Evaluating soluble Axl as a biomarker for glioblastoma: A pilot study.

With current imaging, discriminating tumor progression from treatment effect following immunotherapy or oncolytic virotherapy of glioblastoma (GBM) is challenging. A blood based diagnostic biomarker would therefore be helpful. Axl is a receptor tyrosine kinase that is highly expressed by many cancers including GBM. Axl expression is regulated through enzymatic cleavage of its extracellular domain. The resulting fragment can be detected in serum as soluble Axl (sAxl). sAxl levels can distinguish patients with melanoma, hepatocellular carcinoma, and pancreatic ductal adenocarcinoma from healthy controls. This is a pilot study to determine if sAxl is a candidate biomarker for GBM. The sAxl levels in the serum of 40 healthy volunteers and 20 GBM patients were determined using an enzyme-linked immunosorbent assay (ELISA). Pre- and post- operative sAxl levels were obtained. Volumetric MRI evaluation provided GBM tumor volume metrics. There was no significant difference in the sAxl levels of the volunteers (30.16±1.88 ng/ml) and GBM patients (30.74±1.96 ng/ml) p = 0.27. The postoperative sAxl levels were significantly higher than preoperative levels (32.32±2.26 ng/ml vs 30.74±1.96 ng/ml, p = 0.03). We found no correlation between tumor volume and sAxl levels. Axl expression was low or absent in 6 of 11 (55%) patient derived GBM cell lines. Given the wide range of Axl expression by GBM tumors, sAxl may not be a reliable indicator of GBM. However, given the small sample size in this study, a larger study may be considered.

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.

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.

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.

Minimally invasive trans-sulcal parafascicular surgical resection of cerebral tumors: translating anatomy to early clinical experience.

The minimally invasive port-based trans-sulcal parafascicular surgical corridor (TPSC) has incrementally evolved to provide a safe, feasible, and effective alternative to access subcortical and intraventricular pathologies. A detailed anatomical foundation is important in mitigating cortical and white matter tract injury with this corridor. Thus, the aims of this study are (1) to provide a detailed anatomical construct and overview of TPSCs and (2) to translate an anatomical framework to early clinical experience. Based on regional anatomical constraints, suitable parafascicular entry points were identified and described. Fiber tracts at both minimal and increased risks for each corridor were analyzed. TPSC-managed cases for metastatic or primary brain tumors were retrospectively reviewed. Adult patients 18 years or older with Karnofsky Performance Status (KPS) ≥ 70 were included. Subcortical brain metastases between 2 and 6 cm or primary brain tumors between 2 and 5 cm were included. Patient-specific corridors and trajectories were determined using MRI-tractography. Anatomy: The following TPSCs were described and translated to clinical practice: superior frontal, inferior frontal, inferior temporal, intraparietal, and postcentral sulci. Clinical: Eleven patients (5 males, 6 females) were included (mean age = 52 years). Seven tumors were metastatic, and 4 were primary. Gross total, near total, and subtotal resection was achieved in 7, 3, and 1 patient(s), respectively. Three patients developed intraoperative complications; all recovered from their intraoperative deficits and returned to baseline in 30 days. A detailed TPSC anatomical framework is critical in conducting safe and effective port-based surgical access. This review may represent one of the few early translational TPSC studies bridging anatomical data to clinical subcortical and intraventricular surgical practice.

Epidemiology of male breast cancer.

BACKGROUND: Due to its rarity, few studies have characterized the epidemiology of male breast cancer. The purpose of this study was to determine survival and risk factors for male breast cancer in a large U.S. METHODS: In this study, 19,795 male patients with breast cancer were identified from the National Cancer Database (2004-2014). Patient demographics, tumor characteristics and treatments were analyzed by using descriptive statistics. We used multivariate Cox regression and Kaplan Meier analysis. RESULTS: Over 10 years, the incidence of male breast cancer increased from 7.2% to 10.3%, while mortality decreased from 11% to 3.8%. Socioeconomic factors predicting mortality included income medium, and high vs low (HR = 0.78; 0.68), private vs no insurance (HR = 0.73) and the academic research facility vs community cancer center (HR = 0.79). Significant predictors of all-cause mortality included age (HR = 1.04), tumor size (HR = 1.01), hormone receptor expression (HR = 0.8) and cancer stage I vs II, III, and IV at the time of diagnosis (HR = 1.5, 2.7, 4.4, 9.9 respectively). Other predictors of mortality include surgery (HR = 0.4), chemotherapy (HR = 0.8), radiation (HR = 0.8), and hormonal therapy (HR-0.8). CONCLUSIONS: Socioeconomic factors, cancer stage, tumor characteristics (size and grade), and high Charlson-Dayo score contributed to higher mortality among male patients diagnosed with breast cancer. Surgery was most effective, followed by radiation, chemotherapy, and hormonal therapy. Patients with positive ER or PR expression demonstrated better survival. Adjusting for socioeconomic factors, biomarker identification and timely, appropriately chosen treatment are likely to reduce the risk for mortality.

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.

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.

Microsurgical Anatomy of the Vertical Rami of the Superior Longitudinal Fasciculus: An Intraparietal Sulcus Dissection Study.

BACKGROUND: A number of vertical prolongations of the superior longitudinal fasciculus, which we refer to as the vertical rami (Vr), arise at the level of the supramarginal gyrus, directed vertically toward the parietal lobe. OBJECTIVE: To provide the first published complete description of the white matter tracts (WMT) of the Vr, their relationship to the intraparietal and parieto-occipital sulci (IPS-POS complex), and their importance in neurosurgical approaches to the parietal lobe. METHODS: Subcortical dissections of the Vr and WMT of the IPS were performed. Findings were correlated with a virtual dissection using high-resolution diffusion tensor imaging (DTI) tractography data derived from the Human Connectome Project. Example planning of a transparietal, transsulcal operative corridor is demonstrated using an integrated neuronavigation and optical platform. RESULTS: The Vr were shown to contain component fibers of the superior longitudinal fasciculus (SLF)-II and SLF-III, with contributions from the middle longitudinal fasciculus merging into the medial bank of the IPS. The anatomic findings correlated well with DTI tractography. The line extending from the lateral extent of the POS to the IPS marks an ideal sulcal entry point that we have termed the IPS-POS Kassam-Monroy (KM) Point, which can be used to permit a safe parafascicular surgical trajectory to the trigone. CONCLUSION: The Vr are a newly conceptualized group of tracts merging along the banks of the IPS, mediating connectivity between the parietal lobe and dorsal stream/SLF. We suggest a refined surgical trajectory to the ventricular atrium utilizing the posterior third of the IPS, at or posterior to the IPS-POS Point, in order to mitigate risk to the Vr and its considerable potential for postsurgical morbidity.

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.

MGMT inhibition in ER positive breast cancer leads to CDC2, TOP2A, AURKB, CDC20, KIF20A, Cyclin A2, Cyclin B2, Cyclin D1, ERα and Survivin inhibition and enhances response to temozolomide.

The DNA damage repair enzyme, O6-methylguanine DNA methyltransferase (MGMT) is overexpressed in breast cancer, correlating directly with estrogen receptor (ER) expression and function. In ER negative breast cancer the MGMT promoter is frequently methylated. In ER positive breast cancer MGMT is upregulated and modulates ER function. Here, we evaluate MGMT's role in control of other clinically relevant targets involved in cell cycle regulation during breast cancer oncogenesis. We show that O6-benzylguanine (BG), an MGMT inhibitor decreases CDC2, CDC20, TOP2A, AURKB, KIF20A, cyclin B2, A2, D1, ERα and survivin and induces c-PARP and p21 and sensitizes ER positive breast cancer to temozolomide (TMZ). Further, siRNA inhibition of MGMT inhibits CDC2, TOP2A, AURKB, KIF20A, Cyclin B2, A2 and survivin and induces p21. Combination of BG+TMZ decreases CDC2, CDC20, TOP2A, AURKB, KIF20A, Cyclin A2, B2, D1, ERα and survivin. Temozolomide alone inhibits MGMT expression in a dose and time dependent manner and increases p21 and cytochrome c. Temozolomide inhibits transcription of TOP2A, AURKB, KIF20A and does not have any effect on CDC2 and CDC20 and induces p21. BG+/-TMZ inhibits breast cancer growth. In our orthotopic ER positive breast cancer xenografts, BG+/-TMZ decreases ki-67, CDC2, CDC20, TOP2A, AURKB and induces p21 expression. In the same model, BG+TMZ combination inhibits breast tumor growth in vivo compared to single agent (TMZ or BG) or control. Our results show that MGMT inhibition is relevant for inhibition of multiple downstream targets involved in tumorigenesis. We also show that MGMT inhibition increases ER positive breast cancer sensitivity to alkylator based chemotherapy.

The Survival Effect of Repeat Surgery at Glioblastoma Recurrence and its Trend: A Systematic Review and Meta-Analysis.

BACKGROUND: Glioblastoma (GBM) is a dismal disease managed in the first instance by surgical resection, temozolomide, and radiation. The role of repeat surgery at recurrence remains ill defined. This study aims to quantify the effect of repeat surgery in recurrent GBM on overall survival and determine if a trend in reported effect over time exists. METHODS: Searches of 7 electronic databases from inception to January 2018 were conducted following PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines. There were 2692 articles identified for screening. Prognostic hazard ratios (HRs) derived from multivariate regression analysis were extracted and analyzed using meta-analysis of proportions and linear regression. RESULTS: Eight observational studies reporting prognostic HRs in 10 cohorts were included. They described 1906 recurrent GBM diagnoses, managed by surgery at primary diagnosis, with 709 (37%) undergoing further repeat surgery at recurrence. Repeat surgery was shown to confer a statistically significant survival advantage compared with no surgery at recurrence in the pooled cohort (HR, 0.722; P < 0.001). Newer studies trended toward a more superior prognostic advantage of repeat surgery compared with earlier studies (effect coefficient, 0.856; P = 0.012). CONCLUSIONS: This meta-analysis of contemporary literature suggests that repeat surgery at GBM recurrence in select patients confers a significant, prognostic overall survival advantage independent of other prognostic factors. Furthermore, newer studies are significantly more likely to suggest greater benefit than are older studies. The main limitation is the selection bias inherent in the cohorts pooled for analysis. Larger prospective randomized controlled studies are needed to validate the findings of this study and provide stratification for such benefit justified by quality of life metrics.

Comparison of operative outcomes of eloquent glioma resection performed under awake versus general anesthesia: A systematic review and meta-analysis.

Surgical resection of eloquent glioma can be achieved under general anesthesia (GA) or awake anesthesia (AA). The appeal of AA is that it facilitates intraoperative identification and avoidance of eloquent areas, which has the potential to minimize functional compromise. The aim of this meta-analysis was to compare the operative outcomes of eloquent glioma resection performed under GA compared to AA to assist in optimizing the decision algorithm between the two approaches. Searches of seven electronic databases from inception to December 2017 were conducted following Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. There were 1037 articles identified for screening. Data were extracted and analyzed using meta-analysis of proportions. A total of 9 comparative studies were included for analysis. Resection of glioma involving eloquent areas achieved under AA is mostly comparable in terms of operative and functional outcomes to that of GA. AA did demonstrate significantly lower incidence of postoperative nausea and vomiting (PONV, OR, 0.17; p < 0.001) and shorter length of stay (LOS, MD, -1.76 days; p = 0.02) when compared to GA. Future studies that are larger, prospective, randomized, and include long term quality of life metrics will assist in elucidating the true clinical benefit of AA in resecting glioma involving eloquent areas. This will assist in further developing management protocol of these glioma.

Reanalyzing the "far medial" (transcondylar-transtubercular) approach based on three anatomical vectors: the ventral posterolateral corridor.

Endoscopic endonasal access to the jugular foramen and occipital condyle - the transcondylar-transtubercular approach - is anatomically complex and requires detailed knowledge of the relative position of critical neurovascular structures, in order to avoid inadvertent injury and resultant complications. However, access to this region can be confusing as the orientation and relationships of osseous, vascular, and neural structures are very much different from traditional dorsal approaches. This review aims at providing an organizational construct for a more understandable framework in accessing the transcondylar-transtubercular window. The region can be conceptualized using a three-vector coordinate system: vector 1 represents a dorsal or ventral corridor, vector 2 represents the outer and inner circumferential anatomical limits; in an "onion-skin" fashion, key osseous, vascular, and neural landmarks are organized based on a 360-degree skull base model, and vector 3 represents the final core or target of the surgical corridor. The creation of an organized "global-positioning system" may better guide the surgeon in accessing the far-medial transcondylar-transtubercular region, and related pathologies, and help understand the surgical limits to the occipital condyle and jugular foramen - the ventral posterolateral corridor - via the endoscopic endonasal approach.