Demarcated redness associated with increased vascular density/size: a useful marker of flat-type dysplasia in patients with ulcerative colitis.
ABSTRACT: Background and study aims Recent advances in endoscopic equipment and diagnostic techniques have improved the detection of dysplasia in the inflamed mucosa of patients with ulcerative colitis (UC). However, it remains difficult to endoscopically identify flat-type dysplasia which has been formerly recognized as invisible dysplasia. Patients and methods In this retrospective, single-center study, we endoscopically identified 10 cases of flat-type-predominant dysplasia by targeted biopsy among 38 intramucosal dysplasia lesions from patients with UC who underwent surgical or endoscopic resection from 2007 to 2017. Their endoscopic and histological features were examined, including color changes, intramucosal vascular density/size, and vascular endothelial growth factor (VEGF) expression. Results All flat-type-predominant dysplasias were endoscopically recognized as demarcated red-colored areas and histologically diagnosed as low- (LGDs) or high-grade dysplasias (HGDs). Immunohistochemical examination using resected specimens revealed that flat-type dysplasia was characterized by significantly increased CD34-positive vascular density (LGDs, 1.7-fold, P < 0.01; HGDs, 2.2-fold, P < 0.01) and size (LGDs, 1.03-fold, P < 0.01; HGDs, 1.11-fold, P < 0.01) in the mucosa, compared to adjacent non-neoplastic areas. Increased numbers of vessels were observed at the base of the mucosa in LGDs, whereas HGDs contained increased/enlarged vessels throughout the mucosa. Moreover, VEGF expression was elevated in all dysplastic epithelia. Conclusions Demarcated red-colored areas, histologically characterized by an increased vascular density/size in the mucosa, are an endoscopic sign of formerly invisible flat-type dysplasia in patients with UC and should be considered for targeted biopsy. Prospective studies focusing on the mucosal color change for their early detection would be desirable in the future.
Project description:The aim of this study was to identify risk factors associated with development of high-grade dysplasia (HGD) or colorectal cancer (CRC) in ulcerative colitis (UC) patients diagnosed with low-grade dysplasia (LGD).Patients with histologically confirmed extensive UC, who were diagnosed with LGD between 1993 and 2012 at St Mark's Hospital, were identified and followed up to 1 July 2013. Demographic, endoscopic, and histological data were collected and correlated with the development of HGD or CRC.A total of 172 patients were followed for a median of 48 months from the date of initial LGD diagnosis (interquartile range (IQR), 15-87 months). Overall, 33 patients developed HGD or CRC (19.1% of study population; 20 CRCs) during study period. Multivariate Cox proportional hazard analysis revealed that macroscopically non-polypoid (hazard ratio (HR), 8.6; 95% confidence interval (CI), 3.0-24.8; P<0.001) or invisible (HR, 4.1; 95% CI, 1.3-13.4; P=0.02) dysplasia, dysplastic lesions ?1?cm in size (HR, 3.8; 95% CI, 1.5-13.4; P=0.01), and a previous history of "indefinite for dysplasia" (HR, 2.8; 95% CI, 1.2-6.5; P=0.01) were significant contributory factors for HGD or CRC development. Multifocal dysplasia (HR, 3.9; 95% CI, 1.9-7.8; P<0.001), metachronous dysplasia (HR, 3.5; 95% CI, 1.6-7.5; P=0.001), or a colonic stricture (HR, 7.4; 95% CI, 2.5-22.1; P<0.001) showed only univariate correlation to development of HGD or CRC.Lesions that are non-polypoid or endoscopically invisible, large (?1?cm), or preceded by indefinite dysplasia are independent risk factors for developing HGD or CRC in UC patients diagnosed with LGD.
Project description:OBJECTIVES:A healed intestinal mucosa is the aim of therapy in acute ulcerative colitis (UC). Disruption of mucosal wound healing may lead to severe complications including intestinal fibrosis. This study examined mucosal gene expression in the healing process of acute UC with a special focus on known mediators of fibrosis. METHODS:Endoscopic biopsies from patients with acute, moderate to severe UC were analyzed with a quantitative polymerase chain reaction array for 84 genes involved in fibrosis pathways. All patients were treated with infliximab (anti- tumor necrosis factor). Biopsies were taken before therapy and when disease remission was reached, defined as a Mayo score of ?2, with an endoscopic subscore of 0 or 1. A healthy control group was included. Immunostaining of matrix metallopeptidase 9 and smooth muscle actin was performed. RESULTS:Mucosal biopsies from acute UC (n = 28), remission UC (n = 28), and healthy controls (n = 13) were analyzed. Fibrosis and extracellular matrix-associated genes were upregulated in the endoscopically healed UC mucosa vs controls, with collagen type III alpha 1 chain, actin alpha 2, lysyl oxidase, TIMP metallopeptidase inhibitor 3, and caveolin 1 uniquely showing no overlap with acute disease. Pro- and antifibrotic mediators (interleukin [IL]13 receptor subunit alpha 2, IL1B, IL10, tumor necrosis factor, snail family transcriptional repressor 1, and C-C motif chemokine ligand 2) were upregulated in both acute and healed UC compared with controls. An attenuated pattern of the canonical transforming growth factor beta (TGFB) pathway was observed in acute UC and to a lesser extent in the healed mucosa, except for TGFB2, which was enhanced. DISCUSSION:The endoscopically healed mucosa of UC showed a persisting dysregulation of fibrosis-associated mediators compared with controls, including extracellular matrix remodeling, profibrotic cytokines, and TGFB signaling pathways.
Project description:INTRODUCTION:Monitoring of disease activity is essential in patients with inflammatory bowel disease. Although endoscopic remission is the ideal therapeutic goal, noninvasive biomarkers (blood and fecal) are more acceptable to patients and are less costly. We evaluated the performance of combinations of fecal and blood markers on the detection of endoscopically active disease. METHODS:Patients with ulcerative colitis (UC) or Crohn's disease (CD) on stable medications were recruited. Blood markers included C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), albumin, platelet count (PLT), and hemoglobin. Fecal biomarkers included fecal calprotectin (FCT) and fecal immunochemical test (FIT). These markers were compared with the endoscopic Mayo score for UC and the Simple Endoscopic Score for CD. RESULTS:One hundred thirteen patients (mean age 44.7 years, 63.7% men, 54.9% patients with UC and 45.1% patients with CD) were recruited. FCT correlated well with FIT (r = 0.58), CRP (r = 0.56), ESR (r = 0.40), albumin (r = -0.54), PLT (r = 0.61), and hemoglobin (r = -0.35; all Ps < 0.001). Among 66 patients with endoscopic evaluation, 39.4% with endoscopically active disease had higher FCT, FIT, CRP, ESR, PLT, lower albumin, and hemoglobin compared with those in endoscopic remission (all Ps < 0.01). All 7 markers demonstrated good area under receiver operating characteristics (>0.7), with FCT being the best (0.91) for endoscopically active disease. Combining FCT and FIT improved the specificity to 95%, but the sensitivity decreased to 65.4%. In the subgroup analysis of UC, adding PLT to FIT improved the sensitivity and specificity to 100% and 90.9%, respectively. DISCUSSION:The combined use of fecal biomarkers and blood indexes is superior to the use of fecal biomarkers alone in identifying endoscopically active disease.
Project description:BACKGROUND AND STUDY AIMS:Primary sclerosing cholangitis associated inflammatory bowel disease (PSC-IBD) is characterized by a high risk of colorectal dysplasia. Surveillance colonoscopies with random biopsies have doubtful power for dysplasia detection. Our aim was to prospectively investigate the feasibility and efficacy of pCLE in surveillance colonoscopies in patients with PSC-IBD. PATIENTS AND METHODS:Sixty-nine patients with PSC-IBD underwent colonoscopy in 2 steps. On the way from rectum to cecum, the mucosa was inspected with high definition endoscopy (HDE) and random biopsies were taken according to the standard routine. On the way from cecum to rectum, fluorescein-enhanced pCLE and chromoendoscopy were performed. Regions where random biopsies had been taken, as well as visible lesions, were examined with pCLE and targeted biopsies were taken of lesions suspicious for dysplasia. Two investigators, blinded to histology and endoscopy results, analyzed all pCLE videos off-line. RESULTS:Nineteen biopsies obtained in 13 patients (17 targeted biopsies, 2 random biopsies) revealed the presence of low-grade dysplasia. Thirteen lesions with dysplasia were endoscopically visible but by using pCLE-targeted biopsies, additional endoscopically invisible dysplasias in 4 biopsies obtained from 3 patients were detected. The sensitivity, specificity, and accuracy of pCLE in predicting dysplasia were respectively 89?% (95?% CI: 65?-?98), 96?% (95?% CI: 94?-?97), and 96?% (95?% CI: 94?-?97). pCLE showed a good performance for differentiating neoplastic from non-neoplastic mucosa with negative predictive value of 99?%. CONCLUSIONS:pCLE in PSC-IBD surveillance is feasible and may be a good complement to HDE. Future research should aim at elucidating whether real-time pCLE is applicable in PSC-IBD surveillance.
Project description:BACKGROUND: Cryotherapy is a relatively novel ablation modality for the endoscopic ablation of Barrett's esophagus (BE). Data on the use of pressurized carbon dioxide (CO2) gas for cryoablation are scarce. STUDY AIM: To determine the efficacy and safety of cryospray ablation using pressurized CO2 gas in the treatment of BE with early neoplasia. METHODS: In this prospective single center case series, we aimed to include 30 patients with BE and early neoplasia. Nodular neoplastic lesions were treated with endoscopic mucosal resection (EMR). Residual BE mucosa was treated with cryospray ablation every 4 weeks until the complete BE segment was eliminated or up to seven treatment sessions. If no reduction of the BE segment was observed after two subsequent treatment sessions, cryoablation was terminated. Patients were contacted at days 1 and 4 post-treatment to evaluate the level of discomfort. Endoscopic and histologic follow-up evaluations were performed up to 24 months post-treatment. RESULTS: After the inclusion of 10 patients, insufficient effect of cryoablation was observed, resulting in early termination of the study. In total, seven patients with intramucosal carcinoma (IMC) and three with high grade dysplasia (HGD) were included. Prior EMR was performed in nine patients. A median of 2.5 (IQR 2.0 - 4.0) cryoablation sessions were performed. At 6 months of follow-up, complete eradication of intestinal metaplasia was observed in 11 % (1 /9; one patient died, not treatment or disease related) of the patients and complete eradication of dysplasia in 44 % (4 /9). In three patients, HGD or IMC was detected during follow-up, and was endoscopically treated. Apart from a gastric perforation as a result of gastric distension caused by CO2 gas during the first treatment, cryospray treatments were well tolerated. CONCLUSION: After a short learning curve, cryoablation using CO2 gas was found to be a safe and well tolerated treatment modality. However, in our experience, the efficacy of CO2 cryoablation combined with EMR for nodular lesions is disappointing for the treatment of BE associated neoplasia.
Project description:<h4>Background</h4>Diagnosis of low-grade dysplasia (LGD) is important in the management of ulcerative colitis (UC), but it is often difficult to distinguish LGD from inflammatory regenerative epithelium. The unfolded protein response (UPR) is activated in inflammatory bowel disease and malignancies. We aimed to identify a UPR-related gene that is involved in the development of non-UC and UC-associated colorectal cancer (CRC), and to investigate whether the target gene is useful for the diagnosis of LGD.<h4>Methods</h4>Using our microarray gene expression database of 152 CRCs, we identified activating transcription factor 6 (ATF6) as a target gene. Immunohistochemistry (IHC) of ATF6 were analyzed in 137 surgically resected CRCs, 95 endoscopically resected adenomas and pTis cancers, and 136 samples from 51 UC patients (93 colitis without neoplasia, 31 dysplasia, and 12 UC-associated CRC). The diagnostic accuracy of ATF6 and p53 as markers of LGD was assessed.<h4>Results</h4>ATF6 expression was detectable in all CRCs but not in normal colonic mucosa, was elevated with increase in cellular atypia (adenoma with moderate atypia < severe atypia < pTis CRC, p < 0.001), and higher in dysplasia and CRC than in non-neoplastic colitis (p < 0.001). Notably, the difference between colitis and LGD was significant. Compared to p53-IHC, ATF6-IHC had better diagnostic accuracy for distinguishing LGD from background inflammatory mucosa (sensitivity 70.8 vs. 16.7%, specificity 78.5 vs.71.0%, respectively).<h4>Conclusions</h4>ATF6 was expressed in lesions undergoing pre-cancerous atypical change in both non-UC and UC-associated CRC and may be used to distinguish LGD from inflammatory regenerative epithelium in UC patients.
Project description:<h4>Background</h4>The major limitation of piecemeal endoscopic mucosal resection (EMR) is the inaccurate histological assessment of the resected specimen, especially in cases of submucosal invasion.<h4>Objective</h4>To classify non-pedunculated lesions ≥20 mm based on endoscopic morphological features, in order to identify those that present intramucosal neoplasia (includes low-grade neoplasia and high-grade neoplasia) and are suitable for piecemeal EMR.<h4>Design</h4>A post-hoc analysis from an observational prospective multicentre study conducted by 58 endoscopists at 17 academic and community hospitals was performed. Unbiased conditional inference trees (CTREE) were fitted to analyse the association between intramucosal neoplasia and the lesions' endoscopic characteristics.<h4>Result</h4>542 lesions from 517 patients were included in the analysis. Intramucosal neoplasia was present in 484 of 542 (89.3%) lesions. A conditional inference tree including all lesions' characteristics assessed with white light imaging and narrow-band imaging (NBI) found that ulceration, pseudodepressed type and sessile morphology changed the accuracy for predicting intramucosal neoplasia. In ulcerated lesions, the probability of intramucosal neoplasia was 25% (95%CI: 8.3-52.6%; <i>p</i> < 0.001). In non-ulcerated lesions, its probability in lateral spreading lesions (LST) non-granular (NG) pseudodepressed-type lesions rose to 64.0% (95%CI: 42.6-81.3%; <i>p</i> < 0.001). Sessile morphology also raised the probability of intramucosal neoplasia to 86.3% (95%CI: 80.2-90.7%; <i>p</i> < 0.001). In the remaining 319 (58.9%) non-ulcerated lesions that were of the LST-granular (G) homogeneous type, LST-G nodular-mixed type, and LST-NG flat elevated morphology, the probability of intramucosal neoplasia was 96.2% (95%CI: 93.5-97.8%; <i>p</i> < 0.001).<h4>Conclusion</h4>Non-ulcerated LST-G type and LST-NG flat elevated lesions are the most common non-pedunculated lesions ≥20 mm and are associated with a high probability of intramucosal neoplasia. This means that they are good candidates for piecemeal EMR. In the remaining lesions, further diagnostic techniques like magnification or diagnostic +/- therapeutic endoscopic submucosal dissection should be considered.
Project description:BACKGROUND AND STUDY AIMS: Although endoscopic resection is widely used for the treatment of superficial colorectal neoplasms, the rate of local recurrence of lesions with a positive or indeterminate lateral margin on histologic evaluation is unclear. We aimed to demonstrate the relationship between lateral margin status and local recurrence after the endoscopic resection of intramucosal colorectal neoplasms. PATIENTS AND METHODS: We retrospectively collected the clinical and pathologic data for 844 endoscopically resected colorectal intramucosal neoplasms with a size of 10 mm or larger. We investigated the relationship between the local recurrence rate and the lateral margin status (categorized as LM0 [negative], LM1 [positive], or LMX [indeterminate]). RESULTS: In total, 389 lesions were evaluated as LM0 and showed no local recurrence. Of the 455 lesions evaluated as LMX or LM1, 30 showed local recurrence within a median period of 6.3 months (range, 1.7 - 48.1) from the initial endoscopic resection. The local recurrence rate of the en bloc-LMX group (2.2 %) was significantly lower than that of the piecemeal-LMX group (15.2 %). Of the 30 cases of recurrence, 28 were successfully treated with a second endoscopic resection. Of the two lesions that showed further recurrence, one was treated with a third endoscopic resection, whereas the other - which was a piecemeal-LMX lesion - was eventually diagnosed as invasive cancer and treated with surgery. CONCLUSIONS: The local recurrence rate was lower in the en bloc-LMX group than in the piecemeal-LMX group. Thus, we believe that en bloc-LMX lesions that are completely and confidently resected endoscopically can be treated as en bloc-LM0 lesions.
Project description:<h4>Background</h4>In ulcerative colitis (UC) patients who have achieved mucosal healing, active microscopic colonic mucosal inflammation is commonly observed. We aimed to assess the association between histological activity and disease relapse in endoscopically quiescent UC.<h4>Methods</h4>Ulcerative colitis patients with endoscopically quiescent disease and ≥12 months of follow-up were included. Biopsies were reviewed for the presence of basal plasmacytosis (BPC) and active histological inflammation, defined as a Geboes score (GS) ≥3.2. Primary outcome measures were disease relapse at 18 months and time to first relapse after index colonoscopy.<h4>Results</h4>Seventy-six UC patients (51% male; mean age, 38.6 years; median follow-up [range], 75.2 [2-118] months) were included. Sixty-two percent had an endoscopic Mayo score of 0 at index colonoscopy. Basal plasmacytosis was present in 46% and active histological inflammation in 30% of subjects. Presence of BPC was associated with a significantly shorter time to disease relapse (P = 0.01). Active histological inflammation was significantly associated with clinical relapse at 18 months (P = 0.0005) and shorter time to clinical relapse (P = 0.0006). Multivariate analysis demonstrated active histological inflammation to be independently associated with clinical relapse at 18 months and time to clinical relapse.<h4>Conclusions</h4>In endoscopically quiescent UC, active histological inflammation and the presence of BPC are adjunctive histological markers associated with increased likelihood of disease relapse. Although prospective studies are required, the presence of these histological markers should be a factor considered when making therapeutic decisions in UC.
Project description:<h4>Background</h4>Optical coherence tomography (OCT) has been used for high-resolution endoscopic imaging and diagnosis of specialized intestinal metaplasia, dysplasia, and intramucosal carcinoma of the esophagus. However, the relatively slow image-acquisition rate of the present OCT systems inhibits wide-field imaging and limits the clinical utility of OCT for diagnostic imaging in patients with Barrett's esophagus.<h4>Objective</h4>This study describes a new optical imaging technology, optical frequency-domain imaging (OFDI), derived from OCT, that enables comprehensive imaging of large esophageal segments with microscopic resolution.<h4>Design</h4>A prototype OFDI system was developed for endoscopic imaging. The system was used in combination with a balloon-centering catheter to comprehensively image the distal esophagus in swine.<h4>Results</h4>Volumetric images of the mucosa and portions of the muscularis propria were obtained for 4.5-cm-long segments. Image resolution was 7 microm in depth and 30 microm parallel to the lumen, and provided clear delineation of each mucosal layer. The 3-dimensional data sets were used to create cross-sectional microscopic images, as well as vascular maps of the esophagus. Submucosal vessels and capillaries were visualized by using Doppler-flow processing.<h4>Conclusions</h4>Comprehensive microscopic imaging of the distal esophagus in vivo by using OFDI is feasible. The unique capabilities of this technology for obtaining detailed information of tissue microstructure over large mucosal areas may open up new possibilities for improving the management of patients with Barrett's esophagus.