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Background: The presence of mesorectal fascia (MRF) invasion, grade 4 extramural venous invasion (EMVI), tumour deposits (TD) or extensive or bilateral extramesorectal (lateral) lymph nodes (LLN) on MRI has been suggested to identify patients with indisputable, extensive locally advanced rectal cancer (LARC), at high risk of treatment failure. The aim of this study is to evaluate whether or not intensified chemotherapy prior to neoadjuvant chemoradiotherapy improves the complete response (CR) rate in these patients., Methods: This multicentre, single-arm, open-label, phase II trial will include 128 patients with non-metastatic high-risk LARC (hr-LARC), fit for triplet chemotherapy. To ensure a study population with indisputable, unfavourable prognostic characteristics, hr-LARC is defined as LARC with on baseline MRI at least one of the following characteristics; MRF invasion, EMVI grade 4, enlarged bilateral or extensive LLN at high risk of an incomplete resection, or TD. Exclusion criteria are the presence of a homozygous DPD deficiency, distant metastases, any chemotherapy within the past 6 months, previous radiotherapy within the pelvic area precluding standard chemoradiotherapy, and any contraindication for the planned treatment. All patients will be planned for six two-weekly cycles of FOLFOXIRI (5-fluorouracil, leucovorin, oxaliplatin and irinotecan) prior to chemoradiotherapy (25 × 2 Gy or 28 × 1.8 Gy with concomitant capecitabine). A resection will be performed following radiological confirmation of resectable disease after the completion of chemoradiotherapy. A watch and wait strategy is allowed in case of a clinical complete response. The primary endpoint is the CR rate, described as a pathological CR or a sustained clinical CR one year after chemoradiotherapy. The main secondary objectives are long-term oncological outcomes, radiological and pathological response, the number of resections with clear margins, treatment-related toxicity, perioperative complications, health-related costs, and quality of life., Discussion: This trial protocol describes the MEND-IT study. The MEND-IT study aims to evaluate the CR rate after intensified chemotherapy prior to concomitant chemoradiotherapy in a homogeneous group of patients with locally advanced rectal cancer and indisputably unfavourable characteristics, defined as hr-LARC, in order to improve their prognosis., Trial Registration: Clinicaltrials.gov: NCT04838496 , registered on 02-04-2021 Netherlands Trial Register: NL9790., Protocol Version: Version 3 dd 11-4-2022., (© 2022. The Author(s).)

Purpose: Magnetic resonance imaging-detected extramural venous invasion (mrEMVI) and tumor deposits (TDs) are risk factors for the development of local recurrence and distant metastases (DMs) in rectal cancer. However, little is known about their response to neoadjuvant treatment and its relation to oncologic outcomes. This study evaluated the incidence and features of mrEMVI and TDs before and after neoadjuvant treatment in relation to the development of local recurrence and DMs., Methods and Materials: Patients with cT3/4 rectal cancer without synchronous metastases who underwent surgery in a tertiary referral hospital were retrospectively analyzed. MRI scans were re-evaluated for the presence of mrEMVI, the occurrence of TDs, and response to neoadjuvant therapy (mr-vTRG)., Results: In total, 277 patients were included, of whom 163 (58.8%) presented with mrEMVI. TDs were present in 56.4% of mrEMVI-positive and 9.6% of mrEMVI-negative patients (P < .001). The 5-year DM rate was significantly higher in mrEMVI-positive patients with and without TDs (45.2% and 35.9%, respectively) compared with mrEMVI-negative patients (25.7%; P = .012). After neoadjuvant treatment, the 5-year DM rate of patients with mr-vTRG 3-5 was 46.1%, whereas good responders (mr-vTRG 1-2) had a DM rate similar to mrEMVI-negative patients (25.7% and 25.7%, respectively; P = .002). The occurrence of TDs and larger mrEMVI size resulted in a lower likelihood of regression of mrEMVI., Conclusions: The prevalence of mrEMVI and TDs in cT3-4 rectal cancer is high and is associated with worsened oncologic outcomes. mrEMVI regression (mr-vTRG 1-2), which occured in 25% of the cases, leads to oncologic outcomes similar to those in patients without mrEMVI on baseline MRI., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: The addition of induction chemotherapy (ICT) to neoadjuvant chemoradiotherapy (CRT) has the potential to improve outcomes in patients with locally advanced rectal cancer (LARC). However, patient selection is essential to prevent overtreatment. This study compared the complete response (CR) rate after treatment with and without ICT of LARC patients with prognostically poor characteristics., Methods: All LARC patients who were treated with neoadjuvant CRT, whether or not preceded by ICT, and who underwent surgery or were considered for a wait-and-see strategy between January 2016 and March 2020 in the Catharina Hospital Eindhoven, were retrospectively selected. LARC was defined as any T4 tumour, or a T2/T3 tumour with extramural venous invasion and/or tumour deposits and/or N2 lymph node status, and/or mesorectal fascia involvement (T3 tumours only). Case-control matching was performed based on the aforementioned characteristics., Results: Of 242 patients, 178 (74%) received CRT (CRT-group) and 64 patients (26%) received ICT followed by CRT (ICT-group). In the ICT-group, 3 patients (5%) did not receive the minimum of three cycles. In addition, in this selected cohort, compliance with radiotherapy was 100% in the ICT-group and 97% in the CRT-group. The CR rate was 30% in the ICT-group and 15% in the CRT-group (p = 0.011). After case-control matching, the CR rate was 28% and 9%, respectively (p = 0.013)., Conclusion: Treatment including ICT seemed well tolerated and resulted in a high CR rate. Hence, this treatment strategy may facilitate organ preservation and improve survival in LARC patients with prognostically poor characteristics., Competing Interests: Declaration of competing interest None., (Copyright © 2021 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Background: In patients with rectal cancer, enlarged lateral lymph nodes (LLNs) result in increased lateral local recurrence (LLR) and lower cancer-specific survival (CSS) rates, which can be improved with (chemo)radiotherapy ((C)RT) and LLN dissection (LLND). This study investigated whether different LLN locations affect oncological outcomes., Methods: Patients with low cT3-4 rectal cancer without synchronous distant metastases were included in this multicentre retrospective cohort study. All MRI was re-evaluated, with special attention to LLN involvement and response., Results: More advanced cT and cN category were associated with the occurrence of enlarged obturator nodes. Multivariable analyses showed that a node in the internal iliac compartment with a short-axis (SA) size of at least 7 mm on baseline MRI and over 4 mm after (C)RT was predictive of LLR, compared with a post-(C)RT SA of 4 mm or less (hazard ratio (HR) 5.74, 95 per cent c.i. 2.98 to 11.05 vs HR 1.40, 0.19 to 10.20; P < 0.001). Obturator LLNs with a SA larger than 6 mm after (C)RT were associated with a higher 5-year distant metastasis rate and lowered CSS in patients who did not undergo LLND. The survival difference was not present after LLND. Multivariable analyses found that only cT category (HR 2.22, 1.07 to 4.64; P = 0.033) and margin involvement (HR 2.95, 1.18 to 7.37; P = 0.021) independently predicted the development of metastatic disease., Conclusion: Internal iliac LLN enlargement is associated with an increased LLR rate, whereas obturator nodes are associated with more advanced disease with increased distant metastasis and reduced CSS rates. LLND improves local control in persistent internal iliac nodes, and might have a role in controlling systemic spread in persistent obturator nodes.Members of the Lateral Node Study Consortium are co-authors of this study and are listed under the heading Collaborators., (© The Author(s) 2021. Published by Oxford University Press on behalf of BJS Society Ltd. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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.

This multicentre pilot study investigated the role of peroperative carcinoembryonic antigen (CEA)-specific fluorescence imaging during cytoreductive surgery-hyperthermic intraperitoneal chemotherapy surgery in peritoneal metastasized colorectal cancer. A correct change in peritoneal carcinomatosis index (PCI) owing to fluorescence imaging was seen in four of the 14 included patients. The use of SGM-101 in patients with peritoneally metastasized colorectal carcinoma is feasible, and allows intraoperative detection of tumour deposits and alteration of the PCI. Augmented reality guidance., (© 2020 The Authors. BJS published by John Wiley & Sons Ltd on behalf of BJS Society Ltd.)

Background: In the West, pre-treatment abnormal lateral lymph nodes (LLN+) in patients with a low locally advanced rectal cancer (AJCC Stage III), are treated with neoadjuvant (chemo)radiotherapy (nCRT), without a lateral lymph node dissection (LLND). It has been suggested, however, that LLN+ patients have higher local recurrence (LR) rates than similarly staged patients with abnormal mesorectal lymph nodes only (LLN-), but no comparative data exist. Therefore, we conducted this international multi-center study in the Netherlands and Australia of Stage III rectal cancer patients with either LLN+ or LLN- to compare oncological outcomes from both groups. Materials and Methods: Patients with Stage III low rectal cancer with (LLN+ group) or without (LLN- group) abnormal lateral lymph nodes on pre-treatment MRI were included. Patients underwent nCRT followed by rectal resection surgery with curative intent between 2009 and 2016 with a minimum follow-up of 2-years. No patient had a LLND. Propensity score matching corrected differences in baseline characteristics. Results: Two hundred twenty-three patients could be included: 125 in the LLN+ group and 98 in the LLN- group. Between groups, there were significant differences in cT-stage and in the rate of adjuvant chemotherapy administered. Propensity score matching resulted in 54 patients in each group, with equal baseline characteristics. The 5-year LR rate in the LLN+ group was 11 vs. 2% in the LLN- group ( P = 0.06) and disease-free survival (DFS) was 64 vs. 76%, respectively ( P = 0.09). Five-year overall survival was similar between groups (73 vs. 80%, respectively; P = 0.90). Conclusions: In Western patients with Stage III low rectal cancer, there is a trend toward worse LR rate and DFS rates in LLN+ patients compared to similarly staged LLN- patients. These results suggest that LLN+ patients may currently not be treated optimally with nCRT alone, and the addition of LLND requires further consideration., (Copyright © 2019 Haanappel, Kroon, Schaap, Bedrikovetski, Dudi-Venkata, Lee, Thomas, Liu, van der Valk, Rutten, Beets, Kusters and Sammour.)

Background: Lateral nodal disease in rectal cancer remains a subject of debate and is treated differently in the East and the West. The predictive value of lateral lymph node and MRI-detected extramural vascular invasion (mrEMVI) features on oncological outcomes was assessed in this study., Methods: In this retrospective cohort study, data on patients with cT3-4 rectal cancer within 8 cm from the anal verge were considered over a 5-year period (2009-2013). Lateral lymph node size, malignant features and mrEMVI features were evaluated and related to oncological outcomes., Results: In total, 192 patients were studied, of whom 30 (15·6 per cent) underwent short-course radiotherapy and 145 (75·5 per cent) received chemoradiotherapy. A lateral lymph node short-axis size of 10 mm or more was associated with a significantly higher 5-year lateral/presacral local recurrence rate of 37 per cent, compared with 7·7 per cent in nodes smaller than 10 mm (P = 0·041). Enlarged nodes did not result in a higher 5-year rate of distant metastasis (23 per cent versus 27·7 per cent in nodes smaller than 10 mm; P = 0·563). However, mrEMVI positivity was related to more metastatic disease (5-year rate 43 versus 26·3 per cent in the mrEMVI-negative group; P = 0·014), but not with increased lateral/presacral recurrence. mrEMVI occurred in 46·6 per cent of patients with nodes smaller than 10 mm, compared with 29 per cent in patients with nodes of 10 mm or larger (P = 0·267)., Conclusion: Although lateral nodal disease is more a local problem, mrEMVI mainly predicts distant recurrence. The results of this study showed an unacceptably high local recurrence rate in patients with a short axis of 10 mm or more, despite neoadjuvant (chemo)radiotherapy., (© 2018 BJS Society Ltd Published by John Wiley & Sons Ltd.)

Background: Tumour-targeted fluorescence imaging has the potential to advance current practice of oncological surgery by selectively highlighting malignant tissue during surgery. Carcinoembryonic antigen (CEA) is overexpressed in 90% of colorectal cancers and is a promising target for colorectal cancer imaging. We aimed to assess the tolerability of SGM-101, a fluorescent anti-CEA monoclonal antibody, and to investigate the feasibility to detect colorectal cancer with intraoperative fluorescence imaging., Methods: We did an open-label, pilot study in two medical centres in the Netherlands. In the dose-escalation cohort, we included patients (aged ≥18 years) with primary colorectal cancer with increased serum CEA concentrations (upper limit of normal of ≥3 ng/mL) since diagnosis, who were scheduled for open or laparoscopic tumour resection. In the expansion cohort, we included patients (aged ≥18 years) with recurrent or peritoneal metastases of colorectal cancer, with increasing serum concentrations of CEA since diagnosis, who were scheduled for open surgical resection. We did not mask patients, investigators, or anyone from the health-care team. We assigned patients using a 3 + 3 dose design to 5 mg, 7·5 mg, or 10 mg of SGM-101 in the dose-escalation cohort. In the expansion cohort, patients received a dose that was considered optimal at that moment of the study but not higher than the dose used in the dose-escalation cohort. SGM-101 was administered intravenously for 30 min to patients 2 or 4 days before surgery. Intraoperative imaging was done to identify near-infrared fluorescent lesions, which were resected and assessed for fluorescence. The primary outcome was tolerability and safety of SGM-101, assessed before administration and continued up to 12 h after dosing, on the day of surgery, the first postoperative day, and follow-up visits at the day of discharge and the first outpatient clinic visit. Secondary outcomes were effectiveness of SGM-101 for detection of colorectal cancer, assessed by tumour-to-background ratios (TBR); concordance between fluorescent signal and tumour status of resected tissue; and diagnostic accuracy in both cohorts. This trial is registered with the Nederlands Trial Register, number NTR5673, and ClinicalTrials.gov, number NCT02973672., Findings: Between January, 2016, and February, 2017, 26 patients (nine in the dose-escalation cohort and 17 in the expansion cohort) were included in this study. SGM-101 did not cause any treatment-related adverse events, although three possibly related mild adverse events were reported in three (33%) of nine patients in the dose-escalation cohort and five were reported in three (18%) of 17 patients in the expansion cohort. Five moderate adverse events were reported in three (18%) patients in the expansion cohort, but they were deemed unrelated to SGM-101. No changes in vital signs, electrocardiogram, or laboratory results were found after administration of the maximum dose of 10 mg of SGM-101 in both cohorts. A dose of 10 mg, administered 4 days before surgery, showed the highest TBR (mean TBR 6·10 [SD 0·42] in the dose-escalation cohort). In the expansion cohort, 19 (43%) of 43 lesions were detected using fluorescence imaging and were not clinically suspected before fluorescent detection, which changed the treatment strategy in six (35%) of 17 patients. Sensitivity was 98%, specificity was 62%, and accuracy of fluorescence intensity was 84% in the expansion cohort., Interpretation: This study presents the first clinical use of CEA-targeted detection of colorectal cancer and shows that SGM-101 is safe and can influence clinical decision making during the surgical procedure for patients with colorectal cancer., Funding: Surgimab., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objective: To establish whether a systematized approach to self-assessment in a laparoscopic surgical skills course improves accordance between expert- and self-assessment., Design: A systematic training course in self-assessment using Competency Assessment Tool was introduced into the normal course of evaluation within a Laparoscopic Surgical Skills training course for the test group (n = 30). Differences between these and a control group (n = 30) who did not receive the additional training were assessed., Setting: Catharina Hospital, Eindhoven, The Netherlands (n = 27), and GSL Medical College, Rajahmundry, India (n = 33)., Participants: Sixty postgraduate year 2 and 3 surgical residents who attended the 2-day Laparoscopic Surgical Skills grade 1 level 1 curriculum were invited to participate., Results: The test group (n = 30) showed better accordance between expert- and self-assessment (difference of 1.5, standard deviation [SD] = 0.2 versus 3.83, SD = 0.6, p = 0.009) as well as half the number (7 versus 14) of cases of overreporting. Furthermore, the test group also showed higher overall mean performance (mean = 38.1, SD = 0.7 versus mean = 31.8, SD = 1.0, p < 0.001) than the control group (n = 30). The systematic approach to self-assessment can be viewed as responsible for this and can be seen as "reflection-before-practice" within the framework of reflective practice as defined by Donald Schon., Conclusion: Our results suggest that "reflection-before-practice" in implementing self-assessment is an important step in the development of surgical skills, yielding both better understanding of one's strengths and weaknesses and also improving overall performance., (Copyright © 2017 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)