Citations

Abstract Background Despite advances in medical therapy, many children and adults with ileal Crohn’s disease (CD) progress to fibrostenosis requiring surgery. We aimed to identify MRI and circulating biomarkers associated with the need for surgical management. Methods This prospective, multicenter study included pediatric and adult CD cases undergoing ileal resection and CD controls receiving medical therapy. Noncontrast research MRI examinations measured bowel wall 3-dimensional magnetization transfer ratio normalized to skeletal muscle (normalized 3D MTR), modified Look-Locker inversion recovery (MOLLI) T1 relaxation, intravoxel incoherent motion (IVIM) diffusion-weighted imaging metrics, and the simplified magnetic resonance index of activity (sMaRIA). Circulating biomarkers were measured on the same day as the research MRI and included CD64, extracellular matrix protein 1 (ECM1), and granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibodies (Ab). Associations between MRI and circulating biomarkers and need for ileal resection were tested using univariate and multivariable LASSO regression. Results Our study sample included 50 patients with CD undergoing ileal resection and 83 patients with CD receiving medical therapy; mean participant age was 23.9 ± 13.1 years. Disease duration and treatment exposures did not vary between the groups. Univariate biomarker associations with ileal resection included log GM-CSF Ab (odds ratio [OR], 2.87; P = .0009), normalized 3D MTR (OR, 1.05; P = .002), log MOLLI T1 (OR, 0.01; P = .02), log IVIM perfusion fraction (f; OR, 0.38; P = .04), and IVIM apparent diffusion coefficient (ADC; OR, 0.3; P = .001). The multivariable model for surgery based upon corrected Akaike information criterion included age (OR, 1.03; P = .29), BMI (OR, 0.91; P = .09), log GM-CSF Ab (OR, 3.37; P = .01), normalized 3D MTR (OR, 1.07; P = .007), sMaRIA (OR, 1.14; P = .61), luminal narrowing (OR, 10.19; P = .003), log C-reactive protein (normalized; OR, 2.75; P = .10), and hematocrit (OR, 0.90; P = .13). Conclusion After accounting for clinical and MRI measures of severity, normalized 3D MTR and GM-CSF Ab are associated with the need for surgery in ileal CD.

Abstract Many cancers, including glioblastoma (GBM), have a male-biased sex difference in incidence and outcome. The underlying reasons for this sex bias are unclear but likely involve differences in tumor cell state and immune response. This effect is further amplified by sex hormones, including androgens, which have been shown to inhibit anti-tumor T cell immunity. Here, we show that androgens drive anti-tumor immunity in brain tumors, in contrast to its effect in other tumor types. Upon castration, tumor growth was accelerated with attenuated T cell function in GBM and brain tumor models, but the opposite was observed when tumors were located outside the brain. Activity of the hypothalamus-pituitary-adrenal gland (HPA) axis was increased in castrated mice, particularly in those with brain tumors. Blockade of glucocorticoid receptors reversed the accelerated tumor growth in castrated mice, indicating that the effect of castration was mediated by elevated glucocorticoid signaling. Furthermore, this mechanism was not GBM specific, but brain specific, as hyperactivation of the HPA axis was observed with intracranial implantation of non-GBM tumors in the brain. Together, our findings establish that brain tumors drive distinct endocrine-mediated mechanisms in the androgen-deprived setting and highlight the importance of organ-specific effects on anti-tumor immunity.

Abstract Intratumoral heterogeneity poses a significant challenge to the diagnosis and treatment of glioblastoma (GBM). This heterogeneity is further exacerbated during GBM recurrence, as treatment-induced reactive changes produce additional intratumoral heterogeneity that is ambiguous to differentiate on clinical imaging. There is an urgent need to develop non-invasive approaches to map the heterogeneous landscape of histopathological alterations throughout the entire lesion for each patient. We propose to predictively fuse Magnetic Resonance Imaging (MRI) with the underlying intratumoral heterogeneity in recurrent GBM using machine learning (ML) by leveraging image-localized biopsies with their associated locoregional MRI features. To this end, we develop BioNet, a biologically-informed neural network model, to predict regional distributions of three tissue-specific gene modules: proliferating tumor, reactive/inflammatory cells, and infiltrated brain tissue. BioNet offers valuable insights into the integration of multiple implicit and qualitative biological domain knowledge, which are challenging to describe in mathematical formulations. BioNet performs significantly better than a range of existing methods on cross-validation and blind test datasets. Voxel-level prediction maps of the gene modules by BioNet help reveal intratumoral heterogeneity, which can improve surgical targeting of confirmatory biopsies and evaluation of neuro-oncological treatment effectiveness. The non-invasive nature of the approach can potentially facilitate regular monitoring of the gene modules over time, and making timely therapeutic adjustment. These results also highlight the emerging role of ML in precision medicine.

Abstract Currently available biotherapeutics for the treatment of osteoporosis lack explicit mechanisms for bone localization, potentially limiting efficacy and inducing off-target toxicities. While various strategies have been explored for targeting the bone surface, critical aspects remain poorly understood, including the optimal affinity ligand, the role of binding avidity and circulation time, and, most importantly, whether or not this strategy can enhance the functional activity of clinically relevant protein therapeutics. To investigate, we generated fluorescent proteins (eg, mCherry) with site-specifically attached small molecule (bisphosphonate) or peptide (deca-aspartate, D10) affinity ligands. While both affinity ligands successfully anchored fluorescent protein to the bone surface, quantitative radiotracing revealed only modest femoral and vertebral accumulation and suggested a need for enhanced circulation time. To achieve this, we fused mCherry to the Fc fragment of human IgG1 and attached D10 peptides to each C-terminus. The mCherry-Fc-D10 demonstrated an ~80-fold increase in plasma exposure and marked increases in femoral and vertebral accumulation (13.6% ± 1.4% and 11.4% ± 1.3% of the injected dose/g [%ID/g] at 24 h, respectively). To determine if bone surface targeting could enhance the efficacy of a clinically relevant therapeutic, we generated a bone-targeted sclerostin-neutralizing antibody, anti-sclerostin-D10. The targeted antibody demonstrated marked increases in bone accumulation and retention (20.9 ± 2.5% and 19.5 ± 2.5% ID/g in femur and vertebrae at 7 days) and enhanced effects in a murine model of ovariectomy-induced bone loss (bone volume/total volume, connectivity density, and structure model index all increased [P < .001] vs untargeted anti-sclerostin). Collectively, our results indicate the importance of both bone affinity and circulation time in achieving robust targeting of therapeutic proteins to the bone surface and suggest that this approach may enable lower doses and/or longer dosing intervals without reduction in biotherapeutic efficacy. Future studies will be needed to determine the translational potential of this strategy and its potential impact on off-site toxicities.

Abstract Magnetic resonance imaging (MRI) is a centerpiece of clinical management of brain tumor patients, yet the biology underlying even commonly interpreted imaging changes is unclear. The purpose of this project was to understand what biology is associated with brain tumor edema abundance and if that association was sex distinct. We have developed a two-compartment model of MRI signal intensity to quantitatively estimate relative edema abundance from T2-weighted MRIs. Multiparametric MRIs were preprocessed with bias field correction and intensity normalization. The images were co-registered and segmented for abnormal regions and normal tissue. The segmentations and preprocessed images were utilized in the edema mathematical model to estimate the fraction of extracellular space (Fecs) and fraction of intracellular space (Fics). Through an ongoing image-localized biopsy collection protocol, we analyzed 179 samples (Female: 75; Male: 104) from 55 patients (Female: 21; Male: 34) for bulk RNA-Seq. Samples were characterized by their edema Fecs scores and underwent differential expression, gene set enrichment analysis using MSigDB hallmarks and cellular deconvolution using CIBERSORTx. Through differential expression and gene set enrichment analyses of these spatial biopsies, we have identified sex-distinct gene expression and pathways corresponding to regions of high vs low edema. Within highly edematous regions, male samples were amplified for respiratory pathways, while female samples were suppressed. Connecting changes on MRIs with molecular markers from image-localized biopsies provides an opportunity to identify the biological drivers of brain tumor associated imageable edema. Specifically, elucidating the sex-distinct patterns connecting changes on MRI with cellular populations and molecular pathways could be used to better interpret imaging of patients and interpreting treatment response. Citation Format: Pamela R. Jackson, Lee Curtin, Sara Ranjbar, Kyle W. Singleton, Maciej M. Mrugala, Richard S. Zimmerman, Bernard R. Bendok, Peter Canoll, Kristin R. Swanson. Sex-distinct patterns of molecular pathways associated with brain tumor edema [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6168.

Abstract Background: While brief duration primary care appointments may improve access, they also limit the time clinicians spend evaluating painful conditions. This study aimed to evaluate whether 15-minute primary care appointments resulted in higher rates of opioid prescribing when compared to ≥30-minute appointments. Methods: We performed a retrospective cohort study using electronic health record (EHR), pharmacy, and administrative scheduling data from five primary care practices in Minnesota. Adult patients seen for acute Evaluation & Management visits between 10/1/2015 and 9/30/2017 scheduled for 15-minute appointments were propensity score matched to those scheduled for ≥30-minutes. Sub-groups were analyzed to include patients with acute and chronic pain conditions and prior opioid exposure. Multivariate logistic regression was performed to examine the effects of appointment length on the likelihood of an opioid being prescribed, adjusting for covariates including ethnicity, race, sex, marital status, and prior ED visits and hospitalizations. Results: We identified 45,471 eligible acute primary care visits during the study period with 2.7% (N=1233) of the visits scheduled for 15 minutes and 98.2% (N=44238) scheduled for 30 minutes or longer. Rates of opioid prescribing were significantly lower for opioid naive patients with acute pain scheduled in 15-minute appointments when compared to appointments of 30 minutes of longer (OR 0.55, 95% CI 0.35-0.84). There were no significant differences in opioid prescribing among other sub-groups. Conclusions: For selected indications and for selected patients, shorter duration appointments may not result in greater rates of opioid prescribing for common painful conditions.

Abstract Glioblastoma is a uniquely challenging and aggressive cancer that is practically considered uniformly fatal. This aggressiveness is driven by heterogeneity between and within patients and the diffuse invasion of tumor cells deep into the normal appearing brain tissue surrounding the frank tumor abnormality. We use our unique collection of 1000+ image-localized biopsies across nearly 200 patients to detect sex-distinct patterns of mapping between regional imaging features and underlying regional tumor biology. Specifically, we build mathematical models that fuse locoregional changes on MRI to underlying changes in tumor biology. We apply the resultant spatio-temporal models to serial imaging of patients receiving a variety of standard of care and novel therapeutics to track tumor dynamics under said therapies. This allows us unprecedent insight into the dynamics of each patients tumor under therapy. This includes detecting clonal loss through targeted therapies as well as shifts in the tumor ecosystem under immunotherapies. In this presentation, I will demonstrate how these methods can be brought together to help us detect, decipher and predict tumor dynamics and evolution in patients. Specifically, I will demonstrate the value of these novel combined resources in predicting response to treatment for EGFR-targeted therapies in 3 clinical trials and differentiating response to novel dendritic cells vaccines and CAR T-cell therapies in 2 additional clinical trials. Taken together, these complimentary approaches provide a platform to incorporate inter- and intra- tumoral heterogeneity into accurate predictive models that advance evolutionary- and ecologically-adaptive precision oncology for glioblastoma patients. Citation Format: Kristin R. Swanson. Composing each patient's equation: Deciphering brain tumor dynamics and evolution by integrating multi-regional image-localized biopsies [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr IA003.

Summary We report the case of a male patient with papillary thyroid cancer, familial thoracic aortic aneurysm and dissection, and a variation in the MYH11 gene. Because of considerable tumor bulk in the neck that was not resectable, the patient underwent partial resection at age 14 years. Since then, the patient has received only suppressive thyroid hormone therapy. He is now 71 years old, which is 57 years after the initial resection. The patient received care at our institution from July 2009 to August 2019, during which we documented the stability of multiple calcified masses in the neck. Follow-up examinations at another institution from September 2019 to April 2023 also confirmed the stability of the masses. The underlying cause of this unusually long indolent course of the disease is unclear. Whether extensive tumor calcifications or the MYH11 sequence variation contributed to the disease course is also uncertain. Learning points Papillary thyroid cancer with neck metastases may, in some cases, be stable and remain asymptomatic for decades. If locoregional stability of papillary thyroid cancer is documented for many years, observation may be preferable to extensive neck surgery in selected cases. This is the first report of an MYH11 gene alteration and thoracic aortic aneurysm in a patient with papillary thyroid cancer with indolent neck metastases. Future studies of MYH11 gene alterations in thyroid carcinoma are needed.

AbstractBackgroundImmunotherapies have changed the landscape of late‐stage melanoma; however, data evaluating timely access to immunotherapy are lacking.MethodsA retrospective cohort study utilizing the National Cancer Database was conducted. Stage III and IV melanoma cases diagnosed between 2011 and 2018 that received systemic treatment with either immunotherapy or chemotherapy were included. Chemotherapy included BRAF/MEK inhibitors. Multivariable logistic regression models were utilized to evaluate factors associated with the likelihood of receiving immunotherapy as primary systemic treatment relative to chemotherapy; additionally, Cox proportional hazards models were utilized to incorporate time from diagnosis to primary systemic therapy into the analysis.ResultsThe study population was comprised of 14,446 cases. The cohort included 12,053 (83.4%) immunotherapy and 2393 (16.6%) chemotherapy cases. In multivariable logistic regression analysis, factors significantly associated with immunotherapy receipt included population density, circle distance, year of diagnosis, Breslow thickness, and cancer stage. Immunotherapy timing was evaluated using multivariable Cox regression analysis. Minorities were less likely to receive timely immunotherapy than non‐Hispanic Whites (HR 0.83, CI 0.74–0.93, p = 0.001). Patients at circle distances of 10–49 miles (HR 0.94, CI 0.89–0.99, p = 0.02) and ≥50 miles (HR 0.83, CI 0.77–0.90, p < 0.001) were less likely to receive timely immunotherapy.ConclusionPatients traveling ≥10 miles and minorities have a decreased likelihood of receiving timely immunotherapy administration for primary systemic treatment. Future research is needed to identify what barriers and approaches can be leveraged to address these inequities.

Abstract Background Although response in pediatric low-grade glioma (pLGG) includes volumetric assessment, more simplified 2D-based methods are often used in clinical trials. The study’s purpose was to compare volumetric to 2D methods. Methods An expert neuroradiologist performed solid and whole tumor (including cyst and edema) volumetric measurements on MR images using a PACS-based manual segmentation tool in 43 pLGG participants (213 total follow-up images) from the Pacific Pediatric Neuro-Oncology Consortium (PNOC-001) trial. Classification based on changes in volumetric and 2D measurements of solid tumor were compared to neuroradiologist visual response assessment using the Brain Tumor Reporting and Data System (BT-RADS) criteria for a subset of 65 images using receiver operating characteristic (ROC) analysis. Longitudinal modeling of solid tumor volume was used to predict BT-RADS classification in 54 of the 65 images. Results There was a significant difference in ROC area under the curve between 3D solid tumor volume and 2D area (0.96 vs 0.78, P = .005) and between 3D solid and 3D whole volume (0.96 vs 0.84, P = .006) when classifying BT-RADS progressive disease (PD). Thresholds of 15–25% increase in 3D solid tumor volume had an 80% sensitivity in classifying BT-RADS PD included in their 95% confidence intervals. The longitudinal model of solid volume response had a sensitivity of 82% and a positive predictive value of 67% for detecting BT-RADS PD. Conclusions Volumetric analysis of solid tumor was significantly better than 2D measurements in classifying tumor progression as determined by BT-RADS criteria and will enable more comprehensive clinical management.