Multispecific targeting of glioblastoma with tumor microenvironment-responsive multifunctional engineered NK cells.

Tumor antigen heterogeneity, a severely immunosuppressive tumor microenvironment (TME) and lymphopenia resulting in inadequate immune intratumoral trafficking, have rendered glioblastoma (GBM) highly resistant to therapy. To address these obstacles, here we describe a unique, sophisticated combinatorial platform for GBM: a cooperative multifunctional immunotherapy based on genetically engineered human natural killer (NK) cells bearing multiple antitumor functions including local tumor responsiveness that addresses key drivers of GBM resistance to therapy: antigen escape, immunometabolic reprogramming of immune responses, and poor immune cell homing. We engineered dual-specific chimeric antigen receptor (CAR) NK cells to bear a third functional moiety that is activated in the GBM TME and addresses immunometabolic suppression of NK cell function: a tumor-specific, locally released antibody fragment which can inhibit the activity of CD73 independently of CAR signaling and decrease the local concentration of adenosine. The multifunctional human NK cells targeted patient-derived GBM xenografts, demonstrated local tumor site-specific activity in the tissue, and potently suppressed adenosine production. We also unveil a complex reorganization of the immunological profile of GBM induced by inhibiting autophagy. Pharmacologic impairment of the autophagic process not only sensitized GBM to antigenic targeting by NK cells but promoted a chemotactic profile favorable to NK infiltration. Taken together, our study demonstrates a promising NK cell-based combinatorial strategy that can target multiple clinically recognized mechanisms of GBM progression simultaneously.

Central Nervous System Involvement of Natural Killer and T Cell Neoplasms.

PURPOSE OF REVIEW: Peripheral natural killer (NK) and T cell neoplasms comprise approximately 10-15% of non-Hodgkin lymphomas. There are 27 different subtypes of peripheral NK and T cell neoplasms, each of which is relatively uncommon. Treatment has been largely extrapolated from case series, retrospective reports, and paradigms developed for the aggressive B cell lymphomas. This review explores the current knowledge of the characteristics, outcome, and treatment of CNS T cell and NK neoplasms. RECENT FINDINGS: Primary and secondary CNS NK and T cell malignancies confer significant morbidity and poor prognosis. Despite clinical heterogeneity between the 27 subtypes, high-dose methotrexate-based regimens seem most effective overall. The role of prophylaxis against secondary CNS involvement remains controversial. Autologous stem cell transplant and immunotherapy are potential for promising future therapies. Current understanding of incidence, outcome, and optimal treatment strategies for CNS T cell and NK neoplasms is limited, in large part due to their diversity and rarity. Prognosis is poor, except in a few reports of long-term survival in patients most often treated with combination therapy including high-dose methotrexate. A future prospective study on treatment and outcome in CNS T cell and NK neoplasms is needed to better define these diseases.

The Utility of Liquid Biopsy in Central Nervous System Malignancies.

PURPOSE OF REVIEW: Liquid biopsy is a sampling of tumor cells or tumor nucleotides from biofluids. This review explores the roles of liquid biopsy for evaluation and management of patients with primary and metastatic CNS malignancies. RECENT FINDINGS: Circulating tumor cell (CTC) detection has emerged as a relatively sensitive and specific tool for diagnosing leptomeningeal metastases. Circulating tumor DNA (ctDNA) detection can effectively demonstrate genetic markup of CNS tumors in the cerebrospinal fluid, though its role in managing CNS malignancies is less well-defined. The value of micro RNA (miRNA) detection in CNS malignancies is unclear at this time. Current standard clinical tools for the diagnosis and monitoring of CNS malignancies have limitations, and liquid biopsy may help address clinical practice and knowledge gaps. Liquid biopsy offers exciting potential for the diagnosis, prognosis, and treatment of CNS malignancies, but each modality needs to be studied in large prospective trials to better define their use.

Splenic marginal zone lymphoma: An indolent malignancy leading to the development of neurolymphomatosis.

INTRODUCTION: Acute neuropathic pain and weakness with a sensory level in a patient with a history of lymphoma has a broad differential diagnosis. Evaluation of such a presentation often includes MRI, neurophysiologic studies, and cerebrospinal fluid evaluation. We report a patient with splenic marginal zone lymphoma who developed acute weakness, sensory loss, and neuropathic pain due to neurolymphomatosis. METHODS: Clinical evaluation, MRI of the lumbar spine, cerebrospinal fluid evaluation, electrodiagnostic (EDx) studies, and biopsy of a dorsal nerve root were undertaken. RESULTS: EDx studies were consistent with an acute, acquired demyelinating sensorimotor polyradiculoneuropathy. Treatment with intravenous immunoglobulin and plasma exchange did not lead to clinical improvement. Ultimately, biopsy of a dorsal nerve root was performed and revealed neurolymphomatosis. CONCLUSION: This case emphasizes that, when it can be performed safely, biopsy for suspected neurolymphomatosis is imperative for appropriate diagnosis and treatment. Muscle Nerve 55: 440-444, 2017.

Discordance Between Perceptions and Experience of Lumbar Puncture: A Prospective Study.

Background and Objectives: Novel diagnostic techniques and neurologic biomarkers have greatly expanded clinical indications for CSF studies. CSF is most commonly obtained via lumbar puncture (LP). Although it is generally believed that LPs are well tolerated, there is a lack of supportive data for this claim, and patients anticipate LP to be painful. The objective of this study was to prospectively investigate discordance between patient perception and tolerability of LP. Methods: Adult patients were surveyed before and after LP regarding their perceptions and experience of LP. Physician perceptions were gathered through a web-based survey. Relative risk and Spearman correlation were used to assess the relationship between responses. Paired binomial and paired ordinal responses were compared by McNemar and paired Wilcoxon rank-sum tests. Results: A total of 178 patients completed the surveys. About half of the patients (58%) reported anxiety pre-LP, at median 3.0 of 10. Physicians overpredicted patients' pre-LP anxiety (median score 5.0, p < 0.001). Experienced pain was significantly less than predicted pain (median scores 0 and 3.0, respectively, p < 0.001). Patients who predicted pain were more likely to report pain from LP (relative risk [RR] 1.3). Predicting pain was also correlated with anxiety before LP (p < 0.001). Discussion: LP was generally well tolerated. The majority of patients experienced minimal pain. Anticipation of pain was correlated with both feeling anxious and experiencing pain. The results of this study can be used to reassure patients and providers that LP is indeed not as painful as imagined, which may both reduce pre-LP anxiety and improve LP tolerability.

Practical guidance for telemedicine use in neuro-oncology.

While the COVID-19 pandemic has catalyzed the expansion of telemedicine into nearly every specialty of medicine, few articles have summarized current practices and recommendations for integrating virtual care in the practice of neuro-oncology. This article identifies current telemedicine practice, provides practical guidance for conducting telemedicine visits, and generates recommendations for integrating virtual care into neuro-oncology practice. Practical aspects of telemedicine are summarized including when to use and not use telemedicine, how to conduct a virtual visit, who to include in the virtual encounter, unique aspects of telehealth in neuro-oncology, and emerging innovations.

Contemporary Neuroscience Core Curriculum for Medical Schools.

Medical students need to understand core neuroscience principles as a foundation for their required clinical experiences in neurology. In fact, they need a solid neuroscience foundation for their clinical experiences in all other medical disciplines also, because the nervous system plays such a critical role in the function of every organ system. Due to the rapid pace of neuroscience discoveries, it is unrealistic to expect students to master the entire field. It is also unnecessary, as students can expect to have ready access to electronic reference sources no matter where they practice. In the pre-clerkship phase of medical school, the focus should be on providing students with the foundational knowledge to use those resources effectively and interpret them correctly. This article describes an organizational framework for teaching the essential neuroscience background needed by all physicians. This is particularly germane at a time when many medical schools are re-assessing traditional practices and instituting curricular changes such as competency-based approaches, earlier clinical immersion, and increased emphasis on active learning. This article reviews factors that should be considered when developing the pre-clerkship neuroscience curriculum, including goals and objectives for the curriculum, the general topics to include, teaching and assessment methodology, who should direct the course, and the areas of expertise of faculty who might be enlisted as teachers or content experts. These guidelines were developed by a work group of experienced educators appointed by the Undergraduate Education Subcommittee (UES) of the American Academy of Neurology (AAN). They were then successively reviewed, edited, and approved by the entire UES, the AAN Education Committee, and the AAN Board of Directors.

A retrospective, quantitative assessment of disease burden in patients with leptomeningeal metastases from non-small-cell lung cancer.

BACKGROUND: Improvements in detection and molecular characterization of leptomeningeal metastasis from lung cancer (LC-LM) coupled with cerebrospinal fluid (CSF)-penetrating targeted therapies have altered disease management. A barrier to formal study of these therapies in LM is quantification of disease burden. Also, outcomes of patients with targetable mutations in LC-LM are not well defined. This study employs molecular and radiographic measures of LM disease burden and correlates these with outcome. METHODS: We reviewed charts of 171 patients with LC-LM treated at Memorial Sloan Kettering. A subset had MRI and CSF studies available. Radiographic involvement (n = 76) was scored by number of gadolinium-enhancing sites in 8 locations. CSF studies included cytopathology, circulating tumor cell (CTC) quantification (n = 16), and cell-free DNA (cfDNA) analysis (n = 21). Clinical outcomes were compared with Kaplan-Meier log-rank test and Cox proportional hazards methodologies. RESULTS: Median overall survival was 4.2 months (95% CI: 3.6-4.9); 84 patients (49%) harbored targetable mutations. Among bevacizumab-naïve patients with MRI and CSF cytology at time of LC-LM diagnosis, extent of radiographic involvement correlated with risk of death (hazard ratio [HR]: 1.16; 95% CI: 1.02-1.33; P = 0.03), as did CSF CTC (HR: 3.39, 95% CI: 1.01-11.37; P = 0.048) and CSF cfDNA concentration (HR: 2.58; 95% CI: 0.94-7.05; P = 0.06). Those without a targetable mutation were almost 50% more likely to die (HR: 1.49; 95% CI: 1.06-2.11; P = 0.02). CONCLUSIONS: Extent of radiographic involvement and quantification of CSF CTC and cfDNA show promise as prognostic indicators. These findings support molecular characterization and staging for clinical management, prognostication, and clinical trial stratification of LC-LM.

Clinical presentation, treatment, and outcomes of patients with central nervous system involvement in extranodal natural killer/T-cell lymphoma.

Extranodal natural killer (NK)/T-cell lymphoma (ENKTCL) is a rare type of Non-Hodgkin's lymphoma which rarely metastasizes to the central nervous system (CNS). Ten of 60 patients (16.7%) with ENKTCL followed at Memorial Sloan Kettering Cancer Center (MSKCC) were diagnosed with CNS involvement between 1995 and 2016. Eight patients had systemic disease at the time of CNS diagnosis; one patient never developed systemic disease and another was in remission at the time of CNS relapse. Median overall survival was 3.8 months; at time of this report 9 patients have died and one who underwent autologous stem cell transplant (ASCT) is alive 27 months after CNS diagnosis. Five patients achieved a complete response in the CNS; one is still alive, one died of systemic disease, and three died of infection. CNS ENKTCL portends a grim prognosis, with no standard treatment. Prospective study on ASCT and immunotherapy in CNS ENKTCL is warranted.

Preoperative MRI-radiomics features improve prediction of survival in glioblastoma patients over MGMT methylation status alone.

BACKGROUND: Glioblastoma (GBM) is the most common malignant central nervous system tumor, and MGMT promoter hypermethylation in this tumor has been shown to be associated with better prognosis. We evaluated the capacity of radiomics features to add complementary information to MGMT status, to improve the ability to predict prognosis. METHODS: 159 patients with untreated GBM were included in this study and divided into training and independent test sets. 286 radiomics features were extracted from the magnetic resonance images acquired prior to any treatments. A least absolute shrinkage selection operator (LASSO) selection followed by Kaplan-Meier analysis was used to determine the prognostic value of radiomics features to predict overall survival (OS). The combination of MGMT status with radiomics was also investigated and all results were validated on the independent test set. RESULTS: LASSO analysis identified 8 out of the 286 radiomic features to be relevant which were then used for determining association to OS. One feature (edge descriptor) remained significant on the external validation cohort after multiple testing (p=0.04) and the combination with MGMT identified a group of patients with the best prognosis with a survival probability of 0.61 after 43 months (p=0.0005). CONCLUSION: Our results suggest that combining radiomics with MGMT is more accurate in stratifying patients into groups of different survival risks when compared to with using these predictors in isolation. We identified two subgroups within patients who have methylated MGMT: one with a similar survival to unmethylated MGMT patients and the other with a significantly longer OS.

Neurologic and neuroscience education: Mitigating neurophobia to mentor health care providers.

Neurologic disorders are among the most frequent causes of morbidity and mortality in the United States. Moreover, the current shortfall of neurologists is expected to worsen over the coming decade. As a consequence, many patients with neurologic disorders will be treated by physicians and primary care providers without formal neurologic training. Furthermore, a pervasive and well-described fear of neurology, termed neurophobia, has been identified in medical student cohorts, residents, and among general practitioners. In this article, members of the American Academy of Neurology A.B. Baker Section on Neurological Education review current guidelines regarding neurologic and neuroscience education, contextualize the genesis and the negative consequences of neurophobia, and provide strategies to mitigate it for purposes of mentoring future generations of health care providers.