Glioblastoma multiforme (GBM) overexpresses interleukin 13 receptor α2 (IL-13Rα2), a tumor-restricted receptor that is not present in normal brain. We and others have created targeted therapies that specifically eradicate tumors expressing this promising tumor-restricted biomarker. As these therapies head toward clinical implementation, it is critical to explore mechanisms of potential resistance. We therefore used a potent IL-13Rα2-targeted bacterial cytotoxin to select for naturally occurring "escapee" cells from three different IL-13Rα2-expressing GBM cell lines. We found that these side populations of escapee cells had significantly decreased IL-13Rα2 expression. We examined clinically relevant biologic characteristics of escapee cell lines compared to their parental cell lines and found that they had similar proliferation rates and equal sensitivity to temozolomide and radiation, the standard therapies given to GBM patients. In contrast, our escapee cell lines were less likely to form colonies in culture and migrated more slowly in wound healing assays. Furthermore, we found that escapee cells formed significantly less neurospheres in vitro, suggesting that IL-13Rα2-targeted therapy preferentially targeted the "stem-like" cell population and possibly indicating decreased tumorigenicity in vivo. We therefore tested escapee cells for in vivo tumorigenicity and found that they were significantly less tumorigenic in both subcutaneous and intracranial mouse models compared to matching parental cells. These data, for the first time, establish and characterize the clinically relevant biologic properties of IL-13Rα2-targeted therapy escapees and suggest that these cells may have less malignant characteristics than parental tumors.
Our objective was to exploit a novel ligand-based delivery system for targeting diagnostic and therapeutic agents to cancers that express interleukin 13 receptor alpha 2 (IL13Rα2), a tumor-restricted plasma membrane receptor overexpressed in glioblastoma multiforme (GBM), meningiomas, peripheral nerve sheath tumors, and other peripheral tumors. On the basis of our prior work, we designed a novel IL13Rα2-targeted quadruple mutant of IL13 (TQM13) to selectively bind the tumor-restricted IL13Rα2 with high affinity but not significantly interact with the physiologically abundant IL13Rα1/IL4Rα heterodimer that is also expressed in normal brain. We then assessed the in vitro binding profile of TQM13 and its potential to deliver diagnostic and therapeutic radioactivity in vivo. Surface plasmon resonance (SPR; Biacore) binding experiments demonstrated that TQM13 bound strongly to recombinant IL13Rα2 (Kd∼5 nM). In addition, radiolabeled TQM13 specifically bound IL13Rα2-expressing GBM cells and specimens but not normal brain. Of importance, TQM13 did not functionally activate IL13Rα1/IL4Rα in cells or bind to it in SPR binding assays, in contrast to wtIL13. Furthermore, in vivo targeting of systemically delivered radiolabeled TQM13 to IL13Rα2-expressing subcutaneous tumors was demonstrated and confirmed non-invasively for the first time with 124I-TQM13 positron emission tomography imaging. In addition, 131I-TQM13 demonstrated in vivo efficacy against subcutaneous IL13Rα2-expressing GBM tumors and in an orthotopic synergeic IL13Rα2-positive murine glioma model, as evidenced by statistically significant survival advantage. Our results demonstrate that we have successfully generated an optimized biomarker-targeted scaffolding that exhibited specific binding activity toward the tumor-associated IL13Rα2 in vitro and potential to deliver diagnostic and therapeutic payloads in vivo.
AIMTo develop and validate a simple, reproducible method to assess dural sac size using standard imaging technology.MATERIALS AND METHODSThis study was institutional review board-approved. Two readers, blinded to the diagnoses, measured anterior–posterior (AP) and transverse (TR) dural sac diameter (DSD), and AP vertebral body diameter (VBD) of the lumbar vertebrae using MRI images from 53 control patients with pre-existing MRI examinations, 19 prospectively MRI-imaged healthy controls, and 24 patients with Marfan syndrome with prior MRI or CT lumbar spine imaging. Statistical analysis utilized linear and logistic regression, Pearson correlation, and receiver operating characteristic (ROC) curves.RESULTSAP-DSD and TR-DSD measurements were reproducible between two readers (r = 0.91 and 0.87, respectively). DSD (L1–L5) was not different between male and female controls in the AP or TR plane (p = 0.43; p = 0.40, respectively), and did not vary by age (p = 0.62; p = 0.25) or height (p = 0.64; p = 0.32). AP-VBD was greater in males versus females (p = 1.5 × 10−8), resulting in a smaller dural sac ratio (DSR) (DSD/VBD) in males (p = 5.8 × 10−6). Marfan patients had larger AP-DSDs and TR-DSDs than controls (p = 5.9 × 10−9; p = 6.5 × 10−9, respectively). Compared to DSR, AP-DSD and TR-DSD better discriminate Marfan from control subjects based on area under the curve (AUC) values from unadjusted ROCs (AP-DSD p < 0.01; TR-DSD p = 0.04).CONCLUSIONIndividual vertebrae and L1–L5 (average) AP-DSD and TR-DSD measurements are simple, reliable, and reproducible for quantitating dural sac size without needing to control for gender, age, or height.
Cardiovascular devices and hemodynamic monitoring systems continue to evolve with the goal of allowing for rapid clinical intervention and management. Cardiovascular devices including the CardioMicroelectromechanical (CardioMEMS) device, implantable loop recorder, and right ventricular (RV) leadless pacemaker are now widely used for treatment and monitoring of advanced cardiac conditions, as many of these devices have been shown to significantly improve patient outcomes. Additionally, hemodynamic monitoring devices have shown utility in monitoring patients with aortic aneurysms after endovascular aortic repair (EVAR) for early detection of Type I and Type II endoleaks. There is limited published data regarding the imaging features of these devices. As these devices become more widely used, it is important for radiologists to become familiar with the normal imaging features and potential complications. The goal of this review is to summarize the data regarding the use of leadless cardiovascular devices including the CardioMEMS device, implantable loop recorder, and RV leadless pacemaker, and to present cases demonstrating their utility and normal imaging features.
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