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On the Diagnostics of Neuroblastoma Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 1514 On the Diagnostics of Neuroblastoma Clinical and Experimental Studies KLEOPATRA GEORGANTZI ACTA UNIVERSITATIS UPSALIENSIS ISSN 1651-6206 ISBN 978-91-513-0499-1 UPPSALA urn:nbn:se:uu:diva-364682 2018 Dissertation presented at Uppsala University to be publicly examined in Rosénsalen, Akademiska Barnsjukhuset, ingång 95/96, nbv, Uppsala, Thursday, 20 December 2018 at 13:15 for the degree of Doctor of Philosophy (Faculty of Medicine). The examination will be conducted in Swedish. Faculty examiner: Docent Ingrid Øra (Depertment of Pediatric Oncology, Lunds University). Abstract Georgantzi, K. 2018. On the Diagnostics of Neuroblastoma. Clinical and Experimental Studies. Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 1514. 50 pp. Uppsala: Acta Universitatis Upsaliensis. ISBN 978-91-513-0499-1. Neuroblastoma (NB) is one of the most common childhood cancers. Patients with low stage tumor have high survival rate, while those with advanced stage and/or unfavorable molecular biology have poor prognosis. A correct histopathological diagnosis, clinical stage, and identified genetic aberrations are crucial for treatment stratification according to current protocol. The tumor sample is obtained either by fine needle aspiration, cutting needle biopsy or open biopsy. NB exhibits neuroendocrine differentiation by showing immunoreactivity for chromogranin A (CgA), synaptophysin (syn), and neuron specific enolase (NSE) and 90% of the patients have increased levels of urine catecholamine metabolites. Experimental and clinical NB tumor samples were immunostained for somatostatin receptors (SSTRs) 1-5, somatostatin and CgA. Clinical tumor samples were also immunostained for syn, synaptic vesicle protein 2 (SV2), and vesicle monoamine transporter 1 (VMAT1) and 2 (VMAT 2). Blood samples from 92 patients were analyzed for level of CgA, NSE, and chromogranin B and compared with control groups. The urinary excretion of catecholamine metabolites was analyzed in samples collected at diagnosis. Clinical and laboratory data were extracted from patient records, including information on the diagnostic accuracy of ultrasound guided cutting needle biopsies (UCNB) and potential complications. We found that NB expressed the different SSTRs and that receptor 2 was the most frequently expressed before chemotherapy. Furthermore, NB tumors showed immunoreactivity for SV2, VMAT 1 and VMAT2 alongside CgA and syn. The immunoreactivity of SV2 was comparable to CgA and superior to syn. Patients with NB had higher blood concentrations of CgA and NSE compared with controls. Patients with advanced stage disease, MYCN amplification and 1 p deletion had higher concentrations of both CgA and NSE while only NSE was correlated to outcome with higher concentrations in the deceased patients. A high urinary excretion of homovanillic acid and dopamine were correlated to inferior outcome. UCNB were found to be safe and may provide all necessary diagnostic requirements for adequate therapy stratification according to current treatment protocols. Keywords: Neuroendocrine, Immunohistochemistry, Urinary Catecholamine Metabolites, Markers, Outcome Kleopatra Georgantzi, Research group (Dept. of women´s and children´s health), Neuropediatrics/Paediatric oncology, Akademiska sjukhuset, Uppsala University, SE-75185 Uppsala, Sweden. © Kleopatra Georgantzi 2018 ISSN 1651-6206 ISBN 978-91-513-0499-1 urn:nbn:se:uu:diva-364682 (http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-364682) To Georgina and Elena List of papers This thesis is based on the following papers: I Georgantzi K, Tsolakis AV, Stridsberg M, Jakobson A, Chris- tofferson R, Janson ET. Differentiated expression of somatosta- tin receptor subtypes in experimental models and clinical neu- roblastoma. Pediatr Blood Cancer 2011 Apr;56(4):584-9. II Georgantzi K, Sköldenberg E, Stridsberg M, Kogner P, Jakob- son ., Janson ET, Chistofferson R. Chromogranin A and Neu- ron-Specific Enolase in Neuroblastoma: correlation to stage and prognostic factors. Pediatr Hematol Oncol 2018 Mar;35(2):156-165. III Georgantzi K, Tsolakis AV, Jakobson A, Christofferson R, Janson ET, Grimelius L. Synaptic vesicle protein 2 and vesicu- lar monoamine transporter 1 and 2 are expressed in neuroblas- toma. Manuscript IV Georgantzi K, Sköldenberg E, Janson ET, Jakobson A, Chris- tofferson R. Diagnostic Cutting Needle Biopsies in Neuroblas- toma: a safe and efficient procedure. Submitted Contents Introduction ................................................................................................... 11 Neuroblastoma .......................................................................................... 12 Background and Epidemiology ............................................................ 12 Staging ................................................................................................. 12 Clinical presentation ............................................................................ 14 Neuroendocrine properties of Neuroblastoma ..................................... 15 Diagnostic procedures .......................................................................... 15 Prognostic factors ................................................................................. 16 Treatment ............................................................................................. 17 Somatostatin receptors .............................................................................. 17 Neuron-Specific Enolase .......................................................................... 18 Neuroendocrine markers ........................................................................... 18 General neuroendocrine markers .............................................................. 19 Chromogranin A and chromogranin B ................................................ 19 Synaptophysin ...................................................................................... 19 Synaptic vesicle protein 2 .................................................................... 19 Specific neuroendocrine markers ............................................................. 20 Vesicular monoamine transporters 1 and 2 .......................................... 20 Urine catecholamine metabolites .............................................................. 20 Ultrasound cutting needle biopsies ........................................................... 21 Aims of the study .......................................................................................... 23 Paper I .................................................................................................. 23 Paper II ................................................................................................. 23 Paper III ............................................................................................... 23 Paper IV ............................................................................................... 23 Materials and methods .................................................................................. 24 Patients ...................................................................................................... 24 Paper I .................................................................................................. 24 Paper II ................................................................................................. 24 Paper III ............................................................................................... 25 Paper IV ............................................................................................... 25 Experimental tumors (paper I) .................................................................. 25 Methods .................................................................................................... 25 Tissue samples ..................................................................................... 25 Primary antibodies for immunohistochemistry .................................... 26 Routine immunostaining in paper I and III .......................................... 26 Analysis of immunoreactive cells ........................................................ 27 Immunohistochemical controls ............................................................ 27 Sample analysis (paper II) ................................................................... 28 Statistics ............................................................................................... 28 Ethics ............................................................................................................. 29 Results ........................................................................................................... 30 Immunohistochemical analyses (papers I and III) .................................... 30 Somatostatin receptors, somatostatin and chromogranin A ................. 30 General neuroendocrine markers ......................................................... 30 Monoamine transporters VMAT1 and VMAT2 .................................. 31 Comparison between all five neuroendocrine markers ........................ 31 Circulating biochemical markers (paper II) .............................................. 31 Urine catecholamine metabolites (paper III) ............................................ 32 Ultrasound-guided cutting needle biopsies (paper IV) ............................. 32 Discussion ....................................................................................................
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