Optical Coherence Tomography-Based Functional Stenosis Assessment: FUSION-A Prospective Multicenter Trial.

BACKGROUND: Intravascular imaging and intracoronary physiology may both be used to guide and optimize percutaneous coronary intervention; however, they are rarely used together. The virtual flow reserve (VFR) is an optical coherence tomography (OCT)-based model of fractional flow reserve (FFR) facilitating the assessment of the physiological significance of coronary lesions. We aimed to validate the VFR assessment of intermediate coronary artery stenoses. METHODS: FUSION (Validation of OCT-Based Functional Diagnosis of Coronary Stenosis) was a multicenter, prospective, observational study comparing OCT-derived VFR to invasive FFR. VFR was mathematically derived from a lumped parameter flow model based on 3-dimensional lumen morphology. Patients undergoing coronary angiography with intermediate angiographic stenosis (40%-90%) requiring physiological assessment were enrolled. Investigational sites were blinded to the VFR analysis, and all OCT and FFR data were reviewed by an independent core laboratory. The coprimary end points were the sensitivity and specificity of VFR against FFR as the reference standard, each of which was tested against prespecified performance goals. RESULTS: After core laboratory review, 266 vessels in 224 patients from 25 US centers were included in the analysis. The mean angiographic diameter stenosis was 65.5%±14.9%, and the mean FFR was 0.83±0.11. Overall accuracy, sensitivity, and specificity of VFR versus FFR using a binary cutoff point of 0.80 were 82.0%, 80.4%, and 82.9%, respectively. The 97.5% lower confidence bound met the prespecified performance goal for sensitivity (71.6% versus 70%; P=0.01) and specificity (76.6% versus 75%; P=0.01). The area under the curve was 0.88 (95% CI, 0.84-0.92; P<0.0001). CONCLUSIONS: OCT-derived VFR demonstrates high sensitivity and specificity for predicting invasive FFR. Integrating high-resolution intravascular imaging with imaging-derived physiology may provide synergistic benefits as an adjunct to percutaneous coronary intervention. REGISTRATION: URL: https://clinicaltrials.gov; Unique identifier: NCT04356027.

Off-Peak Near-Infrared-II (NIR-II) Bioimaging of an Immunoconjugate Having Peak Fluorescence Emission in the NIR-I Spectral Region for Improving Tumor Margin Delineation.

The primary treatment for malignant tumors remains to be resection. The strongest predictor of recurrence and postoperative prognosis is whether diseased tissue/cells remain(s) at the surgical margin. Cancer surgery entails surgeons having the capability to visually distinguish between subtle shades of color in attempts of differentiating between diseased tissue and healthy tissue under standard white-light illumination, as such tissue states appear identical at the meso-/macroscopic level. Accordingly, enhancing the capability of surgeons to do so such that they can accurately delineate the tumor margin is of paramount importance. Fluorescence-guided surgery facilitates in enhancing such capability by color-coding the surgical field with overlaid contrasting pseudo-colors from real-time intraoperative fluorescence emission via utilizing fluorescent constructs in tandem. Constructs undergoing clinical trials or that are FDA-approved provide peak fluorescence emission in the visible (405 - 700 nm) or near-infrared-I (NIR-I) spectral region (700-900 nm), whereby differentiation between tissue states progressively improves in sync with using constructs that emit longer wavelengths of light. Here, we repurpose the usage of such fluorescent constructs by establishing feasibility of a tumor-targeting immunoconjugate (cetuximab-IRDye800) having peak fluorescence emission at the NIR-I spectral region to provide improved tumor margin delineation by affording higher tumor-to-background ratios (TBRs) when measuring its off-peak fluorescence emission at the near-infrared-II (NIR-II) spectral region (1000-1700 nm) in in vivo applications. We prepared murine tumor models, administered such immunoconjugate, and imaged such models pre-/post-administration via utilizing imaging systems that separately afforded acquisition of fluorescence emission in the NIR-I or NIR-II spectral region. On doing so, we determined in vivo TBRs, ex vivo TBRs with/-out skin, and ex vivo biodistribution, all via measuring the fluorescence emission of the immunoconjugate at tumor site(s) at both spectral regions. Collectively, we established feasibility of using the immunoconjugate to afford improved tumor margin delineation by providing 2-fold higher TBRs via utilizing the NIR-II spectral region to capture off-peak fluorescence emission from a fluorescent construct having NIR-I peak fluorescence emission.

Targeting intracranial patient-derived glioblastoma (GBM) with a NIR-I fluorescent immunoconjugate for facilitating its image-guided resection.

Glioblastoma multiforme (GBM) is the most aggressive form of primary brain tumor type and is associated with a high mortality rate borne out of such affording a survival rate of only 15 months. GBM aggressiveness is associated with the overexpression of epidermal growth factor receptor (EGFR) and its mutants. Targeting GBM with therapeutics is challenging because the blood-brain barrier (BBB) permits primarily select small-molecule entities across its semipermeable blockade. However, recent preclinical data suggest that large biomolecules, such as the anti-EGFR antibody therapeutic, cetuximab, could be capable of bypassing the BBB despite the relative enormity of its size. As such, we set forth to establish the feasibility of utilizing an EGFR-targeting near-infrared-I (NIR-I) fluorescent construct in the form of an immunoconjugate (cetuxmimab-IRDye800) to achieve visual differentiation between diseased brain tissue arising from a low-passage patient-derived GBM cell line (GBM39) and healthy brain tissue via utilizing orthotopic intracranial murine GBM39 tumor models for in vivo and ex vivo evaluation such that by doing so would establish proof of concept for ultimately facilitating its in vivo fluorescence-guided resection and ex vivo surgical back-table pathological confirmation in the clinic. As anticipated, we were not capable of distinguishing between malignant tumor tissue and healthy tissue in resected intact and slices of whole brain ex vivo under white-light illumination (WLI) due to both the diseased tissue and healthy tissue appearing virtually identical to the unaided eye. However, we readily observed over an average 6-fold enhancement in the fluorescence emission in the resected intact whole brain ex vivo when performing NIR-I fluorescence imaging (FLI) on the cohort of GBM39 tumor models that were administered the immunoconjugate compared to controls. In all, we laid the initial groundwork for establishing that NIR-I fluorescent immunoconjugates (theranostics) such as cetuximab-IRDye800 can bypass the BBB to visually afford GBM39 tumor tissue differentiation for its image-guided surgical removal.

In-vivo optical imaging in head and neck oncology: basic principles, clinical applications and future directions.

Head and neck cancers become a severe threat to human's health nowadays and represent the sixth most common cancer worldwide. Surgery remains the first-line choice for head and neck cancer patients. Limited resectable tissue mass and complicated anatomy structures in the head and neck region put the surgeons in a dilemma between the extensive resection and a better quality of life for the patients. Early diagnosis and treatment of the pre-malignancies, as well as real-time in vivo detection of surgical margins during en bloc resection, could be leveraged to minimize the resection of normal tissues. With the understanding of the head and neck oncology, recent advances in optical hardware and reagents have provided unique opportunities for real-time pre-malignancies and cancer imaging in the clinic or operating room. Optical imaging in the head and neck has been reported using autofluorescence imaging, targeted fluorescence imaging, high-resolution microendoscopy, narrow band imaging and the Raman spectroscopy. In this study, we reviewed the basic theories and clinical applications of optical imaging for the diagnosis and treatment in the field of head and neck oncology with the goal of identifying limitations and facilitating future advancements in the field.