Intraoperative pulmonary neoplasm identification using near-infrared fluorescence imaging.
01 May 2016-European Journal of Cardio-Thoracic Surgery (Oxford University Press)-Vol. 49, Iss: 5, pp 1497-1502
TL;DR: NIR fluorescence imaging could safely identify pulmonary neoplasms after the systemic injection of ICG, and low-dose ICG is sufficient for NIRfluorescence imaging of pulmonary neplasms.
Abstract: Objectives Near-infrared (NIR) fluorescence imaging provides surgeons with real-time visual information during surgery. The purpose of this pilot trial was to evaluate the safety and feasibility of the intraoperative detection of pulmonary neoplasms with NIR fluorescence imaging after low-dose indocyanine green (ICG) injection. Methods Eleven consecutive patients who were scheduled to undergo resection of pulmonary neoplasms were enrolled in this study. ICG (1 mg/kg) was administered intravenously 1 day before surgery, and the retrieved surgical specimens were examined for fluorescence signalling by using NIR fluorescence imaging system on a back table in the operating room. We analysed the fluorescence intensity, pathology, size, depth from the pleural surface and metabolic activity of the pulmonary neoplasms. Results Fluorescence signalling was detected in all specimens except in one from a patient with primary lung cancer. Two false-positive cases that presented no residual tumour with obstructive pneumonitis, after concurrent chemoradiation therapy for primary lung cancer before the operation, were identified, and their fluorescence intensity was 8.6 ± 0.4. The mean fluorescence intensity of the eight pulmonary tumours was 3.4 ± 1.9, and these tumours did not differ in pathology, size, depth from the pleural surface or metabolic activity. Conclusions NIR fluorescence imaging could safely identify pulmonary neoplasms after the systemic injection of ICG. In addition, low-dose ICG is sufficient for NIR fluorescence imaging of pulmonary neoplasms. However, because the passive accumulation of ICG could not be used to discriminate tumours with inflammation, tumour-targeted fluorescence should be developed to solve this problem in the future.
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TL;DR: Visualization of autofluorescent parathyroid gland identification with the use of near infrared light allows high rates of parathyro gland identification and could be a safe, feasible, and noninvasive method for intraoperative identification ofParathyroid glands in real time.
Abstract: Background Identification of parathyroid glands may be challenging during thyroid and parathyroid surgery Accidental resection of the glands may increase the morbidity of the surgery The aim of this study was to evaluate accuracy in identification of autofluorescent parathyroid glands with the use of near infrared light in real time Study Design Patients undergoing thyroid and parathyroid surgery between June and August 2015 were included in the study During the procedure, the surgical field was exposed to near infrared laser light in order to analyze the intensity of the fluorescence of different tissues (parathyroid glands, thyroid glands, and background) Surgical images were recorded and analyzed Results Twenty-eight patients were included in the study Nineteen patients were women and 9 were men Seven patients had primary hyperparathyroidism, 4 had hyperthyroidism, 3 had goiters, and 11 had thyroid cancer Three patients had mixed pathologies, including 2 patients with thyroid cancer and primary hyperparathyroidism and 1 patient with goiter and primary hyperparathyroidism Identification of autofluorescent parathyroid glands was achieved in all patients with near infrared light The mean fluorescent intensity of parathyroid glands was 406 (±265), thyroid glands 318 (±223), and background 166 (±154) Parathyroid glands demonstrated statistically higher fluorescence intensity compared with the thyroid gland and background (p Conclusions Visualization of autofluorescent parathyroid glands with the use of near infrared light allows high rates of parathyroid gland identification and could be a safe, feasible, and noninvasive method for intraoperative identification of parathyroid glands in real time Further clinical studies must be performed to determine the cost-effectiveness and clinical application of this method
95 citations
TL;DR: The existing preclinical and clinical data on IFI in thoracic surgery, which demonstrated that IFI with second window indocyanine green (TumorGlow®) can identify subcentimeter pulmonary nodules, anterior mediastinal masses, and mesothelioma, is reviewed.
Abstract: Intraoperative fluorescence imaging (IFI) can improve real-time identification of cancer cells during an operation. Phase I clinical trials in thoracic surgery have demonstrated that IFI with second window indocyanine green (TumorGlow® ) can identify subcentimeter pulmonary nodules, anterior mediastinal masses, and mesothelioma, while the use of a folate receptor-targeted near-infrared agent, OTL38, can improve the specificity for diagnosing tumors with folate receptor expression. Here, we review the existing preclinical and clinical data on IFI in thoracic surgery.
60 citations
Cites methods from "Intraoperative pulmonary neoplasm i..."
...Kim et al(58) reported the identification of pulmonary neoplasms with NIR imaging using an ICG dose of 1 mg/kg 24 hours before surgery in 11 patients.(58) Tumor fluorescence was seen in 8 of 9 patients with pulmonary neoplasms as well as in 2 patients with no residual tumor who had postobstructive pneumonitis following neoadjuvant chemoradiation....
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TL;DR: In this review, recent advances in the development of activatable fluorescence probes are summarized and insights into their advantages and limitations when used for tumor imaging are provided.
47 citations
TL;DR: This review describes some of the key studies that demonstrate the applications of intraoperative near-infrared fluorescence imaging in Thoracic surgery.
Abstract: Thoracic surgery faces many unique challenges that require innovative solutions. The increase in utilization of minimally invasive practices, poor overall cancer survival and significant morbidity of key operations remain key obstacles to overcome. Intraoperative fluorescence imaging is a process by which fluorescent dyes and imaging systems are used as adjuncts for surgeons in the operating room. Other surgical subspecialists have shown that intraoperative fluorescence imaging can be applied as a practical adjunct to their practices. Thoracic surgeons over the last 15 years have also used intraoperative fluorescence imaging for sentinel lymph node mapping, lung mapping, oesophageal conduit vascular perfusion and lung nodule identification. This review describes some of the key studies that demonstrate the applications of intraoperative near-infrared fluorescence imaging.
45 citations
TL;DR: This is the first study to demonstrate that the optimal NIR contrast agent dose varies by tumor histology, and lower dose ICG (2 to 3 mg/kg) is superior for nonprimary lung cancers, and high dose ICGs (4 to 5 mg/ kg) are superior for lung cancers.
Abstract: Background Near-infrared (NIR) imaging using the second time window of indocyanine green (ICG) allows localization of pulmonary, pleural, and mediastinal malignancies during surgery. Based on empirical evidence, we hypothesized that different histologic tumor types fluoresce optimally at different ICG doses. Study Design Patients with thoracic tumors biopsy-proven or suspicious for malignancy were enrolled in an NIR imaging clinical trial. Patients received a range of ICG doses 1 day before surgery: 1 mg/kg (n = 8), 2 mg/kg (n = 8), 3 mg/kg (n = 13), 4 mg/kg (n = 8), and 5 mg/kg (n = 8). Intraoperatively, NIR imaging was performed. The endpoint was to identify the highest tumor-to-background fluorescence ratio (TBR) for each tumor type at each dose. Final pathology confirmed tumor histology. Results Of 45 patients, 41 had malignancies (18 non-small cell lung cancers [NSCLC], 3 pulmonary neuroendocrine tumors, 13 thoracic metastases, 4 thymomas, 3 mesotheliomas). At doses of 4 to 5 mg/kg, the TBR from primary NSCLC vs other malignancies was no different (2.70 vs 3.21, p = 1.00). At doses of 1 to 3 mg/kg, the TBR was greater for the NSCLCs (3.19 vs 1.49, p = 0.0006). Background fluorescence from the heart or ribs was observed in 1 of 16 cases at 1 to 2 mg/kg, 5 of 13 cases at 3 mg/kg, and 14 of 16 cases at 4 to 5 mg/kg; this was a major determinant of dose optimization. Conclusions This is the first study to demonstrate that the optimal NIR contrast agent dose varies by tumor histology. Lower dose ICG (2 to 3 mg/kg) is superior for nonprimary lung cancers, and high dose ICG (4 to 5 mg/kg) is superior for lung cancers. This will have major implications as more intraoperative imaging trials surface in other specialties, will significantly reduce costs and may facilitate wider application.
41 citations
References
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TL;DR: This work has been supported by the Department of the Army and the National Institutes of Health, and the author acknowledges the support and encouragement of the National Cancer Institute.
28,811 citations
"Intraoperative pulmonary neoplasm i..." refers background in this paper
...The inflammatory state features vascular changes that are similar to those of tumours, which leads to an increased proliferation of endothelial cells, perivascular mast cells and microvascular density; thus, ICG is equally likely to accumulate in tumours and inflamed tissue [23, 24]....
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TL;DR: The concept of NIR fluorescence imaging for cancer surgery is introduced, the clinical trial literature to date is examined, and the key issues pertaining to imaging system and contrast agent optimization are outlined.
Abstract: Optical imaging that exploits invisible near-infrared (NIR) fluorescent light (700–900 nm) has the potential to improve cancer surgery outcomes, minimize anaesthesia time and lower health-care costs via its improved contrast and depth of tissue penetration relative to visible light. This Review introduces the concept of NIR fluorescence imaging and examines imaging system and contrast agent optimization. Paradigm shifts in surgery arise when surgeons are empowered to perform surgery faster, better and less expensively than current standards. Optical imaging that exploits invisible near-infrared (NIR) fluorescent light (700–900 nm) has the potential to improve cancer surgery outcomes, minimize the time patients are under anaesthesia and lower health-care costs largely by way of its improved contrast and depth of tissue penetration relative to visible light. Accordingly, the past few years have witnessed an explosion of proof-of-concept clinical trials in the field. In this Review, we introduce the concept of NIR fluorescence imaging for cancer surgery, examine the clinical trial literature to date and outline the key issues pertaining to imaging system and contrast agent optimization. Although NIR seems to be superior to many traditional imaging techniques, its incorporation into routine care of patients with cancer depends on rigorous clinical trials and validation studies.
1,069 citations
"Intraoperative pulmonary neoplasm i..." refers background in this paper
...Near-infrared (NIR) fluorescence imaging was recently introduced to enable real-time intraoperative visualization of the lymph nodes draining a tumour, cancer or premalignant lesion, as well as the vital structures, vascularization and perfusion [5]....
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TL;DR: Fluorescent imaging using indocyanine green (ICG) has the potential to detect liver cancers through the visualization of the disordered biliary excretion of ICG in cancer tissues and noncancerous liver tissues compressed by the tumor.
Abstract: BACKGROUND:
We have often encountered difficulties in identifying small liver cancers during surgery. Fluorescent imaging using indocyanine green (ICG) has the potential to detect liver cancers through the visualization of the disordered biliary excretion of ICG in cancer tissues and noncancerous liver tissues compressed by the tumor.
METHODS:
ICG had been intravenously injected for a routine liver function test in 37 patients with hepatocellular carcinoma (HCC) and 12 patients with metastasis of colorectal carcinoma (CRC) before liver resection. Surgical specimens were investigated using a near-infrared light camera system. Among the 49 subjects, the 26 patients examined during the latter period of the study (20 with HCC and 6 with metastasis) underwent ICG-fluorescent imaging of the liver surfaces before resection.
RESULTS:
ICG-fluorescent imaging identified all of the microscopically confirmed HCCs (n = 63) and CRC metastases (n = 28) in surgical specimens. Among the 63 HCCs, 8 tumors (13%, including 5 early HCCs) were not evident grossly unless observed by ICG-fluorescent imaging. Five false-positive nodules (4 large regenerative nodules and 1 bile duct proliferation) were identified among the fluorescent lesions. Well-differentiated HCCs appeared as uniformly fluorescing lesions with higher lesion-to-liver contrast than that of moderately or poorly differentiated HCCs (162.6 [71.1-218.2] per pixel vs 67.7 [-6.3-211.2] per pixel, P < .001), while CRC metastases were delineated as rim-fluorescing lesions. Fluorescent microscopy confirmed that fluorescence originated in the cytoplasm and pseudoglands of HCC cells and in the noncancerous liver parenchyma surrounding metastases. ICG-fluorescent imaging before resection identified 21 of the 41 HCCs (51%) and all of the 16 metastases that were examined.
CONCLUSIONS:
ICG-fluorescent imaging enables the highly sensitive identification of small and grossly unidentifiable liver cancers in real time, enhancing the accuracy of liver resection and operative staging. Cancer 2009. © 2009 American Cancer Society.
676 citations
"Intraoperative pulmonary neoplasm i..." refers background or methods in this paper
...The optimal dose and injection interval of ICG in pulmonary neoplasms may be different from that in HCC because ICG is primarily excreted through the biliary system....
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...5 mg/kg in an initial clinical trial [6], and a recent study showed that the use of a relatively low dose of ICG (0....
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...Intraoperative assessment of the tumour margin by using NIR fluorescence imaging with ICG was introduced in 2009 for both colorectal hepatic metastases and HCC [6]....
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...first to demonstrate intraoperative visualization of both colorectal hepatic metastases and hepatocellular carcinoma (HCC) using NIR fluorescence imaging several hours to days after the intravenous injection of indocyanine green (ICG) [6]....
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...Ishizawa et al. were the first to demonstrate intraoperative visualization of both colorectal hepatic metastases and hepatocellular carcinoma (HCC) using NIR fluorescence imaging several hours to days after the intravenous injection of indocyanine green (ICG) [6]....
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TL;DR: A review of published literature on the toxicity of 19 widely used fluorophores was conducted by searching 26 comprehensive biomedical and chemical literature databases and analyzing the retrieved material.
Abstract: Fluorophores are potentially useful for in vivo cancer diagnosis. Using relatively inexpensive and portable equipment, optical imaging with fluorophores permits real-time detection of cancer. However, fluorophores can be toxic and must be investigated before they can be administered safely to patients. A review of published literature on the toxicity of 19 widely used fluorophores was conducted by searching 26 comprehensive biomedical and chemical literature databases and analyzing the retrieved material. These fluorophores included Alexa Fluor 488 and 514, BODIPY FL, BODIPY R6G, Cy 5.5, Cy 7, cypate, fluorescein, indocyanine green, Oregon green, 8-phenyl BODIPY, rhodamine 110, rhodamine 6G, rhodamine X, rhodol, TAMRA, Texas red, and Tokyo green. Information regarding cytotoxicity, tissue toxicity, in vivo toxicity, and mutagenicity was included. Considerable toxicity-related information was available for the Food and Drug Administration (FDA)-approved compounds indocyanine green and fluorescein, but published information on many of the non-FDA-approved fluorophores was limited. The information located was encouraging because the amounts of fluorophore used in molecular imaging probes are typically much lower than the toxic doses described in the literature. Ultimately, the most effective and appropriate probes for use in patients will be determined by their fluorescent characteristics and the safety of the conjugates.
396 citations
"Intraoperative pulmonary neoplasm i..." refers methods in this paper
...5 mg/kg was usually applied for the intraoperative detection of colorectal liver metastases with NIR fluorescence imaging [10] instead of 5 mg/kg, which is the maximum intravenous dose for humans [11]....
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TL;DR: Evidence is provided that in vivo pharmacokinetics of ICG in breast tumors may be a useful diagnostic tool for differentiation of benign and malignant pathologies.
Abstract: We investigate the uptake of a nontargeted contrast agent by breast tumors using a continuous wave diffuse optical tomography apparatus. The instrument operates in the near-infrared spectral window and employs 16 sources and 16 detectors to collect light in parallel on the surface of the tumor-bearing breast (coronal geometry). In our protocol an extrinsic contrast agent, Indocyanine Green (ICG), was injected by bolus. Three clinical scenarios with three different pathologies were investigated. A two-compartment model was used to analyze the pharmacokinetics of ICG and preprocess the data, and diffuse optical tomography was used for imaging. Localization and delineation of the tumor was achieved in good agreement with a priori information. Moreover, different dynamical features were observed for differing pathologies. The malignant cases exhibited slower rate constants (uptake and outflow) compared to healthy tissue. These results provide further evidence that in vivo pharmacokinetics of ICG in breast tumors may be a useful diagnostic tool for differentiation of benign and malignant pathologies.
282 citations
"Intraoperative pulmonary neoplasm i..." refers background in this paper
...This technology has also shown possible application in surgery for breast tumours [16] and gastric cancer [17]....
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