Tohru Sato

Prevalence of Nonpolypoid (Flat and Depressed) Colorectal Neoplasms in Asymptomatic and Symptomatic Adults

CONTEXT Colorectal cancer is the second leading cause of cancer death in the United States. Prevention has focused on the detection and removal of polypoid neoplasms. Data are limited on the significance of nonpolypoid colorectal neoplasms (NP-CRNs). OBJECTIVES To determine the prevalence of NP-CRNs in a veterans hospital population and to characterize their association with colorectal cancer. DESIGN, SETTING, AND PATIENTS Cross-sectional study at a veterans hospital in California with 1819 patients undergoing elective colonoscopy from July 2003 to June 2004. MAIN OUTCOME MEASURES Endoscopic appearance, location, size, histology, and depth of invasion of neoplasms. RESULTS The overall prevalence of NP-CRNs was 9.35% (95% confidence interval [95% CI], 8.05%-10.78%; n = 170). The prevalence of NP-CRNs in the subpopulations for screening, surveillance, and symptoms was 5.84% (95% CI, 4.13%-8.00%; n = 36), 15.44% (95% CI, 12.76%-18.44%; n = 101), and 6.01% (95% CI, 4.17%-8.34%; n = 33), respectively. The overall prevalence of NP-CRNs with in situ or submucosal invasive carcinoma was 0.82% (95% CI, 0.46%-1.36%; n = 15); in the screening population, the prevalence was 0.32% (95% CI, 0.04%-1.17%; n = 2). Overall, NP-CRNs were more likely to contain carcinoma (odds ratio, 9.78; 95% CI, 3.93-24.4) than polypoid lesions, irrespective of the size. The positive size-adjusted association of NP-CRNs with in situ or submucosal invasive carcinoma was also observed in subpopulations for screening (odds ratio, 2.01; 95% CI, 0.27-15.3) and surveillance (odds ratio, 63.7; 95% CI, 9.41-431). The depressed type had the highest risk (33%). Nonpolypoid colorectal neoplasms containing carcinoma were smaller in diameter as compared with the polypoid ones (mean [SD] diameter, 15.9 [10.2] mm vs 19.2 [9.6] mm, respectively). The procedure times did not change appreciably as compared with historical controls. CONCLUSION In this group of veteran patients, NP-CRNs were relatively common lesions diagnosed during routine colonoscopy and had a greater association with carcinoma compared with polypoid neoplasms, irrespective of size.

Role for CXCR6 in Recruitment of Activated CD8+ Lymphocytes to Inflamed Liver

Hepatic infiltration of activated CD8 lymphocytes is a major feature of graft-vs-host disease (GvHD). Chemoattractant cytokines and their receptors are key regulators of lymphocyte trafficking, but the involvement of chemoattractant receptors in the physiologic recruitment of cells into the inflamed liver has not been defined. The present study examines the role of the chemokine receptor CXCR6, which is highly expressed by liver-infiltrating CD8 T cells. Hepatic accumulation of donor CD8, but not donor CD4, lymphocytes was significantly reduced in GvHD induced by transfer of CXCR6−/−, H-2Db lymphocytes into BDF1, H-2Dbxd recipients. To determine whether altered recruitment contributes to the reduced accumulation, CXCR6−/− or wild-type splenic lymphocytes participating in an active GvHD response were isolated and transferred i.v. into secondary recipients with active GvHD, and the short term (6-h) recruitment of transferred cells to the inflamed liver was assessed. CXCR6−/− CD8 (but not CD4) cells displayed a significant (33%) reduction in liver localization, whereas frequencies in blood of CXCR6−/− and wild-type CD8 cells were similar. Proliferation and apoptosis of liver-infiltrating donor CD8 cells were unaffected. We conclude that CXCR6 helps mediate the recruitment of activated CD8 lymphocytes in GvHD-induced hepatitis and may be a useful target to treat pathological inflammation in the liver.

CD8 + recent thymic emigrants home to and efficiently repopulate the small intestine epithelium

Prevailing knowledge dictates that naive αβ T cells require activation in lymphoid tissues before differentiating into effector or memory T cells capable of trafficking to nonlymphoid tissues. Here we demonstrate that CD8+ recent thymic emigrants (RTEs) migrated directly into the small intestine. CCR9, CCL25 and α4β7 integrin were required for gut entry of CD8+ RTEs. After T cell receptor stimulation, intestinal CD8+ RTEs proliferated and acquired a surface phenotype resembling that of intraepithelial lymphocytes. CD8+ RTEs efficiently populated the gut of lymphotoxin-α-deficient mice, which lack lymphoid organs. These studies challenge the present understanding of naive αβ T cell trafficking and suggest that RTEs may be involved in maintaining a diverse immune repertoire at mucosal surfaces.*Note: In the version of this article initially published, the vertical axis label ‘FITC’ is missing from the right column in Figure 1a. The correct figure is presented here. The error has been corrected in the PDF version of the article.

Lymphocyte Electrotaxis In Vitro and In Vivo

Electric fields are generated in vivo in a variety of physiologic and pathologic settings, including penetrating injury to epithelial barriers. An applied electric field with strength within the physiologic range can induce directional cell migration (i.e., electrotaxis) of epithelial cells, endothelial cells, fibroblasts, and neutrophils suggesting a potential role in cell positioning during wound healing. In the present study, we investigated the ability of lymphocytes to respond to applied direct current (DC) electric fields. Using a modified Transwell assay and a simple microfluidic device, we show that human PBLs migrate toward the cathode in physiologically relevant DC electric fields. Additionally, electrical stimulation activates intracellular kinase signaling pathways shared with chemotactic stimuli. Finally, video microscopic tracing of GFP-tagged immunocytes in the skin of mouse ears reveals that motile cutaneous T cells actively migrate toward the cathode of an applied DC electric field. Lymphocyte positioning within tissues can thus be manipulated by externally applied electric fields, and may be influenced by endogenous electrical potential gradients as well.

Colonoscopy With Clipping Is Useful in the Diagnosis and Treatment of Diverticular Bleeding

BACKGROUND & AIMS Diverticular bleeding is the most common cause of acute severe lower gastrointestinal bleeding (LGIB) in Western countries. Diagnostic and therapeutic approaches, including endoscopy, radiology, or surgery, have not been standardized. We investigated colonoscopy as a first-line modality to diagnose and manage patients with LGIB. METHODS We performed a retrospective study of data collected from 2 tertiary Veterans hospitals of 64 patients (61 men, 76 ± 11 years) with acute severe diverticular bleeding, based on colonoscopy examination. We assessed primary hemostasis using endoscopic clipping for diverticular bleeding and described the bleeding stigmata. We measured early (<30 days) and late rebleeding, blood transfusion requirements, hospital stay and complications. RESULTS Patients received 3.1 ± 3.0 and 0.9 ± 2.2 U of blood before and after colonoscopy, respectively. Twenty-four of the 64 patients (38%) had diverticular stigmata of recent hemorrhage; and 21 of these patients (88%) were treated successfully using endoscopic clips, without complication or early rebleeding. Hospital stays averaged 6.4 ± 5.6 days. Endoscopic clipping provided primary hemostasis in 9/12 patients (75%) with active diverticular bleeding. During 35 ± 18 months of follow-up, late recurrent diverticular bleeding occurred in 22% of the patients (14/64) after a mean time period of 22 months; 5 of the patients (21%) with stigmata of recent hemorrhage who received clip treatment had rebleeding at 43 months. Rebleeding was self-limited in 8 patients (57%), was clipped in 4 (29%), or was embolized in 2 (14%). CONCLUSIONS Colonoscopy can be a safe first-line diagnostic and therapeutic approach for patients with severe LGIB. Endoscopic clipping provides hemostasis of active diverticular bleeding. Recurrent bleeding occurs in about 21% of patients who were treated with clips, at approximately 4 years; most bleeding is self-limited or can be retreated by endoscopic clipping.

Role of angiotensin II in ischemia/reperfusion-induced leukocyte-endothelium interactions in the colon

The aims of the present study were to determine the effects and mechanisms of angiotensin II (Ang II) on leukocyte‐endothelium interactions and the role of Ang II in a novel model of ischemia/reperfusion (I/R) in the mouse colon. Ang II dose‐dependently increased leukocyte rolling and adhesion in colonic venules. Importantly, Ang II‐induced leukocyte rolling was completely inhibited by immunoneutralization of P‐selectin, and leukocyte adhesion was abolished in lymphocyte function antigen‐1 (LFA‐1)‐deficient mice. The P‐selectin‐dependent rolling was found to be a precondition for the subsequent LFA‐1‐dependent leukocyte adhesion. Moreover, Ang II‐induced leukocyte responses involved generation of reactive oxygen species and up‐regulation of CXC chemokines. Notably, CXC chemokines, but not Ang II, stimulated leukocyte chemotaxis in vitro. I/R increased gene expression of angiotensin converting enzyme (ACE) in the colon and plasma concentrations of Ang II. Inhibition of ACE and the type 1 angiotensin (AT1) receptor significantly decreased the I/R‐induced leukocyte adhesion. Taken together, these novel findings demonstrate that Ang II exerts potent pro‐inflammatory effects in the colonic microcirculation and that inhibition of Ang II expression or function protects against I/R‐induced leukocyte responses in the colon. Thus, it is suggested that Ang II is a major target to control pathological inflammation in the colon.

Real-time optical diagnosis for diminutive colorectal polyps using narrow-band imaging: the VALID randomised clinical trial

Background Diminutive (≤5 mm) colorectal polyps are common, and overwhelmingly benign. Routinely, after polypectomy, they are examined pathologically to determine the surveillance intervals. Advances in equipment and techniques, such as narrow-band imaging (NBI) colonoscopy, now permit reliable real-time optical diagnosis. Methods We conducted a randomised single-masked study involving three institutions to determine whether optical diagnosis of diminutive colorectal polyps meets clinical practice standards and reduces the need for histopathology. We randomly assigned eligible patients undergoing routine high-definition colonoscopy to optical diagnosis using near focus versus standard view, using computer-generated block sequence. By validated criteria, we rendered an optical diagnosis and a confidence level (high vs low) for all polyps, using NBI. Our primary endpoint was the number of accurate high-confidence optical diagnoses compared with central blinded pathology in the two groups. We analysed data using intention to treat. Findings We enrolled 558 subjects, and randomly assigned 281 to near focus and 277 to standard view optical diagnosis. We detected 1309 predominantly diminutive (74.5%) and neoplastic (60.0%) polyps. Endoscopists were significantly more likely, OR 2.2 (95% CI 1.6 to 3.0, p<0.0001), to make a high-confidence optical diagnosis with near focus (85.1%) than standard (72.6%) view. High-confidence diagnoses had 96.4% and 92.0% negative predictive value, respectively. Of all polyps, 75.3% (95% CI71.3% to 78.9%) had a high-confidence accurate prediction using near focus, compared with 63.1% (95% CI 58.5% to 67.6%) using standard view. Optical versus histopathological diagnosis showed excellent agreement between the surveillance intervals, 93.5% in near focus and 92.2% in standard view. The median diagnosis time was 14 s. Conclusions Real-time optical diagnosis using NBI colonoscopy may replace the pathology diagnosis for the majority of diminutive colorectal polyps. Using colonoscopy with near focus view increases the confidence level of the optical diagnosis. Optical diagnosis would be a paradigm shift in clinical practice of colonoscopy for colorectal cancer screening. Trial registration number ClinicalTrials.gov Identifier: NCT01288833.

Large Sessile Serrated Polyps Can Be Safely and Effectively Removed by Endoscopic Mucosal Resection.

BACKGROUND & AIMS As many as 50% of large sessile serrated adenomas/polyps (SSPs) are removed incompletely, which is significant because SSPs have been implicated in the development of interval cancers. It is unclear if endoscopic mucosal resection (EMR) is an optimal method for removal of SSPs. We assessed the efficacy and safety of removal of SSPs 10 mm and larger using a standardized inject-and-cut EMR technique. METHODS We performed a retrospective analysis of colonoscopy data, collected over 7 years (2007-2013) at 2 centers, from 199 patients with proximal colon SSPs 10 mm and larger (251 polyps) removed by EMR by 4 endoscopists. The primary outcome measure was local recurrence. The secondary outcome measure was safety. RESULTS At the index colonoscopy, patients had a median of 1 serrated lesion (range, 1-12) and 1 nonserrated neoplastic lesion (range, 0-15). The mean SSP size was 15.9 ± 5.3 mm; most were superficially elevated (84.5%) and located in the ascending colon (51%), and 3 SSPs (1.2%) had dysplasia. Surveillance colonoscopies were performed on 138 patients (69.3%) over a mean follow-up period of 25.5 ± 17.4 months. Of these patients, 5 had local recurrences (3.6%; 95% confidence interval, 0.5%-6.7%), detected after 17.8 ± 15.4 months, with a median size of 4 mm. No patients developed postprocedural bleeding, perforation, or advanced colon cancer, or had a death related to the index colorectal lesion during the study period. CONCLUSIONS Inject-and-cut EMR is a safe and effective technique for the resection of SSPs. Less than 5% of patients have a local recurrence, which is usually small and can be treated endoscopically.

P-Selectin and P-Selectin Glycoprotein Ligand 1 Mediate Rolling of Activated CD8+ T Cells in Inflamed Colonic Venules.

Background Activated T cells regulate inflammatory diseases in the intestinal tract; however, the adhesive mechanisms governing CD8+ T-cell recruitment in the colon are not known. Methods Herein, we used a graft-versus-host disease (GvHD) model to study CD8+ T-cell rolling and adhesion in the large intestine by use of intravital fluorescence microscopy. Graft-versus-host disease was induced by transferring 50 × 106 allogeneic donor splenocytes from BDF1, B6, H-2b mice to recipient BDF1, H-2bxd mice. After 8 days, rhodamine-labeled CD8+ T cells (4 × 106) from healthy and GvHD mice were injected into both healthy and GvHD recipient mice, and CD8+ T-cell-endothelium interactions were studied in the colon. Results Activated CD8+ T cells from GvHD mice expressed higher levels of P-selectin ligand and decreased levels of L-selectin. Immunoneutralization of P-selectin and P-selectin glycoprotein ligand 1 reduced CD8+ T-cell rolling and adhesion in inflamed colonic venules by more than 71%. Inhibition of E-selectin had no effect on GvHD-induced CD8+ T-cell-endothelium interactions. Conclusions We conclude that P-selectin and P-selectin glycoprotein ligand 1 are dominating molecules in supporting adhesive interactions of CD8+ T cells in inflamed colonic venules and may be useful targets to protect against pathological inflammation in the large bowel.

Interleukin-10 mediates the protective effect of Linomide by reducing CXC chemokine production in endotoxin-induced liver injury

The immunomodulator Linomide has been shown to protect against septic liver injury by reducing hepatic accumulation of leukocytes although the detailed anti‐inflammatory mechanisms remain elusive. This study examined the effect of Linomide on the production of CXC chemokines, including macrophage inflammatory protein‐2 (MIP‐2) and cytokine‐induced neutrophil chemoattractant (KC) and interleukin‐10 (IL‐10) in lipopolysaccharide (LPS)/D‐galactosamine (Gal)‐induced liver injury in mice. It was found that pretreatment with 300 mg kg−1 of Linomide markedly suppressed leukocyte recruitment, perfusion failure, and hepatocellular damage and apoptosis in the liver of endotoxemic mice. Administration of Linomide inhibited endotoxin‐induced gene expression of MIP‐2 and KC and significantly reduced the hepatic production of MIP‐2 and KC by 63 and 80%, respectively. Moreover, it was found that Linomide increased the liver content of IL‐10 by more than three‐fold in endotoxemic mice. The protective effect of Linomide against endotoxin‐induced inflammation and liver injury was abolished in IL‐10‐deficient mice, suggesting that the beneficial effect of Linomide is dependent on the function of IL‐10. Taken together, these novel findings suggest that the protective effect of Linomide is mediated via local upregulation of IL‐10, which in turn decreases the generation of CXC chemokines and pathological recruitment of leukocytes in the liver of endotoxemic mice.