scholarly journals Side-by-Side Comparison of uPAR-Targeting Optical Imaging Antibodies and Antibody Fragments for Fluorescence-Guided Surgery of Solid Tumors

2021 ◽  
Author(s):  
Victor M. Baart ◽  
Labrinus van Manen ◽  
Shadhvi S. Bhairosingh ◽  
Floris A. Vuijk ◽  
Luisa Iamele ◽  
...  
Keyword(s):  
Antibody Fragments ◽  
Ductal Adenocarcinoma ◽  
Resection Margins ◽  
Urokinase Plasminogen Activator Receptor ◽  
In Vivo Models ◽  
Guided Surgery ◽  
Imaging Characteristics ◽  
Biodistribution Studies ◽  
Fluorescence Guided Surgery ◽  
Cell Assays

Abstract Purpose Radical resection is paramount for curative oncological surgery. Fluorescence-guided surgery (FGS) aids in intraoperative identification of tumor-positive resection margins. This study aims to assess the feasibility of urokinase plasminogen activator receptor (uPAR) targeting antibody fragments for FGS in a direct comparison with their parent IgG in various relevant in vivo models. Procedures Humanized anti-uPAR monoclonal antibody MNPR-101 (uIgG) was proteolytically digested into F(ab’)2 and Fab fragments named uFab2 and uFab. Surface plasmon resonance (SPR) and cell assays were used to determine in vitro binding before and after fluorescent labeling with IRDye800CW. Mice bearing subcutaneous HT-29 human colonic cancer cells were imaged serially for up to 120 h after fluorescent tracer administration. Imaging characteristics and ex vivo organ biodistribution were further compared in orthotopic pancreatic ductal adenocarcinoma (BxPc-3-luc2), head-and-neck squamous cell carcinoma (OSC-19-luc2-GFP), and peritoneal carcinomatosis (HT29-luc2) models using the clinical Artemis fluorescence imaging system. Results Unconjugated and conjugated uIgG, uFab2, and uFab specifically recognized uPAR in the nanomolar range as determined by SPR and cell assays. Subcutaneous tumors were clearly identifiable with tumor-to-background ratios (TBRs) > 2 after 72 h for uIgG-800F and 24 h for uFab2-800F and uFab-800F. For the latter two, mean fluorescence intensities (MFIs) dipped below predetermined threshold after 72 h and 36 h, respectively. Tumors were easily identified in the orthotopic models with uIgG-800F consistently having the highest MFIs and uFab2-800F and uFab-800F having similar values. In biodistribution studies, kidney and liver fluorescence approached tumor fluorescence after uIgG-800F administration and surpassed tumor fluorescence after uFab2-800F or uFab-800F administration, resulting in interference in the abdominal orthotopic mouse models. Conclusions In a side-by-side comparison, FGS with uPAR-targeting antibody fragments compared with the parent IgG resulted in earlier tumor visualization at the expense of peak fluorescence intensity.

scholarly journals Validation of a Three-Dimensional Head and Neck Spheroid Model to Evaluate Cameras for NIR Fluorescence-Guided Cancer Surgery

2021 ◽  
Vol 22 (4) ◽  
pp. 1966
Author(s):  
Claire Egloff-Juras ◽  
Ilya Yakavets ◽  
Victoria Scherrer ◽  
Aurélie Francois ◽  
Lina Bezdetnaya ◽  
...  
Keyword(s):  
Head And Neck ◽  
Near Infrared ◽  
Tumor Model ◽  
Resection Margins ◽  
Fluorescence Signal ◽  
Multicellular Tumor Spheroid ◽  
Guided Surgery ◽  
Nir Fluorescence ◽  
Fluorescence Guided Surgery

Near-infrared (NIR) fluorescence-guided surgery is an innovative technique for the real-time visualization of resection margins. The aim of this study was to develop a head and neck multicellular tumor spheroid model and to explore the possibilities offered by it for the evaluation of cameras for NIR fluorescence-guided surgery protocols. FaDu spheroids were incubated with indocyanine green (ICG) and then included in a tissue-like phantom. To assess the capability of Fluobeam® NIR camera to detect ICG in tissues, FaDu spheroids exposed to ICG were embedded in 2, 5 or 8 mm of tissue-like phantom. The fluorescence signal was significantly higher between 2, 5 and 8 mm of depth for spheroids treated with more than 5 µg/mL ICG (p < 0.05). The fluorescence intensity positively correlated with the size of spheroids (p < 0.01), while the correlation with depth in the tissue-like phantom was strongly negative (p < 0.001). This multicellular spheroid model embedded in a tissue-like phantom seems to be a simple and reproducible in vitro tumor model, allowing a comparison of NIR cameras. The ideal configuration seems to be 450 μm FaDu spheroids incubated for 24 hours with 0.05 mg/ml of ICG, ensuring the best stability, toxicity, incorporation and signal intensity.

scholarly journals Evaluation of Ac-Lys0(IRDye800CW)Tyr3-octreotate as a novel tracer for SSTR2-targeted molecular fluorescence guided surgery in meningioma

2021 ◽  
Author(s):  
Bianca M. Dijkstra ◽  
Marion de Jong ◽  
Marcus C. M. Stroet ◽  
Fritz Andreae ◽  
Sebastiaan E. Dulfer ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Ex Vivo ◽  
Specific Binding ◽  
Somatostatin Receptor ◽  
Receptor Subtype ◽  
Tumor Uptake ◽  
In Vivo Models ◽  
Guided Surgery ◽  
Fluorescence Guided Surgery ◽  
Molecular Fluorescence

Abstract Purpose Meningioma recurrence rates can be reduced by optimizing surgical resection with the use of intraoperative molecular fluorescence guided surgery (MFGS). We evaluated the potential of the fluorescent tracer 800CW-TATE for MFGS using in vitro and in vivo models. It targets somatostatin receptor subtype 2 (SSTR2), which is overexpressed in all meningiomas. Methods Binding affinity of 800CW-TATE was evaluated using [177Lu] Lu-DOTA-Tyr3-octreotate displacement assays. Tumor uptake was determined by injecting 800CW-TATE in (SSTR2-positive) NCI-H69 or (SSTR2-negative) CH-157MN xenograft bearing mice and FMT2500 imaging. SSTR2-specific binding was measured by comparing tumor uptake in NCI-H69 and CH-157MN xenografts, blocking experiments and non-targeted IRDye800CW-carboxylate binding. Tracer distribution was analyzed ex vivo, and the tumor-to-background ratio (TBR) was calculated. SSTR2 expression was determined by immunohistochemistry (IHC). Lastly, 800CW-TATE was incubated on frozen and fresh meningioma specimens and analyzed by microscopy. Results 800CW-TATE binding affinity assays showed an IC50 value of 72 nM. NCI-H69 xenografted mice showed a TBR of 21.1. 800CW-TATE detection was reduced after co-administration of non-fluorescent DOTA-Tyr3-octreotate or administration of IRDye800CW. CH-157MN had no tumor specific tracer staining due to absence of SSTR2 expression, thereby serving as a negative control. The tracer bound specifically to SSTR2-positive meningioma tissues representing all WHO grades. Conclusion 800CW-TATE demonstrated sufficient binding affinity, specific SSTR2-mediated tumor uptake, a favorable biodistribution, and high TBR. These features make this tracer very promising for use in MFGS and could potentially aid in safer and a more complete meningioma resection, especially in high-grade meningiomas or those at complex anatomical localizations.

Optical imaging probes and their potential contribution to radiotracer development

2016 ◽  
Vol 55 (02) ◽  
pp. 51-62 ◽  
Author(s):  
S. Hermann ◽  
M. Schäfers ◽  
C. Höltke ◽  
A. Faust
Keyword(s):  
Optical Imaging ◽  
Fluorescent Dyes ◽  
Great Influence ◽  
Potential Contribution ◽  
Preclinical Evaluation ◽  
Guided Surgery ◽  
Fluorescence Guided Surgery ◽  
Imaging Probes ◽  
Unspecific Binding

SummaryOptical imaging has long been considered a method for histological or microscopic investigations. Over the last 15 years, however, this method was applied for preclinical molecular imaging and, just recently, was also able to show its principal potential for clinical applications (e.g. fluorescence-guided surgery). Reviewing the development and preclinical evaluation of new fluorescent dyes and target-specific dye conjugates, these often show characteristic patterns of their routes of excretion and biodistribution, which could also be interesting for the development and optimization of radiopharmaceuticals. Especially ionic charges show a great influence on biodistribution and netcharge and charge-distribution on a conjugate often determines unspecific binding or background signals in liver, kidney or intestine, and other organs.Learning from fluorescent probe behaviour in vivo and translating this knowledge to radio-pharmaceuticals might be useful to further optimize emerging and existing radiopharmaceuticals with respect to their biodistribution and thereby availability for binding to their targets.

scholarly journals Pre-Operative Imaging and Pathological Diagnosis of Localized High-Grade Pancreatic Intra-Epithelial Neoplasia without Invasive Carcinoma

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 945
Author(s):  
Ryota Sagami ◽  
Kentaro Yamao ◽  
Jun Nakahodo ◽  
Ryuki Minami ◽  
Masakatsu Tsurusaki ◽  
...  
Keyword(s):  
Pancreatic Duct ◽  
Invasive Carcinoma ◽  
Current Knowledge ◽  
Precancerous Lesions ◽  
Ductal Adenocarcinoma ◽  
Pancreatic Ducts ◽  
High Grade ◽  
Cytologic Examination ◽  
Imaging Characteristics ◽  
Retention Cysts

Pancreatic ductal adenocarcinoma (PDAC) arises from precursor lesions, such as pancreatic intra-epithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasm (IPMN). The prognosis of high-grade precancerous lesions, including high-grade PanIN and high-grade IPMN, without invasive carcinoma is good, despite the overall poor prognosis of PDAC. High-grade PanIN, as a lesion preceding invasive PDAC, is therefore a primary target for intervention. However, detection of localized high-grade PanIN is difficult when using standard radiological approaches. Therefore, most studies of high-grade PanIN have been conducted using specimens that harbor invasive PDAC. Recently, imaging characteristics of high-grade PanIN have been revealed. Obstruction of the pancreatic duct due to high-grade PanIN may induce a loss of acinar cells replaced by fibrosis and lobular parenchymal atrophy. These changes and additional inflammation around the branch pancreatic ducts (BPDs) result in main pancreatic duct (MPD) stenosis, dilation, retention cysts (BPD dilation), focal pancreatic parenchymal atrophy, and/or hypoechoic changes around the MPD. These indirect imaging findings have become important clues for localized, high-grade PanIN detection. To obtain pre-operative histopathological confirmation of suspected cases, serial pancreatic-juice aspiration cytologic examination is effective. In this review, we outline current knowledge on imaging characteristics of high-grade PanIN.

Combined chemotherapy and EUS-guided intra-tumoral 32-P implantation for locally advanced pancreatic ductal adenocarcinoma: a pilot study

Endoscopy ◽  
2021 ◽  
Author(s):  
Jeevinesh Naidu ◽  
Dylan Bartholomeusz ◽  
Joshua Zobel ◽  
Romina Safaeian ◽  
William Hsieh ◽  
...  
Keyword(s):  
Locally Advanced ◽  
Adelaide Hospital ◽  
Response To Treatment ◽  
Ductal Adenocarcinoma ◽  
Resection Margins ◽  
R0 Resection ◽  
Royal Adelaide Hospital ◽  
Combined Chemotherapy ◽  
Radioactive Phosphorus ◽  
18Fdg Pet

Aim: This study evaluated clinical outcomes of combined chemotherapy and Endoscopic Ultrasound (EUS) guided intra-tumoral radioactive phosphorus-32 (32P OncoSil) implantation in locally advanced pancreatic adenocarcinoma (LAPC). Methods: Consecutive patients with a new histological diagnosis of LAPC were recruited over 20 months. Baseline CT and 18FDG PET-CT were performed and repeated after 12 weeks to assess response to treatment. Following 2 cycles of conventional chemotherapy, patients underwent EUS-guided 32P OncoSil implantation followed by a further six cycles of chemotherapy. Results: Twelve patients with LAPC (8M:4F; median age 69 years, IQR 61.5-73.3) completed the treatment. Technical success was 100% and no procedural complications were reported. At 12 weeks, there was a median reduction of 8.2cm3 (95% CI 4.95-10.85; p=0.003) in tumour volume, with minimal or no 18FDG uptake in 9 (75%) patients. Tumour downstaging was achieved in 6 (50%) patients, leading to successful resection in 5 (42%) patients, of which 4 patients (80%) had clear (R0) resection margins. Conclusions: EUS guided 32P OncoSil implantation is feasible and well tolerated and was associated with a 42% rate of surgical resection in our cohort. However, further evaluation in a larger randomized multicenter trial is warranted. (32P funded by OncoSil Medical Ltd, equipment and staff funded by the Royal Adelaide Hospital, ClinicalTrials.gov number, NCT03003078).

Predicting Surgical Margins in Patients With Borderline Resectable and Locally Advanced Pancreatic Cancer Undergoing Resection

2021 ◽  
pp. 000313482110111
Author(s):  
Weizheng Ren ◽  
Dimitrios Xourafas ◽  
Stanley W. Ashley ◽  
Thomas E. Clancy
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Univariate Analysis ◽  
Locally Advanced ◽  
Advanced Pancreatic Cancer ◽  
Ductal Adenocarcinoma ◽  
Resection Margins ◽  
Borderline Resectable ◽  
Stepwise Selection ◽  
R1 Resection ◽  
Positive Resection Margins

Background Many patients with borderline resectable/locally advanced pancreatic ductal adenocarcinoma (borderline resectable [BR]/locally advanced [LA] pancreatic ductal adenocarcinoma [PDAC]) undergoing resection will have positive resection margins (R1), which is associated with poor prognosis. It might be useful to preoperatively predict the margin (R) status. Methods Data from patients with BR/LA PDAC who underwent a pancreatectomy between 2008 and 2018 at Brigham and Women’s Hospital were retrospectively reviewed. Logistic regression analysis was used to evaluate the association between R status and relevant preoperative factors. Significant predictors of R1 resection on univariate analysis ( P < .1) were entered into a stepwise selection using the Akaike information criterion to define the final model. Results A total of 142 patients with BR/LA PDAC were included in the analysis, 60(42.3%) had R1 resections. In stepwise selection, the following factors were identified as positive predictors of an R1 resection: evidence of lymphadenopathy at diagnosis (OR = 2.06, 95% CI: 0.99-4.36, P = .056), the need for pancreaticoduodenectomy (OR = 3.81, 96% CI: 1.15-15.70, P = .040), extent of portal vein/superior mesenteric vein involvement at restaging (<180°, OR = 3.57, 95% CI: 1.00-17.00, P = .069, ≥180°, OR = 7,32, 95% CI: 1.75-39.87, P = .010), stable CA 19-9 serum levels (less than 50% decrease from diagnosis to restaging, OR = 2.27, 95% CI: 0.84-6.36 P = .107), and no preoperative FOLFIRINOX (OR = 2.17, 95% CI: 0.86-5.64, P = .103). The prognostic nomogram based on this model yielded a probability of achieving an R1 resection ranging from <5% (0 factors) to >70% (all 5 factors). Conclusions Relevant preoperative clinicopathological characteristics accurately predict positive resection margins in patients with BR/LA PDAC before resection. With further development, this model might be used to preoperatively guide surgical decision-making in patients with BR/LA PDAC.

Unexpected Binding of Tozuleristide “Tumor Paint” to Cerebral Vascular Malformations: A Potentially Novel Application of Fluorescence-Guided Surgery

Neurosurgery ◽  
2021 ◽  
Author(s):  
Andrew J Kobets ◽  
David Nauen ◽  
Amy Lee ◽  
Alan R Cohen
Keyword(s):  
Near Infrared ◽  
Vascular Malformations ◽  
Cns Tumors ◽  
Matrix Metalloproteinase 2 ◽  
Cerebrovascular Lesions ◽  
Cavernous Malformations ◽  
Guided Surgery ◽  
Fluorescence Guided Surgery ◽  
Cerebral Vascular Malformations ◽  
Cerebral Vascular

Abstract BACKGROUND Fluorescence-guided surgery (FGS) is under investigation as a means to improve the extent of resection for primary central nervous system (CNS) tumors. Tozuleristide, known also as “Tumor Paint,” is an investigational tumor-targeting agent covalently conjugated to a derivative of the fluorescent dye indocyanine green. OBJECTIVE To report the finding of avid intraoperative fluorescence of tozuleristide on cerebral vascular malformations. METHODS Our institution is participating in a phase 2/3 study of intraoperative near-infrared fluorescence detection of pediatric primary CNS tumors in patients receiving intravenous tozuleristide and imaged with the Canvas system. Our site enrolled 2 patients with intracranial lesions, suspected preoperatively of possibly being gliomas that proved to be cavernous vascular malformations after resection. RESULTS Each lesion had a dark blue mulberry appearance and each fluoresced avidly with tozuleristide. Each was completely resected, and the patients recovered without deficit. Pathological assessment showed cavernous angioma for both cases. Tozuleristide fluorescence is postulated to result from binding to matrix metalloproteinase-2 and annexin A2, and literature review demonstrates expression of both these ligands on multiple cerebrovascular lesions, including cavernous malformations. CONCLUSION This finding deserves further investigation to determine if tozuleristide “Tumor Paint” may have a wider role in the identification of non-neoplastic intracranial pathologies.

Utility of fluorescence-guided surgery in the laparoscopic approach of peritoneal carcinomatosis: two cases in our center

2021 ◽  
Vol 99 (4) ◽  
pp. 311-312
Author(s):  
María del Pilar Gutiérrez Delgado ◽  
Joaquín Carrasco Campos ◽  
Santiago Mera Velasco ◽  
Julio Santoyo Santoyo
Keyword(s):  
Peritoneal Carcinomatosis ◽  
Laparoscopic Approach ◽  
Guided Surgery ◽  
Fluorescence Guided Surgery

scholarly journals Translation of c-Met Targeted Image-Guided Surgery Solutions in Oral Cavity Cancer—Initial Proof of Concept Data

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2674
Author(s):  
Tessa Buckle ◽  
Maarten van Alphen ◽  
Matthias N. van Oosterom ◽  
Florian van Beurden ◽  
Nina Heimburger ◽  
...  
Keyword(s):  
Oral Cavity ◽  
Oral Cavity Cancer ◽  
Ex Vivo ◽  
Intermediate Step ◽  
Guided Surgery ◽  
Fluorescence Guided Surgery ◽  
Tumor Identification ◽  
Imaging Results ◽  
Pathological Evaluation ◽  
Fluorescence Camera

Intraoperative tumor identification (extension/margins/metastases) via receptor-specific targeting is one of the ultimate promises of fluorescence-guided surgery. The translation of fluorescent tracers that enable tumor visualization forms a critical component in the realization of this approach. Ex vivo assessment of surgical specimens after topical tracer application could help provide an intermediate step between preclinical evaluation and first-in-human trials. Here, the suitability of the c-Met receptor as a potential surgical target in oral cavity cancer was explored via topical ex vivo application of the fluorescent tracer EMI-137. Freshly excised tumor specimens obtained from ten patients with squamous cell carcinoma of the tongue were incubated with EMI-137 and imaged with a clinical-grade Cy5 prototype fluorescence camera. In-house developed image processing software allowed video-rate assessment of the tumor-to-background ratio (TBR). Fluorescence imaging results were related to standard pathological evaluation and c-MET immunohistochemistry. After incubation with EMI-137, 9/10 tumors were fluorescently illuminated. Immunohistochemistry revealed c-Met expression in all ten specimens. Non-visualization could be linked to a more deeply situated lesion. Tumor assessment was improved via video representation of the TBR (median TBR: 2.5 (range 1.8–3.1)). Ex vivo evaluation of tumor specimens suggests that c-Met is a possible candidate for fluorescence-guided surgery in oral cavity cancer.

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