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.

Immunotherapy as a New Therapeutic Approach for Brain and Spinal Cord Tumors.

Historically, the central nervous system (CNS) was considered an immune-privileged organ. However, recent studies have shown that the immune system plays a significant role in the CNS. Thus, there is renewed interest in applying cancer immunotherapy to CNS malignancies with the hope of generating a robust anti-tumor immune response and creating long-lasting immunity in patients. There has been some work with non-specific immunotherapy such as IL-2 for brain metastasis. Unfortunately, the results from non-specific immunotherapy studies were lackluster, so the focus has shifted to more specific CNS immunotherapies including cancer vaccines, immune checkpoint inhibitors, oncolytic virus therapy, and chimeric antigen receptor (CAR) T cell therapy. With respect to cancer vaccines, rindopepimut has been well-studied in glioblastoma (GBM) patients with the EGFRvIII mutation, with early results from phase II trials showing possible efficacy in carefully selected GBM patients. Other antigen-specific CNS tumor vaccines are still in the early stages. Immune checkpoint inhibitors are amongst the most promising and widely studied CNS immunotherapy strategies. Anti-PD-1 showed promising results in many non-CNS solid tumors, however, results from early clinical trials show poor efficacy for anti-PD-1 in GBM patients. Anti-PD-1 is also under investigation for CNS metastasis and showed some efficacy in non-small cell lung cancer and renal cell carcinoma patients. Anti-PD-1 is under early stage investigation for other CNS tumors such as chordoma. Oncolytic virus therapy is the strategy of infecting tumor cells with a virus that in turn triggers an innate immune response leading to tumor cell lysis. Oncolytic viruses currently under investigation include several adenovirus-based therapies and a herpes simplex virus-based therapy. Phase I studies have demonstrated the safety of oncolytic virus therapies in GBM patients. Current studies are evaluating the efficacy of these therapies both alone and in combination with other immunotherapy approaches such as checkpoint inhibition in patients with CNS tumors. CAR T cell therapy is a newer immunotherapy approach. CAR T cell therapies, directed against EGFRvIII mutation and HER-2 mutation, demonstrate an acceptable safety profile, although there is no conclusive evidence of the survival benefit of these therapies in early trials. Studies are currently underway to determine optimal tumor-specific antigen selection and modality of administration for CAR T cell therapy. Overall, the prognosis is generally poor for patients with CNS malignancies. The promising results of cancer immunotherapy for non-CNS tumors have created significant interest in applying these therapies for CNS malignancies. Preliminary results have not demonstrated robust efficacy for CNS immunotherapy. However, it is important to keep in mind that the field is still in its infancy and many clinical trials are still early-phase. Several, clinical trials are currently underway to further explore the role of immunotherapy for CNS malignancies.

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.

Case Series in the Utility of Invasive Blood Pressure Monitoring in Microvascular Decompression.

BACKGROUND: The utility of arterial lines in microvascular decompression (MVD) is not well described. OBJECTIVE: To examine the safety and costs of arterial lines compared with noninvasive blood pressure (NIBP) monitoring in MVDs. METHODS: We retrospectively reviewed patients undergoing MVD from 2012 to 2020. Patients were grouped by procedure date from 2012 to 2014 and 2015 to 2020, reflecting our institution's decreasing trend in arterial line placement around 2014 to 2015. Patient features, intraoperative characteristics, and postoperative complications were collected for all cases. Statistical differences were evaluated using chi-squared analyses and t-tests. RESULTS: Eight hundred fifty-eight patients underwent MVDs, with 204 between 2012 and 2014 and 654 between 2015 and 2020. Over time, the frequency of arterial line placement decreased from 64.2% to 30.1%, P < .001. Arterial lines involved 11 additional minutes of preincision time, P < .001. Patients with arterial lines required both increased doses and costs of vasoactive medications intraoperatively. Patients receiving arterial lines demonstrated no significant differences in complications compared with patients with NIBP monitoring. On average, patients with arterial lines incurred $802 increased costs per case compared with NIBP monitoring. CONCLUSION: NIBP monitoring in MVDs provides neurologically and hemodynamically safe outcomes compared with invasive blood pressure monitoring. For patients without significant cardiopulmonary risk factors, NIBP monitoring may be a cost-effective alternative in MVDs.

Risk factors for surgical intervention in patients with primary spinal infection on initial presentation.

OBJECTIVE: Treatment of primary spinal infection includes medical management with or without surgical intervention. The objective of this study was to identify risk factors for the eventual need for surgery in patients with primary spinal infection on initial presentation. METHODS: From January 2010 to July 2019, 275 patients presented with primary spinal infection. Demographic, infectious, imaging, laboratory, treatment, and outcome data were retrospectively reviewed and collected. Thirty-three patients were excluded due to insufficient follow-up (≤ 90 days) or death prior to surgery. RESULTS: The mean age of the 242 patients was 58.8 ± 13.6 years. The majority of the patients were male (n = 130, 53.7%), White (n = 150, 62.0%), and never smokers (n = 132, 54.5%). Fifty-four patients (22.3%) were intravenous drug users. One hundred fifty-four patients (63.6%) ultimately required surgery while 88 (36.4%) never needed surgery during the duration of follow-up. There was no significant difference in age, gender, race, BMI, or comorbidities between the surgery and no-surgery groups. On univariate analysis, the presence of an epidural abscess (55.7% in the no-surgery group vs 82.5% in the surgery group, p < 0.0001), the median spinal levels involved (2 [interquartile range (IQR) 2-3] in the no-surgery group vs 3 [IQR 2-5] in the surgery group, p < 0.0001), and active bacteremia (20.5% in the no-surgery vs 35.1% in the surgery group, p = 0.02) were significantly different. The cultured organism and initial laboratory values (erythrocyte sedimentation rate, C-reactive protein, white blood cell count, creatinine, and albumin) were not significantly different between the groups. On multivariable analysis, the final model included epidural abscess, cervical or thoracic spine involvement, and number of involved levels. After adjusting for other variables, epidural abscess (odds ratio [OR] 3.04, 95% confidence interval [CI] 1.64-5.63), cervical or thoracic spine involvement (OR 2.03, 95% CI 1.15-3.61), and increasing number of involved levels (OR 1.16, 95% CI 1.01-1.35) were associated with greater odds of surgery. Fifty-two surgical patients (33.8%) underwent decompression alone while 102 (66.2%) underwent decompression with fusion. Of those who underwent decompression alone, 2 (3.8%) of 52 required subsequent fusion due to kyphosis. No patient required hardware removal due to persistent infection. CONCLUSIONS: At time of initial presentation of primary spinal infection, the presence of epidural abscess, cervical or thoracic spine involvement, as well as an increasing number of involved spinal levels were potential risk factors for the eventual need for surgery in this study. Additional studies are needed to assess for risk factors for surgery and antibiotic treatment failure.

The safety and efficacy of dexamethasone in the perioperative management of glioma patients.

OBJECTIVE: In this single-institution retrospective cohort study, the authors evaluated the effect of dexamethasone on postoperative complications and overall survival in patients with glioma undergoing resection. METHODS: A total of 435 patients who underwent resection of a primary glioma were included in this retrospective cohort study. The inclusion criterion was all patients who underwent resection of a primary glioma at a tertiary medical center between 2014 and 2019. RESULTS: The use of both pre- and postoperative dexamethasone demonstrated a trend toward the development of postoperative wound infections (3% vs 0% in single use or no use, p = 0.082). No association was detected between dexamethasone use and the development of new-onset hyperglycemia (p = 0.149). On multivariable Cox proportional hazards analysis, dexamethasone use was associated with a greater hazard of death (overall p = 0.017); this effect was most pronounced for preoperative (only) dexamethasone use (hazard ratio 3.0, p = 0.062). CONCLUSIONS: Combined pre- and postoperative dexamethasone use may increase the risk of postoperative wound infection, and dexamethasone use, specifically preoperative use, may negatively impact survival. These findings highlight the potential for serious negative consequences with dexamethasone 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.

Mutation status and postresection survival of patients with non-small cell lung cancer brain metastasis: implications of biomarker-driven therapy.

OBJECTIVE: Non-small cell lung cancer (NSCLC) is the most common primary tumor to develop brain metastasis. Prognostic markers are needed to better determine survival after neurosurgical resection of intracranial disease. Given the importance of mutation subtyping in determining systemic therapy and overall prognosis of NSCLC, the authors examined the prognostic value of mutation status for postresection survival of patients with NSCLC brain metastasis. METHODS: The authors retrospectively analyzed all cases of NSCLC brain metastasis with available molecular testing data that were resected by a single surgeon at a single academic center from January 2009 to February 2019. Mutation status, demographic characteristics, clinical factors, and treatments were analyzed. Association between predictive variables and overall survival after neurosurgery was determined with Cox regression. RESULTS: Of the included patients (n = 84), 40% were male, 76% were smokers, the mean ± SD Karnofsky Performance Status was 85 ± 14, and the mean ± SD age at surgery was 63 ± 11 years. In total, 23%, 26%, and 4% of patients had EGFR, KRAS, and ALK/ROS1 alterations, respectively. On multivariate analysis, survival of patients with EGFR (HR 0.495, p = 0.0672) and KRAS (HR 1.380, p = 0.3617) mutations were not significantly different from survival of patients with wild-type (WT) tumor. However, the subgroup of patients with EGFR mutation who also received tyrosine kinase inhibitor (TKI) therapy had significantly prolonged survival (HR 0.421, p = 0.0471). In addition, postoperative stereotactic radiosurgery (HR 0.409, p = 0.0177) and resected tumor diameter < 3 cm (HR 0.431, p = 0.0146) were also significantly associated with prolonged survival, but Graded Prognostic Assessment score ≤ 1.0 (HR 2.269, p = 0.0364) was significantly associated with shortened survival. CONCLUSIONS: Patients with EGFR mutation who receive TKI therapy may have better survival after resection of brain metastasis than patients with WT tumor. These results may inform counseling and decision-making regarding the appropriateness of resection of NSCLC brain metastasis.

Combination checkpoint therapy with anti-PD-1 and anti-BTLA results in a synergistic therapeutic effect against murine glioblastoma.

Clinical trials involving anti-programmed cell death protein-1 (anti-PD-1) failed to demonstrate improved overall survival in glioblastoma (GBM) patients. This may be due to the expression of alternative checkpoints such as B- and T- lymphocyte attenuator (BTLA) on several immune cell types including regulatory T cells. Murine GBM models indicate that there is significant upregulation of BTLA in the tumor microenvironment (TME) with associated T cell exhaustion. We investigate the use of antibodies against BTLA and PD-1 on reversing immunosuppression and increasing long-term survival in a murine GBM model. C57BL/6 J mice were implanted with the murine glioma cell line GL261 and randomized into 4 arms: (i) control, (ii) anti-PD-1, (iii) anti-BTLA, and (iv) anti-PD-1 + anti-BTLA. Kaplan-Meier curves were generated for all arms. Flow cytometric analysis of blood and brains were done on days 11 and 16 post-tumor implantation. Tumor-bearing mice treated with a combination of anti-PD-1 and anti-BTLA therapy experienced improved overall long-term survival (60%) compared to anti-PD-1 (20%) or anti-BTLA (0%) alone (P = .003). Compared to monotherapy with anti-PD-1, mice treated with combination therapy also demonstrated increased expression of CD4+ IFN-γ (P < .0001) and CD8+ IFN-γ (P = .0365), as well as decreased levels of CD4+ FoxP3+ regulatory T cells on day 16 in the brain (P = .0136). This is the first preclinical investigation into the effects of combination checkpoint blockade with anti-PD-1 and anti-BTLA treatment in GBM. We also show a direct effect on activated immune cell populations such as CD4+ and CD8 + T cells and immunosuppressive regulatory T cells through this combination therapy.

Sustained localized delivery of immunotherapy to lymph nodes reverses immunosuppression and increases long-term survival in murine glioblastoma.

Introduction: Despite the advent of immunotherapy as a promising therapeutic, glioblastoma (GBM) remains resistant to using checkpoint blockade due to its highly immunosuppressive tumor milieu. Moreover, current anti-PD-1 treatment requires multiple infusions with adverse systemic effects. Therefore, we used a PCL:PEG:PCL polymer gel loaded with anti-PD-1 and implanted at the site of lymph nodes in an attempt to maximize targeting of inactivated T cells as well as mitigate unnecessary systemic exposure. Methods: Mice orthotopically implanted with GL261 glioma cells were injected with hydrogels loaded with anti-PD-1 in one of the following locations: cervical lymph nodes, inguinal lymph nodes, and the tumor site. Mice treated systemically with anti-PD-1 were used as comparative controls. Kaplan-Meier curves were generated for all arms, with ex vivo flow cytometric staining for L/D, CD45, CD3, CD4, CD8, TNF-α and IFN-y and co-culture ELISpots were done for immune cell activation assays. Results: Mice implanted with PCL:PEG:PCL hydrogels carrying anti-PD-1 at the site of their lymph nodes showed significantly improved survival outcomes compared to mice systemically treated with anti-PD-1 (P = .0185). Flow cytometric analysis of brain tissue and co-culture of lymph node T cells from mice implanted with gels demonstrated increased levels of IFN-y and TNF-α compared to mice treated with systemic anti-PD-1, indicating greater reversal of immunosuppression compared to systemic treatment. Conclusions: Our data demonstrate proof of principle for using localized therapy that targets lymph nodes for GBM. We propose an alternative treatment paradigm for developing new sustained local treatments with immunotherapy that are able to eliminate the need for multiple systemic infusions and their off-target effects.

Web-Based Calculator Predicts Surgical-Site Infection After Thoracolumbar Spine Surgery.

BACKGROUND: Surgical-site infection (SSI) after spine surgery leads to increased length of stay, reoperation, and worse patient quality of life. We sought to develop a web-based calculator that computes an individual's risk of a wound infection following thoracolumbar spine surgery. METHODS: We performed a retrospective review of consecutive patients undergoing elective degenerative thoracolumbar spine surgery at a tertiary-care institution between January 2016 and December 2018. Patients who developed SSI requiring reoperation were identified. Regression analysis was performed and model performance was assessed using receiver operating curve analysis to derive an area under the curve. Bootstrapping was performed to check for overfitting, and a Hosmer-Lemeshow test was employed to evaluate goodness-of-fit and model calibration. RESULTS: In total, 1259 patients were identified; 73% were index operations. The overall infection rate was 2.7%, and significant predictors of SSI included female sex (odds ratio [OR] 3.0), greater body mass index (OR 1.1), active smoking (OR 2.8), worse American Society of Anesthesiologists physical status (OR 2.1), and greater surgical invasiveness (OR 1.1). The prediction model had an optimism-corrected area under the curve of 0.81. A web-based calculator was created: https://jhuspine2.shinyapps.io/Wound_Infection_Calculator/. CONCLUSIONS: In this pilot study, we developed a model and simple web-based calculator to predict a patient's individualized risk of SSI after thoracolumbar spine surgery. This tool has a predictive accuracy of 83%. Through further multi-institutional validation studies, this tool has the potential to alert both patients and providers of an individual's SSI risk to improve informed consent, mitigate risk factors, and ultimately drive down rates of SSIs.

Preclinical efficacy of ribavirin in SHH and group 3 medulloblastoma.

OBJECTIVE: Medulloblastoma, the most common pediatric brain malignancy, has Sonic Hedgehog (SHH) and group 3 (Myc driven) subtypes that are associated with the activity of eukaryotic initiation factor 4E (eIF4E), a critical mediator of translation, and enhancer of zeste homolog 2 (EZH2), a histone methyltransferase and master regulator of transcription. Recent drug repurposing efforts in multiple solid and hematologic malignancies have demonstrated that eIF4E and EZH2 are both pharmacologically inhibited by the FDA-approved antiviral drug ribavirin. Given the molecular overlap between medulloblastoma biology and known ribavirin activity, the authors investigated the preclinical efficacy of repurposing ribavirin as a targeted therapeutic in cell and animal models of medulloblastoma. METHODS: Multiple in vitro assays were performed using human ONS-76 (a primitive SHH model) and D425 (an aggressive group 3 model) cells. The impacts of ribavirin on cellular growth, death, migration, and invasion were quantified using proliferation and Cell Counting Kit-8 (CCK-8) assays, flow cytometry with annexin V (AnnV) staining, scratch wound assays, and Matrigel invasion chambers, respectively. Survival following daily ribavirin treatment (100 mg/kg) was assessed in vivo in immunodeficient mice intracranially implanted with D425 cells. RESULTS: Compared to controls, ribavirin treatment led to a significant reduction in medulloblastoma cell growth (ONS-76 proliferation assay, p = 0.0001; D425 CCK-8 assay, p < 0.0001) and a significant increase in cell death (flow cytometry for AnnV, ONS-76, p = 0.0010; D425, p = 0.0284). In ONS-76 cells, compared to controls, ribavirin significantly decreased cell migration and invasion (Matrigel invasion chamber assay, p = 0.0012). In vivo, ribavirin significantly extended survival in an aggressive group 3 medulloblastoma mouse model compared to vehicle-treated controls (p = 0.0004). CONCLUSIONS: The authors demonstrate that ribavirin, a clinically used drug known to inhibit eIF4E and EZH2, has significant antitumor effects in multiple preclinical models of medulloblastoma, including an aggressive group 3 animal model. Ribavirin may represent a promising targeted therapeutic in medulloblastoma.

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.

A review of glioblastoma immunotherapy.

INTRODUCTION: Glioblastoma is a very aggressive cancer with dismal prognosis despite standard of care including surgical resection, radiation therapy, and chemotherapy. There is interest in applying immunotherapy to glioblastoma as this modality has demonstrated remarkable improvements in the management of several solid tumors including melanoma, renal cell carcinoma, and non-small cell lung cancer. This review aims to provide an overview of the current state of glioblastoma immunotherapy. METHODS: Literature search was performed on PubMed between 1961 and 2020. RESULTS: Initial clinical trials of checkpoint inhibitors and vaccine therapy for glioblastoma have largely been disappointing for both primary and recurrent glioblastoma. This failure has been attributed to glioblastoma's highly immunosuppressive environment and multiple mechanisms of therapy resistance including high tumor heterogeneity, low mutational burden, systemic immunosuppression, and local immune dysfunction. CONCLUSIONS: Current clinical trials are exploring combination therapy and novel treatment strategies beyond immune checkpoint therapies and vaccine therapy such as CAR T cells. There is also an effort to establish synergy between immunotherapy and current standard of care. Furthermore, recent advances in personalized neoantigen vaccines suggest a shift towards personalized, patient-specific GBM treatment.

Alternative Checkpoints as Targets for Immunotherapy.

PURPOSE OF REVIEW: Immunotherapy has shown an unprecedented response in treatment of tumors. However, challenges such as lack of cytotoxic lymphocytes to mount an immune response or development of resistance to therapy can limit efficacy. Here, we discuss alternative checkpoints that can be targeted to improve cytotoxic lymphocyte function while harnessing other components of the immune system. RECENT FINDINGS: Blockade of alternative checkpoints has improved anti-tumor immunity in mouse models and is being tested clinically with encouraging findings. In addition to modulating T cell function directly, alternative checkpoints can also regulate activity of myeloid cells and regulatory T cells to affect anti-tumor response. Combination of immune checkpoint inhibitors can improve treatment of tumors by activating multiple arms of the immune system.

The Effects of Postoperative Neurological Deficits on Survival in Patients With Single Brain Metastasis.

BACKGROUND: The prognosis for brain metastasis is poor, and surgical resection is part of the standard of care for these patients as it has been shown to improve median overall survival. Development of neurological deficits after surgical resection has been associated with worsened outcomes in patients with glioblastoma. The effect of postoperative neurological deficits on survival in patients with single brain metastasis has not been studied to date. OBJECTIVE: To evaluate the association between postoperative neurological deficits and median overall survival. METHODS: A single-institution retrospective cohort study was performed on all patients with single brain metastasis undergoing surgical resection by a single neurosurgeon. RESULTS: A total of 121 patients met the inclusion criteria for this study. Among them 61% of patients presented with a preoperative deficit, and 26% of patients had a new postoperative deficit. However, most postoperative deficits resolved and only 3.3% of patients developed a new permanent postoperative deficit. Median overall survival in patients with a new postoperative deficit was 2.4 mo, whereas mOS in patients without a postoperative deficit was 12.6 mo (P < .0001). CONCLUSION: This study suggests that a new neurological deficit is associated with worsened outcomes after surgical resection of a single brain metastasis. This finding has potential implications for patient selection and counseling as the patients most likely to benefit from surgical resection are the patients who are most likely to have resolution of a preoperative deficit.

A novel predictive model of intraoperative blood loss in patients undergoing elective lumbar surgery for degenerative pathologies.

BACKGROUND CONTEXT: Intraoperative blood loss (IOBL) is unavoidable during surgery; however, high IOBL is associated with increased morbidity and increased risk for requiring allogenic blood transfusion, itself associated with poorer outcomes. PURPOSE: Here we sought to develop and validate a predictive calculator for IOBL that could be used by surgeons to estimate likely blood loss. STUDY DESIGN/SETTING: Retrospective cohort. PATIENT SAMPLE: Series of consecutive patients who underwent elective lumbar spine surgery for degenerative pathologies over a 27-month period at a single tertiary care center. OUTCOME MEASURES: Primary outcome was IOBL. Secondary outcome was the occurrence of "major intraoperative bleeding," defined as IOBL exceeding 1 L. METHODS: Charts of included patients were reviewed for medical comorbidities, preoperative laboratory data, surgical plan, and anesthesia records. Univariate linear regressions were performed to find significant predictors of IOBL, which were then subjected to a multivariate analysis to identify the final model. Model training was performed using 70% of the included cohort and external validation was performed using 30% of the cohort. Results of the model were deployed as a freely available online calculator. RESULTS: We identified 1,281 patients who met inclusion/exclusion criteria. Mean age was 60±15 years, mean Charlson Comorbidity score was 1.1±1.6, and 51.8% were male. There were no significant differences between the training and validation cohorts with regard to any of the demographic variables or intraoperative variables; tranexamic acid use and surgical invasiveness were also similar in both cohorts. Multivariate analysis identified body mass index (ßₙ=7.14; 95% confidence interval [3.15, 11.13]; p<.001), surgical invasiveness (ßₙ=29.18; [24.62, 33.74]; p<.001), tranexamic acid use (ßₙ=-0.093; [-0.171, -0.014]; p=.02), and surgical duration (ßₙ=2.13; [1.75, 2.51]; p<.001) as significant predictors of IOBL. The model had an overall fit of r=0.693 in the validation cohort. Construction of a receiver-operating curve for predicting major IOBL showed a C-statistic of 0.895 within the validation cohort. CONCLUSION: Here we identify and validate a model for predicting IOBL in patients undergoing lumbar spine surgery. The model was a moderately strong predictor of absolute IOBL and was demonstrated to predict the occurrence of major IOBL with a high degree of accuracy. We propose it may have future utility when counseling patients about surgical morbidity and the probability of requiring transfusion.

ACT001 reduces the expression of PD-L1 by inhibiting the phosphorylation of STAT3 in glioblastoma.

ACT001, which is derived from an ancient anti-inflammatory drug, has been shown to cross the blood-brain barrier in preclinical studies and has demonstrated anti-glioblastoma (GBM) activity in clinical trials. However, its pharmacological potential for anti-GBM immune response modulation remains unclear. The chemical structure of ACT001 indicates that it may bind to STAT3 and thus modulate antitumor immune response. Methods: Bioinformatics and immunohistochemistry (IHC) were used to assess STAT3 and PD-L1 expression in gliomas. Western blotting, RT-PCR and immunofluorescence were used to detect PD-L1 and p-STAT3 expression in glioma cells exposed to ACT001. Chromatin immunoprecipitation, an ACT001-Biotin probe, and a dual-luciferase reporter assay were used to detect direct modulation. The in vivo efficacy of ACT001 was evaluated in GL261 murine glioma model. Survival analyses were conducted using the log-rank (Mantel-Cox) test. Results: Bioinformatic analysis of 1,837 samples from 4 public glioma datasets showed that STAT3 mRNA expression was correlated with the degree of malignancy and therapeutic resistance and that STAT3 mRNA expression was related to immunosuppression, leukocyte infiltration, and PD-L1 expression. IHC staining of 53 tissue samples confirmed that relatively high phosphorylated STAT3 and PD-L1 protein expression was associated with a relatively advanced World Health Organization (WHO) glioma grade. Next, we confirmed that ACT001 treatment reduced PD-L1 expression and STAT3 phosphorylation. An ACT001-biotin probe was used to verify that ACT001 bound to STAT3. We also demonstrated that STAT3 bound to the PD-L1 promoter. The inhibition of PD-L1 expression and STAT3 phosphorylation by ACT001 could be rescued by STAT3 overexpression. Additionally, ACT001 inhibited GBM growth and decreased PD-L1 expression in vivo. The expression of the M2 markers CD206 and CD163 was decreased, while that of the antitumor immune markers iNOS and IFNγ was increased by ACT001 in vivo. Conclusion: Our results demonstrate that STAT3 plays a key role in immunosuppression of glioma and is inhibited by ACT001. ACT001 inhibits PD-L1 transcription and modulates anti-tumor immune response in glioma bearing mice. These findings will help us to understand the mechanism of ACT001 in GBM therapy.

Incidental durotomy: predictive risk model and external validation of natural language process identification algorithm.

OBJECTIVE: Incidental durotomy is a common complication of elective lumbar spine surgery seen in up to 11% of cases. Prior studies have suggested patient age and body habitus along with a history of prior surgery as being associated with an increased risk of dural tear. To date, no calculator has been developed for quantifying risk. Here, the authors' aim was to identify independent predictors of incidental durotomy, present a novel predictive calculator, and externally validate a novel method to identify incidental durotomies using natural language processing (NLP). METHODS: The authors retrospectively reviewed all patients who underwent elective lumbar spine procedures at a tertiary academic hospital for degenerative pathologies between July 2016 and November 2018. Data were collected regarding surgical details, patient demographic information, and patient medical comorbidities. The primary outcome was incidental durotomy, which was identified both through manual extraction and the NLP algorithm. Multivariable logistic regression was used to identify independent predictors of incidental durotomy. Bootstrapping was then employed to estimate optimism in the model, which was corrected for; this model was converted to a calculator and deployed online. RESULTS: Of the 1279 elective lumbar surgery patients included in this study, incidental durotomy occurred in 108 (8.4%). Risk factors for incidental durotomy on multivariable logistic regression were increased surgical duration, older age, revision versus index surgery, and case starts after 4 pm. This model had an area under curve (AUC) of 0.73 in predicting incidental durotomies. The previously established NLP method was used to identify cases of incidental durotomy, of which it demonstrated excellent discrimination (AUC 0.97). CONCLUSIONS: Using multivariable analysis, the authors found that increased surgical duration, older patient age, cases started after 4 pm, and a history of prior spine surgery are all independent positive predictors of incidental durotomy in patients undergoing elective lumbar surgery. Additionally, the authors put forth the first version of a clinical calculator for durotomy risk that could be used prospectively by spine surgeons when counseling patients about their surgical risk. Lastly, the authors presented an external validation of an NLP algorithm used to identify incidental durotomies through the review of free-text operative notes. The authors believe that these tools can aid clinicians and researchers in their efforts to prevent this costly complication in spine surgery.

Cost-benefit analysis of tranexamic acid and blood transfusion in elective lumbar spine surgery for degenerative pathologies.

OBJECTIVE: Blood transfusions are given to approximately one-fifth of patients undergoing elective lumbar spine surgery, and previous studies have shown that transfusions are accompanied by increased complications and additional costs. One method for decreasing transfusions is administration of tranexamic acid (TXA). The authors sought to evaluate whether the cost of TXA is offset by the decrease in blood utilization in lumbar spine surgery patients. METHODS: The authors retrospectively reviewed patients who underwent elective lumbar or thoracolumbar surgery for degenerative conditions at a tertiary care center between 2016 and 2018. Patients who received intraoperative TXA (TXA patients) were matched with patients who did not receive TXA (non-TXA patients) by age, sex, BMI, ASA (American Society of Anesthesiologists) physical status class, and surgical invasiveness score. Primary endpoints were intraoperative blood loss, number of packed red blood cell (PRBC) units transfused, and total hemostasis costs, defined as the sum of TXA costs and blood transfusion costs throughout the hospital stay. A subanalysis was then performed by substratifying both cohorts into short-length (1-4 levels) and long-length (5-8 levels) spinal constructs. RESULTS: Of the 1353 patients who met inclusion criteria, 68 TXA patients were matched to 68 non-TXA patients. Patients in the TXA group had significantly decreased mean intraoperative blood loss (1039 vs 1437 mL, p = 0.01). There were no differences between the patient groups in the total costs of blood transfusion and TXA (p = 0.5). When the 2 patient groups were substratified by length of construct, the long-length construct group showed a significant net cost savings of $328.69 per patient in the TXA group (p = 0.027). This result was attributable to the finding that patients undergoing long-length construct surgeries who were given TXA received a lower amount of PRBC units throughout their hospital stay (2.4 vs 4.0, p = 0.007). CONCLUSIONS: TXA use was associated with decreased intraoperative blood loss and significant reductions in total hemostasis costs for patients undergoing surgery on more than 4 levels. Furthermore, the use of TXA in patients who received short constructs led to no additional net costs. With the increasing emphasis put on value-based care interventions, use of TXA may represent one mechanism for decreasing total care costs, particularly in the cases of larger spine constructs.