The Case for Neurosurgical Intervention in Cancer Neuroscience.

The emerging field of cancer neuroscience reshapes our understanding of the intricate relationship between the nervous system and cancer biology; this new paradigm is likely to fundamentally change and advance neuro-oncological care. The profound interplay between cancers and the nervous system is reciprocal: Cancer growth can be induced and regulated by the nervous system; conversely, tumors can themselves alter the nervous system. Such crosstalk between cancer cells and the nervous system is evident in both the peripheral and central nervous systems. Recent advances have uncovered numerous direct neuron-cancer interactions at glioma-neuronal synapses, paracrine mechanisms within the tumor microenvironment, and indirect neuroimmune interactions. Neurosurgeons have historically played a central role in neuro-oncological care, and as the field of cancer neuroscience is becoming increasingly established, the role of neurosurgical intervention is becoming clearer. Examples include peripheral denervation procedures, delineation of neuron-glioma networks, development of neuroprostheses, neuromodulatory procedures, and advanced local delivery systems. The present review seeks to highlight key cancer neuroscience mechanisms with neurosurgical implications and outline the future role of neurosurgical intervention in cancer neuroscience.

Recurrent Glioblastoma-Molecular Underpinnings and Evolving Treatment Paradigms.

Glioblastoma is the most common and lethal central nervous system malignancy with a median survival after progression of only 6-9 months. Major biochemical mechanisms implicated in glioblastoma recurrence include aberrant molecular pathways, a recurrence-inducing tumor microenvironment, and epigenetic modifications. Contemporary standard-of-care (surgery, radiation, chemotherapy, and tumor treating fields) helps to control the primary tumor but rarely prevents relapse. Cytoreductive treatment such as surgery has shown benefits in recurrent glioblastoma; however, its use remains controversial. Several innovative treatments are emerging for recurrent glioblastoma, including checkpoint inhibitors, chimeric antigen receptor T cell therapy, oncolytic virotherapy, nanoparticle delivery, laser interstitial thermal therapy, and photodynamic therapy. This review seeks to provide readers with an overview of (1) recent discoveries in the molecular basis of recurrence; (2) the role of surgery in treating recurrence; and (3) novel treatment paradigms emerging for recurrent glioblastoma.

Combination immunotherapy with vaccine and oncolytic HSV virotherapy is time dependent.

PURPOSE: Oncolytic virotherapy or immunovirotherapy is a strategy that utilizes viruses to selectively infect and kill tumor cells while also stimulating an immune response against the tumor. Early clinical trials in both pediatric and adult patients using oncolytic herpes simplex viruses (oHSVs) have demonstrated safety and promising efficacy; however, combinatorial strategies designed to enhance oncolysis while also promoting durable T cell responses for sustaining disease remission are likely required. We hypothesized that combining the direct tumor cell killing and innate immune stimulation by oHSV with a vaccine that promotes T cell mediated immunity may lead to more durable tumor regression. EXPERIMENTAL DESIGN: To this end, we investigated the preclinical efficacy and potential synergy of combining oHSV with a self-assembling nanoparticle vaccine co-delivering peptide antigens and Toll-like receptor-7 and -8 agonists (TLR-7/8a) (referred to as SNAPvax™), that induces robust tumor specific T cell immunity. We then assessed how timing of the treatments (i.e., vaccine before or after oHSV) impacts T cell responses, viral replication, and preclinical efficacy. RESULTS: The sequence of treatments was critical, as survival was significantly enhanced when the SNAPvax™ vaccine was given prior to oHSV. Increased clinical efficacy was associated with reduced tumour volume and increases in virus replication and tumor antigen specific CD8+ T cells. CONCLUSIONS: These findings substantiate the criticality of combination immunotherapy timing and provide preclinical support for combining SNAPvax with oHSV as a promising treatment approach for both pediatric and adult tumors.

The first neurosurgical service in Texas: neurosurgery at the University of Texas Medical Branch (1937-2023).

The authors present a historical analysis of the first neurosurgical service in Texas. Initially established as a subdivision within the Department of Surgery in the early 1900s, this service eventually evolved into the Department of Neurosurgery at the University of Texas Medical Branch (UTMB). The pivotal contributions of individual chiefs of neurosurgery throughout the years are highlighted, emphasizing their roles in shaping the growth of the neurosurgery division. The challenges faced by the neurosurgical division are documented, with particular attention given to the impact of hurricanes on Galveston Island, Texas, which significantly disrupted hospital operations. Additionally, a detailed account of recent clinical and research expansions is presented, along with the future directions envisioned for the Department of Neurosurgery. This work offers a comprehensive historical narrative of the neurosurgical service at UTMB, chronicling its journey of growth and innovation, and underscoring its profound contributions to Galveston's healthcare services, extending its impact beyond the local community.

Improved immunostaining of nanostructures and cells in human brain specimens through expansion-mediated protein decrowding.

Proteins are densely packed in cells and tissues, where they form complex nanostructures. Expansion microscopy (ExM) variants have been used to separate proteins from each other in preserved biospecimens, improving antibody access to epitopes. Here, we present an ExM variant, decrowding expansion pathology (dExPath), that can expand proteins away from each other in human brain pathology specimens, including formalin-fixed paraffin-embedded (FFPE) clinical specimens. Immunostaining of dExPath-expanded specimens reveals, with nanoscale precision, previously unobserved cellular structures, as well as more continuous patterns of staining. This enhanced molecular staining results in observation of previously invisible disease marker-positive cell populations in human glioma specimens, with potential implications for tumor aggressiveness. dExPath results in improved fluorescence signals even as it eliminates lipofuscin-associated autofluorescence. Thus, this form of expansion-mediated protein decrowding may, through improved epitope access for antibodies, render immunohistochemistry more powerful in clinical science and, perhaps, diagnosis.

Development of an educational method to rethink and learn oncological brain surgery in an "a la carte" connectome-based perspective.

BACKGROUND: Understanding the structural connectivity of white matter tracts (WMT) and their related functions is a prerequisite to implementing an "a la carte" "connectomic approach" to glioma surgery. However, accessible resources facilitating such an approach are lacking. Here we present an educational method that is readily accessible, simple, and reproducible that enables the visualization of WMTs on individual patient images via an atlas-based approach. METHODS: Our method uses the patient's own magnetic resonance imaging (MRI) images and consists of three main steps: data conversion, normalization, and visualization; these are accomplished using accessible software packages and WMT atlases. We implement our method on three common cases encountered in glioma surgery: a right supplementary motor area tumor, a left insular tumor, and a left temporal tumor. RESULTS: Using patient-specific perioperative MRIs with open-sourced and co-registered atlas-derived WMTs, we highlight the critical subnetworks requiring specific surgical monitoring identified intraoperatively using direct electrostimulation mapping with cognitive monitoring. The aim of this didactic method is to provide the neurosurgical oncology community with an accessible and ready-to-use educational tool, enabling neurosurgeons to improve their knowledge of WMTs and to better learn their oncologic cases, especially in glioma surgery using awake mapping. CONCLUSIONS: Taking no more than 3-5 min per patient and irrespective of their resource settings, we believe that this method will enable junior surgeons to develop an intuition, and a robust 3-dimensional imagery of WMT by regularly applying it to their cases both before and after surgery to develop an "a la carte" connectome-based perspective to glioma surgery.

Intraoperative functional remapping unveils evolving patterns of cortical plasticity.

The efficiency with which the brain reorganizes following injury not only depends on the extent and the severity of the lesion, but also on its temporal features. It is established that diffuse low-grade gliomas (DLGG), brain tumours with a slow-growth rate, induce a compensatory modulation of the anatomo-functional architecture, making this kind of tumours an ideal lesion model to study the dynamics of neuroplasticity. Direct electrostimulation (DES) mapping is a well-tried procedure used during awake resection surgeries to identify and spare cortical epicentres which are critical for a range of functions. Because DLGG is a chronic disease, it inevitably relapses years after the initial surgery, and thus requires a second surgery to reduce tumour volume again. In this context, contrasting the cortical mappings obtained during two sequential neurosurgeries offers a unique opportunity to both identify and characterize the dynamic (i.e. re-evolving) patterns of cortical re-arrangements. Here, we capitalized on an unprecedented series of 101 DLGG patients who benefited from two DES-guided neurosurgeries usually spaced several years apart, resulting in a large DES dataset of 2082 cortical sites. All sites (either non-functional or associated with language, speech, motor, somatosensory and semantic processing) were recorded in Montreal Neurological Institute (MNI) space. Next, we used a multi-step approach to generate probabilistic neuroplasticity maps that reflected the dynamic rearrangements of cortical mappings from one surgery to another, both at the population and individual level. Voxel-wise neuroplasticity maps revealed regions with a relatively high potential of evolving reorganizations at the population level, including the supplementary motor area (SMA, Pmax = 0.63), the dorsolateral prefrontal cortex (dlPFC, Pmax = 0.61), the anterior ventral premotor cortex (vPMC, Pmax = 0.43) and the middle superior temporal gyrus (STG Pmax = 0.36). Parcel-wise neuroplasticity maps confirmed this potential for the dlPFC (Fisher's exact test, PFDR-corrected = 6.6 × 10-5), the anterior (PFDR-corrected = 0.0039) and the ventral precentral gyrus (PFDR-corrected = 0.0058). A series of clustering analyses revealed a topological migration of clusters, especially within the left dlPFC and STG (language sites); the left vPMC (speech arrest/dysarthria sites) and the right SMA (negative motor response sites). At the individual level, these dynamic changes were confirmed for the dlPFC (bilateral), the left vPMC and the anterior left STG (threshold free cluster enhancement, 5000 permutations, family-wise error-corrected). Taken as a whole, our results provide a critical insight into the dynamic potential of DLGG-induced continuing rearrangements of the cerebral cortex, with considerable implications for re-operations.

Challenges in, and recommendations for, hyperspectral imaging in ex vivo malignant glioma biopsy measurements.

The visualization of protoporphyrin IX (PPIX) fluorescence with the help of surgical microscopes during 5-aminolevulinic acid-mediated fluorescence-guided resection (FGR) of gliomas is still limited at the tumor margins. Hyperspectral imaging (HI) detects PPIX more sensitively but is not yet ready for intraoperative use. We illustrate the current status with three experiments and summarize our own experience using HI: (1) assessment of HI analysis algorithm using pig brain tissue, (2) a partially retrospective evaluation of our experience from HI projects, and (3) device comparison of surgical microscopy and HI. In (1), we address the problem that current algorithms for evaluating HI data are based on calibration with liquid phantoms, which have limitations. Their pH is low compared to glioma tissue; they provide only one PPIX photo state and only PPIX as fluorophore. Testing the HI algorithm with brain homogenates, we found proper correction for optical properties but not pH. Considerably more PPIX was measured at pH 9 than at pH 5. In (2), we indicate pitfalls and guide HI application. In (3), we found HI superior to the microscope for biopsy diagnosis (AUC = 0.845 ± 0.024 (cut-off 0.75 µg PPIX/ml) vs. 0.710 ± 0.035). HI thus offers potential for improved FGR.

The clinical significance of radiological changes associated with gliadel implantation in patients with recurrent high grade glioma.

Gliadel occasionally induces edema following its implantation. We aimed to correlate such post-surgical radiological changes to its efficacy and subsequent survival. Fifty-six patients with recurrent high grade glioma were treated between 2005 and 2016 with Gliadel implantation. Volumetric measurements of MRI features, including FLAIR abnormalities, tumor bulk (volume of gadolinium enhancement on T1) and resection cavity volumes over time were conducted. To assess dynamics over time, linear regression trendlines for each of these were calculated and examined to correlate with survival. Median follow-up after resection was 21.5 months. Median survival post-Gliadel implantation and overall survival since diagnosis were 12 months and 22 months, respectively. A subgroup of patients (n = 6) with a transient increase in FLAIR changes volume over time survived significantly longer post-Gliadel compared to those who did not demonstrate such change (36 vs 12 months, p = .03). Positive trends, representing overall growth in volume over time, of tumor bulk and resection cavity predicted survival in multivariate analyses (hazard ratios 7.9 and 84, p = .003 and .002, respectively). Increase in tumor bulk and resection cavity over time were associated with decreased survival, while transient FLAIR increase was a favorable prognostic factor. This may represent a transient inflammatory process in the tumor, possibly stemming from a presumed immune-mediated anti-tumor response.

Risk factors and prognostic implications of surgery-related strokes following resection of high-grade glioma.

Surgery-related strokes are an important cause of morbidity following resection of high-grade glioma (HGG). We explored the incidence, risk factors and clinical consequences of intra-operative ischemic strokes in surgeries for resection of HGG. We retrospectively followed a cohort of 239 patients who underwent surgical resection of HGG between 2013 and 2017. Tumor types included both isocitrate dehydrogenase (IDH) wildtype glioblastoma and IDH-mutant WHO grade 4 astrocytoma. We analyzed pre- and post-operative demographic, clinical, radiological, anesthesiology and intraoperative neurophysiology data, including overall survival and functional outcomes. Acute ischemic strokes were seen on postoperative diffusion-weighted imaging (DWI) in 30 patients (12.5%), 13 of whom (43%) developed new neurological deficits. Infarcts were more common in insular (23%, p = 0.019) and temporal surgeries (57%, p = 0.01). Immediately after surgery, 35% of patients without infarcts and 57% of those with infarcts experienced motor deficits (p = 0.022). Six months later, rates of motor deficits decreased to 25% in the non-infarcts group and 37% in the infarcts group (p = 0.023 and 0.105, respectively) with a significantly lower Karnofsky-Performance Score (KPS, p = 0.001). Intra-operative language decline in awake procedures was a significant indicator of the occurrence of intra-operative stroke (p = 0.029). In conclusion, intraoperative ischemic events are more common in insular and temporal surgeries for resection of HGG and their intra-operative detection is limited. These strokes can impair motor and speech functions as well as patients' performance status.

Immunotherapy approaches for the treatment of diffuse midline gliomas.

Diffuse midline gliomas (DMG) are a highly aggressive and universally fatal subgroup of pediatric tumors responsible for the majority of childhood brain tumor deaths. Median overall survival is less than 12 months with a 90% mortality rate at 2 years from diagnosis. Research into the underlying tumor biology and numerous clinical trials have done little to change the invariably poor prognosis. Continued development of novel, efficacious therapeutic options for DMGs remains a critically important area of active investigation. Given that DMGs are not amenable to surgical resection, have only limited response to radiation, and are refractory to traditional chemotherapy, immunotherapy has emerged as a promising alternative treatment modality. This review summarizes the various immunotherapy-based treatments for DMG as well as their specific limitations. We explore the use of cell-based therapies, oncolytic virotherapy or immunovirotherapy, immune checkpoint inhibition, and immunomodulatory vaccination strategies, and highlight the recent clinical success of anti-GD2 CAR-T therapy in diffuse intrinsic pontine glioma (DIPG) patients. Finally, we address the challenges faced in translating preclinical and early phase clinical trial data into effective standardized treatment for DMG patients.

Clinical and prognostic implications of rim restriction following glioma surgery.

Rim restriction surrounding the resection cavity of glioma is often seen on immediate post-op diffusion-weighted imaging (DWI). The etiology and clinical impact of rim restriction are unknown. We evaluated the incidence, risk factors and clinical consequences of this finding. We evaluated patients that underwent surgery for low-grade glioma (LGG) and glioblastoma (GBM) without stroke on post-operative imaging. Analyses encompassed pre- and postoperative clinical, radiological, intraoperative monitoring, survival, functional and neurocognitive outcomes. Between 2013 and 2017, 63 LGG and 209 GBM patients (272 in total) underwent surgical resection and were included in our cohort. Post-op rim restriction was demonstrated in 68 patients, 32% (n = 20) of LGG and 23% (n = 48) of GBM patients. Risk factors for restriction included temporal tumors in GBM (p = 0.025) and insular tumors in LGG (p = 0.09), including longer surgery duration in LGG (p = 0.008). After a 1-year follow-up, LGG patients operated on their dominant with post-op restriction had a higher rate of speech deficits (46 vs 9%, p = 0.004). Rim restriction on postoperative imaging is associated with longer duration of glioma surgery and potentially linked to brain retraction. It apparently has no direct clinical consequences, but is linked to higher rates of speech deficits in LGG dominant-side surgeries.

Standard clinical approaches and emerging modalities for glioblastoma imaging.

Glioblastoma (GBM) is the most common primary adult intracranial malignancy and carries a dismal prognosis despite an aggressive multimodal treatment regimen that consists of surgical resection, radiation, and adjuvant chemotherapy. Radiographic evaluation, largely informed by magnetic resonance imaging (MRI), is a critical component of initial diagnosis, surgical planning, and post-treatment monitoring. However, conventional MRI does not provide information regarding tumor microvasculature, necrosis, or neoangiogenesis. In addition, traditional MRI imaging can be further confounded by treatment-related effects such as pseudoprogression, radiation necrosis, and/or pseudoresponse(s) that preclude clinicians from making fully informed decisions when structuring a therapeutic approach. A myriad of novel imaging modalities have been developed to address these deficits. Herein, we provide a clinically oriented review of standard techniques for imaging GBM and highlight emerging technologies utilized in disease characterization and therapeutic development.

The Evolving Role of Neurosurgical Intervention for Central Nervous System Tumors.

Since its inception, greater than a century ago, neurosurgery has represented the fundamental trait-d'union between clinical management, scientific investigation, and therapeutic advancements in the field of brain tumors. During the years, oncological neurosurgery has evolved as a self-standing subspecialty, due to technical progress, equipment improvement, evolution of therapeutic paradigms, and the progressively crucial role that it plays in the execution of complex therapeutic strategies and modern clinical trials.

Cerebellar High-Grade Glioma: A Translationally Oriented Review of the Literature.

World Health Organization (WHO) grade 4 gliomas of the cerebellum are rare entities whose understanding trails that of their supratentorial counterparts. Like supratentorial high-grade gliomas (sHGG), cerebellar high-grade gliomas (cHGG) preferentially affect males and prognosis is bleak; however, they are more common in a younger population. While current therapy for cerebellar and supratentorial HGG is the same, recent molecular analyses have identified features and subclasses of cerebellar tumors that may merit individualized targeting. One recent series of cHGG included the subclasses of (1) high-grade astrocytoma with piloid features (HGAP, ~31% of tumors); (2) H3K27M diffuse midline glioma (~8%); and (3) isocitrate dehydrogenase (IDH) wildtype glioblastoma (~43%). The latter had an unusually low-frequency of epidermal growth factor receptor (EGFR) and high-frequency of platelet-derived growth factor receptor alpha (PDGFRA) amplification, reflecting a different composition of methylation classes compared to supratentorial IDH-wildtype tumors. These new classifications have begun to reveal insights into the pathogenesis of HGG in the cerebellum and lead toward individualized treatment targeted toward the appropriate subclass of cHGG. Emerging therapeutic strategies include targeting the mitogen-activated protein kinases (MAPK) pathway and PDGFRA, oncolytic virotherapy, and immunotherapy. HGGs of the cerebellum exhibit biological differences compared to sHGG, and improved understanding of their molecular subclasses has the potential to advance treatment.

Therapeutic cancer vaccines for pediatric malignancies: advances, challenges, and emerging technologies.

Though outcomes for pediatric cancer patients have significantly improved over the past several decades, too many children still experience poor outcomes and survivors suffer lifelong, debilitating late effects after conventional chemotherapy, radiation, and surgical treatment. Consequently, there has been a renewed focus on developing novel targeted therapies to improve survival outcomes. Cancer vaccines are a promising type of immunotherapy that leverage the immune system to mediate targeted, tumor-specific killing through recognition of tumor antigens, thereby minimizing off-target toxicity. As such, cancer vaccines are orthogonal to conventional cancer treatments and can therefore be used alone or in combination with other therapeutic modalities to maximize efficacy. To date, cancer vaccination has remained largely understudied in the pediatric population. In this review, we discuss the different types of tumor antigens and vaccine technologies (dendritic cells, peptides, nucleic acids, and viral vectors) evaluated in clinical trials, with a focus on those used in children. We conclude with perspectives on how advances in combination therapies, tumor antigen (eg, neoantigen) selection, and vaccine platform optimization can be translated into clinical practice to improve outcomes for children with cancer.

Spatial Multiplexing of Fluorescent Reporters for Imaging Signaling Network Dynamics.

In order to analyze how a signal transduction network converts cellular inputs into cellular outputs, ideally one would measure the dynamics of many signals within the network simultaneously. We found that, by fusing a fluorescent reporter to a pair of self-assembling peptides, it could be stably clustered within cells at random points, distant enough to be resolved by a microscope but close enough to spatially sample the relevant biology. Because such clusters, which we call signaling reporter islands (SiRIs), can be modularly designed, they permit a set of fluorescent reporters to be efficiently adapted for simultaneous measurement of multiple nodes of a signal transduction network within single cells. We created SiRIs for indicators of second messengers and kinases and used them, in hippocampal neurons in culture and intact brain slices, to discover relationships between the speed of calcium signaling, and the amplitude of PKA signaling, upon receiving a cAMP-driving stimulus.

Design and Rationale for First-in-Human Phase 1 Immunovirotherapy Clinical Trial of Oncolytic HSV G207 to Treat Malignant Pediatric Cerebellar Brain Tumors.

Brain tumors represent the most common pediatric solid neoplasms and leading cause of childhood cancer-related morbidity and mortality. Although most adult brain tumors are supratentorial and arise in the cerebrum, the majority of pediatric brain tumors are infratentorial and arise in the posterior fossa, specifically the cerebellum. Outcomes from malignant cerebellar tumors are unacceptable despite aggressive treatments (surgery, radiation, and/or chemotherapy) that are harmful to the developing brain. Novel treatments/approaches such as oncolytic virotherapy are urgently needed. Preclinical and prior clinical studies suggest that genetically engineered oncolytic herpes simplex virus (HSV-1) G207 can safely target cerebellar malignancies and has potential to induce an antitumor immune response at local and distant sites of disease, including spinal metastases and leptomeningeal disease. Herein, we outline the rationale, design, and significance of a first-in-human immunotherapy Phase 1 clinical trial targeting recurrent cerebellar malignancies with HSV G207 combined with a single low-dose of radiation (5 Gy), designed to enhance virus replication and innate and adaptive immune responses. We discuss the unique challenges of inoculating virus through intratumoral catheters into cerebellar tumors. The trial utilizes a single arm open-label traditional 3 + 3 design with four dose cohorts. The primary objective is to assess safety and tolerability of G207 with radiation in recurrent/progressive malignant pediatric cerebellar tumors. After biopsy to prove recurrence/progression, one to four intratumoral catheters will be placed followed by a controlled-rate infusion of G207 for 6 h followed by the removal of catheters at the bedside. Radiation will be given within 24 h of virus inoculation. Patients will be monitored closely for toxicity and virus shedding. Efficacy will be assessed by measuring radiographic response, performance score, progression-free and overall survival, and quality of life. The data obtained will be invaluable in our efforts to produce more effective and less toxic therapies for children with high-grade brain tumors.

A novel in situ multiplex immunofluorescence panel for the assessment of tumor immunopathology and response to virotherapy in pediatric glioblastoma reveals a role for checkpoint protein inhibition.

Immunotherapy with oncolytic herpes simplex virus-1 therapy offers an innovative, targeted, less-toxic approach for treating brain tumors. However, a major obstacle in maximizing oncolytic virotherapy is a lack of comprehensive understanding of the underlying mechanisms that unfold in CNS tumors/associated microenvironments after infusion of virus. We demonstrate that our multiplex biomarker screening platform comprehensively informs changes in both topographical location and functional states of resident/infiltrating immune cells that play a role in neuropathology after treatment with HSV G207 in a pediatric Phase 1 patient. Using this approach, we identified robust infiltration of CD8+ T cells suggesting activation of the immune response following virotherapy; however there was a corresponding upregulation of checkpoint proteins PD-1, PD-L1, CTLA-4, and IDO revealing a potential role for checkpoint inhibitors. Such work may ultimately lead to an understanding of the governing pathobiology of tumors, thereby fostering development of novel therapeutics tailored to produce optimal responses.