Single wall carbon nanotube (SWCNT) constructs were covalently appended with radiometal-ion chelates (1,4,7,4,7, or desferrioxamine B [DFO]) and the tumor neovascular-targeting antibody E4G10. The E4G10 antibody specifically targeted the monomeric vascular endothelial-cadherin (VE-cad) epitope expressed in the tumor angiogenic vessels. The construct specific activity and blood compartment clearance kinetics were significantly improved relative to corresponding antibodyalone constructs. We performed targeted radioimmunotherapy with a SWCNT- ([ 225 Ac]DOTA) (E4G10) construct directed at the tumor vasculature in a murine xenograft model of human colon adenocarcinoma (LS174T). The specific construct reduced tumor volume and improved median survival relative to controls. We also performed positron emission tomographic (PET) radioimmunoimaging of the tumor vessels with a SWCNT- ([ 89 Zr]DFO)(E4G10) construct in the same murine LS174T xenograft model and compared the results to appropriate controls. Dynamic and longitudinal PET imaging of LS174T tumor-bearing mice demonstrated rapid blood clearance (,1 hour) and specific tumor accumulation of the specific construct. Incorporation of the SWCNT scaffold into the construct design permitted us to amplify the specific activity to improve the signal-to-noise ratio without detrimentally impacting the immunoreactivity of the targeting antibody moiety. Furthermore, we were able to exploit the SWCNT pharmacokinetic (PK) profile to favorably alter the blood clearance and provide an advantage for rapid imaging. Near-infrared three-dimensional fluorescent-mediated tomography was used to image the LS174T tumor model, collect antibody-alone PK data, and calculate the number of copies of VE-cad epitope per cell. All of these studies were performed as a single administration of construct and were found to be safe and well tolerated by the murine model. These data have implications that support further imaging and radiotherapy studies using a SWCNT-based platform and focusing on the tumor vessels as the target.

Background Aortic diseases, including aortic aneurysms, are the 12th leading cause of death in the United States. The incidence of descending thoracic aortic aneurysms is estimated at 10.4 per 100,000 patient-years. Growing evidence suggests that stress measurements derived from structural analysis of aortic geometries predict clinical outcomes better than diameter alone. Methods Twenty-five patients undergoing clinical and radiologic surveillance for thoracic aortic aneurysms were retrospectively identified. Custom MATLAB algorithms were employed to extract aortic wall and intraluminal thrombus geometry from computed tomography angiography scans. The resulting reconstructions were loaded with 120 mm Hg of pressure using finite element analysis. Relationships among peak wall stress, aneurysm growth, and clinical outcome were examined. Results The average patient age was 71.6 ± 10.0 years, and average follow-up time was 17.5 ± 9 months (range, 6 to 43). The mean initial aneurysm diameter was 47.8 ± 8.0 mm, and the final diameter was 52.1 ± 10.0 mm. Mean aneurysm growth rate was 2.9 ± 2.4 mm per year. A stronger correlation (r = 0.894) was found between peak wall stress and aneurysm growth rate than between maximal aortic diameter and growth rate (r = 0.531). Aneurysms undergoing surgical intervention had higher peak wall stresses than aneurysms undergoing continued surveillance (300 ± 75 kPa versus 229 ± 47 kPa, p = 0.01). Conclusions Computational peak wall stress in thoracic aortic aneurysms was found to be strongly correlated with aneurysm expansion rate. Aneurysms requiring surgical intervention had significantly higher peak wall stresses. Peak wall stress may better predict clinical outcome than maximal aneurysmal diameter, and therefore may guide clinical decision-making.

Rationale Glioblastoma is characterized by an aggressive and aberrant vascular network that promotes tumor progression and hinders effective treatment; the median survival is 16 months despite standard-of-care therapies. There is a need to improve therapeutic options for this disease. We hypothesized that antibody targeting of the vascular endothelium (VE) of glioblastoma with cytotoxic short-range, high-energy alpha particles would be an effective therapeutic approach. Methods E4G10, an antibody directed at an epitope of monomeric VE cadherin, is expressed in tumor neovasculature and on endothelial progenitor cells in the bone marrow. E4G10 was labeled with alpha particle emitting 225Actinium (225Ac). Pharmacokinetic studies investigated the tissue distribution and blood clearance of the 225Ac-E4G10 radioimmunoconstruct in a transgenic Ntva-mouse model of high-grade glioblastoma. Histological analysis was used to demonstrate local therapeutic effects in treated brain tumor sections. Radioimmunotherapy with 225Ac-E4G10 was performed in Ntva-mice to assess overall survival alone and in combination with temozolomide, the standard-of-care chemotherapeutic agent. Results 225Ac-E4G10 was found to accumulate in tissues expressing the target antigen. Antivascular alpha-particle therapy of glioblastoma in the transgenic Ntva-model resulted in significantly improved survival compared to controls and potent control of tumor growth. Adding the chemotherapeutic temozolomide to the treatment increased survival to 30 days (versus 9 days for vehicle treated animals). Histological analyses showed a remodeled glioblastoma vascular microenvironment. Conclusion Targeted alpha-particle anti-vascular therapy is shown for the first time to be effective in increasing overall survival in a solid tumor in a clinically relevant transgenic glioblastoma mouse model.

Background Limited data exist regarding the effect of conversion from laparoscopic to open colectomy on perioperative and oncologic outcomes in colon cancer. Study Design The National Cancer Data Base was used to identify patients who underwent colectomy for non-metastatic colon cancer (2010–2012). Patients were stratified into three groups: laparoscopic/robotic-assisted colectomy (MIC), converted colectomy (CC), and open colectomy (OC). Multivariable modeling was applied to compare outcomes from CC and MIC to OC while adjusting for patient, clinical, and tumor characteristics. Results Of 104,400 patients, 40,328 (38.6 %) underwent MIC, 57,928 (55.5 %) OC, and 6144 (5.9 %) CC. After adjustment, the rate of positive surgical margins was not significantly different between CC and OC (p = 0.44). However, with adjustment, CC versus OC was associated with shorter hospital length of stay (4 % decrease, 95 % CI 2–5 %, p < 0.0001) and lower odds of 30-day mortality (OR 0.77, 95 % CI 0.64–0.94, p = 0.0112). Adjusted overall survival was similar between CC and OC (p = 0.34). Conclusions Conversion from laparoscopic to open colectomy was not associated with compromised oncologic outcomes, while maintaining improved short-term outcomes despite being attempted in only 45 % of patients. This data suggests that utilization of laparoscopic colectomy should be attempted for patients with colon cancer.