Clinical course of ventriculoperitoneal shunting for hydrocephalus following glioblastoma surgery: a systematic review and meta-analysis.

BACKGROUND: Surgical resection of glioblastoma (GBM) remains a cornerstone in the current treatment paradigm. The postoperative evolution of hydrocephalus necessitating ventriculoperitoneal shunting (VPS) continues to be defined. Correspondingly the objective of this study was to aggregate pertinent metadata to better define the clinical course of VPS for hydrocephalus following glioblastoma surgery in light of contemporary management. METHODS: Searches of multiple electronic databases from inception to November 2023 were conducted following PRISMA guidelines. Articles were screened against pre-specified criteria. Outcomes were pooled by random-effects meta-analyses where possible. RESULTS: A total of 12 cohort studies satisfied all selection criteria, describing a total of 6,098 glioblastoma patients after surgery with a total of 261 (4%) of patients requiring postoperative VPS for hydrocephalus. Meta-analysis demonstrated the estimated pooled rate of symptomatic improvement following VPS was 78% (95% CI 66-88), and the estimated pooled rate of VPS revision was 24% (95% CI 16-33). Pooled time from index glioblastoma surgery to VPS surgery was 4.1 months (95% CI 2.8-5.3), and pooled survival time for index VPS surgery was 7.3 months (95% CI 5.4-9.4). Certainty of these outcomes were limited by the heterogenous and palliative nature of postoperative glioblastoma management. CONCLUSIONS: Of the limited proportion of glioblastoma patients requiring VPS surgery for hydrocephalus after index surgery, 78% patients are expected to show symptom improvement, and 24% can expect to undergo revision surgery. An individualized approach to each patient is required to optimize both index glioblastoma and VPS surgeries to account for anatomy and goals of care given the poor prognosis of this tumor overall.

In vivo efficacy of decitabine as a natural killer cell-mediated immunotherapy against isocitrate dehydrogenase mutant gliomas.

OBJECTIVE: Isocitrate dehydrogenase (IDH) mutations are found in more than 80% of low-grade gliomas and in the majority of secondary glioblastomas. IDH mutation (IDHmut) leads to aberrant production of an oncogenic metabolite that promotes epigenetic dysregulation by inducing hypermethylation to suppress transcription of various tumor suppressor genes. Hypermethylation in IDHmut gliomas leads to transcriptional repression of NKG2D ligands, especially UL16-binding protein (ULBP)-1 and ULBP-3, and subsequent evasion of natural killer (NK) cell-mediated lysis. The demethylating agent 5-aza-2'deoxycytodine (decitabine [DAC]) is a DNA methyltransferase 1 inhibitor that prevents hypermethylation and is capable of restoring NKG2D ligand expression in IDHmut gliomas to resensitize them to NK cells. Given its capacity for sustained epigenetic reprogramming, the authors hypothesized that DCA would be an effective immunotherapeutic agent in treating IDHmut gliomas in an NK cell-dependent manner by upregulating epigenetically repressed activating NKG2D ligands in IDHmut tumors. In this study, the authors sought to use a glioma stem cell, preclinical animal model to determine the efficacy of DAC in IDHmut and IDH wild-type (IDHwt) tumors, and to characterize whether the activity of DAC in gliomas is dependent on NK cell function. METHODS: Xenograft models of IDHwt and IDHmut gliomas were established in athymic-nude mice. When tumors were grossly visible and palpable, mice were treated with either DCA or dimethylsulfoxide intraperitoneally every 7 days. Tumor sizes were measured every 2 to 3 days. After the animals were euthanized, xenografts were harvested and analyzed for the following: tumor expression of NKG2D ligands, tumor susceptibility to human and murine NK cells, immunohistochemistry for NK infiltration, and tumor-infiltrating lymphocyte characterization. RESULTS: DAC significantly inhibited the growth of IDHmut xenografts in the athymic nude mice. This effect was abrogated with NK cell depletion. Ex vivo analysis of tumor cells from harvested xenografts confirmed that DAC increased NKG2D ligand ULBP-1 and ULBP-3 expressions, and enhanced susceptibility to lysis of both human and murine IDHmut glial cells with corresponding NK cells. Immunohistochemical analysis of the xenografts indicated that DCA-treated IDHmut gliomas had a greater level of NK infiltration into the tumor compared with the negative control. Finally, DCA radically altered the tumor-infiltrating lymphocyte landscape of IDHmut glioma xenografts by increasing NK cells, dendritic cells, and M1 macrophages, while decreasing suppressive monocyte infiltration. CONCLUSIONS: DCA displayed novel immunotherapeutic functions in IDHmut gliomas. This effect was critically dependent on NK cells. Additionally, DCA significantly altered the tumor immune landscape in IDHmut gliomas from suppressive to proinflammatory.

History of atopy confers improved outcomes in IDH mutant and wildtype lower grade gliomas.

PURPOSE: A history of atopy or allergy has been shown to be protective against the development of glioma, however the effect of atopy on patient outcomes, especially in conjunction with the survival benefit associated with IDH mutation, has not yet been investigated, and is the focus of the study we present here. METHODS: Low grade glioma (LGG) data from the TCGA was downloaded, along with IDH, TERT, 1p/19q and ATRX mutational status and genetic alterations. History of asthma, eczema, hay fever, animal, or food allergies, as documented in TCGA, was used to determine patient atopy status. Patients with missing variables were excluded from the study. RESULTS: 374 LGG studies were included. Patients with a history of atopy demonstrated longer overall survival (OS) compared to those without (145.3 vs. 81.5 months, p = 00.0195). IDH mutant patients with atopy had longer OS compared those without atopy (158.8 vs. 85 months, p = 0.035). Multivariate cox regression analysis demonstrated that the effects of atopy on survival were independent of IDH and histological grade, (p = 0.002, HR 0.257, 95% 0.109-0.604), (p = < 0.001, HR 0.217, 95% 0.107-0.444), and (p = 0.004, HR 2.72, 95% 1.373-5.397), respectively. In terms of treatment outcomes, patients with atopy did not differ in treatment response compared to their counterpart. Pathway analysis demonstrated an upstream activation of the BDNF pathway (p = 0.00027). CONCLUSION: A history of atopy confers a survival benefit in patients with diffuse low-grade glioma. Activation of the BDNF pathway may drive the observed differences.

Risk factors for perioperative mortality after revascularization for acute aortic occlusion.

OBJECTIVE: Acute aortic occlusion (AAO) is a life-threatening event necessitating prompt revascularization to the pelvis and lower extremities. Because of its uncommon nature, outcomes after revascularization for AAO are not well characterized. Our aim was to describe the perioperative morbidity and mortality associated with revascularization and to identify the patients at highest risk. METHODS: A retrospective chart review was performed of patients who presented to our institution from 2006 to 2017 with acute distal aortic occlusion. Patients with a prior aortofemoral bypass were excluded, but those with aortoiliac stents were included. Baseline demographics and comorbidities, preoperative clinical presentation and imaging, procedural details, and postoperative hospital course were reviewed. The primary outcome was 30-day mortality, and major complications were evaluated as secondary outcomes. Logistic regression models were constructed to identify factors associated with 30-day mortality. RESULTS: We identified 65 patients who underwent revascularization for AAO. Median age was 63 years (range, 35-89 years), and 64.6% were male; 56.4% of patients presented within 24 hours of symptom onset, and 43.8% were treated within 6 hours of presentation. There were particularly high rates of prior coronary artery disease (62.3%) and chronic obstructive pulmonary disease (41.0%); 18.5% had prior iliac stents. Preoperative imaging in 44 patients showed occlusion of the inferior mesenteric artery in 36.0% and both internal iliac arteries in 34.7%. Treatments for revascularization included axillobifemoral bypass (55.4%), aortoiliac thromboembolectomy (15.4%), aortobifemoral bypass (13.9%), and aortoiliac stenting (15.4%). Overall 30-day mortality was 27.7% and was not affected by treatment modality. Mortality was highest in patients older than 60 years (40.5% vs 10.7%; P = .01) and those presenting with lactate elevation (45.5% vs 5.9%; P = .004) or motor deficit in at least one extremity (36.6% vs 9.5%; P = .03). Univariate predictors of 30-day mortality were age ≥60 years (odds ratio [OR], 5.68; 95% confidence interval [CI], 1.45-22.26; P = .01), presentation with motor deficit (OR, 5.48; 95% CI, 1.12-26.86; P = .04), presentation with elevated lactate level (OR, 13.33; 95% CI, 1.58-11.57; P = .02), history of prior stroke (OR, 4.80; 95% CI, 1.21-18.97; P = .03), and bilateral internal iliac artery occlusion (OR, 7.11; 95% CI, 1.54-32.91; P = .01). At least one postoperative complication was observed in 78.5% of patients, including acute kidney injury (56.9%, with 21.5% requiring hemodialysis), respiratory complications (46.2%), cardiovascular complications (33.9%), major amputation (15.4%, bilateral in 7.7%), and bowel ischemia (10.8%). CONCLUSIONS: Even with prompt revascularization and despite the chosen treatment modality, AAO carries high risk of mortality and numerous life-threatening complications. Older patients presenting with elevated lactate levels, motor deficit, and bilateral internal iliac artery occlusions are at the highest risk of perioperative mortality. These factors may aid in risk stratification and managing expectations in this critically ill population.

Management of Refractory Post-operative Osteomyelitis and Discitis: A Case Report.

Vertebral osteomyelitis/discitis is a relatively rare disease but is a known potential complication of spinal surgical intervention. In general, the first-line treatment for this condition is targeted antibiotic therapy with surgical intervention only utilized in refractory cases with evidence of extensive damage, structural instability, or abscess formation. However, surgical best practices have not been established for osteomyelitis, including indications for anterior lateral interbody fusion (ALIF), posterior lateral interbody fusion (PLIF), or direct lateral interbody fusion (DLIF). This case provides a discussion of the indications that led to a direct lateral approach in the setting of refractory osteomyelitis/discitis, supporting factors that led to its success, and the efficacy of utilizing intraoperative neuromonitoring in cases of infection.

All-trans retinoic acid induces durable tumor immunity in IDH-mutant gliomas by rescuing transcriptional repression of the CRBP1-retinoic acid axis.

Diffuse gliomas are epigenetically dysregulated, immunologically cold, and fatal tumors characterized by mutations in isocitrate dehydrogenase (IDH). Although IDH mutations yield a uniquely immunosuppressive tumor microenvironment, the regulatory mechanisms that drive the immune landscape of IDH mutant (IDHm) gliomas remain unknown. Here, we reveal that transcriptional repression of retinoic acid (RA) pathway signaling impairs both innate and adaptive immune surveillance in IDHm glioma through epigenetic silencing of retinol binding protein 1 (RBP1) and induces a profound anti-inflammatory landscape marked by loss of inflammatory cell states and infiltration of suppressive myeloid phenotypes. Restorative retinoic acid therapy in murine glioma models promotes clonal CD4 + T cell expansion and induces tumor regression in IDHm, but not IDH wildtype (IDHwt), gliomas. Our findings provide a mechanistic rationale for RA immunotherapy in IDHm glioma and is the basis for an ongoing investigator-initiated, single-center clinical trial investigating all-trans retinoic acid (ATRA) in recurrent IDHm human subjects.

Clinical characteristics of familial and sporadic pediatric cerebral cavernous malformations and outcomes.

OBJECTIVE: Cerebral cavernous malformation (CCM) is a subtype of the vascular malformations found within the cerebral cortex. Although rare and usually discovered incidentally, these vascular abnormalities can predispose patients to spontaneous cerebral hemorrhage and subsequently lead to a myriad of neurological symptoms at presentation such as seizures and other focal neurological deficits. Although the symptoms and presentations of CCM have been adequately described in the adult population, disease characteristics and outcomes have not been extensively described in the pediatric population. Furthermore, the etiology of CCM-e.g., familial versus sporadic disease, as well as the risk factors for hemorrhage and neurological deficits and predictors of clinical and surgical outcomes-has not been adequately explored in the pediatric population. The current study attempts to classify and characterize differences in the clinical presentation, characteristics, and outcomes of CCMs between familial and sporadic cases within the pediatric population. METHODS: A retrospective review identified 131 pediatric patients with radiographically confirmed diagnosis of CCM. All pertinent demographic and clinical variables were collected. CCM lesions were characterized using T2-weighted and susceptibility-weighted angiography (SWAN) MRI. Statistical analysis was conducted using the t-test for continuous variables, whereas categorical variables were analyzed with the Fisher exact test or chi-square test. Multivariate analysis was performed using a Cox proportional hazards model with R version 4.2.0. RESULTS: This retrospective study identified 131 pediatric CCM patients with a mean age of 8.4 years, and 54% (n = 71) were male. Twenty-seven percent (n = 35) were identified as cases with familial CCM, with the remainder classified as sporadic. The most common symptoms at presentation included generalized symptoms (headaches, nausea, and vomiting) or seizures, with a large proportion of patients also presenting as asymptomatic. No significant differences were observed in severity of symptoms between patients harboring different forms of the disease. Patients with familial CCM were noted to have a larger lesion size on average (5.26 cm3 vs 1.6 cm3, p = 0.047). These patients also had a shorter progression-free follow-up interval, with 50% of patients showing progression by 888 days, compared with only 15% of sporadic CCM patients during the same period (p = 0.0019). Familial etiology of the disease and larger average lesion volume were independent, significant predictors of disease progression (p = 0.001, HR 3.29, 95% CI 1.65-6.54) and future hemorrhage (p = 0.023, HR 1.1, 95% CI 1.01-1.10), respectively. CONCLUSIONS: Familial and sporadic CCMs tend to present with similar characteristics within the pediatric population. Patients with the familial form of the disease have an increased risk of progressive disease in terms of further hemorrhagic events.

Headlight and loupe-based fluorescein detection system in brain tumor surgery: a first-in-human experience.

Fluorescein is an agent that accumulates in areas of blood-brain barrier breakdown and is commonly used in neurosurgical oncology to assist with lesion localization and visualizing the extent of resection. It is considered to be cost-effective and has a favorable safety profile. Studies on the utilization of fluorescein demonstrate an improved extent of tumor resection and increased overall survival. Currently, fluorescein detection systems are all microscope based, leading to limitations such as decreased maneuverability, limited visualization of the entire operative field, and significant cost associated with obtaining and maintaining a neurosurgical operating microscope. Three consecutive craniotomy patients for tumor resection were included, and surgery was carried out under loupe fluorescence guidance using the ReVeal 450 System, and also a surgical microscope for comparison. Loupe-mounted fluorescence system enabled excellent visualization of fluorescence in all three cases. In this manuscript, we describe our experience with a loupe-mounted fluorescein detection system in three patients with malignant gliomas. We found that the loupe-mounted system offered excellent ability to visualize fluorescein fluorescence. Although loupe-mounted systems are not an alternative to surgical microscopes, they could be a useful surgical adjunct for superficial lesions and in low-middle income counties.

A Novel 5-Aminolevulinic Acid-Enabled Surgical Loupe System-A Consecutive Brain Tumor Series of 11 Cases.

BACKGROUND: The concept of maximally safe resection (MSR) has been shown to improve clinical outcomes in the treatment of high-grade gliomas (HGGs). To achieve MSR, surgical adjuncts such as functional imaging, neuronavigation, intraoperative mapping, ultrasound, and fluorescence-guided surgery are routinely used. 5-Aminolevulinic acid (5-ALA) is an oral agent that has been increasingly adopted in fluorescence-guided resection of HGG. In randomized clinical trials of 5-ALA, it has been shown to increase the extent of resection and progression-free survival in HGG. Current commercially available 5-ALA detection systems are all microscope-based and can sometimes be cumbersome to use. OBJECTIVE: To present our experience using a novel 5-ALA-enabled surgical loupe system. METHODS: 5-ALA-enabled loupes were used in 11 consecutive patients with either suspected HGG on magnetic resonance imaging or recurrence of known lesions. Lesion appearance was examined under white light, 5-ALA loupes, and a 5-ALA microscope. Tumor specimens were checked for fluorescence and sent for pathologic examination. RESULTS: In our experience, a 5-ALA-enabled surgical loupe system offers excellent visualization of 5-ALA in patients with HGG. In 10 of 11 patients, fluorescent tissue was confirmed to be high-grade glioma by pathology. In 1 patient, tissue was not fluorescent, and final pathology was World Health Organization grade I meningioma. CONCLUSION: A 5-ALA-enabled surgical loupe system offers excellent intraoperative visualization of 5-ALA fluorescence in HGG and can be a viable surgical adjunct for achieving MSR of HGG.

Machine Learning Identification of Immunotherapy Targets in Low-Grade Glioma Using RNA Sequencing Expression Data.

OBJECTIVE: Immunotherapy has revolutionized cancer treatment in the past decade, but significant hurdles remain. Human studies with immune checkpoint inhibitors targeting programmed cell death protein have demonstrated suboptimal efficacy in the setting of low-grade gliomas (LGGs). Identification of mechanisms leading to inadequate anti-tumor immunity is paramount. The current study evaluates and validates barriers to immunotherapy using a novel machine learning algorithm. METHODS: We utilized The Cancer Genome Atlas (TCGA) to generate expression levels of 28 immune genes related to known immunotherapeutic targets or lymphocyte cytolytic activity. We created training and testing groups and 3 machine learning models to determine the genes most highly correlated to cytolytic activity (CYT). The 3 models were run through multiple regression by exhaustive selection, LASSO, and random forest. We validated computational results by comparing expression of pertinent genes in patient-derived glioma samples. RESULTS: Our models demonstrated linearity, a low mean-squared error, and consistent results with respect to the most important variables. Expression of ICOS, IDO1, and CD40 were the most important variables in all models and demonstrated positive correlation with CYT. Other variables included TIGIT and CD137. Genetic analysis from 3 IDH-mutants (IDHm) and 3 IDH-wild type (IDHwt) patient-derived glioma samples validated TCGA data and demonstrated lower levels of CYT in IDHm gliomas compared with IDHwt. CONCLUSIONS: This novel methodology has elucidated 3 potential targets for immunotherapy development in LGGs. We also demonstrated a novel method of analyzing data using advanced statistical techniques that can be further used in developing treatments for other diseases as well.

Percutaneous fixation for the treatment of metastatic spinal disease provides effective symptom palliation with low rates of hardware failure.

BACKGROUND: The incidence of survival from metastatic spinal disease (MSD) continues to rise. However, open surgery for MSD is associated with significant perioperative morbidity, while minimally invasive percutaneous pedicle screw fixation (MIPPSF) offers reduced tissue trauma, less blood loss, and a reduction in complications. Lytic bone disease plus perioperative radiation further increase risk for instrument failure, especially in long construct MIPPSF. Here, we compared 6 short construct and 14 long construct outcomes for MIPPSF performed in MSD patients, including multiple myeloma (MM). METHODS: For 20 patients undergoing MIPPSF for MSD, we evaluated disease type, location, the extent of surgery, outcomes, and survival rates. Statistical comparisons were performed between long-segment construct and short-segment construct patients utilizing Kaplan-Meier survival curves, Mann-Whitney U, and Chi-squared tests. RESULTS: No instrument failure and comparable symptomatic relief were observed for both short and long MIPPSF constructs. However, long construct patients experienced; a higher incidence of postoperative complications, including screw loosening, but exhibited longer overall survivals (likely related to underlying type of MSD, with MM patients making up the largest portion of long construct patients). CONCLUSION: Long construct MIPPSF in MSD did not have increased risk of construct failure and offered effective symptomatic relief, including for MM patients, without introducing a greater risk construct instability.

Characterization of systemic immunosuppression by IDH mutant glioma small extracellular vesicles.

BACKGROUND: Gliomas are the most common primary brain tumors and are universally fatal. Mutations in the isocitrate dehydrogenase genes (IDH1 and IDH2) define a distinct glioma subtype associated with an immunosuppressive tumor microenvironment. Mechanisms underlying systemic immunosuppression in IDH mutant (mutIDH) gliomas are largely unknown. Here, we define genotype-specific local and systemic tumor immunomodulatory functions of tumor-derived glioma small extracellular vesicles (TEX). METHODS: TEX produced by human and murine wildtype and mutant IDH glioma cells (wtIDH and mutIDH, respectively) were isolated by size exclusion chromatography (SEC). TEX morphology, size, quantity, molecular profiles and biodistribution were characterized. TEX were injected into naive and tumor-bearing mice, and the local and systemic immune microenvironment composition was characterized. RESULTS: Using in vitro and in vivo glioma models, we show that mutIDH TEX are more numerous, possess distinct morphological features and are more immunosuppressive than wtIDH TEX. mutIDH TEX cargo mimics their parental cells, and induces systemic immune suppression in naive and tumor-bearing mice. TEX derived from mutIDH gliomas and injected into wtIDH tumor-bearing mice reduce tumor-infiltrating effector lymphocytes, dendritic cells and macrophages, and increase circulating monocytes. Astonishingly, mutIDH TEX injected into brain tumor-bearing syngeneic mice accelerate tumor growth and increase mortality compared with wtIDH TEX. CONCLUSIONS: Targeting of mutIDH TEX represents a novel therapeutic approach in gliomas.

Autophagy inhibition is the next step in the treatment of glioblastoma patients following the Stupp era.

It has now been nearly 15 years since the last major advance in the treatment of patients with glioma. "The addition of temozolomide to radiotherapy for newly diagnosed glioblastoma resulted in a clinically meaningful and statistically significant survival benefit with minimal additional toxicity". Autophagy is primarily a survival pathway, literally self-eating, that is utilized in response to stress (such as radiation and chemotherapy), enabling clearance of effete protein aggregates and multimolecular assemblies. Promising results have been observed in patients with glioma for over a decade now when autophagy inhibition with chloroquine derivatives coupled with conventional therapy. The application of autophagy inhibitors, the role of immune cell-induced autophagy, and the potential role of novel cellular and gene therapies, should now be considered for development as part of this well-established regimen.

Hormonal Fertility Therapy as Potential Risk Factor for Cerebrospinal Fluid Leak After Endoscopic Endonasal Surgery: Case Study and Literature Review.

BACKGROUND: Endoscopic endonasal approaches have been shown to be as effective as transcranial approaches for sinonasal malignancies involving the skull base. Although they are associated with less risk than an open cranial resection, cerebrospinal fluid (CSF) leaks remain a main concern. Some drugs can raise the intracranial pressure and exacerbate the risk of a postoperative CSF leak. In this case report, we present a 32-year-old woman who was treated via endoscopic endonasal approach for an olfactory neuroblastoma and later underwent fertility preservation treatment with leuprolide, which likely led to a delayed CSF leak. CASE DESCRIPTION: A 32-year-old woman diagnosed with a large invasive olfactory neuroblastoma underwent resection via an endonasal transcribriform approach and repair of skull base defect using a pericranial flap. Forty-seven days post operation the patient returned, presenting with a clear nasal discharge. Magnetic resonance imaging raised concern for focal flap necrosis, while computed tomography cisternogram revealed a defect in the pericranial flap. The defect was debrided and repaired; a postoperative lumbar drain was placed and showed an opening pressure of 26 cm of water. Discussion with the patient revealed that she received fertility preservation treatment with leuprolide followed by oocyte retrieval 32 days before presentation of her delayed CSF leak. CONCLUSIONS: Leuprolide or any drug that can potentially increase intracranial pressure should be held for 3 months after surgery or until after a skull base defect has fully healed.