Ashley Aaroe

Erdheim-Chester disease (ECD) and Rosai-Dorfman disease (RDD) are rare non-Langerhans cell histiocytoses (non-LCHs), for which therapeutic options are limited. MAPK pathway activation through BRAFV600E mutation or other genomic alterations is a histiocytosis hallmark and correlates with a favorable response to BRAF inhibitors and the MEK inhibitor cobimetinib. However, there has been no systematic evaluation of alternative MEK inhibitors. To assess the efficacy and safety of the MEK inhibitor trametinib, we retrospectively analyzed the outcomes of 26 adult patients (17 with ECD, 5 with ECD/RDD, 3 with RDD, and 1 with ECD/LCH) treated with orally administered trametinib at 4 major US care centers. The most common treatment-related toxicity was rash (27% of patients). In most patients, the disease was effectively managed at low doses (0.5-1.0 mg trametinib daily). The response rate of the 17 evaluable patients was 71% (73% [8/11] without a detectable BRAFV600E achieving response). At a median follow-up of 23 months, treatment effects were durable, with a median time-to-treatment failure of 37 months, whereas the median progression-free and overall survival were not reached (at 3 years, 90.1% of patients were alive). Most patients harbored mutations in BRAF (either classic BRAFV600E or other BRAF alterations) or alterations in other genes involved in the MAPK pathway, eg, MAP2K, NF1, GNAS, or RAS. Most patients required lower than standard doses of trametinib but were responsive to lower doses. Our data suggest that the MEK inhibitor trametinib is an effective treatment for ECD and RDD, including those without the BRAFV600E mutation.

Immunotherapy has revolutionized cancer treatment over the past decade. As it is increasingly introduced into routine clinical practice, immune-related complications have become more frequent. Accurate diagnosis and treatment are essential, with the goal of reduced patient morbidity. This review aims to discuss the various clinical manifestations, diagnosis, treatments, and prognosis of neurologic complications associated with the use of immune checkpoint inhibitors, adoptive T-cell therapies, and T-cell redirecting therapies. We also outline a suggested clinical approach related to the clinical use of these agents.

Glioblastoma (GBM) tumor microenvironment (TME) is a highly heterogeneous and complex system, which in addition to cancer cells, consists of various resident brain and immune cells as well as cells in transit through the tumor such as marrow-derived immune cells. The TME is a dynamic environment which is heavily influenced by alterations in cellular composition, cell-to-cell contact and cellular metabolic products as well as other chemical factors, such as pH and oxygen levels. Emerging evidence suggests that GBM cells appear to reprogram their the TME, and hijack microenvironmental elements to facilitate rapid proliferation, invasion, migration, and survival thus generating treatment resistance. GBM cells interact with their microenvironment directly through cell-to-cell by interaction mediated by cell-surface molecules, or indirectly through apocrine or paracrine signaling via cytokines, growth factors, and extracellular vehicles. The recent discovery of neuron–glioma interfaces and neurotransmitter-based interactions has uncovered novel mechanisms that favor tumor cell survival and growth. Here, we review the known and emerging evidence related to the communication between GBM cells and various components of its TME, discuss models for studying the TME and outline current studies targeting components of the TME for therapeutic purposes.

An Editor-in-Chief leads the editorial team and supervises the daily tasks required to prepare articles for publication, while at the same time managing the overall content and style of the journal. To become Editor-in-Chief, one must have dedicated work ethic, close attention to detail, passion for the editorial process, and a keen ability to work with and give feedback to section editors and authors. For this article, we interviewed Dr. Steven L. Lewis, Dr. Joseph E. Safdieh, and Dr. S. Andrew Josephson about their collective experience of becoming Editors-in-Chief of Continuum, Neurology Today, and JAMA Neurology, respectively. We have compiled tips for aspiring medical writers and editors, based on their expert advice, to guide trainees in this potential career path.

BACKGROUND: A growing number of patients with cancer receive checkpoint inhibitor (CPI) based immunotherapy. Peripheral nervous system toxicities including myositis, myasthenia gravis and inflammatory neuropathy are distinct from their non immunotherapy-related equivalents, with unique clinical presentations and therapeutic considerations. METHODS: Patients with CPI myositis and non-fatigable ptosis were identified, and clinical data was retrospectively extracted from the electronic medical record in compliance with MD Anderson Cancer Center Institutional Review Board guidelines. RESULTS: 14 patients were identified. Average maximum creatine kinase (CK) was 3571 U/L (range 20-19,794). 9 patients had electromyography and nerve conduction studies documented in our system; all had electrodiagnostic evidence of myopathy and two had evidence of concomitant myasthenia gravis by electrodecrement. Two muscle biopsies revealed myositis with inflammatory T-cell infiltrate. 6 had positive anti-striated muscle antibody titers, 9/14 had concomitant myocarditis, 2 had hepatitis, 2 had pneumonitis and 1 had thyroiditis. All received high dose steroids, 11 received plasma exchange, 4 received rituximab, 4 received tacrolimus and 2 received tocilizumab. 7/14 patients died (50%). Mean time from initial neurology consultation for symptoms to death was 6.46 months (range .3-24). 5 patients had documented clinical stabilization or mild improvement on post-discharge follow-up. CONCLUSIONS: While ptosis in patients receiving CPI can initially suggest myasthenia gravis, in patients with rapid onset and ultimately fixed deficits there should be a high index of suspicion for immunotherapy related restricted localized myositis. Myositis may coincide with other toxicities, such as myocarditis and pneumonitis, and can be fatal despite aggressive treatment. Deficits persist on post-discharge follow-up, suggesting protracted recovery for patients who survive.

MET oncogene encodes a receptor-tyrosine-kinase which drives cell proliferation, invasion and angiogenesis in a number of solid cancers including GBM where the incidence of MET amplification is 2-5%. Tepotinib is a highly selective blood-brain-barrier penetrant oral c-MET inhibitor recently FDA approved for MET-exon-14 altered non-small cell lung cancer (NSCLC). Here, we report complete radiographic response to tepotinib in a patient with newly-diagnosed disseminated GBM harboring MET amplification. A 29-years-old male presented with progressive headache. MRI brain showed a large heterogeneously enhancing intraventricular mass with epicenter in the right lateral ventricular trigone and enhancing nodules in bilateral cerebellum. MRI spine showed multifocal enhancement along the periphery of the cervicothoracic spinal cord and cauda equina concerning for leptomeningeal disease. He underwent right temporal lobectomy and subtotal resection of the mass. His KPS was 90 post-surgery due to dizziness. Pathology was consistent with GBM, IDH wild-type, MGMT-unmethylated and MET amplification at 7q31.2. He completed proton craniospinal irradiation at 3600cGy followed by boost to the tumor bed at 2400cGy without concurrent temozolomide (TMZ) due to the large radiation field. He completed two cycles of adjuvant TMZ which was put on hold due to myelosuppression. He subsequently started tepotinib monotherapy at 1000mg daily obtained on a compassionate IND. MRIs after one month of therapy showed resolution of areas of enhancement in the brain and spine. He had grade 1 creatinine elevation and abdominal discomfort and dose was reduced to 500mg daily after two cycles. Nineteen weeks after initiation of tepotinib, his complete response persists, and he remains clinically stable with mild chronic dizziness. Trials of targeted therapy in molecularly-unselected GBM have been largely disappointing, however, this case demonstrates the promise of targeting MET using tepotinib in GBM. A clinical trial of tepotinib in MET-amplified GBM and NSCLC brain metastasis is currently underway at MD Anderson.