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Objective: A single center prospective non-randomized study to assess a systematically developed anatomically-based sentinel lymph node (SLN) algorithm in cervical cancer., Methods: Consecutive women with FIGO 2009 stage 1A2-2A1 cervical cancer undergoing robotic radical hysterectomy/trachelectomy between September 2014 and January 2023 had cervically injected Indocyanine Green (ICG) as a tracer for detection of pelvic SLN. An anatomically based surgical algorithm was adhered to; defining SLNs as the juxtauterine mapped nodes within the upper and lower paracervical lymphatic pathways including separate removal of the parauterine lymphovascular tissue (PULT). A completion pelvic lymphadenectomy was performed. Ultrastaging and immunohistochemistry was performed on SLNs, including the PULT., Results: 181 women were included for analysis. Median histologic tumor size was 14.0 mm (range 2-80 mm). The bilateral mapping rate was 98.3%. As per protocol an interim analysis rejected H 0 and inclusion stopped at 29 node positive women, all identified by at least one metastatic ICG-defined SLN. One woman awaiting histology at study-closure was node positive and included in the analysis. Sensitivity was 100% (95% CI, 88.4%-100%) and NPV 100% (95% CI, 97.6%-100%). In node positive women, the proximal obturator position harbored 46.1% of all SLN metastases representing the only position in 40% and 10% had isolated metastases in the PULT., Conclusions: Strictly adhering to an anatomically based SLN-algorithm including identification of parallell lymphatics within major pathways, partilularly the obturator compartment, assessment of the PULT, restricting nodal dissection to the removal of SLNs accurately identifies pelvic nodal metastatic disease in early-stage cervical cancer., Competing Interests: Declaration of competing interest Jan Persson have received honoraria for proctoring and lectures from the manufacturer of the da Vinci system. Céline Lönnerfors have received honoraria for lectures from the manufacturer of the da Vinci system. The other authors report no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Retinal arterial macroaneurysms are characterized by the acquired fusiform or saccular dilatations of the retinal artery. Angiotensin II (Ang II) is a major signal molecule of the renin-angiotensin system, which exerts a range of pathogenic actions that are relevant to retinal vascular abnormalities. We aimed to study the effect of Ang II on retinal vessels and explore its relationship with retinal aneurysmal disease. C57BL/6J male mice were administered Ang II at 1000 ng/kg/min for 28 days, and the mice given saline served as controls. The mice in the treatment group were treated once daily by gastric gavage of candesartan cilexetil (an antagonist of Ang II type 1 (AT1) receptor) at 100 mg/kg/day. The in vivo imaging of murine retinas was performed using fundus photography, optical coherence tomography, fluorescein angiography, and indocyanine green angiography at 7th, 14th, and 28th days of infusion. At the end of the infusion and treatment, the morphological changes were evaluated by histopathological examination and electron microscopy; the levels of related proteins in murine retinas were examined by antibody array and Western blot analyses. We found that Ang II infusion induced aneurysm formation in mice retina, which presented as either solitary aneurysms or retinal arterial beading. The aneurysm formation was often accompanied with vessel leakage. Moreover, Ang II infusion itself may result in increased vascular permeability and ganglion cell and inner plexiform layer thickening. The blockade of AT1 receptors by systemic administration of candesartan cilexetil alleviated the Ang II-induced retinal vasculopathy. The protein level analysis further showed that Ang II upregulated IL-1β, PDGFR-β, and MMP-9 expression, and the expression of IL-1β could be inhibited by AT1 receptor antagonist. Our study provides evidence that Ang II is a crucial factor in retinal aneurysm formation and vessel leakage. It is probably the combined effect of Ang II on vessel inflammatory response, pericyte function, and extracellular matrix remodeling that predisposes the retinal arterial wall to aneurysm formation and blood-retinal barrier breakdown., (Copyright © 2021. Published by Elsevier Ltd.)

Choroidal neovascularization (CNV), a feature of neovasular age-related macular degeneration (AMD), acts as a leading cause of vision loss in the elderly. Shikonin (SHI), a natural bioactive compound extracted from Chinese herb radix arnebiae, exerts anti-inflammatory and anti-angiogenic roles and also acts as a potential pyruvate kinase M2 (PKM2) inhibitor in macrophages. The major immune cells macrophages infiltrate the CNV lesions, where the production of pro-angiognic cytokines from macrophage facilitates the development of CNV. PKM2 contributes to the neovascular diseases. In this study, we found that SHI oral gavage alleviated the leakage, area and volume of mouse laser-induced CNV lesion and inhibited macrophage infiltration without ocular cytotoxicity. Moreover, SHI inhibited the secretion of pro-angiogenic cytokine, including basic fibroblast growth factor (FGF2), insulin-like growth factor-1 (IGF1), chemokine (C-C motif) ligand 2 (CCL2), placental growth factor and vascular endothelial growth factor (VEGF), from primary human macrophages by down-regulating PKM2/STAT3/CD163 pathway, indicating a novel potential therapy strategy for CNV., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: To investigate the prevalence of lymph nodes and lymph node metastases (LNMs) in the upper paracervical lymphovascular tissue (UPLT) in early stage cervical cancer., Methods: In this prospective study consecutive women with stage IA1-IB1 cervical cancer underwent a pelvic lymphadenectomy including identification of sentinel nodes (SLNs) as part of a nodal staging procedure in conjunction with a robotic radical hysterectomy (RRH) or robotic radical trachelectomy (RRT). Indocyanine green (ICG) was used as tracer. The UPLT was separately removed and defined as "SLN-parametrium" and, as all SLN tissue, subjected to ultrastaging and immunohistochemistry. Primary endpoint was prevalence of lymph nodes and metastatic lymph nodes in the UPLT. Secondary endpoints were complications associated with removal of the UPLT., Results: One hundred and forty-five women were analysed. Nineteen (13.1%) had pelvic LNMs, all identified by at least one metastatic SLN. In 76 women (52.4%) at least one UPLT lymph node was identified. Metastatic UPLT lymph nodes were identified in six women of which in three women (2.1% of all women and 15.8% of node positive women) without lateral pelvic LNMs. Thirteen women had lateral pelvic SLN LNMs with either no (n = 5) or benign (n = 8) UPLT lymph nodes. No intraoperative complications occurred due to the removal of the UPLT., Conclusion: Removal of the UPLT should be an integral part of the SLN concept in early stage cervical cancer., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: To describe the incidence of adverse reactions to indocyanine green (ICG) administered during sentinel lymph node (SLN) biopsy for endometrial cancer, and to propose an ICG management algorithm for these patients., Methods: All patients who underwent surgery for endometrial cancer with SLN biopsy using ICG from 1/2017 to 8/2020 were identified using a single-institution prospective database. Surgical adverse events (SAEs) related to the procedure were identified. A review of the literature was performed., Results: In all, 1414 patients met inclusion criteria and were evaluated. Sixty-seven (4.7%) patients had a history of either an iodine or contrast allergy. No patients had a history of documented ICG allergy. Among patients with an iodine or contrast allergy, 65 (97%) received a corticosteroid with or without diphenhydramine prior to ICG administration. One hundred five patients (7.4%) experienced 116 SAEs. Among these patients, 3 experienced potentially allergic SAEs possibly related to ICG administration. After thorough chart review, however, the likelihood these SAEs were due to ICG appeared low. No patients experienced an anaphylactic response after ICG admission., Conclusion: There were no anaphylactic reactions to ICG intracervical administration during 1414 consecutive SLN biopsies, including in patients with a documented iodine or contrast allergy. Intracervical injection of ICG is safe, and premedication using corticosteroids with or without diphenhydramine prior to SLN biopsy is a reasonable strategy in patients with iodinated contrast allergy., Competing Interests: Declaration of Competing Interest Outside the submitted work, Dr. Abu-Rustum reports institutional grants from Stryker/Novadaq, Olympus, and GRAIL. Dr. Leitao reports personal fees from J&J/Ethicon and Intuitive Surgical, Inc. The other authors have no potential conflicts of interest to disclose., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: It is difficult to distinguish between a tumor and its liver segment with traditional use of indocyanine green (ICG) alone. In the present study, a method was used to limit ICG to the liver segment adjacent to a tumor. A spectrally-distinct fluorescently-labeled tumor-specific antibody against human carcinoembryonic antigen-related cell-adhesion molecules was used to label the metastatic tumor in a patient-derived orthotopic xenograft mouse model to enable color-coded visualization and distinction of a colon-cancer liver metastases and its adjacent liver segment., Materials and Methods: Nude mice received surgical orthotopic implantation in the liver of colon-cancer liver metastases derived from two patients. An anti- carcinoembryonic antigen-related cell-adhesion molecules monoclonal antibody (mAb 6G5j) was conjugated to a near-infrared dye IR700DX (6G5j-IR700DX). After three weeks, mice received 6G5j-IR700DX via tail-vein injection 48 hours before surgery. ICG was intravenously injected after ligation of the left or left lateral Glissonean pedicle resulting in labeling of the segment with preserved blood-flow in the liver. Imaging was performed with the Pearl Trilogy and FLARE Imaging Systems., Results: The metastatic liver tumor had a clear fluorescence signal due to selective tumor targeting by 6G5j-IR700DX, which was imaged on the 700 nm channel. The adjacent liver segment, with preserved blood-flow in the liver, had a clear fluorescence ICG 800 nm signal, while the left or left lateral segment had no fluorescence signal. Overlay of the images showed clear color-coded differentiation between the tumor fluorescing at 700 nm and the adjacent liver segment fluorescing at 800 nm., Conclusions: Color-coding of a liver tumor and uninvolved liver segment has the potential for improved liver resection., Competing Interests: Declaration of competing interest HN, YT, JY, and RMH are or were non-salaried affiliates of AntiCancer, Inc. The other authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objectives: To evaluate the role of cervical re-injection of indocyanine green (ICG) to increase the detection rate of sentinel lymph node (SLN) in patients with endometrial cancer (EC) who underwent robotic-assisted surgical staging., Methods: We retrospectively identified consecutive EC patients undergoing robotic-assisted staging with SLN biopsy at our Institution between June 2016 and April 2020. Patients were excluded if they had open abdominal surgical approach, neoadjuvant chemotherapy, and advanced stage [International Federation of Gynecology and Obstetrics (FIGO) stage III-IV] at diagnosis. According to our SLN protocol, in case of either unilateral or no SLN detection, we performed an ipsilateral or bilateral cervical re-injection of ICG., Results: In total, 251 patients meeting inclusion criteria were included in the analysis. At first injection, bilateral detection was achieved in 184 (73.3%), unilateral detection in 57 (22.7%), and no detection in 10 (4.0%) patients. Cervical re-injection was performed in 51 of 67 patients with failed bilateral mapping. After cervical re-injection, bilateral detection rate increased to 94.5% (222/235), while unilateral and no detection were 5.1% (12/235) and 0.4% (1/235), respectively., Conclusions: Our results suggest that cervical re-injection of ICG, in case of failed bilateral mapping of SLN, brings about a significant improvement in SLN detection rates, therefore reducing the number of side-specific required lymphadenectomies., Competing Interests: Declaration of Competing Interest The Authors declare no conflicts of interest., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: We previously reported useful methods that can be implemented to identify intersegmental boundary lines (IBLs) by using an intravenous indocyanine green (ICG) fluorescence imaging system (ICG-FS) during a thoracoscopic anatomical segmentectomy (TAS). The aim of this study was to evaluate the recently released third-generation ICG-FS that features an emphasizing xenon-light source for IBL identification., Methods: We prospectively studied cases involving 106 consecutive patients who underwent TAS. Intraoperatively, we used the third-generation ICG-FS, the conventional ICG methods (CIM) emphasizing xenon-light (CIM-X), and the spectra-A method (SAM) emphasizing xenon-light (SAM-X), for IBL identification. Furthermore, 16 of the 106 patients (15%) could be simultaneously evaluated using old-generation ICG-FSs, CIM, and SAM. All images were completely quantified for illuminance and for three colors, red, green, and blue., Results: IBLs were successfully identified in all the patients (100%) with no adverse events. The SAM-X significantly increased the illuminance, especially in the resecting segments, compared to the CIM (39.0 versus 22.2, P < 0.01) and SAM (39.0 versus 29.3, P < 0.01), with enhanced red color compared to the CIM (33.1 versus 21.9, P < 0.01) and SAM (33.1 versus 14.0, P < 0.01). Furthermore, the SAM-X significantly increased the illuminance contrast compared to the CIM-X (34.1 versus 15.3, P < 0.01)., Conclusions: The present study suggests that the SAM-X potentially provided images with the highest visibility and colorfulness compared to the older generation ICG-FSs or CIM-X. Secure IBL identification can be more easily and safely performed using the SAM-X., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The purpose of this study is to evaluate outflow pathways from subconjunctival blebs and to identify their identity. Post-mortem porcine (n = 20), human (n = 1), and bovine (n = 1) eyes were acquired, and tracers (fluorescein, indocyanine green, or fixable/fluorescent dextrans) were injected into the subconjunctival space to create raised blebs where outflow pathways were visualized qualitatively and quantitatively. Rodents with fluorescent reporter transgenes were imaged for structural comparison. Concurrent optical coherence tomography (OCT) was obtained to study the structural nature of these pathways. Using fixable/fluorescent dextrans, tracers were trapped to the bleb outflow pathway lumen walls for histological visualization and molecular identification using immunofluorescence against lymphatic and blood vessel markers. Bleb outflow pathways could be observed using all tracers in all species. Quantitative analysis showed that the nasal quadrant had more bleb-related outflow pathways compared to the temporal quadrant (nasal: 1.9±0.3 pathways vs. temporal: 0.7±0.2 pathways; p = 0.003). However, not all blebs resulted in an outflow pathway (0-pathways = 18.2%; 1-pathway = 36.4%; 2-pathways = 38.6%; and 3-pathways = 6.8%). Outflow signal was validated as true luminal pathways using optical coherence tomography and histology. Bicuspid valves were identified in the direction of flow in porcine eyes. Immunofluorescence of labeled pathways demonstrated a lymphatic (Prox-1 and podoplanin) but not a blood vessel (CD31) identity. Therefore, subconjunctival bleb outflow occurs in discrete luminal pathways. They are lymphatic as assessed by structural identification of valves and molecular identification of lymphatic markers. Better understanding of lymphatic outflow may lead to improved eye care for glaucoma surgery and ocular drug delivery., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

To expand clinical applications of indocyanine green (ICG) by overcoming its several drawbacks such as self-aggregation under physiological conditions, poor aqueous photostability, lack of target specificity and rapid renal elimination from the body, the functionalized polymeric nanogels with pH-responsive benzoic-imine cross-linkages employed as carriers for ICG delivery were developed by one-step cross-linking of the branched poly(ethylenimine)-g-methoxy poly(ethylene glycol) (PEI-g-mPEG) copolymer with hydrophobic terephthalaldehyde (TPA) molecules in aqueous solution of pH 7.4. Based on the findings of fluorescence, dynamic and static light scattering, and transmission electron microscopy measurements, the resulting polymeric nanogels exhibited a spherical structure comprising multiple hydrophobic benzoic-imine-rich microdomains covered by positively-charged PEI networks capable of holding large amounts of water, and hydrophilic mPEG segments. Moreover, the cross-linking of more TPA molecules with PEI-g-mPEG segments led to the formation of more microdomains inside the polymeric nanogels, thus making the colloidal structure more hydrophobic and compact. More importantly, through the electrostatic attraction of amphiphilic ICG molecules with protonated PEI segments as well as their hydrophobic association with microdomains upon π-π stacking, the ICG species can be efficiently encapsulated into the nanogels. Notably, the robust ICG-loaded nanogels showed several outstanding properties, including (1) significantly enhanced the photo-stability of ICG in phosphate buffer, (2) considerably retarded ICG leakage from nanogels at pH 7.8, (3) acid-triggered ICG release by the cleavage of benzoic-imine bonds in response to pH reduction from 7.8 to 6.4. This work demonstrates that the pH-responsive polymeric nanogels have promising potential for tumor-targeted ICG delivery., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Inadequate blood flow is an important risk factor for anastomotic leakage. Indocyanine green (ICG) fluorescence imaging allows intraoperative assessment of intestinal blood flow. This study determined the risk factor of anastomotic hypoperfusion in colorectal surgery using ICG fluorescence imaging., Methods: This study included 74 consecutive patients who underwent colorectal surgery between April 2017 and March 2018. ICG was injected intravenously after dividing the mesentery and central vessels along the planned transection line, but before completing the anastomosis. Intraoperative blood flow was evaluated using ICG fluorescence imaging. With regard to the patient-, tumor-, and surgery-related factors, anastomotic perfusion was evaluated based on the changed transection line and prolonged (more than 60 s) perfusion time., Results: Intraoperative ICG fluorescence imaging was performed in all patients, and no adverse events were associated with ICG injection. Based on the perfusion assessment, we changed the transection line in six patients (8.1%). The prolonged perfusion time was observed in nine patients (12.2%). The postoperative course was uneventful in 63 (85.1%) patients, but one patient (1.4%) had postoperative anastomotic leakage. The changed transection line was significantly associated with anticoagulation therapy (P = 0.029). Well-known risk factors, including surgical site, sex, smoking, blood loss, operative time, and preoperative chemoradiotherapy, were not related to the changed transection line. Prolonged ICG perfusion time was not associated with any patient-, tumor-, or surgery-related factors., Conclusions: The evaluation of intraoperative blood flow using ICG fluorescence imaging may be able to detect anastomotic hypoperfusion, and anticoagulation therapy is a risk factor of anastomotic hypoperfusion in colorectal surgery., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: To identify predictors of unsuccessful sentinel lymph node (SLN) mapping in patients with apparent early-stage endometrial cancer (EC) undergoing surgical staging with cervical injection of indocyanine green and SLN biopsy., Methods: We retrospectively identified consecutive patients with EC with attempted SLN biopsy between June 2014 and June 2016 at our institution. Patients were grouped according to whether they had a successful procedure, defined as the bilateral identification of SLNs, or an unsuccessful procedure, defined as unilateral or no SLN mapping. Logistic regression was used to evaluate predictors of an unsuccessful procedure., Results: Among 327 patients included in the analysis, 256 (78.3%) had a successful procedure and 71 (21.7%) had an unsuccessful procedure (15.0% unilateral SLN mapping, 6.7% no mapping). The rate of successful procedure increased from 57.7% to 83.3% between the first and last quarters of the 2-year study period, which represented the learning curve for the technique. The mean (SD) operative time decreased from 164 (55) to 137 (37) minutes. By multivariable analysis, lysis of adhesions at the beginning of surgery (odds ratio, 3.07; 95% CI, 1.56-6.07) and the presence of enlarged lymph nodes (odds ratio, 4.69; 95% CI, 1.82-12.11) were independently associated with an unsuccessful procedure., Conclusions: Lysis of adhesions at the beginning of surgery and the presence of enlarged lymph nodes independently affect the bilateral detection of SLNs., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Tracheobronchial ischemia and necrosis are uncommon causes of pulmonary complications that can be lethal on development. Surgical manipulation considering tracheal blood flow is important in radical esophagectomy with extensive lymph node dissection. This study introduces a novel method for assessing tracheal blood perfusion using indocyanine green (ICG) fluorescence imaging., Materials and Methods: Twenty patients who underwent esophagectomy with lymph node dissection for esophageal cancer were prospectively enrolled in this study. Tracheal blood flow after esophagectomy was quantitatively assessed using ICG fluorescence imaging. Region-of-interest software was used, and a time-intensity curve was created for the quantitative assessment of tracheal blood flow., Results: We assessed ICG fluorescence imaging of the trachea during esophagectomy for esophageal cancer in all 20 cases. In the quantitative assessment of this pilot study, postoperative tracheal ischemic change and sputum discharge disorder tended to be associated with decreased tracheal blood flow (P = 0.084, P = 0.044). Resection of the right bronchial artery (BA) tended to be associated with decreased tracheal blood flow (P = 0.109), but the preoperative treatment, including chemotherapy and chemoradiotherapy, did not influence tracheal blood flow (P = 0.861, P = 0.435). The subgroup analysis of the preoperative chemoradiation group showed that the tracheal blood flow was significantly reduced with right BA resection compared with right BA preservation (P = 0.049)., Conclusions: We assessed ICG fluorescence imaging of the trachea during esophagectomy for esophageal cancer. Further studies are needed to explore the significance of the assessment of tracheal blood flow during esophagectomy using ICG fluorescence imaging., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Fluorescence-mediated photoplethysmography (FM-PPG) is the first routine clinical methodology by which to quantifiably measure tissue blood perfusion in absolute terms (mL blood/sec ∗ mm 2 tissue). The FM-PPG methodology has been described in detail previously in this journal (MVR 114, 2017, 92-100), along with initial proof-of-concept measurements of blood perfusion in both ocular and forearm skin tissues. The motivation for the current study was to investigate whether FM-PPG can be used readily and routinely under realistic clinical conditions. The vehicle for doing this was to measure medial foot capillary blood flow, i.e., tissue perfusion, in 7 normal subjects, mean = 6.76 ± 2.29 E-005 mL/(sec ∙ mm 2 ), and lesion-free areas of 8 type-2 diabetic patients with skin ulceration, mean = 4.67 + 3.15 E-005 mL/(sec ∙ mm 2 ). Thus, perfusion in the diabetics was found to be moderately lower than that in the normal control subjects. Earlier skin perfusion measurements in medial forearms of 4 normal subjects, mean = 2.64 + 0.22 E-005 mL/(sec ∙ mm 2 ), were lower than both the normal and diabetic foot perfusion measurements. Variability in the heartbeat-to-heartbeat blood perfusion pulses in the skin capillaries, defined as the ratio of the standard deviation among beat-to-beat pulses divided by the mean perfusion of those pulses, was determined for each subject. Average variability in foot skin was 21% in the diabetic population, versus 16% for normal subjects; and it was 18% in forearm skin. We conclude that absolute quantitative FM-PPG measurement of skin blood perfusion at the level of nutritive capillaries is feasible routinely under clinical conditions, allowing for quantitative measurement of skin tissue blood perfusion in absolute terms., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Retinal diseases such as proliferative diabetic retinopathy and neovascular AMD are characterized by the formation of new blood vessels. Current imaging techniques such as fluorescein and ICG angiography help to identify areas of vascular leakage but are limited in their applicability due to their nonspecific nature. However, as new treatment paradigms emerge in an effort to have patient specific treatments, the development of new imaging techniques that are capable of identifying patient specific biomarkers will become crucial for the success of these approaches. In this study, we create and characterize an endoglin (CD105) targeted imaging probe that can be used for indocyanine green (ICG) molecular angiography. This anti-endoglin-ICG bioconjugate has a self-quenching "off-on" capacity to enable high contrast imaging of proliferative blood vessels at a molecular level in vivo. Using the laser CNV mouse model we demonstrate an approximate 3-fold increase in lesion visualization compared to non-targeting controls., (Copyright © 2018. Published by Elsevier Ltd.)

Background: Merkel cell carcinoma (MCC) is a relatively rare skin cancer with high rates of regional lymph node involvement and metastatic spread. National Comprehensive Cancer Network guidelines recommend sentinel lymph node biopsy (SLNB) for staging purposes. The goal of this study is to report our experience utilizing indocyanine green (ICG) fluorescence-based technology to aid in SLNB detection in MCC., Methods: Consecutive MCC patients who underwent SLNB with radioisotope lymphoscintigraphy, with intraoperative handheld gamma probe, and ICG-based fluorescence imaging from 2012 to 2017 were prospectively studied (Cohort A). A group of historical controls that underwent SLNB for MCC with radioisotope lymphoscintigraphy and vital blue dye (VBD) (lymphazurin or methylene blue dye) was also analyzed (Cohort B)., Results: Twenty-four consecutive patients underwent SLNB with lymphoscintigraphy and ICG-based fluorescence and 11 controls underwent SLNB with lymphoscintigraphy and VBD. The localization rate by node with VBD was 63.6% and ICG-based fluorescence was 94.8%. For two patients, a positive sentinel lymph node (SLN) was detected only by ICG-based fluorescence and the nodes were not detected by gamma probe and one patient's only positive node was identified via ICG fluorescence only. VBD or gamma probe did not identify any unique positive SLNs in either cohort B or either cohort, respectively., Conclusions: In this study, we indicate that ICG-based fluorescence is not only feasible to augment SLN identification, but it has a higher node localization rate as compared to blue dye and it was able to identify positive SLNs otherwise missed by gamma probe. This study suggests the importance of utilizing two modalities to augment SLN identification and that ICG-based fluorescence may be able to identify nodes that would have been otherwise missed by gamma probe. We will continue to follow these patients and enroll more patients in this prospective study to further determine the role that ICG-based fluorescence has in identifying sentinel lymph nodes in MCC., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Head and neck melanoma is associated with a high false negative (FN) sentinel lymph node biopsy (SLNB) rate. If techniques are developed that can decrease FN SLNBs, better prognostic information will be obtained, and it may be possible to improve overall survival as patients are assigned to the appropriate adjuvant management. Our group previously demonstrated that the combination of lymphoscintigraphy and indocyanine green (ICG) fluorescence-based technology was feasible for SLNB in primary melanoma., Methods: Consecutive head and neck cutaneous melanoma patients who underwent radioisotope lymphoscintigraphy and ICG-based fluorescence imaging by the senior author (B.G.) from 2012 to 2015 were prospectively enrolled for analysis. Patients were followed postoperatively by the multidisciplinary melanoma team. Main outcome variables were FN rate of SLNB. Length of follow-up was date of surgery to the date of last follow-up/death., Results: There were 10 positive SLNBs, 51 true negative SLNBs, and one FN SLNB. False negative rate was 9.1%, false negative incidence was 1.6%, sensitivity was 91%, and specificity was 100%. Mean follow-up was 27.6, 17.6, and 16.5 mo for true negative, true positive, and FN patients, respectively., Conclusions: We report the largest cohort of patients with head and neck cutaneous melanoma undergoing SLNB using both a combination of radioactive tracer, gamma probe, and ICG-based fluorescence identification. Our results demonstrate that using concomitant gamma probe-based radioactivity detection and ICG-based fluorescence for SLN identification in head and neck melanoma is reliable, reproducible and, thus far, has produced a low rate of FN SLNB., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Our previous report suggested that fluorescence thoracoscopic anatomical segmentectomy (TAS) using intravenous (IV) indocyanine green (ICG) injection is safe, feasible, and efficacious for identifying segmental boundaries. However, contrast visualization in the conventional indocyanine green mode (CIM) remains relatively obscure in smoking-related comorbidities. Our aim was to evaluate the safety and efficacy of recently released Spectra-A with CIM by simultaneous observation., Materials and Methods: We postoperatively analyzed captive imaging using histogram counts in 29 patients who underwent TAS and previously reported that Δ indicates the index of visualization obtained by subtraction from its representative illuminated signal quantities of maximum pixels so that light-shade, intensity-removed image signals are obtained., Results: Sixteen (55.2%) patients were male, and 13 (44.8%) were female. Segmental boundaries were successfully visualized in all patients (100%). The histogram count widths in dim and bright segments with CIM were 13.3 ± 3.8 and 52.5 ± 12.2, and those with Spectra-A were 19.4 ± 6.1 and 118.1 ± 37.4, respectively. The mean value was 4.3-fold higher for ΔSpa-A (61.4 ± 33.2) than for ΔCIM (14.2 ± 8.5) (P < 0.01). In 14 (48.3%) patients, the segmental boundary could not be clearly visualized using CIM but was explicitly identified using Spectra-A., Conclusions: Spectra-A is a safe and promising noninvasive alternative like CIM, and more effective because of overcoming the limitation of CIM, but its use should be studied further to determine its usefulness in identifying segmental boundaries., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Fluorescence-mediated photoplethysmography (FM-PPG) was developed to facilitate determination of tissue microvascular (capillary) blood perfusion, requiring intra-venous injection of a small bolus (~0.33mL) of dye (25mg/mL ICG) and acquisition of high-speed angiogram images (>15images/s). The methodology is applicable to microvascular capillary beds of tissues that can be optically imaged, directly or laparoscopically. Proof of concept of the methodology and feasibility of its implementation are demonstrated in human forearm skin and in the choroid of a monkey eye, determined to have blood perfusion rates on the order of 1e-5mL/(s·mm 2 ) and 10e-5mL/(s·mm 2 ), respectively. Ability to obtain absolute quantified tissue perfusion data ultimately can provide the means by which to characterize blood flow information at the nutritive capillary-vessel level in an objective and universally understood manner, in much the same sense that body temperature or blood pressure are., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: To describe and evaluate a reproducible, anatomically based surgical algorithm, including reinjection of tracer to enhance technical success rate, for detection of pelvic sentinel lymph nodes (SLNs) in endometrial cancer (EC)., Methods: A prospective study of 102 consecutive women with high risk EC scheduled for robotic surgery was conducted. Following cervical injection of a fluorescent dye, an algorithm for trans- and retroperitoneal identification of tracer display in the lower and upper paracervical pathways was strictly adhered to. To enhance the technical success rate, this included ipsilateral reinjection of tracer in case of non-display of any lymphatic pathway. The lymphatic pathways were kept intact by opening the avascular planes. To minimize disturbance from leaking dye, removal of SLNs was first performed along the lower paracervical (presacral) pathways followed by the more caudal upper paracervical pathways. In each pathway, the juxtauterine node with an afferent lymph vessel was defined as an SLN. After removal of SLNs, a complete pelvic and, unless contraindicated, infrarenal paraaortic lymph node dissection was performed., Results: The bilateral detection rate including tracer reinjection was 96%. All 24 (23.5%) node positive patients had at least one metastatic SLN. Presacral lymph node metastases were discovered in 33.3% of the node positive patients. One patient (4.2%) had an isolated presacral lymph node metastasis., Conclusions: The described cranial-to-caudal anatomically based surgical SLN algorithm, including a presacral dissection and reinjection of tracer, results in a high SLN detection rate and identified all patients with lymph node metastases., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objectives: To analyze detection-rate(DR) and diagnostic-accuracy (A) of sentinel-nodes(SLNs) mapping following hysteroscopic-injection of tracer. To compare DR and A between tracers: ICG and Tc99m., Methods: Evaluation of endometrial-cancer patients who underwent SLNs mapping after hysteroscopic-peritumoral-injection of tracer±lymphadenectomy. Analysis of DR (overall-bilateral-aortic) and A in the entire cohort and comparison between tracers., Results: 202 procedures were performed from January/2005 to February/2017. Mean age:60years (28-82); mean BMI: 26.8 kg/m 2 (15-47). In 133 cases (65.8%) hysterectomy and mapping procedure were performed laparoscopically. The overall-DR of the technique was 93.2% (179/192) (10 cases were excluded: 9 for technical-equipment failure; 1 for vagal reaction). Bilateral pelvic mapping was found in 59.7% of cases (107/179) and was more frequent in the ICG group (72.8% vs 53.3%; p: 0.012). In 50.8% of cases (91/179) SLNs were mapped both in pelvic and aortic nodes, and in 5 cases (2.8%) only in the aortic area. The mean number of detected SLNs was 3.7 (1-8). 22 patients (12.3%) had nodal involvement: 10-(45.5%)-macrometastases; 5-(22.7%)-micrometastases; 7-(31.8%)-ITCs. In 6 cases (27.3%) only aortic nodes were positive; in 5 cases (22.7%) both pelvic and aortic nodes and in 11 cases (50%) only pelvic nodes were involved. Three false-negative results were found, all in the Tc99m group. All had isolated aortic metastases with negative pelvic nodes. Overall-sensitivity was 86.4% (95%CI: 68.4-100) and overall-negative-predictive-value (NPV) was 96.4% (95%CI 86.7-100). No differences in terms of overall-DR, overall-sensitivity and overall-NPV were found between the two tracers., Conclusions: Hysteroscopic-injection of tracer for SLNs mapping in endometrial cancer is as accurate as cervical injection with a higher DR in the aortic area. ICG improves bilateral-DR. Further investigation is warranted on this topic., (Copyright © 2017 Elsevier Inc. All rights reserved.)

A clinical method for characterizing the state of micro-vasculature vasomotion is demonstrated, based on observing in capillaries the dynamics of autologously re-injected erythrocytes containing ICG dye. Since a manifestation of vasomotion is transient erythrocyte pausing, vasomotion state within a field of capillaries is characterized by an histogram plot of the number of paused erythrocytes as a function of pause duration during a fixed period of observation, then the ratio of long-pausing to short-pausing erythrocytes was calculated. The method was first applied to the posterior pole retinal vasculatures of anesthetized-monkey eyes, and normal vasomotion state during air-breathing was compared to the state induced by O 2 -breathing, known to cause mild arteriolar vasoconstriction in the mature eye. Subsequently, the effects of other antagonists to normal arteriolarvasotonia state (long-standing experimentally-induced ocular hypertension and branch-vein occlusion, as well as tissue edema) were similarly characterized and the results compared to those obtained during baseline air-breathing. The feasibility of applying the histogram characterization of vasomotion state to human eyes and skin was also preliminarily explored., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: Sentinel lymph node mapping, alone or in combination with pelvic lymphadenectomy, is considered a standard approach in staging of patients with cervical or endometrial cancer [1-3]. The goal of this video is to demonstrate the use of indocyanine green (ICG) and color-segmented fluorescence when performing lymphatic mapping in patients with gynecologic malignancies., Methods: Injection of ICG is performed in two cervical sites using 1mL (0.5mL superficial and deep, respectively) at the 3 and 9 o'clock position. Sentinel lymph nodes are identified intraoperatively using the Pinpoint near-infrared imaging system (Novadaq, Ontario, CA). Color-segmented fluorescence is used to image different levels of ICG uptake demonstrating higher levels of perfusion. A color key on the side of the monitor shows the colors that coordinate with different levels of ICG uptake. Color-segmented fluorescence may help surgeons identify true sentinel nodes from fatty tissue that, although absorbing fluorescent dye, does not contain true nodal tissue. It is not intended to differentiate the primary sentinel node from secondary sentinel nodes. The key ranges from low levels of ICG uptake (gray) to the highest rate of ICG uptake (red)., Results: Bilateral sentinel lymph nodes are identified along the external iliac vessels using both standard and color-segmented fluorescence. No evidence of disease was noted after ultra-staging was performed in each of the sentinel nodes., Conclusion: Use of ICG in sentinel lymph node mapping allows for high bilateral detection rates. Color-segmented fluorescence may increase accuracy of sentinel lymph node identification over standard fluorescent imaging. The following are the supplementary data related to this article., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: To describe the anatomy of uterine lymphatic drainage following cervical or fundal tracer injection to enable standardization of a pelvic sentinel lymph node (SLN) concept in endometrial cancer (EC)., Methods: A prospective consecutive study of women with EC was conducted. A fluorescent dye (Indocyanine green) was injected into the cervix (n=60) or the uterine fundus (n=30). A systematic trans- and retroperitoneal mapping of uterine lymphatic drainage was performed. Positions of the pelvic SLNs, defined by afferent lymph vessels, and lymph node metastases were compared., Results: Two consistent lymphatic pathways with pelvic SLNs were identified irrespective of injection site; an upper paracervical pathway (UPP) with draining medial external and/or obturator lymph nodes and a lower paracervical pathway (LPP) with draining internal iliac and/or presacral lymph nodes. Bilateral display of at least one pelvic pathway following cervical and fundal injection occurred in 98% and 80% respectively (p=0.005). Bilateral display of both pelvic pathways occurred in 30% and 20% respectively (p=0.6) as the LPP was less often displayed. Nearly one third of the 19% node positive patients had metastases along the LPP. No false negative SLNs were identified., Conclusions: Based on uterine lymphatic anatomy a bilateral detection of at least one SLN in both the UPP and LPP should be aimed for. Absence of display of the LPP may warrant a full presacral lymphadenectomy. Although pelvic pathways and positions of SLNs are independent of the tracer injection site, cervical injection is preferable due to a higher technical success rate., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background and Aims: With the debate over extent of lymphadenectomy in endometrial cancer, sentinel lymph node (SLN) mapping may provide a focused approach to evaluate the most relevant lymph nodes (LN) while minimizing the complications. We evaluated SLN mapping using filtered technetium(99), indocyanine green (ICG), and blue dye., Methods: Prospective evaluation of 100 patients who underwent SLN mapping by using submucosal and deep stromal cervical injections of technetium(99), ICG, and blue dye as part of the staging for endometrial cancer., Results: 286 SLNs were mapped (2.9 per patient) in 92% of patients. The bilateral detection rate was 76%. ICG had a significantly higher SLN detection rate than blue dye in both overall (87% vs 71%, respectively; p=0.005) and bilateral (65% vs 43%, respectively; p=0.002) detection, but similar SLN detection rates compared to technetium(99) in both overall (87% vs 88%, respectively; p=0.83) and bilateral (65% vs 71%, respectively; p=0.36) detection. In eight cases, the SLN was in the para-aortic area and in 14 cases in the pre-sacral, hypogastric vein, or parametrial area. In nine cases, the SLN was positive for metastasis, and in seven cases the SLN was the only positive node. One SLN was falsely negative. No complications or anaphylactic reactions occurred., Conclusion: Intra-operative SLN mapping using cervical injection is feasible in patients with endometrial cancer and yields adequate detection rates. It allows mapping of SLNs in areas (pre-sacral, hypogastric vein, parametrial) not routinely sampled. Given the poorer performance of blue dye, surgeons may omit its use if a combination of ICG and technetium(99) is used., (Copyright © 2015 Elsevier Inc. All rights reserved.)

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 surgery. The current study aims to optimize dosage and timing of ICG administration., Materials and Methods: Liver tumors were induced in 18 male WAG/Rij rats by subcapsular inoculation of CC531 rat colorectal cancer cells into three distinct liver lobes. Rats were divided in two groups: imaging after 24 and 48 h or 72 and 96 h after intravenous ICG administration. In each time group, rats were allocated to three dose groups: 0.04, 0.08, or 0.16 mg ICG. Intraoperative imaging and ex vivo measurements were performed using the Mini-FLARE imaging system and confirmed by fluorescence microscopy. Fluorescence intensity was quantified using the Mini-FLARE software and the difference between tumor signal and liver signal (tumor-to-liver ratio; TLR) was calculated., Results: In all 18 rats, all colorectal liver metastases (n = 34), some as small as 1.2 mm, were identified using ICG and the Mini-FLARE imaging system. Average tumor-to-liver ratio (TLR) over all groups was 3.0 ± 1.2. TLR was significantly higher in the 72 h time group compared with other time points. ICG dose did not significantly influence TLR, but a trend was found favoring the 0.08 mg dose group. Fluorescence microscopy demonstrated a clear fluorescent rim around the tumor., Conclusions: This study demonstrates that colorectal cancer liver metastases can be clearly identified during surgery using ICG and the Mini-FLARE imaging system, with optimal timing of 72 h post-injection and an optimal dose of 0.08 mg (0.25 mg/kg) ICG. NIR fluorescence imaging has the potential to improve intraoperative detection of micrometastases and, thus, the completeness of resection., (Copyright © 2012 Elsevier Inc. All rights reserved.)

This is the first report on results proving that fluorescence of exogenous dyes inside the human brain can be excited and detected non-invasively at the surface of the adult head. Boli of indocyanine green (ICG) were intravenously applied to healthy volunteers, and the passage of the contrast agent in the brain was monitored by detecting the corresponding fluorescence signal following pulsed laser excitation at 780 nm. Our hypothesis that the observed fluorescence signal contains a considerable cortical fraction was corroborated by performing measurements with picosecond temporal resolution and analyzing distributions of times of arrival of photons, hence taking advantage of the well-known depth selectivity of that method. Our experimental findings are explained by Monte Carlo simulations modeling the head as a layered medium and taking into account realistic bolus kinetics within the extra- and intracerebral compartment. Although a particular non-specific dye (ICG) was used, the results clearly demonstrate that fluorescence-mediated imaging of the adult human brain is generally feasible. In particular, we will discuss how these results serve as proof of concept for non-invasive fluorescence brain imaging and may thus open the door towards optical molecular imaging of the human brain.

This study reinvestigates the spectral properties of ICG (Indocyanine green) in vivo, the role of quenching, and the possibility of an interaction of ICG with blood components and/or vessel walls. ICG quenching as a function of concentration was studied by spectrophotometry on whole blood samples from golden hamsters. Fluorescence ICG characteristics were evaluated by front-face fluorometry. In vivo, fluorescence measurements were performed on the femoral artery of golden hamsters. In vitro, on whole blood samples, fluorescence intensity is modified by ICG quenching as concentration increases above 80 microgram/ml. The maximum fluorescence peak is not affected and remains centered at 832 nm. The in vivo measurements display a similar fluorescence intensity shape, which is affected only by ICG concentrations. However, the maximum fluorescence emission peak is modified significantly with time. Between 0 and 120 min, four phases can be distinguished in which a wavelength shift from 826 to 835 nm is observed. The wavelength shift with change in fluorescence intensity observed in vivo could be due to a localization of ICG molecules in sites more hydrophobic than serum proteins. It is possible to hypothesize the presence of an endothelium-bound form with a specific fluorescence spectrum. The amphiphilic properties of ICG are consistent with fixation of some ICG molecules on sites other than plasmatic proteins after injection. The process of fixation of ICG molecules on surface components or within the vascular endothelium could be due to a change in the microenvironment of some ICG molecules., (Copyright 1998 Academic Press.)