The regions included in our voxel-based definition of eloquence showed a high degree of association with performing biopsy compared to resection.We present a simple, robust, unbiased, and clinically relevant method for assessing tumor location and eloquence in lower-grade gliomas.
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| 9. |
- 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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| 10. |
- Sjåvik, Kristin, et al.
(författare)
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Venous thromboembolism prophylaxis in meningioma surgery - a population based comparative effectiveness study of routine mechanical prophylaxis with or without preoperative low molecular weight heparin
- 2016
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Ingår i: World Neurosurgery. - : Elsevier BV. - 1878-8750 .- 1878-8769. ; 88, s. 320-326
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Tidskriftsartikel (refereegranskat)abstract
- Object: Venous thromboembolism (VTE) is a serious complication after intracranial meningioma surgery. To what extent systemic prophylaxis with pharmacotherapy is beneficial with respect to VTE risk, or associated with increased risk of bleeding and postoperative hemorrhage, remains debated. The current study aimed to clarify the risk-benefit of prophylactic pharmacotherapy initiated the evening before craniotomy for meningioma. METHODS: In a Scandinavian population-based cohort we conducted a retrospective review of 979 operations for intracranial meningioma between 2007 and 2013 at three neurosurgical centers with population-based referral. We compared two different treatment strategies analyzing frequencies of VTE and proportions of postoperative intracranial hematomas requiring surgery or intensified subsequent observation or care (ICU or other intensified observation and/or treatment). One neurosurgical center favored preoperative prophylaxis with low-molecular weight heparin (LMWH) ("LMWH routine group") in addition to mechanical prophylaxis, while two centers favored mechanical prophylaxis with LMWH only given as needed in cases of delayed mobilization ("LMWH as needed group"). RESULTS: In the LMWH routine group, VTE was diagnosed after 24/626 operations (3.9%), while VTE was diagnosed after 11/353 (3.1%) operations in the LMWH as needed group (p=0.56). Clinically relevant postoperative hematomas occurred after 57/626 operations (9.1%) in the LMWH routine group compared to 23/353 (6.5%) in the LMWH as needed group (p=0.16). Surgically evacuated postoperative hematomas occurred after 19/626 operations (3.0%) in the LMWH routine group compared to 8/353 operations (2.3%) in the LMWH as needed group (p=0.26). CONCLUSION: There is no benefit of routine preoperative LMWH starting before intracranial meningioma surgery. Neither could we for primary outcomes detect a significant increase in clinically relevant postoperative hematomas secondary to this regimen. We suggest that "as-needed" perioperative administration of LMWH, reserved for patients with excess risk due to delayed mobilization, is effective and also appears to be the safest strategy.
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