Deep learning identifies inflamed fat as a risk factor for lymph node metastasis in early colorectal cancer.

The spread of early-stage (T1 and T2) adenocarcinomas to locoregional lymph nodes is a key event in disease progression of colorectal cancer (CRC). The cellular mechanisms behind this event are not completely understood and existing predictive biomarkers are imperfect. Here, we used an end-to-end deep learning algorithm to identify risk factors for lymph node metastasis (LNM) status in digitized histopathology slides of the primary CRC and its surrounding tissue. In two large population-based cohorts, we show that this system can predict the presence of more than one LNM in pT2 CRC patients with an area under the receiver operating curve (AUROC) of 0.733 (0.67-0.758) and patients with any LNM with an AUROC of 0.711 (0.597-0.797). Similarly, in pT1 CRC patients, the presence of more than one LNM or any LNM was predictable with an AUROC of 0.733 (0.644-0.778) and 0.567 (0.542-0.597), respectively. Based on these findings, we used the deep learning system to guide human pathology experts towards highly predictive regions for LNM in the whole slide images. This hybrid human observer and deep learning approach identified inflamed adipose tissue as the highest predictive feature for LNM presence. Our study is a first proof of concept that artificial intelligence (AI) systems may be able to discover potentially new biological mechanisms in cancer progression. Our deep learning algorithm is publicly available and can be used for biomarker discovery in any disease setting. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Prediction of disease recurrence or residual disease after primary endoscopic resection of pT1 colorectal cancer-results from a large nationwide Danish study.

PURPOSE: Risk assessment of disease recurrence in pT1 colorectal cancer is crucial in order to select the appropriate treatment strategy. The study aimed to develop a prediction model, based on histopathological data, for the probability of disease recurrence and residual disease in patients with pT1 colorectal cancer. METHODS: The model dataset consisted of 558 patients with pT1 CRC who had undergone endoscopic resection only (n = 339) or endoscopic resection followed by subsequent bowel resection (n = 219). Tissue blocks and slides were retrieved from Pathology Departments from all regions in Denmark. All original slides were evaluated by one experienced gastrointestinal pathologist (TPK). New sections were cut and stained for haematoxylin and eosin (HE) and immunohistochemical markers. Missing values were multiple imputed. A logistic regression model with backward elimination was used to construct the prediction model. RESULTS: The final prediction model for disease recurrence demonstrated good performance with AUC of 0.75 [95% CI 0.72-0.78], HL chi-squared test of 0.59 and scaled Brier score of 10%. The final prediction model for residual disease demonstrated medium performance with an AUC of 0.68 [0.63-0.72]. CONCLUSION: We developed a prediction model for the probability of disease recurrence in pT1 CRC with good performance and calibration based on histopathological data. Together with lymphatic and venous invasion, an involved resection margin (0 mm) as opposed to a margin of ≤ 1 mm was an independent risk factor for both disease recurrence and residual disease.

Risk of recurrence after local resection of T1 rectal cancer: a meta-analysis with meta-regression.

BACKGROUND: T1 rectal cancer (RC) patients are increasingly being treated by local resection alone but uniform surveillance strategies thereafter are lacking. To determine whether different local resection techniques influence the risk of recurrence and cancer-related mortality, a meta-analysis was performed. METHODS: A systematic search was conducted for T1RC patients treated with local surgical resection. The primary outcome was the risk of RC recurrence and RC-related mortality. Pooled estimates were calculated using mixed-effect logistic regression. We also systematically searched and evaluated endoscopically treated T1RC patients in a similar manner. RESULTS: In 2585 unique T1RC patients (86 studies) undergoing local surgical resection, the overall pooled cumulative incidence of recurrence was 9.1% (302 events, 95% CI 7.3-11.4%; I2 = 68.3%). In meta-regression, the recurrence risk was associated with histological risk status (p < 0.005; low-risk 6.6%, 95% CI 4.4-9.7% vs. high-risk 28.2%, 95% CI 19-39.7%) and local surgical resection technique (p < 0.005; TEM/TAMIS 7.7%, 95% CI 5.3-11.0% vs. other local surgical excisions 10.8%, 95% CI 6.7-16.8%). In 641 unique T1RC patients treated with flexible endoscopic excision (16 studies), the risk of recurrence (7.7%, 95% CI 5.2-11.2%), cancer-related mortality (2.3%, 95% CI 1.1-4.9), and cancer-related mortality among patients with recurrence (30.0%, 95% CI 14.7-49.4%) were comparable to outcomes after TEM/TAMIS (risk of recurrence 7.7%, 95% CI 5.3-11.0%, cancer-related mortality 2.8%, 95% CI 1.2-6.2% and among patients with recurrence 35.6%, 95% CI 21.9-51.2%). CONCLUSIONS: Patients with T1 rectal cancer may have a significantly lower recurrence risk after TEM/TAMIS compared to other local surgical resection techniques. After TEM/TAMIS and endoscopic resection the recurrence risk, cancer-related mortality and cancer-related mortality among patients with recurrence were comparable. Recurrence was mainly dependent on histological risk status.

Malignant colorectal polyps: endoscopic polypectomy and watchful waiting is not inferior to subsequent bowel resection. A nationwide propensity score-based analysis.

BACKGROUND AND AIMS: The optimal treatment of patients with malignant colorectal polyps is unsettled. The surgical dilemma following polypectomy is selecting between watchful waiting (WW) and subsequent bowel resection (SBR), but the long-term survival outcomes have not been established yet. This nationwide study compared survival of patients after WW or SBR. METHODS: Danish nationwide study with 100% follow-up of all patients with malignant colorectal polyps (the Danish Colorectal Cancer Group database) in a 10-year period from 2001 to 2011. All patients' charts and histological reports were individually reviewed. Survival rates were calculated with Cox proportional hazard model after propensity score matching. RESULTS: A total of 692 patients were included (WW, 424 (61.3%), SBR, 268 (38.7%)) with a mean follow-up of 7.5 years (3-188 months). Following propensity score matching, there was no significant difference in overall or disease-free survival (p = 0.344 and p = 0.184) or rate of local recurrence (WW, 7.2%, SBR, 2%, p = 0.052) or distant metastases (WW, 3.3%, SBR, 4.6%, p = 0.77). In the SBR group, there was no residual tumor or lymph node metastases in the resected specimen in 82.5% of the patients. CONCLUSION: Subsequent bowel resection may not be superior to endoscopic polypectomy and watchful waiting with regard to overall and disease-free survival in patients with malignant colorectal polyps.

Increased perirenal fat area is not associated with adverse outcomes after laparoscopic total mesorectal excision for rectal cancer.

INTRODUCTION: Intraabdominal visceral obesity may increase technical challenges during laparoscopic rectal resection and hypothetically therefore increase the risk of perioperative complications. The aim of this study was to analyze intraabdominal obesity by means of perirenal fat against risk of adverse outcomes in patients undergoing laparoscopic rectal cancer surgery. METHODS: This study was a single-institution retrospective analysis of consecutive patients undergoing laparoscopic total mesorectal surgery for rectal cancer between January 2009 and January 2013. Abdominal CT scans with intravenous contrast were assessed in a blinded manner to estimate the perirenal fat area (cm2). RESULT: A total of 195 patients were included (median age 70 years (range 27-87), 58 women and 137 men) for analysis. There was a moderate correlation between BMI and perirenal fat area (r = 0.499, p = 0.001). Perirenal fat area was not associated with any of the measured adverse outcomes. Patients with BMI ≥ 30 had significantly higher intraoperative blood loss (191 mL, p = 0.001). CONCLUSION: Perirenal fat area was not an important predictor of adverse outcomes in patients undergoing laparoscopic rectal cancer surgery.

A Comparative Study of Single-Port Laparoscopic Surgery Versus Robotic-Assisted Laparoscopic Surgery for Rectal Cancer.

INTRODUCTION: Conventional laparoscopic surgery is the treatment of choice for many abdominal procedures. To further reduce surgical trauma, new minimal invasive procedures such as single-port laparoscopic surgery (SPLS) and robotic assisted laparoscopic surgery (RALS) have emerged. The aim of this study was to compare the early results of SPLS versus RALS in the treatment of rectal cancer. METHODS: We performed a retrospective analysis of prospectively collected data on patients who had undergone SPLS (n = 36) or RALS (n = 56) in the period between 2010 and 2012. Operative and short-term oncological outcomes were compared. RESULTS: The RALS group had fewer patients with low rectal cancer and more patients with mid-rectal tumors (P = .017) and also a higher rate of intraoperative complications (14.3% vs 0%, P = .021). The rate of postoperative complications did not differ (P = .62). There were no differences in circumferential resection margins, distal resection margins, or completeness of the mesorectal fascia. The RALS group had a larger number of median harvested lymph nodes (27 vs 13, P = .001). The SPLS group had fewer late complications (P = .025). There were no locoregional recurrences in either of the groups. There was no difference in median follow-up time between groups (P = .58). CONCLUSION: Both SPLS and RALS may have a role in rectal surgery. The short-term oncological outcomes were similar, although RALS harvested more lymph nodes than the SPLS procedure. However, SPLS seems to be safer with regard to intraoperative and late postoperative complications.

The short-term outcomes of conventional and single-port laparoscopic surgery for rectal cancer: a comparative non-randomized study.

BACKGROUND: Single-port laparoscopic surgery (SPLS) has evolved as an alternative method to conventional laparoscopic surgery (CLS). The aim of this study is to evaluate the results of SPLS compared to CLS in the treatment of rectal cancer. MATERIAL AND METHODS: Prospectively collected data of patients who had undergone either CLS (n = 194) or SPLS (n = 36) for rectal cancer in the period between 2009 and 2012 were retrospectively analyzed. RESULTS: Median operative time was higher in patients with SPLS (p = 0.01), but the median operative blood loss was significantly lower (p = 0.006). No significant difference was found in intraoperative- (p = 0.14) or postoperative complication rate (p = 0.4) or 30-day mortality (p = 0.62). A tendency towards fewer late complications in the SPLS-group was seen (11.1% vs. 25.3%), but the difference was not significant (p = 0.084). CONCLUSION: SPLS for rectal cancer is a safe method in a selected group of patients. Further studies are needed to confirm the benefits of SPLS. Operative time is longer, but the intraoperative blood loss is reduced.

Inflammatory response after transanal total mesorectal excision.

INTRODUCTION: The advantages of transanal total mesorectal excision (taTME) would be a reduction of the hernia rate and surgical trauma. The present study reports data for patients undergoing taTME and compares the post-operative immune response in taTME with those of conven-tional laparoscopic surgery (CLS) and single-port laparo-scopic surgery (SPLS). METHODS: A comparative cohort study in patients with rectal cancer undergoing taTME. C-reactive protein (CRP) and white blood cell count (WBC) were measured pre-operatively and on post-operative days one, two, three and four. RESULTS: A total of 40 patients were included in taTME, 20 patients in CLS and 20 in SPLS. Patients' demographics (except for clinical staging), R0 resection and post-operative complication rates were comparable. The length of abdom-inal incisio-n was significantly lower by taTME than by both SPLS and CLS (p < 0.001). Distant resection margin was shorter in the taTME group (p < 0.01), and the quality of specimen differed between groups (p < 0.01). CRP and WBC increased significantly in each group (p < 0.05), but there was no difference between the groups. CONCLUSIONS: There is no difference in the inflammatory response in patients with rectal cancer undergoing taTME surgery compared with CLS and SPLS. We therefore conclude that the length/presence of abdominal incision does not further reduce the post-operative inflammatory stress response in minimally invasive procedures. The surgical trauma extends beyond the abdominal incision and depends on the intra-abdominal handling of the tissue. FUNDING: none. TRIAL REGISTRATION: ID NCT00157972, ethical approval ID H-1-2011-007, H-15000540.

Low incidence of perineal hernia repair after abdominoperineal resection for rectal cancer.

INTRODUCTION: Perineal hernia may be a long-term complication to conventional abdominoperineal resection or proctocolectomy. We analysed the incidence of post-operative perineal hernia repair and described patient-reported outcome measures (PROMS) after perineal hernia repair. METHODS: This was a nationwide retrospective analysis of consecutive Danish patients undergoing conventional abdominoperineal resection or proctocolectomy for rectal cancer from 1 January 2004 to 31 December 2014 combined with patients undergoing a subsequent repair for a perineal hernia during the follow-up period from 1 January 2004 to 31 December 2016. Patients were sent a quality of life questionnaire (HerQles A) and related PROMS. RESULTS: The incidence of perineal hernia repair was 0.83%. A total of 2,170 patients underwent proctocolectomy and conventional abdominoperineal resection, and 18 patients had a subsequent perineal hernia repair. Four patients developed a clinical hernia recurrence, another four patients reported moderate/severe perineal pain or heaviness during physical activity and complained of poor perception of health, and one patient reported that the perineal hernia repair had a negative impact on sexual function. CONCLUSIONS: The incidence of perineal hernia repair was below 1% after conventional abdominoperineal resection and proctocolectomy. PROMS and risk of recurrence may benefit from centralising perineal hernia repair. FUNDING: none. TRIAL REGISTRATION: not relevant.

Watchful waiting versus colorectal resection after polypectomy for malignant colorectal polyps.

INTRODUCTION: Unexpected malignancy in removed colorectal polyps is reported in up to 9% of cases. The introduction of screening for colorectal cancer will inevitably increase the number of removed colorectal polyps and therefore also the incidence of malignant polyps. The treatment strategy is either watchful waiting or subsequent colorectal resection. The aim of this study was to perform a preliminary evaluation of the oncological results of polypectomy for malignant polyps with or without subsequent resection, including the patients' long-term survival. METHODS: This was a retrospective analysis of prospectively collected data on 50 patients with unexpected malignancy after a polypectomy treated between January 2003 and January 2008. A total of 27 patients (54%) were treated with watchful waiting, and 23 (46%) underwent subsequent surgery. The Mann-Whitney U-test and chi-square test were used to compare the results between the two groups. RESULTS: There were more patients in the surgery group with positive resection margins after the polypectomy (p = 0.002). No difference was found regarding tumour differentiation grade, lymphovascular invasion, local recurrence or distant metastasis. Intraoperative complications occurred in three patients (13%, 95% confidence interval: 0-28%). In all, 16 of the 23 operated patients had no residual tumour. Overall long-term survival was higher among the operated patients (p = 0.005), but there was no difference in cancer-free survival (p = 0.071). CONCLUSION: Overtreatment of patients with malignant colorectal polyps seems to occur. Which patients benefit from further surgery has yet to be determined. FUNDING: not relevant. TRIAL REGISTRATION: not relevant.

[Transanal minimally invasive surgery for distal rectal cancer treatment]. / Transanal minimally invasive surgery til behandling af lav rectumcancer.

Laparoscopic total mesorectal excision (LTME) has become the standard surgical treatment of rectal cancer. There is however technical challenges when operating patients with a narrow pelvis with tumours located in distal or middle part of the rectum. We describe a case of a 71-year-old male operated for a rectal cancer by LTME assisted by transanal approach. The patient had an uneventful post-operative course. Follow-up showed no signs of recurrence.

The outcome of rectal cancer after early salvage surgery following transanal endoscopic microsurgery seems promising.

INTRODUCTION: Transanal endoscopic microsurgery (TEM) allows locally complete resection of early rectal cancer as an alternative to conventional radical surgery. In patients with unfavourable post-TEM histology, salvage surgery can be performed. The aim of this study was to evaluate the results of early radical surgery after TEM for rectal cancer. MATERIAL AND METHODS: From 1997 to 2010, 86 TEM procedures were performed in 79 patients due to rectal cancer. Early salvage surgery was performed in 25 patients. Data were obtained from the patients' charts and reviewed retrospectively. Perioperative data and oncological outcome were analysed. RESULTS: No patients received preoperative chemotherapy. The median time to salvage surgery was 37 days. Five patients underwent laparoscopic surgery. The median operative time was 165 min (range: 101-341 min, 95% confidence interval (CI): 156-214 min) and the median blood loss 275 ml (range: 0-1,275 ml, 95% CI: 232-530 ml). The 30-day mortality was 8% (95% CI: 1-19%, n = 2). Intraoperative perforation occurred in 20% (95% CI: 3-37%, n = 5). The median number of harvested lymph nodes was 12 (range: 3-25, 95% CI: 9-14) and the median circumferential resection margin (CRM) was 10 mm (range: 0-20 mm, 95% CI: 5-12 mm). Only one patient (4%, 95%CI: 1-12%) had a positive CRM. The median follow-up time was 25 months (range: 3-80 months). There was no local recurrence. Distant metastasis occurred in 4% (95% CI: 1-12%, n = 1). CONCLUSION: Early salvage surgery after TEM seems to be safe despite a high risk of specimen perforation during the operation. FUNDING: not relevant. TRIAL REGISTRATION: not relevant.