Safety and feasibility of near-infrared fluorescence imaging with inhaled indocyanine green to assess the pulmonary parenchyma in six normal dogs.

This study aims to confirm the feasibility of near-infrared (NIR) fluorescence imaging for sentinel lymph node (SLN) biopsy in vulvar cancer and to compare the tracer indocyanine green (ICG) bound to human serum albumin (HSA) versus ICG alone. Women received 99mTc-nanocolloid and patent blue for SLN detection. Subsequently, women randomly received ICG:HSA or ICG alone. In 24 women, 35 SLNs were intraoperatively detected. All SLNs detected were radioactive and NIR fluorescent and 27 (77%) were blue. No significant difference was found between ICG:HSA and ICG alone. This trial confirms the feasibility of NIR fluorescence imaging for SLN mapping in vulvar cancer.

OBJECTIVE To evaluate the usefulness of injection of indocyanine green (ICG) solution with near-infrared (NIR) fluorescence imaging for transcutaneous detection of sentinel lymph nodes (SLNs) and their associated lymphatic vessels in the oral mucosa of healthy dogs. ANIMALS 6 adult purpose-bred research hounds. PROCEDURES Each dog was sedated, and 1 mL of ICG solution was injected into the gingival mucosa dorsal to the right maxillary canine tooth. Subsequently, NIR fluorescence imaging was used to transcutaneously detect the lymphatic vessels and SLNs. The distance between the injection site and each SLN was measured. Time to first evidence of node fluorescence was recorded, and velocity of ICG movement was calculated. A slide preparation of a fine-needle aspiration sample of the fluorescing structure underwent cytologic examination (to confirm presence of lymphatic tissue) and NIR fluorescence imaging (to confirm presence of ICG). RESULTS The ipsilateral mandibular lymphocentrum was the SLN in all dogs. The time to visually detectable fluorescence ranged from 4 to 15 minutes (mean ± SD, 8.8 ± 3.76 minutes). The mean velocity was 1.94 ± 0.93 cm/min. Fluorescence was not observed in the contralateral lymph nodes. Each fluorescing structure was confirmed to be lymphatic tissue, and NIR fluorescence imaging revealed that ICG was present in the sampled SLN. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that injection of ICG solution with NIR fluorescence imaging can be used to transcutaneously identify SLNs along with associated lymphatic vessels in the oral mucosa of healthy dogs. Time from injection to identification of fluorescence was rapid with prolonged retention of material within the SLN, indicating that this procedure could be performed during surgery.

Objective: To investigate the feasibility of near-infrared fluorescence imaging (NIRFI) to assist in determining the resection range of radiation intestinal injury (RII). Methods: A descriptive cohort study was conducted. Clinical data of 10 RII patients who presented intestinal obstruction and received operation with more than 100 cm of small intestine had been resected atGeneral Department of Jinling Hospital from October 2014 to January 2015 were retrospectively analyzed. The Novadaq SPY Intra-operative Imaging System was used in capturing and viewing fluorescent images. Firstly, the dense adhesion was mobilized and the obstructive intestine was fully freed under laparoscopy, then entering into abdomen from the corresponding incision. The surgeon determined the resection range according to the color of the intestinal serous layer of the diseased intestinal wall, the thickness of the intestinal wall, and the degree of swelling of the mesentery. Afterwards, intra-operative NIRFI was performed by intravenous injection of 2 ml indocyanine green (ICG) and the imaging results of the diseased intestinal arteriovenous phase were observed and recorded. The evaluation criteria for the final resection range were mainly based on the changes in mesenteric arterial phase imaging. In RII lesions, mesenteric vessels in mesenteric artery phase were disordered, and the comb-like distribution of normal mesenteric vessels completely disappeared. Only the clouded appearance in the intestinal wall was observed. Imaging results of the diseased intestinal tissue during the development phase and mesenteric vein phase were not significantly different from normal intestinal tissue. Intraoperative and postoperative conditions under NIRFI-assisted positioning, including the resection range, anastomosis site, operation-related complications, hospitalization time and cost were recorded. Data of abdominal contrast-enhanced CT and gastrointestinal angiography during 5 years of follow-up were collected to evaluate whether there was anastomotic stenosis or insufficient resection of diseased bowel. Results: Based on the imaging of mesenteric arterial phase of NIRFI, the median resection length of the small intestine was 185 (120-260) cm. After NIRFI imaging, only local lesion of ileum was excised in 6 patients, and jejunum-ileum anastomosis was performed to preserve ileocecal flap. No serious complications such as anastomotic leakage and anastomotic hemorrhage, or chronic intestinal failure such as short bowel syndrome occurred. The median hospitalization time was 32 (22-51) days, and the median hospitalization cost was 142 000 (90 000-175 000) RMB. The hospitalization time and cost were mainly used for the enteral and parenteral nutrition support treatment during the perioperative period. All the patients had normal oral diet and/or oral enteral nutrient. After 5 years of follow-up, no recurrence was found. Abdominal contrast-enhanced CT and gastrointestinal angiography showed no thickening of the intestinal wall or stenosis of the lumen. Conclusion: Mesenteric arterial phase imagingof NIRFI can help surgeons to determine the site and range of resection of RII lesions.

Objective: Lingual lymph node (LLN) metastasis is regarded as an indicator of unfavorable prognosis and a crucial sign of the high degree of primary tumor aggressiveness. However, detecting LLN metastasis is an important but frequently overlooked aspect of diagnosis and surgical treatment planning. The study aims to identify LLNs by intraoperative near-infrared (NIR) fluorescence imaging with indocyanine green absorbed into human serum albumin (ICG: HSA) and describe the presence of lymphatic drainage channels from the floor of the mouth in patients with tongue carcinoma.Materials and Methods: 21 patients diagnosed with cT1-T4 squamous cell carcinoma (SCC) of the tongue margin and scheduled to undergo tumor resection and unilateral neck dissection were enrolled. After exposing the neck, the patients were injected with 0.3 ml of ICG: HSA (500 μM) in three quadrants around the tumor, excluding the mucous membrane of the basal region cavity. Employing a near-infrared fluorescence imaging system, the fluorescence of levels I, II, III, and IV was measured during neck dissection.Results: LLNs were detected in four patients and were identified as metastatic LLNs in all 21 patients. The near-infrared fluorescence imaging system showed the existence of lymphatic drainage channels in the floor of the mouth. In patients receiving peritumoral injection of ICG: HSA, the mean fluorescence intensity (MFI)of metastatic lymph nodes (LNs) (178.4 ± 64.39, mean ± SD) was higher than that in non-metastatic LNs (132.0 ± 76.5, mean ± SD) (p < 0.05).Conclusion: NIR fluorescence imaging with ICG: HSA could be used for intraoperative identification of LLNs and assist in the determination of metastatic lymph nodes for tongue carcinoma patients. Additionally, this finding demonstrates the feasibility of near-infrared fluorescence imaging in defining lymphatic drainage channels in the head and neck.

BackgroundThis pilot study aimed to evaluate the feasibility of near-infrared fluorescence imaging for primary tumor localization, lymph node mapping, and metastatic lymph node detection in colorectal cancer (CRC) using indocyanine green (ICG).MethodsA total of 11 patients with CRC were prospectively enrolled. ICG (25 mg dissolved in 30 mL sterile water) was intravenously injected preoperatively, and the fluorescence intensity of the primary tumor, lymph nodes, and normal tissues, as well as the signal-to-background ratio (SBR) and contrast-to-noise ratio (CNR) were measured at 0.5, 1, 2, 4, and 24 h after ICG injection.ResultsThe primary tumor could be located intraoperatively, and the tumor boundary was clear at 2–4 h. There was good contrast in the fluorescence intensity between tumor and normal tissues (SBR =2.11±0.36, CNR =8.74±0.35). The lymph node detection rate was 95% (38/40), and the SBR threshold of lymph nodes was 1.13.ConclusionsThis pilot study showed that primary tumor localization and lymph node mapping in CRC is feasible using near-infrared fluorescence imaging technology, though metastatic lymph nodes cannot be discriminated from benign ones. In addition, cancer nodules missed by both white light mode and palpation by the surgeon were unexpectedly found, resulting in a change in the surgical prognosis in 9.1% (1/11) of patients.

Introduction: Near-infrared fluorescence (NIRF) imaging is an emerging technology with several important applications in oncologic surgery. Using fluorescent dyes and dedicated camera systems, real-time intraoperative imaging is provided to guide surgical procedures and allow for instant decision-making. NIRF imaging has the potential to improve the Sentinel Node Biopsy (SNB) procedure for staging of oral cavity cancer by facilitating intraoperative visual identification of the sentinel lymph node (SN). Also, NIRF imaging may be used in the search of head and neck unknown primaries (CUP) in combination with transoral robotic surgery (TORS). The feasibility of NIRF imaging for intraoperative SN detection was investigated in a series of oral cavity cancer patients. In addition, our initial experience of using NIRF imaging during TORS for detection of oropharyngeal cancer will also be reported (ongoing study). Methods: (1) A prospective study of patients with primary oral squamous cell carcinoma (OSCC) planned for tumor resection and SNB. Thirty patients were injected peritumorally with a bimodal tracer (ICG-99mTc-Nanocoll) followed by lymphoscintigraphy (LSG) and SPECT/CT to define the SNs and their anatomical location preoperatively. SNs were detected intraoperatively with a hand-held gamma-probe and a hand-held NIRF camera. (2) In a minor prospective series of patients with oropharyngeal cancer undergoing TORS Indocyanin Green (ICG) was systematically injected preoperatively. The aim was to guide primary tumor detection using the firefly NIRF modality incorporated in the Da Vinci Si robotic system. Results: (1) In the SNB study, 29 of 30 subjects (97%), all preoperatively defined SNs could be identified intraoperatively using a combination of radioactive and fluorescence guidance. Eleven of 94 SNs (12%) could only be identified in vivo using NIRF imaging and the majority of those were located in level 1 close to the primary tumor. (2) In the pilot ICG TORS study, the additional use of ICG for primary tumor identification was varying. Conclusions: Intraoperative NIRF imaging as a tool to guide cancer surgery seems promising and further exploration of this novel technology is warranted. A combined fluorescent and radioactive tracer for SNB is feasible and the additional use of NIRF imaging may improve the accuracy of SN identification in oral cancer patients. Intraoperative fluorescence guidance seems of particular value, when SNs are located in close proximity to the injection site. Combined TORS and NIRF imaging showed with a varying quality the localization of the oropharyngeal cancer. The combined procedure may have a potential role in the diagnostic algorithm in head and neck CUP patients facilitating the detection of the primary tumor. Citation Format: Christian von Buchwald, Anders Christensen, Niclas Rubek, Karina Juhl, Birgitte Charabi, Jann Mortensen, Katalin Kiss, Andreas Kjær. Real-time near-infrared fluorescence tracer imaging to guide sentinel node biopsy and tumor detection in head and neck cancer [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; April 23-25, 2017; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(23_Suppl):Abstract nr IA13.

The intraoperative distinction between normal and abnormal pituitary tissue is crucial during pituitary adenoma surgery to obtain a complete tumor resection while preserving endocrine function. Near-infrared (NIR) fluorescence imaging is a technique to intraoperatively visualize tumors by using indocyanine green (ICG), a contrast agent allowing visualization of differences in tissue vascularization. Although NIR fluorescence imaging has been described in pituitary surgery, it has, in contrast to other surgical areas, never become widely used. To evaluate NIR fluorescence imaging in pituitary surgery, both qualitatively and quantitatively, and to assess the additional value of resecting adenoma tissue under NIR fluorescence guidance. We included 10 patients planned to undergo transnasal transsphenoidal selective adenomectomy. Patients received multiple intravenous administrations of 5 mg ICG, up to a maximum of 15 mg per patient. Endoscopic NIR fluorescence imaging was performed at multiple points in time. The NIR fluorescent signal in both the adenoma and pituitary gland was obtained, and the fluorescence contrast ratio was assessed. Four patients had Cushing disease, 1 had acromegaly, and 1 had a prolactinoma. Four patients had a nonfunctioning macroadenoma. In 9 of 10 patients with a histologically proven pituitary adenoma, the normal pituitary gland showed a stronger fluorescent signal than the adenoma. A fluorescence contrast ratio of normal pituitary gland to adenoma of 1.5 ± 0.2 was obtained. In 2 patients; adenoma resection was actually performed under NIR fluorescence guidance instead of under white light. NIR fluorescence imaging can easily and safely be implemented in pituitary surgery. The timing of ICG administration is important for optimal results and warrants further study. It appears that injection of ICG can best be postponed until some part of the normal pituitary gland is identified. Subsequent repeated low-dose ICG administrations improved the distinction between adenoma and gland.

.Significance: Near-infrared (NIR) fluorescence imaging using indocyanine green (ICG) has proven to be a feasible application for real-time intraoperative assessment of tissue perfusion, although quantification of NIR fluorescence signals is pivotal for standardized assessment of tissue perfusion.Aim: Four patients are described with possible compromised bowel perfusion after mesenteric resection. Based on these patients we want to emphasize the difficulties in the quantification of NIR fluorescence imaging for perfusion analysis.Approach: During image-guided fluorescence assessment, 5 mg of ICG () was intravenously administered by the anesthesiologist. NIR fluorescence imaging was done with the open camera system of Quest Medical Imaging. Fluorescence data taken from the regions of interest (bowel at risk, transition zone of bowel at risk and adjacent normally perfused bowel, and normally perfused reference bowel) were quantitatively analyzed after surgery for fluorescence intensity-and perfusion time-related parameters.Results: Bowel perfusion, as assessed clinically by independent surgeons based on NIR fluorescence imaging, resulted in different treatment strategies, three with excellent clinical outcome, but one with a perfusion related complication. Post-surgery quantitative analysis of fluorescence dynamics showed different patterns in the affected bowel segment compared to the unaffected reference segments for the four patients.Conclusions: Similar intraoperative fluorescence results could lead to different surgical treatment strategies, which demonstrated the difficulties in interpretation of uncorrected fluorescence signals. Real-time quantification and standardization of NIR fluorescence perfusion imaging could probably aid surgeons in the nearby future.

Background: Near-infrared (NIR) fluorescence imaging using indocyanine green (ICG) is a promising technique to obtain real-time assessment of the extent and number of colorectal liver metastases during liver surgery. The current study aims to optimize dosage and timing of ICG administration. Materials and methods: The Mini-FLARE imaging system was used for real-time identification of liver tumors in 18 rats. Liver tumors were measured at 24, 48, 72 or 96 hours after administration of 0.04, 0.08, or 0.16 mg ICG (0.13, 0.26 or 0.53 mg / kg, respectively). Guided by these results, intraoperative identification of liver metastases was performed in 12 patients undergoing liver resection. NIR fluorescence imaging was performed 24 or 48 hours after administration of 10 or 20 mg ICG (0.13 or 0.26 mg / kg, respectively). After intraoperative imaging, resection specimens were sliced to examine internal fluorescent patterns using the Mini-FLARE imaging system. Subsequently, frozen tissue sections were measured for fluorescence using the Nuance multispectral imager. Results: Using NIR fluorescence imaging and ICG, all colorectal liver metastases (N = 34), could be identified in all rats. Average tumor-to-liver (TLR) ratio over all groups was 3.0 ± 1.2. Liver signal was lower in the 72 h time group compared to other time points, resulting in a significantly higher TLR. ICG dose did not significantly influence TLR, but a trend was found favoring the 0.08 mg dose group. Clinically, during intraoperative NIR fluorescence imaging, all superficially located metastases (&amp;lt; 1 cm beneath liver capsule) were identified (N = 18). Average TLR was 11.1 ± 5.1 and no significant differences between time-points or doses were found. Liver signal was comparable to pre-injection signal at 24 to 48 hours post-injection, eliminating the need to test other time-points. In all patients, a fluorescent rim around the tumor was found, as described in earlier studies. Using fluorescence microscopy, this clear fluorescent rim was localized in stromal tissue in the transition area between tumor and normal liver tissue in all liver metastases. In this area, multiple cell types that are involved in tissue inflammation (e.g. granulocytes, lymphocytes) were found. In two patients, additional small (2 – 8 mm) metastases were identified using NIR fluorescence that were otherwise missed preoperatively and intraoperatively using only visual inspection and ultrasound. Conclusions: This study demonstrates that colorectal cancer liver metastases can be clearly identified during surgery using ICG and the Mini-FLARE imaging system. NIR fluorescence imaging has the potential to improve intraoperative detection of in particular small and superficially located liver metastases and can therefore be seen as an addition to the conventional imaging modalities. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4140. doi:10.1158/1538-7445.AM2011-4140

ObjectiveIn ovarian cancer, two of the most important prognostic factors for survival are completeness of staging and completeness of cytoreductive surgery. Therefore, intra-operative visualization of tumor lesions is of great importance. Preclinical data already demonstrated tumor visualization in a mouse-model using near-infrared (NIR) fluorescence imaging and indocyanine green (ICG) as a result of enhanced permeability and retention (EPR). The aim of this study was to determine feasibility of intraoperative ovarian cancer metastases imaging using NIR fluorescence imaging and ICG in a clinical setting.MethodsTen patients suspected of ovarian cancer scheduled for staging or cytoreductive surgery were included. Patients received 20 mg ICG intravenously after opening the abdominal cavity. The mini-FLARE NIR fluorescence imaging system was used to detect NIR fluorescent lesions.Results6 out of 10 patients had malignant disease of the ovary or fallopian tube, of which 2 had metastatic disease outside the pelvis. Eight metastatic lesions were detected in these 2 patients, which were all NIR fluorescent. However, 13 non-malignant lesions were also NIR fluorescent, resulting in a false-positive rate of 62%. There was no significant difference in tumor-to-background ratio between malignant and benign lesions (2.0 vs 2.0; P=0.99).ConclusionsThis is the first clinical trial demonstrating intraoperative detection of ovarian cancer metastases using NIR fluorescence imaging and ICG. Despite detection of all malignant lesions, a high false-positive rate was observed. Therefore, NIR fluorescence imaging using ICG based on the EPR effect is not satisfactory for the detection of ovarian cancer metastases. The need for tumor-specific intraoperative agents remains.Trial RegistrationISRCTN Registry ISRCTN16945066

The main aims of this study are to investigate the clinical application value of using indocyanine green fluorescence imaging for ensuring complete resection of tumour tissue during hepatectomy and to evaluate the diagnostic efficacy of near-infrared (NIR) fluorescence imaging system using indocyanine green in hepatectomy. After undergoing liver resection at the Affiliated Hospital of Southwest Medical University from July 2017 to May 2018, 35 eligible patients were included in this study. The liver surface and resection margin were intraoperatively assessed by intraoperative ultrasonography and NIR fluorescence imaging, after intravenous administration of indocyanine green (0.5 mg/kg) 72-96 h prior to surgery. The intraoperative observations were compared with the pathological findings in the liver. In the 35 patients, a total of 53 lesions were found, of which 42 were malignant lesions. The analysis results showed that the sensitivity and accuracy of detection using NIR fluorescence imaging were significantly higher than with intraoperative ultrasonography (P < 0.05). However, there was no difference between contrast-enhanced helical computed tomography and NIR fluorescence imaging in finding lesions (P > 0.05). In addition, 11 new suspicious lesions were detected only by NIR fluorescence imaging in the liver surface and resection margin during surgery, four of which were hepatocellular carcinoma. We also detected four vein tumour thrombi using the NIR fluorescence navigation system. The NIR fluorescence navigation system enables the identification of small tumours, residual cancer tissues in resection margin and venous tumour embolies in real time and enhances the accuracy and integrity of liver resection.

Near Infrared Fluorescence Imaging After Intravenous Indocyanine Green: Initial Clinical Experience With Open Partial Nephrectomy for Renal Cortical Tumors

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 0.62mg (1.6mL of 0.5mM) 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.

"Correction: Feasibility of near-infrared fluorescence imaging for sentinel lymph node evaluation of the oral cavity in healthy dogs" published on 01 Oct 2018 by American Veterinary Medical Association.

BackgroundsRadioactive tracer-based detection has been proposed as a standard procedure in identifying sentinel nodes for cN0 oral/oropharyngeal carcinoma. However, access to radioactive isotopes may be limited in some surgical centers, and there is potential risk of the radioactive tracers to the operators. This study was designed to evaluate the feasibility of near-infrared fluorescence imaging with indocyanine green combined with blue dye mapping in sentinel node biopsy for cN0 oral/oropharyngeal carcinoma.MethodsTwenty-six cases of previously untreated oral/oropharyngeal carcinoma staged cT1-2N0M0 were enrolled in this study. One milliliter of indocyanine green (5 mg/ml) and 1.5 ml of methylene blue (1 mg/ml) were injected sequentially around the primary tumor in a four-quadrant pattern before skin incision. After elevation of the platysma flap and posterior retraction of the sternocleidomastoid muscle, fluorescence images were taken with a near-infrared detector, with special attention paid to any blue-dyed lymph nodes. Lymph nodes identified first with fluorescent hot spots with or without blue dye were defined as sentinel nodes, and they were harvested and sent for pathologic study.ResultsSentinel nodes were successfully harvested in all 26 cases. The number of sentinel nodes (SNs) per case varied from 1 to 9, with an average of 3.4. Routine pathology demonstrated occult metastasis exclusively in SNs in four cases (15.4 %). No tracer-associated side effects occurred in this series.ConclusionsNear-infrared imaging using indocyanine green combined with methylene blue mapping is a feasible and reliable new method for SN biopsy in cN0 oral/oropharyngeal carcinoma.