Purpose: The heterodimeric transcription factor HIF-2 is arguably the most important driver of clear cell renal cell carcinoma (ccRCC). Although considered undruggable, structural analyses at the University of Texas Southwestern Medical Center (UTSW, Dallas, TX) identified a vulnerability in the a subunit, which heterodimerizes with HIF1b, ultimately leading to the development of PT2385, a first-in-class inhibitor. PT2385 was safe and active in a first-in-human phase I clinical trial of patients with extensively pretreated ccRCC at UTSW and elsewhere. There were no dose-limiting toxicities, and disease control !4 months was achieved in 42% of patients.Patients and Methods: We conducted a prospective companion substudy involving a subset of patients enrolled in the phase I clinical trial at UTSW (n ¼ 10), who were treated at the phase II dose or above, involving multiparametric MRI, blood draws, and serial biopsies for biochemical, whole exome, and RNAsequencing studies.Results: PT2385 inhibited HIF-2 in nontumor tissues, as determined by a reduction in erythropoietin levels (a pharmacodynamic marker), in all but one patient, who had the lowest drug concentrations. PT2385 dissociated HIF-2 complexes in ccRCC metastases, and inhibited HIF-2 target gene expression. In contrast, HIF-1 complexes were unaffected. Prolonged PT2385 treatment resulted in the acquisition of resistance, and we identified a gatekeeper mutation (G323E) in HIF2a, which interferes with drug binding and precluded HIF-2 complex dissociation. In addition, we identified an acquired TP53 mutation elsewhere, suggesting a possible alternate mechanism of resistance.Conclusions: These findings demonstrate a core dependency on HIF-2 in metastatic ccRCC and establish PT2385 as a highly specific HIF-2 inhibitor in humans. New approaches will be required to target mutant HIF-2 beyond PT2385 or the closely related PT2977 (MK-6482).

VNC images derived from novel dual layer spectral detector CT demonstrate attenuation values similar to unenhanced images in all tissues evaluated except for subcutaneous fat. Further study is needed to determine if attenuation thresholds currently used clinically for common pathology should be adjusted, particularly for lesions containing fat.

Focused ultrasound combined with bubble-based agents serves as a non-invasive way to open the blood-brain barrier (BBB). Passive acoustic detection was well studied recently to monitor the acoustic emissions induced by the bubbles under ultrasound energy, but the ability to perform reliable BBB opening with a real-time feedback control algorithm has not been fully evaluated. This study focuses on characterizing the acoustic emissions of different types of bubbles: Optison, Definity, and a custom-made nanobubble. Their performance on reliable BBB opening under real-time feedback control based on acoustic detection was evaluated both in-vitro and in-vivo. The experiments were conducted using a 0.5 MHz focused ultrasound transducer with in-vivo focal pressure ranges from 0.1–0.7 MPa. Successful feedback control was achieved with all three agents when combining with infusion injection. Localized opening was confirmed with Evans blue dye leakage. Microscopic images were acquired to review the opening effects. Under similar total gas volume, nanobubble showed a more reliable opening effect compared to Optison and Definity (p < 0.05). The conclusions obtained from this study confirm the possibilities of performing stable opening using a feedback control algorithm combined with infusion injection. It also opens another potential research area of BBB opening using sub-micron bubbles.

Purpose Detection of small renal masses is increasing with the use of cross-sectional imaging, although many incidental lesions have negligible metastatic potential. Among malignant masses, clear cell renal cell carcinoma is the most prevalent and aggressive subtype, and a method to identify such histology would aid in risk stratification. Our goal was to evaluate a likelihood scale for multiparametric magnetic resonance imaging in the diagnosis of clear cell histology. Methods Patients with cT1a masses who underwent MRI and partial or radical nephrectomy from December 2011 to July 2015 were retrospectively reviewed. Seven radiologists with different levels of experience and blinded to final pathology independently reviewed studies based on a predefined algorithm, and applied a clear cell likelihood score: 1) definitely not, 2) probably not, 3) equivocal, 4) probably, and 5) definitely. Binary classification determined the accuracy of clear cell versus ‘all other’ histologies, and inter-observer agreement was calculated with a weighted κ statistic. Results In total, 110 patients with 121 masses were identified. Mean tumor size was 2.4 cm and 50% were clear cell. Defining clear cell as scores ≥4 demonstrated sensitivity and specificity of 78% and 80%, respectively, while scores ≥3 were 95% and 58%, respectively. Inter-observer agreement was moderate to good, with a mean κ of 0.53. Conclusions A clear cell likelihood score with MRI can reasonably identify clear cell histology in small renal masses, and may reduce the number of diagnostic renal mass biopsies. Standardization of imaging protocols and reporting criteria are needed to improve inter-observer reliability.

• SHINKEI provides homogeneous and superior fat suppression, shown by higher nerve and muscle-to-fat ratios. • SHINKEI shows better nerve signal-to-noise and contrast-to-noise ratios than 3DIRTSE. • SHINKEI enables nerve-selective images with increased conspicuity of smaller LS plexus branches. • SHINKEI should be considered in routine MR neurography of the LS plexus.

The strong correlation with myelin water imaging and its low coefficient of variation suggest that ihMT has the potential to become a new structural imaging marker of myelin. The substantial orientational dependence of ihMT should be taken into account when evaluating and quantitatively interpreting ihMT results.

Purpose To determine the diagnostic performance and inter-reader agreement of a standardized diagnostic algorithm for determining the histologic type of small (<=4cm) renal masses (SRM) with multiparametric magnetic resonance imaging (MRI). Materials and Methods This single-center, retrospective, HIPAA-compliant, IRB-approved study included 103 patients with 109 SRM, resected between December 2011 and July 2015. The requirement for informed consent was waived. Pre-surgical renal MRIs were reviewed by 7 radiologists with diverse experience. Eleven MRI features were assessed and a standardized diagnostic algorithm used to determine the most likely histologic diagnosis, which was compared to histopathology after surgery. Inter-reader variability was tested with Cohen’s κ. Regression models using MRI features were used to predict the histopathologic diagnosis with 5% significance level. Results Clear-cell (ccRCC) and papillary type renal cell carcinomas (pRCC) were diagnosed with respective sensitivities of 85% (47/55) and 80% (20/25), and specificities of 76% (41/54) and 94% (79/84). Inter-reader agreement was moderate-to-substantial (ccRCC, κ=0.58; pRCC, κ=0.73). Signal intensity of the lesion on T2-weighted images (T2W) and degree of contrast enhancement during corticomedullary phase (CE) were independent predictors of ccRCC (T2W OR: 3.19 CI95%: [1.4, 7.1], p=0.003; CE OR: 4.45 [1.8, 10.8], p<0.001) and pRCC (CE OR: 0.053 [0.02, 0.2], p<0.001), both with substantial inter-reader agreement (T2W, κ=0.69; CE, κ=0.71). Lower performance was observed for chromophobe histology, oncocytomas, and minimal-fat angiomyolipomas, [ranges, sensitivity=14%(1/7)–67%(4/6), specificity=97%(100/103)–99%(101/102)], with fair-to-moderate inter-reader agreement (κ=0.23–0.43). Segmental enhancement inversion was an independent predictor of oncocytomas (OR: 16.21 [1.0, 275.4], p=0.049), with moderate inter-reader agreement (κ=0.49). Conclusion The proposed standardized MRI-based diagnostic algorithm had a diagnostic accuracy of 81% (88/109) and 91% (99/109) for the diagnosis of ccRCC and pRCC, respectively, while achieving moderate to substantial inter-reader agreement among 7 radiologists.

Treatment of prosthetic joint infection (PJI) usually requires surgical replacement of the infected joint and weeks of antibiotic therapy, due to the formation of biofilm. We introduce a non-invasive method for thermal destruction of biofilm on metallic implants using high-frequency (>100 kHz) alternating magnetic fields (AMF). In vitro investigations demonstrate a >5-log reduction in bacterial counts after 5 minutes of AMF exposure. Confocal and scanning electron microscopy confirm removal of biofilm matrix components within 1 minute of AMF exposure, and combination studies of antibiotics and AMF demonstrate a 5-log increase in the sensitivity of Pseudomonas aeruginosa to ciprofloxacin. Finite element analysis (FEA) simulations demonstrate that intermittent AMF exposures can achieve uniform surface heating of a prosthetic knee joint. In vivo studies confirm thermal damage is confined to a localized region (<2 mm) around the implant, and safety can be achieved using acoustic monitoring for the presence of surface boiling. These initial studies support the hypothesis that AMF exposures can eradicate biofilm on metal implants, and may enhance the effectiveness of conventional antibiotics.