Summary Chordoma is a rare bone cancer that is aggressive, locally invasive, and has a poor prognosis. Chordomas are thought to arise from transformed remnants of notochord and have a predilection ...for the axial skeleton, with the most common sites being the sacrum, skull base, and spine. The gold standard treatment for chordomas of the mobile spine and sacrum is en-bloc excision with wide margins and postoperative external-beam radiation therapy. Treatment of clival chordomas is unique from other locations with an enhanced emphasis on preservation of neurological function, typified by a general paradigm of maximally safe cytoreductive surgery and advanced radiation delivery techniques. In this Review, we highlight current standards in diagnosis, clinical management, and molecular characterisation of chordomas, and discuss current research.
Human cancers are complex ecosystems composed of cells with distinct phenotypes, genotypes, and epigenetic states, but current models do not adequately reflect tumor composition in patients. We used ...single-cell RNA sequencing (RNA-seq) to profile 430 cells from five primary glioblastomas, which we found to be inherently variable in their expression of diverse transcriptional programs related to oncogenic signaling, proliferation, complement/immune response, and hypoxia. We also observed a continuum of stemness-related expression states that enabled us to identify putative regulators of stemness in vivo. Finally, we show that established glioblastoma subtype classifiers are variably expressed across individual cells within a tumor and demonstrate the potential prognostic implications of such intratumoral heterogeneity. Thus, we reveal previously unappreciated heterogeneity in diverse regulatory programs central to glioblastoma biology, prognosis, and therapy.
T cell dysfunction contributes to tumor immune escape in patients with cancer and is particularly severe amidst glioblastoma (GBM). Among other defects, T cell lymphopenia is characteristic, yet ...often attributed to treatment. We reveal that even treatment-naïve subjects and mice with GBM can harbor AIDS-level CD4 counts, as well as contracted, T cell-deficient lymphoid organs. Missing naïve T cells are instead found sequestered in large numbers in the bone marrow. This phenomenon characterizes not only GBM but a variety of other cancers, although only when tumors are introduced into the intracranial compartment. T cell sequestration is accompanied by tumor-imposed loss of S1P1 from the T cell surface and is reversible upon precluding S1P1 internalization. In murine models of GBM, hindering S1P1 internalization and reversing sequestration licenses T cell-activating therapies that were previously ineffective. Sequestration of T cells in bone marrow is therefore a tumor-adaptive mode of T cell dysfunction, whose reversal may constitute a promising immunotherapeutic adjunct.
Low‐Grade Gliomas Forst, Deborah A.; Nahed, Brian V.; Loeffler, Jay S. ...
The oncologist (Dayton, Ohio),
April 2014, Volume:
19, Issue:
4
Journal Article
Peer reviewed
Open access
Low‐grade gliomas (LGGs) are a diverse group of primary brain tumors that often arise in young, otherwise healthy patients and generally have an indolent course with longer‐term survival in ...comparison with high‐grade gliomas. Treatment options include observation, surgery, radiation, chemotherapy, or a combined approach, and management is individualized based on tumor location, histology, molecular profile, and patient characteristics. Moreover, in this type of brain tumor with a relatively good prognosis and prolonged survival, the potential benefits of treatment must be carefully weighed against potential treatment‐related risks.
We review in this article current management strategies for LGG, including surgery, radiotherapy, and chemotherapy. In addition, the importance of profiling the genetic and molecular properties of LGGs in the development of targeted anticancer therapies is also reviewed. Finally, given the prevalence of these tumors in otherwise healthy young patients, the impact of treatment on neurocognitive function and quality of life is also evaluated.
This article reviews current management strategies for low‐grade gliomas (LGG), including surgery, radiotherapy, and chemotherapy. In addition, the importance of profiling the genetic and molecular properties of LGGs in the development of targeted anticancer therapies is also reviewed. Finally, given the prevalence of these tumors in otherwise healthy young patients, the impact of treatment on neurocognitive function and quality of life is also evaluated.
Extracellular vesicles (EVs) carry RNA, DNA, proteins, and lipids. Specifically, tumor-derived EVs have the potential to be utilized as disease-specific biomarkers. However, a lack of methods to ...isolate tumor-specific EVs has limited their use in clinical settings. Here we report a sensitive analytical microfluidic platform (
HB-Chip) that enables tumor-specific EV-RNA isolation within 3 h. Using the
HB-Chip, we achieve 94% tumor-EV specificity, a limit of detection of 100 EVs per μL, and a 10-fold increase in tumor RNA enrichment in comparison to other methods. Our approach allows for the subsequent release of captured tumor EVs, enabling downstream characterization and functional studies. Processing serum and plasma samples from glioblastoma multiforme (GBM) patients, we can detect the mutant EGFRvIII mRNA. Moreover, using next-generation RNA sequencing, we identify genes specific to GBM as well as transcripts that are hallmarks for the four genetic subtypes of the disease.
Concern over rising healthcare expenditures has led to increased scrutiny of medical practices. As medical liability and malpractice risk rise to crisis levels, the medical-legal environment has ...contributed to the practice of defensive medicine as practitioners attempt to mitigate liability risk. High-risk specialties, such as neurosurgery, are particularly affected and neurosurgeons have altered their practices to lessen medical-legal risk. We present the first national survey of American neurosurgeons' perceptions of malpractice liability and defensive medicine practices.
A validated, 51-question online-survey was sent to 3344 practicing U.S. neurosurgeon members of the American Association of Neurological Surgeons, which represents 76% of neurosurgeons in academic and private practices.
A total of 1028 surveys were completed (31% response rate) by neurosurgeons representing diverse sub-specialty practices. Respondents engaged in defensive medicine practices by ordering additional imaging studies (72%), laboratory tests (67%), referring patients to consultants (66%), or prescribing medications (40%). Malpractice premiums were considered a "major or extreme" burden by 64% of respondents which resulted in 45% of respondents eliminating high-risk procedures from their practice due to liability concerns.
Concerns and perceptions about medical liability lead practitioners to practice defensive medicine. As a result, diagnostic testing, consultations and imaging studies are ordered to satisfy a perceived legal risk, resulting in higher healthcare expenditures. To minimize malpractice risk, some neurosurgeons have eliminated high-risk procedures. Left unchecked, concerns over medical liability will further defensive medicine practices, limit patient access to care, and increase the cost of healthcare delivery in the United States.
Chimeric antigen receptor (CAR)-T-cell therapy for solid tumors is limited due to heterogeneous target antigen expression and outgrowth of tumors lacking the antigen targeted by CAR-T cells directed ...against single antigens. Here, we developed a bicistronic construct to drive expression of a CAR specific for EGFRvIII, a glioblastoma-specific tumor antigen, and a bispecific T-cell engager (BiTE) against EGFR, an antigen frequently overexpressed in glioblastoma but also expressed in normal tissues. CART.BiTE cells secreted EGFR-specific BiTEs that redirect CAR-T cells and recruit untransduced bystander T cells against wild-type EGFR. EGFRvIII-specific CAR-T cells were unable to completely treat tumors with heterogenous EGFRvIII expression, leading to outgrowth of EGFRvIII-negative, EGFR-positive glioblastoma. However, CART.BiTE cells eliminated heterogenous tumors in mouse models of glioblastoma. BiTE-EGFR was locally effective but was not detected systemically after intracranial delivery of CART.BiTE cells. Unlike EGFR-specific CAR-T cells, CART.BiTE cells did not result in toxicity against human skin grafts in vivo.
We recently reported that BRAF V600E is the principal oncogenic driver of papillary craniopharyngioma, a highly morbid intracranial tumor commonly refractory to treatment. Here, we describe our ...treatment of a man age 39 years with multiply recurrent BRAF V600E craniopharyngioma using dabrafenib (150mg, orally twice daily) and trametinib (2mg, orally twice daily). After 35 days of treatment, tumor volume was reduced by 85%. Mutations that commonly mediate resistance to MAPK pathway inhibition were not detected in a post-treatment sample by whole exome sequencing. A blood-based BRAF V600E assay detected circulating BRAF V600E in the patient's blood. Re-evaluation of the existing management paradigms for craniopharyngioma is warranted, as patient morbidity might be reduced by noninvasive mutation testing and neoadjuvant-targeted treatment.
Monitoring patient response to treatment is challenging for most cancers, but it is particularly difficult in glioblastoma multiform, the most common and aggressive form of malignant brain tumor. ...These tumors exhibit a high degree of heterogeneity which may not be reflected in a biopsy. To determine if the current standard of care is effective, glioma patients are monitored using MRI or CT scans, an effective but sometimes misleading approach due to the phenomenon of pseudoprogression. As such, there is incredible need for a minimally invasive "liquid biopsy" to assist in molecularly characterizing the tumors while also aiding in the identification of true progression in glioblastoma. This review details the status and potential impact for circulating tumor cells, extracellular vesicles, ctDNA, and ctRNA, putative circulating biomarkers found in the blood in glioblastoma patients. As mutation-based therapy becomes more prevalent in gliomas, blood-based analyses may offer a non-invasive method of identifying mutations. The ability to obtain serial "liquid biopsies" will provide unique opportunities to study the evolution of tumors and mechanisms of treatment resistance and monitor for mutational changes in response to therapy.
Neurosurgical education in the US has changed significantly as a consequence of the novel coronavirus (COVID-19) pandemic. Institutional social distancing requirements have resulted in many ...neurosurgical programs utilizing video conferencing for educational activities. However, it is unclear how or if these practices should continue after the pandemic. The objective of this study was to characterize virtual education in neurosurgery and understand how it should be utilized after COVID-19.
A 24-question, 3-part online survey was administered anonymously to all 117 US neurosurgical residency programs from May 15, 2020, to June 15, 2020. Questions pertained to the current use of virtual conferencing, preferences over traditional conferences, and future inclinations. The Likert scale (1 = strongly disagree, 3 = neutral, 5 = strongly agree) was used. Comparisons were calculated using the Mann-Whitney U-test. Statistical significance was set at 0.05.
One-hundred eight responses were recorded. Overall, 38 respondents (35.2%) were attendings and 70 (64.8%) were trainees. Forty-one respondents (38.0%) indicated attending 5-6 conferences per week and 70 (64.8%) attend national virtual conferences. When considering different conference types, there was no overall preference (scores < 3) for virtual conferences over traditional conferences. In regard to future use, respondents strongly agreed that they would continue the practice at some capacity after the pandemic (median score 5). Overall, respondents agreed that virtual conferences would partially replace traditional conferences (median score 4), whereas they strongly disagreed with the complete replacement of traditional conferences (median score 1). The most common choices for the partial replacement of tradition conferences were case conferences (59/108, 55%) and board preparation (64/108, 59%). Lastly, there was a significant difference in scores for continued use of virtual conferencing in those who attend nationally sponsored conferences (median score 5, n = 70) and those who do not (median score 4, n = 38; U = 1762.50, z = 2.97, r = 0.29, p = 0.003).
Virtual conferences will likely remain an integral part of neurosurgical education after the COVID-19 pandemic has abated. Across the country, residents and faculty report a preference for continued use of virtual conferencing, especially virtual case conferences and board preparation. Some traditional conferences may even be replaced with virtual conferences, in particular those that are more didactic. Furthermore, nationally sponsored virtual conferences have a positive effect on the preferences for continued use of virtual conferences.
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