Use of fluorescence imaging and indocyanine green during laparoscopic cholecystectomy: Results of an international Delphi survey.

BACKGROUND: Published empirical data have increasingly suggested that using near-infrared fluorescence cholangiography during laparoscopic cholecystectomy markedly increases biliary anatomy visualization. The technology is rapidly evolving, and different equipment and doses may be used. We aimed to identify areas of consensus and nonconsensus in the use of incisionless near-infrared fluorescent cholangiography during laparoscopic cholecystectomy. METHODS: A 2-round Delphi survey was conducted among 28 international experts in minimally invasive surgery and near-infrared fluorescent cholangiography in 2020, during which respondents voted on 62 statements on patient preparation and contraindications (n = 12); on indocyanine green administration (n = 14); on potential advantages and uses of near-infrared fluorescent cholangiography (n = 18); comparing near-infrared fluorescent cholangiography with intraoperative x-ray cholangiography (n = 7); and on potential disadvantages of and required training for near-infrared fluorescent cholangiography (n = 11). RESULTS: Expert consensus strongly supports near-infrared fluorescent cholangiography superiority over white light for the visualization of biliary structures and reduction of laparoscopic cholecystectomy risks. It also offers other advantages like enhancing anatomic visualization in obese patients and those with moderate to severe inflammation. Regarding indocyanine green administration, consensus was reached that dosing should be on a milligrams/kilogram basis, rather than as an absolute dose, and that doses >0.05 mg/kg are necessary. Although there is no consensus on the optimum preoperative timing of indocyanine green injections, the majority of participants consider it important to administer indocyanine green at least 45 minutes before the procedure to decrease the light intensity of the liver. CONCLUSION: Near-infrared fluorescent cholangiography experts strongly agree on its effectiveness and safety during laparoscopic cholecystectomy and that it should be used routinely, but further research is necessary to establish optimum timing and doses for indocyanine green.

Liposomal prednisolone inhibits vascular inflammation and enhances venous outward remodeling in a murine arteriovenous fistula model.

Arteriovenous fistulas (AVF) for hemodialysis access have a 1-year primary patency rate of only 60%, mainly as a result of maturation failure that is caused by insufficient outward remodeling and intimal hyperplasia. The exact pathophysiology remains unknown, but the inflammatory vascular response is thought to play an important role. In the present study we demonstrate that targeted liposomal delivery of prednisolone increases outward remodeling of the AVF in a murine model. Liposomes accumulate in the post-anastomotic area of the venous outflow tract in which the vascular pathology is most prominent in failed AVFs. On a histological level, we observed a reduction of lymphocytes and granulocytes in the vascular wall. In addition, a strong anti-inflammatory effect of liposomal prednisolone on macrophages was demonstrated in vitro. Therefore, treatment with liposomal prednisolone might be a valuable strategy to improve AVF maturation.

Near-infrared fluorescence sentinel lymph node detection in gastric cancer: A pilot study.

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.

Intraoperative fluorescence imaging to localize tumors and sentinel lymph nodes in rectal cancer.

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.

Sentinel Lymph Node Biopsy in Vulvar Cancer Using Combined Radioactive and Fluorescence Guidance.

OBJECTIVE: Near-infrared (NIR) fluorescence imaging using indocyanine green (ICG) has recently been introduced to improve the sentinel lymph node (SLN) procedure. Several optical tracers have been successfully tested. However, the optimal tracer formulation is still unknown. This study evaluates the performance of ICG-technetium-99m (99mTc)-nanocolloid in relation to 2 most commonly used ICG-based formulas during SLN biopsy in vulvar cancer. METHODS AND MATERIALS: Twelve women who planned to undergo SLN biopsy for stage I vulvar cancer were prospectively included. Sentinel lymph node mapping was performed using the dual-modality radioactive and NIR fluorescence tracer ICG-99mTc-nanocolloid. All patients underwent combined SLN localization using NIR fluorescence and the (current) gold standard using blue dye and radioactive guidance. RESULTS: In all 12 patients, at least 1 SLN was detected during surgery. A total of 21 lymph nodes (median 2; range, 1-3) were resected. Median time between skin incision and first SLN detection was 8 (range, 1-22) minutes. All resected SLNs were both radioactive and fluorescent, although only 13 (62%) of 21 SLNs stained blue. Median brightness of exposed SLNs, expressed as signal-to-background ratio, was 5.4 (range, 1.8-11.8). Lymph node metastases were found in 3 patients. CONCLUSIONS: Near-infrared fluorescence-guided SLN mapping is feasible and outperforms blue dye staining. Premixing ICG with 99mTc-nanocolloid provides real-time intraoperative imaging of the SN and seems to be the optimal tracer combination in terms of intraoperative detection rate of the SN (100%). Moreover, ICG-99mTc-nanocolloid allows the administration of a 5-times lower injected dose of ICG (compared with ICG and ICG absorbed to human serum albumin) and can be injected up to 20 hours before surgery.

First experience on laparoscopic near-infrared fluorescence imaging of hepatic uveal melanoma metastases using indocyanine green.

BACKGROUND: Uveal melanoma is the most common primary intraocular tumor in adults, and up to 50% of patients will develop liver metastases. Complete surgical resection of these metastases can improve 5-year survival, but only a few patients are eligible for radical surgical treatment. The aim of this study was to introduce a near-infrared (NIR) fluorescence laparoscope during minimally invasive surgery for intraoperative identification of uveal melanoma hepatic metastases and to use it to provide guidance during resection. METHODS: Three patients diagnosed with one solitary liver metastasis from uveal melanoma are presented. Patients received 10 mg indocyanine green (ICG) intravenously 24 hours before surgery. A NIR fluorescence laparoscope was used to detect malignant liver lesions. RESULTS: In all 3 patients, laparoscopic NIR fluorescence imaging using ICG successfully identified uveal melanoma metastases. In 2 patients, multiple additional lesions were identified by inspection and NIR fluorescence imaging, which were not identified by preoperative conventional imaging. In one patient, one additional lesion, not identified by computed tomography, magnetic resonance imaging, laparoscopic ultrasonography, and inspection, was observed with NIR fluorescence imaging only. Importantly, NIR fluorescence imaging provided guidance during resection of these metastases. CONCLUSIONS: We describe the successful use of laparoscopic identification and resection of uveal melanoma liver metastases using NIR fluorescence imaging and ICG. This procedure is minimally invasive and should be used as complementary to conventional techniques for the detection and resection of liver metastases.

Real-time near-infrared fluorescence guided surgery in gynecologic oncology: a review of the current state of the art.

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.

Expression of uPAR in tumor-associated stromal cells is associated with colorectal cancer patient prognosis: a TMA study.

BACKGROUND: The receptor for urokinase-type plasminogen activator (uPAR) is associated with cancer development and progression. Within the tumor microenvironment uPAR is expressed by malignant cells as well as tumor-associated stromal cells. However, the contribution of uPAR expression in these stromal cells to malignancy and patient survival in colorectal cancer is still unclear. This study compares the association of uPAR expression in both colorectal tumor-associated stromal cells and neoplastic cells with clinico-pathological characteristics and patient survival using tissue micro arrays (TMA). METHODS: Immunohistochemical staining of uPAR expression was performed on tumor tissue from 262 colorectal cancer patients. Kaplan-Meier, log rank, and uni- and multivariate Cox's regression analyses were used to calculate associations between uPAR expression and patient survival. RESULTS: In the colorectal tumor-associated stromal microenvironment, uPAR is expressed in macrophages, (neoangiogenic) endothelial cells and myofibroblasts. uPAR expression in tumor-associated stromal cells and neoplastic cells (and both combined) were negatively associated with overall survival (OS) and Disease Free Survival (DFS). Uni- and multivariate Cox's regression analysis for combined uPAR expression in tumor-associated stromal and neoplastic cells showed significant and independent negative associations with OS and DFS. Only uPAR expression in tumor-associated stromal cells showed independent significance in the uni- and multivariate analysis for DFS. CONCLUSION: This study demonstrates a significant independent negative association between colorectal cancer patient survival and uPAR expression in especially tumor-associated stromal cells.

Near-infrared fluorescence imaging of both colorectal cancer and ureters using a low-dose integrin targeted probe.

BACKGROUND: Irradical tumor resections and iatrogenic ureteral injury remain a significant problem during lower abdominal surgery. The aim of the current study was to intraoperatively identify both colorectal tumors and ureters in subcutaneous and orthotopic animal models using cRGD-ZW800-1 and near-infrared (NIR) fluorescence. METHODS: The zwitterionic fluorophore ZW800-1 was conjugated to the tumor specific peptide cRGD (targeting integrins) and to the a-specific peptide cRAD. One nmol cRGD-ZW800-1, cRAD-ZW800-1, or ZW800-1 alone was injected in mice bearing subcutaneous HT-29 human colorectal tumors. Subsequently, cRGD-ZW800-1 was injected at dosages of 0.25 and 1 nmol in mice bearing orthotopic HT-29 tumors transfected with luciferase2. In vivo biodistribution and ureteral visualization were investigated in rats. Fluorescence was measured intraoperatively at several time points after probe administration using the FLARE imaging system. RESULTS: Both subcutaneous and orthotopic tumors could be clearly identified using cRGD-ZW800-1. A significantly higher signal-to-background ratio was observed in mice injected with cRGD-ZW800-1 (2.42 ± 0.77) compared with mice injected with cRAD-ZW800-1 or ZW800-1 alone (1.21 ± 0.19 and 1.34 ± 0.19, respectively) when measured at 24 h after probe administration. The clearance of cRGD-ZW800-1 permitted visualization of the ureters and also generated minimal background fluorescence in the gastrointestinal tract. CONCLUSIONS: This study appears to be the first to demonstrate both clear tumor demarcation and ureteral visualization after a single intravenous injection of a targeted NIR fluorophore. As a low dose of cRGD-ZW800-1 provided clear tumor identification, clinical translation of these results should be possible.

Near-infrared fluorescence sentinel lymph node mapping in breast cancer: a multicenter experience.

Near-infrared (NIR) fluorescence imaging using indocyanine green (ICG) has the potential to improve the sentinel lymph node (SLN) procedure by facilitating percutaneous and intraoperative identification of lymphatic channels and SLNs. Previous studies suggested that a dose of 0.62 mg (1.6 mL of 0.5 mM) ICG is optimal for SLN mapping in breast cancer. The aim of this study was to evaluate the diagnostic accuracy of NIR fluorescence for SLN mapping in breast cancer patients when used in conjunction with conventional techniques. Study subjects were 95 breast cancer patients planning to undergo SLN procedure at either the Dana-Farber/Harvard Cancer Center (Boston, MA, USA) or the Leiden University Medical Center (Leiden, the Netherlands) between July 2010 and January 2013. Subjects underwent the standard-of-care SLN procedure at each institution using (99)Technetium-colloid in all subjects and patent blue in 27 (28 %) of the subjects. NIR fluorescence-guided SLN detection was performed using the Mini-FLARE imaging system. SLN identification was successful in 94 of 95 subjects (99 %) using NIR fluorescence imaging or a combination of both NIR fluorescence imaging and radioactive guidance. In 2 of 95 subjects, radioactive guidance was necessary for initial in vivo identification of SLNs. In 1 of 95 subjects, NIR fluorescence was necessary for initial in vivo identification of SLNs. A total of 177 SLNs (mean 1.9, range 1-5) were resected: 100 % NIR fluorescent, 88 % radioactive, and 78 % (of 40 nodes) blue. In 2 of 95 subjects (2.1 %), SLNs-containing macrometastases were found only by NIR fluorescence, and in one patient this led to upstaging to N1. This study demonstrates the safe and accurate application of NIR fluorescence imaging for the identification of SLNs in breast cancer patients, but calls into question what technique should be used as the gold standard in future studies.

Intraoperative near-infrared fluorescence imaging of parathyroid adenomas with use of low-dose methylene blue.

BACKGROUND: Intraoperative identification of parathyroid adenomas can be challenging. We hypothesized that low-doses methylene blue (MB) and near-infrared fluorescence (NIRF) imaging could be used to identify parathyroid adenomas intraoperatively. METHODS: MB was injected intravenously after exploration at a dose of 0.5 mg/kg into 12 patients who underwent parathyroid surgery. NIRF imaging was performed using the Mini-FLARE imaging system. RESULTS: In 10 of 12 patients, histology confirmed a parathyroid adenoma. In 9 of these patients, NIRF could clearly identify the parathyroid adenoma during surgery. Seven of these 9 patients had a positive preoperative (99m) Tc-sestamibi single photon emission CT (SPECT) scan. Importantly, in 2 patients, parathyroid adenomas could be identified only using NIRF. CONCLUSION: This is the first study to show that low-dose MB can be used as NIRF tracer for identification of parathyroid adenomas, and suggests a correlation with preoperative (99m) Tc-sestamibi SPECT scanning.

Optimization of near-infrared fluorescence cholangiography for open and laparoscopic surgery.

BACKGROUND: During laparoscopic cholecystectomy, common bile duct (CBD) injury is a rare but severe complication. To reduce the risk of injury, near-infrared (NIR) fluorescent cholangiography using indocyanine green (ICG) has recently been introduced as a novel method of visualizing the biliary system during surgery. To date, several studies have shown feasibility of this technique; however, liver background fluorescence remains a major problem during fluorescent cholangiography. The aim of the current study was to optimize ICG dose and timing for NIR cholangiography using a quantitative intraoperative camera system during open hepatopancreatobiliary (HPB) surgery. Subsequently, these results were validated during laparoscopic cholecystectomy using a laparoscopic fluorescence imaging system. METHODS: Twenty-seven patients who underwent NIR imaging using the Mini-FLARE image-guided surgery system during open HPB surgery were analyzed to assess optimal dosage and timing of ICG administration. ICG was intravenously injected preoperatively at doses of 5, 10, and 20 mg, and imaged at either 30 min (early) or 24 h (delayed) post-injection. Next, the optimal doses found for early and delayed imaging were applied to two groups of seven patients (n = 14) undergoing laparoscopic NIR fluorescent cholangiography during laparoscopic cholecystectomy. RESULTS: Median liver-to-background contrast was 23.5 (range 22.1­35.0), 16.8 (range 11.3­25.1), 1.3 (range 0.7­7.8), and 2.5 (range 1.3­3.6) for 5 mg/30 min, 10 mg/30 min, 10 mg/24 h, and 20 mg/24 h, respectively. Fluorescence intensity of the liver was significantly lower in the 10 mg delayed-imaging dose group compared with the early imaging 5 and 10 mg dose groups (p = 0.001), which resulted in a significant increase in CBD-to-liver contrast ratio compared with the early administration groups (p < 0.002). These findings were qualitatively confirmed during laparoscopic cholecystectomy. CONCLUSION: This study shows that a prolonged interval between ICG administration and surgery permits optimal NIR cholangiography with minimal liver background fluorescence.

Near-infrared fluorescence-guided resection of colorectal liver metastases.

BACKGROUND: The fundamental principle of oncologic surgery is the complete resection of malignant cells. However, small tumors are often difficult to find during surgery using conventional techniques. The objectives of this study were to determine if optical imaging, using a contrast agent already approved for other indications, could improve hepatic metastasectomy with curative intent, to optimize dose and timing, and to determine the mechanism of contrast agent accumulation. METHODS: The high tissue penetration of near-infrared (NIR) light was exploited by use of the FLARE (Fluorescence-Assisted Resection and Exploration) image-guided surgery system and the NIR fluorophore indocyanine green in a clinical trial of 40 patients undergoing hepatic resection for colorectal cancer metastases. RESULTS: A total of 71 superficially located (< 6.2 mm beneath the liver capsule) colorectal liver metastases were identified and resected using NIR fluorescence imaging. Median tumor-to-liver ratio was 7.0 (range, 1.9-18.7) and no significant differences between time points or doses were found. Indocyanine green fluorescence was seen as a rim around the tumor, which is shown to be entrapment around cytokeratin 7-positive hepatocytes compressed by the tumor. Importantly, in 5 of 40 patients (12.5%, 95% confidence interval = 5.0-26.6), additional small and superficially located lesions were detected using NIR fluorescence, and were otherwise undetectable by preoperative computed tomography, intraoperative ultrasound, visual inspection, and palpation. CONCLUSIONS: NIR fluorescence imaging, even when used with a nontargeted, clinically available NIR fluorophore, is complementary to conventional imaging and able to identify missed lesions by other modalities.

Intraoperative near infrared fluorescence guided identification of the ureters using low dose methylene blue: a first in human experience.

PURPOSE: Near infrared fluorescence imaging is a promising technique that offers real-time visual information during surgery. In this study we report the first clinical results to our knowledge of ureteral imaging using near infrared fluorescence after a simple peripheral infusion of methylene blue. Furthermore, we assessed the optimal timing and dose of methylene blue. MATERIALS AND METHODS: A total of 12 patients who underwent lower abdominal surgery were included in this prospective feasibility study. Near infrared fluorescence imaging was performed using the Mini-FLARE™ imaging system. To determine optimal timing and dose, methylene blue was injected intravenously at doses of 0.25, 0.5 or 1 mg/kg after exposure of the ureters. Imaging was performed for up to 60 minutes after injection. RESULTS: In all patients both ureters could be clearly visualized within 10 minutes after infusion of methylene blue. The signal lasted at least up to 60 minutes after injection. The mean signal-to-background ratio of the ureter was 2.27 ± 1.22 (4), 2.61 ± 1.88 (4) and 3.58 ± 3.36 (4) for the 0.25, 0.5 and 1 mg/kg groups, respectively. A mixed model analysis was used to compare signal-to-background ratios among dose groups and times, and to assess the relationship between dose and time. A significant difference among time points (p <0.001) was found. However, no difference was observed among dose groups (p = 0.811). CONCLUSIONS: This study demonstrates the first successful use of near infrared fluorescence using low dose methylene blue for the identification of the ureters during lower abdominal surgery.

Ex vivo sentinel node mapping in colon cancer combining blue dye staining and fluorescence imaging.

BACKGROUND: The sentinel lymph node procedure has been proposed to improve nodal staging in colon cancer patients. The aim of this study was to assess the added value of near-infrared (NIR) fluorescence imaging to conventional blue dye staining for ex vivo sentinel lymph node mapping. MATERIALS AND METHODS: We included 22 consecutive patients undergoing surgery for colon cancer. After tumor resection, we submucosally injected a premixed cocktail of the near-infrared lymphatic tracer HSA800 and blue dye around the tumor for detection of sentinel lymph nodes. We used the Mini-FLARE imaging system for fluorescence imaging. RESULTS: In 95% of patients, we identified at least one sentinel lymph node. Overall, a total of 77 sentinel lymph nodes were identified, 77 of which were fluorescent (100%) and 70 of which were blue (91%). Sentinel lymph nodes that were located deeper in the mesenteric fat could easily be located by NIR fluorescence. In four of five patients with lymph node metastases, tumor cells were present in at least one of the sentinel lymph nodes. CONCLUSIONS: This study shows the successful use and added value of the NIR fluorescence tracer HSA800 to conventional blue dye for the ex vivo sentinel lymph node procedure in colon cancer.

Near-infrared fluorescence sentinel lymph node mapping of the oral cavity in head and neck cancer patients.

OBJECTIVES: Elective neck dissection is frequently performed during surgery in head and neck cancer patients. The sentinel lymph node (SLN) procedure can prevent the morbidity of a neck dissection and improve lymph node staging by fine pathology. Near-infrared (NIR) fluorescence imaging is a promising technique to identify the sentinel lymph node (SLN) intraoperatively. This feasibility study explored the use of indocyanine green adsorbed to human serum albumin (ICG:HSA) for SLN mapping in head and neck cancer patients. MATERIALS AND METHODS: A total of 10 consecutive patients with oral cavity or oropharyngeal cancer and a clinical N0 neck were included. After exposure of the neck, 1.6 mL of ICG:HSA (500 µM) was injected at four quadrants around the tumor. During the neck dissection, levels I-IV were measured for fluorescence using the Mini-FLARE imaging system. RESULTS: In all 10 patients, NIR fluorescence imaging enabled visualization of one or more SLNs. A total of 17 SLNs were identified. The mean contrast between the fluorescent signal of the lymph nodes and of the surrounding tissue was 8.7±6.4. In 3 patients, of which 1 was false-negative, lymph node metastases were found. After administration of ICG:HSA, the average number of fluorescent lymph nodes significantly increased over time (P<0.001). CONCLUSION: This study demonstrated feasibility to detect draining lymph nodes in head and neck cancer patients using NIR fluorescence imaging. However, the fluorescent tracer quickly migrated beyond the SLN to higher tier nodes.

Image-guided hepatopancreatobiliary surgery using near-infrared fluorescent light.

BACKGROUND: Improved imaging methods and surgical techniques have created a new era in hepatopancreatobiliary (HPB) surgery. Despite these developments, visual inspection, palpation, and intraoperative ultrasound remain the most utilized tools during surgery today. This is problematic, though, especially in laparoscopic HPB surgery, where palpation is not possible. Optical imaging using near-infrared (NIR) fluorescence can be used for the real-time assessment of both anatomy (e.g., sensitive detection and demarcation of tumours and vital structures) and function (e.g., assessment of luminal flow and tissue perfusion) during both open and minimally invasive surgeries. METHODS: This article reviews the published literature related to preclinical development and clinical applications of NIR fluorescence imaging during HPB surgery. RESULTS: NIR fluorescence imaging combines the use of otherwise invisible NIR fluorescent contrast agents and specially designed camera systems, which are capable of detecting these contrast agents during surgery. Unlike visible light, NIR fluorescent light can penetrate several millimetres through blood and living tissue, thus providing improved detectability. Applications of this technique during HPB surgery include tumour imaging in liver and pancreas, and real-time imaging of the biliary tree. CONCLUSIONS: NIR fluorescence imaging is a promising new technique that may someday improve surgical accuracy and lower complications.

Randomized comparison of near-infrared fluorescence lymphatic tracers for sentinel lymph node mapping of cervical cancer.

OBJECTIVE: Near-infrared fluorescence imaging using indocyanine green (ICG) has recently been introduced as a novel technique for sentinel lymph node (SLN) mapping in early-stage cervical cancer. Although preclinical research has shown that ICG adsorbed to human serum albumin (ICG:HSA) improves its performance, the need for HSA has not yet been confirmed in cervical cancer patients. The current randomized study aims to determine whether ICG:HSA offers advantages over using ICG alone. METHODS: Eighteen consecutive early-stage cervical cancer patients scheduled to undergo pelvic lymphadenectomy were included. Prior to surgery, 1.6 mL of 500 µM ICG:HSA or 500 µM ICG alone was injected transvaginally in 4 quadrants around the tumor. The Mini-FLARE imaging system was used for intraoperative NIR fluorescence detection and quantitation. RESULTS: SLNs were identified intraoperatively in 78% of the patients. Patient and tumor characteristics were equally distributed over both treatment groups. No significant difference in signal-to-background ratio (9.3 vs. 10.1, P=.72) or average number of detected SLNs (2.9 vs 2.7, P=.84) was found between the ICG:HSA group and the ICG alone group, respectively. CONCLUSIONS: In conclusion, this double-blind, randomized trial showed no advantage of ICG:HSA over ICG alone for the SLN procedure in early-stage cervical cancer. Further optimization is required to improve the intraoperative detection rate.

Randomized comparison of near-infrared fluorescence imaging using indocyanine green and 99(m) technetium with or without patent blue for the sentinel lymph node procedure in breast cancer patients.

BACKGROUND: Near-infrared (NIR) fluorescence imaging using indocyanine green (ICG) has the potential to improve sentinel lymph node (SLN) mapping of breast cancer. We performed a randomized clinical trial to assess the value of blue dyes when used in combination with NIR fluorescence. We also preliminarily examined the possibility of performing SLN mapping without radiotracers. METHODS: Clinical trial subjects were 24 consecutive breast cancer patients scheduled to undergo SLN biopsy. All patients received standard of care using 99(m) technetium-nanocolloid and received 1.6 mL of 500 µM ICG injected periareolarly. Patients were randomly assigned to undergo SLN biopsy with or without patent blue. To assess the need for radiocolloids to localize the SLN or SLNs, the surgeon did not use the handheld gamma probe during the first 15 min after the axillary skin incision. RESULTS: SLN mapping was successful in 23 of the 24 patients. No significant difference was found in signal-to-background ratio between the groups with and without patent blue (8.3 ± 3.8 vs. 10.3 ± 5.7, respectively, P = 0.32). In both groups, 100 % of SLNs were radioactive and fluorescent, and in the patent blue group, only 84 % of SLNs were stained blue. In 25 % of patients, the use of the gamma probe was necessary to localize the SLN within the first 15 min. CONCLUSIONS: This study shows that there is no benefit of using patent blue for SLN mapping in breast cancer patients when using NIR fluorescence and 99(m) technetium-nanocolloid. NIR fluorescence imaging outperformed patent blue in all patients.