Background:Symptomatic posttreatment edema (SPTE) is a complication that may develop after radiotherapy for intracranial meningiomas. Our study aims at reviewing rates of SPTE in a large cohort of a single institution and identifying possible predictive factors. Methods:We retrospectively analyzed data of 293 patients with 304 intracranial meningiomas irradiated at our institution between 2005 and 2018. We evaluated rates of SPTE and investigated numerous factors by univariate and multivariate analysis. Kaplan Meier analysis was used for estimation of actuarial local control and overall survival. Results:Median age was 60 years. Meningiomas were treated with fractionated stereotactic radiation therapy (70 %), single fraction stereotactic radiosurgery (24 %) or fractionated stereotactic radiosurgery (6 %). Median imaging follow-up was 60 months, actuarial 10 year local control rate for patients with grade 1 meningiomas who received radiotherapy as definitive treatment was 99 %. Local control at 5 years was 94 % for grade 1 meningioma, 57 % and 53 % for grade 2 and 3 respectively. Sixteen patients (5.5 %) developed SPTE, median time to onset was 3 months (range 1-26 months). the higher rates of SPTE observed were in midline (13 %) and convexity (9 %), compared to skull base tumors (2 %). On univariate analysis, age > 60 years (p > 0.03), pretreatment peritumoral edema (p = 0.014), medline location (p = 0.018), tumor size > 30 mm (p = 0.015) and grade 2 histology (p = 0.03) were predictive of SPTE. On multivariate analysis, only tumor location and size remained statistically significant. Conclusions:Based on our results, patients at high risk of SPTE can be identified based on patient and tumor characteristics. The best treatment technique in high risk patients is yet to be defined.

Standard systemic treatment has not been established for refractory meningioma. This retrospective study aimed to identify prognostic factors for overall survival and document outcomes of systemic therapies. We reviewed patients with meningioma followed at CHUM hospital between 2006 and 2022. Only patients with progression after first-line treatment were included. Among 750 patients, 107 (14%) experienced progression after first-line treatment. They were divided into two groups: Group 1 (n = 69, 64%) received salvage local treatments, and Group 2 (n = 38, 36%) received additional salvage systemic treatments. The median follow-up time from diagnosis was 7.5 years. 10-year OS was 88.3% (Group 1) vs. 67.2% (Group 2) (p = 0.009). Mean survival after stopping systemic treatment was 8.94 months. Key prognostic factors for poorer survival included age ≥ 65 (HR = 2.82; p = 0.009), WHO grade 2 or 3 (HR = 4.25; p = 0.004), and progression after second-line treatment (HR = 4.77; p = 0.004). Bevacizumab was associated with a mPFS of 12 months and 1-year OS of 64,6%, whereas non-Bevacizumab treatments—including Hydroxyurea, Somatostatin, and Sunitinib—were associated with a mPFS of 7 months and 1-year OS of 52,6%. This study highlights the fatal nature of recurrent meningiomas and the urgent need for systemic treatments that can improve their survival.

2085 Background: Meningiomas are the most common brain tumors, with no established standard systemic treatment for refractory cases after surgical and radiotherapeutic interventions. This study aims to identify prognostic factors for overall survival in refractory meningioma and document patient evolution with systemic treatments. Methods: In a retrospective study, we identified patients with meningioma initially followed at CHUM university hospital between 2006 and 2022. Patients with progression after first-line treatment and over 6 months of follow-up were included. The population was divided into two: group 1 received surgery and/or radiotherapy for progression, and group 2 received additional systemic treatments. Survival analysis with Kaplan-Meier curves and group comparisons (Log-Rank, Fisher's Exact Tests) were conducted. Results: A total of750 patients with meningioma were identified. 99 (13%) progressed after first-line treatment. Among them, 70 (9%) were categorized in group 1 and 29 (4%), in group 2. The median follow-up time from diagnosis was 7.5 years. The overall 10-year survival rate was higher in group 1 compared to group 2 (88% vs 62%). Prognostic factors affecting survival were identified as the following: disease progression after second-line treatment, age ≥ 65 years, and grade 2 or 3. When comparing PFS-1 after first-line treatment, they were similar between group 1 and group 2 (mPFS-1: 2.63 vs 3.49 years; p = 0.421). However, PFS-2 after second-line treatment was significantly shorter in group 2 (mPFS-2 : 12.6 vs 2.3 years ; p < 0.001). Age of ≥ 65 years (10-year survival: 57% vs 89%; p < 0.001) and higher grades (10 year survival: 90% grade 1 vs 58% - grade 2 vs 75% - grade 3; p = 0.027) were associated with lower survival rates. The number of lesions (unique or multiple) and localization (supra or infratentorial) of tumors had no significant impact on survival (p=0.257; p = 0.482). Regarding systemic treatments, 7 patients (25%) received Bevacizumab. It was the treatment associated with the longest PFS (mPFS = 22.5 months) when compared to Hydroxyurea (n=18 [62%], mPFS = 4 months), Somatostatin (n = 5 [17%], mPFS = 8 months), a combination of Hydroxyurea and Somatostatin (n=7 [24%], mPFS = 8 months) and Sunitinib (n=3 [10%], mPFS = 14 months). For patients discontinuing systemic treatment, median survival was 5 months. Systemic treatments were well-tolerated. Among moderate to severe side effects (grade ≥ 2), we documented bradycardia (Somatostatin, n=1), elevated liver enzymes (Sunitinib, n=1), anemia and neutropenia (Hydroxyurea, n=3) and proteinuria (Bevacizumab, n=1). Conclusions: Prognostic factors for survival in meningioma include age ≥ 65 years, grades 2 and 3, and the occurrence of a second progression. Our study highlights Bevacizumab in systemic treatment strategies which was well tolerated in our patients.

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The trafficking of autoreactive leucocytes across the blood-brain barrier endothelium is a hallmark of multiple sclerosis pathogenesis. Although the blood-brain barrier endothelium represents one of the main CNS borders to interact with the infiltrating leucocytes, its exact contribution to neuroinflammation remains understudied. Here, we show that Mcam identifies inflammatory brain endothelial cells with pro-migratory transcriptomic signature during experimental autoimmune encephalomyelitis. In addition, MCAM was preferentially upregulated on blood-brain barrier endothelial cells in multiple sclerosis lesions in situ and at experimental autoimmune encephalomyelitis disease onset by molecular MRI. In vitro and in vivo, we demonstrate that MCAM on blood-brain barrier endothelial cells contributes to experimental autoimmune encephalomyelitis development by promoting the cellular trafficking of TH1 and TH17 lymphocytes across the blood-brain barrier. Last, we showcase ST14 as an immune ligand to brain endothelial MCAM, enriched on CD4+ T lymphocytes that cross the blood-brain barrier in vitro, in vivo and in multiple sclerosis lesions as detected by flow cytometry on rapid autopsy derived brain tissue from multiple sclerosis patients. Collectively, our findings reveal that MCAM is at the centre of a pathological pathway used by brain endothelial cells to recruit pathogenic CD4+ T lymphocyte from circulation early during neuroinflammation. The therapeutic targeting of this mechanism is a promising avenue to treat multiple sclerosis.

The migration of circulating leukocytes into the central nervous system (CNS) is a key driver of multiple sclerosis (MS) pathogenesis. The monoclonal antibody natalizumab proved that pharmaceutically obstructing this process is an effective therapeutic approach for treating relapsing-remitting MS (RRMS). Unfortunately, the clinical efficacy of natalizumab is somewhat offset by its incapacity to control the progressive forms of MS (PMS) and by life-threatening side effects in RRMS rising from the expression of its molecular target, very late antigen 4 (VLA4), on most immune cells and consequent impairment of CNS immunosurveillance. Here, we identified dual immunoglobulin domain containing cell adhesion molecule (DICAM) as a cell trafficking molecule preferentially expressed by T helper 17 (TH17)–polarized CD4+ T lymphocytes. We found that DICAM expression on circulating CD4+ T cells was increased in patients with active RRMS and PMS disease courses, and expression of DICAM ligands was increased on the blood-brain barrier endothelium upon inflammation and in MS lesions. Last, we demonstrated that pharmaceutically neutralizing DICAM reduced murine and human TH17 cell trafficking across the blood-brain barrier in vitro and in vivo, and alleviated disease symptoms in four distinct murine autoimmune encephalomyelitis models, including relapsing-remitting and progressive disease models. Collectively, our data highlight DICAM as a candidate therapeutic target to impede the migration of disease-inducing leukocytes into the CNS in both RRMS and PMS and suggest that blocking DICAM with a monoclonal antibody may be a promising therapeutic approach.

Glioblastoma is the most common malignant primary central nervous system tumor in adults and is associated with a poor prognosis. The benefit of adding concomitant followed by adjuvant temozolomide to radiotherapy after maximal safe resection was demonstrated by Stupp and colleagues in 2005 and has since remained the standard of care. This regimen conferred a statistically significant benefit with a 2-year survival rate of 26.5% compared to 10.4% in patients treated with radiotherapy alone. Our primary goal was to retrospectively assess the clinical outcomes of patients with glioblastoma treated at our institution over the past 15 years by comparing the overall survival (OS) and progression-free survival (PFS) from our cohort to data from the pivotal trial. Our secondary objective was to create a comprehensive database with clinical and pathological information in order to identify predictive and prognostic factors. We reviewed the clinical records of patients treated for glioblastoma from January 2005 to November 2019 at our center. We extracted data on survival and calculated OS and PFS using the Kaplan-Meier method. 617 patient charts were reviewed, out of which 17 were excluded because of missing data. The remaining 600 patients were included. Baseline demographic information was similar to that of the Stupp cohort, with the exception of a larger proportion of patients aged 50 or above (76% versus 69%, respectively). The median OS at our center was 14.3 months, 95% confidence interval [12.8-15.2], which was comparable to that of the original trial (14.6 months [13.2-16.8]). PFS was better in our cohort at 6 months (74.2% [70.7-77.7] versus 53.9% [48.1-59.6]) and 12 months (36.3% [32.5-40.2] versus 26.9% [21.8-32.1]), and comparable thereafter. Our study confirms that the data from the Stupp trial are reproducible in a Canadian academic center setting. Our database will allow us to explore potentially new predictive factors.

Background and Objectives In multiple sclerosis (MS), peripheral immune cells use various cell trafficking molecules to infiltrate the CNS where they cause damage.The objective of this study was to investigate the involvement of coxsackie and adenovirus receptor-like membrane protein (CLMP) in the migration of immune cells into the CNS of patients with MS. Methods Expression of CLMP was measured in primary cultures of human brain endothelial cells (HBECs) and human meningeal endothelial cells (HMECs), postmortem brain samples, and peripheral blood mononuclear cells (PBMCs) from patients with MS and controls by RNA sequencing, quantitative PCR, immunohistochemistry, and flow cytometry. In vitro migration assays using HBECs and HMECs were performed to evaluate the function of CLMP. Results Using bulk RNA sequencing of primary cultures of human brain and meningeal endothelial cells (ECs), we have identified CLMP as a new potential cell trafficking molecule upregulated in inflammatory conditions. We first confirmed the upregulation of CLMP at the protein level on TNF alpha-activated and IFN gamma-activated primary cultures of human brain and meningeal ECs. In autopsy brain specimens from patients with MS, we demonstrated an overexpression of endothelial CLMP in active MS lesions when compared with normal control brain tissue. Flow cytometry of human PBMCs demonstrated an increased frequency of CLMP+ B lymphocytes and monocytes in patients with MS, when compared with that in healthy controls. The use of a blocking antibody against CLMP reduced the migration of immune cells across the human brain and meningeal ECs in vitro. Finally, we found CLMP+ immune cell infiltrates in the perivascular area of parenchymal lesions and in the meninges of patients with MS. Discussion Collectively, our data demonstrate that CLMP is an adhesion molecule used by immune cells to access the CNS during neuroinflammatory disorders such as MS. CLMP could represent a target for a new treatment of neuroinflammatory conditions.

This review summarizes existing vestibular schwannoma (VS) disease-specific and non-disease-specific patient-reported outcome measure (PROM) tools for quality of life (QoL) and audio-vestibular symptoms, compares QoL across treatment modalities, and discusses the potential role of psychological variables in QoL and recovery after surgical resection of VS. VS treatment success was previously assessed according to various factors such as the extent of tumor resection, facial nerve function, and hearing preservation. However, the literature demonstrates recent shifts away from using such physician-reported “objective” outcomes as benchmarks for success towards more patient-perceived “subjective” measures. A number of PROM tools have been developed to assess QoL and other measures in patients with VS. This has allowed us to better understand and quantify the impact of the disease and of the treatments on our patient population. However, there are important considerations to be made when applying PROM in clinical settings such as understanding the concept of Minimal Clinically Important Difference (MCID). The use of disease-specific PROMs, such as the PANQOL, as a primary outcome in VS research is encouraged. When doing so, PROM scales should incorporate the concept of MCID to distinguish statistically significant from clinically significant findings and should further investigate the role of non-medical variables, such as psychological variables, on QoL and recovery trajectories in patients with VS. Actual literature does not seem to indicate a clinically significant difference in patient-reported outcomes among treatment modalities.

Medulloblastoma is an aggressive primary brain tumor that is extremely rare in adults; therefore, prospective studies are limited. We reviewed the information of all MB patients treated at the CHUM between 2006 and 2017. We divided our cohort by age and further divided adult patients (53%) in two groups, those diagnosed between 2006–2012 and 2013–2017. In our adult population, median follow up was 26 months and SHH-activated MB comprised 39% of tumors. Adult 5yOS was 80% and first-line therapy led to a 5yPFS of 77%. The absence of radiosensitizing chemotherapy (100% vs. 50%; p = 0.033) negatively influenced 5yPFS. 96% of adult patients received radiotherapy and 48% of them received concomitant radiosensitizing chemotherapy. Complete surgical resection was performed on 85% of adults, but the extent of resection did not have a discernable impact on survival and did not change with time. Adjuvant chemotherapy did not clearly affect prognosis (5yOS 80% vs. 67%, p = 0.155; 5yPFS 78% vs. 67%, p = 0.114). From 2006–2012, the most common chemotherapy regimen (69%) was Cisplatinum, Lomustine and Vincristine, which was replaced in 2013 by Cisplatinum, Etoposide and Cyclophosphamide (77%) with a trend for worse survival. Nine patients recurred and seven of these (78%) were treated with palliative chemotherapy. In conclusion, we did not identify prognostic demographic or tumor factors in our adult MB population. The presence of radiosensitizing chemotherapy was associated with a more favorable PFS. Cisplatinum, Lomustine and Vincristine regimen might be a better adjuvant chemotherapy regimen.

OBJECTIVE:To investigate the involvement of interleukin (IL)-26 in neuroinflammatory processes in multiple sclerosis (MS), in particular in blood-brain barrier (BBB) integrity.METHODS:Expression of IL-26 was measured in serum, CSF, in vitro differentiated T helper (TH) cell subsets, and postmortem brain tissue of patients with MS and controls by ELISA, quantitative PCR, and immunohistochemistry. Primary human and mouse BBB endothelial cells (ECs) were treated with IL-26 in vitro and assessed for BBB integrity. RNA sequencing was performed on IL-26-treated human BBB ECs. Myelin oligodendrocyte glycoprotein35-55 experimental autoimmune encephalomyelitis (EAE) mice were injected IP with IL-26. BBB leakage and immune cell infiltration were assessed in the CNS of these mice using immunohistochemistry and flow cytometry.RESULTS:IL-26 expression was induced in TH lymphocytes by TH17-inducing cytokines and was upregulated in the blood and CSF of patients with MS. CD4+IL-26+ T lymphocytes were found in perivascular infiltrates in MS brain lesions, and both receptor chains for IL-26 (IL-10R2 and IL-20R1) were detected on BBB ECs in vitro and in situ. In contrast to IL-17 and IL-22, IL-26 promoted integrity and reduced permeability of BBB ECs in vitro and in vivo. In EAE, IL-26 reduced disease severity and proinflammatory lymphocyte infiltration into the CNS, while increasing infiltration of Tregs.CONCLUSIONS:Our study demonstrates that although IL-26 is preferentially expressed by TH17 lymphocytes, it promotes BBB integrity in vitro and in vivo and is protective in chronic EAE, highlighting the functional diversity of cytokines produced by TH17 lymphocytes.

L’acromégalie est une maladie morbide associée à un taux de mortalité deux à quatre fois plus élevé que dans la population générale. Elle requiert une approche thérapeutique multimodale. Dans ce contexte, nous sommes intéressés à l’effet du traitement médical préopératoire sur le taux de guérison de l’acromégalie post-opératoire. Les objectifs de cette étude sont de: (1) déterminer le taux de rémission chez les patients acromégales traités dans notre institution et (2) identifier les facteurs prédicteurs de rémission et plus particulièrement le rôle du traitement médical préopératoire. Cette étude rétrospective comprend des patients acromégales et opérés par le même opérateur. La rémission est définie par une normalisation du taux d’IGF-1 et la suppression de l’hormone de croissance après un test de tolérance au glucose oral. Dans cette analyse intérimaire, 36 patients (20 femmes) ont été inclus, avec un âge moyen de 48,6 (± 13,0) ans et une moyenne de durée de suivi de 38,2 (± 28,1) mois. Le taux de rémission a été de 58,3 %. De plus, 11 patients (30,6 %) ont obtenu un contrôle biochimique, avec un traitement médical adjuvant. L’analyse multivariée démontre que les patients âgés de 50 ans et plus et ceux dont la taille de l’adénome est de moins de 16 mm ont plus de chances d’être en rémission postopératoire (OR = 10,1 (IC 95 %: 1,1; 89,9; p = 0,038) et OR = 10,2 (IC 95 %: 1,2; 88,6; p = 0,036) respectivement). Le traitement médical préopératoire ne semble pas conférer un avantage en termes de rémission post-opératoire (OR = 0,5; IC 95 %: 0,1; 3,3; p = 0,438). Ces analyses préliminaires démontrent que les patients atteints d’acromégalie bénéficient de la chirurgie transphénoïdale endoscopique. L’âge et le diamètre de l’adénome sont associés à la rémission. Cependant, la médication préopératoire ne semble pas être associée à un plus haut taux de rémission postopératoire.

The presence of B lymphocyte-associated oligoclonal immunoglobulins in the cerebrospinal fluid is a classic hallmark of multiple sclerosis (MS). The clinical efficacy of anti-CD20 therapies supports a major role for B lymphocytes in MS development. Although activated oligoclonal populations of pathogenic B lymphocytes are able to traffic between the peripheral circulation and the central nervous system (CNS) in patients with MS, molecular players involved in this migration have not yet been elucidated. In this study, we demonstrated that activated leukocyte cell adhesion molecule (ALCAM/CD166) identifies subsets of proinflammatory B lymphocytes and drives their transmigration across different CNS barriers in mouse and human. We also showcased that blocking ALCAM alleviated disease severity in animals affected by a B cell-dependent form of experimental autoimmune encephalomyelitis. Last, we determined that the proportion of ALCAM(+) B lymphocytes was increased in the peripheral blood and within brain lesions of patients with MS. Our findings indicate that restricting access to the CNS by targeting ALCAM on pathogenic B lymphocytes might represent a promising strategy for the development of next-generation B lymphocyte-targeting therapies for the treatment of MS.

Abstract BACKGROUND Before 2012, Temozolomide (TMZ) was used for low-grade gliomas (LGG) to avoid Lomustine toxicity. After 2012 RTOG data, Procarbazine, Lomustine and Vincristine (PCV) given sequentially with radiotherapy became standard treatment with the side effects burden associated. METHODS We retrospectively reviewed our SARDO clinical database of patients with low-grade glioma LGG grades 2 and 3 between 2006 and 2017 at CHUM University Health Center. Molecular profile for these tumors is reflex and standard in our institution since 2016. RESULTS A total of 123 patients were identified with grade 2 and grade 3 LGG; 37 (30%) treated with PCV and 86 (70%) received TMZ. Median follow up was 11mo for PCV 11mo vs 22mo TMZ. Both groups were balanced in terms of median age, sex, neurologic symptoms and surgery rate. 53% patients had tumor untested for IDH1-2 and codeletion1p19q because of diagnostic before 2016. Disparities were noted with a predominance of grade 3 in the TMZ group (74% vs 27%, p< 0.01). TMZ was the preferred regimen before 2012 (100% vs 43%) and PCV became the standard of care after 2012 (0% vs 57%). Radiation use as first line treatment was 90%. The 4y OS was not significantly longer for PCV 50% compared with TMZ 47% with mOS between both groups (PCV NR vs TMZ 39.9mo, p=0.158). When controlled for tumor grade, the 2y OS was 80% for PCV vs 64% for TMZ,p=0.542. The 4y PFS was trendly longer for PCV group 78% than TMZ group 45%, p=0.148. CONCLUSION As we are still waiting for the prospective ongoing prospective trials comparing these 2 regimens, PCV and radiation are still standard of care regimens for grade 2 and 3 LGG. This retrospective data is not reassuring for a replacement for PCV with TMZ.

Abstract INTRODUCTION Medulloblastoma (MB) is an aggressive primary brain tumor rare in adults. Prospective studies in adults are limited by the small number of patients. METHODS We retrospectively reviewed all MB patients treated at the CHUM between 2006 and 2017 in our clinical database adult SARDO. We don’t have the children follow up. We divided our cohort in 2 groups, those diagnosed between 2006–2013 and those diagnosed between 2014–2017. RESULTS 49 patients were treated, 23 (47%) were children referred for radiation only from a pediatric center and 26 (53%) were adults. Median follow up of adults was 26 months. At 5 years, the entire cohort OS was 58%, but specifically for adults, the 5yOS was 80%. First line therapy had a 5y PFS 77% for adults, negatively influenced by the absence of adjuvant radiotherapy (83% vs 0%; p < 0.001) and the absence of adjuvant chemotherapy (80% vs 39%; p < 0.008). 96% of adult patients received radiotherapy and 52% of them received concomitant radiosensitizing chemotherapy with no impact on survival. Complete surgical resection was performed on 88% of patients, but the extent of resection did not have an impact on survival and did not change with time. From 2006–2013, the most common chemotherapy treatment (80%) in adults was Vincristine, Cisplatin and Lomustine. From 2014–2017, the chemotherapy was replaced by Cisplatin, Etoposide and Cyclophosphamide in 82% with no impact on survival (specific mortality for this chemo 3yOS 100% for both, 3y PFS 100%). Non Cisplatin based chemotherapy regimens were associated with decrease in PFS (67% at 3y). 78% of the progressive patients received second line chemo. CONCLUSION In our adult MB population, the demographic and tumor factors did’nt have an impact on prognosis but adjuvant radiotherapy and chemotherapy had a favorable impact on survival especially with Cisplatin, Etoposide and Cyclophosphamide regimen.

CD70 is the unique ligand of CD27 and is expressed on immune cells only upon activation. Therefore, engagement of the costimulatory CD27/CD70 pathway is solely dependent on upregulation of CD70. However, the T cell-intrinsic effect and function of human CD70 remain underexplored. Herein, we describe that CD70 expression distinguishes proinflammatory CD4 + T lymphocytes that display an increased potential to migrate into the central nervous system (CNS). Upregulation of CD70 on CD4 + T lymphocytes is induced by TGF-β1 and TGF-β3, which promote a pathogenic phenotype. In addition, CD70 is associated with a T H 1 and T H 17 profile of lymphocytes and is important for T-bet and IFN-γ expression by both T helper subtypes. Moreover, adoptive transfer of CD70 −/− CD4 + T lymphocytes induced less severe experimental autoimmune encephalomyelitis (EAE) disease than transfer of WT CD4 + T lymphocytes. CD70 + CD4 + T lymphocytes are found in the CNS during acute autoimmune inflammation in humans and mice, highlighting CD70 as both an immune marker and an important costimulator of highly pathogenic proinflammatory T H 1/T H 17 lymphocytes infiltrating the CNS.