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Despite its indolent evolution, vitreoretinal lymphoma (VRL) has a poor prognosis due to a major risk of relapse in the central nervous system (CNS) and may necessitate aggressive therapy. However, the use of high-dose chemotherapy with autologous stem cell transplantation (HCT-ASCT) is poorly documented. We retrospectively analysed from the French LOC network database the adult immunocompetent patients treated with HCT-ASCT for isolated VRL. Thirty-eight patients underwent consolidation with HCT-ASCT for isolated VRL between 2008 and 2019 after induction chemotherapy. Twenty patients had primary VRL, and 18 had an isolated VRL relapse of a primary CNS lymphoma. Three patients underwent HCT-ASCT in first-line treatment, 24 in second-line treatment, and 11 in subsequent lines. At HCT-ASCT, the median age was 61 years, and the median KPS was 90. Thirty-two patients (84%) received high-dose thiotepa-based HCT. One patient (3%) died from HCT-ASCT toxicity. Nineteen (50%) patients relapsed after HCT-ASCT, including 17 cases occurring in the brain. The median progression-free survival, brain-free survival and overall survival from HCT-ASCT were 96, 113 and 92 months, respectively. HCT-ASCT represents an effective therapeutic strategy for select VRL patients, with a tolerable safety profile. However, the risk of subsequent brain relapse remains significant., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Purpose: Patients with IDH-mutant 1p/19q-codeleted grade 3 oligodendroglioma (O3 IDHmt/Codel ) benefit from adding alkylating agent chemotherapy to radiotherapy (RT). However, the optimal chemotherapy regimen between procarbazine, 1-(2-Chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU), and vincristine (PCV) and temozolomide (TMZ) remains unclear given the lack of randomized trial data comparing both regimens., Methods: The objective was to assess the overall survival (OS) and progression-free survival (PFS) associated with first-line PCV/RT versus TMZ/RT in patients newly diagnosed with O3 IDHmt/Codel . We included patients with histologically proven O3 IDHmt/Codel (according to WHO criteria) from the French national prospective cohort Prise en charge des OLigodendrogliomes Anaplasiques (POLA). All tumors underwent central pathological review. OS and PFS from surgery were estimated using the Kaplan-Meier method and Cox regression model., Results: 305 newly diagnosed patients with O3 IDHmt/Codel treated with RT and chemotherapy between 2008 and 2022 were included, of which 67.9% of patients (n = 207) were treated with PCV/RT and 32.1% with TMZ/RT (n = 98). The median follow-up was 78.4 months (IQR, 44.3-102.7). The median OS was not reached (95% CI, Not reached [NR] to NR) in the PCV/RT group and was 140 months (95% CI, 110 to NR) in the TMZ/RT group (log-rank P = .0033). On univariable analysis, there was a significant difference in favor of PCV/RT in both 5-year (PCV/RT: 89%, 95% CI, 85 to 94; TMZ/RT: 75%, 95% CI, 66 to 84) and 10-year OS (PCV/RT: 72%, 95% CI, 61 to 85; TMZ/RT: 60%, 95% CI, 49 to 73), which was confirmed using the multivariable Cox model adjusted for age, type of surgery, gender, Eastern Cooperative Oncology Group performance status, and CDKN2A homozygous deletion (hazard ratio, 0.53 for PCV/RT, 95% CI, 0.30 to 0.92, P = .025)., Conclusion: In patients with newly diagnosed O3 IDHmt/Codel from the POLA cohort, first-line PCV/RT was associated with better OS outcomes compared with TMZ/RT. Our data suggest that the improved safety profile associated with TMZ comes at the cost of inferior efficacy in this population. Further investigation using prospective randomized studies is warranted.

Background/aim: Treatment of primary central nervous system lymphoma (PCNSL) includes high dose methotrexate-based polychemotherapy (HD-MTX). This study aimed to identify early predictive factors of methotrexate (MTX) delayed elimination., Patients and Methods: We prospectively included all patients with newly-diagnosed PCNSL. Daily serum and urinary creatinine and ionogram were collected. We generated two independent cohorts: a training cohort (TC) and a confirmatory cohort (CC)., Results: We included for analysis 64 cures of HD-MTX (20 patients) in the TC and 59 cures (22 patients) in the CC. Median elimination time of MTX was 95 h and 96 h in the TC and CC, respectively. In multivariate analysis, older age (p=0.004), low Karnofsky Performance Status (p=0.036) and high urinary K + (p=0.001) were associated with delayed MTX elimination. An optimal cutoff for urinary K + was defined. In the CC, we confirmed that high urinary K + (p=0.004) remained associated with delayed MTX elimination., Conclusion: High urinary K + may be predictive of delayed MTX elimination in primary central nervous system lymphoma. Its relevance as a decision-making factor needs to be validated in additional prospective studies., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Results of conventional induction chemotherapies in primary central nervous system lymphoma (PCNSL) need to be improved. Ibrutinib, a BTK inhibitor, and lenalidomide, an immunomodulatory drug, have shown promising results at relapse, supporting to further assess their individual use in combination with high-dose methotrexate-based chemotherapy., Methods: Patients with newly diagnosed PCNSL were randomized to receive four 28-day cycles of ibrutinib or lenalidomide in combination with R-MPV (rituximab, methotrexate, procarbazine, vincristine and prednisone) in a 3 + 3 design. Responders then received a consolidation with R-Cytarabine and an intensive chemotherapy with autologous stem cell transplantation. The objective of the phase IB study was to define the recommended phase II dose (RP2D) based on the dose-limiting toxicity (DLT) occurring during the first induction cycle., Results: Twenty-six patients (median age 52) were randomized. Four DLTs were observed: one grade 5 aspergillosis and pneumocystosis, one grade 4 catheter-related infection and two grade 3 increased alanine aminotransferase levels. RP2D of ibrutinib and lenalidomide were 560 mg daily (D3-14 and D17-28) and 15 mg daily (D1-21) respectively, in combination with R-MPV. In both arms, the most frequent grade ≥3 treatment-related adverse events were hepatic cytolysis, neutropenia and infections. One grade 4 Lyell's syndrome was reported at cycle 2 in the lenalidomide arm. After 4 induction cycles, the overall response rates were 76.9% and 83.3% in the lenalidomide and ibrutinib arm, respectively., Conclusion: Targeted induction therapies combining lenalidomide or ibrutinib with R-MPV are feasible for first-line PCNSL. The safety profile is consistent with the known safety profiles of R-MPV and both targeted therapies. The phase II part of the study is ongoing., Trial Registration: NCT04446962., (© 2024. The Author(s).)

Background: Oncogenic FGFR-TACC fusions are present in 3-5% of high-grade gliomas (HGGs). Fexagratinib (AZD4547) is an oral FGFR1-3 inhibitor with preclinical activity in FGFR-TACC+ gliomas. We tested its safety and efficacy in patients with recurrent FGFR-TACC + HGGs., Patients and Methods: TARGET (NCT02824133) is a phase I/II open-label multicenter study that included adult patients with FGFR-TACC + HGGs relapsing after ≥1 line of standard chemoradiation. Patients received fexagratinib 80 mg bd on a continuous schedule until disease progression or unacceptable toxicity. The primary endpoint was the 6-month progression-free survival rate (PFS6)., Results: Twelve patients with recurrent IDH wildtype FGFR-TACC + HGGs (all FGFR3-TACC3+) were included in the efficacy cohort (male/female ratio = 1.4, median age = 61.5 years). Most patients (67%) were included at the first relapse. The PFS6 was 25% (95% confidence interval 5-57%), with a median PFS of 1.4 months. All patients without progression at 6 months ( n  = 3) were treated at first recurrence (versus 56% of those in progression) and remained progression-free for 14-23 months. The best response was RANO partial response in 1 patient (8%), stable disease in 5 (42%), and progressive disease in 6 (50%). Median survival was 17.5 months from inclusion. Grade 3 toxicities included lymphopenia, hyperglycaemia, stomatitis, nail changes, and alanine aminotransferase increase ( n  = 1 each). No grade 4-5 toxicities were seen. A 32-gene signature was associated with the benefit of FGFR inhibition in FGFR3-TACC3 + HGGs., Conclusions: Fexagratinib exhibited acceptable toxicity but limited efficacy in recurrent FGFR3-TACC3 + HGGs. Patients treated at first recurrence appeared more likely to benefit, yet additional evidence is required., Competing Interests: A.P. and M.S. declare having received travel support from Astra Zeneca. The other authors have declared no conflict of interest relevant to this paper., (© The Author(s) 2024. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Purpose: Several retrospective studies and meta-analyses of Peptide Radionuclide Radiation Therapy in meningiomas suggest six-month progression-free survival improvement for WHO grade 1 and 2 meningiomas. In the present study, we aimed to evaluate the impact of such treatment on three-dimensional volume growth rate (3DVGR) in nonanaplastic meningiomas., Methods: The authors performed a retrospective study including eight patients treated with Lutathera®. Millimetric 3D T1-weighted with gadolinium enhancement magnetic resonance imaging sequences were requested for volume measurement. Then, tumor growth rate was classified following a previously described 3DVGR classification (Graillon et al.)., Results: Patients harbored seven WHO grade 2 meningiomas and one aggressive WHO grade 1. All patients, except one, underwent four treatment cycles. 3DVGR significantly decreased at 3, 6, and 12 months after treatment initiation analyzing each lesion separately. Mean and median 3DVGR from all patients were respectively at 29.5% and 44.5%/6 months before treatment initiation, then at 16.5% and 25%/6 months at three months post-treatment initiation, 9.5% and 4.5%/6 months after 6 months, as well as 9.5% and 10.5%/6 months after 12 months. At 3, 6, and 12 months after treatment initiation, 4/8, 6/7, and 5/6 patients were class 2 (stabilization or severe 3DVGR slowdown), respectively. No patient was class 1 at 6 and 12 months, suggesting a lack of drug response., Conclusion: In nonanaplastic meningiomas, Lutathera®'s antitumoral activity appeared delayed and more likely observed at six months, while no major response was observed under treatment. Moreover, its antitumoral activity persisted for 12-18 months following treatment initiation., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Here, the results of a phase 1/2 single-arm trial (NCT03744026) assessing the safety and efficacy of blood-brain barrier (BBB) disruption with an implantable ultrasound system in recurrent glioblastoma patients receiving carboplatin are reported. A nine-emitter ultrasound implant was placed at the end of tumor resection replacing the bone flap. After surgery, activation to disrupt the BBB was performed every four weeks either before or after carboplatin infusion. The primary objective of the Phase 1 was to evaluate the safety of escalating numbers of ultrasound emitters using a standard 3 + 3 dose escalation. The primary objective of the Phase 2 was to evaluate the efficacy of BBB opening using magnetic resonance imaging (MRI). The secondary objectives included safety and clinical efficacy. Thirty-three patients received a total of 90 monthly sonications with carboplatin administration and up to nine emitters activated without observed DLT. Grade 3 procedure-related adverse events consisted of pre syncope (n = 3), fatigue (n = 1), wound infection (n = 2), and pain at time of device connection (n = 7). BBB opening endpoint was met with 90% of emitters showing BBB disruption on MRI after sonication. In the 12 patients who received carboplatin just prior to sonication, the progression-free survival was 3.1 months, the 1-year overall survival rate was 58% and median overall survival was 14.0 months from surgery., (© 2024. The Author(s).)

Background: Temozolomide (TMZ) oral suspension (Ped-TMZ, KIZFIZO ® ) is being developed for the treatment of relapsed or refractory neuroblastoma, a rare cancer affecting infants and young children. The study assessed the safety and the bioequivalence of this novel pediatric formulation with existing TMZ oral capsules., Methods: In vitro dissolution profiles and the bioequivalence were evaluated following the European Medicines Agency "Guidelines on the investigation of Bioequivalence". The phase I, multicenter, randomized, open-label, crossover, single-dose bioequivalence study enrolled 36 adult patients with glioblastoma multiforme or lower-grade glioma. Each patient received 200 mg/m 2 Ped-TMZ suspension and TMZ capsules (Temodal ® ) on 2 consecutive days, with the order being randomly assigned. Fourteen blood samples were collected up to 10 h post-dosing. Bioequivalence was assessed by comparing the 90% confidence interval for the ratio of the geometric means of maximum TMZ plasma concentration (C max ) and the area under the curve (AUCt). Other endpoints included further pharmacokinetic parameters and safety., Results: Both formulations exhibited a fast in vitro dissolution profile with more than 85% of TMZ dissolved within 15 min. For the bioequivalence study, thirty patients completed the trial as per the protocol. The ratio of Ped-TMZ/TMZ capsule geometric means (90% CI) for AUCt and C max were 97.18% (95.05-99.35%) and 107.62% (98.07-118.09%), respectively, i.e., within the 80-125% bioequivalence limits. No buccal toxicity was associated with Ped-TMZ liquid formulation., Conclusions: This study showed that Ped-TMZ oral suspension and TMZ oral capsule treatment are immediate release and bioequivalent medicines. There were also no unexpected safety signals or local toxicity (funded by ORPHELIA Pharma; ClinicalTrials.gov number, NCT04467346).

Background: Pharmacological synergisms are an attractive anticancer strategy. However, with more than 5000 approved-drugs and compounds in clinical development, identifying synergistic treatments represents a major challenge., Methods: High-throughput screening was combined with target deconvolution and functional genomics to reveal targetable vulnerabilities in glioblastoma. The role of the top gene hit was investigated by RNA interference, transcriptomics and immunohistochemistry in glioblastoma patient samples. Drug combination screen using a custom-made library of 88 compounds in association with six inhibitors of the identified glioblastoma vulnerabilities was performed to unveil pharmacological synergisms. Glioblastoma 3D spheroid, organotypic ex vivo and syngeneic orthotopic mouse models were used to validate synergistic treatments., Findings: Nine targetable vulnerabilities were identified in glioblastoma and the top gene hit RRM1 was validated as an independent prognostic factor. The associations of CHK1/MEK and AURKA/BET inhibitors were identified as the most potent amongst 528 tested pairwise drug combinations and their efficacy was validated in 3D spheroid models. The high synergism of AURKA/BET dual inhibition was confirmed in ex vivo and in vivo glioblastoma models, without detectable toxicity., Interpretation: Our work provides strong pre-clinical evidence of the efficacy of AURKA/BET inhibitor combination in glioblastoma and opens new therapeutic avenues for this unmet medical need. Besides, we established the proof-of-concept of a stepwise approach aiming at exploiting drug poly-pharmacology to unveil druggable cancer vulnerabilities and to fast-track the identification of synergistic combinations against refractory cancers., Funding: This study was funded by institutional grants and charities., Competing Interests: Declaration of interests The authors have declared no conflict of interest., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: Primary central nervous system lymphoma (PCNSL) is a rare, chemo and radio-sensitive tumor limited to the central nervous system. The incidence of PCSNL increases notably in the elderly population which represented approximately half of the patients. The limit of 'elderly' population remained debated and nonuniform, including 60 years as a cutoff for brain radiotherapy, 65 years for autologous stem-cell transplantation, and 70 years for the last clinical trials. Current therapeutic options include first line treatment based on high-dose methotrexate based polychemotherapy, consolidation chemotherapy, and adapted autologous stem cell transplantation for highly selected patients. At relapse, single agent targeted therapies or salvage chemotherapy followed by intensive consolidation are promising therapeutic options. Nevertheless, improving management of elderly patients is an urgent medical need that currently remains unresolved., Objective: We will focus on elderly patients with PCNSL and their specificities including clinical presentations, available therapeutic options and adaptations to be made., Conclusion: To improve survival, it will be necessary to personalized and adapt the treatments, to each patient and his comorbidities, to increase their effectiveness and limit their toxicity in this frail population. Finally, inclusion of these patients in clinical trials is one of the major challenges to significantly change PCNSL elderly patient prognosis., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: The purpose of this study is to develop a European Organisation for Research and Treatment of Cancer Quality of Life Group (EORTC QLG) questionnaire that captures the full range of physical, mental, and social health-related quality of life (HRQOL) issues relevant to disease-free cancer survivors. In this phase III study, we pretested the provisional core questionnaire (QLQ-SURV111) and aimed to identify essential and optional scales., Methods: We pretested the QLQ-SURV111 in 492 cancer survivors from 17 countries with one of 11 cancer diagnoses. We applied the EORTC QLG decision rules and employed factor analysis and item response theory (IRT) analysis to assess and, where necessary, modify the hypothesized questionnaire scales. We calculated correlations between the survivorship scales and the QLQ-C30 summary score and carried out a Delphi survey among healthcare professionals, patient representatives, and cancer researchers to distinguish between essential and optional scales., Results: Fifty-four percent of the sample was male, mean age was 60 years, and, on average, time since completion of treatment was 3.8 years. Eleven items were excluded, resulting in the QLQ-SURV100, with 12 functional and 9 symptom scales, a symptom checklist, 4 single items, and 10 conditional items. The essential survivorship scales consist of 73 items., Conclusions: The QLQ-SURV100 has been developed to assess comprehensively the HRQOL of disease-free cancer survivors. It includes essential and optional scales and will be validated further in an international phase IV study., Implications for Cancer Survivors: The availability of this questionnaire will facilitate a standardized and robust assessment of the HRQOL of disease-free cancer survivors., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Median survival with glioblastoma remains in the range of 12 months on population levels. Only few patients survive for more than 5 years. Patient and disease features associated with long-term survival remain poorly defined., Methods: European Organization for Research and Treatment of Cancer (EORTC) 1419 (ETERNITY) is a registry study supported by the Brain Tumor Funders Collaborative in the US and the EORTC Brain Tumor Group. Patients with glioblastoma surviving at least 5 years from diagnosis were identified at 24 sites in Europe, US, and Australia. In patients with isocitrate dehydrogenase (IDH) wildtype tumours, prognostic factors were analysed using the Kaplan-Meier method and the Cox proportional hazards model. A population-based reference cohort was obtained from the Cantonal cancer registry Zurich., Results: At the database lock of July 2020, 280 patients with histologically centrally confirmed glioblastoma (189 IDH wildtype, 80 IDH mutant, 11 incompletely characterised) had been registered. In the IDH wildtype population, median age was 56 years (range 24-78 years), 96 patients (50.8%) were female, 139 patients (74.3%) had tumours with O 6 -methylguanine DNA methyltransferase (MGMT) promoter methylation. Median overall survival was 9.9 years (95% confidence interval [95% CI] 7.9-11.9). Patients without recurrence experienced longer median survival (not reached) than patients with one or more recurrences (8.92 years) (p < 0.001) and had a high rate (48.8%) of MGMT promoter-unmethylated tumours., Conclusions: Freedom from progression is a powerful predictor of overall survival in long-term survivors with glioblastoma. Patients without relapse often have MGMT promoter-unmethylated glioblastoma and may represent a distinct subtype of glioblastoma., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: C.H. has received a research grant for protected time by the Filling the Gap foundation and honoraria for lecture from Vifor; E.L.R. has received honoraria for lectures or advisory board from Bayer, Janssen, Leo Pharma, Pierre Fabre, Seattle Genetics; J.C. has received research funding from Servier and Merck and consultant for Servier; R.S. reports consultation for Bayer, Astra Zeneca; W.W. reports consultation for Apogenix, Astra Zeneca, Bayer, Enterome, Medac, MSD and Roche/Genentech with honoraria paid to the Medical Faculty at the University of Heidelberg; F.D. has received honoraria for lectures or advisory board participation from Novocure; P.R. has received honoraria for lectures or advisory board participation from Bristol-Myers Squibb, Boehringer Ingelheim, Debiopharm, Merck Sharp and Dohme, Midatech, Novocure, QED, and Roche and research support from Merck Sharp and Dohme and Novocure; P.H. has received honoraria for lectures or advisory board participation or consulting from Bayer, Lilly, medac, Novartis, Novocure and Seagen; A.H. has received honoraria for lectures, consultation or advisory board participation from Novocure and Novartis; G.L. has received funding for a consulting or advisory role from Bayer, AbbVie, Orbus Therapeutics, BrainFarm, Health4U, Novartis, Braun and Janssen, and funding for travel from Roche, Bayer, and Ipsen; D.K. has received honoraria for lectures, consultation or advisory board participation from Novocure and BrainLab; M.G. reports honoraria from Roche, Novartis, UCB, AbbVie, Daiichi Sankyo, Novocure, Seagen, Bayer, Janssen-Cilag, Medac, Merck, Kyowa Kirin, travel support from Novocure and Medac, research grant from Novocure; D.R. reports support from Agenus, Agios; AnHeart Therapeutics, Avita Biomedical, Inc., Blue Rock Therapeutics, Bristol Myers Squibb, Boston Biomedica, CureVac AG, Del Mar Pharma, DNAtrix, Enterome, Hoffman-LaRoche, Ltd, Imvax, Janssen, Kiyatec, Medicenna Therapeutics, Neuvogen, Novartis, Novocure, Pyramid Bio, Sumitomo Dainippon Pharma. Vivacitas Oncology, Inc, Y-mabs Therapeutics; M.v.d.B has received honoraria for consultancy from Genenta, Servier, Astra Zeneca, Boehringer-Ingelheim, Carthera, Nerviano, Chimerix, Roche, Fore Biotherapeutics, Menarini-Stemline, Incyte and Sumitomo Pharma Oncology; F.L. received research funding from the Fonds Erasme; U.H. reports honoraria for lectures and and/or advisory board participation from Medac, Janssen, Bayer; E.R. reports travels grants BMS, Pfizer, MSD, Sanofi, Roche, Karyo labs Honorarium MSD, Servier; AF.C. received honoraria for lectures and/or advisory board participation from Gilead, Novartis; R.Ru. has received honoraria for lectures or consultation or advisory board from UCB, Novocure, Bayer, Genenta; M.P. 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; P.W. has received research support from Astra Zeneca/Medimmune, Beigene, Celgene, Chimerix, Eli Lily, Genentech/Roche, Kazia, MediciNova, Merck, Novartis, Nuvation Bio, Puma, Servier, Vascular Biogenics, VBI Vaccines and honoraria for advisory board participation or serving on data safety monitoring board from Astra Zeneca, Bayer, Black Diamond, Celularity, Chimerix, Day One Bio, Genenta, Novartis, Prelude Therapeutics, Sapience, Servier, Sagimet, Vascular Biogenics, VBI Vaccines; MW has received research grants from Quercis and Versameb, and honoraria for lectures or advisory board participation or consulting from Bayer, Medac, Merck (EMD), Novartis, Orbus, and Philogen. All remaining authors declare that they have no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

68 Ga-DOTATOC PET could be a noninvasive, highly sensitive, and specific technique for the challenging diagnosis of optic nerve sheath meningioma (ONSM). Our objective was to report the use and results of 68 Ga-DOTATOC PET in suspected ONSM. Twelve subjects who underwent 68 Ga-DOTATOC PET for suspected ONSM in our department were retrospectively included. Standardised clinical and radiological data were collected. The PET examination results were classified as positive or negative, and lesion standardised uptake values (SUV max ) were recorded. 68 Ga-DOTATOC PET confirmed positive uptake in six cases (SUV max > 5), leading to ONSM diagnoses followed by radiation therapy in patients with vision loss. Six 68 Ga-DOTATOC PET scans were considered negative (SUV max < 5); these comprised one case of neurosarcoidosis, one cavernous malformation, and four uncertain diagnoses, leading to further investigation. 68 Ga-DOTATOC PET was helpful in tumour volume delineation before radiation therapy, leading to a decrease in dose exposure. Noninvasive 68 Ga-DOTATOC PET should be performed before treating nonhistologically proven meningiomas with radiotherapy or stereotactic radiosurgery, particularly in cases of uncertain diagnosis with MRI, which characterises most ONSM cases. PET SUV max thresholds to distinguish meningioma from nonspecific uptake in other lesions need to be adapted to ONSM. 68 Ga-DOTATOC PET improves the intraorbital lesion diagnostic approach and therefore impacts therapeutic management.

Multi-recurrent high-grade meningiomas remain an unmet medical need in neuro-oncology when iterative surgeries and radiation therapy sessions fail to control tumor growth. Nevertheless, the last 10years have been marked by multiple advances in the comprehension of meningioma tumorigenesis via the discovery of new driver mutations, the identification of activated intracellular signaling pathways, and DNA methylation analyses, providing multiple potential therapeutic targets. Today, Anti-VEGF and mTOR inhibitors are the most used and probably the most active drugs in aggressive meningiomas. Peptide radioactive radiation therapy aims to target SSTR2A receptors, which are strongly expressed in meningiomas, but have an insufficient effect in most aggressive meningiomas, requiring the development of new techniques to increase the dose applied to the tumor. Based on the multiple potential intracellular targets, multiple targeted therapy clinical trials targeting Pi3K-Akt-mTOR and MAP kinase pathways as well as cell cycle and particularly, cyclin D4-6 are ongoing. Recently discovered driver mutations, SMO, Akt, and PI3KCA, offer new targets but are mostly observed in benign meningiomas, limiting their clinical relevance mainly to rare aggressive skull base meningiomas. Therefore, NF2 mutation remains the most frequent mutation and main challenging target in high-grade meningioma. Recently, inhibitors of focal adhesion kinase (FAK), which is involved in tumor cell adhesion, were tested in a phase 2 clinical trial with interesting but insufficient activity. The Hippo pathway was demonstrated to interact with NF2/Merlin and could be a promising target in NF2-mutated meningiomas with ongoing multiple preclinical studies and a phase 1 clinical trial. Recent advances in immune landscape comprehension led to the proposal of the use of immunotherapy in meningiomas. Except in rare cases of MSH2/6 mutation or high tumor mass burden, the activity of PD-1 inhibitors remains limited; however, its combination with various radiation therapy modalities is particularly promising. On the whole, therapeutic management of high-grade meningiomas is still challenging even with multiple promising therapeutic targets and innovations., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Positron emission tomography (PET) is a powerful tool that can help physicians manage primary brain tumours at diagnosis and follow-up. In this context, PET imaging is used with three main types of radiotracers: 18 F-FDG, amino acid radiotracers, and 68 Ga conjugated to somatostatin receptor ligands (SSTRs). At initial diagnosis, 18 F-FDG helps to characterize primary central nervous system (PCNS) lymphomas and high-grade gliomas, amino acid radiotracers are indicated for gliomas, and SSTR PET ligands are indicated for meningiomas. Such radiotracers provide information on tumour grade or type, assist in directing biopsies and help with treatment planning. During follow-up, in the presence of symptoms and/or MRI modifications, the differential diagnosis between tumour recurrence and post-therapeutic changes, in particular radiation necrosis, may be challenging, and there is strong interest in using PET to evaluate therapeutic toxicity. PET may also contribute to identifying specific complications, such as postradiation therapy encephalopathy, encephalitis associated with PCNS lymphoma, and stroke-like migraine after radiation therapy (SMART) syndrome associated with glioma recurrence and temporal epilepsy, originally illustrated in this review. This review summarizes the main contribution of PET to the diagnosis, management, and follow-up of brain tumours, specifically gliomas, meningiomas, and primary central nervous system lymphomas., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Background: "Biopsy-only" glioblastoma (BO-GBM) is a heterogeneous, understudied group of patients associated with a poor outcome. Our objective was to explore the pattern of care and prognosis associated with BO-GBM in our center., Methods: Patients with IDH wild-type BO-GBM included in a prospective regional cohort initiated in 2014 and closed in 2017 were retrospectively reviewed for patient characteristics, MRI findings, treatment allocation, and delivery., Results: Of 535 patients included in the cohort, 137 patients were included in the present analysis. The median age was 66 years old and the median KPS was 70. Forty-six patients (33.6%) were referred to radiotherapy and chemotherapy (RT-TMZ) regimen, 75 (54.7%), considered unfitted for RT, received chemotherapy upfront (CT) and 16 (11.7%) were referred to palliative care (PC). Regarding the first group, 91% of patients completed the RT-TMZ. In the CT group, 11 of 75 patients (14.7%) underwent radiotherapy after chemotherapy upfront. Median overall survival was 12.3 months (95% CI, 15.30-24.16), 5.7 months (95% CI, 6.22-9.20), and 1.9 months (95% CI, 1.43-5.08) in RT-TMZ, CT, and PC groups, respectively. In multivariate analyses, progression-free survival was impacted by baseline KPS ( P < .001) and MGMT status ( P = .004). Overall survival was impacted by baseline KPS ( P < .001) and age ( P = .030)., Conclusion: BO-GBM constitute a large and heterogeneous population in which one-third of patients is amenable to the standard of care, with survival outcome close to one of the patients who underwent surgery. Reliable criteria are needed to help select patients for adequate treatment while new strategies are warranted for BO-GBM unfit for RT., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology and the European Association of Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Depressive symptoms are common among patients with glioblastoma, but patients are often not treated with antidepressants. There is only limited evidence on the association of antidepressant drug use with survival in glioblastoma. We performed a pooled analysis of patients treated within the CENTRIC, CORE, AVAglio and ACT-IV trials to explore the relation of antidepressant drug use with progression-free (PFS) and overall survival (OS) at baseline, at the start of maintenance therapy and at the start of maintenance cycle 4. We further assessed the association of antidepressant drugs with seizure, cognition, fatigue and a diagnosis of depression. Among more than 1700 patients, we found no significant association between the use of antidepressants at baseline or at the start of maintenance therapy and PFS or OS. However, we found OS, but not PFS, to be significantly worse in patients using antidepressants at the start of maintenance cycle 4. After adjustment for antiepileptic drug use and despite showing a trend for increased risk, seizures were not significantly associated with antidepressant drug use, nor was there a change in mini mental state examination (MMSE) scores or fatigue by antidepressant drug use at baseline. However, there was a significant positive association between antidepressant use at the start of maintenance treatment and fatigue during maintenance treatment. The association of antidepressant use at the start of maintenance cycle 4 with inferior OS of glioblastoma patients requires independent confirmation and further study. Further prospective trials should evaluate efficacy, side effects and associations with outcome of antidepressants in glioblastoma., (© 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: Incidence and characteristics of pseudoprogression in isocitrate dehydrogenase-mutant high-grade gliomas (IDHmt HGG) remain to be specifically described., Methods: We analyzed pseudoprogression characteristics and explored the possibility of pseudoprogression misdiagnosis in IDHmt HGG patients, treated with radiotherapy (RT) (with or without chemotherapy [CT]), included in the French POLA network. Pseudoprogression was analyzed in patients with MRI available for review (reference cohort, n = 200). Pseudoprogression misdiagnosis was estimated in this cohort and in an independent cohort (control cohort, n = 543) based on progression-free survival before and after first progression., Results: In the reference cohort, 38 patients (19%) presented a pseudoprogression after a median time of 10.5 months after RT. Pseudoprogression characteristics were similar across IDHmt HGG subtypes. In most patients, it consisted of the appearance of one or several infracentimetric, asymptomatic, contrast-enhanced lesions occurring within 2 years after RT. The only factor associated with pseudoprogression occurrence was adjuvant PCV CT. Among patients considered as having a first true progression, 7 out of 41 (17%) in the reference cohort and 35 out of 203 (17%) in the control cohort were retrospectively suspected to have a misdiagnosed pseudoprogression. Patients with a misdiagnosed pseudoprogression were characterized by a time to event and an outcome similar to that of patients with a pseudoprogression but presented with larger and more symptomatic lesions., Conclusion: In patients with an IDHmt HGG, pseudoprogression occurs later than in IDH-wildtype glioblastomas and seems not only frequent but also frequently misdiagnosed. Within the first 2 years after RT, the possibility of a pseudoprogression should be carefully considered., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Primary central nervous system lymphoma (PCNSL) is a rare and distinct entity within diffuse large B-cell lymphoma presenting with variable response rates probably to underlying molecular heterogeneity., Patients and Methods: To identify and characterize PCNSL heterogeneity and facilitate clinical translation, we carried out a comprehensive multi-omic analysis [whole-exome sequencing, RNA sequencing (RNA-seq), methylation sequencing, and clinical features] in a discovery cohort of 147 fresh-frozen (FF) immunocompetent PCNSLs and a validation cohort of formalin-fixed, paraffin-embedded (FFPE) 93 PCNSLs with RNA-seq and clinico-radiological data., Results: Consensus clustering of multi-omic data uncovered concordant classification of four robust, non-overlapping, prognostically significant clusters (CS). The CS1 and CS2 groups presented an immune-cold hypermethylated profile but a distinct clinical behavior. The 'immune-hot' CS4 group, enriched with mutations increasing the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) and nuclear factor-κB activity, had the most favorable clinical outcome, while the heterogeneous-immune CS3 group had the worse prognosis probably due to its association with meningeal infiltration and enriched HIST1H1E mutations. CS1 was characterized by high Polycomb repressive complex 2 activity and CDKN2A/B loss leading to higher proliferation activity. Integrated analysis on proposed targets suggests potential use of immune checkpoint inhibitors/JAK1 inhibitors for CS4, cyclin D-Cdk4,6 plus phosphoinositide 3-kinase (PI3K) inhibitors for CS1, lenalidomide/demethylating drugs for CS2, and enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) inhibitors for CS3. We developed an algorithm to identify the PCNSL subtypes using RNA-seq data from either FFPE or FF tissue., Conclusions: The integration of genome-wide data from multi-omic data revealed four molecular patterns in PCNSL with a distinctive prognostic impact that provides a basis for future clinical stratification and subtype-based targeted interventions., Competing Interests: Disclosure GA reports grants from Biogen, Novartis, Roche, Sanofi, Abbvie, Pfizer, and CSL Behring, outside the submitted work. AA reports research grant with an unrestricted grant from Bristol Myers Squibb (BMS). All other authors have declared no conflicts of interest., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Glioblastoma (GBM) is the most frequent and aggressive primary brain tumor in adults. Recently, we demonstrated that plasma denaturation profiles of glioblastoma patients obtained using Differential Scanning Fluorimetry can be automatically distinguished from healthy controls with the help of Artificial Intelligence (AI). Here, we used a set of machine-learning algorithms to automatically classify plasma denaturation profiles of glioblastoma patients according to their EGFR status. We found that Adaboost AI is able to discriminate EGFR alterations in GBM with an 81.5% accuracy. Our study shows that the use of these plasma denaturation profiles could answer the unmet neuro-oncology need for diagnostic predictive biomarker in combination with brain MRI and clinical data, in order to allow for a rapid orientation of patients for a definitive pathological diagnosis and then treatment. We complete this study by showing that discriminating another mutation, MGMT, seems harder, and that post-surgery monitoring using our approach is not conclusive in the 48 h that follow the surgery.