Clinical challenges of consensus molecular subtype CMS4 colon cancer in the era of precision medicine.

Over the past decade, our understanding of the diversity of colorectal cancer (CRC) has expanded significantly, raising hopes of tailoring treatments more precisely for individual patients. A key achievement in this direction was the establishment of the consensus molecular classification, particularly identifying the challenging consensus molecular subtype (CMS) CMS4 associated with poor prognosis. Due to its aggressive nature, extensive research is dedicated to the CMS4 subgroup. Recent years have unveiled molecular and microenvironmental features at the tissue level specific to CMS4 CRC. This has paved the way for mechanistic studies and the development of preclinical models. Simultaneously, efforts have been made to easily identify patients with CMS4 CRC. Reassessing clinical trial results through the CMS classification lens has improved our understanding of the therapeutic challenges linked to this subtype. Exploration of the biology of CMS4 CRC is yielding potential biomarkers and novel treatment approaches. This overview aims to provide insights into the clinico-biological characteristics of the CMS4 subgroup, the molecular pathways driving this subtype, and available diagnostic options. We also emphasize the therapeutic challenges associated with this subtype, offering potential explanations. Finally, we summarize the current tailored treatments for CMS4-CRC emerging from fundamental and preclinical studies.

Management after local excision of small rectal cancers. Indications for completion total mesorectal excision and possible alternatives.

The treatment of superficial rectal cancers (local excision, or proctectomy with total mesorectal excision (TME) remains controversial. Endoscopy and endorectal ultrasonography are essential for the precise initial definition of these small cancers. During endoscopy, the depth of the lesion can be estimated using virtual chromoendoscopy with magnification, thereby aiding the assessment of the possibilities of local excision. Current international recommendations indicate completion proctectomy after wide local excision for cases where the pathologic examination reveals poorly-differentiated lesions, lymphovascular invasion, grade 2 or 3 tumor budding, and incomplete resection. But debate persists regarding whether the depth of submucosal invasion can accurately predict the risk of lymph node spread. Recent data from the literature suggest that the depth of submucosal invasion should no longer, by itself, be an indication for additional oncological surgery. Adjuvant radio-chemotherapy could be an alternative to completion proctectomy in patients with pT1 rectal cancer and unfavorable histopathological criteria. A Dutch randomized controlled trial is underway to validate this strategy.

Management of adult intestinal stomas: The 2023 French guidelines.

AIM: Digestive stoma are frequently performed. The last French guidelines have been published twenty years ago. Our aim was to update French clinical practice guidelines for the perioperative management of digestive stoma and stoma-related complications. METHODS: A systematic literature review of French and English articles published between January 2000 and May 2022 was performed. Only digestive stoma for fecal evacuation in adults were considered. Stoma in children, urinary stoma, digestive stoma for enteral nutrition, and rare stoma (Koch, perineal) were not included. RESULTS: Guidelines include the surgical landmarks to create digestive stoma (ideal location, mucocutaneous anastomosis, utility of support rods, use of prophylactic mesh), the perioperative clinical practice guidelines (patient education, preoperative ostomy site marking, postoperative equipment, prescriptions, and follow-up), the management of early stoma-related complications (difficulties for nursing, high output, stoma necrosis, retraction, abscess and peristomal skin complications), and the management of late stoma-related complications (stoma prolapse, parastomal hernia, stoma stenosis, late stoma retraction). A level of evidence was assigned to each statement. CONCLUSION: These guidelines will be very useful in clinical practice, and allow to delete some outdated dogma.

Transcriptomic Signatures of MSI-High Metastatic Colorectal Cancer Predict Efficacy of Immune Checkpoint Inhibitors.

PURPOSE: Microsatellite instability (MSI) is currently the only predictive biomarker of efficacy of immune checkpoint inhibitors (ICI) in metastatic colorectal cancers (mCRC). However, 10% to 40% of patients with MSI mCRC will experience a primary resistance to ICI. EXPERIMENTAL DESIGN: In two cohorts of patients with MSI mCRC treated with ICI (exploratory, N = 103; validation, N = 35), 3' RNA sequencing was performed from primary tumors. Previously described single-cell transcriptomic signatures of tumor microenvironment (TME) were analyzed. RESULTS: In the exploratory cohort, the unsupervised clustering allowed the identification of three clusters of tumors with distinct transcriptional profiles: cluster A ("stromalHIGH-proliferationLOW"), cluster B ("stromalHIGH-proliferationMED"), and cluster C ("stromalLOW-proliferationHIGH"), with an enrichment of patients progressing at first disease assessment under ICI in cluster A (30% vs. 12% in cluster B and 8.1% in cluster C; P = 0.074). Progression-free survival (PFS) was also significantly shorter in patients belonging to cluster A, compared with clusters B or C (P < 0.001) with 2-year PFS rates of 33.5%, 80.5%, and 78.3%, respectively. In multivariate analysis, PFS was still significantly longer in patients belonging to cluster B [HR, 0.19; 95% confidence interval (CI), 0.08-0.45; P < 0.001] and cluster C (HR, 0.25; 95% CI, 0.10-0.59; P = 0.02), compared with patients belonging to cluster A. The association of this clustering with PFS under ICI was confirmed in the validation cohort. PFS related to non-ICI-based regimens was not significantly different according to cluster. CONCLUSIONS: This unsupervised transcriptomic classification identified three groups of MSI mCRCs with different compositions of TME cells and proliferative capacities of TME/tumor cells. The "stromalHIGH-proliferationLOW" cluster is associated with a poorer prognosis with ICI treatment.

A Preclinical Validation of Iron Oxide Nanoparticles for Treatment of Perianal Fistulizing Crohn's Disease.

Fistulizing anoperineal lesions are severe complications of Crohn's disease (CD) that affect quality of life with a long-term risk of anal sphincter destruction, incontinence, permanent stoma, and anal cancer. Despite several surgical procedures, they relapse in about two-thirds of patients, mandating innovative treatments. Ultrasmall particles of iron oxide (USPIO) have been described to achieve in vivo rapid healing of deep wounds in the skin and liver of rats thanks to their nanobridging capability that could be adapted to fistula treatment. Our main purpose was to highlight preclinical data with USPIO for the treatment of perianal fistulizing CD. Twenty male Sprague Dawley rats with severe 2,4,6-trinitrobenzenesulfonic acid solution (TNBS)-induced proctitis were operated to generate two perianal fistulas per rat. At day 35, two inflammatory fistulas were obtained per rat and perineal magnetic resonance imaging (MRI) was performed. After a baseline MRI, a fistula tract was randomly drawn and topically treated either with saline or with USPIO for 1 min (n = 17 for each). The rats underwent a perineal MRI on postoperative days (POD) 1, 4, and 7 and were sacrificed for pathological examination. The primary outcome was the filling or closure of the fistula tract, including the external or internal openings. USPIO treatment allowed the closure and/or filling of all the treated fistulas from its application until POD 7 in comparison with the control fistulas (23%). The treatment with USPIO was safe, permanently closed the fistula along its entire length, including internal and external orifices, and paved new avenues for the treatment of perianal fistulizing Crohn's disease.

Nonmetastatic ypt0 rectal cancer after neoadjuvant treatment and total mesorectal excision: Lessons from a retrospective multicentric cohort of 383 patients.

BACKGROUND: A better understanding of pathological features and oncological survival in ypT0 rectal cancer after neoadjuvant chemoradiotherapy is required to improve patient selection criteria for rectal-preserving approach by local excision. Our aim was to define risk of lymph node metastasis and oncological outcomes in ypT0 rectal cancer after chemoradiotherapy and total mesorectal excision. METHODS: All consecutive patients who underwent total mesorectal excision for a nonmetastatic rectal adenocarcinoma classified ypT0 after neoadjuvant chemoradiotherapy, with or without locoregional lymph node involvement (ypN+ or ypN-), in 14 French academic centers between 2002 and 2015 were included. Data were collected retrospectively. Overall and disease-free survival were explored. RESULTS: Among the 383 ypT0 patients, 6% were ypN+ (23/283). Before chemoradiotherapy, 86% (327/380) were staged cT3-T4 and 41% (156/378) were staged cN+. The risk of ypN+ did not differ between cT3-T4 and cT1-T2 patients (P = .345) or between cN+ and cN- patients (P = .384). After a median follow-up of 61.1 months, we observed 95% confidence interval (92%-97%) of 5-year overall survival and 93% confidence interval (91%-96%) of 5-year disease-free survival. In Cox multivariate analysis, overall survival was altered by intra-abdominal septic complications (hazard ratio = 2.53, confidence interval [1.11-5.78], P = .028). Regarding disease-free survival, ypN+ status and administration of adjuvant chemotherapy were associated with a reduced disease-free survival (P = .001 for both). cT3/T4 staging and cN+ staging did not modify overall survival (P = .332 and P = .450) nor disease-free survival (P = .862 and P = .124). CONCLUSION: The risk of lymph node metastasis and the oncological survival do not depend on the initial cT or cN staging in cases of ypT0 complete rectal tumor regression.

Emergency surgery for obstructive splenic flexure colon cancer: results of a multicentric study of the French Surgical Association (AFC).

Management of malignant left-sided colonic obstruction remains challenging and requires a stoma in 40-65% of patients. In those with obstructive splenic flexure colon cancer (OSFCC), a debate still exists regarding the most appropriate surgery. The aim of this muticenter study was to report and compare the different surgical procedures in OSFCC patients with a special focus on operative and histological characteristics and survival outcomes including 12-month stoma-free survival. Between 2000 and 2015, 2325 patients were treated for obstructive colon cancer in centers members of the French National Surgical Association (AFC). Among them, 198 underwent surgery for OSFCC and were retrospectively analyzed. Patients with OSFCC and proximal colonic ischemia or perforation were excluded. Four procedures were performed: decompressing stoma (DS, 39%), splenic flexure colectomy (SFC, 39%), subtotal colectomy (STC, 17%,) and left hemicolectomy (LHC, 5%). All patients treated with LHC underwent a Hartmann's procedure. There was no significant difference between groups for postoperative mortality and morbidity. Hospital stay was significantly longer after DS. The length of the specimen, longitudinal resection margins and number of harvested lymph nodes were significantly higher in the STC group. There was no difference for overall and disease-free survival. Stoma-free survival was significantly lower after LHC (62%) in comparison with the other groups (p < 0.0001). At the end of follow-up, 50% of patients who underwent LHC had a permanent stoma. In OSFCC patients without proximal colonic ischemia or peritonitis, LHC should no longer be recommended due to a high risk of permanent stoma.

Impact of laparoscopy on oncological outcomes after colectomy for stage III colon cancer: A post-hoc multivariate analysis from PETACC8 European randomized clinical trial.

BACKGROUND: In colon cancer (CC), surgery remains the mainstay of treatment with curative intent. Despite several clinical trials comparing open and laparoscopic approaches, data on long-term outcomes for stage III CC are lacking. METHODS: This post-hoc analysis of the European PETACC8 randomized phase 3 trial included patients from 340 sites between December 2005 and November 2009, with long follow-up (median 7.56 years). Patients were randomly assigned to FOLFOX or FOLFOX+cetuximab after colonic resection. The surgical approach was left to the referring surgeon's discretion. RESULTS: Among 2555 patients included, 1796 (70.29%) were operated on by open surgery and 759 (29.71%) by laparoscopy. The 5-year OS rate was better after laparoscopic resection (85.4%, 95%CI 82.5-87.7) than after open surgery (80.2%, 95%CI 78.2-82.0; p = 0.002). The 5-year DFS rate was also better after laparoscopy (p = 0.016). However, in multivariate analysis using a propensity matching, the surgical approach was not found to be an independent prognostic factor for OS or DFS. OS (p = 0.0243) and DFS (p = 0.035) were increased after laparoscopic surgery in KRAS/BRAF WT sub-group CONCLUSION: We showed that laparoscopic resection has comparable long-term outcomes to open surgery in patients with stage III CC. For those with RAS and BRAF WT CC, laparoscopic colectomy may favorably impact survival.

Monitoring of C-reactive protein decreases length of stay after laparoscopic total mesorectal excision for cancer: a prospective case-matched study in 236 patients.

AIM: The aim of this study was to evaluate a discharge strategy driven by monitoring of C-reactive protein (CRP) in a homogeneous group of patients undergoing laparoscopic total mesorectal excision with sphincter-saving surgery for rectal cancer (TME). METHOD: One hundred and thirteen patients who underwent a TME had CRP monitoring on postoperative day (POD) 5. Patients were discharged on POD 6 if the CRP level was ≤100 mg/L. Patients were matched (according to age, gender, body mass index, neoadjuvant pelvic irradiation and type of anastomosis) to 123 control patients who underwent the same operation with the same postoperative care but without CRP monitoring. RESULTS: Postoperative 3-month overall [CRP group 62/113 (55%) vs controls 73/123 (59%); p = 0.487] and severe (i.e. Clavien-Dindo grade 3 and above) [CRP group 17/113 (15%) vs controls 19/123 (15%); p = 0.931] morbidity rates were similar between groups. Mean length of hospital stay (LHS) was significantly shorter in the CRP group (CRP group 9.7 ± 14 days vs controls 11.6 ± 7 days; p < 0.001). Discharge occurred on POD 6 in 55/113 (49%) patients from the CRP group vs 7/123 (6%) from the control group (p < 0.001). The rehospitalization rate [CRP group 19/113 (17%) vs controls 13/123 (11%); p = 0.177] was similar between groups. The CRP level on POD 5 had a diagnostic property to assess an anastomotic leakage with an area under the curve of 0.81. CONCLUSION: In patients who underwent TME, a discharge strategy based on CRP monitoring significantly decreased LHS without increasing morbidity, mortality or rehospitalization rates.