◥Purpose: Intratumoral heterogeneity (ITH) challenges the molecular characterization of clear cell renal cell carcinoma (ccRCC) and is a confounding factor for therapy selection. Most approaches to evaluate ITH are limited by two-dimensional ex vivo tissue analyses. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can noninvasively assess the spatial landscape of entire tumors in their natural milieu. To assess the potential of DCE-MRI, we developed a vertically integrated radiogenomics colocalization approach for multi-region tissue acquisition and analyses. We investigated the potential of spatial imaging features to predict molecular subtypes using histopathologic and transcriptome correlatives.Experimental Design: We report the results of a prospective study of 49 patients with ccRCC who underwent DCE-MRI prior to nephrectomy. Surgical specimens were sectioned to match the MRI acquisition plane. RNA sequencing data from multi-region tumor sampling (80 samples) were correlated with percent enhancement on DCE-MRI in spatially colocalized regions of the tumor. Independently, we evaluated clinical applicability of our findings in 19 patients with metastatic RCC (39 metastases) treated with first-line antiangiogenic drugs or checkpoint inhibitors.Results: DCE-MRI identified tumor features associated with angiogenesis and inflammation, which differed within and across tumors, and likely contribute to the efficacy of antiangiogenic drugs and immunotherapies. Our vertically integrated analyses show that angiogenesis and inflammation frequently coexist and spatially anti-correlate in the same tumor. Furthermore, MRI contrast enhancement identifies phenotypes with better response to antiangiogenic therapy among patients with metastatic RCC.Conclusions: These findings have important implications for decision models based on biopsy samples and highlight the potential of more comprehensive imaging-based approaches.

IntroductionFalls are a leading cause of head injury in the USA. Stair-related fall injuries are common and often more serious than same level falls. Alcohol is a known contributor to unintentional injuries, and often associated with fall-related injuries, specifically falls occurring on stairs. The objective was to examine the association between alcohol use and head injuries (traumatic brain injuries (TBIs) or craniomaxillofacial (CMF) injuries) among persons aged 15–64 presenting to an emergency department (ED) with an injury resulting from a fall on stairs.MethodsUsing the 2019 National Electronic Injury Surveillance System, US ED records were examined. Injuries due to falling on stairs were retrieved, with the role of alcohol in the outcome of TBI and CMF injuries examined. Prevalence ratios (PR), adjusted for covariates (blood alcohol level screening, patient demographics, drug use, disposition) were obtained from average marginal predictions derived from logistic regression models.ResultsAn estimated 687 902 patient visits related to falls on stairs occurred during the study period. Patients who presented with alcohol intoxication had a higher prevalence of TBI (PR 2.7 95% CI 2.3 to 3.1) and CMF injuries (PR 2.5; 95% CI 2.3 to 2.8). PRs were more pronounced among patients with blood alcohol concentration ≥0.1, as was hospital admission.ConclusionsStair-related falls represent a common cause of ED visits for falls in the USA. Alcohol intoxication had a detrimental effect on the prevalence of TBI and CMF. A multimodal treatment approach may be beneficial given the complex interrelationship between the injury type and alcohol.

No abstract

Normally induced by hypoxia, hypoxia-inducible factor 2 alpha (HIF2a) is arguably the most important driver of kidney cancer. HIF2a is constitutively activated following von Hippel-Lindau (VHL) gene inactivation, which is the signature event of the most common type of kidney cancer, clear cell renal cell carcinoma (ccRCC). HIF2a functions as a heterodimeric transcription factor in partnership with the constitutive HIF1b subunit and regulates a program of gene expression that promotes cell proliferation, stemness, and angiogenesis. While as a transcription factor HIF2a had escaped drug targeting, structural studies revealed an unusual cavity, which became the foundation for the development of small molecule inhibitors such as PT2385 (a first-in-class drug), or the related PT2399 tool compound and the recently FDA-approved PT2977 (also called belzutifan). PT drugs bind a small pocket in the PAS-B domain of HIF2a inducing a conformational change that triggers dissociation from its obligatory partner HIF1b. PT drugs are highly specific - they do not bind the close paralog HIF1a and do not induce changes in gene expression in cells devoid of HIF2a. Using an extensive library of patient-derived xenografts (PDXs), we previously showed that PT drugs have activity against 50% of ccRCCs implanted in mice, and similar observations were made in the clinic. Perhaps unsurprisingly, sensitive tumors showed higher HIF2a levels. Here, we leverage the specificity of PT2385 to develop a HIF2a tracer for positron emission tomography (PET). By substituting a native fluorine atom for 18F, we generated [18F]PT2385. [18F]PT2385 was able to discriminate HIF2a-expressing ccRCCs from tumors that did not express HIF2a in mice simultaneously implanted with both. These data set the foundation for an investigator new drug (IND) approval from the FDA, and a clinical trial that is currently accruing patients (NCT04989959). [18F]PT2385 PET may have applications in identifying kidney cancer patients most likely to respond to HIF2a-targeted therapies, the identification of other tumors relying on HIF2a, and beyond oncology. Reporting on a hypoxia sensor, a HIF2a radiotracer may be a useful ischemia probe. In summary, we report the development of a novel radiotracer with extensive potential applications currently being evaluated in humans. Citation Format: Sashi Debnath, Christina Stevens, Olivia Brandenburg, Justin Sovich, Paulina Gonzalez, Qian (Janie) Qin, Sydney Haldeman, Vanina Toffessi Tcheuyap, Alana Christie, Pawan Thapa, Ning Zhou, Aditi Mulgaonkar, Guiyang Hao, Jeffrey Miyata, Deyssy Carrillo, Jeffrey Cadeddu, Payal Kapur, Jon Anderson, Ivan Pedrosa, Marianna Dakanali, Orhan Oz, Xiankai Sun, James Brugarolas. Development of a novel HIF2a PET tracer: From proof of concept to a clinical trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2478.

<p>DCE-NG vs. Normalized Gene expression</p>