Search

In the development of telemanipulated surgical robots, a class of continuum robots known as concentric tube robots has drawn particular interest for clinical applications in which space is a major limitation. One such application is transnasal surgery, which is used to access surgical sites in the sinuses and at the skull base. Current techniques for performing these procedures require surgeons to maneuver multiple rigid tools through the narrow confines of the nasal passages, leaving them with limited dexterity at the surgical site. In this article, we present a complete robotic system for transnasal surgery featuring concentric tube manipulators. It illustrates a bagging concept for sterility, and intraoperatively interchangeable instruments that work in conjunction with it, which were developed with operating room workflow compatibility in mind. The system also includes a new modular, portable surgeon console, a variable view-angle endoscope to facilitate surgical field visualization, and custom motor control electronics. Furthermore, we demonstrate elastic instability avoidance for the first time on a physical prototype in a geometrically accurate surgical scenario, which facilitates use of higher curvature tubes than could otherwise be used safely in this application. From a surgical application perspective, this article presents the first robotic approach to removing tumors growing behind the eyes in the orbital apex region, which has not been attempted previously with a surgical robot.

Open surgical approaches are still often employed in neurosurgery, despite the availability of neuroendoscopic approaches that reduce invasiveness. The challenge of maneuvering instruments at the tip of the endoscope makes neuroendoscopy demanding for the physician. The only way to aim tools passed through endoscope ports is to tilt the entire endoscope; but, tilting compresses brain tissue through which the endoscope passes and can damage it. Concentric tube robots can provide necessary dexterity without endoscope tilting, while passing through existing ports in the endoscope and carrying surgical tools in their inner lumen. In this article, we describe the mechatronic design of a new concentric tube robot that can deploy two concentric tube manipulators through a standard neuroendoscope. The robot uses a compact differential drive and features embedded motor control electronics and redundant position sensors for safety. In addition to the mechatronic design of this system, this article contributes experimental validation in the context of colloid cyst removal, comparing our new robotic system to standard manual endoscopy in a brain phantom. The robotic approach essentially eliminated endoscope tilt during the procedure (17.09 $^{\circ }$ for the manual approach vs. 1.16 $^{\circ }$ for the robotic system). The robotic system also enables a single surgeon to perform the procedure—typically in a manual approach one surgeon aims the endoscope and another operates the tools delivered through its ports.

Glioblastomas (GBM) are tumors for which immune-targeted therapies have failed to show clinical benefit and for which few biomarkers provide context for meaningful therapeutic stratification. Radiographic contact of GBM tumors with the lateral ventricle stem cell niche correlates with worse patient prognosis; however, the extent to which proximity to the ventricle impacts antitumor immunity remains unknown. We demonstrate that T cell checkpoint receptor expression is elevated in ventricle-contacting GBM as is the abundance of a specific, suppressive CD32+CD44+HLADhigh myeloid population suggesting a distinct immunoregulatory influence on antitumor immunity in proximity to the lateral ventricle. Phospho-specific mass cytometric profiling revealed extensively impaired immune signaling in ventricle-contacting GBM in response to inflammatory cytokine stimulation, further supporting a suppressive milieu influencing immunity at the lateral ventricle. Collectively, we identify a regulatory impact of ventricle contact on antitumor immunity in the brain, and reveal novel clinically targetable mechanisms of immunomodulation in patients with glioblastoma.Significance StatementWe demonstrate that the immune microenvironment of glioblastoma tumors contacting the lateral ventricle differs from non-contacting tumors. This work connects immune-biology to a radiographically detectable feature, the lateral ventricle, and highlights non-invasive imaging as a means to identify targetable immune features in glioblastoma tumors.

BackgroundGlioblastomas (GBM) account for 60% of adult primary brain tumors. With few advances in therapeutics, median overall survival remains 15-months post-diagnosis. Immunotherapies may provide therapeutic benefit in GBM patients; however, no predictive immune features currently inform therapeutic stratification in GBM. We have shown that, independently of known prognosticators, radiographic tumor contact with the lateral ventricle (C-GBM) correlates with 7-months worse survival prognosis compared to patients with ventricle non-contacting GBM (NC-GBM). This study sought to characterize the GBM immune microenvironment and identify targetable mechanisms of immunosuppression correlating with worse outcomes in C-GBM.MethodsTwelve patients presented with pathologically confirmed primary, IDH wildtype C-GBM and thirteen with NC-GBM. Multiplex immunohistochemistry (mxIHC) was performed on formalin-fixed paraffin embedded (FFPE) tissue for each patient interrogating 8 predictive immune markers (CD3, CD4, CD8, FOXP3, CD68, IBA1, PD-1, and PD-L1). Machine learning tools characterized tumor-infiltrating immune populations and identified biomarkers correlating with C-GBM and patient survival. K-means clustering identified immunological neighborhoods within the tissue and a log odds ratio was used to quantify the likelihood of cell-cell interactions in the tissue.ResultsC-GBM tumors were enriched in monocyte-derived macrophages (MDM) compared to NC-GBM (19 ± 8% vs. 6 ± 2%; pConclusionsThese findings suggest that factors within the periventricular space may influence antitumor immunity within GBM, and have identified clinically targetable immune biomarkers in glioblastoma. The prevalence of T cell niches in GBM tumors suggests the establishment tertiary lymphoid aggregates may be targetable to improve patient outcomes. Lastly, radiologic assessment of lateral ventricle contact by standard-of-care MRI may guide clinical trial design for immunotherapies in neuro-oncology.AcknowledgementsThis study was funded by NIH/NCI grant K00 CA212447 and supported by the Translational Pathology Shared Resource at Vanderbilt University (P30 CA068485).Ethics ApprovalPrimary glioblastoma tumors obtained in accordance with the Declaration of Helsinki and with institutional IRB approval (#131870) along with patient written informed consent.

Glioblastomas (GBM) account for up to 60% of all adult primary brain tumors. With few advances in therapeutics, median overall survival (mOS) remains at 15-months post diagnosis. Success of immunotherapy in peripheral solid tumors may offer an alternative therapeutic approach for patients with GBM tumors; however, no predictive immune features currently inform therapeutic stratification for GBM. Recently, we have identified radiographic tumor contact with the lateral ventricle (LV) as a prognostic indicator of OS, as patients with LV+ GBM survive 7 months less than patients with LV- gliomas. This disparity was independent of known prognostic factors (e.g. KPS, extent of resection). Further, we have identified a correlation between greater immune infiltration and the frequency of tumor subtypes with more favorable prognosis. We therefore hypothesized that differences in overall survival between patients with LV+ and LV- are due, in part, to a uniquely immunosuppressive microenvironment within the LV. Using 35-parameter single-cell mass cytometry (CyTOF) we profiled the immune infiltrate of human GBM tissue acquired in accordance with the Declaration of Helsinki and with the approval of the institutional review board (IRB #131870). Computational approaches (tSNE, Citrus, RAPID) correlated natural killer (NK) cell populations correlating with prognosis. NK cells made of 1–14% of the total immune infiltrate in GBM. Ninety percent of NK cells infiltrating LV- tumors were CD16+CD56dim cytotoxic NK cells (cNK). LV+ gliomas, however, were enriched in CD16+CD56bright immunoregulatory NK cells (irNK). The presence of cNK cells correlated with a 2.5-fold improvement of OS, whereas irNK cells correlated with a 2.2-fold reduction in OS. Further, 30–60% of NK cells infiltrating LV+ tumors expressed checkpoint receptors (TIGIT, TIM3, B7-H3) compared to only 10–20% in LV- tumors. These results suggest that NK cells contribute to immunosuppression in the LV and may serve as alternative targets to T cell-based therapies for GBM.

A goal of cancer research is to reveal cell subsets linked to continuous clinical outcomes to generate new therapeutic and biomarker hypotheses. We introduce a machine learning algorithm, Risk Assessment Population IDentification (RAPID), that is unsupervised and automated, identifies phenotypically distinct cell populations, and determines whether these populations stratify patient survival. With a pilot mass cytometry dataset of 2 million cells from 28 glioblastomas, RAPID identified tumor cells whose abundance independently and continuously stratified patient survival. Statistical validation within the workflow included repeated runs of stochastic steps and cell subsampling. Biological validation used an orthogonal platform, immunohistochemistry, and a larger cohort of 73 glioblastoma patients to confirm the findings from the pilot cohort. RAPID was also validated to find known risk stratifying cells and features using published data from blood cancer. Thus, RAPID provides an automated, unsupervised approach for finding statistically and biologically significant cells using cytometry data from patient samples.

Glioblastomas (GBM) account for 60% of adult primary brain tumors. With few advances in therapeutics, median overall survival remains 15-months post-diagnosis. Immunotherapies may provide therapeutic benefit in GBM patients; however, no predictive immune features currently inform therapeutic stratification in GBM. We have shown that, independently of known prognosticators, radiographic tumor contact with the lateral ventricle (C-GBM) correlates with 7-months worse prognosis compared to patients with ventricle non-contacting GBM (NC-GBM). This study sought to characterize the GBM immune microenvironment and identify targetable mechanisms of immunosuppression correlating with worse outcomes in C-GBM. Primary glioblastoma specimens were resected in accordance with the Declaration of Helsinki (IRB #131870). Twelve patients presented with C-GBM and thirteen with NC-GBM. Machine learning tools applied to mass cytometry data characterized tumor-infiltrating immune populations and identified biomarkers correlating with C-GBM and patient survival. C-GBM tumors were enriched in blood-derived macrophages compared to NC-GBM (19 ± 8% vs. 6 ± 2%; p< 0.001) and depleted in lymphocytes (2.9 ± 1% vs. 7.6 ± 2%; p< 0.001) and tissue-resident microglia (1.8 ± 0.3% vs. 7 ± 3%; p< 0.001). Further, T cells in C-GBM co-expressed the checkpoint receptors PD-1 and TIGIT, suggesting acute T cell exhaustion. Multiplex immunohistochemistry (mxIHC) on matched FFPE tissue provided spatial context to risk-stratifying immune populations, and defined structured immunological niches within the TME. Macrophage-tumor niches were most common (36%), followed by T cell-microglia-tumor niches (26%). Within niches, T cell-T cell interactions were more prevalent (log odds ratio = 0.90) whereas T cell-macrophage interactions were less prevalent (log odds ratio = -1.61). These findings suggest that factors within the periventricular space may influence antitumor immunity within tumors, and identify clinically targetable immune biomarkers in glioblastoma. Notably, radiologic assessment of lateral ventricle contact by standard-of-care MRI may guide clinical trial design for immunotherapies in neuro-oncology.

Background One study has investigated postoperative growth rates following subtotal resection of petroclival meningiomas utilizing linear measurements, which are insensitive to the multidimensional complex growth of meningiomas, to estimate tumor volume. Objective To describe petroclival meningioma growth patterns following less-than-complete resection utilizing volumetric analysis and to identify variables associated with tumor progression. Methods Patients with surgically resected WHO grade I petroclival meningiomas were retrospectively reviewed (1999-2015). Image analysis software was utilized to perform volumetric analyses of tumor size and growth on serial MRI studies. The impact of preoperative and postoperative variables on tumor growth after subtotal resection was analyzed. An increase in tumor volume of at least 20% was defined as "tumor growth." Results Twenty-three patients had immediate preoperative and serial postoperative MRI studies available for review. The mean preoperative tumor volume was 20.9 cm3 (range 0.4-54.6). The mean extent of resection was 75.5% (range 31.5%-100.0%). At a mean follow-up of 24.8 mo, 12 tumors (66.7%) exhibited radiological tumor growth, while 6 tumors did not change in size. The median annual volumetric growth rate was 2.82 cm3/yr (range -0.34 to 10.1). Extent of resection and immediate postoperative tumor volume were significantly correlated with the annual volumetric growth rate following resection. At last follow-up, 3 (13%) patients required further intervention. Conclusion The majority of petroclival meningiomas exhibit growth following subtotal resection. Extent of resection is strongly associated with risk for disease progression following surgery.

The clinical effect of radiographic contact of glioblastoma (GBM) with neurogenic zones (NZ)-the ventricular-subventricular (VSVZ) and subgranular (SGZ) zones-and the corpus callosum (CC) remains unclear and, in the case of the SGZ, unexplored. We investigated (1) if GBM contact with a NZ correlates with decreased survival; (2) if so, whether this effect is associated with a specific NZ; and (3) if radiographic contact with or invasion of the CC by GBM is associated with decreased survival. We retrospectively identified 207 adult patients who underwent cytoreductive surgery for GBM followed by chemotherapy and/or radiation. Age, preoperative Karnofsky performance status score (KPS), and extent of resection were recorded. Preoperative MRIs were blindly analyzed to calculate tumor volume and assess its contact with VSVZ, SGZ, CC, and cortex. Overall (OS) and progression free (PFS) survivals were calculated and analyzed with multivariate Cox analyses. Among the 207 patients, 111 had GBM contacting VSVZ (VSVZ+GBMs), 23 had SGZ+GBMs, 52 had CC+GBMs, and 164 had cortex+GBMs. VSVZ+, SGZ+, and CC+ GBMs were significantly larger in size relative to their respective non-contacting controls. Multivariate Cox survival analyses revealed GBM contact with the VSVZ, but not SGZ, CC, or cortex, as an independent predictor of lower OS, PFS, and early recurrence. We hypothesize that the VSVZ niche has unique properties that contribute to GBM pathobiology in adults.

Objectives This study characterizes primary petroclival meningioma growth rates, before intervention, using volumetric analysis. In addition, predictors of growth are analyzed. Methods Patients with previously untreated petroclival meningiomas were retrospectively reviewed (1999-2015). Image analysis software was used to perform volumetric analyses of tumor size and growth. Three-dimensional segmentation volumetric analyses were compared with volumes estimated utilizing three orthogonal dimensions. Tumor growth was defined as a 15% increase in volume. Results Thirty-four patients who underwent at least two magnetic resonance imaging (MRI) studies before intervention were included. The mean age was 55.2 years, and 65.7% were women. The mean tumor volume at presentation was 5.6 cm (range, 0.1-25.8 cm) as determined from segmentation volumetric analysis. At a mean follow-up of 44.5 months (range, 3.7-125.1 mo), 88.2% of tumors grew. The mean annual volumetric growth rate was 2.38 cm/yr (-0.63 to 25.9 cm/yr). Tumor volume, T2 hyperintensity within the tumor, peritumoral edema, and ataxia and/or cerebellar symptoms at presentation were all significantly associated with greater rates of tumor growth. Ultimately, 10 (29.4%) patients underwent treatment during the follow-up period. Conclusion Our experience demonstrates that the vast majority (88%) of untreated petroclival meningiomas grow; the mean volumetric growth rate was noted to be 2.38 cm/yr. We found a significant association between increased growth rate and larger tumor size at diagnosis, T2 hyperintensity within the tumor, peritumoral edema, and the presence of ataxia and/or cerebellar symptoms.

Glioblastomas make up more than 60% of adult primary brain tumors and carry a median survival of less than 15 months despite aggressive standard therapy. Immunotherapy, which is now standard of care for many solid tumors, offers an appealing therapeutic approach that may improve outcomes for glioblastoma patients. Predictive features in glioblastomas that may inform responsiveness to different immunotherapeutic modalities, however, are still lacking. Recent studies have demonstrated that patients whose tumors show radiographic contact with the lateral ventricles, and thus the stem cell niche of the ventricular-subventricular zone (V-SVZ), have reduced survival outcomes compared to patients whose tumors do not contact the V-SVZ. We therefore hypothesized that tumor contact with the V-SVZ engenders a unique, immunosuppressive microenvironment that promotes tumor growth by suppressing anti-tumor immunity. Glioblastoma tumors, obtained in accordance with the Declaration of Helsinki and with institutional IRB approval (#131870, #030372, #181970), were disaggregated into single-cell suspensions and multi-dimensional single-cell mass cytometry was performed to interrogate >30 immune parameters in thirteen immune populations infiltrating human glioblastomas. Using advanced computational dimensionality-reduction tools (Citrus, t-SNE, FlowSOM, and MEM), we identified distinctions among the abundance and phenotypes of tumor-infiltrating immune cells. Firstly, on the basis of tumor contact with the V-SVZ, Citrus identified differential abundance of five T and myeloid cell subsets among glioblastomas. Secondly, differential expression of five functional immune markers was observed in seven distinct immune cell subsets infiltrating glioblastoma tumors. Further, both immune abundance and marker expression correlated with patient outcome. Manual gating analysis and parallel computational pipelines confirmed that comparable cell subsets could be identified with traditional approaches and unsupervised algorithmic analysis. These results provide key insights into the immune microenvironment of glioblastomas. In addition, several clinically actionable immunotherapeutic targets were uncovered that may be used to optimize treatment strategies for glioblastomas based on V-SVZ contact status.

In glioblastoma, changes in signaling, gene sequence, copy number, or transcript expression can define patient subgroups, but these subgroups are not yet associated with differential outcome for most patients with high-risk, IDH wild-type disease. Single cell interrogation of phospho-protein signaling has successfully revealed novel cell types associated with patient outcomes in blood cancers, suggesting that a comparable approach could be used in brain tumors. The goal of this study was to combine a single cell phospho-protein profiling approach with novel, automated computational analysis to identify abnormal glioblastoma cells that stratify patient clinical risk. Effective tissue dissociation strategies and validated antibody panels were created for mass cytometry analyses of resected glioblastoma tissue. These panels simultaneously measured 45 determinants of neural and glioma cell identity, including transcription factors, phospho-proteins, and surface receptors. 28 glioblastoma tumors were stained and analyzed using traditional gating, existing computational tools, and a new risk assessment population identification algorithm (RAPID, https://www.biorxiv.org/content/10.1101/632208v3). RAPID revealed two malignant cell types closely associated with differential patient outcomes. Glioblastoma negative prognostic (GNP) cells were associated with poor survival and defined by phospho-protein signaling in cells with aberrant neural developmental phenotypes. Glioblastoma positive prognostic (GPP) cells were associated with better progression free survival and defined by increased immunogenic signaling. A Cox proportional-hazards regression model was created to assess the influence of GNP and GPP cells on OS and PFS as continuous variables while accounting for other well-known clinical predictors. Each 1% increase of GNP cells was associated with an 7% increase in annual mortality rate (HR=1.07 [95% CI 1.03–1.12], p=0.001). Tumors containing GNP cells also significantly lacked CD45+ immune cell infiltration (Pearson r=-0.8). The signaling events that define these clinically significant glioblastoma cells represent a useful molecular classification, may indicate responsiveness to immunotherapy, and are themselves important targets of opportunity for new therapeutic approaches.

Recent developments in machine learning implemented dimensionality reduction and clustering tools to classify the cellular composition of patient-derived tissue in multi-dimensional, single cell studies. Current approaches, however, require prior knowledge of either categorical clinical outcomes or cell type identities. These algorithms are not well suited for application in tumor biology, where clinical outcomes can be continuous and censored and cell identities may be novel and plastic. Risk Assessment Population IDentification (RAPID) is an unsupervised, machine learning algorithm that identifies single cell phenotypes and assesses clinical risk stratification as a continuous variable. Single cell mass cytometry evaluated 34 different phospho-proteins, transcription factors, and cell identity proteins in tumor tissue resected from patients bearingIDHwild-type glioblastomas. RAPID identified and characterized multiple biologically distinct tumor cell subsets that independently and continuously stratified patient outcome. RAPID is broadly applicable for single cell studies where atypical cancer and immune cells may drive disease biology and treatment responses.

In recent years, there has been increased recognition of the relationship between type 2 diabetes mellitus (DM) and poor outcomes following a variety of surgical procedures. We sought to study the role of type 2 DM as a prognostic factor affecting the long-term survival of patients undergoing surgical resection of a WHO Grade I meningioma.We conducted a retrospective cohort study on 196 patients who had a WHO Grade I meningioma resected at our institution between 2001 and 2013. The medical record was reviewed to identify a pre-existing diagnosis of type 2 DM. Patient mortality was reviewed by medical record and Social Security Death Index (SSDI). Variables associated with survival in a univariate analysis were included in the multivariate Cox model if P0.10. Variables with probability values0.05 were then removed from the multivariate model in a step-wise fashion.33 (17%) patients had pre-existing diagnoses of type 2 DM prior to clinical presentation. Mean survival time in diabetic patients was 52.1 months compared to 160.9 months in non-diabetics. The decreased survival rate and time in patients with type 2 DM were found to be statistically significant (p=0.008 and p0.0001, respectively). In a multivariate Cox analysis, a pre-existing history of type 2 DM was independently associated with decreased survival following the resection of a WHO Grade I meningioma (HR=2.6, p=0.045).A pre-existing diagnosis of type 2 DM is an independent negative prognostic indicator following the resection of a WHO Grade I meningioma.

This letter presents a new heuristic 3-D volume coverage path planning (VCPP) algorithm for robotic intracerebral hemorrhage evacuation. In contrast to existing 3-D planning techniques, the proposed algorithm generates 3-D paths without first decomposing the volume into series of 2-D planning problems. It considers the morphology of the volume to be covered and minimizes the configuration or task space distance traveled. The algorithm merges elements from existing grid-based and wavefront approaches and accommodates kinematic and environmental constraints, as well as obstacle avoidance. We provide both simulation and experimental demonstrations of the algorithm in the context of intracerebral hemorrhage evacuation where a curved, needle-like robot must suction out blood from within the brain by covering the interior of a semicoagulated blood-filled volume with its tip. We perform a simulation study with 7 patient datasets and compare the distance traveled with our new algorithm using a conventional 2-D layer-by-layer planning approach. We also perform 3 in vitro evacuation experiments on phantoms made to match patient hemorrhage geometries. Our results illustrate that the VCPP algorithm economizes motion and is more efficient than a layer-by-layer CPP approach.

Patients undergoing transsphenoidal surgery (TSS) have an anterior skull base defect that limits the use of positive pressure ventilation post-operatively. Obstructive sleep apnea (OSA) can be seen in these patients and is treated with continuous positive airway pressure (CPAP). In our study we documented the incidence of pre-existing OSA and reported the incidence of diagnosed pneumocephalus and its relationship to OSA. A retrospective review was conducted from a surgical outcomes database. Electronic medical records were reviewed, with an emphasis on diagnosis of OSA and documented symptomatic pneumocephalus. A total of 324 patients underwent 349 TSS for sellar mass resection. The average body mass index of the study cohort was 32.5kg/m(2). Sixty-nine patients (21%) had documented OSA. Only 25 out of 69 (36%) had a documented post-operative CPAP plan. Out of all 349 procedures, there were two incidents of pneumocephalus diagnosed. Neither of the patients had pre-existing OSA. One in five patients in our study had pre-existing OSA. Most patients returned to CPAP use within several weeks of TSS for resection of a sellar mass. Neither of the patients with pneumocephalus had pre-existing OSA and none of the patients with early re-initiation of CPAP developed this complication. This study provides preliminary evidence that resuming CPAP early in the post-operative period might be less dangerous than previously assumed.

Previous authors have identified a number of factors that predict morbidity, mortality, and recurrence in patients undergoing resection of a meningioma. We sought to study a novel potential prognostic indicator: early postoperative visit to the emergency department (ED). We conducted a retrospective cohort study on 239 patients who underwent a meningioma resection at our institution between 2001 and 2013 with over 3 months of follow-up postoperatively. All postoperative entries in the medical record were reviewed to identify any ED visit with a neurologic or wound-related complaint within a 90 day postoperative period. The relationships between ED presentation, tumor grade, and extent of surgical resection with future risk of operative recurrence and mortality were analyzed using Fisher's exact test. Variables associated with increased risks of mortality or operative recurrence in a univariate analysis were then included in the multivariate logistic regression model. Patients with a postoperative ED visit were found to be significantly more likely to die during the follow-up period (23.0% versus 4.85%, p

Introduction Intracranial foreign bodies have the potential to cause several devastating complications including CSF leak, meningitis, hydrocephalus, nerve or vessel injury, and even death [1,3,5]. These risks must be weighed against the risks associated with potential management options and techniques for removal. With the advent of endonasal anterior skull base techniques, safe and efficient options for surgical retrieval and skull base repair have become available [1,2,4]. Methods In the present report, we present three cases involving metallic foreign bodies penetrating anterior cranial fossa via the sinonasal tract, and the management approaches employed. Results The three cases involved [1] a migrated K-wire from nasal reconstruction in the remote past [2], an acute nail-gun injury, and [3] an impaled car antenna. A combined endoscopic and transcranial approach was performed in the former two cases, while in the latter, an EVD was placed due to elevated ICP after the foreign body had been withdrawn. Conclusion Intracranial metallic foreign bodies may have significant potential morbidity. Recent advances in endonasal techniques for anterior skull base access may enhance outcomes through reduced morbidity and mortality, improved speed and precision, shorter hospital stays, and lower post-operative pain [1,2,4]. Technical nuances of these approaches and medical decision-making in the context of various neurosurgical considerations are discussed.

Glioblastomas make up more than 60% of adult primary brain tumors and carry a 15 month overall survival despite aggressive standard-of-care therapy. Recent advances in immunotherapy offer an appealing alternative that may improve outcomes for patients with glioblastoma; however, clinical trials have proven unsuccessful due in part to a lack of predictive features that may inform responsiveness to immunotherapy. We have recently shown a strong correlation between 1) immune infiltration, 2) tumor cell phenotype, and 3) patient outcome. Further, patients whose tumors demonstrate radiographic contact with the ventricular-subventricular zone (V-SVZ) have reduced survival compared to patients whose tumors do not contact the V-SVZ. We therefore hypothesized that the V-SVZ acts as a previously unappreciated immunosuppressive microenvironment within the brain that promotes tumor growth by suppressing anti-tumor immunity. Primary human glioblastomas were disaggregated into single-cell suspensions and mass cytometry (CyTOF) measured >30 parameters in thirteen immune populations infiltrating human glioblastomas. Cutting-edge machine-learning tools identified key differences in the abundance and phenotypes of T cells, B cells, NK cells, microglia, and peripheral macrophages infiltrating ventricle-contacting gliomas. Further, enriched expression of immune checkpoint receptors (PD-1, TIGIT, LAG-3, TIM3) correlated with ventricular contact and outcome. These results provide key insights into the immune microenvironment of glioblastomas and elucidate several clinically actionable immunotherapeutic targets that may be used to optimize treatment strategies for glioblastoma patients based on V-SVZ contact status.

BACKGROUND: Intracerebral hemorrhage (ICH) is one of the deadliest forms of stroke in the United States. Conventional surgical techniques such as craniotomy or stereotactic aspiration disrupt a large volume of healthy brain tissue in their attempts to reach the surgical site. Consequently, the surviving patients suffer from debilitating complications. METHODS: We fabricated a novel MR-conditional steerable needle robot for ICH treatment. The robot system is powered by a custom-designed high power, low-cost pneumatic motor. We tested the robot targeting accuracy and MR-conditionality performance, and performed phantom evacuation experiment under MR image guidance. RESULTS: Experiments demonstrate the robotic hardware is MR-conditional; The robot has the targeting accuracy of 1.26 00B1 1.22mm in bench-top tests. With real-time MRI guidance, the robot successfully reached the desired target and evacuated an 11.3 ml phantom hematoma in 9 minutes. CONCLUSION: MRI-guided steerable needle robotic system is a potentially feasible approach for ICH treatment by providing accurate needle guidance and intraoperative surgical outcome evaluation.

Objective To determine the factors associated with intra- and postoperative cerebrospinal fluid (CSF) leaks in setting of endoscopic transsphenoidal sellar surgery. Study Design Retrospective cohort. Setting Tertiary referral center. Subjects and Methods This study included 806 patients who underwent endoscopic transsphenoidal sellar surgery between 2004 and 2016. The associations between CSF leaks (intra- and postoperative) and patient demographics, medical history, tumor characteristics, and intraoperative repair techniques were analyzed. Results In sum, 205 (25.4%) patients had a CSF leak: 188 (23.3%) intraoperative leaks and 38 (4.7%) postoperative leaks. Twenty-one (2.6%) patients had postoperative leaks after having repair of an intraoperative leak; 55% of patients with a postoperative leak had an intraoperative leak repaired. On multivariate analysis, body mass index (BMI), hydrocephalus, suprasellar extension, and craniopharyngioma significantly predicted intraoperative CSF leaks, while only BMI and hydrocephalus predicted postoperative CSF leaks. Patients having septal flap repairs of CSF leaks had a higher postoperative leak rate relative to other repair techniques (odds ratio, 6.37; P = .013). Rigid reconstruction did not correlate with leaks. Conclusion For this large cohort of patients undergoing endoscopic transsphenoidal sellar surgery, BMI and hydrocephalus were identified as predictors of postoperative CSF leaks, including those occurring after repair of intraoperative leak. These variables may put stress on the surgical repair of sellar defects, and consideration of these risk factors may help counsel patients and guide perioperative decision making in regard to repair strategies and CSF diversion techniques.

Objectives To evaluate the effectiveness of resorbable mesh cranioplasty at reducing postoperative cerebrospinal fluid (CSF) leak and pseudomeningocele formation after translabyrinthine tumor resection. Study design Case series with chart review. Setting Tertiary academic referral center. Patients Fifty-three consecutive cases using a resorbable mesh cranioplasty after translabyrinthine tumor resection were reviewed. Intervention Temporal bone defects were repaired with a dural substitute, layered fat graft, and a resorbable mesh plate secured with screws. Main outcome measures Primary outcome measures included the incidence of postoperative CSF wound leak or rhinorrhea, pseudomeningocele formation, and surgical site infection. Results Fifty-three cases (average age, 54.0 yr; range, 19.3-75.1 yr) were analyzed. The average body mass index was 30.8 kg/m2 (range, 17.9-48.3 kg/m2), and the average tumor size was 18.8 mm (range, 8-38 mm). One patient (1.9%) experienced CSF rhinorrhea on postoperative Day 16, which resolved after transmastoid middle ear and eustachian tube packing. One patient (1.9%) experienced a surgical site infection requiring surgical debridement and mesh removal 4 months after surgery. Compared with 1,441 prior translabyrinthine surgeries analyzed from our institution using a traditional fat graft closure without mesh, the rate of postoperative CSF leak was significantly less using the resorbable mesh cranioplasty technique (p = 0.0483). Conclusion Resorbable mesh cranioplasty is a safe and effective method to reduce postoperative CSF leak and pseudomeningocele formation after translabyrinthine craniotomy for tumor excision.

Temporal lobe encephaloceles are characterized by protrusion of brain parenchyma through a structural defect in the floor of the middle fossa. They have been reported to cause cerebrospinal fluid (CSF) leaks, conductive hearing loss, meningitis, and seizures. The association between temporal encephaloceles and epileptiform activity is particularly rare.All patients who presented to a single tertiary referral center between 2011 and 2014 with intractable seizures and radiographic evidence of a middle cranial fossa encephalocele were evaluated. Five patients from this subset who underwent surgical repair of their encephalocele are presented.Middle cranial fossa approach for encephalocele repair.Postoperative epileptiform activity.Five patients underwent a craniotomy for resection of a temporal lobe encephalocele with repair of a middle fossa floor defect. After surgery, CSF rhinorrhea resolved, when present, and all patients remained seizure-free through their last available follow-up. Range of follow-up time was 3.5 months to 4 years. Average follow-up time was 19.7 months.Temporal lobe encephaloceles are an infrequent cause of seizures. Given that these lesions can be missed with standard imaging modalities, they are likely underdiagnosed upon initial medical evaluation. This diagnosis should be considered in patients with intractable seizures. If an encephalocele is found, focused resection of epileptogenic tissue associated with herniation and repair of the temporal floor defect can provide definitive treatment.

Petroclival meningiomas are most commonly found in women around 50 years of age and have the general tendency to grow and affect several cranial nerves. At presentation, many patients complain of headaches, gait disturbances and cranial neuropathies. Treatment options include surgery, with a variety of surgical approaches, and or radiotherapy. Current trends support subtotal resection with postoperative radiotherapy. This review summarizes the literature of petroclival meningiomas, discussing topics including definitions, genetics, common presenting signs and symptoms, imaging characteristics, natural history, common surgical approaches, surgical outcomes, complications, and radiotherapy.

Objectives To determine the cost of annual magnetic resonance imaging (MRI) surveillance after resection of nonfunctioning pituitary adenomas (NFPAs) and its effectiveness in reducing visual compromise due to tumor recurrence. Design Retrospective case series. Setting Vanderbilt University Medical Center (2003–2011). Participants A total of 120 patients underwent primary transsphenoidal resection and surveillance of NFPAs between 2003 and 2011. Main Outcome Measures Time from initial surgery to most recent imaging or progression. Surveillance MRI costs according to Centers for Medicare and Medicaid database and visual field deficits. Results Patients received 382 surveillance scans at a total cost of $218,477.30. The median follow-up was 47 months (interquartile range [IQR]: 26–76), and the median interval between scans was 357 days (IQR: 225–434). Overall, 50 scans (13%) revealed tumor growth. The cost per scan revealing growth was $4,369.55. The cost to identify 19 patients (16%) with clinically significant growth was $11,498.80 per patient. A total of 5 of 19 patients (26%) experienced new visual deficits prior to intervention. Patients with visual decline tended to have longer scan intervals than those with preserved vision (mean: 239 versus 794 days; p = 0.0584). No patient with annual surveillance imaging experienced visual decline. Conclusions Annual MRI scans are a sensitive and cost-conscious method to identify NFPA recurrence prior to visual decline.

Objective Machine learning (ML) algorithms are powerful tools for predicting patient outcomes. This study pilots a novel approach to algorithm selection and model creation using prediction of discharge disposition following meningioma resection as a proof of concept. Materials and Methods A diversity of ML algorithms were trained on a single-institution database of meningioma patients to predict discharge disposition. Algorithms were ranked by predictive power and top performers were combined to create an ensemble model. The final ensemble was internally validated on never-before-seen data to demonstrate generalizability. The predictive power of the ensemble was compared with a logistic regression. Further analyses were performed to identify how important variables impact the ensemble. Results Our ensemble model predicted disposition significantly better than a logistic regression (area under the curve of 0.78 and 0.71, respectively, p = 0.01). Tumor size, presentation at the emergency department, body mass index, convexity location, and preoperative motor deficit most strongly influence the model, though the independent impact of individual variables is nuanced. Conclusion Using a novel ML technique, we built a guided ML ensemble model that predicts discharge destination following meningioma resection with greater predictive power than a logistic regression, and that provides greater clinical insight than a univariate analysis. These techniques can be extended to predict many other patient outcomes of interest.

Background: Mass cytometry measures 36 or more markers per cell and is an appealing platform for comprehensive phenotyping of cells in human tissue and tumor biopsies. While tissue disaggregation and fluorescence cytometry protocols were pioneered decades ago, it is not known whether established protocols will be effective for mass cytometry and maintain cancer and stromal cell diversity. Methods: Tissue preparation techniques were systematically compared for gliomas and melanomas, patient derived xenografts of small cell lung cancer, and tonsil tissue as a control. Enzymes assessed included DNase, HyQTase, TrypLE, collagenase (Col) II, Col IV, Col V, and Col XI. Fluorescence and mass cytometry were used to track cell subset abundance following different enzyme combinations and treatment times. Results: Mechanical disaggregation paired with enzymatic dissociation by Col II, Col IV, Col V, or Col XI plus DNase for 1 hour produced the highest yield of viable cells per gram of tissue. Longer dissociation times led to increasing cell death and disproportionate loss of cell subsets. Key markers for establishing cell identity included CD45, CD3, CD4, CD8, CD19, CD64, HLA-DR, CD11c, CD56, CD44, GFAP, S100B, SOX2, nestin, vimentin, cytokeratin, and CD31. Mass and fluorescence cytometry identified comparable frequencies of cancer cell subsets, leukocytes, and endothelial cells in glioma (R = 0.97), and tonsil (R = 0.98). Conclusions: This investigation establishes standard procedures for preparing viable single cell suspensions that preserve the cellular diversity of human tissue microenvironments. This article is protected by copyright. All rights reserved.

Introduction Stereotactic radiosurgery (SRS) is increasingly used as an alternative to whole brain radiotherapy (WBRT) following surgical resection of brain metastases. We analyzed the outcomes of postoperative frameless fractionated stereotactic radiosurgery (fSRS) cases for surgically resected brain metastases at our institution. Materials and Methods We performed a retrospective review of 85 patients who underwent fSRS to 87 resection beds from 2006 - 2014 with a median follow-up of 6.4 months. Clinically relevant outcomes were assessed with analysis to determine predictors of these outcomes. Results The median target volume was 9.8 cm­3 (1.1 - 43.1 cm­3). The most frequently used fractionation scheme was 3,000 cGy in five fractions. The rates of local control (LC), distant brain failure (DBF), and overall survival (OS) at one-year were 87%, 52%, and 52%, respectively. Five patients (5.9%) experienced Grade >2 toxicity related to fSRS, including seizures (two), symptomatic radionecrosis (two), and potential treatment-related death (one). A multivariable analysis revealed that tumor volume (p < 0.001) and number of fractions (p < 0.001) were associated with LC, while recursive partitioning analysis (RPA) class (p < .0001), tumor volume (p = .0181), and the number of fractions (p = .0181) were associated with OS. Conclusions Postoperative fSRS for surgically resected brain metastases is well-tolerated and achieves durable LC. Further studies are needed to determine the optimal dose and fractionation for fSRS as well as to compare outcomes with WBRT.

Intracerebral Hemorrhage (ICH) is the deadliest form of stroke and occurs when blood, leaked from a ruptured vessel pools in the brain forming a pool of semi-coagulated blood called a hematoma. 1 in 50 people will have an ICH in their lifetime [1] and the 30-day mortality rate is 43% with half of the deaths occurring in the acute phase, which motivates the need for safe and rapid treatment. However, literature reviews show no significant benefit of surgical removal vs. “watchful waiting”, despite the potential value of decompressing the brain. It has been hypothesized that this is due to the significant disruption of healthy brain tissue required to reach the hemorrhagic site in open brain surgery. Recent studies conducted on phantom models have shown that a robotic needle made from curved, concentric, elastic tubes can reach a hemorrhagic site through a needle-sized path to successfully aspirate the hematoma. This approach has the potential to decompress the brain with far less disruption to surrounding brain tissue [4]. Those initial experiments were conducted under guidance from periodic (low rate) CT [2]. The need for intraoperative imaging was motivated by the fact that the brain shifts during aspiration, collapsing to fill the cavity left by voided blood. This approach has the potential advantage of “one stop shopping”, since ICH is typically diagnosed in the CT scanner. It is appealing to treat ICH immediately after diagnosis, while the patient is still in the scanner. However, CT also has the drawback of requiring ionizing radiation, as well as providing only intermittent images rather than real-time information. In this paper, we consider a Magnetic Resonance Imaging (MRI) guided approach, which provides the converse in terms of both benefits and drawbacks. MRI is not typically used to diagnose ICH, but it can provide detailed soft-tissue and hematoma contrast [3], and fast image updates, enabling real-time monitoring of brain deformation during the aspiration process. Toward performing ICH aspiration with a concentric tube robot in an MRI environment, this paper presents accuracy and MR-compatibility tests for a new MR-compatible robot designed for ICH removal.

Intracerebral hemorrhages (ICHs) occur in 24 out of 100,000 people annually and have high morbidity and mortality rates. The standard treatment is conservative. We hypothesize that a patient-specific, mechanical model coupled with a robotic steerable needle, used to aspirate a hematoma, would result in a minimally invasive approach to ICH management that will improve outcomes. As a preliminary study, three realizations of a tissue aspiration framework are explored within the context of a biphasic finite element model based on Biot's consolidation theory. Short-term transient effects were neglected in favor of steady state formulation. The Galerkin Method of Weighted Residuals was used to solve coupled partial differential equations using linear basis functions, and assumptions of plane strain and homogeneous isotropic properties. All aspiration models began with the application of aspiration pressure sink(s), calculated pressures and displacements, and the use of von Mises stresses within a tissue failure criterion. With respect to aspiration strategies, one model employs an element-deletion strategy followed by aspiration redeployment on the remaining grid, while the other approaches use principles of superposition on a fixed grid. While the element-deletion approach had some intuitive appeal, without incorporating a dynamic grid strategy, it evolved into a less realistic result. The superposition strategy overcame this, but would require empirical investigations to determine the optimum distribution of aspiration sinks to match material removal. While each modeling framework demonstrated some promise, the superposition method's ease of computation, ability to incorporate the surgical plan, and better similarity to existing empirical observational data, makes it favorable.

Objective The majority of patients with vestibular schwannoma (VS) initially experience audiovestibular dysfunction prompting medical evaluation. Over the past several years, the authors have noticed a significant disparity in clinical presentation among patients with preexisting cognitive impairment compared with the general population. The objective of the current study is to review the clinical presentation of 5 consecutive patients with baseline cognitive delay who were ultimately diagnosed with VS. Design Retrospective review. Setting Two tertiary academic referral centers. Patients Consecutive subjects with baseline cognitive impairment who were evaluated for VS between 2010 and 2013. Main outcome measures Presenting symptoms and tumor characteristics. Results Five adult subjects were identified. The most common reasons for seeking medical care included worsening ataxia and headaches, despite the fact that all patients had profound ipsilateral hearing loss. Additionally, 2 patients endorsed facial numbness, and 2 had partial facial paresis. MRI revealed a median preoperative tumor size of 4.7 cm (4.3-5.7 cm), and all patients had varying degrees of hydrocephalus and peritumoral vasogenic edema. Conclusion Preexisting cognitive impairment is a risk factor for late presentation of VS. Patients with normal cognitive function most commonly seek medical care after unilateral hearing loss and tinnitus. In contrast, individuals with poor cognitive capacity may be unable to acknowledge such symptoms or communicate their presence. In such patients, the diagnosis of VS is elusive, and clinicians should maintain a low threshold for imaging to avoid further delays in diagnosis and treatment.

Object The poor outcome of malignant gliomas is largely due to local invasiveness. Previous studies suggest that gliomas secrete excess glutamate and destroy surrounding normal peritumoral brain by means of excitotoxic mechanisms. In this study the authors assessed the effect on survival of 2 glutamate modulators (riluzole and memantine) in rodent glioma models. Methods In an in vitro growth inhibition assay, F98 and 9L cells were exposed to riluzole and memantine. Mouse cerebellar organotypic cultures were implanted with F98 glioma cells and treated with radiation, radiation + riluzole, or vehicle and assessed for tumor growth. Safety and tolerability of intracranially implanted riluzole and memantine CPP:SA polymers were tested in F344 rats. The efficacy of these drugs was tested against the 9L model and riluzole was further tested with and without radiation therapy (RT). Results In vitro assays showed effective growth inhibition of both drugs on F98 and 9L cell lines. F98 organotypic cultures showed reduced growth of tumors treated with radiation and riluzole in comparison with untreated cultures or cultures treated with radiation or riluzole alone. Three separate efficacy experiments all showed that localized delivery of riluzole or memantine is efficacious against the 9L gliosarcoma tumor in vivo. Systemic riluzole monotherapy was ineffective; however, riluzole given with RT resulted in improved survival. Conclusions Riluzole and memantine can be safely and effectively delivered intracranially via polymer in rat glioma models. Both drugs demonstrate efficacy against the 9L gliosarcoma and F98 glioma in vitro and in vivo. Although systemic riluzole proved ineffective in increasing survival, riluzole acted synergistically with radiation and increased survival compared with RT or riluzole alone.

Object The goals of this study were to report the clinical presentation, radiographic findings, operative strategy, and outcomes among patients with temporal bone encephaloceles and cerebrospinal fluid fistulas (CSFFs) and to identify clinical variables associated with surgical outcome. Methods A retrospective case series including all patients who underwent a middle fossa craniotomy or combined mastoid–middle cranial fossa repair of encephalocele and/or CSFF between 2000 and 2012 was accrued from 2 tertiary academic referral centers. Results Eighty-nine consecutive surgeries (86 patients, 59.3% women) were included. The mean age at time of surgery was 52.3 years, and the left side was affected in 53.9% of cases. The mean delay between symptom onset and diagnosis was 35.4 months, and the most common presenting symptoms were hearing loss (92.1%) and persistent ipsilateral otorrhea (73.0%). Few reported a history of intracranial infection (6.7%) or seizures (2.2%). Thirteen (14.6%) of 89 cases had a history of major head trauma, 23 (25.8%) were associated with chronic ear disease without prior operation, 17 (19.1%) occurred following tympanomastoidectomy, and 1 (1.1%) developed in a patient with a cerebral aqueduct cyst resulting in obstructive hydrocephalus. The remaining 35 cases (39.3%) were considered spontaneous. Among all patients, the mean body mass index (BMI) was 35.3 kg/m2, and 46.4% exhibited empty sella syndrome. Patients with spontaneous lesions were statistically significantly older (p = 0.007) and were more commonly female (p = 0.048) compared with those with nonspontaneous pathology. Additionally, those with spontaneous lesions had a greater BMI than those with nonspontaneous disease (p = 0.102), although this difference did not achieve statistical significance. Thirty-two surgeries (36.0%) involved a middle fossa craniotomy alone, whereas 57 (64.0%) involved a combined mastoid–middle fossa repair. There were 7 recurrences (7.9%); 2 patients with recurrence developed meningitis. The use of artificial titanium mesh was statistically associated with the development of recurrent CSFF (p = 0.004), postoperative wound infection (p = 0.039), and meningitis (p = 0.014). Also notable, 6 of the 7 cases with recurrence had evidence of intracranial hypertension. When the 11 cases that involved using titanium mesh were excluded, 96.2% of patients whose lesions were reconstructed with an autologous multilayer repair had neither recurrent CSFF nor meningitis at the last follow-up. Conclusions Patients with temporal bone encephalocele and CSFF commonly present with persistent otorrhea and conductive hearing loss mimicking chronic middle ear disease, which likely contributes to a delay in diagnosis. There is a high prevalence of obesity among this patient population, which may play a role in the pathogenesis of primary and recurrent disease. A middle fossa craniotomy or a combined mastoid–middle fossa approach incorporating a multilayer autologous tissue technique is a safe and reliable method of repair that may be particularly useful for large or multifocal defects. Defect reconstruction using artificial titanium mesh should generally be avoided given increased risks of recurrence and postoperative meningitis.

New approaches to intracerebral hemorrhage management are motivated by its high incidence and 40% mortality rate. Surgery is sometimes attempted to decompress the brain, although patient outcomes are similar regardless of whether surgery occurs. We hypothesize that surgical decompression is not more effective because current open surgical techniques disrupt healthy brain tissue to access the clot formed by the hemorrhage, offsetting the benefits of surgery. To address this, we propose a less invasive needle-based approach in which the clot is debulked from within using a superelastic, precurved aspiration cannula that is deployed from a needle. The tip of this aspiration cannula is controlled by coordinated insertion and retraction of the cannula and needle, as well as axial rotation of the cannula. We describe the design of a sterilizable and biocompatible robot that can control the three degrees of freedom of the needle and cannula. Image guidance is achieved by adapting an approach originally developed for brain biopsy. We provide an optimization method for the selection of the precurvatures of one or more sequentially used aspiration cannulas to maximize hemorrhage evacuation, based on preoperative medical image data. In vitro experiments demonstrate the feasibility of evacuating 83-92% of hemorrhage volume, depending on the number of tubes and deployment method used.