| Background:Part I:Diagnostic value of probe-based confocal laser endomicroscopy and high-definition virtual chromoendoscopy in early esophageal squamous neoplasia.Esophageal carcinoma is the eighth most common cancer and sixth leading cause of death from cancer worldwide.5-year survival rate is 15%-25%, the unsatisfactory rate related to late diagnosis and the propensity to metastasize. Thus, the key factor for a good outcome is early-stage diagnosis. Squamous cell carcinoma (SCC) is the predominant histologic type, especially in China.Standard endoscopy can detect most protruded and depressed esophageal carcinomas, but may miss some flat-type lesions. Lugol iodine chromoendoscopy has been widely used to screen esophageal squamous intraepithelial neoplasia (ESIN) or early SCC and remains the standard procedure for ESIN or SCC. However, the potential discomfort and time-consuming procedure attributed to iodine spraying have decreased its popularity in clinical practice, and false positives have also been reported. Virtual chromoendoscopy technology included narrow-band imaging (NBI) (Olympus, Tokyo, Japan), I-scan (Pentax; Ricoh, Tokyo, Japan), and flexible spectral imaging color enhancement (FICE) (Fujinon; Fujifilm, Tokyo, Japan). NBI and FICE have been shown to be promising replacements for iodine chromoendoscopy. Nevertheless, the role and effectiveness of I-Scan in the screening of esophageal lesions remain to be determined.Confocal laser endomicroscopy (CLE) enables in vivo optical biopsy of GI diseases. Our previous studies suggested that CLE can accurately predict ESIN with a novel surface maturation scoring system, which was validated by using endoscope-based CLE. However, this surface maturation scoring (SMS) system has not been applied in probe-based CLE (pCLE).We conducted this study to test the feasibility and accuracy of I-Scan combined with pCLE for detecting and differentiating esophageal squamous neoplasia (ESN). In this study, I-Scan served as the "red flag" to detect the suspicious sites, whereas pCLE differentiated and guided biopsies.Part II:Evaluation of inflammation activity and neoplasia in ulcerative colitis by probe-based confocal laser endomicroscopy (pCLE) and virtual chromoendoscopy I-Scan.Ulcerative colitis (UC) is a chronic inflammatory bowel disease showing mucosal inflammation from the rectum to the oral side. Crohn and Rosenberg reported the first case of adenocarcinoma complicating UC in 1925. The risk of developing colorectal cancer (CRC) is found to be high in patients with long-term UC. UC associated colorectal cancer (UCACRC) is considered to develop from a non-neoplastic inflammatory epithelium to dysplasia to cancer. Therefore, colonoscopic surveillance in patients with long-standing UC has been recommended. Patients with acute inflammatory infiltrates seen on histological assessment are more likely to experience relapse than are those without infiltrates, studies suggest that severity of inflammation is a risk factor for colorectal neoplasia in UC.Conventional white-light colonoscopy can detect patients with obvious inflammation, but may miss some latent active inflammation and flat-type dysplasia. As the development of novel endoscopy, the image resolution and contrast were highly improved. Chromoendoscopy with indigo carmine or methylene blue can improve the view of the border and surface microstructure of lesions. The novel virtual chromoendoscopy, without the need of any dye, can observe the microstructure of mucosa. NBI can observe the rectal mucosal vascular to distinguish the activity of UC inflammation with a strong correlation with histopathology. No research were focused on I-Scan and UC inflammation activity.Confocal laser endomicrosopy (CLE) allows for real-time endoscopy and histological diagnosis of gastrointestinal diseases. Recently, the use of CLE in the diagnosis of UC was reported. Kiesslich et al. and Watanabe et al. reported on real-time inflammation activity assessment by eCLE. In a study by our team confirmed a simplified classification system of four grades of crypt architecture by eCLE in predicting acute inflammation with histology, and found its good correlation. In this study, the investigators aimed to test the accuracy of the investigators previously proposed simplified classification system of four grades of crypt architecture in evaluating inflammation activity in UC by pCLE.Aims:(1) Investigate the diagnostic value of pCLE in differentiating ESN from nonneoplasia by the novel SMS diagnostic criteria.(2) Test the hypothesis that the screening performance of virtual chromoendoscopy I-Scan is noninferior to iodine chromoendoscopy with regard to detecting ESN.(3) Test the value of pCLE and I-Scan in evaluating the inflammation activity in UC; and test the previously proposed simplified classification system of four.grades of crypt architecture by pCLE.Methods:Part I:Diagnostic value of probe-based confocal laser endomicroscopy and high-definition virtual chromoendoscopy in early esophageal squamous neoplasia.From February 2013 to February 2014, in the Endoscopy Unit of Qilu Hospital, Shandong University, we prospectively recruited for screening consecutive outpatients. They were examined by standard white-light endoscopy (Pentax) by two experienced endoscopists. Then the imaging mode was switched to I-Scan during withdrawal from the esophagus and a focused examination of the esophagus was performed. After the I-Scan procedure, only patients with suspicious lesions were examined by using pCLE for further differentiation. At every target tissue site, an in vivo real-time diagnosis was made by the endoscopists after clearly depicting the diagnostic criteria of SMS as previously reported. At last, all enrolled patients had their esophagus sprayed with iodine solution. Biopsy specimens were obtained by forceps from each suspicious lesion and unstained lesions for histologic diagnosis. Two months later, all the stored pCLE videos were converted to a new video approximately 5 to 10 seconds. Then the pCLE videos were assessed for offline diagnosis by an endoscopist who had made the in vivo diagnosis. A substudy for the assessment of interobserver variability of pCLE was conducted in a randomized order by 2 independent pCLE investigators.2-week interval, all pCLE videos were reassessed by the 2 investigators to evaluate the intraobserver agreement.Part II:Evaluation of inflammation activity and neoplasia in ulcerative colitis by probe-based confocal laser endomicroscopy (pCLE) and virtual chromoendoscopy I-Scan.From March 2013 to October 2014, in the Endoscopy Unit of Qilu Hospital, Shandong University, we prospectively recruited for consecutive outpatients. Inclusion Criteria including:(1) Male or female aged 18-80; (2) patients previously or in-process diagnosed as ulcerative colitis. They were examined by standard white-light endoscopy (Pentax) by two experienced endoscopists. The endoscopists first evaluated the endoscopic features of the distal colon (sigmoid and rectal mucosa), inflammation activity was assessed by the Baron Score in the most severe part. Then switched to I-Scan, to observe the targeted mucosal vascular. After that, the distal tip of the endoscope was placed gently on the observed mucosa with the endomicroscopy mode turned on, the endoscopist evaluated the crypt architecture of four types simultaneously. Biopsies were taken from targeted colon mucosa. Histological assessment were according to the Geboes Index.Results:Part Ⅰ:Diagnostic value of probe-based confocal laser endomicroscopy and high-definition virtual chromoendoscopy in early esophageal squamous neoplasia.A total of 356 patients were included in the final analysis. Of these,240 patients were male (67.4%), and the mean age was 60.2 years (range 33-78 years).In all,117 suspicious lesions with mucosal or vascular pattern abnormalities were detected by the 2 endoscopy modalities in 107 patients.81 lesions were discovered by both I-Scan and Lugol chromoendoscopy; 10 suspicious lesions under I-Scan were normally stained by Lugol iodine,26 LVLs under Lugol chromoendoscopy showed no abnormalities on I-Scan. The agreement between I-Scan and Lugol chromoendoscopy for detection of esophageal abnormalities was good, with a k= 0.751. Altogether,42 patients were histologically proven to have 47 esophageal neoplastic lesions, reaching a detection rate of 11.8%. The detection rate of I-Scan and Lugol chromoendoscopy was 10.4% and 12.9%, respectively. Therefore, noninferiority between I-Scan and Lugol chromoendoscopy groups was concluded with P<0.01 and 95% CI,-7.2% to 2.2% for the difference, which was well within the threshold set for noninferiority。Of the 91 lesions, the sensitivity, specificity, positive predictive value, and negative predictive value of real-time pCLE diagnosis for ESN were 94.6% (95% CI, 81.8-99.3),90.7%(95% CI,79.7-96.9),87.5%(95% CI,73.2-95.8), and 96.1%(95% CI,86.5-99.5), respectively, with a total accuracy of 92.3%(95% CI,84.8-96.9). Offline diagnostic sensitivity, specificity, and accuracy of pCLE were 90.6%,89.1%, and 89.7%, respectively. There was good agreement among the 2 pCLE investigators, with a k= 0.699. The intraobserver agreement was graded as excellent with a mean k value of 0.895.The specificity, positive predictive value, negative predictive value, and accuracy were significantly different between the combination of I-Scan and pCLE and I-Scan alone, with 92.9%(95% CI,84.1-97.6) versus 22.9%(95% CI,13.7-34.4),87.5%(95% CI, 73.2-95.8) versus 40.7%(95% CI,30.5-51.5),84.4%(95% CI,74.4-91.7) versus 61.5% (95% CI,40.6-79.8), and 85.5%(95% CI,77.8-91.3) versus 45.3%(95% CI, 36.1-54.8), respectively (P<0.001). However, the sensitivity of the combination was not satisfactory (74.5%[95% CI,59.6-86.1]).Part II:Evaluation of inflammation activity and neoplasia in ulcerative colitis by probe-based confocal laser endomicroscopy (pCLE) and virtual chromoendoscopy I-Scan.A total of 67 patients were included in the research. Of these,35 patients were male (52.2%), and the mean age was 42.6 years (range 18-68 years).Under conventional white-light colonoscopy,20 cases had a Baron Score of 0,2 cases had a Baron Score of 1,15 cases had a Baron Score of 2 and 16 cases had a Baron Score of 3. The cases with pathologically diagnosed inactive disease (Geboes index of < 3.0) were 20, while the ones with indicated active disease (Geboes index of> 3.0) were 47. We calculate the correlation between Baron Score and Geboes index (Spearman’s r=0.330), there is a good cooreation between conventional active inflammation (Baron Score=1,2 and 3) and Geboes index (Spearman’s r=0.576).In the 67 UC cases,I-Scan detected 24 clear cases and 43 obscure or dilated cases. For the 20 patients with pathologically inactive disease, I-Scan viewed 16 clear cases, 2 obscure or dilated cases. For the 47 ones with pathologically active inflammation, I-Scan viewed 8 cases,39 obscure or dilated cases. There was a correlation between I-Scan finding and the Geboes index (Spearman’s r=0.601).For 20 patients with pathologically inactive disease,18 cases with normal crypt or chronic inflammation (Grade A or B) under pCLE. For 47 pathologically active inflammation cases,46 ones with Grade C or D. There was a strong correlation between pCLE real-time finding and the Geboes index (Spearman’s r=0.856, P< 0.01), also for the pCLE offline findings and Geboes index (Spearman’s r=0.929). There was good interobserver agreement, with kappa values of 0.699. There was also excellent intraobserver agreement, with kappa values of 0.895.Conclusions:Part I:Diagnostic value of probe-based confocal laser endomicroscopy and high-definition virtual chromoendoscopy in early esophageal squamous neoplasia.1. pCLE with targeted biopsies may be promising for diagnosing and differentiating ESN in either real-time or offline settings. The interobserver and intraobserver agreement was good.2. The endomicroscopic diagnostic criteria of the SMS has proven to be applicable to pCLE.3. The screening performance of I-Scan in the detection of ESN is noninferior to that of iodine chromoendoscopy.Part Ⅱ:Evaluation of inflammation activity and neoplasia in ulcerative colitis by probe-based confocal laser endomicroscopy (pCLE) and virtual chromoendoscopy I-Scan.1. pCLE can efficiently grading of the inflammation activity with a good correlation with pathology both realtime and offline.2. The endomicroscopic diagnostic criteria of the 4-grade classification system for crypt architecture has proven to be applicable to pCLE.3. The virtual chromoendoscopy I-Scan is good correlated with histopfthology in evaluating UC inflammation activity.Significance:This study demonstrates, for the first time, that pCLE is promising for diagnosing esophageal squamous neoplasia by using surface maturation scoring (SMS). Demonstrated the 4 features in SMS is suitable for pCLE. The screening performance of I-Scan in the detection of ESN is noninferior to that of iodine chromoendoscopy. pCLE can efficiently graded the inflammation activity of ulcerative colitis, with a good correlation with pathology. The diagnostic criteria of the 4-grade classification system for crypt architecture has proven to be applicable to pCLE. The virtual chromoendoscopy I-Scan is good correlated with histopathology in evaluating UC inflammation activity. |
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