Wouter L. Curvers

Low-Grade Dysplasia in Barrett's Esophagus: Overdiagnosed and Underestimated

OBJECTIVES:Published data on the natural history of low-grade dysplasia (LGD) in Barretts esophagus (BE) are inconsistent and difficult to interpret. We investigated the natural history of LGD in a large community-based cohort of BE patients after reviewing the original histological diagnosis by an expert panel of pathologists.METHODS:Histopathology reports of all patients diagnosed with LGD between 2000 and 2006 in six non-university hospitals were reviewed by two expert pathologists. This panel diagnosis was subsequently compared with the histological outcome during prospective endoscopic follow-up.RESULTS:A diagnosis of LGD was made in 147 patients. After pathology review, 85% of the patients were downstaged to non-dysplastic BE (NDBE) or to indefinite for dysplasia. In only 15% of the patients was the initial diagnosis LGD. Endoscopic follow-up was carried out in 83.6% of patients, with a mean follow-up of 51.1 months. For patients with a consensus diagnosis of LGD, the cumulative risk of progressing to high-grade dysplasia or carcinoma (HGD or Ca) was 85.0% in 109.1 months compared with 4.6% in 107.4 months for patients downstaged to NDBE (P<0.0001). The incidence rate of HGD or Ca was 13.4% per patient per year for patients in whom the diagnosis of LGD was confirmed. For patients downstaged to NDBE, the corresponding incidence rate was 0.49%.CONCLUSIONS:LGD in BE is an overdiagnosed and yet underestimated entity in general practice. Patients diagnosed with LGD should undergo an expert pathology review to purify this group. In case the diagnosis of LGD is confirmed, patients should undergo strict endoscopic follow-up or should be considered for endoscopic ablation therapy.

Endoscopic tri-modal imaging for detection of early neoplasia in Barrett's oesophagus: a multi-centre feasibility study using high-resolution endoscopy, autofluorescence imaging and narrow band imaging incorporated in one endoscopy system

Objective: To investigate the diagnostic potential of endoscopic tri-modal imaging and the relative contribution of each imaging modality (i.e. high-resolution endoscopy (HRE), autofluorescence imaging (AFI) and narrow-band imaging (NBI)) for the detection of early neoplasia in Barrett’s oesophagus. Design: Prospective multi-centre study. Setting: Tertiary referral centres. Patients: 84 Patients with Barrett’s oesophagus. Interventions: The Barrett’s oesophagus was inspected with HRE followed by AFI. All lesions detected with HRE and/or AFI were subsequently inspected in detail by NBI for the presence of abnormal mucosal and/or microvascular patterns. Biopsies were obtained from all suspicious lesions for blinded histopathological assessment followed by random biopsies. Main outcome measures: (1) Number of patients with early neoplasia diagnosed by HRE and AFI; (2) number of lesions with early neoplasia detected with HRE and AFI; and (3) reduction of false positive AFI findings after NBI. Results: Per patient analysis: AFI identified all 16 patients with early neoplasia identified with HRE and detected an additional 11 patients with early neoplasia that were not identified with HRE. In three patients no abnormalities were seen but random biopsies revealed HGIN. After HRE inspection, AFI detected an additional 102 lesions; 19 contained HGIN/EC (false positive rate of AFI after HRE: 81%). Detailed inspection with NBI reduced this false positive rate to 26%. Conclusions: In this international multi-centre study, the addition of AFI to HRE increased the detection of both the number of patients and the number of lesions with early neoplasia in patients with Barrett’s oesophagus. The false positive rate of AFI was reduced after detailed inspection with NBI.

Determinants of perception of heartburn and regurgitation

Background and aim: It is not known why some reflux episodes evoke symptoms and others do not. We investigated the determinants of perception of gastro-oesophageal reflux. Methods: In 32 patients with symptoms suggestive of gastro-oesophageal reflux, 24 hour ambulatory pH and impedance monitoring was performed after cessation of acid suppressive therapy. In the 20 patients who had at least one symptomatic reflux episode, characteristics of symptomatic and asymptomatic reflux episodes were compared. Results: A total of 1807 reflux episodes were detected, 203 of which were symptomatic. Compared with asymptomatic episodes, symptomatic episodes were associated with a larger pH drop (p<0.001), lower nadir pH (p<0.05), and higher proximal extent (p<0.005). Symptomatic reflux episodes had a longer volume and acid clearance time (p<0.05 and p<0.002). Symptomatic episodes were preceded by a higher oesophageal cumulative acid exposure time (p<0.05). The proximal extent of episodes preceding regurgitation was larger than those preceding heartburn; 14.8% of the symptomatic reflux episodes were weakly acidic. In total, 426 pure gas reflux episodes occurred, of which 12 were symptomatic. Symptomatic pure gas reflux was more frequently accompanied by a pH drop than asymptomatic gas reflux (p<0.05). Conclusions: Heartburn and regurgitation are more likely to be evoked when the pH drop is large, proximal extent of the refluxate is high, and volume and acid clearance is delayed. Sensitisation of the oesophagus occurs by preceding acid exposure. Weakly acidic reflux is responsible for only a minority of symptoms in patients off therapy. Pure gas reflux associated with a pH drop (“acid vapour”) can be perceived as heartburn and regurgitation.

Standard endoscopy with random biopsies versus narrow band imaging targeted biopsies in Barrett's oesophagus: a prospective, international, randomised controlled trial

Background White light endoscopy with random biopsies is the standard for detection of intestinal metaplasia (IM) and neoplasia in patients with Barretts oesophagus (BO). Narrow band imaging (NBI) highlights surface patterns that correlate with IM and neoplasia in BO. Objective To compare high-definition white light (HD-WLE) and NBI for detection of IM and neoplasia in BO. Design International, randomised, crossover trial comparing HD-WLE and NBI. Patients referred for BO screening/surveillance at three tertiary referral centres were prospectively enrolled and randomised to HD-WLE or NBI followed by other procedures in 3–8 weeks. During HD-WLE, four quadrant biopsies every 2 cm, together with targeted biopsies of visible lesions (Seattle protocol), were obtained. During NBI examination, mucosal and vascular patterns were noted and targeted biopsies were obtained. All biopsies were read by a single expert gastrointestinal pathologist in a blinded fashion. Results 123 patients with BO (mean age 61; 93% male; 97% Caucasian) with mean circumferential and maximal extents of 1.8 and 3.6 cm, respectively, were enrolled. Both HD-WLE and NBI detected 104/113 (92%) patients with IM, but NBI required fewer biopsies per patient (3.6 vs 7.6, p<0.0001). NBI detected a higher proportion of areas with dysplasia (30% vs 21%, p=0.01). During examination with NBI, all areas of high-grade dysplasia and cancer had an irregular mucosal or vascular pattern. Conclusions NBI targeted biopsies can have the same IM detection rate as an HD-WLE examination with the Seattle protocol while requiring fewer biopsies. In addition, NBI targeted biopsies can detect more areas with dysplasia. Regular appearing NBI surface patterns did not harbour high-grade dysplasia/cancer, suggesting that biopsies could be avoided in these areas.

Chromoendoscopy and narrow-band imaging compared with high-resolution magnification endoscopy in Barrett's esophagus.

BACKGROUND & AIMS The aim of this study was to compare magnified still images obtained with high-resolution white light endoscopy, indigo carmine chromoendoscopy, acetic acid chromoendoscopy, and narrow-band imaging to determine the best technique for use in Barretts esophagus. METHODS We obtained magnified images from 22 areas with the 4 aforementioned techniques. Seven endoscopists with no specific expertise in Barretts esophagus or advanced imaging techniques and 5 international experts in this field evaluated these 22 areas for overall image quality, mucosal image quality, and vascular image quality. In addition, the regularity of mucosal and vascular patterns and the presence of abnormal blood vessels were evaluated, and this was correlated with histology. RESULTS The interobserver agreement for the 3 features of mucosal morphology with white light images ranged from kappa = 0.51 (95% confidence interval [CI]: 0.46-0.55) to kappa = 0.53 (95% CI: 0.50-0.57) for all observers, from kappa = 0.43 (95% CI: 0.33-0.54) to kappa = 0.53 (95% CI: 0.41-0.64) for experts, and from kappa = 0.51 (95% CI: 0.15-0.33) to kappa = 0.64 (95% CI: 0.58-0.70) for nonexperts. The interobserver agreement in these groups did not improve by adding one of the enhancement techniques. The yield for identifying early neoplasia with white light images was 86% for all observers, 90% for experts, and 84% for nonexperts. The addition of enhancement techniques did not improve the yield neoplasia. CONCLUSIONS The addition of indigo carmine chromoendoscopy, acetic acid chromoendoscopy, or narrow-band imaging to white light images did not improve interobserver agreement or yield identifying early neoplasia in Barretts esophagus.

Endoscopic Tri-Modal Imaging Is More Effective Than Standard Endoscopy in Identifying Early-Stage Neoplasia in Barrett's Esophagus

BACKGROUND & AIMS Endoscopic tri-modal imaging (ETMI) incorporates high-resolution endoscopy (HRE), autofluorescence imaging (AFI), and narrow band imaging (NBI). A recent uncontrolled study found that ETMI improved the detection of high-grade dysplasia (HGD) and early carcinoma (Ca) in Barretts esophagus (BE). The aim was to compare ETMI with standard video endoscopy (SVE) for the detection of HGD/Ca with the use of a randomized cross-over design. METHODS Patients referred for work-up of inconspicuous HGD/Ca were eligible and underwent both SVE and ETMI in randomized order within an interval of 6-12 weeks. During ETMI, inspection with HRE was followed by AFI. Detected lesions were inspected in detail with NBI and biopsied, followed by random biopsies. During SVE, any visible lesion was biopsied followed by random biopsies. RESULTS Eighty-seven patients with BE underwent ETMI and SVE. No significant difference was observed in overall histologic yield between ETMI and SVE. ETMI had a significantly higher targeted yield compared with SVE because of AFI. However, the yield of targeted biopsies of ETMI was significantly inferior to the overall yield of SVE. Detailed inspection with NBI reduced the false-positive rate of HRE + AFI from 71% to 48% but misclassified 17% of HGD/Ca lesions as not suspicious. CONCLUSIONS ETMI statistically significant improves the targeted detection of HGD/Ca compared with SVE. Subsequent characterization of lesions with NBI appears to be of limited value. At this stage, ETMI cannot replace random biopsies for detection of lesions or targeted biopsies for characterization of lesions in a high-risk population.

Barrett's oesophagus patients with low-grade dysplasia can be accurately risk-stratified after histological review by an expert pathology panel

Objective Reported malignant progression rates for low-grade dysplasia (LGD) in Barretts oesophagus (BO) vary widely. Expert histological review of LGD is advised, but limited data are available on its clinical value. This retrospective cohort study aimed to determine the value of an expert pathology panel organised in the Dutch Barretts Advisory Committee (BAC) by investigating the incidence rates of high-grade dysplasia (HGD) and oesophageal adenocarcinoma (OAC) after expert histological review of LGD. Design We included all BO cases referred to the BAC for histological review of LGD diagnosed between 2000 and 2011. The diagnosis of the expert panel was related to the histological outcome during endoscopic follow-up. Primary endpoint was development of HGD or OAC. Results 293 LGD patients (76% men; mean 63 years±11.9) were included. Following histological review, 73% was downstaged to non-dysplastic BO (NDBO) or indefinite for dysplasia (IND). In 27% the initial LGD diagnosis was confirmed. Endoscopic follow-up was performed in 264 patients (90%) with a median follow-up of 39 months (IQR 16–72). For confirmed LGD, the risk of HGD/OAC was 9.1% per patient-year. Patients downstaged to NDBO or IND had a malignant progression risk of 0.6% and 0.9% per patient-year, respectively. Conclusions Confirmed LGD in BO has a markedly increased risk of malignant progression. However, the vast majority of patients with community LGD will be downstaged after expert review and have a low progression risk. Therefore, all BO patients with LGD should undergo expert histological review of the diagnosis for adequate risk stratification.

Endoscopic trimodal imaging versus standard video endoscopy for detection of early Barrett's neoplasia: a multicenter, randomized, crossover study in general practice

BACKGROUND Endoscopic trimodal imaging (ETMI) may improve detection of early neoplasia in Barretts esophagus (BE). Studies with ETMI so far have been performed in tertiary referral settings only. OBJECTIVE To compare ETMI with standard video endoscopy (SVE) for the detection of neoplasia in BE patients with an intermediate-risk profile. DESIGN Multicenter, randomized, crossover study. SETTING Community practice. PATIENTS AND METHODS BE patients with confirmed low-grade intraepithelial neoplasia (LGIN) underwent both ETMI and SVE in random order (interval 6-16 weeks). During ETMI, BE was inspected with high-resolution endoscopy followed by autofluorescence imaging (AFI). All visible lesions were then inspected with narrow-band imaging. During ETMI and SVE, visible lesions were sampled followed by 4-quadrant random biopsies every 2 cm. MAIN OUTCOME MEASUREMENTS Overall histological yield of ETMI and SVE and targeted histological yield of ETMI and SVE. RESULTS A total of 99 patients (79 men, 63±10 years) underwent both procedures. ETMI had a significantly higher targeted histological yield because of additional detection of 22 lesions with LGIN/high-grade intraepithelial neoplasia (HGIN)/carcinoma (Ca) by AFI. There was no significant difference in the overall histological yield (targeted+random) between ETMI and SVE. HGIN/Ca was diagnosed only by random biopsies in 6 of 24 patients and 7 of 24 patients, with ETMI and SVE, respectively. LIMITATIONS Inspection, with high-resolution endoscopy and AFI, was performed sequentially. CONCLUSION ETMI performed in a community-based setting did not improve the overall detection of dysplasia compared with SVE. The diagnosis of dysplasia is still being made in a significant number of patients by random biopsies. Patients with a confirmed diagnosis of LGIN have a significant risk of HGIN/Ca. ( CLINICAL TRIAL REGISTRATION NUMBER ISRCTN91816824; NTR867.).

Systematic review of narrow-band imaging for the detection and differentiation of neoplastic and nonneoplastic lesions in the colon (with videos)

Study selection Studies that assessed narrow-band imaging colonoscopy for the detection or the differentiation of lesions in the colon in patients undergoing colonoscopy, regardless of indication (screening, surveillance, symptoms), were eligible for inclusion. For the detection of neoplasia, studies had to compare narrow-band imaging colonoscopy with white-light endoscopy. For the differentiation between neoplastic and non-neoplastic lesions studies had to include histopathologic examination of biopsy or endoscopic resection specimens of the lesions of interest as the reference standard. Studies were required to report sufficient data to construct a 2x2 table of test performance. All classification systems for narrow-band imaging were eligible.

Pharmacokinetics of 6-mercaptopurine in patients with inflammatory bowel disease: implications for therapy.

Proper prospective pharmacokinetic studies of 6-mercaptopurine (6-MP) in inflammatory bowel disease (IBD) patients are lacking. As a result, conflicting recommendations have been made for metabolite monitoring in routine practice. The authors have evaluated 6-MP pharmacokinetics in IBD patients, including the genetic background for thiopurine methyltransferase (TPMT). Red blood cell (RBC) 6-thioguanine nucleotide (6-TGN) and 6-methylmercaptopurine ribonucleotide (6-MMPR) concentrations were measured in 30 IBD patients at 1, 2, 4, and 8 weeks after starting 6-MP, 50 mg once daily. Outcome measures included mean 6-TGN and 6-MMPR concentrations (± 95% confidence interval, CI95%) and their associations with TPMT genotype, 6-MP dose, and hematologic, hepatic, pancreatic, and efficacy parameters during the 8-week period. Steady-state concentrations were reached after 4 weeks, indicating a half-life of approximately 5 days for both 6-TGN and 6-MMPR; the concentrations were 368 (CI95% 284–452) and 2837 (CI95% 2101–3573) pmol/8 × 108 RBCs, respectively. Large interpatient variability occurred at all time points. TPMT genotype correlated with 6-TGN concentrations (0.576, P < 0.01), and patients with mutant alleles had a relative risk (RR) of 12.0 (CI95% 1.7–92.3) of developing leukopenia. A 6-MMPR/6-TGN ratio less than 11 was associated with therapeutic efficacy. Based on this pharmacokinetic analysis, therapeutic drug monitoring is essential for rational 6-MP dosing.