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Background: Carcinoembryonic antigen is overexpressed in colorectal cancer (CRC), making it an optimal target for fluorescence imaging. A phase I/II study was designed to determine the optimal imaging dose of SGM-101 for intraoperative fluorescence imaging of primary and recurrent CRC., Methods: Patients were included and received a single dose of SGM-101 at least 24 h before surgery. Patients who received routine anticancer therapy (i.e., radiotherapy or chemotherapy) also were eligible. A dedicated near-infrared imaging system was used for real-time fluorescence imaging during surgery. Safety assessments were performed and SGM-101 efficacy was evaluated per dose level to determine the most optimal imaging dose., Results: Thirty-seven patients with CRC were included in the analysis. Fluorescence was visible in all primary and recurrent tumors. In seven patients, no fluorescence was seen; all were confirmed as pathological complete responses after neoadjuvant therapy. Two tumors showed false-positive fluorescence. In the 37 patients, a total of 97 lesions were excised. The highest mean intraoperative tumor-to-background ratio (TBR) of 1.9 (p = 0.019) was seen in the 10-mg dose. This dose showed a sensitivity of 96%, specificity of 63%, and negative predictive value of 94%. Nine patients (24%) had a surgical plan alteration based on fluorescence, with additional malignant lesions detected in six patients., Conclusions: The optimal imaging dose was established at 10 mg 4 days before surgery. The results accentuate the potential of SGM-101 and designated a promising base for the multinational phase III study, which enrolled the first patients in June 2019.

Peritoneal metastasis (PM) occurs in about 10% of patients with colorectal cancer (CRC). Fluorescence imaging can enhance contrast between cancerous and benign tissue, enabling the surgeon to clearly visualize PM during cytoreductive surgery. This study assessed the suitability of different biomarkers as potential targets for tumor-targeted imaging of PM of CRC. Tissue samples from primary tumor and PM from patients with CRC were obtained from the pathology archives and immunohistochemical stainings were performed. Overexpression of the epithelial cell adhesion molecule (EpCAM) and carcinoembryonic antigen (CEA) was seen in 100% of PM samples and the expression was strong in >70% of samples. Tyrosine-kinase Met (C-Met) and folate receptor α overexpression was seen in 20% of PM samples. For successful application of tumor-targeted intraoperative fluorescence imaging of PM, biomarkers need to be identified. We demonstrated that both EpCAM and CEA are suitable targets for fluorescence imaging of PM in patients with CRC., Competing Interests: Declaration of conflicting interests:The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Endoscopic ultrasound-guided fine needle aspirations (EUS-FNA) of pancreatic masses suffer from sample errors and low-negative predictive values. Fiber-optic spectroscopy in the visible to near-infrared wavelength spectrum can noninvasively extract physiological parameters from tissue and has the potential to guide the sampling process and reduce sample errors. We assessed the feasibility of single fiber (SF) reflectance spectroscopy measurements during EUS-FNA of pancreatic masses and its ability to distinguish benign from malignant pancreatic tissue. A single optical fiber was placed inside a 19-gauge biopsy needle during EUS-FNA and at least three reflectance measurements were taken prior to FNA. Spectroscopy measurements did not cause any related adverse events and prolonged procedure time with ? 5 ?? min . An accurate correlation between spectroscopy measurements and cytology could be made in nine patients (three benign and six malignant). The oxygen saturation and bilirubin concentration were significantly higher in benign tissue compared with malignant tissue (55% versus 21%, p = 0.038 ; 166 ?? ? mol / L versus 17 ?? ? mol / L , p = 0.039 , respectively). To conclude, incorporation of SF spectroscopy during EUS-FNA was feasible, safe, and relatively quick to perform. The optical properties of benign and malignant pancreatic tissue are different, implying that SF spectroscopy can potentially guide the FNA sampling.

Background: Tumor recurrence after radical resection of hepatic tumors is not uncommon, suggesting that malignant lesions are missed during surgery. Intraoperative navigation using fluorescence guidance is an innovative technique enabling real-time identification of (sub)capsular liver tumors. The objective of the current study was to compare fluorescence imaging (FI) and conventional imaging modalities for laparoscopic detection of both primary and metastatic tumors in the liver., Methods: Patients undergoing laparoscopic resection of a malignant hepatic tumor were eligible for inclusion. Patients received standard of care, including preoperative CT and/or MRI. In addition, 10 mg indocyanine green was intravenously administered 1 day prior to surgery. After introduction of the laparoscope, inspection, FI, and laparoscopic ultrasonography (LUS) were performed. Histopathological examination of resected suspect tissue was considered the gold standard., Results: Twenty-two patients suspected of having hepatocellular carcinoma (n = 4), cholangiocarcinoma (n = 2) or liver metastases from colorectal carcinoma (n = 12), uveal melanoma (n = 2), and breast cancer (n = 2) were included. Two patients were excluded because their surgery was unexpectedly postponed several days. Twenty-six malignancies were resected in the remaining 20 patients. Sensitivity for various modalities was 80 % (CT), 84 % (MRI), 62 % (inspection), 86 % (LUS), and 92 % (FI), respectively. Three metastases (12 %) were identified solely by FI. All 26 malignancies could be detected by combining LUS and FI (100 % sensitivity)., Conclusion: This study demonstrates added value of FI during laparoscopic resections of several hepatic tumors. Although larger series will be needed to confirm long-term patient outcome, the technology already aids the surgeon by providing real-time fluorescence guidance., Competing Interests: Compliance with ethical standardsDisclosuresDr. Frangioni is CEO of Curadel, LLC, a for-profit company that has licensed FLARE® technology from the Beth Israel Deaconess Medical Center. Drs. Boogerd, Drs. Handgraaf, Drs. Lam, Dr. Huurman, Dr. Farina-Sarasqueta, Dr. van de Velde, Dr. Braat, and Dr. Vahrmeijer have no conflicts of interest or financial ties to disclose.

Purpose: The purpose of this study was to identify suitable molecular targets for tumor-specific imaging of pancreatic adenocarcinoma., Procedures: The expression of eight potential imaging targets was assessed by the target selection criteria (TASC)-score and immunohistochemical analysis in normal pancreatic tissue (n = 9), pancreatic (n = 137), and periampullary (n = 28) adenocarcinoma., Results: Integrin α v β 6 , carcinoembryonic antigen (CEA), epithelial growth factor receptor (EGFR), and urokinase plasminogen activator receptor (uPAR) showed a significantly higher (all p < 0.001) expression in pancreatic adenocarcinoma compared to normal pancreatic tissue and were confirmed by the TASC score as promising imaging targets. Furthermore, these biomarkers were expressed in respectively 88 %, 71 %, 69 %, and 67 % of the pancreatic adenocarcinoma patients., Conclusions: The results of this study show that integrin α v β 6 , CEA, EGFR, and uPAR are suitable targets for tumor-specific imaging of pancreatic adenocarcinoma., Competing Interests: The authors declare that they have no conflict of interest.

Aim: To investigate feasibility and accuracy of near-infrared fluorescence imaging using indocyanine green: nanocolloid for sentinel lymph node (SLN) detection in gastric cancer., Methods: A prospective, single-institution, phase I feasibility trial was conducted. Patients suffering from gastric cancer and planned for gastrectomy were included. During surgery, a subserosal injection of 1.6 mL ICG:Nanocoll was administered around the tumor. NIR fluorescence imaging of the abdominal cavity was performed using the Mini-FLARE™ NIR fluorescence imaging system. Lymphatic pathways and SLNs were visualized. Of every detected SLN, the corresponding lymph node station, signal-to-background ratio and histopathological diagnosis was determined. Patients underwent standard-of-care gastrectomy. Detected SLNs outside the standard dissection planes were also resected and evaluated., Results: Twenty-six patients were enrolled. Four patients were excluded because distant metastases were found during surgery or due to technical failure of the injection. In 21 of the remaining 22 patients, at least 1 SLN was detected by NIR Fluorescence imaging (mean 3.1 SLNs; range 1-6). In 8 of the 21 patients, tumor-positive LNs were found. Overall accuracy of the technique was 90% (70%-99%; 95%CI), which decreased by higher pT-stage (100%, 100%, 100%, 90%, 0% for respectively Tx, T1, T2, T3, T4 tumors). All NIR-negative SLNs were completely effaced by tumor. Mean fluorescence signal-to-background ratio of SLNs was 4.4 (range 1.4-19.8). In 8 of the 21 patients, SLNs outside the standard resection plane were identified, that contained malignant cells in 2 patients., Conclusion: This study shows successful use of ICG:Nanocoll as lymphatic tracer for SLN detection in gastric cancer. Moreover, tumor-containing LNs outside the standard dissection planes were identified.

Folate receptor alpha (FRα) is known to be upregulated in a variety of cancers, including non-small cell lung cancer (NSCLC) and breast cancer. To ensure reliable implementation of diagnostic- and therapeutic agents, concordance of FRα expression between biopsy, primary tumor and metastases is important. Using immunohistochemistry (Mab 26B3.F2) these concordances were investigated in 60 NSCLC and 40 breast cancer patients. False positivity of FRα expression on breast and lung cancer biopsies was limited to less than 5%. In NSCLC, FRα expression was shown in 21/34 adenocarcinomas and 4/26 squamous cell carcinomas (SCC). Concordance of FRα expression between biopsy and primary tumor was achieved in respectively 83% and 91% of adenocarcinomas and SCCs. Approximately 80% of all local and distant metastases of NSCLC patients showed concordant FRα expression as their corresponding primary tumor. In breast cancer, FRα positivity was shown in 12/40 biopsies, 20/40 lumpectomies and 6/20 LN metastases, with concordance of 68% between biopsy and primary tumor and 60% between primary tumor and LN metastases. In conclusion, this study shows high concordance rates of FRα expression between biopsies and metastases compared to primary NSCLC and breast cancers, underscoring the applicability of FRα-targeted agents in these patients.

Tumor involvement at the resection margin remains the most important predictor for local recurrence in patients with rectal cancer. A careful description of tumor localization is therefore essential. Currently, endoscopic tattooing with ink is customary, but visibility during laparoscopic resections is limited. Near-infrared (NIR) fluorescence imaging using indocyanine green (ICG) could be an improvement. In addition to localize tumors, ICG can also be used to identify sentinel lymph nodes (SLNs). The feasibility of this new technique was explored in five patients undergoing laparoscopic low anterior resection for rectal cancer. Intraoperative tumor visualization was possible in four out of five patients. Fluorescence signal could be detected 32 ± 18 minutes after incision, while ink could be detected 42 ± 21 minutes after incision (p = 0.53). No recurrence was diagnosed within three months after surgery. Ex vivo imaging identified a mean of 4.2 ± 2.7 fluorescent lymph nodes, which were appointed SLNs. One out of a total of 83 resected lymph nodes contained a micrometastasis. This node was not fluorescent. This technical note describes the feasibility of endoscopic tattooing of rectal cancer using ICG:nanocolloid and NIR fluorescence imaging during laparoscopic resection. Simultaneous SLN mapping was also feasible, but may be less reliable due to neoadjuvant therapy.

Surgery is the cornerstone of oncologic therapy with curative intent. However, identification of tumor cells in the resection margins is difficult, resulting in nonradical resections, increased cancer recurrence and subsequent decreased patient survival. Novel imaging techniques that aid in demarcating tumor margins during surgery are needed. Overexpression of carcinoembryonic antigen (CEA) is found in the majority of gastrointestinal carcinomas, including colorectal and pancreas. We developed ssSM3E/800CW, a novel CEA-targeted near-infrared fluorescent (NIRF) tracer, based on a disulfide-stabilized single-chain antibody fragment (ssScFv), to visualize colorectal and pancreatic tumors in a clinically translatable setting. The applicability of the tracer was tested for cell and tissue binding characteristics and dosing using immunohistochemistry, flow cytometry, cell-based plate assays and orthotopic colorectal (HT-29, well differentiated) and pancreatic (BXPC-3, poorly differentiated) xenogeneic human-mouse models. NIRF signals were visualized using the clinically compatible FLARE™ imaging system. Calculated clinically relevant doses of ssSM3E/800CW selectively accumulated in colorectal and pancreatic tumors/cells, with highest tumor-to-background ratios of 5.1 ± 0.6 at 72 hr postinjection, which proved suitable for intraoperative detection and delineation of tumor boarders and small (residual) tumor nodules in mice, between 8 and 96 hr postinjection. Ex vivo fluorescence imaging and pathologic examination confirmed tumor specificity and the distribution of the tracer. Our results indicate that ssSM3E/800CW shows promise as a diagnostic tool to recognize colorectal and pancreatic cancers for fluorescent-guided surgery applications. If successfully translated clinically, this tracer could help improve the completeness of surgery and thus survival., (© 2015 UICC.)

Near-infrared (NIR) fluorescence imaging has emerged as a promising complimentary technique for intraoperative visualization of tumor tissue, lymph nodes and vital structures. In this review, the current applications and future opportunities of NIR fluorescence imaging in gynecologic oncology are summarized. Several studies indicate that intraoperative sentinel lymph node identification in vulvar cancer using NIR fluorescence imaging outperforms blue dye staining and provides real-time intraoperative imaging of sentinel lymph nodes. NIR fluorescence imaging can penetrate through several millimeters of tissue, revealing structures just below the tissue surface. Hereby, iatrogenic damage to vital structures, such as the ureter or nerves may be avoided by identification using NIR fluorescence imaging. Tumor-targeted probes are currently being developed and have the potential to improve surgical outcomes of cytoreductive and staging procedures, in particular in ovarian cancer. Research in the near future will be necessary to determine whether this technology has additional value in order to facilitate the surgical procedure, reduce morbidity and improve disease-free and overall survival., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Endoscopic transpapillary gallbladder drainage is a new, relatively non-invasive treatment for patients with symptomatic gallbladder disease and a high surgery risk. Placement of an internal pigtail stent is an alternative treatment for percutaneous gallbladder drainage. This procedure can be performed in patients with a temporary contra-indication - in preparatory process to a cholecystectomy - as well as in patients with a prolonged contra-indication where the pigtail stent can remain in situ for a longer period of time. This technique appears to be an effective and safe procedure for patients with acute cholecystitis or symptomatic gallbladder disease and a high surgery risk.