"Dye another day!" - dyes in ophthalmology.

Background: Dyes are substances that are an integral part of ocular procedures and surgeries. In Clinical practice, dyes help in better visualization and aid in diagnoses of ocular surface disorders. In Surgical practice, dyes help in better resolution of the structures that are otherwise naked to the surgeon's eyes. Purpose: To educate ophthalmologists about the importance and uses of dyes. Synopsis: Dyes have become an important part of an ophthalmologists' clinical as well as surgical practice. This video aims at educating the different characteristics, uses, advantages and disadvantages of each dye. Dyes help in identifying the obscure and highlighting the invisible. The indications and contraindications as well as the side effects of each dye are discussed which would help ophthalmologists in the correct usage of these wonder substances. This video will also help the new eye doctors understand and utilize these dyes judiciously which would aid in their learning process and provide better patient care. Highlights: This video highlights the uses, indications, contraindications and side effects of all the dyes used in ophthalmology. Video Link: https://youtu.be/shdV4a6oc20.

Indocyanine green versus technetium-99m with blue dye for sentinel lymph node detection in early-stage cervical cancer: A systematic review and meta-analysis.

BACKGROUND: The fluorescent dye indocyanine green (ICG) has emerged as a promising tracer for intraoperative detection of sentinel lymph nodes (SLNs) in early-stage cervical cancer. Although researchers suggest the SLN detection of ICG is equal to the more conventional combined approach of a radiotracer and blue dye, no consensus has been reached. AIMS: We aimed to assess the differences in overall and bilateral SLN detection rates with ICG versus the combined approach, the radiotracer technetium-99m (99m Tc) with blue dye. METHODS AND RESULTS: We searched MEDLINE, Embase, and the Cochrane Library from inception to January 1, 2020 and included studies reporting on a comparison of SLN detection with ICG versus 99m Tc with blue dye in early-stage cervical cancer. The overall and bilateral detection rates were pooled with random-effects meta-analyses. From 118 studies retrieved seven studies (one cross-sectional; six retrospective cohorts) were included, encompassing 589 patients. No significant differences were found in the pooled overall SLN detection rate of ICG versus 99m Tc with blue dye. Meta-analyses of all studies showed ICG to result in a higher bilateral SLN detection rate than 99m Tc with blue dye; 90.3% (95%CI, 79.8-100.0%) with ICG versus 73.5% (95%CI, 66.4-80.6%) with 99mTc with blue dye. This resulted in a significant and clinically relevant risk difference of 16.6% (95%CI, 5.3-28.0%). With sensitivity analysis, the risk difference of the bilateral detection rate maintained in favor of ICG but was no longer significant (13.2%, 95%CI -0.8-27.3%). CONCLUSION: ICG appears to provide higher bilateral SLN detection rates compared to 99m Tc with blue dye in patients with early-stage cervical cancer. However, in adherence with the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) guidelines, the quality of evidence is too low to provide strong recommendations and directly omit the combined approach of 99m Tc with blue dye.

Sentinel lymph node biopsy in patients with endometrial cancer and an indocyanine green or iodinated contrast reaction - A proposed management algorithm.

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.

The efficacy and safety of indocyanine green-hyaluronic acid mixture (LuminoMark™) for localization in patients with non-palpable breast lesions: a multi-center open-label parallel phase-2 clinical trial.

BACKGROUND: Increasing rates of breast cancer screening have been associated with an increasing frequency of non-palpable breast lesions detection. Preoperative breast lesion localization is essential for optimizing excision accuracy. This study aimed to evaluate the efficacy and safety of indocyanine green (ICG) hyaluronic acid injection as a novel mixture for localization. METHODS: We performed a prospective clinical trial with female patients who underwent surgery for non-palpable breast lesions. All patients were sequentially assigned to the control group (localization with activated charcoal), Test Group 1 (ICG-hyaluronic acid mixture 0.1 mL), or Test Group 2 (ICG-hyaluronic acid mixture 0.2 mL) by 1:1:1 ratio. RESULTS: A total of 44 patients were eligible for this study (Control Group = 14, Test Group 1 = 15, Test Group 2 = 15 patients). Fibroadenoma (n = 17, 38.6%) accounted for the largest proportion of diagnoses, and five patients (11.4%) were diagnosed with malignancies. There were no statistically significant differences in baseline characteristics among the three groups. The marking rate was over 86% in all groups, with no significant intergroup differences. Skin pigmentation was only observed in the control group. The mean accuracy of resection (the greatest diameter of the excised specimen divided by the greatest diameter of the preoperative lesion as observed using ultrasonography, with values closer to 1 reflecting a higher accuracy) was 3.7 in the control group, 2.2 in Test Group 1, and 2.1 in Test Group 2 (p = 0.037 between Controls and Test Group 1, p = 0.744 between Test Group 1 and Test Group 2, and p = 0.026 between Controls and Test Group 2). CONCLUSION: ICG-hyaluronic acid injection is a novel method that was shown to accurately localize non-palpable breast lesions and was associated with no skin pigmentation. Further research is required to apply this method to malignant breast lesions. Trial registration "A Multicenter Open-label, Parallel, Phase 2 Clinical Trial to Evaluate the Efficacy and Safety of LuminoMark™ Inj. (Conc. for Fluorescence) Localization in Patients with Non-palpable Breast Lesions" was prospectively registered as a trial (ClinicalTrials. gov Identifier: NCT03743259, date of registration: May 29, 2018, https://clinicaltrials.gov/ct2/show/NCT03743259 ).

Reverse Lymph Node Mapping Using Indocyanine Green Lymphography: A Step Forward in Minimizing Donor-Site Morbidity in Vascularized Lymph Node Transfer.

BACKGROUND: Reverse lymphatic mapping before harvesting a lymph node flap is crucial to avoid donor-site lymphedema; however, the technique is complex and unavailable in many centers. The authors introduce radioisotope-free reverse lymphatic mapping using indocyanine green and Patent Blue dye. METHODS: The authors conducted a prospective study in patients undergoing free vascularized groin lymph node transfer for postmastectomy upper extremity lymphedema. The day before surgery, 0.2 ml of technetium-99 was injected into the first and second web spaces of the ipsilateral foot. The following day, once the patient was anesthetized, indocyanine green was injected into the same web spaces of the same foot and Patent Blue dye was injected just proximal to the upper margin of the skin paddle of the lymph node flap. The main lymph nodes draining the limb were localized using indocyanine green lymphography and gamma probe. RESULTS: Thirty-nine patients underwent vascularized groin lymph node transfer with or without deep inferior epigastric artery perforator flap breast reconstruction. Navigation of the main lower extremity draining inguinal lymph nodes using the gamma probe and indocyanine green lymphography was identical in all patients. The blue-stained lymphatics in the skin paddle drained to the superficial proximal inguinal lymph node and were targeted for transfer. No donor-site lymphedema was reported, and lymphatic drainage of the lower extremity was preserved in all cases. CONCLUSIONS: Reverse lymphatic mapping using indocyanine green lymphography provides identical results to those using technetium-99 isotope scanning. However, indocyanine green is preferable in terms of safety and reproducibility and also avoids the complexity and hazards of radioisotope mapping. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

pHLIP ICG for delineation of tumors and blood flow during fluorescence-guided surgery.

Fluorescence imaging has seen enduring use in blood flow visualization and is now finding a new range of applications in image-guided surgery. In this paper, we report a translational study of a new fluorescent agent for use in surgery, pHLIP ICG, where ICG (indocyanine green) is a surgical fluorescent dye used widely for imaging blood flow. We studied pHLIP ICG interaction with the cell membrane lipid bilayer, the pharmacology and toxicology in vitro and in vivo (mice and dogs), and the biodistribution and clearance of pHLIP ICG in mice. The pHLIP ICG tumor targeting and imaging efficacy studies were carried out in several murine and human mouse tumor models. Blood vessels were imaged in mice and pigs. Clinical Stryker imaging instruments for endoscopy and open surgery were used in the study. Intravenously administered pHLIP ICG exhibits a multi-hour circulation half-life, offering protracted delineation of vasculature. As it clears from the blood, pHLIP ICG targets tumors and tumor stroma, marking them for surgical removal. pHLIP ICG is non-toxic, marks blood flow for hours after injection, and effectively delineates tumors for improved resection on the day after administration.

Zoledronate and SPIO dual-targeting nanoparticles loaded with ICG for photothermal therapy of breast cancer tibial metastasis.

Currently, nanoparticles (NPs) for cancer photothermal therapy (PTT) have limited in vivo clearance, lack targeting ability and have unsatisfactory therapeutic efficiency. Herein, we report a dual-targeting and photothermally triggered nanotherapeutic system based on superparamagnetic iron oxide (Fe3O4) and indocyanine green (ICG)-entrapped poly-lactide-co-glycolide modified by ZOL (PLGA-ZOL) NPs (ICG/Fe3O4@PLGA-ZOL) for PTT of breast cancer tibial metastasis, which occurs frequently in the clinic and causes challenging complications in breast cancer. In this system, both ICG and Fe3O4 can convert light into heat, while NPs with Fe3O4 and ZOL can be attracted to a specific location in bone under an external magnetic field. Specifically, the dual-targeting and double photothermal agents guaranteed high accumulation in the tibia and perfect PTT efficiency. Furthermore, the in vivo studies showed that ICG/Fe3O4@PLGA-ZOL NPs have extraordinary antitumor therapeutic effects and that these NPs can be accurately located in the medullary cavity of the tibia to solve problems with deep lesions, such as breast cancer tibial metastasis, showing great potential for cancer theranostics.

Safety and completeness of using indocyanine green videoangiography combined with digital subtraction angiography for aneurysm surgery in a hybrid operating theater.

This study aimed to evaluate the safety and completeness of using intraoperative indocyanine green videoangiography (ICGV) combined with intraoperative angiography (IOA) for aneurysm clipping in a hybrid operating room (hOR). All patients who underwent microsurgical clipping in the hOR were identified from prospectively maintained neurosurgical databases. Medical charts and operative videos with ICGV and IOA were reviewed to determine the adequacy of clipping, and clinical and angiographic outcomes were retrospectively analyzed. Fifty-four cerebral aneurysms (ruptured, 31; unruptured, 23) in 50 patients (mean age, 59.4 ± 10.9 y; M:F, 22:28) were evaluated with ICGV and IOA during clipping. Additional IOA led to a clip adjustment during surgery in 9/54 (16.7%) aneurysms for which ICGV had been initially performed. Post-clip perforator compromise occurred in two (3.7%) cases, with a patient with an unruptured aneurysm experiencing permanent injury (grade 3 hemiparesis) and patient with a ruptured aneurysm experiencing transient deficit. Post-clip parent vessel stenosis occurred in one (1.9%) case; however, an ischemic event did not occur because the flow patency was identified by IOA. No other patients with unruptured aneurysms developed new neurologic deficits at discharge. Favorable outcomes (Glasgow Outcome Score [GOS], 4 or 5) were observed in 26/31 patients with ruptured aneurysms. Five patients had unfavorable outcomes (GOS, 2 or 3) from the initial insult. Post-treatment angiography within 1 week showed complete occlusion in 52 (96.3%) aneurysms and minor remnants in two (3.7%) aneurysms. Using combined ICGV and IOA in a hOR may improve the safety and completeness of microsurgical aneurysm clipping.

Anaphylactic Shock After Indocyanine Green Video Angiography During Cerebrovascular Surgery.

BACKGROUND: Indocyanine green (ICG) video angiography has been widely used in cerebrovascular surgery. ICG injection is generally safe, with a low incidence of complications. ICG-related anaphylactic reactions during neurosurgery have been rarely reported. We report the cases of 2 patients who had experienced anaphylactic shock in response to intravenous ICG injection (DID Indocyanine Green [Dongindang, Inc., Gyeonggi-do, Republic of Korea]) during intracranial aneurysm (IA) surgery. CASE DESCRIPTION: The first patient, a 69-year-old woman with an unruptured IA, had been undergoing clipping surgery under general anesthesia. Immediately after ICG injection, her blood pressure suddenly decreased from 140/80 mm Hg to 50/30 mm Hg and she developed a skin rash on her abdomen and all extremities. Chest compression was initiated, and her vital signs gradually recovered to their pre-ICG levels within 10 minutes. The second patient was a 58-year-old woman with an unruptured IA who had been undergoing clipping surgery. After ICG injection, her blood pressure had decreased from 130/80 mm Hg to 60/40 mm Hg, and a rash-like skin lesion was observed on her abdomen. After intravenous injection of norepinephrine and dexamethasone, her blood pressure recovered to its pre-ICG level within 30 minutes and remained stable thereafter. The postoperative ICG skin provocation test findings were positive for both patients; however, only 1 patient showed markedly increased serum tryptase levels. CONCLUSION: Despite the rarity of ICG-related anaphylaxis, clinicians should be aware of this unexpected, but potentially life-threatening, drug reaction in patients undergoing cerebrovascular surgery.

Fluorescent Cholangiography in Laparoscopic Cholecystectomy: An Updated Canadian Experience.

Background. Laparoscopic cholecystectomy (LC) is one of the most common general surgery procedures in Canada with approximately 100 000 cases performed per year. Bile duct injury remains a morbid complication with an incidence rate of 0.3% to 0.5%. Indocyanine green (ICG) fluorescent cholangiography is a noninvasive technology aiding in real-time identification of biliary structures for safe dissection within Calot's triangle. The objectives were to provide an update to our initial experience with ICG aiding in the identification of biliary structures and ensuring that no adverse patient reactions occurred with ICG administration. Methods. Prospective case series from 2016 to 2018 for elective LC with ICG technology performed at a single academic teaching institution. Patient demographics, indications for operation, biliary structures visualized, amount of ICG used, operative times, and complications were recorded. Results. One hundred eight cases were included for review. The cystic duct, common hepatic duct, and common bile duct were identified with ICG in 90%, 48%, and 84% of cases, respectively. ICG simultaneously visualized at least 2 of 3 biliary structures 83.4% of the time. Only 1 biliary structure was identified in 10% of cases. No biliary structures were identified in 6% of cases. Mean initial ICG dose given was 1.65 mL. No adverse patient reactions to ICG were noted. Conclusions. This updated series illustrates that administration of ICG enhances visualization of the biliary system during outpatient LC. ICG is safe and its application should be further studied in early LC for acute cholecystitis.

Peritoneal contamination with ICG-stained cervical secretion as surrogate for potential cervical cancer tumor cell dissemination: A proof-of-principle study for laparoscopic hysterectomy.

INTRODUCTION: Intracorporal colpotomy during radical hysterectomy for cervical cancer is discussed to be a risk factor for peritoneal dissemination of tumor cells. It might lead to increased recurrence rates after laparoscopic radical hysterectomy compared with abdominal hysterectomy, as shown by the recent LACC study. Data on the frequency or mechanisms of peritoneal contamination are missing. We aimed to analyze peritoneal contamination of cervical secretion during intracorporal colpotomy with a novel indocyaningreen (ICG)-based technique. MATERIAL AND METHODS: In this prospective proof-of-principle study, patients undergoing routine laparoscopic or robot-assisted hysterectomy were selected. ICG was specifically applied to the cervical surface and routine surgery was performed. During colpotomy, pictures under white and fluorescence light were taken to evaluate frequency of contamination. RESULTS: By using cervically applied ICG we were able to visualize directly peritoneal contamination with cervical secretion during intracorporal colpotomy. We detected peritoneal contamination in 9/12 (75%) patients undergoing routine laparoscopic hysterectomy. Contamination of laparoscopic instruments occurred in 60% of the patients. When contamination occurred, it was routinely detectable during all steps of colpotomy. There were no adverse effects during surgery. CONCLUSIONS: Peritoneal contamination with cervical secretion frequently occurs during intracorporal colpotomy. This novel technique represents a promising tool for feasible and direct visualization of peritoneal contamination during colpotomy. The technique may be easily implemented in further studies on laparoscopic and abdominal hysterectomy and serve as a quality assessment tool for surgeons and surgical techniques.

NIR-Light-Triggered Anticancer Strategy for Dual-Modality Imaging-Guided Combination Therapy via a Bioinspired Hybrid PLGA Nanoplatform.

A promising approach toward cancer therapy is expected to integrate imaging and therapeutic agents into a versatile nanocarrier for achieving improved antitumor efficacy and reducing the side effects of conventional chemotherapy. Herein, we designed a poly(d,l-lactic- co-glycolic acid) (PLGA)-based theranostic nanoplatform using the double emulsion solvent evaporation method (W/O/W), which is associated with bovine serum albumin (BSA) modifications, to codeliver indocyanine green (ICG), a widely used near-infrared (NIR) dye, and doxorubicin (Dox), a chemotherapeutic drug, for dual-modality imaging-guided chemo-photothermal combination cancer therapy. The resultant ICG/Dox co-loaded hybrid PLGA nanoparticles (denoted as IDPNs) had a diameter of around 200 nm and exhibited excellent monodispersity, fluorescence/size stability, and biocompatibility. It was confirmed that IDPNs displayed a photothermal effect and that the heat induced faster release of Dox, which led to enhanced drug accumulation in cells and was followed by their efficient escape from the lysosomes into the cytoplasm and drug diffusion into the nucleus, resulting in a chemo-photothermal combinatorial therapeutic effect in vitro. Moreover, the IDPNs exhibited a high ability to accumulate in tumor tissue, owing to the enhanced permeability and retention (EPR) effect, and could realize real-time fluorescence/photoacoustic imaging of solid tumors with a high spatial resolution. In addition, the exposure of tumor regions to NIR irradiation could enhance the tumor penetration ability of IDPNs, almost eradicating subcutaneous tumors. In addition, the inhibition rate of IDPNs used in combination with laser irradiation against EMT-6 tumors in tumor-bearing nude mice (chemo-photothermal therapy) was approximately 95.6%, which was much higher than that for chemo- or photothermal treatment alone. Our study validated the fact that the use of well-defined IDPNs with NIR laser treatment could be a promising strategy for the early diagnosis and passive tumor-targeted chemo-photothermal therapy for cancer.

Potential Phototoxicity of Indocyanine Green in Retinal Pigment Epithelial Cells after Angiography under Ambient Illumination.

Indocyanine green (ICG) angiography is an indispensable inspection to diagnose and treat for chorioretinal diseases. In this study, we investigated the phototoxicity of ICG on RPE cells at the levels of residual ICG after angiography under ambient light. After incubation of ARPE-19 cells in a colorless medium containing 0 to 10 µg/mL ICG for 24 hours in the dark or under 2000 lx illumination from a fluorescent lamp, cell viability decreased and cell death rate increased in cultures with more than 5.0 µg/mL ICG under illumination. In culture with 10 µg/mL ICG under illumination, morphology of cells changed to be oval and TUNEL- and malondialdehyde-positive cells increased compared to other cultures with ICG in the dark or without ICG under illumination. Furthermore, the level of intracellular reactive oxygen species was also elevated. On the other hand, toxicity of ICG denatured by illumination was not observed. Blocking green to red light overlapping wavelengths of ICG absorbance exhibited decreased cell death rate. The present study indicated that ICG at the estimated intravenous concentrations after ICG angiography induces potential phototoxicity on human RPE cells via oxidative damage under continuous ambient illumination and that the cytotoxicity is reduced by blocking green to red light wavelengths.

Severe hemodynamic instability after indocyanine green injection during off-pump coronary artery bypass grafting: A case report.

RATIONALE: The increasingly intraoperative use of indocyanine green (ICG) means that it is necessary to be aware of both its advantages and potential adverse effects. PATIENT CONCERNS: A 76-year-old woman developed symptoms of sudden severe hemodynamic instability while undergoing coronary artery bypass grafting with ICG injection to detect the patency of the graft. The main clinical manifestations were a sudden drop in blood pressure and increased heart rate. DIAGNOSES: Severe side effects or allergic reaction of ICG. INTERVENTIONS: Cardiopulmonary bypass (CPB) was established, and an intra-aortic balloon pump was implanted in the left femoral artery after intravenous epinephrine and manual cardiac compression failed. OUTCOMES: The patient was extubated and transferred to the general ward on the third postoperative day. LESSONS: Invasive blood pressure monitoring should be carried out in patients undergoing intraoperative ICG administration. Anesthetists should pay close attention to the patient's hemodynamic fluctuations, and effective emergency measures should be implemented immediately if severe hemodynamic instability occurs.

Ten-Year Retrospective Study on the Management of Spinal Arteriovenous Lesions: Efficacy of a Combination of Intraoperative Digital Subtraction Angiography and Intraarterial Dye Injection.

BACKGROUND: The goal of treatment for spinal arteriovenous lesions is to completely obliterate the shunt. In our institution, intraoperative digital subtraction angiography and intraarterial injection of contrast agent have been used to accurately identify the site of arteriovenous shunts. We describe the intraoperative digital subtraction angiography and intraarterial dye injection procedures and how they may improve surgical outcomes. METHODS: We retrospectively investigated 22 patients with intradural arteriovenous lesions (n = 19) or spinal dural arteriovenous fistulas (n = 3). A microcatheter was used during the procedures to avoid catheter migration. RESULTS: There were 29 procedures performed. To support the surgical procedures, indigo carmine was used 17 times and indocyanine green was used 12 times. There were no complications associated with these procedures. The indocyanine green procedure required a lower concentration of dye in the artery than in the vein to clarify the shunt point and visualized complex lesions more clearly. These methods allowed surgeons to orientate the complex vessel structure. CONCLUSIONS: Intraoperative digital subtraction angiography and intraarterial dye injection are useful tools for management of spinal arteriovenous lesions.