The Association of Preoperative Frailty and Neighborhood-Level Disadvantage with Outcome in Patients with Newly Diagnosed High Grade Glioma.

OBJECTIVE: Individual patient and socioeconomic factors are underexplored prognostic factors for glioblastoma (GBM). Frailty, a measure of physiological vulnerability, and area deprivation, a measure of socioeconomic status, are easily obtained during the preoperative evaluation. These metrics are predictors of outcome and access to treatments for other cancers. Therefore, we sought to determine the association of frailty and neighborhood disadvantage with outcomes of patients with newly diagnosed GBM. METHODS: This was a retrospective review of newly diagnosed patients with GBM undergoing surgery from 2015 through 2020. The 5-factor modified frailty index and national area deprivation index were determined for each patient. RESULTS: There were 244 patients. Compared with patients with "some or no" frailty, patients with "significant" frailty had a shorter median survival: 273 days (95% confidence interval [CI] 126-339) versus 393 days (95% CI 317-458), P = 0.008. The median survival for patients living in the most disadvantaged neighborhoods, 210 days (95% CI 134-334), was significantly lower than for those living in the least, 384 days (95% CI 239-484), P = 0.17. Twenty-five percent of patients living in the most disadvantaged neighborhoods did not receive postoperative chemoradiation compared with 11% of patients in the least disadvantaged neighborhoods, P = 0.046. Similarly, patients of color were less likely to receive standard of care chemoradiation than White patients. CONCLUSIONS: Increasing frailty and neighborhood disadvantage predict worse outcomes in newly diagnosed patients with GBM undergoing surgery. Patients living in the most-deprived neighborhoods are less likely to receive postoperative chemoradiation. Identification of nontraditional predictors of treatment access and survival will inform mitigation strategies and improve outcomes.

Associations Between Residential Greenspace, Socioeconomic Status, and Stroke: A Matched Case-Control Study.

Purpose: Studies have shown increased residential greenspace is associated with improved outcome following stroke. This study sought to determine if residential greenspace is an independent stroke risk factor. Methods: A retrospective 1:4 matched case-control study involving 1174 stroke and 4696 control patients over a 3-year period from Milwaukee County, Wisconsin, was conducted. Greenspace was determined using normalized difference vegetation index (NDVI) for a 250-meter radius surrounding a subject's residence. The area deprivation index (ADI) for the census block tract of a subject's residence was obtained from the Neighborhood Atlas® (University of Wisconsin School of Medicine and Public Health). Relationship between greenspace, ADI, and stroke was determined using conditional logistic regression. Relationships among NDVI, state and national ADI, and proximity to public parks were determined using Spearman's rank-order correlation. Results: NDVI and stroke risk were inversely correlated (odds ratio [OR]: 0.33, 95% CI: 0.111-0.975; P=0.045), with 19% lowered odds of stroke for patients living in the highest greenspace quartile compared to the lowest quartile (OR: 0.81, 95% CI: 0.672-0.984; P=0.045). Patients living in the most deprived ADI quartile had 28% greater stroke risk than those living in the least deprived ADI quartile (OR: 1.28, 95% CI: 1.02-1.6; P=0.029). Non-Hispanic Black patients lived in residential areas with lower greenspace (P<0.001) and neighborhoods of greater state and national ADI (P<0.001 for both) than non-Hispanic White patients. Conclusions: In Milwaukee County, living with greater surrounding greenspace or areas of lower deprivation is associated with lower odds of stroke. NDVI represents an independent risk factor for stroke, not simply a proxy for socioeconomic status.

Stroke Network of Wisconsin (SNOW) Scale Predicts Large Vessel Occlusion Stroke in the Prehospital Setting.

Purpose: In previous trials, the Stroke Network of Wisconsin (SNOW) scale accurately predicted large vessel occlusion (LVO) stroke in the hospital setting. This study evaluated SNOW scale performance in the prehospital setting and its ability to predict LVO or distal medium vessel occlusion (DMVO) in patients suspected of having acute ischemic stroke (AIS), a scenario in which transport time to an endovascular treatment-capable facility (ECSC) is critical. Methods: All potential AIS patients with last-known-well time of ≤24 hours were assessed by Milwaukee County Emergency Medical Services for LVO using SNOW. Patients with a positive SNOW score were transferred to the nearest ECSC. One such facility, Aurora St. Luke's Medical Center (ASLMC), was the source of all patient data analyzed in this study. LVO was defined as occlusion of the intracranial carotid artery, middle cerebral artery (M1) segment, or basilar artery. Results: From March 2018 to February 2019, 345 AIS-suspected patients were transported to ASLMC; 19 patients were excluded because no vascular imaging was performed. Of 326 patients, 32 had confirmed LVO and 21 DMVO. For identifying LVO, SNOW scale sensitivity was 0.88, specificity 0.40, positive predictive value (PPV) 0.14, negative predictive value (NPV) 0.97, and area under the curve (AUC) 0.64. Ability to predict DMVO was similar. Overall, the SNOW scale showed sensitivity of 0.83, specificity of 0.39, PPV of 0.10, NPV of 0.97, and AUC of 0.60 in identifying candidates for endovascular thrombectomy. Conclusions: In a prehospital setting, the SNOW scale has high sensitivity in identifying candidates for endovascular thrombectomy and proved highly reliable in ruling out stroke due to LVO.

AXL receptor is required for Zika virus strain MR-766 infection in human glioblastoma cell lines.

Recent reports have shown that Zika virus (ZIKV) has oncolytic potential against human glioblastoma (GBM); however, the mechanisms underlying its tropism and cell entry are not completely understood. The receptor tyrosine kinase AXL has been identified as an entry receptor for ZIKV in a cell-type-specific manner. Interestingly, AXL is frequently overexpressed in GBM patients. Using commercially available GBM cell lines, we first show that cells expressing AXL are permissive for ZIKV infection, while cells that do not express AXL are not. Furthermore, inhibition of AXL kinase using R428 and antibody blockade of AXL receptor strongly attenuated virus entry in GBM cell lines. Additionally, CRISPR knockout of the AXL gene in GBM cell lines completely abolished ZIKV infection, significantly inhibited viral replication, and significantly reduced apoptosis compared with parental lines. Lastly, introduction of AXL receptor into non-expressing cell lines renders the cells susceptible to ZIKV infection. Together, these findings demonstrate that ZIKV entry into GBM cells in vitro is mediated by the AXL receptor and that following cell entry, productive infection is cytotoxic. Thus, ZIKV is a potential oncolytic virus for GBM.

COVID-19 and Historic Influenza Vaccinations in the United States: A Comparative Analysis.

The COVID-19 vaccination effort is a monumental global challenge. Recognizing and addressing the causes of vaccine hesitancy will improve vaccine uptake. The primary objective of this study was to compare the COVID-19 vaccination rates in US counties to historical vaccination rates for influenza in persons aged 65 and older. The secondary objective was to identify county-level demographic, socioeconomic, and political factors that influence vaccination rates. County level data were obtained from publicly available databases for comparison and to create predictive models. Overall, in US counties the COVID-19 vaccination rate exceeded influenza vaccination rates amongst those aged 65 or older (69.4.0% vs. 44%, p < 0.0001). 2690 (83.4%) of 3224 counties had vaccinated 50% or more of their 65 and older residents in the first seven months of the COVID-19 vaccination roll out. There were 467 (14.5%) of 3223 counties in which the influenza vaccination rate exceeded the COVID-19 vaccination rate. Most of these counties were in the Southern region, were considered politically "red" and had a significantly higher non-Hispanic Black resident population (14.4% vs. 8.2%, p < 0.0001). Interventions intended to improve uptake should account for nuances in vaccine access, confidence, and consider factual social media messaging, especially in vulnerable counties.

The Role of 3D Tractography in Skull Base Surgery: Technological Advances, Feasibility, and Early Clinical Assessment with Anterior Skull Base Meningiomas.

Objective The aim of this study is to determine feasibility of incorporating three-dimensional (3D) tractography into routine skull base surgery planning and analyze our early clinical experience in a subset of anterior cranial base meningiomas (ACM). Methods Ninety-nine skull base endonasal and transcranial procedures were planned in 94 patients and retrospectively reviewed with a further analysis of the ACM subset. Main Outcome Measures (1) Automated generation of 3D tractography; (2) co-registration 3D tractography with computed tomography (CT), CT angiography (CTA), and magnetic resonance imaging (MRI); and (3) demonstration of real-time manipulation of 3D tractography intraoperatively. ACM subset: (1) pre- and postoperative cranial nerve function, (2) qualitative assessment of white matter tract preservation, and (3) frontal lobe fluid-attenuated inversion recovery (FLAIR) signal abnormality. Results Automated 3D tractography, with MRI, CT, and CTA overlay, was produced in all cases and was available intraoperatively. ACM subset : 8 (44%) procedures were performed via a ventral endoscopic endonasal approach (EEA) corridor and 12 (56%) via a dorsal anteromedial (DAM) transcranial corridor. Four cases (olfactory groove meningiomas) were managed with a combined, staged approach using ventral EEA and dorsal transcranial corridors. Average tumor volume reduction was 90.3 ± 15.0. Average FLAIR signal change was -30.9% ± 58.6. 11/12 (92%) patients (DAM subgroup) demonstrated preservation of, or improvement in, inferior fronto-occipital fasciculus volume. Functional cranial nerve recovery was 89% (all cases). Conclusion It is feasible to incorporate 3D tractography into the skull base surgical armamentarium. The utility of this tool in improving outcomes will require further study.

Race, Ethnicity, Neighborhood Characteristics, and In-Hospital Coronavirus Disease-2019 Mortality.

BACKGROUND: Despite many studies reporting disparities in coronavirus disease-2019 (COVID-19) incidence and outcomes in Black and Hispanic/Latino populations, mechanisms are not fully understood to inform mitigation strategies. OBJECTIVE: The aim was to test whether neighborhood factors beyond individual patient-level factors are associated with in-hospital mortality from COVID-19. We hypothesized that the Area Deprivation Index (ADI), a neighborhood census-block-level composite measure, was associated with COVID-19 mortality independently of race, ethnicity, and other patient factors. RESEARCH DESIGN: Multicenter retrospective cohort study examining COVID-19 in-hospital mortality. SUBJECTS: Inclusion required hospitalization with positive SARS-CoV-2 test or COVID-19 diagnosis at three large Midwestern academic centers. MEASURES: The primary study outcome was COVID-19 in-hospital mortality. Patient-level predictors included age, sex, race, insurance, body mass index, comorbidities, and ventilation. Neighborhoods were examined through the national ADI neighborhood deprivation rank comparing in-hospital mortality across ADI quintiles. Analyses used multivariable logistic regression with fixed site effects. RESULTS: Among 5999 COVID-19 patients median age was 61 (interquartile range: 44-73), 48% were male, 30% Black, and 10.8% died. Among patients who died, 32% lived in the most disadvantaged quintile while 11% lived in the least disadvantaged quintile; 52% of Black, 24% of Hispanic/Latino, and 8.5% of White patients lived in the most disadvantaged neighborhoods.Living in the most disadvantaged neighborhood quintile predicted higher mortality (adjusted odds ratio: 1.74; 95% confidence interval: 1.13-2.67) independent of race. Age, male sex, Medicare coverage, and ventilation also predicted mortality. CONCLUSIONS: Neighborhood disadvantage independently predicted in-hospital COVID-19 mortality. Findings support calls to consider neighborhood measures for vaccine distribution and policies to mitigate disparities.

The Evolution of Cerebral Language Localization: Historical Analysis and Current Trends.

Language localization has been an evolving concept over the past 150 years, with the emergence of several important yet conflicting ideologies. The classical theory, starting from the phrenologic work of Gall to the identification of specific regions of language function by Broca, Wernicke, and others, proposed that discrete subcomponents of language were organized into separate anatomic structural regions. The holism theory was postulated in an attempt to disclose that language function was instead attributed to a larger region of the cortex, in which cerebral regions may have the capability of assuming the function of damaged areas. However, this theory was largely abandoned in favor of discrete structural localizationist viewpoints. The subsequent cortical stimulatory work of Penfield led to the development of maps of localization, assigning an eloquent designation to specific regions. The expanding knowledge of cortical and subcortical anatomy allowed for the development of anatomically and functionally integrative language models. In particular, the dual stream model revisited the concept of regional interconnectivity and expanded the concept of eloquence. Advancements in cortical-subcortical stimulation, neurophysiologic monitoring, magnetic resonance diffusion tensor imaging/functional magnetic resonance imaging, awake neurosurgical technique, and knowledge gained by white matter tract anatomy and the Human Connectome Project, shed new light on the dynamic interconnectivity of the cerebrum. New studies are progressively opening doors to this paradigm, showing the dynamic and interdependent nature of language function. In this review, the evolution of language toward the evolving paradigm of dynamic language function and interconnectivity and its impact on shaping the neurosurgical paradigm are outlined.

White Matter-Governed Superior Frontal Sulcus Surgical Paradigm: A Radioanatomic Microsurgical Study-Part I.

BACKGROUND: Frontal subcortical and intraventricular pathologies are traditionally accessed via transcortical or interhemispheric-transcallosal corridors. OBJECTIVE: To describe the microsurgical subcortical anatomy of the superior frontal sulcus (SFS) corridor. METHODS: Cadaveric dissections were undertaken and correlated with magnetic resonance imaging/diffusion-tensor imaging-Tractography. Surgical cases demonstrated clinical applicability. RESULTS: SFS was divided into the following divisions: proximal, precentral sulcus to coronal suture; middle, 3-cm anterior to coronal suture; and distal, middle division to the orbital crest. Anatomy was organized as layered circumferential rings projecting radially towards the ventricles: (1) outer ring: at the level of the SFS, the following lengths were measured: (A) precentral sulcus to coronal suture = 2.29 cm, (B) frontal bone projection of superior sagittal sinus (SSS) to SFS = 2.37 cm, (C) superior temporal line to SFS = 3.0 cm, and (D) orbital crest to distal part of SFS = 2.32 cm; and (2) inner ring: (a) medial to SFS, U-fibers, frontal aslant tract (FAT), superior longitudinal fasciculus I (SLF-I), and cingulum bundle, (b) lateral to SFS, U-fibers, (SLF-II), claustrocortical fibers (CCF), and inferior fronto-occipital fasciculus, and (c) intervening fibers, FAT, corona radiata, and CCF. The preferred SFS parafascicular entry point (SFSP-EP) also referred to as the Kassam-Monroy entry point (KM-EP) bisects the distance between the midpupillary line and the SSS and has the following coordinates: x = 2.3 cm (lateral to SSS), y ≥ 3.5 cm (anterior to CS), and z = parallel corona radiata and anterior limb of the internal capsule. CONCLUSION: SFS corridor can be divided into lateral, medial, and intervening white matter tract segments. Based on morphometric assessment, the optimal SFSP-EP is y ≥ 3.5 cm, x = 2.3 cm, and z = parallel to corona radiata and anterior limb of the internal capsule.

White Matter Governed Superior Frontal Sulcus Surgical Paradigm: A Radioanatomic Microsurgical Study-Part II.

BACKGROUND: Kocher's point (KP) and its variations have provided standard access to the frontal horn (FH) for over a century. Anatomic understanding of white matter tracts (WMTs) has evolved, now positioning us to better inform the optimal FH trajectory. OBJECTIVE: To (1) undertake a literature review analyzing entry points (EPs) to the FH; (2) introduce a purpose-built WMT-founded superior frontal sulcus parafascicular (SFSP)-EP also referred to as the Kassam-Monroy entry point (KM-EP); and (3) compare KM-EP with KP and variants with respect to WMTs. METHODS: (1) Literature review (PubMed database, 1892-2018): (a) stratification based on the corridor: i. ventricular catheter; ii. through-channel endoscopic; or iii. portal; (b) substratification based on intent: i. preoperatively planned or ii. intraoperative (postdural opening) for urgent ventricular drainage. (2) Anatomic comparisons of KM-EP, KP, and variants via (a) cadaveric dissections and (b) magnetic resonance-diffusion tensor imaging computational 3D modeling. RESULTS: A total of 31 studies met inclusion criteria: (a) 9 utilized KP coordinate (1 cm anterior to the coronal suture (y-axis) and 3 cm lateral of the midline (x-axis) approximated by the midpupillary line) and 22 EPs represented variations. All 31 traversed critical subcortical WMTs, specifically the frontal aslant tract, superior longitudinal fasciculus II, and inferior fronto-occipital fasciculus, whereas KM-EP (x = 2.3, y = 3.5) spares these WMTs. CONCLUSION: KP (x = 3, y = 1) conceived over a century ago, prior to awareness of WMTs, as well as its variants, anatomically place critical WMTs at risk. The KM-EP (x = 2.3, y = 3.5) is purpose built and founded on WMTs, representing anatomically safe access to the FH. Correlative clinical safety, which will be directly proportional to the size of the corridor, is yet to be established in prospective studies.

A Feasibility Study of Lavender Aromatherapy in an Awake Craniotomy Environment.

PURPOSE: Integrative medicine interventions are needed for awake craniotomies, as many patients experience anxiety. Lavender aromatherapy significantly reduces anxiety or pain in a variety of surgical procedures. This feasibility study used lavender aromatherapy during awake craniotomies to determine the number of patients who would consent and complete the study, the technicality of lavender aromatherapy use, and acceptance by operating room (OR) staff. METHODS: We approached 40 consecutive patients (≥18 years old). Exclusion criteria were pulmonary issues or sensitivity to lavender. Outcome measures in consented patients were enrollment and completion rates, anxiety and pain as measured by the Visual Analog Scale for Anxiety (VAS-A) and Visual Analog Scale for Pain (VAS-P), and satisfaction with pain control using the Patient Opinion of Pain Management (POPM) survey. RESULTS: Of the 40 patients approached, 4 declined participation or had their surgery cancelled. Of the remaining 36, 4 required increased sedation during surgery and 1 was unable to detect lavender. Thus, 31 patients (77.5%) completed the study. VAS-A and VAS-P scores trended lower after lavender inhalation, but the difference did not reach statistical significance. There was a slight increase in VAS-P score at the OR1 time point. Expectancy for reduction in both anxiety and pain were not significantly different. Improvement in anxiety also was not different, while improvement in pain trended lower (P=0.025). POPM results indicated the majority of patients were either "satisfied" or "very satisfied" with pain management. CONCLUSIONS: This study demonstrated 77.5% completion and the ability to integrate lavender aromatherapy into the OR. Thus, we plan to conduct a randomized clinical trial to assess efficacy of lavender aromatherapy.

Does the method of visualization impact the performance of a new surgical task in novice subjects?

INTRODUCTION: Evolution of optical technology from two-dimensional to three-dimensional (3D) systems has come with an associated loss of stereoscopy and 3D depth perception. This report compares performance of surgical tasks in unbiased subjects using these systems. METHODS: Untrained subjects were randomized into two groups, robotically operated video optical telescopic-microscope (ROVOT) or surgical microscope (microscope). Subjects sutured and tied knots. Completion time, NASA-Task Load Index (TLX), and galvanic skin responses were analyzed. RESULTS: Intergroup analysis of suture completion time indicated that microscope use was significantly faster compared to ROVOT, whether used first or second. Regardless of which methodology was used first, the second modality was faster, indicating a transfer effect. NASA-TLX indicated that mental, performance, effort, and frustration were all greater with ROVOT. CONCLUSION: Task completion time and perceived effort were greater with ROVOT. Task completion times improved with repetition regardless of visual modality.

Initial Experience with Exoscopic-Based Intraoperative Indocyanine Green Fluorescence Video Angiography in Cerebrovascular Surgery: A Preliminary Case Series Showing Feasibility, Safety, and Next-Generation Handheld Form-Factor.

BACKGROUND: Native vessel patency and residual lesion are primary sources of morbidity in cerebrovascular surgery (CVS) that require real-time visualization to inform surgical judgment, as is available in endovascular procedures. Micro Doppler and microscopy-based indocyanine green (ICG) fluorescence are promising evolutions compared with intraoperative angiography (IA), and digital subtraction angiography (DSA) remains the gold standard. Exoscopic visualization in CVS is emerging; however, the feasibility of exoscopic-based ICG (ICG-E) for CVS has not yet been reported. To objective of the study was to provide initial experience with ICG-E video angiography in CVS. METHODS: Retrospective study in which 2 ICG-E form-factors (exoscopic-coupled or self-contained handheld imager) were used to determine native vessel patency and residual and compared with DSA. RESULTS: Eleven patients (8 aneurysms, 3 arteriovenous malformations [AVMs]) were included. ICG-E was feasible in all, providing real-time information leading to operative decisions affecting surgical judgment. For aneurysms, discordance of IA with ICG-E and DSA was 12%. In 1 patient, IA showed non-flow-restrictive branch stenosis; however, both ICG and DSA showed patency. All AVMs were fully obliterated, with 100% concordance among all modalities. ICG averaged 4.2 mg dose/run (1-4 doses/case); 1.25 mg was the lowest dose allowing visualization with no advantage with escalating dosages. There were no intraoperative/perioperative complications. CONCLUSIONS: In this preliminary study, ICG-E was safe and feasible, providing real-time visualization informing surgical decision making. The last 4 cases (2 aneurysms and 2 AVMs) evolved toward a portable handheld device, a readily accessible real-time modality providing contextual anatomic and flow visualization. Larger studies are needed to assess broader safety, dose escalation, and efficacy.

Clinical outcomes following early versus late pharmacologic thromboprophylaxis in patients with traumatic intracranial hemorrhage: a systematic review and meta-analysis.

Venous thromboembolism (VTE) after traumatic brain injury (TBI) with intracranial hemorrhage (ICH) presents a serious yet manageable morbidity and mortality risk. This systematic review and meta-analysis aimed to pool the current literature to evaluate whether or not pharmacologic thromboprophylaxis (PTP) administered early after traumatic ICH significantly changes incidence of VTE or hemorrhagic progression when compared to late administration. Systematic searches of seven electronic databases from their inception to July 2018 were conducted following the appropriate guidelines. One thousand four hundred ninety articles were identified for screening. Outcomes of interest were pooled as odd ratios (ORs) and analyzed using a random-effects model. Eleven comparative studies satisfied selection criteria, yielding a total of 5036 cases. Overall, mean age was 47.6 years and 36% patients were female. PTP was administered early (≤ 72 h from admission) in 2106 (42%) patients and late (> 72 h from admission) in 2922 (58%) cases. There was no statistically significant difference in the incidence of hemorrhagic progression (OR, 0.86; P = 0.450) or all-cause mortality (OR, 0.83; P = 0.347) between the early versus late PTP patient groups. However, incidence of VTE was significantly less in the early PTP patient group (OR, 0.58; P = 0.008). The early administration of PTP after traumatic ICH does not appear to confer a worse prognosis in terms of hemorrhagic progression. However, it seems to confer superior VTE prophylaxis, when compared to late PTP administration. We suggest that early PTP should not be prematurely discounted for patients with ICH in TBI on the assumption of aggravating hemorrhagic progression alone.

An Anatomically-Based Endoscopic Endonasal Model to Navigate the Anterior Ventral Skull Base.

BACKGROUND: Endoscopic endonasal approaches to access the sellar and parasellar regions are challenging in the face of anatomical variations or pathologic conditions. We propose an anatomically-based model including the orbitosellar line (OSL), critical oblique foramen line (COFL), and paramedial anterior line (PAL) facilitating safe, superficial-to-deep dissection triangulating upon the medial opticocarotid recess. METHODS: Five cadaveric heads were dissected to systematically expose the OSL, COFL, and PAL, illustrated with image guidance. Application of the coordinate system and a 6-step dissection sequence is described. RESULTS: The coordinate system consists of 1) the OSL, connecting a) the anterior orbital point, junction of the anterior buttress of the middle turbinate with the agger nasi region, located 34.3 ± 0.9 mm above the intersection of the vertical plane of the lacrimal crest, and the orthogonal plane of the maxillo-ethmoidal suture; b) the posterior orbital point, junction of the optic canal with the lamina papyracea, located 4 ± 0.7 mm below the posterior ethmoidal artery; and c) the medial opticocarotid recess; 2) COFL (15 ± 2.8 mm), connecting the palatovaginal canal, vidian canal, and foramen rotundum; and 3) PAL (39 ± 0.06 mm), connecting the vidian canal with the posterior ethmoidal artery. CONCLUSIONS: OSL, COFL, and PAL form an anatomically-based model for the systematic exposure when accessing the parasellar and sellar regions. Preliminary anatomical data suggest that this model may be of value when normal anatomy is distorted by pathology or anatomic variations.

WEE1 inhibitor, AZD1775, overcomes trastuzumab resistance by targeting cancer stem-like properties in HER2-positive breast cancer.

Although trastuzumab has greatly improved the outcome of HER2-positive breast cancer, the emergence of resistance hampers its clinical benefits. Trastuzumab resistance is a multi-factorial consequence predominantly due to presence of cancer stem-like cells (CSCs). AZD1775, a potent anti-cancer agent targeting WEE1 kinase to drive tumor cells with DNA damage to premature mitosis, has previously shown high efficacies when targeting different cancers with a well-tolerated cytotoxic profile, but has not been evaluated in trastuzumab-resistant (TrR) breast cancer. We sought to investigate the effect of AZD1775 on cancer stem-like cell (CSC) properties, apoptosis, cell cycle regulation in TrR breast cancer. Our study for the first time demonstrated that AZD1775 induces apoptosis and arrests TrR cells at G2/M phase. More importantly, AZD1775 effectively targeted CSC properties by suppressing MUC1 expression levels. AZD1775 administration also induced apoptosis in our in-house patient-derived tumor cell line at passage 0, implying its significant clinical relevance. These findings highlight the potential clinical application of AZD1775 in overcoming trastuzumab resistance in breast cancer.

Awake Surgical Management of Third Ventricular Tumors: A Preliminary Safety, Feasibility, and Clinical Applications Study.

BACKGROUND: Endoscopic and microneurosurgical approaches to third ventricular lesions are commonly performed under general anesthesia. OBJECTIVE: To report our initial experience with awake transsulcal parafascicular corridor surgery (TPCS) of the third ventricle and its safety, feasibility, and limitations. METHODS: A total of 12 cases are reviewed: 6 colloid cysts, 2 central neurocytomas, 1 papillary craniopharyngioma, 1 basal ganglia glioblastoma, 1 thalamic glioblastoma, and 1 ependymal cyst. Lesions were approached using TPCS through the superior frontal sulcus. Pre-, intra-, and postoperative neurocognitive (NC) testing were performed on all patients. RESULTS: No cases required conversion to general anesthesia. Awake anesthesia changed intraoperative management in 4/12 cases with intraoperative cognitive changes that required port re-positioning; 3/4 recovered. Average length of stay (LOS) was 6.1 d ± 6.6. Excluding 3 outliers who had preoperative NC impairment, the average LOS was 2.5 d ± 1.2. Average operative time was 3.00 h ± 0.44. Average awake anesthesia time was 5.05 h ± 0.54. There were no mortalities. CONCLUSION: This report demonstrated the feasibility and safety of awake third ventricular surgery, and was not limited by pathology, size, or vascularity. The most significant factor impacting LOS was preoperative NC deficit. The most significant risk factor predicting a permanent NC deficit was preoperative 2/3 domain impairment combined with radiologic evidence of invasion of limbic structures - defined as a "NC resilience/reserve" in our surgical algorithm. Larger efficacy studies will be required to demonstrate the validity of the algorithm and impact on long-term cognitive outcomes, as well as generalizability of awake TPCS for third ventricular surgery.

Concurrent versus non-concurrent immune checkpoint inhibition with stereotactic radiosurgery for metastatic brain disease: a systematic review and meta-analysis.

BACKGROUND: Immune checkpoint inhibition (ICI) is an emerging immunotherapy for metastatic brain disease (MBD). Current management options include stereotactic radiosurgery (SRS), which has been shown to confer prognostic benefit in combination with ICI. However, the effect, if any, of ICI timing on this benefit is currently unclear. The aim of this study was to evaluate the effect of concurrent ICI with SRS on survival outcomes in MBD compared to non-concurrent ICI administered before or after SRS. METHODS: Searches of 7 electronic databases from inception to April 2018 were conducted following the appropriate guidelines. 1210 articles were identified for screening. Kaplan Meier estimation of 12-month overall survival (OS), local progression free survival (LPFS) and distant progression free survival (DPFS) were pooled as odd ratios (ORs) and analyzed using the random effects model. RESULTS: A total of 8 retrospective observational cohort studies satisfied selection criteria. Compared to non-concurrent ICI, concurrent ICI with SRS conferred a significant 12-month OS benefit (OR = 1.74; p = 0.011), and comparable 12-month LPFS (OR = 2.09; p = 0.154) and DPFS (OR = 0.88; p = 0.839). These significances were reflected in the subgroup of melanoma metastases. CONCLUSION: Based on the trends of our findings, there appears to exist an optimal time window around SRS of which ICI may confer the most survival benefit. However, current literature is limited by a number of clinical parameters requiring further delineation which limits the certainty of these findings. Larger, prospective, and randomized studies will assist in identifying the time period for which ICI can provide the best outcome in MBD managed with SRS.

Thrombolysis After Protamine Reversal of Heparin for Acute Ischemic Stroke After Cardiac Catheterization: Case Report and Literature Review.

BACKGROUND: Patients with an acute ischemic stroke (AIS) following cardiac catheterization (CC) generally do not receive intravenous thrombolysis [intravenous tissue plasminogen activator (IV-tPA)] as it is contraindicated due to the coagulopathy related to the heparin used during the procedure. We report a case of AIS successfully treated with IV thrombolysis following protamine reversal of heparin effect. CASE REPORT: An 87-year-old man with diabetes mellitus, hypertension, neurofibromatosis, and hyperlipidemia underwent elective transradial CC following an abnormal stress test. He had 2 drug-eluting stents for severe stenosis of mid-circumflex and right coronary arteries and received heparin 13,000 IU during procedure. He developed acute left hemiparesis with initial NIH stroke scale (NIHSS) of 4. Computed tomographic scan of the brain and computed tomographic angiogram of head and neck were unremarkable. Bedside activated clotting time was 181. Protamine 40 mg was administered and 30 minutes later, the activated clotting time level was normalized. IV-tPA was administered at 4 hours 25 minutes from his last known well. Within 15 minutes, his NIHSS was 0. Magnetic resonance imaging of brain showed no acute infarction 24 hours after stroke. CONCLUSIONS: There are limited reports of protamine reversal of heparin before IV-tPA administration. To our knowledge, there are only 6 AIS cases including ours. Three cases received 0.6 mg/kg of tPA dose. All have favorable outcomes and no intracranial hemorrhage was reported. Protamine reversal of heparin for AIS after CC seems to be safe. Further studies are needed to confirm the therapeutic safety and efficacy of this strategy.

Olfactory groove and tuberculum sellae meningioma resection by endoscopic endonasal approach versus transcranial approach: A systematic review and meta-analysis of comparative studies.

Intracranial meningiomas such as olfactory groove meningioma (OGM) and tuberculum sellae meningioma (TSM) arising at the anterior skull base are amenable to surgical resection. Traditionally, this has been achieved by transcranial approaches (TCAs), however, there has been an evolution in an endoscopic endonasal approach (EEA) within recent years. The aim of this systematic review and meta-analysis was to determine if the EEA was superior to the TCA in managing these anterior skull base meningioma based on comparative studies only, and highlight the limitations of the current literature. Searches of seven electronic databases from inception to April 2018 were conducted following Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. There were 1479 articles identified for screening. Data were extracted and analyzed using meta-analysis of proportions. A total of 10 comparative studies satisfied criteria for inclusions. Resection by the EEA resulted in significantly less likelihood of worse vision (OR, 0.318; p = 0.039) when compared to TCA in OGM. However, EEA resulted also in significantly greater likelihoods of olfactory loss in OGM (OR, 4.511; p = 0.038) and TSM (OR, 3.075; p = 0.017), and CSF leak (OR, 3.854; p = 0.013) in TSM. In terms of surgical and prognosis outcomes, there was no statistically significant trend in favor of either approach in OGM or TSM. The EEA appears to confer a different postoperative complication profile when compared to the TCA in resecting OGM vs TSM which validates previous case-series comparisons. There is a need for longer-term studies that are larger, prospective, randomized in order to fully elucidate efficacy given slow tendency for progression of meningioma in order to develop a more rigorous approach selection algorithm.