Decker, Paul A.

Abstract Background Although the epidermal growth factor receptor (EGFR) is a frequent oncogenic driver in glioblastoma (GBM), efforts to therapeutically target this protein have been largely unsuccessful. The present preclinical study evaluated the novel EGFR inhibitor WSD-0922. Methods We employed flank and orthotopic patient-derived xenograft models to characterize WSD-0922 and compare its efficacy to erlotinib, a potent EGFR inhibitor that failed to provide benefit for GBM patients. We performed long-term survival studies and collected short-term tumor, plasma, and whole-brain samples from mice treated with each drug. We utilized mass spectrometry to measure drug concentrations and spatial distribution and to assess the impact of each drug on receptor activity and cellular signaling networks. Results WSD-0922 inhibited EGFR signaling as effectively as erlotinib in in vitro and in vivo models. While WSD-0922 was more CNS penetrant than erlotinib in terms of total concentration, comparable concentrations of both drugs were measured at the tumor site in orthotopic models, and the concentration of free WSD-0922 in the brain was significantly less than the concentration of free erlotinib. WSD-0922 treatment provided a clear survival advantage compared to erlotinib in the GBM39 model, with marked suppression of tumor growth and most mice surviving until the end of the study. WSD-0922 treatment preferentially inhibited phosphorylation of several proteins, including those associated with EGFR inhibitor resistance and cell metabolism. Conclusions WSD-0922 is a highly potent inhibitor of EGFR in GBM, and warrants further evaluation in clinical studies.

Background Larger within‐patient variability of lipid levels has been associated with increased risk of cardiovascular disease (CVD); however, measures of lipid variability require ≥3 measurements and are not currently used clinically. We investigated the feasibility of calculating lipid variability within a large electronic health record–based population cohort and assessed associations with incident CVD. Methods and Results We identified all individuals ≥40 years of age who resided in Olmsted County, MN, on January 1, 2006 (index date), without prior CVD, defined as myocardial infarction, coronary artery bypass graft surgery, percutaneous coronary intervention, or CVD death. Patients with ≥3 measurements of total cholesterol, low‐density lipoprotein cholesterol, high‐density lipoprotein cholesterol, or triglycerides during the 5 years before the index date were retained. Lipid variability was calculated using variability independent of the mean. Patients were followed through December 31, 2020 for incident CVD. We identified 19 652 individuals (mean age 61 years; 55% female), who were CVD‐free and had variability independent of the mean calculated for at least 1 lipid type. After adjustment, those with highest total cholesterol variability had a 20% increased risk of CVD (Q5 versus Q1 hazard ratio, 1.20 [95% CI, 1.06–1.37]). Results were similar for low‐density lipoprotein cholesterol and high‐density lipoprotein cholesterol. Conclusions In a large electronic health record–based population cohort, high variability in total cholesterol, high‐density lipoprotein cholesterol, and low‐density lipoprotein cholesterol was associated with an increased risk of CVD, independent of traditional risk factors, suggesting it may be a possible risk marker and target for intervention. Lipid variability can be calculated in the electronic health record environment, but more research is needed to determine its clinical utility.

Abstract Context Metformin is the first-line drug for treating diabetes but has a high failure rate. Objective To identify demographic and clinical factors available in the electronic health record (EHR) that predict metformin failure. Methods A cohort of patients with at least 1 abnormal diabetes screening test that initiated metformin was identified at 3 sites (Arizona, Mississippi, and Minnesota). We identified 22 047 metformin initiators (48% female, mean age of 57 ± 14 years) including 2141 African Americans, 440 Asians, 962 Other/Multiracial, 1539 Hispanics, and 16 764 non-Hispanic White people. We defined metformin failure as either the lack of a target glycated hemoglobin (HbA1c) (<7%) within 18 months of index or the start of dual therapy. We used tree-based extreme gradient boosting (XGBoost) models to assess overall risk prediction performance and relative contribution of individual factors when using EHR data for risk of metformin failure. Results In this large diverse population, we observed a high rate of metformin failure (43%). The XGBoost model that included baseline HbA1c, age, sex, and race/ethnicity corresponded to high discrimination performance (C-index of 0.731; 95% CI 0.722, 0.740) for risk of metformin failure. Baseline HbA1c corresponded to the largest feature performance with higher levels associated with metformin failure. The addition of other clinical factors improved model performance (0.745; 95% CI 0.737, 0.754, P < .0001). Conclusion Baseline HbA1c was the strongest predictor of metformin failure and additional factors substantially improved performance suggesting that routinely available clinical data could be used to identify patients at high risk of metformin failure who might benefit from closer monitoring and earlier treatment intensification.

Abstract Missing MRI sequences are common in radiology due to differences in protocols, time constraints, and image artifacts. Missing sequences are a nuisance for subsequent algorithms, such as automated segmentation algorithms requiring multiple MRI sequences (e.g., HD-GLIO, which requires T2, T1, post-contrast T1 (T1c), and FLAIR). Accurate tumor segmentation is a fundamental step in extracting radiomics analysis to use, for example, to predict the IDH status of glioma or their overall survival. We validated a conditional (pix2pix) and super-resolution GAN (SOUP-GAN) for imputing MRI sequences on 285 adult glioma with complete MRI sequences available. We simulated missing T1 sequences and subsequently imputed them from T1c using pix2pix and from sagittal T1 using SOUP-GAN. Using HD-GLIO, we obtained the true segmentations from the complete MRI sequences. HD-GLIO was also used after replacing the original T1 sequence with the one imputed with pix2pix and SOUP-GAN. Thus, there were three sets of segmentations for each subject. We compared T2 and T1c radiomics features extracted with Pyradiomics using segmentations obtained with complete data with features extracted from segmentation obtained with the imputed T1 sequences using intraclass correlation coefficient (ICC) and Bland-Altman (BA) analysis. Median (interquartile range) ICC for shape features extracted from T2 and T1c were 0.82(0.76-0.92) using pix2pix and 0.89(0.86-0.94) using SOUP-GAN. Median ICC for first-order-statistics features were 0.90(0.83-0.93) for T2 and 0.90(0.88-0.92) for T1c using pix2pix, and 0.61(0.22-0.82) for T2 and 0.42(0.34-0.57) for T1c using SOUP-GAN. Median ICC for texture features were 0.86(0.82-0.87) for T2 and 0.87(0.79-0.90) for T1c using pix2pix, and 0.69(0.47-0.81) for T2 and 0.76(0.65-0.83) for T1c using SOUP-GAN. We show that T2 and T1c shape features (e.g., volumetric analysis) can be adequately extracted from segmentations obtained with an algorithm requiring multiple MRI sequences using T1 sequences imputed with GANs; however, the effect of imputation differed for first-order-statistics and texture features.

Establishing causal links between inherited polymorphisms and cancer risk is challenging. Here, we focus on the single-nucleotide polymorphism rs55705857, which confers a sixfold greater risk of isocitrate dehydrogenase ( IDH) –mutant low-grade glioma (LGG). We reveal that rs55705857 itself is the causal variant and is associated with molecular pathways that drive LGG. Mechanistically, we show that rs55705857 resides within a brain-specific enhancer, where the risk allele disrupts OCT2/4 binding, allowing increased interaction with the Myc promoter and increased Myc expression. Mutating the orthologous mouse rs55705857 locus accelerated tumor development in an Idh1 R132H -driven LGG mouse model from 472 to 172 days and increased penetrance from 30% to 75%. Our work reveals mechanisms of the heritable predisposition to lethal glioma in ~40% of LGG patients.

AbstractIntroductionThere is some evidence that social media interventions can promote smoking cessation. This randomized controlled pilot study is the first to evaluate the feasibility and potential efficacy of a Facebook smoking cessation intervention among Alaska Native (AN) adults.Aims and MethodsRecruitment and data collection occurred from December 2019 to March 2021. Participants were recruited statewide in Alaska using Facebook advertisements with a targeted sample of 60 enrolled. Participants were stratified by gender, age, and rural or urban residence and randomly assigned to receive referral resources on evidence-based cessation treatments (EBCTs) (control, n = 30) or these resources plus a 3-month, closed (private), culturally tailored, Facebook group (intervention, n = 31) that connected participants to EBCT resources and was moderated by two Alaska Native Trained Tobacco Specialists. Assessments were conducted online post-randomization at 1, 3, and 6 months. Outcomes were feasibility (recruitment, retention, and intervention engagement), self-reported use of EBCTs, and biochemically confirmed seven-day point-prevalence smoking abstinence.ResultsOf intervention participants, 90% engaged (eg posted, commented) more than once. Study retention was 57% at 6 months (no group differences). The proportion utilizing EBCTs was about double for intervention compared with the control group participants at 3 and 6 months. Smoking abstinence was higher for intervention than control participants at 3 months (6.5% vs. 0%, p = .16) but comparable at 6 months (6.4% vs. 6.7%, p = .97).ConclusionsWhile additional research is needed to promote long-term cessation, this pilot trial supports recruitment feasibility during the Coronavirus Disease 2019 (COVID-19) pandemic, consumer uptake, and a signal for intervention efficacy on the uptake of cessation treatment and short-term smoking abstinence.ImplicationsThis study is the first evaluation of a social media intervention for smoking cessation among Indigenous people. We learned that statewide Facebook recruitment of AN adults who smoke was feasible and there was a signal for the efficacy of a Facebook intervention on the uptake of EBCT and short-term (3 months) biochemically verified smoking abstinence. Clinically, social media platforms may complement current care models by connecting AN individuals and others living in hard-to-reach communities to cessation treatment resources.

Abstract Background Risk factors for the pathogenesis of chronic rhinosinusitis (CRS) remain largely undetermined, which is likely due to the heterogeneity of the disease. White blood cell counts have been largely unexplored as a risk factor for CRS even though different types of white blood cells are involved in the inflammatory process of CRS. Objective To investigate causal associations between different types of white blood cells on risk of CRS utilizing a Mendelian randomization (MR) analysis. Methods A two-sample MR analysis was performed using respective GWAS summary statistics for the exposure traits (neutrophil count, eosinophil count, basophil count, lymphocyte count, and monocyte count) and outcome trait (CRS). For the exposure traits, the European Bioinformatics Institute database of complete GWAS summary data was used. For the outcome trait, summary statistics for CRS GWAS were obtained from FinnGen. Primary analysis for MR was performed using inverse-variance weighted two-sample MR. Sensitivity analyses included weighted median, MR-Egger, and MR-PRESSO (raw and outlier-corrected). Results Eosinophils were associated with CRS (OR = 1.55 [95%CI 1.38,1.73]; p = 4.3E-14). Eosinophil results were similar across additional MR methods. MR results did not demonstrate significant causal relationships between neutrophils, lymphocytes, monocytes, or basophils with CRS. No significant pleiotropic bias was observed. Conclusions In a two-sample MR analysis, a potential causal link between blood eosinophil counts and CRS has been demonstrated. In addition, causal relationships between blood counts among other white blood cell types and CRS were not found. Further studies involving genetic variation in CRS are needed to corroborate genetic causal effects for CRS.

Abstract Background EGFR targeting antibody-drug conjugates (ADCs) are highly effective against EGFR-amplified tumors, but poor distribution across the blood–brain barrier (BBB) limits their efficacy in glioblastoma (GBM) when administered systemically. We studied whether convection-enhanced delivery (CED) can be used to safely infuse ADCs into orthotopic patient-derived xenograft (PDX) models of EGFRvIII mutant GBM. Methods The efficacy of the EGFR-targeted ADCs depatuxizumab mafodotin (Depatux-M) and Serclutamab talirine (Ser-T) was evaluated in vitro and in vivo. CED was performed in nontumor and tumor-bearing mice. Immunostaining was used to evaluate ADC distribution, pharmacodynamic effects, and normal cell toxicity. Results Dose-finding studies in orthotopic GBM6 identified single infusion of 2 μg Ser-T and 60 μg Depatux-M as safe and effective associated with extended survival prolongation (>300 days and 95 days, respectively). However, with serial infusions every 21 days, four Ser-T doses controlled tumor growth but was associated with lethal toxicity approximately 7 days after the final infusion. Limiting dosing to two infusions in GBM108 provided profound median survival extension of over 200 days. In contrast, four Depatux-M CED doses were well tolerated and significantly extended survival in both GBM6 (158 days) and GBM108 (310 days). In a toxicity analysis, Ser-T resulted in a profound loss in NeuN+ cells and markedly elevated GFAP staining, while Depatux-M was associated only with modest elevation in GFAP staining. Conclusion CED of Depatux-M is well tolerated and results in extended survival in orthotopic GBM PDXs. In contrast, CED of Ser-T was associated with a much narrower therapeutic window.