Chromoendoscopy versus autofluorescence imaging for neoplasia detection in patients with longstanding ulcerative colitis (FIND-UC): an international, multicentre, randomised controlled trial

Background: Patients with longstanding ulcerative colitis (UC) undergo regular dysplasia surveillance because of increased colorectal cancer risk. Previous studies demonstrated that autofluorescence imaging (AFI) and chromoendoscopy (CE) increased dysplasia detection. The aim of this study was to determine whether AFI should be further studied as an alternative method for dysplasia surveillance in patients with longstanding UC. Methods: In this prospective international, randomised trial, 210 patients undergoing colonoscopy surveillance for longstanding UC were randomised between 1 August 2013 and 10 March 2017 for inspection with either AFI or CE (105:105). Randomisation was minimised for a previous history of dysplasia and a previous history of primary sclerosing cholangitis. The main outcome was the relative dysplasia detection rate calculated by the ratio of AFI versus CE. This relative dysplasia detection rate was determined for the proportion of UC patients in which at least one dysplastic lesion was detected and for the mean number of dysplastic lesions per patient. The relative dysplasia detection rate needed to be above 0·67 for both outcomes to support performing a subsequent large non-inferiority trial, using an 80% confidence interval. Analysis was performed per protocol. The trial is registered at Netherlands Trial Register (NTR4062). Findings: AFI detected dysplasia in 13 (12·4%) patients, compared to 20 patients (19·1%) with CE. The relative dysplasia detection rate of CE versus AFI for the proportion of UC patients with at least one dysplastic lesion was 0·65 (80% CI; 0·43-0·99). The mean number of detected dysplastic lesions per patient was 0·13 for AFI compared to 0·37 for CE (relative dysplasia detection rate 0·36, 80% CI; 0·21-0·61). Two patients experienced an adverse event (intraprocedural mild bleeding = 1, abdominal pain = 1) in the AFI-arm and three patients (intraprocedural mild bleeding = 2, perforation = 1) in the CE-arm. Interpretation: In this randomised study comparing AFI with CE for dysplasia surveillance in patients with longstanding UC, AFI did not meet criteria for proceeding to a large non-inferiority trial. Therefore, current AFI technology should not be further investigated as an alternative dysplasia surveillance method. Funding: Olympus Europe and Olympus Keymed, Oxford and Nottingham NIHR biomedical research centres

Mammographic density and ageing:A collaborative pooled analysis of cross-sectional data from 22 countries worldwide

BACKGROUND: Mammographic density (MD) is one of the strongest breast cancer risk factors. Its age-related characteristics have been studied in women in western countries, but whether these associations apply to women worldwide is not known. METHODS AND FINDINGS: We examined cross-sectional differences in MD by age and menopausal status in over 11,000 breast-cancer-free women aged 35-85 years, from 40 ethnicity- and location-specific population groups across 22 countries in the International Consortium on Mammographic Density (ICMD). MD was read centrally using a quantitative method (Cumulus) and its square-root metrics were analysed using meta-analysis of group-level estimates and linear regression models of pooled data, adjusted for body mass index, reproductive factors, mammogram view, image type, and reader. In all, 4,534 women were premenopausal, and 6,481 postmenopausal, at the time of mammography. A large age-adjusted difference in percent MD (PD) between post- and premenopausal women was apparent (-0.46 cm [95% CI: -0.53, -0.39]) and appeared greater in women with lower breast cancer risk profiles; variation across population groups due to heterogeneity (I2) was 16.5%. Among premenopausal women, the √PD difference per 10-year increase in age was -0.24 cm (95% CI: -0.34, -0.14; I2 = 30%), reflecting a compositional change (lower dense area and higher non-dense area, with no difference in breast area). In postmenopausal women, the corresponding difference in √PD (-0.38 cm [95% CI: -0.44, -0.33]; I2 = 30%) was additionally driven by increasing breast area. The study is limited by different mammography systems and its cross-sectional rather than longitudinal nature. CONCLUSIONS: Declines in MD with increasing age are present premenopausally, continue postmenopausally, and are most pronounced over the menopausal transition. These effects were highly consistent across diverse groups of women worldwide, suggesting that they result from an intrinsic biological, likely hormonal, mechanism common to women. If cumulative breast density is a key determinant of breast cancer risk, younger ages may be the more critical periods for lifestyle modifications aimed at breast density and breast cancer risk reduction

Quality of colonoscopy and advances in detection of colorectal lesions: a current overview

Colonoscopy is the gold standard for the detection of colorectal cancer and its precursors. Nevertheless multiple studies have demonstrated a significant miss-rate for polyps and, more importantly, demonstrated the occurrence of interval cancers in the years after colonoscopy. This imperfect protection against colorectal cancer can be explained by multiple factors related to both the endoscopist and the equipment. To ensure the quality of colonoscopy, several quality indicators have been described. These include bowel preparation, cecal intubation rate, withdrawal time, adenoma detection rate and complication rate. Measurement of these quality indicators, followed by awareness, benchmarking and additional training will hopefully optimize daily practice. If these basic quality parameters are well taken care of, advanced colonoscopic techniques will aim at further increasing the detection and differentiation of colonic lesions. In this review, the authors discuss the literature on quality indicators for colonoscopy and give a comprehensive overview of the advanced colonoscopic techniques currently availabl

Diagnostic performance of narrowed spectrum endoscopy, autofluorescence imaging, and confocal laser endomicroscopy for optical diagnosis of colonic polyps: a meta-analysis

Novel endoscopic technologies could allow optical diagnosis and resection of colonic polyps without histopathological testing. Our aim was to establish the sensitivity, specificity, and real-time negative predictive value of three types of narrowed spectrum endoscopy (narrow-band imaging [NBI], image-enhanced endoscopy [i-scan], and Fujinon intelligent chromoendoscopy [FICE]), confocal laser endomicroscopy (CLE), and autofluorescence imaging for differentiation between neoplastic and non-neoplastic colonic lesions. We identified relevant studies through a search of Medline, Embase, PubMed, and the Cochrane Library. Clinical trials and observational studies were eligible for inclusion when the diagnostic performance of NBI, i-scan, FICE, autofluorescence imaging, or CLE had been assessed for differentiation, with histopathology as the reference standard, and for which a 2 × 2 contingency table of lesion diagnosis could be constructed. We did a random-effects bivariate meta-analysis using a non-linear mixed model approach to calculate summary estimates of sensitivity and specificity, and plotted estimates in a summary receiver-operating characteristic curve. We included 91 studies in our analysis: 56 were of NBI, ten of i-scan, 14 of FICE, 11 of CLE, and 11 of autofluorescence imaging (more than one of the investigated modalities assessed in eight studies). For NBI, overall sensitivity was 91·0% (95% CI 88·6-93·0), specificity 85·6% (81·3-89·0), and real-time negative predictive value 82·5% (75·4-87·9). For i-scan, overall sensitivity was 89·3% (83·3-93·3), specificity 88·2% (80·3-93·2), and real-time negative predictive value 86·5% (78·0-92·1). For FICE, overall sensitivity was 91·8% (87·1-94·9), specificity 83·5% (77·2-88·3), and real-time negative predictive value 83·7% (77·5-88·4). For autofluorescence imaging, overall sensitivity was 86·7% (79·5-91·6), specificity 65·9% (50·9-78·2), and real-time negative predictive value 81·5% (54·0-94·3). For CLE, overall sensitivity was 93·3% (88·4-96·2), specificity 89·9% (81·8-94·6), and real-time negative predictive value 94·8% (86·6-98·1). All endoscopic imaging techniques other than autofluorescence imaging could be used by appropriately trained endoscopists to make a reliable optical diagnosis for colonic lesions in daily practice. Further research should be focused on whether training could help to improve negative predictive values. Non

Limited applicability of chromoendoscopy-guided confocal laser endomicroscopy as daily-practice surveillance strategy in Crohn's disease

Patients with longstanding ulcerative colitis have an increased risk for developing colorectal cancer (CRC). Although the risk for ulcerative colitis is well-established, for Crohn's disease data are contradictory. This study aimed to determine the number of patients with Crohn's disease with dysplasia who are undergoing surveillance and to assess the diagnostic accuracy of chromoendoscopy (CE) combined with integrated confocal laser endomicroscopy (iCLE) for differentiating dysplastic versus nondysplastic lesions. Patients with longstanding Crohn's colitis undergoing surveillance colonoscopy were included in this multicenter, prospective, cohort study. Surveillance was performed with CE, and lesions were assessed with iCLE for differentiation. All lesions were removed and sent for pathology as the reference standard. Between 2010 and 2014, a total of 61 patients with Crohn's colitis were included in 5 centers. Seventy-two lesions, of which 7 were dysplastic, were detected in 6 patients (dysplasia detection rate 9.8%); none included high-grade dysplasia or cancer. Combined CE with iCLE for differentiating neoplastic from nonneoplastic lesions had accuracy of 86.7% (95% confidence interval [CI], 78.1-95.3), sensitivity of 42.9% (95% CI, 11.8-79.8), and specificity of 92.4% (95% CI, 80.9-97.6). For CE alone, this was 80.3% (95% CI, 70.7-89.9), 28.6% (95% CI, 5.1-69.7), and 86.4% (95% CI, 80.9-97.6). The study terminated early because of frequent failure of the endoscopic equipment. This study shows a low incidence of dysplastic lesions found during surveillance colonoscopy in patients with longstanding extensive Crohn's colitis. The accuracy of both CE alone and CE in combination with iCLE was relatively good, although the sensitivity for both was poor. Because of frequent equipment failure, iCLE has limited applicability in daily practice as a surveillance strateg

Low interobserver agreement among endoscopists in differentiating dysplastic from non-dysplastic lesions during inflammatory bowel disease colitis surveillance

Objectives. During endoscopic surveillance in patients with longstanding colitis, a variety of lesions can be encountered. Differentiation between dysplastic and non-dysplastic lesions can be challenging. The accuracy of visual endoscopic differentiation and interobserver agreement (IOA) has never been objectified. Material and methods. We assessed the accuracy of expert and nonexpert endoscopists in differentiating (low-grade) dysplastic from non-dysplastic lesions and the IOA among and between them. An online questionnaire was constructed containing 30 cases including a short medical history and an endoscopic image of a lesion found during surveillance employing chromoendoscopy. Results. A total of 17 endoscopists, 8 experts, and 9 nonexperts assessed all 30 cases. The overall sensitivity and specificity for correctly identifying dysplasia were 73.8% (95% confidence interval (CI) 62.1-85.4) and 53.8% (95% CI 42.6-64.7), respectively. Experts showed a sensitivity of 76.0% (95% CI 63.3-88.6) versus 71.8% (95% CI 58.5-85.1, p = 0.434) for nonexperts, the specificity 61.0% (95% CI 49.3-72.7) versus 47.1% (95% CI 34.6-59.5, p = 0.008). The overall IOA in differentiating between dysplastic and non-dysplastic lesions was fair 0.24 (95% CI 0.21-0.27); for experts 0.28 (95% CI 0.21-0.35) and for nonexperts 0.22 (95% CI 0.17-0.28). The overall IOA for differentiating between subtypes was fair 0.21 (95% CI 0.20-0.22); for experts 0.19 (95% CI 0.16-0.22) and nonexpert 0.23 (95% CI 0.20-0.26). Conclusion. In this image-based study, both expert and nonexpert endoscopists cannot reliably differentiate between dysplastic and non-dysplastic lesions. This emphasizes that all lesions encountered during colitis surveillance with a slight suspicion of containing dysplasia should be removed and sent for pathological assessment

IBD-Associated Dysplastic Lesions Show More Chromosomal Instability Than Sporadic Adenomas

BACKGROUND: Patients with longstanding inflammatory bowel disease (IBD; ie, ulcerative colitis and Crohn's disease) have an increased risk of colorectal cancer (CRC). Due to ongoing inflammation, IBD-associated dysplastic lesions can develop. These lesions have an increased risk to progress to cancer compared with sporadic adenomas, which are also found in these patients. Differentiating between these 2 types of dysplasia remains challenging, both clinically and histologically, while treatment strategies may differ. Therefore, the aim of this study was to investigate molecular alterations associated with colorectal dysplasia to cancer progression in IBD and evaluate to what extent these alterations differ from sporadic adenomas. METHODS: DNA copy number aberrations and mutation analyses of 48 genes were performed by next-generation sequencing in 43 IBD-associated dysplastic lesions, 30 of which were dysplastic and 13 of which were cancers. Results were compared with existing DNA copy number and mutation data from 118 sporadic adenomas and 24 sporadic cancers. RESULTS: Inflammatory bowel disease-associated dysplastic lesions harbor patterns of DNA copy number aberrations comparable to carcinomas, which are rare in sporadic adenomas. TP53 mutation was the most frequent mutation observed in IBD-associated dysplastic lesions and in cancers. FBXW7 was mutated significantly more often in IBD-associated dysplastic lesions than in sporadic adenomas. CONCLUSIONS: Inflammatory bowel disease-associated dysplastic lesions show more DNA copy number aberrations than sporadic adenomas. TP53 and FBXW7 mutations appear to be involved in the development of IBD-associated dysplastic lesions and cancer. These findings indicate that IBD-associated dysplastic lesions are more genomically unstable, possibly reflecting a faster progression toward cancer

Peroxisomes and their central role in metabolic interaction networks in humans

Peroxisomes catalyze a number of essential metabolic functions and impairments in any of these are usually associated with major clinical signs and symptoms. In contrast to mitochondria which are autonomous organelles that can catalyze the degradation of fatty acids, certain amino acids and other compounds all by themselves, peroxisomes are non-autonomous organelles which are highly dependent on the interaction with other organelles and compartments to fulfill their role in metabolism. This includes mitochondria, the endoplasmic reticulum, lysosomes, and the cytosol. In this paper we will discuss the central role of peroxisomes in different metabolic interaction networks in humans, including fatty acid oxidation, ether phospholipid biosynthesis, bile acid synthesis, fatty acid alpha-oxidation and glyoxylate metabolism

Blunted fat oxidation upon submaximal exercise is partially compensated by enhanced glucose metabolism in children, adolescents, and young adults with Barth syndrome

Barth syndrome (BTHS) is a rare X-linked condition resulting in abnormal mitochondria, cardioskeletal myopathy, and growth delay; however, the effects of BTHS on substrate metabolism regulation and their relationships with tissue function in humans are unknown. We sought to characterize glucose and fat metabolism during rest, submaximal exercise, and postexercise rest in children, adolescents, and young adults with BTHS and unaffected controls and examine their relationships with cardioskeletal energetics and function. Children/adolescents and young adults with BTHS (n = 29) and children/adolescent and young adult control participants (n = 28, total n = 57) underwent an infusion of 6′6′H2 glucose and U- 13 C palmitate and indirect calorimetry during rest, 30-minutes of moderate exercise (50% (Formula presented.)), and recovery. Cardiac function, cardioskeletal mitochondrial energetics, and exercise capacity were examined via echocardiography, 31 P magnetic resonance spectroscopy, and peak exercise testing, respectively. The glucose turnover rate was significantly higher in individuals with BTHS during rest (33.2 ± 9.8 vs 27.2 ± 8.1 μmol/kgFFM/min, P <.01) and exercise (34.7 ± 11.2 vs 29.5 ± 8.8 μmol/kgFFM/min, P <.05) and tended to be higher postexercise (33.7 ± 10.2 vs 28.8 ± 8.0 μmol/kgFFM/min, P <.06) compared to controls. Increases in total fat (−3.9 ± 7.5 vs 10.5 ± 8.4 μmol/kgFFM/min, P <.0001) and plasma fatty acid oxidation rates (0.0 ± 1.8 vs 5.1 ± 3.9 μmol/kgFFM/min, P <.0001) from rest to exercise were severely blunted in BTHS compared to controls. Conclusion: An inability to upregulate fat metabolism during moderate intensity exercise appears to be partially compensated by elevations in glucose metabolism. Derangements in fat and glucose metabolism are characteristic of the pathophysiology of BTHS. A severely blunted ability to upregulate fat metabolism during a modest level of physical activity is a defining pathophysiologic characteristic in children, adolescents, and young adults with BTHS