A history of stereotactic radiosurgery may predict failure of procedure following percutaneous glycerol rhizotomy for trigeminal neuralgia.

BACKGROUND: Both stereotactic radiosurgery (SRS) and percutaneous glycerol rhizotomy are excellent options to treat TN in patients unable to proceed with microvascular decompression. However, the influence of prior SRS on pain outcomes following rhizotomy is not well understood. METHODS: We retrospectively reviewed all patients undergoing percutaneous rhizotomy at our institution from 2011 to 2022. Only patients undergoing percutaneous glycerol rhizotomy following SRS (SRS-rhizotomy) or those undergoing primary glycerol rhizotomy were considered. We collected basic demographic, clinical, and pain characteristics for each patient. Additionally, we characterized pain presentation and perioperative complications. Immediate failure of procedure was defined as presence of TN pain symptoms within 1-week of surgery, and short-term failure was defined as presence of TN pain symptoms within 3-months of surgery. A multivariate logistic regression model was used to evaluate the relationship of a history SRS and failure of procedure following percutaneous glycerol rhizotomy. RESULTS: Of all patients reviewed, 30 had a history of SRS prior to glycerol rhizotomy whereas 371 underwent primary percutaneous glycerol rhizotomy. Patients with a history of SRS were more likely to endorse V3 pain symptoms, p = 0.01. Additionally, patients with a history of SRS demonstrated higher preoperative BNI pain scores, p = 0.01. Patients with a history of SRS were more likely to endorse preoperative numbness, p < 0.0001. A history of SRS was independently associated with immediate failure [OR = 5.44 (2.06-13.8), p < 0.001] and short-term failure of glycerol rhizotomy [OR = 2.41 (1.07-5.53), p = 0.03]. Additionally, increasing age was found to be associated with lower odds of short-term failure of glycerol rhizotomy [OR = 0.98 (0.97-1.00), p = 0.01] CONCLUSIONS: A history of SRS may increase the risk of immediate and short-term failure following percutaneous glycerol rhizotomy. These results may be of use to patients who are poor surgical candidates and require multiple noninvasive/minimally invasive options to effectively manage their pain.

The Gordian knot of hydrocephalus: constrictive entanglement of distal ventriculoperitoneal shunt catheter.

We recently cared for a patient with a distal ventriculoperitoneal shunt malfunction. The peritoneal catheter was coiled in a scarred pseudocyst, and we encountered strong resistance while attempting to remove the distal shunt catheter. The catheter was successfully removed under laparoscopic guidance and was found to be tightly coiled in a constrictive knot. We describe a technique for managing this unusual presentation to minimize the risk of complications.

Nephrogenic rest vs immature teratoma associated with lumbosacral lipomyelomeningocele: a case report and review of the literature.

BACKGROUND: Lipomyelomeningoceles (LMMs) are subcutaneous lipomas with dural penetration that often present with spinal cord tethering and may lead to neurological deterioration if untreated. This report describes a rare case of an LMM associated with immature nephroblastic tissue, representing a nephrogenic rest (NR) or, less likely, an immature teratoma. CLINICAL PRESENTATION: An 8-day-old infant girl presented to the clinic with a sacral dimple. Imaging demonstrated a tethered spinal cord with low-lying conus medullaris and an LMM. A firm mass was noted in the subcutaneous lipoma. Detethering surgery and removal of the lipoma and mass were performed at the age of 6 months. Pathological examination identified the mass as cartilage, fat, and immature nephroblastic tissue consistent with NR tissue or, less likely, a teratoma with renal differentiation. CONCLUSION: This presentation of an LMM associated with an immature teratoma or NR poses a risk of malignant transformation in patients. As a result, careful surgical dissection, resection, and close clinical follow-up are recommended for these patients.

Reexamining the Role of Postoperative ICU Admission for Patients Undergoing Elective Craniotomy: A Systematic Review.

OBJECTIVES: The standard-of-care for postoperative care following elective craniotomy has historically been ICU admission. However, recent literature interrogating complications and interventions during this postoperative ICU stay suggests that all patients may not require this level of care. Thus, hospitals began implementing non-ICU postoperative care pathways for elective craniotomy. This systematic review aims to summarize and evaluate the existing literature regarding outcomes and costs for patients receiving non-ICU care after elective craniotomy. DATA SOURCES: A systematic review of the PubMed database was performed following PRISMA guidelines from database inception to August 2021. STUDY SELECTION: Included studies were published in peer-reviewed journals, in English, and described outcomes for patients undergoing elective craniotomies without postoperative ICU care. DATA EXTRACTION: Data regarding study design, patient characteristics, and postoperative care pathways were extracted independently by two authors. Quality and risk of bias were evaluated using the Oxford Centre for Evidence-Based Medicine Levels of Evidence tool and Risk Of Bias In Non-Randomized Studies-of Interventions tool, respectively. DATA SYNTHESIS: In total, 1,131 unique articles were identified through the database search, with 27 meeting inclusion criteria. Included articles were published from 2001 to 2021 and included non-ICU inpatient care and same-day discharge pathways. Overall, the studies demonstrated that postoperative non-ICU care for elective craniotomies led to length of stay reduction ranging from 6 hours to 4 days and notable cost reductions. Across 13 studies, 53 of the 2,469 patients (2.1%) intended for postoperative management in a non-ICU setting required subsequent care escalation. CONCLUSIONS: Overall, these studies suggest that non-ICU care pathways for appropriately selected postcraniotomy patients may represent a meaningful opportunity to improve care value. However, included studies varied greatly in patient selection, postoperative care protocol, and outcomes reporting. Standardization and multi-institutional collaboration are needed to draw definitive conclusions regarding non-ICU postoperative care for elective craniotomy.

Development of new brain metastases in triple negative breast cancer.

BACKGROUND: Brain metastases are common in patients with breast cancer, and those with triple negative status have an even higher risk. Triple negative status is currently not considered when managing brain metastases. OBJECTIVE: To determine whether triple negative breast cancer (TNBC) patients with brain metastases have a higher burden of intracranial disease and whether WBRT has a survival benefit in this cohort of patients. METHODS: We conducted a retrospective cohort study with 85 patients meeting the inclusion criteria. RESULTS: 25% of patients had TNBC. 95% of the patients in this study received SRS and 48% received WBRT. The average number of new brain metastases from time of initial brain imaging to radiation therapy was 0.67 ± 1.1 in the non-TNBC status patients and 2.6 ± 3.7 in the triple negative status patients (p = 0.001). A cox proportional hazards model showed that WBRT does not significantly affect overall survival in patients with TNBC (HR 1.48; 95% CI 0.47-4.67; p = 0.50). CONCLUSION: Our findings highlight the highly aggressive intracranial nature of TNBC. The rate of new brain metastasis formation is higher in TNBC patients compared to non-TNBC patients. Furthermore, there is no survival benefit for WBRT in TNBC patients. These findings are relevant for clinicians planning brain radiation for TNBC patients as they may find more brain metastases at the time of brain radiation than they anticipated based on initial brain imaging.

Genome-wide investigation of intragenic DNA methylation identifies ZMIZ1 gene as a prognostic marker in glioblastoma and multiple cancer types.

DNA methylation has long been recognized as a tumor-promoting factor when aberrantly regulated in the promoter region of genes. However, the effect of intragenic DNA methylation remains poorly understood on the clinical aspects of cancer. Here, we first evaluated the significance of intragenic DNA methylation for survival outcomes of cancer patients in a genome-wide manner. Glioblastoma patients with hypermethylated intragenic regions exhibited better survival than hypomethylated patients. Enrichment analyses of intragenic DNA methylation profiles with epigenetic signatures prioritized the intragenic DNA methylation of ZMIZ1 as a possible glioblastoma prognostic marker that is independent of MGMT methylation in IDH1 wild-type patients. This intragenic region harbored molecular signatures of alternative transcription across many cell types. Furthermore, we found that the intragenic region of ZMIZ1 can serve as a molecular marker in multiple cancers including astrocytomas, bladder cancer and renal cell carcinoma according to DNA methylation status. Finally, in vitro and in vivo experiments uncovered the role of ZMIZ1 as a driver of tumor cell migration. Altogether, our results identify ZMIZ1 as a prognostic marker in cancer and highlight the clinical significance of intragenic methylation in cancer.

Combination anti-CXCR4 and anti-PD-1 immunotherapy provides survival benefit in glioblastoma through immune cell modulation of tumor microenvironment.

BACKGROUND: Emerging evidence suggests that myeloid cells play a critical role in glioblastoma (GBM) immunosuppression. Disappointing results of recent checkpoint inhibitor trials suggest that combination immunotherapy with alternative agents could be fruitful in overcoming immunosuppression. Overexpression of chemokine receptor CXCR4 is associated with poor prognosis in GBM. We investigate the treatment effects of combination immunotherapy with anti-PD-1 and anti-CXCR4 in a murine glioma model. METHODS: C57BL/6 mice were implanted with GL261-Luc+ glioma cells and randomized into 4 arms: (1) control (2) anti-PD-1 (3) anti-CXCR4, and (4) anti-PD-1 and anti-CXCR4 therapy. Overall survival and median survival were assessed. Cell populations were assessed by flow cytometry. RESULTS: Combination therapy conferred a significant survival benefit compared to control and monotherapy arms. Mice that received combination therapy demonstrated immune memory and decreased populations of immunosuppressive tumor-infiltrating leukocytes, such as monocytic myeloid-derived suppressor cells and microglia within the brain. Furthermore, combination therapy improved CD4+/CD8+ ratios in the brain as well as contributed to increased levels of pro-inflammatory cytokines. CONCLUSIONS: Anti-CXCR4 and anti-PD-1 combination immunotherapy modulates tumor-infiltrating populations of the glioma microenvironment. Targeting myeloid cells with anti-CXCR4 facilitates anti-PD-1 to promote an antitumor immune response and improved survival rates.

Expression of LAG-3 and efficacy of combination treatment with anti-LAG-3 and anti-PD-1 monoclonal antibodies in glioblastoma.

Like in many tumor types, immunotherapy is currently under investigation to assess its potential efficacy in glioblastoma patients. Trials are under way to assess the efficacy of new immune checkpoint inhibitors including anti-PD-1 or CTLA4. We here investigate the expression and efficacy of a novel immune-checkpoint inhibitor, called LAG-3. We show that LAG-3 is expressed in human glioblastoma samples and in a mouse glioblastoma model we show that knock out or LAG-3 inhibition with a blocking antibody is efficacious against glioblastoma and can be used in combination with other immune checkpoint inhibitors toward complete eradication of the model glioblastoma tumors. From a mechanistic standpoint we show that LAG-3 expression is an early marker of T cell exhaustion and therefore early treatment with LAG-3 blocking antibody is more efficacious than later treatment. These data provide insight and support the design of trials that incorporate LAG-3 in the treatment of glioblastoma.

Longitudinal Pulse-Synchronous Bouncing During Catheter Angiography-A Phenomenon Specific to Spinal Hemangioblastomas.

BACKGROUND: Spinal hemangioblastomas are often evaluated with catheter angiography for both workup and treatment planning. We report a unique longitudinal pulse-synchronous bouncing phenomenon observed during their angiographic evaluation and consider the association of pulse-synchronous bouncing with syringomyelia, another pathologic feature associated with hemangioblastomas. METHODS: Preoperative spinal angiograms and associated magnetic resonance imagings (MRIs) obtained over a 16-year period at a single institution were retrospectively evaluated. Magnetic resonance imaging (MRI) parameters included lesion and syrinx location and size. Angiograms were evaluated for bouncing phenomena. Student's t-test and Chi square test compared characteristics between groups. Linear regression analyses evaluated maximum amplitude of dynamic motion and any associated syrinx. RESULTS: Nineteen hemangioblastoma patients had preoperative angiograms available for review. Eight exhibited bouncing behavior. Between the dynamic and nondynamic cohorts, there was no difference in presence or volume of syrinxes. Lesions in the dynamic cohort trended towards a cervical location (75% vs. 36.3%, P = 0.10). No significant correlation was found between bouncing amplitude and syrinx size (R2 = 0.023). Dural contact may be related to this dynamic behavior since other high-flow lesions like AVMs do not demonstrate this phenomenon, and AVMs are pial-based and more likely to contact stationary dura. Here, there were fewer lesions abutting the thecal sac in the dynamic cohort (50% vs. 81.8%, P = 0.14). CONCLUSIONS: Though no significant relationship was established between this bouncing behavior and syrinx formation, noted trends included a greater range of motion for cervical lesions and limited motion in tumors abutting the thecal sac.

Cortical Laminar Necrosis After Severe Hydrocephalus: Case Report and Review of the Literature.

Objectives: We present a case of cortical laminar necrosis after severe hydrocephalus to highlight considerations for multimodal cerebral autoregulation monitoring to determine mean arterial pressure (MAP) thresholds during neurological emergencies, as well as postoperative head imaging for patients with ventriculoperitoneal shunts (VPS). Methods: A 40-year-old woman with a history of Chiari II malformation and non-communicating hydrocephalus with VPS presented in septic shock from a sacral wound. One week after colostomy for fecal diversion, the patient became comatose and had progressive slowing to full suppression on electroencephalogram (EEG). Results: CT imaging revealed hydrocephalus, most likely due to VPS distal obstruction from intraperitoneal surgery. Despite neurosurgical and neurocritical care management, MRI confirmed diffuse cortical hypoxic ischemic injury. Discussion: The Neurocritical Care Society's Emergency Neurological Life Support (ENLS) protocol for neurological emergencies focuses on managing increased intracranial pressure (ICP) but does not set MAP goals. As ICP may be very high during brain herniation, our case demonstrates that higher MAP may be required to maintain adequate circulation. To determine the optimal MAP target, bedside multimodality monitoring, including ICP monitors, transcranial doppler, and near infrared spectroscopy, can help establish individualized cerebral autoregulation guided thresholds. Outside of a neurological intensive care unit, EEG can monitor cerebral blood flow and indicate windows for intervention before exam or imaging changes. Additionally, our case demonstrates how a post-operative surveillance CT head should be considered for patients with VPS.

Advances in Implant Technologies for Spine Surgery.

Spine implants are becoming increasingly diversified. Taking inspiration from other industries, three-dimensional modeling of the spinal column has helped meet the custom needs of individual patients as both en bloc replacements and pedicle screw designs. Intraoperative tailoring of devices, a common need in the operating room, has led to expandable versions of cages and interbody spacers.

External Validation of Predictive Models for Failed Medical Management of Spinal Epidural Abscess.

OBJECTIVE: There is limited consensus regarding management of spinal epidural abscesses (SEAs), particularly in patients without neurologic deficits. Several models have been created to predict failure of medical management in patients with SEA. We evaluate the external validity of 5 predictive models in an independent cohort of patients with SEA. METHODS: One hundred seventy-six patients with SEA between 2010 and 2019 at our institution were identified, and variables relevant to each predictive model were collected. Published prediction models were used to assign probability of medical management failure to each patient. Predicted probabilities of medical failure and actual patient outcomes were used to create receiver operating characteristic (ROC) curves, with the area under the receiver operating characteristic curve used to quantify a model's discriminative ability. Calibration curves were plotted using predicted probabilities and actual outcomes. The Spiegelhalter z-test was used to determine adequate model calibration. RESULTS: One model (Kim et al) demonstrated good discriminative ability and adequate model calibration in our cohort (ROC = 0.831, P value = 0.83). Parameters included in the model were age >65, diabetes, methicillin-resistant Staphylococcus aureus infection, and neurologic impairment. Four additional models did not perform well for discrimination or calibration metrics (Patel et al, ROC = 0.580, P ≤ 0.0001; Shah et al, ROC = 0.653, P ≤ 0.0001; Baum et al, ROC = 0.498, P ≤ 0.0001; Page et al, ROC = 0.534, P ≤ 0.0001). CONCLUSIONS: Only 1 published predictive model demonstrated acceptable discrimination and calibration in our cohort, suggesting limited generalizability of the evaluated models. Multi-institutional data may facilitate the development of widely applicable models to predict medical management failure in patients with SEA.

Internal neurolysis versus intraoperative glycerin rhizotomy for trigeminal neuralgia.

OBJECTIVE: Internal neurolysis (IN) and intraoperative glycerin rhizotomy (ioGR) are emerging surgical options for patients with trigeminal neuralgia without neurovascular contact. The objective of this study was to compare the neurological outcomes of patients who underwent IN with those of patients who underwent ioGR. METHODS: The authors retrospectively reviewed all patients who underwent IN or ioGR for trigeminal neuralgia at our institution. Patient demographic characteristics and immediate postoperative outcomes, as well as long-term neurological outcomes, were compared. RESULTS: Of 1044 patients who underwent open surgical treatment for trigeminal neuralgia, 56 patients underwent IN and 91 underwent ioGR. Of these 147 patients, 37 had no evidence of intraoperative neurovascular conflict. All patients who underwent IN and 96.7% of patients who underwent ioGR had immediate postoperative pain relief. At last follow-up, patients who underwent IN had lower Barrow Neurological Institute (BNI) pain intensity scores (p = 0.05), better BNI facial numbness scores (p < 0.01), and a greater degree of pain improvement (p = 0.05) compared with those who underwent ioGR. Patients who underwent IN also had significantly lower rates of symptomatic pain recurrence (p < 0.01) at last follow-up over an average of 9.5 months. CONCLUSIONS: IN appears to provide patients with a greater degree of pain relief, lower rates of facial numbness, and lower rates of pain recurrence compared with ioGR. Future prospective studies will better characterize long-term pain recurrence and outcomes.

Patient Safety Indicator 04 Does Not Consistently Identify Failure to Rescue in the Neurosurgical Population.

BACKGROUND: Improving neurosurgical quality metrics necessitates the analysis of patient safety indicator (PSI) 04, a measure of failure to rescue (FTR). OBJECTIVE: To demonstrate that PSI 04 is not an appropriate measure for capturing FTR within neurosurgery. METHODS: We conducted a single-center retrospective cohort study. Patients from January 1, 2017 to June 1, 2021, who sustained a PSI 04-attributed complication (pneumonia, deep vein thrombosis/pulmonary embolism, sepsis, shock/cardiac arrest, or gastrointestinal hemorrhage/acute ulcer), underwent a neurosurgical procedure, had inpatient mortality, and were identified using patient safety indicator 04 (PSI 04) tracking algorithm. The primary outcome was whether the attributed PSI 04 designation was the primary driver of mortality. RESULTS: We identified 67 patients who met the PSI 04 criteria (median age, 61 years; female sex, 43.4%). Nearly 20% of patients met the PSI complication criteria before admission. Patients who underwent emergent bedside procedures were more likely to present with a poor Glasgow Coma Scale ( P = .016), more likely to be intubated before admission ( P = .016), and less likely to have mortality due to a PSI 04-related complication ( P = .002). PSI 04-related complications were identified as the cause of death in only 43.2% of cases. Procedures occurring in the interventional radiology suite (odds ratio, 23.2; 95% CI, 3.5-229.3; P = .003) or the operating room (odds ratio, 6.2; 95% CI, 1.25-39.5; P = .03) were more likely to have mortality because of a PSI 04-related complication compared with bedside procedures. CONCLUSION: In total, 65.7% of patients were inappropriately flagged as meeting PSI 04 criteria. PSI 04 currently identifies patients with complications unrelated to operating room procedures. Improvement in patient safety within neurosurgery necessitates the development of a subspecialty specific measure to capture FTR.

Risk Factor-Guided Early Discharge and Potential Resource Allocation Benefits in Patients with Traumatic Subarachnoid Hemorrhage.

OBJECTIVE: We sought to develop screening criteria predicting the lack of poor neurologic outcomes in patients presenting with traumatic subarachnoid hemorrhage (tSAH) and to evaluate their potential to improve resource allocation in these cases. METHODS: We retrospectively reviewed patients presenting with tSAH to the emergency department (ED) of a tertiary-care institution from 2016 to 2018. We defined good neurologic outcomes as patients with stable/improving neurologic status, who did not require neurosurgical intervention, had no expanding bleed, and needed no hospital readmission. Univariate and multivariate models were generated to predict risk factors inversely associated with good neurologic outcome. RESULTS: A total of 167 patients presented with tSAH from 2016 to 2018. The presence of depressed skull fracture, concomitant spinal fracture, low Glasgow Coma Scale (GCS) score, cranial nerve palsies, disorientation, concomitant hemorrhages, midline shift, increased international normalized ratio (INR), and emergent medical intervention were inversely correlated with likelihood of good neurologic outcome on univariate analysis. Multivariate regression showed that midline shift (odds ratio [OR], 0.22; 95% confidence interval [CI], 0.05-0.89; P = 0.04), GCS score <13 (OR, 0.22; 95% CI, 0.05-0.99; P = 0.05), increased INR (OR, 0.18; 95% CI, 0.03-0.85; P = 0.04), and emergent medical intervention (OR, 0.18; 95% CI, 0.04-0.63; P = 0.01) were independently associated with lower likelihood of good neurologic outcome. Forty-six patients without any factors had good outcomes but were held in the ED or admitted to the hospital. These patients (if instead discharged directly) meant a potential cost savings of $179,172. CONCLUSIONS: In our study, we found multiple risk factors inversely associated with good neurologic outcome, namely low GCS score, midline shift, emergent medical intervention, and INR ≥1.4. Our findings may aid clinicians in determining which tSAH patients are candidates for safe early discharge.

A Potential Role for Steroids in Acute Pain Management in Patients with Trigeminal Neuralgia.

OBJECTIVE: Effective therapies for acute pain management in trigeminal neuralgia (TN) are limited. We aimed to investigate the role of steroids in TN patients experiencing acute pain flares. METHODS: We retrospectively reviewed patients presenting to the emergency department of a tertiary care institution between 2014 and 2020 for acute TN pain flares. Patients were divided into those who received steroids versus those who did not. Presenting characteristics, admission and surgical intervention rates, Barrow Neurological Institute pain scores, pain recurrence rates, and surgical intervention within 6 months of discharge were obtained for each patient. RESULTS: Our cohort comprised 151 patients, of whom 40 (26.5%) received steroids before admission and/or discharge. These patients were less likely to undergo surgical intervention to treat acute pain (P = 0.023). Specifically, patients receiving steroids were less likely to undergo combined glycerin and radiofrequency rhizotomy compared with patients not receiving steroids (P = 0.012). Frequency and dosage of opioid administration did not differ between groups. The steroids group demonstrated a lower average Barrow Neurological Institute pain score on discharge compared with the no steroids group (P = 0.013). Patients receiving steroids for acute pain management were less likely to undergo surgical intervention within 6 months of discharge than patients who did not receive steroids (P = 0.033). CONCLUSIONS: Steroid administration in patients with acute TN pain flares may reduce the likelihood of surgical intervention both during admission and within 6 months of discharge. Future prospective studies should examine the efficacy of steroids as an adjunctive medication in acute TN pain management.

Spinal cord untethering and midline myelotomy for delayed, symptomatic post-traumatic syringomyelia due to retained ballistic fragments: case report.

INTRODUCTION: Post-traumatic syringomyelia is an uncommon complication after traumatic spinal cord injury. This case study details our decision-making and surgical approach for a patient with symptomatic post-traumatic syringomyelia after sustaining a gunshot wound. CASE PRESENTATION: A 24-year-old man with past medical history of distant American Spinal Injury Association Impairment Grade B spinal cord injury due to ballistic injury developed delayed post-traumatic syringomyelia, resulting in unilateral sensory loss and left upper extremity weakness. CT and MR imaging revealed a syrinx spanning his cervical and thoracic spine causing significant spinal cord compression. To relieve achieve decompression and restore CSF flow dynamics, we performed a bony extradural decompression, bullet fragment extraction, spinal cord untethering, and midline myelotomy. Postoperatively, the patient demonstrated clinical and radiographical improvement. DISCUSSION: Post-traumatic syringomyelia is potentially morbid sequalae of spinal cord injuries. Suspicion for post-traumatic syringomyelia should be maintained in patients with delayed, progressive neurologic deficits. In this setting, surgical intervention may require extradural and intradural procedures to mitigate neural compression along the dilated central canal by the syrinx.

Safety and Cost Savings Associated with Reduced Inpatient Hospitalization for Microvascular Decompression.

OBJECTIVES: Microvascular decompression (MVD) has grown as a first-line surgical intervention for severe facial pain from trigeminal neuralgia and/or hemifacial spasm. We sought to examine the safety and cost-benefits of discharging patients with MVD within 1 day of admission. METHODS: We retrospectively reviewed patients undergoing MVD at our institution from 2008 to 2020. Patients were sorted by 1 day, 2 days, or >2 days until discharge and by year from 2008 to 2013, 2014 to 2018, or 2019 to 2020. Patient presenting characteristics, intraoperative measures, and complications were documented. Statistical differences were calculated by one-way analysis of variance and χ2 analyses. RESULTS: Our cohort included 976 patients undergoing MVD, with 231 (23.6%) between 2008 and 2013, 517 (52.9%) between 2014 and 2018, and 228 (23.3%) between 2019 and 2020. Over time, postoperative admission rates to the critical care unit, total inpatient hospital admission times, and Barrow Neurological Institute scores at first follow-up decreased. Postoperative complications, including cerebrospinal fluid leak, decreased significantly. In addition, patients discharged within 1 day of admission incurred a total hospital cost of $26,689, which was $3588 lower than patients discharged within more than 1 day of admission, P < 0.0001. Discharging carefully selected patients who are appropriate for discharge within 1 day of admission could translate to a potential cost-savings of $255,346 per year in our clinical practice. CONCLUSIONS: In our experience, MVDs are a safe, elective intervention. Our findings suggest that postoperative day 1 discharge in patients with an uncomplicated postoperative course may be safe while improving hospital resource use.

Synergy between glutamate modulation and anti-programmed cell death protein 1 immunotherapy for glioblastoma.

OBJECTIVE: Immune checkpoint inhibitors such as anti-programmed cell death protein 1 (anti-PD-1) have shown promise for the treatment of cancers such as melanoma, but results for glioblastoma (GBM) have been disappointing thus far. It has been suggested that GBM has multiple mechanisms of immunosuppression, indicating a need for combinatorial treatment strategies. It is well understood that GBM increases glutamate in the tumor microenvironment (TME); however, the significance of this is not well understood. The authors posit that glutamate upregulation in the GBM TME is immunosuppressive. The authors utilized a novel glutamate modulator, BHV-4157, to determine synergy between glutamate modulation and the well-established anti-PD-1 immunotherapy for GBM. METHODS: C57BL/6J mice were intracranially implanted with luciferase-tagged GL261 glioma cells. Mice were randomly assigned to the control, anti-PD-1, BHV-4157, or combination anti-PD-1 plus BHV-4157 treatment arms, and median overall survival was assessed. In vivo microdialysis was performed at the tumor site with administration of BHV-4157. Intratumoral immune cell populations were characterized with immunofluorescence and flow cytometry. RESULTS: The BHV-4157 treatment arm demonstrated improved survival compared with the control arm (p < 0.0001). Microdialysis demonstrated that glutamate concentration in TME significantly decreased after BHV-4157 administration. Immunofluorescence and flow cytometry demonstrated increased CD4+ T cells and decreased Foxp3+ T cells in mice that received BHV-4157 treatment. No survival benefit was observed when CD4+ or CD8+ T cells were depleted in mice prior to BHV-4157 administration (p < 0.05). CONCLUSIONS: In this study, the authors showed synergy between anti-PD-1 immunotherapy and glutamate modulation. The authors provide a possible mechanism for this synergistic benefit by showing that BHV-4157 relies on CD4+ and CD8+ T cells. This study sheds light on the role of excess glutamate in GBM and provides a basis for further exploring combinatorial approaches for the treatment of this disease.

Enhancing proteasomal processing improves survival for a peptide vaccine used to treat glioblastoma.

Despite its essential role in antigen presentation, enhancing proteasomal processing is an unexploited strategy for improving vaccines. pepVIII, an anticancer vaccine targeting EGFRvIII, has been tested in several trials for glioblastoma. We examined 20 peptides in silico and experimentally, which showed that a tyrosine substitution (Y6-pepVIII) maximizes proteasome cleavage and survival in a subcutaneous tumor model in mice. In an intracranial glioma model, Y6-pepVIII showed a 62 and 31% improvement in median survival compared to control animals and pepVIII-vaccinated mice. Y6-pepVIII vaccination altered tumor-infiltrating lymphocyte subsets and expression of PD-1 on intratumoral T cells. Combination with anti-PD-1 therapy cured 45% of the Y6-pepVIII-vaccinated mice but was ineffective for pepVIII-treated mice. Liquid chromatography-tandem mass spectrometry analysis of proteasome-digested pepVIII and Y6-pepVIII revealed that most fragments were similar but more abundant in Y6-pepVIII digests and 77% resulted from proteasome-catalyzed peptide splicing (PCPS). We identified 10 peptides that bound human and murine MHC class I. Nine were PCPS products and only one peptide was colinear with EGFRvIII, indicating that PCPS fragments may be a component of MHC class I recognition. Despite not being colinear with EGFRvIII, two of three PCPS products tested were capable of increasing survival when administered independently as vaccines. We hypothesize that the immune response to a vaccine represents the collective contribution from multiple PCPS and linear products. Our work suggests a strategy to increase proteasomal processing of a vaccine that results in an augmented immune response and enhanced survival in mice.