Prognosis of glioblastoma patients improves significantly over time interrogating historical controls.

BACKGROUND: Glioblastoma (GBM) is the most common devastating primary brain cancer in adults. In our clinical practice, median overall survival (mOS) of GBM patients seems increasing over time. METHODS: To address this observation, we have retrospectively analyzed the prognosis of 722 newly diagnosed GBM patients, aged below 70, in good clinical conditions (i.e. Karnofsky Performance Status -KPS- above 70%) and treated in our department according to the standard of care (SOC) between 2005 and 2018. Patients were divided into two groups according to the year of diagnosis (group 1: from 2005 to 2012; group 2: from 2013 to 2018). RESULTS: Characteristics of patients and tumors of both groups were very similar regarding confounding factors (age, KPS, MGMT promoter methylation status and treatments). Follow-up time was fixed at 24 months to ensure comparable survival times between both groups. Group 1 patients had a mOS of 19 months ([17.3-21.3]) while mOS of group 2 patients was not reached. The recent period of diagnosis was significantly associated with a longer mOS in univariate analysis (HR=0.64, 95% CI [0.51 - 0.81]), p < 0.001). Multivariate Cox analysis showed that the period of diagnosis remained significantly prognostic after adjustment on confounding factors (adjusted Hazard Ratio (aHR) 0.49, 95% CI [0.36-0.67], p < 0.001). CONCLUSION: This increase of mOS over time in newly diagnosed GBM patients could be explained by better management of potentially associated non-neurological diseases, optimization of validated SOC, better management of treatments side effects, supportive care and participation in clinical trials.

Advances in treatments of patients with classical and emergent neurological toxicities of anticancer agents.

The neurotoxicity associated to the anticancer treatments has received a growing body of interest in the recent years. The development of innovating therapies over the last 20years has led to the emergence of new toxicities. Their diagnosis and management can be challenging in the clinical practice and further research is warranted to improve the understanding of their pathogenic mechanisms. Conventional treatments as radiation therapy and chemotherapy are associated to well-known and under exploration emerging central nervous system (CNS) and peripheral nervous system (PNS) toxicities. The identification of the risk factors and a better understanding of their pathogeny through a "bench to bedside and back again" approach, are the first steps towards the development of toxicity mitigation strategies. New imaging techniques and biological explorations are invaluable for their diagnosis. Immunotherapies have changed the cancer treatment paradigm from tumor cell centered to immune modulation towards an efficient anticancer immune response. The use of the immune checkpoints inhibitors (ICI) and CAR-T cells (chimeric antigen receptor) lead to an increase in the incidence of immune-mediated toxicities and new challenges in the neurological patient's management. The neurological ICI related adverse events (n-irAE) are rare but potentially severe and may present with both CNS and PNS involvement. The most frequent and well characterized, from a clinical and biological standpoint, are the PNS phenotypes: myositis and polyradiculoneuropathy, but the knowledge on CNS phenotypes and their treatments is expanding. The n-irAE management requires a good balance between dampening the autoimmune toxicity without impairing the anticancer immunity. The adoptive cell therapies as CAR-T cells, a promising anticancer strategy, trigger cellular activation and massive production of proinflammatory cytokines inducing frequent and sometime severe toxicity known as cytokine release syndrome and immune effector cell-associated neurologic syndrome. Their management requires a close partnership between oncologist-hematologists, neurologists, and intensivists. The oncological patient's management requires a multidisciplinary clinical team (oncologist, neurologist and paramedical) as well as a research team leading towards a better understanding and a better management of the neurological toxicities.

Molecular and clinical diversity in primary central nervous system lymphoma.

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.

Neurological side effects of radiation therapy.

Radiation therapy (RT) is one of the main treatments administered to patients with cancer. The development of technology has improved RT accuracy by allowing more precise delivery of high doses to the target volumes with reduced exposure of healthy tissue. Life expectancy has increased due to these therapeutic advancements and the patients' quality of life remains a major concern. The adverse events related to RT are quite various and most likely will impair essential neurological functions, e.g. cognitive status. This literature review aims to describe the physiopathological processes, the neurological symptoms as well as the local modifications observed in magnetic resonance imaging following RT. The specific therapeutic options and preventive actions will also be discussed.