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.

Conditional recurrence-free survival of clinical complete responders managed by watch and wait after neoadjuvant chemoradiotherapy for rectal cancer in the International Watch & Wait Database: a retrospective, international, multicentre registry study.

BACKGROUND: Watch and wait is a novel management strategy in patients with rectal cancer who have a clinical complete response after neoadjuvant chemoradiotherapy. Surveillance of these patients is generally intensive, because local regrowth (with the potential for salvage) occurs in 25% of patients, and distant metastases occur in 10% of patients. It is unclear for how long these patients should be followed up. To address this issue, we did conditional survival modelling using the International Watch & Wait Database (IWWD), which is a large-scale registry of patients with a clinical complete response after neoadjuvant chemotherapy who have been managed by a watch-and-wait strategy. METHODS: We did a retrospective, multicentre registry study using a dataset from the IWWD, which includes data from 47 clinics across 15 countries. We selected patients (aged ≥18 years) with rectal cancer who had a clinical complete response after neoadjuvant chemotherapy, and who were subsequently managed by a watch-and-wait strategy between Nov 25, 1991, and Dec 31, 2015. Patients who had not achieved a clinical complete response or who had undergone any surgical procedure were excluded. The criteria used for defining a clinical complete response and the specific surveillance strategies were at the discretion of each participating centre. We used conditional survival modelling to estimate the probability of patients remaining free of local regrowth or distant metastasis for an additional 2 years after sustaining a clinical complete response or being distant metastasis-free for 1, 3, and 5 years from the date of the decision to commence watch and wait. The primary outcomes were conditional local regrowth-free survival at 3 years, and conditional distant metastasis-free survival at 5 years. FINDINGS: We identified 793 patients in the IWWD with clinical complete response who had been managed by a watch-and-wait strategy. Median follow-up was 55·2 months (IQR 36·0-75·6). The probability of remaining free from local regrowth for an additional 2 years if a patient had a sustained clinical complete response for 1 year was 88·1% (95% CI 85·8-90·9), for 3 years was 97·3% (95·2-98·6), and for 5 years was 98·6% (97·6-100·0). The probably of remaining free from distant metastasis for a further 2 years in patients who had a clinical complete response without distant metastasis for 1 year was 93·8% (92·3-95·9), for 3 years was 97·8% (96·6-99·3), and for 5 years was 96·6% (94·0-98·9). INTERPRETATION: These results suggest that the intensity of active surveillance in patients with rectal cancer managed by a watch-and-wait approach could be reduced if they achieve and maintain a clinical complete response within the first 3 years of starting this approach. FUNDING: European Registration of Cancer Care, financed by the European Society of Surgical Oncology, the Champalimaud Foundation Lisbon, the Bas Mulder Award, granted by the Alpe d'HuZes Foundation and the Dutch Cancer Society, the European Research Council Advanced Grant, and the National Institute of Health and Research Manchester Biomedical Research Centre.

Dose-Finding Study of a CEA-Targeting Agent, SGM-101, for Intraoperative Fluorescence Imaging of Colorectal Cancer.

BACKGROUND: Carcinoembryonic antigen is overexpressed in colorectal cancer (CRC), making it an optimal target for fluorescence imaging. A phase I/II study was designed to determine the optimal imaging dose of SGM-101 for intraoperative fluorescence imaging of primary and recurrent CRC. METHODS: Patients were included and received a single dose of SGM-101 at least 24 h before surgery. Patients who received routine anticancer therapy (i.e., radiotherapy or chemotherapy) also were eligible. A dedicated near-infrared imaging system was used for real-time fluorescence imaging during surgery. Safety assessments were performed and SGM-101 efficacy was evaluated per dose level to determine the most optimal imaging dose. RESULTS: Thirty-seven patients with CRC were included in the analysis. Fluorescence was visible in all primary and recurrent tumors. In seven patients, no fluorescence was seen; all were confirmed as pathological complete responses after neoadjuvant therapy. Two tumors showed false-positive fluorescence. In the 37 patients, a total of 97 lesions were excised. The highest mean intraoperative tumor-to-background ratio (TBR) of 1.9 (p = 0.019) was seen in the 10-mg dose. This dose showed a sensitivity of 96%, specificity of 63%, and negative predictive value of 94%. Nine patients (24%) had a surgical plan alteration based on fluorescence, with additional malignant lesions detected in six patients. CONCLUSIONS: The optimal imaging dose was established at 10 mg 4 days before surgery. The results accentuate the potential of SGM-101 and designated a promising base for the multinational phase III study, which enrolled the first patients in June 2019.

Percutaneous Hepatic Perfusion with Melphalan in Patients with Unresectable Ocular Melanoma Metastases Confined to the Liver: A Prospective Phase II Study.

BACKGROUND: Ocular melanoma is the most common primary intraocular malignancy and has a very poor prognosis once liver metastases occur. The aim of this study was to prospectively assess the efficacy and safety of percutaneous hepatic perfusion with melphalan (M-PHP) using the new second-generation (GEN 2) hemofiltration system in patients with ocular melanoma metastases confined to the liver. METHODS: Prospective, single-center, single-arm, phase II study including patients with unresectable ocular melanoma metastases confined to the liver. Treatment consisted of two M-PHP procedures at 6-8 weeks interval. Procedures were performed using the CHEMOSAT (GEN 2) system with 3 mg/kg melphalan. Primary endpoints were overall response rate (ORR) and best overall response (BOR). Secondary endpoints included overall survival (OS), progression-free survival (PFS), hepatic PFS (hPFS), and safety. RESULTS: Sixty-four M-PHP procedures were performed in 35 patients between February 2014 and June 2017. The ORR was 72%. BOR was as follows: complete response in 3%, partial response in 69%, stable disease in 13%, and progressive disease in 16%. There was no treatment-related mortality. Fourteen serious adverse events occurred. At a median follow-up of 19.1 months (range 5.6-69.5), median OS was 19.1 months and was significantly longer in responders than in nonresponders (27.5 vs. 11.9 months, p < 0.001). The 1- and 2-year OS was 77% and 43%, respectively. PFS and hPFS were 7.6 and 11.2 months, respectively. CONCLUSIONS: M-PHP using the GEN 2 filter can achieve a high ORR and prolonged survival in patients with liver-only ocular melanoma metastases.

Watch and wait after a clinical complete response in rectal cancer patients younger than 50 years.

BACKGROUND: Young-onset rectal cancer, in patients less than 50 years, is expected to increase in the coming years. A watch-and-wait strategy is nowadays increasingly practised in patients with a clinical complete response (cCR) after neoadjuvant treatment. Nevertheless, there may be reluctance to offer organ preservation treatment to young patients owing to a potentially higher oncological risk. This study compared patients aged less than 50 years with those aged 50 years or more to identify possible differences in oncological outcomes of watch and wait. METHODS: The study analysed data from patients with a cCR after neoadjuvant therapy in whom surgery was omitted, registered in the retrospective-prospective, multicentre International Watch & Wait Database (IWWD). RESULTS: In the IWWD, 1552 patients met the inclusion criteria, of whom 199 (12.8 per cent) were aged less than 50 years. Patients younger than 50 years had a higher T category of disease at diagnosis (P = 0.011). The disease-specific survival rate at 3 years was 98 (95 per cent c.i. 93 to 99) per cent in this group, compared with 97 (95 to 98) per cent in patients aged over 50 years (hazard ratio (HR) 1.67, 95 per cent c.i. 0.76 to 3.64; P = 0.199). The cumulative probability of local regrowth at 3 years was 24 (95 per cent c.i. 18 to 31) per cent in patients less than 50 years and 26 (23 to 29) per cent among those aged 50 years or more (HR 1.09, 0.79 to 1.49; P = 0.603). Both groups had a cumulative probability of distant metastases of 10 per cent at 3 years (HR 1.00, 0.62 to 1.62; P = 0.998). CONCLUSION: There is no additional oncological risk in young patients compared with their older counterparts when following a watch-and-wait strategy after a cCR. In light of a shared decision-making process, watch and wait should be also be discussed with young patients who have a cCR after neoadjuvant treatment.

Long-term outcomes of clinical complete responders after neoadjuvant treatment for rectal cancer in the International Watch & Wait Database (IWWD): an international multicentre registry study.

BACKGROUND: The strategy of watch and wait (W&W) in patients with rectal cancer who achieve a complete clinical response (cCR) after neoadjuvant therapy is new and offers an opportunity for patients to avoid major resection surgery. However, evidence is based on small-to-moderate sized series from specialist centres. The International Watch & Wait Database (IWWD) aims to describe the outcome of the W&W strategy in a large-scale registry of pooled individual patient data. We report the results of a descriptive analysis after inclusion of more than 1000 patients in the registry. METHODS: Participating centres entered data in the registry through an online, highly secured, and encrypted research data server. Data included baseline characteristics, neoadjuvant therapy, imaging protocols, incidence of local regrowth and distant metastasis, and survival status. All patients with rectal cancer in whom the standard of care (total mesorectal excision surgery) was omitted after neoadjuvant therapy were eligible to be included in the IWWD. For the present analysis, we only selected patients with no signs of residual tumour at reassessment (a cCR). We analysed the proportion of patients with local regrowth, proportion of patients with distant metastases, 5-year overall survival, and 5-year disease-specific survival. FINDINGS: Between April 14, 2015, and June 30, 2017, we identified 1009 patients who received neoadjuvant treatment and were managed by W&W in the database from 47 participating institutes (15 countries). We included 880 (87%) patients with a cCR. Median follow-up time was 3·3 years (95% CI 3·1-3·6). The 2-year cumulative incidence of local regrowth was 25·2% (95% CI 22·2-28·5%), 88% of all local regrowth was diagnosed in the first 2 years, and 97% of local regrowth was located in the bowel wall. Distant metastasis were diagnosed in 71 (8%) of 880 patients. 5-year overall survival was 85% (95% CI 80·9-87·7%), and 5-year disease-specific survival was 94% (91-96%). INTERPRETATION: This dataset has the largest series of patients with rectal cancer treated with a W&W approach, consisting of approximately 50% data from previous cohort series and 50% unpublished data. Local regrowth occurs mostly in the first 2 years and in the bowel wall, emphasising the importance of endoscopic surveillance to ensure the option of deferred curative surgery. Local unsalvageable disease after W&W was rare. FUNDING: European Registration of Cancer Care financed by European Society of Surgical Oncology, Champalimaud Foundation Lisbon, Bas Mulder Award granted by the Alpe d'Huzes Foundation and Dutch Cancer Society, and European Research Council Advanced Grant.

Quality of Life After Curative Resection for Rectal Cancer in Patients Treated With Adjuvant Chemotherapy Compared With Observation: Results of the Randomized Phase III SCRIPT Trial.

BACKGROUND: Adjuvant chemotherapy after curative resection for rectal cancer is the standard of care in several American and European guidelines. OBJECTIVE: The aim of this study was to examine the differences in health-related quality of life over time between patients with rectal cancer who were treated with adjuvant chemotherapy or observation. DESIGN: This is a randomized controlled phase III trial. SETTINGS: Health-related quality-of-life assessments were conducted in Dutch patients from 43 institutes. PATIENTS: Patients with stage II or III rectal cancer who underwent preoperative (chemo)radiotherapy followed by curative surgery (the SCRIPT trial) were included. INTERVENTIONS: Patients were randomly assigned to adjuvant capecitabine monotherapy for 8 cycles or observation. Health-related quality of life was assessed using the European Organization for Research and Treatment of Cancer C30 and CR38 questionnaires at 1 month after surgery (before the start of chemotherapy), and 3, 6, and 12 months after surgery. MAIN OUTCOME MEASURES: The primary outcome measure was the difference in quality of life at 6 months after surgery, just after completion of adjuvant chemotherapy for patients in the treatment group. Second, the difference in health-related quality of life at 12 months after surgery was examined. A statistically significant difference of 5 points was considered clinically relevant. RESULTS: Health-related quality-of-life results of 226 of 233 patients were available. At T3, overall quality of life (C30 summary score) was worse for patients treated with chemotherapy compared with observation (mean 82.3 versus 86.9, p = 0.006), but the difference was not clinically relevant. Patients treated with adjuvant chemotherapy reported clinically relevant worse physical functioning (mean 78.3 versus 87.0, p < 0.001) and more reports of fatigue and dyspnea (35.7 versus 21.0 and 17.1 versus 6.7, p < 0.001). All differences were resolved at 12 months postsurgery. LIMITATIONS: A selection of relatively fit patients willing to be randomly assigned may limit the generalizability of the results. CONCLUSIONS: Although inferior health-related quality of life was reported just after completion of adjuvant chemotherapy, no persistent deterioration in quality of life was detected. See Video Abstract at http://links.lww.com/DCR/A907.

Variation in treatment and survival of older patients with non-metastatic breast cancer in five European countries: a population-based cohort study from the EURECCA Breast Cancer Group.

BACKGROUND: Older patients are poorly represented in breast cancer research and guidelines do not provide evidence based recommendations for this specific group. We compared treatment strategies and survival outcomes between European countries and assessed whether variance in treatment patterns may be associated with variation in survival. METHODS: Population-based study including patients aged ≥ 70 with non-metastatic BC from cancer registries from the Netherlands, Belgium, Ireland, England and Greater Poland. Proportions of local and systemic treatments, five-year relative survival and relative excess risks (RER) between countries were calculated. RESULTS: In total, 236,015 patients were included. The proportion of stage I BC receiving endocrine therapy ranged from 19.6% (Netherlands) to 84.6% (Belgium). The proportion of stage III BC receiving no breast surgery varied between 22.0% (Belgium) and 50.8% (Ireland). For stage I BC, relative survival was lower in England compared with Belgium (RER 2.96, 95%CI 1.30-6.72, P < .001). For stage III BC, England, Ireland and Greater Poland showed significantly worse relative survival compared with Belgium. CONCLUSIONS: There is substantial variation in treatment strategies and survival outcomes in elderly with BC in Europe. For early-stage BC, we observed large variation in endocrine therapy but no variation in relative survival, suggesting potential overtreatment. For advanced BC, we observed higher survival in countries with lower proportions of omission of surgery, suggesting potential undertreatment.

Fluorescent-guided surgery for sentinel lymph node detection in gastric cancer and carcinoembryonic antigen targeted fluorescent-guided surgery in colorectal and pancreatic cancer.

Sentinel lymph node procedures for gastric cancer resections using indocyanine green (ICG) linked to Nanocoll outperformed normal ICG but did not provide information on possible lymph node metastasis. Carcinoembryonic antigen targeted fluorescent imaging using SGM-101 was successful in both pancreatic and colorectal cancer. A large phase III multicentre trial will soon be initiated in colorectal cancer patients.

A quantitative assessment of perfusion of the gastric conduit after oesophagectomy using near-infrared fluorescence with indocyanine green.

INTRODUCTION: Anastomotic leakage is a severe complication after oesophageal resection with gastric conduit reconstruction. Poor perfusion of the gastric conduit plays an important role in the development of anastomotic leakage. Quantitative near-infrared (NIR) fluorescence angiography with indocyanine green (ICG-FA) is an objective technique that can be used for perfusion assessment. This study aims to assess perfusion patterns of the gastric conduit with quantitative ICG-FA. METHODS: In this exploratory study, 20 patients undergoing oesophagectomy with gastric conduit reconstruction were included. A standardized NIR ICG-FA video of the gastric conduit was recorded. Postoperatively, the videos were quantified. Primary outcomes were the time-intensity curves and nine perfusion parameters from contiguous regions of interest on the gastric conduit. A secondary outcome was the inter-observer agreement of subjective interpretation of the ICG-FA videos between six surgeons. The inter-observer agreement was tested with an intraclass correlation coefficient (ICC). RESULTS: In a total of 427 curves, three distinct perfusion patterns were recognized: pattern 1 (steep inflow, steep outflow); pattern 2 (steep inflow, minor outflow); and pattern 3 (slow inflow, no outflow). All perfusion parameters were significantly different between the perfusion patterns. The inter-observer agreement was poor - moderate (ICC:0.345,95%CI:0.164-0.584). DISCUSSION: This was the first study to describe perfusion patterns of the complete gastric conduit after oesophagectomy. Three distinct perfusion patterns were observed. The poor inter-observer agreement of the subjective assessment underlines the need for quantification of ICG-FA of the gastric conduit. Further studies should evaluate the predictive value of perfusion patterns and parameters on anastomotic leakage.

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.

Cysteine Cathepsins in Breast Cancer: Promising Targets for Fluorescence-Guided Surgery.

The majority of breast cancer patients is treated with breast-conserving surgery (BCS) combined with adjuvant radiation therapy. Up to 40% of patients has a tumor-positive resection margin after BCS, which necessitates re-resection or additional boost radiation. Cathepsin-targeted near-infrared fluorescence imaging during BCS could be used to detect residual cancer in the surgical cavity and guide additional resection, thereby preventing tumor-positive resection margins and associated mutilating treatments. The cysteine cathepsins are a family of proteases that play a major role in normal cellular physiology and neoplastic transformation. In breast cancer, the increased enzymatic activity and aberrant localization of many of the cysteine cathepsins drive tumor progression, proliferation, invasion, and metastasis. The upregulation of cysteine cathepsins in breast cancer cells indicates their potential as a target for intraoperative fluorescence imaging. This review provides a summary of the current knowledge on the role and expression of the most important cysteine cathepsins in breast cancer to better understand their potential as a target for fluorescence-guided surgery (FGS). In addition, it gives an overview of the cathepsin-targeted fluorescent probes that have been investigated preclinically and in breast cancer patients. The current review underscores that cysteine cathepsins are highly suitable molecular targets for FGS because of favorable expression and activity patterns in virtually all breast cancer subtypes. This is confirmed by cathepsin-targeted fluorescent probes that have been shown to facilitate in vivo breast cancer visualization and tumor resection in mouse models and breast cancer patients. These findings indicate that cathepsin-targeted FGS has potential to improve treatment outcomes in breast cancer patients.

Colorectal polyps: Targets for fluorescence-guided endoscopy to detect high-grade dysplasia and T1 colorectal cancer.

BACKGROUND: Differentiating high-grade dysplasia (HGD) and T1 colorectal cancer (T1CRC) from low-grade dysplasia (LGD) in colorectal polyps can be challenging. Incorrect recognition of HGD or T1CRC foci can lead to a need for additional treatment after local resection, which might not have been necessary if it was recognized correctly. Tumor-targeted fluorescence-guided endoscopy might help to improve recognition. OBJECTIVE: Selecting the most suitable HGD and T1CRC-specific imaging target from a panel of well-established biomarkers: carcinoembryonic antigen (CEA), c-mesenchymal-epithelial transition factor (c-MET), epithelial cell adhesion molecule (EpCAM), folate receptor alpha (FRα), and integrin alpha-v beta-6 (αvß6). METHODS: En bloc resection specimens of colorectal polyps harboring HGD or T1CRC were selected. Immunohistochemistry on paraffin sections was used to determine the biomarker expression in normal epithelium, LGD, HGD, and T1CRC (scores of 0-12). The differential expression in HGD-T1CRC components compared to surrounding LGD and normal components was assessed, just as the sensitivity and specificity of each marker. RESULTS: 60 specimens were included (21 HGD, 39 T1CRC). Positive expression (score >1) of HGD-T1CRC components was found in 73.3%, 78.3%, and 100% of cases for CEA, c-MET, and EpCAM, respectively, and in <40% for FRα and αvß6. Negative expression (score 0-1) of the LGD component occurred more frequently for CEA (66.1%) than c-MET (31.6%) and EpCAM (0%). The differential expression in the HGD-T1CRC component compared to the surrounding LGD component was found for CEA in 66.7%, for c-MET in 43.1%, for EpCAM in 17.2%, for FRα in 22.4%, and for αvß6 in 15.5% of the cases. Moreover, CEA showed the highest combined sensitivity (65.0%) and specificity (75.0%) for the detection of an HGD-T1CRC component in colorectal polyps. CONCLUSION: Of the tested targets, CEA appears the most suitable to specifically detect HGD and T1 cancer foci in colorectal polyps. An in vivo study using tumor-targeted fluorescence-guided endoscopy should confirm these findings.

Baseline and early digital [ 18 F]FDG PET/CT and multiparametric MRI contain promising features to predict response to neoadjuvant therapy in locally advanced rectal cancer patients: a pilot study.

OBJECTIVE: In this pilot study, we investigated the feasibility of response prediction using digital [ 18 F]FDG PET/computed tomography (CT) and multiparametric MRI before, during, and after neoadjuvant chemoradiation therapy in locally advanced rectal cancer (LARC) patients and aimed to select the most promising imaging modalities and timepoints for further investigation in a larger trial. METHODS: Rectal cancer patients scheduled to undergo neoadjuvant chemoradiation therapy were prospectively included in this trial, and underwent multiparametric MRI and [ 18 F]FDG PET/CT before, 2 weeks into, and 6-8 weeks after chemoradiation therapy. Two groups were created based on pathological tumor regression grade, that is, good responders (TRG1-2) and poor responders (TRG3-5). Using binary logistic regression analysis with a cutoff value of P  ≤ 0.2, promising predictive features for response were selected. RESULTS: Nineteen patients were included. Of these, 5 were good responders, and 14 were poor responders. Patient characteristics of these groups were similar at baseline. Fifty-seven features were extracted, of which 13 were found to be promising predictors of response. Baseline [T2: volume, diffusion-weighted imaging (DWI): apparent diffusion coefficient (ADC) mean, DWI: difference entropy], early response (T2: volume change, DWI: ADC mean change) and end-of-treatment presurgical evaluation MRI (T2: gray level nonuniformity, DWI: inverse difference normalized, DWI: gray level nonuniformity normalized), as well as baseline (metabolic tumor volume, total lesion glycolysis) and early response PET/CT (Δ maximum standardized uptake value, Δ peak standardized uptake value corrected for lean body mass), were promising features. CONCLUSION: Both multiparametric MRI and [ 18 F]FDG PET/CT contain promising imaging features to predict response to neoadjuvant chemoradiotherapy in LARC patients. A future larger trial should investigate baseline, early response, and end-of-treatment presurgical evaluation MRI and baseline and early response PET/CT.

AVOID; a phase III, randomised controlled trial using indocyanine green for the prevention of anastomotic leakage in colorectal surgery.

INTRODUCTION: Anastomotic leakage (AL) is one of the major complications after colorectal surgery. Compromised tissue perfusion at the anastomosis site increases the risk of AL. Several cohort studies have shown that indocyanine green (ICG) combined with fluorescent near-infrared imaging is a feasible and reproducible technique for real-time intraoperative imaging of tissue perfusion, leading to reduced leakage rates after colorectal resection. Unfortunately, these studies were not randomised. Therefore, we propose a randomised controlled trial to assess the value of ICG-guided surgery in reducing AL after colorectal surgery. METHODS AND ANALYSIS: A multicentre, randomised controlled clinical trial will be conducted to assess the benefit of ICG-guided surgery in preventing AL. A total of 978 patients scheduled for colorectal surgery will be included. Patients will be randomised between the Fluorescence Guided Bowel Anastomosis group and the Conventional Bowel Anastomosis group. The primary endpoint is clinically relevant AL (defined as requiring active therapeutic intervention or reoperation) within 90 days after surgery. Among the secondary endpoints are 30-day clinically relevant AL, all-cause postoperative complications, all-cause and AL-related mortality, surgical and non-surgical reinterventions, total surgical time, length of hospital stay and all-cause and AL-related readmittance. ETHICS AND DISSEMINATION: This protocol has been approved by the Medical Ethical Committee Leiden-Den Haag-Delft (METC-LDD) and is registered at ClinicalTrials.gov and trialregister.nl. The results of this study will be reported through peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER: NCT04712032; NL7502.