Curriculum for training in endoscopic mucosal resection in the colon: European Society of Gastrointestinal Endoscopy (ESGE) Position Statement.

Endoscopic mucosal resection (EMR) is the standard of care for the complete removal of large (≥ 10 mm) nonpedunculated colorectal polyps (LNPCPs). Increased detection of LNPCPs owing to screening colonoscopy, plus high observed rates of incomplete resection and need for surgery call for a standardized approach to training in EMR. 1 : Trainees in EMR should have achieved basic competence in diagnostic colonoscopy, < 10-mm polypectomy, pedunculated polypectomy, and common methods of gastrointestinal endoscopic hemostasis. The role of formal training courses is emphasized. Training may then commence in vivo under the direct supervision of a trainer. 2 : Endoscopy units training endoscopists in EMR should have specific processes in place to support and facilitate training. 3: A trained EMR practitioner should have mastered theoretical knowledge including how to assess an LNPCP for risk of submucosal invasion, how to interpret the potential difficulty of a particular EMR procedure, how to decide whether to remove a particular LNPCP en bloc or piecemeal, whether the risks of electrosurgical energy can be avoided for a particular LNPCP, the different devices required for EMR, management of adverse events, and interpretation of reports provided by histopathologists. 4: Trained EMR practitioners should be familiar with the patient consent process for EMR. 5: The development of endoscopic non-technical skills (ENTS) and team interaction are important for trainees in EMR. 6: Differences in recommended technique exist between EMR performed with and without electrosurgical energy. Common to both is a standardized technique based upon dynamic injection, controlled and precise snare placement, safety checks prior to the application of tissue transection (cold snare) or electrosurgical energy (hot snare), and interpretation of the post-EMR resection defect. 7: A trained EMR practitioner must be able to manage adverse events associated with EMR including intraprocedural bleeding and perforation, and post-procedural bleeding. Delayed perforation should be avoided by correct interpretation of the post-EMR defect and treatment of deep mural injury. 8: A trained EMR practitioner must be able to communicate EMR procedural findings to patients and provide them with a plan in case of adverse events after discharge and a follow-up plan. 9: A trained EMR practitioner must be able to detect and interrogate a post-endoscopic resection scar for residual or recurrent adenoma and apply treatment if necessary. 10: Prior to independent practice, a minimum of 30 EMR procedures should be performed, culminating in a trainer-guided assessment of competency using a validated assessment tool, taking account of procedural difficulty (e. g. using the SMSA polyp score). 11: Trained practitioners should log their key performance indicators (KPIs) of polypectomy during independent practice. A guide for target KPIs is provided in this document.

Transanal formation of anastomosis using C-REX device is feasible and effective in high anterior resection.

PURPOSE: C-REX is a novel instrument for creating stapleless colorectal anastomosis by compression. The aim of this study was to evaluate the feasibility and effectiveness of C-REX in open and laparoscopic high anterior resections. METHODS: A prospective clinical safety study on 21 patients reconstructed with C-REX colorectal anastomosis following high anterior resection of the sigmoid colon using two different devices for intraabdominal (n = 6) or transanal (n = 15) placement of the anastomotic rings. Any signs of complications were prospectively monitored by a predefined protocol. Anastomotic contact pressure (ACP) was measured via a catheter-based system, and time for evacuation of the anastomotic rings by the natural route was noted. Blood samples were collected daily, and flexible endoscopy was performed postoperatively to examine macroscopic appearance of the anastomoses. RESULTS: One of six patients operated with the intraabdominal anastomosis technique with an ACP of 50 mBar had to be reoperated because of anastomotic leakage. None of the 15 patients operated with the transanal technique (5 open and 10 laparoscopic procedures) had anastomotic complications, and their ACP ranged between 145 and 300 mBar. C-REX rings were uneventfully expelled by the natural route in all patients after a median of 10 days. Flexible endoscopy showed well-healed anastomoses without stenosis in 17 patients and a moderate subclinical stricture in one patient. CONCLUSION: These results indicate that the novel transanal C-REX device is a feasible and effective method for colorectal anastomosis following high anterior resections, irrespective of open or laparoscopic approach. Moreover, C-REX allows measurement of intraoperative ACP and thereby a quantitative evaluation of the anastomotic integrity.

S100A9 induces reactive oxygen species-dependent formation of neutrophil extracellular traps in abdominal sepsis.

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.

Actin-related protein 2/3 complex regulates neutrophil extracellular trap expulsion and lung damage in abdominal sepsis.

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.

c-Abl kinase regulates neutrophil extracellular trap formation and lung injury in abdominal sepsis.

Sepsis is associated with exaggerated neutrophil responses although mechanisms remain elusive. The aim of this study was to investigate the role of c-Abelson (c-Abl) kinase in neutrophil extracellular trap (NET) formation and inflammation in septic lung injury. Abdominal sepsis was induced by cecal ligation and puncture (CLP). NETs were detected by electron microscopy in the lung and by confocal microscopy in vitro. Plasma levels of DNA-histone complexes, interleukin-6 (IL-6) and CXC chemokines were quantified. CLP-induced enhanced phosphorylation of c-Abl kinase in circulating neutrophils. Administration of the c-Abl kinase inhibitor GZD824 not only abolished activation of c-Abl kinase in neutrophils but also reduced NET formation in the lung and plasma levels of DNA-histone complexes in CLP mice. Moreover, inhibition of c-Abl kinase decreased CLP-induced lung edema and injury. Administration of GDZ824 reduced CLP-induced increases in the number of alveolar neutrophils. Inhibition of c-Abl kinase also markedly attenuated levels of CXC chemokines in the lung and plasma as well as IL-6 levels in the plasma of septic animals. Taken together, this study demonstrates that c-Abl kinase is a potent regulator of NET formation and we conclude that c-Abl kinase might be a useful target to ameliorate lung damage in abdominal sepsis.

Lymphovascular Infiltration, Not Depth of Invasion, is the Critical Risk Factor of Metastases in Early Colorectal Cancer: Retrospective Population-based Cohort Study on Prospectively Collected Data, Including Validation.

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 <60 years (P < 0.001) were identified as independent risk factors whereas deep submucosal invasion was only a dependent (P = 0.025) risk factor and not significant in multivariate analysis (P = 0.075). The incidence of LNM was 51/882 (6%) in absence of the independent risk factors. The Danish validation cohort, confirmed our findings regarding the role of submucosal invasion, LVI, and age. CONCLUSIONS: This is a large study on LNM in T1 CRC, including validation, showing that LVI and perineural invasion, mucinous subtype, and low age constitute independent risk factors, whereas depth of submucosal invasion is not an independent risk factor of LNM. Thus, our findings provide a useful basis for management of patients after local excision of early CRC.

Risk of recurrence after endoscopic resection of nonpedunculated T1 colorectal cancer.

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.

E3 Ubiquitin Ligase Midline 1 Regulates Endothelial Cell ICAM-1 Expression and Neutrophil Adhesion in Abdominal Sepsis.

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.

Water-assisted colonoscopy: an international modified Delphi review on definitions and practice recommendations.

BACKGROUND AND AIMS: Since 2008, a plethora of research studies has compared the efficacy of water-assisted (aided) colonoscopy (WAC) and underwater resection (UWR) of colorectal lesions with standard colonoscopy. We reviewed and graded the research evidence with potential clinical application. We conducted a modified Delphi consensus among experienced colonoscopists on definitions and practice of water immersion (WI), water exchange (WE), and UWR. METHODS: Major databases were searched to obtain research reports that could potentially shape clinical practice related to WAC and UWR. Pertinent references were graded (Grading of Recommendations, Assessment, Development and Evaluation). Extracted data supporting evidence-based statements were tabulated and provided to respondents. We received responses from 55 (85% surveyed) experienced colonoscopists (37 experts and 18 nonexperts in WAC) from 16 countries in 3 rounds. Voting was conducted anonymously in the second and third round, with ≥80% agreement defined as consensus. We aimed to obtain consensus in all statements. RESULTS: In the first and the second modified Delphi rounds, 20 proposed statements were decreased to 14 and then 11 statements. After the third round, the combined responses from all respondents depicted the consensus in 11 statements (S): definitions of WI (S1) and WE (S2), procedural features (S3-S5), impact on bowel cleanliness (S6), adenoma detection (S7), pain score (S8), and UWR (S9-S11). CONCLUSIONS: The most important consensus statements are that WI and WE are not the same in implementation and outcomes. Because studies that could potentially shape clinical practice of WAC and UWR were chosen for review, this modified Delphi consensus supports recommendations for the use of WAC in clinical practice.

Heparin-binding protein is significantly increased in acute pancreatitis.

BACKGROUND: Most patients with acute pancreatitis (AP) experience mild, self-limiting disease with little or no need for hospital care. However, 20-25% of patients develop a more severe and potentially life-threatening condition with progressive systemic inflammatory response syndrome (SIRS) and multiorgan failure, resulting in high morbidity and mortality rates. Predicting disease severity at an early stage is important, as immediate supportive care has been demonstrated to reduce the incidence of SIRS and organ failure, improving patient outcome. Several studies have demonstrated elevated levels of heparin-binding protein (HBP) in patients with sepsis and septic shock, and HBP is believed to play a part in endothelial dysfunction leading to vascular leakage. As HBP levels increase prior to other known biomarkers, HBP has emerged as a promising early predictor of severe sepsis with organ dysfunction. METHODS: Patients admitted to Skåne University Hospital in Malmö between 2010 and 2013 fulfilling the criteria for AP were identified in the emergency department and prospectively enrolled in this study. The primary outcome was measured levels of HBP upon hospital admission in patients with confirmed AP. Correlations among HBP concentrations, disease severity and fluid balance were considered secondary endpoints. The correlation between HBP levels and fluid balance were analysed using Pearson correlation, and the ability of HBP to predict moderately severe/severe AP was assessed using a receiver operating characteristic (ROC) curve. RESULTS: The overall median HBP level in this study was 529 (307-898) ng/ml. There were no significant group differences in HBP levels based on AP severity. Fluid balance differed significantly between patients with mild versus moderately severe and severe pancreatitis, but we found no correlation between HBP concentration and fluid balance. CONCLUSIONS: HBP levels are dramatically increased in patients with AP, and these levels far exceed those previously reported in other conditions. In this study, we did not observe any significant correlation between HBP levels and disease severity or the need for intravenous fluid. Additional studies on HBP are needed to further explore the role of HBP in the pathogenesis of AP and its possible clinical implications.

Transcriptomic Analysis Reveals Differential Expression of Genes between Lung Capillary and Post Capillary Venules in Abdominal Sepsis.

Lung endothelial cell dysfunction plays a central role in septic-induced lung injury. We hypothesized that endothelial cell subsets, capillary endothelial cells (capEC) and post capillary venules (PCV), might play different roles in regulating important pathophysiology in sepsis. In order to reveal global transcriptomic changes in endothelial cell subsets during sepsis, we induced sepsis in C57BL/6 mice by cecal ligation and puncture (CLP). We confirmed that CLP induced systemic and lung inflammation in our model. Endothelial cells (ECs) from lung capillary and PCV were isolated by cell sorting and transcriptomic changes were analyzed by bioinformatic tools. Our analysis revealed that lung capEC are transcriptionally different than PCV. Comparison of top differentially expressed genes (DEGs) of capEC and PCV revealed that capEC responses are different than PCV during sepsis. It was found that capEC are more enriched with genes related to regulation of coagulation, vascular permeability, wound healing and lipid metabolic processes after sepsis. In contrast, PCV are more enriched with genes related to chemotaxis, cell-cell adhesion by integrins, chemokine biosynthesis, regulation of actin filament process and neutrophil homeostasis after sepsis. In addition, we predicted some transcription factor targets that regulate a significant number of DEGs in sepsis. We proposed that targeting certain DEGs or transcriptional factors would be useful in protecting against sepsis-induced lung damage.

Neutrophil Extracellular Traps in Colorectal Cancer Progression and Metastasis.

Neutrophils form sticky web-like structures known as neutrophil extracellular traps (NETs) as part of innate immune response. NETs are decondensed extracellular chromatin filaments comprising nuclear and cytoplasmic proteins. NETs have been implicated in many gastrointestinal diseases including colorectal cancer (CRC). However, the regulatory mechanisms of NET formation and potential pharmacological inhibitors in the context of CRC have not been thoroughly discussed. In this review, we intend to highlight roles of NETs in CRC progression and metastasis as well as the potential of targeting NETs during colon cancer therapy.

Targeting S100A9 Reduces Neutrophil Recruitment, Inflammation and Lung Damage in Abdominal Sepsis.

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.

Extracellular cold-inducible RNA-binding protein regulates neutrophil extracellular trap formation and tissue damage in acute pancreatitis.

Neutrophil extracellular traps (NETs) play a key role in the development of acute pancreatitis (AP). In the present study, we studied the role of extracellular cold-inducible RNA-binding protein (eCIRP), a novel damage-associated-molecular-pattern molecule, in severe AP. C57BL/6 mice underwent retrograde infusion of taurocholate into the pancreatic duct. C23, an eCIRP inhibitor, was given 1 h prior to induction of AP. Pancreatic, lung, and blood samples were collected and levels of citrullinated histone 3, DNA-histone complexes, eCIRP, myeloperoxidase (MPO), amylase, cytokines, matrix metalloproteinase-9 (MMP-9), and CXC chemokines were quantified after 24 h. NETs were detected by electron microscopy in the pancreas and bone marrow-derived neutrophils. Amylase secretion was analyzed in isolated acinar cells. Plasma was obtained from healthy individuals and patients with mild and moderate severe or severe AP. Taurocholate infusion induced NET formation, inflammation, and tissue injury in the pancreas. Pretreatment with C23 decreased taurocholate-induced pancreatic and plasma levels of eCIRP and tissue damage in the pancreas. Blocking eCIRP reduced levels of citrullinated histone 3 and NET formation in the pancreas as well as DNA-histone complexes in the plasma. In addition, administration of C23 attenuated MPO levels in the pancreas and lung of mice exposed to taurocholate. Inhibition of eCIRP reduced pancreatic levels of CXC chemokines and plasma levels of IL-6, HMGB-1, and MMP-9 in mice with severe AP. Moreover, eCIRP was found to be bound to NETs. Coincubation with C23 reduced NET-induced amylase secretion in isolated acinar cells. Patients with severe AP had elevated plasma levels of eCIRP compared with controls. Our novel findings suggest that eCIRP is a potent regulator of NET formation in the inflamed pancreas. Moreover, these results show that targeting eCIRP with C23 inhibits inflammation and tissue damage in AP. Thus, eCIRP could serve as an effective target to attenuate pancreatic damage in patients with AP.

Targeting peptidylarginine deiminase reduces neutrophil extracellular trap formation and tissue injury in severe acute pancreatitis.

Recent evidence suggests that neutrophil extracellular traps (NETs) play an important role in the development of acute pancreatitis (AP). Herein, we examined the role of peptidylarginine deiminase (PAD), which has been shown to regulate NET formation, in severe AP. AP was induced by retrograde of taurocholate infusion into pancreatic duct in C57BL/6 mice. PAD was pharmacologically inhibited using Cl-amidine, a pan-PAD inhibitor. Pancreata were collected, and histones, citrullinated histone 3, chemokines, myeloperoxidase, and NETs were quantified. Chemokines, matrix metalloproteinase-9 (MMP-9), interleukin-6 (IL-6), and DNA-histone complexes were determined in plasma samples. Infusion of taurocholate induced formation of NETs in pancreatic tissues of mice. Pretreatment with Cl-amidine markedly reduced the NET formation in the inflamed pancreas. Moreover, inhibition of PAD decreased the levels of blood amylase as well as edema, acinar cell necrosis, hemorrhage, and neutrophil infiltration in the pancreas of animals with AP. Administration of Cl-amidine attenuated the myeloperoxidase levels in the pancreas and lung of mice exposed to taurocholate. In addition, Cl-amidine decreased pancreatic levels of CXC chemokines, plasma levels of IL-6, and MMP-9 in mice with severe AP. This study shows that Cl-amidine is a potent inhibitor of NET formation in severe AP. Also, our results suggest that PAD regulates pathological inflammation and tissue damage in the inflamed pancreas. Thus, targeting PAD might be a useful strategy to treat patients with severe AP.

Forceps Biopsies Are Not Reliable in the Workup of Large Colorectal Lesions Referred for Endoscopic Resection: Should They Be Abandoned?

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, Skåne University Hospital Malmö, 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 FÓRCEPS NO SON CONFIABLES EN EL ESTUDIO DE LAS LESIONES COLORRECTALES GRANDES REFERIDAS PARA RESECCIÓN ENDOSCÓPICA: ¿DEBERÍAN ABANDONARSE?: Las biopsias se obtienen de forma rutinaria en el estudio de pólipos colorrectales grandes previo a resección endoscópica. OBJETIVO: Analizar que tan confiables son las biopsias en cuanto a reflejar la verdadera histopatología de los pólipos colorrectales grandes, en la rutina clínica. DISEÑO:: Este es un estudio retrospectivo. AJUSTES: Los datos de pacientes sometidos a polipectomía de pólipos colorrectales grandes en la unidad de endoscopia, en Skåne University Hospital Malmö, entre enero de 2014 y diciembre de 2016 fueron examinados. PACIENTES: Un total de 485 lesiones colorrectales se biopsiaron dentro de un año antes de la resección endoscópica completa. Las muestras obtenidas mediante biopsia se compararon con las muestras completas resecadas en términos de concordancia y discordancia, y si el resultado final ascendió o disminuyó de categoría. PRINCIPALES MEDIDAS DE RESULTADO: Concordancia entre muestras obtenidas mediante biopsia y muestras completamente resecadas. RESULTADOS: La mediana de tamaño de lesiones fue de 3 cm (rango 1-11). En 189 casos (39%) las biopsias no proporcionaron un grado de displasia correcto en comparación con la patología final después de la resección completa. 143 casos (29%) y 46 casos (9%) ascendieron y descendieron de categoría, 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 múltiples biopsias. El tiempo desde la biopsia hasta la resección completa no influyó en el resultado erróneo 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 aumentó a 48% en lesiones colorrectales mayores de 4 cm. LIMITACIONES: Este estudio se diseñó para reflejar la rutina clínica, el número de biopsias obtenidas y la técnica de fórceps no fueron estandarizadas, lo que constituye una limitación. CONCLUSIONES: Este estudio demuestra que las biopsias con fórceps negativas a cáncer, de pólipos colorrectales grandes referidas para resección endoscópica, no son confiables. Teniendo en cuenta que la resección endoscópica de lesiones que contienen cáncer superficial es posible, el valor clínico de las biopsias con fórceps en lesiones aptas para la resección endoscópica es cuestionable. Vea el Resumen en video en http://links.lww.com/DCR/A984.

European experience of colorectal endoscopic submucosal dissection: a systematic review of clinical efficacy and safety.

BACKGROUND: 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. MATERIAL AND METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Microvascular Mechanisms of Polyphosphate-Induced Neutrophil-Endothelial Cell Interactions in vivo.

BACKGROUND: Polyphosphates (PolyPs) have been reported to exert pro-inflammatory effects. However, the molecular mechanisms regulating PolyP-provoked tissue accumulation of leukocytes are not known. The aim of the present investigation was to determine the role of specific adhesion molecules in PolyP-mediated leukocyte recruitment. METHODS: PolyPs and TNF-α were intrascrotally administered, and anti-P-selectin, anti-E-selectin, anti-P-selectin glycoprotein ligand-1 (PSGL-1), anti-membrane-activated complex-1 (Mac-1), anti-lymphocyte function antigen-1 (LFA-1), and neutrophil depletion antibodies were injected intravenously or intraperitoneally. Intravital microscopy of the mouse cremaster microcirculation was used to examine leukocyte-endothelium interactions and recruitment in vivo. RESULTS: Intrascrotal injection of PolyPs increased leukocyte accumulation. Depletion of neutrophils abolished PolyP-induced leukocyte-endothelium interactions, indicating that neutrophils were the main leukocyte subtype responding to PolyP challenge. Immunoneutralization of P-selectin and PSGL-1 abolished PolyP-provoked neutrophil rolling, adhesion, and emigration. Moreover, immunoneutralization of Mac-1 and LFA-1 had no impact on neutrophil rolling but markedly reduced neutrophil adhesion and emigration evoked by PolyPs. CONCLUSION: These results suggest that P-selectin and PSGL-1 exert important roles in PolyP-induced inflammatory cell recruitment by mediating neutrophil rolling. In addition, our data show that Mac-1 and LFA-1 are necessary for supporting PolyP-triggered firm adhesion of neutrophils to microvascular endothelium. These novel findings define specific molecules as potential targets for pharmacological intervention in PolyP-dependent inflammatory diseases.

Platelet-derived microparticles regulates thrombin generation via phophatidylserine in abdominal sepsis.

Sepsis is associated with dysfunctional coagulation. Recent data suggest that platelets play a role in sepsis by promoting neutrophil accumulation. Herein, we show that cecal ligation and puncture (CLP) triggered systemic inflammation, which is characterized by formation of IL-6 and CXC chemokines as well as neutrophil accumulation in the lung. Platelet depletion decreased neutrophil accumulation, IL-6, and CXC chemokines formation in septic lungs. Depletion of platelets increased peak thrombin formation and total thrombin generation (TG) in plasma from septic animals. CLP elevated circulating levels of platelet-derived microparticles (PMPs). In vitro generated PMPs were a potent inducer of TG. Interestingly, in vitro wild-type recombinant annexin V abolished PMP-induced thrombin formation whereas a mutant annexin V protein, which does not bind to phosphatidylserine (PS), had no effect. Administration of wild-type, but not mutant annexin V, significantly inhibited thrombin formation in septic animals. Moreover, CLP-induced formation of thrombin-antithrombin complexes were reduced in platelet-depleted mice and in animals pretreated with annexin V. PMP-induced TG attenuated in FXII- and FVII-deficient plasma. These findings suggest that sepsis-induced TG is dependent on platelets. Moreover, PMPs formed in sepsis are a potent inducer of TG via PS exposure, and activation of both the intrinsic and extrinsic pathway of coagulation. In conclusion, these observations suggest that PMPs and PS play an important role in dysfunctional coagulation in abdominal sepsis.