Citations

Abstract The brain is notoriously difficult to access because of its location and protective mechanisms, both internal and external. Imaging-based approaches, such as multiparametric magnetic resonance imaging (mpMRI), provide a method to bypass these obstacles. mpMRI can capture a wide range of data from tumors embedded in brain tissue through various imaging features. However, the biological function captured by each imaging feature remains largely unknown, particularly within the aggressive disease glioblastoma multiforme (GBM). We integrated our GBM SYstems Genetics Network AnaLysis (gbmSYGNAL) gene regulatory network (Plaisier, et al. 2016), based on the multi-omic patient data from The Cancer Genome Atlas (TCGA), with mpMRI-localized patient tumor biopsies. The gbmSYGNAL network was reconstructed within the new image-localized biopsies, and associations revealed a strong connection between the spoiled gradient recalled echo + contrast (SPGR+C) feature and the immune hallmarks of cancer. The SPGR+C method generates an image by employing a contrast agent that bypasses the blood brain barrier (BBB) through leaky blood vessels that have weakened from the force of the rapidly growing GBM tumor. Furthermore, a significant association between SPGR+C signal and the presence of both infiltrating macrophages and T cells indicated that peripheral immune cells may also cross the BBB at these leaky sites. Separately, the mean diffusivity (MD) & T2 features were linked to the sustained angiogenesis hallmark. These features displayed high association with angiogenic genes, such as FLT1, KDR, and PDGFRB, and correlated with the presence of histologically identified vessels. Detection of these disease-relevant functions via mpMRI features has powerful clinical applications, providing a non-invasive approach to GBM diagnosis, prognosis, and treatment direction.

Abstract Brain tumor associated edema is a significant cause of patient morbidity and mortality often requiring continual treatment with differing levels of success across patients. Edema is a broad term that can indicate increased local water as well as diffusely infiltrating tumor cells. Edema is visualized as hyperintense regions on T2-weighted (T2W) magnetic resonance imaging (MRI) and is typically associated with blood-brain barrier (BBB) breakdown and tumor aggressiveness. Understanding the molecular mechanisms driving imaging patterns of “edema” could provide insights into clinical imaging interpretation. We have an ongoing image-guided biopsy study that allows us to link biopsy molecular markers with locoregional MRI patterns of edema. Further, we previously developed a physics-based method to estimate edema abundance (i.e., edema map) from T2W MRIs. Our goal was to identify connections between BBB-associated molecular factors and edema abundance in brain tumors. Our cohort included 38 patients (female: 15, male: 23) with 129 image-guided biopsies (female: 62, male: 67). We correlated image-localized edema map values with the mean transcriptional frequency for 57 genes related to BBB function. Additionally, we examined correlations separately according to patient reported sex (i.e., male and female) and imaging phenotype (i.e., ENH: enhancing and NE: non-enhancing). We utilized multiple comparisons corrections with a 5% false discovery rate to determine significance. For the overall cohort, we observed significant positive correlations for the HIF1A (p< 0.001) and SOX2 markers with edema. For NE samples, significant correlations included APOE (p=0.001), HIF1A (p< 0.001), PIK3CA (p< 0.001), PTCH1 (p< 0.001), and SOX2 (p< 0.001). Amongst female samples, a significant correlation with PTCH1 (p=0.002) was observed. There were no significant correlations noted for male and enhancing sub-cohorts. Significant correlations between molecular markers of BBB and edema map values could lead to clinical biomarkers for edema or tumor aggressiveness.

Abstract Glioblastoma (GBM) is the most aggressive primary brain tumor with a median survival of 14 months. GBMs are challenging to treat due to their heterogeneous nature. It has also been seen that these tumors have sex differences in their cellular subtypes as well as imaging. Radiomics has the potential to provide a non-invasive, spatial understanding of genetic and epigenetic diversity in these complex tumors and to aid in treatment planning. We have an ongoing study to obtain image-localized biopsies from GBM patients, allowing us to complete radiomic analysis and make connections between immunohistochemistry (IHC) and magnetic resonance imaging (MRI) features. We sought to determine if the patterns on imaging were correlated with underlying tumor biology. We focused on immunohistochemistry (IHC) markers of key features of tumor biology including SOX2 for stem-like tumor cells, CD68 for immune response and Ki67 for proliferation kinetics. Our study included 38 patients with a total of 99 biopsies (bxs): 27 males with 77 bxs and 11 females with 22 bxs. Biopsies were sectioned and stained for the SOX2, CD68, and KI67 markers. We computed 18 first-order radiomic features at each biopsy location for patients’ multimodal MRIs: T1W, T1Gd, T2W, FLAIR, apparent diffusion coefficient, diffusion weighted imaging (DWI) and susceptibility weighted imaging. We then performed correlation analysis between each radiomic feature and marker abundance for each IHC stain. Overall, we found sex-distinct patterns connecting imaging with these IHC markers. For example, amongst female patients, DWI held more prominent correlations with SOX2 than in males. Whereas there were more correlations between CD68 IHC abundance and T1Gd imaging features in males compared to females. Taken together, the overall patterns connecting locoregional imaging features to these IHC markers showed sex-distinct patterns suggesting the potential for sex to be an important biological variable when interpreting the biology underlying imaging changes.

Abstract Purpose Accurately predicting the clinical breast cancer subtypes could be extremely helpful for radiologists, pathologists, surgeons, and clinicians and inform future treatment prediction algorithms. Therefore, we evaluate and compare the accuracy of radiomic features extracted from contrast enhanced mammography (CEM) and magnetic resonance imaging (MRI) scans to make predictions to subtypes of breast cancer. Methods This HIPAA-compliant prospective single institution study was approved by the local institutional review board with written informed consent. Women with breast tumors 2 cm or larger underwent dynamic contrast-enhanced MRI and/or CEM for surgical staging. Semi-manual regions of interest were drawn by radiologist using Cancer Imaging Phenomics Toolkit (CaPTk). Radiomic features were obtained using PyRadiomics and MR- and CEM- based classification models were built on a low-dimensional representation of the features obtained via kernel principal component analysis. We subscribed to an ensemble tree-based learning approach called extremely randomized trees (ERT) to predict cancer subtypes captured via immunohistochemistry markers. Results For MRI analysis, 124 women with newly diagnosed breast cancer were included in the analysis comprising 49 HR+HER2-, 37 HR+HER2+, 11 HR-HER2+, and 27 HR-HER2- cases. For CEM analysis, models were built using data from 170 female patients including 74 HR+HER2-, 41 HR+HER2+, 14 HR-HER2+, and 43 HR-HER2-. CEM based model resulted in accuracies of 55%, 72%, 88%, and 71% respectively for HR+HER2-, HR+HER2+, HR-HER2+, and HR-HER2- whereas MRI based model alone led to accuracies of 54%, 62%, 89%, and 76% respectively for HR+HER2-, HR+HER2+, HR-HER2+, and HR-HER2-. Conclusions Radiomic features extracted from CEM and MR were strong predictors of breast cancer subtypes with CEM-based radiomic features performing slightly better, though not statistically significantly better (p = 0.82), than its MRI counterpart.

AbstractBackgroundDisruption of central circadian rhythms likely mediated by changes in microbiota and a decrease in gut-derived metabolites like short chain fatty acids (SCFAs) negatively impacts colonic barrier homeostasis. We aimed to explore the effects of isolated peripheral colonic circadian disruption on the colonic barrier in a mouse model of colitis and explore the mechanisms, including intestinal microbiota community structure and function.MethodsColon epithelial cell circadian rhythms were conditionally genetically disrupted in mice: TS4Cre-BMAL1lox (cBMAL1KO) with TS4Cre as control animals. Colitis was induced through 5 days of 2% dextran sulfate sodium (DSS). Disease activity index and intestinal barrier were assessed, as were fecal microbiota and metabolites.ResultsColitis symptoms were worse in mice with peripheral circadian disruption (cBMAL1KO). Specifically, the disease activity index and intestinal permeability were significantly higher in circadian-disrupted mice compared with control animals (TS4Cre) (P < .05). The worsening of colitis appears to be mediated, in part, through JAK (Janus kinase)-mediated STAT3 (signal transducer and activator of transcription 3), which was significantly elevated in circadian-disrupted (cBMAL1KO) mice treated with DSS (P < .05). Circadian-disrupted (cBMAL1KO) mice also had decreased SCFA metabolite concentrations and decreased relative abundances of SCFA-producing bacteria in their stool when compared with control animals (TS4Cre).ConclusionsDisruption of intestinal circadian rhythms in colonic epithelial cells promoted more severe colitis, increased inflammatory mediators (STAT3 [signal transducer and activator of transcription 3]), and decreased gut microbiota–derived SCFAs compared with DSS alone. Further investigation elucidating the molecular mechanisms behind these findings could provide novel circadian directed targets and strategies in the treatment of inflammatory bowel disease.

Abstract Background Hidradenitis suppurativa (HS) is associated with substantial morbidity. Few studies have addressed the natural history and mortality rates associated with HS. A higher risk of cardiovascular death in patients with HS has been reported. We investigated whether patients with HS have an increased overall risk of death compared with age‐ and gender‐matched referents. Methods We performed a retrospective cohort study of residents of Olmsted County, Minnesota, with incident HS between January 1, 1980, and December 31, 2008, and age‐ and gender‐matched referents. The main outcomes and measures were the overall and cause‐specific risks of death. Results We identified 226 incident cases of HS and 678 age‐ and gender‐matched referents among Olmsted County residents during the study period. Compared to referents, patients with HS had a significantly higher risk of all‐cause death (hazard ratio [HR, 2.48; 95% CI, 1.53–4.03, P < 0.001) and cardiovascular‐ or cerebrovascular‐related death (HR, 2.85; 95% CI, 1.10–7.40, P = 0.03). However, these risks were attenuated by adjusting for smoking history: all‐cause HR, 1.65 (95% CI, 0.97–2.82, P = 0.07) and cardiovascular‐ or cerebrovascular‐related HR, 2.03 (95% CI, 0.71–5.81, P = 0.18). The 71% of patients were former or current smokers at the time of HS diagnosis. Conclusions Hidradenitis suppurativa patients have a substantially increased risk of death from any cause, including cardiovascular or cerebrovascular causes; the risk is especially dependent on smoking history.

OBJECTIVE To examine factors associated with emergency department (ED) transport after hypoglycemia treated by emergency medical services (EMS) and assess the impact of ED transport on severe hypoglycemia recurrence. RESEARCH DESIGN AND METHODS We retrospectively analyzed electronic health records of a multistate advanced life support EMS provider and an integrated healthcare delivery system serving an overlapping geographic area in the upper Midwest. For adults with diabetes treated by EMS for hypoglycemia between 2013 and 2019, we examined rates of ED transport, factors associated with it, and its impact on rates of recurrent hypoglycemia requiring EMS, ED, or hospital care within 3, 7, and 30 days. RESULTS We identified 1,977 hypoglycemia-related EMS encounters among 1,028 adults with diabetes (mean age 63.5 years [SD 17.7], 55.2% male, 87.4% non-Hispanic White, 42.4% rural residents, and 25.6% with type 1 diabetes), of which 46.4% resulted in ED transport (31.1% of calls by patients with type 1 diabetes and 58.0% of calls by patients with type 2 diabetes). Odds of ED transport were lower in patients with type 1 diabetes (odds ratio [OR] 0.44 [95% CI 0.31–0.62] vs. type 2 diabetes) and higher in patients with prior ED visits (OR 1.38 [95% CI 1.03–1.85]). Within 3, 7, and 30 days, transported patients experienced recurrent severe hypoglycemia 2.8, 5.2, and 10.6% of the time, respectively, compared with 7.4, 11.2, and 22.8% of the time among nontransported patients (all P &lt; 0.001). This corresponds to OR 0.58 (95% CI 0.42–0.80) for recurrent severe hypoglycemia within 30 days for transported versus nontransported patients. When subset by diabetes type, odds of recurrent severe hypoglycemia among transported patients were 0.64 (95% CI 0.43–0.96) and 0.42 (95% CI 0.24–0.75) in type 1 and type 2 diabetes, respectively. CONCLUSIONS Transported patients experienced recurrent hypoglycemia requiring medical attention approximately half as often as nontransported patients, reinforcing the importance of engaging patients in follow-up to prevent recurrent events.

Abstract Brain metastases are a challenging manifestation of renal cell carcinoma. We have a limited understanding of brain metastasis tumor and immune biology, drivers of resistance to systemic treatment, and their overall poor prognosis. Current data support a multimodal treatment strategy with radiation treatment and/or surgery. Nonetheless, the optimal approach for the management of brain metastases from renal cell carcinoma remains unclear. To improve patient care, the authors sought to standardize practical management strategies. They performed an unstructured literature review and elaborated on the current management strategies through an international group of experts from different disciplines assembled via the network of the International Kidney Cancer Coalition. Experts from different disciplines were administered a survey to answer questions related to current challenges and unmet patient needs. On the basis of the integrated approach of literature review and survey study results, the authors built algorithms for the management of single and multiple brain metastases in patients with renal cell carcinoma. The literature review, consensus statements, and algorithms presented in this report can serve as a framework guiding treatment decisions for patients. CA Cancer J Clin. 2022;72:454‐489.

Abstract High-grade gliomas represent the most common type of primary adult malignant brain tumor historically diagnosed and graded from histologic criteria alone. Gliomas harboring isocitrate dehydrogenase (IDH) 1 or 2 mutations, which are present in more than 80% of World Health Organization (WHO) grade 2 or 3 tumors, portend a favorable prognosis as compared to IDH-wildtype tumors. However, recent molecular profiling has identified the presence of additional alterations in these lower grade tumors that transform the biology toward an aggressive high-grade phenotype clinically that are independent of histologic grading and confer a worse clinical prognosis. Of these, the loss of CDKN2A/B is the strongest implicated alteration and is sufficient to define a grade 4 tumor in IDH-mutant astrocytomas regardless of histologic appearance. However, there remain no effective therapies targeted at molecular subgroups in aggressive gliomas to date. Here we have profiled the intratumoral heterogeneity via whole exome and RNA sequencing and copy number alteration analysis within a cohort of de-identified IDH-mutant astrocytoma patient tumors collected through the Mayo Clinic and Barrow Neurological Institute (BNI) biorepositories to determine the spatial evolution of aggressive molecular features. Within this cohort we have collected 42 image-localized intratumoral biopsy specimens representing 13 IDH-mutant patient tumors. We identified 11 biopsies from 3 tumors that harbored loss of CDKN2A/B which included 1 tumor that displayed intratumoral heterogeneity of CDKN2A/B expression across subclones. We performed an unsupervised cluster analysis to profile the transcriptional signatures in IDH-mutant astrocytomas across both differential CDKN2A/B status and tumor geographic location comparing contrast enhancing versus non-enhancing regions, and we analyzed the MRI features in IDH-mutant tumors across CDKN2A/B status. We found that tumors with CDKN2A/B alteration demonstrated lower signal intensity on delayed post-contrast T2*W images, which could represent lower pre-contrast T2*, unique contrast agent kinetics, or dissimilar diffusion properties related to increased cellular density and/or greater heterogeneity of cell size. Interestingly, we uncovered spatial heterogeneity of additional molecular drivers of high-grade glioma including KRAS, MYCN, and PDGFRA. While EGFR alterations are rarely reported in IDH-mutant tumors, we identified one treatment naïve patient tumor that harbored EGFR alteration only in the contrast non-enhancing region. Based on this work we propose there is early spatial evolution of aggressive tumor subclones prior to primary tumor diagnosis, and multiregional molecular profiling may better inform tumor biology and predict therapeutic strategies in IDH-mutant astrocytomas. Citation Format: Shannon P. Fortin Ensign, Fulvio D'Angelo, Francesca P. Caruso, Christopher Sereduk, Kyle Singleton, Jennifer Eschbacher, Gina Mazza, Maciej Mrugala, Alyx Porter, Bernard Bendok, Richard Zimmerman, Kris Smith, Peter Nakaji, Kamala Swanson, Junwen Wang, Nathenael Semmineh, Christopher Quarles, Anna Lasorella, Kristin Swanson, Michele Ceccarelli, Antonio Iavarone, Leland Hu, Nhan L. Tran. Multiregional imaging and genomic analysis in high-grade IDH-mutant astrocytoma identifies intratumor subclones with aggressive features [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 770.

Background: Patients with advanced emphysema experience breathlessness due to impaired respiratory mechanics and diaphragm dysfunction. Bronchoscopic lung volume reduction (BLVR) is a minimally invasive bronchoscopic procedure done to reduce hyperinflation and air trapping, promoting atelectasis in the targeted lobe and allowing improved respiratory mechanics. Real-world data on safety and complications outside of clinical trials of BLVR are limited. Methods: We queried the US Food and Drug Administrations (FDA) Manufacturers and User Device Experience database from May 2019 to June 2020 for reports involving BLVR with endobronchial valve (EBV) placement. Events were reviewed for data analysis. Results: We identified 124 cases of complications during BLVR with EBV implantation. The most-reported complication was pneumothorax (110/124, 89%), all of which required chest tube placement. A total of 54 of these cases (54/110, 49%) were complicated by persistent air leak requiring additional interventions. Repeat bronchoscopy was needed to remove the valves in 28 patients, 12 were discharged with a Heimlich valve, and 10 had an additional pleural catheter placed. The other complications of BLVR with EBV placement included respiratory failure (6/124, 5%), pneumonia (4/124, 3%), hemoptysis (2/124, 1.6%), valve migration (1/124, 1%), and pleural effusion (1/124, 1%). A total of 14 deaths were reported during that year. Conclusion: Pneumothorax is the most-reported complication for BLVR with EBV placement, and in 65% of cases, pneumothorax is managed without removing valves. Importantly, 14 deaths were reported during that timeframe. Further studies are needed to estimate the true magnitude of the complications associated with BLVR.