Telehealth in Neurosurgery: 2021 Council of State Neurosurgical Societies National Survey Results.

OBJECTIVE: Telehealth was rapidly adopted during the COVID-19 pandemic. A survey was distributed to neurosurgeons in the United States (U.S.) to understand its use within neurosurgery, what barriers exist, unique issues related to neurosurgery, and opportunities for improvement. METHODS: A survey was distributed via email and used the SurveyMonkey platform. The survey was sent to 3828 practicing neurosurgeons within the U.S., 404 responses were collected between October 30, 2021 and December 4, 2021. RESULTS: During the pandemic, telehealth was used multiple times per week by 60.65% and used daily by an additional 12.78% of respondents. A supermajority (89.84%) of respondents felt that evaluating patients across state lines with telemedicine is beneficial. Most respondents (95.81%) believed that telehealth improves patient access to care. The major criticism of telehealth was the inability to perform a neurological exam. CONCLUSIONS: Telehealth has been widely implemented within the field of neurosurgery during the COVID-19 pandemic and has increased access to care. It has allowed patients to be evaluated remotely, including across state lines. While certain aspects of the neurological exam are suited for video evaluation, sensation and reflexes cannot be adequately assessed. Neurosurgeons believe that telehealth adds value to their ability to deliver care.

Mixed gangliocytoma-pituitary adenoma in MEN1 syndrome: A case report and literature review.

Pituitary adenoma is one of the three most common neoplasms described in multiple endocrine neoplasia type 1 (MEN1), and patients with pituitary adenoma occupies 30-50% of those with MEN1-related tumor. Mixed gangliocytoma-pituitary adenoma (MGPA) is a rare clinical entity in which gangliomatous cells are intermixed with adenomatous cells. This tumor has been estimated to account for 0.52-1.26% of all pituitary tumors. We report a rare case of MGPA in a patient with MEN1. A retrospective chart review was conducted on a patient with MEN1 diagnosed with MGPA in 2019 at a single tertiary academic medical center. A review of the literature was performed on MGPA and pituitary adenoma in MEN1. MGPA is rare, with only 174 cases previously reported in the literature and only three prior case reported in a patient with MEN1. There are multiple hypotheses regarding their pathogenesis, and it is unclear whether the MEN1 gene (menin) plays a role in the pathogenesis of MGPA. This tumor in MEN1 is a rare clinical entity of unknown etiology. Further studies are required with difficulty due to its low incidence.

Socioeconomic Implications of Professional Relationships within Modern Care Delivery Systems.

No physician can successfully deliver high-value patient care in the modern-day health care system in isolation. Delivery of effective patient care requires integrated and collaborative systems that depend on dynamic professional relationships among members of the health care team. An overview of the socioeconomic implications of professional relationships within modern care delivery systems and potential employment models is presented.

Exploiting Cancer's Tactics to Make Cancer a Manageable Chronic Disease.

The history of modern oncology started around eighty years ago with the introduction of cytotoxic agents such as nitrogen mustard into the clinic, followed by multi-agent chemotherapy protocols. Early success in radiation therapy in Hodgkin lymphoma gave birth to the introduction of radiation therapy into different cancer treatment protocols. Along with better understanding of cancer biology, we developed drugs targeting cancer-related cellular and genetic aberrancies. Discovery of the crucial role of vasculature in maintenance, survival, and growth of a tumor opened the way to the development of anti-angiogenic agents. A better understanding of T-cell regulatory pathways advanced immunotherapy. Awareness of stem-like cancer cells and their role in cancer metastasis and local recurrence led to the development of drugs targeting them. At the same time, sequential and rapidly accelerating advances in imaging and surgical technology have markedly increased our ability to safely remove ≥90% of tumor cells. While we have advanced our ability to kill cells from multiple directions, we have still failed to stop most types of cancer from recurring. Here we analyze the tactics employed in cancer evolution; namely, chromosomal instability (CIN), intra-tumoral heterogeneity (ITH), and cancer-specific metabolism. These tactics govern the resistance to current cancer therapeutics. It is time to focus on maximally delaying the time to recurrence, with drugs that target these fundamental tactics of cancer evolution. Understanding the control of CIN and the optimal state of ITH as the most important tactics in cancer evolution could facilitate the development of improved cancer therapeutic strategies designed to transform cancer into a manageable chronic disease.

Dual antivascular function of human fibulin-3 variant, a potential new drug discovery strategy for glioblastoma.

The ECM protein EFEMP1 (fibulin-3) is associated with all types of solid tumor through its cell context-dependent dual function. A variant of fibulin-3 was engineered by truncation and mutation to alleviate its oncogenic function, specifically the proinvasive role in glioblastoma multiforme (GBM) cells at stem-like state. ZR30 is an in vitro synthesized 39-kDa protein of human fibulin-3 variant. It has a therapeutic effect in intracranial xenograft models of human GBM, through suppression of epidermal growth factor receptor/AKT and NOTCH1/AKT signaling in GBM cells and extracellular MMP2 activation. Glioblastoma multiforme is highly vascular, with leaky blood vessels formed by tumor cells expressing endothelial cell markers, including CD31. Here we studied GBM intracranial xenografts, 2 weeks after intratumoral injection of ZR30 or PBS, by CD31 immunohistochemistry. We found a 70% reduction of blood vessel density in ZR30-treated xenografts compared with that of PBS-treated ones. Matrigel plug assays showed the effect of ZR30 on suppressing angiogenesis. We further studied the effect of ZR30 on genes involved in endothelial transdifferentiation (ETD), in 7 primary cultures derived from 3 GBMs under different culture conditions. Two GBM cultures formed mesh structures with upregulation of ETD genes shortly after culture in Matrigel Matrix, and ZR30 suppressed both. ZR30 also downregulated ETD genes in two GBM cultures with high expression of these genes. In conclusion, multifaceted tumor suppression effects of human fibulin-3 variant include both suppression of angiogenesis and vasculogenic mimicry in GBM.

Congress of Neurological Surgeons Systematic Review and Evidence-Based Guidelines on the Role of Emerging and Investigational Therapties for the Treatment of Adults With Metastatic Brain Tumors.

QUESTION: What evidence is available regarding emerging and investigational treatment options for metastatic brain tumors? TARGET POPULATION: Adult patients with brain metastases. INTERSTITIAL MODALITIES: There is insufficient evidence to make a recommendation regarding the routine use of existing local therapies, such as interstitial chemotherapy, brachytherapy, or other local modalities, aside from their use in approved clinical trials. IMMUNE MODULATORS: There is insufficient evidence to make a recommendation regarding the use of immune therapy for brain metastases. MOLECULAR TARGETED AGENTS: Level 1: The use of afatinib is not recommended in patients with brain metastasis due to breast cancer.There is insufficient evidence to make recommendations regarding: the use of epidermal growth factor receptor inhibitors erlotinib and gefitinib in patients with brain metastasis due to nonsmall cell lung cancerthe use of BRAF inhibitors dabrafenib and vemurafenib in the treatment of patients with brain metastases due to metastatic melanomathe use of HER2 agents trastuzumab and lapatinib to treat patients with brain metastases due to metastatic breast cancerthe use of vascular endothelial growth factor agents bevacizumab, sunitinib, and sorafenib in the treatment of patients with solid tumor brain metastases.The full guideline can be found at: https://www.cns.org/guidelines/guidelines-treatment-adults-metastatic-brain-tumors/chapter_9.

Tracking Functional Tumor Cell Subpopulations of Malignant Glioma by Phasor Fluorescence Lifetime Imaging Microscopy of NADH.

Intra-tumoral heterogeneity is associated with therapeutic resistance of cancer and there exists a need to non-invasively identify functional tumor subpopulations responsible for tumor recurrence. Reduced nicotinamide adenine dinucleotide (NADH) is a metabolic coenzyme essential in cellular respiration. Fluorescence lifetime imaging microscopy (FLIM) of NADH has been demonstrated to be a powerful label-free indicator for inferring metabolic states of living cells. Using FLIM, we identified a significant shift towards longer NADH fluorescence lifetimes, suggesting an increase in the fraction of protein-bound NADH, in the invasive stem-like tumor-initiating cell (STIC) subpopulation relative to the tumor mass-forming cell (TMC) subpopulation of malignant gliomas. By applying our previously studied model to transition glioma from a majority of STIC to a majority of TMC in serum-adherent culture conditions following serial passages, we compared changes in NADH states, cellular respirations (oxidative phosphorylation and glycolysis), EGFR expression, and cell-growth speed over passages. We identified a significant positive correlation between free-NADH fraction and cell growth, which was related to an increase of TMC fraction. In comparison, the increase of EGFR and cellular respirations preceded all these changes. In conclusion, FLIM of NADH provides a non-invasive method to monitor the dynamics of tumor heterogeneity before and after treatment.

The role of EGFR double minutes in modulating the response of malignant gliomas to radiotherapy.

EGFR amplification in cells having double minute chromosomes (DM) is commonly found in glioblastoma multiforme (GBM); however, how much it contributes to the current failure to treat GBM successfully is unknown. We studied two syngeneic primary cultures derived from a GBM with and without cells carrying DM, for their differential molecular and metabolic profiles, in vivo growth patterns, and responses to irradiation (IR). Each cell line has a distinct molecular profile consistent with an invasive "go" (with DM) or angiogenic "grow" phenotype (without DM) demonstrated in vitro and in intracranial xenograft models. Cells with DM were relatively radio-resistant and used higher glycolytic respiration and lower oxidative phosphorylation in comparison to cells without them. The DM-containing cell was able to restore tumor heterogeneity by mis-segregation of the DM-chromosomes, giving rise to cell subpopulations without them. As a response to IR, DM-containing cells switched their respiration from glycolic metabolism to oxidative phosphorylation and shifted molecular profiles towards that of cells without DM. Irradiated cells with DM showed the capacity to alter their extracellular microenvironment to not only promote invasiveness of the surrounding cells, regardless of DM status, but also to create a pro-angiogenic tumor microenvironment. IR of cells without DM was found primarily to increase extracellular MMP2 activity. Overall, our data suggest that the DM-containing cells of GBM are responsible for tumor recurrence due to their high invasiveness and radio-resistance and the mis-segregation of their DM chromosomes, to give rise to fast-growing cells lacking DM chromosomes.

A History of the Council of State Neurosurgical Societies.

As neurological surgery evolved into its own subspecialty early in the 20th century, a need arose to create an environment for communication and education among those surgeons working in this burgeoning surgical discipline. As the socioeconomic climate in health care began to change in the United States, an unforeseen need arose that was outside the scope of the American Association of Neurological Surgeons, Congress of Neurological Surgeons, and Society of Neurological Surgeons. The capacity to understand and address the evolving socioeconomic landscape and to offer a platform for advocacy required a new entity. Grassroots efforts of neurosurgeons at the state level ultimately yielded a formal organization of state neurosurgical societies to fill this void by recognizing, understanding, and addressing socioeconomic factors affecting the practice of neurological surgery. This formal organization became the Council of State Neurosurgical Societies (CSNS). The CSNS provides a forum in which state societies can meet to identify, understand, and advocate for policies on behalf of organized neurosurgery. The purpose of this paper is to detail the history of the formation of the CSNS. By understanding this history and the need for the development of the CSNS, it is hoped that its evolving role as a voice for neurological surgeons in the modern era of health care will be made clear.

Human fibulin-3 protein variant expresses anti-cancer effects in the malignant glioma extracellular compartment in intracranial xenograft models.

BACKGROUND: Decades of cytotoxic and more recently immunotherapy treatments for malignant glioma have had limited success due to dynamic intra-tumoral heterogeneity. The dynamic interplay of cancer cell subpopulations has been found to be under the control of proteins in the cancer microenvironment. EGF-containing fibulin-like extracellular matrix protein (EFEMP1) (also fibulin-3) has the multiple functions of suppressing cancer growth and angiogenesis, while promoting cancer cell invasion. EFEMP1-derived tumor suppressor protein (ETSP) retains EFEMP1's anti-growth and anti-angiogenic functions while actually inhibiting cancer cell invasion. METHODS: In this study, we examined the therapeutic effect on glioblastoma multiforme (GBM) of an in vitro synthesized protein, ZR30, which is based on the sequence of ETSP, excluding the signaling peptide. RESULTS: ZR30 showed the same effects as ETSP in blocking EGFR/NOTCH/AKT signaling pathways, when applied to cultures of multiple GBM cell lines and primary cultures. ZR30's inhibition of MMP2 activation was shown not only for GBM cells, but also for other types of cancer cells having overexpression of MMP2. A significant improvement in survival of mice with orthotopic human GBM xenografts was observed after a single, intra-tumoral injection of ZR30. Using a model mimicking the intra-tumoral heterogeneity of GBM with cell subpopulations carrying different invasive and proliferative phenotypes, we demonstrated an equal and simultaneous tumor suppressive effect of ZR30 on both tumor cell subpopulations, with suppression of FOXM1 and activation of SEMA3B expressions in the xenografts. CONCLUSION: Overall, the data support a complementary pleiotrophic therapeutic effect of ZR30 acting in the extracellular compartment of GBM.

Weaponizing human EGF-containing fibulin-like extracellular matrix protein 1 (EFEMP1) for 21st century cancer therapeutics.

De-regulated EFEMP1 gene expression in solid tumors has been widely reported with conflicting roles. We dissected EFEMP1 to identify domains responsible for its cell context-dependent dual functions, with the goal being to construct an EFEMP1-derived tumor-suppressor protein (ETSP) that lacked tumor-promoting function. Exon/intron boundaries of EFEMP1 were used as boundaries of functional modules in constructing EFEMP1 variants, with removal of various module(s), and/or mutating an amino acid residue to convert a weak integrin binding-site into a strong one. A series of in vitro assays on cancerous features, and subcutaneous and intracranial xenograft-formation assays, were carried out for effects from overexpression of wild-type and variant forms of EFEMP1 in two glioma subpopulations characterized as tumor mass-forming cells (TMCs) or stem-like tumor initiating cells (STICs), where EFEMP1 showed cellcontext- dependent dual functions. One of the EFEMP1 variants was identified as the sought-after ETSP, which had a stronger tumor-suppression function in TMCs by targeting EGFR and angiogenesis, and a new tumor-suppression function in STICs by targeting NOTCH signaling and MMP2-mediated cell invasion. Therefore, ETSP may form the basis for further important research to develop a novel cancer therapy to treat many types of cancer by its tumor suppressor effect in the extracellular matrix compartment.

Cell context-dependent dual effects of EFEMP1 stabilizes subpopulation equilibrium in responding to changes of in vivo growth environment.

Conflicting functions of EFEMP1 in cancer have been reported. Using two syngeneic glioma cell lines (U251 and U251-NS) carrying two different principal cell subpopulations that express high or low EGFR, and that are able to interconvert via mis-segregation of chromosome 7 (Chr7), we studied EFEMP1's cell-context-dependent functions in regulating subpopulation equilibrium, here defined by the percentage of cells carrying different copies of Chr7. We found that EFEMP1 attenuated levels of EGFR and cellular respiration in high-EGFR-expressing cells, but increased levels of NOTCH1, MMP2, cell invasiveness, and both oxidative phosphorylation and glycolytic respiration in low-EGFR-expressing cells. Consistently, EFEMP1 suppressed intracranial xenograft formation in U251 and promoted its formation in U251-NS. Interestingly, subpopulation equilibria in xenografts of U251-NS without EFEMP1 overexpression were responsive to inoculum size (1, 10 and 100 thousand cells), which may change the tumor-onset environment. It was not observed in xenografts of U251-NS with EFEMP1 overexpression. The anti-EGFR function of EFEMP1 suppressed acceleration of growth of U251-NS, but not the subpopulation equilibrium, when serially passed under a different (serum-containing adherent) culture condition. Overall, the data suggest that the orthotopic environment of the brain tumor supports EFEMP1 in carrying out both its anti-EGFR and pro-invasive/cancer stem cell-transforming functions in the two glioma cell subpopulations during formation of a single tumor, where EFEMP1 stabilizes the subpopulation equilibrium in response to alterations of the growth environment. This finding implies that EFEMP1 may restrain cancer plasticity in coping with ever-changing tumor microenvironments and/or therapeutic-intervention stresses.

Evaluation of Reported Malignant Transformation of Vestibular Schwannoma: De Novo and After Stereotactic Radiosurgery or Surgery.

OBJECTIVE: To critically analyze each reported case of malignant transformation of vestibular schwannoma (VS) after either stereotactic radiosurgery (SRS) or microsurgery (MS). DATA SOURCES: We searched the Pubmed/Medline database using the relevant key words vestibular schwannoma, acoustic neuroma, malignant, transformation, radiation, induced, stereotactic, radiosurgery, malignancy, GammaKnife, and CyberKnife and combinations thereof. STUDY SELECTION: Inclusion criteria for malignant transformation of VS after SRS included histopathology of initially benign VS, subsequent histopathology confirming malignant VS, reasonable latency period between malignancy and benign diagnoses. DATA EXTRACTION: A neurotologist and a skull base neurosurgeon independently assessed each case report for quality, entry, exclusion criteria, and comparability of extracted data. DATA SYNTHESIS: We calculated median age, latency times, and survival times for each case report. RESULTS: Malignant transformation has been documented to occur after either SRS or MS. Eight cases were included that showed histopathologic evidence of malignant transformation after SRS and MS. Four cases of malignant transformation were included that demonstrated malignant transformation after MS only. Malignant transformation of VS can also occur de novo, and de novo malignant VSs are also encountered, which can confound a causal inference from either SRS or MS. Eighteen cases of primary malignant VS were included. Studies that were identified but not included in the review are summarized and tabulated. We found 12 studies of malignant transformation associated with NF2. CONCLUSION: The potential mechanism leading to malignant transformation of VS seems more obvious for SRS and is less understood for MS. Given a low incidence of de novo malignant schwannoma, the possibility that these are spontaneous events in either setting cannot be ruled out. Risk of malignant transformation of VS after either SRS or MS is not zero; however, the magnitude of this risk is probably minimal based on the evidence from eight histopathologically confirmed cases.

Response assessment criteria for brain metastases: proposal from the RANO group.

CNS metastases are the most common cause of malignant brain tumours in adults. Historically, patients with brain metastases have been excluded from most clinical trials, but their inclusion is now becoming more common. The medical literature is difficult to interpret because of substantial variation in the response and progression criteria used across clinical trials. The Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) working group is an international, multidisciplinary effort to develop standard response and progression criteria for use in clinical trials of treatment for brain metastases. Previous efforts have focused on aspects of trial design, such as patient population, variations in existing response and progression criteria, and challenges when incorporating neurological, neuro-cognitive, and quality-of-life endpoints into trials of patients with brain metastases. Here, we present our recommendations for standard response and progression criteria for the assessment of brain metastases in clinical trials. The proposed criteria will hopefully facilitate the development of novel approaches to this difficult problem by providing more uniformity in the assessment of CNS metastases across trials.

Trigeminal neuralgia.

INTRODUCTION: Trigeminal neuralgia is a sudden, unilateral, brief, stabbing, recurrent pain in the distribution of one or more branches of the fifth cranial nerve. Pain occurs in paroxysms, which can last from a few seconds to several minutes. The frequency of the paroxysms ranges from a few to hundreds of attacks a day. Periods of remission can last for months to years, but tend to shorten over time. The condition can impair activities of daily living and lead to depression. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical question: What are the effects of ongoing treatments in people with trigeminal neuralgia? We searched: Medline, Embase, The Cochrane Library, and other important databases up to September 2013 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found seven studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review, we present information relating to the effectiveness and safety of the following interventions: baclofen; carbamazepine; gabapentin; lamotrigine; oxcarbazepine; microvascular decompression; and destructive neurosurgical techniques (radiofrequency thermocoagulation, glycerol rhizolysis, balloon compression, and stereotactic radiosurgery).