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BackgroundIn recent years, the use of Indocyanine Green (ICG) fluorescence-guided surgery during open and laparoscopic procedures has exponentially expanded across various clinical settings. The European Association of Endoscopic Surgery (EAES) initiated a consensus development conference on this topic with the aim of creating evidence-based statements and recommendations for the surgical community.MethodsAn expert panel of surgeons has been selected and invited to participate to this project. Systematic reviews of the PubMed, Embase and Cochrane libraries were performed to identify evidence on potential benefits of ICG fluorescence-guided surgery on clinical practice and patient outcomes. Statements and recommendations were prepared and unanimously agreed by the panel; they were then submitted to all EAES members through a two-rounds online survey and results presented at the EAES annual congress, Barcelona, November 2021.ResultsA total of 18,273 abstracts were screened with 117 articles included. 22 statements and 16 recommendations were generated and approved. In some areas, such as the use of ICG fluorescence-guided surgery during laparoscopic cholecystectomy, the perfusion assessment in colorectal surgery and the search for the sentinel lymph nodes in gynaecological malignancies, the large number of evidences in literature has allowed us to strongly recommend the use of ICG for a better anatomical definition and a reduction in post-operative complications.ConclusionsOverall, from the systematic literature review performed by the experts panel and the survey extended to all EAES members, ICG fluorescence-guided surgery could be considered a safe and effective technology. Future robust clinical research is required to specifically validate multiple organ-specific applications and the potential benefits of this technique on clinical outcomes.

Osteosarcoma (OS) is characterized by an unfavorable prognosis and high mortality rates, with the local recurrence attributed to residual lesions post‐surgery being a major reason for treatment failure. Precise and tumor‐specific resection guidance to minimize recurrence remains a significant challenge. In the present study, a nanosystem based on aggregation‐induced emission (AIE) molecules with emission in the second near‐infrared window is proposed for the synergistic fluorescence (FL) and chemiluminescence (CL) imaging‐guided surgical resection for the elimination of tumor foci. The designed AIE molecule, BBTD14, exhibits stable FL with a high quantum yield of up to 3.95%, which effectively matches the energy levels of CL high‐energy states, generating the longest emission wavelength of CL reported to date. Targeted tumor imaging‐guided surgery (IGS) is facilitated by FL and CL nanoprobes (FLNP and CLNP) constructed based on BBTD14. During OS surgery, the FLNP, with the stability of FL and a high targeting capability, was first intravenously used to guide the surgical removal of the main tumor. Subsequently, CLNP was locally incubated to facilitate rapid and accurate evaluation of residual tumors at the operative border. High signal‐to‐noise ratio CL imaging was achieved after spraying with hydrogen peroxide, thereby overcoming the limitations of intraoperative frozen sections. The proposed technique also significantly reduced the recurrence rates in OS mouse models and exhibited high marker specificity in ex vivo OS patient pathology samples, confirming its potential in clinical applications and providing a unique perspective for developing IGS. The fluorescence and chemiluminescence nanoprobes (FLNP and CLNP, respectively) within this nanosystem are constructed based on the second near‐infrared aggregation‐induced emission (AIE) dye BBTD14, adorned with anti‐programmed death‐ligand 1 (PD‐L1) antibodies on their surfaces for targeting osteosarcoma cells. Upon near‐infrared light excitation, FLNP generates stable fluorescence, facilitating precise preoperative tumor localization and intraoperative imaging‐guided resection of the primary lesion. Subsequently, CLNP is sprayed onto the surgical wound, producing chemiluminescence with a high signal‐to‐noise ratio when activated by hydrogen peroxide, highlighting millimeter scale residual osteosarcoma tissue, ensuring complete tumor excision, and significantly reducing recurrence rates.

Differentiation of pituitary neuroendocrine tumor (PitNET) tissue from surrounding normal tissue during surgery is challenging. A number of fluorescent agents is available for visualization of tissue discrepancy, with the potential of improving total tumor resection. This review evaluates the availability, clinical and technical applicability of the various fluorescent agents within the field of pituitary surgery. According to PRISMA guidelines, a systematic review was performed to identify reports describing results of in vivo application of fluorescent agents. In this review, 15 publications were included. Sodium Fluorescein (FNa) was considered in two studies. The first study reported noticeable fluorescence in adenoma tissue, the second demonstrated the strongest fluorescence in non-functioning pituitary adenomas. 5-Aminolevulinic acid (5-ALA) was investigated in three studies. One study compared laser-based optical biopsy system (OBS) with photo-diagnostic filter (PD) and found that the OBS was able to detect all microadenomas, even when MRI was negative. The second study retrospectively analyzed twelve pituitary adenomas and found only one positive for fluorescence. The third investigated fifteen pituitary adenomas of which one displayed vague fluorescence. Indocyanine green (ICG) was researched in four studies with variable results. Second-Window ICG yielded no significant difference between functioning and non-functioning adenomas in one study, while a second study displayed 4 times higher fluorescence in tumor tissue than in normal tissue. In three studies, OTL38 showed potential in non-functioning pituitary adenomas. At present, evidence for fluorescent agents to benefit total resection of PitNETs is lacking. OTL38 can potentially serve as a selective fluorescent agent in non-functioning pituitary adenomas in the near future.

Surgical resection is the preferred option for hepatocellular carcinoma (HCC), but surgical navigation technology using indocyanine green still has some drawbacks such as non‐specific imaging, thus it is very important to develop new fluorescence imaging technology. All‐cis hexaphenyl‐1,3‐butadiene derivative (ZZ‐HPB‐NC) with aggregation‐induced emission (AIE) feature has been reported to be quickly turned‐on fluorescent response in the intraoperative frozen‐section slides of HCC. However, the probe did not respond to normal liver tissue around HCC. In order to enhance the diagnostic rate and elucidate the response mechanism, all‐trans configuration EE‐HPB‐NC, was furtherly synthesized. Within two minutes, non‐cancer tissues could be fluorescently labeled by EE‐HPB‐NC by spraying, showing the same effect with ZZ‐HPB‐NC to HCC. The results indicated that the configuration‐induced cross‐identification fluorescence imaging strategy was achieved through the combination of ZZ‐ and EE‐HPB‐NC. Then the mechanism of HPB‐NC localization in HCC lesions was explored, and the binding of HPB‐NC with specific proteins in cells resulted in the AIE effect to label HCC cells. On this basis, the accuracy of specific fluorescence imaging for HCC was further verified on the mouse hepatic neoplasm models, indicating that it has clinical application potential for surgical fluorescence real‐time navigation. Through configuration‐induced cross‐identification fluorescence imaging strategy, ZZ‐HPB‐NC and EE‐HPB‐NC realized the rapid and accurate localization of HCC lesion in the mouse hepatic neoplasm model, providing experimental basis for the subsequent clinical development of a new real‐time fluorescence navigation method during HCC resection.

Complete removal of all tumor tissue with a wide surgical margin is essential for the treatment of osteosarcoma (OS). However, it's difficult, sometimes impossible, to achieve due to the invisible small satellite lesions and blurry tumor boundaries. Besides, intraoperative frozen‐section analysis of resection margins of OS is often restricted by the hard tissues around OS, which makes it impossible to know whether a negative margin is achieved. Any unresected small tumor residuals will lead to local recurrence and worse prognosis. Herein, based on the high expression of B7H3 in OS, a targeted probe B7H3‐IRDye800CW is synthesized by conjugating anti‐B7H3 antibody and IRDye800CW. B7H3‐IRDye800CW can accurately label OS areas after intravenous administration, thereby helping surgeons identify and resect residual OS lesions (<2 mm) and lung metastatic lesions. The tumor‐background ratio reaches 4.42 ± 1.77 at day 3. After incubating fresh human OS specimen with B7H3‐IRDye800CW, it can specifically label the OS area and even the microinvasion area (confirmed by hematoxylin‐eosin [HE] staining). The probe labeled area is consistent with the tumor area shown by magnetic resonance imaging and complete HE staining of the specimen. In summary, B7H3‐IRDye800CW has translational potential in intraoperative resection guidance and rapid pathological diagnosis of OS. Herein, osteosarcoma (OS) targeting probe B7H3‐IRDye800CW is synthesized by conjugating anti‐B7H3 antibody and IRDye800CW. B7H3‐IRDye800CW could help surgeons identify and resect OS lesions after intravenous injection. After incubating the OS specimen with B7H3‐IRDye800CW, it could specifically label the OS invasion area, which is consistent with the tumor area shown by magnetic resonance imaging and hematoxylin‐eosin staining.

Fluorescence‐guided surgery (FGS) aids surgeons with real‐time visualization of small cancer foci and borders, which improves surgical and prognostic efficacy of cancer. Despite the steady advances in imaging devices, there is a scarcity of fluorophores available to achieve optimal FGS. Here, 1) a pH‐sensitive near‐infrared fluorophore that exhibits rapid signal changes in acidic tumor microenvironments (TME) caused by the attenuation of intramolecular quenching, 2) the inherent targeting for cancer based on chemical structure (structure inherent targeting, SIT), and 3) mitochondrial and lysosomal retention are reported. After topical application of PH08 on peritoneal tumor regions in ovarian cancer‐bearing mice, a rapid fluorescence increase (< 10 min), and extended preservation of signals (> 4 h post‐topical application) are observed, which together allow for the visualization of submillimeter tumors with a high tumor‐to‐background ratio (TBR > 5.0). In addition, PH08 is preferentially transported to cancer cells via organic anion transporter peptides (OATPs) and colocalizes in the mitochondria and lysosomes due to the positive charges, enabling a long retention time during FGS. PH08 not only has a significant impact on surgical and diagnostic applications but also provides an effective and scalable strategy to design therapeutic agents for a wide array of cancers. PH08 shows intrinsic targetability to organic anion transporters, which are often overexpressed in cancer cells, and are taken up by tumor cells via endocytosis. The rapid reduction in intramolecular quenching occurs in the acidic tumor microenvironment and lysosomes of cancer cells, realizing enhanced fluorescence emission and a high tumor‐to‐background ratio to detect small peritoneal dissemination of ovarian cancer during intraoperative fluorescence imaging.

Intraoperative guidance using targeted fluorescent tracers can potentially provide surgeons with real-time feedback on the presence of tumor tissue in resection margins. To overcome the limited depth penetration of fluorescent light, combining fluorescence with SPECT/CT imaging and/or gamma-ray tracing has been proposed. Here, we describe the design and preclinical validation of a novel bimodal nanobody-tracer, labeled using a “multifunctional single attachment point” (MSAP) label, integrating a Cy5 fluorophore and a diethylenetriaminepentaacetic acid (DTPA) chelator into a single structure. After conjugation of the bimodal MSAP to primary amines of the anti-HER2 nanobody 2Rs15d and 111In-labeling of DTPA, the tracer’s characteristics were evaluated in vitro. Subsequently, its biodistribution and tumor targeting were assessed by SPECT/CT and fluorescence imaging over 24 h. Finally, the tracer’s ability to identify small, disseminated tumor lesions was investigated in mice bearing HER2-overexpressing SKOV3.IP1 peritoneal lesions. [111In]In-MSAP.2Rs15d retained its affinity following conjugation and remained stable for 24 h. In vivo SPECT/CT and fluorescence images showed specific uptake in HER2-overexpressing tumors with low background. High tumor-to-muscle ratios were obtained at 1h p.i. and remained 19-fold on SPECT/CT and 3-fold on fluorescence images over 24 h. In the intraperitoneally disseminated model, the tracer allowed detection of larger lesions via nuclear imaging, while fluorescence enabled accurate removal of submillimeter lesions. Bimodal nuclear/fluorescent nanobody-tracers can thus be conveniently designed by conjugation of a single-molecule MSAP-reagent carrying a fluorophore and chelator for radioactive labeling. Such tracers hold promise for clinical applications.

Fluorescence molecular imaging plays a vital role in image‐guided surgery. In this context, the urokinase plasminogen activator receptor (uPAR) is an interesting biomarker enabling the detection and delineation of various tumor types due to its elevated expression on both tumor cells and the tumor microenvironment. In this study, anti‐uPAR Nanobodies (Nbs) are generated through llama immunization with human and murine uPAR protein. Extensive in vitro characterization and in vivo testing with radiolabeled variants are conducted to assess their pharmacokinetics and select lead compounds. Subsequently, the selected Nbs are converted into fluorescent agents, and their application for fluorescence‐guided surgery is evaluated in various subcutaneous and orthotopic tumor models. The study yields a panel of high‐affinity anti‐uPAR Nbs, showing specific binding across multiple types of cancer cells in vitro and in vivo. Lead fluorescently‐labeled compounds exhibit high tumor uptake with high contrast at 1 h after intravenous injection across all assessed uPAR‐expressing tumor models, outperforming a non‐targeting control Nb. Additionally, rapid and accurate tumor localization and demarcation are demonstrated in an orthotopic human glioma model. Utilizing these Nbs can potentially enhance the precision of surgical tumor resection and, consequently, improve survival rates in the clinic. This study details the generation and characterization of a panel of high‐affinity anti‐uPAR Nanobodies specific for various cancer types. The selected lead fluorescently‐labeled Nanobody demonstrates rapid and precise tumor localization and demarcation in an orthotopic human glioma model. These outcomes indicate the potential of these Nanobodies for applications in preclinical and clinical settings, providing real‐time guidance during surgical procedures.

High-grade gliomas (HGGs) are characterized by aggressive biological behavior and dismal prognosis. Both 5-aminolevulinic acid (5-ALA) and other fluorescence-guided surgery (FGS) techniques are used to maximize tumor resection while preserving neurological function. The present study synthesizes current evidence and compares these two approaches in the neurosurgical management of HGGs. A systematic literature search was conducted to identify clinical studies evaluating 5-ALA-guided resection and alternative FGS techniques in patients with HGGs. A total of 41 studies were included, comprising 36 in the qualitative review and 5 in the quantitative meta-analysis. Data were extracted regarding study characteristics, patient demographics, tumor type, median progression-free survival, overall survival (OS), pre- and postoperative Karnofsky Performance Status (KPS ≥70 within 30 days), and postoperative neurological deficits (defined as a newly developed decrease in Glasgow Coma Scale score of ≥2 points, hemiparesis, or aphasia). The pooled population consisted of 732 patients, with 503 (68.7%) undergoing 5-ALA-guided resection and 229 (31.3%) treated with FGS. The mean patient age across studies was 57.9 years. The present meta-analysis demonstrated that 5-ALA-guided surgery was associated with improved outcomes in terms of postoperative neurological deficits, maintenance of KPS ≥70, and OS compared with other FGS techniques. However, the presence of publication bias and the heterogeneity of the underlying data limit the strength of these findings and underscores the need for further high-quality comparative trials before definitive conclusions can be drawn regarding the superiority of one method over the other.