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Background The long-term outcome after local excision of T1 colorectal cancer (CRC) remains unknown. The aim of this study was to examine clinical and histopathological risk factors for recurrence in patients with T1 CRC undergoing endoscopic resection. Methods This was a retrospective registry-based population study on prospectively collected data of all patients with nonpedunculated T1 CRC undergoing only local excision (no salvage surgery) in Sweden between 2009 and 2018. Potential risk factors for recurrence, including age, sex, tumor location, resection margins, lymphovascular, perineural, and submucosal invasion, grade of differentiation, and mucinous subtype, were analyzed using univariate and multivariate cox regression. Results Median follow-up time was 60 months, and 28 /602 patients (4.7 %) had a recurrence (13 local and 18 distant). Recurrence rate stratified by submucosal invasion was: Sm1 3.5 % (14 /397), Sm2 6.0 % (8 /133), and Sm3 8.3 % (6 /72), with no significant differences. Resection margins, lymphovascular and perineural invasion, grade of differentiation, mucinous subtype, and age were not significant risk factors for recurrence. In contrast, rectal location was found to be a significant risk factor for tumor recurrence in multivariate analysis (hazard ratio 3.08, P = 0.006). The 3– and 5-year disease-free survival was 96.2 % and 91.1 %, respectively, in T1 CRC patients undergoing endoscopic resection. Conclusion Tumor recurrence was rare (4.7 %) in this large population-based study on recurrence after local excision of nonpedunculated T1 CRC. Rectal location was an independent risk factor for recurrence, suggesting the need for strict surveillance after endoscopic resection of early rectal cancer.

Septic lung damage is associated with endothelial cell and neutrophil activation. This study examines the role of the E3 ubiquitin ligase midline 1 (Mid1) in abdominal sepsis. Mid1 expression was increased in endothelial cells derived from post-capillary venules in septic mice and TNF-α challenge increased Mid1 levels in endothelial cells in vitro. The siRNA-mediated knockdown of Mid1 decreased TNF-α-induced upregulation of ICAM-1 and neutrophil adhesion to endothelial cells. Moreover, Mid1 silencing reduced leukocyte adhesion in post-capillary venules in septic lungs in vivo. The silencing of Mid1 not only decreased Mid1 expression but also attenuated expression of ICAM-1 in lungs from septic mice. Lastly, TNF-α stimulation decreased PP2Ac levels in endothelial cells in vitro, which was reversed in endothelial cells pretreated with siRNA directed against Mid1. Thus, our novel data show that Mid1 is an important regulator of ICAM-1 expression and neutrophil adhesion in vitro and septic lung injury in vivo. A possible target of Mid1 is PP2Ac in endothelial cells. Targeting the Mid1-PP2Ac axis may be a useful way to reduce pathological lung inflammation in abdominal sepsis.

The option to treat early colon cancer (CC) with local resection, as well as trials investigating neoadjuvant treatment, has increased the importance of identifying early-stage disease in the workup. Most CC patients are T- and N-staged preoperatively with CT, although its reliability in staging early CC remains elusive. The aim of this study was to investigate CT-staging accuracy in early CC by evaluating pT and pN stages in patients staged as cT1-2, and cT and cN stages in patients with pT1 tumors.Retrospective population-based cohort study on data from the nationwide Swedish colorectal cancer registry on all CC patients staged as cT1-2 and all patients with pT1 undergoing surgical resection 2009-2018. CT-acquired T- and N-stages were compared with final histopathology. Factors potentially influencing accuracy were analyzed with uni- and multivariate logistic regression.Computed tomography (CT) staged 4849 patients as cT1-2, whereas 2445 (50%) were pT3 and 453 (9%) pT4. Positive predictive value of the cT1-2 stage was 40%. Of 1401 pT1 patients, 624 (45%) were staged as cT1-2, 139 (10%) as cT3, 15 (1%) as cT4 and 623 (44%) as cTx. In all, 1474 (30%) of the cT1-2 patients were pN+, whereas CT staged 1062 (72%) as cN0. A total of 771 patients were staged as cN+, whereas 403 (52%) were pN0. Overall accuracy in determining N+ was 67%, with 26% sensitivity and 88% specificity. Positive and negative predictive values in determining N+ were 48% and 73%, respectively.This nationwide population-based study shows that CT-staging carries a substantial risk of understaging locally advanced tumors as cT1-2 and pT1 tumors as cTx, in addition to poor N-staging. Thus, CT obtained T- and N-staging should not be used for deciding treatment strategies in early CC.

Recent evidence suggests that targeting S100A9 reduces pathological inflammation in abdominal sepsis. Herein, we investigated the role of S100A9 in neutrophil extracellular trap (NET) formation in septic lung damage. NETs were detected by electron microscopy in the lung and by confocal microscopy in vitro. Stimulation of isolated mouse bone marrow-derived neutrophils with S100A9 triggered formation of NETs. Blocking TLR4 and RAGE reduced S100A9-induced generation of NETs and DNA-histone complexes. Moreover, S100A9 challenge increased generation of reactive oxygen species (ROS) in bone marrow neutrophils. Co-incubation with the NADPH oxidase inhibitor not only decreased ROS formation but also attenuated induction of DNA-histone complexes in S100A9-stimulated neutrophils. Abdominal sepsis was induced by cecal ligation and puncture (CLP) in male C57BL/6 mice. Administration of the S100A9 inhibitor ABR-238901 decreased CLP-induced formation of NETs in lungs and DNA-histone complexes in plasma. In addition, transmission electron microscopy revealed that S100A9 was abundantly expressed on NETs in the lungs in CLP mice. By use of intravital microscopy, we found that local injection of NETs increased leukocyte adhesion and migration in the mouse cremaster muscle microvasculature. Notably, treatment with ABR-238901 attenuated NET-induced leukocyte adhesion and extravasation in the cremaster muscle, suggesting that NET-associated S100A9 promotes leukocyte recruitment in vivo. Taken together, these novel findings suggest that S100A9 triggers ROS-dependent formation of NETs via TLR4 and RAGE signaling in neutrophils. Moreover, S100A9 regulates both formation of NETs and NET-induced leukocyte recruitment in vivo. Thus, targeting S100A9 might be useful to ameliorate lung damage in abdominal sepsis.

MRI plays a pivotal role in the staging of early rectal cancer, resulting in allocation of patients to surgery or organ-sparing treatment. In this large population-based retrospective cohort study, MRI substantially understaged pT3 and overstaged pT1 rectal cancer, in addition to unreliable nodal staging. Based on these findings, MRI is not adequate in allocating patients with rectal cancer to organ-sparing treatment.

Neutrophil extracellular trap (NET) formation is a key feature in sepsis. The aim of the present study was to examine the role of the actin cytoskeleton in regulating the expulsion of NETs. Actin-related protein 2/3 (Arp 2/3) complex is an important regulator of F-actin polymerization. Coincubation with CK666, a specific Arp 2/3 inhibitor, decreased 12-phorbol 13-myristate acetate-induced NET formation in vitro. CK666 not only abolished F-actin polymerization but also caused intracellular retention of NETs. Inhibition of Arp 2/3 reduced NET formation on circulating neutrophils and in the bronchoalveolar space in mice undergoing cecal ligation and puncture (CLP). Notably, treatment with CK666 attenuated CLP-induced neutrophil recruitment, edema formation, and tissue damage in the lungs. Moreover, Arp 2/3 inhibition decreased levels of C-X-C motif chemokine ligand 1 (CXCL-1) and interleukin-6 in the lung and plasma of septic animals. Taken together, this study shows that expulsion of NETs is regulated by the actin cytoskeleton and that inhibition of Arp 2/3-dependent F-actin polymerization not only decreases NET formation but also protects against pathological inflammation and tissue damage in septic lung injury. Thus, we suggest that targeting NET release is a novel and useful way to ameliorate lung damage in abdominal sepsis.

OBJECTIVE To identify clinical and histopathological risk factors of LNM in T1 CRC. SUMMARY OF BACKGROUND DATA The requisite of additional surgery after locally resected T1 CRC is dependent on the risk of LNM. Depth of submucosal invasion is used as a key predictor of lymphatic metastases although data are conflicting on its actual impact. METHODS Retrospective population-based cohort study on prospectively collected data on all patients with T1 CRC undergoing surgical resection in Sweden, 2009-2017 and Denmark 2016-2018. The Danish cohort was used for validation. Potential risk factors of LNM investigated were; age, sex, tumor location, submucosal invasion, grade of differentiation, mucinous subtype, lymphovascular, and perineural invasion. RESULTS One hundred fifty out of the 1439 included patients (10%) had LNM. LVI (P < 0.001), perineural invasion (P < 0.001), mucinous subtype (P = 0.006), and age

S100A9, a pro-inflammatory alarmin, is up-regulated in inflamed tissues. However, the role of S100A9 in regulating neutrophil activation, inflammation and lung damage in sepsis is not known. Herein, we hypothesized that blocking S100A9 function may attenuate neutrophil recruitment in septic lung injury. Male C57BL/6 mice were pretreated with the S100A9 inhibitor ABR-238901 (10 mg/kg), prior to cercal ligation and puncture (CLP). Bronchoalveolar lavage fluid (BALF) and lung tissue were harvested for analysis of neutrophil infiltration as well as edema and CXC chemokine production. Blood was collected for analysis of membrane-activated complex-1 (Mac-1) expression on neutrophils as well as CXC chemokines and IL-6 in plasma. Induction of CLP markedly increased plasma levels of S100A9. ABR-238901 decreased CLP-induced neutrophil infiltration and edema formation in the lung. In addition, inhibition of S100A9 decreased the CLP-induced up-regulation of Mac-1 on neutrophils. Administration of ABR-238901 also inhibited the CLP-induced increase of CXCL-1, CXCL-2 and IL-6 in plasma and lungs. Our results suggest that S100A9 promotes neutrophil activation and pulmonary accumulation in sepsis. Targeting S100A9 function decreased formation of CXC chemokines in circulation and lungs and attenuated sepsis-induced lung damage. These novel findings suggest that S100A9 plays an important pro-inflammatory role in sepsis and could be a useful target to protect against the excessive inflammation and lung damage associated with the disease.

Background and study aims Management of T1 rectal cancer is complex and includes several resection methods, making cost comparisons challenging. The aim of this study was to compare costs of endoscopic and surgical resection and to investigate hypothetical cost scenarios for the treatment of T1 rectal cancer. Patients and methods Retrospective population-based cost minimization study on prospectively collected data on T1 rectal cancer patients treated using endoscopic submucosal dissection (ESD), transanal endoscopic microsurgery (TEM), open, laparoscopic, or robotic resection, in Skåne County, Sweden (2011–2017). The hypothetical cost scenarios were based on the distribution of high-risk features of lymph node metastases in a national cohort (2009–2017). Results Eighty-five patients with T1 RC undergoing ESD (n = 16), TEM (n = 17), open (n = 35), laparoscopic (n = 9), and robotic (n = 8) resection were included. ESD had a total 1-year cost of 5165 € and was significantly (P Conclusions This is the first study analyzing total 1-year costs of endoscopic and surgical methods to resect T1 rectal cancer, which showed that the cost of ESD was significantly lower compared to TEM and surgical resection. In fact, based on hypothetical cost scenarios, ESD is still justifiable from a cost perspective even when all high-risk cases are followed by surgery in accordance to guidelines.

Obesity is a growing health problem and challenge to the health care systems in the western world. Available treatment is limited to lifestyle modifications, cognitive therapy, drugs and bariatric surgery. On one hand, lifestyle changes and pharmacological treatment have very limited long-term effects on obesity. On the other hand, bariatric surgery is effective to maintain long-term weigh reduction but is associated with complications and reaches less than 2 % of patients with indication for surgery. Thus, there is a gap in the management of patients with obesity, and endoscopic bariatric therapies might fill that gap by providing effective, repeatable and reversible alternatives for selected patients with obesity. This article introduces endoscopic methods to achieve weight loss with special focus on endoscopic sleeve gastroplasty (ESG). Data in the literature demonstrates that ESG is effective in reducing total and excessive body weight up to two years after the procedure as well as reducing obesity-related co-morbidity. The challenge is that ESG requires advanced endoscopic skills and is not yet available at many centres. A structured training program is needed to disseminate ESG and offer selected patients with obesity an alternative to bariatric surgery in Europe.

Background and study aims Endoscopic submucosal dissection (ESD) allows en bloc resection of large colorectal lesions but ESD experience is limited outside Asia. This study evaluated implementation of ESD in the treatment of colorectal neoplasia in a Western center. Patients and methods Three hundred and one cases of colorectal ESD (173 rectal and 128 colonic lesions) were retrospectively evaluated in terms of outcome, learning curve and complications. Results Median size was 4 cm (range 1 – 12.5). En bloc resection was achieved in 241 cases amounting to an en bloc resection rate of 80 %. R0 resection was accomplished in 207 cases (69 %), RX and R1 were attained in 83 (27 %) and 11 (4 %) cases, respectively. Median time was 98 min (range 10 – 588) and median proficiency was 7.2 cm2/h. Complications occurred in 24 patients (8 %) divided into 12 immediate perforations, five delayed perforations, one immediate bleeding and six delayed bleedings. Six patients (2 %), all with proximal lesions, had emergency surgery. Two hundred and four patients were followed up endoscopically and median follow-up time was 13 months (range 3 – 53) revealing seven recurrences (3 %). En bloc rate improved gradually from 60 % during the first period to 98 % during the last period. ESD proficiency significantly improved between the first study period (3.6 cm2/h) and the last study period (10.8 cm2/h). Conclusions This study represents the largest material on colorectal ESD in the west and shows that colorectal ESD can be implemented in clinical routine in western countries after appropriate training and achieve a high rate of en bloc and R0 resection with a concomitant low incidence of complications. ESD of proximal colonic lesions should be attempted with caution during the learning curve because of higher risk of complications.

BACKGROUND: Biopsies are routinely obtained in the workup of large colorectal polyps before endoscopic resection. OBJECTIVE: This study aimed to examine how reliable biopsies are in terms of reflecting the true histopathology of large colorectal polyps, in the clinical routine. DESIGN: This is a retrospective study. SETTINGS: Data from patients undergoing polypectomy of large colorectal polyps at the endoscopy unit, Skane University Hospital Malmo, between January 2014 and December 2016 were scrutinized. PATIENTS: A total of 485 colorectal lesions were biopsied within 1 year before complete endoscopic removal. Biopsy-obtained specimens were compared with completely resected specimens in terms of concordance and discordance and if the final result was upgraded or downgraded. MAIN OUTCOME MEASURES: The primary outcome measured was the concordance between biopsy-obtained specimens and completely resected specimens. RESULTS: Median lesion size was 3 cm (range 1-11). In 189 cases (39%), biopsies did not provide a correct dysplastic grade compared with final pathology after complete resection. One hundred forty-three cases (29%) and 46 cases (9%) were upgraded and downgraded. The percentage of cases with discordant biopsy results was 40% in cases with 1 biopsy taken and 38% in cases where multiple biopsies had been sampled. Time from biopsy to complete resection did not influence the erroneous outcome of biopsies. Notably, the percentage of discordant biopsy results was 37% and 35% in lesions measuring 1 to 2 cm and 2 to 4 cm. However, this percentage increased to 48% in colorectal lesions larger than 4 cm. LIMITATIONS: This study was designed to reflect the clinical routine, the number of biopsies obtained and forceps technique were hence not standardized, which constitutes a limitation. CONCLUSIONS: This study demonstrates that cancer-negative forceps biopsies of large colorectal polyps, referred for endoscopic resection, are not reliable. Considering that endoscopic resection of lesions containing superficial cancer is plausible, the clinical value of forceps biopsies in lesions suitable for endoscopic resection is questionable. See Video Abstract at http://links.lww.com/DCR/A984. LAS BIOPSIAS CON FORCEPS NO SON CONFIABLES EN EL ESTUDIO DE LAS LESIONES COLORRECTALES GRANDES REFERIDAS PARA RESECCION ENDOSCOPICA: ?DEBERIAN ABANDONARSE?: Las biopsias se obtienen de forma rutinaria en el estudio de polipos colorrectales grandes previo a reseccion endoscopica. OBJETIVO: Analizar que tan confiables son las biopsias en cuanto a reflejar la verdadera histopatologia de los polipos colorrectales grandes, en la rutina clinica. DISENO:: Este es un estudio retrospectivo. AJUSTES: Los datos de pacientes sometidos a polipectomia de polipos colorrectales grandes en la unidad de endoscopia, en Skane University Hospital Malmo, entre enero de 2014 y diciembre de 2016 fueron examinados. PACIENTES: Un total de 485 lesiones colorrectales se biopsiaron dentro de un ano antes de la reseccion endoscopica completa. Las muestras obtenidas mediante biopsia se compararon con las muestras completas resecadas en terminos de concordancia y discordancia, y si el resultado final ascendio o disminuyo de categoria. PRINCIPALES MEDIDAS DE RESULTADO: Concordancia entre muestras obtenidas mediante biopsia y muestras completamente resecadas. RESULTADOS: La mediana de tamano de lesiones fue de 3 cm (rango 1-11). En 189 casos (39%) las biopsias no proporcionaron un grado de displasia correcto en comparacion con la patologia final despues de la reseccion completa. 143 casos (29%) y 46 casos (9%) ascendieron y descendieron de categoria, respectivamente. El porcentaje de casos con resultados de biopsia discordantes fue del 40% en los casos con una sola biopsia tomada y del 38% en los casos en los que se tomaron multiples biopsias. El tiempo desde la biopsia hasta la reseccion completa no influyo en el resultado erroneo de las biopsias. Notablemente, el porcentaje de resultados de biopsia discordantes fue de 37% y 35% en lesiones que midieron 1-2 cm y 2-4 cm, respectivamente. Sin embargo, este porcentaje aumento a 48% en lesiones colorrectales mayores de 4 cm. LIMITACIONES: Este estudio se diseno para reflejar la rutina clinica, el numero de biopsias obtenidas y la tecnica de forceps no fueron estandarizadas, lo que constituye una limitacion. CONCLUSIONES: Este estudio demuestra que las biopsias con forceps negativas a cancer, de polipos colorrectales grandes referidas para reseccion endoscopica, no son confiables. Teniendo en cuenta que la reseccion endoscopica de lesiones que contienen cancer superficial es posible, el valor clinico de las biopsias con forceps en lesiones aptas para la reseccion endoscopica es cuestionable. Vea el Resumen en video en http://links.lww.com/DCR/A984. (Less)

Endoscopic submucosal dissection (ESD) is an advanced method allowing en bloc resection of large and complex lesions in colon and rectum. Herein, the European experience of colorectal ESD was systematically reviewed in the medical literature to determine the clinical efficacy and safety of colorectal ESD in Europe.A systematic search of PubMed for full-text studies including more than 20 cases of colorectal ESD emanating from European centres was performed. Data were independently extracted by two authors using predefined data fields, including efficacy and safety.We included 15 studies containing a total of 1404 colorectal ESD cases (41% in the colon) performed between 2007 and 2018. Lesion size was 40 mm (range 24-59 mm) and procedure time was 102 min (range 48-176 min). En bloc resection rate was 83% (range 67-93%) and R0 resection rate was 70% (range 35-91%). Perforation rate was 7% (range 0-19%) and bleeding rate was 5% (range 0-12%). The percentage of ESD cases undergoing emergency surgery was 2% (range 0-6%). Additional elective surgery was performed in 3% of all cases due to histopathological findings showing deep submucosal invasion or more advanced cancer. The recurrence rate was 4% (range 0-12%) after a median follow-up time of 12 months (range 3-24 months).This review shows that ESD is effective and safe for treating large and complex colorectal lesions in Europe although there is room for improvement. Thus, it is important to develop standardized and high-quality educational programs in colorectal ESD in Europe.

Background and study aims Endoscopic submucosal dissection (ESD) is an established method for en bloc resection of large non-pedunculated colorectal lesions in Asia but dissemination of ESD in Western countries is limited. The aim of this study was to evaluate the role of ESD in the management of malignant non-pedunculated colorectal lesions in a European center. Patients and methods Among 255 patients undergoing colorectal ESD between 2014 and 2016, 29 cases were identified as submucosal invasive cancers and included in this study. The main outcomes were en bloc, R0 and curative resection as well as procedural time, complications and recurrence. Results Median tumor size was 40 mm (range 20 – 70 mm). Thirteen cancers were located in the colon and 16 were located in the rectum. Procedural time was 89 minutes (range 18 – 594 minutes). Complete resection was achieved in 28 cases, en bloc and R0 resection rates were 83 % and 69 %, respectively. Curative resection rate was 38 %. One case had a perforation in the sigmoid colon requiring emergency surgery. No significant bleeding occurred. Six patients underwent additional surgery after ESD, one of whom had residual tumor. One recurrence was detected in 20 patients that were followed-up endoscopically, median follow-up time was 13 months (range 2 – 30 months). Conclusion ESD seems to be a safe and effective method for treating non-pedunculated malignant colorectal lesions after careful patient selection and proper endoscopic training.

Purpose. The Frimand needle holder (FNH) was developed to facilitate palm grip suturing. In the present study, we wanted to examine the impact of the FNH compared with a conventional Hegar-styled needle holder (HSNH) on suture time and surgical stress. Methods. Thirty-two surgeons were enrolled and they performed sets of 3 continuous sutures on a polyurethane pad with premarked insert and exit points and the time for suturing was measured. Surgical stress was quantified by having the surgeons to perform 10 release maneuvers with the FNH and the HSNH on a needle attached to a scale. The scale sent 5 values per second to a computer. The first measurement of each series was regarded as the starting weight and all subsequent measurements were either regarded as neutral, pressure or traction. The sum of these measurements represented total surgical stress. Results. We found that all surgeons reduced their median suturing time by 16% when using FNH for palm grip suturing with no difference between junior and senior surgeons. Moreover, it was observed that FNH decreased median surgical stress by 62% for all surgeons performing palm grip suturing compared with a conventional HSNH. Conclusion. We conclude that the FNH reduces suture time and surgical stress compared with HSNH when performing palm grip suturing. These findings warrant studies in surgical patients in order to evaluate the potential clinical impact of FNH.

Purpose: The finger grip and the palm grip are the most common needle holder grips for hand suturing in surgery. The major advantages of the palm grip are an increased versatility and the possibility to apply controlled force. However, there is a risk for a potential loss of precision and uncontrolled movement of the needle when disengaging the ratchet mechanism of the palmed instrument. The purpose of this study was to develop a new needle holder, referred to as the Frimand needle holder (FNH), and evaluate surgeons' perception of it. It was designed to overcome the above-mentioned disadvantages, hence facilitating palm and finger grip suturing. Moreover, we evaluated suture precision and attitudes related to the use of the finger grip and the palm grip. Methods: Thirty-two surgeons performed sutures utilizing both the palm grip and the finger grip on postmortem porcine skin and small bowels, comparing the FNH to a standard Crile-Wood needle holder (CWNH). The participants assessed the FNH on an evaluation form. Precision was determined by letting the surgeons perform 20 sutures utilizing the finger grip and the palm grip on a polyurethane pad with premarked insert and exit sites. The distance between the designated exit site and the real exit site defined precision and was measured with a digital sliding dimension scale. Results: We found that 28 (88%) of the 32 surgeons use the palm grip to some extent, and 31 surgeons (97%) experienced an advantage when suturing with the FNH using the palm grip. Twenty-four (75%) of the 32 surgeons would prefer to suture with the FNH instead of the CWNH. There was no significant difference in precision between the finger grip and the palm grip. Conclusion: This study presents a new needle holder facilitating palm grip suturing. A majority of the participants preferred the new FNH over the standard CWNH for hand suturing.