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Immune checkpoint inhibitors have been successful across several tumor types; however, their efficacy has been uncommon and unpredictable in glioblastomas (GBM), where <10% of patients show long-term responses. To understand the molecular determinants of immunotherapeutic response in GBM, we longitudinally profiled 66 patients, including 17 long-term responders, during standard therapy and after treatment with PD-1 inhibitors (nivolumab or pembrolizumab). Genomic and transcriptomic analysis revealed a significant enrichment of PTEN mutations associated with immunosuppressive expression signatures in non-responders, and an enrichment of MAPK pathway alterations ( PTPN11 , BRAF ) in responders. Responsive tumors were also associated with branched patterns of evolution from the elimination of neoepitopes as well as with differences in T cell clonal diversity and tumor microenvironment profiles. Our study shows that clinical response to anti-PD-1 immunotherapy in GBM is associated with specific molecular alterations, immune expression signatures, and immune infiltration that reflect the tumor’s clonal evolution during treatment. Genomic, transcriptomic, and microenvironmental analyses of samples from patients with glioblastoma treated with nivolumab or pembrolizumab identifies features associated with treatment response that may help in refining patient stratification.

Abstract BACKGROUND Cytoreductive surgery is considered controversial for primary central nervous system lymphoma (PCNSL). OBJECTIVE To investigate survival following craniotomy or biopsy for PCNSL METHODS The National Cancer Database-Participant User File (NCDB, n = 8936), Surveillance, Epidemiology, and End Results Program (SEER, n = 4636), and an institutional series (IS, n = 132) were used. We retrospectively investigated the relationship between craniotomy, prognostic factors, and survival for PCNSL using case–control design. RESULTS  In NCDB, craniotomy was associated with increased median survival over biopsy (19.5 vs 11.0 mo), independent of subsequent radiation and chemotherapy (hazard ratio [HR] 0.80, P < .001). We found a similar trend with survival for craniotomy vs biopsy in the IS (HR 0.68, P = .15). In SEER, gross total resection was associated with increased median survival over biopsy (29 vs 10 mo, HR 0.68, P < .001). The survival benefit associated with craniotomy was greater within recursive partitioning analysis (RPA) class 1 group in NCDB (95.1 vs 29.1 mo, HR 0.66, P < .001), but was smaller for RPA 2-3 (14.9 vs 10.0 mo, HR 0.86, P < .001). A surgical risk category (RC) considering lesion location and number, age, and frailty was developed. Craniotomy was associated with increased survival vs biopsy for patients with low RC (133.4 vs 41.0 mo, HR 0.33, P = .01), but not high RC in the IS. CONCLUSION Craniotomy is associated with increased survival over biopsy for PCNSL in 3 retrospective datasets. Prospective studies are necessary to adequately evaluate this relationship. Such studies should evaluate patients most likely to benefit from cytoreductive surgery, ie, those with favorable RPA and RC.

Abstract BACKGROUND: Extent of resection (EOR) correlates with glioblastoma outcomes. Resectability and EOR depend on anatomical, clinical, and surgeon factors. Resectability likely influences outcome in and of itself, but an accurate measurement of resectability remains elusive. An understanding of resectability and the factors that influence it may provide a means to control a confounder in clinical trials and provide reference for decision making. OBJECTIVE: To provide proof of concept of the use of the collective wisdom of experienced brain tumor surgeons in assessing glioblastoma resectability. METHODS: We surveyed 13 academic tumor neurosurgeons nationwide to assess the resectability of newly diagnosed glioblastoma. Participants reviewed 20 cases, including digital imaging and communications in medicine-formatted pre- and postoperative magnetic resonance images and clinical vignettes. The selected cases involved a variety of anatomical locations and a range of EOR. Participants were asked about surgical goal, eg, gross total resection, subtotal resection (STR), or biopsy, and rationale for their decision. We calculated a “resectability index” for each lesion by pooling responses from all 13 surgeons. RESULTS: Neurosurgeons’ individual surgical goals varied significantly (P = .015), but the resectability index calculated from the surgeons’ pooled responses was strongly correlated with the percentage of contrast-enhancing residual tumor (R = 0.817, P < .001). The collective STR goal predicted intraoperative decision of intentional STR documented on operative notes (P < .01) and nonresectable residual (P < .01), but not resectable residual. CONCLUSION: In this pilot study, we demonstrate the feasibility of measuring the resectability of glioblastoma through crowdsourcing. This tool could be used to quantify resectability, a potential confounder in neuro-oncology clinical trials.

ABSTRACT Objective: Venous thromboembolic event (VTE) after spine surgery is a rare but potentially devastating complication. With the advent of machine learning, an opportunity exists for more accurate prediction of such events to aid in prevention and treatment. Methods: Seven models were screened using 108 database variables and 62 preoperative variables. These models included deep neural network (DNN), DNN with synthetic minority oversampling technique (SMOTE), logistic regression, ridge regression, lasso regression, simple linear regression, and gradient boosting classifier. Relevant metrics were compared between each model. The top four models were selected based on area under the receiver operator curve; these models included DNN with SMOTE, linear regression, lasso regression, and ridge regression. Separate random sampling of each model was performed 1000 additional independent times using a randomly generated training/testing distribution. Variable weights and magnitudes were analyzed after sampling. Results: Using all patient-related variables, DNN using SMOTE was the top-performing model in predicting postoperative VTE after spinal surgery (area under the curve [AUC] =0.904), followed by lasso regression (AUC = 0.894), ridge regression (AUC = 0.873), and linear regression (AUC = 0.864). When analyzing a subset of only preoperative variables, the top-performing models were lasso regression (AUC = 0.865) and DNN with SMOTE (AUC = 0.864), both of which outperform any currently published models. Main model contributions relied heavily on variables associated with history of thromboembolic events, length of surgical/anesthetic time, and use of postoperative chemoprophylaxis. Conclusions: The current study provides promise toward machine learning methods geared toward predicting postoperative complications after spine surgery. Further study is needed in order to best quantify and model real-world risk for such events.

•Risk factors for inpatient VTE are different from those diagnosed post-discharge.•Patients with EBL> 500cc, corpectomies, osteotomies and foraminotomies have higher rates of post-discharge VTE.•Spinal fractures is a risk factor for inpatient VTE. retrospective chart review. We aimed to determine the perioperative risk factors that lead to inpatient or post-discharge venous thromboembolism (VTE) events after spinal surgery. While many studies relate the risk factors in a post-surgical setting to the incidence of VTE, this study aims to separate these VTE into inpatient and post-discharge categories to examine timing and risk factors. We analyzed 6869 patients from 2009 to 2015 using Current Procedural Technology codes from a single tertiary academic institution. Patients were stratified based on occurrence and setting of VTE then controlled for perioperative characteristics with exclusion criteria being patients undergoing minor spine surgeries or secondary procedures. In 170 VTE events, these factors were associated with increased risk for: Inpatient DVT only: IVC filter (OR 6.380 [3.414−11.924]), longer length of hospital stay (OR 1.083 [1.047−1.120]), a prior history of DVT (OR 3.640 [1.931−6.856]). Post-discharge DVT only: history of PE (OR 45.142 [6.785−300.351]), having a corpectomy (OR 26.670 [3.477−204.548]), and having an osteotomy (OR 18.877 [1.129−315.534]). Inpatient PE only: surgery >4 h (OR 30.820, p < 0.001), fracture (OR 6.913, p = 0.004), IVC filter (OR 3.135, p = 0.029). Post-discharge PE only: corpectomy (OR 541.271, p = 0.009), foraminotomy (OR 40.137, p = 0.013), EBL > 500cc (OR 2467.798, p = 0.002). Time to onset of VTE events was significantly longer for patients undergoing osteotomy (7.43 days) than for patients with fracture (4.28 days), which is consistent with our findings that fracture was an independent predictor of inpatient VTE, and osteotomy was an independent predictor of post-discharge VTE (p = 0.018). Time-to-VTE varies between types of surgeries. Some risk factors are independently associated with VTE at all times during the 30-day postoperative period, while other factors are only associated with either inpatient or post-discharge VTE. Those patients with high-risk features for post-discharge VTE merit increased study for thromboprophylaxis management.

Abstract BACKGROUND Postpartum vertebral artery dissections (ppVADs) are rare but potentially morbid conditions that occur in otherwise healthy patients. OBJECTIVE To evaluate clinical characteristics of ppVADs. METHODS Demographic, clinical, treatment, and outcome data were collected on ppVADs and are presented in a case series of 12 patients and compared to the general cohort. RESULTS In total, 12 patients had ppVADs in our cohort of 310 patients with vertebral artery dissections (VADs). They occurred 11.27 days (95% CI, −0.85 to 23.39) postdelivery. Of these, there were 5 (42%) with a hypertensive disorder of pregnancy, and 4 (33%) who had migraines. A total of 3 (25%) had ischemic strokes and 1 (8%) had a subarachnoid hemorrhage. In total, 2 patients (17%) had unfavorable modified Rankin Scale (mRS, 2-6) at discharge from hospital. Patients with ppVADs more often had bilateral VADs (42% vs 17%, P = .03), had pseudoaneurysms (50% vs 18%, P = .0068), were younger (33.83 years vs 44.32 years, P = .018), and had lower Charlson Comorbidity Index (CCI = 0 vs 0.99, P = .0038). Anticoagulant treatment was used in a similar percentage of patients. Multivariate analysis revealed 3 factors were predictive of change in mRS: CCI (OR = 1.09, 95% CI, 1.02-1.15), stroke (OR = 0.78, 95% CI, 0.65-0.95), and mRS at hospital discharge (OR = 0.80, 95% CI, 0.74-0.87). CONCLUSION There are only 15 isolated ppVADs reported in the literature; this study adds 12 patients with 17 ppVADs. Postpartum VADs occur in younger, healthier patients than in the general cohort, raising questions about mechanism of injury. The majority of ppVADs have good neurological outcomes. Graphical Abstract Graphical Abstract

Background: Patients with simultaneous fractures of the atlas and dens have traditionally been managed according to the dens fracture's morphology, but data supporting this practice are limited. Methods: We retrospectively examined all patients with traumatic atlas fractures at our institution between 2008 and 2016. We used multivariable regression and propensity score matching to compare the presentation, management, and outcomes of patients with isolated atlas fractures to patients with simultaneous atlas-dens fractures. Results: Ninety-nine patients were identified. Patients with isolated atlas fractures were younger (61 ± 22 vs. 77 ± 14, P = 0.0003), had lower median Charlson Comorbidity Index (3 vs. 5, P = 0.0005), had better presenting Nurick myelopathy scores (0 vs. 3, P < 0.0001), and had different mechanisms of injury (P = 0.0011). Multivariable regression showed that having a simultaneous atlas-dens fracture was independently associated with older age (odds ratio [OR] =1.59 [1.22, 2.07], P = 0.001), worse presenting myelopathy (OR = 3.10 [2.04, 4.16], P < 0.001), and selection for surgery (OR = 4.91 [1.10, 21.97], P = 0.037). Propensity score matching yielded balanced populations (Rubin's B = 23.3, Rubin's R = 1.96) and showed that the risk of atlas fracture nonunion was no different among isolated atlas fractures compared to simultaneous atlas-dens fractures (P = 0.304). Age was the only variable independently associated with atlas fracture nonunion (OR = 2.39 [1.15, 5.00], P = 0.020), having a simultaneous atlas-dens fracture was not significant (P = 0.2829). Conclusions: Among patients with atlas fractures, simultaneous fractures of the dens occur in older patients and confer an increased risk of myelopathy and requiring surgical stabilization. Controlling for confounders, the risk of atlas fracture nonunion is equivalent for isolated atlas fractures versus simultaneous atlas-dens fractures.

Abstract BACKGROUND There is growing recognition that perioperative complication rates are similar between hospitals, but mortality rates are lower at high-volume centers. This may be due to differences in the ability to rescue patients from major complications. OBJECTIVE To examine the relationship between hospital caseload and failure to rescue from complications following resection of intracranial neoplasms. METHODS We identified adults in the Nationwide Inpatient Sample diagnosed with glioma, meningioma, brain metastasis, or acoustic neuroma, who underwent surgical resection between 1998 and 2010. We stratified hospitals by low, intermediate, and high surgical volume tertiles and calculated failure to rescue rates (mortality in patients after a major complication). RESULTS A total of 550 054 patients were analyzed. Overall risk-adjusted complication rates were comparable between low- and medium-volume centers, and slightly lower at high-volume centers (15.3% [15.2, 15.5] vs 15.7% [15.5, 15.9] vs 14.3% [14.1, 14.6]). Risk-adjusted mortality decreased with increasing hospital surgical volume (10.3% [10.2, 10.5] vs 9.0% [8.9, 9.1] vs 7.1% [7.0, 7.2]). The overall risk-adjusted failure to rescue rate also decreased with increasing surgical volume (26.9% [26.3, 27.4] vs 24.8% [24.3, 25.3] vs 20.9% [20.5, 21.5]). CONCLUSION While complication rates were similar between high-volume and low-volume hospitals following craniotomy for tumor, mortality rates were substantially lower at high-volume centers. This appears to be due to the ability of high-volume hospitals to rescue patients from major perioperative complications.

ABSTRACT Introduction: Atlas fractures often accompany traumatic dens fractures, but existing literature on the management of simultaneous atlantoaxial fractures is limited. Methods: We examined all patients with traumatic dens fractures at our institution between 2008 and 2018. We used multivariable logistic regression and ordinal logistic regression to identify factors independently associated with presentation with a simultaneous atlas fracture, as well myelopathy severity, fracture nonunion, and selection for surgery. Results: Two hundred and eighty-two patients with traumatic dens fractures without subaxial fractures were identified, including 65 (22.8%) with simultaneous atlas fractures. The distribution of injury mechanisms differed between groups (χ2 P = 0.0360). On multivariable logistic regression, dens nonunion was positively associated with type II fractures (odds ratio [OR] = 2.00, P = 0.038) and negatively associated with having surgery (OR = 0.52, P = 0.049), but not with having a C1 fracture (P = 0.3673). Worse myelopathy severity on presentation was associated with having a severe injury severity score (OR = 102.3, P < 0.001) and older age (OR = 1.28, P = 0.002), but not with having an atlas fracture (P = 0.2446). Having a simultaneous atlas fracture was associated with older age (OR = 1.29, P = 0.024) and dens fracture angulation (OR = 2.62, P = 0.004). Among patients who underwent surgery, C1/C2 posterior fusion was the most common procedure, and having a simultaneous atlas fracture was associated with selection for occipitocervical fusion (OCF) (OR = 14.35, P = 0.010). Conclusions: Among patients with traumatic dens, patients who have simultaneous atlas fractures are a distinct subpopulation with respect to age, mechanism of injury, fracture morphology, and management. Traumatic dens fractures with simultaneous atlas fractures are independently associated with selection for OCF rather than posterior cervical fusion alone.