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.

Ex Vivo Human Tissue Functions as a Testing Platform for the Evaluation of a Nerve-Specific Fluorophore.

Significance: Selecting a nerve-specific lead fluorescent agent for translation in fluorescence-guided surgery is time-consuming and expensive. Preclinical fluorescent agent studies rely primarily on animal models, which are a critical component of preclinical testing, but these models may not predict fluorophore performance in human tissues.

Aim: The primary aim of this study was to evaluate and compare two preclinical models to test tissue-specific fluorophores based on discarded human tissues.

DNA origami drives gene expression in a human cell culture system.

Self-assembling DNA nanoparticles have the potential to significantly advance the targeted delivery of molecular cargo owing to their chemical and architectural flexibility. Recently, it has been demonstrated that the genetic code embedded in DNA nanoparticles produced by the method of DNA origami or related techniques can be recognized and copied by RNA polymerase in vitro. Further, sculpted DNA nanoparticles can serve as a substrate for Cas9-mediated gene modification and gene expression in cell culture.

Patient-specific arterial input function for accurate perfusion assessment in intraoperative fluorescence imaging.

Significance: The arterial input function (AIF) plays a crucial role in correcting the time-dependent concentration of the contrast agent within the arterial system, accounting for variations in agent injection parameters (speed, timing, etc.) across patients. Understanding the significance of the AIF can enhance the accuracy of tissue vascular perfusion assessment through indocyanine green-based dynamic contrast-enhanced fluorescence imaging (DCE-FI).

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.

Real-time identification of life-threatening necrotizing soft-tissue infections using indocyanine green fluorescence imaging.

Significance: Necrotizing soft-tissue infections (NSTIs) are life-threatening infections with a cumulative case fatality rate of 21%. The initial presentation of an NSTI is non-specific, frequently leading to misdiagnosis and delays in care. No current strategies yield an accurate, real-time diagnosis of an NSTI.

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.

Pathologic Femur Fracture in an Immunocompetent Healthy Young Adult due to Acute Osteomyelitis.

An immunocompetent 33-year-old woman presented with a pathologic femur fracture after one month of progressively worsening right thigh pain. Open biopsy demonstrated acute suppurative osteomyelitis despite the lack of clinical risk factors. The polymicrobial infection was successfully treated with three operative procedures and culture-specific antibiotic agents.

Bone Tumor Risk Stratification and Management System: A Consensus Guideline from the ACR Bone Reporting and Data System Committee.

The assessment and subsequent management of a potentially neoplastic bone lesion seen at diagnostic radiography is often complicated by diagnostic uncertainty and inconsistent management recommendations. Appropriate clinical management should be directed by risk of malignancy. Herein, the ACR-sponsored Bone Reporting and Data System (Bone-RADS) Committee, consisting of academic leaders in the fields of musculoskeletal oncology imaging and orthopedic oncology, presents the novel Bone-RADS scoring system to aid in risk assignment and provide risk-aligned management suggestions.

In vitro transcription of self-assembling DNA nanoparticles.

Nucleic acid nanoparticles are playing an increasingly important role in biomolecular diagnostics and therapeutics as well as a variety of other areas. The unique attributes of self-assembling DNA nanoparticles provide a potentially valuable addition or alternative to the lipid-based nanoparticles that are currently used to ferry nucleic acids in living systems. To explore this possibility, we have assessed the ability of self-assembling DNA nanoparticles to be constructed from complete gene cassettes that are capable of gene expression in vitro.

Automated motion artifact correction for dynamic contrast-enhanced fluorescence imaging during open orthopedic surgery.

Indocyanine green (ICG)-based dynamic contrast-enhanced fluorescence imaging (DCE-FI) can objectively assess bone perfusion intraoperatively. However, it is susceptible to motion artifacts due to patient's involuntary respiration during the 4.5-minute DCE-FI data acquisition.

Early identification of life-threatening soft-tissue infection using dynamic fluorescence imaging: first-in-kind clinical study of first-pass kinetics.

Necrotizing soft-tissue infections (NSTIs) are aggressive and deadly. Immediate surgical debridement is standard-of-care, but patients often present with non-specific symptoms, thereby delaying treatment. Because NSTIs cause microvascular thrombosis, we hypothesized that perfusion imaging using indocyanine green (ICG) would show diminished fluorescence signal in NSTI-affected tissues, particularly compared to non-necrotizing, superficial infections.

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.

Use of Freshly Amputated Human Limbs for Pre-Clinical Evaluation of Molecular-Targeted Fluorescent Probes.

We have co-developed a first-in-kind model of fluorophore testing in freshly amputated human limbs. human tissue provides a unique opportunity for the testing of pre-clinical fluorescent agents, collection of imaging data, and histopathologic examination in human tissue prior to performing experiments. Existing pre-clinical fluorescent agent studies rely primarily on animal models, which do not directly predict fluorophore performance in humans and can result in wasted resources and time if an agent proves ineffective in early human trials.

Acceptability and Feasibility of Delivering Decision Aids to Veterans for Management of Knee Osteoarthritis - A Pilot Study.

Introduction: Decision aids are effective tools in facilitating patient-centered care and patient involvement in the decision-making process. Given unique barriers to providing patient-centered care for Veterans, implementation of decision aids may improve overall quality of care. We aimed to assess the acceptability and feasibility of video-based and pamphlet-based decision aid use in Veterans with knee osteoarthritis.

Preclinical evaluation of molecularly targeted fluorescent probes in perfused amputated human limbs.

Significance: This first-in-kind, perfused, and amputated human limb model allows for the collection of human data in preclinical selection of lead fluorescent agents. The model facilitates more accurate selection and testing of fluorophores with human-specific physiology, such as differential uptake and signal in fat between animal and human models with zero risk to human patients. Preclinical testing using this approach may also allow for the determination of tissue toxicity, clearance time of fluorophores, and the production of harmful metabolites.

Applications of artificial intelligence in orthopaedic surgery.

The practice of medicine is rapidly transforming as a result of technological breakthroughs. Artificial intelligence (AI) systems are becoming more and more relevant in medicine and orthopaedic surgery as a result of the nearly exponential growth in computer processing power, cloud based computing, and development, and refining of medical-task specific software algorithms. Because of the extensive role of technologies such as medical imaging that bring high sensitivity, specificity, and positive/negative prognostic value to management of orthopaedic disorders, the field is particularly ripe for the application of machine-based integration of imaging studies, among other applications.

Intraoperative assessment of bone viability through improved analysis and visualization of dynamic contrast-enhanced fluorescence imaging: technique report.

Bone devitalization is believed to be a critical determinant of complications such as infection or nonunion. However, intraoperative assessment of bone devitalization, particularly in open fractures and infections, remains highly subjective resulting in variation in treatment. Optical imaging tools, particularly dynamic contrast-enhanced fluorescence imaging, can provide real-time, intraoperative assessment of bone and soft tissue perfusion, which informs the tissues' ability to heal and fight infection.

Fluorescence guidance improves the accuracy of radiological imaging-guided surgical navigation.

Background: Imaging-based navigation technologies require static referencing between the target anatomy and the optical sensors. Imaging-based navigation is therefore well suited to operations involving bony anatomy; however, these technologies have not translated to soft-tissue surgery. We sought to determine if fluorescence imaging complement conventional, radiological imaging-based navigation to guide the dissection of soft-tissue phantom tumors.

Dynamic contrast-enhanced fluorescence imaging compared with MR imaging in evaluating bone perfusion during open orthopedic surgery.

ICG-based dynamic contrast-enhanced fluorescence imaging (DCE-FI) and intraoperative DCE- magnetic resonance imaging (MRI) have been carried out nearly simultaneously in three lower extremity bone infection cases to investigate the relationship between these two imaging modalities for assessing bone blood perfusion during open orthopedic surgeries. Time-intensity curves in the corresponding regions of interest of two modalities were derived for comparison. The results demonstrated that ICG-based DCE-FI has higher sensitivity to perfusion changes while DCE-MRI provides superior and supplemental depth-related perfusion information.

Epidermal growth factor-targeted fluorescence is unaffected by standard neoadjuvant therapies in human sarcomas.

Curative surgery for other many cancers requires that the tumor be removed with a zone of normal tissue surrounding the tumor with 'negative' margins. Sarcomas, cancers of the bones, muscles, and fat, require WLE for cure. Unfortunately, 'positive' margins occur in 20-25% of sarcoma surgeries, associated with cancer recurrence and reduced survival.

Use of the PRECICE nail for distraction osteogenesis after tumor resection.

Introduction: Reconstructing long bone defects following intercalary tumor resection presents an exciting challenge with a greater range of surgical solutions than more typical situations requiring arthroplasty. Segmental bone transport (distraction osteogenesis) is the least utilized option for intercalary reconstruction; however, it arguably provides patients with the most desirable result. Distraction osteogenesis can be used in the management of multiple skeletal conditions including deformity (congenital or acquired), or in the presence of bone defects (by trauma or planned surgical excision).