Current guidelines for immune-related neurotoxicities recommend discontinuation of immune checkpoint inhibitors (ICIs) and steroid therapy in severe cases. However, the management of ICI-related neuropathies remains less standardised, with intravenous immunoglobulin (IVIg) frequently combined with steroids despite limited evidence. This study aims to evaluate the treatment responses to immune-modulatory treatments in a multicenter French cohort of patients with ICI-related neuropathies. We conducted a retrospective analysis of patients with ICI-related neuropathies from six French centers. Clinical, biological and electrophysiological data were collected at baseline, 3 months, and 6 months. Patients were classified into three groups based on neuropathy type: demyelinating, axonal, or multiradiculopathic. The outcome was defined by changes in the modified Rankin Scale (mRS) and the Inflammatory Neuropathy Cause and Treatment (INCAT) disability scores between baseline and follow-up visits. Forty-eight patients with ICI-related neuropathies were identified including 24 demyelinating neuropathies, 18 axonal neuropathies, and 6 multifocal radiculopathies. Most presented with subacute onset and predominant sensory symptoms. ICIs were discontinued in all patients, and immunomodulatory therapy was initiated for severe cases, primarily steroids alone (n = 25) or steroids combined with IVIg (n = 14). Overall, 90% of patients achieved a favourable and rapid outcome: 11 experienced complete recovery, while 32 showed partial or subtotal improvement. No significant advantage was observed in adding IVIg to steroids when comparing the two treatment groups. In the analysis of other variables, a higher baseline disability score (INCAT) was the only factor significantly associated with poorer outcomes. The following variables did not significantly impact outcomes: neuropathy type, ICI class, treatment type, presence of antiganglioside antibodies, or time to ICI discontinuation and steroid initiation. ICIs were reintroduced in eleven patients, with good tolerance observed. Although limited by its retrospective design, this study did not demonstrate a clear added benefit of IVIg when combined with steroids as first-line treatment for ICI-related neuropathies. Reintroduction of ICIs after resolution of neurological impairment appears safe and feasible.

INTRODUCTION:Immune checkpoint inhibitor (ICI)-related optic neuritis is rare but clinically significant as visual sequelae are reported in around half of affected patients. MATERIALS AND METHODS:We retrospectively collected all cases of ICI-related optic neuropathy referred to two tertiary centers. A systematic review of PubMed, Embase, and Medline was conducted following PRISMA guidelines. Cases were classified into: i) optic neuritis, defined by the presence of consistent symptoms (visual loss, dyschromatopsia, afferent pupillary defect) and optic nerve abnormalities on MRI or visual evoked potentials (VEPs); ii) papillitis, defined by any visual disturbance associated with optic disc oedema and absence of optic neuropathy signs on MRI imaging or VEPs. RESULTS:Fifty cases were identified. The most common presentation was bilateral, painless visual acuity reduction with papilledema. All optic neuritis cases involved vision loss compared to 60 % of papillitis patients, who also reported scotomas, photopsia, or floaters. Papillitis was frequently associated with uveitis, either isolated or as part of Vogt-Koyanagi-Harada-like syndrome, whereas optic neuritis was more often associated with immune-related neurological toxicities, including neuromyelitis optica spectrum disorder. Despite immunomodulatory treatment, visual deficits persisted in 60 % of cases - rising to nearly 80 % in optic neuritis cases. Seven patients with papillitis and one with optic neuropathy resumed ICIs without recurrence. CONCLUSIONS:Two distinct patterns of ICI-induced optic neuropathy emerge: papillitis, usually associated with uveitis and Vogt-Koyanagi-Harada syndrome, and optic neuritis, linked to broader immune-related neurological toxicities and poorer outcomes. Our findings suggest that ICIs may be safely reintroduced after full recovery from ICI-related papillitis.

Introduction Les CAR-T anti-BCMA, efficaces dans le myélome multiple réfractaire ou récidivant (MM R/R), exposent à des complications neurologiques tardives. Nous présentons une évaluation prospective de leur sécurité neurologique à long terme. Objectifs Cette étude prospective monocentrique évalue la sécurité neurologique à longue terme de l’idecabtagene vicleucel (ide-cel) chez les patients atteints de MM R/R, à l’aide d’évaluations cognitives et motrices standardisées. Méthodes Une évaluation neurologique a été conduite chez des patients traités par ide-cel entre novembre 2021 et décembre 2024. Seuls les patients sans progression ont été inclus. Les évaluations, réalisées par un neurologue avant et jusqu’à 20 mois [intervalle 9,8–19,4] post-traitement, comprenaient le Montreal Cognitive Assessement (MoCA) et la sous-échelle motrice de l’Unified Parkinson Disease Rating Scale (UPDRS). Une IRM cérébrale pré-traitement permettait d’exclure les anomalies structurelles. Les cas de neurotoxicité ont été enregistrés rétrospectivement. Résultats Parmi les 88 patients traités par ide-cel, 48 ont été exclus pour une rechute précoce (n=42) ou perte de vue (n=6). Sur les 40 patients éligibles, les scores cognitifs et moteurs sont restés stables entre l’évaluation initiale (MoCA médian de 26 et UPDRS moteur maximal de 4 points) et les évaluations de suivi (MoCA médian de 27 et UPDRS moteur maximal de 3 points). Un syndrome de neurotoxicité associée aux cellules effectrices du system immunitaire (ICANS) a été signalé chez quatre patients (trois grade 1 et un grade 4, nécessitant des soins intensifs). Discussion Sur 20 mois, notre suivi prospectif utilisant MoCA et UPDRS fournit des données sur la sécurité neurologique à long terme de l’ide-cel. La neurotoxicité précoce est bien documentée, tandis que des manifestations tardives isolées (syndrome parkinsonien) sont rares. Les scores cognitifs et moteurs restent stables chez les patients sans progression. Conclusion Notre étude fournit, pour la première fois, des données démontrant une stabilité cognitive et motrice après ide-cel, soutenant une bonne tolérance neurologique à long terme.

Abstract Background Clinical scores incompletely capture outcomes in primary central nervous system lymphoma (PCNSL). We quantified morphologic heterogeneity in pretreatment hematoxylin and eosin (H&E) whole slides. Patients and methods Three independent cohorts of immunocompetent, HIV- and EBV-negative patients treated recently were analyzed: LOC 2023 (122 slides), phase III BLOCAGE-01 (245 slides; NCT02313389 ), and external Barcelona (BCN; 41 slides). UNI embeddings, prototype learning, spatial metrics, and elastic-net Cox regression defined ITH-C. Results Models achieved bootstrap-corrected concordance of 0.797–0.834. Age-, sex-, and KPS-adjusted ITH-C HRs were 1.29 (95% CI 1.01–1.64), 1.27 (1.07–1.51), and 2.13 (1.35–3.37), respectively. Adding ITH-C increased MSKCC C-index from 0.671 to 0.717, 0.560 to 0.593, and 0.588 to 0.706. Spatial transcriptomics linked ITH-C to immune programs. Conclusions Routine H&E encodes prognostic spatial heterogeneity in PCNSL. ITH-C complements clinical scores, supporting prospective risk stratification.

Introduction Les neuropathies induites par les inhibiteurs de checkpoint immunitaire (ICI) sont classiquement prises en charge par l’arrêt des ICI et corticothérapie, mais le bénéfice de l’ajout d’immunoglobulines intraveineuses (IVIG) reste débattu. Objectifs Cette étude vise à évaluer l’efficacité des traitements par immunomodulateurs (corticoïdes±IVIG) dans une cohorte multicentrique française de neuropathies liées aux ICI. Méthodes Une analyse rétrospective a été menée sur une cohorte multicentrique française de patients présentant une neuropathie liée aux ICI. Les données cliniques et paracliniques ont été recueillies au diagnostic, puis à 3 et 6 mois. L’efficacité thérapeutique était évaluée par les variations des scores de Rankin modifiée et INCAT. Résultats 48 patients ont été inclus (24 neuropathies démyélinisantes, 18 axonales, 6 multiradiculopathies), majoritairement caractérisés par un début subaigu et des symptômes sensitifs prédominants. Un traitement a été initié dans les formes sévères : corticoïdes seuls (n=25) ou associés aux IVIG (n=14). Une amélioration rapide a été observée chez 90 % des patients, sans supériorité démontrée de l’association corticoïdes-IVIG. Aucun facteur prédictif d’évolution n’a été identifié en analyse multivariée. La réintroduction des ICI (n=10) a été bien tolérée. Discussion Cette étude confirme l’efficacité des corticostéroïdes dans la prise en charge des neuropathies liées aux ICIs. L’ajout d’IVIG n’améliore pas l’évolution, y compris dans les sous-groupes des neuropathies démyélinisantes ou avec anticorps anti-gangliosides. La réintroduction des ICI après résolution des symptômes semble sûre. Conclusion Notre étude ne supporte pas l’utilisation systématique des IVIG en première intention dans les neuropathies liées aux ICIs même dans les formes démyélinisantes.

BACKGROUND:Immune effector cell-associated neurotoxicity syndrome (ICANS) is a common, serious complication of CAR T-cell therapy for blood cancers. This study evaluates the impact of baseline cognitive status and pre-existing neurological injury on the occurrence of ICANS. METHODS:We conducted a prospective study of adult patients treated with CAR T-cell therapy for aggressive B-cell lymphoma at our centre between May 2020 and December 2023. All patients underwent neurological examination, cerebral MRI and cognitive assessment measured by the Montreal Cognitive Assessment (MoCA). We measured total metabolic tumour volume (TMTV), lactate dehydrogenase (LDH), albumin, ferritin and C-reactive protein (CRP) before CART cell infusion, and serum neurofilament light chain (NfL) levels. We evaluated the impact of these factors on ICANS occurrence using multivariate analysis. RESULTS:Among the 156 adult patients treated with CAR T-cell therapy, 32.7% developed ICANS. The median MoCA score at baseline was 26 [IQR 24; 28]. There was no significant association between the onset of ICANS and baseline cognitive performance (p 0.57). MoCA scores did not differ by ICANS grade. Pre-existing neurological injury were not associated with increased ICANS risk. In multivariable analysis, the use of CD28 CAR T cells was the strongest predictor of ICANS (p = 0.007). Slightly elevated serum NfL levels at leukapheresis predicted ICANS (p = 0.046) supporting its role in predicting risk of neurotoxicity rather than pre-existing neurological disease. CONCLUSIONS:Our results suggest that pre-existing cognitive impairment or neurological history do not increase the risk of ICANS.

PURPOSE OF REVIEW:Chimeric antigen receptor (CAR) T-cell therapies are increasingly used in hematologic malignancies and are now being investigated in autoimmune disorders. This review aims to summarize the spectrum of neurological complications associated with CAR-T. RECENT FINDINGS:While early-onset neurotoxicity is well characterized, other neurological syndromes are increasingly reported. Neurological complications can be provisionally classified into three categories: early-onset immune effector cell-associated neurotoxicity syndrome (ICANS); delayed-onset neurological syndromes specific to single CAR T-cell types; and tumour inflammation-associated neurotoxicity (TIAN). Other postinfusion neurological syndromes have also been observed but with uncertain links to CAR T-cells. Management must be tailored to preserve both neurological function and CAR T-cell efficacy. Ongoing efforts target biomarker development, and risk-adapted strategies, especially in steroid-refractory cases. SUMMARY:As CAR T-cell indications broaden, clinicians must recognize diverse neurological toxicities and implement individualized, evidence-based interventions to improve neurological outcomes.

OUTLOOK FOR THE MANAGEMENT OF GLIOBLASTOMA. Glioblastoma is the most common primary malignant tumour of the central nervous system. The standard treatment consists of surgical resection, followed by concomitant radiochemotherapy and then six courses of adjuvant temozolomide. Tumour-Treating Fields (TTF) extend the median survival to twenty months, at the cost of constant use of a brace and alopecia. These patients require close neuro-oncological monitoring, with clinico-radiological reassessment every two to three months. In the event of progression, there is no standardised treatment, and the therapeutic arsenal is limited. Given that the disease usually progresses inevitably to major functional disability and death in the months or y ears following diagnosis, early supportive care is essential.

2006 Background: UCPVax is a therapeutic vaccine designed to stimulate CD4+ helper T cell responses against telomerase (TERT), a protein highly expressed in glioblastoma (GBM). Temozolomide (TMZ), a standard chemotherapeutic agent in the treatment of GBM, has been shown to induce CD4+ T-cell lymphopenia, which could potentially impair the immune response to the vaccine. We conducted a multicenter, 2-cohort, phase IIa study to evaluate the immunogenicity and efficacy of UCPVax, with or without TMZ, as adjuvant therapy in patients with newly diagnosed GBM following chemoradiation. Methods: Patients with non-mutated IDH1 glioblastoma (GBM) were enrolled one month after completing concurrent radiotherapy and temozolomide (TMZ). Cohort A received the vaccine alone, without additional TMZ, while Cohort B was treated with both the vaccine and six monthly cycles of TMZ. The primary endpoint was the induction of TERT-specific CD4+ T cell responses, assessed ex vivo using the INF-γ ELISpot assay. Secondary endpoints included epitope spreading, clinical outcomes, and safety. Results: Thirty-one GBM patients with unmethylated MGMT status were included in cohort A, and 30 patients (50% with unmethylated MGMT status) were included in cohort B. The vaccine was well tolerated, with no vaccine-related serious adverse events. Vaccine-expanded TERT-specific CD4+ T cells were detectable ex vivo in 25/30 (83%) of patients in cohort A (no additional TMZ) and in 18/26 69% of patients in cohort B (treated with additional TMZ). Epitope spreading was induced in 29 out of 55 evaluable patients (52.7%), corresponding to 15/26 (57.7%) in cohort A and 14/29 (48%) in cohort B. Median overall survival (OS) was significantly improved in patients who developed an epitope spread response compared to those who did not (19.3 vs. 12.8 months, P = 0.03). In the 44 patients with measurable disease at the time of inclusion, the radiological response rate (RR) was 34%, including minor responses. In patients who developed epitope spreading after vaccination (n = 22), the RR was 50%, compared to 18.7% in patients without epitope spreading (P = 0.05). Furthermore, tumor-infiltrating lymphocytes against TERT were detected in 3 vaccinated patients who underwent surgery at recurrence. Conclusions: UCPVax demonstrated robust immunogenicity, even when co-administered with TMZ, and was associated with improved overall survival (OS) in GBM patients who developed an epitope spreading response. These findings support further clinical investigation of TERT-derived CD4+ helper vaccine in GBM patients. Clinical trial information: NCT04280848 .

Background: Novel effective treatments are needed for recurrent IDH mutant high-grade gliomas (IDHm HGGs). The aim of the multicentric, single -arm, phase II REVOLUMAB trial (NCT03925246) was to assess the efficacy and safety of the anti-PD1 Nivolumab in patients with recurrent IDHm HGGs. Patients and methods: Adult patients with IDHm WHO grade 3 -4 gliomas recurring after radiotherapy and >= 1 line of alkylating chemotherapy were treated with intravenous Nivolumab until end of treatment (12 months), progression, unacceptable toxicity, or death. The primary endpoint was the 24 -week progression -free survival rate (24w-PFS) according to RANO criteria. Results: From July 2019 to June 2020, 39 patients with recurrent IDHm HGGs (twenty-one grade 3, thirteen grade 4, five grade 2 with radiological evidence of anaplastic transformation; 39% 1p/19q codeleted) were enrolled. Median time since diagnosis was 5.7 years, and the median number of previous systemic treatments was two. The 24w-PFS was 28.2% (11/39, CI95% 15 -44.9%). Median PFS and OS were 1.84 (CI95% 1.81 -5.89) and 14.7 months (CI95% 9.18 -NR), respectively. Four patients (10.3%) achieved partial response according to RANO criteria. There were no significant differences in clinical or histomolecular features between responders and nonresponders. The safety profile of Nivolumab was consistent with prior studies. Conclusions: We report the results of the first trial of immune checkpoint inhibitors in IDHm gliomas. Nivolumab failed to achieve its primary endpoint. However, treatment was well tolerated, and long-lasting responses were observed in a subset of patients, supporting further evaluation in combination with other agents (e.g. IDH inhibitors).

Abstract BACKGROUND Chimeric antigen receptor T-cell (CAR-T) therapy has revolutionised the landscape of cancer treatment, particularly in haematological malignancies, and while these therapies have demonstrated significant efficacy against malignancies, they are associated with a spectrum of side effects. Cytokine Release Syndrome (CRS) and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) are unique to CAR-T cell therapy and distinguish it from other forms of autoimmune toxicity. Predicting which patients will develop neurotoxicity remains a challenge. The pattern of ICANS is cognitive dysfunction, suggesting a plausible relationship between cognitive status and neurotoxicity. Understanding the interplay between cognitive function and neurotoxicity may provide valuable insights for early detection. The primary endpoint of this study was to investigate whether the cognitive performance of patients at the time of leukapheresis is associated with the subsequent development of ICANS. MATERIAL AND METHODS We report here on a prospective study of an adult patient population with aggressive B-cell lymphoma treated with CAR-T cell therapy at our centre between May 2020 and November 2023. All patients underwent neurological examination, cerebral MRI and global cognitive assessment using the Montreal Cognitive Assessment (MoCA) test with a cut-off of less than 26 points. We retrospectively recorded total metabolic tumour volume (TMTV) and International Prognostic Index (IPI) at lymphodepletion. Biological data including lactate dehydrogenase (LDH), albumin, ferritin and C-reactive protein (CRP) were also collected at the time of treatment. A retrospective analysis of pre-infusion serum neurofilament light chain (NfL) levels at the time of the decision to proceed with CAR-T cell therapy and at the time of treatment was performed. RESULTS 156 patients, median age 64 years (range 21 to 79 years), 55 females / 101 males, all treated for lymphoma, were included in this study. The mean MoCA score was 26 (range 12 to 30 points), 63 patients (40%) had a MoCA test below the cut-off at baseline. Following infusion of CAR T cells, 32% of patients developed ICANS within 6 days (grade 1-2: 72%; grade 3-4: 30%). The most common sign of neurotoxicity was cognitive impairment. In univariate analyses, the occurrence of ICANS was not significantly associated with baseline cognitive performance (p 0.58). As the study is ongoing, an update on the results will be available at the EANO meeting. CONCLUSION Neurotoxicity associated with CAR-T therapies occurs in one third of patients. This study does not suggest an association between the occurrence of ICANS and baseline cognitive performance. Despite progress in understanding the mechanisms underlying neurotoxicity, predicting its occurrence remains a challenge.

Chimeric antigen receptor T-cell (CAR T-cell) therapies have emerged as a promising treatment modality for several malignancies, particularly haematological malignancies, by inducing robust antitumour responses. However, CAR T-cell therapies are associated with a spectrum of adverse events, including neurological complications. We here provide a review of neurological adverse events observed in patients undergoing CAR T-cell therapy, focusing on their incidence, clinical manifestations, underlying mechanisms and potential management strategies.

Introduction Des neuropathies optiques immuno-médiées (NOim) ont été rarement rapportées chez les patients traités par inhibiteurs de checkpoint immunitaire (ICIs). Il est toutefois important de les connaître devant le haut taux de séquelles. Objectifs (i) Décrire les caractéristiques cliniques et paracliniques des atteintes du nerf optique secondaires aux ICIs ; (ii) rapporter l’évolution clinique et la tolérance de la réintroduction des ICIs après cette toxicité. Méthodes Nous rapportons ici tous les cas de NOim adressés à nos services de neurologie et ophtalmologie de l’hôpital Saint-Louis de Paris entre 2018 et 2022, ainsi qu’une analyse systématique de la littérature (Pubmed, Embase et Medline) des cas publiés de NOim. Selon l’évidence ou non d’atteinte du nerf optique à l’IRM ou aux potentiels évoqués visuels, nous avons distingué les cas de papillite et ceux de névrite optique. Résultats Au total, nous avons identifié 38 cas. Le tableau plus commun consiste en un déclin visuel et œdème papillaire bilatéral. Dans les cas de papillite, une uvéite est fréquemment associée (15/21=71 %), tandis que les névrites optiques sont plus souvent associées à d’autres neurotoxicités (5/17=29 %). Dans le 66 % des cas publiés un déficit visuel persiste malgré corticothérapie. Au contraire, nos 3 patients ont tous complètement récupéré. Nous avons donc poursuivi/réintroduit l’ICI chez 2 d’entre eux, sans récidives de toxicité. Discussion Contrairement aux névrites optiques non liées aux ICIs, ces neurotoxicités sont communément bilatérales et ne s’accompagnent pas de douleur oculaire. Si l’analyse des cas publiés a mis en évidence un pronostic sombre des NOim, les 3 patients de notre série ont complètement récupéré. Cette différence peut être liée à un biais de sélection de publication des cas plus graves. Conclusion Un diagnostic rapide des NOim est fondamental pour pouvoir arrêter les ICIs et débuter une corticothérapie afin d’éviter des séquelles. L’évolution de nos patients suggère que les ICIs peuvent être réintroduits dans les cas non graves.

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 pathologic 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.

Abstract BACKGROUND Patients with IDH-mutant, 1p/19q codeleted, grade 3 oligodendroglioma (Olig-3) derive benefit from the addition of alkylating agent chemotherapy to radiotherapy. However, to date, the choice between Procarbazine, Lomustine, and Vincristine (PCV) or Temozolomide (TMZ) as an optimal chemotherapy regimen for these patients remains unclear due to the lack of randomized clinical trial data comparing the two regimens. MATERIAL AND METHODS The objective was to assess the survival outcomes associated with first-line radiotherapy and PCV compared to radiotherapy and TMZ in patients with IDH-mutant, 1p/19q codeleted Olig-3 (WHO 2021). We included patients with histologically-proven IDH-mutant, 1p/19q codeleted Olig-3 from a large prospective French network cohort (POLA). The overall survival (OS) from surgery date was computed using Kaplan-Meier methods and Cox proportional hazards regression model. RESULTS A total of 306 patients with IDH-mutant, 1p/19q codeleted Olig-3 treated with radiotherapy and chemotherapy between 2008 and 2022 were included. In all, 67.6% of patients (n=207, median age at diagnosis 49.3y [IQR: 40.4-58.7]) were treated with PCV and 32.4% with TMZ (n=99, 50.3y [IQR: 43.8-61.2]) as first-line chemotherapy. Baseline characteristics were comparable between patients from both groups. The median follow-up duration was 78.4 months (IQR: 44.4-103.0). Median OS was not reached (95% CI: NR-NR) and 140 months (95% CI: 110-NR) in the PCV and TMZ groups, respectively (log rank test for OS, P=0.0023). On univariate analysis, there was a significant difference in both 5-year (PCV: 89%, 95% CI: 85-94 vs TMZ: 75%, 95% CI: 67-84; P = 0.0014) and 10-year OS (PCV: 73%, 95% CI: 62-85 vs TMZ: 60%, 95%CI: 49-73; P = 0.003) in favor of PCV. In the adjusted analysis for age, extent of resection, gender and Karnofsky performance scale (n=288), a significant OS difference between TMZ and PCV was found in the Cox proportional hazards regression model (TMZ vs. PCV HR 2.01, 95% CI: 1.16-3.50, P=0.013). CONCLUSION In the POLA cohort, among patients with IDH-mutant, 1p/19q codeleted Olig-3 receiving first-line radiotherapy combined with chemotherapy, treatment with PCV was associated with better survival compared to TMZ in both univariate and adjusted analyses. The small sample size and event rate especially in TMZ group warrants further validation. However, these results provide preliminary data on survival outcomes associated with first-line chemotherapy with PCV or TMZ in patients with IDH-mutant, 1p/19q codeleted Olig-3.

PURPOSE:The Lynch syndrome (LS)-glioma association is poorly documented. As for mismatch repair deficiency (MMRd) in glioma, a hallmark of LS-associated tumors, there are only limited data available. We determined MMRd and LS prevalence in a large series of unselected gliomas, and explored the associated characteristics. Both have major implications in terms of treatment, screening, and prevention.METHODS:Somatic next-generation sequencing was performed on 1,225 treatment-naive adult gliomas referred between 2017 and June 2022. For gliomas with ≥1 MMR pathogenic variant (PV), MMR immunohistochemistry (IHC) was done. Gliomas with ≥1 PV and protein expression loss were considered MMRd. Eligible patients had germline testing. To further explore MMRd specifically in glioblastomas, isocitrate dehydrogenase (IDH)-wild type (wt), we performed IHC, and complementary sequencing when indicated, in a series of tumors diagnosed over the 2007-2021 period.RESULTS:Nine gliomas were MMRd (9/1,225; 0.73%). Age at glioma diagnosis was <50 years for all but one case. Eight were glioblastomas, IDH-wt, and one was an astrocytoma, IDH-mutant. ATRX (n = 5) and TP53 (n = 8) PV were common. There was no TERT promoter PV or EGFR amplification. LS prevalence was 5/1,225 (0.41%). One 77-year-old patient was a known LS case. Four cases had a novel LS diagnosis, with germline PV in MSH2 (n = 3) and MLH1 (n = 1). One additional patient had PMS2-associated constitutional mismatch repair deficiency. Germline testing was negative in three MSH6-deficient tumors. In the second series of glioblastomas, IDH-wt, MMRd prevalence was 12.5% in the <40-year age group, 2.6% in the 40-49 year age group, and 1.6% the ≥50 year age group.CONCLUSION:Screening for MMRd and LS should be systematic in glioblastomas, IDH-wt, diagnosed under age 50 years.

Des neuropathies immuno-médiées ont été rapportées dans 0,1–1,2 % des patients traités par inhibiteurs de checkpoint immunitaires (ICIs). Les phénotypes de ces neuropathies étant hétérogènes, différents traitements sont rapportés. (i) Décrire les caractéristiques cliniques et paracliniques d'une série de patients ayant développé une neuropathie secondaire aux ICIs ; (ii) Rapporter leur évolution après suspension des ICIs et un traitement par corticoïdes. Nous avons recueilli tous les cas de neuropathies associées aux ICIs adressés à notre service depuis les services oncologiques des hôpitaux Saint-Louis, Avicenne et Bichat de Paris. Les autres causes de neuropathie, notamment infectieuses, métaboliques et tumorales ont été exclues sur la base des résultats d'IRM cérébrale et/ou médullaire et des analyses sanguines et du liquide cérébro-spinal. Nous avons identifié 12 cas (anti-PD1 = 8, anti-PDL1 = 2, anti-PD1 + anti-CTLA4 = 2). Les phénotypes les plus fréquents étaient celui de neuropathie sensitive axonale longueur-dépendante (42 %) et de méningo-radiculonévrite (42 %). Le délai d'apparition était significativement plus long pour les premiers (31 versus 5 semaines, respectivement). Les ICIs ont été suspendus chez tous les patients et des corticoïdes débutés chez 7 patients avec une évolution favorable (régression complète = 7, partielle = 4, stabilité = 1). Deux phénotypes de neuropathie semblent être associés aux ICIs : des neuropathies sensitives axonales longueur-dépendantes, survenant plus tardivement ; des méningo-radiculonévrites, avec un début plus rapide et un tableau clinique plus grave. L'évolution de cette série de patients souligne la nécessité d'arrêter les ICIs et suggère que des corticoïdes en monothérapie sont efficaces indépendamment du phénotype de la neuropathie. Les neuropathies associées aux ICIs sont rares, mais leur diagnostic est fondamental pour pouvoir arrêter rapidement les ICIs, qui est nécessaire, et débuter une corticothérapie dans les cas plus graves.