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  • 1. Bergenheim, A. Tommy
    et al.
    Roslin, Michael
    Ungerstedt, Urban
    Waldenström, Anders
    Henriksson, Roger
    Ronquist, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Metabolic manipulation of glioblastoma in vivo by retrograde microdialysis of L-2, 4 diaminobutyric acid (DAB)2006In: Journal of Neuro-Oncology, ISSN 0167-594X, E-ISSN 1573-7373, Vol. 80, no 3, p. 285-93Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: To study the metabolic effects in vivo of L-2, 4 diaminobutyric acid (DAB) administered by retrograde microdialysis in glioblastoma and to evaluate the feasibility of the technique. METHODS: In 10 patients with glioblastoma, a stereotactic biopsy was performed followed by implantation of microdialysis catheters. One or two catheters were implanted in tumor tissue and two reference catheters were implanted in normal brain tissue and subcutaneous abdominal tissue, respectively. Tumor catheters were perfused with 80 or 120 mmol/l DAB and reference catheters were perfused with a Ringer solution, all with a flow rate of 2.0 microl/min. Treatment was given for at mean 9.1 (5-19) days. RESULTS: The treatment was well tolerated by the patients with the exception of two patients in whom a transient brain edema appeared. No complications related to the technique were encountered. During treatment, an increase in the extracellular amino acids alanine, glycine, glutamate, aspartate, serine, threonine, and taurine was found demonstrating a significant influence on the intracellular pool of free amino acids induced by DAB. No change in glucose metabolism or glycerol was evident. The metabolism in normal brain was unaffected during treatment. CONCLUSIONS: Retrograde microdialysis is a feasible method for intracerebral administration of drugs to tumor tissue in patients with glioblastoma. We found it possible to deliver DAB to glioblastoma tumors in fully mobilized patients and to assess the metabolic effects induced by the treatment. The changes in extracellular amino acids were in concordance to what was expected from in vitro studies. Elevation of glutamate and taurine may be regarded as markers for an induced cellular toxicity while the unchanged level of glycerol may indicate no direct effects on phospholipase activity and membrane phospholipid composition. The effects were restricted to the tumor compartment. Although an improved survival could possibly be suspected no dramatic effect on outcome could be detected. However, the series was small and, most probably, the time for treatment was too short.

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

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

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

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

  • 4. Boman, Krister K
    et al.
    Hörnquist, Lina
    De Graaff, Lisanne
    Rickardsson, Jenny
    Lannering, Birgitta
    Gustafsson, Göran
    Disability, body image and sports/physical activity in adult survivors of childhood CNS tumors: population-based outcomes from a cohort study2013In: Journal of Neuro-Oncology, ISSN 0167-594X, E-ISSN 1573-7373, Vol. 112, no 1, p. 99-106Article in journal (Refereed)
    Abstract [en]

    Childhood CNS tumor survivors risk health and functional impairments that threaten normal psychological development and self-perception. This study investigated the extent to which health and functional ability predict adult survivors' body image (BI) and self-confidence regarding sports and physical activity. The study cohort covered 708 eligible ≥ 18 year old CNS tumor survivors, and data from 528 (75 %) were analyzed. Disability was estimated using the Health Utilities Index™ Mark2/3, a multidimensional self-report instrument. Physical self-confidence in terms of BI and sports/physical activity-related self-confidence (SPAS) were assessed using the BI and the Sports/Athletics modules of a standardized self-report assessment scale. In adjusted regression models, global health and functional status (GHFS) predicted BI (B = 0.94, 95 % CI 0.69-1.19) and SPAS (B = 0.79, 95 % CI 0.55-1.04). Emotion and pain, and to a lesser degree cognition, speech and vision disability, were associated with poorer BI and SPAS. Gender, sub-diagnosis, and time since diagnosis influenced the relationship between health status and physical self-confidence outcomes. Females had poorer GHFS, BI and SPAS than males. Decreased health and functional ability following childhood CNS cancer intrudes on physical self-confidence, with females being at heightened risk for both disability and negative self-confidence. Identified disability and gender-related risk calls for a follow-up plan that integrates treatment of psychological sequelae in lifetime monitoring of childhood CNS tumor survivors to restore and protect self-image and self-confidence, essential mental health correlates. An expanded plan should recognize the need for such services, optimizing life-long quality of survival for CNS tumor survivors.

  • 5.
    Carlsson, Jörgen
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Ren, Z. P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Wester, K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Sundberg, A. L.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Heldin, Nils-Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Hesselager, G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Persson, M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Gedda, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Lundqvist, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Blomquist, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Nistér, M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Planning for intracavitary anti-EGFR radionuclide therapy of gliomas: Literature review and data on EGFR expression2006In: Journal of Neuro-Oncology, ISSN 0167-594X, E-ISSN 1573-7373, Vol. 77, no 1, p. 33-45Article in journal (Refereed)
    Abstract [en]

    Targeting with radionuclide labelled substances that bind specifically to the epidermal growth factor receptor, EGFR, is considered for intracavitary therapy of EGFR-positive glioblastoma multiforme, GBM. Relevant literature is reviewed and examples of EGFR expression in GBM are given. The therapeutical efforts made so far using intracavitary anti-tenascin radionuclide therapy of GBM have given limited effects, probably due to low radiation doses to the migrating glioma cells in the brain. Low radiation doses might be due to limited penetration of the targeting agents or heterogeneity in the expression of the target structure. In this article we focus on the possibilities to target EGFR on the tumour cells instead of an extracellular matrix component. There seems to be a lack of knowledge on the degree of intratumoral variation of EGFR expression in GBM, although the expression seemed rather homogeneous over large areas in most of the examples (n=16) presented from our laboratory. The observed homogeneity was surprising considering the genomic instability and heterogeneity that generally characterises highly malignant tumours. However, overexpression of EGFR is, at least in primary GBMs, one of the steps in the development of malignancy, and tumour cells that lose or downregulate EGFR will probably be outgrown in an expanding tumour cell population. Thus, loss of EGFR expression might not be the critical factor for successful intracavitary radionuclide therapy. Instead, it is likely that the penetration properties of the targeting agents are critical, and detailed studies on this are urgent.

  • 6. Freyschlag, Christian F
    et al.
    Krieg, Sandro M
    Kerschbaumer, Johannes
    Pinggera, Daniel
    Forster, Marie-Therese
    Cordier, Dominik
    Rossi, Marco
    Miceli, Gabriele
    Roux, Alexandre
    Reyes, Andrés
    Sarubbo, Silvio
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Sierpowska, Joanna
    Robe, Pierre A
    Rutten, Geert-Jan
    Santarius, Thomas
    Matys, Tomasz
    Zanello, Marc
    Almairac, Fabien
    Mondot, Lydiane
    Jakola, Asgeir S
    Zetterling, Maria
    Rofes, Adrià
    von Campe, Gord
    Guillevin, Remy
    Bagatto, Daniele
    Lubrano, Vincent
    Rapp, Marion
    Goodden, John
    De Witt Hamer, Philip C
    Pallud, Johan
    Bello, Lorenzo
    Thomé, Claudius
    Duffau, Hugues
    Mandonnet, Emmanuel
    Imaging practice in low-grade gliomas among European specialized centers and proposal for a minimum core of imaging.2018In: Journal of Neuro-Oncology, ISSN 0167-594X, E-ISSN 1573-7373Article in journal (Refereed)
    Abstract [en]

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

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

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

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

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

  • 7.
    Jeibmann, Astrid
    et al.
    Univ Hosp Munster, Inst Neuropathol, D-48129 Munster, Germany..
    Halama, Kathrin
    Univ Hosp Munster, Inst Neuropathol, D-48129 Munster, Germany..
    Witte, Hanna Theresa
    Univ Hosp Munster, Inst Neuropathol, D-48129 Munster, Germany.;Univ Munster, Inst Neurobiol, D-48149 Munster, Germany..
    Kim, Su Na
    Univ Munster, Inst Neurobiol, D-48149 Munster, Germany..
    Eikmeier, Kristin
    Univ Hosp Munster, Inst Neuropathol, D-48129 Munster, Germany..
    Koos, Bjorn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Klambt, Christian
    Univ Munster, Inst Neurobiol, D-48149 Munster, Germany..
    Paulus, Werner
    Univ Hosp Munster, Inst Neuropathol, D-48129 Munster, Germany..
    Involvement of CD9 and PDGFR in migration is evolutionarily conserved from Drosophila glia to human glioma2015In: Journal of Neuro-Oncology, ISSN 0167-594X, E-ISSN 1573-7373, Vol. 124, no 3, p. 373-383Article in journal (Refereed)
    Abstract [en]

    Platelet-derived growth factor receptor (PDGFR) signaling plays an important role in the biology of malignant gliomas. To investigate mechanisms modulating PDGFR signaling in gliomagenesis, we employed a Drosophila glioma model and genetic screen to identify genes interacting with Pvr, the fly homolog of PDGFRs. Glial expression of constitutively activated Pvr (lambda Pvr) led to glial over migration and lethality at late larval stage. Among 3316 dsRNA strains crossed against the tester strain, 128 genes shifted lethality to pupal stage, including tetraspanin 2A (tsp2A). In a second step knockdown of all Drosophila tetraspanins was investigated. Of all tetraspanin dsRNA strains only knockdown of tsp2A partially rescued the Pvr-induced phenotype. Human CD9 (TSPAN29/MRP-1), a close homolog of tsp2A, was found to be expressed in glioma cell lines A172 and U343MG as well as in the majority of glioblastoma samples (16/22, 73 %). Furthermore, in situ proximity ligation assay revealed close association of CD9 with PDGFR alpha and beta. In U343MG cells, knockdown of CD9 blocked PDGF-BB stimulated migration. In conclusion, modulation of PDGFR signaling by CD9 is evolutionarily conserved from Drosophila glia to human glioma and plays a role in glia migration.

  • 8. Järvelä, Sally
    et al.
    Bragge, Helena
    Paunu, Niina
    Järvelä, Timo
    Paljärvi, Leo
    Kalimo, Hannu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Helén, Pauli
    Kinnula, Vuokko
    Soini, Ylermi
    Haapasalo, Hannu
    Antioxidant enzymes in oligodendroglial brain tumors: association with proliferation, apoptotic activity and survival2006In: Journal of Neuro-Oncology, ISSN 0167-594X, E-ISSN 1573-7373, Vol. 77, no 2, p. 131-40Article in journal (Refereed)
    Abstract [en]

    Purpose of the study was to investigate the relationship between antioxidant enzyme expression and clinicopathological features in oligodendroglial tumors. The expression of antioxidant enzymes and related proteins (AOEs), manganese superoxide dismutase (MnSOD), thioredoxin (Trx), thioredoxin reductase (TrxR) and gammaglutamylcysteine synthetase catalytic and regulatory subunits (GLCL-C and GLCL-R), was studied in 85 oligodendroglial tumors. The material included 71 primary (43 grade II and 28 grade III) and 14 recurrent (6 grade II and 8 grade III) tumors. Fifty-seven cases were pure oligodendrogliomas and 28 were mixed oligoastrocytomas. Immunoreactivity for MnSOD was found in 89%, Trx in 29%, TrxR in 76%, GLCL-C in 70% and GLCL-R in 68% of cases. Increased Trx expression was associated with higher tumor grade, cell proliferation and apoptosis (P=0.006, P=0.001 and P=0.003, Mann-Whitney test). Pure oligodendrogliomas showed more intense staining than oligoastrocytomas, especially for MnSOD (P=0.002, Mann-Whitney test). In the total series Trx was associated with poor prognosis in univariate survival analysis (P=0.0343, log-rank test) and furthermore in Cox multivariate analysis (P=0.009) along with age (P=0.002). The results suggest that the expression of Trx has a correlation to patient outcome and that there may be some association between AOEs, like MnSOD and Trx, and clinicopathological features of oligodendrogliomas.

  • 9. Järvelä, Sally
    et al.
    Nordfors, Kristiina
    Jansson, Miia
    Haapasalo, Joonas
    Helén, Pauli
    Paljärvi, Leo
    Kalimo, Hannu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Kinnula, Vuokko
    Soini, Ylermi
    Haapasalo, Hannu
    Decreased expression of antioxidant enzymes is associated with aggressive features in ependymomas2008In: Journal of Neuro-Oncology, ISSN 0167-594X, E-ISSN 1573-7373, Vol. 90, no 3, p. 283-291Article in journal (Refereed)
    Abstract [en]

    The purpose of this study was to investigate the relationship between antioxidant enzyme expression and clinicopathological features in 67 ependymal tumors. We included into the analysis antioxidant enzymes (AOEs) and related proteins, such as, manganese superoxide dismutase (MnSOD), gammaglutamylcysteine synthetase catalytic and regulatory subunits (GLCL-C and GLCL-R), thioredoxin (Trx) and thioredoxin reductase (TrxR). Their expression was studied in 46 primary (10 grade I, 30 grade II and 6 grade III) and 21 recurrent (3 grade I, 12 grade II and 6 grade III) tumors. Immunoreactivity for MnSOD was found in 87%, GLCL-C in 74%, GLCL-R in 89%, Trx in 72%, TrxR in 54%, of primary tumors. Lower GLCL-C and GLCL-R expression was associated with higher tumor grade (P = 0.047 and 0.049, respectively). MnSOD, GLCL-C and TrxR expressions were significantly higher in tumors located in the spinal cord compared to those in the brain (P = 0.044, 0.046 and 0.004, respectively). In the primary tumors Trx-positivity was found to correlate significantly with patient survival. In univariate survival analysis patients whose tumors did not express Trx had shorter survival (P = 0.045) and there was even more significant association (P = 0.011) when only adults were included in the analysis (in the total material median follow-up time of Trx-positive tumors was 9.7 years and of Trx-negative 5.4 years). The results indicate that AOEs have several biological functions in ependymal tumors. Trx had important prognostic value: all adults with Trx-positive tumors were alive at follow-up (median 7.8 years).

  • 10.
    Lobon-Iglesias, M. J.
    et al.
    Gustave Roussy, Dept Pediat & Adolescent Oncol, Villejuif, France.;Univ Paris Saclay, Villejuif, France.;CNRS, Unite Mixte Rech 8203, Team Target Identificat & Innovat Anticanc Therap, Villejuif, France..
    Giraud, Geraldine
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Gustave Roussy, Dept Pediat & Adolescent Oncol, Villejuif, France.;Univ Paris Saclay, Villejuif, France.
    Castel, D.
    Gustave Roussy, Dept Pediat & Adolescent Oncol, Villejuif, France.;Univ Paris Saclay, Villejuif, France.;CNRS, Unite Mixte Rech 8203, Team Target Identificat & Innovat Anticanc Therap, Villejuif, France..
    Philippe, C.
    Univ Paris Saclay, Villejuif, France.;CNRS, Unite Mixte Rech 8203, Team Target Identificat & Innovat Anticanc Therap, Villejuif, France..
    Debily, M. A.
    Univ Paris Saclay, Villejuif, France.;CNRS, Unite Mixte Rech 8203, Team Target Identificat & Innovat Anticanc Therap, Villejuif, France.;Univ Evry Val dEssone, Evry, France..
    Briandet, C.
    Univ Hosp Dijon, Dept Pediat, Dijon, France..
    Fouyssac, F.
    Univ Hosp Nancy Brabois, Dept Pediat Oncol, Nancy, France..
    de Carli, E.
    Univ Hosp Angers, Dept Pediat Oncol, Angers, France..
    Dufour, C.
    Gustave Roussy, Dept Pediat & Adolescent Oncol, Villejuif, France.;Univ Paris Saclay, Villejuif, France.;CNRS, Unite Mixte Rech 8203, Team Target Identificat & Innovat Anticanc Therap, Villejuif, France..
    Valteau-Couanet, D.
    Gustave Roussy, Dept Pediat & Adolescent Oncol, Villejuif, France.;Univ Paris Saclay, Villejuif, France..
    Sainte-Rose, C.
    Necker Sick Childrens Univ Hosp, Dept Neurosurg, Paris, France.;Paris Descartes Univ, Paris, France..
    Blauwblomme, T.
    Necker Sick Childrens Univ Hosp, Dept Neurosurg, Paris, France.;Paris Descartes Univ, Paris, France..
    Beccaria, K.
    Univ Paris Saclay, Villejuif, France.;CNRS, Unite Mixte Rech 8203, Team Target Identificat & Innovat Anticanc Therap, Villejuif, France.;Necker Sick Childrens Univ Hosp, Dept Neurosurg, Paris, France.;Paris Descartes Univ, Paris, France..
    Zerah, M.
    Necker Sick Childrens Univ Hosp, Dept Neurosurg, Paris, France.;Paris Descartes Univ, Paris, France..
    Puget, S.
    Necker Sick Childrens Univ Hosp, Dept Neurosurg, Paris, France.;Paris Descartes Univ, Paris, France..
    Calmon, R.
    Paris Descartes Univ, Paris, France.;Necker Sick Childrens Univ Hosp, Dept Radiol, Paris, France.;Imagine Inst, Paris, France.;INSERM, U1163, Paris, France..
    Boddaert, N.
    Paris Descartes Univ, Paris, France.;Necker Sick Childrens Univ Hosp, Dept Radiol, Paris, France.;Imagine Inst, Paris, France.;INSERM, U1163, Paris, France..
    Bolle, S.
    Gustave Roussy, Dept Radiotherapy, Villejuif, France..
    Varlet, P.
    Paris Descartes Univ, Paris, France.;St Anne Hosp, Dept Neuropathol, Paris, France..
    Grill, J.
    Gustave Roussy, Dept Pediat & Adolescent Oncol, Villejuif, France.;Univ Paris Saclay, Villejuif, France.;CNRS, Unite Mixte Rech 8203, Team Target Identificat & Innovat Anticanc Therap, Villejuif, France..
    Diffuse intrinsic pontine gliomas (DIPG) at recurrence: is there a window to test new therapies in some patients?2018In: Journal of Neuro-Oncology, ISSN 0167-594X, E-ISSN 1573-7373, Vol. 137, no 1, p. 111-118Article in journal (Refereed)
    Abstract [en]

    Children with diffuse intrinsic pontine glioma (DIPG) need new and more efficient treatments. They can be developed at relapse or at diagnosis, but therefore they must be combined with radiotherapy. Survival of children after recurrence and its predictors were studied to inform the possibility to design early phase clinical trials for DIPG at this stage. Among 142 DIPG patients treated between 1998 and 2014, 114 had biopsy-proven DIPG with histone H3 status available for 83. We defined as long survivors' patients who survived more than 3 months after relapse which corresponds to the minimal life expectancy requested for phase I/II trials. Factors influencing post-relapse survival were accordingly compared between short and long-term survivors after relapse. Fifty-seven percent of patients were considered long survivors and 70% of them had a Lansky Play Scale (LPS) above 50% at relapse. Patients who became steroids-independent after initial treatment for at least 2 months had better survival after relapse (3.7 versus 2.6 months, p = 0.001). LPS above 50% at relapse was correlated with better survival after relapse (3.8 versus 1.8 months, p < 0.001). Patients with H3.1 mutation survived longer after relapse (4.9 versus 2.7 months, p = 0.007). Patients who received a second radiotherapy at the time of relapse had an improved survival (7.5 versus 4 months, p = 0.001). In the two-way ANOVA analysis, steroid-independence and LPS predicted survival best and the type of histone H3 (H3.1 or H3.3) mutated did not improve prediction. Survival of many DIPG patients after relapse over 3 months would make possible to propose specific trials for this condition. Steroid-independence, H3 mutation status and LPS should be considered to predict eligibility.

  • 11.
    Nord, Helena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Pfeifer, Susan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Nilsson, Pelle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Sandgren, Johanna
    Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
    Popova, Svetlana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Strömberg, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Nistér, Monica
    Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
    Díaz de Ståhl, Teresita
    Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
    Novel amplifications in pediatric medulloblastoma identified by genome-wide copy number profiling2012In: Journal of Neuro-Oncology, ISSN 0167-594X, E-ISSN 1573-7373, Vol. 107, no 1, p. 37-49Article in journal (Refereed)
    Abstract [en]

    Medulloblastoma (MB) is a WHO grade IV, invasive embryonal CNS tumor that mainly affects children. The aggressiveness and response to therapy can vary considerably between cases, and despite treatment, ~30% of patients die within 2 years from diagnosis. Furthermore, the majority of survivors suffer long-term side-effects due to severe management modalities. Several distinct morphological features have been associated with differences in biological behavior, but improved molecular-based criteria that better reflect the underlying tumor biology are in great demand. In this study, we profiled a series of 25 MB with a 32K BAC array covering 99% of the current assembly of the human genome for the identification of genetic copy number alterations possibly important in MB. Previously known aberrations as well as several novel focally amplified loci could be identified. As expected, the most frequently observed alteration was the combination of 17p loss and 17q gain, which was detected in both high- and standard-risk patients. We also defined minimal overlapping regions of aberrations, including 16 regions of gain and 18 regions of loss in various chromosomes. A few noteworthy narrow amplified loci were identified on autosomes 1 (38.89-41.97 and 84.89-90.76 Mb), 3 (27.64-28.20 and 35.80-43.50 Mb), and 8 (119.66-139.79 Mb), aberrations that were verified with an alternative platform (Illumina 610Q chips). Gene expression levels were also established for these samples using Affymetrix U133Plus2.0 arrays. Several interesting genes encompassed within the amplified regions and presenting with transcript upregulation were identified. These data contribute to the characterization of this malignant childhood brain tumor and confirm its genetic heterogeneity.

  • 12.
    Ribom, Dan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Neurologi.
    Schoenmaekers, Marjoleine
    Engler, Henry
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Neurologi.
    Evaluation of 11C-methionine PET as a surrogate endpoint after treatment of grade 2 gliomas2005In: Journal of Neuro-Oncology, ISSN 0167-594X, E-ISSN 1573-7373, Vol. 71, no 3, p. 325-332Article in journal (Refereed)
    Abstract [en]

    The aim of the present study was to assess the usefulness of positron emission tomography (PET) as a surrogate endpoint by analysing the uptake variability of 11C-methionine (MET) in follow-up scans.

    A total of 96 PET MET scans were re-evaluated in 32 patients with histologically confirmed supratentorial grade 2 gliomas.

    In untreated patients, all follow-up PET scans showed an increased tumour volume after median 68 weeks, but only 46% of cases had an increased hot spot uptake. An improved outcome was observed in patients with stable hot spot uptake per se (P=0.07) and in combinations with minor increase in tumour volume (P=0.02). After conventional therapy, 52% of PET scans showed a reduced hot spot uptake the first year and 43% were reduced after more than a year. Successful MET decline after therapy did not correlate with outcome.

    PET MET may be a promising surrogate endpoint after treatment of grade 2 gliomas. Evaluation of both hot spot activity and uptake volume on PET may strengthen the association with clinical outcome.

  • 13. Sandén, Emma
    et al.
    Dyberg, Cecilia
    Krona, Cecilia
    Childhood Cancer Research Unit, Department of Women´s and Children´s Health, Karolinska Institutet, Stockholm, Sweden.
    Visse, Edward
    Carén, Helena
    Northcott, Paul A
    Kool, Marcel
    Ståhl, Nils
    Persson, Annette
    Englund, Elisabet
    Johnsen, John I
    Siesjö, Peter
    Darabi, Anna
    Aberrant immunostaining pattern of the CD24 glycoprotein in clinical samples and experimental models of pediatric medulloblastomas2015In: Journal of Neuro-Oncology, ISSN 0167-594X, E-ISSN 1573-7373, Vol. 123, no 1, p. 1-13Article in journal (Refereed)
    Abstract [en]

    The CD24 glycoprotein is a mediator of neuronal proliferation, differentiation and immune suppression in the normal CNS, and a proposed cancer biomarker in multiple peripheral tumor types. We performed a comparative analysis of CD24 gene expression in a large cohort of pediatric and adult brain tumors (n = 813), and further characterized protein expression in tissue sections (n = 39), primary brain tumor cultures (n = 12) and a novel orthotopic group 3 medulloblastoma xenograft model. Increased CD24 gene expression was demonstrated in ependymomas, medulloblastomas, anaplastic astrocytomas and glioblastomas, although medulloblastomas displayed higher expression than all other tumor entities. Preferential expression of CD24 in medulloblastomas was confirmed at protein level by immunostaining and computerized image analysis of cryosections. Morphologies and immunophenotyping of CD24(+) cells in tissue sections tentatively suggested disparate functions in different tumor subsets. Notably, protein staining of medulloblastoma cells was associated with prominent cytoplasmic and membranous granules, enabling rapid and robust identification of medulloblastoma cells in clinical tissue samples, as well as in experimental model systems. In conclusion, our results implicate CD24 as a clinically and experimentally useful medulloblastoma immunomarker. Although our results encourage further functional studies of CD24 as a potential molecular target in subsets of brain tumors, the promiscuous expression of CD24 in vivo highlights the importance of specificity in the future design of such targeted treatment.

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