{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T02:23:31Z","timestamp":1790821411721,"version":"4.1.0"},"reference-count":33,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2020,7,1]],"date-time":"2020-07-01T00:00:00Z","timestamp":1593561600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["314061271 \u2010 TRR 205; KL 2541\/2\u20101"],"award-info":[{"award-number":["314061271 \u2010 TRR 205; KL 2541\/2\u20101"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["314061271 \u2010 TRR 205; RI 2684\/1\u20101"],"award-info":[{"award-number":["314061271 \u2010 TRR 205; RI 2684\/1\u20101"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["pathsocjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pathology"],"published-print":{"date-parts":[[2020,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Phaeochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumours with a hereditary background in over one\u2010third of patients. Mutations in succinate dehydrogenase (SDH) genes increase the risk for PPGLs and several other tumours. Mutations in subunit B (\n                    <jats:italic>SDHB<\/jats:italic>\n                    ) in particular are a risk factor for metastatic disease, further highlighting the importance of identifying\n                    <jats:italic>SDHx<\/jats:italic>\n                    mutations for patient management. Genetic variants of unknown significance, where implications for the patient and family members are unclear, are a problem for interpretation. For such cases, reliable methods for evaluating protein functionality are required. Immunohistochemistry for SDHB (SDHB\u2010IHC) is the method of choice but does not assess functionality at the enzymatic level. Liquid chromatography\u2013mass spectrometry\u2010based measurements of metabolite precursors and products of enzymatic reactions provide an alternative method. Here, we compare SDHB\u2010IHC with metabolite profiling in 189 tumours from 187 PPGL patients. Besides evaluating succinate:fumarate ratios (SFRs), machine learning algorithms were developed to establish predictive models for interpreting metabolite data. Metabolite profiling showed higher diagnostic specificity compared to SDHB\u2010IHC (99.2% versus 92.5%,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.021), whereas sensitivity was comparable. Application of machine learning algorithms to metabolite profiles improved predictive ability over that of the SFR, in particular for hard\u2010to\u2010interpret cases of head and neck paragangliomas (AUC 0.9821 versus 0.9613,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.044). Importantly, the combination of metabolite profiling with SDHB\u2010IHC has complementary utility, as SDHB\u2010IHC correctly classified all but one of the false negatives from metabolite profiling strategies, while metabolite profiling correctly classified all but one of the false negatives\/positives from SDHB\u2010IHC. From 186 tumours with confirmed status of\n                    <jats:italic>SDHx<\/jats:italic>\n                    variant pathogenicity, the combination of the two methods resulted in 185 correct predictions, highlighting the benefits of both strategies for patient management. \u00a9 2020 The Authors.\n                    <jats:italic>The Journal of Pathology<\/jats:italic>\n                    published by John Wiley &amp; Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.\n                  <\/jats:p>","DOI":"10.1002\/path.5472","type":"journal-article","created":{"date-parts":[[2020,5,28]],"date-time":"2020-05-28T02:56:24Z","timestamp":1590634584000},"page":"378-387","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":42,"title":["Metabolomics, machine learning and immunohistochemistry to predict succinate dehydrogenase mutational status in phaeochromocytomas and paragangliomas"],"prefix":"10.1002","volume":"251","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5439-096X","authenticated-orcid":false,"given":"Paal W","family":"Wallace","sequence":"first","affiliation":[{"name":"Institute of Clinical Chemistry and Laboratory Medicine University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universit\u00e4t Dresden  Dresden Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catleen","family":"Conrad","sequence":"additional","affiliation":[{"name":"Institute of Clinical Chemistry and Laboratory Medicine University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universit\u00e4t Dresden  Dresden Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sascha","family":"Br\u00fcckmann","sequence":"additional","affiliation":[{"name":"Institute of Pathology University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universit\u00e4t Dresden  Dresden Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Pang","sequence":"additional","affiliation":[{"name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health  Bethesda MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduardo","family":"Caleiras","sequence":"additional","affiliation":[{"name":"Histopathology Core Unit Spanish National Cancer Research Centre (CNIO), Calle de Melchor Fern\u00e1ndez Almagro  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masanori","family":"Murakami","sequence":"additional","affiliation":[{"name":"Medizinische Klinik and Poliklinik IV Ludwig\u2010Maximilians\u2010Universit\u00e4t M\u00fcnchen  Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esther","family":"Korpershoek","sequence":"additional","affiliation":[{"name":"Department of Pathology Erasmus MC\u2010University Medical Center Rotterdam  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengping","family":"Zhuang","sequence":"additional","affiliation":[{"name":"Surgical Neurology Branch National Institute of Neurological Disorders and Stroke, National Institutes of Health  Bethesda MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Rapizzi","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine University of Florence  Florence Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Kroiss","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Endocrinology, University Hospital University of W\u00fcrzburg  W\u00fcrzburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Volker","family":"Gudziol","sequence":"additional","affiliation":[{"name":"Klinik f\u00fcr Hals\u2010Nasen\u2010Ohrenheilkunde, Kopf\u2010 und Hals\u2010Chirurgie Plastische Operationen, St\u00e4dtisches Klinikum Dresden, Akademisches Lehrkrankenhaus der Technischen Universit\u00e4t Dresden  Dresden Germany"},{"name":"Departments of Otorhinolaryngology University Hospital Carl Gustav Carus, Technische Universit\u00e4t Dresden  Dresden Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henri JLM","family":"Timmers","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Radboud University Medical Centre  Nijmegen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimo","family":"Mannelli","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine University of Florence  Florence Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jens","family":"Pietzsch","sequence":"additional","affiliation":[{"name":"Department of Radiopharmaceutical and Chemical Biology Institute of Radiopharmaceutical Cancer Research, Helmholtz\u2010Zentrum Dresden\u2010Rossendorf  Dresden Germany"},{"name":"Faculty of Chemistry and Food Chemistry School of Science, Technische Universit\u00e4t Dresden  Dresden Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felix","family":"Beuschlein","sequence":"additional","affiliation":[{"name":"Medizinische Klinik and Poliklinik IV Ludwig\u2010Maximilians\u2010Universit\u00e4t M\u00fcnchen  Munich Germany"},{"name":"Department for Endocrinology Diabetology and Clinical Nutrition, Universit\u00e4tsSpital Z\u00fcrich  Zurich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karel","family":"Pacak","sequence":"additional","affiliation":[{"name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health  Bethesda MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mercedes","family":"Robledo","sequence":"additional","affiliation":[{"name":"Hereditary Endocrine Cancer Group, CNIO Madrid, Spain and Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras (CIBERER)  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Klink","sequence":"additional","affiliation":[{"name":"Institute for Clinical Genetics Medical Faculty Carl Gustav Carus, Technische Universit\u00e4t Dresden  Dresden Germany"},{"name":"Department of Genetics Laboratoire National de Sant\u00e9  Dudelange Luxembourg"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mirko","family":"Peitzsch","sequence":"additional","affiliation":[{"name":"Institute of Clinical Chemistry and Laboratory Medicine University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universit\u00e4t Dresden  Dresden Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony J","family":"Gill","sequence":"additional","affiliation":[{"name":"Royal North Shore Hospital, Cancer Diagnosis and Pathology Group Kolling Institute of Medical Research  Sydney Australia"},{"name":"School of Medicine University of Sydney  Sydney Australia"},{"name":"NSW Health Pathology, Department of Anatomical Pathology Royal North Shore Hospital  St Leonards Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arthur S","family":"Tischler","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine Tufts University School of Medicine  Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronald R","family":"de Krijger","sequence":"additional","affiliation":[{"name":"Department of Pathology University Medical Center Utrecht  Utrecht The Netherlands"},{"name":"Princess M\u00e1xima Center for Pediatric Oncology  Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Papathomas","sequence":"additional","affiliation":[{"name":"Institute of Metabolism and Systems Research University of Birmingham, Edgbaston  Birmingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Aust","sequence":"additional","affiliation":[{"name":"Institute of Pathology Tumor and Normal Tissue Bank of the UCC\/NCT Dresden, University Hospital Carl Gustav Carus, Technische Universit\u00e4t Dresden  Dresden Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graeme","family":"Eisenhofer","sequence":"additional","affiliation":[{"name":"Institute of Clinical Chemistry and Laboratory Medicine University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universit\u00e4t Dresden  Dresden Germany"},{"name":"Department of Medicine III University Hospital Dresden  Dresden Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3549-2477","authenticated-orcid":false,"given":"Susan","family":"Richter","sequence":"additional","affiliation":[{"name":"Institute of Clinical Chemistry and Laboratory Medicine University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universit\u00e4t Dresden  Dresden Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,7]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/his.13277"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2007-0709"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers11010103"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2014-1498"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrendo.2016.185"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmoldx.2017.04.009"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2015-3856"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-16-2250"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(09)70164-0"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1097\/PAT.0b013e3283539932"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2014-2151"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41436-018-0106-5"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgmr.2016.12.006"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/path.5331"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1089\/omi.2018.0097"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2890"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkf493"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gks539"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/modpathol.2015.41"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-1809.1936.tb02137.x"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1055\/a-0926-3790"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2019.05.007"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/s42256-019-0052-1"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.32654"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2011-1043"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2014-1870"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.coemr.2019.07.002"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2014.162"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers11040436"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-17-3406"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers11091391"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers12020280"}],"container-title":["The Journal of Pathology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fpath.5472","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/path.5472","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/path.5472","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/pathsocjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/path.5472","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T10:31:28Z","timestamp":1761042688000},"score":1,"resource":{"primary":{"URL":"https:\/\/pathsocjournals.onlinelibrary.wiley.com\/doi\/10.1002\/path.5472"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,7]]},"references-count":33,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2020,8]]}},"alternative-id":["10.1002\/path.5472"],"URL":"https:\/\/doi.org\/10.1002\/path.5472","archive":["Portico"],"relation":{},"ISSN":["0022-3417","1096-9896"],"issn-type":[{"value":"0022-3417","type":"print"},{"value":"1096-9896","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,7]]},"assertion":[{"value":"2019-12-06","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-05-16","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-07-01","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}