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Background: Recently, criteria based on amino acid positron emission tomography (PET) have been proposed for response assessment in diffuse gliomas (PET RANO 1.0). In this study, we compare the prevalence of measurable disease according to PET RANO 1.0 with magnetic resonance imaging (MRI)-based Response Assessment in Neuro-Oncology (RANO) criteria in glioblastoma., Methods: We retrospectively identified patients with newly diagnosed IDH-wild-type glioblastoma who underwent [18F] Fluoroethyltyrosine (FET) PET and MRI after resection or biopsy and before radio-/radiochemotherapy. Two independent investigators analyzed measurable disease according to PET RANO 1.0 or MRI-RANO criteria. Additionally, lesion size, congruency patterns, and uptake intensity on [18F]FET PET images were assessed., Results: We evaluated 125 patients including 49 cases after primary resection and 76 cases after biopsy. Using PET criteria, 113 out of 125 patients (90.4%) had measurable disease, with a median PET-positive volume of 15.34 cm3 (8.83-38.03). With MRI, a significantly lower proportion of patients had measurable disease (57/125, 45.6%; P < .001) with a median sum of maximum cross-sectional diameters of 35.65 mm (26.18-45.98). None of the 12 patients without measurable disease on PET had measurable disease on MRI. Contrariwise, 56/68 patients (82.4%) without measurable disease on MRI exhibited measurable disease on PET. Clinical performance status correlated significantly with PET-positive volume and MRI-based sum of diameters (P < .0059, P < .0087, respectively)., Conclusions: [18F]FET PET identifies a higher number of patients with measurable disease compared to conventional MRI in newly diagnosed glioblastoma. PET-based assessment may serve as a novel baseline parameter for evaluating residual tumor burden and improving patient stratification in glioblastoma studies. Further validation in prospective trials is warranted., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

This joint practice guideline/procedure standard was collaboratively developed by the European Association of Nuclear Medicine (EANM), the Society of Nuclear Medicine and Molecular Imaging (SNMMI), the European Association of Neuro-Oncology (EANO), and the PET task force of the Response Assessment in Neurooncology Working Group (PET/RANO). Brain metastases are the most common malignant central nervous system (CNS) tumors. PET imaging with radiolabeled amino acids and to lesser extent [ 18 F]FDG has gained considerable importance in the assessment of brain metastases, especially for the differential diagnosis between recurrent metastases and treatment-related changes which remains a limitation using conventional MRI. The aim of this guideline is to assist nuclear medicine physicians in recommending, performing, interpreting and reporting the results of brain PET imaging in patients with brain metastases. This practice guideline will define procedure standards for the application of PET imaging in patients with brain metastases in routine practice and clinical trials and will help to harmonize data acquisition and interpretation across centers., Competing Interests: Declarations. Ethical approval: Not applicable. Consent to participate: Not applicable. Consent to publish: Not applicable. Approval: This practice guideline was approved by the Board of Directors of the EANM, SNMMI, EANO and PET/RANO Working Group. Competing interests: AV: has received honoraria for lectures and advisory board participation from Curium, Eisai, General Electrics and Novartis. NT: no disclosures FC: no disclosures. SMC: no disclosures JF: has received honoraria for lectures and consultations from the following for-profit companies: Novartis, Seagen, Sanova, Servier. NG: has received honoraria for lectures from Blue Earth Diagnostics and for advisory board participation from Telix Pharmaceuticals and Servier, and for consultancy services from Telix Pharmaceuticals. JG: has received honoraria for consultation and advisory board participation from Seagan, Brain Lab, research support from Zeiss. EG: has received honoraria for consultation and advisory board participation from AAA/Novartis, Curium/LMI, General Electric, Keosys and Pfizer. RH: has received consultation fees for Telix, Servier, and Nuvation Bio and scientific advisory for Vysioneer,. DJ: has received honoraria for consultation and advisory board participation from Telix Pharmaceuticals, Cellectar and Novartis. IL: no disclosures. ELR: has received a research grant from BMS, and honoraria for advisory board participation from Astra Zeneca, Bayer, Bioderix, Janssen, Leo Pharma, Pfizer, Pierre Fabre, Seagen and Servier. SCS: has received honoraria and consulting fees from Chimerix, Servier, CeCaVa, Miltenyi, Roche and research support from Apollomics and Blue Earth Diagnostics. MJVdB: has received honoraria for consultation and advisory board participation from Servier, Anheart Therapeutics, Fore Biotherapeutics, Genenta, Roche, Chimerix, Mundipharm, Boehringer and Incyte, and research support from Boehringer Ingelheim. DVW: no disclosures. MAV: has received research support to his hospital from NIH, DeNovo Pharma, Infuseon, Therapeutics, Oncosynergy; and honoraria from Servier Pharma, and Biodexa Pharma. PYW: has received research support from Astra Zeneca, Black Diamond, Bristol Meyers Squibb, Chimerix, Eli Lily, Erasca, Global Coalition For Adaptive Research, Kazia, MediciNova, Merck, Novartis, Quadriga, Servier, and VBI Vaccines and honoraria for consultation and advisory board participation from Anheart, Astra Zeneca, Black Diamond, Celularity, Chimerix, Day One Bio, Genenta, Glaxo Smith Kline, Kintara, Merck, Mundipharma, Novartis, Novocure, Prelude Therapeutics, Sagimet, Sapience, Servier, Symbio, Tango, Telix, VBI Vaccines. NLA: has received honoraria for lectures, consultation or advisory board participation from Novartis, Advanced Accelerator Applications, Telix Pharmaceuticals, OncLive, Medsir and Servier, and research funding from Novocure and Telix Pharmaceuticals. MP: has received honoraria for lectures, consultation or advisory board participation from the following for-profit companies: Bayer, Bristol-Myers Squibb, Novartis, Gerson Lehrman Group (GLG), CMC Contrast, GlaxoSmithKline, Mundipharma, Roche, BMJ Journals, MedMedia, Astra Zeneca, AbbVie, Lilly, Medahead, Daiichi Sankyo, Sanofi, Merck Sharp & Dome, Tocagen, Adastra, Gan & Lee Pharmaceuticals, Janssen, Servier, Miltenyi, Böhringer-Ingelheim, Telix, Medscape. IL: has received honoraria for lectures and consultations from Telix Pharmaceuticals and Ribocure., (© 2024. The Author(s).)

Meningiomas are the most common intracranial neoplasms in adults. While most meningiomas are cured by resection, further treatment by radiotherapy may be needed, particularly in WHO grades 2 and 3 tumors which have an increased risk of recurrence, even after conventional therapies. Still, there is an urgent need for novel therapeutic strategies after the exhaustion of local treatment approaches. Radionuclide therapies combine the specificity of tumor-specific antibodies or ligands with the cytotoxic activity of radioactive emitters. Alongside this, integrated molecular imaging allows for a noninvasive assessment of predictive biomarkers as treatment targets. Whereas the concept of "theranostics" has initially evolved in extracranial tumors such as thyroid diseases, neuroendocrine tumors, and prostate cancer, data from retrospective case series and early phase trials underscore the potential of this strategy in meningioma. This review aims to explore the available evidence of radionuclide treatments and ongoing clinical trial initiatives in meningioma. Moreover, we discuss optimal clinical trial design and future perspectives in the field, including compound- and host-specific determinants of the efficacy of "theranostic" treatment approaches., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Theranostics is a new treatment modality integrating molecular imaging with targeted radionuclide therapy. Theranostic agents have received regulatory approval for some systemic cancers and have therapeutic potential in neuro-oncology. As clinical trials are developed to evaluate the efficacy of theranostic agents in brain tumors, specific considerations will have to be considered, taking into account lessons learned from previous studies examining other treatment modalities in neuro-oncology. These include the need for molecular imaging or surgical window-of-opportunity studies to confirm adequate passage across the blood-brain barrier, optimize eligibility criteria, and selection of the most appropriate response criteria and endpoints to address issues such as pseudoprogression. This review will discuss some of the issues that should be considered when designing clinical trials for theranostic agents., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Targeted radionuclide therapy is an emerging therapeutic concept for metastatic cancer that can be considered if a tumor can be delineated by nuclear medicine imaging and also targeted based on the expression of a particular target (thera-nostics). This mode of treatment can also compete with or supplement conventional radiotherapy, for example, if MRI does not fully capture the extent of the disease, including microscopic metastases. Targeted radionuclide therapy for patients with thyroid cancer, with certain somatostatin receptor 2-expressing tumors and with prostate-specific membrane antigen-expressing prostate cancer is approved, and numerous approaches of targeted radionuclide therapy for patients with metastatic cancer are in development (eg, using fibroblast activation protein as a target). Although brain metastases are rare in cancers with approved targeted radionuclide therapies, there is no a priori reason to assume that such treatments would not be effective against brain metastases if the targets are expressed and not shielded by the blood-brain barrier. Here, we discuss the current state of the art and opportunities of targeted radionuclide therapies for patients with brain and leptomeningeal metastases., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

According to the new WHO classification of 2021, gliomas are a heterogeneous group of tumors with very different histology, molecular genetics, and prognoses. In addition to glioblastomas, the most common gliomas, there are also numerous less common gliomas, some of which have a very favorable prognosis. Targeted radionuclide therapy is a therapeutic option that can be attractive if a tumor can be targeted based on its molecular characteristics. It is particularly useful when tumors cannot be completely resected or when conventional imaging does not fully capture the extent of the tumor. Numerous approaches to radionuclide therapy for gliomas are in early development. The most advanced approaches for patients with gliomas in the clinic employ L-type amino acid transporter 1 as an uptake mechanism for radiolabeled amino acids or target somatostatin receptor 2 or gastrin-releasing peptide receptor. Here, we discuss the various target structures of radionuclide therapy in gliomas and provide an outlook for which glioma entities radionuclide therapy could most likely provide a therapeutic alternative., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Abstract: A 64-year-old woman with meningioma presented with left-sided lenticulostriatal ischemia following craniotomy and debulking of a sphenoid wing meningioma. For subsequent radiotherapy planning, an SSTR-targeted PET/CT using the novel ligand 18 F-SiTATE was performed 2.5 months thereafter. The meningioma remnants showed transosseous, intrasellar, and perivascular extension around the internal carotid artery with strong SSTR expression. Moreover, there was focal 18 F-SiTATE uptake in the left caudate and corresponding contrast enhancement due to postischemic blood-brain barrier disruption and reactive SSTR expression. Therefore, increased cortical or subcortical SSTR PET signal may be related to ischemic changes even in the subacute stage after initial stroke., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

The phase-3 INDIGO trial demonstrated that the isocitrate dehydrogenase ( IDH ) inhibitor vorasidenib significantly prolonged progression-free survival and delayed intervention in patients with CNS WHO grade 2 gliomas. However, conventional MRI showed limited response, with only 11% of patients having objective responses. Studies suggest that serial PET imaging with radiolabeled amino acids, such as O -(2-[ 18 F]-fluoroethyl)-L-tyrosine (FET) PET, may provide earlier and more informative assessments of treatment response than MRI. In an initial experience with FET PET, 3 out of 5 patients showed metabolic response to vorasidenib. This highlights FET PET's potential to guide decision-making, though further trials are needed to confirm outcome benefits., Competing Interests: N.G. received honoraria for lectures from Blue Earth Diagnostics, for advisory board participation from Telix Pharmaceuticals and Servier, and for consultancy services from Telix Pharmaceuticals. H.C.P. received travel support from Eli Lilly, MSD, Novartis, Pfizer, and Roche, and received lecture honoraria from Eli Lilly. N.L.A. has received honoraria for lectures, consultation or advisory board participation from Novartis, Advanced Accelerator Applications, Telix Pharmaceuticals, OncLive, MEDSIR, and Servier, and research funding from Novocure and Telix Pharmaceuticals. K.-J.L. received honoraria for consultancy services from Telix Pharmaceuticals. P.L. received honoraria for lectures from Blue Earth Diagnostics, and for advisory board participation from Servier. M.P. received honoraria for lectures, consultation or advisory board participation from the following for-profit companies: Bayer, Bristol-Myers Squibb, Novartis, Gerson Lehrman Group (GLG), CMC Contrast, GlaxoSmithKline, Mundipharma, Roche, BMJ Journals, MedMedia, Astra Zeneca, AbbVie, Lilly, Medahead, Daiichi Sankyo, Sanofi, Merck Sharp & Dome, Tocagen, Adastra, Gan & Lee Pharmaceuticals, Janssen, Servier, Miltenyi, Böhringer Ingelheim, Telix, Medscape, and OncLive. All other authors reported no potential conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Competing Interests: Declarations. Ethics approval: The analysis was performed in compliance with the principles of the Declaration of Helsinki. No identifiable patient data is included in the manuscript, in this respect the right to informational self-determination is not affected. The patient provided written informed consent for the imaging studies within clinical routine. In accordance with the ethics committee of the Ludwig-Maximilians-University of Munich this work is not subject to review. Competing interests: AH reports compensation for scientific consulting by ABX advanced biochemical compounds. JCT reports travel cost reimbursement from Servier. MB received consulting/speaker honoraria from Life Molecular Imaging, GE healthcare, and Roche, and reader honoraria from Life Molecular Imaging. NLA has received honoraria for consultation or advisory board participation from Novartis, Advanced Accelerator Applications, Servier, and Telix Pharmaceuticals; and has received research funding from Novocure. The remaining authors have no relevant financial or non-financial interests to disclose.

Meningiomas are the most common primary intracranial tumors of adults. For meningiomas that progress or recur despite surgical resection and radiotherapy, additional treatment options are limited due to lack of proven efficacy. Meningiomas show recurring molecular aberrations, which may serve as predictive markers for systemic pharmacotherapies with targeted drugs or immunotherapy, radiotherapy or radioligand therapy. Here, we review the evidence for a predictive role of a wide range of molecular alterations and markers including NF2, AKT1, SMO, SMARCE1, PIK3CA, CDKN2A/B, CDK4/6, TERT, TRAF7, BAP1, KLF4, ARID1/2, SUFU, PD-L1, SSTR2A, PR/ER, mTOR, VEGFR, PDGFR, as well as homologous recombination deficiency (HRD), genomic copy number variations, DNA methylation classes and combined gene expression profiles. In our assessment based on the established ESMO ESCAT (European Society for Medical Oncology Scale for Clinical Actionability of molecular Targets) evidence level criteria, no molecular target reached ESCAT I ("ready for clinical use") classification and only mTOR pathway activation and NF2 alterations reached ESCAT II ("investigational") classification, respectively. Our evaluations may guide targeted therapy selection in clinical practice and clinical trial efforts and highlight areas for which additional research is warranted., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Purpose: Current therapy strategies still provide only limited success in the treatment of glioblastoma, the most frequent primary brain tumor in adults. In addition to the characterization of the tumor microenvironment, global changes in the brain of patients with glioblastoma have been described. However, the impact and molecular signature of neuroinflammation distant of the primary tumor site have not yet been thoroughly elucidated., Experimental Design: We performed translocator protein (TSPO)-PET in patients with newly diagnosed glioblastoma (n = 41), astrocytoma WHO grade 2 (n = 7), and healthy controls (n = 20) and compared TSPO-PET signals of the non-lesion (i.e., contralateral) hemisphere. Back-translation into syngeneic SB28 glioblastoma mice was used to characterize Pet alterations on a cellular level. Ultimately, multiplex gene expression analyses served to profile immune cells in remote brain., Results: Our study revealed elevated TSPO-PET signals in contralateral hemispheres of patients with newly diagnosed glioblastoma compared to healthy controls. Contralateral TSPO was associated with persisting epileptic seizures and shorter overall survival independent of the tumor phenotype. Back-translation into syngeneic glioblastoma mice pinpointed myeloid cells as the predominant source of contralateral TSPO-PET signal increases and identified a complex immune signature characterized by myeloid cell activation and immunosuppression in distant brain regions., Conclusions: Neuroinflammation within the contralateral hemisphere can be detected with TSPO-PET imaging and associates with poor outcome in patients with newly diagnosed glioblastoma. The molecular signature of remote neuroinflammation promotes the evaluation of immunomodulatory strategies in patients with detrimental whole brain inflammation as reflected by high TSPO expression., (©2024 The Authors; Published by the American Association for Cancer Research.)

Brain tumor volumes as assessed by magnetic resonance imaging (MRI) do not always spatially overlap with biological tumor volumes (BTV) measured by [ 18 F]Fluoroethyltyrosine positron emission tomography ([ 18 F]FET PET). We prospectively investigated volumetric patterns based on the extent of tumor volume overlap between the two modalities. Eighty-six patients with newly diagnosed glioma who had undergone MRI and [ 18 F]FET PET between 2007 and 2009 were included in this prospective study and (re-)classified according to CNS WHO 2021 (Classification of Tumors of the Central Nervous System by the World Health Organization). Four different patterns of volume overlap were defined mathematically according to the extent of overlap between MRI-based T2 tumor volume (non-enhancing tumor volume, nCEV) and BTVs. Progression-free (PFS) and overall survival (OS) were determined. Seventy patients were diagnosed with isocitrate dehydrogenase wildtype (IDHwt) glioblastoma and 16 with IDH-mutant glioma, respectively. The most common pattern was characterized by a larger non-contrast-enhancing tumor volume (nCEV) that enclosed all or most of the BTV and was observed in 46 patients (54%) (pattern 1). This pattern was more frequent in IDH-mutant gliomas than in IDH-wildtype glioblastoma (81% versus 47%, p = 0.02). In multivariate analyses, pattern 1 was associated with prolonged PFS (HR 0.59; 95 CI 0.34-1.0; p = 0.05), but not OS (HR 0.66; 95 CI 0.4-1.08; p = 0.1). For OS, presence of an IDH mutation (p = 0.05) and lower age (p = 0.03) were associated with prolonged OS. The spatial relation between nCEV and BTV varies within and between glioma entities. Most frequently, a larger nCEV encases the BTV. Some patients show spatially dissociated nCEVs and BTVs. Not accounting for this phenomenon in surgery or radiotherapy planning might lead to undertreatment., (© 2024. The Author(s).)

Meningiomas are the most common primary intracranial tumors in adults and are increasing in incidence due to the aging population and increased access to neuroimaging. While most exhibit nonmalignant behavior, a subset of meningiomas are biologically aggressive and are associated with treatment resistance, resulting in significant neurologic morbidity and even mortality. In recent years, meaningful advances in our understanding of the biology of these tumors have led to the incorporation of molecular biomarkers into their grading and prognostication. However, unlike other central nervous system (CNS) tumors, a unified molecular taxonomy for meningiomas has not yet been established and remains an overarching goal of the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy-Not Official World Health Organization (cIMPACT-NOW) working group. Additionally, clinical equipoise still remains on how specific meningioma cases and patient populations should be optimally managed. To address these existing gaps, members of the International Consortium on Meningiomas including field-leading experts, have prepared this comprehensive consensus narrative review directed toward clinicians, researchers, and patients. Included in this manuscript are detailed overviews of proposed molecular classifications, novel biomarkers, contemporary treatment strategies, trials on systemic therapies, health-related quality-of-life studies, and management strategies for unique meningioma patient populations. In each section, we discuss the current state of knowledge as well as ongoing clinical and research challenges to road map future directions for further investigation., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Purpose: To provide practice guideline/procedure standards for diagnostics and therapy (theranostics) of meningiomas using radiolabeled somatostatin receptor (SSTR) ligands., Methods: This joint practice guideline/procedure standard was collaboratively developed by the European Association of Nuclear Medicine (EANM), the Society of Nuclear Medicine and Molecular Imaging (SNMMI), the European Association of Neurooncology (EANO), and the PET task force of the Response Assessment in Neurooncology Working Group (PET/RANO)., Results: Positron emission tomography (PET) using somatostatin receptor (SSTR) ligands can detect meningioma tissue with high sensitivity and specificity and may provide clinically relevant information beyond that obtained from structural magnetic resonance imaging (MRI) or computed tomography (CT) imaging alone. SSTR-directed PET imaging can be particularly useful for differential diagnosis, delineation of meningioma extent, detection of osseous involvement, and the differentiation between posttherapeutic scar tissue and tumour recurrence. Moreover, SSTR-peptide receptor radionuclide therapy (PRRT) is an emerging investigational treatment approach for meningioma., Conclusion: These practice guidelines will define procedure standards for the application of PET imaging in patients with meningiomas and related SSTR-targeted PRRTs in routine practice and clinical trials and will help to harmonize data acquisition and interpretation across centers, facilitate comparability of studies, and to collect larger databases. The current document provides additional information to the evidence-based recommendations from the PET/RANO Working Group regarding the utilization of PET imaging in meningiomas Galldiks (Neuro Oncol. 2017;19(12):1576-87). The information provided should be considered in the context of local conditions and regulations., (© 2024. The Author(s).)

Background: Microglial activation is one hallmark of Alzheimer disease (AD) neuropathology but the impact of the regional interplay of microglia cells in the brain is poorly understood. We hypothesized that microglial activation is regionally synchronized in the healthy brain but experiences regional desynchronization with ongoing neurodegenerative disease. We addressed the existence of a microglia connectome and investigated microglial desynchronization as an AD biomarker., Methods: To validate the concept, we performed microglia depletion in mice to test whether interregional correlation coefficients (ICCs) of 18 kDa translocator protein (TSPO)-PET change when microglia are cleared. Next, we evaluated the influence of dysfunctional microglia and AD pathophysiology on TSPO-PET ICCs in the mouse brain, followed by translation to a human AD-continuum dataset. We correlated a personalized microglia desynchronization index with cognitive performance. Finally, we performed single-cell radiotracing (scRadiotracing) in mice to ensure the microglial source of the measured desynchronization., Results: Microglia-depleted mice showed a strong ICC reduction in all brain compartments, indicating microglia-specific desynchronization. AD mouse models demonstrated significant reductions of microglial synchronicity, associated with increasing variability of cellular radiotracer uptake in pathologically altered brain regions. Humans within the AD-continuum indicated a stage-depended reduction of microglia synchronicity associated with cognitive decline. scRadiotracing in mice showed that the increased TSPO signal was attributed to microglia., Conclusion: Using TSPO-PET imaging of mice with depleted microglia and scRadiotracing in an amyloid model, we provide first evidence that a microglia connectome can be assessed in the mouse brain. Microglia synchronicity is closely associated with cognitive decline in AD and could serve as an independent personalized biomarker for disease progression., (© 2024. The Author(s).)

Theranostics integrate molecular imaging and targeted radionuclide therapy for personalised cancer therapy. Theranostic treatments have shown meaningful efficacy in randomised clinical trials and are approved for clinical use in prostate cancer and neuroendocrine tumours. Brain tumours represent an unmet clinical need and theranostics might offer effective treatment options, although specific issues need to be considered for clinical development. In this Policy Review, we discuss opportunities and challenges of developing targeted radionuclide therapies for the treatment of brain tumours including glioma, meningioma, and brain metastasis. The rational choice of molecular treatment targets is highlighted, including the potential relevance of different types of targeted radionuclide therapeutics, and the role of the blood-brain barrier and blood-tumour barrier. Furthermore, we discuss considerations for effective clinical trial design and conduct, as well as logistical and regulatory challenges for implementation of radionuclide therapies into neuro-oncological practice. Rational development will foster successful translation of the theranostic concept to brain tumours., Competing Interests: Declaration of interests NLA has received honoraria for consultation or advisory board participation from Novartis, Advanced Accelerator Applications, Servier, and Telix Pharmaceuticals; and has received research funding from Novocure. ELR has received a research grant from Bristol Myers Squibb; and received honoraria for advisory board participation from AstraZeneca, Bayer, Janssen, Leo Pharma, Pfizer, Pierre Fabre, Roche, Seagen, and Servier. GM has received honoraria for speaker activity and travel support from Brainlab and Accuray. MJM has received research funding from Bristol Myers Squibb and travel support from Pierre Fabre. NG received honoraria for lectures from Blue Earth Diagnostics and for advisory board participation from Telix Pharmaceuticals. MN has received speaker fees for educational lectures from AstraZeneca and Brainlab. MS has received consultancy fees from Bracco and speaker fees from AuntMinnie and Fondazione Internazionale Menarini (all paid to institution). AV has received honoraria for consultation or advisory board participation from Curium, Eisai, General Electrics, and Novartis. MW has received research grants from Quercis and Versameb; and honoraria for lectures or advisory board participation or consulting from Bayer, Curevac, Medac, Neurosense, Novartis, Novocure, Orbus, Philogen, Roche, and Servier. MP has received honoraria for lectures, consultation, or advisory board participation from Bayer, Bristol Myers Squibb, Novartis, Gerson Lehrman Group, CMC Contrast, GlaxoSmithKline, Mundipharma, Roche, BMJ Journals, MedMedia, AstraZeneca, AbbVie, Eli Lilly, Medahead, Daiichi Sankyo, Sanofi, Merck Sharp & Dome, Tocagen, Adastra, Gan & Lee Pharmaceuticals, Janssen, Servier, Miltenyi, Böhringer-Ingelheim, Telix, and Medscape. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

PET is increasingly used for target volume definition in the radiotherapy of glioblastoma, as endorsed by the 2023 ESTRO-EANO guidelines. In view of its growing adoption into clinical practice and upcoming PET-based multi-center trials, this paper aims to assist in overcoming common pitfalls of FET PET-based target delineation in glioblastoma., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Cancer immunotherapy with chimeric antigen receptor (CAR) T cells can cause immune effector cell-associated neurotoxicity syndrome (ICANS). However, the molecular mechanisms leading to ICANS are not well understood. Here we examined the role of microglia using mouse models and cohorts of individuals with ICANS. CD19-directed CAR (CAR19) T cell transfer in B cell lymphoma-bearing mice caused microglia activation and neurocognitive deficits. The TGFβ-activated kinase-1 (TAK1)-NF-κB-p38 MAPK pathway was activated in microglia after CAR19 T cell transfer. Pharmacological TAK1 inhibition or genetic Tak1 deletion in microglia using Cx3cr1 CreER :Tak1 fl/fl mice resulted in reduced microglia activation and improved neurocognitive activity. TAK1 inhibition allowed for potent CAR19-induced antilymphoma effects. Individuals with ICANS exhibited microglia activation in vivo when studied by translocator protein positron emission tomography, and imaging mass cytometry revealed a shift from resting to activated microglia. In summary, we prove a role for microglia in ICANS pathophysiology, identify the TAK1-NF-κB-p38 MAPK axis as a pathogenic signaling pathway and provide a rationale to test TAK1 inhibition in a clinical trial for ICANS prevention after CAR19 T cell-based cancer immunotherapy., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Brain tumor diagnostics have significantly evolved with the use of positron emission tomography (PET) and advanced magnetic resonance imaging (MRI) techniques. In addition to anatomical MRI, these modalities may provide valuable information for several clinical applications such as differential diagnosis, delineation of tumor extent, prognostication, differentiation between tumor relapse and treatment-related changes, and the evaluation of response to anticancer therapy. In particular, joint recommendations of the Response Assessment in Neuro-Oncology (RANO) Group, the European Association of Neuro-oncology, and major European and American Nuclear Medicine societies highlighted that the additional clinical value of radiolabeled amino acids compared to anatomical MRI alone is outstanding and that its widespread clinical use should be supported. For advanced MRI and its steadily increasing use in clinical practice, the Standardization Subcommittee of the Jumpstarting Brain Tumor Drug Development Coalition provided more recently an updated acquisition protocol for the widely used dynamic susceptibility contrast perfusion MRI. Besides amino acid PET and perfusion MRI, other PET tracers and advanced MRI techniques (e.g. MR spectroscopy) are of considerable clinical interest and are increasingly integrated into everyday clinical practice. Nevertheless, these modalities have shortcomings which should be considered in clinical routine. This comprehensive review provides an overview of potential challenges, limitations, and pitfalls associated with PET imaging and advanced MRI techniques in patients with gliomas or brain metastases. Despite these issues, PET imaging and advanced MRI techniques continue to play an indispensable role in brain tumor management. Acknowledging and mitigating these challenges through interdisciplinary collaboration, standardized protocols, and continuous innovation will further enhance the utility of these modalities in guiding optimal patient care., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Purpose: According to the World Health Organization classification for tumors of the central nervous system, mutation status of the isocitrate dehydrogenase (IDH) genes has become a major diagnostic discriminator for gliomas. Therefore, imaging-based prediction of IDH mutation status is of high interest for individual patient management. We compared and evaluated the diagnostic value of radiomics derived from dual positron emission tomography (PET) and magnetic resonance imaging (MRI) data to predict the IDH mutation status non-invasively., Methods: Eighty-seven glioma patients at initial diagnosis who underwent PET targeting the translocator protein (TSPO) using [ 18 F]GE-180, dynamic amino acid PET using [ 18 F]FET, and T1-/T2-weighted MRI scans were examined. In addition to calculating tumor-to-background ratio (TBR) images for all modalities, parametric images quantifying dynamic [ 18 F]FET PET information were generated. Radiomic features were extracted from TBR and parametric images. The area under the receiver operating characteristic curve (AUC) was employed to assess the performance of logistic regression (LR) classifiers. To report robust estimates, nested cross-validation with five folds and 50 repeats was applied., Results: TBR GE-180 features extracted from TSPO-positive volumes had the highest predictive power among TBR images (AUC 0.88, with age as co-factor 0.94). Dynamic [ 18 F]FET PET reached a similarly high performance (0.94, with age 0.96). The highest LR coefficients in multimodal analyses included TBR GE-180 features, parameters from kinetic and early static [ 18 F]FET PET images, age, and the features from TBR T2 images such as the kurtosis (0.97)., Conclusion: The findings suggest that incorporating TBR GE-180 features along with kinetic information from dynamic [ 18 F]FET PET, kurtosis from TBR T2 , and age can yield very high predictability of IDH mutation status, thus potentially improving early patient management., (© 2024. The Author(s).)

Background: The PRIDE trial (NOA-28; ARO-2024-01; AG-NRO-06; NCT05871021) is designed to determine whether a dose escalation with 75.0 Gy in 30 fractions can enhance the median overall survival (OS) in patients with methylguanine methyltransferase (MGMT) promotor unmethylated glioblastoma compared to historical median OS rates, while being isotoxic to historical cohorts through the addition of concurrent bevacizumab (BEV). To ensure protocol-compliant irradiation planning with all study centers, a dummy run was planned and the plan quality was evaluated., Methods: A suitable patient case was selected and the computed tomography (CT), magnetic resonance imaging (MRI) and O-(2-[ 18 F]fluoroethyl)-L-tyrosine (FET) positron emission tomography (PET) contours were made available. Participants at the various intended study sites performed radiation planning according to the PRIDE clinical trial protocol. The treatment plans and dose grids were uploaded as Digital Imaging and Communications in Medicine (DICOM) files to a cloud-based platform. Plan quality and protocol adherence were analyzed using a standardized checklist, scorecards and indices such as Dice Score (DSC) and Hausdorff Distance (HD)., Results: Median DSC was 0.89, 0.90, 0.88 for PTV60, PTV60ex (planning target volume receiving 60.0 Gy for the standard and the experimental plan, respectively) and PTV75 (PTV receiving 75.0 Gy in the experimental plan), respectively. Median HD values were 17.0 mm, 13.9 mm and 12.1 mm, respectively. These differences were also evident in the volumes: The PTV60 had a volume range of 219.1-391.3 cc (median: 261.9 cc) for the standard plans, while the PTV75 volumes for the experimental plans ranged from 71.5-142.7 cc (median: 92.3 cc). The structures with the largest deviations in Dice score were the pituitary gland (median 0.37, range 0.00-0.69) and the right lacrimal gland (median 0.59, range 0.42-0.78)., Conclusions: The deviations revealed the necessity of systematic trainings with appropriate feedback before the start of clinical trials in radiation oncology and the constant monitoring of protocol compliance throw-out the study., Trial Registration: NCT05871021., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Sex differences in brain physiology and the mechanisms of drug action have been extensively reported. These biological variances, from structure to hormonal and genetic aspects, can profoundly influence healthy functioning and disease mechanisms and might have implications for treatment and drug development. Molecular neuroimaging techniques may help to disclose sex's impact on brain functioning, as well as the neuropathological changes underpinning several diseases. This narrative review summarizes recent lines of evidence based on PET and SPECT imaging, highlighting sex differences in normal conditions and various neurological disorders., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Valentina Garibotto reports a relationship with Swiss National Science Foundation, by the Velux foundation, by the Schmidheiny foundation, the Boninchi foundation and by the Aetas foundation that includes: funding grants. Nathalie L Albert reports a relationship with Novartis Advanced Accelerator Applications, Telix Pharmaceuticals, Servier, Novocure that includes: consulting or advisory and funding grants. Silvia Morbelli reports a relationship with Italian Ministry of University and Research that includes: funding grants. Kathrin Heinrich reports a relationship with Roche, Taiho, BMS, Merck, Servier, MSD (Institutional), Merck, Janssen, Amgen, Merck, Servier that includes: funding grants and travel reimbursement. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Therapeutic approaches to brain tumors remain a challenge, with considerable limitations regarding delivery of drugs. There has been renewed and increasing interest in translating the popular theranostic approach well known from prostate and neuroendocrine cancer to neurooncology. Although far from perfect, some of these approaches show encouraging preliminary results, such as for meningioma and leptomeningeal spread of certain pediatric brain tumors. In brain metastases and gliomas, clinical results have failed to impress. Perspectives on these theranostic approaches regarding meningiomas, brain metastases, gliomas, and common pediatric brain tumors will be discussed. For each tumor entity, the general context, an overview of the literature, and future perspectives will be provided. Ongoing studies will be discussed in the supplemental materials. As most theranostic agents are unlikely to cross the blood-brain barrier, the delivery of these agents will be dependent on the successful development and clinical implementation of techniques enhancing permeability and retention. Moreover, the international community should strive toward sufficiently large and randomized studies to generate high-level evidence on theranostic approaches with radioligand therapies for central nervous system tumors., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Background and Objectives: 18-kDa translocator protein position-emission-tomography (TSPO-PET) imaging emerged for in vivo assessment of neuroinflammation in Alzheimer's disease (AD) research. Sex and obesity effects on TSPO-PET binding have been reported for cognitively normal humans (CN), but such effects have not yet been systematically evaluated in patients with AD. Thus, we aimed to investigate the impact of sex and obesity on the relationship between β-amyloid-accumulation and microglial activation in AD., Methods: 49 patients with AD (29 females, all Aβ-positive) and 15 Aβ-negative CN (8 female) underwent TSPO-PET ([ 18 F]GE-180) and β-amyloid-PET ([ 18 F]flutemetamol) imaging. In 24 patients with AD (14 females), tau-PET ([ 18 F]PI-2620) was additionally available. The brain was parcellated into 218 cortical regions and standardized-uptake-value-ratios (SUVr, cerebellar reference) were calculated. Per region and tracer, the regional increase of PET SUVr (z-score) was calculated for AD against CN. The regression derived linear effect of regional Aβ-PET on TSPO-PET was used to determine the Aβ-plaque-dependent microglial response (slope) and the Aβ-plaque-independent microglial response (intercept) at the individual patient level. All read-outs were compared between sexes and tested for a moderation effect of sex on associations with body mass index (BMI)., Results: In AD, females showed higher mean cortical TSPO-PET z-scores (0.91 ± 0.49; males 0.30 ± 0.75; p = 0.002), while Aβ-PET z-scores were similar. The Aβ-plaque-independent microglial response was stronger in females with AD (+ 0.37 ± 0.38; males with AD - 0.33 ± 0.87; p = 0.006), pronounced at the prodromal stage. On the contrary, the Aβ-plaque-dependent microglial response was not different between sexes. The Aβ-plaque-independent microglial response was significantly associated with tau-PET in females (Braak-II regions: r = 0.757, p = 0.003), but not in males. BMI and the Aβ-plaque-independent microglial response were significantly associated in females (r = 0.44, p = 0.018) but not in males (BMI*sex interaction: F (3,52)  = 3.077, p = 0.005)., Conclusion: While microglia response to fibrillar Aβ is similar between sexes, women with AD show a stronger Aβ-plaque-independent microglia response. This sex difference in Aβ-independent microglial activation may be associated with tau accumulation. BMI is positively associated with the Aβ-plaque-independent microglia response in females with AD but not in males, indicating that sex and obesity need to be considered when studying neuroinflammation in AD., (© 2024. The Author(s).)

Background: The translocator protein (TSPO) has been proven to have great potential as a target for the positron emission tomography (PET) imaging of glioblastoma. However, there is an ongoing debate about the potential various sources of the TSPO PET signal. This work investigates the impact of the inoculation-driven immune response on the PET signal in experimental orthotopic glioblastoma., Methods: Serial [ 18 F]GE-180 and O -(2-[ 18 F]fluoroethyl)-L-tyrosine ([ 18 F]FET) PET scans were performed at day 7/8 and day 14/15 after the inoculation of GL261 mouse glioblastoma cells (n = 24) or saline (sham, n = 6) into the right striatum of immunocompetent C57BL/6 mice. An additional n = 25 sham mice underwent [ 18 F]GE-180 PET and/or autoradiography (ARG) at days 7, 14, 21, 28, 35, 50 and 90 in order to monitor potential reactive processes that were solely related to the inoculation procedure. In vivo imaging results were directly compared to tissue-based analyses including ARG and immunohistochemistry., Results: We found that the inoculation process represents an immunogenic event, which significantly contributes to TSPO radioligand uptake. [ 18 F]GE-180 uptake in GL261-bearing mice surpassed [ 18 F]FET uptake both in the extent and the intensity, e.g., mean target-to-background ratio (TBR mean ) in PET at day 7/8: 1.22 for [ 18 F]GE-180 vs. 1.04 for [ 18 F]FET, p < 0.001. Sham mice showed increased [ 18 F]GE-180 uptake at the inoculation channel, which, however, continuously decreased over time (e.g., TBR mean in PET: 1.20 at day 7 vs. 1.09 at day 35, p = 0.04). At the inoculation channel, the percentage of TSPO/IBA1 co-staining decreased, whereas TSPO/GFAP (glial fibrillary acidic protein) co-staining increased over time ( p < 0.001)., Conclusion: We identify the inoculation-driven immune response to be a relevant contributor to the PET signal and add a new aspect to consider for planning PET imaging studies in orthotopic glioblastoma models.

Background and Objectives: Corticobasal syndrome (CBS) with underlying 4-repeat tauopathy is a progressive neurodegenerative disease characterized by declining cognitive and motor functions. Biomarkers for assessing pathologic brain changes in CBS including tau-PET, 18 kDa translocator protein (TSPO)-PET, structural MRI, neurofilament light chain (NfL), or glial fibrillary acidic protein (GFAP) have recently been evaluated for differential diagnosis and disease staging, yet their association with disease trajectories remains unclear. Therefore, we performed a head-to-head comparison of neuroimaging (tau-PET, TSPO-PET, structural MRI) and plasma biomarkers (NfL, GFAP) as prognostic tools for longitudinal clinical trajectories in β-amyloid (Aβ)-negative CBS., Methods: We included patients with clinically diagnosed Aβ-negative CBS with clinical follow-up data who underwent baseline structural MRI and plasma-NfL analysis for assessing neurodegeneration, [ 18 F]PI-2620-PET for assessing tau pathology, [ 18 F]GE-180-PET for assessing microglia activation, and plasma-GFAP analysis for assessing astrocytosis. To quantify tau and microglia load, we assessed summary scores of whole-brain, cortical, and subcortical PET signal. For structural MRI analysis, we quantified subcortical and cortical gray matter volume. Plasma NfL and GFAP values were assessed using Simoa-based immunoassays. Symptom progression was determined using a battery of cognitive and motor tests (i.e., Progressive Supranuclear Palsy Rating Scale [PSPRS]). Using linear mixed models, we tested whether the assessed biomarkers at baseline were associated with faster symptom progression over time (i.e., time × biomarker interaction)., Results: Overall, 21 patients with Aβ-negative CBS with ∼2-year clinical follow-up data were included. Patients with CBS with more widespread global tau-PET signal showed faster clinical progression (PSPRS: B/SE = 0.001/0.0005, p = 0.025), driven by cortical rather than subcortical tau-PET. By contrast, patients with higher global [ 18 F]GE-180-PET readouts showed slower clinical progression (PSPRS: B/SE = -0.056/0.023, p = 0.019). No association was found between gray matter volume and clinical progression. Concerning fluid biomarkers, only higher plasma-NfL (PSPRS: B/SE = 0.176/0.046, p < 0.001) but not GFAP was associated with faster clinical deterioration. In a subsequent sensitivity analysis, we found that tau-PET, TSPO-PET, and plasma-NfL showed significant interaction effects with time on clinical trajectories when tested in the same model., Discussion: [ 18 F]PI-2620 tau-PET, [ 18 F]GE-180 TSPO-PET, and plasma-NfL show prognostic potential for clinical progression in patients with Aβ-negative CBS with probable 4-repeat tauopathy, which can be useful for clinical decision-making and stratifying patients in clinical trials.

Response Assessment in Neuro-Oncology (RANO) response criteria have been established and were updated in 2023 for MRI-based response evaluation of diffuse gliomas in clinical trials. In addition, PET-based imaging with amino acid tracers is increasingly considered for disease monitoring in both clinical practice and clinical trials. So far, a standardised framework defining timepoints for baseline and follow-up investigations and response evaluation criteria for PET imaging of diffuse gliomas has not been established. Therefore, in this Policy Review, we propose a set of criteria for response assessment based on amino acid PET imaging in clinical trials enrolling participants with diffuse gliomas as defined in the 2021 WHO classification of tumours of the central nervous system. These proposed PET RANO criteria provide a conceptual framework that facilitates the structured implementation of PET imaging into clinical research and, ultimately, clinical routine. To this end, the PET RANO 1.0 criteria are intended to encourage specific investigations of amino acid PET imaging of gliomas., Competing Interests: Declaration of interests NLA has received honoraria for consultation or advisory board participation from Novartis (Advanced Accelerator Applications), Telix Pharmaceuticals, and Servier; and research funding from Novocure. NG received honoraria for lectures from Blue Earth Diagnostics and honoraria for advisory board participation from Telix Pharmaceuticals. BME is on the advisory board and is a paid consultant for Medicenna, MedQIA, Servier Pharmaceuticals, Siemens, Janssen Pharmaceuticals, Imaging Endpoints, Kazia, Chimerix, Sumitomo Dainippon Pharma Oncology, ImmunoGenesis, Ellipses Pharma, Monteris, Neosoma, Alpheus Medical, Sagimet Biosciences, Sapience Therapeutics, Orbus Therapeutics, and the Global Coalition for Adaptive Research. MJvdB has received honoraria from Roche, AstraZeneca, Servier, Boehringer, Genenta, Fore Biotherapeutics, Incyte, and Nerviano. ELR reports personal financial interests as an advisory board member for Bayer, Janssen, Leo Pharma, Pierre Fabre, Roche, Seattle Genetics, and Servier; and institutional funding from Bristol Myers Squibb. MJM has received research support from Bristol Myers Squibb and travel support from Pierre Fabre. GM has received honoraria for lectures from BrainLab. RR has received research grants from Bayer, and honoraria for lectures or consulting from UCB, Novocure, Genenta, Curevac, and Servier. AMS has received research support to his institution from Medimmune, AVID, Telix Pharmaceuticals, ITM, Fusion, Cyclotek, Adalta, TheraMyc, Curis, Humanigen, and Antengene; funding support from the Medical Research Future Fund, Australian Brain Cancer Mission, Cure Brain Cancer Foundation, National Breast Cancer Foundation, Australian Cancer Research Foundation, National Imaging Facility, and Victorian Cancer Agency; and is a National Health and Medical Research Council Investigator. MS has received honoraria for consultancy from Bracco and honoraria for lectures from GE Healthcare, AuntMinnie, and Fondazione Internazionale Menarini (all paid to their institution). BS has received honoraria for lectures and consultation from Novocure. J-CT has received honoraria for lectures, consultation, or advisory board participation from SeagGen, AAA-Novartis, Novocure, and Munich Surgical Imaging. AV has received honoraria for lectures and advisory board participation from Curium, Eisai, and General Electrics. MW has received research grants from Quercis and Versameb; and honoraria for lectures or advisory board participation or consulting from Bayer, Curevac, Medac, Novartis, Novocure, Orbus, Philogen, Roche, and Servier. PYW has received research support from AstraZeneca, Black Diamond, Bristol Myers Squibb, Celgene, Chimerix, Eli Lilly, Erasca, Genentech/Roche, Kazia, MediciNova, Merck, Novartis, Nuvation Bio, Servier, Vascular Biogenics, and VBI Vaccines; and honoraria for serving as a consultant or on advisory boards for AstraZeneca, Black Diamond, Celularity, Chimerix, Day One Bio, Genenta, GSK, Merck, Mundipharma, Novartis, Novocure, Nuvation Bio, Prelude Therapeutics, Sapience, Servier, Sagimet, Vascular Biogenics, and VBI Vaccines. MP has received honoraria for lectures, consultation, or advisory board participation from Bayer, Bristol Myers Squibb, Novartis, Gerson Lehrman Group, CMC Contrast, GSK, Mundipharma, Roche, BMJ Journals, MedMedia, AstraZeneca, AbbVie, Lilly, Medahead, Daiichi Sankyo, Sanofi, Merck Sharp & Dohme, Tocagen, Adastra, Gan & Lee Pharmaceuticals, and Servier; and travel support from Servier, Roche, and Medsir., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background and Purpose: The PRIDE trial (NOA-28; ARO-2022-12; NCT05871021) is scheduled to start recruitment in October 2023. Its primary objective is to enhance median overall survival (OS), compared to historical median OS rates, in patients with methylguanine methlyltransferase (MGMT) promotor unmethylated glioblastoma by incorporating isotoxic dose escalation to 75 Gy in 30 fractions. To achieve isotoxicity and counteract the elevated risk of radiation necrosis (RN) associated with dose-escalated regimens, the addition of protective concurrent bevacizumab (BEV) serves as an innovative approach. The current study aims to assess the dosimetric feasibility of the proposed concept., Materials and Methods: A total of ten patients diagnosed with glioblastoma were included in this dosimetric analysis. Delineation of target volumes for the reference plans adhered to the ESTRO-EANO 2023 guideline. The experimental plans included an additional volume for the integrated boost. Additionally, the 60 Gy-volume was reduced by using a margin of 1.0 cm instead of 1.5 cm. To assess the risk of symptomatic RN, the Normal Tissue Complication Probability (NTCP) was calculated and compared between the reference and experimental plans., Results: Median NTCP of the reference plan (NTCP ref ) and of the experimental plan (NTCP ex ) were 0.24 (range 0.11-0.29) and 0.42 (range 0.18-0.54), respectively. NTCP ex was a median of 1.77 (range 1.60-1.99) times as high as the NTXP ref . In a logarithmic comparison, the risk of RN is enhanced by a factor of median 2.00 (range 1.66-2.35). The defined constraints for the organs at risk were feasible., Conclusion: When considering the potential protective effect of BEV, which we hypothesized might reduce the risk of RN by approximately two-fold, achieving isotoxicity with the proposed dose-escalated experimental plan for the PRIDE trial seems feasible., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Author(s).)

Purpose: Tumor resection represents the first-line treatment for symptomatic meningiomas, and the extent of resection has been shown to be of prognostic importance. Assessment of tumor remnants with somatostatin receptor PET proves to be superior to intraoperative estimation with Simpson grading or MRI. In this preliminary study, we evaluate the prognostic relevance of postoperative PET for progression-free survival in meningiomas., Methods: We conducted a post hoc analysis on a prospective patient cohort with resected meningioma WHO grade 1. Patients received postoperative MRI and [ 68 Ga]Ga-DOTA-TATE PET/CT and were followed regularly with MRI surveillance scans for detection of tumor recurrence/progression., Results: We included 46 patients with 49 tumors. The mean age at diagnosis was 57.8 ± 1.7 years with a male-to-female ratio of 1:1.7. Local tumor progression occurred in 7/49 patients (14%) after a median follow-up of 52 months. Positive PET was associated with an increased risk for progression (*p = 0.015) and a lower progression-free survival (*p = 0.029), whereas MRI was not. 20 out of 20 patients (100%) with negative PET findings remained recurrence-free. The location of recurrence/progression on MRI was adjacent to regions where postoperative PET indicated tumor remnants in all cases. Gross tumor volumes were higher on PET compared to MRI (*p = 0.032)., Conclusion: Our data show that [ 68 Ga]Ga-DOTA-TATE PET/CT is highly sensitive in revealing tumor remnants in patients with meningioma WHO grade 1. Negative PET findings were associated with a higher progression-free survival, thus improving surveillance. In patients with tumor remnants, additional PET can optimize adjuvant radiotherapy target planning of surgically resected meningiomas., (© 2023. The Author(s).)

Surgical resection represents the standard of care for people with newly diagnosed diffuse gliomas, and the neuropathological and molecular profile of the resected tissue guides clinical management and forms the basis for research. The Response Assessment in Neuro-Oncology (RANO) consortium is an international, multidisciplinary effort that aims to standardise research practice in neuro-oncology. These recommendations represent a multidisciplinary consensus from the four RANO groups: RANO resect, RANO recurrent glioblastoma, RANO radiotherapy, and RANO/PET for a standardised workflow to achieve a representative tumour evaluation in a disease characterised by intratumoural heterogeneity, including recommendations on which tumour regions should be surgically sampled, how to define those regions on the basis of preoperative imaging, and the optimal sample volume. Practical recommendations for tissue sampling are given for people with low-grade and high-grade gliomas, as well as for people with newly diagnosed and recurrent disease. Sampling of liquid biopsies is also addressed. A standardised workflow for subsequent handling of the resected tissue is proposed to avoid information loss due to decreasing tissue quality or insufficient clinical information. The recommendations offer a framework for prospective biobanking studies., Competing Interests: Declaration of interests MS declares consultancy for Bracco and honoraria from GE Healthcare and AuntMinnie. ELR declares honoraria from AbbVie, Adastra, Daiichi Sankyo, LEO Pharma, Seagen, and Tocagen. BME declares advisory board participation and consulting for Medicenna, MedQIA, Servier Pharmaceuticals, Siemens, Janssen Pharmaceuticals, Imaging Endpoints, Kazia, Chimerix, Sumitomo Dainippon Pharma Oncology, ImmunoGenesis, Ellipses Pharma, Monteris, Neosoma, Alpheus Medical, Sagimet Biosciences, Sapience Therapeutics, and the Global Coalition for Adaptive Research. MMK declares consultancy for Blue Earth Diagnostics and research grants from EpicentRx and Blue Earth Diagnostics. NLA declares research grants from Novocure and honoraria from Novartis and Telix. MPM declares consulting for Karyopharm Therapeutics, Mevion Medical Systems, ZappRx, Sapience Therapeutics, and Xoft; being part of the board of directors for Oncoceutics; ownership of WARF patent 14/934,27, Topical Vasoconstrictor Preparations and Methods for Protecting Cells During Cancer Chemotherapy and Radiotherapy; and stock at Chimerix. MvdB declares consultancy for Celgene, BMS, Agios, Boehringer, AbbVie, Bayer, Carthera, Nerviano, and Genenta. MW declares research grants from Quercis and Versameb; honoraria from Novocure and Bayer; and consulting or advisory roles for CureVac, Medac, Novartis, Orbus Therapeutics, Philogen, and Bayer. MAV declares indirect equity and patent royalty interests from Infuseon Therapeutics; honoraria from Chimerix and Midatech; and research grants from DeNovo Pharma, Oncosynergy, Infuseon, and Chimerix. J-CT declares research grants from Novocure and Munich Surgical Imaging; participating on an advisory board for AAA Novartis; and royalties from Springer Publisher. PK, GR, NG, JTH, OS, PNH, MM, LvB, RYH, SMC, and MSB declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Various cellular sources hamper interpretation of positron emission tomography (PET) biomarkers in the tumor microenvironment (TME). We developed an approach of immunomagnetic cell sorting after in vivo radiotracer injection (scRadiotracing) with three-dimensional (3D) histology to dissect the cellular allocation of PET signals in the TME. In mice with implanted glioblastoma, translocator protein (TSPO) radiotracer uptake per tumor cell was higher compared to tumor-associated microglia/macrophages (TAMs), validated by protein levels. Translation of in vitro scRadiotracing to patients with glioma immediately after tumor resection confirmed higher single-cell TSPO tracer uptake of tumor cells compared to immune cells. Across species, cellular radiotracer uptake explained the heterogeneity of individual TSPO-PET signals. In consideration of cellular tracer uptake and cell type abundance, tumor cells were the main contributor to TSPO enrichment in glioblastoma; however, proteomics identified potential PET targets highly specific for TAMs. Combining cellular tracer uptake measures with 3D histology facilitates precise allocation of PET signals and serves to validate emerging novel TAM-specific radioligands.

β-amyloid (Aβ) and tau aggregation as well as neuronal injury and atrophy (ATN) are the major hallmarks of Alzheimer's disease (AD), and biomarkers for these hallmarks have been linked to neuroinflammation. However, the detailed regional associations of these biomarkers with microglial activation in individual patients remain to be elucidated. We investigated a cohort of 55 patients with AD and primary tauopathies and 10 healthy controls that underwent TSPO-, Aβ-, tau-, and perfusion-surrogate-PET, as well as structural MRI. Z-score deviations for 246 brain regions were calculated and biomarker contributions of Aβ (A), tau (T), perfusion (N1), and gray matter atrophy (N2) to microglial activation (TSPO, I) were calculated for each individual subject. Individual ATN-related microglial activation was correlated with clinical performance and CSF soluble TREM2 (sTREM2) concentrations. In typical and atypical AD, regional tau was stronger and more frequently associated with microglial activation when compared to regional Aβ (AD: β T  = 0.412 ± 0.196 vs. β A  = 0.142 ± 0.123, p < 0.001; AD-CBS: β T  = 0.385 ± 0.176 vs. β A  = 0.131 ± 0.186, p = 0.031). The strong association between regional tau and microglia reproduced well in primary tauopathies (β T  = 0.418 ± 0.154). Stronger individual associations between tau and microglial activation were associated with poorer clinical performance. In patients with 4RT, sTREM2 levels showed a positive association with tau-related microglial activation. Tau pathology has strong regional associations with microglial activation in primary and secondary tauopathies. Tau and Aβ related microglial response indices may serve as a two-dimensional in vivo assessment of neuroinflammation in neurodegenerative diseases., (© 2023. The Author(s).)

The 18-kDa translocator protein (TSPO) is gaining recognition as a relevant target in glioblastoma imaging. However, data on the potential prognostic value of TSPO PET imaging in glioblastoma are lacking. Therefore, we investigated the association of TSPO PET imaging results with survival outcome in a homogeneous cohort of glioblastoma patients. Methods: Patients were included who had newly diagnosed, histologically confirmed isocitrate dehydrogenase (IDH)-wild-type glioblastoma with available TSPO PET before either normofractionated radiotherapy combined with temozolomide or hypofractionated radiotherapy. SUV max on TSPO PET, TSPO binding affinity status, tumor volumes on MRI, and further clinical data, such as O 6 -alkylguanine DNA methyltransferase ( MGMT ) and telomerase reverse transcriptase ( TERT ) gene promoter mutation status, were correlated with patient survival. Results: Forty-five patients (median age, 63.3 y) were included. Median SUV max was 2.2 (range, 1.0-4.7). A TSPO PET signal was associated with survival: High uptake intensity (SUV max > 2.2) was related to significantly shorter overall survival (OS; 8.3 vs. 17.8 mo, P = 0.037). Besides SUV max , prognostic factors for OS were age ( P = 0.046), MGMT promoter methylation status ( P = 0.032), and T2-weighted MRI volume ( P = 0.031). In the multivariate survival analysis, SUV max in TSPO PET remained an independent prognostic factor for OS ( P = 0.023), with a hazard ratio of 2.212 (95% CI, 1.115-4.386) for death in cases with a high TSPO PET signal (SUV max > 2.2). Conclusion: A high TSPO PET signal before radiotherapy is associated with significantly shorter survival in patients with newly diagnosed IDH-wild-type glioblastoma. TSPO PET seems to add prognostic insights beyond established clinical parameters and might serve as an informative tool as clinicians make survival predictions for patients with glioblastoma., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

TSPO is a promising novel tracer target for positron-emission tomography (PET) imaging of brain tumors. However, due to the heterogeneity of cell populations that contribute to the TSPO-PET signal, imaging interpretation may be challenging. We therefore evaluated TSPO enrichment/expression in connection with its underlying histopathological and molecular features in gliomas. We analyzed TSPO expression and its regulatory mechanisms in large in silico datasets and by performing direct bisulfite sequencing of the TSPO promotor. In glioblastoma tissue samples of our TSPO-PET imaging study cohort, we dissected the association of TSPO tracer enrichment and protein labeling with the expression of cell lineage markers by immunohistochemistry and fluorescence multiplex stains. Furthermore, we identified relevant TSPO-associated signaling pathways by RNA sequencing.We found that TSPO expression is associated with prognostically unfavorable glioma phenotypes and that TSPO promotor hypermethylation is linked to IDH mutation. Careful histological analysis revealed that TSPO immunohistochemistry correlates with the TSPO-PET signal and that TSPO is expressed by diverse cell populations. While tumor core areas are the major contributor to the overall TSPO signal, TSPO signals in the tumor rim are mainly driven by CD68-positive microglia/macrophages. Molecularly, high TSPO expression marks prognostically unfavorable glioblastoma cell subpopulations characterized by an enrichment of mesenchymal gene sets and higher amounts of tumor-associated macrophages.In conclusion, our study improves the understanding of TSPO as an imaging marker in gliomas by unveiling IDH-dependent differences in TSPO expression/regulation, regional heterogeneity of the TSPO PET signal and functional implications of TSPO in terms of tumor immune cell interactions., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Somatostatin-receptor (SSTR)-targeted PET/CT provides important clinical information in addition to standard imaging in meningioma patients. [ 18 F]SiTATE is a novel, 18 F-labeled SSTR-targeting peptide with superior imaging properties according to preliminary data. We provide the first [ 18 F]SiTATE PET/CT data of a large cohort of meningioma patients., Methods: Patients with known or suspected meningioma undergoing [ 18 F]SiTATE PET/CT were included. Uptake intensity (SUV) of meningiomas, non-meningioma lesions, and healthy organs were assessed using a 50% isocontour volume of interest (VOI) or a spherical VOI, respectively. Also, trans-osseous extension on PET/CT was assessed., Results: A total of 107 patients with 117 [ 18 F]SiTATE PET/CT scans were included. Overall, 231 meningioma lesions and 61 non-meningioma lesions (e.g., post-therapeutic changes) were analyzed. Physiological uptake was lowest in healthy brain tissue, followed by bone marrow, parotid, and pituitary (SUV mean 0.06 ± 0.04 vs. 1.4 ± 0.9 vs. 1.6 ± 1.0 vs. 9.8 ± 4.6; p < 0.001). Meningiomas showed significantly higher uptake than non-meningioma lesions (SUV max 11.6 ± 10.6 vs. 4.0 ± 3.3, p < 0.001). Meningiomas showed significantly higher uptake than non-meningioma lesions (SUVmax 11.6±10.6 vs. 4.0±3.3, p<0.001). 93/231 (40.3%) meningiomas showed partial trans-osseous extension and 34/231 (14.7%) predominant intra-osseous extension. 59/231 (25.6%) meningioma lesions found on PET/CT had not been reported on previous standard imaging., Conclusion: This is the first PET/CT study using an 18 F-labeled SSTR-ligand in meningioma patients: [ 18 F]SiTATE provides extraordinary contrast in meningioma compared to healthy tissue and non-meningioma lesions, which leads to a high detection rate of so far unknown meningioma sites and osseous involvement. Having in mind the advantageous logistic features of 18 F-labeled compared to 68 Ga-labeled compounds (e.g., longer half-life and large-badge production), [ 18 F]SiTATE has the potential to foster a widespread use of SSTR-targeted imaging in neuro-oncology., (© 2023. The Author(s).)

The bone marrow in the skull is important for shaping immune responses in the brain and meninges, but its molecular makeup among bones and relevance in human diseases remain unclear. Here, we show that the mouse skull has the most distinct transcriptomic profile compared with other bones in states of health and injury, characterized by a late-stage neutrophil phenotype. In humans, proteome analysis reveals that the skull marrow is the most distinct, with differentially expressed neutrophil-related pathways and a unique synaptic protein signature. 3D imaging demonstrates the structural and cellular details of human skull-meninges connections (SMCs) compared with veins. Last, using translocator protein positron emission tomography (TSPO-PET) imaging, we show that the skull bone marrow reflects inflammatory brain responses with a disease-specific spatial distribution in patients with various neurological disorders. The unique molecular profile and anatomical and functional connections of the skull show its potential as a site for diagnosing, monitoring, and treating brain diseases., Competing Interests: Declaration of interests M. Brendel received speaker honoraria from GE healthcare, Roche, and Life Molecular Imaging and is an advisor of Life Molecular Imaging. J.H. reports personal fees, research grants, and non-financial support from Merck, Bayer, Novartis, Roche, Biogen, and Celgene and non-financial support of the Guthy-Jackson Charitable Foundation—none in relation to this study. C.P. is inventor in a patent “Oral Phenylbutyrate for Treatment of Human 4-Repeat Tauopathies” (EP 23 156 122.6) filed by LMU Munich. T.K. has received speaker honoraria and/or personal fees for advisory boards from Bayer Healthcare, Teva Pharma, Merck, Novartis, Sanofi/Genzyme, Roche, and Biogen as well as grant support from Novartis and Chugai Pharma—none in relation to this study. M.K. has been on advisory boards for Biogen, medDay Pharmaceuticals, Novartis, and Sanofi; has received grant support from Sanofi and Biogen; and has received speaker fees from Abbvie, Almirall, Biogen, medDay Pharmaceuticals, Merck Serono, Novartis, Roche, Sanofi, and Teva—none in relation to this study. R.P. has received speaker honoraria, research support, and consultancy fees from Janssen, Eli Lilly, Biogen, Wilmar Schwabe, Takeda, Novo Nordisk, and Bayer Healthcare. N.K. has received speaker honoraria from Novartis and Regeneron and research grants from Regeneron—none in relationship to this study. M.I.T., H.S.B., M.N., and A.E. received speaker honoraria from Miltenyi Biotec—none in relation to this study. A.E. is co-founder of Deep Piction and 1X1 Biotech., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)