By contributing to noninvasive molecular imaging and radioguided surgery, nuclear medicine has been instrumental in the realization of precision medicine. During the last decade, it has also become apparent that nuclear medicine (e.g., in the form of bimodal/hybrid tracers) can help to empower fluorescenceguided surgery. More specifically, when using hybrid tracers, lesions can be noninvasively identified and localized with a high sensitivity and precision (guided by the radioisotope) and ultimately resected under real-time optical guidance (fluorescent dye). This topical review discusses early clinical successes, preclinical directions, and key aspects that could have an impact on the future of this field.

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With the rise of fluorescence-guided surgery, it has become evident that different types of fluorescence signals can provide value in the surgical setting. Hereby a different range of targets have been pursued in a great variety of surgical indications. One of the future challenges lies in combining complementary fluorescent readouts during one and the same surgical procedure, so-called multi-wavelength fluorescence guidance. In this review we summarize the current clinical state-of-the-art in multi-wavelength fluorescence guidance, basic technical concepts, possible future extensions of existing clinical indications and impact that the technology can bring to clinical care.

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In penile squamous cell carcinoma (pSCC), primary surgery aims to obtain oncologically safe margins while minimizing mutilation. Surgical guidance provided by receptor-specific tracers could potentially improve margin detection and reduce unnecessary excision of healthy tissue.Here, we present the first results of a prospective feasibility study for real-time intraoperative visualization of pSCC using a fluorescent mesenchymal-epithelial transition factor (c-MET) receptor targeting tracer (EMI-137). MethodsEMI-137 tracer performance was initially assessed ex vivo (N=10) via incubation of freshly excised pSCC in a solution containing EMI-137 (500 nM). The in vivo potential of c-MET targeting and intraoperative tumour visualization was assessed after intravenous administration of EMI-137 in five pSCC patients scheduled for surgical resection using a Cyanine-5 (Cy5) fluorescence camera.Fluorescence imaging results were related to standard pathological tumour evaluation and c-MET immunohistochemistry. Three of the five in vivo patients also underwent a sentinel node resection after local administration of the hybrid tracer indocyanine green (ICG)-99m Tcnanocolloid, which could be imaged using a near-infrared fluorescence camera. ResultsNo tracer-related adverse events were encountered. Both ex vivo and in vivo, EMI-137 enabled c-MET based tumour visualization in all patients. Histopathological analyses showed that all pSCC's expressed c-MET, with expression levels of ≥70% in 14/15 patients. Moreover, the highest c-MET 4 4 expression levels were seen on the outside rim of the tumours, and a visual correlation was found between c-MET expression and fluorescence signal intensity. No complications were encountered when combining primary tumour targeting with lymphatic mapping. As such, simultaneous use of Cy5 and ICG in the same patient proved to be feasible. ConclusionFluorescence imaging of c-MET receptor-expressing pSCC tumours after intravenous injection of EMI-137 was shown to be feasible and can be combined with fluorescence-based lymphatic mapping. This combination is unique and paves the way towards further development of this surgical guidance approach.

To our knowledge this is the first study demonstrating the feasibility of intraoperative navigation based on preoperatively acquired 3-dimensional single photon emission computerized tomography/computerized tomography images. Although confirmation of successful target localization (eg using γ tracing or fluorescence imaging) remains indispensable, this opens the way to translate 3-dimensional functional imaging data to the operating room.

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To identify predictive pathological factors for local recurrence (LR) and to study the impact of LR on survival in patients treated with glansectomy for penile squamous cell carcinoma (pSCC). Patients and MethodsWe retrospectively studied patients treated with glansectomy at international, high-volume reference centres. We analysed histopathological predictors of LR, stratified patients into risk groups based on the number of risk factors present, and studied the impact of LR on survival outcomes using Kaplan-Meier survival analysis and stepwise Cox proportional hazards regression models. Subsequently, we performed sensitivity analyses excluding margin-positive cases, pT3 disease, and cN+ disease, or all of these factors. ResultsAcross nine institutions, 897 patients were included, of whom 94 experienced LR. On multivariable analysis, presence of high-grade disease and pT3 stage were independent predictors of LR. LR-free survival rates significantly differed according to the number of risk factors present, with a hazard ratio (HR) of 1.90 (95% confidence interval [CI] 1.17-3.07; P = 0.01) for the intermediate-risk group (one risk factor) and 6.11 (95% CI 3.47-10.77; P < 0.001) for the high-risk group (two risk factors), using the low-risk group (no risk factors) as reference. Patients who experienced LR had significantly worse overall survival (OS; HR 2.89, 95% CI 2.02-4.14; P < 0.001) and cancer-specific survival (CSS; HR 5.64, 95% CI 3.45-9.22; P < 0.001). LR (HR 3.82, 95% CI 2.14-6.8; P < 0.001), lymphovascular invasion and cN status were significant predictors of decreased CSS. LR remained a strong predictor of both OS and CSS in all sensitivity analyses. ConclusionsPathological T3 stage and presence of high-grade disease were independent histopathological predictors of LR after glansectomy for primary pSCC, which allowed risk stratification into three groups with significantly different risk of developing LR. Additionally, LR is related to poor OS and CSS, indicating that LR is a manifestation of underlying aggressive disease and clearly challenging the dogma of using organ-sparing surgery whenever possible since survival is unaffected by higher LR rates.