SafeHeal Colovac Colorectal Anastomosis Protection Device evaluation (SAFE-2) pivotal study: an international randomized controlled study to evaluate the safety and effectiveness of the Colovac Colorectal Anastomosis Protection Device.

AIM: Although proximal faecal diversion is standard of care to protect patients with high-risk colorectal anastomoses against septic complications of anastomotic leakage, it is associated with significant morbidity. The Colovac device (CD) is an intraluminal bypass device intended to avoid stoma creation in patients undergoing low anterior resection. A preliminary study (SAFE-1) completed in three European centres demonstrated 100% protection of colorectal anastomoses in 15 patients, as evidenced by the absence of faeces below the CD. This phase III trial (SAFE-2) aims to evaluate the safety and effectiveness of the CD in a larger cohort of patients undergoing curative rectal cancer resection. METHODS: SAFE-2 is a pivotal, multicentre, prospective, open-label, randomized, controlled trial. Patients will be randomized in a 1:1 ratio to either the CD arm or the diverting loop ileostomy arm, with a recruitment target of 342 patients. The co-primary endpoints are the occurrence of major postoperative complications within 12 months of index surgery and the effectiveness of the CD in reducing stoma creation rates. Data regarding quality of life and patient's acceptance and tolerance of the device will be collected. DISCUSSION: SAFE-2 is a multicentre randomized, control trial assessing the efficacy and the safety of the CD in protecting low colorectal anastomoses created during oncological resection relative to standard diverting loop ileostomy. TRIAL REGISTRATION: NCT05010850.

Robotic beyond total mesorectal excision for locally advanced rectal cancers: Perioperative and oncological outcomes from a multicentre case series.

BACKGROUND: Around 20% of rectal tumors are locally advanced with invasion into adjacent structures at presentation. These may require surgical resections beyond boundaries of total mesorectal excision (bTME) for radicality. Robotic bTME is under investigation. This study reports perioperative and oncological outcomes of robotic bTME for locally advanced rectal cancers. MATERIALS AND METHODS: A multicentre, retrospective analysis of prospectively collected robotic bTME resections (July 2015-November 2020). Demographics, clinicopathological features, short-term outcomes, recurrences, and survival were investigated. RESULTS: One-hundred-sixty-eight patients (eight centres) were included. Median age and BMI were 60.0 (50.0-68.7) years and 24.0 (24.4-27.7) kg/m2. Female sex was prevalent (n = 95, 56.8%). Fifty patients (29.6%) were ASA III-IV. Neoadjuvant chemoradiotherapy was given to 125 (74.4%) patients. Median operative time was 314.0 (260.0-450.0) minutes. Median estimated blood loss was 150.0 (27.5-500.0) ml. Conversion to laparotomy was seen in 4.8%. Postoperative complications occurred in 77 (45.8%) patients; 27.3% and 3.9% were Clavien-Dindo III and IV, respectively. Thirty-day mortality was 1.2% (n = 2). R0 rate was 92.9%. Adjuvant chemotherapy was offered to 72 (42.9%) patients. Median follow-up was 34.0 (10.0-65.7) months. Distant and local recurrences were seen in 35 (20.8%) and 15 patients (8.9%), respectively. Overall survival (OS) at 1, 3, and 5-years was 91.7, 82.1, and 76.8%. Disease-free survival (DFS) at 1, 3, and 5-years was 84.0, 74.5, and 69.2%. CONCLUSION: Robotic bTME is technically safe with relatively low conversion rate, good OS, and acceptable DFS in the hands of experienced surgeons in high volume centres. In selected cases robotic approach allows for high R0 rates during bTME.

Surgical Techniques and Related Perioperative Outcomes After Robot-assisted Minimally Invasive Gastrectomy (RAMIG): Results From the Prospective Multicenter International Ugira Gastric Registry.

OBJECTIVE: To gain insight in global practice of RAMIG and evaluated perioperative outcomes using an international registry. BACKGROUND: The techniques and perioperative outcomes of robot-assisted minimally invasive gastrectomy (RAMIG) for gastric cancer vary substantially in literature. METHODS: Prospectively registered RAMIG-cases for gastric cancer (≥10 per center) were extracted from 25 centers in Europe, Asia and South-America. Techniques for the resection, reconstruction, anastomosis and lymphadenectomy were analyzed, and related to perioperative surgical and oncological outcomes. Complications were uniformly defined by the Gastrectomy Complications Consensus Group. RESULTS: Between 2020-2023, 759 patients underwent total (n=272), distal (n=465) or proximal (n=22) gastrectomy (RAMIG). After total gastrectomy with Roux-en-Y-reconstruction, anastomotic leakage rates were 8% with hand-sewn (n=9/111) and 6% with linear stapled anastomoses (n=6/100). After distal gastrectomy with Roux-en-Y (67%) or Billroth-II-reconstruction (31%), anastomotic leakage rates were 3% with linear stapled (n=11/433) and 0% with hand-sewn anastomoses (n=0/26). Extent of lymphadenectomy consisted of D1+ (28%), D2 (59%) or D2+ (12%). Median nodal harvest yielded 31 nodes [IQR 21-47] after total and 34 nodes [IQR 24-47] after distal gastrectomy. R0-resection rates were 93% after total and 96% distal gastrectomy. Hospital stay was 9 days after total and distal gastrectomy, and was 3 days shorter without perianastomotic drains versus routine drain placement. Postoperative 30-day mortality was 1%. CONCLUSIONS: This large multicenter study provided a worldwide overview of current RAMIG-techniques with their respective perioperative outcomes. These outcomes demonstrated high surgical quality, set a quality standard for RAMIG and can be considered an international reference for surgical standardization.

Chemotherapy-Related Amenorrhea and Quality of Life Among Premenopausal Women With Breast Cancer.

Importance: Younger survivors of breast cancer frequently report more treatment-related symptoms, mostly related to the menopausal transition. Objective: To assess factors associated with chemotherapy-related amenorrhea (CRA) and to evaluate its association with long-term quality of life (QOL). Design, Setting, and Participants: The prospective, longitudinal Cancer Toxicities Study, a multicenter French cohort study, includes women with a diagnosis of stage I to III breast cancer and collects data approximately yearly after diagnosis. The current study reports outcomes up to 4 years after diagnosis for participants enrolled from 2012 to 2017. Participants included premenopausal women younger than 50 years treated with chemotherapy and not receiving adjuvant ovarian function suppression. Data analysis was performed from September 2021 to June 2023. Exposures: Clinical, socioeconomic, tumor, and treatment characteristics assessed at diagnosis (for the analysis of factors associated with CRA) and persistent CRA (for the QOL analysis). Main Outcomes and Measures: The main outcome of interest was CRA at year 1 (Y1), year 2 (Y2), and year 4 (Y4) after diagnosis. Generalized estimating equations assessed associations of exposure variables with CRA. In the QOL analysis, QOL at Y4 (assessed with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaires C30 and BR23) was the outcome of interest. Multivariable random-effect mixed models assessed the association of persistent CRA (ie, never recovering menses after treatment) with QOL. Results: Among 1636 women, the mean (SD) age at diagnosis was 42.2 (5.6) years. Overall, 1242 of 1497 women (83.0%) reported CRA at Y1, 959 of 1323 women (72.5%) reported it at Y2, and 599 of 906 women (66.1%) reported it at Y4. Older age vs 18 to 34 years (adjusted odds ratio [OR] for 35 to 39 years, 1.84 [95% CI, 1.32 to 2.56]; adjusted OR for 40 to 44 years, 5.90 [95% CI, 4.23 to 8.24]; and adjusted OR for ≥45 years, 21.29 [95% CI, 14.34 to 31.61]) and receipt of adjuvant tamoxifen (adjusted OR, 1.97 [95% CI, 1.53 to 2.53]) were associated with higher likelihood of CRA. In the QOL analysis, 416 of 729 women (57.1%) had persistent CRA. However, late menses recovery among women aged 18 to 34 years with no menses at Y2 were reported by 11 of 21 women (52.4%) between Y2 and Y4. Persistent CRA was associated with worse insomnia (mean difference vs recovery at any time, 9.9 points [95% CI, 3.2 to 16.5 points]; P = .004), systemic therapy-related adverse effects (mean difference, 3.0 points [95% CI, 0.2 to 5.8 points]; P = .04), and sexual functioning (mean difference, -9.2 points [95% CI, -14.3 to -4.1 points]; P < .001) at Y4. Conclusions and Relevance: In this cohort study of premenopausal women with breast cancer, persistent CRA was common, although some women recovered menses late, and was associated with worse long-term QOL. This study can help inform risk communication, personalized counseling, and early supportive care referrals for such patients.

GRECCAR 14 - a multicentric, randomized, phase II-III study evaluating the tailored management of locally advanced rectal carcinoma after a favourable response to induction chemotherapy: Study protocol.

AIM: Total neoadjuvant treatment (TNT) is becoming standard in patients with locally advanced rectal carcinoma (LARC). Preoperative chemoradiotherapy (CRT) has proven side effects on bowel and genitourinary function. An early tumoral response to induction chemotherapy demonstrates its high prognostic value. Tailored management could be used as an alternative to systematic CRT. The GRECCAR 14 trial will attempt to personalize treatment strategy according to the patient's early tumour response to intensive chemotherapy with the aim of achieving the best toxicity-efficiency ratio. METHOD: GRECCAR 14 is a multicentric, randomized, two-arm, phase II-III noninferiority trial. Patients with mid or low LARC with a predictive circumferential resection margin ≤2 mm or T3c-d stage with extramural venous invasion will be included. Evaluation of the tumoral response will be performed after six courses of high-dose FOLFIRINOX chemotherapy. Good responders (GRs) will be defined by a 60% decrease in tumoral volume on magnetic resonance imaging. Patients will be randomized to CRT before surgery. The primary endpoints will be R0 resection for phase II and the 3-year disease-free survival (DFS) for phase III. RESULTS: Tailored management of LARC is becoming an exciting challenge for the modality of neoadjuvant treatment and for the type of surgery or its omission. Neoadjuvant FOLFIRINOX has established efficacy, with a significant increase in the 3-year DFS. Better control of systemic disease must be accompanied by the same locoregional control, with the lowest morbidity. Our previous GRECCAR 4 trial demonstrated the high value of the early tumoral response after induction chemotherapy and the long-term safety of tailored management for GRs. CONCLUSION: If GRECCAR 14 demonstrates the ability to tailor TNT for LARC, this could lead to changes in clinical practice.

International standardization and optimization group for intersphincteric resection (ISOG-ISR): modified Delphi consensus on anatomy, definition, indication, surgical technique, specimen description and functional outcome.

AIM: Intersphincteric resection (ISR) is an oncologically complex operation for very low-lying rectal cancers. Yet, definition, anatomical description, operative indications and operative approaches to ISR are not standardized. The aim of this study was to standardize the definition of ISR by reaching international consensus from the experts in the field. This standardization will allow meaningful comparison in the literature in the future. METHOD: A modified Delphi approach with three rounds of questionnaire was adopted. A total of 29 international experts from 11 countries were recruited for this study. Six domains with a total of 37 statements were examined, including anatomical definition; definition of intersphincteric dissection, intersphincteric resection (ISR) and ultra-low anterior resection (uLAR); indication for ISR; surgical technique of ISR; specimen description of ISR; and functional outcome assessment protocol. RESULTS: Three rounds of questionnaire were performed (response rate 100%, 89.6%, 89.6%). Agreement (≥80%) reached standardization on 36 statements. CONCLUSION: This study provides an international expert consensus-based definition and standardization of ISR. This is the first study standardizing terminology and definition of deep pelvis/anal canal anatomy from a surgical point of view. Intersphincteric dissection, ISR and uLAR were specifically defined for precise surgical description. Indication for ISR was determined by the rectal tumour's maximal radial infiltration (T stage) below the levator ani. A new surgical definition of T3isp was reached by consensus to define T3 low rectal tumours infiltrating the intersphincteric plane. A practical flowchart for surgical indication for uLAR/ISR/abdominoperineal resection was developed. A standardized ISR surgical technique and functional outcome assessment protocol was defined.

Is Delaying a Coloanal Anastomosis the Ideal Solution for Rectal Surgery?: Analysis of a Multicentric Cohort of 564 Patients From the GRECCAR.

OBJECTIVES: To assess the specific results of delayed coloanal anastomosis (DCAA) in light of its 2 main indications. BACKGROUND: DCAA can be proposed either immediately after a low anterior resection (primary DCAA) or after the failure of a primary pelvic surgery as a salvage procedure (salvage DCAA). METHODS: All patients who underwent DCAA intervention at 30 GRECCAR-affiliated hospitals between 2010 and 2021 were retrospectively included. RESULTS: Five hundred sixty-four patients (male: 63%; median age: 62 years; interquartile range: 53-69) underwent a DCAA: 66% for primary DCAA and 34% for salvage DCAA. Overall morbidity, major morbidity, and mortality were 57%, 30%, and 1.1%, respectively, without any significant differences between primary DCAA and salvage DCAA ( P = 0.933; P = 0.238, and P = 0.410, respectively). Anastomotic leakage was more frequent after salvage DCAA (23%) than after primary DCAA (15%), ( P = 0.016).Fifty-five patients (10%) developed necrosis of the intra-abdominal colon. In multivariate analysis, intra-abdominal colon necrosis was significantly associated with male sex [odds ratio (OR) = 2.67 95% CI: 1.22-6.49; P = 0.020], body mass index >25 (OR = 2.78 95% CI: 1.37-6.00; P = 0.006), and peripheral artery disease (OR = 4.68 95% CI: 1.12-19.1; P = 0.030). The occurrence of this complication was similar between primary DCAA (11%) and salvage DCAA (8%), ( P = 0.289).Preservation of bowel continuity was reached 3 years after DCAA in 74% of the cohort (primary DCAA: 77% vs salvage DCAA: 68%, P = 0.031). Among patients with a DCAA mannered without diverting stoma, 75% (301/403) have never required a stoma at the last follow-up. CONCLUSIONS: DCAA makes it possible to definitively avoid a stoma in 75% of patients when mannered initially without a stoma and to save bowel continuity in 68% of the patients in the setting of failure of primary pelvic surgery.

Evaluation of the SafeHeal Colovac+ anastomosis protection device after low anterior resection for rectal cancer: the safe anastomosis feasibility evaluation (SAFE) 2019 trial.

BACKGROUND: Protective ileostomy (PI) is the current standard of care to protect the anastomosis after low anterior resection (LAR) for rectal cancer, but is associated with significant morbidity. Colovac is an anastomosis protection device designed to shield the anastomosis from fecal content. A second version (Colovac+) was developed to limit the migration risk during the implantation period. The objective of this clinical trial was to evaluate the preliminary efficacy and safety of the Colovac+. METHODS: This was a prospective, multicenter, pilot study aiming to enroll 15 patients undergoing LAR with Colovac+ placement. After 10 days, a CT scan was performed to evaluate the anastomosis and the Colovac+ was retrieved endoscopically. During the 10-day implantation and 3-month follow-up period, we collected data regarding predefined efficacy and safety endpoints. The primary endpoint was the rate of major (Clavien-Dindo III-V) postoperative complications related to the Colovac+ or LAR procedure. RESULTS: A total of 25 patients were included (68% male), of whom 15 were consecutively treated with the Colovac+ and Vacuum Loss Alert System. The Colovac+ was successfully implanted in all 15 patients. No major discomfort was reported during the implantation period. The endoscopic retrieval was performed in 14/15 (93%) patients. The overall major postoperative morbidity rate was 40%, but none of the reported complications were related to the Colovac+. A device migration occurred in 2 (13%) patients, but these were not associated with AL or stoma conversion. Overall, Colovac+ provided effective fecal diversion in all 15 patients and was able to avoid the PI in 11/15 (73%) patients. CONCLUSIONS: Colovac+ provides a safe and effective protection of the anastomosis after LAR, and avoids the PI in the majority (73%) of patients. The improved design reduces the overall migration rate and limits the clinical impact of a migration.

Iatrogenic ureteral injury during colorectal surgery has a significant impact on patient outcomes: a French multicentric retrospective cohort study.

AIM: The long-term urological sequelae after iatrogenic ureteral injury (IUI) during colorectal surgery are not clearly known. The aims of this work were to report the incidence of IUI and to analyse the long-term consequences of urological late complications and their impact on oncological results of IUI occurring during colorectal surgery through a French multicentric experience (GRECCAR group). METHOD: All the patients who presented with IUI during colorectal surgery between 2010 and 2019 were retrospectively included. Patients with ureteral involvement needing en bloc resection, delayed ureteral stricture or noncolorectal surgery were not considered. RESULTS: A total of 202 patients (93 men, mean age 63 ± 14 years) were identified in 29 centres, corresponding to 0.32% of colorectal surgeries (n = 63 562). Index colorectal surgery was mainly oncological (n = 130, 64%). IUI was diagnosed postoperatively in 112 patients (55%) after a mean delay of 11 ± 9 days. Intraoperative diagnosis of IUI was significantly associated with shorter length of stay (21 ± 22 days vs. 34 ± 22 days, p < 0.0001), lower rates of postoperative hydronephrosis (2% vs. 10%, p = 0.04), anastomotic complication (7% vs. 22.5%, p = 0.002) and thromboembolic event (0% vs. 6%, p = 0.02) than postoperative diagnosis of IUI. Delayed chemotherapy because of IUI was reported in 27% of patients. At the end of the follow-up [3 ± 2.6 years (1 month-13 years)], 72 patients presented with urological sequalae (36%). Six patients (3%) required a nephrectomy. CONCLUSION: IUI during colorectal surgery has few consequences for the patients if recognized early. Long-term urological sequelae can occur in a third of patients. IUI may affect oncological outcomes in colorectal surgery by delaying adjuvant chemotherapy, especially when the ureteral injury is not diagnosed peroperatively.

MRI restaging of rectal cancer: The RAC (Response-Anal canal-CRM) analysis joint consensus guidelines of the GRERCAR and GRECCAR groups.

PURPOSE: To develop guidelines by international experts to standardize data acquisition, image interpretation, and reporting in rectal cancer restaging with magnetic resonance imaging (MRI). MATERIALS AND METHODS: Evidence-based data and experts' opinions were combined using the RAND-UCLA Appropriateness Method to attain consensus guidelines. Experts provided recommendations for reporting template and protocol for data acquisition were collected; responses were analysed and classified as "RECOMMENDED" versus "NOT RECOMMENDED" (if ≥ 80% consensus among experts) or uncertain (if < 80% consensus among experts). RESULTS: Consensus regarding patient preparation, MRI sequences, staging and reporting was attained using the RAND-UCLA Appropriateness Method. A consensus was reached for each reporting template item among the experts. Tailored MRI protocol and standardized report were proposed. CONCLUSION: These consensus recommendations should be used as a guide for rectal cancer restaging with MRI.

Hybrid laparoscopic versus fully robot-assisted minimally invasive esophagectomy: an international propensity-score matched analysis of perioperative outcome.

BACKGROUND: Currently, little is known regarding the optimal technique for the abdominal phase of RAMIE. The aim of this study was to investigate the outcome of robot-assisted minimally invasive esophagectomy (RAMIE) in both the abdominal and thoracic phase (full RAMIE) compared to laparoscopy during the abdominal phase (hybrid laparoscopic RAMIE). METHODS: This retrospective propensity-score matched analysis of the International Upper Gastrointestinal International Robotic Association (UGIRA) database included 807 RAMIE procedures with intrathoracic anastomosis between 2017 and 2021 from 23 centers. RESULTS: After propensity-score matching, 296 hybrid laparoscopic RAMIE patients were compared to 296 full RAMIE patients. Both groups were equal regarding intraoperative blood loss (median 200 ml versus 197 ml, p = 0.6967), operational time (mean 430.3 min versus 417.7 min, p = 0.1032), conversion rate during abdominal phase (2.4% versus 1.7%, p = 0.560), radical resection (R0) rate (95.6% versus 96.3%, p = 0.8526) and total lymph node yield (mean 30.4 versus 29.5, p = 0.3834). The hybrid laparoscopic RAMIE group showed higher rates of anastomotic leakage (28.0% versus 16.6%, p = 0.001) and Clavien Dindo grade 3a or higher (45.3% versus 26.0%, p < 0.001). The length of stay on intensive care unit (median 3 days versus 2 days, p = 0.0005) and in-hospital (median 15 days versus 12 days, p < 0.0001) were longer for the hybrid laparoscopic RAMIE group. CONCLUSIONS: Hybrid laparoscopic RAMIE and full RAMIE were oncologically equivalent with a potential decrease of postoperative complications and shorter (intensive care) stay after full RAMIE.

Baseline quality of life and chemotherapy toxicities in patients with early breast cancer.

BACKGROUND: The authors used the French breast cancer Cancer and Toxicities (CANTO) cohort to study the associations between baseline quality of life and chemotherapy dose-reductions (CDRs) or postchemotherapy-toxicities (PCTs). METHODS: In total, 3079 patients with breast cancer who received chemotherapy were included in this analysis. The associations between baseline physical functioning (PF) and fatigue measured using the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire Core 30, and two endpoints-CDRs during adjuvant or neoadjuvant chemotherapy; and selected PCTs were estimated with odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) using logistic regression models. RESULTS: Among the 3079 patients from the CANTO cohort who were included, 718 (33.0%) received chemotherapy in the neoadjuvant setting, and 2361 (67.0%) received chemotherapy as adjuvant treatment. The chemotherapy included taxanes in 94.2% of patients and anthracyclines in 90.5% of patients. Overall, 15.5% of patients experienced CDRs and, 31.0% developed PCTs. Women with low baseline PF scores (<83) had higher multivariate odds of developing CDRs compared with those who had PF scores ≥83 (OR, 1.54; 95% CI, 1.13-2.09). The corresponding OR for PCTs was 1.50 (95% CI, 1.13-2.00). Women with high baseline fatigue scores had higher odds of CDRs (OR, 1.43; 95% CI, 1.13-1.76) and PCTs (OR, 1.32; 95% CI, 1.10-1.59). CONCLUSIONS: By using the national CANTO cohort, baseline PF and fatigue were independently associated with CDRs and PCTs.

Determination of biomarkers associated with neoadjuvant treatment response focusing on colibactin-producing Escherichia coli in patients with mid or low rectal cancer: a prospective clinical study protocol (MICARE).

INTRODUCTION: The management of mid and low rectal cancer is based on neoadjuvant chemoradiotherapy (CRT) followed by standardised surgery. There is no biomarker in rectal cancer to aid clinicians in foreseeing treatment response. The determination of factors associated with treatment response might allow the identification of patients who require tailored strategies (eg, therapeutic de-escalation or intensification). Colibactin-producing Escherichia coli (CoPEC) has been associated with aggressive colorectal cancer and could be a poor prognostic factor. Currently, no study has evaluated the potential association between intestinal microbiota composition and tumour response to CRT in mid and low rectal cancer. The aim of this study is to assess the association between response to neoadjuvant CRT and faecal intestinal microbiota composition and/or CoPEC prevalence in patients with mid or low rectal cancer. METHODS AND ANALYSIS: This is a non-randomised bicentric prospective clinical study with a recruitment capacity of 200 patients. Three stool samples will be collected from participants with histological-proven adenocarcinome of mid or low rectum who meet eligibility criteria of the study protocol: one before neoadjuvant treatment start, one in the period between CRT end and surgery and one the day before surgery. In each sample, CoPEC will be detected by culture in special media and molecular (PCR) approaches. The global microbiota composition will be also assessed by the bacterial 16S rRNA gene sequencing. Neoadjuvant CRT response and tumour regression grade will be described using the Dworak system at pathological examination. Clinical data and survival outcomes will also be collected and investigated. ETHICS AND DISSEMINATION: MICARE was approved by the local ethics committee (Comité de Protection des Personnes Sud-Est II, 18 December 2019. Reference number 2019-A02493-54 and the institutional review board. Patients will be required to provide written informed consent. Results will be published in a peer reviewed journal. TRIAL REGISTRATION NUMBER: NCT04103567.

The landscape of cancer-associated fibroblasts in colorectal cancer liver metastases.

Rationale: Patients with colorectal cancer die mainly due to liver metastases (CRC-LM). Although the tumor microenvironment (TME) plays an important role in tumor development and therapeutic response, our understanding of the individual TME components, especially cancer-associated fibroblasts (CAFs), remains limited. Methods: We analyzed CRC-LM CAFs and cancer cells by single-cell transcriptomics and used bioinformatics for data analysis and integration with related available single-cell and bulk transcriptomic datasets. We validated key findings by RT-qPCR, western blotting, and immunofluorescence. Results: By single-cell transcriptomic analysis of 4,397 CAFs from six CRC-LM samples, we identified two main CAF populations, contractile CAFs and extracellular matrix (ECM)-remodeling/pro-angiogenic CAFs, and four subpopulations with distinct phenotypes. We found that ECM-remodeling/pro-angiogenic CAFs derive from portal resident fibroblasts. They associate with areas of strong desmoplastic reaction and Wnt signaling in low-proliferating tumor cells engulfed in a stiff extracellular matrix. By integrating public single-cell primary liver tumor data, we propose a model to explain how different liver malignancies recruit CAFs of different origins to this organ. Lastly, we found that LTBP2 plays an important role in modulating collagen biosynthesis, ECM organization, and adhesion pathways. We developed fully human antibodies against LTBP2 that depleted LTBP2+ CAFs in vitro. Conclusion: This study complements recent reports on CRC-LM CAF heterogeneity at the single-cell resolution. The number of sequenced CAFs was more than one order of magnitude larger compared to existing data. LTBP2 targeting by antibodies might create opportunities to deplete ECM-remodeling CAFs in CRC-LMs. This might be combined with other therapies, e.g., anti-angiogenic compounds as already done in CRC. Moreover, we showed that in intrahepatic cholangiocarcinoma, in which ECM-remodeling CAF proportion is similar to that of CRC-LM, several genes expressed by ECM-remodeling CAFs, such as LTBP2, were associated with survival.

A multicentre, prospective cohort study of handsewn versus stapled intracorporeal anastomosis for robotic hemicolectomy.

AIM: Robotic right hemicolectomy is gaining in popularity due to the recognized technical benefits associated with the robotic platform. However, there is a lack of standardization regarding the optimal anastomotic technique in this cohort of patients, namely stapled or handsewn intra- or extra-corporeal anastomosis. The ergonomic benefit associated with the robotic platform lends itself to intracorporeal anastomosis (ICA). The aim of this study was to compare the short-term clinical outcomes of stapled versus handsewn ICA. METHOD: A multicentre prospective cohort study was undertaken across four high-volume robotic centres in France between September 2018 and December 2020. All adult patients undergoing an elective robotic right hemicolectomy with an ICA performed and a minimum postoperative follow-up of 30 days were included. The primary endpoint of our study was anastomotic leak within 30 days postoperatively. RESULTS: A total of 144 patients underwent robotic right hemicolectomy: 92 (63.8%) had a stapled ICA and 52 (36.1%) a handsewn ICA. The operative indication was adenocarcinoma in 90% with a stapled ICA compared with 62% in the handsewn ICA group (p < 0.001). The overall operating time was longer in the handsewn ICA group compared with the stapled ICA group (219 min vs. 193 min; p = 0.001). The anastomotic leak rate was 3.3% in stapled ICA and 3.8% in handsewn ICA (p = 1.00). There was no difference in the rate or severity of postoperative morbidity. CONCLUSION: ICA robotic hemicolectomy is technically safe and is associated with low rates of anastomotic leak overall and equivalent clinical outcomes between the two techniques.

Tailored Management with Highly-Selective Diversion for Low Colorectal Anastomosis: Biochemical Postoperative Follow-Up and Long-Term Results from a Single-Institution Cohort.

BACKGROUND: Defunctioning stoma (DS) can decrease the rate of symptomatic anastomotic leakage (AL). Since 2010, we have used tailored, highly selective DS management for low colorectal anastomosis (LCRA). METHODS: In total, 433 rectal cancer patients underwent the same standardized procedure. Non-stoma (NS) management was used in patients with no surgical difficulties as well as good colonic preparation and quality of anastomoses. In all other cases, DS was used. C-reactive protein was measured during postoperative follow-up. Imbalance in the initial population was adjusted using propensity-score matching according to sex, age, body mass index, tumor location, and American Society of Anesthesiologists score. Rate of AL within 30 days, 5-year overall survival, local relapse-free survival, and disease-free survival were recorded. RESULTS: Anastomosis was mostly ultra-low and was performed equally by laparoscopy or robotic surgery. The overall rate of AL was 13.4%, with no significant differences between groups (DS, 12.2%; NS, 14.6%; p = 0.575). Operative time, blood loss, and hospital stay were significantly lower for NS patients. The rate of secondary stoma was 11.4% overall. Pathological results were similar, with a 98% R0 resection rate. With a median follow-up of 5.5 years for the NS and DS groups, the overall survival was 84.9% and 73.4%, respectively (p = 0.064), disease-free survival was 67.0% and 55.8%, respectively (p = 0.095), and local relapse-free survival was 95.2% and 88.7%, respectively (p = 0.084). The long-term, stoma-free rate was 89.1% overall. CONCLUSIONS: Tailoring DS for LCRA seems safe and could provide potential benefits in postoperative morbidity with the same long-term oncological results in NS patients. Prospective, multicentric studies should validate this approach.

Tailored Strategy for Locally Advanced Rectal Carcinoma (GRECCAR 4): Long-term Results From a Multicenter, Randomized, Open-Label, Phase II Trial.

BACKGROUND: Systematic preoperative radiochemotherapy and total mesorectal excision are the standard of care for locally advanced rectal carcinoma. Some patients can be over- or undertreated. OBJECTIVE: This study aimed to investigate the long-term oncological, functional, and late morbidity outcomes after tailored radiochemotherapy and induction high-dose chemotherapy. DESIGN: This is a prospective, phase II, multicenter, open-label study at 16 tertiary centers in France. SETTINGS: Patients were operated on by surgeons from the French GRECCAR group. PATIENTS: Two hundred six patients were randomly assigned to treatment: good responders after chemotherapy (≥75% tumor volume reduction) to immediate surgery (arm A) or standard radiochemotherapy (capecitabine 50) plus surgery (arm B) and poor responders to capecitabine 50 (arm C) or intensive radiochemotherapy (capecitabine 60; 60 Gy irradiation; arm D) before surgery. INTERVENTIONS: Treatment was tailored according to MRI response to induction chemotherapy. RESULTS: After induction treatment, 194 patients were classified as good (n = 30, 15%) or poor (n = 164, 85%) responders; they were included in arms A and B (16 and 14 patients) or C and D (113 and 51 patients). The primary objective was obtained: R0 resection rates (90% CI) in the 4 arms were 100% (74-100), 100% (85-100), 83% (72-91), and 88% (77-95). At 5 years, overall survival rates were 90% (47.3-98.5), 93.3% (61.3-99.0), 84.3% (71.0-91.8), and 86.1% (71.6-93.5); disease-free survival rates were 80% (40.9-94.6), 89.5% (64.1-97.3), 72.9% (58.5-82.9), and 72.8% (57.7-83.2); local recurrence rates were 0%, 0%, 2.1% (0.3-13.9), and 9.3% (3.6-23.0); and metastasis rates were 20% (5.4-59.1), 10.5% (2.7-35.9), 18% (31.8-94.6), and 18.8% (10.2-33.0). Late morbidity and quality-of-life evaluations showed no significant difference between arms. LIMITATIONS: Limitations were due to the small number of patients randomly assigned in the good responder arms, especially arm A without radiotherapy. CONCLUSION: Tailoring preoperative radiochemotherapy based on induction treatment response appears to be promising. Future prospective trials should confirm this strategy. See Video Abstract at http://links.lww.com/DCR/B761 . REGISTRATION: URL: https://www.clinicaltrials.gov ; Identifier: NCT01333709. ESTRATEGIA HECHA A MEDIDA PARA EL TRATAMIENTO DEL CARCINOMA DE RECTO LOCALMENTE AVANZADO GRECCAR RESULTADOS A LARGO PLAZO DE UN ESTUDIO ALEATRIO MULTICNTRICO Y ABIERTO DE FASE II: ANTECEDENTES:La radio-quimioterapia pré-operatoria sistemáticas y la excisión total del mesorrecto son el estándar en el tratamiento del carcinoma de recto localmente avanzado. En éste sentido, algunos pacientes podrían recibir un sobre o un infra-tratamiento.OBJETIVO:Evaluar los resultados oncológicos, funcionales y de morbilidad a largo plazo después de radio-quimioterapia personalizada y quimioterapia de inducción a dosis elevadas.DISEÑO:Estudio aleatório multicéntrico y abierto de Fase II° realizado en 16 centros terciarios en Francia.AJUSTE:Aquellos pacientes operados por cirujanos del grupo GRECCAR francés.PACIENTES:206 pacientes fueron asignados aleatoriamente al tratamiento: los buenos respondedores después de quimioterapia (reducción del volumen tumoral ≥75%) a la cirugía inmediata (brazo A) o a la radio-quimioterapia estándar (Cap 50) asociada a la cirugía (brazo B); los malos respondedores a Cap 50 (brazo C) o a la radio-quimioterapia intensiva (Cap 60 (irradiación de 60 Gy) (brazo D) previas a la cirugía.INTERVENCIONES:Tratamiento adaptado según la respuesta de la RM a la TC de inducción.RESULTADOS:Después del tratamiento de inducción, 194 pacientes fueron clasificados como buenos (n = 30, 15%) o malos (n = 164, 85%) respondedores, y se incluyeron en los brazos A y B (16 y 14 pacientes) o C y D (113 y 51 pacientes). Se alcanzó el objetivo principal: las tasas de resección R0 [intervalo de confianza del 90%] en los cuatro brazos respectivamente, fueron del 100% [74-100], 100% [85-100], 83% [72-91] y 88% [77-95]. A los 5 años, las tasas fueron: de sobrevida global 90% [47,3-98,5], 93,3% [61,3-99,0], 84,3% [71,0-91,8], 86,1% [71,6-93,5]; de sobrevida libre a la enfermedad 80% [40,9-94,6], 89,5% [64,1-97,3], 72,9% [58,5-82,9], 72,8% [57,7-83,2]; de recidiva local 0, 0, 2,1% [0,3-13,9], 9,3% [3,6-23,0]; de metástasis 20% [5,4-59,1], 10,5% [2,7-35,9], 18% [31,8-94,6], 18,8% [10,2-33,0]. La evaluación tardía de la morbilidad y la calidad de vida no mostraron diferencias significativas entre los brazos.LIMITACIONES:Debido al pequeño número de pacientes asignados al azar en los brazos de buenos respondedores, especialmente en el brazo A de aquellos sin radioterapia.CONCLUSIÓN:Parecería muy prometedor el adaptar la radio-quimioterapia pré-operatoria basada en la respuesta al tratamiento de inducción. Estudios prospectivos en el futuro podrán confirmar la presente estrategia. Consulte Video Resumen en http://links.lww.com/DCR/B761 . (Traducción-Dr. Xavier Delgadillo )IDENTIFICADOR DE CLINICALTRIALS.GOV:NCT01333709. Groupe de REcherche Chirurgicale sur le CAncer du Rectum.