Targeted Fluorescence-Guided Surgery in Patients with High-Risk Neuroblastoma: Current Insights and Future Directions

Targeted Fluorescence-Guided Surgery in Patients with High-Risk Neuroblastoma: Current Insights and Future Directions | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 2 June 2025 V1 Latest version Share on Targeted Fluorescence-Guided Surgery in Patients with High-Risk Neuroblastoma: Current Insights and Future Directions Authors : Ilham Shoja 0009-0007-1839-7156 , Nicholas Martin , Maryann Madappallil , Cameron Jeter 0000-0001-5303-5897 , Michael Morrow , and Chien-An A. Hu 0009-0007-9741-411X [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.174884425.50250759/v1 351 views 176 downloads Contents Abstract Supplementary Material Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Neuroblastoma (NB) is one of the most common pediatric malignancies. Approximately half of patients diagnosed with this disease are classified as “high-risk,” which is defined as metastasized or aggressive NB with a poor prognosis if not treated properly. Treatment of high-risk neuroblastoma (HRNB) often requires an integrated approach involving chemotherapy, surgery, immunotherapy, radiotherapy, cancer vaccines, and autologous stem cell transplantation. As HRNB is highly infiltrative, frequently wraps around blood vessels, and is often difficult to differentiate from normal tissues, a surgical procedure that employs tools which optimize real-time, intraoperative visualization of the tumor is essential. This is now achievable by a tracer that is cancer target-specific and a fluorescence-labeled monoclonal antibody (mAb) that can improve the quality of complete tumor removal. Fluorescence-guided surgery (FGS) has been proven to provide qualitative and quantitative imaging and real-time mapping of tumors using tumor-specific targets for HRNB. GD2, a disialoganglioside glycolipid, and a clinically significant tumor-associated antigen, has been shown to overexpress on the surface of NB cells and is minimally expressed in normal cells. The tumor-selective anti-GD2 monoclonal antibody (anti-GD2 mAb) has been used in immunotherapy in treating HRNB patients with success and has demonstrated clear benefit. Thus, fluorescence-tagged anti-GD2 mAb could function as a visual tracer that guides surgical procedures specific for HRNB to optimize tumor resection with greater accuracy, thereby lowering the risk of surgical complications and reducing the incidence of relapse. We provide a critical review of current treatment strategies and future applications of targeted FGS in HRNB treatment. Targeted Fluorescence-Guided Surgery in Patients with High-Risk Neuroblastoma: Current Insights and Future Directions Ilham Shoja, Nicholas Martin, Maryann Madappallil, Cameron Jeter, Michael Morrow, and Chien-An A. Hu* Department of Biomedical Sciences, Kansas College of Osteopathic Medicine, Kansas Health Science University, Wichita, Kansas 67202, USA (*, Corresponding author) Neuroblastoma, High risk, Fluorescence-guided surgery, Cancer-specific target, GD2 Abbreviations: NB, neuroblastoma, HRNB, high-risk NB, GD2, disialoganglioside, anti-GD2mAb, monoclonal antibody raised against GD2 Running Title: Targeted Fluorescence-Guided Surgery in High-Risk Neuroblastoma Abstract Neuroblastoma (NB) is one of the most common pediatric malignancies. Approximately half of patients diagnosed with this disease are classified as “high-risk,” which is defined as metastasized or aggressive NB with a poor prognosis if not treated properly. Treatment of high-risk neuroblastoma (HRNB) often requires an integrated approach involving chemotherapy, surgery, immunotherapy, radiotherapy, cancer vaccines, and autologous stem cell transplantation. As HRNB is highly infiltrative, frequently wraps around blood vessels, and is often difficult to differentiate from normal tissues, a surgical procedure that employs tools which optimize real-time, intraoperative visualization of the tumor is essential. This is now achievable by a tracer that is cancer target-specific and a fluorescence-labeled monoclonal antibody (mAb) that can improve the quality of complete tumor removal. Fluorescence-guided surgery (FGS) has been proven to provide qualitative and quantitative imaging and real-time mapping of tumors using tumor-specific targets for HRNB. GD2, a disialoganglioside glycolipid, and a clinically significant tumor-associated antigen, has been shown to overexpress on the surface of NB cells and is minimally expressed in normal cells. The tumor-selective anti-GD2 monoclonal antibody (anti-GD2 mAb) has been used in immunotherapy in treating HRNB patients with success and has demonstrated clear benefit. Thus, fluorescence-tagged anti-GD2 mAb could function as a visual tracer that guides surgical procedures specific for HRNB to optimize tumor resection with greater accuracy, thereby lowering the risk of surgical complications and reducing the incidence of relapse. We provide a critical review of current treatment strategies and future applications of targeted FGS in HRNB treatment. Neuroblastoma (NB) and High-risk NB (HRNB) Recent advances in tumor biology, cancer genetics, radiomics, chemotherapy, and immunotherapy have transformed our understanding of neuroblastoma (NB). NB is a type of cancer that develops in very primitive nerve cells (or neuroblasts) found in the sympathetic ganglia in an embryo or fetus. It appears most commonly in infants and children, accounting for 6% of all pediatric cancers and 15% of cancer-related deaths in children (Siegel et al. 2023). The median age at diagnosis is 17 months, rarely occurring in adults. NB ranges from tumors that are localized and may resolve spontaneously to widely metastatic and aggressive disease (Brodeur 2018). The tumor typically arises in three locations: the abdomen, the thorax, and the neck. Approximately 65% of all cases occur in the abdomen, usually due to a primary mass in the adrenal medulla. Metastasis occurs most commonly from a primary mass in the pelvis or thorax and spreads to the liver, lungs, bones, or bone marrow. The Children’s Oncology Group (COG) classifies NB into low-, intermediate-, and high-risk groups. Patients with low- and intermediate-risk NB typically only require standard surgery and have a favorable prognosis, with the 5-year survival rate exceeding 90% (Cohn et al. 2009). High-risk NB (HRNB) refers to an aggressive form that is based on several key factors including age, disease stage, and tumor biology and genetics. In general, patients older than 18 months at diagnosis with metastatic disease (especially stage 4), in whom cancer has spread to distant organs such as the bone, bone marrow, liver, or lymph nodes, are considered high-risk. Additionally, HRNB is associated with specific genetic features, such as MYCN amplification, chromosomal 1p loss, or 11q deletions, all of which indicate rapid tumor growth and poor prognosis. Over 50% of NB patients in the United States are categorized as high-risk, with an overall 5-year survival rate of about 50% despite treatment with intensive chemotherapy, surgery, radiotherapy, immunotherapy, and/or autologous stem cell transplantation (Irwin et al. 2021). As surgery is always required in NB treatment, a more precise method using tumor-specific targeting and mapping prior to surgical intervention is crucial to facilitate the complete removal of affected tissues. Treatment for patients with HRNB is divided into the following three phases: (1) Induction phase including chemotherapy and surgical resection, (2) Consolidation phase that may include myeloablative therapy, human stem cell therapy, and/or radiation therapy to the site of the primary tumor and residual metastatic sites, and (3) Post-consolidation phase that usually includes immunotherapy with GM-CSF and isotretinoin therapy (Jacobson, Clark, and Chung 2023) (Fig. 1). Medical Imaging in NB Conventional medical imaging plays a central role in the identification, diagnosis, and staging of NB. Recent staging systems, such as the International Neuroblastoma Risk Group Staging System, emphasize pretreatment risk stratification using image-defined risk factors, including tumor involvement of adjacent vessels and structures (Swift et al. 2018). Imaging also helps differentiate NB from Wilms tumor by characterizing abdominal masses as renal versus extrarenal. Ultrasound is typically the initial modality due to its accessibility, low cost, and absence of ionizing radiation. Most patients subsequently undergo CT and/or MRI for more definitive characterization and staging, although no consensus exists regarding the superior modality (Brisse et al. 2011). Nuclear medicine imaging is crucial for diagnosing and staging NB, as well as monitoring treatment response. Meta-iodobenzylguanidine imaging, with its high specificity, is the standard for detecting metastatic disease and is staged using the modified Curie score, which holds prognostic significance for high-risk NB (Swift et al. 2018). New PET-compatible agents are being developed, offering advantages over traditional SPECT imaging, such as improved resolution and whole-body imaging (Samim et al. 2021). Despite its essential role, conventional imaging has limitations. While IDRFs guide treatment and surgical planning, they often lack specificity. For example, imaging might suggest NB tumor invasion into organs like the liver or kidney, yet accurately determining the extent of involvement intraoperatively can be difficult. Fluorescence-guided surgery (FGS) could address this gap by providing real-time visualization, enhancing surgical precision. FGS may also detect small areas of tumor involvement that conventional imaging, especially lower-resolution modalities like nuclear medicine, might miss. In essence, FGS could complement traditional imaging by overcoming its spatial and intraoperative limitations (Fig. 1). Current treatment of NB and HRNB Low- or intermediate-risk patients with NB typically only need surgery with minimal need for additional chemotherapy (Qiu and Matthay 2022). HRNB is often resistant to standard treatments and requires an aggressive, multi-modal therapeutic approach. In recent years, approximately 50% of children diagnosed with metastatic HRNB at the time of diagnosis now survive, ten times greater than the survival rate in the 1980s. This can be attributed to the combinatorial treatment of multi-agent chemotherapy, advanced surgery, proton radiation therapy, including proton and liquid radiation, immunotherapy, cancer vaccines, and/or stem cell rescue (Wahba, Wolters, and Foster 2023). Chemotherapy for NB As part of the induction phase of treatment, many children with HRNB receive a multi-drug combination of chemotherapy before surgery to shrink tumors and lower the risk of recurrence. Research has identified combinations of chemotherapeutic agents that are most effective with the fewest side effects. For example, one of the established induction chemotherapy regimens is the Rapid COJEC protocol, which includes a combination of cyclophosphamide, vincristine, doxorubicin, and etoposide. This regimen has been shown to improve response rates in patients, allowing them to proceed to high-dose therapy and subsequent autologous stem cell transplantation (Tolbert and Matthay 2018). Additionally, incorporation of agents like topotecan can enhance the efficacy of treatment, particularly in cases where patients do not achieve a complete response after initial therapy (Amoroso 2018). Other research has studied the use of high-dose myeloablative therapy with agents like thiotepa and melphalan, which have demonstrated effectiveness in treating MYCN-amplified NB, a common genetic alteration in HRNB. These findings further support the need for intensive induction chemotherapy followed by consolidation therapy (Moreno et al. 2018; Yamazaki et al. 2021). The combination of these approaches aims to not only shrink tumors effectively but also prepare patients for subsequent surgical resection and minimize the risk of metastasis and recurrence. Standard surgery for NB and HRNB Surgical resection is the foundation for curative treatment in most solid tumors. However, discriminating cancerous tissue from healthy tissue can be challenging. Overall survival strongly correlates with the presence of residual cancer cells after resection, known as positive tumor margins. Having positive margins on pathology is associated with increased local recurrence and poor prognosis in numerous cancers including HRNB (Van Keulen et al. 2022). Surgeons rely on high-resolution visual and tactile cues to delineate cancerous tissue from healthy adjacent tissue. Current surgical protocol involves standard visual field or white-light images, which is not sensitive nor specific enough to resect HRNB completely. Another important consideration is that complications such as hemorrhage and/or iatrogenic organ damage can occur during resection of HRNB, given that the tumor often encases major blood vessels and infiltrates adjacent organs. (Allmen et al. 2016). Thus, it is of great importance to achieve optimal tumor resection while preserving healthy tissue to optimize survival and decrease morbidity and mortality. Surgical augmentation with FGS Given that oncologic surgery relies heavily on visual and tactile cues, the success of fluorescent contrast dyes and advanced imaging in other surgeries has driven interest in FGS for oncology. FGS is a relatively new intraoperative imaging technique that uses exogenous fluorescent agents to enable real-time tumor visualization. Most FDA-approved FGS probes, such as 5-aminolevulinic acid (5-ALA), hexaminolevulinate, and pafolacianine, target generic tumor markers rather than specific malignancies (Lotan et al. 2019; Hadjipanayis and Stummer 2019; Tanyi et al. 2021). For instance, 5-ALA selectively accumulates in certain pediatric brain tumors, facilitating enhanced tumor margin visualization, diagnosis of secondary tumors, and regional lymph node assessment during neurosurgery (Nguyen and Tsien 2013; Schupper et al. 2022). FGS offers significant qualitative and quantitative advantages in oncologic surgery. Studies on gliomas show FGS enhances real-time tumor visualization, allowing better differentiation from healthy tissue and improved margin identification (Hadjipanayis and Stummer 2019). It also enables detection of microscopic tumor remnants invisible under standard lighting, improving extent of resection and lowering postoperative tumor volumes—key factors in reducing recurrence. Quantitatively, FGS increases rates of gross total resection and improves progression-free and overall survival (Liu et al. 2024; Zheng et al. 2024). Importantly, FGS integrates seamlessly into the surgical workflow, enhancing planning, resection bed assessment, and margin analysis using specialized cameras after administration of a fluorescent agent. There has been a shift in the field of FGS towards the development of targeted probes that specifically bind surface markers on cancerous cells for molecular imaging. For example, targeted fluorescence imaging has been used in treating colorectal cancer (CRC) by targeting carcinoembryonic antigen (CEA), a tumor marker overexpressed in more than 90% of CRC cells. SGM-101 is a monoclonal antibody raised against CEA and conjugated to a near-infrared (NIR) fluorophore. SGM-101 targets and binds to CEA, enabling surgeons to visualize and distinguish tumor tissues from healthy tissues in real-time using a NIR camera. This technology can even detect small metastatic nodules that might otherwise remain undetected. SGM-101 has been shown safe in clinical trials with no treatment-related adverse events (Gutowski et al. 2017; Hollandsworth et al. 2021). Similarly, Panitumumab-IRDye800, a targeting agent that shows promise in improving detection of primary and metastatic disease in head and neck cancer. Panitumumab-IRDye800 combines panitumumab, a humanized monoclonal antibody targeting the epidermal growth factor receptor (EGFR), with the near-infrared fluorescent dye IRDye800. This conjugate has been utilized for imaging tumors that express EGFR. Upon administration of panitumumab-IRDye800, the panitumumab moiety targets and binds to EGFR expressed on tumor cells, and IRDye800 facilitates intraoperative tumor detection. This results in clear delineation of involved structures, reducing complications, and aids in precise surgical interventions while improving outcomes (White et al. 2024) (Fig. 1). Target-Specific Probes for HRNB In the context of HRNB, the use of GD2-targeted FGS has shown promise in pre-clinical trials. GD2 is a disialoganglioside synthesized from ceramide via a complex pathway involving sialyltransferases and glycosyltransferases (Kholodenko et al. 2018). GD2 contributes to both immune system suppression and facilitating metastatic progression of HRNB. GD2 is highly overexpressed in most NB tumors and serves as a clinically significant target for treatment. For example, anti-GD2 immunotherapy has been proven to be effective in treating patients with residual NB following surgery. GD2-specific tracers, such as anti-GD2-IRDye800CW and anti-GD2-ICGH, have been developed and evaluated for their efficacy in NB. These tracers combine the specificity of anti-GD2 with NIR fluorescent dyes to facilitate high uptake in NB cells, resulting in enhanced, high-contrast imaging quality and discrimination of tissue involved with tumor during surgery. This improved imaging significantly aids in the precise surgical removal of HRNB. Side effects, such as neuropathic pain, are generally mild and manageable, highlighting the potential of these tracers to improve surgical outcomes in NB treatment (Wellens et al. 2020) (Table 1). Importantly, immunotherapy using anti-GD2mAb has been used in standard of care treatment for HRNB patients (Holmes et al. 2020; Desai et al. 2022; Zheng et al. 2024). Pre-clinical studies utilizing in vitro NB cell models and in vivo human NB organoid rodent models have demonstrated the effectiveness of anti-GD2-IRDye800CW in enhancing tumor visualization during surgery. Thus, GD2-targeted FGS represents a significant advancement in the surgical management of HRNB and provides qualitative and quantitative information for accurate diagnosis and precision surgery potentially leading to improved outcomes and better overall prognosis (Zirngibl et al. 2021). By leveraging the specific expression of GD2 on NB cells and the properties of fluorescence imaging, GD2-targeted therapy remains a cornerstone in the treatment of NB due to its specificity and effectiveness (Fig. 1, Table 2). This approach not only improves the thoroughness of tumor resection but also reduces the risk of residual disease and minimizes damage to healthy tissues, leading to better overall outcomes for patients (Goldstein et al. 2021). However, several limitations must be considered. (1) Current evidence, while promising, is largely based on pre-clinical models, and the efficacy and safety of GD2-specific tracers requires further validation in clinical trials. (2) Although evidence suggests that allowing a post-injection period of 24-48 hours after GD2-specific tracer injection may enhance high-contrast tumor accumulation in NB patients, the current literature does not provide a definitive answer as to the optimal timing for the injection of tracer. This highlights the need for additional research to determine the most effective timing for maximal absorption of GD2-specific tracers in NB. Demonstration of high tracer uptake and enhanced imaging quality for NB removal is promising, but there is a critical need for clinical research to validate these results in human subjects. Recommendations for Future Probes Clinical trials are essential to assess the safety, efficacy, and overall impact of GD2-specific tracers on surgical outcomes and long-term survival in patients with NB (Wellens et al. 2020; Van Keulen et al. 2022; Seah, Cheng, and Vendrell 2023). We anticipate that future therapeutic modalities for HRNB should extend beyond GD2-targeted FGS. A multidisciplinary approach should be employed to improve patient outcomes. This approach may involve a combination of targeted FGS surgery, multi-modal chemotherapy, radiation therapy, and immunotherapy, to address the complexity of HRNB and enhance treatment efficacy. Novel therapeutic targets beyond GD2 are actively being explored to overcome resistance mechanisms and improve treatment responses (Fig. 1). HRNB cells rely on the alternative nonhomologous end-joining (alt-NHEJ) pathway for survival, making key DNA repair proteins—Lig3, Lig1, and PARP1—promising targets. Their inhibition leads to double-strand break accumulation and increased cell death, though off-target effects remain a significant challenge (Newman et al. 2017). USP14, a deubiquitinating enzyme, has also emerged as a target. Inhibition with b-AP15 suppresses NB cell proliferation and induces apoptosis, although its long-term safety profile is not yet established (Yu et al. 2019). Similarly, inhibition of Mps1, a mitotic checkpoint kinase, triggers apoptosis in xenograft models of HRNB, although these models may not fully replicate human NB biology, limiting direct clinical translation (Simon Serrano et al. 2020). These findings underscore the promise of alternative therapeutic targets while highlighting the need for further safety and translational research. Other Cell Surface Markers Cell surface markers play a crucial role in the diagnosis, prognosis, and treatment of HRNB. Markers such as GD2 that are highly expressed in HRNBs and can be used to stratify patients into different risk categories, guiding the intensity of treatment needed. Other cell surface markers also offer potential therapeutic targets, each with unique advantages and limitations in preclinical models (Table 2). NTRK1/TrkA, a receptor associated with favorable prognosis, can be targeted with tyrosine kinase inhibitors, but its expression is limited to a subset of NB cases. NCAM/CD56 is widely expressed in NB and other neuroectodermal tumors, offering broad applicability; however, its presence in normal neural and non-neural tissues raises concerns about off-target effects. EpCAM, another promising marker, is highly expressed in NB and involved in tumor progression, yet its expression in some normal epithelial cells limits specificity. Similarly, B7-H3, which is overexpressed in NB and linked to immune evasion, and ALCAM/CD166, which is highly expressed in aggressive NB, both face challenges due to their presence in normal tissues, particularly in the nervous system (Table 2). Advancements in FGS enhances the utility of these markers by enabling precise tumor visualization using fluorophores like IRDye800CW and ICG (Fig. 1, Table 2). Imaging modalities such as NIR-I, NIR-II, SPY, short-wave infrared (SWIR), diffuse optical tomography (DOT), and fluorescence lifetime imaging microscopy (FLIM) further improve tumor detection and surgical accuracy while reducing harm to healthy tissues. Integrating these targets with advanced imaging techniques may lead to more personalized and effective therapies for NB. Optical Imaging for targeted FGS in HRNB Optical imaging modalities, including NIR-I, NIR-II, SPY, SWIR, DOT, and FLIM, are transforming FGS in HRNB by significantly enhancing tumor visualization and enabling the precise resection of affected tissue. NIR-I (700–1000 nm) and NIR-II (1000–1700 nm) are preferred for deep tissue imaging due to their reduced photon scattering, autofluorescence, and absorption by biological tissues (Seah, Cheng, and Vendrell 2023, 19486). NIR-I imaging, employed with FDA-approved fluorophores like indocyanine green (ICG), is widely used in procedures such as sentinel lymph node mapping and gastrointestinal cancer surgeries due to its ability to reduce photon scattering and autofluorescence (Van Keulen et al. 2022; Seah, Cheng, and Vendrell 2023). NIR-II, with its deeper tissue penetration and superior image clarity, has demonstrated efficacy in hepatocellular carcinoma surgeries by identifying residual malignant tissue undetectable in the NIR-I window. FGS typically employs NIR dyes; however, there is growing interest in SWIR due to its reduced autofluorescence, absorption, and scattering. Privitera and colleagues (2023) designed and built a first-of-its-kind multispectral NIR-I/SWIR fluorescence imaging system, demonstrating higher contrast and clearer visualization of NB tumors than NIR imaging alone. This makes SWIR particularly useful in delicate surgeries involving tumors near critical structures like nerves and vessels. Similarly, DOT provides three-dimensional maps of tumor vasculature and tissue oxygenation, aiding in procedures for highly vascularized tumors, including NB and breast cancer. SPY imaging systems, initially designed for perfusion assessment, have been integrated into head and neck cancer resection, offering real-time imaging of vascular structures and tumor margins. FLIM, which measures fluorescence decay times, is a valuable tool in brain tumor surgeries, particularly for glioblastomas, as it distinguishes cancerous tissues from healthy ones based on metabolic and molecular differences (Van Keulen et al. 2022; Seah, Cheng, and Vendrell 2023). These advanced imaging modalities in addition to FGS allow surgeons to more accurately delineate tumor margins, identify residual disease, and minimize damage to surrounding healthy tissues, ultimately improving surgical outcomes and reducing recurrence rates. Their integration into clinical practice continues to expand, driven by ongoing advancements in fluorophore development, imaging systems, and surgical workflows. Conclusion and Future Perspectives Neuroblastoma (NB), a malignancy arising from primitive neuroblast cells of the autonomic nervous system, is the most common extracranial solid tumor in children, accounting for approximately 10% of pediatric cancer-related deaths (Siegel et al. 2023). Despite advances in multimodal therapy, including the integration of anti-GD2 antibody treatment, management of high-risk neuroblastoma (HRNB) patients remains a formidable challenge, with many patients relapsing due to poorly understood mechanisms of resistance (Yang, Li, and Yang 2013; Qiu and Matthay 2022; Sutton et al. 2023). HRNB is often diagnosed in patients over 18 months of age with metastatic disease or specific genetic abnormalities, such as MYCN amplification, and typically presents as an aggressive, infiltrative tumor wrapped around critical blood vessels and organs. Standard treatment for HRNB involves high-dose chemotherapy, surgery, radiation therapy, immunotherapy (such as anti-GD2 mAb), and stem cell transplantation, yet the complex nature of the disease necessitates precision-targeted approaches to improve outcomes. Medical imaging is essential for identifying, diagnosing, and staging NB. Ultrasound, CT, and MRI evaluate tumor extent and treatment response, with ultrasound preferred initially for its accessibility and safety. MIBG nuclear imaging remains the gold standard for detecting metastases, offering high specificity and prognostic value (Samim et al. 2021). Advances in PET and SPECT continue to improve diagnostic accuracy, resolution, and whole-body tumor visualization. Despite these advancements, conventional imaging techniques have limitations, particularly in intraoperative decision-making. Fluorescence-guided surgery (FGS) has emerged as a promising solution, offering real-time visualization of disease to distinguish tumors from adjacent normal tissue and reduce intraoperative complications (Wellens et al. 2020; Van Keulen et al. 2022). The use of anti-GD2-IRDye800CW tracers in preclinical models has demonstrated significant improvements in tumor visualization and surgical resection accuracy, highlighting the potential for GD2-targeted FGS to enhance survival rates and reduce relapse in HRNB (Holmes et al. 2020; Desai et al. 2022; Zheng et al. 2024). Additionally, optical imaging advancements such as near-infrared (NIR-I and NIR-II), short-wave infrared imaging (SWIR), diffuse optical tomography (DOT), SPY, and fluorescence lifetime imaging microscopy (FLIM) complement targeted tracers by providing high-contrast, quantitative imaging capabilities. These technologies address the limitations of conventional imaging, such as the difficulty in delineating tumor margins or detecting small areas of residual disease, thereby improving intraoperative decision-making and overall treatment precision. In this era of precision oncology, targeted FGS has the potential to revolutionize and redefine the HRNB surgery paradigm by providing real-time, high-resolution imaging, leading to accurate tumor localization and complete resection. This can aid intraoperative decision-making, reduce complications, and potentially improve overall surgical outcomes for patients with HRNB. Future directions in HRNB management should focus on optimizing the timing and dosing of GD2-specific tracers, conducting clinical trials to validate preclinical findings, and exploring alternative cell surface markers like NTRK1/TrkA, NCAM/CD56, and B7-H3 to address resistance and broaden therapeutic options. Additionally, further integration of advanced imaging modalities, including novel PET tracers and multimodal intraoperative imaging approaches, may enhance the ability to assess disease burden and treatment response in real time. The synergy between conventional imaging, nuclear medicine techniques, and FGS holds the potential to refine precision oncology approaches, reduce treatment-associated morbidity, and improve long-term outcomes for children with HRNB. As imaging technologies continue to evolve, their role in redefining surgical standards for NB and other pediatric cancers will likely expand, paving the way for more effective and personalized treatment strategies. Declarations Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Competing interests The authors declare that they have no competing interests. Conflicts of Interest The authors declare no conflicts of interest. Funding Not applicable. Authors’ contributions IS, NM, MM, and CAH conceived and outlined the review. IS, NM, MM, MM, and CAH contributed to the literature searching and manuscript drafting. CJ and MM provided critical feedback and editing the manuscript. All the authors critically revised the manuscript, read and approved the final manuscript. Acknowledgements The authors want to thank the administrative support from Drs. Robin Durrett, DO, and David Ninan, DO, KansasCOM. TABLE 1 Comparison of methodology, results, and side effects in studies utilizing GD2-targeted FGS for HRNB visualization and resection GD2-specific tracer injection prior to procedure Antibody used Percentage of NB cells uptake Side effects References 48 hours Dinutuximab-beta ~80% Mild injection site pain, transient fever Wellens et al. 2020 24-48 hours Dinutuximab-beta > 80% Mild rash, mild hypotension, transient fever Zirngibl et al. 2021 24 hours Naxitamab ~75% Mild injection site reactions, transient fever Mabe et al. 2022 24 hours Dinutuximab ~70% Mild injection site reactions, mild nausea, transient fever Stip et al. 2023 6-24 hours Naxitamab Variable, ~60% None reported Keyel et al. 2023 GD2, disialoganglioside 2; FGS, fluorescence-guided surgery; HRNB, high-risk neuroblastoma; NB, neuroblastoma TABLE 2 Cell surface markers of NB. Comparison of advantages and limitations of each marker as a treatment target Cell surface marker Advantages Limitations References ALCAM/CD166 Highly expressed in aggressive NB Expression in normal tissues, particularly in the nervous system Wachowiak et al. 2016 EpCAM Highly expressed in NB Expression in some normal epithelial cells Liu et al. 2018 B7-H3 Overexpressed in NB Expression in some normal tissues Majzner et al. 2019 NTRK1/TrkA Potential for targeted treatment by tyrosine kinase inhibitors Not all NBs express NTRK1/TrkA Funke et al. 2021 GD2 Highly expressed in aggressive NB cells, limited expression in normal tissues Neuropathic pain due to minimal presentation of GD2 in peripheral nerves Chan and Chan 2022 NCAM/CD56 Expressed in NB and other neuroectodermal tumors Expression in normal neural and non-neural tissues Heinly and Grant 2022 ALCAM, activated leukocyte cell adhesion molecule; CD166, cluster of differentiation 166; EpCAM, epithelial cell adhesion molecule; B7-H3, B7 homolog 3; NTRK1, neurotrophic receptor tyrosine kinase 1; TrkA, tropomyosin receptor kinase A; GD2, disialoganglioside 2; NCAM, neural cell adhesion molecule; CD56, cluster of differentiation 56; NB, neuroblastoma FIGURE 1 Schematic Presentation of Treatment Strategies for Different Grades of Neuroblastoma (NB). 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Zirngibl, Felix, Sara M Ivasko, Laura Grunewald, Anika Klaus, Silke Schwiebert, Peter Ruf, Horst Lindhofer, et al. “GD2-Directed Bispecific Trifunctional Antibody Outperforms Dinutuximab Beta in a Murine Model for Aggressive Metastasized Neuroblastoma.” Journal for ImmunoTherapy of Cancer 9, no. 7 (July 2021). https://doi.org/10.1136/jitc-2021-002923. Supplementary Material File (ilham table 1 final.docx) Download 15.55 KB File (ilham table 2 final.docx) Download 15.65 KB Information & Authors Information Version history V1 Version 1 02 June 2025 Copyright This work is licensed under a Non Exclusive No Reuse License. Keywords cancer biology developmental therapeutics neuroblastoma pediatric oncology surgery Authors Affiliations Ilham Shoja 0009-0007-1839-7156 Kansas Health Science University Kansas College of Osteopathic Medicine View all articles by this author Nicholas Martin Kansas Health Science University Kansas College of Osteopathic Medicine View all articles by this author Maryann Madappallil Kansas Health Science University Kansas College of Osteopathic Medicine View all articles by this author Cameron Jeter 0000-0001-5303-5897 Kansas Health Science University Kansas College of Osteopathic Medicine View all articles by this author Michael Morrow Kansas Health Science University Kansas College of Osteopathic Medicine View all articles by this author Chien-An A. Hu 0009-0007-9741-411X [email protected] Kansas Health Science University Kansas College of Osteopathic Medicine View all articles by this author Metrics & Citations Metrics Article Usage 351 views 176 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Ilham Shoja, Nicholas Martin, Maryann Madappallil, et al. Targeted Fluorescence-Guided Surgery in Patients with High-Risk Neuroblastoma: Current Insights and Future Directions. Authorea . 02 June 2025. DOI: https://doi.org/10.22541/au.174884425.50250759/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu . 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