Differences in the molecular organisation of tumours along the colon are linked to interactions within the tumour ecosystem.

Tumours exhibit significant heterogeneity in their molecular profiles across patients, largely influenced by the tissue of origin, where certain driver gene mutations are predominantly associated with specific cancer types. Here, we unveil an additional layer of complexity: some cancer types display anatomic location-specific mutation profiles akin to tissue-specificity. To better understand this phenomenon, we concentrate on colon cancer. While prior studies have noted changes of the frequency of molecular alterations along the colon, the underlying reasons and whether those changes occur rather gradual or are distinct between the left and right colon, remain unclear. Developing and leveraging stringent statistical models on molecular data from 522 colorectal tumours from The Cancer Genome Atlas, we reveal disparities in molecular properties between the left and right colon affecting many genes. Interestingly, alterations in genes responsive to environmental cues and properties of the tumour ecosystem, including metabolites which we quantify in a cohort of 27 colorectal cancer patients, exhibit continuous trends along the colon. Employing network methodologies, we uncover close interactions between metabolites and genes, including drivers of colon cancer, showing continuous abundance or alteration profiles. This underscores how anatomic biases in the composition and interactions within the tumour ecosystem help explaining gradients of carcinogenesis along the colon.

Circulating tumor DNA in patients with locally advanced rectal cancer treated with multimodal treatment.

Background: The management of locally advanced rectal cancer (LARC) relies on a multimodal approach. Neither instrumental work-up nor molecular biomarkers are currently available to identify a risk-adapted strategy. Objectives: We aim to investigate the role of circulating tumor DNA (ctDNA) and its clearance at different timepoints during chemo-radiotherapy (CRT) and correlate them with clinical outcomes. Design: Between November 2014 and November 2019, we conducted a monocentric prospective observational study enrolling consecutive patients with LARC managed with neoadjuvant standard CRT (capecitabine and concomitant pelvic long-course radiotherapy), followed by consolidation capecitabine in selected cases and surgery. Methods: Blood samples for ctDNA were obtained at pre-planned timepoints. We evaluated the correlation of baseline variant allele frequency (VAF) with pathologic complete response (pCR) down-staging, node regression (pN0), event-free survival (EFS), and overall survival (OS). Results: Among 112 screened patients, 61 were enrolled. In all, 38 (62%) had a positive ctDNA at baseline with VAF > 0 and 23 had negative ctDNA (VAF = 0). Among patients with negative ctDNA, 30% had a complete response, while only 13% of positive ctDNA patients had pCR [odds ratio (OR) 0.35 (95% confidence interval (CI): 0.10-1.26), p = 0.11]. Similarly, 96% and 74% of pN0 were observed among negative and positive ctDNA patients, respectively [OR 0.13 (95% CI: 0.02-1.07), p = 0.058]. The presence of a baseline VAF > 0 was associated with a trend toward a lower EFS compared with VAF = 0 patients [hazard ratio (HR) = 2.30, 95% CI: 0.63-8.36, p = 0.21]. Within the limitations of small sample size, no difference in OS was observed according to the baseline ctDNA status (HR = 1.18, 95% CI: 0.35-4.06, p = 0.79). Conclusion: Within the limitations of a reduced number of patients, patients with baseline negative ctDNA seem to show a higher probability of pN0 status and a trend toward improved EFS. Prospective translational studies are required to define the role of ctDNA analysis in the multimodal treatment of LARC.

Tumour-specific mesorectal excision for rectal cancer: Systematic review and meta-analysis of oncological and functional outcomes.

BACKGROUND: Tumour-specific mesorectal excision (TSME) practice for rectal cancer only relies on small retrospective studies. This study aimed to perform a systematic review and meta-analysis to assess the oncological and functional outcomes of TSME practice. METHODS: A systematic review protocol was drawn to include all the studies that compared partial versus total mesorectal excision (PME vs TME) practised for rectal adenocarcinoma up to 16 cm from the anal verge. A systematic literature search was conducted on EMBASE-Medline, Pubmed and Cochrane Library. Reports were screened for the study's outcomes: oncological radicality, postoperative anastomotic leak risk and functional outcomes. Included studies were appraised for risk-of-bias and meta-analysed. Evidence was rated with the GRADE approach. RESULTS: Twenty-seven studies were included, consisting of 12325 patients (PME n = 4460, 36.2%; TME n = 7865, 63.8%). PME was performed for tumours higher than 10 cm from the anal verge in 54.5% of patients. There was no difference between PME and TME in circumferential resection margin positivity (OR 1.31, 95%CI 0.43-3.95, p = 0.64; I2 = 38%), and local recurrence risk (HR 1.05, 95%CI 0.52-2.10, p = 0.90; I2 = 40%). The postoperative leak risk (OR 0.42, 95%CI 0.27-0.67, p < 0.001; I2 = 60%) and the major low anterior resection syndrome risk (OR 0.34, 95%CI 0.28-0.40, p < 0.001; I2 = 0%) were lower after PME surgery. No difference was found in urinary incontinence (OR 0.68, 95%CI 0.13-3.67, p = 0.66) and urinary retention after early catheter removal (OR 2.00, 95%CI 0.24-16.51, p = 0.52). CONCLUSIONS: Evidence from this meta-analysis shows that TSME for rectal cancer has good oncological results and leads to the best-fitted functional results possible for the patient's condition.

Updates on Robotic CME for Right Colon Cancer: A Qualitative Systematic Review.

BACKGROUND: Complete mesocolic excision (CME) is a surgical technique introduced with the aim of ameliorating the oncologic results of colectomy. Various experiences have demonstrated favorable oncologic results of CME in comparison with standard colectomy, in which the principles of CME are not respected. The majority of the literature refers to open or laparoscopic CME. This review analyses current evidence regarding robotic CME for right colectomy. METHODS: An extensive Medline (Pub Med) search for relevant case series, restricted to papers published in English, was performed, censoring video vignettes and case reports. RESULTS: Fourteen studies (ten retrospective, four comparative series of robotic versus laparoscopic CME) were included, with patient numbers ranging from 20 to 202. Four different approaches to CME are described, which also depend on the robotic platform utilized. Intraoperative and early clinical results were good, with a low conversion and anastomotic leak rate and a majority of Clavien-Dindo complications being Grades I and II. Oncologic adequacy of the surgical specimens was found to be good, although a homogeneous histopathologic evaluation was not provided. CONCLUSIONS: Further large studies are warranted to define long-term oncologic results of robotic right colectomy with CME and its eventual benefits in comparison to laparoscopy.

Fluorescence-guided D3 lymphadenectomy in robotic right colectomy with complete mesocolic excision.

BACKGROUND: In robotic right hemicolectomy for cancer, appropriate lymphadenectomy is essential. Visualization of draining lymph nodes and blood flow with near-infrared (NIR) fluorescence DaVinci® imaging system is a recent development. We present the technique of robotic right colectomy with complete mesocolic excision (CME) and D3 lymphadenectomy using Indocyanine Green (ICG) endoscopic submucosal injection to intraoperatively identify tumour lymphatic basin. METHODS: The day before surgery, in patients scheduled for robotic right colectomy an endoscopic submucosal injection of 3 mg of ICG solution around the tumor is realized. Robotic right hemicolectomy is performed with suprapubic trocars layout and "bottom to up dissection", realizing a CME with central vessel ligation and D3 lymphadenectomy. Site of primary tumor and lymphatic basin are visible with the FireflyTM camera modality. RESULTS: From July 2016 to July 2020, 85 patients received a robotic right colectomy with CME and D3 lymphadenectomy. In 50 patients, ICG submucosal injection was performed: visualisation of the site of primary tumour and of LN in the D3 area was possible in all cases; in 17/50 patients (34%), LN out from anatomical lymphatic basin were identified. No side effects were observed. CONCLUSIONS: In this series, submucosal ICG injection showed to be feasible and safe. The accuracy in identification of D3 lymphatic basin was high, thus permitting an image-guided radical lymphadenectomy. Fluorescent technology represents an interesting innovation to ameliorate surgery of colon cancer.

Correction to: Robotic Versus Laparoscopic Right Colectomy with Complete Mesocolic Excision for the Treatment of Colon Cancer: Perioperative Outcomes and 5-Year Survival in a Consecutive Series of 202 Patients.

Dario Ribero's affiliation is corrected as reflected here.

Robotic right colectomy with complete mesocolic excision and indocyanine green guidance.

BACKGROUND: Robotic complete mesocolic excision (CME) has recently emerged as promising technique to enhance oncologic results in hemicolectomy for cancer. The potential near-infrared (NIR) fluorescence with indocyanine-green (ICG) dye for lymphatic mapping is under investigation and few small case-series are reported. METHODS: ICG solution was endoscopically injected the day before surgery in patients undergoing robotic right colectomy with CME using the Da Vinci Xi® system and the bottom to up technique. During surgery the ICG was excited by light in the near-infrared (NIR) spectrum of the Firefly™ system, of the Da Vinci Xi® system for image comparison in standard white light and NIR, and real-time visualization of the lymphatic drainage. RESULTS: Twenty patients affected by right colon cancer underwent robotic right colectomy with the bottom to up technique. No cases converted to open surgery were observed. During surgery, a fluorescent mapping of draining lymph nodes, was visualized in all the 20 patients. In seven patients (35%), lymph nodes outside the standard lymphatic basin were identified and removed. CONCLUSIONS: The association of robotic right colectomy with the bottom to up technique and ICG-guided lymphadenectomy is a feasible and safe procedure. ICG lymphatic mapping may help to perform a correct CME, although the independent impact of these procedures on oncologic outcome deserves further investigations.

Double indocyanine green technique of robotic right colectomy: Introduction of a new technique.

In robotic right hemicolectomy for colorectal cancer (CRC), appropriate lymphadenectomy and anastomotic leak prevention are critical. Visualisation of lymph nodes and blood flow with near-infrared (NIR) fluorescence DaVinci® imaging system is a recent development. Herein, we present an improved robotic modified complete mesocolic excision (mCME) technique using indocyanine green (ICG) fluorescence. Before surgery, ICG is injected into the submucosa around the tumour with endoscopy for intraoperative detection of lymph nodes. Robotic mCME with central vascular ligation is performed, supplemented in most of the cases with selective extended lymphadenectomy. Intestinal blood flow before anastomosis is evaluated by administering ICG intravenously and NIR visualisation. Visualisation of the lymph nodes with ICG facilitates standard mCME lymphadenectomy and enables extended lymphadenectomy. Blood flow of the intestinal walls of the anastomotic site can be assessed and determines the extent of intestinal resection. Robotic double ICG technique for robotic right hemicolectomy enables improved lymphadenectomy and warrants the extent of intestinal resection; thus, becoming a strong candidate for gold standard in robotic resections of the right colon for CRC.

Robotic Versus Laparoscopic Right Colectomy with Complete Mesocolic Excision for the Treatment of Colon Cancer: Perioperative Outcomes and 5-Year Survival in a Consecutive Series of 202 Patients.

BACKGROUND: During the past decade, the concept of complete mesocolic excision (CME) has emerged as a possible strategy to minimize recurrence for right colon cancers. The purpose of this study was to compare robotic versus laparoscopic CME in performing right colectomy for cancer. METHODS: Pertinent data of all patients who underwent robotic or laparoscopic right colectomy with CME using a Pfannenstiel incision and intracorporeal anastomosis performed between October 2005 and November 2015 were entered in a prospectively maintained database. RESULTS: A total of 202 patients underwent robotic (n = 101) or laparoscopic (n = 101) right colectomy within the study period. Patient characteristics were equivalent between groups. The robotic group showed a statistically significant reduction in conversion rate (0% vs. 6.9%, p = 0.01) but a longer operative time (279 min vs. 236 min, p < 0.001) compared with the laparoscopic group. There were no other differences in perioperative clinical or pathological outcomes. Five-years overall survival was 77 versus 73 months for the robotic versus laparoscopic groups (p = 0.64). The disease-free survival (DFS) rates were 85% and 83% for the robotic versus laparoscopic groups (p = 0.58). Among UICC stage III patients, there was a slight but not significant difference in 5-year DFS for the robotic group (81 vs. 68 months; p = 0.122). CONCLUSIONS: Both approaches for right colectomy with CME were safe and feasible and resulted in excellent survival. Robotic assistance was beneficial for performing intracorporeal anastomosis and dissection as evidenced by the lower conversion rates. Further robotic experience may shorten the operative time.

Green indocyanine fluorescence in robotic abdominal surgery.

Fluorescent imaging with indocyanine green (ICG) is an emerging technology that is gaining acceptance for being a valid tool in surgeons' decision making. ICG binds to plasma lipoproteins if injected intravenously and, when excited by near-infrared light, provides anatomic information about organs vascularization and tissues perfusion. If injected in tissues, it migrates in the lymphatic system, therefore enabling the identification of lymphatic draining pathways of different organs. In this paper we address specific applications of ICG fluorescence in robotic general surgery.