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This incurability and short survival time means that, despite its rarity (average incidence of 3.2 per 100,000 persons), there has been an increased effort to try to treat this disease. Standard of care in newly diagnosed glioblastoma is maximal tumour resection followed by initial concomitant radiotherapy and temozolomide (TMZ) and then further chemotherapy with TMZ. Imaging techniques are key not only to diagnose the extent of the affected tissue but also for surgery planning and even for intraoperative use. Eligible patients may combine TMZ with tumour treating fields (TTF) therapy, which delivers low-intensity and intermediate-frequency electric fields to arrest tumour growth. Nonetheless, the blood\u2013brain barrier (BBB) and systemic side effects are obstacles to successful chemotherapy in GBM; thus, more targeted, custom therapies such as immunotherapy and nanotechnological drug delivery systems have been undergoing research with varying degrees of success. This review proposes an overview of the pathophysiology, possible treatments, and the most (not all) representative examples of the latest advancements.<\/jats:p>","DOI":"10.3390\/pharmaceutics15030928","type":"journal-article","created":{"date-parts":[[2023,3,14]],"date-time":"2023-03-14T03:29:16Z","timestamp":1678764556000},"page":"928","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Highlighted Advances in Therapies for Difficult-To-Treat Brain Tumours Such as Glioblastoma"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4196-6808","authenticated-orcid":false,"given":"Nuno","family":"Cruz","sequence":"first","affiliation":[{"name":"Instituto de Biof\u00edsica e Engenharia Biom\u00e9dica, Faculdade de Ci\u00eancias, Universidade de Lisboa, 1749-016 Lisboa, Portugal"},{"name":"iMED.ULisboa, Research Institute for Medicines, Faculdade de Farm\u00e1cia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal"}]},{"given":"Manuel","family":"Herculano-Carvalho","sequence":"additional","affiliation":[{"name":"Instituto de Medicina Molecular Jo\u00e3o Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal"},{"name":"Department of Neurosurgery, Hospital de Santa Maria, Centro Hospitalar Universit\u00e1rio Lisboa Norte (CHULN), 1649-028 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3467-8525","authenticated-orcid":false,"given":"Diogo","family":"Roque","sequence":"additional","affiliation":[{"name":"Instituto de Medicina Molecular Jo\u00e3o Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal"},{"name":"Department of Neurosurgery, Hospital de Santa Maria, Centro Hospitalar Universit\u00e1rio Lisboa Norte (CHULN), 1649-028 Lisboa, Portugal"}]},{"given":"Cl\u00e1udia C.","family":"Faria","sequence":"additional","affiliation":[{"name":"Instituto de Medicina Molecular Jo\u00e3o Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal"},{"name":"Department of Neurosurgery, Hospital de Santa Maria, Centro Hospitalar Universit\u00e1rio Lisboa Norte (CHULN), 1649-028 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5533-9413","authenticated-orcid":false,"given":"Rita","family":"Casc\u00e3o","sequence":"additional","affiliation":[{"name":"Instituto de Medicina Molecular Jo\u00e3o Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal"}]},{"given":"Hugo Alexandre","family":"Ferreira","sequence":"additional","affiliation":[{"name":"Instituto de Biof\u00edsica e Engenharia Biom\u00e9dica, Faculdade de Ci\u00eancias, Universidade de Lisboa, 1749-016 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1046-4031","authenticated-orcid":false,"given":"Catarina Pinto","family":"Reis","sequence":"additional","affiliation":[{"name":"Instituto de Biof\u00edsica e Engenharia Biom\u00e9dica, Faculdade de Ci\u00eancias, Universidade de Lisboa, 1749-016 Lisboa, Portugal"},{"name":"iMED.ULisboa, Research Institute for Medicines, Faculdade de Farm\u00e1cia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8048-7896","authenticated-orcid":false,"given":"Nuno","family":"Matela","sequence":"additional","affiliation":[{"name":"Instituto de Biof\u00edsica e Engenharia Biom\u00e9dica, Faculdade de Ci\u00eancias, Universidade de Lisboa, 1749-016 Lisboa, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"iv1","DOI":"10.1093\/neuonc\/nou223","article-title":"CBTRUS Statistical Report: Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2007\u20132011","volume":"16","author":"Ostrom","year":"2014","journal-title":"Neuro Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1007\/s00401-016-1545-1","article-title":"The 2016 World Health Organization Classification of Tumors of the Central Nervous System: A Summary","volume":"131","author":"Louis","year":"2016","journal-title":"Acta Neuropathol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1093\/neuonc\/noab106","article-title":"The 2021 WHO Classification of Tumors of the Central Nervous System: A Summary","volume":"23","author":"Louis","year":"2021","journal-title":"Neuro Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2402","DOI":"10.1200\/JCO.2017.73.0119","article-title":"Adult Glioblastoma","volume":"35","author":"Alexander","year":"2017","journal-title":"J. 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