Prognostic Implications of MRI-Detected EMVI and Tumor Deposits and Their Response to Neoadjuvant Therapy in cT3 and cT4 Rectal Cancer.

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.

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.

Lateral Lymph Node Metastases in Locally Advanced Low Rectal Cancers May Not Be Treated Effectively With Neoadjuvant (Chemo)Radiotherapy Only.

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.

Safety and effectiveness of SGM-101, a fluorescent antibody targeting carcinoembryonic antigen, for intraoperative detection of colorectal cancer: a dose-escalation pilot study.

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.

"Reflection-Before-Practice" Improves Self-Assessment and End-Performance in Laparoscopic Surgical Skills Training.

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.