First-in-human Study of ABY-029, a Novel Fluorescent Peptide that Targets Epidermal Growth Factor Receptor, Applied to Soft-Tissue Sarcomas.

ABY-029, an anti-epidermal growth factor receptor (EGFR) Affibody® molecule conjugated to IRDye 800CW, recently underwent first-in-human testing in soft-tissue sarcoma (STS). FDA Exploratory Investigational New Drug status was obtained for the Phase 0 clinical trial in which study objectives were to determine whether biological variance ratio (BVR) of 10 was achievable, fluorescence intensity correlated with EGFR expression, and doses were well tolerated. Patients (N=12) with STS were recruited based on positive EGFR immunohistochemical staining of diagnostic biopsies.

Whole-body fluorescence cryotomography identifies a fast-acting, high-contrast, durable contrast agent for fluorescence-guided surgery.

Imaging of tumor-specific fluorescent contrast agents to guide tumor removal has been shown to improve outcomes and is now standard practice for some neurosurgical procedures. However, many agents require administration hours before surgery, a practical challenge, and may exhibit inconsistent concordance with contrast-enhanced MRI (CE-MRI), the current standard for diagnosing and guiding glioma removal. A fluorescent agent that accurately marks tumor shortly after administration and is otherwise similar to CE-MRI would help overcome these shortcomings.

Two-color fluorescence-guided surgery for head and neck cancer resections.

Significance: Head and neck squamous cell carcinoma (HNSCC) has the sixth highest incidence worldwide, with cases annually. Surgery is the primary treatment option for HNSCC, during which surgeons balance two main goals: (1) complete cancer resection and (2) preservation of normal tissues to ensure post-surgical quality of life. Unfortunately, these goals are not synergistic, where complete cancer resection is often limited by efforts to preserve normal tissues, particularly nerves, and reduce life-altering comorbidities.

Robust Real-time Segmentation of Bio-Morphological Features in Human Cherenkov Imaging during Radiotherapy via Deep Learning.

Cherenkov imaging enables real-time visualization of megavoltage X-ray or electron beam delivery to the patient during Radiation Therapy (RT). Bio-morphological features, such as vasculature, seen in these images are patient-specific signatures that can be used for verification of positioning and motion management that are essential to precise RT treatment. However until now, no concerted analysis of this biological feature-based tracking was utilized because of the slow speed and accuracy of conventional image processing for feature segmentation.

Onward to Better Surgery - the Critical Need for Improved Ex Vivo Testing and Training Methods.

Guided surgery has demonstrated significant improvements in patient outcomes in some disease processes. Interest in this field has led to substantial growth in the technologies under investigation. Most likely no single technology will prove to be "best," and combinations of macro- and microscale guidance-using radiological imaging navigation, probes (activatable, perfusion, and molecular-targeted; large- and small-molecule), autofluorescence, tissue intrinsic optical properties, bioimpedance, and other characteristics-will offer patients and surgeons the greatest opportunity for high-success/low-morbidity medical interventions.

single-cell therapeutic response imaging facilitated by the TRIPODD fluorescence imaging platform.

: Small molecule drugs such as tyrosine kinase inhibitors (TKIs) targeting tumoral molecular dependencies have become standard of care for numerous cancer types. Notably, epidermal growth factor receptor (EGFR) TKIs (e.g.

Quantitative pharmacokinetic and biodistribution studies for fluorescent imaging agents.

Pharmacokinetics and biodistribution studies are essential for characterizing fluorescent agents . However, few simple methods based on fluorescence imaging are available that account for tissue optical properties and sample volume differences. We describe a method for simultaneously quantifying mean fluorescence intensity of whole blood and homogenized tissues in glass capillary tubes for two fluorescent agents, ABY-029 and IRDye 680LT, using wide-field imaging and tissue-specific calibration curves.

Quantifying Imaging Agent Binding and Dissociation in 3-D Cancer Spheroid Tissue Culture Using Paired-Agent Principles.

Binding kinetics play an important role in cancer diagnosis and therapeutics. However, current methods of quantifying binding kinetics fail to consider the three-dimensional environment that drugs and imaging agents experience in biological tissue. In response, a methodology to assay agent binding and dissociation in 3-D tissue culture was developed using paired-agent molecular imaging principles.

Improved intraoperative identification of close margins in oral squamous cell carcinoma resections using a dual aperture fluorescence ratio approach: first in-human results.

Significance: Surgical excision is the main treatment for solid tumors in oral squamous cell carcinomas, where wide local excision (achieving a healthy tissue margin of around the excised tumor) is the goal as it results in reduced local recurrence rates and improved overall survival.

Aim: No clinical methods are available to assess the complete surgical margin intraoperatively while the patient is still on the operating table; and while recent intraoperative back-bench fluorescence-guided surgery approaches have shown promise for detecting "positive" inadequate margins (), they have had limited success in the detection of "close" inadequate margins (1 to 5 mm). Here, a dual aperture fluorescence ratio (dAFR) approach was evaluated as a means of improving detection of close margins.

Subsurface fluorescence time-of-flight imaging using a large-format single-photon avalanche diode sensor for tumor depth assessment.

Significance: Fluorescence guidance is used clinically by surgeons to visualize anatomical and/or physiological phenomena in the surgical field that are difficult or impossible to detect by the naked eye. Such phenomena include tissue perfusion or molecular phenotypic information about the disease being resected. Conventional fluorescence-guided surgery relies on long, microsecond scale laser pulses to excite fluorescent probes.

Multiplex Ultrasound Imaging of Perfluorocarbon Nanodroplets Enabled by Decomposition of Postvaporization Dynamics.

Despite the real-time, nonionizing, and cost-effective nature of ultrasound imaging, there is a dearth of methods to visualize two or more populations of contrast agents simultaneously─a technique known as multiplex imaging. Here, we present a new approach to multiplex ultrasound imaging using perfluorocarbon (PFC) nanodroplets. The nanodroplets, which undergo a liquid-to-gas phase transition in response to an acoustic trigger, act as activatable contrast agents.

Neoadjuvant Therapies Do Not Reduce Epidermal Growth Factor Receptor (EGFR) Expression or EGFR-Targeted Fluorescence in a Murine Model of Soft-Tissue Sarcomas.

Purpose: ABY-029, an epidermal growth factor receptor (EGFR)-targeted, synthetic Affibody peptide labeled with a near-infrared fluorophore, is under investigation for fluorescence-guided surgery of sarcomas. To date, studies using ABY-029 have occurred in tumors naïve to chemotherapy (CTx) and radiation therapy (RTx), although these neoadjuvant therapies are frequently used for sarcoma treatment in humans. The goal of this study was to evaluate the impact of CTx and RTx on tumor EGFR expression and ABY-029 fluorescence of human soft-tissue sarcoma xenografts in a murine model.

A deep learning algorithm to detect cutaneous squamous cell carcinoma on frozen sections in Mohs micrographic surgery: A retrospective assessment.

Intraoperative margin analysis is crucial for the successful removal of cutaneous squamous cell carcinomas (cSCC). Artificial intelligence technologies (AI) have previously demonstrated potential for facilitating rapid and complete tumour removal using intraoperative margin assessment for basal cell carcinoma. However, the varied morphologies of cSCC present challenges for AI margin assessment.

Equivalent efficacy of indoor daylight and lamp-based 5-aminolevulinic acid photodynamic therapy for treatment of actinic keratosis.

Background: Photodynamic therapy (PDT) is widely used as a treatment for actinic keratoses (AK), with new sunlight-based regimens proposed as alternatives to lamp-based treatments. Prescribing indoor daylight activation could help address the seasonal temperature, clinical supervision, and access variability associated with outdoor treatments.

Objective: To compare the AK lesion clearance efficacy of indoor daylight PDT treatment (30 min of 5-aminolevulinic acid (ALA) pre-incubation, followed by 2 h of indoor sunlight) versus a lamp-based PDT treatment (30 min of ALA preincubation, followed by 10 min of red light).

Stealth Liposomes Encapsulating a Potent ACAT1/SOAT1 Inhibitor F12511: Pharmacokinetic, Biodistribution, and Toxicity Studies in Wild-Type Mice and Efficacy Studies in Triple Transgenic Alzheimer's Disease Mice.

Cholesterol is essential for cellular function and is stored as cholesteryl esters (CEs). CEs biosynthesis is catalyzed by the enzymes acyl-CoA:cholesterol acyltransferase 1 and 2 (ACAT1 and ACAT2), with ACAT1 being the primary isoenzyme in most cells in humans. In Alzheimer's Disease, CEs accumulate in vulnerable brain regions.

Paired-agent imaging as a rapid margin screening method in Mohs micrographic surgery.

Background: Mohs micrographic surgery is a procedure used for non-melanoma skin cancers that has 97-99% cure rates largely owing to 100% margin analysis enabled by sectioning with real-time, iterative histologic assessment. However, the technique is limited to small and aggressive tumors in high-risk areas because the histopathological preparation and assessment is very time intensive. To address this, paired-agent imaging (PAI) can be used to rapidly screen excised specimens and identify tumor positive margins for guided and more efficient microscopic evaluation.

Evaluating Receptor-Specific Fresh Specimen Staining for Tumor Margin Detection in Clinical Breast Specimens.

Purpose: Reliable and rapid identification of tumor in the margins of breast specimens during breast-conserving surgery to reduce repeat surgery rates is an active area of investigation. Dual-stain difference imaging (DDSI) is one of many approaches under evaluation for this application. This technique aims to topically apply fluorescent stain pairs (one targeted to a receptor-of-interest and the other a spectrally distinct isotype), image both stains, and compute a normalized difference image between the two channels.

A deep learning algorithm to detect cutaneous squamous cell carcinoma on frozen sections in Mohs micrographic surgery: a retrospective assessment.

Importance: Intraoperative margin analysis is crucial for the successful removal of cutaneous squamous cell carcinomas (cSCC). Artificial intelligence technologies (AI) have previously demonstrated potential for facilitating rapid and complete tumor removal using intraoperative margin assessment for basal cell carcinoma. However, the varied morphologies of cSCC present challenges for AI margin assessment.

Proceduralist criteria for evaluating interface utility of novel imaging modalities in early phase clinical trials: evaluating the need for standardized criteria.

Accelerating innovation in the space of fluorescence imaging for surgical applications has increased interest in safely and expediently advancing these technologies to clinic through Food and Drug Administration-(FDA-) compliant trials. Conventional metrics for early phase trials include drug safety, tolerability, dosing, and pharmacokinetics. Most procedural imaging technologies rely on administration of an exogenous fluorophore and concurrent use of an imaging system; both of which must receive FDA approval to proceed to clinic.

OregonFluor enables quantitative intracellular paired agent imaging to assess drug target availability in live cells and tissues.

Non-destructive fluorophore diffusion across cell membranes to provide an unbiased fluorescence intensity readout is critical for quantitative imaging applications in live cells and tissues. Commercially available small-molecule fluorophores have been engineered for biological compatibility, imparting high water solubility by modifying rhodamine and cyanine dye scaffolds with multiple sulfonate groups. The resulting net negative charge, however, often renders these fluorophores cell-membrane-impermeant.

Fluorescence molecular optomic signatures improve identification of tumors in head and neck specimens.

Background: Fluorescence molecular imaging using ABY-029, an epidermal growth factor receptor (EGFR)-targeted, synthetic Affibody peptide labeled with a near-infrared fluorophore, is under investigation for surgical guidance during head and neck squamous cell carcinoma (HNSCC) resection. However, tumor-to-normal tissue contrast is confounded by intrinsic physiological limitations of heterogeneous EGFR expression and non-specific agent uptake.

Objective: In this preliminary study, radiomic analysis was applied to optical ABY-029 fluorescence image data for HNSCC tissue classification through an approach termed "optomics.