Massively Parallel Sequencing of Esophageal Brushings Enables an Aneuploidy-Based Classification of Patients With Barrett's Esophagus.

BACKGROUND & AIMS: Aneuploidy has been proposed as a tool to assess progression in patients with Barrett's esophagus (BE), but has heretofore required multiple biopsies. We assessed whether a single esophageal brushing that widely sampled the esophagus could be combined with massively parallel sequencing to characterize aneuploidy and identify patients with disease progression to dysplasia or cancer. METHODS: Esophageal brushings were obtained from patients without BE, with non-dysplastic BE (NDBE), low-grade dysplasia (LGD), high-grade dysplasia (HGD), or adenocarcinoma (EAC). To assess aneuploidy, we used RealSeqS, a technique that uses a single primer pair to interrogate ∼350,000 genome-spanning regions and identify specific chromosome arm alterations. A classifier to distinguish NDBE from EAC was trained on results from 79 patients. An independent validation cohort of 268 subjects was used to test the classifier at distinguishing patients at successive phases of BE progression. RESULTS: Aneuploidy progression was associated with gains of 1q, 12p, and 20q and losses on 9p and 17p. The entire chromosome 8q was often gained in NDBE, whereas focal gain of 8q24 was identified only when there was dysplasia. Among validation subjects, a classifier incorporating these features with a global measure of aneuploidy scored positive in 96% of EAC, 68% of HGD, but only 7% of NDBE. CONCLUSIONS: RealSeqS analysis of esophageal brushings provides a practical and sensitive method to determine aneuploidy in BE patients. It identifies specific chromosome changes that occur early in NDBE and others that occur late and mark progression to dysplasia. The clinical implications of this approach can now be tested in prospective trials.

Maximizing the Effectiveness of Colonoscopy in the Prevention of Colorectal Cancer.

Colonoscopy is a proven screening test for colorectal cancer; maximizing its effectiveness is the best way to decrease interval colorectal cancer. The adenoma detection rate can be improved by monitoring physician detection rates. Assistive devices and innovative endoscopic equipment may also decrease adenoma miss rates. Complete polypectomy of adenomatous lesions and recommending the proper date for the next examination are important considerations. Advanced polypectomy techniques including endoscopic mucosal resection and endoscopic mucosal dissection have a clear role in the nonsurgical management of large laterally spreading adenomatous polyps that previously would have required surgical resection.

Cryotherapy and Radiofrequency Ablation for Eradication of Barrett's Esophagus with Dysplasia or Intramucosal Cancer.

BACKGROUND AND AIMS: Endoscopic ablation therapy has become the mainstay of treatment of Barrett's associated dysplasia and intramucosal cancer (IMC). The widely available techniques for ablation are radiofrequency ablation (RFA) and cryotherapy. Our aim was to compare eradication rates of metaplasia and dysplasia with both these modalities. PATIENTS AND METHODS: Retrospective review of prospectively collected database of patients who underwent endoscopic therapy for Barrett's dysplasia or IMC from 2006 to 2011 was performed. Demographic features, comorbidities, and endoscopic data including length of Barrett's segment, hiatal hernia size, interventions during the endoscopy and histological results were reviewed. RESULTS: Among 154 patients included, 73 patients were in the RFA and 81 patients were in the cryotherapy group. There was complete eradication of intestinal metaplasia (CE-IM) in 81 (52.6%), complete eradication of dysplasia (CE-D) in 133 (86.4%), and persistent dysplasia or cancer in 19 patients (12.3%). Compared to RFA, cryotherapy patients were found to be older and less likely to have undergone endoscopic mucosal resection. On multivariate analysis, patients who underwent RFA had a threefold higher odds of having CE-IM than those who underwent cryotherapy (odds ratio [OR] 2.9, 95% confidence interval [CI] 1.4-6.0, p = 0.004), but CE-D were similar between the two groups (OR 1.7, 95% CI 0.66-4.3, p = 0.28). CONCLUSIONS: Endoscopic therapy is highly effective in eradication of Barrett's associated neoplasia. Patients who underwent cryotherapy were equally likely to achieve CE-D but not CE-IM than patients who underwent RFA. Patient characteristics and preferences may effect choice of treatment selection and outcomes.

Correlation between endoscopic forceps biopsies and endoscopic mucosal resection with endoscopic ultrasound in patients with Barrett's esophagus with high-grade dysplasia and early cancer.

BACKGROUND: Patients with Barrett's esophagus (BE) and high-grade dysplasia (HGD) or intramucosal cancer (IMC) on endoscopic forceps biopsies are referred to endoscopic therapy even though forceps biopsies do not reflect the disease extent accurately. Endoscopic mucosal resection (EMR) and endoscopic ultrasound (EUS) are frequently used for staging prior to endoscopic therapy. Our aims were to evaluate: (1) if endoscopic forceps biopsies correlated with EMR histology in these patients; (2) the utility of EUS compared to EMR; and (3) if accuracy of EUS varied based on grade of differentiation of tumor. METHODS: This is a retrospective review of patients referred to endoscopic therapy of BE with HGD or early esophageal adenocarcinoma (EAC) who underwent EMR from 2006 to 2011. Age, race, sex, length of Barrett's segment, hiatal hernia size, number of endoscopies and biopsy results and EUS findings were abstracted. RESULTS: A total of 151 patients underwent EMR. In 50 % (75/151) of patients, EMR histology was consistent with endoscopic forceps biopsy findings. EMR resulted in change in diagnosis with upstaging in 21 % (32/151) and downstaging in 29 % (44/151). In patients with HGD on EMR, EUS staging was T0 in 74.1 % (23/31) but upstaged in 25.8 % (8/31). In patients with IMC on EMR, EUS findings were T1a in 23.6 % (9/38), upstaged in 18.4 % (7/38) and downstaged in 57.8 % (22/38). EUS accurately identified EMR histology in all submucosal cancers. Grade of differentiation was reported in 24 cancers on EMR histology. There was no correlation between grade and EUS staging. CONCLUSIONS: EUS is of limited utility in accurate staging of BE patients with HGD or early EAC. Endoscopic forceps biopsy correlated with EMR findings in only 50 % of patients. Irrespective of the endoscopic forceps biopsy results, all BE patients with visible lesions should be referred to EMR.

Association of procedure length on outcomes and adverse events of endoscopic retrograde cholangiopancreatography.

OBJECTIVE: The aims of this study were to determine the effects of length of procedure on endoscopic retrograde cholangiopancreatography (ERCP) outcomes and adverse events. METHODS: All ERCP procedures, performed by experienced advanced endoscopists, in patients without prior papillary intervention from 2006 to 2008 were reviewed. Procedures were arbitrarily divided into two groups: shorter procedures (SP), with a duration shorter than the overall mean procedure length, and longer procedures (LP), with a duration longer than overall mean procedure length. Length of procedure was defined as the time from endoscope insertion to endoscope removal. RESULTS: Two hundred and ninety-five procedures were included in the analysis. Mean procedure length was 45.6 ± 30.1 min. One hundred and seventy-seven procedures (60%) were SP and 118 (40%) were LP. There were no differences between the groups with regard to patients' ages, genders, race, or trainee participation. SP cases were more likely to be biliary vs pancreatic or bi-ductal evaluations (P = 0.03). LP had significantly higher complexity scores (34% with >3 vs 13%; P = 0.046) and were more likely to require pre-cut papillotomy (39% vs 15%; P < 0.001). There was no significant difference between the groups in overall completion rates (91.5% LP vs 96% SP; P = 0.10) or adverse events (10.2% LP vs 6.2% SP; P = 0.21). However, LP cases were associated with higher rates of post-ERCP bleeding (4.2% vs 0.6%; P = 0.029). CONCLUSION: There was no significant difference in outcomes or overall adverse events between shorter and longer ERCP procedures. However, longer procedures were associated with higher procedure complexity, higher utilization of pre-cut technique, and increased risk of bleeding.

Diagnosis and management of gallbladder calculus disease.

BACKGROUND: The number and rate of cholecystectomy are increasing worldwide, although indications for operative treatment remain empirical, and several issues in the understanding of the condition are not concisely outlined. Our intention is to summarize and interpret current opinion regarding the indications and timing of cholecystectomy in calculous gallbladder disease. METHODS: Publications concerned with gallstone disease and related topics were searched for in MEDLINE using PubMed and summarized according to clinical scenarios with an emphasis on recent research. RESULTS: Only one randomized controlled trial has investigated the management (conservative vs. surgery) of patients with acute cholecystitis and several have compared early with deferred surgery. Two RCTs have examined treatment of uncomplicated, symptomatic gallstone disease. Apart from these, the overwhelming majority of publications are retrospective case series. CONCLUSIONS: Recent literature confirms that cholecystectomy for an asymptomatic or incidental gallstone is not justified. Symptomatic, uncomplicated gallstone disease may be classified into four severity groups based on severity and frequency of pain attacks, which may guide indication for cholecystectomy. Most patients below the age of 70 seem to prefer operative treatment. Acute cholecystitis may be treated with early operation if reduction of hospital days is an issue. Patients older than 70 years with significant comorbidities may forego surgical treatment without undue hazard. Symptoms following cholecystectomy remain in 25% or more and recent evidence suggest these are caused by a functional gastrointestinal disorder.

Post-cholecystectomy symptoms were caused by persistence of a functional gastrointestinal disorder.

AIM: To classify gallstone disease as a basis for assessment of post-cholecystectomy symptoms. METHODS: One hundred and fifty three patients with a clinical and ultrasonographic diagnosis of gallstones filled out a structured questionnaire on abdominal pain symptoms and functional gastrointestinal disorder (FGID) before and at six months after cholecystectomy. Symptom frequency groups (SFG) were categorized according to frequency of pain attacks. According to certain pain characteristics in gallstone patients, a gallstone symptom score was accorded on a scale from one to ten. A visual analogue scale was used to quantify pain. Operative specimens were examined for size and magnitude of stone contents as well as presence of bacteria. Follow-up took place after six months with either a consultation or via a mailed questionnaire. Results were compared with those obtained pre-operatively to describe and analyze symptomatic outcome. RESULTS: SFG groups were categorized as severe (24.2%), moderate (38.6%), and mild (22.2%) attack frequency, and a chronic pain condition (15%). Pain was cured or improved in about 90% of patients and two-thirds of patients obtained complete symptom relief. Patients with the most frequent pain episodes were less likely to obtain symptom relief. FGID was present in 88% of patients pre-operatively and in 57% post-operatively (P = 0.244). Those that became asymptomatic or improved with regard to pain also had most relief from FGID (P = 0.001). No pre-operative FGID meant almost complete cure. CONCLUSION: Only one third of patients with FGID experienced postoperative relief, indicating that FGID was a dominant cause of post-cholecystectomy 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 Barrett's 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.

Effect of the time of day on the success and adverse events of ERCP.

BACKGROUND: Physician fatigue and decreased concentration have been proposed as causes of lower completion and adenoma detection rates in afternoon colonoscopies compared with morning colonoscopies. ERCP is a technically demanding and highly operator-dependent procedure, and its success may similarly be affected in the afternoon compared with the morning. OBJECTIVE: To compare cannulation success and adverse events between ERCP procedures performed in the morning and afternoon. DESIGN: Retrospective cohort study. SETTING: Tertiary referral center. PATIENTS: Patients with no previous papillary intervention who underwent ERCP at our institution between November 2006 and November 2008. MAIN OUTCOME MEASUREMENTS: Cannulation success, procedure completion rates, length of procedures, and adverse events. RESULTS: A total of 296 patients were studied; 114 patients (38.5%) underwent a procedure in the morning and 182 patients (61.5%) underwent a procedure in the afternoon. There were 139 male patients (47.0%). The mean patient age was 59.1 years. The deep cannulation success rate was 95.3% overall, with similar rates when performed in the morning (98.3%) and afternoon (94.0%) (P = .08). When the start time was evaluated as a continuous hour-by-hour variable, there was also no significant difference in deep cannulation success rates (P = .30). Procedure completion rates were similar in both groups (morning, 93.9%; 94.0%, afternoon; P = .97). Adverse events (8.8% for morning procedures vs 7.1% for afternoon procedures, P = .61) and length of procedures (40 minutes for morning procedures vs 40 minutes for afternoon procedures, P = .87) were also similar between the 2 groups. LIMITATIONS: Small sample size and retrospective study. CONCLUSIONS: The timing of ERCP, morning versus afternoon, does not seem to affect cannulation success, procedure completion rates, length of procedures, or adverse events.

Durability of radiofrequency ablation in Barrett's esophagus with dysplasia.

BACKGROUND & AIMS: Radiofrequency ablation (RFA) can eradicate dysplasia and intestinal metaplasia in patients with dysplastic Barrett's esophagus (BE), and reduce rates of esophageal adenocarcinoma. We assessed long-term rates of eradication, durability of neosquamous epithelium, disease progression, and safety of RFA in patients with dysplastic BE. METHODS: We performed a randomized trial of 127 subjects with dysplastic BE; after cross-over subjects were included, 119 received RFA. Subjects were followed for a mean time of 3.05 years; the study was extended to 5 years for patients with eradication of intestinal metaplasia at 2 years. Outcomes included eradication of dysplasia or intestinal metaplasia after 2 and 3 years, durability of response, disease progression, and adverse events. RESULTS: After 2 years, 101 of 106 patients had complete eradication of all dysplasia (95%) and 99 of 106 had eradication of intestinal metaplasia (93%). After 2 years, among subjects with initial low-grade dysplasia, all dysplasia was eradicated in 51 of 52 (98%) and intestinal metaplasia was eradicated in 51 of 52 (98%); among subjects with initial high-grade dysplasia, all dysplasia was eradicated in 50 of 54 (93%) and intestinal metaplasia was eradicated in 48 of 54 (89%). After 3 years, dysplasia was eradicated in 55 of 56 of subjects (98%) and intestinal metaplasia was eradicated in 51 of 56 (91%). Kaplan-Meier analysis showed that dysplasia remained eradicated in >85% of patients and intestinal metaplasia in >75%, without maintenance RFA. Serious adverse events occurred in 4 of 119 subjects (3.4%); the rate of stricture was 7.6%. The rate of esophageal adenocarcinoma was 1 per 181 patient-years (0.55%/patient-years); there was no cancer-related morbidity or mortality. The annual rate of any neoplastic progression was 1 per 73 patient-years (1.37%/patient-years). CONCLUSIONS: In subjects with dysplastic BE, RFA therapy has an acceptable safety profile, is durable, and is associated with a low rate of disease progression, for up to 3 years.

Cryotherapy for Barrett's esophagus and esophageal cancer.

PURPOSE OF REVIEW: To summarize the recent literature on endoscopic spray cryotherapy for the treatment of Barrett's esophagus and esophageal cancer. RECENT FINDINGS: Endoscopic spray cryotherapy is a relatively new ablative modality for the treatment of gastrointestinal diseases. Spray cryotherapy rapidly cools tissues by spraying them with either liquid nitrogen or rapidly expanding carbon dioxide gas. Initial, nonrandomized and uncontrolled studies show success rates comparable to other ablative modalities for the treatment of Barrett's esophagus with high-grade dysplasia, with complete eradication of dysplasia seen in 87-96% and complete eradication of intestinal metaplasia in 57-96% of treated patients. In early-stage esophageal cancer, spray cryotherapy appears to have a unique role, eliminating mucosal cancer in 75% of patients, including those who have failed other modalities. Patient tolerance of the procedure is very good. Limitations of current studies include small sample sizes and short durations of follow-up, and further studies are needed to validate the promising early results. SUMMARY: Endoscopic spray cryotherapy is a promising ablative modality for treatment of Barrett's esophagus and esophageal cancer.

Hypoxemia during moderate sedation for gastrointestinal endoscopy: causes and associations.

BACKGROUND/AIMS: Although prolonged hypoxemia (henceforth referred to as hypoxemia) is not uncommon during moderate sedation for endoscopy, there are only sparse data regarding its relationship with medications, endoscopic intubations and ventilation patterns. We aimed to study these relationships. METHODS: 123 patients enrolled in the control arm of a randomized trial of ventilation monitoring during endoscopy were analyzed. Hypoxemia was defined as oxygen saturation of <90% for ≥15 s, and apnea as lack of respiratory activity for ≥15 s. RESULTS: There were 132 hypoxemic events; 46 (35%) and 112 (85%) events occurred within 1 and 5 min of medication administration/endoscopic intubations, and conversely, 46/638 (7%) and 112/638 (18%) of all medication administration/endoscopic intubations led to hypoxemia in 1 and 5 min, respectively. Apnea, abnormal ventilation and normal ventilation were associated with 36, 30 and 34% of all hypoxemia events, respectively. However, only 101/268 (38%) apnea/abnormal ventilation events led to hypoxemia. Significant predictors of apnea were total dose of meperidine/fentanyl 1.3 (1.02-1.6) and total dose of midazolam 0.84 (0.71-0.99). CONCLUSIONS: Hypoxemia occurs typically within 5 min of medication administration or endoscope intubation and only one third of all apnea/abnormal ventilation events eventually lead to hypoxemia.

Esophagectomy for clinical high-grade dysplasia.

OBJECTIVE: Esophageal high-grade dysplasia/tumor in situ (HGD/Tis) management is in evolution. However, treatment decisions must be made on clinical staging, which may not reflect pathologic staging. Long-term randomized trial information, large treatment series, and cancer registry data do not exist to guide treatment decisions. This evaluation of esophagectomy for clinically diagnosed HGD (cHGD) serves as a reference point for future therapies. METHODS: From a 1296-patient prospective esophagectomy database, 134 patients were diagnosed with cHGD (HGD without detectable mass at biopsy) before esophagectomy (mean age 60 ± 10 years, 120 [90%] male, and 132 [99%] Caucasian). Median follow-up was 7.1 years. RESULTS: Histopathologic cell type was adenocarcinoma in 124 (93%) patients. Pathologic T (tumor) classification (pT) was 77 (57%) pHGD, 46 (34%) pT1a, eight (6%) pT1b, and one each (1%) indefinite for dysplasia, low-grade dysplasia, and pT2. Three (2%) had regional lymph node metastases (pT1N1M0). There was one hospital death (0.7%) and four deaths from recurrent cancer. Survival at 1 month, 6 months, and 5, 10, and 15 years was 99%, 97%, 96%, 94%, 82%, and 75%, respectively. Survival was at least that of a matched population. Older age and poor lung function predicted worse survival. Sixteen patients developed nonesophageal cancers, 6.1 times greater than expected. CONCLUSIONS: Despite clinical staging errors, survival following esophagectomy for cHGD is excellent. The diagnosis of cHGD does not alter survival referenced to the matched general population; however, cHGD patients appear to be at increased risk of second nonesophageal primary cancers. Therapy for cHGD should be patient specific, because patient and not cancer characteristics determine survival.

Does anesthesiologist-directed sedation for ERCP improve deep cannulation and complication rates?

OBJECTIVES: While some gastroenterologists provide their own sedation for endoscopic retrograde cholangiopancreatography (ERCP), others utilize anesthesiologists. There is limited information comparing cannulation success and complication rates between these two approaches. Theoretically, anesthesiologist-directed sedation (ADS) may lead to an improved deep cannulation rate by virtue of using deeper and more constant levels of sedation and by removing the minute-by-minute medication management and physiologic monitoring responsibilities from the endoscopy team. AIMS: To compare ERCP deep cannulation success and complications between gastroenterologist-directed sedation (GDS) and ADS. METHODS: All ERCPs completed by senior advanced endoscopists at a tertiary referral center over a 2-year period were reviewed. During the first year, all ERCP sedation was performed with GDS utilizing a narcotic and a benzodiazepine. Due to a change in division policy and practice, during the second year, all ERCP sedation was provided by ADS. Patients with prior papillary interventions were excluded. Demographics, procedure indications, deep cannulation success, sedation provider, and procedural complications were recorded. RESULTS: A total of 367 patients were studied: 178 (48.5%) GDS and 189 (51.5%) ADS. There was no difference in the groups with respect to race, age, and gender. Four patients (2.3%) in the GDS group could not be sedated. There were two deaths, one in each group; one death was due to cholangitis/sepsis and the other was due to post-ERCP pancreatitis. The overall cannulation success rates were similar between the two groups (94.4% vs. 95.2%, P = 0.36). CONCLUSIONS: Deep ductal cannulation rates between GDS and ADS are similar.

Safety and efficacy of endoscopic spray cryotherapy for Barrett's esophagus with high-grade dysplasia.

BACKGROUND: Endoscopic ablation to treat Barrett's esophagus (BE) with high-grade dysplasia (HGD) is associated with a decreased incidence of esophageal adenocarcinoma. Endoscopic spray cryotherapy (CRYO) demonstrates promising preliminary data. OBJECTIVE: To assess the safety and efficacy of CRYO in BE with HGD. DESIGN: Multicenter, retrospective cohort study. SETTING: Nine academic and community centers; treatment period, 2007 to 2009. PATIENTS: Subjects with HGD confirmed by 2 pathologists. Previous EMR was allowed if residual HGD remained. INTERVENTIONS: CRYO with follow-up biopsies. MAIN OUTCOME MEASUREMENTS: Complete eradication of HGD with persistent low-grade dysplasia, complete eradication of all dysplasia with persistent nondysplastic intestinal metaplasia, and complete eradication of all intestinal metaplasia. RESULTS: Ninety-eight subjects (mean age 65.4 years, 83% male) with BE and HGD (mean length 5.3 cm) underwent 333 treatments (mean 3.4 treatments per subject). There were no esophageal perforations. Strictures developed in 3 subjects. Two subjects reported severe chest pain managed with oral narcotics. One subject was hospitalized for bright red blood per rectum. Sixty subjects had completed all planned CRYO treatments and were included in the efficacy analysis. Fifty-eight subjects (97%) had complete eradication of HGD, 52 (87%) had complete eradication of all dysplasia with persistent nondysplastic intestinal metaplasia, and 34 (57%) had complete eradication of all intestinal metaplasia. Subsquamous BE was found in 2 subjects (3%). LIMITATIONS: Nonrandomized, retrospective study with no control group, short follow-up (10.5 months), lack of centralized pathology, and use of surrogate outcome for decreased cancer risk. CONCLUSIONS: CRYO is a safe and well-tolerated therapy for BE and HGD. Short-term results suggest that CRYO is highly effective in eradicating HGD.