Bedside Utilization of Intestinal Pathology in Preterm Infants with Surgical Necrotizing Enterocolitis.

Necrotizing enterocolitis (NEC) is one of the most common conditions requiring emergency surgery in the neonatal intensive care unit and is associated with multiorgan dysfunction, multiple systemic morbidities, and mortality. The resected bowel commonly shows evidence of coagulative necrosis, inflammation, interstitial hemorrhages, and reparative changes on the pathology examination. The severity of these pathological abnormalities may correlate with the disease's severity and pace of progression and may assist in the prediction of clinical outcomes.

Photoacoustic imaging for non-invasive assessment of biomarkers of intestinal injury in experimental necrotizing enterocolitis.

Background: Necrotizing enterocolitis (NEC) is an often-lethal disease of the premature infant intestinal tract, exacerbated by significant diagnostic difficulties. In NEC, the intestine exhibits hypoperfusion and dysmotility, contributing to disease pathogenesis. However, these features cannot be accurately and quantitively assessed with current imaging modalities.

Characterizing breast cancer response to neoadjuvant therapy based on biophysical modeling and multiparametric magnetic resonance imaging data.

Personalized medicine efforts are focused on identifying biomarkers to guide individualizing neoadjuvant therapy regimens. In this work, we aim to validate a previously developed image data-driven mathematical modeling approach for dynamic characterization of breast cancer response to neoadjuvant therapy using a large, multi-site cohort. We retrospectively analyzed patients enrolled in the BMMR2 ACRIN 6698 subset at 10 institutions.

Photoacoustic Imaging for Non-Invasive Assessment of Physiological Biomarkers of Intestinal Injury in Experimental Necrotizing Enterocolitis.

Background: Necrotizing enterocolitis (NEC) is an often-lethal disease of the premature infants' intestinal tract that is exacerbated by significant difficulties in early and accurate diagnosis. In NEC disease, the intestine often exhibits hypoperfusion and dysmotility, which contributes to advanced disease pathogenesis. However, these physiological features cannot be accurately and quantitively assessed within the current constraints of imaging modalities frequently used in the clinic (plain film X-ray and ultrasound).

Myocardial Elasticity Imaging Correlates with Histopathology in a Model of Anthracycline-Induced Cardiotoxicity.

Background: There is considerable focus on developing strategies for identifying subclinical cardiac decline prior to cardiac failure. Myocardial tissue elasticity changes may precede irreversible cardiac damage, providing promise for an early biomarker for cardiac decline. Biomarker strategies are of particular interest in cardio-oncology due to cardiotoxic effects of anti-neoplastic therapies, particularly anthracycline-based chemotherapeutics.

Photoacoustic Imaging as a Novel Non-invasive Biomarker to Assess Intestinal Tissue Oxygenation and Motility in Neonatal Rats.

Background: Within the premature infant intestine, oxygenation and motility play key physiological roles in healthy development and disease such as necrotizing enterocolitis. To date, there are limited techniques to reliably assess these physiological functions that are also clinically feasible for critically ill infants. To address this clinical need, we hypothesized that photoacoustic imaging (PAI) can provide non-invasive assessment of intestinal tissue oxygenation and motility to characterize intestinal physiology and health.

Photoacoustic Imaging as a Novel Non-Invasive Biomarker to Assess Intestinal Tissue Oxygenation and Motility in Neonatal Rats.

Background: Within the premature infant intestine, oxygenation and motility play key physiological roles in healthy development and disease such as necrotizing enterocolitis. To date, there are limited techniques to reliably assess these physiological functions that are also clinically feasible for critically ill infants. To address this clinical need, we hypothesized that photoacoustic imaging (PAI) can provide non-invasive assessment of intestinal tissue oxygenation and motility to characterize intestinal physiology and health.

Reproducibility assessment of a biomechanical model-based elasticity imaging method for identifying changes in left ventricular mechanical stiffness.

Purpose: Cardiotoxicity of antineoplastic therapies is increasingly a risk to cancer patients treated with curative intent with years of life to protect. Studies highlight the importance of identifying early cardiac decline in cancer patients undergoing cardiotoxic therapies. Accurate tools to study this are a critical clinical need.

Dynamic characterization of breast cancer response to neoadjuvant therapy using biophysical metrics of spatial proliferation.

Current tools to assess breast cancer response to neoadjuvant chemotherapy cannot reliably predict disease eradication, which if possible, could allow early cessation of therapy. In this work, we assessed the ability of an image data-driven mathematical modeling approach for dynamic characterization of breast cancer response to neoadjuvant therapy. We retrospectively analyzed patients enrolled in the I-SPY 2 TRIAL at the Atrium Health Wake Forest Baptist Comprehensive Cancer Center.

Developing a biomechanical model-based elasticity imaging method for assessing hormone receptor positive breast cancer treatment-related myocardial stiffness changes.

Assessing cardiotoxicity as a result of breast cancer therapeutics is increasingly important as breast cancer diagnoses are trending younger and overall survival is increasing. With evidence showing that prevention of cardiotoxicity plays a significant role in increasing overall survival, there is an unmet need for accurate non-invasive methods to assess cardiac injury due to cancer therapies. Current clinical methods are too coarse and emerging research methods have not yet achieved clinical implementation.

Chief cell plasticity is the origin of metaplasia following acute injury in the stomach mucosa.

Objective: Metaplasia arises from differentiated cell types in response to injury and is considered a precursor in many cancers. Heterogeneous cell lineages are present in the reparative metaplastic mucosa with response to injury, including foveolar cells, proliferating cells and spasmolytic polypeptide-expressing metaplasia (SPEM) cells, a key metaplastic cell population. Zymogen-secreting chief cells are long-lived cells in the stomach mucosa and have been considered the origin of SPEM cells; however, a conflicting paradigm has proposed isthmal progenitor cells as an origin for SPEM.

Clinical assessment of a biophysical model for distinguishing tumor progression from radiation necrosis.

Purpose: The efficacy of an imaging-driven mechanistic biophysical model of tumor growth for distinguishing radiation necrosis from tumor progression in patients with enhancing lesions following stereotactic radiosurgery (SRS) for brain metastasis is validated.

Methods: We retrospectively assessed the model using 73 patients with 78 lesions and histologically confirmed radiation necrosis or tumor progression. Postcontrast T1-weighted MRI images were used to extract parameters for a mechanistic reaction-diffusion logistic growth model mechanically coupled to the surrounding tissue.

Human placental-derived stem cell therapy ameliorates experimental necrotizing enterocolitis.

Necrotizing enterocolitis (NEC), a life-threatening intestinal disease, is becoming a larger proportionate cause of morbidity and mortality in premature infants. To date, therapeutic options remain elusive. Based on recent cell therapy studies, we investigated the effect of a human placental-derived stem cell (hPSC) therapy on intestinal damage in an experimental NEC rat pup model.

Group 2 Innate Lymphoid Cells Coordinate Damage Response in the Stomach.

Background & Aims: Severe injury to the lining of the stomach leads to changes in the epithelium (reprogramming) that protect and promote repair of the tissue, including development of spasmolytic polypeptide-expressing metaplasia (SPEM) and tuft and foveolar cell hyperplasia. Acute gastric damage elicits a type-2 inflammatory response that includes production of type-2 cytokines and infiltration by eosinophils and alternatively activated macrophages. Stomachs of mice that lack interleukin 33 (IL33) or interleukin 13 (IL13) did not undergo epithelial reprogramming after drug-induced injury.

Characterization of multicellular breast tumor spheroids using image data-driven biophysical mathematical modeling.

Multicellular tumor spheroid (MCTS) systems provide an in vitro cell culture model system which mimics many of the complexities of an in vivo solid tumor and tumor microenvironment, and are often used to study cancer cell growth and drug efficacy. Here, we present a coupled experimental-computational framework to estimate phenotypic growth and biophysical tumor microenvironment properties. This novel framework utilizes standard microscopy imaging of MCTS systems to drive a biophysical mathematical model of MCTS growth and mechanical interactions.

Accounting for intraoperative brain shift ascribable to cavity collapse during intracranial tumor resection.

For many patients with intracranial tumors, accurate surgical resection is a mainstay of their treatment paradigm. During surgical resection, image guidance is used to aid in localization and resection. Intraoperative brain shift can invalidate these guidance systems.

Toward Image Data-Driven Predictive Modeling for Guiding Thermal Ablative Therapy.

Objective: Accurate prospective modeling of microwave ablation (MWA) procedures can provide powerful planning and navigational information to physicians. However, patient-specific tissue properties are generally unavailable and can vary based on factors such as relative perfusion and state of disease. Therefore, a need exists for modeling frameworks that account for variations in tissue properties.

Leveraging Mathematical Modeling to Quantify Pharmacokinetic and Pharmacodynamic Pathways: Equivalent Dose Metric.

Treatment response assays are often summarized by sigmoidal functions comparing cell survival at a single timepoint to applied drug concentration. This approach has a limited biophysical basis, thereby reducing the biological insight gained from such analysis. In particular, drug pharmacokinetic and pharmacodynamic (PK/PD) properties are overlooked in developing treatment response assays, and the accompanying summary statistics conflate these processes.

Translating preclinical MRI methods to clinical oncology.

The complexity of modern in vivo magnetic resonance imaging (MRI) methods in oncology has dramatically changed in the last 10 years. The field has long since moved passed its (unparalleled) ability to form images with exquisite soft-tissue contrast and morphology, allowing for the enhanced identification of primary tumors and metastatic disease. Currently, it is not uncommon to acquire images related to blood flow, cellularity, and macromolecular content in the clinical setting.

modeling of interstitial pressure in a porcine model: approximation of poroelastic properties and effects of enhanced anatomical structure modeling.

The purpose of this investigation is to test whether a poroelastic model with enhanced structure can capture interstitial pressure dynamics in a brain undergoing mock surgical loads. Using interstitial pressure data from a porcine study, we use an inverse model to reconstruct material properties in an effort to capture these brain tissue dynamics. Four distinct models for the reconstruction of parameters are investigated (full anatomical condition description, condition without dural septa description, condition without ventricle boundary description, and the conventional fully saturated model).

Biophysical model-based parameters to classify tumor recurrence from radiation-induced necrosis for brain metastases.

Purpose: Stereotactic radiosurgery (SRS) is used for local control treatment of patients with intracranial metastases. As a result of SRS, some patients develop radiation-induced necrosis. Radiographically, radiation-induced necrosis can appear similar to tumor recurrence in magnetic resonance (MR) T -weighted contrast-enhanced imaging, T -weighted MR imaging, and Fluid-Attenuated Inversion Recovery (FLAIR) MR imaging.

Applying dynamic contrast enhanced MSOT imaging to intratumoral pharmacokinetic modeling.

Examining the dynamics of an agent in the tumor microenvironment can offer critical insights to the influx rate and accumulation of the agent. Intratumoral kinetic characterization in the setting can further elicudate distribution patterns and tumor microenvironment. Dynamic contrast-enhanced Multispectral Optoacoustic Tomographic imaging (DCE-MSOT) acquires serial MSOT images with the administration of an exogenous contrast agent over time.

Precision Medicine with Imprecise Therapy: Computational Modeling for Chemotherapy in Breast Cancer.

Medical oncology is in need of a mathematical modeling toolkit that can leverage clinically-available measurements to optimize treatment selection and schedules for patients. Just as the therapeutic choice has been optimized to match tumor genetics, the delivery of those therapeutics should be optimized based on patient-specific pharmacokinetic/pharmacodynamic properties. Under the current approach to treatment response planning and assessment, there does not exist an efficient method to consolidate biomarker changes into a holistic understanding of treatment response.

Variable Cell Line Pharmacokinetics Contribute to Non-Linear Treatment Response in Heterogeneous Cell Populations.

We develop a combined experimental-mathematical framework to investigate heterogeneity in the context of breast cancer treated with doxorubicin. We engineer a cell line to over-express the multi-drug resistance 1 protein (MDR1), an ATP-dependent pump that effluxes intracellular drug. Co-culture experiments mixing the MDR1-overexpressing line with its parental line are evaluated via fluorescence microscopy.

Toward quantitative quasistatic elastography with a gravity-induced deformation source for image-guided breast surgery.

Biomechanical breast models have been employed for applications in image registration and diagnostic analysis, breast augmentation simulation, and for surgical and biopsy guidance. Accurate applications of stress-strain relationships of tissue within the breast can improve the accuracy of biomechanical models that attempt to simulate breast deformations. Reported stiffness values for adipose, glandular, and cancerous tissue types vary greatly.