Minimally Invasive transCervical oEsophagectomy (MICE) for oesophageal cancer: prospective cohort study (IDEAL stage 2A).

BACKGROUND: Minimally invasive transcervical oesophagectomy is a surgical technique that offers radical oesophagectomy without the need for transthoracic access. The aim of this study was to evaluate the safety and feasibility of the minimally invasive transcervical oesophagectomy procedure and to report the refinement of this technique in a Western cohort. METHODS: A single-centre prospective cohort study was designed as an IDEAL stage 2A study. Patients with oesophageal cancer (cT1b-4a N0-3 M0) who were scheduled for oesophagectomy with curative intent were eligible for inclusion in the study. The main outcome parameter was the postoperative pulmonary complication rate and the secondary outcomes were the anastomotic leakage, recurrent laryngeal nerve palsy, and R0 resection rates, as well as the lymph node yield. RESULTS: In total, 75 patients underwent minimally invasive transcervical oesophagectomy between January 2021 and November 2023. Several modifications to the surgical technique were registered, evaluated, and implemented in the context of IDEAL stage 2A. A total of 12 patients (16%) had postoperative pulmonary complications, including pneumonia (4 patients) and pleural effusion with drainage or aspiration (8 patients). Recurrent laryngeal nerve palsy was observed in 33 of 75 patients (44%), with recovery in 30 of 33 patients (91%). A total of 5 of 75 patients (7%) had anastomotic leakage. The median number of resected lymph nodes was 29 (interquartile range 22-37) and the R0 resection rate was 96% (72 patients). CONCLUSION: Introducing minimally invasive transcervical oesophagectomy for oesophageal cancer in a Dutch institution is associated with a low rate of postoperative pulmonary complications and a high rate of temporary recurrent laryngeal nerve palsy.

Intraoperative molecular imaging of colorectal lung metastases with SGM-101: a feasibility study.

PURPOSE: Metastasectomy is a common treatment option for patients with colorectal lung metastases (CLM). Challenges exist with margin assessment and identification of small nodules, especially during minimally invasive surgery. Intraoperative fluorescence imaging has the potential to overcome these challenges. The aim of this study was to assess feasibility of targeting CLM with the carcinoembryonic antigen (CEA) specific fluorescent tracer SGM-101. METHODS: This was a prospective, open-label feasibility study. The primary outcome was the number of CLM that showed a true positive fluorescence signal with SGM-101. Fluorescence positive signal was defined as a signal-to-background ratio (SBR) ≥ 1.5. A secondary endpoint was the CEA expression in the colorectal lung metastases, assessed with the immunohistochemistry, and scored by the total immunostaining score. RESULTS: Thirteen patients were included in this study. Positive fluorescence signal with in vivo, back table, and closed-field bread loaf imaging was observed in 31%, 45%, and 94% of the tumors respectively. Median SBRs for the three imaging modalities were 1.00 (IQR: 1.00-1.53), 1.45 (IQR: 1.00-1.89), and 4.81 (IQR: 2.70-7.41). All tumor lesions had a maximum total immunostaining score for CEA expression of 12/12. CONCLUSION: This study demonstrated the potential of fluorescence imaging of CLM with SGM-101. CEA expression was observed in all tumors, and closed-field imaging showed excellent CEA specific targeting of the tracer to the tumor nodules. The full potential of SGM-101 for in vivo detection of the tracer can be achieved with improved minimal invasive imaging systems and optimal patient selection. TRIAL REGISTRATION: The study was registered in ClinicalTrial.gov under identifier NCT04737213 at February 2021.

Quantification of indocyanine green near-infrared fluorescence bowel perfusion assessment in colorectal surgery.

BACKGROUND: Indocyanine green near-infrared fluorescence bowel perfusion assessment has shown its potential benefit in preventing anastomotic leakage. However, the surgeon's subjective visual interpretation of the fluorescence signal limits the validity and reproducibility of the technique. Therefore, this study aimed to identify objective quantified bowel perfusion patterns in patients undergoing colorectal surgery using a standardized imaging protocol. METHOD: A standardized fluorescence video was recorded. Postoperatively, the fluorescence videos were quantified by drawing contiguous region of interests (ROIs) on the bowel. For each ROI, a time-intensity curve was plotted from which perfusion parameters (n = 10) were derived and analyzed. Furthermore, the inter-observer agreement of the surgeon's subjective interpretation of the fluorescence signal was assessed. RESULTS: Twenty patients who underwent colorectal surgery were included in the study. Based on the quantified time-intensity curves, three different perfusion patterns were identified. Similar for both the ileum and colon, perfusion pattern 1 had a steep inflow that reached its peak fluorescence intensity rapidly, followed by a steep outflow. Perfusion pattern 2 had a relatively flat outflow slope immediately followed by its plateau phase. Perfusion pattern 3 only reached its peak fluorescence intensity after 3 min with a slow inflow gradient preceding it. The inter-observer agreement was poor-moderate (Intraclass Correlation Coefficient (ICC): 0.378, 95% CI 0.210-0.579). CONCLUSION: This study showed that quantification of bowel perfusion is a feasible method to differentiate between different perfusion patterns. In addition, the poor-moderate inter-observer agreement of the subjective interpretation of the fluorescence signal between surgeons emphasizes the need for objective quantification.

Robot-assisted thoracic surgery for stages IIB-IVA non-small cell lung cancer: retrospective study of feasibility and outcome.

Robot-assisted thoracic surgery (RATS) for higher stages non-small cell lung carcinoma (NSCLC) remains controversial. This study reports the feasibility of RATS in patients with stages IIB-IVA NSCLC. A single-institute, retrospective study was conducted with patients undergoing RATS for stages IIB-IVA NSCLC, from January 2015 until January 2020. Unforeseen N2 disease was excluded. Data were collected from the Dutch Lung Cancer Audit database. Conversion rate, radical (R0) resection rate, local recurrence rate and complications were analyzed, as were risk factors for conversion. RATS was performed in 95 patients with NSCLC clinical or pathological stages IIB (N = 51), IIIA (N = 39), IIIB (N = 2) and IVA (N = 3). 10.5% had received neoadjuvant chemoradiotherapy. Pathological staging was T3 in 33.7% and T4 in 34.7%. RATS was completed in 77.9% with a radical resection rate of 94.8%. Lobectomy was performed in 67.4% of the total resections. Conversion was for strategic (18.9%) and emergency (3.2%) reasons. Pneumonectomy (p = 0.001), squamous cell carcinoma (p < 0.001), additional resection of adjacent structures (p = 0.025) and neoadjuvant chemoradiation (p = 0.017) were independent risk factors for conversion. Major post-operative complications occurred in ten patients (10.5%) including an in-hospital mortality of 2.1% (n = 2). Median recurrence-free survival was estimated at 39.4 months (CI 16.4-62.5). Two- and 5-year recurrence-free survival rates were 53.8% and 36.7%, respectively. This study concludes that RATS is safe and feasible in higher staged NSCLC tumors after exclusion of unforeseen N2 disease. It brings new perspective on the potential of RATS in higher stages, dealing with larger and more invasive tumors.

Data-Driven Identification of Targets for Fluorescence-Guided Surgery in Non-Small Cell Lung Cancer.

PURPOSE: Intraoperative identification of lung tumors can be challenging. Tumor-targeted fluorescence-guided surgery can provide surgeons with a tool for real-time intraoperative tumor detection. This study evaluated cell surface biomarkers, partially selected via data-driven selection software, as potential targets for fluorescence-guided surgery in non-small cell lung cancers: adenocarcinomas (ADC), adenocarcinomas in situ (AIS), and squamous cell carcinomas (SCC). PROCEDURES: Formalin-fixed paraffin-embedded tissue slides of resection specimens from 15 patients with ADC and 15 patients with SCC were used and compared to healthy tissue. Molecular targets were selected based on two strategies: (1) a data-driven selection using > 275 multi-omics databases, literature, and experimental evidence; and (2) the availability of a fluorescent targeting ligand in advanced stages of clinical development. The selected targets were carbonic anhydrase 9 (CAIX), collagen type XVII alpha 1 chain (collagen XVII), glucose transporter 1 (GLUT1), G protein-coupled receptor 87 (GPR87), transmembrane protease serine 4 (TMPRSS4), carcinoembryonic antigen (CEA), epithelial cell adhesion molecule (EpCAM), folate receptor alpha (FRα), integrin αvß6 (αvß6), and urokinase-type plasminogen activator receptor (uPAR). Tumor expression of these targets was assessed by immunohistochemical staining. A total immunostaining score (TIS, range 0-12), combining the percentage and intensity of stained cells, was calculated. The most promising targets in ADC were explored in six AIS tissue slides to explore its potential in non-palpable lesions. RESULTS: Statistically significant differences in TIS between healthy lung and tumor tissue for ADC samples were found for CEA, EpCAM, FRα, αvß6, CAIX, collagen XVII, GLUT-1, and TMPRSS4, and of these, CEA, CAIX, and collagen XVII were also found in AIS. For SCC, EpCAM, uPAR, CAIX, collagen XVII, and GLUT-1 were found to be overexpressed. CONCLUSIONS: EpCAM, CAIX, and Collagen XVII were identified using concomitant use of data-driven selection software and clinical evidence as promising targets for intraoperative fluorescence imaging for both major subtypes of non-small cell lung carcinomas.

Use of fluorescence imaging and indocyanine green during laparoscopic cholecystectomy: Results of an international Delphi survey.

BACKGROUND: Published empirical data have increasingly suggested that using near-infrared fluorescence cholangiography during laparoscopic cholecystectomy markedly increases biliary anatomy visualization. The technology is rapidly evolving, and different equipment and doses may be used. We aimed to identify areas of consensus and nonconsensus in the use of incisionless near-infrared fluorescent cholangiography during laparoscopic cholecystectomy. METHODS: A 2-round Delphi survey was conducted among 28 international experts in minimally invasive surgery and near-infrared fluorescent cholangiography in 2020, during which respondents voted on 62 statements on patient preparation and contraindications (n = 12); on indocyanine green administration (n = 14); on potential advantages and uses of near-infrared fluorescent cholangiography (n = 18); comparing near-infrared fluorescent cholangiography with intraoperative x-ray cholangiography (n = 7); and on potential disadvantages of and required training for near-infrared fluorescent cholangiography (n = 11). RESULTS: Expert consensus strongly supports near-infrared fluorescent cholangiography superiority over white light for the visualization of biliary structures and reduction of laparoscopic cholecystectomy risks. It also offers other advantages like enhancing anatomic visualization in obese patients and those with moderate to severe inflammation. Regarding indocyanine green administration, consensus was reached that dosing should be on a milligrams/kilogram basis, rather than as an absolute dose, and that doses >0.05 mg/kg are necessary. Although there is no consensus on the optimum preoperative timing of indocyanine green injections, the majority of participants consider it important to administer indocyanine green at least 45 minutes before the procedure to decrease the light intensity of the liver. CONCLUSION: Near-infrared fluorescent cholangiography experts strongly agree on its effectiveness and safety during laparoscopic cholecystectomy and that it should be used routinely, but further research is necessary to establish optimum timing and doses for indocyanine green.

Near-Infrared Fluorescence Tumor-Targeted Imaging in Lung Cancer: A Systematic Review.

Lung cancer is the most common cancer type worldwide, with non-small cell lung cancer (NSCLC) being the most common subtype. Non-disseminated NSCLC is mainly treated with surgical resection. The intraoperative detection of lung cancer can be challenging, since small and deeply located pulmonary nodules can be invisible under white light. Due to the increasing use of minimally invasive surgical techniques, tactile information is often reduced. Therefore, several intraoperative imaging techniques have been tested to localize pulmonary nodules, of which near-infrared (NIR) fluorescence is an emerging modality. In this systematic review, the available literature on fluorescence imaging of lung cancers is presented, which shows that NIR fluorescence-guided lung surgery has the potential to identify the tumor during surgery, detect additional lesions and prevent tumor-positive resection margins.

Fluorescence-guided surgery in colorectal cancer; A review on clinical results and future perspectives.

BACKGROUND: Colorectal cancer is the fourth most diagnosed malignancy worldwide and surgery is one of the cornerstones of the treatment strategy. Near-infrared (NIR) fluorescence imaging is a new and upcoming technique, which uses an NIR fluorescent agent combined with a specialised camera that can detect light in the NIR range. It aims for more precise surgery with improved oncological outcomes and a reduction in complications by improving discrimination between different structures. METHODS: A systematic search was conducted in the Embase, Medline and Cochrane databases with search terms corresponding to 'fluorescence-guided surgery', 'colorectal surgery', and 'colorectal cancer' to identify all relevant trials. RESULTS: The following clinical applications of fluorescence guided surgery for colorectal cancer were identified and discussed: (1) tumour imaging, (2) sentinel lymph node imaging, (3) imaging of distant metastases, (4) imaging of vital structures, (5) imaging of perfusion. Both experimental and FDA/EMA approved fluorescent agents are debated. Furthermore, promising future modalities are discussed. CONCLUSION: Fluorescence-guided surgery for colorectal cancer is a rapidly evolving field. The first studies show additional value of this technique regarding change in surgical management. Future trials should focus on patient related outcomes such as complication rates, disease free survival, and overall survival.

Fundamentals and developments in fluorescence-guided cancer surgery.

Fluorescence-guided surgery using tumour-targeted imaging agents has emerged over the past decade as a promising and effective method of intraoperative cancer detection. An impressive number of fluorescently labelled antibodies, peptides, particles and other molecules related to cancer hallmarks have been developed for the illumination of target lesions. New approaches are being implemented to translate these imaging agents into the clinic, although only a few have made it past early-phase clinical trials. For this translational process to succeed, target selection, imaging agents and their related detection systems and clinical implementation have to operate in perfect harmony to enable real-time intraoperative visualization that can benefit patients. Herein, we review key aspects of this imaging cascade and focus on imaging approaches and methods that have helped to shed new light onto the field of intraoperative fluorescence-guided cancer surgery with the singular goal of improving patient outcomes.

The ESSO core curriculum committee update on surgical oncology.

INTRODUCTION: Surgical oncology is a defined specialty within the European Board of Surgery within the European Union of Medical Specialists (UEMS). Variation in training and specialization still occurs across Europe. There is a need to align the core knowledge needed to fulfil the criteria across subspecialities in surgical oncology. MATERIAL AND METHODS: The core curriculum, established in 2013, was developed with contributions from expert advisors from within the European Society of Surgical Oncology (ESSO), European Society for Radiotherapy and Oncology (ESTRO) and European Society of Medical Oncology (ESMO) and related subspeciality experts. RESULTS: The current version reiterates and updates the core curriculum structure needed for current and future candidates who plans to train for and eventually sit the European fellowship exam for the European Board of Surgery in Surgical Oncology. The content included is not intended to be exhaustive but, rather to give the candidate an idea of expectations and areas for in depth study, in addition to the practical requirements. The five elements included are: Basic principles of oncology; Disease site specific oncology; Generic clinical skills; Training recommendations, and, lastly; Eligibility for the EBSQ exam in Surgical Oncology. CONCLUSIONS: As evidence-based care for cancer patients evolves through research into basic science, translational research and clinical trials, the core curriculum will evolve, mature and adapt to deliver continual improvements in cancer outcomes for patients.

Intraoperative near-infrared fluorescence imaging of parathyroid adenomas with use of low-dose methylene blue.

BACKGROUND: Intraoperative identification of parathyroid adenomas can be challenging. We hypothesized that low-doses methylene blue (MB) and near-infrared fluorescence (NIRF) imaging could be used to identify parathyroid adenomas intraoperatively. METHODS: MB was injected intravenously after exploration at a dose of 0.5 mg/kg into 12 patients who underwent parathyroid surgery. NIRF imaging was performed using the Mini-FLARE imaging system. RESULTS: In 10 of 12 patients, histology confirmed a parathyroid adenoma. In 9 of these patients, NIRF could clearly identify the parathyroid adenoma during surgery. Seven of these 9 patients had a positive preoperative (99m) Tc-sestamibi single photon emission CT (SPECT) scan. Importantly, in 2 patients, parathyroid adenomas could be identified only using NIRF. CONCLUSION: This is the first study to show that low-dose MB can be used as NIRF tracer for identification of parathyroid adenomas, and suggests a correlation with preoperative (99m) Tc-sestamibi SPECT scanning.

Image-guided cancer surgery using near-infrared fluorescence.

Paradigm shifts in surgery arise when surgeons are empowered to perform surgery faster, better and less expensively than current standards. Optical imaging that exploits invisible near-infrared (NIR) fluorescent light (700-900 nm) has the potential to improve cancer surgery outcomes, minimize the time patients are under anaesthesia and lower health-care costs largely by way of its improved contrast and depth of tissue penetration relative to visible light. Accordingly, the past few years have witnessed an explosion of proof-of-concept clinical trials in the field. In this Review, we introduce the concept of NIR fluorescence imaging for cancer surgery, examine the clinical trial literature to date and outline the key issues pertaining to imaging system and contrast agent optimization. Although NIR seems to be superior to many traditional imaging techniques, its incorporation into routine care of patients with cancer depends on rigorous clinical trials and validation studies.

Near-infrared fluorescence-guided resection of colorectal liver metastases.

BACKGROUND: The fundamental principle of oncologic surgery is the complete resection of malignant cells. However, small tumors are often difficult to find during surgery using conventional techniques. The objectives of this study were to determine if optical imaging, using a contrast agent already approved for other indications, could improve hepatic metastasectomy with curative intent, to optimize dose and timing, and to determine the mechanism of contrast agent accumulation. METHODS: The high tissue penetration of near-infrared (NIR) light was exploited by use of the FLARE (Fluorescence-Assisted Resection and Exploration) image-guided surgery system and the NIR fluorophore indocyanine green in a clinical trial of 40 patients undergoing hepatic resection for colorectal cancer metastases. RESULTS: A total of 71 superficially located (< 6.2 mm beneath the liver capsule) colorectal liver metastases were identified and resected using NIR fluorescence imaging. Median tumor-to-liver ratio was 7.0 (range, 1.9-18.7) and no significant differences between time points or doses were found. Indocyanine green fluorescence was seen as a rim around the tumor, which is shown to be entrapment around cytokeratin 7-positive hepatocytes compressed by the tumor. Importantly, in 5 of 40 patients (12.5%, 95% confidence interval = 5.0-26.6), additional small and superficially located lesions were detected using NIR fluorescence, and were otherwise undetectable by preoperative computed tomography, intraoperative ultrasound, visual inspection, and palpation. CONCLUSIONS: NIR fluorescence imaging, even when used with a nontargeted, clinically available NIR fluorophore, is complementary to conventional imaging and able to identify missed lesions by other modalities.

Ex vivo sentinel node mapping in colon cancer combining blue dye staining and fluorescence imaging.

BACKGROUND: The sentinel lymph node procedure has been proposed to improve nodal staging in colon cancer patients. The aim of this study was to assess the added value of near-infrared (NIR) fluorescence imaging to conventional blue dye staining for ex vivo sentinel lymph node mapping. MATERIALS AND METHODS: We included 22 consecutive patients undergoing surgery for colon cancer. After tumor resection, we submucosally injected a premixed cocktail of the near-infrared lymphatic tracer HSA800 and blue dye around the tumor for detection of sentinel lymph nodes. We used the Mini-FLARE imaging system for fluorescence imaging. RESULTS: In 95% of patients, we identified at least one sentinel lymph node. Overall, a total of 77 sentinel lymph nodes were identified, 77 of which were fluorescent (100%) and 70 of which were blue (91%). Sentinel lymph nodes that were located deeper in the mesenteric fat could easily be located by NIR fluorescence. In four of five patients with lymph node metastases, tumor cells were present in at least one of the sentinel lymph nodes. CONCLUSIONS: This study shows the successful use and added value of the NIR fluorescence tracer HSA800 to conventional blue dye for the ex vivo sentinel lymph node procedure in colon cancer.

Near-infrared fluorescence sentinel lymph node mapping of the oral cavity in head and neck cancer patients.

OBJECTIVES: Elective neck dissection is frequently performed during surgery in head and neck cancer patients. The sentinel lymph node (SLN) procedure can prevent the morbidity of a neck dissection and improve lymph node staging by fine pathology. Near-infrared (NIR) fluorescence imaging is a promising technique to identify the sentinel lymph node (SLN) intraoperatively. This feasibility study explored the use of indocyanine green adsorbed to human serum albumin (ICG:HSA) for SLN mapping in head and neck cancer patients. MATERIALS AND METHODS: A total of 10 consecutive patients with oral cavity or oropharyngeal cancer and a clinical N0 neck were included. After exposure of the neck, 1.6 mL of ICG:HSA (500 µM) was injected at four quadrants around the tumor. During the neck dissection, levels I-IV were measured for fluorescence using the Mini-FLARE imaging system. RESULTS: In all 10 patients, NIR fluorescence imaging enabled visualization of one or more SLNs. A total of 17 SLNs were identified. The mean contrast between the fluorescent signal of the lymph nodes and of the surrounding tissue was 8.7±6.4. In 3 patients, of which 1 was false-negative, lymph node metastases were found. After administration of ICG:HSA, the average number of fluorescent lymph nodes significantly increased over time (P<0.001). CONCLUSION: This study demonstrated feasibility to detect draining lymph nodes in head and neck cancer patients using NIR fluorescence imaging. However, the fluorescent tracer quickly migrated beyond the SLN to higher tier nodes.

Intraoperative prediction of postoperative flap outcome using the near-infrared fluorophore methylene blue.

Methylene blue (MB) is a near-infrared fluorophore that provides a stable visual map of skin perfusion after intravenous injection. We explored the capability of MB to predict submental flap postoperative outcome using a single intraoperative measurement. Submental flaps were created in N = 15 pigs and imaged using the FLARE imaging system immediately after surgery and at 72 hours. Using the first 3 pigs, optimal MB dosing was found to be 2.0 mg/kg. Training and validation sets of 6 pigs each were then used for receiver operating characteristic analysis. In the training set, a contrast-to-background ratio (CBR) threshold of 1.24 provided the highest sensitivity and specificity to predict tissue necrosis at 72 hours. In the validation set, this threshold provided a prediction sensitivity of 95.3% and a specificity of 98.0%. We demonstrate that a single intraoperative near-infrared measurement can predict submental flap outcome at 72 hours.

Quantitative assessment of nipple perfusion with near-infrared fluorescence imaging.

Preserving the nipple-areolar complex with a nipple-sparing mastectomy improves cosmesis compared with skin-sparing mastectomy. However, complications such as necrosis of the nipple-areolar complex significantly affect cosmetic outcome. Many factors influence nipple-areolar perfusion, and no consensus currently exists on optimal incisional choice. This study evaluates 2 nipple-sparing mastectomy incision models using near-infrared fluorescence to assess perfusion quantitatively. The periareolar and radial incisions were compared with 2 control models in Yorkshire pigs (N = 6). Methylene blue and indocyanine green were injected intravenously, and near-infrared fluorescence images were recorded at 3 time points: before surgery, immediately after (0 hour), and 3 days postoperatively. Contrast-to-background ratio was used to assess perfusion. At 72 hours, radial incisions showed a statistically significantly higher perfusion compared with periareolar incisions (P < 0.05). Based on our findings, radial incisions for nipple-sparing mastectomy may be preferable due to higher perfusion; however, clinical trials are necessary for further assessment.

Simultaneous assessment of luminal integrity and vascular perfusion of the gastrointestinal tract using dual-channel near-infrared fluorescence.

Anastomotic complications such as stenosis and leakage in the gastrointestinal (GI) tract can cause high patient morbidity and mortality. To identify the potential preconditions of these complications intraoperatively, we explored the use of two 700 nm near-infrared (NIR) fluorophores administered intraluminally: (1) chlorella, an over-the-counter herbal supplement containing high concentrations of chlorophyll, and (2) methylene blue (MB). In parallel, we administered the 800 nm NIR fluorophore indocyanine green (ICG) intravenously to assess vascular function. Dual-channel, real-time intraoperative imaging and quantitation of the contrast to background ratio (CBR) were performed under normal conditions or after anastomosis or leakage of the stomach and intestines in 35 kg Yorkshire pigs using the Fluorescence-Assisted Resection and Exploration (FLARE) imaging system. Luminal integrity could be assessed with relatively high sensitivity with either chlorella or MB, although chlorella provided significantly higher CBR. ICG angiography provided assessment of blood perfusion of normal, ischemic, and anastomotic areas of the GI tract. Used simultaneously, 700 nm (chlorella or MB) and 800 nm (ICG) NIR fluorescence permitted independent assessment of luminal integrity and vascular perfusion of the GI tract intraoperatively and in real time. This technology has the potential to identify critical complications, such as anastomotic leakage, intraoperatively, when correction is still possible.