Abstract
Surgical guidance with fluorescence has been demonstrated in individual clinical trials for decades, but the scientific and commercial conditions exist today for a dramatic increase in clinical value. In the past decade, increased use of indocyanine green based visualization of vascular flow, biliary function, and tissue perfusion has spawned a robust growth in commercial systems that have near-infrared emission imaging and video display capabilities. This recent history combined with major preclinical innovations in fluorescent-labeled molecular probes, has the potential for a shift in surgical practice toward resection guidance based upon molecular information in addition to conventional visual and palpable cues. Most surgical subspecialties already have treatment management decisions partially based upon the immunohistochemical phenotype of the cancer, as assessed from molecular pathology of the biopsy tissue. This phenotyping can inform the surgical resection process by spatial mapping of these features. Further integration of the diagnostic and therapeutic value of tumor metabolism sensing molecules or immune binding agents directly into the surgical process can help this field mature. Maximal value to the patient would come from identifying the spatial patterns of molecular expression in vivo that are well known to exist. However, as each molecular agent is advanced into trials, the performance of the imaging system can have a critical impact on the success. For example, use of pre-existing commercial imaging systems are not well suited to image receptor targeted fluorophores because of the lower concentrations expected, requiring orders of magnitude more sensitivity. Additionally the imaging system needs the appropriate dynamic range and image processing features to view molecular probes or therapeutics that may have nonspecific uptake or pharmacokinetic issues which lead to limitations in contrast. Imaging systems need to be chosen based upon objective performance criteria, and issues around calibration, validation, and interpretation need to be established before a clinical trial starts. Finally, as early phase trials become more established, the costs associated with failures can be crippling to the field, and so judicious use of phase 0 trials with microdose levels of agents is one viable paradigm to help the field advance, but this places high sensitivity requirements on the imaging systems used. Molecular-guided surgery has truly transformative potential, and several key challenges are outlined here with the goal of seeing efficient advancement with ideal choices. The focus of this vision 20/20 paper is on the technological aspects that are needed to be paired with these agents.
Highlights
HISTORICAL DEVELOPMENTS TO CURRENT STATUSIn the past decade, there has been rapid growth in clinical use in fluorescence to guide surgical procedures, and recent Food and Drug Administration (FDA) 510(k) clearance of four new systems in the last two years
This paper describes the key issues of imaging technologies, molecule evaluation plans, and choices of when to advance into human trials, and some of the economics needed to develop a viable paradigm for molecular-guided surgery
The other major paradigm utilized in the nuclear medicine world is that of microdose studies, where imaging is done at subpharmacodynamic dose levels (FDA specifies this as
Summary
There has been rapid growth in clinical use in fluorescence to guide surgical procedures, and recent FDA 510(k) clearance of four new systems in the last two years. Since metabolic and immunologic probes largely exist in tissue at the micromolar to nanomolar concentration ranges, photoacoustic tomography imaging may result in limited value Still, research into these devices continues, and it may be that innovations in the contrast agents make these more attractive for commercial advancement into clinical trials. The devices which are commercially available for fluorescence molecular imaging are largely based upon traditional methods of broad field optical excitation using LEDs or laser illumination, coupled with optical filtering of the remitted light, focused onto a lower cost imaging sensor These workhorse systems have advanced significantly in the past decade, to the point where there are a dozen companies competing with FDA approved systems for this emerging clinical surgery market.
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