Submillimeter-Resolution Fluorescence Laparoscopy of Pancreatic Cancer in a Carcinomatosis Mouse Model Visualizes Metastases Not Seen with Standard Laparoscopy

Cao, Hop S. Tran; Kaushal, Sharmeela; Menen, Rhiana; Metildi, Cristina; Lee, Claudia; Snyder, Cynthia S.; Talamini, Mark A.; Hoffman, Robert M.; Bouvet, Michael

doi:10.1089/lap.2011.0181

Cited by 19 publications

(19 citation statements)

References 14 publications

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“…In particular, the use of fluorescence-based laparoscopy for detection of pancreatic cancer has been assessed by several researchers using fluorescent-labeled proteins to aid in the surgical resection of malignant tissues. 30–33 Most of these studies found that fluorescence laparoscopy provided a simple and real-time approach for imaging to localize primary and possibly metastatic pancreatic lesions.…”

Section: Discussionmentioning

confidence: 99%

ImmunoPET and Near-Infrared Fluorescence Imaging of Pancreatic Cancer with a Dual-Labeled Bispecific Antibody Fragment

et al. 2017

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Dual-targeted imaging agents have shown improved targeting efficiencies in comparison to single-targeted entities. The purpose of this study was to quantitatively assess the tumor accumulation of a dual-labeled heterobifunctional imaging agent, targeting two overexpressed biomarkers in pancreatic cancer, using positron emission tomography (PET) and near-infrared fluorescence (NIRF) imaging modalities. A bispecific immunoconjugate (heterodimer) of CD105 and tissue factor (TF) Fab′ antibody fragments was developed using click chemistry. The heterodimer was dual-labeled with a radionuclide (64Cu) and fluorescent dye. PET/NIRF imaging and biodistribution studies were performed in four-to-five week old nude athymic mice bearing BxPC-3 (CD105/TF+/+) or PANC-1 (CD105/TF−/−) tumors xenografts. A blocking study was conducted to investigate the specificity of the tracer. Ex vivo tissue staining was performed to compare TF/CD105 expression in tissues with PET tracer uptake to validate in vivo results. PET imaging of 64Cu-NOTA-heterodimer-ZW800 in BxPC-3 tumor xenografts revealed enhanced tumor uptake (21.0 ± 3.4 %ID/g; n = 4) compared to the homodimer of TRC-105 (9.6 ± 2.0 %ID/g; n=4; p < 0.01) and ALT-836 (7.6 ± 3.7 %ID/g; n=4; p < 0.01) at 24 h post-injection. Blocking studies revealed that tracer uptake in BxPC-3 tumors could be decreased by four-fold with TF blocking and two-fold with CD105 blocking. In the negative model (PANC-1), heterodimer uptake was significantly lower than that found in the BxPC-3 model (3.5 ± 1.1 %ID/g; n=4; p < 0.01). The specificity was confirmed by the successful blocking of CD105 or TF, which demonstrated the dual targeting with 64Cu-NOTA-heterodimer-ZW800 provided an improvement in overall tumor accumulation. Also, fluorescence imaging validated the PET imaging, allowing for clear delineation of the xenograft tumors. Dual-labeled heterodimeric imaging agents, like 64Cu-NOTA-heterodimer-ZW800, may increase the overall tumor accumulation in comparison to single-targeted homodimers, leading to improved imaging of cancer and other related diseases.

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Section: Discussionmentioning

confidence: 99%

ImmunoPET and Near-Infrared Fluorescence Imaging of Pancreatic Cancer with a Dual-Labeled Bispecific Antibody Fragment

et al. 2017

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“…In subsequent studies, we showed that fluorescence laparoscopy could identify tumors pre-labeled with GFP before implantation (16,17). …”

Section: Discussionmentioning

confidence: 99%

“…Toward this goal, we have recently developed a fluorescence laparoscope that permits facile and rapid identification and localization of GFP-expressing primary and metastatic tumors while maintaining adequate visualization of the surrounding tissue for proper surgical orientation and navigation (16,17). …”

Section: Introductionmentioning

confidence: 99%

Tumor-Specific Fluorescence Antibody Imaging Enables Accurate Staging Laparoscopy in an Orthotopic Model of Pancreatic Cancer

Cao

Kaushal

Metildi

et al. 2011

HGE

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Background/Aims Laparoscopy is important in staging pancreatic cancer, but false negatives remain problematic. Making tumors fluorescent has the potential to improve the accuracy of staging laparoscopy. Methodology Orthotopic and carcinomatosis models of pancreatic cancer were established with BxPC-3 human pancreatic cancer cells in nude mice. Alexa488-anti-CEA conjugates were injected via tail vein 24 hours prior to laparoscopy. Mice were examined under bright field laparoscopic (BL) and fluorescence laparoscopic (FL) modes. Outcomes measured included time to identification of primary tumor for the orthotopic model and number of metastases identified within 2 minutes for the carcinomatosis model. Results FL enabled more rapid and accurate identification and localization of primary tumors and metastases than BL. Using BL took statistically significantly longer time than FL. More metastatic lesions were detected and localized under FL compared to BL and with greater accuracy, with sensitivities of 96% vs. 40%, respectively, when compared to control. FL was sensitive enough to detect metastatic lesions <1mm. Conclusions The use of fluorescence laparoscopy with tumors labeled with fluorophore-conjugated anti-CEA antibody permits rapid detection and accurate localization of primary and metastatic pancreatic cancer in an orthotopic model. The results of the present report demonstrate the future clinical potential of fluorescence laparoscopy.

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“…Laparoscopic surgical systems have recently been enhanced with a fluorescence excitation light that enables imaging of fluorescently labeled tumors and metastases as well as the surrounding anatomy in orthotopic mouse models of cancer [8]. The ideal system would maximize the fluorescent intensity of tumor tissue, minimize background fluorescence, and maintain the ability for the surgeon to visualize surrounding tissues to allow for spatial orientation and surgical navigation.…”

Section: Development Of Fluorescence Laparoscopymentioning

confidence: 99%

“…With the proper filters, the sensitivity and accuracy of staging laparoscopy were significantly improved, allowing for the detection of tumor deposits that were less than 1 mm in size [8]. A second-generation fluorescence laparoscope utilized LED lighting, which was an improvement of our previously described method of fluorescence laparoscopy and allowed for enhanced tumor detection without compromising background illumination [10].…”

Section: Development Of Fluorescence Laparoscopymentioning

confidence: 99%

Current status and future perspectives of fluorescence-guided surgery for cancer

DeLong

Hoffman

Bouvet

2015

Expert Review of Anticancer Therapy

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Summary Curative cancer surgery is dependent on the removal of all tumor and metastatic cancer cells. Preoperative imaging, intraoperative inspection and palpation, and pathological margin confirmation aid the surgeon, but these methods are lacking in sensitivity and can be highly subjective. Techniques in fluorescence-guided surgery (FGS) are emerging that selectively illuminate cancer cells, enhancing the distinction between tumors and surrounding tissues with the potential for single-cell sensitivity. FGS enhances tumor detection, surgical navigation, margin confirmation, and in some cases can be combined with therapeutic techniques to eliminate microscopic disease. In this review, we describe the preclinical developments and currently used techniques for FGS.

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Submillimeter-Resolution Fluorescence Laparoscopy of Pancreatic Cancer in a Carcinomatosis Mouse Model Visualizes Metastases Not Seen with Standard Laparoscopy

Abstract: The use of FL enables the identification of tumor foci that cannot be seen with standard laparoscopy. The technology described in this report has important potential for the clinical development of FL.

Cited by 19 publications

References 14 publications

ImmunoPET and Near-Infrared Fluorescence Imaging of Pancreatic Cancer with a Dual-Labeled Bispecific Antibody Fragment

ImmunoPET and Near-Infrared Fluorescence Imaging of Pancreatic Cancer with a Dual-Labeled Bispecific Antibody Fragment

Tumor-Specific Fluorescence Antibody Imaging Enables Accurate Staging Laparoscopy in an Orthotopic Model of Pancreatic Cancer

Current status and future perspectives of fluorescence-guided surgery for cancer

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