Circulating tumour DNA and risk of recurrence in patients with asymptomatic versus symptomatic colorectal cancer.

BACKGROUND: Multiple initiatives aim to develop circulating tumour DNA (ctDNA) tests for early cancer detection in asymptomatic individuals. The few studies describing ctDNA-testing in both asymptomatic and symptomatic patients report lower ctDNA detection in the asymptomatic patients. Here, we explore if asymptomatic patients differ from symptomatic patients e.g. by including a 'low-ctDNA-shedding' and 'less-aggressive' subgroup. METHODS: ctDNA assessment was performed in two independent cohorts of consecutively recruited patients with asymptomatic colorectal cancer (CRC) (Cohort#1: n = 215, Cohort#2: n = 368) and symptomatic CRC (Cohort#1: n = 117, Cohort#2: n = 722). RESULTS: After adjusting for tumour stage and size, the odds of ctDNA detection was significantly lower in asymptomatic patients compared to symptomatic patients (Cohort#1: OR: 0.4, 95%CI: 0.2-0.8, Cohort#2: OR: 0.7, 95%CI: 0.5-0.9). Further, the recurrence risk was lower in asymptomatic patients (Cohort#1: sHR: 0.6, 95%CI: 0.3-1.2, Cohort#2: sHR: 0.6, 95%CI: 0.4-1.0). Notably, ctDNA-negative asymptomatic patients had the lowest recurrence risk compared to the symptomatic patients (Cohort#1: sHR: 0.2, 95%CI: 0.1-0.6, Cohort#2: sHR: 0.3, 95%CI: 0.2-0.6). CONCLUSIONS: Our study suggests that asymptomatic patients are enriched for a 'low-ctDNA-shedding-low-recurrence-risk' subgroup. Such insights are needed to guide ctDNA-based early-detection initiatives and should prompt discussions about de-escalation of therapy and follow-up for ctDNA-negative asymptomatic CRC patients.

Colon CApsule endoscopy compared to conventional COlonoscopy in patients with colonic DIverticulitis: the study protocol for a randomised controlled superiority trial (CACODI trial).

INTRODUCTION: Follow-up after an episode of colonic diverticulitis is a common indication for colonoscopy, even though studies have shown a low risk of positive findings in this population. Our objective is to investigate colon capsule endoscopy (CCE) as a follow-up examination in patients with colonic diverticulitis compared with colonoscopy, particularly regarding patient satisfaction and clinical performance. METHODS AND ANALYSIS: We will conduct a single-centre prospective randomised controlled trial. Patients seen at Odense University Hospital with acute diverticulitis confirmed by CT will be included and randomised to either follow-up by colonoscopy or CCE. Detection of suspected cancer, more than two polyps or any number of polyps larger than 9 mm in CCE will generate an invitation to a diagnostic colonoscopy for biopsies or polyp removal. We will compare colonoscopy and CCE regarding patient satisfaction and tolerance, the number of complete examinations, the number of patients referred to a subsequent colonoscopy after CCE and the prevalence of diverticula, polyps, cancers and other abnormal findings. ETHICS AND DISSEMINATION: Informed consent will be obtained from all participants before randomisation. The study was approved by the regional ethics committee (ref. S-20210127) and the Danish Data Protection Agency (ref. 22/43235). After completion of the trial, we plan to publish two articles in high-impact journals. One article on both primary and secondary outcomes. TRIAL REGISTRATION NUMBER: NCT05700981.

Surgical efficacy and learning curves of laparoscopic complete mesocolic excision with intracorporeal anastomosis for right-sided colon cancer: A retrospective two-center cohort study.

BACKGROUND: There is a potential benefit on long-term outcomes following complete mesocolic excision (CME) for right-sided colon cancer when compared to conventional colectomy. This study aims to analyze the learning curve and short-term outcomes of laparoscopic CME with intracorporeal anastomosis (ICA) for right-sided colon cancer in the hands of experienced colorectal surgeons. METHODS: A two-center cohort study of consecutive patients undergoing right-sided colectomy from September 2021 to May 2022 at two tertiary colorectal centers in Denmark. Learning curves of surgical time were estimated using a cumulative sum analysis (CUSUM). RESULTS: A total of 61 patients were included. According to the CUSUM analysis, 32 cases were needed to obtain a peak in operative time, resulting in a decrease in time consumption (group 1/learning phase: 217.2 min [SD 53.6] and group 2/plateau phase 191.6 min [SD 45.1], p = 0.05). There was a nonsignificant reduction in the rates of severe surgical complications (Clavien-Dindo > 3) (13% vs. 7%, p = 0.67) between the two groups, while the length of hospital stay remained constant (median 3.0 days, interquartile range, IQR [2.0; 4.0]). CONCLUSION: The learning curve of laparoscopic CME with ICA for right-sided colon cancer demonstrated that 32 cases were needed to obtain a plateau phase expressed by operative time.

Impact of Whole Genome Doubling on Detection of Circulating Tumor DNA in Colorectal Cancer.

OBJECTIVE: Circulating tumor DNA (ctDNA) is a candidate biomarker of cancer with practice-changing potential in the detection of both early and residual disease. Disease stage and tumor size affect the probability of ctDNA detection, whereas little is known about the influence of other tumor characteristics on ctDNA detection. This study investigates the impact of tumor cell whole-genome doubling (WGD) on the detection of ctDNA in plasma collected preoperatively from newly diagnosed colorectal cancer (CRC) patients. METHODS: WGD was estimated from copy numbers derived from whole-exome sequencing (WES) data of matched tumor and normal DNA from 833 Danish CRC patients. To explore if tumor WGD status impacts ctDNA detection, we applied tumor-informed ctDNA analysis to preoperative plasma samples from all patients. RESULTS: Patients with WGD+ tumors had 53% increased odds of being ctDNA positive (OR = 1.53, 95%CI: 1.12-2.09). After stratification for UICC stage, the association persisted for Stage I (OR = 2.44, 95%CI: 1.22-5.03) and Stage II (OR = 1.76, 95%CI: 1.11-2.81) but not for Stage III (OR = 0.83, 95%CI: 0.44-1.53) patients. CONCLUSION: The presence of WGD significantly increases the probability of detecting ctDNA, particularly for early-stage disease. In patients with more advanced disease, the benefit of WGD on ctDNA detection is less pronounced, consistent with increased DNA shedding from these tumors, making ctDNA detection less dependent on the amount of ctDNA released per tumor cell.

Colon capsule endoscopy following incomplete colonoscopy in routine clinical settings.

BACKGROUND: Colon capsule endoscopy (CCE) was introduced in our department on two indications; following incomplete colonoscopy as an alternative to CT colonography, and in patients with a history of incomplete colonoscopy as an alternative to anesthesia-assisted (AA) colonoscopy. We aimed to compare the quality of CCE, defined by completion rate and polyp detection rate (PDR), with that of CT colonography and AA colonoscopy, respectively. METHODS: Patients referred for CCE from May 2020 until November 2021 were consecutively included in this prospective cohort study. Demographics, indication and CCE outcomes were registered from the electronic patient record. Completion rate and PDR in CCE as an alternative to CT colonography were compared with those of a historical cohort undergoing CT colonography following incomplete colonoscopy. Completion rate and PDR in CCE as an alternative to AA colonoscopy were compared with those of a time true parallel cohort undergoing AA colonoscopy. RESULTS: In 65 patients undergoing CCE, 36 (57%) were referred as an alternative to CT colonography. The completion rate in this group was 44% compared to 96% in CT colonography (p < 0.001). The PDR in complete CCE in this group was 75% in CCE compared to 20% in CT colonography (p < 0.001). The remaining 27 (43%) of the sample were referred for CCE as an alternative to AA colonoscopy. The completion rate in this group was 33% compared to 100% in AA colonoscopy (p < 0.001). The PDR in complete CCE in this group was 78% in CCE compared to 35% in AA colonoscopy (p = 0.013). CONCLUSIONS: The completion rate of CCE following incomplete colonoscopy is inferior to that of CT colonography and AA colonoscopy. The PDR of CCE was high, indicating an acceptable sensitivity in complete investigations, but in our settings the completion rate of CCE on this indication is unacceptably low. CLINICAL TRIAL REGISTRATION: NCT04307901 (ClinicalTrials.gov, March 13, 2020).

Robotic vs. TaTME Rectal Surgery (ROTA STUDY) Matched Cohort Trial for Mid to Low Rectal Cancer Surgery Evaluation Trial in the Hands of an Experienced Surgeon.

Background: Recent novel surgical techniques for resection of low rectal cancer have been introduced and these approaches have the potential to overcome anatomical limitations like obesity, narrow male pelvis and bulky and low tumours. Two of these procedures are robotic low anterior resection (RLAR) and transanal total mesorectal excision (TaTME).Both approaches have distinct advantages and limitations. There has been no head to head trial comparing RLAR and TaTME for patients with mid to low rectal cancer undergoing surgery by experienced surgeons. Previous studies looking at the oncological outcomes of either TaTME or robotic TME included many centres where the surgeons were on a learning curve and hence the true oncological outcomes and clinical benefits can not be measured accurately. Method: The inclusion criteria include experienced surgeons defined as minimum of 60 prior procedures with RLAR or TaTME. Successful oncological and clinical outcomes are defined as circumferential resection margin (CRM) ≥1 mm with limited postoperative morbidity (absence of Clavien-Dindo grade III-IV complications within 30 days after surgery). Local and distal recurrence rates with DFS over 3 years will be measured as primary outcome.Data will be collected prospectively and entered in a dedicated database. Discussion: The primary objective of this study is to conduct a multicentre prospective trial to investigate clinical outcomes, in particular disease free survival (DFS) in patients undergoing RLAR and TaTME. The additional goal is to investigate other efficacy measures, complications rates, health economic aspects and patient reported health related quality of life.This paper describes an important trial conducted in expert centres to establish the needed knowledge for a detailed comparison of outcomes for TaTME versus RLAR.This trial is the first comparative study, comparing TaTME and RLAR, seeking to establish foothold for tailor-made surgical treatment of low rectal cancer patients. Trial registration: The trial is registered in clinicaltrials.gov September 2019. Clinicaltrials.gov id: NCT04200027.

Circulating Tumor DNA in Stage III Colorectal Cancer, beyond Minimal Residual Disease Detection, toward Assessment of Adjuvant Therapy Efficacy and Clinical Behavior of Recurrences.

PURPOSE: Sensitive methods for risk stratification, monitoring therapeutic efficacy, and early relapse detection may have a major impact on treatment decisions and patient management for stage III colorectal cancer patients. Beyond assessing the predictive power of postoperative ctDNA detection, we explored the added benefits of serial analysis: assessing adjuvant chemotherapy (ACT) efficacy, early relapse detection, and ctDNA growth rates. EXPERIMENTAL DESIGN: We recruited 168 patients with stage III colorectal cancer treated with curative intent at Danish and Spanish hospitals between 2014 and 2019. To quantify ctDNA in plasma samples (n = 1,204), 16 patient-specific somatic single-nucleotide variants were profiled using multiplex-PCR, next-generation sequencing. RESULTS: Detection of ctDNA was a strong recurrence predictor postoperatively [HR = 7.0; 95% confidence interval (CI), 3.7-13.5; P < 0.001] and directly after ACT (HR = 50.76; 95% CI, 15.4-167; P < 0.001). The recurrence rate of postoperative ctDNA-positive patients treated with ACT was 80% (16/20). Only patients who cleared ctDNA permanently during ACT did not relapse. Serial ctDNA assessment after the end of treatment was similarly predictive of recurrence (HR = 50.80; 95% CI, 14.9-172; P < 0.001), and revealed two distinct rates of exponential ctDNA growth, slow (25% ctDNA-increase/month) and fast (143% ctDNA-increase/month; P < 0.001). The ctDNA growth rate was prognostic of survival (HR = 2.7; 95% CI, 1.1-6.7; P = 0.039). Serial ctDNA analysis every 3 months detected recurrence with a median lead-time of 9.8 months compared with standard-of-care computed tomography. CONCLUSIONS: Serial postoperative ctDNA analysis has a strong prognostic value and enables tumor growth rate assessment. The novel combination of ctDNA detection and growth rate assessment provides unique opportunities for guiding decision-making.See related commentary by Morris and George, p. 438.

[Asymptomatic amoebiasis colitis detected during colonoscopy].

In this case report, a tumour was found in the coecum under a colonoscopy, performed after positive screening test for colorectal cancer in an asymptomatic 61-year-old man. Pathology from biopsies showed numerous trophozoites in the lamina propria, compatible with Entamoeba histolytica. In faecal samples, E. histolytica was detected by species-specific real-time polymerase chain reaction. Infection caused by E. histolytica can occur several years after exposure. If E. histolytica is detected, treatment is always recommended as prevention for later development of invasive infection.

The value of contrast-enhanced laparoscopic ultrasound during robotic-assisted surgery for primary colorectal cancer.

AIM: The aim of this study was to assess the potential clinical value of contrast enhanced laparoscopic ultrasonography (CE-LUS) as a screening modality for liver metastases during robotic assisted surgery for primary colorectal cancer (CRC). METHOD: A prospective, descriptive (feasibility) study including 50 consecutive patients scheduled for robotic assisted surgery for primary CRC. CE-LUS was performed by 2 experienced specialists. Only patients without metastatic disease were included. Follow-up was obtained with contrast-enhanced CT imaging at 3 and 12 months postoperatively. RESULTS: Fifty patients were included; 45 patients were available for final analysis. The patients were equally distributed between stage I, II, and III according to the TNM classification system. No liver metastasis was detected during LUS and CE-LUS. CE-LUS was easy to perform and there was no complication. Follow-up revealed no liver metastasis in any of the patients. CONCLUSION: CE-LUS did not increase the detection rate of occult liver metastasis during robotic assisted primary CRC surgery. The use of CE-LUS as a screening modality for detection of liver metastasis cannot be recommended based on this study, but larger controlled studies on high-risk patients seem relevant.