Near-infrared Fluorescence Guidance Research Articles

Synergistic luminescent radicals and precursors as type-I photosensitizers for near-infrared fluorescence-guided tumor therapy

Near-infrared (NIR) fluorescence-guided photodynamic therapy (PDT) shows great potential as a cancer treatment modality. However, its application in solid tumors is limited by the scarcity of NIR molecules and the oxygen dependence of conventional photosensitizers. Here, two novel radical nanoparticles (TTM-3PDMAC:HTTM-3PDMAC@NPs and TTM-PDMAC:HTTM-PDMAC@NPs) are developed as type-I photosensitizers by combining luminescent radicals and their precursors. The unique encapsulation of these nanoparticles effectively addresses the limitations of radicals being insoluble and non-fluorescent in water, thus preserving the NIR emission of the radicals. Notably, the superoxide radicals generated by these nanoparticles upon light irradiation have been demonstrated to originate from both the radicals and their precursors. In vivo experiments demonstrated that TTM-3PDMAC:HTTM-3PDMAC@NPs exhibit significant efficacy in treating hypoxic tumor with minimal side effects. Overall, this PDT strategy based on synergistic combination of luminescent radicals and precursors provides novel insights for achieving accurate and efficient PDT under NIR fluorescence guidance.

ASO Visual Abstract: A Novel Injection Protocol Using Voluven®-Assisted Indocyanine Green with Improved Near-Infrared Fluorescence Guidance in Breast Cancer Sentinel Lymph Node Mapping: A Translational Study.

ASO Visual Abstract: A Novel Injection Protocol Using Voluven®-Assisted Indocyanine Green with Improved Near-Infrared Fluorescence Guidance in Breast Cancer Sentinel Lymph Node Mapping: A Translational Study.

A Novel Injection Protocol Using Voluven®-Assisted Indocyanine Green with Improved Near-Infrared Fluorescence Guidance in Breast Cancer Sentinel Lymph Node Mapping—A Translational Study

BackgroundNear-infrared (NIR) fluorescence-guided surgery with indocyanine green (ICG) has been demonstrated to provide high sensitivity in sentinel lymph node biopsy (SLNB) for breast cancer but has several limitations, such as unstable pharmacokinetics, limited fluorescence brightness, and undesired diffusion to neighboring tissues. This paper investigates the use of Voluven® as the solvent for ICG fluorescence-guided SLNB (ICG-SLNB).MethodsThe photophysical properties of ICG in water and Voluven® were evaluated in laboratory experiments and in a mouse model. Nine patients with early breast cancer underwent subareolar injection of diluted ICG (0.25 mg/ml) for ICG-SLNB. Six of the nine patients received ICG dissolved in Voluven® (ICG:Voluven®), while three were administered ICG dissolved in water (ICG:water); a repetitive injection-observation protocol was followed for all patients. The mapping image quality was evaluated.ResultsLaboratory experiments and in vivo mouse study showed improved fluorescence and better targeting using Voluven® as the solvent. ICG-SLNB with a repetitive injection-observation protocol was successfully performed in all nine patients. ICG:Voluven® administration had an overall better signal-to-background ratio (SBR) in sequential sentinel lymph nodes. The rates of transportation within the lymphatics were also improved using ICG:Voluven® compared with ICG:water.ConclusionsFrom basic research to animal models to in-human trial, our study proposes a repetitive injection-observation technique with ICG:Voluven®, which is characterized by better transportation and more stable mapping quality for ICG-SLNB in breast cancer patients.

Superiority of indocyanine green-enhanced near-infrared fluorescence-guided imaging for laparoscopic lymph node dissection in patients with early-stage endometrial cancer: A retrospective cohort study

ObjectiveLaparoscopic pelvic lymph node dissection (LPND), which is an effective therapy for endometrial cancer, is challenging because of the complexity of the procedure and the occurrence of postoperative complications. This study aimed to explore whether indocyanine green (ICG)-enhanced near-infrared (NIR) fluorescence-guided LPND is superior to LPND in the context of early-stage endometrial carcinoma. MethodsIn this retrospective study, we included the medical records of 190 patients with early-stage endometrioid adenocarcinoma who underwent LPND at the Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine between January 2019 and January 2021. Depending on whether ICG-enhanced NIR fluorescence guidance was used, the patients were assigned to the ICG group or non-ICG group. Patients were followed-up for one year after surgery. Data on demographic characteristics, pathological results, operative outcomes, and complications were collected and analyzed. ResultsThe baseline characteristics were comparable between the ICG group and non-ICG group, including age, BMI, pregnancy history, and preoperative hemoglobin. For surgical outcomes, the patients in ICG group had significantly lower intraoperative blood loss (50 mL vs. 120 mL, p < 0.001), less postoperative pelvic drainage time (4.14 ± 1.44 d vs. 5.70 ± 1.89 d, p = 0.001), shorter duration of hospital stay (5.26 ± 1.41 d vs. 7.37 ± 1.85 d, p = 0.003), higher number of positive pelvic lymph nodes (PLNs) (1 vs. 0, p = 0.003), and more PLN-positive cases (16.0% vs. 3.6%, p = 0.003) than the patients in non-ICG group. However, no significant differences were noted in blood transfusion requirement, operative time, hemoglobin level decreases, number of PLNs harvested, or the presence of lymphocysts between the two groups. ConclusionOur study showed that ICG-enhanced NIR fluorescence-guided operation may improve the accuracy and safety of LPND.

Intraoperative Near-Infrared Fluorescence Guided Surgery Using Indocyanine Green (ICG) for the Resection of Sarcomas May Reduce the Positive Margin Rate: An Extended Case Series.

Simple SummarySarcomas are rare cancers that can arise all over the body, with many occurring in younger people. Treatment is usually based around surgery to remove the tumour. It is crucial to remove all of the tumour to minimise the chance of the tumour coming back. Currently, surgeons review scans of the tumour and plan the operation beforehand, but it can be difficult to relate the scans to what the surgeon sees during the operation. Currently, there are no established technologies to help them identify the tumour during the operation. Here we have given patients a harmless dye (indocyanine green) prior to the operation, which makes the tumour glow on a screen when seen by a camera during the operation, helping the surgeon to identify and remove the tumour. This resulted in the surgeon being able to remove all of the tumour more often, reducing the chances of it coming back.Background: Sarcomas are rare, aggressive cancers which can occur in any region of the body. Surgery is usually the cornerstone of curative treatment, with negative surgical margins associated with decreased local recurrence and improved overall survival. Indocyanine green (ICG) is a fluorescent dye which accumulates in sarcoma tissue and can be imaged intraoperatively using handheld near-infrared (NIR) cameras, theoretically helping guide the surgeon’s resection margins. Methods: Patients operated on between 20 February 2019 and 20 October 2021 for intermediate to high grade sarcomas at our centres received either conventional surgery, or were administered ICG pre-operatively followed by intra-operative NIR fluorescence guidance during the procedure. Differences between the unexpected positive margin rates were compared. Results: 115 suitable patients were identified, of which 39 received ICG + NIR fluorescence guided surgery, and 76 received conventional surgery. Of the patients given ICG, 37/39 tumours fluoresced, and surgeons felt the procedure was guided by the intra-operative images in 11 cases. Patients receiving ICG had a lower unexpected positive margin rate (5.1% vs. 25.0%, p = 0.01). Conclusions: The use of NIR fluorescence cameras in combination with ICG may reduce the unexpected positive margin rate for high grade sarcomas. A prospective, multi-centre randomised control trial is now needed to validate these results.

Technologic (R)Evolution Leads to Detection of More Sentinel Nodes in Patients with Melanoma in the Head and Neck Region.

Sentinel lymph node (SN) biopsy (SNB) has proven to be a valuable tool for staging melanoma patients. Since its introduction in the early 1990s, this procedure has undergone several technologic refinements, including the introduction of SPECT/CT, as well as radioguidance and fluorescence guidance. The purpose of the current study was to evaluate the effect of this technologic evolution on SNB in the head and neck region. The primary endpoint was the false-negative (FN) rate. Secondary endpoints were number of harvested SNs, overall operation time, operation time per harvested SN, and postoperative complications. Methods: A retrospective database was queried for cutaneous head and neck melanoma patients who underwent SNB at The Netherlands Cancer Institute between 1993 and 2016. The implementation of new detection techniques was divided into 4 groups: 1993-2005, with preoperative lymphoscintigraphy and intraoperative use of both a γ-ray detection probe and patent blue (n = 30); 2006-2007, with addition of preoperative road maps based on SPECT/CT (n = 15); 2008-2009, with intraoperative use of a portable γ-camera (n = 40); and 2010-2016, with addition of near-infrared fluorescence guidance (n = 192). Results: In total, 277 patients were included. At least 1 SN was identified in all patients. A tumor-positive SN was found in 59 patients (21.3%): 10 in group 1 (33.3%), 3 in group 2 (20.0%), 6 in group 3 (15.0%), and 40 in group 4 (20.8%). Regional recurrences in patients with tumor-negative SNs resulted in an overall FN rate of 11.9% (group 1, 16.7%; group 2, 0%; group 3, 14.3%; group 4, 11.1%). The number of harvested nodes increased with advancing technologies (P = 0.003), whereas Breslow thickness and operation time per harvested SN decreased (P = 0.003 and P = 0.017, respectively). There was no significant difference in percentage of tumor-positive SNs, overall operation time, and complication rate between the different groups. Conclusion: The use of advanced detection technologies led to a higher number of identified SNs without an increase in overall operation time, possibly indicating an improved surgical efficiency. Operation time per harvested SN decreased; the average FN rate remained 11.9% and was unchanged over 23 y. There was no significant change in postoperative complication rate.

Intraoperative Near-infrared Fluorescence (NIR) Imaging With Indocyanine Green (ICG) Can Identify Bone and Soft Tissue Sarcomas Which May Provide Guidance for Oncological Resection.

Complete excision of sarcomas to maximize function without compromising the oncological outcome can be challenging. The aim of this study was to investigate the feasibility and potential drawbacks of near-infrared (NIR) fluorescence imaging with indocyanine green during resection of bone and soft tissue sarcomas. Eleven patients with high-grade sarcomas were enrolled in the study. All patients received intravenous indocyanine green (75 mg) between 16 and 24 hours before the resection. Sarcomas were resected under NIR guidance and specimens were sent for routine histopathological analysis. Majority of treatment naive tumors demonstrated fluorescence. There were no adverse events from the indocyanine green administration. In 3 cases, the fluorescence was reported by the surgeon to have been of definite guidance leading to further tissue resection to improve the margin. This is the first report of NIR fluorescence guidance in the setting of open sarcoma surgery. The technique is acceptable to patients and surgeons and was able to guide resection. Multicenter studies are required to assess the utility of this technique in a large cohort of patients with regards to quantification of fluorescence, resection guidance, and longer follow-up period.

Sentinel lymph node biopsy in oral–oropharyngeal squamous cell carcinoma: standards, new technical procedures, and clinical advances

To provide substantial coverage and critical appraisal of standards as well as new technical procedures and clinical advances concerning sentinel lymph node biopsy (SNB) in oral squamous cell carcinoma (OSCC). The MEDLINE database was searched via the PubMed interface up to January 2019 for the following MeSH heading: “sentinel lymph node biopsy” and “squamous cell carcinoma of head and neck”. SNB exists as an alternative to elective neck dissection (END) in OSCC. Pre-surgical planar lymphoscintigraphy with intra-operative hand-held gamma probe allows using SNB. Furthermore, the contribution of pre-surgical SPECT/CT improves the sentinel lymph node (SLN) roadmap in sites that are closer to the injection site. Portable gamma camera and freehand SPECT are not yet routine clinical practice, but can further improve intra-operative SLN detection. However, the difficulty in detecting SLNs located closer to the injection site persists. SNB with combined radioactive and near-infrared fluorescence guidance is an attractive option for improving spatial resolution of radio-guided techniques while maintaining depth penetration. Numerous studies have demonstrated that SNB can be proposed for accurate histopathological staging of the neck and the guidelines support the introduction of SNB as an alternative to END in T1/T2 N0 OSCC patients. New hybrid imaging techniques, which are offering new possibilities to assist clinicians and surgeons in localizing the site of uptake in sentinel node detection, need to be confirmed in ongoing and future clinical trials. In the future, the integration of new PET tracers could continue along the route mapped out in SNB.

P1.16-008 Near-Infrared Fluorescence-Guided Pulmonary Segmentectomy Following Endobronchial Indocyanine Green Injection

Near infrared (NIR) fluorescence-guided pulmonary segmentectomy following endobronchial or intravenous indocyanine green (ICG) administration has been developed and reported. The aim of this study is to prospectively validate the feasibility and safety of NIR fluorescence-guided pulmonary segmentectomy following endobrochial ICG injection using navigational bronchoscopy. Patients who underwent pulmonary segmentectomy were prospectively enrolled in this study. Using preoperative CT datasets a 3D image of target segments was reconstructed for lung volumetry and a bronchial road map was created to determine the bronchus for ICG injection. The ICG concentration was 0.125 mg/mL. Immediately after intubation the ICG was injected into the target bronchi using an ultrathin bronchoscope followed by air flushing to expedite ICG dispersion to the periphery. A NIR thoracoscope (PINPOINT, Novadaq) was used to detect ICG fluorescence and determine intersegmental plane for pulmonary segmentectomy. Usefulness and safety of this technique were evaluated by 1) whether ICG demarcation lines correspond to intersegmental lines expected from pulmonary veins, 2) whether large bronchi and vessels in adjacent segments emerge when dividing intersegmental planes using electrical cautery. The patients were followed up to 1 month after surgery to see if any complication existed. Eight male and 7 female patients with a mean age of 66.5 ± 9.6 years were enrolled. Segmentectomy regions included right S1, S2, S6, S8 and S10 segments, and left S1+2+3, lingular, S6, S8, S9+10, and basilar segments. The average bronchoscopic procedure time was 14.3 ± 8.0 minutes. Vital signs were kept stable before and after the bronchoscopic procedure. The mean injected volume of ICG solution was 21.2 ± 8.8 mL as per a case. In 13 out of 15 cases (86.7%), NIR fluorescence guidance was recognized as effective for pulmonary segmentectomy. Intersegmental plane could not be determined in 2 cases likely due to insufficient air flushing, leading to the failure of ICG dispersion to the periphery. There were no complications developed intraoperatively. The average operation time was 193 ± 41 minutes, with a mean bleeding of 110 ± 101 mL. The average duration of drainage was 3.1 ± 1.0 days. Recurrent air leakage happened on postoperative day 6 in 1 case. Otherwise, no procedure related adverse event was noted. NIR fluorescence-guided pulmonary segmentectomy following endobrochial ICG injection using navigational bronchoscopy appeared to be safe and feasible. Sufficient air flushing may be the key for clear ICG demarcation of referred segments.

Laparoscopic detection and resection of occult liver tumors of multiple cancer types using real-time near-infrared fluorescence guidance

BackgroundTumor recurrence after radical resection of hepatic tumors is not uncommon, suggesting that malignant lesions are missed during surgery. Intraoperative navigation using fluorescence guidance is an innovative technique enabling real-time identification of (sub)capsular liver tumors. The objective of the current study was to compare fluorescence imaging (FI) and conventional imaging modalities for laparoscopic detection of both primary and metastatic tumors in the liver.MethodsPatients undergoing laparoscopic resection of a malignant hepatic tumor were eligible for inclusion. Patients received standard of care, including preoperative CT and/or MRI. In addition, 10 mg indocyanine green was intravenously administered 1 day prior to surgery. After introduction of the laparoscope, inspection, FI, and laparoscopic ultrasonography (LUS) were performed. Histopathological examination of resected suspect tissue was considered the gold standard.ResultsTwenty-two patients suspected of having hepatocellular carcinoma (n = 4), cholangiocarcinoma (n = 2) or liver metastases from colorectal carcinoma (n = 12), uveal melanoma (n = 2), and breast cancer (n = 2) were included. Two patients were excluded because their surgery was unexpectedly postponed several days. Twenty-six malignancies were resected in the remaining 20 patients. Sensitivity for various modalities was 80 % (CT), 84 % (MRI), 62 % (inspection), 86 % (LUS), and 92 % (FI), respectively. Three metastases (12 %) were identified solely by FI. All 26 malignancies could be detected by combining LUS and FI (100 % sensitivity).ConclusionThis study demonstrates added value of FI during laparoscopic resections of several hepatic tumors. Although larger series will be needed to confirm long-term patient outcome, the technology already aids the surgeon by providing real-time fluorescence guidance.

Intraoperative Identification of a Normal Pituitary Gland and an Adenoma Using Near-Infrared Fluorescence Imaging and Low-Dose Indocyanine Green.

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

Extra-luminal detection of assumed colonic tumor site by near-infrared laparoscopy.

Localization of colorectal tumors during laparoscopic surgery is generally performed by tattooing into the submucosal layer of the colon. However, faint and diffuse tattoos may lead to difficulties in recognizing cancer sites, resulting in inappropriate resection of the colon. We previously demonstrated that yttrium oxide nanoparticles doped with the rare earth ions (ytterbium and erbium) (YNP) showed strong near-infrared (NIR) emission under NIR excitation (1550nm emission with 980nm excitation). NIR light can penetrate deep tissues. In this study, we developed an NIR laparoscopy imaging system and demonstrated its use for accurate resection of the colon in swine. The NIR laparoscopy system consisted of an NIR laparoscope, NIR excitation laser diode, and an NIR camera. Endo-clips coated with YNP (NIR clip), silicon rubber including YNP (NIR silicon mass), and YNP solution (NIR ink) were prepared as test NIR markers. We used a swine model to detect an assumed colon cancer site using NIR laparoscopy, followed by laparoscopic resection. The NIR markers were fixed at an assumed cancer site within the colon by endoscopy. An NIR laparoscope was then introduced into the abdominal cavity through a laparoscopy port. NIR emission from the markers in the swine colon was successfully recognized using the NIR laparoscopy imaging system. The position of the markers in the colon could be identified. Accurate resection of the colon was performed successfully by laparoscopic surgery under NIR fluorescence guidance. The presence of the NIR markers within the extirpated colon was confirmed, indicating resection of the appropriate site. NIR laparoscopic surgery is useful for colorectal cancer site recognition and accurate resection using laparoscopic surgery.

Image-guided tumor resection using real-time near-infrared fluorescence in a syngeneic rat model of primary breast cancer

Tumor involvement of resection margins is found in a large proportion of patients who undergo breast-conserving surgery. Near-infrared (NIR) fluorescence imaging is an experimental technique to visualize cancer cells during surgery. To determine the accuracy of real-time NIR fluorescence imaging in obtaining tumor-free resection margins, a protease-activatable NIR fluorescence probe and an intraoperative camera system were used in the EMR86 orthotopic syngeneic breast cancer rat model. Influence of concentration, timing and number of tumor cells were tested in the MCR86 rat breast cancer cell line. These variables were significantly associated with NIR fluorescence probe activation. Dosing and tumor size were also significantly associated with fluorescence intensity in the EMR86 rat model, whereas time of imaging was not. Real-time NIR fluorescence guidance of tumor resection resulted in a complete resection of 17 out of 17 tumors with minimal excision of normal healthy tissue (mean minimum and a mean maximum tumor-free margin of 0.2 ± 0.2 mm and 1.3 ± 0.6 mm, respectively). Moreover, the technique enabled identification of remnant tumor tissue in the surgical cavity. Histological analysis revealed that the NIR fluorescence signal was highest at the invasive tumor border and in the stromal compartment of the tumor. In conclusion, NIR fluorescence detection of breast tumor margins was successful in a rat model. This study suggests that clinical introduction of intraoperative NIR fluorescence imaging has the potential to increase the number of complete tumor resections in breast cancer patients undergoing breast-conserving surgery.