The local microenvironment drives activation of neutrophils in human brain tumors.

Neutrophils are abundant immune cells in the circulation and frequently infiltrate tumors in substantial numbers. However, their precise functions in different cancer types remain incompletely understood, including in the brain microenvironment. We therefore investigated neutrophils in tumor tissue of glioma and brain metastasis patients, with matched peripheral blood, and herein describe the first in-depth analysis of neutrophil phenotypes and functions in these tissues. Orthogonal profiling strategies in humans and mice revealed that brain tumor-associated neutrophils (TANs) differ significantly from blood neutrophils and have a prolonged lifespan and immune-suppressive and pro-angiogenic capacity. TANs exhibit a distinct inflammatory signature, driven by a combination of soluble inflammatory mediators including tumor necrosis factor alpha (TNF-ɑ) and Ceruloplasmin, which is more pronounced in TANs from brain metastasis versus glioma. Myeloid cells, including tumor-associated macrophages, emerge at the core of this network of pro-inflammatory mediators, supporting the concept of a critical myeloid niche regulating overall immune suppression in human brain tumors.

Vorasidenib in IDH1- or IDH2-Mutant Low-Grade Glioma.

BACKGROUND: Isocitrate dehydrogenase (IDH)-mutant grade 2 gliomas are malignant brain tumors that cause considerable disability and premature death. Vorasidenib, an oral brain-penetrant inhibitor of mutant IDH1 and IDH2 enzymes, showed preliminary activity in IDH-mutant gliomas. METHODS: In a double-blind, phase 3 trial, we randomly assigned patients with residual or recurrent grade 2 IDH-mutant glioma who had undergone no previous treatment other than surgery to receive either oral vorasidenib (40 mg once daily) or matched placebo in 28-day cycles. The primary end point was imaging-based progression-free survival according to blinded assessment by an independent review committee. The key secondary end point was the time to the next anticancer intervention. Crossover to vorasidenib from placebo was permitted on confirmation of imaging-based disease progression. Safety was also assessed. RESULTS: A total of 331 patients were assigned to receive vorasidenib (168 patients) or placebo (163 patients). At a median follow-up of 14.2 months, 226 patients (68.3%) were continuing to receive vorasidenib or placebo. Progression-free survival was significantly improved in the vorasidenib group as compared with the placebo group (median progression-free survival, 27.7 months vs. 11.1 months; hazard ratio for disease progression or death, 0.39; 95% confidence interval [CI], 0.27 to 0.56; P<0.001). The time to the next intervention was significantly improved in the vorasidenib group as compared with the placebo group (hazard ratio, 0.26; 95% CI, 0.15 to 0.43; P<0.001). Adverse events of grade 3 or higher occurred in 22.8% of the patients who received vorasidenib and in 13.5% of those who received placebo. An increased alanine aminotransferase level of grade 3 or higher occurred in 9.6% of the patients who received vorasidenib and in no patients who received placebo. CONCLUSIONS: In patients with grade 2 IDH-mutant glioma, vorasidenib significantly improved progression-free survival and delayed the time to the next intervention. (Funded by Servier; INDIGO ClinicalTrials.gov number, NCT04164901.).

Ischemic Stroke in Cancer: Mechanisms, Biomarkers, and Implications for Treatment.

Ischemic stroke is an important cause of morbidity and mortality in cancer patients. The underlying mechanisms linking cancer and stroke are not completely understood. Long-standing and more recent evidence suggests that cancer-associated prothrombotic states, along with treatment-related vascular toxicity, such as with chemotherapy and immunotherapy, contribute to an increased risk of ischemic stroke in cancer patients. Novel biomarkers, including coagulation, platelet and endothelial markers, cell-free DNA, and extracellular vesicles are being investigated for their potential to improve risk stratification and patient selection for clinical trials and to help guide personalized antithrombotic strategies. Treatment of cancer-related stroke poses unique challenges, including the need to balance the risk of recurrent stroke and other thromboembolic events with that of bleeding associated with antithrombotic therapy. In addition, how and when to restart cancer treatment after stroke remains unclear. In this review, we summarize current knowledge on the mechanisms underlying ischemic stroke in cancer, propose an etiological classification system unique to cancer-related stroke to help guide patient characterization, provide an overview of promising biomarkers and their clinical utility, and discuss the current state of evidence-based management strategies for cancer-related stroke. Ultimately, a personalized approach to stroke prevention and treatment is required in cancer patients, considering both the underlying cancer biology and the individual patient's risk profile.

Acute ischaemic stroke in active cancer versus non-cancer patients: stroke characteristics, mechanisms and clinical outcomes.

BACKGROUND AND PURPOSE: Demographics, clinical characteristics, stroke mechanisms and long-term outcomes were compared between acute ischaemic stroke (AIS) patients with active cancer (AC) versus non-cancer patients. METHODS: Using data from 2003 to 2021 in the Acute STroke Registry and Analysis of Lausanne, a retrospective cohort study was performed comparing patients with AC, including previously known and newly diagnosed cancers, with non-cancer patients. Patients with inactive cancer were excluded. Outcomes were the modified Rankin Scale (mRS) score at 3 months, death and cerebrovascular recurrences at 12 months before and after propensity score matching. RESULTS: Amongst 6686 patients with AIS, 1065 (15.9%) had a history of cancer. After excluding 700 (10.4%) patients with inactive cancer, there were 365 (5.5%) patients with AC and 5621 (84%) non-cancer AIS patients. Amongst AC patients, 154 (42.2%) strokes were classified as cancer related. In multivariable analysis, patients with AC were older (adjusted odds ratio [aOR] 1.02, 95% confidence interval [CI] 1.00-1.03), had fewer vascular risk factors and were 48% less likely to receive reperfusion therapies (aOR 0.52, 95% CI 0.35-0.76). Three-month mRS scores were not different in AC patients (aOR 2.18, 95% CI 0.96-5.00). At 12 months, death (adjusted hazard ratio 1.91, 95% CI 1.50-2.43) and risk of cerebrovascular recurrence (sub-distribution hazard ratio 1.68, 95% CI 1.22-2.31) before and after propensity score matching were higher in AC patients. CONCLUSIONS: In a large institutional registry spanning nearly two decades, AIS patients with AC had less past cerebrovascular disease but a higher 1-year risk of subsequent death and cerebrovascular recurrence compared to non-cancer patients. Antithrombotic medications at discharge may reduce this risk in AC patients.

Primary diffuse large B-cell lymphoma of the central nervous system identified with CSF biomarkers.

BACKGROUND: Diagnosis of primary diffuse large B-cell lymphoma of the central nervous system (PCNSL) is challenging and often delayed. MRI imaging, CSF cytology and flow cytometry have a low sensitivity and even brain biopsies can be misleading. We report three cases of PCNSL with various clinical presentation and radiological findings where the diagnosis was suggested by novel CSF biomarkers and subsequently confirmed by brain biopsy or autopsy. CASE PRESENTATIONS: The first case is a 79-year-old man with severe neurocognitive dysfunction and static ataxia evolving over 5 months. Brain MRI revealed a nodular ventriculitis. An open brain biopsy was inconclusive. The second case is a 60-year-old woman with progressive sensory symptoms in all four limbs, evolving over 1 year. Brain and spinal MRI revealed asymmetric T2 hyperintensities of the corpus callosum, corona radiata and corticospinal tracts. The third case is a 72-year-old man recently diagnosed with primary vitreoretinal lymphoma of the right eye. A follow-up brain MRI performed 4 months after symptom onset revealed a T2 hyperintense fronto-sagittal lesion, with gadolinium uptake and perilesional edema. In all three cases, CSF flow cytometry and cytology were negative. Mutation analysis on the CSF (either by digital PCR or by next generation sequencing) identified the MYD88 L265P hotspot mutation in all three cases. A B-cell clonality study, performed in case 1 and 2, identified a monoclonal rearrangement of the immunoglobulin light chain lambda (IGL) and kappa (IGK) gene. CSF CXCL-13 and IL-10 levels were high in all three cases, and IL-10/IL-6 ratio was high in two. Diagnosis of PCNSL was later confirmed by autopsy in case 1, and by brain biopsy in case 2 and 3. CONCLUSIONS: Taken together, 5 CSF biomarkers (IL-10, IL-10/IL-6 ratio, CXCL13, MYD88 mutation and monoclonal IG gene rearrangements) were strongly indicative of a PCNSL. Using innovative CSF biomarkers can be sensitive and complementary to traditional CSF analysis and brain biopsy in the diagnosis of PCNSL, potentially allowing for earlier diagnosis and treatment.

Safety and anti-tumor activity of lisavanbulin administered as 48-hour infusion in patients with ovarian cancer or recurrent glioblastoma: a phase 2a study.

PURPOSE: Lisavanbulin (BAL101553) is the prodrug of avanbulin (BAL27862), a microtubule-destabilizing agent. The goal of this study (NCT02895360) was to characterize the safety, tolerability and antitumor activity of lisavanbulin administered as a 48-hour intravenous (IV) infusion at the recommended Phase 2 dose (RP2D) of 70 mg/m2. Results from the Phase 1 dose-escalation portion of the study identifying the RP2D have been previously reported. Here, we present the findings from the Phase 2a portion of this study. Methods. This multi-center, open-label study included patients with ovarian, fallopian-tube, or primary peritoneal cancer that was either platinum-resistant or refractory (11 patients), or with first recurrence of glioblastoma (12 patients). Lisavanbulin was administered as a 48-hour IV infusion on Days 1, 8, and 15 of a 28-day cycle. Results. Lisavanbulin was well tolerated in both patient cohorts. Thirteen patients (56.5%) developed 49 adverse events assessed as related to study treatment. The majority were mild or moderate; four were grade 3/4. Sixteen SAEs were reported in nine patients (39.1%), with none considered related to study treatment. No AEs led to permanent treatment discontinuation. Three patients in the ovarian cancer cohort had stable disease with lesion size reductions after two cycles of treatment; in the glioblastoma cohort, one patient showed partial response with a > 90% glioblastoma area reduction as best response, and one patient had stable disease after eight cycles of treatment. Conclusion. This study demonstrated a favorable safety and tolerability profile of 48-hour continuous IV infusion of lisavanbulin in patients with solid extracranial tumors or glioblastoma. Clinicaltrials.gov registration: NCT02895360.

[Management of brain metastases in 2022]. / Prise en charge des métastases cérébrales en 2022.

Brain metastases (BM) are a common occurrence of systemic cancers. Technical improvements in neuroimaging offer additional tools for an early detection of BM, to target them precisely and differentiate these lesions from other cerebral pathologies. The therapeutic tools have also evolved from neurosurgery and whole brain therapy to include stereotactic radiosurgery, targeted and immune therapies. Given the numerous treatment options available, a multidisciplinary approach is essential to offer the patient a personalized approach to optimize the sequence and combination of treatments to offer the best outcome possible. This article aims to review key elements of diagnosis, risk stratification and modern treatment paradigms in the diagnosis and management of BM.

Les métastases cérébrales (MC) sont une manifestation fréquente des cancers systémiques. Les améliorations des techniques de radiologie offrent des options supplémentaires pour détecter de manière précoce les MC, les cibler avec précision et les différencier d'autres pathologies. Les outils thérapeutiques se sont également élargis pour inclure des techniques de radiothérapie stéréotaxiques, des thérapies ciblées et des immunothérapies. Au vu des nombreuses options de traitement pour les patients souffrant de MC, une approche multidisciplinaire doit impérativement être favorisée pour personnaliser le traitement de chaque patient et améliorer le pronostic. Cet article décrit les éléments clés du diagnostic, de la stratification du risque et les paradigmes modernes de la prise en charge et des traitements des patients avec MC.

Therapeutic Drug Monitoring of Newer Antiepileptic Drugs: A Randomized Trial for Dosage Adjustment.

OBJECTIVE: Therapeutic drug monitoring (TDM) of antiepileptic drugs (AEDs) is widely established for older generation AEDs, whereas there is limited evidence about newer AEDs. Our aim is to assess the benefit of TDM of newer generation AEDs in epilepsy. METHODS: We performed a randomized, controlled trial comparing systematic with rescue TDM of lamotrigine, levetiracetam, oxcarbazepine, topiramate, brivaracetam, zonisamide, or pregabalin. Participants were adults with epilepsy, in whom treatment with newer generation AEDs was initiated or needed adjustment. In the systematic TDM arm, AED plasma levels were available at each appointment, whereas in the rescue TDM arm, levels were known only if a study endpoint was reached (inefficacy or adverse events). The primary outcome was the proportion of participants followed 1 year without reaching one of the predefined endpoints. RESULTS: A total of 151 participants were enrolled; global retention in the study was similar in both arms (56% overall, 58% in the systematic, and 53% in the rescue TDM arm, p = 0.6, Cox regression). There was no difference in terms of outcome regarding treatment efficacy or tolerability. Partial adherence of clinicians to TDM (adjusting or not AED dosage based on blood levels) did not explain this lack of benefit. INTERPRETATION: This study provides class A evidence that systematic drug level monitoring of newer generation AEDs does not bring tangible benefits in the management of patients with epilepsy. Poor correlation between clinical effects and drug levels likely accounts for this finding. However, TDM is useful in several situations, such as pregnancy, as well as when there are compliance issues. ANN NEUROL 2020;87:22-29.

Physical approaches to treat glioblastoma.

PURPOSE OF REVIEW: Glioblastoma (GBM) patients have a poor prognosis despite the use of modern synergistic multimodal treatment strategies, with a progression-free survival estimated at 7-8 months, a median survival of 14-16 months and 5-year overall survival of 9.8%. RECENT FINDINGS: Physical methods hold the promise to act synergistically with classical treatments to improve the outcome of GBM patients. Fluorescent guided surgery with 5-aminolevulinic acid and tumor-treating fields therapy have already shown positive results in randomized phase III trials and have been incorporated in the standard management. Other techniques such as photodynamic therapy (PDT) and focused ultrasound, often combined whit microbubbles, are reaching clinical development. SUMMARY: Several clinical trials to evaluate the feasibility and efficacy of ultrasound devices to disrupt the blood-brain barrier are ongoing. PDT enables the creation of a safety margin or treatment of non-resecable tumors. However, randomized trials are urgently required to validate the efficacy of these promising approaches. We aim to critically review physical approaches to treat GBM, focusing on available clinical trial data.

Neurotoxicity associated with cancer immunotherapy: immune checkpoint inhibitors and chimeric antigen receptor T-cell therapy.

PURPOSE OF REVIEW: Immune checkpoint inhibitors (ICPI) and chimeric antigen receptor T cells (CAR-T) represent novel therapies recently approved to treat a number of human cancers. As both approaches modulate the immune system, they can generate a number of immune-related adverse events (irAEs), including a large spectrum of novel neurological toxicities. These are of special interest given their potential severity and risk of compromising further oncologic treatment. We aim to provide a comprehensive review of the literature and discuss their optimal management. RECENT FINDINGS: In contrast to irAEs involving other organs, neurological complications of ICPI are uncommon, may present throughout the course of treatment and involve the peripheral and central nervous system, including polyneuropathy, myositis, myasthenia gravis, demyelinating polyradiculopathy, myelitis, encephalitis and others. If started early, ICPI-related neurologic irAEs are usually responsive to steroids. In contrast, as many as 40% of patients undergoing CAR-T therapy will develop neurologic complications in the form of a cytokine-release-associated encephalopathy. It includes delirium, aphasia, tremor/myoclonus, seizure and seizure-like activity. SUMMARY: irAEs associated with CAR-T and ICPI therapy constitute new entities. Early identification and treatment are essential to optimize the functional outcome and further oncologic management of the patient.

Neurological Adverse Events Associated with Immune Checkpoint Inhibitors: Diagnosis and Management.

PURPOSE OF REVIEW: Immune checkpoint inhibitors represent a major step forward in the field of oncologic immunotherapy these last years and have significantly increased survival of cancer patients in an ever-growing number of indications. These agents block specific immune checkpoint molecules (programmed cell death protein 1 and its ligand as well as cytotoxic T-lymphocyte-associated antigen 4) that normally downregulate the immune response. These new agents show a specific range of adverse effects induced by abnormal immunologic activation. RECENT FINDINGS: Many different neurologic adverse events have been described, including encephalitis, myelopathy, aseptic meningitis, meningoradiculitis, Guillain-Barré-like syndrome, peripheral neuropathy (including mononeuropathy, mononeuritis multiplex, and polyneuropathy) as well as myasthenic syndrome. Immune checkpoint inhibitors have shown promising results in cancer but can possibly induce autoimmune disorders. Although rare, neurological adverse events require prompt recognition and treatment to avoid substantial morbidity.

[Revised WHO classification 2016 of gliomas : what's new ?] / Nouvelle classification OMS 2016 des gliomes : quels changements ?

The revised WHO classification 2016 of central nervous system tumours incorporates molecular biomarkers in addition to histological features in an « integrated diagnosis ¼. Thus, it refines classification with more homogenous diagnosis groups in order to improve prognosis and to guide treatment, notably for gliomas. This article firstly summarized the new concept of this revised classification, some basis of the molecular genetics of gliomas and practical application of the « integrated diagnosis ¼. It analyses the impact of this classification on the diagnosis and outcome of gliomas performed at the University Institute of Pathology - CHUV, Lausanne from October 2015 to November 2016.

La nouvelle classification OMS 2016 des tumeurs du système nerveux central amène un grand renouveau puisqu'elle prend maintenant en compte des données de biologie moléculaire et aboutit à un « diagnostic intégré ¼. Elle définit ainsi des groupes diagnostiques plus homogènes en termes de pronostic et de valeur prédictive à un traitement, notamment pour les gliomes. Après un rappel sur le concept de cette nouvelle classification, les notions de base sur la génétique moléculaire des gliomes et l'application pratique du diagnostic intégré, une analyse de l'impact de cette classification sur le diagnostic et le devenir des gliomes portés à l'Institut universitaire de pathologie du CHUV d'octobre 2015 à novembre 2016 est rapportée.

Neurologic complications of immune checkpoint inhibitors.

PURPOSE OF REVIEW: In recent years, advances in the understanding of the regulatory mechanisms of the immune system has led to the development of new approaches for cancer treatment. Currently, immune checkpoint inhibitors are the first successful examples of this approach and several agents that target cytotoxic lymphocyte-associated protein 4 (CTLA-4) and programmed cell death-1 (PD-1) have been approved for various oncologic situations. The aim of this review is to describe the neurologic adverse event profiles for these new immune therapeutic approaches and to discuss their appropriate management. RECENT FINDINGS: The immune checkpoint inhibitor ipilimumab against CTLA-4 and nivolumab or pembrolizumab against PD-1 show a unique spectrum of toxic effects. The most common toxicities include rash, colitis, hepatitis, endocrinopathies, and pneumonitis. Neurologic side-effects are rare but include cases of immune polyneuropathies, Guillain Barré syndrome, myasthenia gravis, posterior reversible encephalopathy syndrome, aseptic meningitis, enteric neuropathy, transverse myelitis as well as immune encephalitis. SUMMARY: It is essential that neurologic immune-related adverse events are recognized and treated as soon as possible, as early treatment increases the odds of a complete recovery.

Current management of low-grade gliomas.

PURPOSE OF REVIEW: The management of patients suffering from low-grade gliomas (LGGs) remains a challenge in absence of a definite curative therapy. The median survival is highly variable, from 2 years (high-risk disease) to over 15 years (low risk). The aim of this review is to provide a practical step-by-step evaluation of the available treatment options for patients with LGGs. RECENT FINDINGS: Next to clinical prognostic markers, both the isocitrate dehydrogenase (IDH) mutation status and the status of 1p/19q codeletion are key prognostic factors for the optimal management of patients with LGG. Two recent randomized phase III clinical trials were performed in LGGs. They first compared the efficacy of radiation versus temozolomide (TMZ) chemotherapy in high-risk LGGs. The second trial compared radiation versus radiation combined with procarbazine, lomustine and vincristine chemotherapy. SUMMARY: Regarding molecular prognostic factors, IDH wild-type LGGs have the worst prognosis, independent of therapy, whereas patients with mutated IDH, codeleted 1p/19q LGGs fared best regarding progression-free survival (PFS). In high-risk LGGs, PFS is similar regardless of whether patients have been treated with radiation or TMZ. In the second trial, patients who were treated with combination radiation and chemotherapy showed significant longer overall survival.

[Neurological complications of anticancer treatments]. / Complications neurologiques des traitements anticancéreux.

After bone marrow toxicity, neurological toxicities are the second most common complications of cancer. They can be observed throughout the course of the disease or even after the end of treatment. Establishing the correct diagnosis may be a challenge but is of outmost importance to minimize the risk of long-term neurological deficits and to improve the quality of life of the patients. This review will focus on neurological complications induced by chemotherapeutic agents. As the life expectancy and number of treatment lines used in cancer patients increases, these complications are bound to become more frequent and should be aware to neurologists.

[Multidisciplinar approach to the management of gliomas]. / Prise en charge des tumeurs cérébrales primaires: une approche multidisciplinaire.

Gliomas represent two thirds of all primary brain tumors. Their prognosis depends directly upon their level of differentiation. On MRI, tumoral aggressivity is highlighted by contrast uptake and the infiltrative nature of the lesion. Clinical suspicion must however be confirmed by histology and molecular markers become essential to refine the diagnosis and tailor the treatment. Isocytrate dehydrogenase (IDH) mutations, codeletion of 1p and 19q and the presence of methylation of the MGMT promoter identify a subgroup of gliomas with better prognosis and may help predict response to treatment. Management of patients with primary brain tumors should always be defined in multidisciplinar tumor boards involving neurosurgeons, oncologists, radiation oncologists, neuropathologists and neuroradiologists.

[Acute neurorehabilitation in neurooncology: Swiss Pilot Project and review of the litterature]. / Neurorééducation aiguë neuro-oncologique: projet pilote et revue de la literature.

New treatment modalities in oncology, radiation oncology and surgery have led to a significant improvement in life expectancy for cancer patients. Some will however develop severe neurologic deficits that will impact their quality of life. To limit this impact, it is essential to offer optimal neurorehabilitation. In this context, a pilot project of early and intensive neurorehabilitation for brain tumor patients has been set up. A collaboration between the teams of neurooncology, acute neurorehabilitation and neurosurgery from the CHUV and the Clinique La Lignière allows an intensive and direct neurorehabilitation following neurosurgery. This neuroreeducation has allowed 75% of the patients included in this program to return home.

Diagnosis and treatment of primary CNS lymphoma in immunocompetent patients: guidelines from the European Association for Neuro-Oncology.

The management of primary CNS lymphoma is one of the most controversial topics in neuro-oncology because of the complexity of the disease and the very few controlled studies available. In 2013, the European Association of Neuro-Oncology created a multidisciplinary task force to establish evidence-based guidelines for immunocompetent adults with primary CNS lymphoma. In this Review, we present these guidelines, which provide consensus considerations and recommendations for diagnosis, assessment, staging, and treatment of primary CNS lymphoma. Specifically, we address aspects of care related to surgery, systemic and intrathecal chemotherapy, intensive chemotherapy with autologous stem-cell transplantation, radiotherapy, intraocular manifestations, and management of elderly patients. The guidelines should aid clinicians in their daily practice and decision making, and serve as a basis for future investigations in neuro-oncology.

Recent developments and controversies in primary central nervous system lymphoma.

PURPOSE OF REVIEW: Primary central nervous system lymphoma (PCNSL) is a rare tumor, and its optimal management is a matter of controversy. Recent developments of collaborative groups devoted to PCNSL have allowed to conduct randomized trials addressing important issues. In addition, genome wide analysis provided new insights in the PCNSL tumorigenesis. RECENT FINDINGS: The purpose of the present review is to focus on the most recent findings in the management and the biological advances of PCNSL. SUMMARY: Cumulating data challenge the role of consolidation radiotherapy after high-dose methotrexate-based polychemotherapy, especially in the elderly, in order to reduce delayed neurotoxicity, support intensive chemotherapy with autologous stem cell transplantation as a therapeutic option in PCNSL, confirm the interest for adding rituximab in the initial treatment, and suggest the importance of B-cell receptor/Toll-like receptor/nuclear factor kappa B signaling pathway activation in PCNSL as a promising target for novel therapies.