Quiñones‐Hinojosa, Alfredo

Abstract OBJECTIVE Our goal is to identify new pathways perturbed in and which may lead to GRS. METHODS We collected brain transcriptome levels from healthy controls (n=5), patients with GRS (n=9), glioma without seizures (non-GRS, n=8), and idiopathic temporal lobe epilepsy (iTLE, n=7) using Illumina-based poly-A capture high-throughput RNA sequencing approach. Differential gene expression analysis was conducted to ascertain expression differences between the four groups. We identified molecular pathways enriched for differentially expressed genes (DEG) using Ingenuity Pathway Analysis. DEGs were defined as those with log2 fold change ≥ 2 and q-value < 0.01 when compared to GRS. RESULTS Principal component analysis revealed that diagnostic grouping was the main determinant of the transcriptome variance. We identified 212 DEGs in the GRS vs. non-GRS analysis. Among these, 108 genes were up-regulated and 104 genes were down-regulated. Among the genes that were down‐regulated, there was significant enrichment for those involved in acute phase response signaling and immune cell trafficking (e.g. H19, BMP5, CXCL8). Compared to iTLE samples, there were 1015 DEGs in the GRS samples. Among these 877 genes were up-regulated and 138 genes were down-regulated. There was significant enrichment for genes involved in cell-to-cell signaling among those that were either uniquely up‐regulated (e.g. NRK, RGS10, SLC4A4, and SELPLG) or down‐regulated in the GRS samples (e.g. SLC9A3 –Na+/H+ exchanger; SLC5A5-sodium-glucose co-transporter family). Further, two of the most down-regulated genes in samples with GRS, SCLC17A6- vesicular glutamate transporter 2 and FOSB, have previously been shown to be involved in glutamatergic transmission. CONCLUSIONS Our findings suggest that inflammation-related processes and alterations in cell-to cell signaling may underlie the pathogenesis of GRS. Our results also provide support for perturbations in glutamatergic transmission in GRS. Our findings require replication in larger human cohorts and functional experiments to explore the function of the genes perturbed in GRS.

Bioreducible nanoparticles were engineered for safe and effective systemic siRNA delivery, including crossing the blood–brain barrier to achieve in vivo gene silencing in an orthotopic glioblastoma mouse model.

Abstract PURPOSE: Preoperative stereotactic radiosurgery (SRS) for symptomatic brain metastases has arisen as a therapeutic option for patients with brain lesions, potentially reducing radionecrosis risk, leptomeningeal disease risk, as well as delays in systemic therapy after craniotomy. The purpose of our work is to analyze the current evidence regarding 1-year local control (LC) and RN rates in the preoperative and postoperative settings. METHODS AND MATERIALS: Population, Intervention, Control, Outcomes, Study Design/Preferred Reporting Items for Systematic Reviews and Meta-analyses and Meta-analysis of Observational Studies in Epidemiology guidelines were used to select articles in which patients had “large” brain metastases (&gt;4 cm3 or &gt;2 cm in diameter) solely treated with preoperative or postoperative SRS and 1-year LC and/or rates of RN reported. Radiosurgery was stratified by timing: preoperatively or postoperatively. Random effects meta-analyses using timing of SRS relative to surgery as covariates were conducted. Meta-regression and Wald-type tests were used to determine the effect of increasing tumor size on the summary estimate, where the null hypothesis was rejected for p &lt; 0.05. RESULTS: Fifteen studies were included (of 314 screened), published between 2012 and 2018 with 854 brain metastases. Preoperative SRS was delivered in 229 lesions. The 1-year LC random effects estimate was 79.1% (95% confidence interval [CI]: 55.9–95.0%; I 2 = 80%) for preoperative SRS and 80.5% (95% CI: 66.3–91.5%; I 2 = 93%) for postoperative SRS (p=0.9). Radionecrosis incidence random effects estimate was 2.1% (95% CI: 0.1–8.6%; I 2 = 36%) for preoperative SRS and 6.3% (95% CI: 1.1–15.4%; I 2 = 90%) for postoperative SRS (p=0.52). CONCLUSIONS: Rates of 1-year LC and RN incidence are similar after preoperative SRS as compared to postoperative SRS for large brain metastases. Results from ongoing prospective clinical trials studying preoperative SRS are important to further investigate these two techniques.

Abstract Around fifteen to thirty percent of stage IV breast cancer metastasizes to the brain, severely decreasing the quality of life of these patients by causing neurological decline and eventually death. In metastatic cancers there is a small subset of cells in the primary tumor bulk called Metastatic Tumor Initiating Cells (MTICs) which are able to escape and produce a niche establishment at distal sites where they can quickly become resistant to surgery and radiation. Melatonin has shown an inhibitory role in the viability and invasiveness of breast cancer and in modulating the expression of proteins related to Breast Cancer Stem Cells (BCSCs). These findings suggest its potential anti-metastatic role in different breast cancer cell lines. In this study we aimed to evaluate the effects of melatonin treatment in vitro for breast cancer brain metastasis. The cell line MDA-BT was originally obtained from MDA-MB-231, passed through the rat’s heart and then isolated once engrafted as a tumor in the brain. After a dose response assay, cells were treated with melatonin at doses of 1500 and 3000 µM for 48hrs. Clonogenic assay, MTT, as well as a stem cell signature through RT-qPCR, including CD44, CD24 and ALDH1 markers, were performed to evaluate the malignancy of the MTICs. The results showed that melatonin at high doses impacts morphology, declines viability, reduces colony formation ability, and decreases stemness in MDA-BT cells. Therefore, our findings highlight melatonin as a relevant therapeutic candidate to target breast cancer brain metastases.

Abstract Patients with primary cancers often develop delayed brain metastases. One of the most common cancer types and sources of brain metastasis is lung cancer. For metastasis from lung cancer the 3-year survival is &lt; 5%. Cancer cells in circulation are responsible for metastatic spread. The mechanical microenvironment plays an important role in cancer cells behavior. When cancer cells reach the bloodstream they are exposed to hemodynamic shear stress. It has been shown that most of the circulating tumor cells die once they reach the bloodstream, but the biology of the survival cells is poorly understood. We designed a microfluidics system that simulated the mechanical stress in the human circulating system such as turbulence, change in pressure (0.4-15dyn/cm2) and flow rate (1.06–106.1mm/s). Lung adenocarcinoma cells (A549) were put into circulation and collected after 72 hours. It was found that, 1.4±0.3% of the cells survived, and viability was evaluated by LDH and calcein. CD133, SOX2, and NANOG were downregulated and EMT genes were upregulated in the circulating cancer cells (CCCs) compared with cells in static-suspension or 2D. After re-seeding in 2D, CCCs overexpressed CD133. Female athymic nude rats (6-8weeks,n=16) received intracardiac injections of CCCs or 2D cells (GFP-LUC lentivirus traduced). Bioluminescence imaging was performed every week; the survival in of the CCCs group was lower than the 2D group. One-way ANOVA test was used to analyze survival and gene expression. Survival data was plotted on a Kaplan-Meier curve and compared using the Mantel-Cox logrank test, p=&lt; 0.05. We have isolated a cellular subpopulation of lung adenocarcinoma with high resistance to hemodynamic shear stress that shows a higher metastatic capacity and genetic plasticity compared with cells growing in suspension or 2D. Targeting these cells would potentially allow us to develop personalized treatments to help to stop metastatic spread and improve actual therapeutical strategies.

Abstract Purpose: In glioma surgery, it is critical to maximize tumor resection without compromising adjacent noncancerous brain tissue. Optical coherence tomography (OCT) is a noninvasive, label-free, real-time, high-resolution imaging modality that has been explored for glioma infiltration detection. Here, we report a novel artificial intelligence (AI)-assisted method for automated, real-time, in situ detection of glioma infiltration at high spatial resolution. Experimental Design: Volumetric OCT datasets were intraoperatively obtained from resected brain tissue specimens of 21 patients with glioma tumors of different stages and labeled as either noncancerous or glioma-infiltrated on the basis of histopathology evaluation of the tissue specimens (gold standard). Labeled OCT images from 12 patients were used as the training dataset to develop the AI-assisted OCT-based method for automated detection of glioma-infiltrated brain tissue. Unlabeled OCT images from the other 9 patients were used as the validation dataset to quantify the method detection performance. Results: Our method achieved excellent levels of sensitivity (∼100%) and specificity (∼85%) for detecting glioma-infiltrated tissue with high spatial resolution (16 μm laterally) and processing speed (∼100,020 OCT A-lines/second). Conclusions: Previous methods for OCT-based detection of glioma-infiltrated brain tissue rely on estimating the tissue optical attenuation coefficient from the OCT signal, which requires sacrificing spatial resolution to increase signal quality, and performing systematic calibration procedures using tissue phantoms. By overcoming these major challenges, our AI-assisted method will enable implementing practical OCT-guided surgical tools for continuous, real-time, and accurate intraoperative detection of glioma-infiltrated brain tissue, facilitating maximal glioma resection and superior surgical outcomes for patients with glioma.

OBJECTIVEEpilepsy is common among patients with supratentorial brain tumors; approximately 40%–70% of patients with glioma develop brain tumor–related epilepsy (BTRE). Intraoperative localization of the epileptogenic zone during surgical tumor resection (real-time data) may improve intervention techniques in patients with lesional epilepsy, including BTRE. Accurate localization of the epileptogenic signals requires electrodes with high-density spatial organization that must be placed on the cortical surface during surgery. The authors investigated a 360° high-density ring-shaped cortical electrode assembly device, called the “circular grid,” that allows for simultaneous tumor resection and real-time electrophysiology data recording from the brain surface.METHODSThe authors collected data from 99 patients who underwent awake craniotomy from January 2008 to December 2018 (29 patients with the circular grid and 70 patients with strip electrodes), of whom 50 patients were matched-pair analyzed (25 patients with the circular grid and 25 patients with strip electrodes). Multiple variables were then retrospectively assessed to determine if utilization of this device provides more accurate real-time data and improves patient outcomes.RESULTSMatched-pair analysis showed higher extent of resection (p = 0.03) and a shorter transient motor recovery period during the hospitalization course (by approximately 6.6 days, p ≤ 0.05) in the circular grid patients. Postoperative versus preoperative Karnofsky Performance Scale (KPS) score difference/drop was greater for the strip electrode patients (p = 0.007). No significant difference in postoperative seizures between the 2 groups was present (p = 0.80).CONCLUSIONSThe circular grid is a safe, feasible tool that grants direct access to the cortical surgical surface for tissue resection while simultaneously monitoring electrical activity. Application of the circular grid to different brain pathologies may improve intraoperative epileptogenic detection accuracy and functional outcomes, while decreasing postoperative complications.

Background Endoscopic resection (ER) for uncommon sinonasal malignancies (SNMs) has been reported to confer superior surgical outcomes compared to open resection (OR) based on indirect comparisons of limited evidence. Objective The aim of this study was to pool all direct comparative studies in the literature to validate this potential superior association. Methods Systematic searches of 7 electronic databases from their inception to April 2019 were conducted following Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. There were 1001 articles identified for screening. Outcomes of interest were pooled as risk ratios (RRs) and mean difference (MD) and analyzed using a random-effects model. Results There were 10 studies included in this meta-analysis, with 900 SNM patients in total where ER and OR were utilized in 399 (44%) and 501 (56%) cases, respectively. Compared to OR, random-effects (RE) modeling indicated ER resulted in statistically comparable complications (RR = 0.68; P-effect = .12) and recurrence (RR = 0.84; P-effect = .35). ER was associated with significantly shorter length of stay (LOS) compared to OR (MD = −2.9 days; P-effect <.01). Conclusions The use of ER to manage SNM was associated with significantly favorable reduction in LOS compared to OR. However, with respect to other surgical outcomes and recurrence, the current literature does not indicate either ER or OR as statistically superior. Therefore, until greater validation of these associations can be proven, expectations that ER for SNMs confers superior surgical outcomes compared to OR should be tempered.