COMPARATIVE STUDY TO EVALUATE THE ROLE OF ICG DYE VS LIGHTED URETERAL STENT (U KIT) TO PREVENT INTRAOPERATIVE URETERIC INJURY UNDER NIR FLUORESCENCE IN TOTAL LAPAROSCOPIC HYSTERECTOMY" MASTER IN MINIMAL ACCESS SURGERY
World Laparoscopy Hospital
DECEMBER 2020 to NOVEMBER 2021

ACKNOWLEDGEMENT

Relevant anatomy of the ureter, illustrating its course from the renal pelvis to the bladder. Note the ureter's proximity at the pelvic brim to the infundibulopelvic ligament.

 

Berard (1841) and Simon (1869) reported the earliest recorded repairs of ureteral injuries in gynecologic surgery. While the exact details of this procedure are unknown, the ureter and its course were poorly understood. In the early 1900s, Dr John Sampson, then a young faculty member at Johns Hopkins University, conducted the first systematic study of the ureter. During the next 100 years, as the surgical management for gynecologic disease progressed, many contributions were made to the understanding of the etiology, prevention, diagnosis, and treatment of iatrogenic ureteral injuries.
 

The 6 most common mechanisms of operative ureteral injury are as follows:
• Crushing from misapplication of a clamp
• Ligation with a suture
• Transsection (partial or complete)
• Angulation of the ureter with secondary obstruction
• Ischemia from ureteral stripping or electrocoagulation
• Resection of a segment of ureter
• Any combination of these injuries may occur. Factors that predispose a patient to iatrogenic urologic injury incllude the following: • Uterus size larger than 12 weeks' gestation
• Ovarian cysts 4 cm or larger
• Endometriosis
• Pelvic inflammatory disease
• Prior intra-abdominal surgery36
• Radiation therapy
• Advanced malignancy
• Anatomical anomalies of the urinary tract Ureteral injuries can be either expected or unexpected.

They may be the result of carelessness or due to a technically challenging procedure. 
 

 

 

The pathophysiology of ureteral injury depends on many factors, including the type of injury and when the injury is identified. Ureteral injuries may have numerous consequences, including the following: Spontaneous resolution and healing of the injured ureter
• Hydronephrosis
• Ureteral necrosis with urinary extravasation
• Ureteral stricture formation
• Uremia
• Spontaneous resolution and healing

If the injury to the ureter is minor, easily reversible, and noticed immediately, the ureter may heal completely and without consequence. Inadvertent ligation of the ureter is an example of such an injury. If this injury is noticed in a timely fashion, the suture can be cut off the ureter without significant injury.
 

If complete ligation of the ureter occurs, the urine from the ipsilateral kidney is prevented from draining into the bladder, leading to hydronephrosis and progressive deterioration of ipsilateral kidney function. These events may occur with or without symptoms. If the urine in this obstructed system becomes infected, the patient will almost certainly become septic with pyonephrosis.
 

In complete unrecognized ligation of the ureter, a section of the ureteral wall necroses because of pressure-induced ischemia. The ischemic segment of the ureter eventually weakens, leading to urinary extravasation into the periureteral tissues. If the urinary extravasation drains into the adjacent peritoneum, urinary ascites may develop. If the urinary ascites is infected, peritonitis may ensue. If the peritoneum has remained closed, a urinoma may form in the retroperitoneum.
 

Ureteral stricture may occur when the adventitial layer of the ureter is stripped or electrocoagulated. When the adventitia, the outer layer of the ureter that contains the ureteral blood supply, is disturbed by either stripping or electrocoagulation, ischemia to a particular segment of ureter may result. Ischemic strictures of the ureter may then develop, leading to obstruction and hydronephrosis of the ipsilateral kidney.  
 

Uremia results when ureteral injury causes total urinary obstruction. This may result from bilateral ureteral injury or from a unilateral injury occurring in a solitary functioning kidney. Anuria is the only immediate sign of imminent uremia. These cases require immediate intervention to preserve renal function.
 

Near-infrared fluorescence (NIRF) is an emerging translational, intravascular imaging modality that has the ability to capture a wide range of in vivo pathobiological processes. NIRF molecular imaging entails (1) injecting targeted or activatable NIRF molecular imaging agents, which consist of fluorescent conjugates (e.g., NIR fluorophores conjugated to an antibody, peptide, or small molecule) that concentrate in atheroma and bind to molecular targets, and (2) detecting the fluorophore emission signal from a NIRF catheter and console detection system.37 After injecting targeted fluorophores, excitation light from the near-infrared spectrum (650–900 nm) is directed at the arterial wall and used to stimulate fluorophores from ground state (S0) to an excited state. The excited fluorophores emit energy in the form of photons (fluorescence emission) and then return to the ground state, and are then available for further excitation. Fluorescence emission occurs at a lower energy and a longer wavelength, and this emission light is detectable with a high sensitivity charge-coupled device (CCD) camera and appropriate emission filter that attenuates the initial shorter wavelength excitation light (34). Compared to visible light range fluorescence detection, characteristics of NIRF imaging that make it a highly sensitive imaging modality include: (A) less light absorption by hemoglobin, lipid, and water, allowing deeper penetration of light into tissue; and (B) reduced background tissue autofluorescence, allowing for high signal-to-background ratio.
 

Near-infrared fluorescence (NIRF) imaging is an emerging clinical technology that requires administration of a fluorescence-imaging agent that can be excited at near-infrared (NIR) wavelengths of ≥760nm. Upon illuminating tissue surfaces with penetrating NIR light to excite the imaging agent within the tissues, the generated fluorescence is collected to form a two-dimensional (2D) image demarking the tissue deposition of the NIRF imaging agent. While far-red and NIR light between the wavelength ranges of 690–900 nm penetrate deeply in tissues, endogenous chromophore fluorescence when excited by light of wavelengths <780 nm, creates a high autofluorescence background for molecularly targeting exogenous imaging agents in tissues. The tissue depth to which the NIRF imaging can detect NIRF imaging agents is dependent upon their brightness and the sensitivity of the device, but has been estimated to be between 3 and 4 cm beneath the tissue surfaces in intensified devices1 and <2 cm in others.40 Three-dimensional tomographic imaging using 2D projection data as well as time-dependent and independent methods has been developed for small animal imaging but, owing to these limitations in tissue penetration, has not been translated to clinical imaging.

The exciting concept of conjugating a NIR excitable fluorophore to a small molecule, protein or antibody that targets an extracellular disease marker for diagnostic, molecular imaging has been postulated for years by several investigators.41-43 The use of NIRF imaging for molecularly guided surgical resection of cancers could dramatically reduce residual tumour burden as well as surgical morbidity associated with excising sufficient tissues to avoid having positive surgical margins. However, the tissue depth, concentration and dose at which a “first-in-humans” imaging agent can be detected in tissues depends upon several factors but, most importantly, upon the sensitivity of the imaging device. Unlike positron emission tomography, scintigraphy, single-photon emission and the γ probe used to detect radiolabelled molecular targeting agents for diagnostic imaging and intraoperative detection, fluorescence imaging devices do not have phantoms and standards to assess performance metrics, and there are no traceable standards to quantify or compare performance between fluorescence imaging devices. 

NIR-excited fluorophore used clinically is indocyanine green (ICG). Since 1956, ICG has been approved by the US Food and Drug Administration for intravenous (i.v.) administration at a concentration of 2.5 mgml−1 with doses of up to 25mg in adults, 12.5mg in children and 6.25mg in infants. ICG has been used in the clinic as a reagent for determining cardiac output, hepatic function and ophthalmic angiography. It has an excellent record of safety, and there is no demonstrable evidence of phototoxicity associated with its use. After administration, ICG binds tightly to plasma proteins and has a half-life of several minutes in blood circulation, which allows repeated intraoperative i.v. administration for fluorescence angiography. In the plasma, the absorption and emission peaks of ICG are shifted towards longer wavelengths, to around 807 and 822nm,10 respectively, but still reside in the “optical window” of the tissues. Compared with other NIR-excited fluorophores, the quantum efficiency (QE) of ICG is low and reported to be 0.02 at 780 nm excitation and 830 nm emission;44 it is comparatively unstable once reconstituted in saline; and it has no functional group for conjugation to compound for molecular imaging. Using ICG as a non-specific blood vascular imaging agent, NIRF angiography has been used intraoperatively in coronary, neurosurgical and vascular surgeries8 as well for non-invasive assessment of superficial perfusion.

Most recently, ICG has been used in off-label intradermal and subcutaneous administrations at varying doses for evaluating the lymphatic circulation to identify sentinel lymph nodes (SLNs) in surgical oncology, assess lymphovenous anastomoses (LVA) surgery46 and non-invasively map the lymphatic vasculature. Indeed, “ICG lymphography” has been found to be superior to lymphoscintigraphy for diagnostic imaging of early lymphoedema in upper extremities20 and enables early diagnosis of lymphoedema before the onset of symptoms. Yet, the doses of ICG and the design of devices used in these and other clinical studies vary widely, suggesting variable device performance. Although the architecture can be dramatically different among these devices, the core components are (i) the light source for exciting ICG; (ii) optical filters for separating emitted fluorescent signals from strong backscattered excitation light and ambient light signals; and (iii) an area detector for sensing the emitted fluorescent signals. Undoubtedly, the performance of a device is ultimately determined by these core components. requiring different dosages of ICG ranging from micrograms to milligrams per injection for visualizing the lymphatics.
 

ICG fluorescence imaging systems incident light sources used to excite ICG; the optics that allow for collection of ICG fluorescence and rejection of ambient and backscattered incident light; and the area detector used to register the collected light. 

Schematic of indocyanine green (ICG)-based near-infrared fluorescence imaging system consisting of the incident light source, collection optics and area detector. (a) Represents the spectra of 785-nm laser diode, 780-nm light-emitting diode (LED) and xenon lamp, showing the laser diode with narrow bandwidth, the LED with relatively wide bandwidth and xenon with very broad bandwidth, and (b) the focus lens and emission filter. (c) A plot of signal-to-noise ratio (SNR) vs contrast for different charge-coupled device (CCD)-based detectors with integration time of 200 ms. Both front-illuminated intensified CCD (FICCD) and backilluminated intensified CCD (BICCD) are superior to the other types of CCD cameras (Zhu et al25). BCCD, back-illuminated CCD; EMCCD, electron-multiplying CCD; FCCD, frontilluminated CCD; OD, optical density. 
 

The commonly used excitation light sources in ICG fluorescence imaging systems in order of increasing spectral bandwidth are (i) laser diodes; (ii) lightemitting diodes (LEDs); and (iii) filtered lamp sources, which have typical spectra. Because rejection of backscattered excitation light is performed spectrally through the use of interference filters, laser diodes enable the greatest sensitivity, since the “background” arising from “leakage” of backscattered excitation light is the lowest. By contrast, LEDs generate a broader band of wavelengths with relatively lower power output, requiring tens of LEDs integrated together for milliwatts per square centimetre of incident light. For the filtered lamp sources, the lamp sources are filtered to generate excitation light with a narrow band, but the generated excessive heat needs to be dissipated to extend the lifetime of the filter. In addition, the filtered lamp sources have low efficiencies, making it difficult to couple into an optical fibre. Hence, laser diodes and LEDs are widely adopted in the ICG fluorescence imaging systems used clinically.  
 

 

 

Without exception, all ICG fluorescence imaging systems have detection sensitivities that are limited by background signals (or noise floor) that arise from one or more of the following: (i) the spectral overlap between the backscattered excitation light and collected ICG fluorescence allowing nonfluorescent signals to be registered as fluorescence; (ii) a “blue shifting” of optical filters that allows passage of non-collimated, backscattered excitation light not normally incident on the filter surface, and (iii) the limited optical density of optical filters that allows passage of a small amount of ambient and excitation light that is still significant compared with the weak, collected ICG fluorescence.47 If light that does not originate from the fluorescent dye resident in the tissues is collected, then it represents the “noise floor” making it less probable that the device can image small quantities of a NIRF agent in tissues.
 

Currently, charge-coupled device (CCD) detectors are primarily used in ICG fluorescence imaging systems and depend upon integrating the collected photons over millisecond time frames. The CCD detectors used can be divided into (i) front- and back-illuminated CCDs (FCCDs and BCCDs), (ii) electron-multiplying CCDs (EMCCDs) and (iv) intensified CCDs (ICCD), including front- and back- illuminated ICCD based on their configurations. Most imaging systems employed in humans use either FCCD or BCCDs. FCCDs are constructed in a fashion similar to the human eye by orienting polysilicon gates at the front, wiring in the middle and photodiodes for light collection at the back. This configuration blocks incident light from reaching the photodiodes resulting in relatively low QE. BCCDs contain the same elements, but by rearranging the gate structure to the back of the photosensitive area of the CCDs and by reducing the thickness of the silicon layer via proprietary etching techniques, BCCDs have more than two-fold improvement in QE than do their front-illuminated counterparts. Unlike a conventional CCD, an EMCCD has an additional electron-emitting register installed between the normal serial register and the output amplifier to multiply weak signals. The EM register is split up into several hundred stages, and each stage acts as an avalanche diode to multiply the signal. The degree of multiplication gain can be controlled by varying the clock voltages applied to the EM register.
 

Lymph node mapping for identification of tumour draining lymph nodes for resection and subsequent pathological application in many cancers is commonly performed intraoperatively using blue dyes and/or transcutaneously and intraoperatively with non-specific technetium-99m (99mTc) radiocolloid. While emerging technologies employ i.v. administration of ultrasmall superparamagnetic iron oxide particle48 and intradermally administered radiolabelled mannose sugar, tilmanocept,49 intradermal and subcutaneous administration of ICG to locate draining lymph nodes represents an emerging area in nodal staging. The primary advantages of using a radiolabelled fluorescent molecule or NIR active compound is the direct relationship between the regions of fluorescence emitted from tissue surfaces within the surgical FOV.  
 

It is first utilized the fluorescence properties of ICG for SLN detection in patients with early breast cancer using the PDE prototype device using 25mg of ICG in 5ml of water. Intraoperatively, sentinel nodes were found by visually following the green-stained lymphatic vessels to the first-draining SLNs that were fluorescent. 
 

NIRF imaging has been used to characterize lymphoedema of the upper and lower extremities using both PDE2,and FDPM devices.Interpretation of NIRF images include aberrant lymphatic vasculature as seen comparatively to normal lymphatic vasculature.  
 

TaTME is a relatively new procedure50 for the curative resection of rectal tumors. It was developed to overcome the difficult dissection at the lower third of the rectum, especially in obese male patients and/or bulky tumors. Some retrospective series have reported that enhanced visualization of the dissection plane allowed better nerve preservation, improved resection margins, and improved functional outcomes compared with laparoscopic TME.51-52 However, the bottom-up transanal approach is not without complications. Incidence of iatrogenic urethral injuries has been reported, ranging from 1% to 6.7% during TaTME procedures. An international inquiry reported 34 urethral injuries from 32 surgical teams worldwide between 2010 and 2017, resulting in a significant postoperative morbidity rate of 26%. However, there is still concern that urologic injuries during TaTME may be underreported and that their incidence might be related to surgeon experience. Therefore, enhancement of urethral visualization should be considered useful and advantageous in the early learning experience. Several bioimaging modalities exist that can improve urethral identification, including ICG NIR fluorescence. Different systems have been successfully used to detect the urethra by ICG fluorescence imaging such as the IRIS ureteral kit or the PINPOINT laparoscopic system with intraurethral ICG injection or infiltration adjacent to the catheter in the urethra, respectively. Experimental studies demonstrated that direct ICG instillation into the urethra or through a urine catheter for NIR fluorescence imaging seem to be easily applicable and clinically reproducible during TaTME. Although an open-label clinical feasibility study with intraoperative direct instillation of ICG into the urethra for low rectal cancers was terminated because of technique failures, implementation of the technique has been described by some authors. Barnes et al53 evaluated the efficacy of two novel methods in cadaveric models. In the first, ICG mixed with silicone was infiltrated into 10-Fr one-way Foley catheter and allowed to set for 1 wk. In the second, new preclinical IRDye 800BK was infiltrated directly into the urethra via the urethral meatus prior to dissection. Both methods were effective in identifying the fluorescence located only within the urethra. IRDye 800BK provided a greater depth of penetration than the ICG-silicone mix, suggesting it could be a more satisfactory alternative to ICG. In addition, Barberio et al demonstrated the superior brightness of nearinfrared coating of equipment (NICE) coated catheter compared with ICGbased solutions in cadaveric experiments by exhibiting a higher fluorescence intensity than urinary catheters filled with ICG. In conclusion, no final specific recommendations can be drawn from the clinical use of ICG fluorescence imaging to identify and prevent urethral injuries during TaTME procedures.
 

The incidence of iatrogenic urethral injuries (IUI) ranges from 0.24% to 1.95% in colorectal surgery, and rectal cancer is considered a risk factor for IUI because of the close proximity of the ureters to the dissection plane, similar to the risk with deep pelvic endometriosis.54-55 Despite its low incidence, IUI significantly affects postoperative morbidity, mortality, length of stay and hospital charges. Visualization of the ureters is thus advocated during pelvic surgery by the visible peristalsis that occurs when the ureter is gently pressed (Kelly’s sign). However, adhesions, obesity, and an incorrect plane of dissection contribute to the lack of or incorrect recognition of the ureter, which can jeopardize its integrity. For that reason, a selective use of prophylactic urethral stents in high risk procedures is commonly accepted, but there is no sufficient evidence to support a decrease in IUI or intraoperative identification. In that setting, interest in fluorescence imaging has been increasing over time. While contrasting results were found for intravenous administration of methylene blue dye to urethral detection in colorectal surgery, ICG FA proved to be a viable alternative to real-time ureter identification and IUI prevention. Before surgery, a 6-Fr catheter is placed into the urethral orifice by cystoscopy. As ICG binds to the proteins of the ureteric epithelium,56 a retrograde injection of 5 mg ICG diluted in 2 mL of distilled water is made, and infrared emission is captured by the filtered lens system and electronically converted into green color visualizing ureter location. The technique has proven to be safe and helpful to identify the ureter in several small case-series who underwent minimally invasive pelvic surgery. As a catheter insertion of only 1 cm is required, there is a lower risk of IUI during catheterization than during conventional endoscopic stenting procedures, thus avoiding additional cystoscopies to remove the catheter. Furthermore, ICG urethral instillation is less expensive than other fluorescence-based systems such as illuminated catheters.

White et al58 recently evaluated the safety and efficacy of intraurethral ICG FA along with any potential benefit related to the technique during colorectal robotic surgery. In their experience involving 16 patients, there were short procedure times, low morbidity, and reliable urethral identification and avoidance. The United States Food and Drug Administration approval of ICG is limited to intravenous use.59Therefore, disclosure of intraurethral off-label use would be needed. In contrast, new intravenous fluorescent dyes with renal clearance, such as fluorescein sodium and IRDye® 800-BK have been used in experimental models to test the penetration of fluorescence in the ureters, with promising results for surgical practice. Additionally, the formulation of ICG in a liposome-based delivery system allows its excretion in urine in animal models and seems a promising fluorophore solution. In conclusion, evidence supporting the use of intraurethral ICG instillation in order to improve intraoperative ureter detection is based on few noncomparative feasibility studies involving mixed pelvic surgeries. Despite the efficacy demonstrated in ordinary or complex situations, no study exclusively focused on rectal cancer resections exists to date. It remains to be proven whether this innovation significantly affects surgical procedures and provides clinical benefits by reducing IUI.
 

Lateral pelvic lymph node dissection (LLND) allows the removal of the nodal compartment along the common iliac, internal iliac, and obturator arteries. The lymphatic stations are considered a major cause of locoregional recurrence in rectal cancer and are treated with preoperative chemoradiotherapy and curative resection.60 While it is widely accepted to perform LLND in selected patients with rectal cancer and lateral lymph nodes that are clinically positive, the Japanese Society for Cancer of the Colon and Rectum guidelines recommend LLND even when lateral lymph node metastasis is not detected by preoperative or intraoperative diagnosis. Indeed, LLND is associated with a lower rate of local recurrence compared with TME alone despite no significant differences in either overall survival or local recurrence-free survival.61 As ICG fluorescence imaging has proven to be a useful tool for identifying lymphatic drainage in colorectal surger, ICG-enhanced NIR fluorescenceguided imaging has been used to improve the accuracy and the completeness of LLND. In such cases, ICG fluorescence imaging is carried out the injection of ICG dye into the submucosal layer on the distal side of the tumor through the anus immediately before surgery. In a comparative retrospective series of 42 mid and low rectal cancer patients, the ICG group experienced a significantly lower intraoperative blood loss and a larger number of harvested lateral pelvic lymph nodes. The use of ICG may improve the safety of LLND that is affected by the technical difficulties of the procedure, complicated pelvic wall anatomy, and the effects of preoperative radiation on the tissues. In that setting, real-time identification of lateral pelvic nodes could help to distinguish lymphatic tissue from vascular and nervous structures, thus avoiding postoperative genitourinary dysfunction and providing better surgical staging. However, evidence is still limited and additional studies are needed to address the real clinical advantages and standardization of this technique. 

A sentinel node (SN) is defined as the first node in the regional peritumoral area that drains the tumor. SN biopsy, in addition to conventional resection, may add clinically significant prognostic information in colorectal surgery. NIR laparoscopy with ICG mapping allowed easy intraoperative identification of mesocolic lymphatic drainage and SN during colorectal oncologic resections. Similarly Noura et al62 described the detection of SN by ICG with an NIR system in 25 patients who had no preoperative diagnosis of metastatic lateral pelvic lymph nodes. The success rate of detecting the lateral SN was 92%, and 100% concordance was observed between SN and dissected lateral lymph nodes status. That preliminary study highlighted the feasibility and reliability of lateral SN biopsy as a potential discriminator to perform LLND, but the sensitivity may be compromised by preoperative neoadjuvant chemoradiotherapy.
 

Several reports have described the intraoperative identification of colonic tumors by NIR with ICG fluorescence imaging, with satisfactory results[95-98]. Accurate identification of the location of colorectal tumors is crucial in minimally invasive surgery because of the lack of tactile perception, especially for cancer at an early stage because of its small size or location on a movable part of the colon. As for rectal cancer, precise tumor site localization allows achieving a clear and safe distal resection margin, which may affect not only oncological outcomes but also bowel function and quality of life. In that setting, endoscopic tattooing of rectal tumors, both with a high-definition fluorescence imaging system (Karl Storz GmbH & Co. KG, Tuttlingen, Germany) and the PINPOINT® endoscopic fluorescence imaging system (PINPOINT system; Novadaq Technologies Inc., Mississauga, ON, Canada), is feasible and has clinical advantages. In a comparative retrospective series, 342 patients scheduled for laparoscopic colorectal resection were enrolled after propensity score matching. The tumor was tattooed in 114 patients. In a subgroup analysis of 160 patients who underwent anterior resection, the tattooed group had a significantly shorter operative time (unlike right and left colectomy), less blood loss, and a shorter hospital stay than the non-tattooed group. In addition, Goo et al compared 200 tattooed colorectal cancer patients (44 rectal cancers) with 879 non-tattooed patients (300 rectal cancers) to evaluate the effect of preoperative colonoscopic tattooing with ICG on adequate lymph node harvest in colorectal cancer. They found that preoperative tattooing in T1 colorectal cancer significantly improved adequate lymph node harvest, with a higher number of retrieved lymph nodes in rectal cancer than in colon cancer.

Fluorescence technology to localize rectal tumors has been developed not only in the field of imaging systems, but also by ICG formulation. Fenestrated peritumoral capillaries and impaired lymphatic drainage delay the washout of large molecules from tumors, which has been described as the enhanced permeability and retention effect.65 The formulation of ICG as a liposomebased delivery system improved tumor-specific localization in experimental models, with the advantages of intravenous injection and better results than free ICG.66-67 Finally, there are limited data on the role of ICG in the detection of peritoneal carcinomatosis of colorectal origin. Cytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy is the only potentially curative option in patients with limited peritoneal metastases.68 Intraoperative injection of ICG seems a useful tool to identify peritoneal metastases and detect additional subclinical malignant peritoneal nodules, resulting in modification of the planned surgery in 29% of patients.  
 

In 2005, when Kitai et al. introduced fluorescence-guided surgery (FGS) for breast cancer sentinel node biopsy using indocyanine green (ICG), a new era of image-guided surgery69 was initiated. Some new systems can even merge these fluorescent images with white light images and help to better orientate intraoperatively. Currently, there are only five FGS contrast agents approved  for clinical use by the American Food and Drug Administration (FDA), as well as by European Medicines Agency (EMA), i.e., fluorescein, ICG, methylene blue, and 5-alanine.
 

In gynecologic malignancies, the concept of SNB is not new. Historically, vulvar cancer was one of the first malignancies for which this concept was evaluated. In endometrial cancer, the most common gynecologic malignancy, two randomized clinical trials investigated the efficacy of this technique. However, these trials did not support the hypothesis of improved survival after lymphadenectomy in the early stage of the disease.
 

Even though radiocolloid and blue dye are the most commonly used tracers for SNB in a majority of cancers based on a recent survey among American gynecologic oncologists, ICG was most commonly used for SNB in endometrial cancer (97.3% of the responders) and in cervical cancer (92.5%). The first application of ICG for the SNB procedure in endometrial cancer was published by Furukawa et al., in which fluorescent nodes were detected in 83% of patients, with all cases found bilaterally.72 No false-negative nodes were found. The first minimally invasive SNB in endometrial cancer was published by Rossi et al., with the detection of sentinel nodes in 85% of cases (17 patients).73 In 60% of cases, positive nodes were found bilaterally, with no false-negative cases. In a study that compared ICG with isosulfan blue (IB),  the nodes were found with the naked eye in 77% of cases with IB and in 97% of cases when using the fluorescent properties of ICG.  
 

The first experience in cervical cancer sentinel node biopsy using ICG was published by Crane et al., in which a mixture of ICG and patent blue was injected for lymph node staining.74 SNB fluorescence was observed in 60% of cases (6 patients). Once pelvic lymphadenectomy was performed, additional nodes (11 ones) showed fluorescence with one fluorescent node harboring metastases. No false-negative results were found, and SNBs were found bilaterally in half of the cases. The detection rate in tumors below 2 cm was 80% and only 40% in larger tumors. 

An application of this procedure in cervical cancer is of the highest importance since up to 20% of patients with early cervical cancer present with lymph node metastases. The accurate detection of nodal disease impacts 5-year survival, which decreases from 92 to 64% for those with lymph node metastases. The application of sentinel node biopsy may decrease the long-term morbidity rate related to lymphadenectomy that occurs in up to 20% of those undergoing the more radical procedure. 
 

The first description of an ICG use in vulvar cancer SNB was presented by Crane et al. in 10 patients and showed that this technique was feasible but only in patients with a BMI below 25 kg/m2. It was associated with limited penetration of fluorescence through extensive adipose tissue in the groin. This issue was also highlighted in a publication by Prader et al., in which the authors also found that in the group with BMI > 30 kg/m2, sentinel nodes were found in 93.3% of patients when radiocolloid was used and in 86.7% of patients in the ICG group. In a publication by Verbeek et al., if ICG was mixed with radiocolloid in 12 patients with early stage vulvar cancer, the detection rate of sentinel nodes was 100%
 

In the systematic review from 2019, 10 articles were analyzed with a detection rate of 90.3%. Concerning ICG and radiocolloid in seven ovarian cancer patients, the detection rate was 100%. In a series of five patients using only ICG, sentinel nodes were detected in all cases.
 

In this malignancy, only a case report presenting a successful sentinel node mapping in vaginal cancer is available. ICG was injected into the bilateral side of the tumor. Sentinel nodes were found bilaterally in the obturator fossa.
 

The issue of the injection site in uterine cancer or of the cervical injection in endometrial cancer is still debatable. Sentinel nodes might be visible using two fluorophores during the same operation. In a study by Laios et al., the fluorescence properties of methylene blue were used. Methylene blue and ICG were visible in two patients sharing common lymphatic structures no matter the injection site.77In one case, the lymph nodes were stained with both fluorophores. However, in the second case, the true positive para-aortic sentinel node was only stained with ICG after uterine fundus injection but not with MB after cervical injection. Similar multispectral fluorescence imaging during prostatectomy was proposed using fluorescein and ICG mixed with radiocolloid. Undoubtedly, multispectral image-guided surgery will soon be a perfect tool to differentiate anatomical structures from different fluorophores.  
 

Enhancements in surgical techniques that will help to improve oncologic outcomes are among the key objectives of any surgical research. Total mesorectal excision (TME) proposed by RJ Heald revolutionized the surgical technique for several cancers, as well as the concept of embryological planes. This led to an improved local control after rectal cancer surgery.78This idea was also adopted in other organ-specific surgical techniques. Embryologically based compartmental surgery was also proposed by Höckel et al., in the treatment of gynecologic cancer.
 

The concept of uterine transplantation is emerging, although it is still in its infancy period. During donor hysterectomy, normally, both uterine tubes are transected. In the case of pregnancy, the recipient of the uterus has to undergo an in vitro fertilization (IVF). It is hypothesized that transplantation made together with the uterine tubes may facilitate a spontaneous conception. In the study by Farag et al., they investigated ex vivo and in vivo relative fluorescence, as well as the fluorescence intensity ratio,79 using ICG angiography. Vascular perfusion for uterine tubes originates from uteroovarian vasculature alone. This is especially important since a less extensive dissection for bilateral arterial and veins is currently proposed during transplantation. Additionally, the authors found differences in the location of utero-ovarian vessels. The length of utero-ovarian vessels may also help with an easier re-anastomosis and a safer surgery. This study may pave the way for complex uterus and attached uterine tubes transplantation, based on a tailored separation of utero-ovarian vasculature with fluorescence guidance, and facilitate a spontaneous conception.
 

The surgical treatment of cervical cancer requires an extensive conventional radical hysterectomy, which is sometimes associated with a poor blood supply of the ureters postoperatively. This may lead to complex postoperative complications such as ischemic necrosis of the ureter, urinary fistula, or stenosis of the ureter. Possible prevention of such complications might be proposed by preserving the ureteral branch of the uterine artery. A report of two cases with ureteral branch-sparing hysterectomy was presented using fluorescence angiography for the identification of a ureteral branch Additionally, with this fluorescence angiography technique, the authors also evaluated the perfusion of the uterine artery and ureter. No postoperative complications related to the ureter vasculature were reported.
 

Vaginal cuff dehiscence represents a severe complication after hysterectomy. The implementation of robotic surgery increased the rate of this complication, with a rate of 0.6% for abdominal hysterectomy and up to 3.16% after robotic hysterectomy. Vaginal cuff angiography using ICG was performed after robotic hysterectomy in 20 patients. No difference in terms of vaginal cuff dehiscence prevention was observed for monopolar or ultrasonic devices. Only longer instrument activation times in the open cuff showed a decreased cuff perfusion. A similar study was performed for laparoscopic hysterectomy . The added value of ICG guidance to vaginal cuff angiography and flap reconstructing is improving the technique, as it is now used in daily practice. Then, another point is that it helps to decrease the morbidity rates.
 

 

Postoperative complications after bilateral groin lymphadenectomy is not a rare situation. However, a wound breakdown is a difficult complication to treat. In the literature, a case was reported with such a complication, and a pedunculated left anterolateral thigh flap was presented. A fluorescence angiography with ICG for flap viability was performed without any further complications associated with flap healing. Two months after the operation, the patient received radiotherapy. 
 

From a surgical standpoint, the key to successful uterus transplantation is the quality of vascular anastomoses. An occlusion of anastomoses is complex and might be associated with inadequate anticoagulation, poor graft fixation, low immunosuppression, inadequate surgical technique, patient’s age, and mutations associated with venous thromboembolism. Kengelbach et al. used different techniques in a sheep model for intraoperative and postoperative blood flow measurements using ICG, as well as Doppler flowmetry.
 

Trachelectomy is performed in early stage cervical cancer among patients desiring future fertility. There is some extensive literature evidence regarding its safety, as well as good outcomes associated with 16 to 23% of the pregnancy rate. However, one of the questions associated with surgical steps is the preservation of the uterine artery during this operation. In the group of 20 patients, half of them underwent uterine artery sparing trachelectomy, and the second half, uterine n