Macrophage migration inhibitory factor as a therapeutic target in neuro-oncology: A review.

Primary central nervous system (CNS) tumors affect tens of thousands of patients each year, and there is a significant need for new treatments. Macrophage migration inhibitory factor (MIF) is a cytokine implicated in multiple tumorigenic processes such as cell proliferation, vascularization, and immune evasion and is therefore a promising therapeutic target in primary CNS tumors. There are several MIF-directed treatments available, including small-molecule inhibitors, peptide drugs, and monoclonal antibodies. However, only a small number of these drugs have been tested in preclinical models of primary CNS tumors, and even fewer have been studied in patients. Moreover, the brain has unique therapeutic requirements that further make effective targeting challenging. In this review, we summarize the latest functions of MIF in primary CNS tumor initiation and progression. We also discuss advances in MIF therapeutic development and ongoing preclinical studies and clinical trials. Finally, we discuss potential future MIF therapies and the strategies required for successful clinical translation.

Clinical Neurologic Features and Evaluation of PTEN Hamartoma Tumor Syndrome: A Systematic Review.

BACKGROUND AND OBJECTIVES: PTEN hamartoma tumor syndrome (PHTS) is a well-recognized hereditary tumor syndrome and is now also recognized as a common cause of monogenic autism spectrum disorder. There is a vast spectrum of phenotypic variability across individuals with PHTS, and in addition to neurodevelopmental challenges, patients with PHTS may experience a wide variety of neurologic challenges, many of which have only recently been described. Thus, this systematic review aimed to summarize the breadth of the current knowledge of neurologic conditions in individuals with PHTS. METHODS: We conducted a systematic review using the MEDLINE and EMBASE databases until January 2023. We included studies that reported neurologic signs, symptoms, and diagnoses in patients with a diagnosis of PHTS. Two independent reviewers extracted data (neurologic diagnoses and patient details) from each study. Case reports, case series, prospective studies, and therapeutic trials were included. We assessed the quality of evidence using the appropriate tool from the JBI, depending on study design. RESULTS: One thousand nine hundred ninety-six articles were screened, and 90 articles met the inclusion criteria. The majority of the included studies were case reports (49/90, 54%) or small case series (31/90, 34%). Epilepsy secondary to cerebral malformations, neurologic deficits from spinal or cranial arteriovenous malformations, and rare tumors such as dysplastic cerebellar gangliocytoma are among the more severe neurologic features reported across patients with PHTS. One interventional randomized control trial examining neurocognitive endpoints was identified and did not meet its efficacy endpoint. DISCUSSION: Our systematic review defines a broad scope of neurologic comorbidities occurring in individuals with PHTS. Neurologic findings can be categorized by age at onset in individuals with PTHS. Our study highlights the need for additional clinical trial endpoints, informed by the neurologic challenges faced by individuals with PHTS.

Clinical Approach to Genetic Cerebral Arteriopathy in the Adult Patient With Ischemic Stroke.

Genetic arteriopathies leading to stroke in adults constitute a diverse group of cerebrovascular disorders with distinct etiologies, pathophysiologic mechanisms, and clinical presentations. As imaging modalities better delineate subtle changes in cerebral vasculature and access to genetic testing increases, the detection rate for these conditions is expected to rise, particularly among young adults with idiopathic cerebral arteriopathy and stroke. Adults with stroke in the setting of a genetic cerebral arteriopathy often present with few traditional stroke risk factors and, in certain cases, have characteristic clinical features, cerebrovascular imaging findings, and often concurrent systemic vasculopathy, such as aortopathy, which are important to recognize. Given that there are over 50 recognized genetic cerebral arteriopathies that can cause ischemic and hemorrhagic stroke in young adults, it can be a significant diagnostic challenge for the practicing neurologist when faced with a genetic cerebral arteriopathy, because clinical algorithms for a systematic approach to genetic cerebral arteriopathies are lacking. In this review, we present a phenotype-driven, clinically oriented algorithm to guide the diagnostic workup when suspecting a genetic cerebral arteriopathy in an adult patient while highlighting the genetic basis of each disease, molecular mechanisms, clinical manifestations, diagnostic approaches, and emerging therapeutic strategies. Moreover, given the lack of widely available gene panels for diagnostic germline testing for genetic cerebral arteriopathies, we propose key genes to be tested and focused on in each clinical scenario, to better decipher the underlying diagnosis in these rare conditions.

Tumor-related epilepsy in high-grade glioma: a large series survival analysis.

PURPOSE: Seizures are a common clinical occurrence in high-grade glioma (HGG). While many studies have explored seizure incidence and prevalence in HGG, limited studies have examined the prognostic effect of seizures occurring in the post-diagnosis setting. This study aims to assess the impact of seizure presentation on HGG survival outcomes. METHODS: Single-center retrospective review identified 950 patients with histologically-confirmed high-grade glioma. Seizure presentation was determined by clinical history and classified as early onset (occurring within 30 days of HGG presentation) or late onset (first seizure occurring after beginning HGG treatment). The primary outcome, hazard ratios for overall survival and progression-free survival, was assessed with multivariable Cox proportional-hazards models. IDH1 mutation status (assessed through immunohistochemistry) was only consistently available beginning in 2015; subgroup analyses were performed in the subset of patients with known IDH1 status. RESULTS: Epileptic activity before (HR = 0.81, 95% CI = 0.68-0.96, P = 0.017) or after (HR = 0.74, 95% CI = 0.60-0.91, P = 0.005) HGG diagnosis associated with improved overall survival. Additionally, late seizure onset significantly associated with lower odds of achieving partial (OR = 0.25, 95% CI = 0.12-0.53, P = < 0.001) or complete (OR = 0.30, 95% CI = 0.18-0.50, P < 0.001) seizure control than patients with early seizure onset. CONCLUSIONS: Clinical seizures both at the time of diagnosis and later during the HGG treatment course are associated with improved overall survival. This association potentially persists for both IDH1-wildtype and IDH1-mutant patients, but further study is required.

miR-644a is a tumor cell-intrinsic mediator of sex bias in glioblastoma.

Background: Biological sex is an important risk factor for glioblastoma (GBM), with males having a higher incidence and poorer prognosis. The mechanisms for this sex bias are thought to be both tumor intrinsic and tumor extrinsic. MicroRNAs (miRNAs), key post-transcriptional regulators of gene expression, have been previously linked to sex differences in various cell types and diseases, but their role in the sex bias of GBM remains unknown. Methods: We leveraged previously published paired miRNA and mRNA sequencing of 39 GBM patients (22 male, 17 female) to identify sex-biased miRNAs. We further interrogated a separate single-cell RNA sequencing dataset of 110 GBM patients to examine whether differences in miRNA target gene expression were tumor cell intrinsic or tumor cell extrinsic. Results were validated in a panel of patient-derived cell models. Results: We identified 10 sex-biased miRNAs (adjusted < 0.1), of which 3 were more highly expressed in males and 7 more highly expressed in females. Of these, miR-644a was higher in females, and increased expression of miR-644a target genes was significantly associated with decreased overall survival (HR 1.3, p = 0.02). Furthermore, analysis of an independent single-cell RNA sequencing dataset confirmed sex-specific expression of miR-644a target genes in tumor cells (p < 10-15). Among patient derived models, miR-644a was expressed a median of 4.8-fold higher in females compared to males. Conclusions: Our findings implicate miR-644a as a candidate tumor cell-intrinsic regulator of sex-biased gene expression in GBM.

Exploring the neurological features of individuals with germline PTEN variants: A multicenter study.

OBJECTIVE: PTEN, a known tumor suppressor gene, is a mediator of neurodevelopment. Individuals with germline pathogenic variants in the PTEN gene, molecularly defined as PTEN hamartoma tumor syndrome (PHTS), experience a variety of neurological and neuropsychiatric challenges during childhood, including autism spectrum disorder (ASD). However, the frequency and nature of seizures and the utilization of allied health services have not been described. METHODS: Young patients with PHTS and sibling controls were recruited across five centers in the United States and followed every 6-12 months for a mean of 2.1 years. In addition to the history obtained from caregivers, neurodevelopmental evaluations and structured dysmorphology examinations were conducted, and brain MRI findings, received therapies, and epilepsy characteristics were reported. RESULTS: One hundred and seven patients with PHTS (median age 8.7 years; range 3-21 years) and 38 controls were enrolled. ASD and epilepsy were frequent among patients with PHTS (51% and 15%, respectively), with generalized epilepsy strongly associated with ASD. Patients with epilepsy often required two antiseizure medications. Neuroimaging revealed prominent perivascular spaces and decreased peritrigonal myelination in individuals with PHTS-ASD. Allied therapy use was frequent and involved physical, occupational, speech, and social skills therapies, with 89% of all patients with PHTS, regardless of ASD diagnosis, utilizing at least one service. INTERPRETATION: This prospective, longitudinal study highlights the wide neurological spectrum seen in young individuals with PHTS. ASD is common in PHTS, comorbid with epilepsy, and allied health services are used universally. Our findings inform care discussions with families about neurological outcomes in PHTS.

Cell-free DNA fragmentomics and second malignant neoplasm risk in patients with PTEN hamartoma tumor syndrome.

Individuals with PTEN hamartoma tumor syndrome (PHTS) harbor pathogenic germline PTEN variants that confer a significantly increased lifetime risk of various organ-specific cancers including second primary malignant neoplasms (SMNs). Currently, there are no reliable biomarkers that can predict individual-level cancer risk. Despite the highly promising value of cell-free DNA (cfDNA) as a biomarker for underlying sporadic cancers, the utility of cfDNA in individuals with known cancer-associated germline variants and subclinical cancers remains poorly understood. We perform ultra-low-pass whole-genome sequencing (ULP-WGS) of cfDNA from plasma samples from patients with PHTS and cancer as well as those without cancer. Analysis of cfDNA reveals that patients with PHTS and SMNs have distinct cfDNA size distribution, aberrant genome-wide fragmentation, and differential fragment end motif frequencies. Our work provides evidence that cfDNA profiles may be used as a marker for SMN risk in patients with PHTS.

Practical guidance for direct oral anticoagulant use in the treatment of venous thromboembolism in primary and metastatic brain tumor patients.

Management of venous thromboembolism (VTE) in patients with primary and metastatic brain tumors (BT) is challenging because of the risk of intracranial hemorrhage (ICH). There are no prospective clinical trials evaluating safety and efficacy of direct oral anticoagulants (DOACs), specifically in patients with BT, but they are widely used for VTE in this population. A group of neuro-oncology experts convened to provide practical clinical guidance for the off-label use of DOACs in treating VTE in patients with BT. We searched PubMed for the following terms: BTs, glioma, glioblastoma (GBM), brain metastasis, VTE, heparin, low-molecular-weight heparin (LWMH), DOACs, and ICH. Although prospective clinical trials are needed, the recommendations presented aim to assist clinicians in making informed decisions regarding DOACs for VTE in patients with BT.

Exploiting convergent phenotypes to derive a pan-cancer cisplatin response gene expression signature.

Precision medicine offers remarkable potential for the treatment of cancer, but is largely focused on tumors that harbor actionable mutations. Gene expression signatures can expand the scope of precision medicine by predicting response to traditional (cytotoxic) chemotherapy agents without relying on changes in mutational status. We present a new signature extraction method, inspired by the principle of convergent phenotypes, which states that tumors with disparate genetic backgrounds may evolve similar phenotypes independently. This evolutionary-informed method can be utilized to produce consensus signatures predictive of response to over 200 chemotherapeutic drugs found in the Genomics of Drug Sensitivity in Cancer (GDSC) Database. Here, we demonstrate its use by extracting the Cisplatin Response Signature (CisSig). We show that this signature can predict cisplatin response within carcinoma-based cell lines from the GDSC database, and expression of the signatures aligns with clinical trends seen in independent datasets of tumor samples from The Cancer Genome Atlas (TCGA) and Total Cancer Care (TCC) database. Finally, we demonstrate preliminary validation of CisSig for use in muscle-invasive bladder cancer, predicting overall survival in a small cohort of patients who undergo cisplatin-containing chemotherapy. This methodology can be used to produce robust signatures that, with further clinical validation, may be used for the prediction of traditional chemotherapeutic response, dramatically increasing the reach of personalized medicine in cancer.

EGFR Pathway Expression Persists in Recurrent Glioblastoma Independent of Amplification Status.

BACKGROUND: Glioblastoma mortality is driven by tumour progression or recurrence despite administering a therapeutic arsenal consisting of surgical resection, radiation, and alkylating chemotherapy. The genetic changes underlying tumour progression and chemotherapy resistance are poorly understood. METHODS: In this study, we sought to define the relationship between EGFR amplification status, EGFR mRNA expression, and EGFR pathway activity. We compared RNA-sequencing data from matched primary and recurrent tumour samples (n = 40 patients, 20 with EGFR amplification). RESULTS: In the setting of glioblastoma recurrence, the EGFR pathway was overexpressed regardless of EGFR-amplification status, suggesting a common genomic endpoint in recurrent glioblastoma, although EGFR amplification did associate with higher EGFR mRNA expression. Three of forty patients in the study cohort had EGFR-amplified tumours and received targeted EGFR therapy. Their molecular subtypes and clinical outcomes did not significantly differ from patients who received conventional chemotherapy. CONCLUSION: Our findings suggest that while the EGFR amplification may confer a unique molecular profile in primary glioblastoma, pathway analysis reveals upregulation of the EGFR pathway in recurrence, regardless of amplification status. As such, the EGFR pathway may be a key mediator of glioblastoma progression.

Impacts of Climate Change and Air Pollution on Neurologic Health, Disease, and Practice: A Scoping Review.

BACKGROUND AND OBJECTIVES: Although the international community collectively seeks to reduce global temperature rise to less than 1.5°C before 2100, irreversible environmental changes have already occurred, and as the planet warms, these changes will continue to occur. As we witness the effects of a warming planet on human health, it is imperative that neurologists anticipate how the epidemiology and incidence of neurologic disease may change. In this review, we organized our analysis around 3 key themes related to climate change and neurologic health: extreme weather events and temperature fluctuations, emerging neuroinfectious diseases, and pollutant impacts. Across each of these themes, we appraised and reviewed recent literature relevant to neurologic disease and practice. METHODS: Studies were identified using search terms relating to climate change, pollutants, and neurologic disease in PubMed, OVID MEDLINE, EMBASE, PsycInfo, and gray literature. Studies published between 1990 and 2022 were included if they pertained to human incidence or prevalence of disease, were in English, and were relevant to neurologic disease. RESULTS: We identified a total of 364 articles, grouped into the 3 key themes of our study: extreme weather events and temperature fluctuations (38 studies), emerging neuroinfectious diseases (37 studies), and pollutant impacts (289 studies). The included studies highlighted the relationships between neurologic symptom exacerbation and temperature variability, tick-borne infections and warming climates, and airborne pollutants and cerebrovascular disease incidence and severity. DISCUSSION: Temperature extremes and variability both associated with stroke incidence and severity, migraine headaches, hospitalization in patients with dementia, and multiple sclerosis exacerbations. Exposure to airborne pollutants, especially PM2.5 and nitrates, associated with stroke incidence and severity, headaches, dementia risk, Parkinson disease, and MS exacerbation. Climate change has demonstrably expanded favorable conditions for zoonotic diseases beyond traditional borders and poses the risk of disease in new, susceptible populations. Articles were biased toward resource-rich regions, suggesting a discordance between where research occurs and where changes are most acute. As such, 3 key priorities emerged for further study: neuroinfectious disease risk mitigation, understanding the pathophysiology of airborne pollutants on the nervous system, and methods to improve delivery of neurologic care in the face of climate-related disruptions.

Phase IIa Study of SurVaxM Plus Adjuvant Temozolomide for Newly Diagnosed Glioblastoma.

PURPOSE: Despite intensive treatment with surgery, radiation therapy, temozolomide (TMZ) chemotherapy, and tumor-treating fields, mortality of newly diagnosed glioblastoma (nGBM) remains very high. SurVaxM is a peptide vaccine conjugate that has been shown to activate the immune system against its target molecule survivin, which is highly expressed by glioblastoma cells. We conducted a phase IIa, open-label, multicenter trial evaluating the safety, immunologic effects, and survival of patients with nGBM receiving SurVaxM plus adjuvant TMZ following surgery and chemoradiation (ClinicalTrials.gov identifier: NCT02455557). METHODS: Sixty-four patients with resected nGBM were enrolled including 38 men and 26 women, in the age range of 20-82 years. Following craniotomy and fractionated radiation therapy with concurrent TMZ, patients received four doses of SurVaxM (500 µg once every 2 weeks) in Montanide ISA-51 plus sargramostim (granulocyte macrophage colony-stimulating factor) subcutaneously. Patients subsequently received adjuvant TMZ and maintenance SurVaxM concurrently until progression. Progression-free survival (PFS) and overall survival (OS) were reported. Immunologic responses to SurVaxM were assessed. RESULTS: SurVaxM plus TMZ was well tolerated with no serious adverse events attributable to SurVaxM. Of the 63 patients who were evaluable for outcome, 60 (95.2%) remained progression-free 6 months after diagnosis (prespecified primary end point). Median PFS was 11.4 months and median OS was 25.9 months measured from first dose of SurVaxM. SurVaxM produced survivin-specific CD8+ T cells and antibody/immunoglobulin G titers. Apparent clinical benefit of SurVaxM was observed in both methylated and unmethylated patients. CONCLUSION: SurVaxM appeared to be safe and well tolerated. The combination represents a promising therapy for nGBM. For patients with nGBM treated in this manner, PFS may be an acceptable surrogate for OS. A large randomized clinical trial of SurVaxM for nGBM is in progress.

Machine Learning Using Gene-Sets to Infer miRNA Function.

miRNA are regulators of cell phenotype, and there is clear evidence that these small posttranscriptional modifiers of gene expression are involved in defining a cellular response across states of development and disease. Classical methods for elucidating the repressive effect of a miRNA on its targets involve controlling for the many factors influencing miRNA action, and this can be achieved in cell lines, but misses tissue and organism level context which are key to a miRNA function. Also, current technology to carry out this validation is limited in both generalizability and throughput. Methodologies with greater scalability and rapidity are required to better understand the function of these important species of RNA. To this end, there is an increasing store of RNA expression level data incorporating both miRNA and mRNA, and in this chapter, we describe how to use machine learning and gene-sets to translate the knowledge of phenotype defined by mRNA to putative roles for miRNA. We outline our approach to this process and highlight how it was done for our miRNA annotation of the hallmarks of cancer using the Cancer Genome Atlas (TCGA) dataset. The concepts we present are applicable across datasets and phenotypes, and we highlight potential pitfalls and challenges that may be faced as they are used.

First clinical experience with belzutifan in von Hippel-Lindau disease associated CNS hemangioblastoma.

We present two cases of von Hippel-Lindau (VHL) disease-associated hemangioblastomas in the CNS treated with the newly approved HIF-2α inhibitor, belzutifan. The first case is a 31-year-old female with confirmed pathogenic germline VHL mutation who presented with multiple hemangioblastomas. The patient was started on belzutifan, and a brisk reduction in perilesional edema was observed after 2 months of treatment. The second patient is a 30-year-old male with familial VHL disease. Imaging revealed multiple cerebellar hemangioblastomas, and follow-up imaging after three cycles of belzutifan revealed a reduction in perilesional edema. Both patients tolerated belzutifan well, with only anemia and fatigue. We highlight our initial experience and early imaging findings associated with belzutifan in VHL disease-associated CNS hemangioblastomas.

Network potential identifies therapeutic miRNA cocktails in Ewing sarcoma.

MicroRNA (miRNA)-based therapies are an emerging class of targeted therapeutics with many potential applications. Ewing Sarcoma patients could benefit dramatically from personalized miRNA therapy due to inter-patient heterogeneity and a lack of druggable (to this point) targets. However, because of the broad effects miRNAs may have on different cells and tissues, trials of miRNA therapies have struggled due to severe toxicity and unanticipated immune response. In order to overcome this hurdle, a network science-based approach is well-equipped to evaluate and identify miRNA candidates and combinations of candidates for the repression of key oncogenic targets while avoiding repression of essential housekeeping genes. We first characterized 6 Ewing sarcoma cell lines using mRNA sequencing. We then estimated a measure of tumor state, which we term network potential, based on both the mRNA gene expression and the underlying protein-protein interaction network in the tumor. Next, we ranked mRNA targets based on their contribution to network potential. We then identified miRNAs and combinations of miRNAs that preferentially act to repress mRNA targets with the greatest influence on network potential. Our analysis identified TRIM25, APP, ELAV1, RNF4, and HNRNPL as ideal mRNA targets for Ewing sarcoma therapy. Using predicted miRNA-mRNA target mappings, we identified miR-3613-3p, let-7a-3p, miR-300, miR-424-5p, and let-7b-3p as candidate optimal miRNAs for preferential repression of these targets. Ultimately, our work, as exemplified in the case of Ewing sarcoma, describes a novel pipeline by which personalized miRNA cocktails can be designed to maximally perturb gene networks contributing to cancer progression.

Extracellular miRNA biomarkers in neurologic disease: is cerebrospinal fluid helpful?

Aim: The aim of our work is to aggregate data from publications of cerebrospinal fluid extracellular miRNA to identify candidate diagnostic biomarkers, and those warranting further study. Materials & methods: Data were pooled from nine studies, encompassing 864 patients across 16 diseases. Unsupervised clustering grouped patients by a broad category of diseases. Results & conclusion: Compared with healthy controls, in patients with Alzheimer's disease, hsa-miR-767-5p was overexpressed (p < 0.001) and in patients with Huntington's disease, hsa-miR-361-3p was underexpressed (p < 10-4). We also define a subset of extracellular miRNA as candidate biomarkers that are robustly detected across patients, studies and diseases; thereby, warranting further study.

UV decontamination of personal protective equipment with idle laboratory biosafety cabinets during the COVID-19 pandemic.

Personal protective equipment (PPE) is crucially important to the safety of both patients and medical personnel, particularly in the event of an infectious pandemic. As the incidence of Coronavirus Disease 2019 (COVID-19) increases exponentially in the United States and many parts of the world, healthcare provider demand for these necessities is currently outpacing supply. In the midst of the current pandemic, there has been a concerted effort to identify viable ways to conserve PPE, including decontamination after use. In this study, we outline a procedure by which PPE may be decontaminated using ultraviolet (UV) radiation in biosafety cabinets (BSCs), a common element of many academic, public health, and hospital laboratories. According to the literature, effective decontamination of N95 respirator masks or surgical masks requires UV-C doses of greater than 1 Jcm-2, which was achieved after 4.3 hours per side when placing the N95 at the bottom of the BSCs tested in this study. We then demonstrated complete inactivation of the human coronavirus NL63 on N95 mask material after 15 minutes of UV-C exposure at 61 cm (232 µWcm-2). Our results provide support to healthcare organizations looking for methods to extend their reserves of PPE.

Mathematical Modeling of ceRNA-Based Interactions.

Competing endogenous RNA (ceRNA) molecules have emerged as key players in regulating gene expression, increasing the complexity of the range of possible dynamics within a cell. The actions of competing RNA typically are sponging behaviors, in a manner that fine-tunes gene expression, but there are particular network structures that may show destabilization due to ceRNA interactions. In this chapter, we discuss how these interactions can be modeled and probed from a mathematical, first-principles perspective.

Continuous electroencephalography characteristics and acute symptomatic seizures in COVID-19 patients.

OBJECTIVE: As concerns regarding neurological manifestations in COVID-19 (coronavirus disease 2019) patients increase, limited data exists on continuous electroencephalography (cEEG) findings in these patients. We present a retrospective cohort study of cEEG monitoring in COVID-19 patients to better explore this knowledge gap. METHODS: Among 22 COVID-19 patients, 19 underwent cEEGs, and 3 underwent routine EEGs (<1 h). Demographic and clinical variables, including comorbid conditions, discharge disposition, survival and cEEG findings, were collected. RESULTS: cEEG was performed for evaluation of altered mental status (n = 17) or seizure-like events (n = 5). Five patients, including 2 with epilepsy, had epileptiform abnormalities on cEEG. Two patients had electrographic seizures without a prior epilepsy history. There were no acute neuroimaging findings. Periodic discharges were noted in one-third of patients and encephalopathic EEG findings were not associated with IV anesthetic use. CONCLUSIONS: Interictal epileptiform abnormalities in the absence of prior epilepsy history were rare. However, the discovery of asymptomatic seizures in two of twenty-two patients was higher than previously reported and is therefore of concern. SIGNIFICANCE: cEEG monitoring in COVID-19 patients may aid in better understanding an epileptogenic potential of SARS-CoV2 infection. Nevertheless, larger studies utilizing cEEG are required to better examine acute epileptic risk in COVID-19 patients.