Alvarado-Estrada, Keila

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 < 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=< 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.

Background and Study Aims/Objective Metastatic brain tumors are the most common type of adult brain tumors. Treatment involves surgery and/or radiation therapy. Surgery is typically reserved for patients with good neurologic function, solitary and accessible lesions, symptomatic lesions, and/or those with good systemic control of their primary cancer. Deep-seated lesions, however, are typically treated with palliative options including radiation and medical therapies. We summarize our personal experience with minimally invasive surgical approaches for these deep-seated metastatic brain tumors using tubular retractors with exoscopic visualization. Material and Methods Patients with deep-seated metastatic brain tumors who were operated on from January 2016 to December 2017 by the senior author were collected prospectively. “Deep seated” was defined as any subcortical location below the deepest adjacent sulcus in close proximity to the basal ganglia and/or thalamus. “Minimally invasive” was defined as the use of tubular retractors with exoscopic visualization. Results A total of 15 consecutive patients with an average ± standard deviation age of 63 ± 12 years underwent surgical resection of a deep-seated metastasis. The tumor was located in the centrum semiovale in seven (47%) (3 corticospinal tract, 2 superior longitudinal fasciculus, 1 visual tract, 1 inferior frontal occipital fasciculus), basal ganglia in three (20%), thalamus in two (13%), and cerebellum in three (20%). Median percentage resection was 100% (interquartile range:100–100%), and, following surgery, seven (47%), seven (47%), and one (7%) had an improved, stable, and worse Karnofsky Performance Score, respectively. No patients had notable local complications including stroke, infection, hemorrhage, and/or seizure. All patients underwent postoperative stereotactic radiosurgery. Conclusion This minimally invasive approach can be used to achieve extensive resection with minimal morbidity for arguably the highest risk metastatic brain tumors.