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  • 301.
    Nyholm, Dag
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Johansson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Estrada, Matias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Aquilonius, Sten-Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Circadian rhythmicity in levodopa pharmacokinetics in patients with Parkinson disease2010In: Clinical neuropharmacology, ISSN 0362-5664, E-ISSN 1537-162X, Vol. 33, no 4, p. 181-185Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES:: The purpose of this study was to compare daytime and nighttime plasma pharmacokinetics (PK) of levodopa in patients with Parkinson disease. METHODS:: Four-hour plasma profiles of levodopa were captured in 8 patients with Parkinson disease after the second daily levodopa dose and after the identical dose at bedtime. Patients were fasting 2 hours before and 2 hours after dose intakes, except standardized amounts of tap water. Body position was upright during daytime testing and supine during nighttime testing. Four patients were additionally tested at daytime in supine position. RESULTS:: The absorption rate was significantly delayed at nighttime dosing. The time at which the maximum peaks occurred was delayed from 25 (15-240) to 105 (20-240) minutes, respectively. Maximum concentrations were significantly lower at night, but the plasma exposure (area under the curve, 0-4 hours) was unaffected. Supine daytime plasma PK was in between day and night results. CONCLUSIONS:: There is a slower absorption rate of levodopa during nighttime, probably related to delayed gastric emptying. However, the extent of absorption and bioavailability were unaffected. As the effect of posture on plasma PK was less than the effect of nighttime, this study suggests that the circadian rhythm has a pronounced effect on gastric emptying and absorption rate. Nevertheless, body position may also be an important factor, and it can be recommended that levodopa tablets be taken in upright position that probably should be sustained for at least 30 minutes.

  • 302.
    Nyholm, Dag
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Lewander, Tommy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Gomes-Trolin, Cecilia
    Bäckström, Tobias
    Panagiotidis, Georgios
    Ehrnebo, Mats
    Nyström, Christer
    Aquilonius, Sten-Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Pharmacokinetics of levodopa/carbidopa microtablets versus levodopa/benserazide and levodopa/carbidopa in healthy volunteers2012In: Clinical neuropharmacology, ISSN 0362-5664, E-ISSN 1537-162X, Vol. 35, no 3, p. 111-117Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: To compare bioavailability and pharmacokinetics of single doses of 3 different levodopa formulations given orally in healthy volunteers. Two marketed formulations, standard levodopa/carbidopa, 100/25 mg (LC-100), and dispersible levodopa/benserazide, 100/25 mg (LB-100), were used as reference formulations for a newly developed dispersible microtablet formulation of levodopa/carbidopa, 5/1.25 mg (LC-5). The microtablets are intended for individualized dosing of levodopa/carbidopa in Parkinson disease by means of an electronic dose dispenser with a built-in diary for symptom registration.

    METHODS: A single-dose, open, randomized, 3-way crossover study was performed in 19 healthy subjects. Concentrations of levodopa, carbidopa, and the metabolite 3-O-MD in plasma were determined after intake of 100 mg of levodopa, that is, one tablet of reference formulations and 20 microtablets of the new formulation.

    RESULTS: The LC-5 microtablets were bioequivalent to the LC-100 tablets in area under the curve (AUC) and maximum concentration in plasma (Cmax) for levodopa, and to the LB-100 tablets in AUC. The dispersible levodopa/benserazide formulation showed earlier time to Cmax and significantly higher Cmax for levodopa in plasma compared to the microtablets. Carbidopa showed larger interindividual variation in AUC and Cmax than levodopa, and the bioequivalence comparison LC-5/LC-100 for this compound did not reach the target. Nevertheless, comparison of 3-O-MD levels for LC-5/LC-100, assuming proportionality to levodopa levels, demonstrated bioequivalence.

    CONCLUSIONS: The new levodopa/carbidopa microtablets had a pharmacokinetic profile that would allow for a convenient switch of therapy from standard tablets. Frequent dose administration of levodopa/carbidopa microtablets with an electronic dose dispenser might offer an optimal oral drug delivery in Parkinson disease.

  • 303.
    Nyholm, Dag
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Lewander, Tommy
    Johansson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    LeWitt, Peter A.
    Lundqvist, Christofer
    Aquilonius, Sten-Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Enteral Levodopa/Carbidopa infusion in advanced Parkinson disease: Long-term exposure2008In: Clinical neuropharmacology, ISSN 0362-5664, E-ISSN 1537-162X, Vol. 31, no 2, p. 63-73Article in journal (Refereed)
    Abstract [en]

    Objectives: In patients with advanced Parkinson disease, levodopa/carbidopa formulated as a gel suspension (Duodopa) permits continuous delivery into the small intestine using a portable pump, resulting in less variability in levodopa concentrations and fewer motor fluctuations and dyskinesias than with oral levodopa administration. This is a retrospective analysis of the long-term clinical experience with this agent. Methods: All but 1 of the patients who had received enteral levodopa infusion treatment between January 1, 1991, and June 30, 2002, consented to a review of their hospital charts. Results: Of the 65 patients with initial testing of the treatment, 86% opted for continued treatment via percutaneous endoscopic gastrostomy or gastrojejunostomy. Total exposure to levodopa infusion was 216 patient-years (mean, 3.7 years). Maximum treatment duration was 10.7 years. Fifty-two patients were treated for 1 year or longer. The adverse effect profile of levodopa/carbidopa infusion was similar to that observed with oral administration of levodopa. Seven deaths occurred, all considered unrelated to the treatment. Intestinal tube problems, including dislocation of the intestinal tube to the stomach, were the most common technical problem, occurring in 69% of the patients during the first year. The optimal daily dose of levodopa decreased by an average of 5% during follow-up. Conclusions: The safety of enteral infusion of levodopa/ carbidopa formulated as a gel suspension was found acceptable. For most patients, the technical challenges posed by the enteral infusion system were offset by the improvement in motor fluctuations and dyskinesias offered by this technique.

  • 304.
    Nyholm, Dag
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Odin, Per
    Johansson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Chatamra, Krai
    Locke, Charles
    Dutta, Sandeep
    Othman, Ahmed A
    Pharmacokinetics of Levodopa, Carbidopa, and 3-O-Methyldopa Following 16-hour Jejunal Infusion of Levodopa-Carbidopa Intestinal Gel in Advanced Parkinson's Disease Patients2013In: AAPS Journal, ISSN 1550-7416, E-ISSN 1550-7416, Vol. 15, no 2, p. 316-323Article in journal (Refereed)
    Abstract [en]

    Motor complications of Parkinson's disease (PD) are a consequence of pulsatile dopaminergic stimulation from standard oral levodopa therapy. Levodopa-carbidopa intestinal gel (LCIG) is infused continuously via an intrajejunal percutaneous gastrostomy tube. This was the first study designed to characterize the full pharmacokinetic profiles of levodopa, carbidopa, and levodopa metabolite, 3-O-methyldopa (3-OMD) with 16-h LCIG infusion. Nineteen advanced PD patients (mean age, 65 years) who were on LCIG therapy for ≥30 days were enrolled. Patients received their individualized LCIG infusion doses, and serial pharmacokinetic samples were collected. Eighteen patients completed the study; 19 were assessed for safety. Mean (SD) total levodopa and carbidopa doses were 1,580 (403) and 395 (101) mg, respectively. Mean (SD) C (avg) (μg/mL) were 2.9 (0.84) for levodopa, 17.1 (4.99) for 3-OMD, and 0.22 (0.08) for carbidopa. The degree of fluctuation [defined as (C (max) - C (min))/C (avg)] in levodopa, 3-OMD, and carbidopa plasma concentrations was very low (0.52, 0.21, and 0.96, respectively) during hours 2-16 of infusion. Accordingly, the within-subject coefficients of variation in levodopa, 3-OMD, and carbidopa concentrations were low (13%, 6%, and 19%, respectively). Three patients (16%) reported ≥1 treatment-emergent adverse event; none were considered severe. Continuous intrajejunal LCIG infusion maintained stable plasma levodopa levels over 16 h. Consistent exposure has been shown to reduce motor and nonmotor complications associated with oral medications. LCIG was well tolerated, consistent with previous reports.

  • 305.
    Nyholm, Dag
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Stepien, V.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Levodopa fractionation in Parkinson's disease: half of the patients use more than four daily doses after 5 years2012In: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 19, no S1, p. 24-24Article in journal (Other academic)
  • 306.
    Nyholm, Dag
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Stepien, Victoria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Levodopa Fractionation in Parkinson's Disease2014In: Journal of Parkinson's Disease, ISSN 1877-718X, Vol. 4, no 1, p. 89-96Article in journal (Refereed)
    Abstract [en]

    Background:

    Fractionation of daily levodopa dosage is one strategy to manage the almost inevitable development of symptom fluctuations in Parkinson's disease (PD). However, it is not known from the literature how levodopa fractionation is performed in routine clinical practice.

    Objective:

    The objective of this study was to capture how anti-parkinsonian medications were used, in particular how the daily dose was fractionated (defined as >4 doses/day).

    Methods:

    A pharmacoepidemiological study was undertaken at Uppsala University Hospital. Medical records of PD patients with ≥4 years' disease duration who visited the Neurology Clinic between January and October 2011 were retrospectively reviewed. Times to dose fractionation, to dyskinesias and to hallucinations were calculated using Kaplan-Meier analyses.

    Results:

    175 patients (47% women) were included. Median age at PD onset was 63 years (range 36-83). Median disease duration was 9.0 years. Dose fractionation was used in 85% of patients. The median time to fractionation was 5.0 years. Patients developing dyskinesias had a significantly earlier age at onset than those who did not.

    Conclusions:

    Fractionation of levodopa dosage into >4 daily doses was common. It occurred when wearing-off of the levodopa response is expected to present, i.e. after 5 years in 50% of patients. The study highlights the importance of individualizing and frequently adjusting levodopa dosage, already from the initiation of therapy.

  • 307.
    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.

  • 308. Ohlsson, Monica
    et al.
    Hedberg, Carola
    Brådvik, Björn
    Lindberg, Christopher
    Tajsharghi, Homa
    Danielsson, Olof
    Melberg, Atle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Udd, Bjarne
    Martinsson, Tommy
    Oldfors, Anders
    Hereditary myopathy with early respiratory failure associated with a mutation in A-band titin2012In: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 135, no 6, p. 1682-1694Article in journal (Refereed)
    Abstract [en]

    Hereditary myopathy with early respiratory failure and extensive myofibrillar lesions has been described in sporadic and familial cases and linked to various chromosomal regions. The mutated gene is unknown in most cases. We studied eight individuals, from three apparently unrelated families, with clinical and pathological features of hereditary myopathy with early respiratory failure. The investigations included clinical examination, muscle histopathology and genetic analysis by whole exome sequencing and single nucleotide polymorphism arrays. All patients had adult onset muscle weakness in the pelvic girdle, neck flexors, respiratory and trunk muscles, and the majority had prominent calf hypertrophy. Examination of pulmonary function showed decreased vital capacity. No signs of cardiac muscle involvement were found. Muscle histopathological features included marked muscle fibre size variation, fibre splitting, numerous internal nuclei and fatty infiltration. Frequent groups of fibres showed eosinophilic inclusions and deposits. At the ultrastructural level, there were extensive myofibrillar lesions with marked Z-disc alterations. Whole exome sequencing in four individuals from one family revealed a missense mutation, g.274375T>C; p.Cys30071Arg, in the titin gene (TTN). The mutation, which changes a highly conserved residue in the myosin binding A-band titin, was demonstrated to segregate with the disease in all three families. High density single nucleotide polymorphism arrays covering the entire genome demonstrated sharing of a 6.99 Mb haplotype, located in chromosome region 2q31 including TTN, indicating common ancestry. Our results demonstrate a novel and the first disease-causing mutation in A-band titin associated with hereditary myopathy with early respiratory failure. The typical histopathological features with prominent myofibrillar lesions and inclusions in muscle and respiratory failure early in the clinical course should be incentives for analysis of TTN mutations.

  • 309. Oosterloo, Mayke
    et al.
    Bijlsma, Emilia K
    van Kuijk, Sander Mj
    Minkels, Floor
    de Die-Smulders, Christine Em
    Clinical and genetic characteristics of late-onset Huntington's disease.2018In: Parkinsonism & Related Disorders, ISSN 1353-8020, E-ISSN 1873-5126, article id S1353-8020(18)30490-5Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The frequency of late-onset Huntington's disease (>59 years) is assumed to be low and the clinical course milder. However, previous literature on late-onset disease is scarce and inconclusive.

    OBJECTIVE: Our aim is to study clinical characteristics of late-onset compared to common-onset HD patients in a large cohort of HD patients from the Registry database.

    METHODS: Participants with late- and common-onset (30-50 years)were compared for first clinical symptoms, disease progression, CAG repeat size and family history. Participants with a missing CAG repeat size, a repeat size of ≤35 or a UHDRS motor score of ≤5 were excluded.

    RESULTS: Of 6007 eligible participants, 687 had late-onset (11.4%) and 3216 (53.5%) common-onset HD. Late-onset (n = 577) had significantly more gait and balance problems as first symptom compared to common-onset (n = 2408) (P < .001). Overall motor and cognitive performance (P < .001) were worse, however only disease motor progression was slower (coefficient, -0.58; SE 0.16; P < .001) compared to the common-onset group. Repeat size was significantly lower in the late-onset (n = 40.8; SD 1.6) compared to common-onset (n = 44.4; SD 2.8) (P < .001). Fewer late-onset patients (n = 451) had a positive family history compared to common-onset (n = 2940) (P < .001).

    CONCLUSIONS: Late-onset patients present more frequently with gait and balance problems as first symptom, and disease progression is not milder compared to common-onset HD patients apart from motor progression. The family history is likely to be negative, which might make diagnosing HD more difficult in this population. However, the balance and gait problems might be helpful in diagnosing HD in elderly patients.

  • 310.
    Pauzuolis, Mindaugas
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Biology Education Centre.
    Eich, Torsten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Burman, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Quantification of γδ T cells and HLA-DR+ NK cells does not predict emergence of new contrast enhancing lesions in MS patients suspending natalizumab treatment2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 6, article id e0179095Article in journal (Refereed)
    Abstract [en]

    Background

    Natalizumab (NTZ) is a drug that has been widely used in the treatment of multiple sclerosis (MS). NTZ is very effective in suppressing inflammation, but if treatment is suspended many patients will experience relapses.

    Objective

    To investigate if quantification of γδ T cells and HLA-DR+ NK cells could predict early disease reactivation after NTZ suspension.

    Methods

    Absolute counts of γδ T cells and HLA-DR+ NK cells in whole blood were determined with flow cytometry in fifteen patients treated with NTZ. NTZ treatment was then withdrawn and patients were followed with clinical visits and MR investigations.

    Results

    Patients with recurrent disease had higher absolute counts of γδ T cells 129 (+/- 156) cells/μl in comparison to patients with stable disease 50.0 (+/- 51.0) cells/mu l but the difference was not statistically significant and largely driven by outliers. Patients with recurrent and stable disease had similar absolute counts of HLA-DR+ NK cells.

    Conclusion

    Quantification of γδ T cells and HLA-DR+ NK cells could not predict active disease after NTZ suspension.

  • 311.
    Pedder, H.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Jin, Zhe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Aronica, E.
    Birnir, Bryndis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    GABA-A channel subunit expression in human glioma correlates with tumour histology and clinical outcome2012In: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 19, no S1, p. 67-67Article in journal (Other academic)
  • 312. Pedroso, José Luiz
    et al.
    Povoas Barsottini, Orlando Graziani
    Lin, Ling
    Melberg, Atle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Oliveira, Acary S B
    Mignot, Emmanuel
    A Novel de novo Exon 21 DNMT1 Mutation Causes Cerebellar Ataxia, Deafness, and Narcolepsy in a Brazilian Patient2013In: Sleep, ISSN 0161-8105, E-ISSN 1550-9109, Vol. 36, no 8, p. 1257-1259Article in journal (Refereed)
    Abstract [en]

    STUDY OBJECTIVES: Autosomal dominant cerebellar ataxia, deafness and narcolepsy (ADCA-DN) is caused by DNMT1 mutations. Diagnosing the syndrome can be difficult, as all clinical features may not be present at onset, HLA-DQB1*06:02 is often negative, and sporadic cases occur. We report on clinical and genetic findings in a 31-year-old woman with cerebellar ataxia, deafness, and narcolepsy, and discuss diagnostic challenges.

    DESIGN: Clinical and genetic investigation in a patient and family members.

    SETTING: Ataxia clinic, São Paulo, Brazil.

    PATIENTS OR PARTICIPANTS: One patient and her family members.

    INTERVENTIONS: N/A.

    MEASUREMENTS AND RESULTS: Narcolepsy was supported by polysomnographic and multiple sleep latency testing. HLA-DQB1*06:02 was positive. CSF hypocretin-1 was 191 pg/mL (normal values > 200 pg/mL). Mild brain atrophy was observed on MRI, with cerebellar involvement. The patient, her asymptomatic mother, and 3 siblings gave blood samples for genetic analysis. DNMT1 exons 20 and 21 were sequenced. Haplotyping of polymorphic markers surrounding the mutation was performed. The proband had a novel DNMT1 mutation in exon 21, p.Cys596Arg, c.1786T > C. All 4 parental haplotypes could be characterized in asymptomatic siblings without the mutation, indicating that the mutation is de novo in the patient.

    CONCLUSIONS: The Brazilian patient reported here further adds to the worldwide distribution of ADCA-DN. The mutation is novel, and illustrates a sporadic case with de novo mutation. We believe that many more cases with this syndrome are likely to be diagnosed in the near future, mandating knowledge of this condition and consideration of the diagnosis.

  • 313. Persson, H.
    et al.
    Kumlien, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Ericson, M.
    Tomson, Torbjörn
    No apparent effect of surgery for temporal lobe epilepsy in heart rate variability2006In: Epilepsy Research, ISSN 0920-1211, E-ISSN 1872-6844, Vol. 70, no 2-3, p. 127-132Article in journal (Refereed)
    Abstract [en]

    Background: Impaired cardiac autonomic function may contribute to the risk of sudden unexpected death in epilepsy (SUDEP). Clinical observations indicate that successful epilepsy surgery is associated with a reduced risk of SUDEP. However, in a previous study we found impaired cardiac control pre-surgically in patients with poor outcome of surgery, indicating an a priori lower risk in responders to epilepsy surgery. We have now examined the effect of surgery on cardiac autonomic control in the same patients.

    Methods: We used 24 h EKG recordings to assess heart rate variability (HRV) by spectral analysis in 21 consecutive patients after temporal lobe epilepsy surgery. The HRV was compared with healthy controls, with pre-surgical HRV in the same patients, and analyzed in relation to seizure control 1 year after surgery.

    Results: The patients with poor outcome after surgery had significantly lower SD of RR-intervals, total power, very low frequency power and low frequency power than matched healthy controls. The patients with favorable outcome did not differ from the controls, and the postoperative HRV was not different from HRV before surgery in any of the patient groups.

    Conclusion: We could not demonstrate any effect on HRV of temporal lobe epilepsy surgery in these patients. The observed lower HRV in the poor outcome group was present already before epilepsy surgery as previously reported. Although our results need confirmation in a larger study, the observations suggest that the increased risk of SUDEP in patients failing epilepsy surgery may be due to a common factor predisposing to surgical failure, impaired HRV as well as to an increased risk of SUDEP.

  • 314. Persson, Håkan
    et al.
    Kumlien, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Ericson, Mats
    Tomson, Torbjörn
    Circadian variation in heart-rate variability in localization-related epilepsy2007In: Epilepsia, ISSN 0013-9580, E-ISSN 1528-1167, Vol. 48, no 5, p. 917-922Article in journal (Refereed)
    Abstract [en]

    Purpose: Case-control studies of sudden unexpected death in epilepsy (SUDEP) have reported that SUDEP is more likely to occur during sleep and thus presumably during night hours. The circadian variation of heart-rate variability (HRV) might be of relevance to this risk. We examined night versus daytime HRV in patients with newly diagnosed and refractory localization-related epilepsy, assessing the effects of drug treatment and epilepsy surgery on the night/daytime HRV ratio. Methods: We used spectral analysis to assess HRV and calculated the night-time (00.00-05.00)/daytime (07.30-21.30) ratio of HRV in 14 patients with newly diagnosed localization-related epilepsy before and during carbamazepine (CBZ) treatment and in 21 patients with temporal lobe epilepsy before and after epilepsy surgery. Both groups were compared with age- and sex-matched controls. Results: No significant differences were found from controls in the night/daytime ratios of HRV whether compared before or after initiation of treatment with CBZ in newly diagnosed epilepsy patients. When patients were used as their own controls, night/daytime ratios of standard deviation of RR intervals (p = 0.04) and total power (p = 0.04) were significantly lower during treatment than before. Compared with those of controls, the night/daytime ratios were lower in epilepsy surgery patients before surgery [low-frequency power (p = 0.04); high-frequency power (p = 0.04)]. Night/daytime ratios did not change significantly after surgery. Conclusions: The HRV of the patients was more affected during night-time when the risk of SUDEP seems to be highest in such patients.

  • 315. Plantman, Stefan
    et al.
    Zelano, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Novikova, Liudmila N.
    Novikov, Lev N.
    Cullheim, Staffan
    Neuronal myosin-X is upregulated after peripheral nerve injury and mediates laminin-induced growth of neurites2013In: Molecular and Cellular Neuroscience, ISSN 1044-7431, E-ISSN 1095-9327, Vol. 56, p. 96-101Article in journal (Refereed)
    Abstract [en]

    The successful outcome of peripheral neuronal regeneration is attributed both to the growth permissive milieu and the intrinsic ability of the neuron to initiate appropriate cellular responses such as changes in gene expression and cytoskeletal rearrangements. Even though numerous studies have shown the importance of interactions between the neuron and the extracellular matrix (ECM) in axonal outgrowth, the molecular mechanisms underlying the contact between ECM receptors and the cellular cytoskeleton remain largely unknown. Unconventional myosins constitute an important group of cytoskeletal-associated motor proteins. One member of this family is the recently described myosin-X. This protein interacts with several members of the axon growth-associated ECM receptor family of integrins and could therefore be important in neuronal outgrowth. In this study, using radioactive in situ hybridization, we found that expression of myosin-X mRNA is upregulated in adult rat sensory neurons and spinal motoneurons after peripheral nerve injury, but not after central injury. Thus, myosin-X was upregulated after injuries that can-be followed by axonal regeneration. We also found that the protein is localized to neuronal growth cones and that silencing of myosin-X using RNA interference impairs the integrin-mediated growth of neurites on laminin, but has no effect on non-integrin mediated growth on N-cadherin.

  • 316. Plantman, Stefan
    et al.
    Zelano, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Risling, Marten
    Cullheim, Staffan
    Neuronal Myosin-X is upregulated after peripheral nerve injury and mediates laminin-induced growth of neurites2012In: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 29, no 10, p. A178-A178Article in journal (Other academic)
  • 317.
    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.

  • 318. Press, R
    et al.
    Askmark, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Svenningsson, A
    Andersen, O
    Axelson, Hans W
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Strömberg, U
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Wahlin, A
    Isaksson, C
    Johansson, J-E J
    Hägglund, H
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Autologous haematopoietic stem cell transplantation: a viable treatment option for CIDP2014In: Journal of Neurology, Neurosurgery and Psychiatry, ISSN 0022-3050, E-ISSN 1468-330X, Vol. 85, no 6, p. 618-624Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Only 70-80% of patients with chronic inflammatory demyelinating polyneuropathy (CIDP) respond satisfactorily to the established first-line immunomodulatory treatments. Autologous haematopoietic stem cell transplantation (AHSCT) has been performed as a last treatment resort in a few therapy-refractory cases with CIDP. We describe the results of AHSCT in 11 consecutive Swedish patients with therapy-refractory CIDP with a median follow-up time of 28 months.

    METHOD: Case data were gathered retrospectively for AHSCT treatments in 11 patients with CIDP refractory to the first-line immunomodulatory treatments, intravenous high-dose immunoglobulin, corticosteroids and plasma exchange and to one or more second-line treatments used in 10 of the 11 patients.

    RESULTS: The median Inflammatory Neuropathy Cause and Treatment (INCAT) score within 1 month prior to AHSCT was 6 and the Rankin score 4. Total INCAT and Rankin scores improved significantly within 2-6 months after AHSCT and continued to do so at last follow-up. The motor action potential amplitudes (CMAP) improved already within 4 months (median) after AHSCT. Three of the 11 patients relapsed during the follow-up period, requiring retransplantation with AHSCT in one. Eight of the 11 patients maintained drug-free remission upon last follow-up. AHSCT was safe but on the short term associated with a risk of cytomegalovirus (CMV) and Epstein-Barr virus reactivation, CMV disease, haemorrhagic cystitis and pancreatitis.

    CONCLUSIONS: Our results though hampered by the limited number of patients and the lack of a control group suggest AHSCT to be efficacious in therapy-refractory CIDP, with a manageable complication profile. Confirmation of these results is necessary through randomised controlled trials.

  • 319. Press, Rayomand
    et al.
    Askmark, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Andersen, Oluf
    Inflammatoriska polyneuropatier kan behandlas framgångsrikt2012In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 109, no 19, p. 950-954Article in journal (Refereed)
  • 320. Pålhagen, S E
    et al.
    Dizdar, N
    Hauge, T
    Holmberg, B
    Jansson, R
    Linder, J
    Nyholm, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Sydow, O
    Wainwright, M
    Widner, H
    Johansson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Interim analysis of long-term intraduodenal levodopa infusion in advanced Parkinson disease2012In: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 126, no 6, p. e29-e33Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: This interim 12-month analysis is a part of an open-label, observational, prospective study on health outcomes and cost impact of levodopa/carbidopa intestinal gel (LCIG, Duodopa) in Parkinson disease (PD). The specific aim was to investigate clinical and health-related quality of life (HRQoL) effects in routine care.

    METHODS: Unified PD rating scale (UPDRS) was the primary efficacy measurement. PD QoL questionnaire 39 (PDQ-39) assessed HRQoL. Subjects were assessed at baseline, ≥3 months after surgery, and then every 3 months.

    RESULTS: Twenty-seven treatment-naïve subjects when started with LCIG showed a decrease in UPDRS score that was statistically significant throughout the year: UPDRS total score (mean ± SD), baseline = 52.1 ± 16.1, N = 27, month 0 (first visit; at least 3 months after permanent LCIG) = 43.1 ± 16.7, N = 27, P = 0.003; month 12 = 42.5 ± 22.6, n = 25, P = 0.017. PDQ-39 results also showed a tendency for improvement: PDQ-39 (mean ± SD), baseline = 33.6 ± 10.8, N = 27, month 0 = 27.1 ± 11.8, N = 27, P = 0.001; 12 months = 28.8 ± 12.8, n = 23, P = 0.126.

    CONCLUSIONS: LCIG provides functional improvement beginning at first visit that is sustained for 12 months.

  • 321.
    Pålhagen, Sven E.
    et al.
    Karolinska Univ Hosp, Dept Neurol, SE-14186 Stockholm, Sweden.
    Sydow, Olof
    Karolinska Univ Hosp, Dept Neurol, SE-14186 Stockholm, Sweden.
    Johansson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Nyholm, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Holmberg, Björn
    Sahlgrens Univ Hosp, Dept Clin Neurosci, Gothenburg, Sweden.
    Widner, Håkan
    Skane Univ Hosp, Dept Neurol, Lund, Sweden.
    Dizdar, Nil
    Linkoping Univ, Dept Neurol, Linkoping, Sweden; Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden.
    Linder, Jan
    Norrlands Univ Hosp, Neuroctr, Dept Neurol, Umea, Sweden.
    Hauge, Tove
    Molde Hosp HNR, Dept Neurol, Molde, Norway.
    Jansson, Rasmus
    Sundsvall Hosp, Dept Geriatr Med & Rehabil, Sundsvall, Sweden.
    Bergmann, Lars
    AbbVie Inc, N Chicago, IL USA.
    Kjellander, Susanna
    AbbVie AB, Solna, Sweden.
    Marshall, Thomas S.
    AbbVie Inc, N Chicago, IL USA.
    Levodopa-carbidopa intestinal gel (LCIG) treatment in routine care of patients with advanced Parkinson's disease: An open-label prospective observational study of effectiveness, tolerability and healthcare costs2016In: Parkinsonism & Related Disorders, ISSN 1353-8020, E-ISSN 1873-5126, Vol. 29, p. 17-23Article in journal (Refereed)
    Abstract [en]

    Background: Continuous infusion of levodopa-carbidopa intestinal gel (LCIG) can effectively manage motor and non-motor complications in advanced Parkinson's disease (PD). Healthcare costs, quality of life (QoL), effectiveness, and tolerability were assessed in routine care treatment with LCIG. Methods: The seventy-seven patients enrolled in this prospective, open-label, 3-year study in routine medical care were LCIG-naive (N = 37), or had previous LCIG treatment for <2 (N = 22), or >= 2 (N = 18) years. Healthcare costs were collected monthly. PD symptoms and QoL were assessed with the Unified Parkinson's Disease Rating Scale (UPDRS), 39-item Parkinson's Disease Questionnaire (PDQ-39), and EuroQoL 5-Dimension Visual Analog Scale (EQ-5D VAS); LCIG dose, safety, and tolerability were monitored. Results: Mean monthly costs per patient ( 8226 5952) were similar across cohorts, remained steady during 3-year follow-up, and increased with PD severity and QoL impairment. In LCIG-naive patients, significant improvements compared to baseline were observed on the UPDRS total score and PDQ-39 summary index score through 18 months (n = 24; UPDRS, p = 0.033; PDQ-39, p = 0.049). Symptom control was maintained during 3-year follow-up in LCIG-experienced cohorts. Small changes in mean daily LCIG dose were observed. Adverse events were common and generally related to the device, procedure, levodopa, or laboratory evaluations. Conclusions: Costs in LCIG-treated patients were stable over 3 years. LCIG treatment led to significant improvements in motor function and QoL over 18 months in LCIG-naive patients and no worsening was observed in LCIG-experienced patients over 3 years despite natural PD progression over time. The longterm safety was consistent with the established LCIG profile.

  • 322.
    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.

  • 323.
    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.

  • 324.
    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.

  • 325.
    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.

  • 326. Rahne, Karl-Erik
    et al.
    Tagesson, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Nyholm, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Motor fluctuations and Helicobacter pylori in Parkinson's disease2013In: Journal of Neurology, ISSN 0340-5354, E-ISSN 1432-1459, Vol. 260, no 12, p. 2974-2980Article in journal (Refereed)
    Abstract [en]

    The presence of Helicobacter pylori(HP) in the gastrointestinal tract may limit the absorption of levodopa.The objectives of this study were to investigate whether HPinfection may affect the clinical response to levodopa aswell as levodopa dose requirement in patients with Par-kinson’s disease (PD) as well as to investigate whether HPinfection may affect plasma levels of vitamin B12, folicacid, and homocysteine. Seventy-five patients with PDdiagnosed at least 4 years ago were included. Symptomfluctuations were assessed by UPDRS-IV and the WOQ9wearing-off-scale. Plasma levels of vitamin B12, folic acid,and homocysteine were analyzed. Screening for HP wasperformed with a 13C-labeled urea breath test (DiabactUBT). A propensity-matched analysis was made where each patient in the HP-infected group was matched withone patient in the non-infected group with respect to age and gender. Of the 75 included patients, 20 were HPinfected (27 %). Median Hoehn & Yahr scores were 3 inboth HP infected patients and the matched group (n=20).HP-infected patients had decreased ‘‘complications of therapy’’ with average total UPDRS-IV score of 4.8±3.0vs. 7.7±3.8 (p\0.05), despite no significant differencein levodopa equivalent dose. Wearing-off and sleep disturbance were significantly less common in the HP group(p\0.05). There were no differences regarding vitaminB12, folic acid, or homocysteine values. HP infection in patients with PD may result in a decreased occurrence of symptom fluctuations according to this small study. This finding may be due to altered absorption of levodopa in the gastrointestinal tract in patients with HP infection, but further studies are required

  • 327.
    Raininko, Raili
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Mattsson, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Metabolite concentrations in supraventricular white matter from teenage to early old age: A short echo time 1H magnetic resonance spectroscopy (MRS) study2010In: Acta Radiologica, ISSN 0284-1851, E-ISSN 1600-0455, Vol. 51, no 3, p. 309-315Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Age- and sex-related changes of metabolites in healthy adult brains have been examined with different (1)H magnetic resonance spectroscopy (MRS) methods in varying populations, and with differing results. A long repetition time and short echo time technique reduces quantification errors due to T(1) and T(2) relaxation effects and makes it possible to measure metabolites with short T(2) relaxation times. PURPOSE: To examine the effect of age on the metabolite concentrations measured by (1)H MRS in normal supraventricular white matter using a long repetition time (TR) and a short echo time (TE). MATERIAL AND METHODS: Supraventricular white matter of 57 healthy subjects (25 women, 32 men), aged 13 to 72 years, was examined with a single-voxel MRS at 1.5T using a TR of 6000 ms and a TE of 22 ms. Tissue water was used as a reference in quantification. Results: Myoinositol increased slightly and total N-acetyl aspartate (NAA) decreased slightly with increasing age. Glutamine/glutamate complex (Glx) showed U-shaped age dependence, with highest concentrations in the youngest and oldest subjects. No significant age dependence was found in total choline and total creatine. No gender differences were found. Macromolecule/ lipid (ML) fractions were reliably measurable only in 36/57 or even fewer subjects and showed very large deviations. CONCLUSION: The concentrations of several metabolites in cerebral supraventricular white matter are age dependent on (1)H MRS, even in young and middle-aged people, and age dependency can be nonlinear. Each (1)H MRS study of the brain should therefore take age into account, whereas sex does not appear to be so important. The use of macromolecule and lipid evaluations is compromised by less successful quantification and large variations in healthy people.

  • 328.
    Raininko, Raili
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Melberg, Atle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Radiological aspects of genetic disorders with adult-onset CNS symptoms2011In: The Neuroradiology Journal, ISSN 1971-4009, Vol. 1, p. 24-37Article in journal (Refereed)
  • 329. 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.

  • 330.
    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)
  • 331.
    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.

  • 332.
    Ribom, D
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience, Neurology.
    Andrae, J
    Frielingsdorf, M
    Hartman, M
    Nister, M
    Smits, A
    Prognostic value of platelet derived growth factor alpha receptor expression in grade 2 astrocytomas and oligoastrocytomas2002In: J Neurol Neurosurg Psychiatry, Vol. 72, no 6, p. 782-87Article in journal (Refereed)
  • 333.
    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.

  • 334.
    Ribom, D
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience, Neurology.
    Engler, E
    Smits, A
    Potential significance of (11)C-methionine PET as a marker for the radiosensitivity of low-grade gliomas2002In: Eur J Nucl Med, Vol. 29, no 5, p. 632-40Article in journal (Refereed)
  • 335.
    Ribom, D
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience, Neurology.
    Eriksson, A
    Hartman, M
    Engler, H
    Nilsson, A
    Långström, B
    Bolander, H
    Bergström, M
    Smits, A
    Positron emission tomography (11)C-methionine and survival in patients with low-grade gliomas2001In: Cancer, Vol. 92, no 6, p. 1541-9Article in journal (Refereed)
  • 336.
    Ribom, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    In Search of Prognostic Factors in Grade 2 Gliomas2002Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Grade 2 gliomas are malignant brain tumours affecting otherwise healthy adults. Although the long-term prognosis is poor, many patients are well and may have a high quality of life for several years. There is, however, a large variability in the natural course of the disease which makes it essential to identify patients who might benefit from early surgery or radio-therapy. The aim of the present thesis was to define new and clinically useful prognostic markers that may assist in the initial treatment decision and in patient follow-up.

    A retrospective study of 189 patients with gliomas WHO grade 2 showed no advantage in survival of early tumour resection or radiotherapy, and confirmed that histological subtype and patient age are the most important predictors of survival (I). In 89 patients, the pre-treatment uptake of 11C-methionine (MET) measured with positron emission tomography (PET) was identified as a prognostic marker for survival (II). At the time of tumour progression, irradiated tumours demonstrated signs of a residual radiotherapeutic effect that correlated with the pre-treatment uptake of MET (III). Pre-treatment uptake of MET may, therefore, be important both in predicting the natural course of the disease and the response after treatment. Immunohistochemical staining of 40 tumour samples showed an inverse association between the number of tumour cells expressing platelet-derived growth factor alpha receptor (PDGFRa) and survival (IV). Also, a reduction was observed in the number of receptor-positive cells after malignant transformation, supporting the prognostic value of PDGFRa.

    Lumbar puncture was performed in eight patients with newly diagnosed low-grade gliomas to identify three important growth factors in tumour development. Neither PDGF nor vascular endothelial growth factor (VEGF) were detected in the cerebrospinal fluid (CSF), and fibroblast growth factor 2 (FGF-2) was measurable at extremely low concentrations in two of the patients (V). A proteome screening of the CSF, using two-dimensional gel electrophoresis and mass spectrometry, detected alpha 2-HS glycoprotein at significantly higher concentrations than in a control group (VI). This glycoprotein emerges as a novel substance in glioma research and may be of great interest because of its suggested involvement in the embryonic development of the neocortex.

    List of papers
    1. On the issue of early and aggressive treatment in grade 2 gliomas
    Open this publication in new window or tab >>On the issue of early and aggressive treatment in grade 2 gliomas
    Show others...
    2003 (English)In: Journal of Cancer Research and Clinical Oncology, ISSN 0171-5216, E-ISSN 1432-1335, Vol. 129, no 3, p. 154-160Article in journal (Refereed) Published
    Abstract [en]

    Purpose

    To study the effects of surgery and timing of radiotherapy on patient survival in grade 2 gliomas.

    Methods

    One hundred and eighty-nine patients with diffuse astrocytomas, oligoastrocytomas, and oligodendrogliomas, World Health Organization grade 2, treated between 1982 and 2000 were identified. The impact of treatment given and clinical parameters were studied in univariate- and multivariate survival analyses.

    Results

    Median survival for the whole patient sample was 6.4 years and the 5-year survival rate was 60%. Macroscopic total resection was beneficial in the univariate analysis (P=0.03) but not when adjusting for confounders. Early subtotal resection did not prolong survival. Early radiotherapy was associated with a shorter survival time compared to delayed or no irradiation (P=0.004). However, this difference was mainly due to an unequal distribution of prognostic factors and was not significant in the multivariate analysis. The most important predictors for long survival time were young age (P<0.001), oligodendroglioma histology (P<0.001), and small tumour size (P=0.02).

    Conclusions

    Early conventional treatment with surgery and radiotherapy had no positive effect on patient survival. This opens up the possibility of trying and evaluating other first-line treatment regimens in this disease.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-90046 (URN)10.1007/s00432-003-0423-0 (DOI)12712330 (PubMedID)
    Available from: 2002-10-25 Created: 2002-10-25 Last updated: 2017-12-14Bibliographically approved
    2. Positron emission tomography (11)C-methionine and survival in patients with low-grade gliomas
    Open this publication in new window or tab >>Positron emission tomography (11)C-methionine and survival in patients with low-grade gliomas
    Show others...
    2001 In: Cancer, Vol. 92, no 6, p. 1541-9Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-90047 (URN)
    Available from: 2002-10-25 Created: 2002-10-25Bibliographically approved
    3. Potential significance of (11)C-methionine PET as a marker for the radiosensitivity of low-grade gliomas
    Open this publication in new window or tab >>Potential significance of (11)C-methionine PET as a marker for the radiosensitivity of low-grade gliomas
    2002 In: Eur J Nucl Med, Vol. 29, no 5, p. 632-40Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-90048 (URN)
    Available from: 2002-10-25 Created: 2002-10-25Bibliographically approved
    4. Prognostic value of platelet derived growth factor alpha receptor expression in grade 2 astrocytomas and oligoastrocytomas
    Open this publication in new window or tab >>Prognostic value of platelet derived growth factor alpha receptor expression in grade 2 astrocytomas and oligoastrocytomas
    Show others...
    2002 In: J Neurol Neurosurg Psychiatry, Vol. 72, no 6, p. 782-87Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-90049 (URN)
    Available from: 2002-10-25 Created: 2002-10-25Bibliographically approved
    5. Growth factor analysis of low-grade glioma CSF: PDGF and VEGF are not detectable
    Open this publication in new window or tab >>Growth factor analysis of low-grade glioma CSF: PDGF and VEGF are not detectable
    2003 (English)In: Neurological Sciences, ISSN 1590-1874, E-ISSN 1590-3478, Vol. 24, no 2, p. 70-73Article in journal (Refereed) Published
    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.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-64954 (URN)12827542 (PubMedID)
    Available from: 2007-04-25 Created: 2007-04-25 Last updated: 2017-11-30Bibliographically approved
    6. Elevated levels of alpha-2-Heremans-Schmid glycoprotein in CSF of patients with low-grade gliomas
    Open this publication in new window or tab >>Elevated levels of alpha-2-Heremans-Schmid glycoprotein in CSF of patients with low-grade gliomas
    2003 (English)In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 24, no 2, p. 94-99Article in journal (Refereed) Published
    Abstract [en]

    Little is known about the expression of mitogens and other tumour-related substances in the cerebrospinal fluid (CSF) of glioma patients. The aim of the current study was to determine the presence of aberrant proteins in the CSF of patients with low-grade gliomas. Lumbar puncture was performed in 8 adult patients with supratentorial low-grade gliomas at the time of diagnosis and in 7 controls. Two-dimensional gel electrophoresis and matrix-assisted laser desorption/ionisation time of flight mass spectrometry were used to detect and quantify deviant proteins in the CSF. Two isoforms of alpha(2)-Heremans-Schmid glycoprotein (AHSG) were identified and demonstrated in higher levels in patients with low-grade gliomas compared with the control group consisting of patients with mixed neurological diagnoses (p = 0.001 and p = 0.04, respectively). In 1 patient, the level of AHSG was significantly reduced after gross total resection of the tumour. AHSG appears in the present proteome screening as a novel substance in glioma research. This glycoprotein is expressed in the fetal human brain and is believed to be involved in the embryonic development of the neocortex. Further analyses are planned to determine the significance of the increased levels of AHSG in the CSF of patients with low-grade gliomas.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-90051 (URN)10.1159/000071082 (DOI)12853704 (PubMedID)
    Available from: 2002-10-25 Created: 2002-10-25 Last updated: 2017-12-14Bibliographically approved
  • 337.
    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.

  • 338.
    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.

  • 339.
    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.

  • 340.
    Ribom, Dan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Smits, Anja
    Hartman, Magdalena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Persson, Lennart
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Blomquist, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    On the issue of early and aggressive treatment in grade 2 gliomas2003In: Journal of Cancer Research and Clinical Oncology, ISSN 0171-5216, E-ISSN 1432-1335, Vol. 129, no 3, p. 154-160Article in journal (Refereed)
    Abstract [en]

    Purpose

    To study the effects of surgery and timing of radiotherapy on patient survival in grade 2 gliomas.

    Methods

    One hundred and eighty-nine patients with diffuse astrocytomas, oligoastrocytomas, and oligodendrogliomas, World Health Organization grade 2, treated between 1982 and 2000 were identified. The impact of treatment given and clinical parameters were studied in univariate- and multivariate survival analyses.

    Results

    Median survival for the whole patient sample was 6.4 years and the 5-year survival rate was 60%. Macroscopic total resection was beneficial in the univariate analysis (P=0.03) but not when adjusting for confounders. Early subtotal resection did not prolong survival. Early radiotherapy was associated with a shorter survival time compared to delayed or no irradiation (P=0.004). However, this difference was mainly due to an unequal distribution of prognostic factors and was not significant in the multivariate analysis. The most important predictors for long survival time were young age (P<0.001), oligodendroglioma histology (P<0.001), and small tumour size (P=0.02).

    Conclusions

    Early conventional treatment with surgery and radiotherapy had no positive effect on patient survival. This opens up the possibility of trying and evaluating other first-line treatment regimens in this disease.

  • 341.
    Ribom, Dan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Westman-Brinkmalm, Ann
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Davidsson, Pia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Elevated levels of alpha-2-Heremans-Schmid glycoprotein in CSF of patients with low-grade gliomas2003In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 24, no 2, p. 94-99Article in journal (Refereed)
    Abstract [en]

    Little is known about the expression of mitogens and other tumour-related substances in the cerebrospinal fluid (CSF) of glioma patients. The aim of the current study was to determine the presence of aberrant proteins in the CSF of patients with low-grade gliomas. Lumbar puncture was performed in 8 adult patients with supratentorial low-grade gliomas at the time of diagnosis and in 7 controls. Two-dimensional gel electrophoresis and matrix-assisted laser desorption/ionisation time of flight mass spectrometry were used to detect and quantify deviant proteins in the CSF. Two isoforms of alpha(2)-Heremans-Schmid glycoprotein (AHSG) were identified and demonstrated in higher levels in patients with low-grade gliomas compared with the control group consisting of patients with mixed neurological diagnoses (p = 0.001 and p = 0.04, respectively). In 1 patient, the level of AHSG was significantly reduced after gross total resection of the tumour. AHSG appears in the present proteome screening as a novel substance in glioma research. This glycoprotein is expressed in the fetal human brain and is believed to be involved in the embryonic development of the neocortex. Further analyses are planned to determine the significance of the increased levels of AHSG in the CSF of patients with low-grade gliomas.

  • 342. Rofes, Adrià
    et al.
    Mandonnet, Emmanuel
    Godden, John
    Baron, Marie Hélène
    Colle, Henry
    Darlix, Amelie
    de Aguiar, Vânia
    Duffau, Hugues
    Herbet, Guillaume
    Klein, Martin
    Lubrano, Vincent
    Martino, Juan
    Mathew, Ryan
    Miceli, Gabriele
    Moritz-Gasser, Sylvie
    Pallud, Johan
    Papagno, Costanza
    Rech, Fabien
    Robert, Erik
    Rutten, Geert-Jan
    Santarius, Thomas
    Satoer, Djaina
    Sierpowska, Joanna
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Skrap, Miran
    Spena, Giannantonio
    Visch, Evy
    De Witte, Elke
    Zetterling, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Wager, Michel
    Survey on current cognitive practices within the European Low-Grade Glioma Network: towards a European assessment protocol.2017In: Acta Neurochirurgica, ISSN 0001-6268, E-ISSN 0942-0940, Vol. 159, no 7, p. 1167-1178Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The European Low-Grade Glioma network indicated a need to better understand common practices regarding the managing of diffuse low-grade gliomas. This area has experienced great advances in recent years.

    METHOD: A general survey on the managing of diffuse low-grade gliomas was answered by 21 centres in 11 European countries. Here we focused on specific questions regarding perioperative and intraoperative cognitive assessments.

    RESULTS: More centres referred to the same speech and language therapist and/or neuropsychologist across all assessments; a core of assessment tools was routinely used across centres; fluency tasks were commonly used in the perioperative stages, and object naming during surgery; tasks that tapped on attention, executive functions, visuospatial awareness, calculation and emotions were sparsely administered; preoperative assessments were performed 1 month or 1 week before surgery; timing for postoperative assessments varied; finally, more centres recommended early rehabilitation, whenever needed.

    CONCLUSIONS: There is an emerging trend towards following similar practices for the management of low-grade gliomas in Europe. Our results are descriptive and formalise current discussions in our group. Also, they contribute towards the development of a European assessment protocol.

  • 343. Rohlin, Anna
    et al.
    Wernersson, Josephine
    Engwall, Yvonne
    Wiklund, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Bjoerk, Jan
    Nordling, Margareta
    Parallel Sequencing Used in Detection of Mosaic Mutations: Comparison With Four Diagnostic DNA Screening Techniques2009In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 30, no 6, p. 1012-1020Article in journal (Refereed)
    Abstract [en]

    We have made an evaluation of mutation detection techniques for their abilities to detect mosaic mutations. In this study, Sanger sequencing, single-strand conformation polymorphism (SSCP)/heteroduplex analysis (HD), protein truncation test (PTT), and denaturating high-performance liquid chromatography (DHPLC) were compared with parallel sequencing. In total DNA samples from nine patients were included in this study. Mosaic mutations were artificially constructed from seven of these samples, which were from heterozygote mutation carriers with the mutant allele present at 50%. The mutations analyzed were as follows: c.646C>T, c.2626C>T, c.2828C>A, c.1817_1818insA, c.2788dupA, c.416_419delAAGA, and c.607delC in the APC gene. The lowest degree of mutant alleles detected with SSCP/HD and DHPLC varied between 5% and 25%, and between 15% and 50% for Sanger sequencing. Three of the mutations were analyzed with PTT with considerable variations in detection levels (from 10 to 100%). Using parallel sequencing a detection frequency down to 1% was reached, but to achieve this high sensitivity sufficient coverage was required. Two patients with natural mosaic mutations were also included in this study. These two mutations had previously been identified with Sanger sequencing (NF2 c.1026_1027delGA) and SSCP/HD (APC c.2700_2701delTC). In conclusion, all the evaluated methods are applicable for mosaic mutation screening even though combinations of the conventional methods should be used to reach an adequate sensitivity. Sanger sequencing alone is not sensitive enough to detect low mosaic levels. Parallel sequencing seems to be the ultimate choice but the possibilities to use this technique is today limited by its complexity, economics, and availability of instruments. Hum Mutat 30, 1012-1020, 2009.

  • 344.
    Ronne-Engström, Elisabeth
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Enblad, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Lundström, E
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Outcome After Spontaneous Subarachnoid Hemorrhage Measured With the EQ-5D2011In: Stroke, ISSN 0039-2499, E-ISSN 1524-4628, Vol. 42, no 11, p. 3284-3286Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND PURPOSE: The EQ-5D measures quality of life based on self-reported health status in 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. In this study, the EQ-5D was evaluated as an outcome measure for patients with subarachnoid hemorrhage.

    METHODS: The EQ-5D was completed in 710 patients 9 months after subarachnoid hemorrhage. Relevant demographic and clinical factors were evaluated as predictors of the 5 outcome dimensions in a series of linear regression models.

    RESULTS: Worse health status in mobility, self-care, and usual activities was predicted by increasing age and by a more severe disease as indicated by the presence of an aneurysm, worse clinical condition at admission, or more blood on the CT scan. Younger age and female gender predicted worse health status regarding anxiety/depression. '

    CONCLUSIONS: The evaluation of the EQ-5D reveals age-related differences in the nature of the challenges faced by these patients.

  • 345.
    Ronne-Engström, Elisabeth
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Enblad, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Lundström, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Health-related quality of life at median 12 months after aneurysmal subarachnoid hemorrhage, measured with EuroQoL-5D2013In: Acta Neurochirurgica, ISSN 0001-6268, E-ISSN 0942-0940, Vol. 155, no 4, p. 587-593Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    A measurement of quality of life (QoL) should cover the important aspects of daily life and be easy to perform. Ease of performance is especially important for patients with spontaneous subarachnoid haemorrhage (SAH), since fatigue and cognitive disabilities are known sequeles. EuroQoL (EQ-5D) is a preference-based instrument measuring QoL, based on self-reported health status in five dimensions: Mobility, Self-Care, Usual Activities, Pain/Discomfort and Anxiety/Depression. In the present study EuroQoL was used in patients with aneurysmal SAH (aSAH) in comparison with a Swedish reference population. We also determined the extent to which demographic characteristics and clinical parameters predicted outcome.

    METHODS:

    Seven hundred fifty-five patients with aSAH were studied after a median 12 months. The proportion of patients in the best QoL category for each dimension was compared with the corresponding proportion in an age matched reference population. Disease severity was measured using the World Federation of Neurosurgical Societies' SAH grading system and the Fisher scale. The extent to which demographic and clinical factors predicted outcome was evaluated using linear regression.

    RESULTS:

    Aneurysmal SAH patients generally had a worse QoL compared with the reference population, in all five dimensions of EQ-5D. In the patient population, disease severity predicted worse outcome in all five dimensions. Female gender and surgery as treatment method (in the case of anterior aneurysms) predicted worse outcome in Usual Activities and Anxiety/Depression.

    CONCLUSION:

    The nature of the sequeles after SAH depends on severity of disease, gender and treatment method. These factors should be more emphasised in planning rehabilitation.

  • 346.
    Roodakker, Kenney R.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Elsir, Tamador
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology. Karolinska Inst, Karolinska Univ Hosp, Dept Oncol Pathol, Canc Ctr Karolinska R8 05, Stockholm, Sweden.
    Edqvist, Per-Henrik D
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hägerstrand, Daniel
    Karolinska Inst, Karolinska Univ Hosp, Dept Oncol Pathol, Canc Ctr Karolinska R8 05, Stockholm, Sweden.
    Carlson, Joseph
    Karolinska Inst, Karolinska Univ Hosp, Dept Oncol Pathol, Canc Ctr Karolinska R8 05, Stockholm, Sweden.
    Lysiak, Malgorzata
    Linkoping Univ, Dept Cell Biol, Linkoping, Sweden.
    Henriksson, Roger
    Umea Univ, Dept Radiat Sci & Oncol, Umea, Sweden.; Reg Canc Ctr, Stockholm, Sweden.
    Pontén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rosell, Johan
    Linkoping Univ, Reg Canc Ctr South East Sweden, Linkoping, Sweden.; Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden.
    Söderkvist, Peter
    Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden.; Linkoping Univ, Dept Adv Home Care, Linkoping, Sweden.
    Stupp, Roger
    Univ Zurich Hosp, Dept Oncol, Zurich, Switzerland.
    Tchougounova, Elena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Nistér, Monica
    Karolinska Inst, Karolinska Univ Hosp, Dept Oncol Pathol, Canc Ctr Karolinska R8 05, Stockholm, Sweden.
    Malmström, Annika
    Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden.; Linkoping Univ, Dept Adv Home Care, Linkoping, Sweden.
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology. Univ Gothenburg, Sahlgrenska Acad, Dept Clin Neurosci & Rehabil, Inst Neurosci & Physiol, Gothenburg, Sweden.
    PROX1 is a novel pathway-specific prognostic biomarker for high-grade astrocytomas; results from independent glioblastoma cohorts stratified by age and IDH mutation status.2016In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 45, p. 72431-72442Article in journal (Refereed)
    Abstract [en]

    PROX1 is a transcription factor with an essential role in embryonic development and determination of cell fate. In addition, PROX1 has been ascribed suppressive as well as oncogenic roles in several human cancers, including brain tumors. In this study we explored the correlation between PROX1 expression and patient survival in high-grade astrocytomas. For this purpose, we analyzed protein expression in tissue microarrays of tumor samples stratified by patient age and IDH mutation status. We initially screened 86 unselected high-grade astrocytomas, followed by 174 IDH1-R132H1 immunonegative glioblastomas derived from patients aged 60 years and older enrolled in the Nordic phase III trial of elderly patients with newly diagnosed glioblastoma. Representing the younger population of glioblastomas, we studied 80 IDH-wildtype glioblastomas from patients aged 18-60 years. There was no correlation between PROX1 protein and survival for patients with primary glioblastomas included in these cohorts. In contrast, high expression of PROX1 protein predicted shorter survival in the group of patients with IDH-mutant anaplastic astrocytomas and secondary glioblastomas. The prognostic impact of PROX1 in IDH-mutant 1p19q non-codeleted high-grade astrocytomas, as well as the negative findings in primary glioblastomas, was corroborated by gene expression data extracted from the Cancer Genome Atlas. We conclude that PROX1 is a new prognostic biomarker for 1p19q non-codeleted high-grade astrocytomas that have progressed from pre-existing low-grade tumors and harbor IDH mutations.

  • 347.
    Roodakker, Kenney Roy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Towards new tools for clinical evaluation and visualization of tumor growth in patients with glioma2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Gliomas are derived from glial cells and are the most common type of primary brain tumors in adults. Gliomas are classified by the World Health Organization (WHO) according to their malignancy grade and histological and molecular features. Malignancy grades range from I to IV. WHO grade I tumors are benign tumors, mostly occurring in childhood. High-grade gliomas (WHO grades III and IV) are undifferentiated and fast-growing tumors, with glioblastoma being the most common and malignant form. Patients with glioblastomas have a median survival of only 15 months. Clinical outcomes vary, however, and markers are needed to assist in the decision-making process and management of these patients. PROX1 is a transcription factor critical for embryonic development, with a role in cell cycle control and progenitor cell differentiation. Apart from its role in normal central nervous system development, PROX1 has been ascribed both tumor suppressive and oncogenic roles in several human cancers. The role of PROX1 as a prognostic factor for survival in patients with glioblastomas was the focus of paper I.

    Gliomas WHO grade II, also called diffuse low-grade gliomas (DLGGs), are well-differentiated tumors that occur mainly in adult life, with a peak incidence at around 30–35 years of age and a median survival of 5–10 years. DLGGs grow continuously at a rate of a few mm per year and have a strong tendency to infiltrate the white matter tracts surrounding the tumor. Eventually these tumors transform into high-grade gliomas, but, as is the case with glioblastomas, there is a large variety of clinical outcomes. For radiological diagnosis, magnetic resonance imaging (MRI) is routinely used, often in combination with advanced MRI. Positron emission tomography with amino acid tracers provides additional diagnostic accuracy. From a histological as well as imaging point of view, DLGGs are heterogeneous tumors. The heterogeneity of DLGGs, in particular the correlation between radiological and histological tumor features, was the focus of paper II & paper III.

    Seizures are amongst the most common presenting symptoms of patients with gliomas. Seizure semiology in patients with brain tumors and other structural brain lesions is closely related to the anatomical location of the lesion and the involvement of functional networks. A possible dynamic interplay between the anatomical region of seizure onset and connected target areas within the network was the focus of paper IV.

    List of papers
    1. PROX1 is a novel pathway-specific prognostic biomarker for high-grade astrocytomas; results from independent glioblastoma cohorts stratified by age and IDH mutation status.
    Open this publication in new window or tab >>PROX1 is a novel pathway-specific prognostic biomarker for high-grade astrocytomas; results from independent glioblastoma cohorts stratified by age and IDH mutation status.
    Show others...
    2016 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 45, p. 72431-72442Article in journal (Refereed) Published
    Abstract [en]

    PROX1 is a transcription factor with an essential role in embryonic development and determination of cell fate. In addition, PROX1 has been ascribed suppressive as well as oncogenic roles in several human cancers, including brain tumors. In this study we explored the correlation between PROX1 expression and patient survival in high-grade astrocytomas. For this purpose, we analyzed protein expression in tissue microarrays of tumor samples stratified by patient age and IDH mutation status. We initially screened 86 unselected high-grade astrocytomas, followed by 174 IDH1-R132H1 immunonegative glioblastomas derived from patients aged 60 years and older enrolled in the Nordic phase III trial of elderly patients with newly diagnosed glioblastoma. Representing the younger population of glioblastomas, we studied 80 IDH-wildtype glioblastomas from patients aged 18-60 years. There was no correlation between PROX1 protein and survival for patients with primary glioblastomas included in these cohorts. In contrast, high expression of PROX1 protein predicted shorter survival in the group of patients with IDH-mutant anaplastic astrocytomas and secondary glioblastomas. The prognostic impact of PROX1 in IDH-mutant 1p19q non-codeleted high-grade astrocytomas, as well as the negative findings in primary glioblastomas, was corroborated by gene expression data extracted from the Cancer Genome Atlas. We conclude that PROX1 is a new prognostic biomarker for 1p19q non-codeleted high-grade astrocytomas that have progressed from pre-existing low-grade tumors and harbor IDH mutations.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-303717 (URN)10.18632/oncotarget.11957 (DOI)000387452100004 ()27626492 (PubMedID)
    Funder
    The King Gustaf V's Jubilee FoundationSwedish Cancer SocietyThe Karolinska Institutet's Research Foundation
    Available from: 2016-09-22 Created: 2016-09-22 Last updated: 2018-08-08Bibliographically approved
    2. Extension of diffuse low-grade gliomas beyond radiological borders as shown by the coregistration of histopathological and magnetic resonance imaging data
    Open this publication in new window or tab >>Extension of diffuse low-grade gliomas beyond radiological borders as shown by the coregistration of histopathological and magnetic resonance imaging data
    Show others...
    2016 (English)In: Journal of Neurosurgery, ISSN 0022-3085, E-ISSN 1933-0693, Vol. 125, no 5, p. 1155-1166Article in journal (Refereed) Published
    Abstract [en]

    Background: Magnetic resonance imaging tends to underestimate the extent of diffuse low-grade gliomas (DLGGs). With the aim of studying the presence of tumor cells outside the radiological border, the authors developed a method of correlating MRI findings with histological data in patients with suspected DLGGs in whom en bloc resections were performed.

    Methods: Five patients with suspected DLGG suitable for en bloc resection were recruited from an ongoing prospective study. Sections of the entire tumor were immunostained with antibodies against mutated IDH1 protein (IDH1-R132H). Magnetic resonance images were coregistered with corresponding IDH1 images. The growth pattern of tumor cells in white and gray matter was assessed in comparison with signal changes on corresponding MRI slices.

    Results: Neuropathological assessment revealed DLGG in 4 patients and progression to WHO Grade III glioma in 1 patient. The tumor core consisted of a high density of IDH1-R132H–positive tumor cells and was located in both gray and white matter. Tumor cells infiltrated along the peripheral fibers of the white matter tracts. In all cases, tumor cells were found outside the radiological tumor border delineated on T2-FLAIR MRI sequences.

    Conclusions: The authors present a new method for the coregistration of histological and radiological characteristics of en bloc–removed infiltrative brain tumors that discloses tumor invasion at the radiological tumor borders. This technique can be applied to evaluate the sensitivity of alternative imaging methods to detect scattered tumor cells at tumor borders. Accurate methods for detection of infiltrative tumor cells will improve the possibility of performing radical tumor resection. In future studies, the method could also be used for in vivo studies of tumor invasion.

    Keywords
    diffuse low-grade glioma, magnetic resonance imaging, tumor border, tumor cell infiltration, oncology
    National Category
    Neurology
    Identifiers
    urn:nbn:se:uu:diva-281052 (URN)10.3171/2015.10.JNS15583 (DOI)000386106100013 ()26918468 (PubMedID)
    Funder
    Erik, Karin och Gösta Selanders Foundation
    Available from: 2016-03-17 Created: 2016-03-17 Last updated: 2019-01-08Bibliographically approved
    3. Region-by-region analysis of PET, MRI, and histology in en bloc-resected oligodendrogliomas reveals intra-tumoral heterogeneity
    Open this publication in new window or tab >>Region-by-region analysis of PET, MRI, and histology in en bloc-resected oligodendrogliomas reveals intra-tumoral heterogeneity
    Show others...
    2019 (English)In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 46, no 3, p. 569-579Article in journal (Refereed) Published
    National Category
    Radiology, Nuclear Medicine and Medical Imaging
    Research subject
    Computerized Image Processing
    Identifiers
    urn:nbn:se:uu:diva-356591 (URN)10.1007/s00259-018-4107-z (DOI)000457151600005 ()30109401 (PubMedID)
    Funder
    Erik, Karin och Gösta Selanders Foundation
    Available from: 2018-08-14 Created: 2018-08-08 Last updated: 2019-04-06Bibliographically approved
    4. Functional Connectivity Changes of the Brain Related to Ecstatic Seizures
    Open this publication in new window or tab >>Functional Connectivity Changes of the Brain Related to Ecstatic Seizures
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    INTRODUCTION The origin of ecstatic seizures has previously been linked to the temporal lobe and/or the anteriordorsal insula. The aim of this study was to further investigate a possible anatomical–functional network, involving theinsula, possibly behind these seizures. In this article we describe changes in seizure semiology and MRI connectivityprior to and after the surgical removal of a hypothalamic hamartoma, in order to scrutinize the functional connectivitychanges of the brain related to ecstatic seizures. METHODS A clinical/neurological longitudinal follow-up study wasconducted after hamartoma removal in a patient with a history of gelastic and ecstatic seizures prior to surgery. Datafrom MRI investigations performed at three different time points were merged with clinical information on presurgicalsemiology and its development 1-year and 11-years postsurgically. Native MRI sequences were analyzed within theMontreal Neurological Institute (MNI) space to create a region of interest (ROI) of the lesion volume. The white matterarchitecture of an average brain from the Human Connectome Project (HCP) template was used to reconstruct thewhite matter bundles according to the ROI in our MRI investigations. The reconstructed white matter connectivity wasanalyzed using cortical and subcortical areas imported from Freesurfer© atlas and displayed as circle graphs.RESULTS The clinical course of the ecstatic symptoms merged with the connectivity analysis showed three potentialareas of the brain possibly involved in ecstatic seizures: the left superior frontal gyrus, the brainstem and the leftthalamus. The white matter pathways between hypothalamus-thalamus and brainstem were particularly representedwhen the ecstatic phenomena were present, whereas the absence of ecstatic seizures in the postoperative periodseemed to be connected with the predominant involvement of the fronto-thalamic-brainstem network. CONCLUSIONWe suggest that a balance of the networks between the thalamus, the brain stem and the frontal lobe is crucial inorder to experience ecstatic seizures. Our results indicate that the frontal lobe is involved in the inhibitoryeffect/negative reinforce, while the brain stem and a gelastic seizure may elicit a positive trigger/reinforce of theecstatic seizure. Additionally, our findings suggest a possible connection between gelastic and ecstatic seizures. Thisnew information about the possible functional organization supports the notion that it is a network rather than just asingle trigger zone that produces the complex pattern of symptoms seen in patients with ecstatic epileptic seizures.

    Keywords
    Ecstatic seizure – gelastic seizure – epilepsy – human connectome project – white matter – connectogram
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-356839 (URN)
    Available from: 2018-08-08 Created: 2018-08-08 Last updated: 2018-08-08
  • 348.
    Roodakker, Kenney Roy
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Alhuseinalkhudhur, Ali
    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.
    Al-Jaff, Mohammed
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Visual Information and Interaction. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis and Human-Computer Interaction.
    Georganaki, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Zetterling, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Berntsson, Shala G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Danfors, Torsten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Strand, Robin
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Visual Information and Interaction. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis and Human-Computer Interaction.
    Edqvist, Per-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Dimberg, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    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.
    Region-by-region analysis of PET, MRI, and histology in en bloc-resected oligodendrogliomas reveals intra-tumoral heterogeneity2019In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 46, no 3, p. 569-579Article in journal (Refereed)
  • 349.
    Rostedt Punga, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Nygren, Ingela
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Askmark, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Stålberg, Erik V.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Monozygous twins with neuromuscular transmission defects at opposite sides of the motor endplate2009In: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 119, no 3, p. 207-211Article in journal (Refereed)
    Abstract [en]

    Disorders affecting the postsynaptic side of the neuromuscular junction include autoimmune myasthenia gravis (MG) as well as some of the congenital myasthenic syndromes (CMS). Lambert-Eaton myasthenic syndrome (LEMS) is an acquired autoimmune neuromuscular disorder in which autoantibodies are directed against the presynaptic calcium channels. Here we describe two monozygous twin brothers: case 1 was diagnosed with an indeterminate form of acquired postsynaptic neuromuscular junction defect at age 32 and case 2 with LEMS at age 47. Case 1 presented clinically with mild generalized myasthenic weakness, neurophysiological examination revealed disturbed neuromuscular transmission along with probable myositis and serum analysis regarding antibodies against the acetylcholine receptor and muscle-specific tyrosine kinase was negative. Case 2 presented with proximal muscle fatigue accompanied by areflexia at rest and antibodies against the P/Q-type voltage-gated calcium channels were present. Neurophysiologically, case 2 had reduced baseline compound motor action potential amplitudes on neurography, decrement on low-frequency repetitive nerve stimulation (RNS) and pathological increment on high frequency RNS. To our knowledge this is the first case report of its kind and adds an intriguing contrast to the more common diagnosis of CMS in monozygous twins.

     

  • 350.
    Roy, Ananya
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Swedish Univ Agr Sci, Dept Biomed Sci & Vet Publ Hlth, Uppsala, Sweden..
    Attarha, Sanaz
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Weishaupt, Holger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Edqvist, Per-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Swartling, Fredrik J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Bergqvist, Michael
    Umea Univ, Dept Radiat Sci, Umea, Sweden..
    Siebzehnrubl, Florian A.
    Cardiff Univ, Sch Biosci, European Canc Stem Cell Res Inst, Cardiff, S Glam, Wales..
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology. Gothenburg Univ, Sahlgrenska Acad, Dept Clin Neurosci, Inst Neurosci & Physiol, Gothenburg, Sweden..
    Pontén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Tchougounova, Elena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Serglycin as a potential biomarker for glioma: association of serglycin expression, extent of mast cell recruitment and glioblastoma progression2017In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 15, p. 24815-24827Article in journal (Refereed)
    Abstract [en]

    Serglycin is an intracellular proteoglycan with a unique ability to adopt highly divergent structures by glycosylation with variable types of glycosaminoglycans (GAGs) when expressed by different cell types. Serglycin is overexpressed in aggressive cancers suggesting its protumorigenic role. In this study, we explored the expression of serglycin in human glioma and its correlation with survival and immune cell infiltration. We demonstrate that serglycin is expressed in glioma and that increased expression predicts poor survival of patients. Analysis of serglycin expression in a large cohort of low- and high-grade human glioma samples reveals that its expression is grade dependent and is positively correlated with mast cell (MC) infiltration. Moreover, serglycin expression in patient-derived glioma cells is significantly increased upon MC co-culture. This is also accompanied by increased expression of CXCL12, CXCL10, as well as markers of cancer progression, including CD44, ZEB1 and vimentin.In conclusion, these findings indicate the importance of infiltrating MCs in glioma by modulating signaling cascades involving serglycin, CD44 and ZEB1. The present investigation reveals serglycin as a potential prognostic marker for glioma and demonstrates an association with the extent of MC recruitment and glioma progression, uncovering potential future therapeutic opportunities for patients.

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