Faculty Bibliography

Breast cancer presents a significant global health challenge, necessitating continued innovation in diagnostic and therapeutic approaches. Recent advances have led to the identification of cancer-associated fibroblasts, which are highly prevalent in breast cancers and express fibroblast activation proteins (FAPs), as critical targets. FAP-specific radiotracers, when used with PET/CT and SPECT/CT, have significant potential for improving early breast cancer detection, staging, treatment response monitoring, and therapeutic intervention. This review provides insight into FAP-targeted molecular imaging, exploring advanced techniques for protein status assessment, development of early-phase targeted therapies, and other emerging applications. The advent of FAP-targeted imaging stands to significantly enhance personalized oncologic care, leading to improved breast cancer management and overall patient outcomes.

Chimeric antigen receptor (CAR) T cell therapy is a revolutionary form of immunotherapy that has proven to be efficacious in the treatment of many hematologic cancers. CARs are modified T lymphocytes that express an artificial receptor specific to a tumor-associated antigen. These engineered cells are then reintroduced to upregulate the host immune responses and eradicate malignant cells. While the use of CAR T cell therapy is rapidly expanding, little is known about how common side effects such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity (ICANS) present radiographically. Here we provide a comprehensive review of how side effects present in different organ systems and how they can be optimally imaged. Early and accurate recognition of the radiographic presentation of these side effects is critical to the practicing radiologist and their patients so that these side effects can be promptly identified and treated.

Breast ultrasound is a valuable adjunctive tool to mammography in detecting breast cancer, especially in women with dense breasts. Ultrasound also plays an important role in staging breast cancer by assessing axillary lymph nodes. However, its utility is limited by operator dependence, high recall rate, low positive predictive value and low specificity. These limitations present an opportunity for artificial intelligence (AI) to improve diagnostic performance and pioneer novel uses of ultrasound. Research in developing AI for radiology has flourished over the past few years. A subset of AI, deep learning, uses interconnected computational nodes to form a neural network, which extracts complex visual features from image data to train itself into a predictive model. This review summarizes several key studies evaluating AI programs' performance in predicting breast cancer and demonstrates that AI can assist radiologists and address limitations of ultrasound by acting as a decision support tool. This review also touches on how AI programs allow for novel predictive uses of ultrasound, particularly predicting molecular subtypes of breast cancer and response to neoadjuvant chemotherapy, which have the potential to change how breast cancer is managed by providing non-invasive prognostic and treatment data from ultrasound images. Lastly, this review explores how AI programs demonstrate improved diagnostic accuracy in predicting axillary lymph node metastasis. The limitations and future challenges in developing and implementing AI for breast and axillary ultrasound will also be discussed.

HER2 (Human Epidermal Growth Factor Receptor 2)-positive breast cancer is characterized by amplification of the HER2 gene and is associated with more aggressive tumor growth, increased risk of metastasis, and poorer prognosis when compared to other subtypes of breast cancer. HER2 expression is therefore a critical tumor feature that can be used to diagnose and treat breast cancer. Moving forward, advances in HER2 in vivo imaging, involving the use of techniques such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT), may allow for a greater role for HER2 status in guiding the management of breast cancer patients. This will apply both to patients who are HER2-positive and those who have limited-to-minimal immunohistochemical HER2 expression (HER2-low), with imaging ultimately helping clinicians determine the size and location of tumors. Additionally, PET and SPECT could help evaluate effectiveness of HER2-targeted therapies, such as trastuzumab or pertuzumab for HER2-positive cancers, and specially modified antibody drug conjugates (ADC), such as trastuzumab-deruxtecan, for HER2-low variants. This review will explore the current and future role of HER2 imaging in personalizing the care of patients diagnosed with breast cancer.

Cancer immunotherapies are drugs that modulate the body's own immune system as an anticancer strategy. Checkpoint inhibitor immunotherapies interfere with cell surface binding proteins that function to promote self-recognition and tolerance, ultimately leading to upregulation of the immune response. Given the striking success of these agents in early trials in melanoma and lung cancer, they have now been studied in many types of cancer and have become a pillar of anticancer therapy for many tumor types. However, abundant upregulation results in a new class of side effects, known as immune-related adverse events (IRAEs). It is critical for the practicing radiologist to be able to recognize these events to best contribute to care for patients on checkpoint inhibitor immunotherapy. Here, we provide a comprehensive system-based review of immune-related adverse events and associated imaging findings. Further, we detail the best imaging modalities for each as well as describe problem solving modalities. Given that IRAEs can be subclinical before becoming clinically apparent, radiologists may be the first provider to recognize them, providing an opportunity for early treatment. Awareness of IRAEs and how to best image them will prepare radiologists to make a meaningful contribution to patient care as part of the clinical team.

Freeman-Sheldon syndrome (FSS) is characterized by congenital contractures resulting from dominant point mutations in the embryonic isoform of muscle myosin. To investigate its disease mechanism, we used Drosophila models expressing FSS myosin mutations Y583S or T178I in their flight and jump muscles. We isolated these muscles from heterozygous mutant Drosophila and performed skinned fiber mechanics. The most striking mechanical alteration was an increase in active muscle stiffness. Y583S/+ and T178I/+ fibers' elastic moduli increased 70 and 77%, respectively. Increased stiffness contributed to decreased power generation, 49 and 66%, as a result of increased work absorbed during the lengthening portion of the contractile cycle. Slower muscle kinetics also contributed to the mutant phenotype, as shown by 17 and 32% decreases in optimal frequency for power generation, and 27 and 41% slower muscle apparent rate constant 2πb. Combined with previous measurements of slower in vitro actin motility, our results suggest a rate reduction of at least one strongly bound cross-bridge cycle transition that increases the time myosin spends strongly bound to actin, t_on. Increased t_on was further supported by decreased ATP affinity and a 16% slowing of jump muscle relaxation rate in T178I heterozygotes. Impaired muscle function caused diminished flight and jump ability of Y583S/+ and T178I/+ Drosophila. Based on our results, assuming that our model system mimics human skeletal muscle, we propose that one mechanism driving FSS is elevated muscle stiffness arising from prolonged t_on in developing muscle fibers.

KEY POINTS:Hypertrophic cardiomyopathy (HCM) is a genetic disease that causes thickening of the heart's ventricular walls and is a leading cause of sudden cardiac death. HCM is caused by missense mutations in muscle proteins including myosin, but how these mutations alter muscle mechanical performance in largely unknown. We investigated the disease mechanism for HCM myosin mutation R249Q by expressing it in the indirect flight muscle of Drosophila melanogaster and measuring alterations to muscle and flight performance. Muscle mechanical analysis revealed R249Q decreased muscle power production due to slower muscle kinetics and decreased force production; force production was reduced because fewer mutant myosin cross-bridges were bound simultaneously to actin. This work does not support the commonly proposed hypothesis that myosin HCM mutations increase muscle contractility, or causes a gain in function; instead, it suggests that for some myosin HCM mutations, hypertrophy is a compensation for decreased contractility. ABSTRACT:Hypertrophic cardiomyopathy (HCM) is an inherited disease that causes thickening of the heart's ventricular walls. A generally accepted hypothesis for this phenotype is that myosin heavy chain HCM mutations increase muscle contractility. To test this hypothesis, we expressed an HCM myosin mutation, R249Q, in Drosophila indirect flight muscle (IFM) and assessed myofibril structure, skinned fibre mechanical properties, and flight ability. Mechanics experiments were performed on fibres dissected from 2-h-old adult flies, prior to degradation of IFM myofilament structure, which started at 2 days old and increased with age. Homozygous and heterozygous R249Q fibres showed decreased maximum power generation by 67% and 44%, respectively. Decreases in force and work and slower overall muscle kinetics caused homozygous fibres to produce less power. While heterozygous fibres showed no overall slowing of muscle kinetics, active force and work production dropped by 68% and 47%, respectively, which hindered power production. The muscle apparent rate constant 2πb decreased 33% for homozygous but increased for heterozygous fibres. The apparent rate constant 2πc was greater for homozygous fibres. This indicates that R249Q myosin is slowing attachment while speeding up detachment from actin, resulting in less time bound. Decreased IFM power output caused 43% and 33% decreases in Drosophila flight ability and 19% and 6% drops in wing beat frequency for homozygous and heterozygous flies, respectively. Overall, our results do not support the increased contractility hypothesis. Instead, our results suggest the ventricular hypertrophy for human R249Q mutation is a compensatory response to decreases in heart muscle power output.

K146N is a dominant mutation in human β-cardiac myosin heavy chain, which causes hypertrophic cardiomyopathy. We examined how Drosophila muscle responds to this mutation and integratively analyzed the biochemical, physiological and mechanical foundations of the disease. ATPase assays, actin motility, and indirect flight muscle mechanics suggest at least two rate constants of the cross-bridge cycle are altered by the mutation: increased myosin attachment to actin and decreased detachment, yielding prolonged binding. This increases isometric force generation, but also resistive force and work absorption during cyclical contractions, resulting in decreased work, power output, flight ability and degeneration of flight muscle sarcomere morphology. Consistent with prolonged cross-bridge binding serving as the mechanistic basis of the disease and with human phenotypes, 146N/+ hearts are hypercontractile with increased tension generation periods, decreased diastolic/systolic diameters and myofibrillar disarray. This suggests that screening mutated Drosophila hearts could rapidly identify hypertrophic cardiomyopathy alleles and treatments.

The epicardium contributes to multiple cardiac lineages and is essential for cardiac development and regeneration. However, the mechanism of epicardium formation is unclear. This study aimed to establish the cellular and molecular mechanisms underlying the dissociation of pro-epicardial cells (PECs) from the pro-epicardium (PE) and their subsequent translocation to the heart to form the epicardium. We used lineage tracing, conditional deletion, mosaic analysis and ligand stimulation in mice to determine that both villous protrusions and floating cysts contribute to PEC translocation to myocardium in a CDC42-dependent manner. We resolved a controversy by demonstrating that physical contact of the PE with the myocardium constitutes a third mechanism for PEC translocation to myocardium, and observed a fourth mechanism in which PECs migrate along the surface of the inflow tract to reach the ventricles. Epicardial-specific Cdc42 deletion disrupted epicardium formation, and Cdc42 null PECs proliferated less, lost polarity and failed to form villous protrusions and floating cysts. FGF signaling promotes epicardium formation in vivo, and biochemical studies demonstrated that CDC42 is involved in the trafficking of FGF receptors to the cell membrane to regulate epicardium formation.