Publications by authors named "Nynke S van den Berg"

70 Publications

A narrative review of fluorescence imaging in robotic-assisted surgery.

Laparosc Surg 2021 Jul 25;5. Epub 2021 Jul 25.

Department of Research, Intuitive Surgical, Inc., Sunnyvale, CA, USA.

Objective: In this review, we provide examples of applications of fluorescence imaging in urologic, gynecologic, general, and endocrine surgeries.

Background: While robotic-assisted surgery has helped increase the availability of minimally invasive procedures across surgical specialties, there remains an opportunity to reduce adverse events associated with open, laparoscopic, and robotic-assisted methods. In 2011, fluorescence imaging was introduced as an option to the da Vinci Surgical System, and has been standard equipment since 2014. Without interfering with surgical workflow, this fluorescence technology named Firefly allows for acquisition and display of near-infrared fluorescent signals that are co-registered with white light endoscopic images. As a result, robotic surgeons of all specialties have been able to explore the clinical utility of fluorescence guided surgery.

Methods: Literature searches were performed using the PubMed and MEDLINE databases using the keywords "robotic-assisted fluorescence surgery", "ICG robotic surgery", and "fluorescence guided surgery" covering the years 2011-2020.

Conclusions: Real-time intraoperative fluorescence guidance has shown great potential in helping guide surgeons in both simple and complex surgical interventions. Indocyanine green is one of the most widely-used imaging agents in fluorescence guided surgery, and other targeted, near-infrared imaging agents are in various stages of development. Fluorescence is becoming a reliable tool that can help surgeons in their decision-making process in some specialties, while explorations continue in others.
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http://dx.doi.org/10.21037/ls-20-98DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8452263PMC
July 2021

Assessing the value of volume navigation during ultrasound-guided radiofrequency- and microwave-ablations of liver lesions.

Eur J Radiol Open 2021 8;8:100367. Epub 2021 Jul 8.

Interventional Molecular Imaging Laboratory, Department of Radiology, Leiden University Medical Center, Albinusdreef 2, 2300 RC, Leiden, the Netherlands.

Purpose: The goal of our study was to determine the influence of ultrasound (US)-coupled volume navigation on the use of computed tomography (CT) during minimally-invasive radiofrequency and microwave ablation procedures of liver lesions.

Method: Twenty-five patients with 40 liver lesions of different histological origin were retrospectively analysed. Lesions were ablated following standard protocol, using 1) conventional US-guidance, 2) manual registered volume navigation (VNav), 3) automatic registered (VNav) or 4) CT-guidance. In case of ultrasonographically inconspicuous lesions, conventional US-guidance was abandoned and VNav was used. If VNav was also unsuccessful, the procedure was either continued with VNav or CT-guidance. The number, size and location of the lesions targeted using the different approaches were documented.

Results: Of the 40 lesions, sixteen (40.0 %) could be targeted with conventional US-guidance only, sixteen (40.0 %) with VNav, three (7.5 %) with VNav and five (12.5 %) only through the use of CT-guidance. Of the three alternatives (VNav, VNav and CT only) the mean size of the lesions targeted using VNav (9.1 ± 4.6 mm) was significantly smaller from those targeted using US-guidance only (20.4 ± 9.4 mm; p < 0.001). The location of the lesions did not influence the selection of the modality used to guide the ablation.

Conclusions: In our cohort, VNav allowed the ablation procedure to become less dependent on the use of CT. VNav supported the ablation of lesions smaller than those that could be ablated with US only and doubled the application of minimally-invasive US-guided ablations.
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http://dx.doi.org/10.1016/j.ejro.2021.100367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8273361PMC
July 2021

Metastatic and sentinel lymph node mapping using intravenously delivered Panitumumab-IRDye800CW.

Theranostics 2021 24;11(15):7188-7198. Epub 2021 May 24.

Department of Otolaryngology - Division of Head and Neck Surgery, Stanford University School of Medicine, Stanford, CA, United States.

Sentinel lymph node biopsy (SLNB) is a well-established minimally invasive staging procedure that maps the spread of tumour metastases from their primary site to the regional lymphatics. Currently, the procedure requires the local peri-tumoural injection of radiolabelled and/or optical agents, and is therefore operator dependent, disruptive to surgical workflow and restricted largely to a small subset of malignancies that can be readily accessed externally for local tracer injection. The present study set out to determine whether intravenous (IV) infusion of a tumor-targeted tracer could identify sentinel and metastatic lymph nodes (LNs) in order to overcome these limitations. We examined 27 patients with oral squamous cell carcinoma (OSCC), 18 of whom were clinically node negative (cN0). Patients were infused intravenously with 50mg of Panitumumab-IRDye800CW prior to surgical resection of their primary tumour with neck dissection and/or SLNB. Lymphadenectomy specimens underwent fluorescence molecular imaging to evaluate tracer distribution to LNs. A total of 960 LNs were analysed, of which 34 (3.5%) contained metastatic disease. Panitumumab-IRDye800CW preferentially localized to metastatic and sentinel LNs as evidenced by a higher fluorescent signal relative to other lymph nodes. The median MFI of metastatic LNs was significantly higher than the median MFI of benign LNs (0.06 versus 0.02, p < 0.05). Furthermore, selecting the highest five fluorescence intensity LNs from individual specimens resulted in 100% sensitivity, 85.8% specificity and 100% negative predictive value (NPV) for the detection of occult metastases and 100% accuracy for clinically staging the neck. In the cN+ cohort, assessment of the highest 5 fluorescence LNs per patient had 87.5% sensitivity, 93.2% specificity and 99.1% NPV for the detection of metastatic nodes. When intravenously infused, a tumour-targeted tracer localized to sentinel and metastatic lymph nodes. Further validation of an IV tumor-targeted tracer delivery approach for SLNB could dramatically change the practice of SLNB, allowing its application to other malignancies where the primary tumour is not accessible for local tracer injection.
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http://dx.doi.org/10.7150/thno.55389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8210603PMC
July 2021

EGFR-targeted intraoperative fluorescence imaging detects high-grade glioma with panitumumab-IRDye800 in a phase 1 clinical trial.

Theranostics 2021 21;11(15):7130-7143. Epub 2021 May 21.

Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA.

: First-line therapy for high-grade gliomas (HGGs) includes maximal safe surgical resection. The extent of resection predicts overall survival, but current neuroimaging approaches lack tumor specificity. The epidermal growth factor receptor (EGFR) is a highly expressed HGG biomarker. We evaluated the safety and feasibility of an anti-EGFR antibody, panitumuab-IRDye800, at subtherapeutic doses as an imaging agent for HGG. : Eleven patients with contrast-enhancing HGGs were systemically infused with panitumumab-IRDye800 at a low (50 mg) or high (100 mg) dose 1-5 days before surgery. Near-infrared fluorescence imaging was performed intraoperatively and , to identify the optimal tumor-to-background ratio by comparing mean fluorescence intensities of tumor and histologically uninvolved tissue. Fluorescence was correlated with preoperative T1 contrast, tumor size, EGFR expression and other biomarkers. : No adverse events were attributed to panitumumab-IRDye800. Tumor fragments as small as 5 mg could be detected and detection threshold was dose dependent. In tissue sections, panitumumab-IRDye800 was highly sensitive (95%) and specific (96%) for pathology confirmed tumor containing tissue. Cellular delivery of panitumumab-IRDye800 was correlated to EGFR overexpression and compromised blood-brain barrier in HGG, while normal brain tissue showed minimal fluorescence. Intraoperative fluorescence improved optical contrast in tumor tissue within and beyond the T1 contrast-enhancing margin, with contrast-to-noise ratios of 9.5 ± 2.1 and 3.6 ± 1.1, respectively. : Panitumumab-IRDye800 provided excellent tumor contrast and was safe at both doses. Smaller fragments of tumor could be detected at the 100 mg dose and thus more suitable for intraoperative imaging.
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http://dx.doi.org/10.7150/thno.60582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8210618PMC
July 2021

Molecular imaging of a fluorescent antibody against epidermal growth factor receptor detects high-grade glioma.

Sci Rep 2021 Mar 11;11(1):5710. Epub 2021 Mar 11.

Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, 94305, USA.

The prognosis for high-grade glioma (HGG) remains dismal and the extent of resection correlates with overall survival and progression free disease. Epidermal growth factor receptor (EGFR) is a biomarker heterogeneously expressed in HGG. We assessed the feasibility of detecting HGG using near-infrared fluorescent antibody targeting EGFR. Mice bearing orthotopic HGG xenografts with modest EGFR expression were imaged in vivo after systemic panitumumab-IRDye800 injection to assess its tumor-specific uptake macroscopically over 14 days, and microscopically ex vivo. EGFR immunohistochemical staining of 59 tumor specimens from 35 HGG patients was scored by pathologists and expression levels were compared to that of mouse xenografts. Intratumoral distribution of panitumumab-IRDye800 correlated with near-infrared fluorescence and EGFR expression. Fluorescence distinguished tumor cells with 90% specificity and 82.5% sensitivity. Target-to-background ratios peaked at 14 h post panitumumab-IRDye800 infusion, reaching 19.5 in vivo and 7.6 ex vivo, respectively. Equivalent or higher EGFR protein expression compared to the mouse xenografts was present in 77.1% HGG patients. Age, combined with IDH-wildtype cerebral tumor, was predictive of greater EGFR protein expression in human tumors. Tumor specific uptake of panitumumab-IRDye800 provided remarkable contrast and a flexible imaging window for fluorescence-guided identification of HGGs despite modest EGFR expression.
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http://dx.doi.org/10.1038/s41598-021-84831-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7952570PMC
March 2021

Technologic (R)Evolution Leads to Detection of More Sentinel Nodes in Patients with Melanoma in the Head and Neck Region.

J Nucl Med 2021 Oct 26;62(10):1357-1362. Epub 2021 Feb 26.

Department of Head and Neck Surgery and Oncology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam, The Netherlands.

Sentinel lymph node (SN) biopsy (SNB) has proven to be a valuable tool for staging melanoma patients. Since its introduction in the early 1990s, this procedure has undergone several technologic refinements, including the introduction of SPECT/CT, as well as radioguidance and fluorescence guidance. The purpose of the current study was to evaluate the effect of this technologic evolution on SNB in the head and neck region. The primary endpoint was the false-negative (FN) rate. Secondary endpoints were number of harvested SNs, overall operation time, operation time per harvested SN, and postoperative complications. A retrospective database was queried for cutaneous head and neck melanoma patients who underwent SNB at The Netherlands Cancer Institute between 1993 and 2016. The implementation of new detection techniques was divided into 4 groups: 1993-2005, with preoperative lymphoscintigraphy and intraoperative use of both a γ-ray detection probe and patent blue ( = 30); 2006-2007, with addition of preoperative road maps based on SPECT/CT ( = 15); 2008-2009, with intraoperative use of a portable γ-camera ( = 40); and 2010-2016, with addition of near-infrared fluorescence guidance ( = 192). In total, 277 patients were included. At least 1 SN was identified in all patients. A tumor-positive SN was found in 59 patients (21.3%): 10 in group 1 (33.3%), 3 in group 2 (20.0%), 6 in group 3 (15.0%), and 40 in group 4 (20.8%). Regional recurrences in patients with tumor-negative SNs resulted in an overall FN rate of 11.9% (group 1, 16.7%; group 2, 0%; group 3, 14.3%; group 4, 11.1%). The number of harvested nodes increased with advancing technologies ( = 0.003), whereas Breslow thickness and operation time per harvested SN decreased ( = 0.003 and = 0.017, respectively). There was no significant difference in percentage of tumor-positive SNs, overall operation time, and complication rate between the different groups. The use of advanced detection technologies led to a higher number of identified SNs without an increase in overall operation time, possibly indicating an improved surgical efficiency. Operation time per harvested SN decreased; the average FN rate remained 11.9% and was unchanged over 23 y. There was no significant change in postoperative complication rate.
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http://dx.doi.org/10.2967/jnumed.120.246819DOI Listing
October 2021

Intraoperative Fluorescence-Guided Surgery in Head and Neck Squamous Cell Carcinoma.

Laryngoscope 2021 03 3;131(3):529-534. Epub 2020 Jul 3.

Department of Otolaryngology - Head and Neck Surgery, Stanford University School of Medicine, Stanford, CA, U.S.A.

The rate of positive margins in head and neck cancers has remained stagnant over the past three decades and is consistently associated with poor overall survival. This suggests that significant improvements must be made intraoperatively to ensure negative margins. We discuss the important role of fluorescence imaging to guide surgical oncology in head and neck cancer. This review includes a general overview of the principles of fluorescence, available fluorophores used for fluorescence imaging, and specific clinical applications of fluorescence-guided surgery, as well as challenges and future directions in head and neck surgical oncology. Laryngoscope, 131:529-534, 2021.
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http://dx.doi.org/10.1002/lary.28822DOI Listing
March 2021

A protease-activated, near-infrared fluorescent probe for early endoscopic detection of premalignant gastrointestinal lesions.

Proc Natl Acad Sci U S A 2021 01;118(1)

Department of Radiology, Bio-X Program and Molecular Imaging Program, Stanford University School of Medicine, Stanford, CA 94305;

Fluorescence imaging is currently being actively developed for surgical guidance; however, it remains underutilized for diagnostic and endoscopic surveillance of incipient colorectal cancer in high-risk patients. Here we demonstrate the utility and potential for clinical translation of a fluorescently labeled cathepsin-activated chemical probe to highlight gastrointestinal lesions. This probe stays optically dark until it is activated by proteases produced by tumor-associated macrophages and accumulates within the lesions, enabling their detection using an endoscope outfitted with a fluorescence detector. We evaluated the probe in multiple murine models and a human-scale porcine model of gastrointestinal carcinogenesis. The probe provides fluorescence-guided surveillance of gastrointestinal lesions and augments histopathological analysis by highlighting areas of dysplasia as small as 400 µm, which were visibly discernible with significant tumor-to-background ratios, even in tissues with a background of severe inflammation and ulceration. Given these results, we anticipate that this probe will enable sensitive fluorescence-guided biopsies, even in the presence of highly inflamed colorectal tissue, which will improve early diagnosis to prevent gastrointestinal cancers.
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http://dx.doi.org/10.1073/pnas.2008072118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817203PMC
January 2021

Co-administered antibody improves penetration of antibody-dye conjugate into human cancers with implications for antibody-drug conjugates.

Nat Commun 2020 11 9;11(1):5667. Epub 2020 Nov 9.

Department of Otolaryngology - Head and Neck Surgery, Stanford University School of Medicine, 900 Blake Wilbur Drive, Stanford, CA, 94305, USA.

Poor tissue penetration remains a major challenge for antibody-based therapeutics of solid tumors, but proper dosing can improve the tissue penetration and thus therapeutic efficacy of these biologics. Due to dose-limiting toxicity of the small molecule payload, antibody-drug conjugates (ADCs) are administered at a much lower dose than their parent antibodies, which further reduces tissue penetration. We conducted an early-phase clinical trial (NCT02415881) and previously reported the safety of an antibody-dye conjugate (panitumumab-IRDye800CW) as primary outcome. Here, we report a retrospective exploratory analysis of the trial to evaluate whether co-administration of an unconjugated antibody could improve the intratumoral distribution of the antibody-dye conjugate in patients. By measuring the multiscale distribution of the antibody-dye conjugate, this study demonstrates improved microscopic antibody distribution without increasing uptake (toxicity) in healthy tissue when co-administered with the parent antibody, supporting further clinical investigation of the co-administration dosing strategy to improve the tumor penetration of ADCs.
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http://dx.doi.org/10.1038/s41467-020-19498-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7652891PMC
November 2020

Effect of Formalin Fixation for Near-Infrared Fluorescence Imaging with an Antibody-Dye Conjugate in Head and Neck Cancer Patients.

Mol Imaging Biol 2021 04 19;23(2):270-276. Epub 2020 Oct 19.

Department of Otolaryngology-Head and Neck Surgery, Stanford University School of Medicine, Stanford, CA, USA.

Purpose: This study evaluated the effect of formalin fixation for near-infrared (NIR) fluorescence imaging of an antibody-dye complex (panitumumab-IRDye800CW) that was intravenously administered to patients with head and neck squamous cell carcinoma (HNSCC) scheduled to undergo surgery of curative intent.

Procedures: HNSCC patients were infused with 25 or 50 mg of panitumumab-IRDye800CW followed by surgery 1-5 days later. Following resection, primary tumor specimens were imaged in a closed-field fluorescence imaging device, before and after formalin fixation. The fluorescence images of formalin-fixed specimens were compared with images prior to formalin fixation. Regions of interest were drawn on the primary tumor and on the adjacent normal tissue on the fluorescence images. The mean fluorescence intensity (MFI) and tumor-to-background ratios (TBRs) of the fresh and formalin-fixed tissues were compared.

Results: Of the 30 enrolled patients, 20 tissue specimens were eligible for this study. Formalin fixation led to an average of 10 % shrinkage in tumor specimen size (p < 0.0001). Tumor MFI in formalin-fixed specimens was on average 10.9 % lower than that in the fresh specimens (p = 0.0002). However, no statistical difference was found between the TBRs of the fresh specimens and those of the formalin-fixed specimens (p = 0.85).

Conclusions: Despite the 11 % decrease in MFI between fresh and formalin-fixed tissue specimens, the relative difference between tumor and normal tissue as measured in TBR remained unchanged. This data suggests that evaluation of formalin-fixed tissue for assessing the accuracy of fluorescence-guided surgery approaches could provide a valid, yet more flexible, alternative to fresh tissue analysis.

Trial Registration: NCT02415881.
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http://dx.doi.org/10.1007/s11307-020-01553-1DOI Listing
April 2021

Photoacoustic Molecular Imaging for the Identification of Lymph Node Metastasis in Head and Neck Cancer Using an Anti-EGFR Antibody-Dye Conjugate.

J Nucl Med 2021 05 2;62(5):648-655. Epub 2020 Oct 2.

Department of Radiology, Stanford University School of Medicine, Stanford, California

The presence of lymph node (LN) metastases is an essential prognostic indicator in patients with head and neck squamous cell carcinoma (HNSCC). This study assessed photoacoustic molecular imaging (PAMI) of the antiepidermal growth factor receptor antibody (panitumumab) conjugated to a near-infrared fluorescent dye, IRDye800CW (panitumumab-IRDye800CW; pan800), for the identification of occult metastatic LNs in patients with HNSCC ( = 7). After in vitro photoacoustic imaging characterization of pan800, PAMI was performed on excised neck specimens from patients infused with pan800 before surgery. Freshly obtained neck specimens were imaged with 3-dimensional, multiwavelength spectroscopic PAMI (wavelengths of 680, 686, 740, 800, 860, 924, and 958 nm). Harvested LNs were then imaged with a closed-field near-infrared fluorescence imager and histologically examined by the pathologist to determine their metastatic status. In total, 53 LNs with a maximum diameter of 10 mm were analyzed with photoacoustic and fluorescence imaging, of which 4 were determined to be metastatic on the final histopathologic report. Photoacoustic signals in the LNs corresponding to accumulated pan800 were spectrally unmixed using a linear least-square-error classification algorithm. The average thresholded photoacoustic signal intensity corresponding to pan800 was 5-fold higher for metastatic LNs than for benign LNs (2.50 ± 1.09 arbitrary units [a.u.] vs. 0.53 ± 0.32 a.u., < 0.001). Fluorescence imaging showed that metastatic LNs had a 2-fold increase in fluorescence signal compared with benign LNs ex vivo ( < 0.01, 0.068 ± 0.027 a.u. vs. 0.035 ± 0.018 a.u.). Moreover, the ratio of the average of the highest 10% of the photoacoustic signal intensity over the total average, representative of the degree of heterogeneity in the pan800 signal in LNs, showed a significant difference between metastatic LNs and benign LNs (11.6 ± 13.4 vs. 1.8 ± 0.7, < 0.01) and an area under the receiver-operating-characteristic curve of 0.96 (95% CI, 0.91-1.00). The data indicate that PAMI of IRDye800-labeled tumor-specific antibody may have the potential to identify occult LN metastasis perioperatively in HNSCC patients.
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http://dx.doi.org/10.2967/jnumed.120.245241DOI Listing
May 2021

Safety and Stability of Antibody-Dye Conjugate in Optical Molecular Imaging.

Mol Imaging Biol 2021 02 3;23(1):109-116. Epub 2020 Sep 3.

Department of Otolaryngology-Head and Neck Surgery, Stanford University School of Medicine, 900 Blake Wilbur Drive, Stanford, CA, 94305, USA.

Purpose: The development of molecularly targeted tracers is likely to improve the accuracy of diagnostic, screening, and therapeutic tools. Despite the many therapeutic antibodies that are FDA-approved with known toxicity, only a limited number of antibody-dye conjugates have been introduced to the clinic. Thorough evaluation of the safety, stability, and pharmacokinetics of antibody conjugates in the clinical setting compared with their parental components could accelerate the clinical approval of antibodies as agents for molecular imaging. Here we investigate the safety and stability of a near-infrared fluorescent dye (IRDye800CW) conjugated panitumumab, an approved therapeutic antibody, and report on the product stability, pharmacokinetics, adverse events, and QTc interval changes in patients.

Procedures: Panitumumab-IRDye800CW was made under good manufacturing practice (GMP) conditions in a single batch on March 26, 2014, and then evaluated over 4.5 years at 0, 3, and 6 months, and then at 6-month intervals thereafter. We conducted early phase trials in head and neck, lung, pancreas, and brain cancers with panitumumab-IRDye800CW. Eighty-one patients scheduled to undergo standard-of-care surgery were infused with doses between 0.06 to 2.83 mg/kg of antibody. Patient ECGs, blood samples, and adverse events were collected over 30-day post-infusion for analysis.

Results: Eighty-one patients underwent infusion of the study drug at a range of doses. Six patients (7.4 %) experienced an adverse event that was considered potentially related to the drug. The most common event was a prolonged QTc interval which occurred in three patients (3.7 %). Panitumumab-IRDye800CW had two OOS results at 42 and 54 months while meeting all other stability testing criteria.

Conclusions: Panitumumab-IRDye800CW was safe and stable to administer over a 54-month window with a low rate of adverse events (7.4 %) which is consistent with the rate associated with panitumumab alone. This data supports re-purposing therapeutic antibodies as diagnostic imaging agents with limited preclinical toxicology studies.
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http://dx.doi.org/10.1007/s11307-020-01536-2DOI Listing
February 2021

Comparison of Panitumumab-IRDye800CW and 5-Aminolevulinic Acid to Provide Optical Contrast in a Model of Glioblastoma Multiforme.

Mol Cancer Ther 2020 09 30;19(9):1922-1929. Epub 2020 Jun 30.

Department of Otolaryngology, University of Alabama at Birmingham, Birmingham, Alabama.

Maximal safe resection of malignant tissue is associated with improved progression-free survival and better response to radiation and chemotherapy for patients with glioblastoma (GBM). 5-Aminolevulinic acid (5-ALA) is the current FDA-approved standard for intraoperative brain tumor visualization. Unfortunately, autofluorescence in diffuse areas and high fluorescence in dense tissues significantly limit discrimination at tumor margins. This study is the first to compare 5-ALA to an investigational new drug, panitumumab-IRDye800CW, in the same animal model. A patient-derived GBM xenograft model was established in 16 nude mice, which later received injections of 5-ALA, panitumumab-IRDye800CW, IRDye800CW, 5-ALA and IRDye800CW, or 5-ALA and panitumumab-IRDye800CW. Brains were prepared for multi-instrument fluorescence imaging, IHC, and quantitative analysis of tumor-to-background ratio (TBR) and tumor margin accuracy. Statistical analysis was compared with Wilcoxon rank-sum or paired test. Panitumumab-IRDye800CW had a 30% higher comprehensive TBR compared with 5-ALA ( = 0.0079). SDs for core and margin regions of interest in 5-ALA-treated tissues were significantly higher than those found in panitumumab-IRDye800CW-treated tissues ( = 0.0240 and = 0.0284, respectively). Panitumumab-IRDye800CW specificities for tumor core and margin were more than 10% higher than those of 5-ALA. Higher AUC for panitumumab-IRDye800CW indicated strong capability to discriminate between normal and malignant brain tissue when compared with 5-ALA. This work demonstrates that panitumumab-IRDye800CW shows potential as a targeting agent for fluorescence intraoperative detection of GBM. Improved margin definition and surgical resection using panitumumab-IRDye800 has the potential to improve surgical outcomes and survival in patients with GBM compared with 5-ALA.
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http://dx.doi.org/10.1158/1535-7163.MCT-19-0819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483817PMC
September 2020

Design of Optical-Imaging Probes by Screening of Diverse Substrate Libraries Directly in Disease-Tissue Extracts.

Angew Chem Int Ed Engl 2020 10 26;59(43):19143-19152. Epub 2020 Aug 26.

Department of Pathology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA, 94305, USA.

Fluorescently quenched probes that are specifically activated in the cancer microenvironment have great potential application for diagnosis, early detection, and surgical guidance. These probes are often designed to target specific enzymes associated with diseases by direct optimization using single purified enzymes. However, this can result in painstaking chemistry efforts to produce a probe with suboptimal performance when applied in vivo. We describe here an alternate, unbiased activity-profiling approach in which whole tissue extracts are used to directly identify optimal peptide sequences for probe design. Screening of tumor extracts with a hybrid combinatorial substrate library (HyCoSuL) identified a combination of natural and non-natural amino-acid residues that was used to generate highly efficient tumor-specific probes. This new strategy simplifies and enhances the process of probe optimization without any a priori knowledge of enzyme targets and has the potential to be applied to diverse disease states using clinical or animal-model tissue samples.
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http://dx.doi.org/10.1002/anie.202006719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8163102PMC
October 2020

Tumour-specific fluorescence-guided surgery for pancreatic cancer using panitumumab-IRDye800CW: a phase 1 single-centre, open-label, single-arm, dose-escalation study.

Lancet Gastroenterol Hepatol 2020 08 14;5(8):753-764. Epub 2020 May 14.

Department of Surgery, Stanford University School of Medicine, Stanford University, CA, USA. Electronic address:

Background: Complete surgical resection remains the primary curative option for pancreatic ductal adenocarcinoma, with positive margins in 30-70% of patients. In this study, we aimed to evaluate the use of intraoperative tumour-specific imaging to enhance a surgeon's ability to detect visually occult cancer in real time.

Methods: In this single-centre, open-label, single-arm study, done in the USA, we enrolled patients who had clinically suspicious or biopsy-confirmed pancreatic ductal adenocarcinomas and were scheduled for curative surgery. Eligible patients were 19 years of age or older with a life expectancy of more than 12 weeks and a Karnofsky performance status of at least 70% or an Eastern Cooperative Oncology Group or Zubrod level of one or lower, who were scheduled to undergo curative surgery. Patients were sequentially enrolled into each dosing group and 2-5 days before surgery, patients were intravenously infused with 100 mg of unlabelled panitumumab followed by 25 mg, 50 mg, or 75 mg of the near-infrared fluorescently labelled antibody (panitumumab-IRDye800CW). The primary endpoint was to determine the optimal dose of panitumumab-IRDye800CW in identifying pancreatic ductal adenocarcinomas as measured by tumour-to-background ratio in all patients. The tumour-to-background ratio was defined as the fluorescence signal of the tumour divided by the fluorescence signal of the surrounding healthy tissue. The dose-finding part of this study has been completed. This study is registered with ClinicalTrials.gov, NCT03384238.

Findings: Between April, 2018, and July, 2019, 16 patients were screened for enrolment onto the study. Of the 16 screened patients, two (12%) patients withdrew from the study and three (19%) were not eligible; 11 (69%) patients completed the trial, all of whom were clinically diagnosed with pancreatic ductal adenocarcinoma. The mean tumour-to-background ratio of primary tumours was 3·0 (SD 0·5) in the 25 mg group, 4·0 (SD 0·6) in the 50 mg group, and 3·7 (SD 0·4) in the 75 mg group; the optimal dose was identified as 50 mg. Intraoperatively, near-infrared fluorescence imaging provided enhanced visualisation of the primary tumours, metastatic lymph nodes, and small (<2 mm) peritoneal metastasis. Intravenous administration of panitumumab-IRDye800CW at the doses of 25 mg, 50 mg, and 75 mg did not result in any grade 3 or higher adverse events. There were no serious adverse events attributed to panitumumab-IRDye800CW, although four possibly related adverse events (grade 1 and 2) were reported in four patients.

Interpretation: To our knowledge, this study presents the first clinical use of panitumumab-IRDye800CW for detecting pancreatic ductal adenocarcinomas and shows that panitumumab-IRDye800CW is safe and feasible to use during pancreatic cancer surgery. Tumour-specific intraoperative imaging might have added value for treatment of patients with pancreatic ductal adenocarcinomas through improved patient selection and enhanced visualisation of surgical margins, metastatic lymph nodes, and distant metastasis.

Funding: National Institutes of Health and the Netherlands Organization for Scientific Research.
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http://dx.doi.org/10.1016/S2468-1253(20)30088-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7367758PMC
August 2020

Intraoperative Molecular Imaging for Assessment of Peripheral Margins in Oral Squamous Cell Carcinoma.

Front Oncol 2019 10;9:1476. Epub 2020 Jan 10.

Department of Pathology, Stanford University School of Medicine, Stanford, CA, United States.

Complete surgical resection is the standard of care for treatment of oral cancer although the positive margin rate remains 15-30%. Tissue sampling from the resected specimen and from the wound bed for frozen section analysis (FSA) remains the mainstay for intraoperative margin assessment but is subject to sampling error and can require the processing of multiple samples. We sought to understand if an imaging strategy using a tumor-targeted fluorescently labeled antibody could accurately identify the closest peripheral margin on the mucosal surface of resected tumor specimen, so that this "sentinel margin" could be used to guide pathological sampling. Twenty-nine patients with oral squamous cell carcinoma scheduled for surgical resection were consented for the study and received systemic administration of a tumor-targeted fluorescently labeled antibody (Panitumumab IRDye800CW). After surgical resection, the tumor specimen was imaged using a closed-field fluorescent imaging device. Relevant pathological data was available for five patients on retrospective review. For each of these five patients, two regions of highest fluorescence intensity at the peripheral margin and one region of lowest fluorescence intensity were identified, and results were correlated with histology to determine if the region of highest fluorescence intensity along the mucosal margin (i.e., the sentinel margin) was truly the closest margin. Imaging acquisition of the mucosal surface of the specimen immediately after surgery took 30 s. In all of the specimens, the region of highest fluorescence at the specimen edge had a significantly smaller margin distance than other sampled regions. The average margin distance at the closest, "sentinel," margin was 3.2 mm compared to a margin distance of 8.0 mm at other regions ( < 0.0001). This proof-of-concept study suggests that, when combined with routine FSA, fluorescent specimen imaging can be used to identify the closest surgical margin on the specimen. This approach may reduce sampling error of intraoperative evaluation, which should ultimately improve the ability of the surgeon to identify the sentinel margin. This rapid sentinel margin identification improves the surgeon's orientation to areas most likely to be positive in the surgical wound bed and may expedite pathology workflow.
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http://dx.doi.org/10.3389/fonc.2019.01476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6965069PMC
January 2020

Predicting Therapeutic Antibody Delivery into Human Head and Neck Cancers.

Clin Cancer Res 2020 06 24;26(11):2582-2594. Epub 2020 Jan 24.

Department of Otolaryngology - Head and Neck Surgery, Stanford University School of Medicine, Stanford, California.

Purpose: The efficacy of antibody-based therapeutics depends on successful drug delivery into solid tumors; therefore, there is a clinical need to measure intratumoral antibody distribution. This study aims to develop and validate an imaging and computation platform to directly quantify and predict antibody delivery into human head and neck cancers in a clinical study.

Experimental Design: Twenty-four patients received systemic infusion of a near-infrared fluorescence-labeled therapeutic antibody followed by surgical tumor resection. A computational platform was developed to quantify the extent of heterogeneity of intratumoral antibody distribution. Both univariate and multivariate regression analyses were used to select the most predictive tumor biological factors for antibody delivery. Quantitative image features from the pretreatment MRI were extracted and correlated with fluorescence imaging of antibody delivery.

Results: This study not only confirmed heterogeneous intratumoral antibody distribution in-line with many preclinical reports, but also quantified the extent of interpatient, intertumor, and intratumor heterogeneity of antibody delivery. This study demonstrated the strong predictive value of tumor size for intratumoral antibody accumulation and its significant impact on antibody distribution in both primary tumor and lymph node metastasis. Furthermore, this study established the feasibility of using contrast-enhanced MRI to predict antibody delivery.

Conclusions: This study provides a clinically translatable platform to measure antibody delivery into solid tumors and yields valuable insight into clinically relevant antibody tumor penetration, with implications in the selection of patients amenable to antibody therapy and the design of more effective dosing strategies.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-3717DOI Listing
June 2020

Endoscopic Fluorescence-Guided Surgery for Sinonasal Cancer Using an Antibody-Dye Conjugate.

Laryngoscope 2020 12 19;130(12):2811-2817. Epub 2019 Dec 19.

Department of Otolaryngology, Stanford University School of Medicine, Stanford, California, U.S.A.

Objective: Endoscopic resection of sinonasal squamous cell carcinoma has become the standard of care, but challenges remain in obtaining clear resection margins. The current study evaluated the feasibility of endoscopic fluorescence-guided surgery (FGS) to improve surgical resection in a human sinus surgical model.

Methods: A fluorescence endoscope optimized for near-infrared (NIR) fluorescence detection was evaluated in a phantom study. Various endoscope diameters (4 and 10 mm) and viewing angles (0, 30, and 45 degrees) were evaluated to determine the sensitivity of the system for IRDye800CW detection at various working distances (1-5 cm). Endoscopic FGS was then validated in a three-dimensional human sinus surgical model to which squamous cell tumors derived from mice were inserted. Mice had received intravenous panitumumab-IRDye800CW and upon fluorescence-guided tumor resection, mean fluorescence intensity (MFI) and tumor-to-background ratio (TBR) were calculated in in situ and ex vivo settings.

Results: A significantly higher fluorescence intensity was found when using the 10-mm diameter endoscope compared to the 4mm diameter endoscope (P < .001). No significant difference in MFI was found among the viewing angles of the 4-mm diameter endoscope. Using the human sinus model, the highest MFI and TBR were obtained at a 1-cm working distance compared to longer working distances.

Conclusion: We demonstrate that clinically acceptable TBRs were obtained with several working distances to discriminate tumor tissue from adjacent normal tissue in a human sinus model, and that endoscopic FGS may have great potential in identifying residual tumor tissue regions during surgery. Laryngoscope, 2019.
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http://dx.doi.org/10.1002/lary.28483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7754277PMC
December 2020

Optical molecular imaging can differentiate metastatic from benign lymph nodes in head and neck cancer.

Nat Commun 2019 11 6;10(1):5044. Epub 2019 Nov 6.

Department of Otolaryngology-Head and Neck Surgery, Stanford University School of Medicine, 900 Blake Wilbur Drive, Stanford, CA, 94305, USA.

Identification of lymph node (LN) metastasis is essential for staging of solid tumors, and as a result, surgeons focus on harvesting significant numbers of LNs during ablative procedures for pathological evaluation. Isolating those LNs most likely to harbor metastatic disease can allow for a more rigorous evaluation of fewer LNs. Here we evaluate the impact of a systemically injected, near-infrared fluorescently-labeled, tumor-targeting contrast agent, panitumumab-IRDye800CW, to facilitate the identification of metastatic LNs in the ex vivo setting for head and neck cancer patients. Molecular imaging demonstrates a significantly higher mean fluorescence signal in metastatic LNs compared to benign LNs in head and neck cancer patients undergoing an elective neck dissection. Molecular imaging to preselect at-risk LNs may thus allow a more rigorous examination of LNs and subsequently lead to improved prognostication than regular neck dissection.
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http://dx.doi.org/10.1038/s41467-019-13076-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6834597PMC
November 2019

Probe-based fluorescence dosimetry of an antibody-dye conjugate to identify head and neck cancer as a first step to fluorescence-guided tissue preselection for pathological assessment.

Head Neck 2020 01 1;42(1):59-66. Epub 2019 Oct 1.

Department of Otolaryngology - Division of Head and Neck Surgery, Stanford University School of Medicine, Stanford, California.

Background: Despite the rapid growth of fluorescence imaging, accurate sampling of tissue sections remains challenging. Development of novel technologies to improve intraoperative assessment of tissue is needed.

Methods: A novel contact probe-based fluorescence dosimeter device, optimized for IRDye800CW quantification, was developed. After evaluation of the device in a phantom setup, its clinical value was defined ex vivo in patients with head and neck squamous cell carcinoma who received panitumumab-IRDye800CW.

Results: Ten patients were enrolled with a total of 216 data points obtained. Final histopathology showed tumor in 119 spots and normal tissue in 97 spots. Fluorescence-to-excitation ratios in tumor tissue were more than three times higher than those in normal tissue. The area under the curve was 0.86 (95% CI: 0.81-0.91) for tumor detection.

Conclusions: Fluorescence-guided tissue preselection using a fluorescence dosimeter could have substantial impact on tissue sampling for frozen section analysis and potentially reduce sampling errors.
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http://dx.doi.org/10.1002/hed.25964DOI Listing
January 2020

Intraoperative Tumor Assessment Using Real-Time Molecular Imaging in Head and Neck Cancer Patients.

J Am Coll Surg 2019 12 27;229(6):560-567.e1. Epub 2019 Sep 27.

Department of Otolaryngology, Division of Head and Neck Surgery, Stanford University School of Medicine, Stanford, CA. Electronic address:

Background: In head and neck cancer, surgical resection using primarily visual and tactile feedback is considered the gold standard for solid tumors. Due to high numbers of tumor-involved surgical margins, which are directly correlated to poor clinical outcomes, intraoperative optical imaging trials have rapidly proliferated over the past 5 years. However, few studies report on intraoperative in situ imaging data that could support surgical resection. To demonstrate the clinical application of in situ surgical imaging, we report on the imaging data that are directly (ie in real-time) available to the surgeon.

Study Design: Fluorescence intensities and tumor-to-background ratios (TBRs) were determined from the intraoperative imaging data-the view as seen by the surgeon during tumor resection-of 20 patients, and correlated to patient and tumor characteristics including age, sex, tumor site, tumor size, histologic differentiation, and epidermal growth factor receptor (EGFR) expression. Furthermore, different lighting conditions in regard to surgical workflow were evaluated.

Results: Under these circumstances, intraoperative TBRs of the primary tumors averaged 2.2 ± 0.4 (range 1.5 to 2.9). Age, sex, tumor site, and tumor size did not have a significant effect on open-field intraoperative molecular imaging of the primary tumors (p > 0.05). In addition, variation in EGFR expression levels or the presence of ambient light did not seem to alter TBRs.

Conclusions: We present the results of successful in situ intraoperative imaging of primary tumors alongside the optimal conditions with respect to both molecular image acquisition and surgical workflow. This study illuminates the potentials of open-field molecular imaging to assist the surgeon in achieving successful cancer removal.
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http://dx.doi.org/10.1016/j.jamcollsurg.2019.09.007DOI Listing
December 2019

Fluorescence molecular imaging for identification of high-grade dysplasia in patients with head and neck cancer.

Oral Oncol 2019 10 12;97:50-55. Epub 2019 Aug 12.

Department of Pathology, Stanford University School of Medicine, 291 Campus Drive, Stanford, CA 94305, United States. Electronic address:

Objective: High-grade dysplasia is associated with a risk of malignant transformation, and it is necessary to distinguish from normal epithelium or low-grade dysplasia, especially in the intraoperative setting. We hypothesize that an anti-epidermal growth factor receptor (EGFR) contrast agent can be used to differentiate high-grade dysplasia from low-grade dysplasia and normal epithelium.

Materials And Methods: Patients with biopsy proven head and neck squamous cell carcinoma (HNSCC) were enrolled in a clinical trial using systemically injected fluorescently labeled anti-EGFR antibody (panitumumab-IRDye800CW) (NCT02415881). Paraffin embedded tumor specimens from 11 patients were evaluated by fluorescence histopathology. Hematoxylin and eosin (H&E) slides were reviewed by a board-certified pathologist, and regions of invasive squamous cell carcinoma, high-grade dysplasia and low-grade dysplasia were delineated. EGFR expression was assessed for each patient by way of immunohistochemistry.

Results: 11 patients were included in the study with a total of 219 areas on tissue sections analyzed; 68 normal epithelium, 53 low-grade dysplasia, 48 high-grade dysplasia, and 50 malignant regions. The signal-to-background ratio (SBR) increased proportionally with increasing grade of dysplasia; normal epithelium (1.5 ± 0.1), low-grade dysplasia (1.8 ± 0.1), high-grade dysplasia: (2.3 ± 0.2). High-grade dysplasia had a significantly higher SBR when compared to normal or low-grade dysplasia (p < 0.05). Fluorescence histopathology positively correlated with EGFR expression by immunohistochemistry, which also increased proportionally with increasing degree of dysplasia.

Conclusion: Molecular imaging with an anti-EGFR agent can successfully discriminate high-grade dysplastic lesions from low-grade dysplasia and normal epithelium.
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http://dx.doi.org/10.1016/j.oraloncology.2019.08.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6907742PMC
October 2019

The Sentinel Margin: Intraoperative Specimen Mapping Using Relative Fluorescence Intensity.

Clin Cancer Res 2019 08 29;25(15):4656-4662. Epub 2019 May 29.

Department of Otolaryngology-Division of Head and Neck Surgery, Stanford University School of Medicine, Stanford, California.

Purpose: Despite major advancements in surgical oncology, the positive margin rate for primary head and neck cancer resection remains around 15%-30%. In particular, the deep surface margin is the most challenging to adequately assess. Inadequate margins are directly correlated to poor survival, and as such, mitigation of these rates is critical to improve patient outcomes. We have developed an imaging strategy that utilizes fluorescence intensity peaks (relative to background signal) of an injected anti-EGFR antibody conjugated to a fluorescent probe to locate potential close or positive margins on the deep surface of the resected tumor specimen.

Experimental Design: Twelve patients with head and neck cancer scheduled for surgery received systemic administration of a tumor-specific contrast-agent (panitumumab-IRDye800CW). After surgical resection, the tumor specimen was imaged using a fluorescence imager. The three highest fluorescence intensity-peaks on the deep surface of the specimen were isolated and correlated to histology to determine the margin distance at these regions.

Results: Relative fluorescence peak intensities identified the closest margin on the deep surface of the specimen within 2.5 minutes. The highest intensity peak consistently (100%) detected the closest margin to the tumor. The difference in tumor margin distance between the first and second highest fluorescence intensity peak averaged 2.1 ± 1.4 mm. The tumor-margin difference between the second and third highest peak averaged 1.6 ± 0.6 mm.

Conclusions: Fluorescence intensity peaks can identify the region on the specimen where tumor is closest to specimen's edge on the deep surface. This technique could have broad applications in obtaining adequate margins in oncological surgery.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-0319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7021202PMC
August 2019

Optimal Dosing Strategy for Fluorescence-Guided Surgery with Panitumumab-IRDye800CW in Head and Neck Cancer.

Mol Imaging Biol 2020 02;22(1):156-164

Department of Otolaryngology-Head and Neck Surgery, Stanford University, 875 Blake Wilbur Drive, Palo Alto, CA, 94304, USA.

Purpose: To identify the optimal dosing strategy for fluorescence-guided surgery in patients with head and neck squamous cell carcinoma, we conducted a dose-ranging study evaluating the anti-epidermal growth factor receptor (EGFR) therapeutic antibody, panitumumab, that was fluorescently labeled with the near-infrared dye IRDye800CW.

Procedures: Patients (n = 24) received either 0.5 or 1.0 mg/kg panitumumab-IRDye800CW in the weight-based dosing group or 25 or 50 mg panitumumab-IRDye800CW in the fixed dosing group. Following surgery, whole primary specimens were imaged in a closed-field device and the mean fluorescence intensity (MFI) and tumor-to-background ratio (TBR) were assessed. Clinical variables, including dose, time of infusion-to-surgery, age, unlabeled dose, gender, primary tumor site, and tumor size, were analyzed to evaluate the factors affecting the fluorescence intensity in order to identify the optimal dose for intraoperative fluorescence imaging.

Results: A total of 24 primary tumor specimens were imaged and analyzed in this study. Although no correlations between TBR and dose of panitumumab-IRDye800CW were found, there were moderate-strong correlations between the primary tumor MFI and panitumumab-IRDye800CW dose for fixed dose (mg) (R = 0.42) and for dose/weight (mg/kg) (R = 0.54). Results indicated that the optimal MFI was at approximately 50 mg for fixed dose and 0.75 mg/kg for dose/weight. No significant differences were found for the primary tumor MFI and TBRs between the weight-based dosing and the fixed dosing groups. MFIs significantly increased when the infusion-to-surgery window was reduced to within 2 days (vs. 3 days or more, p < 0.05).

Conclusions: Antibody-based imaging for surgical resection is under investigation in multiple clinical trials. Our data suggests that a fixed dose of 50 mg is an appropriate diagnostic dose for successful surgical fluorescence imaging.
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http://dx.doi.org/10.1007/s11307-019-01358-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017887PMC
February 2020

CD47-Targeted Near-Infrared Photoimmunotherapy for Human Bladder Cancer.

Clin Cancer Res 2019 06 19;25(12):3561-3571. Epub 2019 Mar 19.

Department of Urology, Stanford University School of Medicine, Stanford, California.

Purpose: Near-infrared photoimmunotherapy (NIR-PIT) is a localized molecular cancer therapy combining a photosensitizer-conjugated mAb and light energy. CD47 is an innate immune checkpoint widely expressed on bladder cancer cells, but absent from luminal normal urothelium. Targeting CD47 for NIR-PIT has the potential to selectively induce cancer cell death and minimize damage to normal urothelium.

Experimental Design: The cytotoxic effect of NIR-PIT with anti-CD47-IR700 was investigated in human bladder cancer cell lines and primary human bladder cancer cells derived from fresh surgical samples. Phagocytosis assays were performed to evaluate macrophage activity after NIR-PIT. Anti-CD47-IR700 was administered to murine xenograft tumor models of human bladder cancer for molecular imaging and NIR-PIT.

Results: Cytotoxicity in cell lines and primary bladder cancer cells significantly increased in a light-dose-dependent manner with CD47-targeted NIR-PIT. Phagocytosis of cancer cells significantly increased with NIR-PIT compared with antibody alone ( = 0.0002). fluorescence intensity of anti-CD47-IR700 in tumors reached a peak 24-hour postinjection and was detectable for at least 14 days. After a single round of CD47-targeted NIR-PIT, treated animals showed significantly slower tumor growth compared with controls ( < 0.0001). Repeated CD47-targeted NIR-PIT treatment further slowed tumor growth ( = 0.0104) and improved survival compared with controls.

Conclusions: CD47-targeted NIR-PIT increased direct cancer cell death and phagocytosis resulting in inhibited tumor growth and improved survival in a murine xenograft model of human bladder cancer.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-3267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7039531PMC
June 2019

The Clinical Application of Fluorescence-Guided Surgery in Head and Neck Cancer.

J Nucl Med 2019 06 7;60(6):758-763. Epub 2019 Feb 7.

Division of Head and Neck Surgery, Department of Otolaryngology, Stanford University School of Medicine, Stanford, California

Although surgical resection has been the primary treatment modality of solid tumors for decades, surgeons still rely on visual cues and palpation to delineate healthy from cancerous tissue. This may contribute to the high rate (up to 30%) of positive margins in head and neck cancer resections. Margin status in these patients is the most important prognostic factor for overall survival. In addition, second primary lesions may be present at the time of surgery. Although often unnoticed by the medical team, these lesions can have significant survival ramifications. We hypothesize that real-time fluorescence imaging can enhance intraoperative decision making by aiding the surgeon in detecting close or positive margins and visualizing unanticipated regions of primary disease. The purpose of this study was to assess the clinical utility of real-time fluorescence imaging for intraoperative decision making. Head and neck cancer patients ( = 14) scheduled for curative resection were enrolled in a clinical trial evaluating panitumumab-IRDye800CW for surgical guidance (NCT02415881). Open-field fluorescence imaging was performed throughout the surgical procedure. The fluorescence signal was quantified as signal-to-background ratios to characterize the fluorescence contrast of regions of interest relative to background. Fluorescence imaging was able to improve surgical decision making in 3 cases (21.4%): identification of a close margin ( = 1) and unanticipated regions of primary disease ( = 2). This study demonstrates the clinical applications of fluorescence imaging on intraoperative decision making. This information is required for designing phase III clinical trials using this technique. Furthermore, this study is the first to demonstrate this application for intraoperative decision making during resection of primary tumors.
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http://dx.doi.org/10.2967/jnumed.118.222810DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6581234PMC
June 2019

Detection of visually occult metastatic lymph nodes using molecularly targeted fluorescent imaging during surgical resection of pancreatic cancer.

HPB (Oxford) 2019 07 2;21(7):883-890. Epub 2019 Feb 2.

Department of Surgery, Stanford University, Stanford, CA, USA. Electronic address:

Background: Although most patients with PDAC experience distant failure after resection, a significant portion still present with local recurrence. Intraoperative fluorescent imaging can potentially facilitate the visualization of involved peritumoral LNs and guide the locoregional extent of nodal dissection. Here, the efficacy of targeted intraoperative fluorescent imaging was examined in the detection of metastatic lymph nodes (LNs) during resection of pancreatic ductal adenocarcinoma (PDAC).

Methods: A dose-escalation prospective study was performed to assess feasibility of tumor detection within peripancreatic LNs using cetuximab-IRDye800 in PDAC patients. Fluorescent imaging of dissected LNs was analyzed ex vivo macroscopically and microscopically and fluorescence was correlated with histopathology.

Results: A total of 144 LNs (72 in the low-dose and 72 in the high-dose cohort) were evaluated. Detection of metastatic LNs by fluorescence was better in the low-dose (50 mg) cohort, where sensitivity and specificity was 100% and 78% macroscopically, and 91% and 66% microscopically. More importantly, this method was able to detect occult foci of tumor (measuring < 5 mm) with a sensitivity of 88% (15/17 LNs).

Conclusion: This study provides proof of concept that intraoperative fluorescent imaging with cetuximab-IRDye800 can facilitate the detection of peripancreatic lymph nodes often containing subclinical foci of disease.
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http://dx.doi.org/10.1016/j.hpb.2018.11.008DOI Listing
July 2019

Rapid, non-invasive fluorescence margin assessment: Optical specimen mapping in oral squamous cell carcinoma.

Oral Oncol 2019 01 21;88:58-65. Epub 2018 Nov 21.

Department of Otolaryngology, Stanford University School of Medicine, 900 Blake Wilbur Drive, Stanford, CA 94305, United States. Electronic address:

Objective: Surgical resection remains the primary treatment for the majority of solid tumors. Despite efforts to obtain wide margins, close or positive surgical margins (<5 mm) are found in 15-30% of head and neck cancer patients. Obtaining negative margins requires immediate, intraoperative feedback of margin status. To this end, we propose optical specimen mapping of resected tumor specimens immediately after removal.

Materials And Methods: A first-in-human pilot study was performed in patients (n = 8) after infusion of fluorescently labeled antibody, panitumumab-IRDye800 to allow surgical mapping of the tumor specimen. Patients underwent standard of care surgical resection for head and neck squamous cell carcinoma (HNSCC). Optical specimen mapping was performed on the primary tumor specimen and correlated with pathological findings after tissue processing.

Results: Optical mapping of the specimen had a 95% sensitivity and 89% specificity to detect cancer within 5 mm (n = 160) of the cut surface. To detect tumor within 2 mm of the specimen surface, the sensitivity of optical specimen mapping was 100%. The maximal observed penetration depth of panitumumab-IRDye800 through human tissue in our study was 6.3 mm.

Conclusion: Optical specimen mapping is a highly sensitive and specific method for evaluation of margins within <5 mm of the tumor mass in HNSCC specimens. This technology has potentially broad applications for ensuring adequate tumor resection and negative margins in head and neck cancers.
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http://dx.doi.org/10.1016/j.oraloncology.2018.11.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6530934PMC
January 2019

Recommendations for reporting on emerging optical imaging agents to promote clinical approval.

Theranostics 2018 22;8(19):5336-5347. Epub 2018 Oct 22.

Department of Otolaryngology, Stanford University, Stanford, CA.

Intraoperative fluorescence imaging is particularly well-suited for surgical applications due to its inherently high sensitivity, resolution, and ability to provide images in real-time. To date, the intraoperative observation of fluorescence has largely been subjective. With the need to show objective evidence in order to demonstrate the benefit of this technique, quantitative data needs to be provided to overseeing regulatory bodies. Standardization of fluorescence imaging protocols would improve reproducibility and minimize inter- and intra-institution variance. This would allow studies to be conducted using the same injection techniques, imaging times, reconstruction methods, and analyses. Here, we provide recommendations for standardized methodologies with the goal of setting a minimum requirement for reporting fluorescence-guided surgery results based on both qualitative and (semi-) quantitative data collection. Clinical trials using fluorescence-guided surgery should present results of three critical elements; 1) intra-operative imaging, 2) specimen mapping and pathology correlation, and 3) target validation. Qualitative analyses should consist of a bright field image, black-and-white fluorescence image, pseudo-colored fluorescence overlay image, and/or heat-map whereby fluorescence signal intensity differences are displayed on a color spectrum. Quantitative analyses should include 1) intraoperative data (consisting of images or video, raw numeric values and ratios); 2) specimen mapping, for correlation of fluorescence with the presence of disease (performed using fresh tissue); and 3) target validation (designed to determine fluorescence intensity relative to receptor density of a specific area). Including the aforementioned methods of both qualitative and quantitative analyses will ensure that trial results are comparable and could be collated in future studies to expedite FDA approval.
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http://dx.doi.org/10.7150/thno.27384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6276089PMC
September 2019

Three-Dimensional Tumor Margin Demarcation Using the Hybrid Tracer Indocyanine Green-Tc-Nanocolloid: A Proof-of-Concept Study in Tongue Cancer Patients Scheduled for Sentinel Node Biopsy.

J Nucl Med 2019 06 30;60(6):764-769. Epub 2018 Nov 30.

Interventional Molecular Imaging Laboratory, Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands

For radical resection of squamous cell carcinoma of the oral cavity, a tumor-free margin of at least 5 mm is required. Unfortunately, establishing in-depth margins is a surgical conundrum. Knowing that the hybrid sentinel node (SN) tracer indocyanine green (ICG)-Tc-nanocolloid generates temporary tattoolike markings at the site of administration, we studied the ability to apply this tracer for tumor margin demarcation combined with SN biopsy. Nineteen patients with clinical T1-T2 oral tongue tumors received the traditional superficial 3 or 4 deposits of ICG-Tc-nanocolloid (0.1 mL each), and in 12 patients additional deposits were placed deeply using ultrasound guidance (total of 6; 0.07 mL each). SN mapping was performed using lymphoscintigraphy and SPECT/CT. Before and directly after tumor excision, fluorescence imaging was performed to monitor the tracer deposits in the patient (fluorescent deposits were not used to guide the surgical excision). At pathologic examination, primary tumor samples were studied in detail. The number of tracer depositions did not induce a significant difference in the number of SNs visualized ( = 0.836). Reproducible and deep tracer deposition proved to be challenging. The fluorescent nature of ICG-Tc-nanocolloid supported in vivo and ex vivo identification of the tracer deposits surrounding the tumor. Pathologic examination indicated that in 66.7% (8/12), all fluorescence was observed within the resection margins. This study indicates that tumor margin demarcation combined with SN identification has potential but that some practical challenges need to be overcome if this technique is to mature as a surgical guidance concept. Future studies need to define whether the technology can improve the radical nature of the resections.
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http://dx.doi.org/10.2967/jnumed.118.220202DOI Listing
June 2019
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