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Smits, Anja
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Publications (10 of 97) Show all publications
Latini, F., Fahlström, M., Berntsson, S. G., Larsson, E.-M., Smits, A. & Ryttlefors, M. (2019). A novel radiological classification system for cerebral gliomas: The Brain-Grid. PLoS ONE, 14(1), Article ID e0211243.
Open this publication in new window or tab >>A novel radiological classification system for cerebral gliomas: The Brain-Grid
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2019 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, no 1, article id e0211243Article in journal (Refereed) Published
Abstract [en]

PURPOSE: Standard radiological/topographical classifications of gliomas often do not reflect the real extension of the tumor within the lobar-cortical anatomy. Furthermore, these systems do not provide information on the relationship between tumor growth and the subcortical white matter architecture. We propose the use of an anatomically standardized grid system (the Brain-Grid) to merge serial morphological magnetic resonance imaging (MRI) scans with a representative tractographic atlas. Two illustrative cases are presented to show the potential advantages of this classification system.

METHODS: MRI scans of 39 patients (WHO grade II and III gliomas) were analyzed with a standardized grid created by intersecting longitudinal lines on the axial, sagittal, and coronal planes. The anatomical landmarks were chosen from an average brain, spatially normalized to the Montreal Neurological Institute (MNI) space and the Talairach space. Major white matter pathways were reconstructed with a deterministic tracking algorithm on a reference atlas and analyzed using the Brain-Grid system.

RESULTS: In all, 48 brain grid voxels (areas defined by 3 coordinates, axial (A), coronal (C), sagittal (S) and numbers from 1 to 4) were delineated in each MRI sequence and on the tractographic atlas. The number of grid voxels infiltrated was consistent, also in the MNI space. The sub-cortical insula/basal ganglia (A3-C2-S2) and the fronto-insular region (A3-C2-S1) were most frequently involved. The inferior fronto-occipital fasciculus, anterior thalamic radiation, uncinate fasciculus, and external capsule were the most frequently associated pathways in both hemispheres.

CONCLUSIONS: The Brain-Grid based classification system provides an accurate observational tool in all patients with suspected gliomas, based on the comparison of grid voxels on a morphological MRI and segmented white matter atlas. Important biological information on tumor kinetics including extension, speed, and preferential direction of progression can be observed and even predicted with this system. This novel classification can easily be applied to both prospective and retrospective cohorts of patients and increase our comprehension of glioma behavior.

National Category
Clinical Medicine
Identifiers
urn:nbn:se:uu:diva-375437 (URN)10.1371/journal.pone.0211243 (DOI)000456700400066 ()30677090 (PubMedID)
Note

De 2 sista författarna delar sistaförfattarskapet.

Available from: 2019-01-29 Created: 2019-01-29 Last updated: 2019-03-07Bibliographically approved
Smits, A. & Jakola, A. S. (2019). Clinical Presentation, Natural History, and Prognosis of Diffuse Low-Grade Gliomas. Neurosurgery clinics of North America, 30(1), 35-42
Open this publication in new window or tab >>Clinical Presentation, Natural History, and Prognosis of Diffuse Low-Grade Gliomas
2019 (English)In: Neurosurgery clinics of North America, ISSN 1042-3680, E-ISSN 1558-1349, Vol. 30, no 1, p. 35-42Article, review/survey (Refereed) Published
Abstract [en]

Diffuse low-grade gliomas (DLGGs) are primary brain tumors characterized by slow growth but extensive infiltration into the surrounding brain. Patients are typically 30 to 40 years at disease onset and present with focal or focal to bilateral tonic-clonic seizures. The tumor will transform into a malignant glioma and eventually lead to death, but after varying lengths of time. The specific features of DLGG impose a major challenge to decide optimal treatment strategies and timing of treatment, while maintaining patients' quality of life. We discuss the clinical challenges at disease onset with regard to the natural history and long-term prognosis.

Keywords
Diffuse low-grade gliomas, Natural history, Prognosis, Symptoms
National Category
Medical and Health Sciences Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-366909 (URN)10.1016/j.nec.2018.08.002 (DOI)000454661500005 ()30470403 (PubMedID)
Available from: 2018-11-26 Created: 2018-11-26 Last updated: 2019-01-28Bibliographically approved
Zanello, M., Goodden, J. R., Colle, H., Wager, M., De Witt Hamer, P. C., Smits, A., . . . Pallud, J. (2019). Predictors of Epileptic Seizures and Ability to Work in Supratentorial Cavernous Angioma Located Within Eloquent Brain Areas. Neurosurgery, 85(4), E702-E713
Open this publication in new window or tab >>Predictors of Epileptic Seizures and Ability to Work in Supratentorial Cavernous Angioma Located Within Eloquent Brain Areas
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2019 (English)In: Neurosurgery, ISSN 0148-396X, E-ISSN 1524-4040, Vol. 85, no 4, p. E702-E713Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: The postoperative outcomes and the predictors of seizure control are poorly studied for supratentorial cavernous angiomas (CA) within or close to the eloquent brain area.

OBJECTIVE: To assess the predictors of preoperative seizure control, postoperative seizure control, and postoperative ability to work, and the safety of the surgery.

METHODS: Multicenter international retrospective cohort analysis of adult patients benefitting from a functional-based surgical resection with intraoperative functional brain mapping for a supratentorial CA within or close to eloquent brain areas.

RESULTS: A total of 109 patients (66.1% women; mean age 38.4 ± 12.5 yr), were studied. Age >38 yr (odds ratio [OR], 7.33; 95% confidence interval [CI], 1.53-35.19; P = .013) and time to surgery > 12 mo (OR, 18.21; 95% CI, 1.11-296.55; P = .042) are independent predictors of uncontrolled seizures at the time of surgery. Focal deficit (OR, 10.25; 95% CI, 3.16-33.28; P < .001) is an independent predictor of inability to work at the time of surgery. History of epileptic seizures at the time of surgery (OR, 7.61; 95% CI, 1.67-85.42; P = .003) and partial resection of the CA and/or of the hemosiderin rim (OR, 12.02; 95% CI, 3.01-48.13; P < .001) are independent predictors of uncontrolled seizures postoperatively. Inability to work at the time of surgery (OR, 19.54; 95% CI, 1.90-425.48; P = .050), Karnofsky Performance Status ≤ 70 (OR, 51.20; 95% CI, 1.20-2175.37; P = .039), uncontrolled seizures postoperatively (OR, 105.33; 95% CI, 4.32-2566.27; P = .004), and worsening of cognitive functions postoperatively (OR, 13.71; 95% CI, 1.06-176.66; P = .045) are independent predictors of inability to work postoperatively.

CONCLUSION: The functional-based resection using intraoperative functional brain mapping allows safe resection of CA and the peripheral hemosiderin rim located within or close to eloquent brain areas.

Keywords
Cavernous angioma, Epilepsy, Intraoperative brain mapping, Outcome, Return to work, Seizures, Surgery
National Category
Clinical Medicine Neurology Surgery
Identifiers
urn:nbn:se:uu:diva-380937 (URN)10.1093/neuros/nyz063 (DOI)000491255600026 ()30924504 (PubMedID)
Available from: 2019-04-02 Created: 2019-04-02 Last updated: 2019-12-10Bibliographically approved
Roodakker, K. R., Alhuseinalkhudhur, A., Al-Jaff, M., Georganaki, M., Zetterling, M., Berntsson, S. G., . . . Smits, A. (2019). Region-by-region analysis of PET, MRI, and histology in en bloc-resected oligodendrogliomas reveals intra-tumoral heterogeneity. European Journal of Nuclear Medicine and Molecular Imaging, 46(3), 569-579
Open this publication in new window or tab >>Region-by-region analysis of PET, MRI, and histology in en bloc-resected oligodendrogliomas reveals intra-tumoral heterogeneity
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2019 (English)In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 46, no 3, p. 569-579Article in journal (Refereed) Published
National Category
Radiology, Nuclear Medicine and Medical Imaging
Research subject
Computerized Image Processing
Identifiers
urn:nbn:se:uu:diva-356591 (URN)10.1007/s00259-018-4107-z (DOI)000457151600005 ()30109401 (PubMedID)
Funder
Erik, Karin och Gösta Selanders Foundation
Available from: 2018-08-14 Created: 2018-08-08 Last updated: 2019-04-06Bibliographically approved
Corell, A., Carstam, L., Smits, A., Henriksson, R. & Jakola, A. S. (2018). Age and surgical outcome of low-grade glioma in Sweden. Acta Neurologica Scandinavica, 138(4), 359-368
Open this publication in new window or tab >>Age and surgical outcome of low-grade glioma in Sweden
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2018 (English)In: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 138, no 4, p. 359-368Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Low-grade gliomas (LGG) are slow-growing primary brain tumors that typically affect young adults. Advanced age is widely recognized as a poor prognostic factor in LGG. The impact of age on postoperative outcome in this patient group has not been systemically studied.

METHODS: We performed a nationwide register-based study with data from the Swedish Brain Tumor Registry (SBTR) for all adults diagnosed with a supratentorial LGG (WHO grade II astrocytoma, oligoastrocytoma, or oligodendroglioma) during 2005-2015. Patient- and tumor-related characteristics, postoperative complications, and survival were compared between three different age groups (18-39 years, 40-59 years, and ≥60 years).

RESULTS: We identified 548 patients; 204 patients (37.2%) aged 18-39 years, 227 patients (41.4%) aged 40-59 years, and 117 patients (21.4%) ≥60 years of age. Unfavorable preoperative prognostic factors (eg, functional status and neurological deficit) were more common with increased age (P < .001). In addition, overall survival was significantly impaired in those 60 years and above (P < .001). We observed a clear dose-response for age with separation of survival curves at 50 years. Biopsy was more common in patients ≥60 years (P < .001). Subgroup analysis of patients with resection revealed a higher amount of postoperative neurological deficits in older patients (P = .029).

CONCLUSION: In general, older patients with LGG have several unfavorable prognostic factors compared with younger patients but seem to tolerate surgery in a comparable fashion. However, more neurological deficits were observed following resections in elderly. Our data further support a cutoff at 50 years rather than 40 years for selection of high-risk patients.

Keywords
astrocytoma, elderly patients, glioma, low-grade glioma, neurosurgery, oligoastrocytoma, oligodendroglioma
National Category
Neurology Surgery
Identifiers
urn:nbn:se:uu:diva-354621 (URN)10.1111/ane.12973 (DOI)000443931400014 ()29900547 (PubMedID)
Funder
Swedish Research Council, 2017-00944
Available from: 2018-06-25 Created: 2018-06-25 Last updated: 2018-11-06Bibliographically approved
Näslund, O., Smits, A., Förander, P., Laesser, M., Bartek, J., Gempt, J., . . . Jakola, A. S. (2018). Amino acid tracers in PET imaging of diffuse low-grade gliomas: a systematic review of preoperative applications. Acta Neurochirurgica
Open this publication in new window or tab >>Amino acid tracers in PET imaging of diffuse low-grade gliomas: a systematic review of preoperative applications
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2018 (English)In: Acta Neurochirurgica, ISSN 0001-6268, E-ISSN 0942-0940Article in journal (Refereed) Published
Abstract [en]

Positron emission tomography (PET) imaging using amino acid tracers has in recent years become widely used in the diagnosis and prediction of disease course in diffuse low-grade gliomas (LGG). However, implications of preoperative PET for treatment and prognosis in this patient group have not been systematically studied. The aim of this systematic review was to evaluate the preoperative diagnostic and prognostic value of amino acid PET in suspected diffuse LGG. Medline, Cochrane Library, and Embase databases were systematically searched using keywords "PET," "low-grade glioma," and "amino acids tracers" with their respective synonyms. Out of 2137 eligible studies, 28 met the inclusion criteria. Increased amino acid uptake (lesion/brain) was consistently reported among included studies; in 25-92% of subsequently histopathology-verified LGG, in 83-100% of histopathology-verified HGG, and also in some non-neoplastic lesions. No consistent results were found in studies reporting hot spot areas on PET in MRI-suspected LGG. Thus, the diagnostic value of amino acid PET imaging in suspected LGG has proven difficult to interpret, showing clear overlap and inconsistencies among reported results. Similarly, the results regarding the prognostic value of PET in suspected LGG and the correlation between uptake ratios and the molecular tumor status of LGG were conflicting. This systematic review illustrates the difficulties with prognostic studies presenting data on group-level without adjustment for established clinical prognostic factors, leading to a loss of additional prognostic information. We conclude that the prognostic value of PET is limited to analysis of histological subgroups of LGG and is probably strongest when using kinetic analysis of dynamic FET uptake parameters.

Keywords
Amino acid, Biopsy, Glioma, PET, Prognosis
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-352015 (URN)10.1007/s00701-018-3563-3 (DOI)000434978600021 ()29797098 (PubMedID)
Available from: 2018-05-31 Created: 2018-05-31 Last updated: 2018-11-12Bibliographically approved
Lugano, R., Vemuri, K., Yu, D., Bergqvist, M., Smits, A., Essand, M., . . . Dimberg, A. (2018). CD93 promotes β1 integrin activation and fibronectin fibrillogenesis during tumor angiogenesis.. Journal of Clinical Investigation, 128(8), 3280-3297
Open this publication in new window or tab >>CD93 promotes β1 integrin activation and fibronectin fibrillogenesis during tumor angiogenesis.
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2018 (English)In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 128, no 8, p. 3280-3297Article in journal (Refereed) Published
Abstract [en]

Tumor angiogenesis occurs through regulation of genes that orchestrate endothelial sprouting and vessel maturation, including deposition of a vessel-associated extracellular matrix. CD93 is a transmembrane receptor that is up-regulated in tumor vessels in many cancers, including high-grade glioma. Here, we demonstrate that CD93 regulates integrin-β1-signaling and organization of fibronectin fibrillogenesis during tumor vascularization. In endothelial cells and mouse retina, CD93 was found to be expressed in endothelial filopodia and to promote filopodia formation. The CD93 localization to endothelial filopodia was stabilized by interaction with multimerin-2 (MMRN2), which inhibited its proteolytical cleavage. The CD93-MMRN2 complex was required for activation of integrin-β1, phosphorylation of focal adhesion kinase (FAK) and fibronectin fibrillogenesis in endothelial cells. Consequently, tumor vessels in gliomas implanted orthotopically in CD93-deficient mice showed diminished activation of integrin-β1 and lacked organization of fibronectin into fibrillar structures. These findings demonstrate a key role of CD93 in vascular maturation and organization of the extracellular matrix in tumors, identifying it as a potential target for therapy.

Keywords
Brain cancer, Fibronectin, Oncology, Vascular Biology, endothelial cells
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-350902 (URN)10.1172/JCI97459 (DOI)000440461500015 ()29763414 (PubMedID)
Funder
Swedish Cancer Society, CAN 2014/832Swedish Cancer Society, CAN 2017/502Swedish Cancer Society, CAN 2015/1216Swedish Childhood Cancer Foundation, PR2015-0133Swedish Childhood Cancer Foundation, NCP2015-0075Swedish Research Council, 2016-02495
Available from: 2018-05-17 Created: 2018-05-17 Last updated: 2018-11-08Bibliographically approved
Wenger, A., Werlenius, K., Hallner, A., Bergh Thorén, F., Farahmand, D., Tisell, M., . . . Carén, H. (2018). Determinants for Effective ALECSAT Immunotherapy Treatment on Autologous Patient-Derived Glioblastoma Stem Cells.. Neoplasia, 20(1), 25-31
Open this publication in new window or tab >>Determinants for Effective ALECSAT Immunotherapy Treatment on Autologous Patient-Derived Glioblastoma Stem Cells.
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2018 (English)In: Neoplasia, ISSN 1522-8002, E-ISSN 1476-5586, Vol. 20, no 1, p. 25-31Article in journal (Refereed) Published
Abstract [en]

Glioblastoma (GBM) is the most aggressive primary brain tumor with a median survival of less than 15 months, emphasizing the need for better treatments. Immunotherapy as a treatment for improving or aiding the patient's own immune defense to target the tumor has been suggested for GBM. A randomized clinical trial of adoptive cell transfer using ALECSAT (Autologous Lymphoid Effector Cells Specific Against Tumor Cells) is currently ongoing in Sweden. Here we performed a paired pre-clinical study to investigate the composition and in vitro effect of ALECSAT and identify determinants for the effect using autologous GBM-derived cancer stem cells (CSC), immunocytochemistry and flow cytometry. We show a clear dose-response relationship of ALECSAT on CSC, suggesting that the number of infused cells is of importance. In addition, the in vitro effect of ALECSAT on CSC correlated significantly to the blood count of T helper (Th) cells in the patient indicating a potential benefit of collecting cells for ALECSAT preparation at an even earlier stage when patients generally have a better blood count. The factors identified in this study will be important to consider in the design of future immunotherapy trials to achieve prolonged survival.

National Category
Basic Medicine
Identifiers
urn:nbn:se:uu:diva-335343 (URN)10.1016/j.neo.2017.10.006 (DOI)000418566000003 ()29190492 (PubMedID)
Funder
Swedish Cancer SocietySwedish Research CouncilSwedish Society for Medical Research (SSMF)Wenner-Gren FoundationsAFA Insurance
Available from: 2017-12-04 Created: 2017-12-04 Last updated: 2018-01-25Bibliographically approved
Berntsson, S. G., Merrell, R. T., Amirian, E. S., Armstrong, G. N., Lachance, D., Smits, A., . . . Melin, B. S. (2018). Glioma-related seizures in relation to histopathological subtypes: a report from the glioma international case-control study. Journal of Neurology, 265(6), 1432-1442
Open this publication in new window or tab >>Glioma-related seizures in relation to histopathological subtypes: a report from the glioma international case-control study
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2018 (English)In: Journal of Neurology, ISSN 0340-5354, E-ISSN 1432-1459, Vol. 265, no 6, p. 1432-1442Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: The purpose of this study was to evaluate the distribution of glioma-related seizures and seizure control at the time of tumor diagnosis with respect to tumor histologic subtypes, tumor treatment and patient characteristics, and to compare seizure history preceding tumor diagnosis (or study enrollment) between glioma patients and healthy controls.

METHODS: The Glioma International Case Control study (GICC) risk factor questionnaire collected information on demographics, past medical/medication history, and occupational history. Cases from eight centers were also asked detailed questions on seizures in relation to glioma diagnosis; cases (n = 4533) and controls (n = 4171) were also asked about seizures less than 2 years from diagnosis and previous seizure history more than 2 years prior to tumor diagnosis, including childhood seizures.

RESULTS: Low-grade gliomas (LGGs), particularly oligodendrogliomas/oligoastrocytomas, had the highest proportion of glioma-related seizures. Patients with low-grade astrocytoma demonstrated the most medically refractory seizures. A total of 83% of patients were using only one antiepileptic drug (AED), which was levetiracetam in 71% of cases. Gross total resection was strongly associated with reduced seizure frequency (p < 0.009). No significant difference was found between glioma cases and controls in terms of seizure occurring more than 2 years before diagnosis or during childhood.

CONCLUSIONS: Our study showed that glioma-related seizures were most common in low-grade gliomas. Gross total resection was associated with lower seizure frequency. Additionally, having a history of childhood seizures is not a risk factor ***for developing glioma-related seizures or glioma.

Keywords
Epileptic seizures, Glioma-related seizures, Observational study (cohort, case–control), Primary brain tumor
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-349379 (URN)10.1007/s00415-018-8857-0 (DOI)000434462300023 ()29687214 (PubMedID)
Available from: 2018-04-26 Created: 2018-04-26 Last updated: 2018-08-30Bibliographically approved
Zhang, L., He, L., Lugano, R., Roodakker, K. R., Bergqvist, M., Smits, A. & Dimberg, A. (2018). IDH mutation status is associated with distinct vascular gene expression signatures in lower-grade gliomas. Neuro-Oncology, 20(11), 1505-1516
Open this publication in new window or tab >>IDH mutation status is associated with distinct vascular gene expression signatures in lower-grade gliomas
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2018 (English)In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 20, no 11, p. 1505-1516Article in journal (Refereed) Published
Abstract [en]

Background: Vascular gene expression patterns in lower-grade gliomas (LGGs; diffuse World Health Organization [WHO] grades II–III gliomas) have not been thoroughly investigated. The aim of this study was to molecularly characterize LGG vessels and determine if tumor isocitrate dehydrogenase (IDH) mutation status affects vascular phenotype.

Methods: Gene expression was analyzed using an in-house dataset derived from microdissected vessels and total tumor samples from human glioma in combination with expression data from 289 LGG samples available in the database of The Cancer Genome Atlas. Vascular protein expression was examined by immunohistochemistry in human brain tumor tissue microarrays (TMAs) representing WHO grades II–IV gliomas and nonmalignant brain samples. Regulation of gene expression was examined in primary endothelial cells in vitro.

Results: Gene expression analysis of WHO grade II glioma indicated an intermediate stage of vascular abnormality, less severe than that of glioblastoma vessels but distinct from normal vessels. Enhanced expression of laminin subunit alpha 4 (LAMA4) and angiopoietin 2 (ANGPT2) in WHO grade II glioma was confirmed by staining of human TMAs. IDH wild-type LGGs displayed a specific angiogenic gene expression signature, including upregulation of ANGPT2 and serpin family H (SERPINH1), connected to enhanced endothelial cell migration and matrix remodeling. Transcription factor analysis indicated increased transforming growth factor beta (TGFβ) and hypoxia signaling in IDH wild-type LGGs. A subset of genes specifically induced in IDH wild-type LGG vessels was upregulated by stimulation of endothelial cells with TGFβ2, vascular endothelial growth factor, or cobalt chloride in vitro.

Conclusion: IDH wild-type LGG vessels are molecularly distinct from the vasculature of IDH-mutated LGGs. TGFβ and hypoxia-related signaling pathways may be potential targets for anti-angiogenic therapy of IDH wild-type LGG.

Keywords
angiogenesis, ANGPT2, glioma, IDH, tumor vessel
National Category
Basic Medicine Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-352016 (URN)10.1093/neuonc/noy088 (DOI)000448665500010 ()29846705 (PubMedID)
Funder
Swedish Cancer Society, CAN 2015/1216; CAN 2014/832; CAN 2017/502Swedish Childhood Cancer Foundation, PR2015-0133; NCP2015-0075Swedish Research Council, 2016-02495
Available from: 2018-05-31 Created: 2018-05-31 Last updated: 2019-01-08Bibliographically approved
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