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  • 1.
    Andrae, Johanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Molander, Catrin
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Funa, Keiko
    Nistér, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Platelet-derived growth factor-B and -C and active α-receptors in medulloblastoma cells2002In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 296, no 3, p. 604-611Article in journal (Refereed)
    Abstract [en]

    The malignant childhood brain tumor medulloblastoma belongs to the group of primitive neuroectodermal tumours (PNETs). Medulloblastomas are thought to arise from remnants of the transient external germinal layer in the cerebellum. Proliferation, differentiation, and motility of cells in the central nervous system are regulated by growth factors, e.g., platelet-derived growth factor (PDGF). Recently, it was shown that higher level of PDGF α-receptor expression is characteristic of metastatic medulloblastomas. We have investigated five medulloblastoma/PNET cell lines and found that the PDGF α-receptor is actively signalling in most of them, an activity most likely driven by endogenously produced PDGF-C. PDGF-C is normally present in cells of the developing external germinal layer and our results are consistent with the idea that medulloblastomas are derived from such cells undergoing early neuronal differentiation. Moreover, the expression of PDGF and its receptors was associated with neuronal characteristics, but not with high levels of c-myc expression in the medullablastoma cells.

  • 2.
    Babateen, Omar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Jin, Zhe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Bhandage, Amol K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Korol, Sergiy V
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Westermark, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Forsberg Nilsson, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Uhrbom, Lene
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Birnir, Bryndis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Etomidate, propofol and diazepam potentiate GABA-evoked GABAA currents in a cell line derived from Human glioblastoma2015In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 748, p. 101-107Article in journal (Refereed)
    Abstract [en]

    GABAA receptors are pentameric chloride ion channels that are opened by GABA. We have screened a cell line derived from human glioblastoma, U3047MG, for expression of GABAA receptor subunit isoforms and formation of functional ion channels. We identified GABAA receptors subunit α2, α3, α5, β1, β2, β3, δ, γ3, π, and θ mRNAs in the U3047MG cell line. Whole-cell GABA-activated currents were recorded and the half-maximal concentration (EC50) for the GABA-activated current was 36μM. The currents were activated by THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) and enhanced by the benzodiazepine diazepam (1μM) and the general anesthetics etomidate and propofol (50μM). In line with the expressed GABAA receptors containing at least the α3β3θ subunits, the receptors were highly sensitive to etomidate (EC50=55nM). Immunocytochemistry identified expression of the α3 and β3 subunit proteins. Our results show that the GABAA receptors in the glial cell line are functional and are modulated by classical GABAA receptor drugs. We propose that the U3047MG cell line may be used as a model system to study GABAA receptors function and pharmacology in glial cells.

  • 3.
    Babateen, Omar M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Jin, Zhe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Bhandage, Amol K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Korol, Sergiy V.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Westermark, Bengt
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Nilsson, Karin Forsberg
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Uhrbom, Lene
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Birnir, Bryndis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    GABA-A receptor currents in a cell line (U3047MG) derived from a human glioblastoma tumor are enhanced by etomidate, propofol and diazepam2014In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 211, no S696, p. 100-100, article id P74Article in journal (Other academic)
  • 4.
    Ballagi, A E
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Odin, P
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Othberg-Cederström, A
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Duan, W M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Lindvall, O
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Funa, K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Platelet-derived growth factor receptor expression after neural grafting in a rat model of Parkinson's disease1994In: Cell Transplantation, ISSN 0963-6897, E-ISSN 1555-3892, Vol. 3, no 6, p. 453-460Article in journal (Refereed)
    Abstract [en]

    Platelet-derived growth factor (PDGF) has trophic effect on dopaminergic neurons in vitro. We have previously shown dynamic changes in the expression of PDGF in embryonic mesencephalic grafts and surrounding host striatal tissue following intracerebral transplantation in a rat model of Parkinson's disease. In this study the expression of the PDGF receptors was examined in the same model using immunohistochemistry. Most ventral mesencephalic (VM) cells from E13-E15 rat embryos possessed both PDGF alpha- and beta-receptors before implantation. Double immunofluorescence staining revealed that about 10% of the cells also expressed tyrosine hydroxylase (TH). The PDGF alpha-receptor was detectable in the graft up to 1 wk after transplantation but had disappeared at 3 wk. In the host tissue, scattered glial cells were positive for the alpha-receptor but the expression was unchanged following transplantation. The beta-receptor expression almost completely disappeared from the grafted tissue by 4 h following transplantation, and only a few cells of the host striatum showed immunoreactivity. However, after 3 wk beta-receptor positive cells were again detectable in the graft. These cells appeared to be endothelial cells as identified by an antibody against von Willebrand's factor. Our data suggest that PDGF might act locally on embryonic dopaminergic cells in an autocrine or juxtacrine manner before and shortly after transplantation, and on surrounding glial cells in a paracrine manner after transplantation. Furthermore, PDGF-BB might influence neovascularization in the graft.

  • 5.
    Berntsson, Shala G.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Merrell, Ryan T
    Amirian, E Susan
    Armstrong, Georgina N
    Lachance, Daniel
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Zhou, Renke
    Jacobs, Daniel I
    Wrensch, Margaret R
    Olson, Sara H
    Il'yasova, Dora
    Claus, Elizabeth B
    Barnholtz-Sloan, Jill S
    Schildkraut, Joellen
    Sadetzki, Siegal
    Johansen, Christoffer
    Houlston, Richard S
    Jenkins, Robert B
    Bernstein, Jonine L
    Lai, Rose
    Shete, Sanjay
    Amos, Christopher I
    Bondy, Melissa L
    Melin, Beatrice S
    Glioma-related seizures in relation to histopathological subtypes: a report from the glioma international case-control study2018In: Journal of Neurology, ISSN 0340-5354, E-ISSN 1432-1459, Vol. 265, no 6, p. 1432-1442Article in journal (Refereed)
    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.

  • 6.
    Berntsson, Shala Ghaderi
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Falk, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Savitcheva, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Godau, Andrea
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Zetterling, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Hesselager, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Larsson, Elna-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Perfusion and diffusion MRI combined with (11)C-methionine PET in the preoperative evaluation of suspected adult low-grade gliomas2013In: Journal of Neuro-Oncology, ISSN 0167-594X, E-ISSN 1573-7373, Vol. 114, no 2, p. 241-249Article in journal (Refereed)
    Abstract [en]

    Perfusion and diffusion magnetic resonance imaging (pMRI, dMRI) are valuable diagnostic tools for assessing brain tumors in the clinical setting. The aim of this study was to determine the correlation of pMRI and dMRI with (11)C-methionine positron emission tomography (MET PET) in suspected low-grade gliomas (LGG) prior to surgery. Twenty-four adults with suspected LGG were enrolled in an observational study and examined by MET PET, pMRI and dMRI. Histological tumor diagnosis was confirmed in 23/24 patients (18 gliomas grade II, 5 gliomas grade III). The maximum relative cerebral blood volume (rCBVmax) and the minimum mean diffusivity (MDmin) were measured in tumor areas with highest MET uptake (hotspot) on PET by using automated co-registration of MRI and PET scans. A clearly defined hotspot on PET was present in all 23 tumors. Regions with rCBVmax corresponded with hotspot regions in all tumors, regions with MDmin corresponded with hotspot regions in 20/23 tumors. The correlation between rCBVmax (r = 0.19, P = 0.38) and MDmin (r = -0.41, P = 0.053) with MET uptake in the hotspot was not statistically significant. Taken into account the difficulties of measuring perfusion abnormalities in non-enhancing gliomas, this study demonstrates that co-registered MET PET and pMRI facilitates the identification of regions with rCBVmax. Furthermore, the lack of a clear positive correlation between tumor metabolism in terms of MET uptake and tumor vascularity measured as rCBVmax suggests that combined pMRI/PET provides complementary baseline imaging data in these tumors.

  • 7.
    Berntsson, Shala Ghaderi
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Wibom, Carl
    Sjöström, Sara
    Henriksson, Roger
    Brännström, Thomas
    Broholm, Helle
    Johansson, Christoffer
    Fleming, Sarah J
    McKinney, Patricia A
    Bethke, Lara
    Houlston, Richard
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Andersson, Ulrika
    Melin, Beatrice S
    Analysis of DNA repair gene polymorphisms and survival in low-grade and anaplastic gliomas2011In: Journal of Neuro-Oncology, ISSN 0167-594X, E-ISSN 1573-7373, Vol. 105, no 3, p. 531-538Article in journal (Refereed)
    Abstract [en]

    The purpose of this study was to explore the variation in DNA repair genes in adults with WHO grade II and III gliomas and their relationship to patient survival. We analysed a total of 1,458 tagging single-nucleotide polymorphisms (SNPs) that were selected to cover DNA repair genes, in 81 grade II and grade III gliomas samples, collected in Sweden and Denmark. The statistically significant genetic variants from the first dataset (P < 0.05) were taken forward for confirmation in a second dataset of 72 grade II and III gliomas from northern UK. In this dataset, eight gene variants mapping to five different DNA repair genes (ATM, NEIL1, NEIL2, ERCC6 and RPA4) which were associated with survival. Finally, these eight genetic variants were adjusted for treatment, malignancy grade, patient age and gender, leaving one variant, rs4253079, mapped to ERCC6, with a significant association to survival (OR 0.184, 95% CI 0.054-0.63, P = 0.007). We suggest a possible novel association between rs4253079 and survival in this group of patients with low-grade and anaplastic gliomas that needs confirmation in larger datasets.

  • 8.
    Berntsson, Shala
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Malmer, Beatrice
    Bondy, Melissa
    Qu, Mingqi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Tumor-associated epilepsy and glioma: are there common genetic pathways?2009In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 48, no 7, p. 955-963Article, review/survey (Refereed)
    Abstract [en]

    Background. Patients with glioma exhibit a great variability in clinical symptoms apart from variations in response to therapy and survival. Many patients present with epileptic seizures at disease onset, especially in case of low-grade gliomas, but not all have seizures. A large proportion of patients develop refractory seizures. It is likely that the variability in epileptic symptoms cannot exclusively be explained by tumor-related factors, but rather reflects complex interaction between tumor-related, environmental and hereditary factors. Material and methods. No data exist on susceptibility genes associated with epileptic symptoms in patients with glioma. However, an increasing number of candidate genes have been proposed for other focal epilepsies such as temporal lobe epilepsy. Some of the susceptibility candidate genes associated with focal epilepsy may contribute to epileptic symptoms also in patients with glioma. Results. This review presents an update on studies on genetic polymorphisms and focal epilepsy and brings forward putative candidate genes for tumor-associated epilepsy, based on the assumption that common etiological pathways may exist for glioma development and glioma-associated seizures. Conclusion. Genes involved in the immune response, in synaptic transmission and in cell cycle control are discussed that may play a role in the pathogenesis of tumor growth as well as epileptic symptoms in patients with gliomas.

  • 9.
    Carstam, Louise
    et al.
    Sahlgrens Univ Hosp, Dept Neurosurg, Gothenburg, Sweden; Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Gothenburg, Sweden.
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology. Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Gothenburg, Sweden.
    Milos, Peter
    Linköping Univ Hosp, Dept Neurosurg, Linköping, Sweden.
    Corell, Alba
    Sahlgrens Univ Hosp, Dept Neurosurg, Gothenburg, Sweden.
    Henriksson, Roger
    Reg Canc Ctr Stockholm Gotland, Stockholm, Sweden; Univ Umeå, Dept Radiat Sci & Oncol, Umeå, Sweden.
    Bartek, Jiri Jr
    Karolinska Univ Hosp, Dept Neurosurg, Stockholm, Sweden; Karolinska Inst, Dept Neurosci, Stockholm, Sweden; Karolinska Inst, Dept Med, Stockholm, Sweden; Copenhagen Univ Hosp, Rigshosp, Dept Neurosurg, Copenhagen, Denmark.
    Jakola, Asgeir Store
    Sahlgrens Univ Hosp, Dept Neurosurg, Gothenburg, Sweden; Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Gothenburg, Sweden; St Olavs Univ Hosp HF, Dept Neurosurg, Trondheim, Norway.
    Neurosurgical patterns of care for diffuse low-grade gliomas in Sweden between 2005 and 20152018In: Neurooncology Practice, ISSN 2054-2577, Vol. 6, no 2, p. 124-133Article in journal (Refereed)
    Abstract [en]

    Background: In the last decade, increasing evidence has evolved for early and maximal safe resection of diffuse low-grade gliomas (LGGs) regarding survival. However, changes in clinical practice are known to occur slowly and we do not know if the scientific evidence has yet resulted in changes in neurosurgical patterns of care.

    Methods: The Swedish Brain Tumor Registry was used to identify all patients with a first-time histopathological diagnosis of LGG between 2005 and 2015. For analysis of surgical treatment patterns, we subdivided assessed time periods into 2005-2008, 2009-2012, and 2013-2015. Population-based data on patient and disease characteristics, surgical management, and outcomes were extracted.

    Results: A total of 548 patients with diffuse World Health Organization grade II gliomas were identified: 142 diagnosed during 2005-2008, 244 during 2009-2012, and 162 during 2013-2015. Resection as opposed to biopsy was performed in 64.3% during 2005-2008, 74.2% during 2009-2012, and 74.1% during 2013-2015 (P = .08). There was no difference among the 3 periods regarding overall survival (P = .11). However, post hoc analysis of data from the 4 (out of 6) centers that covered all 3 time periods demonstrated a resection rate of 64.3% during 2005-2008, 77.4% during 2009-2012, and 75.4% during 2013-2015 (P = .02) and longer survival of patients diagnosed 2009 and onward (P = .04).

    Conclusion: In this nationwide, population-based study we observed a shift over time in favor of LGG resection. Further, a positive correlation between the more active surgical strategy and longer survival is shown, although no causality can be claimed because of possible confounding factors.

  • 10.
    Corell, Alba
    et al.
    Department of Neurosurgery, Sahlgrenska University Hospital, Gothenburg, Sweden; Institute of Neuroscience and Physiology, University of Gothenburg, Sahlgrenska Academy, Gothenburg, Sweden.
    Carstam, L
    Department of Neurosurgery, Sahlgrenska University Hospital, Gothenburg, Sweden; Institute of Neuroscience and Physiology, University of Gothenburg, Sahlgrenska Academy, Gothenburg, Sweden.
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Institute of Neuroscience and Physiology, University of Gothenburg, Sahlgrenska Academy, Gothenburg, Sweden.
    Henriksson, R
    Regional Cancer Centre Stockholm, Gotland, Sweden; Department of Radiation Science and Oncology, University hospital, Umeå, Sweden.
    Jakola, A S
    Department of Neurosurgery, Sahlgrenska University Hospital, Gothenburg, Sweden; Institute of Neuroscience and Physiology, University of Gothenburg, Sahlgrenska Academy, Gothenburg, Sweden; Department of Neurosurgery, St. Olavs University Hospital, Trondheim, Norway.
    Age and surgical outcome of low-grade glioma in Sweden2018In: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 138, no 4, p. 359-368Article in journal (Refereed)
    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.

  • 11.
    Danfors, Torsten
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Ribom, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Berntsson, Shala G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Epileptic seizures and survival in early disease of grade 2 gliomas2009In: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 16, no 7, p. 823-831Article in journal (Refereed)
    Abstract [en]

    Background and purpose

    The aims of this study were (i) to determine the correlation between seizure activity and the metabolic rate of the tumour measured by 11Cmethionine PET (MET PET) in patients with grade 2 gliomas, and (ii) to assess the prognostic impact of early seizure manifestations on patient survival.

    Methods

    In this retrospective review, early seizure manifestations were studied in 101 patients with supratentorial grade 2 gliomas subjected to MET PET as part of the pretreatment tumour investigation. Seizure manifestations as a variable was then used in multivariate survival analyses, together with established prognostic factors for this patient group.

    Results

    Of all 101 cases, 88 patients had seizures at tumour presentation. Fortyseven were seizure free at the early stage of the disease, whereas 54 had recurrent seizures. Patients with seizures at tumour presentation had a more favourable outcome before and after (P = 0.006) adjustment for conventional prognostic factors. However, for those who continued to have seizures early in the disease, the outcome was worse (P = 0.003). We found no significant correlation between MET PET and the seizure manifestations of the patients.

    Conclusion

    The presence and termination of early seizure manifestations may be favourable prognostic factors in patients with low-grade gliomas.

     

  • 12. De Bustos, C
    et al.
    Smits, Anja
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience. neurologi.
    Strömberg, B
    Collins, V P
    Nistér, M
    Afink, G
    A PDGFRA promoter polymorphism, which disrupts the binding of ZNF148, is associated with primitive neuroectodermal tumours and ependymomas2005In: J Med Genet, Vol. 42, p. 31-37Article in journal (Refereed)
  • 13.
    Duffau, Hugues
    et al.
    Montpellier Med Univ Ctr, Hop Guide Chauliac, Dept Neurosurg, Montpellier, France.;Inst Neurosci, INSERM U1051, Montpellier, France.;Univ Montpellier, Montpellier, France..
    Mandonnet, Emmanuel
    Lariboisiere Hosp, AP HP, Dept Neurosurg, Paris, France.;Univ Paris 07, Paris, France.;IMNC, UMR 8165, Orsay, France..
    Pallud, Johan
    St Anna Hosp, Dept Neurosurg, Paris, France.;Paris Descartes Univ, Sorbonne Paris Cite, Paris, France.;INSERM, U894, Ctr Psychiat & Neurosci, Paris, France..
    Krieg, Sandro
    Tech Univ Munich, Klinikum Rechts Isar, Dept Neurosurg, Munich, Germany..
    Gil Robles, Santiago
    Hosp Univ Quiron, Madrid, Spain.;Bio Cruces Res, Bilbao, Spain..
    Hamer, Philip de Witt
    Vrije Univ Amsterdam Med Ctr, Neurosurg Ctr Amsterdam, Amsterdam, Netherlands..
    Schucht, Philippe
    Univ Hosp Bern, Dept Neurosurg, Bern, Switzerland..
    Zetterling, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Santarius, Thomas
    Univ Cambridge, Addenbrookes Hosp, Dept Neurosurg, Cambridge, England..
    Colle, Henry
    AZ St Luca, Funct Neurosurg, Ghent, Belgium..
    Ryan, Mathew
    Leeds Gen Infirm, Dept Neurosurg, Leeds, W Yorkshire, England..
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology. Univ Gothenburg, Sahlgrenska Acad, Dept Clin Neurosci, Inst Neurosci & Physiol, Gothenburg, Sweden..
    von Campe, Gord
    Med Univ Graz, Dept Neurosurg, Graz, Austria..
    Bello, Lorenzo
    Univ Milan, Dept Oncol & Hematooncol, Neurosurg Oncol Unit, Milan, Italy.;IRCCS, Humanitas Res Hosp, Milan, Italy..
    Forster, Marie-Therese
    Goethe Univ, Dept Neurosurg, Frankfurt, Germany..
    Sarubbo, Silvio
    Santa Chiara Hosp, Struct & Funct Connectiv Lab, Trento, Italy..
    Spena, Giannantonio
    Spedali Civil Brescia, Clin Neurochirurg, Brescia, Italy..
    Baron, Marie-Helene
    CHRU Jean Minjoz, Dept Oncol Radiotherapie, Besancon, France..
    Yordanova, Yordanka
    Percy Army Training Hosp, Neurosurg Dept, Clamart, France..
    Darlix, Amelie
    Inst Regional Canc Montpellier ICM, Dept Med Oncol, Montpellier, France..
    Viegas, Catarina
    Hosp Garcia Orta, Dept Neurosurg, Almada, Portugal..
    Almairac, Fabien
    Univ Hosp Nice, Dept Neurosurg, Nice, France..
    Martino, Juan
    Hosp Univ Marques Valdecilla, Fdn Inst Invest Marques Valdecilla IDIVAL, Dept Neurol Surg, Avda Valdecilla S-N, Santander, Spain.;Inst Salud Carlos III, Avda Valdecilla S-N, Santander, Spain..
    Goodden, John
    Dept Neurosurg, Leeds, W Yorkshire, England..
    Chumas, Paul
    Dept Neurosurg, Leeds, W Yorkshire, England..
    Freyschlag, Christian
    Med Univ Innsbruck, Dept Neurosurg, Innsbruck, Austria..
    Robe, Pierre
    Univ Med Ctr Utrecht, Dept Neurosurg, Utrecht, Netherlands..
    Wager, Michel
    Univ Poitiers Hosp, INSERM U1084, Neurosurg Dept, Poitiers, France..
    Polivka, Marc
    Lariboisiere Hosp, AP HP, Dept Neuropathol, Paris, France..
    Giakoumettis, Dimitris
    Neurosurg Evangelismos Hosp, Athens, Greece..
    Robert, Erik
    AZ SintLucas & AZ Maria Middelares, Dept of Aphasiol, Ghent, Belgium..
    Guillevin, Remy
    Univ Poitiers Hosp, Neuroradiol Dept, Poitiers, France..
    Grivas, Athanasios
    Univ Glasgow, Queen Elizabeth Univ Hosp, Inst Neurol Sci, Dept Neurosurg, Glasgow, Lanark, Scotland..
    Fontaine, Denys
    Univ Hosp Nice, Dept Neurosurg, Nice, France..
    van Geemen, Kim
    Brain Res Ctr Amsterdam, Amsterdam, Netherlands..
    Lubrano, Vincent
    Univ Toulouse, CHU Toulouse, Toulouse NeuroImaging Ctr, INSERM UMR 1214,ToNIC, Toulouse, France..
    Rutten, Geert-Jan
    St Elisabeth Tweesteden Hosp, Dept Neurosurg, Tilburg, Netherlands..
    Barone, Fabio
    Cannizzaro Gen Hosp, Dept Neurosurg & Gamma Knife, Catania, Italy..
    Rofes, Adria
    Trinity Coll Dublin, Global Brain Hlth Inst, Dublin, Ireland..
    Rech, Fabien
    CHRU Nancy, Serv Neurochirurg, Nancy, France..
    Rigau, Valerie
    Gui Chauliac Hosp, Dept Pathol, Montpellier, France..
    Wagemakers, Michiel
    Univ Med Ctr, Neurosurg Dept, Groningen, Belgium..
    Papagno, Costanza
    Univ Trento, CeRiN & CIMeC, Rovereto, Italy..
    Aerts, Annelies
    AZ Sint Lucas, Ghent, Belgium.;Artevelde Univ Coll, Ghent, Belgium..
    Visch-Brink, Evy
    Erasmus MC, Dept Neurol, Rotterdam, Netherlands.;Erasmus MC, Dept Neurosurg, Rotterdam, Netherlands..
    Tate, Matthew
    Northwester Med Group, Dept Neurosurg, Chicago, IL USA..
    Garg, Neha
    Univ Delhi, Delhi, India..
    Klein, Martin
    Vrije Univ Amsterdam Med Ctr, Clin Neuropsychol Dept, Amsterdam, Netherlands..
    Satoer, Djaina
    Erasmus MC, Dept Neurol, Rotterdam, Netherlands.;Erasmus MC, Dept Neurosurg, Rotterdam, Netherlands..
    de Witte, Elke
    Vrije Univ Brussel, Neurolinguist Dept, Brussels, Belgium..
    Van Brussel, Lore
    Onze Lieve Vrouw Hosp, Neurosurg Dept, Moorselbaan, Aalst, Belgium..
    Reyes, Andres
    Univ Groningen, Dept Clin Linguist, Groningen, Netherlands.;EMCL Univ Potsdam, Potsdam, Germany.;El Bosque Univ, Expt Psychol Lab, Fac Psychol, Bogota, Colombia.;Inst Neurosci, Bogota, Colombia..
    van Ierschot, Fleur
    Univ Trent, Ctr Mind Brain Sci, Trento, Italy.;Univ Groningen, Fac Arts, Groningen, Belgium.;Macquarie Univ, Dept Cognit Sci, Sydney, NSW, Australia..
    Veenstra, Wencke
    Univ Groningen, Dept Linguist, Groninge, Belgium..
    Snijders, Tom
    Univ Med Ctr Utrecht, Dept Neurol & Neurosurg Hosp, Brain Ctr Rudolf Magnus, Utrecht, Netherlands..
    Taillandier, Luc
    CHU Nancy, Neurol Dept, Nancy, France..
    Blonski, Marie
    CHU Nancy, Neurol Dept, Nancy, France..
    Evidenced-based medicine in glioma: molecular biology is only part of the story2017In: The Lancet Oncology, ISSN 1470-2045, E-ISSN 1474-5488, Vol. 18, no 8, p. E429-E429Article in journal (Refereed)
  • 14. Ek, Lena
    et al.
    Almkvist, Ove
    Kristoffersen Wiberg, Maria
    Stragliotto, Giuseppe
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Early cognitive impairment in a subset of patients with presumed low-grade glioma2010In: Neurocase, ISSN 1355-4794, E-ISSN 1465-3656, Vol. 16, no 6, p. 503-511Article in journal (Refereed)
    Abstract [en]

    We investigated the presence of cognitive impairment, in adults with presumed low-grade glioma at early stage of disease prior to major treatments, in relation to neurological symptoms and radiological characteristics of the tumour. Sixteen patients were evaluated. A subset of patients was identified with clearly impaired cognition. Patients with cognitive impairment often had large tumours in the left frontal lobe, were relatively young, and most of them were males. We conclude that cognitive dysfunction may be present already at early stage of disease, and that early identification of patients at risk is warranted.

  • 15. Ek, Lena
    et al.
    Smits, Anja
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience. Neurologi.
    Påhlson, Anneli
    Almkvist, Ove
    Analysis of cognitive dysfunction in patients with low-grade glioma2005In: Journal of Clinical Psychology in Medical Settings, Vol. 12, no 2, p. 165-173Article in journal (Refereed)
  • 16. Elsir, T.
    et al.
    Qu, M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Berntsson, Shala G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Orrego, A.
    Olofsson, T.
    Lindström, M. S.
    Nistér, M.
    von Deimling, A.
    Hartmann, C.
    Ribom, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    PROX1 is a predictor of survival for gliomas WHO grade II2011In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 104, no 11, p. 1747-1754Article in journal (Refereed)
    Abstract [en]

    Background:The clinical course of World Health Organisation grade II gliomas remains variable and their time point of transformation into a more malignant phenotype is unpredictable. Identification of biological markers that can predict prognosis in individual patients is of great clinical value. PROX1 is a transcription factor that has a critical role in the development of various organs. PROX1 has been ascribed both oncogenic and tumour suppressive functions in human cancers. We have recently shown that PROX1 may act as a diagnostic marker for high-grade gliomas. The aim of this study was to address the prognostic value of PROX1 in grade II gliomas.Methods:A total of 116 samples were evaluated for the presence of PROX1 protein. The number of immunopositive cells was used as a variable in survival analysis, together with established prognostic factors for this patient group.Results:Higher PROX1 protein was associated with poor outcome. In the multivariate analysis, PROX1 was identified as an independent factor for survival (P=0.024), together with the presence of mutated isocitrate dehydrogenase 1 R132H protein, and with combined losses of chromosomal arms 1p/19q in oligodendrocytic tumours.Conclusion:PROX1 is a novel predictor of survival for grade II gliomas.

  • 17.
    Elsir, Tamador
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Edqvist, Per-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Carlson, Joseph
    Ribom, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Bergqvist, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Ekman, Simon
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Popova, Svetlana N
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Pontén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nistér, Monica
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    A study of embryonic stem cell-related proteins in human astrocytomas: Identification of Nanog as a predictor of survival2014In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 134, no 5, p. 1123-1131Article in journal (Refereed)
    Abstract [en]

    Recent studies suggest that the regulatory networks controlling the functions of stem cells during development may be abnormally active in human cancers. An embryonic stem cell (ESC) gene signature was found to correlate with a more undifferentiated phenotype of several human cancer types including gliomas, and associated with poor prognosis in breast cancer. In the present study, we used tissue microarrays of 80 low-grade (WHO grade II) and 98 high-grade human gliomas (WHO grade III and IV) to investigate the presence of the ESC-related proteins Nanog, Klf4, Oct4, Sox2 and c-Myc by immunohistochemistry. While similar patterns of co-expressed proteins between low- and high-grade gliomas were present, we found up-regulated protein levels of Nanog, Klf4, Oct4 and Sox2 in high-grade gliomas. Survival analysis by Kaplan-Meier analysis revealed a significant shorter survival in the subgroups of low-grade astrocytomas (n=42) with high levels of Nanog protein (p=0.0067) and of Klf4 protein (p=0.0368), in high-grade astrocytomas (n=85) with high levels of Nanog (p=0.0042), Klf4 (p=0.0447), and c-Myc (p=0.0078) and in glioblastomas only (n=71) with high levels of Nanog (p=0.0422) and of c-Myc (p= 0.0256). In the multivariate model, Nanog was identified as an independent prognostic factor in the subgroups of low-grade astrocytomas (p=0.0039), high-grade astrocytomas (p=0.0124) and glioblastomas only (p=0.0544), together with established clinical variables in these tumors. These findings provide further evidence for the joint regulatory pathways of ESC-related proteins in gliomas and identify Nanog as one of the key players in determining clinical outcome of human astrocytomas.

  • 18.
    Elsir, Tamador
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Lindström, Mikael S
    Nistér, Monica
    Transcription factor PROX1: its role in development and cancer.2012In: Cancer Metastasis Review, ISSN 0167-7659, E-ISSN 1573-7233, Vol. 31, no 3-4, p. 793-805Article, review/survey (Refereed)
    Abstract [en]

    The homeobox gene PROX1 is critical for organ development during embryogenesis. The Drosophila homologue, known as prospero has been shown to act as a tumor suppressor by controlling asymmetric cell division of neuroblasts. Likewise, alterations in PROX1 expression and function are associated with a number of human cancers including hematological malignancies, carcinomas of the pancreas, liver and the biliary system, sporadic breast cancer, Kaposiform hemangioendothelioma, colon cancer, and brain tumors. PROX1 is involved in cancer development and progression and has been ascribed both tumor suppressive and oncogenic properties in a variety of different cancer types. However, the exact mechanisms through which PROX1 regulates proliferation, migration, and invasion of cancer cells are by large unknown. This review provides an update on the role of PROX1 in organ development and on its emerging functions in cancer, with special emphasis on the central nervous system and glial brain tumors.

  • 19.
    Falk, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Fahlström, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Rostrup, Egill
    Berntsson, Shala
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Zetterling, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Morell, Arvid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Larsson, Henrik B W
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Larsson, Elna-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Discrimination between glioma grades II and III in suspected low-grade gliomas using dynamic contrast-enhanced and dynamic susceptibility contrast perfusion MR imaging: a histogram analysis approach2014In: Neuroradiology, ISSN 0028-3940, E-ISSN 1432-1920, Vol. 56, no 12, p. 1031-1038Article in journal (Refereed)
    Abstract [en]

    Introduction

    Perfusion magnetic resonance imaging (MRI) can be used in the pre-operative assessment of brain tumours. The aim of this prospective study was to identify the perfusion parameters from dynamic contrast-enhanced (DCE) and dynamic susceptibility contrast (DSC) perfusion imaging that could best discriminate between grade II and III gliomas.

    Methods

    MRI (3 T) including morphological ((T2 fluid attenuated inversion recovery (FLAIR) and T1-weighted (T1W)+Gd)) and perfusion (DCE and DSC) sequences was performed in 39 patients with newly diagnosed suspected low-grade glioma after written informed consent in this review board-approved study. Regions of interests (ROIs) in tumour area were delineated on FLAIR images co-registered to DCE and DSC, respectively, in 25 patients with histopathological grade II (n = 18) and III (n  = 7) gliomas. Statistical analysis of differences between grade II and grade III gliomas in histogram perfusion parameters was performed, and the areas under the curves (AUC) from the ROC analyses were evaluated.

    Results

    In DCE, the skewness of transfer constant (k trans) was found superior for differentiating grade II from grade III in all gliomas (AUC 0.76). In DSC, the standard deviation of relative cerebral blood flow (rCBF) was found superior for differentiating grade II from grade III gliomas (AUC 0.80).

    Conclusions

    Histogram parameters from k trans (DCE) and rCBF (DSC) could most efficiently discriminate between grade II and grade III gliomas.

  • 20.
    Falk Delgado, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Fahlström, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Markus, Nilsson
    Bioimaging center, Lunds Universitet.
    Ghaderi Berntsson, Shala
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Zetterling, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    van Westen, Danielle
    Clinical Sciences, Lunds Universitet.
    Lätt, Jimmy
    MR Department, Center for medical imaging and physiology, Lund University Hospital.
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Larsson, Elna-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Preoperative diffusion kurtosis imaging in suspected low-grade gliomas: A prospective study of diffusional properties in tumour and perilesional regions with histopathological correlationsManuscript (preprint) (Other academic)
  • 21.
    Falk Delgado, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden..
    Fahlström, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Nilsson, Markus
    Lund Univ, Bioimaging Ctr, Lund, Sweden..
    Berntsson, Shala G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Zetterling, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Libard, Sylwia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    van Westen, Danielle
    Lund Univ, Clin Sci Lund, Diagnost Radiol, Lund, Sweden..
    Lätt, Jimmy
    Skane Univ Healthcare, Dept Imaging & Funct, Lund, Sweden..
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Larsson, Elna-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Diffusion kurtosis imaging of gliomas grades II and III: a study of perilesional tumor infiltration, tumor grades and subtypes at clinical presentation2017In: Radiology and Oncology, ISSN 1318-2099, E-ISSN 1581-3207, Vol. 51, no 2, p. 121-129Article in journal (Refereed)
    Abstract [en]

    Background. Diffusion kurtosis imaging (DKI) allows for assessment of diffusion influenced by microcellular structures. We analyzed DKI in suspected low-grade gliomas prior to histopathological diagnosis. The aim was to investigate if diffusion parameters in the perilesional normal-appearing white matter (NAWM) differed from contralesional white matter, and to investigate differences between glioma malignancy grades II and III and glioma subtypes (astrocytomas and oligodendrogliomas).

    Patients and methods. Forty-eight patients with suspected low-grade glioma were prospectively recruited to this institutional review board-approved study and investigated with preoperative DKI at 3T after written informed consent. Patients with histologically proven glioma grades II or III were further analyzed (n=35). Regions of interest (ROIs) were delineated on T2FLAIR images and co-registered to diffusion MRI parameter maps. Mean DKI data were compared between perilesional and contralesional NAWM (student's t-test for dependent samples, Wilcoxon matched pairs test). Histogram DKI data were compared between glioma types and glioma grades (multiple comparisons of mean ranks for all groups). The discriminating potential for DKI in assessing glioma type and grade was assessed with receiver operating characteristics (ROC) curves.

    Results. There were significant differences in all mean DKI variables between perilesional and contralesional NAWM (p=< 0.000), except for axial kurtosis (p=0.099). Forty-four histogram variables differed significantly between glioma grades II (n=23) and III (n=12) (p=0.003-0.048) and 10 variables differed significantly between ACs (n=18) and ODs (n=17) (p=0.011-0.050). ROC curves of the best discriminating variables had an area under the curve (AUC) of 0.657-0.815.

    Conclusions. Mean DKI variables in perilesional NAWM differ significantly from contralesional NAWM, suggesting altered microstructure by tumor infiltration not depicted on morphological MRI. Histogram analysis of DKI data identifies differences between glioma grades and subtypes.

  • 22. Freyschlag, Christian F
    et al.
    Krieg, Sandro M
    Kerschbaumer, Johannes
    Pinggera, Daniel
    Forster, Marie-Therese
    Cordier, Dominik
    Rossi, Marco
    Miceli, Gabriele
    Roux, Alexandre
    Reyes, Andrés
    Sarubbo, Silvio
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Sierpowska, Joanna
    Robe, Pierre A
    Rutten, Geert-Jan
    Santarius, Thomas
    Matys, Tomasz
    Zanello, Marc
    Almairac, Fabien
    Mondot, Lydiane
    Jakola, Asgeir S
    Zetterling, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Rofes, Adrià
    von Campe, Gord
    Guillevin, Remy
    Bagatto, Daniele
    Lubrano, Vincent
    Rapp, Marion
    Goodden, John
    De Witt Hamer, Philip C
    Pallud, Johan
    Bello, Lorenzo
    Thomé, Claudius
    Duffau, Hugues
    Mandonnet, Emmanuel
    Imaging practice in low-grade gliomas among European specialized centers and proposal for a minimum core of imaging.2018In: Journal of Neuro-Oncology, ISSN 0167-594X, E-ISSN 1573-7373, Vol. 139, no 3, p. 699-711Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Imaging studies in diffuse low-grade gliomas (DLGG) vary across centers. In order to establish a minimal core of imaging necessary for further investigations and clinical trials in the field of DLGG, we aimed to establish the status quo within specialized European centers.

    METHODS: An online survey composed of 46 items was sent out to members of the European Low-Grade Glioma Network, the European Association of Neurosurgical Societies, the German Society of Neurosurgery and the Austrian Society of Neurosurgery.

    RESULTS: A total of 128 fully completed surveys were received and analyzed. Most centers (n = 96, 75%) were academic and half of the centers (n = 64, 50%) adhered to a dedicated treatment program for DLGG. There were national differences regarding the sequences enclosed in MRI imaging and use of PET, however most included T1 (without and with contrast, 100%), T2 (100%) and TIRM or FLAIR (20, 98%). DWI is performed by 80% of centers and 61% of centers regularly performed PWI.

    CONCLUSION: A minimal core of imaging composed of T1 (w/wo contrast), T2, TIRM/FLAIR, PWI and DWI could be identified. All morphologic images should be obtained in a slice thickness of ≤ 3 mm. No common standard could be obtained regarding advanced MRI protocols and PET.

    IMPORTANCE OF THE STUDY: We believe that our study makes a significant contribution to the literature because we were able to determine similarities in numerous aspects of LGG imaging. Using the proposed "minimal core of imaging" in clinical routine will facilitate future cooperative studies.

  • 23.
    Giacobini, MaiBritt M J
    et al.
    Department of Histology and Neurobiology, Karolinska Institute, Stockholm Sweden.
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Funa, K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Westermark, B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Olson, L
    Department of Histology and Neurobiology, Karolinska Institute, Stockholm Sweden.
    Differential effects of platelet-derived growth factors on fetal hippocampal and cortical grafts: evidence from intraocular transplantation in rats1992In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 136, no 2, p. 227-231Article in journal (Refereed)
    Abstract [en]

    Effects of platelet-derived growth factor-AA (PDGF-AA) and platelet-derived growth factor-BB (PDGF-BB) on developing parietal cortex (E16) and hippocampal (E18-E19) grafts were studied using the in vivo method of intraocular transplantation. Survival and growth of grafts in the anterior eye chamber of adult host rats under the influence of regular treatments with 0.5 ng (in a 100 ng/ml concentration) PDGF-AA or PDGF-BB was followed and compared to those receiving vehicle solution alone (0.5 mg HSA/ml Hanks). Both PDGF-AA and PDGF-BB increased the volume of transplanted cortical grafts. PDGF-BB also exerted trophic effects on grafted hippocampal tissue whereas PDGF-AA seemed to inhibit hippocampal growth. Histological and immunohistochemical studies revealed an increase in the density of astroglial elements in PDGF-AA- and PDGF-BB-treated cortical grafts whereas the PDGF-AA- and PDGF-BB-treated hippocampal grafts maintained a cytoarchitecture closely resembling that of control grafts. These findings support in vitro experiments showing that developing glial cells are stimulated by PDGFs and we further propose regional differences of action of PDGFs in the developing central nervous system.

  • 24. Hägerstrand, Daniel
    et al.
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Eriksson, Anna
    Sigurdardottir, Sunna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Olofsson, Tommie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Hartman, Magdalena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Nistér, Monica
    Kalimo, Hannu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Östman, Arne
    Gene expression analyses of grade II gliomas and identification of rPTPbeta/ as a candidate oligodendroglioma marker2008In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 10, no 1, p. 2-9Article in journal (Refereed)
    Abstract [en]

    Grade 11 gliomas are morphologically and clinically heterogeneous tumors for which histopathological typing remains the major tool for clinical classification. To what extent the major histological subtypes-astrocytomas, oligodendrogliomas, and oligoastrocytomas-constitute true biological entities is largely unresolved. Furthermore, morphological classification is often ambiguous and would be facilitated by specific subtype markers. In this study, 23 grade II gliomas were expression-profiled and subjected to hierarchical clustering. All six oligodendrogliomas were grouped together in one of two major clusters; a significant correlation was thus observed between gene expression and histopathological subtype. Supervised analyses were performed to identify genes differentiating oligodendrogliomas from other grade II tumors. In a leave-one-out test using 10 features for classification, 20 out of 23 tumors were correctly classified. Among the most differentially expressed genes was rPT beta/zeta. The expression of the rPTP beta/zeta protein in oligodendrogliomas and astrocytomas was further validated by immunohistochemistry in an independent set of tumors. All 11 oligodendrogliomas of this set displayed strong staining. In contrast, neoplastic astrocytes were mostly negative for rPTP beta/zeta staining. In summary, this study demonstrates a correlation between gene expression pattern and histological subtype in grade 11 gliomas. Furthermore, the results from the immunohistochemical analyses of rPTP beta/zeta expression should prompt further evaluation of this protein as a novel oligodendroglioma marker.

  • 25. Langenkamp, Elise
    et al.
    Zhang, Lei
    Lugana, Roberta
    Huang, Hua
    Elsir, Tomador
    Bazzar, Wesam
    Lööf, Johan
    Trendelenburg, George
    Pontén, Fredrik
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Dimberg, Anna
    High expression of the C-type lectin CD93 in glioblastoma vasculature enhancesvessel function by regulating cytoskeletal rearrangements and leads to poor survival2015In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445Article in journal (Other academic)
  • 26.
    Langenkamp, Elise
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Zhang, Lei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lugano, Roberta
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Huang, Hua
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Elhassan, Tamador Elsir Abu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Georganaki, Maria
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Bazzar, Wesam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lööf, Johan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Trendelenburg, George
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Pontén, Fredrik
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Dimberg, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Elevated Expression of the C-Type Lectin CD93 in the Glioblastoma Vasculature Regulates Cytoskeletal Rearrangements That Enhance Vessel Function and Reduce Host Survival2015In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 75, no 21, p. 4504-4516Article in journal (Refereed)
    Abstract [en]

    Glioblastoma is an aggressive brain tumor characterized by an abnormal blood vasculature that is hyperpermeable. Here, we report a novel role for CD93 in regulating angiogenesis in this setting by modulating cell-cell and cell-matrix adhesion of endothelial cells. Tissue microarray analysis demonstrated that vascular expression of CD93 was correlated with poor survival in a clinical cohort of patients with high-grade astrocytic glioma. Similarly, intracranial growth in the GL261 mouse model of glioma was delayed significantly in CD93(-/-) hosts, resulting in improved survival compared with wild-type mice. This effect was associated with increased vascular permeability and decreased vascular perfusion of tumors, indicating reduced vessel functionality in the absence of CD93. RNAi-mediated attenuation of CD93 in endothelial cells diminished VEGF-induced tube formation in a three-dimensional collagen gel. CD93 was required for efficient endothelial cell migration and proper cell polarization in vitro. Further, in endothelial cells where CD93 was attenuated, decreased cell spreading led to a severe reduction in cell adhesion, a lack of proper cell contacts, a loss of VE-cadherin, and aberrant actin stress fiber formation. Our results identify CD93 as a key regulator of glioma angiogenesis and vascular function, acting via cytoskeletal rearrangements required for cell-cell and cell-matrix adhesion.

  • 27.
    Latini, Francesco
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Fahlström, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Berntsson, Shala G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Larsson, Elna-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology. Institute of Neuroscience and Physiology, Department of Clinical Neuroscience, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Ryttlefors, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    A novel radiological classification system for cerebral gliomas: The Brain-Grid2019In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, no 1, article id e0211243Article in journal (Refereed)
    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.

  • 28.
    Libard, Sylwia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Popova, Svetlana N
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Department of Pathology, Uppsala University Hospital, Uppsala, Sweden.
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Kärjä, Vesa
    Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland.
    Pietiläinen, Timo
    Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland.
    Hämäläinen, Kirsi M
    Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland.
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Hesselager, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery. Department of Neurosurgery, Uppsala University Hospital, Sweden.
    Bergqvist, Michael
    Department of radiation sciences, Umeå University, Sweden.
    Ekman, Simon
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Zetterling, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Nilsson, Pelle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Pfeifer, Susan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    de Ståhl, Teresita Diaz
    Department of Oncology-Pathology, Karolinska Institutet, Cancer Center Karolinska, Karolinska University Hospital, Stockholm, Sweden.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Ponten, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Human cytomegalovirus tegument protein pp65 is detected in all intra- and extra-axial brain tumours independent of the tumour type or grade2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 9, p. e108861-Article in journal (Refereed)
    Abstract [en]

    Human cytomegalovirus (HCMV) has been indicated being a significant oncomodulator. Recent reports have suggested that an antiviral treatment alters the outcome of a glioblastoma. We analysed the performance of commercial HCMV-antibodies applying the immunohistochemical (IHC) methods on brain sample obtained from a subject with a verified HCMV infection, on samples obtained from 14 control subjects, and on a tissue microarray block containing cores of various brain tumours. Based on these trials, we selected the best performing antibody and analysed a cohort of 417 extra- and intra-axial brain tumours such as gliomas, medulloblastomas, primary diffuse large B-cell lymphomas, and meningiomas. HCMV protein pp65 immunoreactivity was observed in all types of tumours analysed, and the IHC expression did not depend on the patient's age, gender, tumour type, or grade. The labelling pattern observed in the tumours differed from the labelling pattern observed in the tissue with an active HCMV infection. The HCMV protein was expressed in up to 90% of all the tumours investigated. Our results are in accordance with previous reports regarding the HCMV protein expression in glioblastomas and medulloblastomas. In addition, the HCMV protein expression was seen in primary brain lymphomas, low-grade gliomas, and in meningiomas. Our results indicate that the HCMV protein pp65 expression is common in intra- and extra-axial brain tumours. Thus, the assessment of the HCMV expression in tumours of various origins and pathologically altered tissue in conditions such as inflammation, infection, and even degeneration should certainly be facilitated.

  • 29.
    Lindberg, Nanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Kastemar, Marianne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Olofsson, T
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Uhrbom, Lene
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Oligodendrocyte progenitor cells can act as cell of origin for experimental glioma2009In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 28, no 23, p. 2266-2275Article in journal (Refereed)
    Abstract [en]

    Gliomas are primary brain tumors mainly affecting adults. The cellular origin is unknown. The recent identification of tumor-initiating cells in glioma, which share many similarities with normal neural stem cells, has suggested the cell of origin to be a transformed neural stem cell. In previous studies, using the RCAS/tv-a mouse model, platelet-derived growth factor B (PDGF-B)-induced gliomas have been generated from nestin or glial fibrillary acidic protein-expressing cells, markers of neural stem cells. To investigate if committed glial progenitor cells could be the cell of origin for glioma, we generated the Ctv-a mouse where tumor induction would be restricted to myelinating oligodendrocyte progenitor cells (OPCs) expressing 2',3'-cyclic nucleotide 3'-phosphodiesterase. We showed that PDGF-B transfer to OPCs could induce gliomas with an incidence of 33%. The majority of tumors resembled human WHO grade II oligodendroglioma based on close similarities in histopathology and expression of cellular markers. Thus, with the Ctv-a mouse we have showed that the cell of origin for glioma may be a committed glial progenitor cell.

  • 30.
    Lugano, Roberta
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Vemuri, Kalyani
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Yu, Di
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bergqvist, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg.
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Johansson, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Dejana, Elisabetta
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Dimberg, Anna
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    CD93 promotes β1 integrin activation and fibronectin fibrillogenesis during tumor angiogenesis.2018In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 128, no 8, p. 3280-3297Article in journal (Refereed)
    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.

  • 31.
    Lundström, Erik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Rehabilitation Medicine.
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Borg, Jörgen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Rehabilitation Medicine.
    Terént, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Four-fold increase in direct costs of stroke-survivors with spas-ticity compared to stroke-survivors without spasticity: the first year after the event2010In: Stroke, ISSN 0039-2499, E-ISSN 1524-4628, Vol. 41, no 2, p. 319-324Article in journal (Refereed)
    Abstract [en]

    Background and Purpose:

    The prevalence of spasticity after first-ever stroke is approximately 20%, but there are no health economic studies on costs associated with spasticity after stroke. The objective of our study was to estimate direct costs of stroke with spasticity for patients surviving up to one year after the stroke event in comparison to costs of stroke without spastic-ity.

    Methods:

    A representative sample of first-ever stroke patients hospitalized at Uppsala University Hospital was eligible for our cross-sectional survey. All direct costs during one year were identified for each patient, includ-ing costs for hospitalization (acute and rehabilitation), primary health care, medication, and costs for municipality services. The Swedish currency (SEK) was converted into Purchasing Power Parities US dollar (PPP$).

    Results:

    Median age (inter-quartile range) was 73 years (18), and the proportion of women was 48%. The majority of the direct costs (78%) were associated with hospitalization, whereas 20% was associated with municipality services during one year after first-ever stroke. Only 1% of all direct costs were related to primary health care and 1% to medication. The level of costs for stroke patients was correlated with the presence of spasticity, as measured with modified Ashworth Scale (rs = 0.524), and with the degree of disability, as measured with modified Rankin Scale (rs = 0.624). The mean (median, inter-quartile range) direct cost for stroke patients with spasticity was PPP$ 84 195 (72 116, 53 707) compared to PPP$ 21 842 (12 385, 17 484) for stroke patients without spasticity (P < 0.001).

    Conclusions:

    Direct costs for stroke patients with spasticity are four times higher than direct costs for non-spasticity stroke patients during the first year after the event.

  • 32.
    Lundström, Erik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Terént, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Borg, Jörgen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Rehabilitation Medicine.
    Risk factors for stroke-related pain 1 year after first-ever stroke2009In: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 16, no 2, p. 188-193Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE:

    To estimate the prevalence of stroke-related pain and to explore its relation to spasticity.

    DESIGN:

    Cross-sectional survey.

    PATIENTS AND METHODS:

    One hundred and forty patients were examined at 1 year after first-ever stroke. Pain was assessed by a structured interview and categorized as stroke-related or not, pain intensity by use of the visual analogue scale (VAS), spasticity by use of the modified Ashworth scale, stroke severity and the presence of specific neurological impairments by use of the National Institute of Health Stroke Scale (NIHSS), and depression by use of the Montgomery-Asberg Depression Scale.

    RESULTS:

    Pain was reported by 68 patients (49%) with a mean VAS of 42 (95% CI 36-47). In 29 patients (21%), pain was categorized as stroke-related pain. Univariate analyses demonstrated correlations between stroke-related pain and total NIHSS score, paresis, sensory disturbance, depression and spasticity respectively. A multiple regression analysis demonstrated an independent association of stroke-related pain with paresis (OR = 3.1, 95% CI 1.2-7.7), sensory disturbance (OR = 3.1, 95% CI 1.1-8.9) and depression (OR = 4.1, 95% CI 1.4-13).

    CONCLUSIONS:

    The estimated prevalence of stroke-related pain was 21%. Stroke-related pain was associated with sensorimotor impairments and depression, but not with spasticity as an independent variable.

  • 33.
    Lundström, Erik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Terént, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Borg, Jörgen
    Time-course and determinants of spasticity during the first six months following first-ever stroke2010In: Journal of Rehabilitation Medicine, ISSN 1650-1977, E-ISSN 1651-2081, Vol. 42, no 4, p. 296-301Article in journal (Refereed)
    Abstract [en]

    Purpose:

    To explore the occurrence of and risk factors for spasticity until six months after first-ever stroke.

    Methods:

    Forty-nine patients were examined at day 2-10, at one month, and at six months. The Modified Ashworth Scale (MAS) was used to assess resistance to passive movements. A comprehensive clinical examination was performed to identify other positive signs of the upper motor neuron syndrome, in accordance with a broader definition of spasticity, and to evaluate if spasticity was disabling. Neurological impairments were determined by use of the National Institutes of Health Stroke Scale and global disability by use of the modified Rankin Scale.

    Results:

    Spasticity was present in two patients (4%) at day 2-10, in 13 patients (27%) at one month, and in 11 patients (23%) at six months. Severe paresis at day 2-10 was associated with a 10-fold higher risk for spasticity at one month (OR=10, 95% CI 2-48). Disabling spasticity was present  in one patient at one month and in 6 patients (13%) at six months.

    Conclusions:

    Spasticity according to MAS usually occurs within one month and disabling spasticity later in a subgroup. Severe paresis of the arm is a risk factor for spasticity.

  • 34. Nikkhah, G
    et al.
    Odin, P
    Smits, A
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Tingström, A
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Othberg, A
    Brundin, P
    Funa, K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Lindvall, O
    Platelet-derived growth factor promotes survival of rat and human mesencephalic dopaminergic neurons in culture1993In: Experimental Brain Research, ISSN 0014-4819, E-ISSN 1432-1106, Vol. 92, no 3, p. 516-523Article in journal (Refereed)
    Abstract [en]

    The effect of two isoforms of platelet-derived growth factor (PDGF), PDGF-AA and PDGF-BB, was tested on dissociated cell cultures of ventral mesencephalon from rat and human embryos. PDGF-BB but not PDGF-AA reduced the progressive loss of tyrosine hydroxylase- (TH)-positive neurons in rat and human cell cultures. The mean number of TH-positive cells in the PDGF-BB-treated rat culture was 64% and 106% higher than in the control cultures after 7 and 10 days in vitro, respectively. Corresponding figures for human TH-positive neurons were 90% and 145%. The influence of PDGF-BB was specific for TH-positive neurons and not a general trophic effect, since no change of either total cell number or metabolic activity was found. In PDGF-BB-treated cultures of human but not rat tissue the TH-positive neurons had longer neurites than observed in control or PDGF-AA-treated cultures. These data indicate that PDGF-BB may act as a trophic factor for mesencephalic dopaminergic neurons and suggest that administration of PDGF-BB could ameliorate degeneration and possibly promote axonal sprouting of these neurons in vivo.

  • 35.
    Näslund, Olivia
    et al.
    Sahlgrenska Academy, Gothenburg, Sweden.
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology. Sahlgrens Acad, Inst Physiol & Neurosci, Gothenburg, Sweden.
    Förander, Petter
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden; Karolinska Inst, Dept Med, Stockholm, Sweden; Karolinska Univ Hosp, Dept Neurosurg, Stockholm, Sweden.
    Laesser, Mats
    Univ Gothenburg, Sahlgrenska Acad, Inst Clin Sci, Dept Radiol, Gothenburg, Sweden; St Olavs Hosp, Dept Neurosurg, Trondheim, Norway.
    Bartek, Jiri
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden; Karolinska Inst, Dept Med, Stockholm, Sweden; St Olavs Hosp, Dept Neurosurg, Trondheim, Norway; Rigshosp, Dept Neurosurg, Copenhagen Univ Hosp, Copenhagen, Denmark.
    Gempt, Jens
    Tech Univ Munich, Dept Neurosurg, Klinikum Rechts Isar, Munich, Germany.
    Liljegren, Ann
    Sahlgrens Univ Hosp, Dept Radiol, Gothenburg, Sweden.
    Daxberg, Eva-Lotte
    Sahlgrens Univ Hosp, Dept Radiol, Gothenburg, Sweden.
    Jakola, Asgeir Store
    Sahlgrens Acad, Inst Physiol & Neurosci, Gothenburg, Sweden; Sahlgrens Univ Hosp, Med Lib, Gothenburg, Sweden; Sahlgrens Univ Hosp, Dept Neurosurg, Gothenburg, Sweden.
    Amino acid tracers in PET imaging of diffuse low-grade gliomas: a systematic review of preoperative applications2018In: Acta Neurochirurgica, ISSN 0001-6268, E-ISSN 0942-0940Article in journal (Refereed)
    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.

  • 36.
    Popova, Svetlana N
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Bergqvist, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science.
    Dimberg, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Edqvist, Per-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Ekman, Simon
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Hesselager, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Ponten, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Sooman, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Subtyping of gliomas of various WHO grades by the application of immunohistochemistry2014In: Histopathology, ISSN 0309-0167, E-ISSN 1365-2559, Vol. 64, no 3, p. 365-379Article in journal (Refereed)
    Abstract [en]

    Aims

    In 2010, four subtypes (classical, proneural, mesenchymal, and neural) of glioblastoma multiforme (GBM) were defined by molecular genetic analyses. The objective of this study was to assess whether gliomas, independently of the type and grade, could be subdivided into protein-based subtypes.

    Methods and results

    A tissue microarray (TMA) approach was applied to incorporate tissue samples of low-grade and high-grade gliomas into five TMAs. High expression levels of epidermal growth factor receptor (EGFR), CD44, c-MER proto-oncogene tyrosine kinase (MERTK), platelet-derived growth factor receptor α, p53, oligodendrocyte transcription factor 2 (OLIG2) and isocitrate dehydrogenase 1 with the R132H mutation were assessed using immunohistochemistry (IHC). Glioma could be subdivided into four subtypes by IHC. The majority of the low-grade gliomas were of the proneural subtype, i.e. high p53 expression (63% of grade II). The classical subtype, with high EGFR and low p53 expression, was most common in GBMs (39%), followed by the proneural (29%) and mesenchymal (with high CD44 and MERTK expression) (29%) subtypes, a frequency that is in line with previously published data based on molecular genetics.

    Conclusions

    Assessment of the expression of the five proteins EGFR, CD44, MERTK, p53 and OLIG2 is sufficient for subtyping gliomas, and can be recommended for implementation in clinical practice for both low-grade and high-grade gliomas.

  • 37.
    Påhlson, Anneli
    et al.
    Department of Neurology, University Hospital Örebro, Sweden.
    Ek, Lena
    Ahlström, Gerd
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Pitfalls in the assessment of disability in individuals with low-grade gliomas2003In: Journal of Neuro-Oncology, Vol. 65, no 2, p. 149-158Article in journal (Refereed)
    Abstract [en]

    In this study, the presence of motor and cognitive disability is described in a cohort of patients with low-grade glioma recruited from a geographical area with a well-defined population located in the middle of Sweden. The study group consisted of 35 patients, of which 24 were evaluated by both a neurologist and a neuropsychologist, and 11 only by a neurologist. The test battery according to EFIT (Edinburgh Functional Impairment Test) was used by the neurologist to measure impairments of limb function, memory and speech. Patients were asked to self-evaluate their deficits in motor function and cognition by responding to a specific questionnaire. In addition, a neuropsychological test battery was used by an experienced neuropsychologist who had no previous contact with the patients. In general, motor impairment was mild and predominantly found in the upper limb. Neuropsychological assessment revealed moderate or severe cognitive impairment in more than half of the patients. This impairment was not detected by neurological examination, and only to some extent reported by the patients them selves. The results show statistical differences in cognitive function, memory and language as recorded by the three assessors. In conclusion, this study demonstrates the usefulness of neuropsychological assessment as a complement to neurological examination to detect cognitive dysfunction in patients with low-grade gliomas

  • 38.
    Põlajeva, Jelena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Bergström, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Edqvist, Per-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Lundequist, Anders
    Sjösten, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Nilsson, Gunnar
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Bergqvist, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Pontén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Westermark, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Pejler, Gunnar
    Forsberg Nilsson, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Tchougounova, Elena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Glioma-derived macrophage migration inhibitory factor (MIF) promotes mast cell recruitment in a STAT5-dependent manner2014In: Molecular Oncology, ISSN 1574-7891, E-ISSN 1878-0261, Vol. 8, no 1, p. 50-58Article in journal (Refereed)
    Abstract [en]

    Recently, glioma research has increased its focus on the diverse types of cells present in brain tumors. We observed previously that gliomas are associated with a profound accumulation of mast cells (MCs) and here we investigate the underlying mechanism. Gliomas express a plethora of chemoattractants. First, we demonstrated pronounced migration of human MCs toward conditioned medium from cultures of glioma cell lines. Subsequent cytokine array analyses of media from cells, cultured in either serum-containing or -free conditions, revealed a number of candidates which were secreted in high amounts in both cell lines. Among these, we then focused on macrophage migration inhibitory factor (MIF), which has been reported to be pro-inflammatory and -tumorigenic. Infiltration of MCs was attenuated by antibodies that neutralized MIF. Moreover, a positive correlation between the number of MCs and the level of MIF in a large cohort of human glioma tissue samples was observed. Further, both glioma-conditioned media and purified MIF promoted differential phosphorylation of a number of signaling molecules, including signal transducer and activator of transcription 5 (STAT5), in MCs. Inhibition of pSTAT5 signaling significantly attenuated the migration of MCs toward glioma cell-conditioned medium shown to contain MIF. In addition, analysis of tissue microarrays (TMAs) of high-grade gliomas revealed a direct correlation between the level of pSTAT5 in MCs and the level of MIF in the medium. In conclusion, these findings indicate the important influence of signaling cascades involving MIF and STAT5 on the recruitment of MCs to gliomas.

  • 39.
    Põlajeva, Jelena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Sjösten, Anna M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Lager, Nina
    Kastemar, Marianne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Waern, Ida
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Westermark, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Pejler, Gunnar
    Uhrbom, Lene
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Tchougounova, Elena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Mast Cell Accumulation in Glioblastoma with a Potential Role for Stem Cell Factor and Chemokine CXCL122011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 9, article id e25222Article in journal (Refereed)
    Abstract [en]

    Glioblastoma multiforme (GBM) is the most common and malignant form of glioma with high mortality and no cure. Many human cancers maintain a complex inflammatory program triggering rapid recruitment of inflammatory cells, including mast cells (MCs), to the tumor site. However, the potential contribution of MCs in glioma has not been addressed previously. Here we report for the first time that MCs infiltrate KRas+Akt-induced gliomas, using the RCAS/TV-a system, where KRas and Akt are transduced by RCAS into the brains of neonatal Gtv-a- or Ntv-a transgenic mice lacking Ink4a or Arf. The most abundant MC infiltration was observed in high-grade gliomas of Arf-/- mice. MC accumulation could be localized to the vicinity of glioma-associated vessels but also within the tumor mass. Importantly, proliferating MCs were detected, suggesting that the MC accumulation was caused by local expansion of the MC population. In line with these findings, strong expression of stem cell factor (SCF), i.e. the main MC growth factor, was detected, in particular around tumor blood vessels. Further, glioma cells expressed the MC chemotaxin CXCL12 and MCs expressed the corresponding receptor, i.e. CXCR4, suggesting that MCs could be attracted to the tumor through the CXCL12/CXCR4 axis. Supporting a role for MCs in glioma, strong MC infiltration was detected in human glioma, where GBMs contained significantly higher MC numbers than grade II tumors did. Moreover, human GBMs were positive for CXCL12 and the infiltrating MCs were positive for CXCR4. In conclusion, we provide the first evidence for a role for MCs in glioma.

  • 40.
    Qu, Mingqi
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Aronica, Eleonora
    Boer, Karin
    Fällmar, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Kumllien, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Nistér, Monica
    Wester, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Pontén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    DLG3/SAP102 protein expression in malformations of cortical development: A study of human epileptic cortex by tissue microarray2009In: Epilepsy Research, ISSN 0920-1211, E-ISSN 1872-6844, Vol. 84, no 1, p. 33-41Article in journal (Refereed)
    Abstract [en]

    The human DLG3 gene encodes the synapse-associated protein 102 (SAP102), which is concentrated in the postsynaptic densities of excitatory synapses and involved in receptor-mediated synaptic transmission via binding to the NR2B subunit of the NMDA receptor. In this study, we investigated the expression and cellular distribution of the DLG3/SAP102 protein in human epileptic cortex. Tissue microarrays of a large number of specimens from patients operated for medically intractable epilepsy were used for immunohistochemical screening with anti-DLG3 antibody. The cellular distribution of the protein was further investigated in samples of malformations of cortical development, and the amount of DLG3 protein in the total homogenate and in the postsynaptic membrane fraction of these samples was quantified by Western blot. We found a strictly neuronal expression of DLG3/SAP102 in epileptogenic cortex as well as in non-epileptic human cortex used for control. In focal cortical dysplasia and tuberous sclerosis complex, the protein was expressed in most neurons including dysplastic neurons, but not in giant cells. Increased expression of DLG3 protein was observed in the postsynaptic membrane fraction of patients with focal cortical dysplasia. Double-labeling experiments confirmed the exclusive neuronal character of the DLG3 expressing cells and the co-localization of the DLG3 protein with the NR2B subunit. Our results suggest a putative role for DLG3/SAP102 in cortical hyperexcitability and epileptogenicity of malformations of cortical development.

  • 41.
    Qu, Mingqi
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Jiao, Hong
    Zhao, Jian
    Ren, Zhi-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Kere, Juha
    Nistér, Monica
    Molecular Genetic and Epigenetic analysis of NCX2/SLC8A2 at 19q13.3 in Human Gliomas2010In: Neuropathology and Applied Neurobiology, ISSN 0305-1846, E-ISSN 1365-2990, Vol. 36, no 3, p. 198-210Article in journal (Refereed)
    Abstract [en]

    Aim

    Loss of heterozygosity (LOH) at 19q13.3 is a common genetic change in human gliomas, indicating yet unknown glial-specific tumour suppressor genes in this chromosome region. NCX2/SLC8A2 located on chromosome 19q13.32 encodes a Na(+)/Ca(2+)exchanger, which contributes to intracellular Ca(2+)homeostasis. Its expression is restricted to brain, and it is neither present in other normal tissues nor in gliomas at any significant level. The aim of this study was to investigate if NCX2 might be a tumour suppressor gene involved in glioma.

    Methods

    We performed a systematic analysis of NCX2 in 42 human gliomas using microsatellite analysis for evaluation of LOH at 19q, DNA sequencing and DNA methylation analysis.

    Results

    Except for three known intragenic SNPs, rs12459087, rs7259674, and rs8104926, no NCX2 sequence variations were detected in any of the tumour samples. Furthermore, a CpG island in the 5' promoter region of NCX2 was unmethylated. Interestingly, the CpG sites of three gene-body CpG islands located in exon 2, intron 2-3 and exon 3 and of a 5' CpG rich area relevant to so called CpG island shore of NCX2 were methylated in all 8 glioma samples and in 3 established glioma cell lines tested. Surprisingly, NCX2 could be activated by addition of the DNA methylation inhibitor 5-aza-2'-deoxycytidine to glioma cell lines in which NCX2 was completely silent.

    Conclusion

    Results indicate that DNA methylation may play a key role in the transcriptional silencing of NCX2.

  • 42.
    Qu, Mingqi
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Olofsson, Tommie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Sigurdardottir, Sunna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    You, Chao
    Kalimo, Hannu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Nistér, Monica
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Ren, Zhi-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Genetically distinct astrocytic and oligodendroglial components in oligoastrocytomas2007In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 113, no 2, p. 129-136Article in journal (Refereed)
    Abstract [en]

    Oligoastrocytomas are glial tumours consisting of a mixture of neoplastic astrocytic and oligodendroglial cells. Genetic alterations of oligoastrocytomas include loss of heterozygosity of chromosomes 1p and/or 19q (LOH 1p/19q), typically occurring in oligodendrogliomas, and mutations of TP53, frequently occurring in astrocytomas. To investigate whether these neoplastic cell types in oligoastrocytomas have different genetic profiles, we examined the two different components of oligoastrocytomas in comparison with the histological diagnosis of the specific tumour area for LOH 1p/19q and TP53 mutations by using microdissection technique. We found a variety of lost markers for 1p and 19q, and the presence of two different TP53 mutations in the tumour samples. In the majority of cases (9/11), the oligodendroglial and astrocytic components of an individual oligoastrocytoma displayed the same genotype. We present two cases of biphasic oligoastrocytomas with aberrant findings, suggesting the coexistence of genetically and morphologically distinct tumour cell clones in these tumours. In one case, the oligodendroglial part of the tumour showed LOH19q, whereas the astrocytic part showed TP53 mutation (codon 273). In another case, we found LOH 1p/19q in the oligodendroglial component, but two retained areas on chromosome 1p in the astrocytic component of the tumour. No evidence was found for the coexistence of tumour cells with the two genotypical changes within the same morphological region of one individual tumour. The two cases of biphasic oligoastrocytomas in our sample that display a different genotype in the astrocytic and oligodendroglial part of the tumour show that different components of an oligoastrocytoma may be derived from different cell clones during neoplastic transformation.

  • 43. Reijneveld, Jaap C
    et al.
    Taphoorn, Martin J B
    Coens, Corneel
    Bromberg, Jacoline E C
    Mason, Warren P
    Hoang-Xuan, Khê
    Ryan, Gail
    Hassel, Mohamed Ben
    Enting, Roelien H
    Brandes, Alba A
    Wick, Antje
    Chinot, Olivier
    Reni, Michele
    Kantor, Guy
    Thiessen, Brian
    Klein, Martin
    Verger, Eugenie
    Borchers, Christian
    Hau, Peter
    Back, Michael
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Golfinopoulos, Vassilis
    Gorlia, Thierry
    Bottomley, Andrew
    Stupp, Roger
    Baumert, Brigitta G
    Health-related quality of life in patients with high-risk low-grade glioma (EORTC 22033-26033): a randomised, open-label, phase 3 intergroup study.2016In: The Lancet Oncology, ISSN 1470-2045, E-ISSN 1474-5488, Vol. 17, no 11, p. 1533-1542Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Temozolomide chemotherapy versus radiotherapy in patients with a high-risk low-grade glioma has been shown to have no significant effect on progression-free survival. If these treatments have a different effect on health-related quality of life (HRQOL), it might affect the choice of therapy. We postulated that temozolomide compromises HRQOL and global cognitive functioning to a lesser extent than does radiotherapy.

    METHODS: We did a prospective, phase 3, randomised controlled trial at 78 medical centres and large hospitals in 19 countries. We enrolled adult patients (aged ≥18 years) with histologically confirmed diffuse (WHO grade II) astrocytoma, oligodendroglioma, or mixed oligoastrocytoma, with a WHO performance status of 2 or lower, without previous chemotherapy or radiotherapy, who needed active treatment other than surgery. We randomly assigned eligible patients (1:1) using a minimisation technique, stratified by WHO performance status (0-1 vs 2), age (<40 years vs ≥40 years), presence of contrast enhancement on MRI, chromosome 1p status (deleted vs non-deleted vs indeterminate), and the treating medical centre, to receive either radiotherapy (50·4 Gy in 28 fractions of 1·8 Gy for 5 days per week up to 6·5 weeks) or temozolomide chemotherapy (75 mg/m(2) daily, for 21 of 28 days [one cycle] for 12 cycles). The primary endpoint was progression-free survival (results published separately); here, we report the results for two key secondary endpoints: HRQOL (assessed using the European Organisation for Research and Treatment of Cancer's [EORTC] QLQ-C30 [version 3] and the EORTC Brain Cancer Module [QLQ-BN20]) and global cognitive functioning (assessed using the Mini-Mental State Examination [MMSE]). We did analyses on the intention-to-treat population. This study is closed and is registered at EudraCT, number 2004-002714-11, and at ClinicalTrials.gov, number NCT00182819.

    FINDINGS: Between Dec 6, 2005, and Dec 21, 2012, we randomly assigned 477 eligible patients to either radiotherapy (n=240) or temozolomide chemotherapy (n=237). The difference in HRQOL between the two treatment groups was not significant during the 36 months' follow-up (mean between group difference [averaged over all timepoints] 0·06, 95% CI -4·64 to 4·75, p=0·98). At baseline, 32 (13%) of 239 patients who received radiotherapy and 32 (14%) of 236 patients who received temozolomide chemotherapy had impaired cognitive function, according to the MMSE scores. After randomisation, five (8%) of 63 patients who received radiotherapy and three (6%) of 54 patients who received temozolomide chemotherapy and who could be followed up for 36 months had impaired cognitive function, according to the MMSE scores. No significant difference was recorded between the groups for the change in MMSE scores during the 36 months of follow-up.

    INTERPRETATION: The effect of temozolomide chemotherapy or radiotherapy on HRQOL or global cognitive functioning did not differ in patients with low-grade glioma. These results do not support the choice of temozolomide alone over radiotherapy alone in patients with high-risk low-grade glioma.

    FUNDING: Merck Sharp & Dohme-Merck & Co, National Cancer Institute, Swiss Cancer League, National Institute for Health Research, Cancer Research UK, Canadian Cancer Society Research Institute, National Health and Medical Research Council, European Organisation for Research and Treatment of Cancer Cancer Research Fund.

  • 44.
    Remahl, Ingela Nilsson
    et al.
    Svenska neurologföreningen.
    Fredrikson, Sten
    Svenska neurologföreningen.
    Gunnarsson, Martin
    Svenska neurologföreningen.
    Hietala, Albert
    Stridh, Lars
    Jood, Katarina
    Burman, Joachim
    Johansson, Rune
    Jensen, Svend Marup
    Petersson, Jesper
    Zarrinkobb, Laleh
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Svenska neurologföreningen: Antalet neurologer som behöver fördubblas under den kommande tioårsperioden2012In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 109, no 19, p. 970-970Article in journal (Refereed)
  • 45.
    Ren, Zhi-Ping
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Olofsson, Tommie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Qu, Mingqi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Hesselager, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Soussi, Thierry
    Kalimo, Hannu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Nistér, Monica
    Molecular genetic analysis of p53 intratumoral heterogeneity in human astrocytic brain tumors2007In: Journal of Neuropathology and Experimental Neurology, ISSN 0022-3069, E-ISSN 1554-6578, Vol. 66, no 10, p. 944-954Article in journal (Refereed)
    Abstract [en]

    We investigated genetic heterogeneity of astrocytic gliomas using p53 gene mutations as a marker. Different parts of morphologically heterogeneous astrocytic gliomas were micro-dissected, and direct DNA sequencing of p53 gene exons 5 through 8 was performed. Thirty-five glioma samples and tumor-adjacent normal-appearing brain tissue from I I patients were analyzed. Sixteen different p53 gene mutations were found in 7 patients. We found that some tumors were devoid of p53 gene mutations, whereas other tumors carried I or often several (up to 3) different mutations. The mutations were present in grade II, III, and IV astrocytic glioma areas. Both severe functionally dead mutants and mutants with remaining transcriptional activity could be observed in the same tumor. We observed that morphologically different parts of a glioma could carry different or similar mutations in the p53 gene and could be either associated or not associated with the locus of heterozygosity at the mutant site. Coexistence of p53 gene mutations and the locus of heterozygosity was common, at least in astrocytomas grade III and in glioblastomas, and also occurred in astrocytoma grade 11 areas. These results support the notion that intratumoral heterogeneity in brain tumors originates from different molecular defects. Our results are of importance for a further understanding of the molecular mechanisms behind failure to treat glioma patients.

  • 46.
    Ribom, D
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Andrae, J
    Frielingsdorf, M
    Hartman, M
    Nistér, M
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Prognostic value of platelet derived growth factor alpha receptor expression in grade 2 astrocytomas and oligoastrocytomas2002In: Journal of Neurology, Neurosurgery and Psychiatry, ISSN 0022-3050, E-ISSN 1468-330X, Vol. 72, no 6, p. 782-787Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE:

    To determine whether the expression of platelet derived growth factor alpha receptor (PDGFRalpha) in low grade astrocytomas and oligoastrocytomas is associated with survival.

    METHODS:

    Formalin fixed and paraffin embedded tumour samples of 40 consecutive patients with supratentorial diffuse astrocytomas and oligoastrocytomas of WHO grade 2, resected between 1986 and 1993, were used for immunohistochemical staining. The fraction of tumour cells expressing PDGFRalpha protein was quantified and entered into univariate and multivariate survival analyses. Changes in PDGFalpha expression over time were analysed in seven patients in whom reoperations had been performed.

    RESULTS:

    Patients with a relatively high fraction of PDGFRalpha expressing cells had a more favourable outcome in both univariate (p = 0.04) and multivariate analyses (p = 0.02). Expression of PDGFRalpha was greater in oligoastrocytomas than in astrocytomas (p = 0.05). In four reoperated patients with histologically confirmed malignant transformation, there was a marked decrease in the number of cells expressing the receptor.

    CONCLUSIONS:

    There is an association between high PDGFRalpha expression and long survival time in patients with grade 2 astrocytomas and oligoastrocytomas. The findings suggest that expression of the receptor may be a useful prognostic marker in such patients.

  • 47.
    Ribom, Dan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Adner, Johan
    Eriksson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Persson, Lennart
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Lågmaligna gliom i Uppsala/Örebroregionen: Prognostiska faktorer och överlevnad bland 119 studerade patienter2000In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 97, no 36, p. 3880-3884Article in journal (Other academic)
  • 48.
    Ribom, Dan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Engler, Henry
    Uppsala University.
    Blomquist, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Potential significance of 11C-methionine PET as a marker for the radiosensitivity of low-grade gliomas2002In: European Journal of Nuclear Medicine, ISSN 0340-6997, E-ISSN 1432-105X, Vol. 29, no 5, p. 632-640Article in journal (Refereed)
    Abstract [en]

    The role for radiotherapy in patients with low-grade gliomas remains controversial. Two large prospective studies have failed to demonstrate a radiotherapeutic dose-response effect, and EORTC trial 22845 found no difference in survival between patients receiving adjuvant radiotherapy and those who received radiotherapy at tumour progression. The aim of this retrospective study was to analyse the patterns of carbon-11 methionine (MET) uptake on positron emission tomography (PET) in tumours treated with immediate radiotherapy and in those treated with delayed radiotherapy at the time of tumour progression. The 21 adult patients studied had histologically confirmed low-grade gliomas and had undergone a pre-treatment PET scan and a follow-up PET scan at the time of progression. Eleven of the patients had undergone initial radiotherapy a median of 5 weeks after the surgical procedure. The median time to progression was 3.5 years for this group, compared with 1.6 years for the group with delayed radiotherapy ( P=0.06). At the time of progression, non-irradiated tumours had a significantly higher MET uptake ( P=0.02) and a larger uptake volume ( P=0.008) compared with baseline, whereas irradiated tumours showed no statistically significant change. We observed a correlation between high pre-treatment uptake of MET and reduction in MET uptake in response to radiotherapy ( P=0.008). All irradiated tumours recurred within the radiation field. In conclusion, our results demonstrate signs of a residual radiation effect at the time of tumour progression in low-grade gliomas with high pre-treatment uptake of MET. Pre-treatment methionine uptake may be a marker for the radiosensitivity of low-grade gliomas.

  • 49.
    Ribom, Dan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Eriksson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Hartman, Magdalena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Engler, Henry
    Uppsala University Positron Emission Tomography Center, University Hospital, Uppsala, Sweden.
    Nilsson, Anna
    Uppsala University Positron Emission Tomography Center, University Hospital, Uppsala, Sweden.
    Långstrom, Bengt
    Uppsala University Positron Emission Tomography Center, University Hospital, Uppsala, Sweden.
    Bolander, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Bergstrom, Mats
    Uppsala University Positron Emission Tomography Center, University Hospital, Uppsala, Sweden.
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Positron emission tomography 11C-methionine and survival in patients with low-grade gliomas2001In: Cancer, ISSN 0008-543X, E-ISSN 1097-0142, Vol. 92, no 6, p. 1541-1549Article in journal (Refereed)
    Abstract [en]

    BACKGROUND

    Considerable numbers of patients with low-grade gliomas experience an early malignant course and may benefit from aggressive treatment. These patients are difficult to identify using established prognostic factors. A retrospective study was performed to determine whether the 11C-methionine uptake in tumor is a survival factor in adult patients with supratentorial gliomas classified as World Health Organization Grade 2.

    METHODS

    The authors identified 89 patients with histologically confirmed low-grade gliomas in whom an 11C-methionine positron emission tomography (PET) scan had been performed as part of the diagnostic tumor investigation from 1983 to 1998. Clinical data were collected, and the PET scans were re-evaluated according to a fixed protocol. The 11C-methionine uptake in the tumor and relevant clinical parameters were entered into univariate and multivariate survival analyses.

    RESULTS

    At the end of the study, 49 patients (55.1%) had died. The median overall survival was 5.7 years. Low methionine uptake was significantly favorable in the multivariate survival analysis (P = 0.04) along with oligodendroglioma (P = 0.003). In the histologic subgroups, 11C-methionine uptake was an important survival factor among patients with astrocytomas (P = 0.05) and oligodendrogliomas (P = 0.03). Tumor resection was a favorable prognostic factor in patients with high methionine uptake (P = 0.01) but not in patients with low uptake.

    CONCLUSIONS

    Baseline 11C-methionine PET is a prognostic indicator in patients with low-grade gliomas. The results imply that PET is a valuable tool in the clinical management of these patients and may assist in the selection of patients for therapy.

  • 50.
    Ribom, Dan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Pietras, Kristian
    Ludwiginstitutet för Cancerforskning.
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Growth factor analysis of low-grade glioma CSF: PDGF and VEGF are not detectable2003In: Neurological Sciences, ISSN 1590-1874, E-ISSN 1590-3478, Vol. 24, no 2, p. 70-73Article in journal (Refereed)
    Abstract [en]

    Platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF) and fibroblast growth factor 2 (FGF-2) are involved in the development of grade 2 gliomas. The aim of the present study was to determine the presence of these growth factors in the cerebrospinal fluid (CSF) and to assess their usefulness as biological markers. CSF was collected from 7 adult patients with newly diagnosed supratentorial low-grade gliomas by lumbar puncture and was analysed together with matched serum samples using radioreceptor and enzyme-linked immunosorbant assays. Neither PDGF nor VEGF were detected in the CSF, and FGF-2 was measurable at extremely low concentrations in only 2 of 7 patients. Serum levels were within normal limits. We conclude that these growth factors are not released into the CSF in any significant amounts and are therefore not suitable as biological markers in grade 2 gliomas.

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