15-keto-PGE2 acts as switched agonist of EP receptors

Prostaglandin E2 (PGE2) is well-known as an endogenous proinflammatory prostanoid synthesized from arachidonic acid by the activation of cyclooxygenase-2. E type prostanoid (EP) receptors are cognates for PGE2 that have four main subtypes: EP1 to EP4. Of these, the EP2 and EP4 prostanoid receptors have been shown to couple to Gαs-protein and can activate adenylyl cyclase to form cAMP. Studies suggest that EP4 receptors are involved in colorectal homeostasis and cancer development, but further work is needed to identify the roles of EP2 receptors in these functions. After sufficient inflammation has been evoked by PGE2, it is metabolized to 15-keto-PGE2. Thus, 15-keto-PGE2 has long been considered an inactive metabolite of PGE2. However, it may have an additional role as a biased and/or partial agonist capable of taking over the actions of PGE2 to gradually terminate reactions. Here, using cell-based experiments and in silico simulations, we show that PGE2-activated EP4 receptor–mediated signaling may evoke the primary initiating reaction of the cells, which would take over the 15-keto-PGE2–activated EP2 receptor–mediated signaling after PGE2 is metabolized to 15-keto-PGE2. The present results shed light on new aspects of 15-keto-PGE2, which may have important roles in passing on activities to EP2 receptors from PGE2-stimulated EP4 receptors as a “switched agonist.” This novel mechanism may be significant for gradually terminating PGE2-evoked inflammation and/or maintaining homeostasis of colorectal tissues/cells functions

Cellular density‐dependent increases in HIF‐1α compete with c‐Myc to down‐regulate human EP4 receptor promoter activity through Sp‐1‐binding region

The up‐regulated expression of E‐type prostanoid (EP) 4 receptors has been implicated in carcinogenesis; however, the expression of EP4 receptors has also been reported to be weaker in tumor tissues than in normal tissues. Indeed, EP4 receptors have been suggested to play a role in the maintenance of colorectal homeostasis. This study aimed to examine the underlying mechanisms/reasons for why inconsistent findings have been reported regarding EP4 receptor expression levels in homeostasis and carcinogenesis by focusing on cellular densities. Thus, the human colon cancer HCA‐7 cells, which retain some functional features of normal epithelia, and luciferase reporter genes containing wild‐type or mutated EP4 receptor promoters were used for elucidating the cellular density‐dependent mechanisms about the regulation of EP4 receptor expression. In silico analysis was also utilized for confirming the relevance of the findings with respect to colon cancer development. We here demonstrated that the expression of EP4 receptors was up‐regulated by c‐Myc by binding to Sp‐1 under low cellular density conditions, but was down‐regulated under high cellular density conditions via the increase in the expression levels of HIF‐1α protein, which may pull out c‐Myc and Sp‐1 from DNA‐binding. The tightly regulated EP4 receptor expression mechanism may be a critical system for maintaining homeostasis in normal colorectal epithelial cells. Therefore, once the system is altered, possibly due to the transient overexpression of EP4 receptors, it may result in aberrant cellular proliferation and transformation to cancerous phenotypes. However, at the point, EP4 receptors themselves and their mediated homeostasis would be no longer required

Un estudio piloto para evaluar la seguridad y eficacia de la insuflación de dióxido de carbono durante la disección submucosa endoscópica colorrectal con el paciente bajo sedación consciente

15 páginasBackground Endoscopic submucosal dissection (ESD) is accepted as one of the treatments for en bloc resection of large superficial colorectal lesions. This procedure is performed by using air insufflation, is time consuming, and is associated with severe abdominal discomfort. The safety and efficacy of carbon dioxide (CO2) insufflation during colonoscopy already has been assessed in some trials. Objective To assess the safety and efficacy of CO2 insufflation instead of air insufflation during colorectal ESD with the patient under conscious sedation. Design A case-control series with a historical control. Patients A total of 35 consecutive patients were enrolled in this study. Another 35 consecutive patients who previously received colorectal ESDs by using air insufflation were included as a historical control. Interventions Arterial partial pressure of CO2 (pCO2) was measured before and after each procedure with the total dose of midazolam used as an index of abdominal discomfort. Main Outcome Measurements and Results The mean (standard deviation [SD]) operation time was 90 ± 57 minutes in the CO2 group and 100 ± 80 minutes in the control group (not significant). In the CO2 group, the mean (SD) dose of midazolam was significantly lower than that of the control group; 5.6 ± 4.9 mg and 9.7 ± 5.9 mg, respectively (P = .005). Blood analysis revealed a slight pCO2 elevation in the CO2 group; however, only 2 patients complained of mild abdominal discomfort. Limitations Abdominal discomfort and pCO2 were not evaluated in the control group. Conclusions This study strongly suggests that CO2 insufflation is safe and effective during lengthy colonic endoscopic procedures, eg, ESD, with the patient under conscious sedation.Fondo La disección submucosa endoscópica (DES) se acepta como uno de los tratamientos para la resección en bloque de grandes lesiones colorrectales superficiales. Este procedimiento se realiza mediante insuflación de aire, requiere mucho tiempo y se asocia con molestias abdominales graves. La seguridad y eficacia de la insuflación de dióxido de carbono (CO2) durante la colonoscopia ya se ha evaluado en algunos ensayos. Objetivo Evaluar la seguridad y eficacia de la insuflación de CO2 en lugar de la insuflación de aire durante la ESD colorrectal con el paciente bajo sedación consciente. Diseño Una serie de casos y controles con un control histórico. Pacientes Un total de 35 pacientes consecutivos se inscribieron en este estudio. Se incluyeron como control histórico otros 35 pacientes consecutivos que previamente recibieron ESD colorrectal mediante insuflación de aire. Intervenciones La presión arterial parcial de CO2 (pCO2) se midió antes y después de cada procedimiento con la dosis total de midazolam utilizada como índice de malestar abdominal. Principales medidas de resultado y resultados El tiempo quirúrgico medio (desviación estándar [DE]) fue de 90 ± 57 minutos en el grupo de CO2 y de 100 ± 80 minutos en el grupo de control (no significativo). En el grupo de CO2, la dosis media (DE) de midazolam fue significativamente menor que la del grupo de control; 5,6 ± 4,9 mg y 9,7 ± 5,9 mg, respectivamente (p = 0,005). El análisis de sangre reveló una ligera elevación de pCO2 en el grupo de CO2; sin embargo, solo 2 pacientes se quejaron de molestias abdominales leves. Limitaciones En el grupo control no se evaluaron las molestias abdominales ni la pCO2. Conclusiones Este estudio sugiere fuertemente que la insuflación de CO2 es segura y eficaz durante procedimientos endoscópicos colónicos prolongados, por ejemplo, ESD, con el paciente bajo sedación consciente

Tratamiento endoscópico de grandes tumores colorrectales superficiales: serie de casos de 200 disecciones submucosas endoscópicas (con video)

7 páginasBackground Endoscopic submucosal dissection (ESD) is accepted as a minimally invasive treatment for early gastric cancer; however, it is not widely used in the colorectum because of its technical difficulty. Objective To determine the feasibility of using ESD for treating large superficial colorectal tumors and to evaluate the clinical outcome. Design and Setting Case series conducted at the National Cancer Center Hospital in Tokyo. Patients A total of 198 consecutive patients were treated for 200 lesions. Interventions Procedures were performed, before July 2004, by using a monopolar needle knife or an insulation-tipped knife (IT knife). After July 2004, the procedures were performed by using a bipolar needle knife or an IT knife. After injection of glycerol and sodium hyaluronate acid into the submucosal (sm) layer, a circumferential incision was made and sm dissection was performed endoscopically. Main Outcome Measurements The en bloc resection rate was 84% and the curative resection rate was 83%. Results Among the 200 ESDs, 51 involved tubular adenomas, 99 intramucosal cancers, 22 minute sm cancers, and 28 sm deep cancers. The median operation time was 90 minutes, and the mean size of resected specimens was 38 mm (range, 20-150 mm). Perforations occurred in 10 cases (5%) and postoperative bleeding in 4 cases (2%), but only 1 perforation case needed emergency surgery, because endoscopic clipping was ineffective. Limitations No long-term outcome data yet. Conclusions ESD is a feasible technique for treating large superficial colorectal tumors, because it provides a higher en bloc resection rate and is less invasive than surgical resection.Fondo La disección submucosa endoscópica (DES) se acepta como un tratamiento mínimamente invasivo para el cáncer gástrico temprano; sin embargo, no es muy utilizado en el colorrectal por su dificultad técnica. meta Determinar la viabilidad del uso de ESD para el tratamiento de tumores colorrectales superficiales grandes y evaluar el resultado clínico. Diseño y Ambientación Serie de casos realizada en el Hospital del Centro Nacional del Cáncer en Tokio. pacientes Un total de 198 pacientes consecutivos fueron tratados por 200 lesiones. Intervenciones Los procedimientos se realizaron, antes de julio de 2004, utilizando un bisturí de aguja monopolar o un bisturí con punta aislante (cuchillo IT). Después de julio de 2004, los procedimientos se realizaron con bisturí de aguja bipolar o bisturí IT. Después de la inyección de glicerol y ácido hialuronato de sodio en la capa submucosa (sm), se realizó una incisión circunferencial y la disección de sm se realizó endoscópicamente. Mediciones de resultados principales La tasa de resección en bloque fue del 84% y la tasa de resección curativa fue del 83%. resultados Entre los 200 ESD, 51 involucraron adenomas tubulares, 99 cánceres intramucosos, cánceres de 22 minutos y 28 cánceres de profundidad. El tiempo medio de operación fue de 90 minutos y el tamaño medio de las muestras resecadas fue de 38 mm (rango, 20-150 mm). Ocurrieron perforaciones en 10 casos (5%) y sangrado postoperatorio en 4 casos (2%), pero solo 1 caso de perforación requirió cirugía de emergencia, porque el clipaje endoscópico fue ineficaz. Limitaciones Aún no hay datos de resultados a largo plazo. conclusión La ESD es una técnica factible para el tratamiento de tumores colorrectales superficiales de gran tamaño, ya que proporciona una mayor tasa de resección en bloque y es menos invasiva que la resección quirúrgica

Diagnostic Process Using Endoscopy for Biliary Strictures: A Narrative Review

The diagnostic process for biliary strictures remains challenging in some cases. A broad differential diagnosis exists for indeterminate biliary strictures, including benign or malignant lesions. The diagnosis of indeterminate biliary strictures requires a combination of physical examination, laboratory testing, imaging modalities, and endoscopic procedures. Despite the progress of less invasive imaging modalities such as transabdominal ultrasonography, computed tomography, and magnetic resonance imaging, endoscopy plays an essential role in the accurate diagnosis, including the histological diagnosis. Imaging findings and brush cytology and/or forceps biopsy under fluoroscopic guidance with endoscopic retrograde cholangiopancreatography (ERCP) are widely used as the gold standard for the diagnosis of biliary strictures. However, ERCP cannot provide an intraluminal view of the biliary lesion, and its outcomes are not satisfactory. Recently, peroral cholangioscopy, confocal laser endomicroscopy, endoscopic ultrasound (EUS), and EUS-guided fine-needle aspiration have been reported as useful for indeterminate biliary strictures. Appropriate endoscopic modalities need to be selected according to the patient’s condition, the lesion, and the expertise of the endoscopist. The aim of this review article is to discuss the diagnostic process for indeterminate biliary strictures using endoscopy

Diagnostic Process Using Endoscopy for Biliary Strictures: A Narrative Review

The diagnostic process for biliary strictures remains challenging in some cases. A broad differential diagnosis exists for indeterminate biliary strictures, including benign or malignant lesions. The diagnosis of indeterminate biliary strictures requires a combination of physical examination, laboratory testing, imaging modalities, and endoscopic procedures. Despite the progress of less invasive imaging modalities such as transabdominal ultrasonography, computed tomography, and magnetic resonance imaging, endoscopy plays an essential role in the accurate diagnosis, including the histological diagnosis. Imaging findings and brush cytology and/or forceps biopsy under fluoroscopic guidance with endoscopic retrograde cholangiopancreatography (ERCP) are widely used as the gold standard for the diagnosis of biliary strictures. However, ERCP cannot provide an intraluminal view of the biliary lesion, and its outcomes are not satisfactory. Recently, peroral cholangioscopy, confocal laser endomicroscopy, endoscopic ultrasound (EUS), and EUS-guided fine-needle aspiration have been reported as useful for indeterminate biliary strictures. Appropriate endoscopic modalities need to be selected according to the patient’s condition, the lesion, and the expertise of the endoscopist. The aim of this review article is to discuss the diagnostic process for indeterminate biliary strictures using endoscopy

Comparison of Endoscopic Ultrasound-Guided Fine-Needle Aspiration and Biopsy Device for Lymphadenopathy

Background. Accurate diagnosis of benign and malignant lymphadenopathy is important for determining the appropriate treatment and prognosis. This study evaluated the diagnostic accuracy and usefulness of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) with a conventional needle compared to endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB) with a Franseen needle for diagnosing lymphadenopathy. Methods. Patients who underwent EUS-FNA or EUS-FNB for mediastinal or abdominal lymphadenopathy between July 2013 and August 2020 were enrolled in the study. The outcomes between EUS-FNA patients (July 2013 to January 2017; 22-gauge conventional needle; Group A) and EUS-FNB patients (February 2017 to August 2020; 22-gauge Franseen needle; Group B) were compared. Results. A total of 154 patients (Group A: 83; Group B: 71) were analyzed. The diagnostic accuracy (differentiating between malignant and benign lesions) was 88.0% (95% confidence interval [CI], 79.2–93.3%) in Group A and 95.8% (95% CI, 88.3–98.8%) in Group B. Group B had high diagnostic accuracy, but there was no difference between the groups (p=0.14). Group B had significantly fewer passes (median 2, interquartile range (IQR): 2-4) than Group A (median 3, IQR: 3-4) (p<0.001). No procedural adverse events occurred in either group. Conclusions. Although the diagnostic accuracy between the groups was not statistically significant, EUS-FNB with a Franseen needle provided high diagnostic accuracy and required fewer passes to establish a diagnosis. Thus, EUS-FNB is useful for diagnosing lymphadenopathy