Could the motor unit number index be an early prognostic biomarker for amyotrophic lateral sclerosis?

OBJECTIVE: To evaluate the associations between motor unit number index (MUNIX) and disease progression and prognosis in amyotrophic lateral sclerosis (ALS) in a large-scale longitudinal study. METHODS: MUNIX was performed at the patient's first visit, at 3, 6, and 12 months in 4 muscles. MUNIX data from the patients were compared with those from 38 age-matched healthy controls. Clinical data included the revised ALS functional rating scale (ALSFRS-R), the forced vital capacity (FVC), and the survival of the patients. RESULTS: Eighty-two patients were included at baseline, 62 were evaluated at three months, 48 at six months, and 33 at twelve months. MUNIX score was lower in ALS patients compared to controls. At baseline, MUNIX was correlated with ALSFRS-R and FVC. Motor unit size index (MUSIX) was correlated with patient survival. Longitudinal analyses showed that MUNIX decline was greater than ALSFRS-R decline at each evaluation. A baseline MUNIX score greater than 378 predicted survival over the 12-month period with a sensitivity of 82% and a specificity of 56%. CONCLUSIONS: This longitudinal study suggests that MUNIX could be an early quantitative marker of disease progression and prognosis in ALS. SIGNIFICANCE: MUNIX might be considered as potential indicator for monitoring disease progression.

REVOLUMAB: A phase II trial of nivolumab in recurrent IDH mutant high-grade gliomas.

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 non-responders. 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).

Radio-chemotherapy feasibility for biopsy-only unresectable IDH wild-type glioblastomas (BO-GBM).

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.

Primary central nervous system lymphoma (PCNSL) in older patients.

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.

Prognostic value of circulating lymphocyte subsets in primary central nervous system lymphoma.

BACKGROUND: Immunity plays an important role in CNS-DLBCL development. CNS-DLBCL predictive factors need to be improved. OBJECTIVE: To evaluate the predictive value of circulating lymphocyte subsets in PCNSL patients. METHODS: We prospectively analyzed blood lymphocyte immunophenotyping (LIP) in newly CNS-DLBCL referred to our institution between December 2013 and January 2020. LIP analysis was performed before rituximab and chemotherapy administration. The clinical, radiological, histological, biological and treatment data were retrospectively collected. RESULTS: Fifty-three patients were included with a median age of 69.7 (range 21.7-87.5). Median KPS was 60 (range 30-100). Thirty-three patients (64%) presented with one or several lymphopenias: 21 (40%), 24 (46%) and 9 (17%) NK, T and B lymphopenias respectively. Only 11 patients (21%) had normal LIP. Median CD4+/CD8+ ratio was 2.11 (range 0.54-9.11). This ratio was normal, low or high in 27%, 28% and 44% of patients respectively. The presence of steroids did not impact LIP results. Complete, partial responses, stable and progressive disease (PD) were observed in 24 (50%), 10 (21%), 4 (8%), and 10 (21%) patients respectively. CD4+/CD8+ ratio tended to be different between refractory (PD patients) and non-refractory patients (p = 0.077, ROC AUC: 0.684). Median progression-free survival (PFS) and overall survival (OS) were 14.7 (95%CI 6.5-22.9) and 43.2 (95%CI 21.6-64.9) months, respectively. In multivariate analyses, adjusted by KPS, a CD4+/CD8+ ratio > 1.97 was associated with poor PFS [p = 0.043, HR = 3.32 (1.02-4.88)] and tended to be associated with worse OS (p = 0.064). CONCLUSION: LIP at baseline may predict refractory disease and exhibits a prognostic value in CNS-DLBCL patients.

Adult H3K27M mutated thalamic glioma patients display a better prognosis than unmutated patients.

BACKGROUND: Adult thalamic gliomas are a rare entity whose management is challenging for physicians. The aim of this study is to describe the characteristics and prognostic factors of thalamic gliomas in adult patients. METHODS: We retrospectively analyzed the clinical, neuro-radiological, histological, and molecular characteristics of all cases of adult thalamic glioma in our regional center. RESULTS: We included 38 adult patients. Median age at diagnosis was 56.5 years old (range, 24-80). Median KPS at diagnosis was 70%. Two-thirds of patients presented with tumor necrosis on MRI. Bithalamic lesions were present in four patients. The median volume of enhancement associated with lesions was relatively small (14 mm3). Two patients had undergone partial surgical resection. All other patients underwent biopsy. Median PFS was 7.1 months (95% CI [3.7-10.5]) and median OS was 15.6 months (95% CI [11.7-19.6]). Among 20 patients with available tumor samples for molecular analyses, only 4 (20%) presented with H3K27M mutation. Patients with H3K27M mutation had longer survival compared to those without. Finally, we identified a long-term survivor population characterized by a younger age, no cognitive impairment, low steroid dose treatment and the presence of H3K27M mutation. CONCLUSION: Thalamic adult glioma differs from bithalamic glioma in children with regards to its clinical, radiological and molecular profiles. Long-term survival is observed in young patients with limited symptoms and H3K27M mutation. A larger prospective cohort is needed to validate these findings.