Srinivas Gaddam

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.

Risk Factors for Progression of Low-Grade Dysplasia in Patients With Barrett's Esophagus

BACKGROUND & AIMS Data vary on the progression of low-grade dysplasia (LGD) in patients with Barretts esophagus (BE); in patients with LGD, we investigated the incidence of high-grade dysplasia (HGD) and esophageal adenocarcinoma (EAC) and compared progression in patients with different forms of LGD (prevalent vs incident and multifocal vs unifocal). We assessed the effects of consensus diagnosis of LGD on progression rates to HGD and EAC among expert pathologists. METHODS In a multicenter outcomes project, 210 patients with BE and LGD (classified as incident, prevalent, or persistent) were included. Patients were followed up for an average of 6.2 years (959.6 patient-years). Persistent LGD was defined as detection of LGD on ≥2 consecutive occasions during the follow-up period and extent as either unifocal (LGD at one level of BE segment) or multifocal (>1 level). Histology specimens were reviewed by 2 blinded pathologists. RESULTS Six patients developed EAC (incidence of 0.44%/year), and 21 developed HGD (incidence of 1.6%/year). The incidence of the combination of HGD and EAC was 1.83%/year. There were no associations between presence of prevalent, incident, or persistent LGD and the extent of LGD with progression rates. Based on consensus diagnosis of 88 reviewed specimens, there was no difference in the progression of LGD to either EAC (the incidence based on analyses by the local pathologist was 0.18%/year, the incidence when there was agreement between the local and one central pathologist was 0.21%/year, and the incidence when all 3 pathologists were in agreement was 0.39%/year) or combined HGD and EAC (0.94%/year, 0.87%/year, and 0.84%/year, respectively). CONCLUSIONS Overall, patients with BE and LGD have a low annual incidence of EAC, similar to nondysplastic BE. There are no risk factors for progression and there is significant interobserver variation in diagnosis, even among expert pathologists.

Patients With Nondysplastic Barrett's Esophagus Have Low Risks for Developing Dysplasia or Esophageal Adenocarcinoma

BACKGROUND & AIMS The risks of dysplasia and esophageal adenocarcinoma (EAC) are not clear for patients with nondysplastic Barretts esophagus (NDBE); the rate of progression has been overestimated in previous studies. We studied the incidences of dysplasia and EAC and investigated factors associated with progression of BE. METHODS The BE study is a multicenter outcomes project of a large cohort of patients with BE. Neoplasia was graded as low-grade dysplasia, high-grade dysplasia (HGD), or EAC. Patients followed up for at least 1 year after the index endoscopy examination were included, whereas those diagnosed with dysplasia and EAC within 1 year of diagnosis with BE (prevalent cases) were excluded. Of 3334 patients with BE, 1204 met the inclusion criteria (93.7% Caucasian; 88% male; mean age, 59.3 y) and were followed up for a mean of 5.52 years (6644.5 patient-years). RESULTS Eighteen patients developed EAC (incidence, 0.27%/y; 95% confidence interval [CI], 0.17-0.43) and 32 developed HGD (incidence, 0.48%/y; 95% CI, 0.34-0.68). The incidence of HGD and EAC was 0.63%/y (95% CI, 0.47-0.86). There were 217 cases of low-grade dysplasia (incidence, 3.6%/y; 95% CI, 3.2-4.1). Five and 10 years after diagnosis, 98.6% (n = 540) and 97.1% (n = 155) of patients with NDBE were cancer free, respectively. The length of the BE was associated significantly with progression (EAC <6 cm, 0.09%/y vs EAC ≥ 6 cm, 0.65%/y; P = 0.001). CONCLUSIONS There is a lower incidence of dysplasia and EAC among patients with NDBE than previously reported. Because most patients are cancer free after a long-term follow-up period, surveillance intervals might be lengthened, especially for patients with shorter segments of BE.

The diagnostic accuracy of 22-gauge and 25-gauge needles in endoscopic ultrasound-guided fine needle aspiration of solid pancreatic lesions: a meta-analysis

BACKGROUND AND STUDY AIMS It is uncertain if needle gauge impacts the diagnostic accuracy of endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) of pancreatic mass lesions. Our aim was to use meta-analysis to more robustly define the diagnostic accuracy of EUS-FNA for pancreatic masses using 22 G and 25 G needles. PATIENTS AND METHODS Studies were identified by searching nine medical databases for reports published between 1994 and 2011, using a reproducible search strategy comprised of relevant terms. Only studies comparing the overall diagnostic accuracy of 22 G vs. 25 G EUS needles that used surgical histology or at least 6 months clinical follow up for a gold standard were included. Two reviewers independently scored the identified studies for methodology and abstracted pertinent data. When required, the original investigators were contacted to provide additional data. Pooling was conducted by both fixed-effects and random-effects models. Diagnostic characteristics (sensitivity, specificity, positive and negative likelihood ratios) with 95% confidence intervals (CIs) were calculated. RESULTS Eight studies involving 1292 subjects met the defined inclusion criteria. Of the 1292 patients, 799 were in the 22 G group and 565 were in the 25 G group (both needles were used in 72 patients). The pooled sensitivity and specificity of the 22 G needle were 0.85 (95%CI 0.82-0.88) and 1 (95%CI 0.98-1) respectively. The pooled sensitivity and specificity of the 25 G needle were 0.93 (95%CI 0.91-0.96) and 0.97 (95%CI 0.93-0.99) respectively. The bivariate generalized linear random-effect model indicated that the 25 G needle is associated with a higher sensitivity (P = 0.0003) but comparable specificity (P = 0.97) to the 22 G needle. CONCLUSIONS This meta-analysis suggests 25 G needle systems are more sensitive than 22 G needles for diagnosing pancreatic malignancy.

Longer inspection time is associated with increased detection of high-grade dysplasia and esophageal adenocarcinoma in Barrett's esophagus

BACKGROUND Current guidelines recommend that endoscopic surveillance of Barretts esophagus (BE) be performed by using a strict biopsy protocol. However, novel methods to improve BE surveillance are still needed. OBJECTIVE To evaluate the impact of Barretts inspection time (BIT) on yield of surveillance. DESIGN Post hoc analysis of data obtained from a clinical trial. SETTING Five tertiary referral centers. PATIENTS Patients undergoing BE surveillance. INTERVENTIONS Coordinators prospectively recorded the time spent inspecting the BE mucosa with a stopwatch. MAIN OUTCOME MEASUREMENTS Endoscopically suspicious lesions, high-grade dysplasia (HGD)/esophageal adenocarcinoma (EAC). RESULTS A total of 112 patients underwent endoscopic surveillance by 11 individual endoscopists. Patients with longer BITs were more likely to have an endoscopically suspicious lesion (P < .001) and more endoscopically suspicious lesions (P = .0001) and receive a diagnosis of HGD/EAC (P = .001). There was a direct correlation between the endoscopists mean BIT per centimeter of BE and the detection of patients with HGD/EAC (ρ = .63, P = .03). Endoscopists who had an average BIT longer than 1 minute per centimeter of BE detected more patients with endoscopically suspicious lesions (54.2% vs 13.3%, P = .04), and there was a trend toward a higher detection rate of HGD/EAC (40.2% vs 6.7%, P = .06). LIMITATIONS Post hoc analysis of an enriched study population and experienced endoscopists at tertiary referral centers. CONCLUSIONS Longer time spent inspecting the BE segment is associated with the increased detection of HGD/EAC. Taking additional time to perform a thorough examination of the BE mucosa may serve as an easy and widely available method to improve the yield of BE surveillance.

Higher adenoma detection rates with cap-assisted colonoscopy: a randomised controlled trial

Objective Cap-assisted colonoscopy (CAC) uses a small plastic transparent cap attached to the tip of the colonoscope that can depress and flatten colonic folds and thus improve visualisation of their proximal aspects. The aim of this study was to compare CAC with standard colonoscopy (SC; high-definition white light) for adenoma detection rates. Design This is a prospective randomised controlled trial. Setting The study was performed in a tertiary-care Veterans Affairs Medical Center in the USA. Patients Subjects undergoing screening or surveillance colonoscopy were enrolled. Interventions Subjects were randomised to undergo either CAC or SC. Main outcome measures The outcome measures were the proportion of subjects with at least one adenoma, the number of adenomas detected per subject, insertion time, caecal intubation rates and complications. Results 420 subjects were enrolled and included in the study (210 in each group). The proportion of subjects with at least one adenoma was higher with CAC compared to SC (69% vs 56%, p=0.009). CAC also detected a higher number of adenomas per subject (2.3 vs 1.4, p<0.001). The caecal intubation time was shorter with CAC (3.29 min vs 3.98 min, p<0.001). The caecal intubation rates were similar in the two groups (99% vs 98%, p=0.37). There were no complications associated with CAC or SC. Conclusions CAC detected a 13% higher number of subjects with at least one adenoma and 59% higher adenomas per subject. CAC is a safe, effective and practical means to improve adenoma detection rates. Clinical Trial Registration NCT 01211132.

Feasibility of MicroRNAs as Biomarkers for Barrett's Esophagus Progression: A Pilot Cross-Sectional, Phase 2 Biomarker Study

OBJECTIVES:Risk stratification of Barretts esophagus (BE) using biomarkers remains an important goal. We evaluated feasibility and clinical accuracy of novel microRNA (miRNA) biomarkers for prediction of BE dysplasia.METHODS:Paired fresh-frozen and hematoxylin/eosin specimens from a prospective tissue repository where only biopsies with the lesion of interest (i.e., intestinal metaplasia (IM) or high-grade dysplasia (HGD)/esophageal adenocarcinoma (EAC)) occupying >50% of biopsy area were included. Tissue miRNA expression was determined by microarrays and validated by quantitative reverse transcription-PCR (qRT-PCR). Three groups were compared—group A, IM tissues from BE patients without dysplasia; group B, IM tissues from group C patients; and group C, dysplastic tissues from BE patients with HGD/EAC.RESULTS:Overall, 22 BE patients, 11 with and without dysplasia (mean age 64±8.2 and 63±11.6 years, respectively, all Caucasian males) were evaluated. Nine miRNAs were identified by high-throughout analysis (miR-15b, -21, -192, -205, 486-5p, -584, -1246, let-7a, and -7d) and qRT-PCR confirmed expression of miR-15b, -21, 486-5p, and let-7a. Two of 4 miRNAs (miR-145 and -203, but not -196a and -375) previously described in BE patients also exhibited differential expression. Sensitivity and specificity of miRNAs for HGD/EAC were miR-15b: 87 and 80%, miR-21: 93 and 70%, miR-203: 87 and 90%, miR-486-5p: 82 and 55%, and miR-let-7a: 88 and 70%. MiRNA-15b, -21, and -203 exhibited field effects (i.e., groups A and B tissues while histologically similar yet exhibited different miRNA expression).CONCLUSIONS:This pilot study demonstrates feasibility of miRNAs to discriminate BE patients with and without dysplasia with reasonable clinical accuracy. However, the specific miRNAs need to be evaluated further in future prospective trials.

A prospective, single-blind, randomized, controlled trial of EUS-guided FNA with and without a stylet.

BACKGROUND Most endosonographers use an EUS needle with an internal stylet during EUS-guided FNA (EUS-FNA). Reinserting the stylet into the needle after every pass is tedious and time-consuming, and there are no data to suggest that it improves the quality of the cytology specimen. OBJECTIVE To compare the samples obtained by EUS-FNA with and without a stylet for (1) the degree of cellularity, adequacy, contamination, and amount of blood and (2) the diagnostic yield of malignancy. DESIGN Prospective,single-blind, randomized, controlled trial. SETTING Two tertiary care referral centers. PATIENTS Patients referred for EUS-FNA of solid lesions. INTERVENTION Patients underwent EUS-FNA of the solid lesions, and 2 passes each were made with a stylet and without a stylet in the needle. The order of the passes was randomized, and the cytopathologists reviewing the slides were blinded to the stylet status of passes. MAIN OUTCOME MEASUREMENTS Degree of cellularity, adequacy, contamination, amount of blood, and the diagnostic yield of malignancy in the specimens. RESULTS A total of 101 patients with 118 lesions were included in final analysis; 236 FNA passes were made, each with and without a stylet. No significant differences were seen in the cellularity (P = .98), adequacy of the specimen (P = .26), contamination (P = .92), or significant amount of blood (P = .61) between specimens obtained with and without a stylet. The diagnostic yield of malignancy was 55 of 236 specimens (23%) in the with-stylet group compared with 66 of 236 specimens (28%) in the without-stylet group (P = .29). LIMITATIONS Endosonographers were not blinded to the stylet status of the passes. CONCLUSIONS Using a stylet during EUS-FNA does not confer any significant advantage with regard to the quality of the specimen obtained or the diagnostic yield of malignancy. ( CLINICAL TRIAL REGISTRATION NUMBER NCT 01213290).

Weight loss can lead to resolution of gastroesophageal reflux disease symptoms: A prospective intervention trial

Objective:Weight gain is an important risk factor for gastroesophageal reflux disease (GERD); however, whether weight loss can lead to resolution of GERD symptoms is not clear. Our aim was to measure the impact of weight loss on GERD symptoms.

Adequacy of esophageal squamous mucosa specimens obtained during endoscopy: are standard biopsies sufficient for postablation surveillance in Barrett's esophagus?

BACKGROUND After endoscopic eradication therapy (EET) for Barretts esophagus (BE), surveillance of residual/recurrent intestinal metaplasia/dysplasia including subsquamous tissue is performed by using biopsy forceps. OBJECTIVE The goal of this study was to compare the adequacy of biopsy specimens obtained from neo-squamous (post-EET patients) and native (non-BE patients) squamous mucosa. DESIGN A case-control study using squamous biopsy specimens obtained at 2 tertiary referral centers was conducted. INTERVENTIONS Two experienced GI pathologists reviewed specimens from patients with neo- (post-EET patients) and native (non-BE patients) squamous mucosa in a blinded fashion after developing standardized criteria to assess tissue depth. MAIN OUTCOME MEASUREMENTS The primary outcome was the proportion of biopsy specimens that contained any amount of lamina propria. RESULTS A total of 193 biopsy specimens (1692 tissue pieces) from 104 patients were reviewed: 163 neo- and 30 native squamous. Of all biopsy specimens, only 37% contained any amount of lamina propria, and, furthermore, fewer than 4% of specimens had sufficient lamina propria (ie, more than two thirds of the entire squamous tissue present). When examining individual squamous tissue pieces, fewer than 11% contained lamina propria. No statistically significant differences in the presence of lamina propria were detected between neo- and native squamous mucosa. CONCLUSION The majority of esophageal squamous biopsy specimens obtained during endoscopy do not demonstrate lamina propria and subepithelial structures. This is true for both neo- and native squamous mucosa. Biopsy specimens of neo-squamous mucosa obtained after EET appear to be inadequate to exclude subsquamous intestinal metaplasia/dysplasia because lamina propria is not present in more than 60% of specimens. This has larger implications in the clinical management of BE patients after EET.