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Introduction: Standardisation has the potential to serve as a measure to mitigate complication rates. The objective was to assess the impact of standardisation by implementing a colorectal bundle (CB), which comprises nine elements, on the complication rates in left-sided colorectal resections., Patients and Methods: This prospective, multicentre, observational, cohort trial was conducted in Switzerland at nine participating hospitals. During the control period, each patient was treated in accordance with the local standard protocol at their respective hospital. In the CB period, all patients were treated in accordance with the CB. The primary endpoint was the Comprehensive Complication Index (CCI) at 30 days., Results: A total of 1141 patients were included (723 in the No CB group and 418 in the CB group). Median age was 66 years and 50.6% were female. Median CCI before and after CB implementation was 0.0 (Interquartile Range [IQR]: 0.0-20.9). A hurdle model approach was used for the analysis. The CB was not associated with the presence or severity of complications. Older age (Odds Ratio [OR] 1.02, 95% Confidence Intervall [CI]: 1.00-1.03), surgery for malignancy (OR 1.34, 95% CI: 1.01-1.92), emergency surgery (OR 2.19, 95% CI: 1.31-3.41), elevated nutritional risk score (OR 1.13, 95% CI: 1.01-1.24) and Body-Mass Index (OR 1.04, 95% CI: 1.00-1.06) were associated with higher odds of postoperative complications. In a supplementary per-protocol analysis, for each additional item of the CB fulfilled, the odds of anastomotic leakage (AL) were 24% lower (OR 0.76, 95% CI: 0.64-0.93)., Conclusions: Dedicated teams can establish high quality colorectal services in a network of hospitals with a joint standard. The study can serve as a model for other healthcare settings to conduct and implement quality improvement programs. The consistent implementation of the CB items can reduce the occurrence of AL., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Anastomotic leakage (AL), a severe complication following colorectal surgery, arises from defects at the anastomosis site. This study evaluates the feasibility of predicting AL using machine learning (ML) algorithms based on preoperative data., Methods: We retrospectively analyzed data including 21 predictors from patients undergoing colorectal surgery with bowel anastomosis at four Swiss hospitals. Several ML algorithms were applied for binary classification into AL or non-AL groups, utilizing a five-fold cross-validation strategy with a 90% training and 10% validation split. Additionally, a holdout test set from an external hospital was employed to assess the models' robustness in external validation., Results: Among 1244 patients, 112 (9.0%) suffered from AL. The Random Forest model showed an AUC-ROC of 0.78 (SD: ± 0.01) on the internal test set, which significantly decreased to 0.60 (SD: ± 0.05) on the external holdout test set comprising 198 patients, including 7 (3.5%) with AL. Conversely, the Logistic Regression model demonstrated more consistent AUC-ROC values of 0.69 (SD: ± 0.01) on the internal set and 0.61 (SD: ± 0.05) on the external set. Accuracy measures for Random Forest were 0.82 (SD: ± 0.04) internally and 0.87 (SD: ± 0.08) externally, while Logistic Regression achieved accuracies of 0.81 (SD: ± 0.10) and 0.88 (SD: ± 0.15). F1 Scores for Random Forest moved from 0.58 (SD: ± 0.03) internally to 0.51 (SD: ± 0.03) externally, with Logistic Regression maintaining more stable scores of 0.53 (SD: ± 0.04) and 0.51 (SD: ± 0.02)., Conclusion: In this pilot study, we evaluated ML-based prediction models for AL post-colorectal surgery and identified ten patient-related risk factors associated with AL. Highlighting the need for multicenter data, external validation, and larger sample sizes, our findings emphasize the potential of ML in enhancing surgical outcomes and inform future development of a web-based application for broader clinical use., (© 2024. The Author(s).)

Objective: To assess whether administration of surgical antimicrobial prophylaxis (SAP) versus absence of SAP is associated with a decreased risk of surgical site infections (SSI) after low-risk cholecystectomies (LR-CCE)., Summary Background Data: Current guidelines do not recommend routine SAP administration prior to LR-CCE., Methods: This cohort study included adult patients who underwent LR-CCE and were documented by the Swissnoso SSI surveillance system between 1/2009-12/2020 at 66 Swiss hospitals. LR-CCE was specified as elective endoscopic surgery, age <70, no active cholecystitis, ASA score <3, operating time <120 minutes without implantation of foreign material. Exposure was defined as the administration of cefuroxime or cefazoline ± metronidazole within 120 minutes prior to incision versus no SAP administration. Our main outcome was occurrence of SSI until day 30. Logistic regression models were used to adjust for institutional, patient, and perioperative variables., Results: Of 44 682 surveilled adult cholecystectomy patients, 12 521 (8 726 women [69.7%]; median [IQR] age, 49.0 [38.1-58.2] years), fulfilled inclusion criteria. SSI was identified in 143 patients (1.1%). SAP was administered in 9 269 patients (74.0%) and was associated with a lower SSI rate (adjusted odds ratio [aOR], 0.50; 95% CI, 0.35-0.70; P < 0.001). The number needed to treat to prevent one SSI episode is 100., Conclusions: The overall LR-CCE SSI rate was 1.1%. SAP was associated with a 50% lower overall SSI rate. Patients undergoing LR-CCE may benefit from routine surgical antimicrobial prophylaxis., Competing Interests: Conflict of interest statement: RS received an unrestricted research grant from BBraun, Sempach, Switzerland., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: For high-risk patients receiving right-sided colectomy, stoma formation is a safety strategy. Options are anastomosis with loop ileostomy, end ileostomy, or split stoma. The aim is to compare the outcome of these three options., Methods: This retrospective cohort study included all patients who underwent right sided colectomy and stoma formation between January 2008 and December 2021 at two tertial referral centers in Switzerland. The primary outcome was the stoma associated complication rate within one year., Results: A total of 116 patients were included. A total of 20 patients (17%) underwent primary anastomosis with loop ileostomy (PA group), 29 (25%) received an end ileostomy (ES group) and 67 (58%) received a split stoma (SS group). Stoma associated complication rate was 43% (n = 21) in PA and in ES group and 50% (n = 34) in SS group (n.s.). A total of 30% (n = 6) of patients in PA group needed reoperations, whereas 59% (n = 17) in ES and 58% (n = 39) in SS group had reoperations (P = 0.07). Wound infections occurred in 15% (n = 3) in PA, in 10% (n = 3) in ES, and in 30% (n = 20) in SS group (P = 0.08). A total of 13 patients (65%) in PA, 7 (24%) in ES, and 29 (43%) in SS group achieved stoma closure (P = 0.02). A total of 5 patients (38%) in PA group, 2 (15%) in ES, and 22 patients (67%) in SS group had a stoma-associated rehospitalization (P < 0.01)., Conclusion: Primary anastomosis and loop ileostomy may be an option for selected patients. Patients with end ileostomies have fewer stoma-related readmissions than those with a split stoma, but they have a lower rate of stoma closure., Clinical Trial Registration: Trial not registered., (© 2024. The Author(s).)

Background: Esophageal cancer surgery is technically highly demanding. During the past decade robot-assisted surgery has successfully been introduced in esophageal cancer treatment. Various techniques are being evaluated in different centers. In particular, advantages and disadvantages of continuously sutured (COSU) or linear-stapled (LIST) gastroesophageal anastomoses are debated. Here, we comparatively analyzed perioperative morbidities and short-term outcomes in patients undergoing hybrid robot-assisted esophageal surgery following neoadjuvant chemoradiotherapy (nCRT), with COSU or LIST anastomoses in a single center., Methods: Following standardized, effective, nCRT, 53 patients underwent a hybrid Ivor Lewis robot-assisted esophagectomy with COSU (n = 32) or LIST (n = 21) gastroesophageal anastomoses. Study endpoints were intra- and postoperative complications, in-hospital morbidity and mortality. Duration of operation, intensive care unit (ICU) and overall hospital stay were also evaluated. Furthermore, rates of rehospitalization, endoscopies, anastomotic stenosis and recurrence were assessed in a 90-day follow-up., Results: Demographics, ASA scores and tumor characteristics were comparable in the two groups. Median duration of operation was similar in patients with COSU and LIST anastomosis (467 vs. 453 min, IQR 420-521 vs. 416-469, p = 0.0611). Major complications were observed in 4/32 (12.5%) and 4/21 (19%) patients with COSU or LIST anastomosis, respectively (p = 0.697). Anastomotic leakage was observed in 3/32 (9.3%) and 2/21 (9.5%) (p = 1.0) patients with COSU or LIST anastomosis, respectively. Pleural empyema occurred in 1/32 (3.1%) and 2/21 (9.5%) (p = 0.555) patients, respectively. Mortality was similar in the two groups (1/32, 3.1% and 1/21, 4.7%, p = 1.0). Median ICU stay did not differ in patients with COSU or LIST anastomosis (p = 0.255), whereas a slightly, but significantly (p = 0.0393) shorter overall hospital stay was observed for COSU, as compared to LIST cohort (median: 20 vs. 21 days, IQR 17-22 vs. 18-28)., Conclusions: COSU is not inferior to LIST in the performance of gastroesophageal anastomosis in hybrid Ivor Lewis operations following nCRT., (© 2022. The Author(s).)

Background: Tumor infiltration with cytotoxic CD8+ T-cells is associated with a favorable outcome in several neoplasms, including thyroid cancer. The chemokine axis CXCR4/SDF-1 correlates with more aggressive tumors, but little is known concerning the prognostic relevance in relation to the tumor immune microenvironment of differentiated thyroid cancer (DTC)., Methods: A tissue microarray (TMA) of 37 tumor specimens of primary DTC was analyzed by immunohistochemistry (IHC) for the expression of CD8+, CXCR4, phosphorylated CXCR4 and SDF-1. A survival analysis was performed on a larger collective (n = 456) at RNA level using data from The Cancer Genome Atlas (TCGA) papillary thyroid cancer cohort., Results: Among the 37 patients in the TMA-cohort, the density of CD8+ was higher in patients with less advanced primary tumors (median cells/TMA-punch: 12.5 (IQR: 6.5, 12.5) in T1-2 tumors vs. 5 (IQR: 3, 8) in T3-4 tumors, p = 0.05). In the TCGA-cohort, CXCR4 expression was higher in patients with cervical lymph node metastasis compared to N0 or Nx stage (CXCR4 high/low 116/78 vs. 97/116 vs. 14/35, respectively, p = 0.001). Spearman's correlation analysis of the TMA-cohort demonstrated that SDF-1 was significantly correlated with CXCR4 (r = 0.4, p = 0.01) and pCXCR4 (r = 0.5, p = 0.002). In the TCGA-cohort, density of CD8+ correlated with CXCR4 and SDF-1 expression (r = 0.58, p < 0.001; r = 0.4, p < 0.001). The combined marker analysis of the TCGA cohort demonstrated that high expression of both, CXCR4 and SDF-1 was associated with reduced overall survival in the CD8 negative TCGA cohort (p = 0.004)., Conclusion: These findings suggest that the prognostic significance of CXCR4 and SDF-1 in differentiated thyroid cancer depends on the density of CD8 positive T-lymphocytes. Further studies with larger sample sizes are needed to support our findings and inform future investigations of new treatment and diagnostic options for a more personalized approach for patients with differentiated thyroid cancer., (© 2022. The Author(s).)

Background: Laparoscopic (LSC) Heller myotomy (HM) is considered the standard procedure for the treatment of achalasia. Robotic platforms, established over the last years, provide important advantages to surgeons, such as binocular 3-dimensional vision and improvement of fine motor control. However, whether perioperative outcomes and long-term results of robotic-assisted laparoscopic (RAL) HM are similar or even superior to LSC technique, especially concerning long-term follow-up, is still debated. Therefore, the aim of the present study was to evaluate intra- and postoperative results as well as long-term quality of life after RAL compared to LSC surgery for achalasia in a single high-volume visceral surgery center., Methods: Between August 2007 and April 2020, 43 patients undergoing minimally invasive HM for achalasia in a single high-volume Swiss visceral surgery center, were included in the present study. Intra- and postoperative outcome parameters were collected and evaluated, and a long-term follow-up was performed using the gastroesophageal-reflux disease health-related quality of life (GERD-Hr-QuoL) questionnaire., Results: A total of 11 patients undergoing RAL and 32 undergoing LSC HM were analyzed. Baseline demographics and clinical characteristics were similar. A trend (p = 0.052) towards a higher number of patients with ASA III score treated with RAL was detectable. Operation time was marginally, but significantly, shorter in LSC (140 min, IQR: 136-150) than in RAL (150 min, IQR: 150-187, p = 0.047). Postoperative complications graded Clavien-Dindo ≥ 3 were only observed in one patient in each group. Length of hospital stay was similar in both groups (LSC: 11 days, IQR: 10-13 vs. RAL: 11 days, IQR: 10-14, p = 0.712). Long-term follow-up (LSC: median 89 months, vs. RAL: median 28 months, p = 0.001) showed comparable results and patients from both groups expressed similar levels of satisfaction (p = 0.181)., Conclusions: LSC and RAL HM show similar peri- and postoperative results and a high quality of life, even in long-term (> 24 months) follow-up. Prospective, randomized, controlled multicenter trials are needed to overcome difficulties associated to small sample sizes in a rare condition and to confirm the equality or demonstrate the superiority of robotic-assisted procedures for achalasia. Meanwhile, the choice of the treatment technique could be left to the operating surgeon's preferences., (© 2022. The Author(s).)

Neoadjuvant chemo-radiotherapy (nCRT) of locally advanced rectal cancer is associated with challenging surgical treatment and increased postoperative morbidity. Robotic technology overcomes laparoscopy limitations by enlarged 3D view, improved anatomical transection accuracy, and physiologic tremor reduction. Patients with UICC stage II-III rectal cancer, consecutively referred to our institution between March 2015 and June 2020 (n = 102) were treated with robotic (Rob-G, n = 38) or laparoscopic (Lap-G, n = 64) low anterior resection (LAR) for total meso-rectal excision (TME) following highly standardized and successful nCRT treatment. Feasibility, conversion rates, stoma creation, morbidity and clinical/pathological outcome were comparatively analysed. Sex, age, BMI, ASA scores, cTN stages and tumour distance from dentate line were comparable in the two groups. Robotic resection was always feasible without conversion to open surgery, which was necessary in 11/64 (17%) Lap-G operations (p = 0.006). Primary or secondary stomata were created in 17/38 (45%) Rob-G and 52/64 (81%) Lap-G patients (p < 0.001). Major morbidity occurred in 7/38 (18.4%) Rob-G and 6/64 (9.3%) Lap-G patients (p = 0.225). Although median operation time was longer in Rob-G compared with Lap-G (376; IQR: 330-417 min vs. 300; IQR: 270-358 min; p < 0.001), the difference was not significant in patients (Rob-G, n = 6; Lap-G, n = 10) with ≥30 BMI (p = 0.106). Number of resected lymph nodes, ypTN staging and circumferential resection margins (CRM) were comparable. Resection was complete in 87% of Rob-G and 89% of Lap-G patients (p = 0.750). Robotic LAR is not inferior to laparoscopic LAR following nCRT. Larger, randomized studies are needed to confirm lower conversion in robotic, compared to laparoscopic resection., (© 2021. The Author(s), under exclusive licence to Springer-Verlag London Ltd., part of Springer Nature.)

Objective: The novel picture archiving and communication system (PACS), compatible with virtual reality (VR) software, displays cross-sectional images in VR. VR magnetic resonance cholangiopancreatography (MRCP) was tested to improve the anatomical understanding and intraoperative performance of minimally invasive cholecystectomy (CHE) in surgical trainees., Design: We used an immersive VR environment to display volumetric MRCP data (Specto VR TM ). First, we evaluated the tolerability and comprehensibility of anatomy with a validated simulator sickness questionnaire (SSQ) and examined anatomical landmarks. Second, we compared conventional MRCP and VR MRCP by matching three-dimensional (3D) printed models and identifying and measuring common bile duct stones (CBDS) using VR MRCP. Third, surgical trainees prepared for CHE with either conventional MRCP or VR MRCP, and we measured perioperative parameters and surgical performance (validated GOALS score)., Setting: The study was conducted out at Clarunis, University Center for Gastrointestinal and Liver Disease, Basel, Switzerland., Participants: For the first and second study step, doctors from all specialties and years of experience could participate. In the third study step, exclusively surgical trainees were included. Of 74 participating clinicians, 34, 27, and 13 contributed data to the first, second, and third study phases, respectively., Results: All participants determined the relevant biliary structures with VR MRCP. The median SSQ score was 0.75 (IQR: 0, 3.5), indicating good tolerability. Participants selected the corresponding 3D printed model faster and more reliably when previously studying VR MRCP compared to conventional MRCP: We obtained a median of 90 s (IQR: 55, 150) and 72.7% correct answers with VR MRCP versus 150 s (IQR: 100, 208) and 49.6% correct answers with conventional MRCP, respectively ( p  < 0.001). CBDS was correctly identified in 90.5% of VR MRCP cases. The median GOALS score was higher after preparation with VR MRCP than with conventional MRCP for CHE: 16 (IQR: 13, 22) and 11 (IQR: 11, 18), respectively ( p  = 0.27)., Conclusions: VR MRCP allows for a faster, more accurate understanding of displayed anatomy than conventional MRCP and potentially leads to improved surgical performance in CHE in surgical trainees., Competing Interests: P.C. Cattin is the inventor and owner of the VR application (Specto VRTM) described in this study. The other authors have no conflicts of interest or financial ties to disclose., (© 2022 Staubli, Maloca, Kuemmerli, Kunz, Dirnberger, Allemann, Gehweiler, Soysal, Droeser, Däster, Hess, Raptis, Kollmar, von Flüe, Bolli and Cattin.)

Background: Robotic-assisted colorectal surgery has gained more and more popularity over the last years. It seems to be advantageous to laparoscopic surgery in selected situations, especially in confined regions like a narrow male pelvis in rectal surgery. Whether robotic-assisted, left-sided colectomies can serve as safe training operations for less frequent, low anterior resections for rectal cancer is still under debate. Therefore, the aim of this study was to evaluate intra- and postoperative results of robotic-assisted laparoscopy (RAL) compared to laparoscopic (LSC) surgery in left-sided colectomies., Methods: Between June 2015 and December 2019, 683 patients undergoing minimally invasive left-sided colectomies in two Swiss, high-volume colorectal centers were included. Intra- and postoperative outcome parameters were collected and analyzed., Results: A total of 179 patients undergoing RAL and 504 patients undergoing LSC were analyzed. Baseline characteristics showed similar results. Intraoperative complications occurred in 0.6% of RAL and 2.0% of LSC patients (p = 0.193). Differences in postoperative complications graded Dindo ≥ 3 were not statistically significant (RAL 3.9% vs. LSC 6.3%, p = 0.227). Occurrence of anastomotic leakages showed no statistically significant difference [RAL n = 2 (1.1%), LSC n = 8 (1.6%), p = 0.653]. Length of hospital stay was similar in both groups. Conversions to open surgery were significantly higher in the LSC group (6.2% vs.1.7%, p = 0.018), while stoma formation was similar in both groups [RAL n = 1 (0.6%), LSC n = 5 (1.0%), p = 0.594]. Operative time was longer in the RAL group (300 vs. 210.0 min, p < 0.001)., Conclusion: Robotic-assisted, left-sided colectomies are safe and feasible compared to laparoscopic resections. Intra- and postoperative complications are similar in both groups. Most notably, the rate of anastomotic leakages is similar. Compared to laparoscopic resections, the analyzed robotic-assisted resections have longer operative times but less conversion rates. Further prospective studies are needed to confirm the safety of robotic-assisted, left-sided colectomies as training procedures for low anterior resections., (© 2022. The Author(s).)

Purpose: Overall complication and leak rates in colorectal surgery showed only minor improvements over the last years and remain still high. While the introduction of the WHO Safer Surgery Checklist has shown a reduction of overall operative mortality and morbidity in general surgery, only minor attempts have been made to improve outcomes by standardizing perioperative processes in colorectal surgery. Nevertheless, a number of singular interventions have been found reducing postoperative complications in colorectal surgery. The aim of the present study is to combine nine of these measures to a catalogue called colorectal bundle (CB). This will help to standardize pre-, intra-, and post-operative processes and therefore eventually reduce complication rates after colorectal surgery., Methods: The study will be performed among nine contributing hospitals in the extended north-western part of Switzerland. In the 6-month lasting control period the patients will be treated according to the local standard of each contributing hospital. After a short implementation phase all patients will be treated according to the CB for another 6 months. Afterwards complication rates before and after the implementation of the CB will be compared., Discussion: The overall complication rate in colorectal surgery is still high. The fact that only little progress has been made in recent years underlines the relevance of the current project. It has been shown for other areas of surgery that standardization is an effective measure of reducing postoperative complication rates. We hypothesize that the combination of effective, individual components into the CB can reduce the complication rate., Trial Registration: Registered in ClinicalTrials.gov on 11/03/2020; NCT04550156., Highlights: Purpose: Overall complications in colorectal surgery remain still highStandardizing can reduce overall operative mortality and morbidityOnly minor attempts have been made to standardize perioperative processes in colorectal surgerySingular interventions have been found reducing postoperative complicationsThe aim is to combine nine of these measures to a colorectal bundle (CB)The CB will help to reduce complication rates after colorectal surgery Methods: The observational study will be performed among nine hospitals in SwitzerlandSix month the patients will be treated according to the local standardsAfterwards patients will be treated according to the CB for another six monthsComplication rates before and after the implementation of the CB will be compared Discussion: Only little progress has been made to reduce complication rate in colorectal surgeryStandardization is an effective measure of reducing complication ratesThe combination of effective, individual components into the CB can reduce the complication rate., Competing Interests: Author BW has received research support from freiwilliger akademischer Gesellschaft. Author MvS has received research support from Bangerter Stiftung and Waldmeier Wohlfahrtsfond. There are no non-financial interests., (Copyright: © 2022 The Author(s).)

Introduction: Inguinal hernia repairs are commonly performed procedures. The surgical techniques vary from open procedures to minimally invasive and robotic-assisted surgeries and include totally extra-peritoneal hernia repairs (TEP) and robotic transabdominal pre-peritoneal hernia repairs (rTAPP). So far, there is no randomized and blinded clinical trial comparing these two surgical approaches. Our objective is to investigate whether rTAPP is associated with a decreased postoperative level of pain., Methods: This is a prospective, single center, randomized and blinded clinical trial. Patients will receive either rTAPP or TEP for uni- or bilateral inguinal hernias. All patients and assessors of the study are blinded to the randomization. The perioperative setting is standardized, and all surgeons will perform both rTAPP and TEP to eliminate surgeons` bias. Primary endpoint is the assessment of pain while coughing 24 hours after surgery using the numeric rating scale (NRS). Secondary endpoints include the assessment of multiple pain and quality of life questionnaires at several defined times according to the study schedule. Furthermore, intra- and postoperative complications, duration until discharge, procedure time, duration of postoperative sick leave and the recurrence rate will be evaluated., Registry: The trial has been registered at ClinicalTrials.gov under the registry number NCT05216276., Highlights: Trial comparing robotic and conventional minimal-invasive inguinal hernia repairRandomized and patient/assessor blinded trialEarly postoperative pain as primary outcome (24 hours)Secondary patient outcomes include pain and quality of life scores up to one yearFurther secondary outcomes: complications, costs, surgeon's stress level., Competing Interests: The authors have no competing interests to declare., (Copyright: © 2022 The Author(s).)

Purpose: Robotic-assisted procedures are increasingly used in esophageal cancer surgery. We compared postoperative complications and early oncological outcomes following hybrid robotic-assisted thoracoscopic esophagectomy (Rob-E) and open Ivor Lewis esophagectomy (Open-E), performed in a single mid-volume center, in the context of evolving preoperative patient and tumor characteristics over two decades., Methods: We evaluated prospectively collected data from a single center from 1999 to 2020 including 321 patients that underwent Ivor Lewis esophagectomy, 76 underwent Rob-E, and 245 Open-E. To compare perioperative outcomes, a 1:1 case-matched analysis was performed. Endpoints included postoperative morbidity and 30-day mortality., Results: Preoperative characteristics revealed increased rates of adenocarcinomas and wider use of neoadjuvant treatment over time. A larger number of patients with higher ASA grades were operated with Rob-E. In case-matched cohorts, there were no differences in the overall morbidity (69.7% in Rob-E, 60.5% in Open-E, p value 0.307), highest Clavien-Dindo grade per patient (43.4% vs. 38.2% grade I or II, p value 0.321), comprehensive complication index (median 20.9 in both groups, p value 0.401), and 30-day mortality (2.6% in Rob-E, 3.9% in Open-E, p value 1.000). Similar median numbers of lymph nodes were harvested (24.5 in Rob-E, 23 in Open-E, p value 0.204), and comparable rates of R0-status (96.1% vs. 93.4%, p value 0.463) and distribution of postoperative UICC stages (overall p value 0.616) were observed., Conclusions: Our study demonstrates similar postoperative complications and early oncological outcomes after Rob-E and Open-E. However, the selection criteria for Rob-E appeared to be less restrictive than those of Open-E surgery., (© 2022. The Author(s).)

Objective: The use of machine learning (ML) has revolutionized every domain of medicine. Surgeons are now using ML models for disease detection and outcome prediction with high precision. ML-guided colorectal surgeries are more efficient than conventional surgical procedures. The primary aim of this paper is to provide an overview of the latest research on "ML in colorectal surgery", with its viable applications., Methods: PubMed, Google Scholar, Medline, and Cochrane library were searched., Results: After screening, 27 articles out of 172 were eventually included. Among all of the reviewed articles, those found to fit the criteria for inclusion had exclusively focused on ML in colorectal surgery, with justified applications. We identified existing applications of ML in colorectal surgery. Additionally, we discuss the benefits, risks, and safety issues., Conclusions: A better, more sustainable, and more efficient method, with useful applications, for ML in surgery is possible if we and data scientists work together to address the drawbacks of the current approach. Potential problems related to patients' perspectives also need to be resolved. The development of accurate technologies alone will not solve the problem of perceived unreliability from the patients' end. Confidence can only be developed within society if more research with precise results is carried out.

Background: Focal nodular hyperplasia (FNH) is typically considered a benign tumor of the liver without malignant potential. The co-occurrence of FNH and hepatocellular carcinoma (HCC) has been reported in rare cases. In this study we sought to investigate the clonal relationship between these lesions in a patient with FNH-HCC co-occurrence., Methods: A 74-year-old female patient underwent liver tumor resection. The resected nodule was subjected to histologic analyses using hematoxylin and eosin stain and immunohistochemistry. DNA extracted from microdissected FNH and HCC regions was subjected to whole exome sequencing. Clonality analysis were performed using PyClone., Results: Histologic analysis reveals that the nodule consists of an FNH and two adjoining HCC components with distinct histopathological features. Immunophenotypic characterization and genomic analyses suggest that the FNH is clonally related to the HCC components, and is composed of multiple clones at diagnosis, that are likely to have progressed to HCC through clonal selection and/or the acquisition of additional genetic events., Conclusion: To the best of our knowledge, our work is the first study showing a clonal relationship between FNH and HCC. We show that FNH may possess the capability to undergo malignant transformation and to progress to HCC in very rare cases., Competing Interests: Competing interestsM.S.M. has received speaker’s honoraria from Thermo Fisher and honoraria as an advisory board member from Novartis. The other authors declare no competing interests., (© The Author(s) 2022.)

Hepatocellular carcinomas (HCCs) usually arise from chronic liver disease (CLD). Precancerous cells in chronically inflamed environments may be 'epigenetically primed', sensitising them to oncogenic transformation. We investigated whether epigenetic priming in CLD may affect HCC outcomes by influencing the genomic and transcriptomic landscapes of HCC. Analysis of DNA methylation arrays from 10 paired CLD-HCC identified 339 shared dysregulated CpG sites and 18 shared differentially methylated regions compared with healthy livers. These regions were associated with dysregulated expression of genes with relevance in HCC, including ubiquitin D (UBD), cytochrome P450 family 2 subfamily C member 19 (CYP2C19) and O-6-methylguanine-DNA methyltransferase (MGMT). Methylation changes were recapitulated in an independent cohort of nine paired CLD-HCC. High CLD methylation score, defined using the 124 dysregulated CpGs in CLD and HCC in both cohorts, was associated with poor survival, increased somatic genetic alterations and TP53 mutations in two independent HCC cohorts. Oncogenic transcriptional and methylation dysregulation is evident in CLD and compounded in HCC. Epigenetic priming in CLD sculpts the transcriptional landscape of HCC and creates an environment favouring the acquisition of genetic alterations, suggesting that the extent of epigenetic priming in CLD could influence disease outcome., (© 2021 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

The use of patient-derived organoids (PDO) as a valuable alternative to in vivo models significantly increased over the last years in cancer research. The ability of PDOs to genetically resemble tumor heterogeneity makes them a powerful tool for personalized drug screening. Despite the extensive optimization of protocols for the generation of PDOs from colorectal tissue, there is still a lack of standardization of tissue handling prior to processing, leading to microbial contamination of the organoid culture. Here, using a cohort of 16 patients diagnosed with colorectal carcinoma (CRC), we aimed to test the efficacy of phosphate-buffered saline (PBS), penicillin/streptomycin (P/S), and Primocin, alone or in combination, in preventing organoid cultures contamination when used in washing steps prior to tissue processing. Each CRC tissue was divided into 5 tissue pieces, and treated with each different washing solution, or none. After the washing steps, all samples were processed for organoid generation following the same standard protocol. We detected contamination in 62.5% of the non-washed samples, while the use of PBS or P/S-containing PBS reduced the contamination rate to 50% and 25%, respectively. Notably, none of the organoid cultures washed with PBS/Primocin-containing solution were contaminated. Interestingly, addition of P/S to the washing solution reduced the percentage of living cells compared to Primocin. Taken together, our results demonstrate that, prior to tissue processing, adding Primocin to the tissue washing solution is able to eliminate the risk of microbial contamination in PDO cultures, and that the use of P/S negatively impacts organoids growth. We believe that our easy-to-apply protocol might help increase the success rate of organoid generation from CRC patients., Competing Interests: Authors AZ and SR were employed by Viollier AG. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Marinucci, Ercan, Taha-Mehlitz, Fourie, Panebianco, Bianco, Gallon, Staubli, Soysal, Zettl, Rauthe, Vosbeck, Droeser, Bolli, Peterli, von Flüe, Ng, Kollmar, Coto-Llerena and Piscuoglio.)

Background: Complete upside-down stomach (cUDS) hernias are a subgroup of large hiatal hernias characterized by high risk of life-threatening complications and technically challenging surgical repair including complex mediastinal dissection. In a prospective, comparative clinical study, we evaluated intra- and postoperative outcomes, quality of life and symptomatic recurrence rates in patients with cUDS undergoing robot-assisted, as compared to standard laparoscopic repair (the RATHER-study)., Methods: All patients with cUDS herniation requiring elective surgery in our institution between July 2015 and June 2019 were evaluated. Patients undergoing primary open surgery or additional associated procedures were not considered. Primary endpoints were intra- and postoperative complications, 30-day morbidity, and mortality. During the 8-53 months follow-up period, patients were contacted by telephone to assess symptoms associated to recurrence, whereas quality of life was evaluated utilizing the Gastroesophageal Reflux Disease-Health-Related Quality of Life (GERD-HRQL) questionnaire., Results: A total of 55 patients were included. 36 operations were performed with robot-assisted (Rob-G), and 19 with standard laparoscopic (Lap-G) technique. Patients characteristics were similar in both groups. Median operation time was 232 min. (IQR: 145-420) in robot-assisted vs. 163 min. (IQR:112-280) in laparoscopic surgery (p < 0.001). Intraoperative complications occurred in 5/36 (12.5%) cases in the Rob-G group and in 5/19 (26%) cases in the Lap-G group (p = 0.28). No conversion was necessary in either group. Minor postoperative complications occurred in 13/36 (36%) Rob-G patients and 4/19 (21%) Lap-G patients (p = 0.36). Mortality or major complications did not occur in either group. Two asymptomatic recurrences were observed in the Rob-G group only. No patient required revision surgery. Finally, all patients expressed satisfaction for treatment outcome, as indicated by similar GERD-HRQL scores., Conclusion: While robot-assisted surgery provides additional precision, enhanced visualization, and greater feasibility in cUDS hiatal hernia repair, its clinical outcome is at least equal to that obtained by standard laparoscopic surgery., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.)

Systematic perturbation screens provide comprehensive resources for the elucidation of cancer driver genes. The perturbation of many genes in relatively few cell lines in such functional screens necessitates the development of specialized computational tools with sufficient statistical power. Here we developed APSiC (Analysis of Perturbation Screens for identifying novel Cancer genes) to identify genetic drivers and effectors in perturbation screens even with few samples. Applying APSiC to the shRNA screen Project DRIVE, APSiC identified well-known and novel putative mutational and amplified cancer genes across all cancer types and in specific cancer types. Additionally, APSiC discovered tumor-promoting and tumor-suppressive effectors, respectively, for individual cancer types, including genes involved in cell cycle control, Wnt/β-catenin and hippo signalling pathways. We functionally demonstrated that LRRC4B, a putative novel tumor-suppressive effector, suppresses proliferation by delaying cell cycle and modulates apoptosis in breast cancer. We demonstrate APSiC is a robust statistical framework for discovery of novel cancer genes through analysis of large-scale perturbation screens. The analysis of DRIVE using APSiC is provided as a web portal and represents a valuable resource for the discovery of novel cancer genes., (© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Background: Growing consideration in quality of life (QoL) has changed the therapeutic strategy in patients suffering from diverticular disease. Patients' well-being plays a crucial role in the decision-making process. However, there is a paucity of studies investigating patients' or surgery-related factors influencing the postoperative gastrointestinal function. The aim of this study was to investigate in a predictive model patients or surgical variables that allow better estimation of the postoperative gastrointestinal QoL., Methods: This observational study retrospectively analyzed patients undergoing elective laparoscopic sigmoidectomy for diverticulitis between 2004 and 2017. The one-time postoperative QoL was assessed with the gastrointestinal quality of life index (GIQLI) in 2019. A linear regression model with stepwise selection has been applied to all patients and surgery-related variables., Results: Two hundred seventy-two patients with a mean age of 62.30 ± 9.74 years showed a mean GIQLI of 116.39±18.25 at a mean follow-up time of 90.4±33.65 months. Women (n=168) reported a lower GIQLI compared to male (n=104; 112.85±18.79 vs 122.11±15.81, p<0.001). Patients with pre-operative cardiovascular disease (n=17) had a worse GIQLI (106.65 ±22.58 vs 117.08±17.66, p=0.010). Finally, patients operated less than 5 years ago (n=63) showed a worse GIQLI compared to patients operated more than 5 years ago (n=209; 111.98±19.65 vs 117.71±17.63, p=0.014)., Conclusions: Female gender and the presence of pre-operative cardiovascular disease are predictive for a decreased postoperative gastrointestinal QoL. Furthermore, patients' estimation of gastrointestinal functioning seems to improve up to 5 years after surgery., (© 2021. The Author(s).)

Background: Nestin, a class VI intermediate filament protein of the cytoskeleton, and CD34, a transmembrane phosphoglycoprotein, are markers of progenitor cells. This study aimed to evaluate their expression and clinical significance in colorectal cancer., Methods: A clinically annotated tissue microarray, including 599 patients with colorectal cancer, was analyzed by immunohistochemistry. Furthermore, nestin and CD34 correlations with HIF-1a and a panel of cytokines and chemokines were assessed using quantitative reverse transcription PCR and The Cancer Genome Atlas dataset., Results: Expression of nestin and CD34 was observed only in the tumor stroma. Patients displaying high expression of nestin and CD34 demonstrated higher rates of T1 and T2 tumors ( p  = .020), lower vascular invasion ( p  < .001) and improved 5-year overall survival (65%; 95% CI = 55-73 vs 45%; 95% CI = 37-53) after adjusting for clinicopathological characteristics (HR: 0.67; 95% CI = 0.46-0.96). A moderate to strong correlation ( r  = 0.37-0.78, p  < .03) of nestin and CD34 was demonstrated for the following markers; HIF-1α, CD4, CD8, FOXP3, IRF1, GATA3, CCL2, CCL3, CXCL12 and CCL21., Conclusions: Combined expression of nestin and CD34 expression is associated with better overall survival possibly by modulating a favorable immune response.

Aim: Increasing attention has been given to postoperative gastrointestinal functional outcome and quality of life after sigmoid resection for diverticulitis. Conversely, very little has been described about postoperative urogenital functional outcome and even less about its potential relationship to the type of vascular approach. The aim of this study was to evaluate whether central ligation of the inferior mesenteric artery (IMA) compared with peripheral dissection could impair urinary and sexual function in the long term., Method: Patients undergoing elective laparoscopic sigmoid resection for diverticulitis from 2004 to 2017 were retrospectively analysed. They were asked to complete the American Urological Association Symptom Index (AUASI) questionnaire. Men received the five-item version of the International Index of Erectile Function (IIEF-5) questionnaire. Patients were then divided according to the type of vascular resection., Results: A response rate of the 36.4% to the AUASI and 43.8% to the IIEF-5 questionnaires was achieved. Three hundred and twenty four patients with a mean age of 62 ± 9.85 years were analysed for their urinary function (IMA preserved n = 217; IMA resected n = 107) in a median follow-up of 87 months. Furthermore, 115 men with a mean age of 60 ± 8.97 years were investigated for their sexual function (IMA preserved n = 80; IMA resected n = 35) in a median follow-up of 89 months. No difference (AUASI: 8 ± 6.32 IMA preserved vs. 7 ± 6.26 IMA resected, P = 0.204; IIEF-5: 15 ± 7.67 IMA preserved vs. 15 ± 8.61 IMA resected, P = 0.674) was found regarding the type of vascular approach during sigmoid resection., Conclusions: No association was found between the type of vascular approach and the long-term urogenital functional outcome in patients undergoing sigmoid resection for diverticulitis., (© 2020 The Association of Coloproctology of Great Britain and Ireland.)

Background: By improved surgical technique such as total mesorectal excision (TME), multimodal treatment and advances in imaging survival and an increased rate of sphincter preservation have been achieved in rectal cancer surgery. Minimal-invasive approaches such as laparoscopic, robotic and transanal-TME (ta-TME) enhance recovery after surgery. Nevertheless, disorders of bowel, anorectal and urogenital function are still common and need attention., Purpose: This review aims at exploring the causes of dysfunction after anterior resection (AR) and the accordingly preventive strategies. Furthermore, the indication for low AR in the light of functional outcome is discussed. The last therapeutic strategies to deal with bowel, anorectal, and urogenital disorders are depicted., Conclusion: Functional disorders after rectal cancer surgery are frequent and underestimated. More evidence is needed to define an indication for non-operative management or local excision as alternatives to AR. The decision for restorative resection should be made in consideration of the relevant risk factors for dysfunction. In the case of restoration, a side-to-end anastomosis should be the preferred anastomotic technique. Further high-evidence clinical studies are required to clarify the benefit of intraoperative neuromonitoring. While the function of ta-TME seems not to be superior to laparoscopy, case-control studies suggest the benefits of robotic TME mainly in terms of preservation of the urogenital function. Low AR syndrome is treated by stool regulation, pelvic floor therapy, and transanal irrigation. There is good evidence for sacral nerve modulation for incontinence after low AR.

Rationale: Adenylosuccinate lyase (ADSL) is an essential enzyme for de novo purine biosynthesis. Here we sought to investigate the putative role of ADSL in colorectal carcinoma (CRC) carcinogenesis and response to antimetabolites. Methods: ADSL expression levels were assessed by immunohistochemistry or retrieved from The Cancer Genome Atlas (TCGA) dataset. The effects of ADSL silencing or overexpression were evaluated on CRC cell proliferation, cell migration and cell-cycle. In vivo tumor growth was assessed by the chicken chorioallantoic membrane (CAM). Transfected cell lines or patient-derived organoids (PDO) were treated with 5-fluorouracil (5-FU) and 6-mercaptopurine (6-MP) and drug response was correlated with ADSL expression levels. Metabolomic and transcriptomic profiling were performed to identify dysregulated pathways and ADSL downstream effectors. Mitochondrial respiration and glycolytic capacity were measured using Seahorse; mitochondrial membrane potential and the accumulation of ROS were measured by FACS using MitoTracker Red and MitoSOX staining, respectively. Activation of canonical pathways was assessed by immunohistochemistry and immunoblotting. Results: ADSL expression is significantly increased in CRC tumors compared to non-tumor tissue. ADSL-high CRCs show upregulation of genes involved in DNA synthesis, DNA repair and cell cycle. Accordingly, ADSL overexpression accelerated progression through the cell cycle and significantly increased proliferation and migration in CRC cell lines. Additionally, ADSL expression increased tumor growth in vivo and sensitized CRCs to 6-MP in vitro , ex vivo (PDOs) and in vivo (CAM model). ADSL exerts its oncogenic function by affecting mitochondrial function via alteration of the TCA cycle and impairment of mitochondrial respiration. The KEAP1-NRF2 and mTORC1-cMyc axis are independently activated upon ADSL overexpression and may favor the survival and proliferation of ROS-accumulating cells, favoring DNA damage and tumorigenesis. Conclusions: Our results suggest that ADSL is a novel oncogene in CRC, modulating mitochondrial function, metabolism and oxidative stress, thus promoting cell cycle progression, proliferation and migration. Our results also suggest that ADSL is a predictive biomarker of response to 6-mercaptopurine in the pre-clinical setting., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: Fascin is the main actin cross-linker protein that regulates adhesion dynamics and stabilizes cell protrusion, such as filopodia. In human cancer, fascin expression correlates with aggressive clinical features. This study aimed to determine the expression patterns of fascin-1 and assessed its prognostic significance in colorectal cancer., Methods: One hundred eleven specimens of patients with primary resectable colorectal cancer were examined via immunohistochemistry for the expression of fascin-1, and the results were correlated with clinicopathological characteristics and survival data., Results: Fascin-1 staining displayed strong intensity in the cytoplasm of the colorectal cancer cells and endothelial cells of tumor blood vessels. Moderate to high fascin-1 expression was associated with progressive anatomic disease extent (p < 0.001), higher T classification (p = 0.007), the presence of lymph node (p < 0.001) and distant metastasis (p = 0.002), high grade tumors (p = 0.002) and vascular invasion (p < 0.001). Patients displaying moderate and high fascin-1 expression demonstrated a significantly worse 5-year overall survival [HR; 3.906, (95%CI) = 1.250-12.195] and significantly worse 3-year progression-free survival [HR; 3.448, (95%CI) = 1.401-8.475] independent of other clinicopathological characteristics. Besides, high fascin-1 expression in early-stage cancer only was associated with a dismal prognosis., Conclusions: High fascin-1 expression in colorectal cancer is an independent negative prognostic factor for survival, increasing the risk for disease recurrence or death almost by sevenfold. Fascin-1 expression could be potentially utilized to identify high-risk patients prone to metastasis already in early-stage disease.

Purpose: The management of perforated diverticulitis with generalized peritonitis is still controversial and no preferred standardized therapeutic approach has been determined. We compared surgical outcomes between Hartmann's procedure (HP) and primary anastomosis (PA) in patients with Hinchey III and IV perforated diverticulitis., Methods: Multicenter retrospective analysis of 131 consecutive patients with Hinchey III and IV diverticulitis operated either with HP or PA from 2015 to 2018. Postoperative morbidity was compared after adjustment for known risk factors in a multivariate logistic regression., Results: Sixty-six patients underwent HP, while PA was carried out in 65 patients, 35.8% of those were defunctioned. HP was more performed in older patients (74.6 vs. 61.2 years, p < .001), with Hinchey IV diverticulitis (37% vs. 7%, p < .001) and in patients with worse prognostic scores (P-POSSUM Physiology Score, p < .001, Charlson Comorbidity Index p < .001). Major morbidity and mortality were higher in HP compared to PA (30.3% vs. 9.2%, p = .002 and 10.6% vs. 0%, p = .007, respectively) with lower stoma reversal rate (43.9% vs. 86.9%, p < .001). In a multivariate logistic regression, PA was independently associated with lower postoperative morbidity and mortality (OR 0.24, 95% CI 0.06-0.96, p = .044)., Conclusions: In comparison to PA, HP is associated with a higher morbidity, higher mortality, and a lower stoma reversal rate. Although a higher prevalence of risk factors in HP patients may explain these outcomes, a significant increase in morbidity and mortality persisted in a multivariate logistic regression analysis that was stratified for the identified risk factors.

Transcriptional enhancer factor domain family member 4 (TEAD4) is a downstream effector of the conserved Hippo signaling pathway, regulating the expression of genes involved in cell proliferation and differentiation. It is up-regulated in several cancer types and is associated with metastasis and poor prognosis. However, its role in hepatocellular carcinoma (HCC) remains largely unexplored. Using data from The Cancer Genome Atlas, we found that TEAD4 was overexpressed in HCC and was associated with aggressive HCC features and worse outcome. Overexpression of TEAD4 significantly increased proliferation and migration rates in HCC cells in vitro as well as tumor growth in vivo . Additionally, RNA sequencing analysis of TEAD4 -overexpressing HCC cells demonstrated that TEAD4 overexpression was associated with the up-regulation of genes involved in epithelial-to-mesenchymal transition, proliferation, and protein-folding pathways. Among the most up-regulated genes following TEAD4 overexpression were the 70-kDa heat shock protein (HSP70) family members HSPA6 and HSPA1 A. Chromatin immunoprecipitation-quantitative real-time polymerase chain reaction experiments demonstrated that TEAD4 regulates HSPA6 and HSPA1A expression by directly binding to their promoter and enhancer regions. The pharmacologic inhibition of HSP70 expression in TEAD4 -overexpressing cells reduced the effect of TEAD4 on cell proliferation. Finally, by overexpressing TEAD4 in yes-associated protein ( YAP )/transcriptional coactivator with PDZ binding motif ( TAZ )-knockdown HCC cells, we showed that the effect of TEAD4 on cell proliferation and its regulation of HSP70 expression does not require YAP and TAZ, the main effectors of the Hippo signaling pathway. Conclusion: A novel Hippo-independent mechanism for TEAD4 promotes cell proliferation and tumor growth in HCC by directly regulating HSP70 family members., (© 2021 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of the American Association for the Study of Liver Diseases.)

Since colorectal cancer (CRC) remains one of the most common malignancies, a tremendous amount of studies keep taking place in this field. Over the past 25 years, a notable part of the scientific community has focused on the association between the immune system and colorectal cancer. A variety of studies have shown that high densities of infiltrating CD8+ T-cells are associated with improved disease-free and overall survival in CRC. Stromal cell-derived factor-1 (SDF-1) is a protein that regulates leukocyte trafficking and is variably expressed in several healthy and malignant tissues. There is strong evidence that SDF-1 has a negative prognostic impact on a variety of solid tumors. However, the existing data do not provide sufficient evidence that the expression of SDF-1 has an influence on CRC. Knowing nowadays, that the microenvironment plays a crucial role in the development of cancer, we hypothesized that the expression of SDF-1 in CRC could influence the prognostic significance of CD8+ T-cells, as an indicator of the essential role of the immune microenvironment in cancer development. Therefore, we explored the combined prognostic significance of CD8+ T-cell density and SDF-1 expression in a large CRC collective. We analyzed a tissue microarray of 613 patient specimens of primary CRCs by immunohistochemistry (IHC) for the CD8 + T-cells density and the expression of SDF-1 by tumor cells and tumor-infiltrating immune cells. Besides, we analyzed the expression of SDF-1 at the RNA level in The Cancer Genome Atlas cohort. We found that the combined high CD8+ T-cell infiltration and expression of SDF-1 shows a favorable 5-year overall survival rate (66%; 95% CI 48-79%) compared to tumors showing a high expression of CD8+ T-cell only (55%; 95% CI 45-64%; p = 0.0004). After stratifying the patients in nodal negative and positive groups, we found that the prognostic significance of CD8+ T-cell density in nodal positive colorectal cancer depends on SDF-1 expression. Univariate and multivariate Hazard Cox regression survival analysis considering the combination of both markers revealed that the combined high expression of SDF-1 and CD8+ T-cell density was an independent, favorable, prognostic marker for overall survival (HR = 0.34, 95% CI 0.17-0.66; p = 0.002 and HR = 0.45, 95% CI 0.23-0.89; p = 0.021, respectively). In our cohort there was a very weak correlation between SDF-1 and CD8+ T-cells (r s  = 0.13, p = 0.002) and in the trascriptomic expression of these two immune markers display a weak correlation (r s  = 0.28, p < 0.001) which was significantly more pronounced in stage III cancers (r s  = 0.40, p < 0.001). The combination of high CD8+ T-cell density and expression of SDF-1 represents an independent, favorable, prognostic condition in CRC, mostly in patients with stage III disease.

Background: Disease recurrence in colorectal cancer constitutes a major cause of significant cancer-associated morbidity and mortality. MAP17 is a small protein, and its overexpression in malignant tumors has been correlated with aggressive tumor phenotypes. The aim of the present study was to investigate the expression patterns of MAP17 in colorectal cancer specimens and to assess its clinical significance., Patients and Methods: Surgical specimens of 111 patients with primary resectable colorectal cancer constituted the study population. Expression of MAP17 was assessed by immunohistochemistry, and the results were correlated with clinical and survival data., Results: MAP17 was expressed in cancer cells and endothelial cells of tumor blood vessels. Expression of MAP17 more than 10% was correlated with advanced disease stage (p < 0.001), higher T classification (p = 0.007), the presence of lymph node metastasis (p < 0.001), vascular (p = 0.013) and perineural invasion (p = 0.012). Patients exhibiting MAP17 expression of more than 30% in cancer cells compared to those expressing MAP17 less than 10% demonstrated a significantly worse 3-year progression-free survival (35.2 vs. 91%, p < 0.001) and 5-year overall survival (40.8 vs. 91%, p < 0.001). Cox regression analysis confirmed MAP17 expression of more than 30% as a prognostic marker of progression free survival (HR 0.136, 95% CI = 0.056-0.329, p < 0.001) and overall survival (HR 0.144 [95% CI) = 0.049-0.419, p < 0.001) independent of other clinicopathological characteristics. Statistically significantly worse 3-year progression-free survival and 5-year overall survival was demonstrated in the subgroup analysis of patients with early stage cancer only and high expression of MAP17., Conclusions: High MAP17 expression in patients with colorectal cancer is a significant risk factor for cancer-associated morbidity and mortality already in early stage disease., (© 2021 S. Karger AG, Basel.)

Immune cell infiltration in colorectal cancer effectively predicts clinical outcome. IL22, produced by immune cells, plays an important role in inflammatory bowel disease, but its relevance in colorectal cancer remains unclear. Here, we addressed the prognostic significance of IL22 + cell infiltration in colorectal cancer and its effects on the composition of tumor microenvironment. Tissue microarrays (TMA) were stained with an IL22-specific mAb, and positive immune cells were counted by expert pathologists. Results were correlated with clinicopathologic data and overall survival (OS). Phenotypes of IL22-producing cells were assessed by flow cytometry on cell suspensions from digested specimens. Chemokine production was evaluated in vitro upon colorectal cancer cell exposure to IL22, and culture supernatants were used to assess neutrophil migration in vitro Evaluation of a testing ( n = 425) and a validation TMA ( n = 89) revealed that high numbers of IL22 tumor-infiltrating immune cells were associated with improved OS in colorectal cancer. Ex vivo analysis indicated that IL22 was produced by CD4 + and CD8 + polyfunctional T cells, which also produced IL17 and IFNγ. Exposure of colorectal cancer cells to IL22 promoted the release of the neutrophil-recruiting chemokines CXCL1, CXCL2, and CXCL3 and enhanced neutrophil migration in vitro Combined survival analysis revealed that the favorable prognostic significance of IL22 in colorectal cancer relied on the presence of neutrophils and was enhanced by T-cell infiltration. Altogether, colorectal cancer-infiltrating IL22-producing T cells promoted a favorable clinical outcome by recruiting beneficial neutrophils capable of enhancing T-cell responses., (©2020 American Association for Cancer Research.)

Background: Pancreatic cancer (PC) remains one of the most devastating malignant diseases, predicted to become the second leading cause of cancer-related death by 2030. Despite advances in surgical techniques and in systemic therapy, the 5-year relative survival remains a grim 9% for all stages combined. The extent of lymphadenectomy has been discussed intensively for decades, given that even in early stages of PC, lymph node (LN) metastasis can be detected in approximately 80%., Purpose: The primary objective of this review was to provide an overview of the current literature evaluating the role of lymphadenectomy in resected PC. For this, we evaluated randomized controlled studies (RCTs) assessing the impact of extent of lymphadenectomy on OS and studies evaluating the prognostic impact of anatomical site of LN metastasis and the impact of the number of resected LNs on OS., Conclusions: Lymphadenectomy plays an essential part in the multimodal treatment algorithm of PC and is an additional therapeutic tool to increase the chance for surgical radicality and to ensure correct staging for optimal oncological therapy. Based on the literature from the last decades, standard lymphadenectomy with resection of at least ≥ 15 LNs is associated with an acceptable postoperative complication risk and should be recommended to obtain local radicality and accurate staging of the disease. Although radical surgery including appropriate lymphadenectomy of regional LNs remains the only chance for long-term tumor control, future studies specifically assessing the impact of neoadjuvant therapy on extraregional LNs are warranted.

Background: Preoperative skin antisepsis is an essential component of safe surgery. However, it is unclear how many antiseptic paints are needed to eliminate bacteria prior to incision. This study compared microbial skin counts after two and three antiseptic paints., Methods: We conducted a prospective cohort study in non-emergency patients receiving a cardiac/abdominal surgery with standardized, preoperative skin antisepsis consisting of an alcoholic compound and either povidone iodine (PI) or chlorhexidine (CHX). We obtained three skin swabs from the participant's thorax/abdomen using a sterile template with a 25 cm 2 window: After collection of the first swab prior to skin antisepsis, and once the second and third application of PI/CHX had dried out, we obtained a second and third swab, respectively. Our primary outcome was the reduction in microbial skin counts after two and three paints of PI/CHX., Results: Among the 239 enrolled patients, there was no significant difference in the reduction of mean square root-transformed microbial skin counts with three versus two paints (P = 0.2). But distributions of colony forming units (CFUs) decreased from paint 2 to 3 in a predefined analysis (P = 0.002). There was strong evidence of an increased proportion of patients with zero CFU after paint 3 versus paint 2 (P = 0.003). We did not identify risk factors for insufficient reduction of microbial skin counts after two paints, defined as the detection of > 5 CFUs and/or ≥ 1 pathogens., Conclusions: In non-emergency surgical patients, three antiseptic paints may be superior to two paints in reducing microbial skin colonization prior to surgery.

Fibroblast activation protein α (FAP) plays an important role in tissue remodeling and helps tumor cells invade surrounding tissue. We sought to investigate FAP as a prognostic molecular marker in colorectal cancer (CRC) using immunohistochemical and transcriptomic data. FAP expression and clinicopathological information were obtained from The Cancer Genome Atlas data set. The association of FAP expression and tissue cellular heterogeneity landscape was explored using the xCell method. We evaluated FAP protein expression in a cohort of 92 CRCs and 19 non-tumoral tissues. We observed that FAP was upregulated in tumors both at the mRNA and protein levels, and its expression was associated with advanced stages, poor survival, and consensus molecular subtype 4. FAP expression was also associated with angiogenesis and collagen degradation. We observed an enrichment in immune-cell process-related genes associated with FAP overexpression. Colorectal cancers with high FAP expression display an inflamed phenotype enriched for macrophages and monocytes. Those tumors showed enrichment for regulatory T cell populations and depletion of T H 1 and natural killer T cells, pointing to an immunosuppressive environment. Colorectal cancers with high levels of stromal FAP are associated with aggressive disease progression and survival. Our results suggest that FAP plays additional roles in tumor progression such as modulation of angiogenesis and immunoregulation in the tumor microenvironment., (Copyright © 2020 Coto-Llerena, Ercan, Kancherla, Taha-Mehlitz, Eppenberger-Castori, Soysal, Ng, Bolli, von Flüe, Nicolas, Terracciano, Fani and Piscuoglio.)

Background: Predicting the dignity of pancreatic lesions is still a diagnostic challenge. The differentiation between benign changes in chronic pancreatitis from pancreatic cancer remains difficult. Therefore, the aim of this study was to evaluate whether early dual time point kinetics of pancreatic lesions in 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) may be helpful to differentiate pancreatic lesions., Methods: We prospectively analyzed 64 patients (pancreatic cancer n = 45 and chronic pancreatitis n = 19) scheduled for dual time point FDG-PET/computed tomography scan for pancreatic lesions from 2005 to 2014. Studies were performed 60 and 90 minutes after application of F-FDG. Histological samples were collected for all patients, either by resection or by biopsy. Semiquantitative analysis was performed using the minimum, the maximum, and the average standardized uptake value (SUV) from the two different sets of images. To increase sensitivity and specificity, a formula addressing the weighting of standardized uptake values was created., Results: With a sensitivity of 82.6%, specificity of 77.8%, accuracy of 79.7%, positive predictive value of 90.5%, and negative predictive value of 63.6% SUVmax@time1 > 3.45 was the most reliable single quantitative parameter for malignancy of the pancreatic lesions. Weighting of standardized uptake values produced a formula that showed an even better profile., Conclusions: In patients with suspicious pancreatic lesions, the simplified dual time point FDG-PET/computed tomography may represent a valuable diagnostic tool in characterizing pancreatic lesions.

Background: The benefit of a perianal block as an adjunct to general or regional anaesthesia is debated. This RCT aimed to compare pain at 24 h and up to 14 days after proctological surgery in patients with and without a perianal block., Methods: Between January 2018 and April 2019, patients were allocated to receive a perianal block with ropivacaine or placebo as an adjunct to anaesthesia. Patients, surgeons and assessors were blinded. The primary outcome was pain measured on a numerical rating scale (NRS) after 24 h. Secondary outcomes were need for rescue analgesia, and pain after 1, 2, 3, 6 and 12 h. The mean, rest and maximum NRS scores were measured for 14 days., Results: A total of 138 patients were included, of whom 46 and 44 received general anaesthesia with or without ropivacaine respectively, and 23 and 25 received spinal anaesthesia with or without ropivacaine respectively (P = 0·858). The mean NRS score differed significantly at 24 h (mean(s.d.) 1·1(0·1) versus 2·3(0·2); P < 0·001), but not at 1 h (1·4(0·2) versus 2·2(0·3); P = 0·051). The NRS score was lower with use of ropivacaine at 2 h (1·0(0·2) versus 1·6(0·2); P = 0·045), 3 h (0·9(0·2) versus 1·5(0·2); P = 0·022), 6 h (1·1(0·2) versus 1·8(0·2); P = 0·042) and 12 h (1·2(0·2) versus 1·8(0·2); P = 0·034). The use of oral morphine equivalents was 10·2(1·4) and 16·6(2·5) mg with and without ropivacaine respectively (P = 0·028). The mean and maximum NRS scores within 14 days were lower when ropivacaine was used (95 per cent c.i. for difference 0·14 to 0·49 (P = 0·002) and 0·39 to 0·63 (P < 0·001) respectively). There was no injection-associated morbidity., Conclusion: Perianal block as an adjunct to general or regional anaesthesia should be recommended for proctological surgery. It yields a reduction in pain, a reduced need for opioids, and a faster recovery with minimal risk of adverse events. Registration number: NCT03405922 ( http://www.clinicaltrials.gov)., (© 2020 BJS Society Ltd Published by John Wiley & Sons Ltd.)

Objective: The ideal location of specimen extraction in laparoscopic-assisted colorectal surgery is still debatable. The aim of this study was to compare the incidence of incisional hernias and surgical site infections in patients undergoing elective laparoscopic resection for recurrent sigmoid diverticulitis by performing specimen extraction through left lower transverse incision or Pfannenstiel-Kerr incision., Methods: A total of 269 patients operated between January 2014 and December 2017 were retrospectively screened for inclusion in the study. Patients with specimen extraction through left lower transverse incision (LLT) and patients with specimen extraction through Pfannenstiel-K incision (P-K) were matched in 1:1 proportion regarding age, sex, comorbidities, and previous abdominal surgery. The incidence of incisional hernias and surgical site infections were compared by using Fisher's exact test., Results: After matching 77 patients in the LLT group and 77 patients in the P-K group, they were found to be homogenous regarding the above mentioned descriptive characteristics. No patients in the P-K group developed an incisional hernia compared with 10 patients (13%) in the LLT group (p = 0.001). All these patients required hernia repair with mesh augmentation. The rate of surgical site infections was 1/77 in the P-K group and 0/77 in the LLT group (p = 1.0). In the P-K group, a wound protector was used in 86% of patients whereas in the LLT group, 39% of the wounds were protected during specimen extraction (p < 0.0001)., Conclusion: The Pfannenstiel-Kerr incision may be the preferred extraction site compared with the left lower transverse incision given the significant reduction of the risk of incisional hernias.

Objectives: Analysis of tumor immune infiltration has been suggested to outperform tumor, node, metastasis staging in predicting clinical course of colorectal cancer (CRC). Infiltration by cells expressing OX40, a member of the tumor necrosis factor receptor family, or CD16, expressed by natural killer cells, monocytes, and dendritic cells, has been associated with favorable prognosis in patients with CRC. We hypothesized that assessment of CRC infiltration by both OX40+ and CD16+ cells might result in enhanced prognostic significance., Methods: Colorectal cancer infiltration by OX40 and CD16 expressing cells was investigated in 441 primary CRCs using tissue microarrays and specific antibodies, by immunohistochemistry. Patients' survival was evaluated by Kaplan-Meier and log-rank tests. Multivariate Cox regression analysis, hazard ratios, and 95% confidence intervals were also used to evaluate prognostic significance of OX40+ and CD16+ cell infiltration., Results: Colorectal cancer infiltration by OX40+ and CD16+ cells was subclassified into 4 groups with high or low infiltration levels in all possible combinations. High levels of infiltration by both OX40+ and CD16+ cells were associated with lower pT stage, absence of peritumoral lymphocytic (PTL) inflammation, and a positive prognostic impact. Patients bearing tumors with high infiltration by CD16+ and OX40+ cells were also characterized by significantly longer overall survival, as compared with the other groups. These results were confirmed by analyzing an independent validation cohort., Conclusions: Combined infiltration by OX40+ and CD16+ immune cells is an independent favorable prognostic marker in CRC. The prognostic value of CD16+ immune cell infiltration is significantly improved by the combined analysis with OX40+ cell infiltration.

Background: Metastatic disease in colorectal cancer represents a major cause of significant cancer-associated morbidity and mortality. L1CAM is a stem cell marker, cell adhesion molecule, belongs to the immunoglobulin superfamily of cell adhesion molecules (IgCAM) and it is aberrantly expressed in several different types of human solid tumors. The aim of the present study was to assess the expression patterns of L1CAM and its clinical significance in colorectal cancer. Patients and methods: Surgical specimens of 109 patients with primary resectable colorectal cancer were examined for L1CAM expression via immunohistochemistry and the results were correlated with clinical and survival data. Results: L1CAM expression was significantly correlated with advanced stage of disease ( p  < .001), higher T classification ( p  = .040), the presence of lymph node ( p  < .001) and distant metastasis ( p  = .011). Patients displaying high L1CAM expression demonstrated a dismal three-year progression free survival (29.7% vs 87.1%, p  < .001) and five-year overall survival (39.9% vs 87.7%, p  < .001). Multivariate analysis using Cox proportional hazard models revealed high L1CAM expression as a prognostic marker of dismal progression free (HR 0.187, 95%CI = 0.075-0.467, p  < .0001) and overall survival (HR 0.154, 95%CI = 0.049-0.483, p  = .001) independent of other clinicopathological characteristics. Subgroup analysis comprised of patients with early stage disease only presented as well significantly worse progression free and overall survival when L1CAM exhibited high expression. Conclusions: Colorectal cancer patients displaying high expression of L1CAM harbor high risk for metastasis already in early stage disease identifying therefore a group of patients prone to dismal prognosis.

Background and Objective: Breast cancer stem cells are considered to be a major cause of disease recurrence in breast cancer as they appear to be chemoresistant. Fascin-1 and MAP17 are stem cell markers whose excessive expression in tumors is associated with aggressive tumor phenotypes. The aim of the present study was to investigate the expression patterns of fascin-1 and MAP17 in breast cancer and to assess their clinical significance., Methods: Expression of fascin-1 and MAP17 was assessed via immunohistochemistry in surgical specimens of a cohort comprised of 127 patients with resectable breast cancer. Results were correlated with clinicopathological characteristics and survival data. Progression-free survival (PFS) was defined as the primary outcome of the present study., Results: Fascin-1 and MAP17 expression were strongly associated with the presence of triple-negative cancers (p < 0.0001). Tumors displaying high expression of fascin-1 presented correlations with high tumor grade (p = 0.002) and high expression of Ki-67 (p = 0.004). PFS of patients exhibiting high expression of fascin-1 and MAP17 in cancer cells in the first 5 years after surgery was significantly worse than in patients with low expression of the two markers (47.8%, 95% confidence interval [CI] 33-51 vs. 80.5%, 95% CI 47-56; p = 0.012) and independent of other clinicopathological characteristics (hazard ratio 0.171, 95% CI 0.034-0.869; p = 0.033)., Conclusion: Combined expression of fascin-1 and MAP17 in breast cancer cells is associated with a significantly worse 5-year PFS, therefore recognizing a group of patients with high risk for early disease recurrence.

Idiopathic localised dilatation of the intestine (ILDI) presenting in adults is rare and difficult to diagnose. Only 18 cases have been reported in the literature. We report a case of a 32-year-old woman presenting with abdominal pain and intermittent small bowel obstruction. After detailed radiological studies, the patient, known for Crohn's disease, was scheduled for laparoscopy in the suspicion of small bowel stricture. A localised dilatation of the ileum was found intraoperatively and subsequently resected. A systematic review of this rare pathology in adults is carried out. ILDI should be part of the differential diagnosis in patients with unexplained abdominal pain or gastrointestinal bleeding in the presence of segmental dilatation of the intestine. Surgical resection is the treatment of choice., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Despite improvements in therapy of colorectal cancer, some patients will present occurrence of recurrence either locally or distantly. Tumor metastasis constitutes the major cause of cancer-associated morbidity and mortality. Nectin-1 belongs to the family of immunoglobulin-like cell adhesion molecules that contribute to the formation of cell-cell adhesions and regulate a series of cellular activities including cell polarization, differentiation, movement, proliferation, and survival. Expression of Nectin-1 in malignant tumors has been associated with aggressive tumor phenotypes., Objectives: The aim of the present study was to assess Nectin-1 expression patterns in colorectal cancer and to investigate its clinical significance., Methods: Nectin-1 expression was assessed via immunohistochemistry in surgical specimens of a cohort comprised of 111 patients with primary resectable colorectal cancer. Results were correlated with clinicopathological characteristics and survival data. Progression-free survival was defined as the primary outcome of the present study., Results: Nectin-1 was strongly expressed in the cytoplasm of colorectal cancer cells. High Nectin-1 expression was associated with advanced stage of disease (p = 0.012) and lymph node metastasis (p = 0.007). Progression-free survival of patients exhibiting high expression of Nectin-1 in the first 36 months after surgery was significantly worse compared to patients with low expression of Nectin-1 (55.7%, 95% CI = 47-70, vs. 82.1%, 95% CI = 69-93, p = 0.014) and independent of other clinicopathological characteristics (HR = 0.389, 95% CI = 0.156-0.972, p = 0.043)., Conclusion: Nectin-1 expression in colorectal cancer is associated with a significantly worse 3-year progression-free survival identifying therefore a group of patients with high risk for early disease recurrence., (© 2019 S. Karger AG, Basel.)

Purpose: Laparoscopic rectosigmoid resection is the standard surgical treatment for recurrent sigmoid diverticulitis. However, speaking of mesenterium division, no unique standard procedure is actually provided. Surgeons can perform it at the level of either the sigmoid vessels or the inferior mesenteric vessels. The objective of this study was to compare intra- and postoperative complications of both techniques., Methods: From a prospective collected database of patients that underwent elective laparoscopic sigmoid resection between January 2004 and December 2014, a retrospective analysis according to the selected operative technique was performed., Results: A total of 1016 patients were operated, and a pedicle division of the mesenteric vessels was performed in 280 patients (central group 27.6%) while a peripheral division was performed in 736 patients (peripheral group 72.4%). Comparison of these two groups demonstrated no statistically significant difference regarding age or stage of disease. Thirteen patients (1.3%) developed anastomotic leak; among them, nine belonged to the peripheral group (1.2 vs 1.4% p = 0.794). Twenty-four patients (2.4%) developed postoperative rectal bleeding but only in nine cases was a bleeding of the anastomosis confirmed using endoscopy (seven peripheral group vs two central group, 0.95 vs 0.7% p = 0.712). Moreover, postoperative morbidity did not significantly differ between the two groups. A very low mortality rate was observed, with 2 deaths (both in the peripheral group)., Conclusions: Ligation of inferior mesenteric vessels does not seem to affect anastomotic healing; both surgical techniques presented similar incidence of anastomotic bleeding. In this analysis, we could not identify any significant difference in overall morbidity and mortality.

Background: Centralization of esophageal cancer surgery to high-volume institutions has been shown to improve perioperative outcomes in several studies. However, there is an ongoing debate, whether defined minimal annual hospital volumes for esophagectomies are required for quality assurance. The aim of the study was to assess perioperative outcomes of esophagectomies in a single institution in Switzerland., Methods: Data from a database of esophagectomies performed between 2004 and 2013 was analyzed. Perioperative morbidity of esophagectomies due to cancer was assessed according to the Clavien-Dindo classification. Postoperative mortality was defined as death from any cause within the same hospital stay., Results: A total of 143 operations (125 transthoracic esophagectomies, 18 extended transhiatal gastrectomies) were performed in the surveyed 10-year period. Two surgeons performed 91 % of all procedures. Postoperative morbidity was 43.4 %. Complications with a Clavien-Dindo score of III/IV (requiring surgical, endoscopic, or radiological intervention) occurred in 19 cases (13.4 %). The overall anastomotic leak rate was 3.5 %. Pulmonary complications were the most frequent postoperative problems involving 21 % of patients. In-hospital mortality was 0.7 %. Mean length of hospital stay was 17 days in patients with no complications and 22 days if there were any complications (p < 0.001)., Conclusion: Esophageal cancer surgery is complex and has a significant risk of morbidity. The most common postoperative problems are pulmonary complications, usually responding well to non-invasive treatment. Appropriate patient selection and preparation, high surgeon volume, and a comprehensive multidisciplinary care pathway can provide a low perioperative mortality rate in a mid-volume institution.

Background: Germline mutations in DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2 cause autosomal dominantly inherited Lynch syndrome. Lynch syndrome patients and their families benefit from life-saving intensive cancer surveillance. Approximately one in 30 colorectal cancers arises in the setting of Lynch syndrome., Objective: The aim of this study was to assess the detection rate of Lynch syndrome at our institution after introduction of systematic immunohistochemical screening for MMR deficiency in colorectal cancers from 2011 to 2015., Design: Following the recommendations by the Evaluation of Genomic Applications in Practice and Prevention working group all colorectal cancers were immunohistochemically stained for the presence of MMR proteins MLH1, PMS2, MSH2 and MSH6, independent of clinical criteria. In the case of loss of MLH1, the somatic BRAF mutation V600E was assessed with molecular testing and/or immunohistochemistry. Clinical follow-up of potential Lynch syndrome carriers (patients with tumours showing loss of MLH1 expression with absence of BRAFV600E, loss of PMS2, MSH2 or MSH6) was evaluated., Results: Of all patients (n = 486), loss of MMR protein expression was found in 73 (15.0%) tumours. Twenty-eight (6.0%) were classified as potential Lynch syndrome carriers. Of the genetically tested potential Lynch syndrome carriers (10 out of 28 patients), 40% were first diagnosed with Lynch syndrome., Conclusions: Implementation of systematic immunohistochemistry screening for Lynch syndrome showed that 6% of colorectal cancers were potentially Lynch-syndrome related. Tumour board protocols should systematically contain information on MMR status of all colorectal cancers and, in MMR deficient cases, include clear recommendations for genetic counselling for all potential Lynch syndrome patients.