Barrett's Esophagus

Number: 0728

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses Barrett's esophagus.

1. Medical Necessity

   Aetna considers radiofrequency ablation medically necessary for the treatment of members with Barrett's esophagus (BE) who have histological confirmation of low-grade dysplasia (LGD) by 2 or more endoscopies 3 or more months apart.

   Aetna considers any of the following interventions medically necessary for the treatment of members with BE who have high-grade dysplasia (HGD) by biopsy:

   • Endoscopic mucosal resection
   • Esophagectomy
   • Fundoplication
   • Photodynamic therapy
   • Radiofrequency ablation.

2. Experimental and Investigational

   Aetna considers any of the following interventions experimental and investigational for the treatment of members with BE:

   • Argon plasma coagulation
   • Chemoradiation therapy
   • Cryotherapy / cryoablation
   • Gastrectomy
   • Laser therapy
   • Multi-polar electro-coagulation
   • Ultrasonic therapy.

   Aetna considers the following experimental and investigational because their effectiveness for these indications has not been established:

   • Artificial intelligence for detection of early neoplasia in BE
   • Barrett’s esophagus fluorescence in situ hybridization (FISH) assay (e.g., MolDX)
   • Bariatric surgery (e.g., gastric bypass) for the treatment for BE  (see CPB 0157 - Obesity Surgery for medical necessity criteria for bariatric surgery)
   • Biomarker panels (e.g., genetic biomarkers including mutational load, methylation DNA biomarkers (e.g., EsoGuard) and microRNA [tissue biomarkers]) for the management of BE
   • Capsule endoscopy of the esophagus for the management of BE
   • Confocal laser endomicroscopy and Fuji Intelligent Chromo Endoscopy (FICE) for detecting dysplasia in BE and in post-ablation BE
   • Cytosponge for screening and surveillance of BE
   • Envisage Test (DNA methylation) for the determination of progression of pre-cancerous BE to esophageal cancer
   • Esopredict for predicting progression of Barrett’s esophagus to high-grade dysplasia or cancer
   • Evaluation of esophageal microbiota and mitochondrial DNA deletions for detection of BE
   • Extracellular microRNAs (miRNAs) as biomarkers for BE
   • Genome-wide association studies for early intervention or surveillance of BE
   • Measurements of serum levels of adipokines and insulin for the management of BE
   • Optical coherence tomography for evaluation of BE
   • p53 as a genomic biomarker for prediction of neoplastic progression in BE
   • Polygenic risk score for early intervention or surveillance of BE
   • SOX2 expression testing for prediction of neoplastic progression in BE
   • TissueCypher for determining the risk of progression from BE to HGD or cancer
   • Use of markers of intestinal phenotype (CDX2, Das-1, Hep Par 1, SOX9, and villin)
   • Use of mucin glycoprotein immunostains
   • Use of mutation analysis for risk assessment and diagnosis of BE
   • Volumetric laser endomicroscopy for evaluation of BE.

3. Related Policies

   • CPB 0157 - Obesity Surgery
   • CPB 0375 - Photodynamic Therapy,
   • CPB 0492 - Radiofrequency Tumor Ablation,
   • CPB 0588 - Capsule Endoscopy,
   • CPB 0686 - Oral and Esophageal Brush Biopsy - for wide-area transepithelial sampling (WATS) for surveillance of BE
   • CPB 0738 - Upper Gastrointestinal Endoscopy and Gastrointestinal Biopsy - for Endoscopic Submucosal Dissection (ESD) for the treatment of Barrett's esophagus
   • CPB 0783 - In Vivo Analysis of Gastro-Intestinal and Urothelial Lesions

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
CPT codes covered if selection criteria are met:
43100	Excision of lesion, esophagus, with primary repair; cervical approach
43101	thoracic or abdominal approach
43107	Total or near esophagectomy, without thoracotomy; with pharyngogastrostomy or cervical esophagogastrostomy, with or without pyloroplasty (transhiatal)
43108	with colon interposition or small intestine reconstruction, including intestine mobilization, preparation, and anastamosis(es)
43112	Total or near esophagectomy, with thoracotomy; with pharyngogastrostomy or cervical esophagogastrostomy, with or without pyloroplasty
43113	with colon interposition or small intestine reconstruction, including intestine mobilization, preparation, and anastamosis(es)
43116	Partial esophagectomy, cervical, with free intestinal graft, including microvascular anastamosis, obtaining the graft and intestinal reconstruction
43117	Partial esophagectomy, distal two-thirds, with thoracotomy and separate abdominal incision, with or without proximal gastrectomy; with thoracic esophagogastrostomy, with or without pyloroplasty (Ivor Lewis)
43118	with colon interposition or small intestine reconstruction, including intestine mobilization, preparation, and anastamosis(es)
43121	Partial esophagectomy, distal two-thirds, with thoracotomy only, with or without proximal gastrectomy, with thoracic esophagogastrostomy, with or without pyloroplasty
43122	Partial esophagectomy, thoracoabdominal or abdominal approach, with or without proximal gastrectomy; with esophagogastrostomy, with or without pyloroplasty
43123	with colon interposition or small intestine reconstruction, including intestine mobilization, preparation, and anastamosis(es)
43124	Total or partial esophagectomy, without reconstruction (any approach), with cervical esophagostomy
43211	Esophagoscopy, flexible, transoral; with endoscopic mucosal resection
43217	Esophagoscopy, rigid or flexible; with removal of tumor(s), polyp(s), or other lesion(s) by snare technique
43229	Esophagoscopy, flexible, transoral; with ablation of tumor(s), polyp(s), or other lesion(s) (includes pre- and post-dilation and guide wire passage, when performed) [radiofrequency ablation]
43254	Esophagogastroduodenoscopy, flexible, transoral; with endoscopic mucosal resection
43270	Esophagogastroduodenoscopy, flexible, transoral; with ablation of tumor(s), polyp(s), or other lesion(s) (includes pre- and post-dilation and guide wire passage, when performed) [radiofrequency ablation]
43279	Laparoscopy, surgical, esophagomyotomy (Heller type), with fundoplasty, when performed
43280	Laparoscopy, surgical, esophagogastric fundoplasty (eg, Nissen, Toupet procedures)
43286	Esophagectomy, total or near total, with laparoscopic mobilization of the abdominal and mediastinal esophagus and proximal gastrectomy, with laparoscopic pyloric drainage procedure if performed, with open cervical pharyngogastrostomy or esophagogastrostomy (ie, laparoscopic transhiatal esophagectomy)
43287	Esophagectomy, distal two-thirds, with laparoscopic mobilization of the abdominal and lower mediastinal esophagus and proximal gastrectomy, with laparoscopic pyloric drainage procedure if performed, with separate thoracoscopic mobilization of the middle and upper mediastinal esophagus and thoracic esophagogastrostomy (ie, laparoscopic thoracoscopic esophagectomy, Ivor Lewis esophagectomy)
43288	Esophagectomy, total or near total, with thoracoscopic mobilization of the upper, middle, and lower mediastinal esophagus, with separate laparoscopic proximal gastrectomy, with laparoscopic pyloric drainage procedure if performed, with open cervical pharyngogastrostomy or esophagogastrostomy (ie, thoracoscopic, laparoscopic and cervical incision esophagectomy, McKeown esophagectomy, tri-incisional esophagectomy)
43325	Esophagogastric fundoplasty; with fundic patch (Thal-Nissen procedure)
43327	Esophagogastric fundoplasty partial or complete; laparotomy
43328	thoracotomy
+43338	Esophageal lengthening procedure (eg collis gastroplasty or wedge gastroplasty) (list separately in addition to code for primary procedure)
+ 96570	Photodynamic therapy by endoscopic application of light to ablate abnormal tissue via activation of photosensitive drug(s); first 30 minutes (List separately in addition to code for endoscopy or bronchoscopy procedures of lung and esophagus)
+ 96571	each additional 15 minutes (List separately in addition to code for endoscopy or bronchoscopy procedures of lung and esophagus)
CPT codes not covered for indications listed in the CPB:
Optical coherence tomography, Evaluation of esophageal microbiota and mitochondrial DNA deletions, polygenic risk score, Extracellular microRNAs as biomarker, Artificial intelligence for detection of early neoplasia in BE - no specific code :
0108U	Gastroenterology (Barrett’s esophagus), whole slide–digital imaging, including morphometric analysis, computer-assisted quantitative immunolabeling of 9 protein biomarkers (p16, AMACR, p53,CD68, COX-2, CD45RO, HIF1a, HER-2, K20) and morphology, formalin-fixed paraffin-embedded tissue, algorithm reported as risk of progression to high-grade dysplasia or cancer
0114U	Gastroenterology (Barrett’s esophagus), VIMand CCNA1 methylation analysis, esophageal cells, algorithm reported as likelihood for Barrett’s esophagus
0398U	Gastroenterology (Barrett esophagus), P16, RUNX3, HPP1, and FBN1 DNA methylation analysis using PCR, formalin-fixed paraffin-embedded (FFPE) tissue, algorithm reported as risk score for progression to high-grade dysplasia or cancer as a risk score for progression to high-grade dysplasia or esophageal cancer
43206	Esophagoscopy, flexible, transoral; with optical endomicroscopy
43252	Esophagogastroduodenoscopy, flexible, transoral; with optical endomicroscopy
43620	Gastrectomy, total; with esophagoenterostomy
43621	Gastrectomy, total; with Roux-en-Y reconstruction
43622	Gastrectomy, total; with formation of intestinal pouch, any type
43631	Gastrectomy, partial, distal; with gastroduodenostomy
43632	Gastrectomy, partial, distal; with gastrojejunostomy
43633	Gastrectomy, partial, distal; with Roux-en-Y reconstruction
43634	Gastrectomy, partial, distal; with formation of intestinal pouch
43644	Laparoscopy, surgical, gastric restrictive procedure; with gastric bypass and Roux-en-Y gastroenterostomy (roux limb 150 cm or less)
43645	Laparoscopy, surgical, gastric restrictive procedure; with gastric bypass and small intestine reconstruction to limit absorption
43770 - 43775	Bariatric Surgery - Laparoscopy
43842 - 43848	Gastric restrictive procedure, gastric bypass
43842 - 43848	Gastric restrictive procedure, open port component only
81228	Cytogenomic constitutional (genome-wide) microarray analysis; interrogation of genomic regions for copy number variants (eg, Bacterial Artificial Chromosome [BAC] or oligo-based comparative genomic hybridization [CGH] microarray analysis)
81229	interrogation of genomic regions for copy number and single nucleotide polymorphism (SNP) variants for chromosomal abnormalities
81277	interrogation of genomic regions for copy number and loss-of-heterozygosity variants for chromosomal abnormalities
88364	In situ hybridization (eg, FISH), per specimen; each additional single probe stain procedure (List separately in addition to code for primary procedure)
88365	In situ hybridization (eg, FISH), per specimen; initial single probe stain procedure
88366	In situ hybridization (eg, FISH), per specimen; each multiplex probe stain procedure
91110	Gastrointestinal tract imaging, intraluminal (e.g., capsule endoscopy), esophagus through ileum, with physician interpretation and report
91111	Gastrointestinal tract imaging, intraluminal (e.g., capsule endoscopy), esophagus with physician interpretation and report
HCPCS codes covered if selection criteria are met:
J9600	Injection, porfimer sodium, 75 mg
HCPCS codes not covered for indications listed in the CPB:
Cytosponge - no specific code:
Q0083 - Q0085	Chemotherapy administration
ICD-10 codes covered if selection criteria are met:
K22.710	Barrett's esophagus with low grade dysplasia
K22.711	Barrett's esophagus with high grade dysplasia
K22.719	Barrett's esophagus with dysplasia, unspecified
ICD-10 codes not covered for indications listed in the CPB:
K22.70	Barrett's esophagus without dysplasia
Envisage test (DNA methylation):
CPT codes not covered for indications listed in the CPB:
0386U	Gastroenterology (Barrett’s esophagus), P16, RUNX3, HPP1, and FBN1 methylation analysis, prognostic and predictive algorithm reported as a risk score for progression to high-grade dysplasia or esophageal cancer
ICD-10 codes not covered for indications listed in the CPB:
C15.3 – C15.9	Malignant neoplasm of esophagus
K22.710 – K22.719	Barrett's esophagus with dysplasia

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Background

Barrett's esophagus (BE), a complication of chronic esophagitis, is characterized by metaplasia in the epithelial lining the esophagus.  The resulting cellular change is a pre-malignant phase that may lead to esophageal cancer.  While the exact cause of BE is unclear, it may arise as a result of damage to the esophagus caused by chronic gastric reflux secondary to gastro-esophageal reflux disease (GERD).  Thus, it is not surprising that BE is more commonly seen in patients with GERD.  In addition to GERD, other risk factors for BE include age (50 years or older), ethnicity (Caucasian), and male sex.  Diagnosis of BE is based on endoscopic biopsy of the esophagus.  Short-segment (less than 2 to 3 cm) and long-segment (greater than 2 to 3 cm) BE are distinguished solely on the length of metaplastic epithelium above the esophago-gastric junction (Rajan et al, 2001).  Emphasis is often placed on long-segment BE because these patients reportedly are at higher risk of developing adenocarcinoma than patients with short-segment BE.  However, Schnell and colleagues (1992) reported that patients with short-segment BE exhibited the same incidence of esophageal cancer as their counterparts with long-segment BE.  This provided a rationale for surveillance of patients with short-segment BE.

Barrett esophagus is a precancerous condition, and endoscopic biopsies to screen for high-grade dysplasia (HGD) or esophageal adenocarcinoma (EAC) are recommended based on previously reported incidence rates of HGD and EAC of 0.5% and 0.9%, respectively. However, recent study findings suggest that incidence rates are lower than previously reported. To estimate the incidence of HGD or EAC in patients with BE in a population-based cohort,Hvid-Jensen, et al. (2011) analyzed data from pathology and cancer registries on 11,028 patients in Denmark who had been diagnosed with BE through endoscopic biopsy. During a median 5.2 years of follow-up, the incidence of EAC was 1.2 cases per 1000 person-years). The incidence rate of HGD or EAC combined was 2.6 cases per 1000 person-years, yielding a standardized incidence ratio of 21.1. Diagnosis of low-grade dysplasia at baseline or during follow-up increased the risk for HGD or EAC fivefold. The incidence rate of EAC among patients without low-grade dysplasia was 1.0 case per 1000 person-years (95% CI, 0.7 to 1.3) (0.1% per person-year), and the incidence rate among those with low-grade dysplasia was 5.1 cases per 1000 person-years (95% CI, 3.0 to 8.6) (0.51% per person-year). Although this study reaffirms that BE is a significant risk factor for development of EAC, the absolute risk of 0.12% is considerably lower than earlier estimates of 0.8% and, more recently, 0.5%, which have been used as a basis for current screening and surveillance recommendations. Another recent, large population-based study estimated incidence of EAC at 0.13% (Bhat, et al., 2011). On the basis of these estimates, the relative risk for EAC in patients with BE compared with the general population drops from a previously cited range of 30 to 40 to approximately 11. In an accompanying editorial, Kahrilis (2011) commented that these risk estimates have been progressively decreasing as issues of publication bias, duplicate counting, and inclusion of prevalent cancers have been taken into account.

The key to the management of BE is the level of dysplasia that endoscopic biopsies reveal.  Most patients with BE will need to undergo future endoscopies to assure there is no progression of the condition.  For BE patients with no signs of dysplasia on 2 consecutive endoscopic biopsies, the American College of Gastroenterology (ACG) recommended a follow-up endoscopy at 3 years.  For patients with low-grade dysplasia (LGD) as the highest grade after a follow-up endoscopy with concentrated biopsies in the area of dysplasia, the ACG recommended annual endoscopy until there is no dysplasia.  The finding of high-grade dysplasia (HGD), believed to be the stage that occurs before esophageal cancer, requires a repeat endoscopy or intervention, depending on the extent of the dysplasia.  Focal HGD (less than 5 crypts) may be followed with 3-month surveillance (Sampliner, 2002).

The Society for Surgery of the Alimentary Tract (SSAT)’s guideline on the management of patients with BE (SSAT, 2002) stated that treatments include surveillance endoscopy and biopsy; medical therapy such as PPIs, H-2 receptor antagonists, and prokinetic agents; surgical anti-reflux procedure such as fundoplication (e.g., Nissen, Hill, Belsey, Dor, Toupet procedures); as well as photodynamic therapy (PDT); other energy sources; and excisional techniques.  While the SSAT guideline (2002) considered PDT, other energy sources, and excisional techniques as investigational procedures, an article on BE that appeared on the ACG’s website considers PDT an accepted option for the treatment of BE (Azodo and Romero, 2006).  It stated that if BE patients are diagnosed with HGD, there are 4 options:

1. Do nothing/surveillance endoscopy and biopsy. Note: HGD can regress to LGD or it may progress to esophageal cancer; or
2. Increase dosage of acid suppression medications, and have another endoscopic examination in 3 months ;or
3. Esophagectomy; or
4. PDT.

In June 2003, the United States Food and Drug Administration (FDA) approved PDT with Photofrin for the treatment of HGD in patients with BE who do not undergo esophagectomy.  The FDA approval is based on 2-year follow-up data from phase I and II clinical studies (Overholt, 2003).  The data indicated that patients who received PDT with Photofrin had an 80 % chance of being cancer-free, while controls had a 50 % chance of being cancer-free.  These researchers found that porfimer-PDT with supplemental Nd:YAG photo-ablation and continuous treatment with omeprazole reduced the length of Barrett's mucosa, and eliminated HGD.

Furthermore, PDT plus maintenance medical therapy has been reported to lower the incidence of esophageal cancer in BE patients.  In a randomized, controlled, phase III clinical trial, Overholt and colleagues (2005) examined the impact of porfimer sodium (POR) and PDT on patients with BE and with HGD.  A total of 485 patients were screened, with 208 in the intent-to-treat group and 202 in the safety population.  Patients were randomized on a 2:1 basis to compare PDT with POR plus omeprazole (PORPDT) with omeprazole only (OM).  The main outcome measure was complete HGD ablation occurring at any time during the study period.  There was a significant difference (p < 0.0001) in favor of PORPDT (77 %; [106/138]) compared with OM (39 %; [27/70]) in complete ablation of HGD at any time during the study period.  The occurrence of esophageal adenocarcinoma in the PORPDT group (13 %; n = 18) was markedly lower (p < 0.006) compared with the OM group (28 %; n = 20).  The safety profile showed 94 % of patients in the PORPDT group and 13 % of patients in the OM group had treatment-related adverse effects.  The authors concluded that PORPDT in conjunction with omeprazole is an effective therapy for ablating HGD in patients with BE and in reducing the incidence of esophageal adenocarcinoma.  In addition, Foroulis and Thorpe (2006) reported that PDT is effective in ablating HGD/intra-mucosal adenocarcinoma complicating BE in the majority of cases, while it also seems to be quite effective in treating T1b/limited T2 adenocarcinomas.

An assessment of PDT for Barrett’s esophagus by the National Institute for Clinical Excellence (2004) found “Current evidence on the safety of photodynamic therapy for high-grade dysplasia in Barrett's oesophagus appears adequate to support the use of this procedure.  Photodynamic therapy appears efficacious in downgrading dysplasia in Barrett's oesophagus, when used for the treatment of high-grade dysplasia (a premalignant lesion).  However, its efficacy in preventing the progression of Barrett's oesophagus to invasive cancer is not clear.”

Available guidelines on the management of BE indicated that surgery may be necessary if pharmacotherapy has failed.  Surgery may include fundoplication and esophagectomy.  Conio and colleagues (2005) stated that esophagectomy remains the standard treatment for patients with HGD and superficial adenocarcinoma.  However, since the morbidity and mortality rate for esophagectomy is high, and some patients are not surgical candidates, alternative treatments have gained popularity.  In this regard, ablative techniques such as argon plasma coagulation (APC), cryotherapy, laser therapy, multi-polar electro-coagulation (MPEC), PDT, radiofrequency ablation, and ultrasonic therapy have been employed for this purpose.  However, the effectiveness of many of these ablative interventions (except for PDT) has not been established especially the long-term control of cancer risk.

Endoscopic treatments offer an effective alternative to esophagectomy for patients with BE and HGD. Menon, et al. (2010) conducted a comprehensive literature search to identify studies of endoscopic treatments for BE or EAC. Ninety-nine papers on 101 studies (n=3,042 participants) were included in the review. There were 12 comparative studies (seven were randomized controlled trials, five were cohort studies with uncontrolled allocation to treatment groups). The authors reported that the quality of the included studies was low, with methods and outcomes inconsistently reported across the trials. Rates of complete eradication of BE at three months post treatment were: argon plasma coagulation 85.5% (n=435, range zero to 100%), cryoablation 81.8% (n=11), thermocoagulation 100% (n=13), endoscopic mucosal resection 100% (n=1), laser ablation 77.3% (n=75, range 22.2% to 100%), multipolar electro-coagulation 88.5% (n=26) and radiofrequency ablation 69% (n=171, range 21.9% to 97.7%). Rates of complete eradication across seven techniques of photodynamic therapy varied from zero to 56.4%. Complete eradication rates of HGD at three months post-treatment were: argon plasma coagulation 85.7% (n=7), cryoablation 100% (n=1), endoscopic mucosal resection 96.3% (n=27, range 92.9% to 100%), radiofrequency ablation 90.3% (n=103, range 90.2% to 90.9%) and combined photodynamic therapy and endoscopic mucosal resection 66.7% (n=3). Rates of complete eradication across seven techniques of photodynamic therapy varied from zero to 100%. The investigators stated that further research was required to identify the endoscopic treatments that provided the best outcomes for patients with BE in relation to long-term safety, esophageal cancer prevention, continuation of drug therapy, optimal frequency of post-treatment endoscopic surveillance and quality of life after different endoscopic treatments.

Stein and Feith (2005) stated that endoscopic ablation are associated with high tumor recurrence rates and persistence of pre-malignant BE.  Also, Shaheen (2005) stated that ablative therapies hold promise for individuals with superficial cancer or HGD.  Most series using these modalities featured relatively short follow-up, and longer-term outcomes will be necessary to better describe the effects of these therapies.

Spechler (2005) noted that endoscopic ablative therapies may not be effective if neoplastic cells have invaded the submucosa or disseminated through mucosal lymphatic channels, and a number of studies suggested that the endoscopic therapies usually leave metaplastic or neoplastic epithelium with malignant potential behind.  Limited data suggested that intensive endoscopic surveillance might be a reasonable approach for elderly or infirm patients, but some patients managed in this fashion have developed incurable esophageal cancers.

An assessment of argon plasma coagulation by the Institute for Clinical Effectiveness and Health Policy (IECS) found that, with the respect to BE, studies have not demonstrated complete disappearance of dysplastic lesions.  Cases of microscopic persistence has been found, and the impact that this treatment may have in the development of malignant lesions in the long-term is unknown (Pichon Riviere et al, 2005).  In a prospective, randomized, un-blinded, controlled trial (n = 40), Ackroyd et al (2004) evaluated the safety and effectiveness of APC in the ablation of BE in patients who have undergone anti-reflux surgery.  Patients in the control group received endoscopic surveillance.  Treatment was repeated until either no Barrett's epithelium remained or a maximum of 6 treatment sessions.  One month after the final treatment, complete ablation was achieved in 12 patients.  In the remaining 8 patients, a reduction of over 95 % was observed.  One patient died of an unrelated cause at 9 months.  At one year, 1 patient with residual Barrett's epithelium regressed completely, while relapse of BE was observed in another patient because of fundoplication failure.  Buried glands were observed in 35 % patients at 1 month, but only 5 % at 1 year.  Dysplasia was never observed.  In the surveillance group, partial regression was observed in 11 patients, and in 3 patients with short-segment BE, regression was complete.  The length of BE increased in 2 patients.  While 2 patients had LGD initially, this was not evident at 1 year.  Overall, complete ablation was achieved in 63 % (12/19) patients in the ablation group, and 15 % (3/20) in the surveillance group (p < 0.01).  These researchers concluded that APC of BE is safe and effective.  The effects are durable, and buried glands may resolve with time.  Moreover, the authors stated that long-term follow-up studies are needed to evaluate the impact of APC on cancer risk.  A randomized trial comparing APC with PDT found that both were equally effective in eradicating Barrett’s mucosa.  However, APC was less effective than PDT in eradicating dysplasia within the Barrett’s segment (Ragunath et al, 2005).

In December 2007, the CryoSpray Ablation system (CSA Medical, Inc.) received FDA 510(k) marketing clearance as a cryosurgical tool for destruction of unwanted tissue during general surgery, specifically for endoscopic applications.  The cryo-catheter applies liquid nitrogen thereby destroying unwanted tissue by the application of extreme cold to a selected site.  However, the clinical effectiveness of cryotherapy in the management of patients with BE has not been established.

In a review on argon plasma coagulation, bipolar cautery, and cryotherapy for the treatment of BE, Dumot and Greenwald (2008) stated that endoscopic cryotherapy ablation is a relatively new technique with studies focusing on HGD and early-stage cancer in high-risk patients.  It has an acceptable safety profile, and early results showed response in a significant number of patients in whom other modalities have failed.  The authors noted that future developments with cryospray ablation technology may improve outcomes especially with uneven surfaces, with dosing capable of reaching the submucosa.  Moreover, in the updated guidelines for the diagnosis, surveillance and therapy of BE by the Practice Parameters Committee of the American College of Gastroenterology, Wang and Sampliner (2008) stated that endoscopic cryotherapy has also been reported to eliminate BE, although there is very limited data about its efficacy; and cryotherapy is beginning clinical trials.

In a prospective, single-center, pilot study (n = 11), Johnston and associates (2005) assessed the safety and the effectiveness of cryotherapy on patients with a long-standing history of BE; with degrees of dysplasia ranging from none to multi-focal HGD.  Subjects were also treated with 40 mg rabeprazole thrice-daily during the treatment period.  Elimination of acid reflux was confirmed via 24-hour esophageal pH studies.  Cryoablation was applied hemi-circumferentially to 4-cm long segments at monthly intervals, until the entire segment of BE was eliminated.  There was reversal of BE in all patients.  In 78 % (9/11) patients who completed the protocol, there was complete endoscopic and histologic reversal of BE.  There was no subsquamous specialized intestinal metaplasia at the 6-month follow-up, and no complications occurred.  The authors concluded that based on preliminary results, low-pressure spray cryoablation of BE under direct endoscopic visualization is safe and easy to perform.  Its relative lack of patient discomfort and its simplicity and demonstrated effectiveness make it a modality that should be further explored in the ablation of gastrointestinal mucosal lesions such as BE and perhaps early esophageal cancer.  It is interesting to note that Johnston (2005) stated that it has yet to be determined if the risks associated with ablative interventions are less than the risk of BE progressing to cancer.  The author also stated that it remains to be seen if endoscopic ablative therapy can eliminate or significantly reduce the risk of cancer, eliminate the need for surveillance endoscopy, or is cost-effective.

In a review on endoscopic ablation of metaplasia and dysplasia in patients with BE, Wolfsen (2005) stated that the FDA’s approval for the use of porfimer sodium PDT was an important milestone, as this treatment has been proven to safely ablate Barrett's glandular epithelium including HGD, and significantly decrease the risk for the development of invasive cancer.  The author noted that newer methods of mucosal ablation, such as the radiofrequency balloon, have been developed for the treatment of patients with BE.  These newly developed techniques are able to treat large fields of glandular epithelium in a short treatment procedure.  It will be extremely important to document the safety, durability, and effectiveness of these devices in preventing the development of esophageal carcinoma.  Ultimately, the impact of successful Barrett's ablation on the incidence of Barrett's carcinoma, and the need for post-ablation surveillance endoscopy must be determined.

The British Society of Gastroenterology’s guidelines for the diagnosis and management of BE (Watson et al, 2005) stated that endoscopic ablation remains experimental, and should be carried out only in the context of prospective, randomized trials.

Dunkin and associates (2006) ascertained the optimal treatment parameters for the ablation of human esophageal epithelium using a balloon-based bipolar radiofrequency (RF) energy electrode.  Immediately prior to esophagectomy, participants underwent esophagoscopy and ablation of 2 separate, 3-cm long, circumferential segments of non-tumor-bearing esophageal epithelium using a balloon-based bipolar RF energy electrode.  Subjects were randomized to one of three energy density groups: 8, 10, or 12 J/cm2.  Radiofrequency energy was applied one time (1x) proximally and two times (2x) distally.  Following resection, sections from each ablation zone were evaluated using hematoxylin-eosin and diaphorase.  Histological endpoints were complete epithelial ablation (yes/no), maximum ablation depth, and residual ablation thickness after tissue slough.  Outcomes were compared according to energy density group and 1x versus 2x treatment.  A total of 13 male subjects (aged 49 to 85 years) with esophageal adenocarcinoma underwent the ablation procedure followed by total esophagectomy.  Complete epithelial removal occurred in the following zones: 10 J/cm2 (2x) and 12 J/cm2 (1x and 2x).  The maximum depth of injury was the muscularis mucosae: 10 and 12 J/cm2 (both 2x).  A second treatment (2x) did not significantly increase the depth of injury.  Maximum thickness of residual ablation after tissue slough was only 35 micron.  The authors concluded that complete removal of the esophageal epithelium without injury to the submucosa or muscularis propria is possible using this balloon-based RF electrode at 10 J/cm2 (2x) or 12 J/cm2 (1x or 2x).  A second application (2x) does not significantly increase ablation depth.  These data have been used to select the appropriate settings for treating intestinal metaplasia in trials currently under way.

Hubbard and Velanovich (2007) presented their early experience of the effects of endoluminal ablation using radiofrequency on the reflux symptoms and completeness of ablation in post-fundoplication patients.  A total of 7 patients who have had either a laparoscopic or open Nissen fundoplication and BE underwent endoscopic endoluminal ablation of the Barrett's metaplasia using the Barrx device (RF ablation).  Pre-procedure, none of the patients had significant symptoms related to GERD.  One to 2 weeks after the ablation, patients were questioned as to the presence of symptoms.  Pre-procedure and post-procedure, they completed the GERD-HRQL symptom severity questionnaire (best possible score = 0; worst possible score = 50).  Patients had follow-up endoscopy to assess completeness of ablation 3 months after the original treatment.  All patients completed the ablation without complications.  No patients reported recurrence of their GERD symptoms.  The median pre-procedure total GERD-HRQL score was 2, compared to a median post-procedure score of 1.  One patient had residual Barrett's metaplasia at 3 months follow-up, requiring re-ablation.  The authors concluded that this preliminary report of a small number of patients demonstrated that endoscopic endoluminal RF ablation of Barrett's metaplasia using the Barrx device is safe and effective in patients who have already undergone anti-reflux surgery.  There appears to be no disruption in the fundoplication or recurrence of GERD-related symptoms.  Nevertheless, longer-term follow-up with more patients is needed.

In a study published in the New England Journal of Medicine, Shaheen et al (2009) evaluated if endoscopic RF ablation could eradicate dysplastic BE and reduce the rate of neoplastic progression.  A total of 127 patients with dysplastic BE were randomly assigned in a 2:1 ratio to receive either RF ablation (ablation group) or a sham procedure (control group).  Randomization was stratified according to the grade of dysplasia and the length of BE.  Primary outcomes at 12 months included the complete eradication of dysplasia and intestinal metaplasia.  In the intention-to-treat analyses, among patients with LGD, complete eradication of dysplasia occurred in 90.5 % of those in the ablation group, as compared with 22.7 % of those in the control group (p < 0.001).  Among patients with HGD, complete eradication occurred in 81.0 % of those in the ablation group, as compared with 19.0 % of those in the control group (p < 0.001).  Overall, 77.4 % of patients in the ablation group had complete eradication of intestinal metaplasia, as compared with 2.3 % of those in the control group (p < 0.001).  Patients in the ablation group had less disease progression (3.6 % versus 16.3 %, p = 0.03) and fewer cancers (1.2 % versus 9.3 %, p = 0.045).  Patients reported having more chest pain after the ablation procedure than after the sham procedure.  In the ablation group, 1 patient had upper gastrointestinal hemorrhage, and 5 patients (6.0 %) had esophageal stricture.  The authors concluded that in patients with dysplastic BE, RF ablation was associated with a high rate of complete eradication of both dysplasia and intestinal metaplasia and a reduced risk of disease progression.

Early studies focused exclusively on the efficacy of radiofrequency ablation for patients with low-grade dysplasia; rather, such patients commonly have been included as a subgroup in eradication trials that have involved primarily patients without dysplasia or patients with high-grade dysplasia, a feature that can confound the interpretation of study results. The report of the AIM Dysplasia Trial (Shaheen, et al., 2011) included only 32 subjects with low grade dysplasia achieving mid-term (three year) followup.

In an editorial that accompanied the afore-mentioned study, Bergman (2009) stated that "[p]ersonally, I think it is still too early to promote radiofrequency ablation for patients with nondysplastic Barrett's esophagus.  Is complete response after ablation maintained over time, thus reducing the risk of progression to high-grade dysplasia or cancer?  Will ablation improve patients' quality of life and decrease costs, as compared with the surveillance strategy?  More important, can we define a stratification index predicting disease progression or response to therapy?  We run the risk of losing the momentum to enroll patients in a trial that is required at this stage: a randomized comparison of endoscopic surveillance and radiofrequency ablation for nondysplastic Barrett's esophagus.  Such a study might truly revolutionize the management of this condition and answer the question as to whether radiofrequency ablation is great just for some or justified for many".

In an editorial commenting on the study by Shaheen et al (2009), Johnson (2009) stated that these data are consistent with recent study findings demonstrating the effectiveness of photodynamic ablative therapy for patients with HGD and mucosal adenocarcinoma.  The editorialist noted, however, that  less-radical strategies, such as ablation and endoscopic mucosal resection only of visible lesions, seem to offer patients excellent efficacy with negligible morbidity or mortality.  The editorialist stated that the finding by Shaheen et al of decreased incidence of cancer in the radiofrequency ablation group should be viewed with caution, noting that malignancies were so rare in this cohort that a single incident cancer would have resulted in a loss of statistical significance.

Johnson (2009) stated that, although a growing amount of data seems to support the use of endoscopic ablative therapy in BE with HGD, whether the results achieved by expert academic investigators in Shaheen et al can be extrapolated to procedures performed by less-experienced endoscopists in a community-practice setting remains to be seen.

Wani et al (2009) determined the cancer incidence in BE patients after ablative therapy and compared these rates to cohort studies of BE patients not undergoing ablation.  A MEDLINE search of the literature on the natural history and ablative modalities in BE patients was performed.  Patients with non-dysplastic BE (ND-BE), LGD, or HGD and follow-up of at least 6 months were included.  The rate of cancer in patients undergoing ablation and from the natural history data was calculated using weighted-average incidence rates (WIR).  A total of 53 articles met the inclusion criteria for the natural history data.  Pooled natural history data showed cancer incidence of 5.98/1,000 patient-years (95 % CI: 5.05 to 6.91) in ND-BE; 16.98/1,000 patient-years (95 % CI: 13.1 to 20.85) in LGD; and 65.8/1,000 patient-years (95 % CI: 49.7 to 81.8) in HGD patients.  A total of 65 articles met the inclusion criteria for BE patients undergoing ablation (1,457 patients, ND-BE; 239 patients, LGD; and 611 patients, HGD).  The WIR for cancer was 1.63/1,000 patient-years (95 % CI: 0.07 to 3.34) for ND-BE; 1.58/1,000 patient-years (95 % CI: 0.66 to 3.84) for LGD; and 16.76/1,000 patient-years (95 % CI: 10.6 to 22.9) for HGD patients.  The authors concluded that compared to historical reports of the natural history of BE, ablation may be associated with a reduction in cancer incidence, although such a comparison is limited by likely heterogeneity between treatment and natural history studies.  The greatest benefit of ablation was observed in BE patients with HGD.  The authors also stated that ablation of ND-BE awaits evidence demonstrating that the costs and risks associated with the procedure are out-weighed by the benefits before widespread use of this is adopted in clinical practice.  Similarly, spontaneous regression of LGD has been demonstrated in the majority of BE patients, and the vast majority of subjects with ND and LGD will not benefit from ablation therapy.

In the position statement, the AGA suggests that endoscopic eradication therapy could be a therapeutic option for patients with confirmed LGD in BE, acknowledging that there are controversies about the management of dysplasia in this population and that the risk of progression to cancer can vary.  The AGA supports "shared decision making" with respect to whether or not endoscopic eradication or surveillance is preferred for each individual.

Shaheen and Frantz (2010) evaluated timing and patient selection for endoscopic ablative therapy in BE.  Most recent data described radiofrequency ablation (RFA), but other data pertain to PDT and other modalities.  Most studies are cohort or case series.  Reversion to squamous epithelium is the most common primary outcome.  Cancer incidence data are scarce.  Radiofrequency ablation appears well-tolerated.  The main side-effect is chest pain, which can be managed with oral analgesics.  Stricture occurs in 0 to 8 % and is amenable to endoscopic dilatation.  Infrequent side-effects include bleeding and perforation.  Complete reversion to squamous epithelium occurs in more than 90 % of non-dysplastic and LGD and more than 80 % in HGD patients, and the treatment appears durable for at least 2 to 5 years of available follow-up.  Treatment of low-grade or non-dysplastic disease may be cost-effective.  Data on PDT suggest that all-cause mortality is similar to surgery for dysplastic BE.  The stricture rate appears higher, and rates of complete reversion to neosquamous epithelium are lower than that of RFA, although definitive comparisons are lacking.  The authors concluded that the excellent efectiveness, side-effect profile, and cost-effectiveness appear to make RFA the intervention of choice in cases of HGD.  Radiofrequency ablation for LGD may be of value in young patients and/or those with long segment or multi-focal disease.  Treatment of non-dysplastic BE is of uncertain value.  Photodynamic therapy appears to have a higher stricture rate and to be more expensive than RFA.

Shaheen et al (2010) evaluated the influence of dysplastic BE on quality of life (QoL) and examined if endoscopic treatment of dysplastic BE with RFA improves QoL.  These researchers analyzed changes in QoL in the AIM Dysplasia Trial, a multi-center study of patients with dysplastic BE who were randomly allocated to RFA therapy or a sham intervention.  They developed a 10-item questionnaire to assess the influence of dysplastic BE on QoL.  The questionnaire was completed by patients at baseline and 12 months.  A total of 127 patients were randomized to RFA (n = 84) or sham (n = 43).  At baseline, most patients reported worry about esophageal cancer (71 % RFA, 85 % sham) and esophagectomy (61 % RFA, 68 % sham).  Patients also reported depression, impaired QoL, worry, stress, and dissatisfaction with the condition of their esophagus.  Of those randomized, 117 patients completed the study to the 12-month end point.  Compared with the sham group, patients treated with RFA had significantly less worry about esophageal cancer (p = 0.003) and esophagectomy (p = 0.009).  They also had significantly reduced depression (p = 0.02), general worry about the condition of their esophagus (p ≤0.001), impact on daily QoL (p = 0.009), stress (p = 0.03), dissatisfaction with the condition of their esophagus (p ≤0.001), and impact on work and family life (p = 0.02).  The authors concluded that inclusion in the treatment group of this randomized, sham-controlled trial of RFA was associated with improvement in disease-specific health-related quality of life.  This improvement appears secondary to a perceived decrease in the risk of cancer.  The major drawback pf this study was that while the methodology employed to develop this tool provides high content validity, the test-retest reliability of the tool and its convergent validity have not been established.  Furthermore, a reference time-frame was not created in the questionnaire and it may need adjustment based on the intervention considered.  Further work is needed to define the operating characteristics of this tool.

dos Santos et al (2010) reported their initial experience with RFA in association with anti-reflux procedure for Barrett's metaplasia and LGD.  A total of 14 patients (10 male and 4 female patients) presented with Barrett's metaplasia (n = 11) or LGD (n = 3) were included in the study.  Median age was 60 years (38 to 80 years).  The severity of BE was classified by length (in cms), appearance (circumferential/non-circumferential), and histology (1, normal; 2, Barrett's metaplasia; and 3, LGD).  Radiofrequency ablation was performed with the HALO 360 degrees or 90 degrees systems.  Median follow-up was 17 months.  The mean number of ablative procedures undertaken was 2.6 (range of 1 to 6).  There was no mortality, but there were 2 peri-operative complications after the anti-reflux procedure (pneumonia, n = 1; atrial fibrillation, n = 1).  One patient had mild dysphagia requiring a single dilation 2 months after ablation.  The mean length of BE decreased from 6.2 to 1.2 cm after treatment (p = 0.001).  Barrett's grade decreased significantly (p = 0.003).  Before therapy, circumferential BE was present in 13 patients.  At last endoscopy, only 1 patient had circumferential BE present.  The number of RFA treatments was significantly (p < 0.05) associated with success.  All patients receiving 3 or more treatments had complete resolution of Barrett's metaplasia.  The authors concluded that RFA performed either before or after an anti-reflux procedure is safe.  This approach is effective for reducing or eliminating metaplasia and dysplasia.  They stated that long-term studies will be necessary to determine whether this approach can provide durable control of both reflux and BE.

Shaheen et al (2011) assessed long-term rates of eradication, durability of neosquamous epithelium, disease progression, and safety of RFA in patients with dysplastic BE.  The investigators 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.  The investigators reported that, 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 greater than 85 % of patients and intestinal metaplasia in greater than 75 %, without maintenance RFA. Serious adverse events occurred in 4 of 119 subjects (3.4 %); the rate of stricture was 7.6 %.  Five of 119 subjects (4.2 %) who received any RFA as part of this trial have experienced disease progression.  In an overall observation period of 363 years, this corresponds to an annual rate of overall disease progression of 1/73 patient-years, or 1.37 % per patient per year, and an annual rate of progression to EAC of 1/181 patient-years, or 0.55 % per patient per year.  Stratified by baseline histology at study entry, for subjects enrolled with LGD, the annual rate of overall disease progression was 1/49 patient-years, or 2.04 % per patient per year, and the annual rate of progression to EAC was 1/197 patient-years, or 0.51 % per patient per year.  Among subjects enrolled with HGD, the annual rate of overall disease progression was 1/166 patient-years, or 0.60 % per patient per year, and the annual rate of progression to EAC was 1/166 patient-years, or 0.60 % per patient per year.

Phoa and colleagues (2014) found that radiofrequency ablation reduced the risk of progression to high grade dysplasia and esophageal adenocarcinoma in carefully selected patients with BE and low grade dysplasia.  In this multicenter trial, 136 patients with low-grade dysplasia confirmed by expert pathologists were randomly assigned in a 1:1 ratio to undergo either radiofrequency ablation or surveillance (control group).  Ablation reduced the risk of progression to high-grade dysplasia or adenocarcinoma from 26.5 % to 1.5 %, an absolute risk reduction of 25.0 %, corresponding to a number needed to treat of 4.0.  Ablation also reduced the risk of progression to adenocarcinoma, from 8.8 % to 1.5 %, an absolute risk reduction of 7.4 %.  For patients in the ablation group, 92.6 % of dysplasia and 88.2 % of intestinal metaplasia was completely eradicated compared with 27.9 % of dysplasia and 0 % of intestinal metaplasia among patients in the control group.  Treatment-related adverse events occurred in 19.1 % of patients in the ablation group; however, these were mild.  The most common adverse event was esophageal stricture (11.8 %), which resolved with a median of 1 endoscopic dilation.

An accompanying editorial (Mönkemüller, 2014) noted that several important points should be emphasized before proceeding with ablation procedures for all patients with Barrett esophagus and low-grade dysplasia.  Only patients with expert pathologist–confirmed low-grade dysplasia were enrolled in this trial.  Of patients initially diagnosed with low-grade dysplasia, only 15 % will have the diagnosis confirmed by an expert center; thus 85 % of patients diagnosed with low-grade dysplasia would not be eligible for this procedure.  In addition, despite expert confirmation of low-grade dysplasia, a large percentage of patients (28 %) in the study by Phoa et al had regression of their lesion over time.  In this trial, histological confirmation of a 1-time low-grade dysplasia by an expert pathologist was the most important selection criteria.  Thus, it is possible that selecting only patients with low-grade dysplasia on multiple endoscopies may further refine the process of selecting patients at risk of progression.  The editorialist also noted that exclusive participation of expert centers in this trial may render the results less reproducible in general practice (Mönkemüller, 2014).

Bennett et al (2012) performed an international, multi-disciplinary, systematic, evidence-based review of different management strategies for patients with BE and dysplasia or early-stage EA.  The authors used a Delphi process to develop consensus statements.  The authors stated that, despite generally low quality of evidence, they were able to achieve consensus around several clinical statements, including: patients that receive ablative or surgical therapy require endoscopic follow-up; endoscopic therapy for HGD is preferred to surveillance; endoscopic therapy for HGD is preferred to surgery; the combination of endoscopic resection and radiofrequency ablation is the most effective therapy; and after endoscopic removal of lesions from patients with HGD, all areas of BE should be ablated.  The authors stated that they focused on statements concerning HGD and EA as evidence relating to LGD is particularly weak. The authors explained  that they "focused on patient populations with high-risk disease rather than including those statements about LGD, a condition for which there are even less objective data in the literature."

Das and colleagues (2009) carried out an economic analysis evaluating the cost-effectiveness of endoscopic ablation of non-dysplastic BE.  A Markov model evaluated 3 competing strategies in a hypothetical 50-year-old cohort with non-dysplastic BE from a societal perspective.  Strategy I -- natural history of Barrett's disease (without surveillance); strategy II -- surveillance performed according to the ACG practice guidelines; strategy III -- endoscopic ablative therapy.  The model was biased against ablative therapy with a conservative estimate of complete response and continued standard surveillance even after complete ablation.  All potential complications were accounted for, and an incomplete histological response after ablation was presumed to have the same risk of progression as untreated Barrett's.  Transitional probabilities, discounted cost, and utility values to estimate quality-adjusted life-years (QALY) were obtained from published information.  Direct costs were used in the analysis.  In baseline analysis, the ablative strategy yielded the highest QALY and was more cost-effective than endoscopic surveillance.  In a Monte Carlo analysis, the relative risk of developing cancer in the strategy based on endoscopic ablation was decreased compared with the other strategies.  In threshold analysis, the critical determinants of cost-effectiveness of the ablative strategy were rate of complete response to ablation, total cost of ablation, and risk of progression to dysplasia.  The authors concluded that within the limits of the model, ablation for non-dysplastic BE is more cost-effective than endoscopic surveillance.  They stated that clinical trials of ablative therapy in non-dysplastic BE are needed to establish its effectiveness in reducing cancer risk.

The Society of Thoracic Surgeons' practice guideline on the management of BE with HGD (Fernando et al, 2009) stated that RF ablation may be effective for ablation of HGD; however, further trials are needed before this can be recommended in preference to currently available ablative therapies.

In a review on BE and new therapeutic modalities, Sharma and Fleischer (2007) stated that as longer-term trial outcomes become available for circumferential and focal ablation, if the current safety and effectiveness result remain favorable and durable, and if cost-effectiveness studies are favorable, they may offer this therapy to selected patients with non-dysplastic intestinal metaplasia to reduce their risk for progression to dysplasia and cancer.

Roorda et al (2007) presented their early experience with RF energy ablation therapy for BE with and without dysplasia.  They performed HALO(360) ablation followed by twice-daily PPI and 3-monthly surveillance for up to 12 months.  If metaplasia or dysplasia were present at follow-up, the patients received a second ablation.  A total of 13 patients (12 males) were treated, 3 with HGD, 4 with LGD, and 6 with non-dysplastic intestinal metaplasia.  The mean baseline BE length was 6 cm (range of 2 to 12); 9 patients had an hiatal hernia and 2 had a prior fundoplication.  Esophageal pH less than 4.0 for less than 4 % of time was achieved only in 5/13 patients.  A mean of 1.4 ablation sessions were performed, without serious adverse events or strictures.  Complete eradication of BE was achieved in 6/13 (46 %) patients.  The mean endoscopic surface regression was 84 % (from a mean length of 6 +/- 1 cm to 1.2 +/- 0.5 cm, p < 0.001).  Complete elimination of dysplasia was achieved in 5/7 (71 %) patients.  Ablation efficacy was better in those patients who had maximal pH control (p < 0.05).  HALO(360) ablation of BE with or without dysplasia is safe, well-tolerated and effective in the community setting.  Follow-up ablation further reverses residual BE or dysplasia.  The authors stated that early results of this technology are promising.  Moreover, further study will be needed to address the durability of effect and its cost-effectiveness.

Furthermore, Ganz et al (2008) reported that endoscopic circumferential RF ablation is a promising modality for the treatment of BE that contains HGD.  In this study, researchers used registry data to identify 142 patients with BE (mean length, 6 cm) and HGD who underwent circumferential ablation at any of 16 academic and community medical centers in the United States.  HGD was confirmed by at least 2 pathologists.  After the initial ablative therapy, patients had follow-up endoscopy at 3-month intervals with repeat circumferential ablation.  Prior endoscopic mucosal resection for focal lesions had been performed in 17 % of participants.  At 1-year follow-up, biopsy data were available for 92 of the 142 patients; the data showed complete HGD responses in 90.2 % and complete remission of specialized columnar metaplasia in 62.5 %.  No patients were referred for esophagectomy, and no serious adverse events were reported.  Commenting on this study, Johnson (2008) noted that several aspects of the study are troubling.  Johnson stated that the 1-year follow-up period might not be adequate to assess the results fully, and the histologic analysis (which can vary considerably) was not standardized.  The commentator noted that the lack of data on 50 of the 142 patients is concerning, and an intention-to-treat analysis would dramatically lower the "success" rates.  Nonetheless, the commentator stated, the combination of endoscopic mucosal resection of focal lesions followed by ablation of residual BE seems particularly attractive compared with esophagectomy.  The commentator concluded that longer follow-up and more-complete data collection are necessary to assess more accurately the true efficacy of circumferential ablation.

Of all the academic medical centers in the United States, Mayo Clinic has performed the most RF ablation procedures to treat BE.  Its website on BE (2008) states that RF ablation is a fairly new procedure that is still being studied.  However, research shows that more than 70 % of those treated are free of dysplasia up to 12 months after treatment.  Complications can include esophageal perforation (rupture) and strictures (narrowing).  The long-term effectiveness of ablation procedures in preventing cancer is still being studied.

The American College of Gastroenterology's updated guidelines for the diagnosis, surveillance and therapy of BE (Wang and Sampliner, 2008) stated that "further evaluation of the most recent technology; radiofrequency ablation is awaited.  Cryotherapy is beginning clinical trials and older technologies are becoming more refined (e.g., photodynamic therapy with the development of new agents).  Documentation of the frequency and duration of the surveillance protocol after endoscopic ablation therapy requires careful study".

In a review, McAllaster et al (2009) noted that traditionally, esophagectomy has been the standard treatment for BE with HGD.  This practice is supported by studies revealing unexpected adenocarcinoma in 29 to 50 % of esophageal resection specimens for HGD.  In addition, esophagectomy employed prior to tumor invasion of the muscularis mucosa results in 5-year survival rates in excess of 80 %.  Although esophagectomy can result in improved survival rates for early-stage cancer, it is accompanied by significant morbidity and mortality.  Recently, more accurate methods of surveillance and advances in endoscopic therapies have allowed scientists and clinicians to develop treatment strategies with lower morbidity for HGD.  Early data suggested that carefully selected patients with HGD can be managed safely with endoscopic therapy, with outcomes comparable to surgery, but with less morbidity.  This is an especially attractive approach for patients that either can not tolerate or decline surgical esophagectomy.  For patients that are surgical candidates, high-volume centers have demonstrated improved morbidity and mortality rates for esophagectomy.  The addition of laparoscopic esophagectomy adds a less invasive surgical resection to the treatment armanentarium.  The authors concluded that esophagectomy will remain the gold-standard treatment of BE with HGD until clinical research validates the role of endoscopic therapies.

In a review of the literature, Gilbert et al (2011) stated that the general prevalence of BE is estimated at 1.6 to 3 % and follows a demographic distribution similar to EAC.  Both short-segment (less than 3 cm) and long-segment (greater than or equal to 3 cm) BE confer a significant risk for EAC that is increased by the development of dysplasia.  The author stated that the treatment for flat high-grade dysplasia is endoscopic radiofrequency ablation therapy.  The author noted that the benefits of ablation for non-dysplastic BE and BE with low-grade dysplasia have yet to be validated.

In summary, there is adequate evidence to support the use of endoscopic mucosal resection, esophagectomy, fundoplication, PDT, and RFA in the treatment of patients with BE who have dysplasia when medical therapy has failed.  On the other hand, although the data to support the use of other ablative interventions in the treatment of BE are promising, more well-designed (larger, randomized, double-blinded) studies are needed to draw any definitive conclusions.

Jankowski and Odze (2009) stated that gastro-intestinal cancers account for about 25 % of all cancer deaths in the Western world.  There is a need for a preventive strategy that can utilize biomarkers in order to stratify patients into appropriate screening or surveillance programs.  In cancer biology, the best biomarkers are germline adenomatous polyposis coli mutations, which are highly predictive of colon cancer.  In other areas, such as BE, despite early excellent success in identifying the importance of p16, p53, and aneuploidy in esophageal adenocarcinoma pathogenesis, useful biomarkers are still not widely used in clinical practice.  New molecular biomarkers may be identified in the next decade, such as epigenetic methylation patterns and genetic polymorphisms.  In the meantime, clinicians must rely on robust, inexpensive methods such as standard histopathology.  Dysplasia is still the mainstay of cancer prediction in most inflammatory disorders of the gastrointestinal tract and is an independent marker of cancer risk.

In a retrospective cohort study, Barthel et al (2010) examined the response of tumor-associated BE to chemoradiation therapy.  The study cohort consisted of 43 patients with stage I to IVA esophageal adenocarcinoma associated with BE who received either neoadjuvant or definitive chemoradiation therapy and underwent either esophagectomy or surveillance.  Main outcome measurement was the presence and extent of BE after chemoradiation therapy of esophageal adenocarcinoma associated with endoscopically documented pre-treatment BE.  Barrett's esophagus persisted after chemoradiation therapy in 93 % (40/43) of cases (95 % CI: 83 % to 99 %).  Twenty-seven patients received neoadjuvant chemoradiation therapy before esophagectomy.  Persistent BE was detected in all 27 surgical specimens (100 %).  In 59 % (16/27) of the cases, there was complete pathologic tumor response.  Sixteen patients received definitive chemoradiation therapy.  Persistent pre-treatment BE was identified in 88 % (14/16) by surveillance endoscopy (95 % CI: 60 % to 98 %).  The mean length of BE before and after chemoradiation was 6.6 cm and 5.8 cm, respectively (p = 0.38).  The authors concluded that chemoradiation therapy of esophageal adenocarcinoma (EAC) does not eliminate tumor-associated BE, nor does it affect the length of the BE segment.  Moreover, it should be noted that Hvid-Jensen  and colleagues (2011) found that the rate of progression from BE to LGD then to HGD is much smaller than previously thought.  These investigators stated that BE is a strong risk factor for EAC, but the absolute annual risk, 0.12 %, is much lower than the assumed risk of 0.5 %, which is the basis for current surveillance guidelines.

Wani (2012) discussed the various controversies that surround the management of LGD in BE.  Data on the clinical course of LGD patients with regards to rates of progression to HGD and EAC are highly variable.  Recent data suggested that the rate of progression to EAC may be similar to that of patients with non-dysplastic BE (0.4 to 0.5 % per year).  There is significant inter-observer variability in the diagnosis of LGD even among expert gastro-intestinal pathologists.  Data on various endoscopic eradication therapies (EET) specifically in this patient population are limited.  Eradication of LGD and intestinal metaplasia can be achieved by RFA.  Although treatment appears to be durable for up to 3 years, progression to HGD and EAC can occur, high-lighting the need for close endoscopic surveillance even after EET.  The authors concluded that there is a need to risk-stratify BE patients with LGD to identify patients most likely to progress using a reliable and objective system that incorporates clinical features, advanced imaging techniques and biomarkers.  If such a high-risk group could be identified, they may benefit from EET, whereas, the majority may be managed conservatively.

Bremholm and associates (2012) noted that BE is a pre-malignant condition in the esophagus.  Esophageal adenocarcinomas have the fastest increase of incidence of all solid tumors in the western world.  Barrett's esophagus is defined as areas with macroscopic visible columnar epithelium and intestinal metaplasia oral of the anatomical gastroesophageal junction.  The extent of the endoscopic findings is described by the Prague classification.  The metaplasia is histologically confirmed by the presence of intestinal metaplasia.  The diagnosis of BE can only be made by a combined macroscopic and microscopic examination.  The histological description should include evaluation of dysplasia, and if present it should be classified as LGD or HGD.  All patients are offered relevant anti-reflux treatment with PPI or surgery.  Ablation or mucosal resection of metaplastic epithelia with or without LGD is experimental and it is not recommended outside controlled studies.  Treatment of HGD and carcinoma in-situ is handled in departments treating esophageal cancer.  Follow-up with endoscopy and biopsy can be offered.  Follow-up endoscopy with biopsy can only be recommended after thorough information to the patients, as evidence for the value is scarce.

The National Institute for Health and Clinical Excellence (NICE)’s clinical guideline on “Ablative therapy for the treatment of Barrett's oesophagus” (NICE, 2010) recommended that “Consider using radiofrequency ablation alone or photodynamic therapy alone for flat high-grade dysplasia, taking into account the evidence of their long-term efficacy, cost and complication rates”.

The American Gastroenterological Association’s medical position statement on the management of Barrett's esophagus (ACG, 2011) recommended that “endoscopic eradication therapy with radiofrequency ablation (RFA), photodynamic therapy (PDT), or endoscopic mucosal resection (EMR) rather than surveillance for treatment of patients with confirmed high-grade dysplasia within Barrett's esophagus (strong recommendation, moderate-quality evidence)”.

The American Society for Gastrointestinal Endoscopy’s guideline on “The role of endoscopy in Barrett's esophagus and other premalignant conditions of the esophagus” (ASGE, 2012) recommended that “eradication with endoscopic resection or radiofrequency ablation (RFA) be considered for flat HGD in select cases because of its superior efficacy (compared with surveillance) and side effect profile (compared with esophagectomy)

Velanovich (2012) noted that Barrett's esophagus is a pathologic change of the normal squamous epithelium of the esophagus to specialized columnar metaplasia.  Barrett's esophagus is a result of prolonged exposure of the esophagus to gastro-duodenal refluxate.  Although Barrett's itself is not symptomatic, and, in fact, patients with Barrett's esophagus may be completely asymptomatic, it does identify patients at higher risk of developing esophageal adenocarcinoma.  Traditionally, anti-reflux surgery was reserved for patients with symptoms, because it was believed that anti-reflux surgery did not eliminate Barrett's esophagus and reduce cancer risk.  Rationale for the treatment of Barrett's esophagus beyond treating symptoms of gastro-esophageal reflux disease stems from the hope to decrease, if not eliminate, the risk of adenocarcinoma.  Treatment options ranged from medical acid suppression without surveillance to resection.  Ablation, particularly endoscopic radiofrequency ablation, has become the standard of care for Barrett's esophagus with high-grade dysplasia.  Its role in non-dysplastic or low-grade dysplastic Barrett's is less clear.  Combined endoscopic mucosal resection with ablation is effective in nodular high-grade Barrett's esophagus.  Resection should be reserved for patients with persistent high-grade dysplasia despite multiple attempts at endoscopic ablation or resection or for patients with evidence of carcinoma.

Spechler (2013) stated that the American Gastroenterological Association (AGA) defines Barrett's esophagus as the condition in which any extent of metaplastic columnar epithelium that predisposes to cancer development replaces the squamous epithelium that normally lines the distal esophagus.  Although cardiac mucosa may be metaplastic, its malignant predisposition is not clear, and the AGA still requires the demonstration of intestinal metaplasia (with goblet cells) for a diagnosis of Barrett's esophagus.  The AGA generally recommends endoscopic eradication therapy for patients with high-grade dysplasia, who otherwise develop esophageal adenocarcinoma at the rate of 6 % per year.  Endoscopic therapy is often curative for mucosal neoplasms in Barrett's esophagus because the risk of lymph node metastases is only 1 to 2 %.  American gastroenterologists generally do not recommend endoscopic therapy for patients whose neoplasms involve any portion of the submucosa because of the high rate of lymph node metastases that has been described in these cases.  The management of low-grade dysplasia is disputed because of poor agreement among pathologists on the diagnosis and because of contradictory data on the natural history, but the AGA recommends that radiofrequency ablation (RFA) should be a therapeutic option for patients with confirmed low-grade dysplasia in Barrett's esophagus.  Arguments for using RFA to treat non-dysplastic Barrett's metaplasia are based on the premise that RFA decreases cancer risk, but no study has established that premise.  In the absence of definitive data, concerns about the frequency and importance of buried metaplastic glands and recurrent metaplasia should temper enthusiasm for treating non-dysplastic Barrett's esophagus with RFA.

Almond and Barr (2014) stated that the management of BE and associated neoplasia has evolved considerably in recent years.  Modern endoscopic strategies including endoscopic resection and mucosal ablation can eradicate dysplastic Barrett's and prevent progression to invasive esophageal cancer.  However, several aspects of Barrett's management remain controversial including the stage in the disease process at which to intervene, and the choice of endoscopic or surgical therapy.  These investigators performed a review of articles pertaining to the management of BE with or without associated neoplasia in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.  Medline, Embase and Cochrane databases were searched to identify literature relevant to 8 pre-defined areas of clinical controversy.  The following search terms were used: Barrett's esophagus; dysplasia; intramucosal carcinoma; endotherapy; endoscopic resection; ablation; esophagectomy.  A significant body of evidence exists to support early endoscopic therapy for HGD.  Although not supported by randomized controlled trial (RCT) evidence, endoscopic therapy is now favored ahead of esophagectomy for most patients with HGD.  Focal intra-mucosal (T1a) carcinomas can be managed effectively using endoscopic and surgical therapy, however surgery should be considered the 1st line therapy where there is sub-mucosal invasion (T1b).  The authors stated that treatment of LGD is not supported at present due to widespread over-reporting of the disease.  The role of surveillance endoscopy in non-dysplastic Barrett's remains controversial.

Almond et al (2014) identified systematically all reports of endoscopic treatment of LGD, and assessed outcomes in terms of disease progression, eradication of dysplasia and intestinal metaplasia, and complication rates.  These researchers performed a systematic review of articles reporting endoscopic treatment of LGD in accordance with PRISMA guidelines.  Medline and Embase databases were searched to identify the relevant literature.  Rates of complete eradication of intestinal metaplasia (CE-IM) and dysplasia (CE-D) were reported.  The pooled incidence of progression to cancer was calculated following endoscopic therapy.  A total of 37 studies met the inclusion criteria, reporting outcomes of endoscopic therapy for 521 patients with LGD.  The pooled incidence of progression to cancer was 3.90 (95 % CI: 1.27 to 9.10) per 1,000 patient-years.  CE-IM and CE-D were achieved in 67.8 (95 % CI: 50.2 to 81.5) and 88.9 (83.9 to 92.5) % of patients, respectively.  The commonest adverse event was stricture formation.  The authors concluded that reports of endoscopic therapy were heterogeneous and follow-up periods were short.  There is a high likelihood of historical over-diagnosis of LGD.  Endoscopic therapy, particularly RFA, appears safe and effective at eradicating LGD, but does not eliminate the risk of progression to cancer.

In a review on “Barrett’s esophagus” published in the New England Journal of Medicine, Spechler and Souza (2014) stated that some physicians have proposed that RFA should be offered to all patients with BE, dysplastic or non-dysplastic, arguing that endoscopic surveillance is not an effective cancer-prevention strategy and that RFA is safe and effective for eradicating Barrett's metaplasia.  However, the effectiveness of RFA for preventing cancer in patients with ND-BE has not been established in long-term studies, and there are at least 2 reasons why the risk of cancer may not be eliminated, even when RFA eradicates all visible evidence of Barrett's metaplasia.  First, patients with BE frequently have metaplastic glands in the lamina propria underneath the esophageal squamous epithelium, usually within 1 cm of its junction with metaplasia.   The overlying squamous epithelium hides this sub-squamous intestinal metaplasia from the endoscopist and may protect it from RFA.  The rate at which sub-squamous intestinal metaplasia progresses to a malignant state is not known, but cancers have been found in these sub-squamous metaplastic glands.  Another reason to suspect that RFA might not eliminate the risk of cancer is the observation that Barrett's metaplasia can recur over time.  Early studies suggested that the recurrence rate after RFA was low, but more recent studies have shown recurrences of Barrett's metaplasia, sometimes with dysplasia and cancer, in up to 33 % of patients at 2 years.  The long-term cancer risk associated with recurrent Barrett's metaplasia after RFA is not known.  These investigators noted that since the frequency and importance of sub-squamous intestinal metaplasia and recurrent Barrett's metaplasia have not yet been determined, the effectiveness of RFA for cancer prevention in patients with ND-BE is unclear.  They stated that these uncertainties suggest that patients should continue to undergo endoscopic surveillance even after apparently successful eradication of metaplasia by means of RFA.  Moreover, they noted that one study used a decision-analytic Markov model to explore the cost-effectiveness of RFA for 50-year old men with BE and concluded that it was cost-effective for those with dysplasia but not for those with non-dysplastic metaplasia.  At this time, the authors do not recommend RFA for the general population of patients with ND-BE.

Fuji Intelligent Chromo Endoscopy (FICE)

According to the manufacturer, "[a]s a basic principle, F.I.C.E. imaging is implemented based on Spectral Estimation Technology.  Spectral Estimation Technology takes an ordinary endoscopic image from the video processor and arithmetically processes, estimates and produces an image of a given, dedicated wavelength of light.  Now, for the first time ever, this technology is put to practical use in the field of endoscopy by Fujinon.  The expected advantage of this new digital processing system is a dramatic enhancement in the detection and identification of pathologic changes.  The F.I.C.E. system is expected to enable doctors to supplement differences in experiences and to diagnose clinical findings more accurately than ever before.  In contrast to a system in which an optical filter is used, this digital processing system is able to switchover between an ordinary image and a F.I.C.E. image in a split second."

In a review on advanced imaging of the gastro-intestinal tract Goetz and Kiesslich (2009) stated that digital chromoendoscopy techniques such as narrow band imaging, i-scan, or FICE offer new possibilities of easily and reversibly obtaining enhanced tissue contrast.  Advanced imaging techniques have provided the endoscopist with an armamentarium of novel modalities for detection, characterization and microscopy of lesions during endoscopy.  In addition, functional and molecular imaging give insight into dynamic processes of tissues in their natural surroundings.  

A meta-analysis by Qumseya et al (2013) found that advanced imaging technologies increased diagnostic yield by 34 %. The increase in yield was similar for FICE, chromoendoscopy and narrow-band imaging.  However, there are insufficient data to determine whether this increase in diagnostic yield results in improved clinical outcomes.

According to ClinicalTrials.gov, a service of the National Institutes of Health, a clinical trial on the role of the FICE for the detection of dysplasia in BE and in post-ablation BE was suspended recently (2011).

Germline Mutations in Barrett Esophagus / Esophageal Adenocarcinoma

Barrett esophagus occurs in 1 % to 10 % of the general population and is believed to be the precursor of EAC.  The incidence of EAC has increased 350 % in the past 30 years without clear etiology.  Finding pre-disposition genes may improve pre-morbid risk assessment, genetic counseling, and management.  Genome-wide multi-platform approaches may lead to the identification of genes important in BE/EAC development.  Orloff et al (2011) identified risk alleles or mutated genes associated with BE/EAC.  Model-free linkage analyses of 21 concordant-affected sibling pairs with BE/EAC and 11 discordant sibling pairs (2005 to 2006) were carried out.  Significant germline genomic regions in independent prospectively accrued series of 176 white patients with BE/EAC and 200 ancestry-matched controls (2007 to 2010) were validated and fine mapped.  Integrating data from these significant genomic regions with somatic gene expression data from 19 BE/EAC tissues yielded 12 "priority" candidate genes for mutation analysis (2010).  Genes that showed mutations in cases but not in controls were further screened in an independent prospectively accrued validation series of 58 cases (2010).  Main outcome measures were identification of germline mutations in genes associated with BE/EAC cases, and functional interrogation of the most commonly mutated gene.  Three major genes, MSR1, ASCC1, and CTHRC1 were associated with BE/EAC (all p < 0.001).  In addition, 13 patients (11.2 %) with BE/EAC carried germline mutations in MSR1, ASCC1, or CTHRC1.  MSR1 was the most frequently mutated, with 8 of 116 (proportion, 0.069; 95 % CI: 0.030 to 0.130; p < 0.001) cases with c.877C>T (p.R293X).  An independent validation series confirmed germline MSR1 mutations in 2 of 58 cases (proportion, 0.035; 95 % CI: 0.004 to 0.120; p = 0.09).  MSR1 mutation resulted in CCND1 up-regulation in peripheral-protein lysate.  Immunohistochemistry of BE tissues in MSR1-mutation carriers showed increased nuclear expression of CCND1.  The authors concluded that MSR1 was significantly associated with the presence of BE/EAC in derivation and validation samples, although it was only present in a small percentage of the cases.  They stated that future independent studies are needed to replicate their data in other patient populations to confirm the conclusions.  Furthermore, larger cohort studies may be necessary to determine the usefulness of these genes and their variant in risk assessment and pre-morbid diagnosis.

MicroRNAs as Biomarkers for Barrett's Esophagus Progression

Bansal et al (2011) evaluated feasibility and clinical accuracy of novel microRNA (miRNA) biomarkers for prediction of BE dysplasia.  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 HGD/EAC) occupying greater than 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.  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 %, respectively.  MiRNA-15b, -21, and -203 exhibited field effects (i.e., groups A and B tissues while histologically similar yet exhibited different miRNA expression).  The authors concluded that this pilot study demonstrated 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.

Mallick et al (2016) reviewed studies that have investigated this to identify microRNAs with high biomarker potential for screening and disease monitoring in BE. PubMed and Embase databases were searched for studies that quantified esophageal epithelial microRNAs.  Publications reporting microRNA comparisons of normal, non-dysplastic BE, BE with HGD, and EAC tissues using both unbiased discovery and independent validation phases were reviewed.  A total of 11 studies on microRNA expression differences between normal epithelium and non-dysplastic BE (7 studies), HGD (4) or EAC (7), or between non-dysplastic BE and HGD (3) or EAC (6) were identified, and the findings of their validation phase were analyzed.  Increased miR-192, -194, and -215, and reduced miR-203 and -205 expression in BE compared to normal was noticed by all 4-6 of the 7 studies that examined these microRNAs.  In heterogeneity tests of the reported fold-change values, the I (2) statistics were 7.9 to 17.1 % (all p < 0.05).  Elevated miR-192, -194, and -215, and diminished miR-203 and -205 levels were also noted for comparisons of HGD or EAC against normal.  In contrast, a consistent microRNA expression difference was absent for the comparisons of HGD or EAC against BE.  The authors concluded that microRNAs miR-192, -194, -203, -205, and -215 are promising tissue biomarkers for diagnosing BE.  Cross-sectional data suggested that microRNAs may have a limited role in separating BE from HGD/EAC epithelia but need further testing in longitudinal follow-up studies.

Confocal Laser Endomicroscopy

Probe-based confocal laser endomicroscopy (pCLE) is an imaging technique that allows real-time in-vivo histological assessment of BE.

In a prospective, multi-center, randomized, clinical trial, Wallace and colleagues (2012) evaluated if use of pCLE in addition to high-definition white light (HDWL) could aid in determination of residual BE.  After an initial attempt at ablation, patients were followed-up either with HDWL endoscopy or HDWL plus pCLE, with treatment of residual metaplasia or neoplasia based on endoscopic findings and pCLE used to avoid over-treatment.  Main outcome measurements included the proportion of optimally treated patients, defined as those with residual BE who were treated and had complete ablation plus those without BE who were not treated and had no evidence of disease at follow-up.  The study was halted at the planned interim analysis based on a priori criteria.  After enrollment was halted, all patients who had been randomized were followed to study completion.  Among the 119 patients with follow-up, there was no difference in the proportion of patients achieving optimal outcomes in the 2 groups (15/57, 26 % for HDWL; 17/62, 27 % with HDWL + pCLE).  Other outcomes were similar in the 2 groups.  The authors concluded that this study yielded no evidence that the addition of pCLE to HDWL imaging for detection of residual BE or neoplasia can provide improved treatment.

Bertani et al (2012) stated that many endoscopic imaging modalities have been developed and introduced into clinical practice to enhance the diagnostic capabilities of upper endoscopy.  In the past, detection of dysplasia and carcinoma of esophagus had been dependent on biopsies taken during standard white-light endoscopy (WLE).  Recently high-resolution (HR) endoscopy enables us to visualize esophageal mucosa but resolution for glandular structures and cells is still low.  Probe-based confocal laser endomicroscopy is a new promising diagnostic technique by which details of glandular and vascular structures of mucosal layer can be observed.  However, the clinical utility of this new diagnostic tool has not yet been fully explored in a clinical setting.

Although there are a variety of advanced imaging modalities for Barrett's esophagus in development, there are few studies directly comparing these modalities. Leggett, et al. (2016) compared probe-based confocal endomicroscopy with volumetric endomicroscopy in ex vivo endoscopic mucosal resection specimens. The sensitivity, specificity, and diagnostic accuracy of probe-based confocal endomicroscopy for detection of BE dysplasia was 76% (95% confidence interval [CI], 59-88), 79% (95% CI, 53-92), and 77% (95% CI, 72-82), respectively. The use of volumetric laser endoscopy using a new algorithm showed a sensitivity of 86% (95% CI, 69-96), specificity of 88% (95% CI, 60-99), and diagnostic accuracy of 87% (95% CI, 86-88).

Guidelines from the Society for Thoracic Surgeons (Fernando, et al., 2009) state: “Advanced endoscopic imaging technologies, such as narrow-band imaging, auto-fluorescence, and confocal laser endo-microscopy have been used in attempts to improve detection of dysplasia. Another approach is the use of vital stains, such as methylene blue, acetic acid, or indigo carmine, which can help direct and reduce the number of biopsies required to detect HGD with a segment of Barrett’s. These promising modalities have not currently demonstrated superiority to existing biopsy protocols.”

Guidelines on management of BE from the American Gastroenterological Association (2011) state: "For the routine endoscopic evaluation of Barrett’s esophagus, the use of chromoendoscopy or electronic chromoendoscopy or advanced imaging techniques such as confocal laser endomicroscopy is not necessary. These technologies may be helpful in guiding the performance of biopsies in patients who are known to have dysplasia and in patients who have mucosal irregularities detected by white light endoscopy. Quality of Evidence: Low.”

Guidelines on the role of endoscopy in Barrett’s esophagus and other premalignant conditions of the esophagus from the American Society for Gastrointestinal Endoscopy (2012) state: “Adjuncts to white-light endoscopy used to improve the sensitivity for the detection of BE and dysplastic BE include chromoendoscopy, electrical enhanced imaging, magnification, and confocal endoscopy. These techniques are still in development and are discussed in detail elsewhere.” An ASGE guidelilne on upper endoscopic surveillance (Hirota, et al., 2011) states: "The use of chromoendoscopy and enhanced endoscopic imaging to highlight an area for targeted biopsies shows promise, but the results appear to be poorly reproducible."

Guidelines from the Danish Society of Gastroenterology and Hepatology (Bremholm et al, 2012) state: "There is at present no evidence that routine use of chromoendoscopy or narrow band imaging (NBI), neither for diagnosis nor biopsy guidance, increases the number of or the precision of diagnostic findings. However, improved endoscopic image modalities (High Definition Endoscopy, Zoom-technique and NBI) is likely to improve the identification of dysplasia, and may possibly be used in targeting biopsies in follow-up endoscopies of BE."

A consensus statement (2012) concluded, based on "very low" quality evidence: "For evaluation of patients with BE, the use of high-resolution endoscopes and targeted biopsies of every suspicious lesion followed by 4-quadrant biopsies every 1–2 cm are recommended. Agreement: A 60 %, A 38 %, U 1 %, D 0 %, D 1 %. Evidence: Very low." The consensus statement explained: "A high-resolution endoscope (850,000 pixels) should be used to evaluate patients with BE. Standard-resolution endoscopes are not recommended, although there is scant scientific evidence for this recommendation. Evidence that greater resolution improves diagnosis is only available and supports narrow band imaging, but for chromoendoscopy there was no superiority to chromoendoscopy over standard endoscopy, although acetic acid spraying can improve visualization of lesions. Even with high-resolution endoscopes, 4-quadrant biopsies are still necessary after careful evaluation of the BE segment to exclude synchronous neoplastic lesions."

Guidelines on BE from the British Society of Gastroenterology (Fitzgerald et al, 2014) state: “Other imaging techniques that have showed some value in Barrett’s oesophagus include confocal laser endomicroscopy, spectroscopy and optical coherence tomography; however, further studies are needed to clarify whether they can improve diagnostic accuracy during Barrett’s oesophagus surveillance.”

Current guidelines on from Alberta Health Services (2014) on management of patients with early esophageal cancer, dysplastic and non-dysplastic Barrett’s esophagus make no recommendation for confocal laser endomicroscopy.

The French National Authority for Health (HAS, 2014) has initiated a review of  endomicroscopic optical techniques for BE. The review protocol state that esophageal endomicroscopy does not replace histological examination. Histology provides the information necessary to diagnose and characterize lesions, and the depth of viewing of endomicroscopy is insufficient to assess invasion and thus guide treatment modalities (endoscopic or surgical). The HAS noted that the use of endomicroscopy could be justified with the development of endosopic treatment of neoplastic lesions localized to the mucosa. The forthcoming HAS review will focus on this issue.

An American Gastroentrological Association White Paper (Sharma, et al., 2015) summarized the opinions of participants in a two-day workshop on endoscopic imaging-enhancing technologies. The workshop summary stated that several enhanced imaging technologies are now available to endoscopists for the management of patients with Barrett's esophagus. Narrow-band imaging and confocal laser endoscopy have reached preservation and incorporation of valuable endoscopic innovation (PIVI) thresholds for eliminating random biopsies during BE surveillance in some studies at referral centers. The workshop summary stated, however, that these techniques ideally need to be validated in larger cohorts and in nonacademic centers. "As it stands today, detailed endoscopic examination with [high-definition white-light endoscopy] HDWLE and random 4-quadrant biopsy remains the standard of care." However, the workshop panelists agreed that in the hands of endoscopists who have met the PIVI thresholds with specific enhanced imaging techniques, use of the technique in BE patients is appropriate. The worshop summary stated that quality metrics (such as the BE inspection time) need to be developed and adopted for BE examination to ensure that BE patients receive high-quality endoscopic examinations. 

The Preservation and Incorporation of Valuable Endoscopic Innovation (PIVI) initiative implemented by the American Society of Gastrointestinal Endoscopy (ASGE)  recommends that, before replacing the current Seattle protocol, a targeted imaging technique should have a per patient sensitivity of at least 90%, an NPV of at least 98%, and a specificity of at least 80% in the detection of high-grade dysplasia or early adenocarcinoma. A systematic evidence review by the American Society for Gastrointestinal Endoscopy found that that targeted biopsies with acetic acid chromoendoscopy, electronic chromoendoscopy by using narrow-band imaging, and endoscope-based CLE meet the thresholds set by the ASGE PIVI, at least when performed by endoscopists with expertise in advanced imaging techniques. The ASGE Technology Committee endorsed nonpreferentially using any of these advanced imaging modalities to guide targeted biopsies for the detection of dysplasia during surveillance of patients with previously nondysplastic BE, thereby replacing the currently used random biopsy protocols.

A meta-analysis by Fugazza et al (2016) of confocal laser endomicroscopy for gastrointestinal and pancreobiliary diseases demonstrated that confocal laser endoscopy yields a “per biopsy” pooled sensitivity of 58% and a pooled specificity of 90%, which was slightly increased to 79% sensitivity in the “per patient” analysis. The authors concluded, therefore, based on the PIVI initiative requirements, using CLE for the surveillance of BE does not appear to be sensitive enough to replace the Seattle biopsy protocol. The authors noted. however, that a recent multicenter RCT showed that combining CLE with high-definition WLE surpassed the PIVI threshold, with a per patient sensitivity of 95%, an NPV of 98% and a specificity of 92% [citing Canto, et al., 2014)]. The authors state that this study suggests tht the combined use of CLE with high-definition WLE or NBI may be considered a valuable diagnostic tool for premalignant and malignant lesions. The authors concluded "[n]evertheless, prospective medicoeconomic studies have yet to be conducted."

American College of Gastroentrology guidelines on BE (Shaheen et al, 2016) state that "A wide variety of other image enhancement techniques have been studied including methylene blue staining, acetic acid staining, indigo carmine staining, autofluorescence endoscopy, confocal laser endomicroscopy, volumetric laser endomicroscopy, spectroscopy, and molecular imaging, but none of these methods appear ready for widespread clinical use at present."

Gastrectomy

UpToDate reviews on “Management of Barrett's esophagus” (Spechler, 2015) and “Barrett's esophagus: Treatment of high-grade dysplasia or early cancer with endoscopic resection” (Bergman, 2015) do not mention gastrectomy as a management tool.

Bariatric Surgery

Furthermore, the ACG’ clinical guideline on “Diagnosis and management of Barrett's esophagus” (Shaheen et al, 2016) does not mention bariatric surgery as a therapeutic option.

Biomarker Panels

Eluri and colleagues (2015) noted that risk stratification in BE is challenging. These investigators evaluated the ability of a panel of genetic markers to predict progression to HGD or EAC.  In this case-control study, these researchers assessed a measure of genetic instability, the mutational load (ML), in predicting progression to HGD or EAC.  Cases had non-dysplastic BE or LGD at baseline and developed HGD/EAC greater than or equal to 1 year later.  Controls were matched 2:1, had non-dysplastic BE or LGD, and no progression at follow-up.  Formalin-fixed, paraffin-embedded tissue was micro-dissected for the epithelium.  Loss of heterozygosity (LOH) and microsatellite instability (MSI) were assessed; ML was calculated from derangements in 10 genomic loci.  High-clonality LOH mutations were assigned a value of 1, low-clonality mutations were assigned a value of 0.5, and MSI 0.75 at the first loci, and 0.5 for additional loci.  These values were summed to the ML.  Receiver operator characteristic (ROC) curves were created.  There were 69 patients (46 controls and 23 cases).  Groups were similar in age, follow-up time, baseline histology, and the number of micro-dissected targets.  Mean ML in pre-progression biopsies was higher in cases (2.21) than in controls (0.42; p < 0.0001).  Sensitivity was 100 % at ML greater than or equal to 0.5 and specificity was 96 % at ML greater than or equal to 1.5.  Accuracy was highest at 89.9 % for ML greater than or equal to 1; ROC curves for ML greater than or equal to 1 demonstrated an area under the curve (AUC) of 0.95.  The authors concluded that ML in pre-progression BE tissue predicted progression to HGD or EAC.  Moreover, they stated that although further validation is needed, ML may have utility as a biomarker in endoscopic surveillance of BE.

Findlay et al (2016) stated that BE is a common and important precursor lesion of EAC; 1/3 of patients with BE are asymptomatic, and the ability to predict the risk of progression of metaplasia to dysplasia and EAC (and therefore guide management) is limited. There is an urgent need for clinically useful biomarkers of susceptibility to both BE and risk of subsequent progression.  These researches identified, reviewed, and meta-analyzed genetic biomarkers reported to predict both.  A systematic review of the PubMed and Embase databases was performed in May 2014.  Study and evidence quality were appraised using the revised American Society of Clinical Oncology guidelines, and modified Recommendations for Tumor Marker Scores.  Meta-analysis was performed for all markers assessed by more than 1 study.  A total of 251 full-text articles were reviewed; 52 were included.  A total of 33 germline markers of susceptibility were identified (level of evidence II to III); 17 were included; 5 somatic markers of progression were identified; meta-analysis demonstrated significant associations for chromosomal instability (level of evidence II).  One somatic marker of progression/relapse following photodynamic therapy was identified.  However, a number of failings of methodology and reporting were identified.  This was the first systematic review and meta-analysis to evaluate genetic biomarkers of BE susceptibility and risk of progression.  The authors concluded that while a number of limitations of study quality tempered the utility of those markers identified, some-in particular, those identified by genome-wide association studies, and chromosomal instability for progression-appear plausible, although robust validation is needed.  Moreover, these researchers stated that the overall evidence base was characterized by widespread methodological issues, which limited the immediate clinical utility of these markers.  They stated that larger studies with more robust design are needed to validate these markers, identify novel variants, and incorporate them into clinical practice.

The ACG updated its guidance for the best practices in caring for patients with BE (Shaheen et al, 2016). These guidelines continue to endorse screening of high-risk patients for BE; however, routine screening is limited to men with reflux symptoms and multiple other risk factors.  Acknowledging recent data on the low risk of malignant progression in patients with non-dysplastic BE, endoscopic surveillance intervals are attenuated in this population; patients with non-dysplastic BE should undergo endoscopic surveillance no more frequently than every 3 to 5 years.  Neither routine use of biomarker panels nor advanced endoscopic imaging techniques (beyond high-definition endoscopy) is recommended at this time.  Endoscopic ablative therapy is recommended for patients with BE and HGD, as well as T1a EAC.  Based on recent level 1 evidence, endoscopic ablative therapy is also recommended for patients with BE and LGD, although endoscopic surveillance continues to be an acceptable alternative.  Given the relatively common recurrence of BE after ablation, the guidelines suggested post-ablation endoscopic surveillance intervals.  The authors noted that although many of the recommendations provided were based on weak evidence or expert opinion, this document provided a pragmatic framework for the care of the patient with BE.

Measurements of Serum Levels of Adipokines and Insulin

Chandar et al (2015) stated that metabolically active visceral fat may be associated with esophageal inflammation, metaplasia, and neoplasia. These researchers performed a meta-analysis to evaluate the association of serum adipokines and insulin with BE.  They performed a systematic search of multiple electronic databases, through April 2015, to identify all studies reporting associations between leptin, adiponectin, insulin, insulin resistance, and risk of BE in adults.  Comparing the highest study-specific category with the reference category for each hormone, these investigators estimated the summary adjusted odds ratio (aOR) and 95 % CI, using a random effects model.  They identified 9 observational studies (10 independent cohorts; 1,432 patients with BE total, and 3,550 control subjects).  Meta-analysis revealed that high serum level of leptin was associated with 2-fold higher risk of BE (BE cases versus population control subjects in 5 studies: aOR, 2.23; 95 % CI: 1.31 to 3.78; I(2), 59 %).  Total serum level of adiponectin was not associated with BE (BE cases versus population control subjects in 5 studies: aOR, 0.79; 95 % CI: 0.46 to 1.34; I(2), 65 %), although 1 study observed decreased risk of BE with increased level of low-molecular-weight adiponectin.  High serum level of insulin was associated with increased risk of BE (BE cases versus population control subjects in 3 studies: aOR, 1.74; 95 % CI: 1.14 to 2.65; I(2), 0), whereas insulin resistance was not associated with increased risk of BE (BE cases versus GERD control subjects in 2 studies: aOR, 0.98; 95 % CI: 0.42 to 2.30; I(2), 64 %).  The authors concluded that increased serum levels of leptin and insulin are associated with increased risk of BE, compared with population control subjects.  In contrast, increased total serum levels of adiponectin and insulin do not seem to modify BE risk.  They stated that well-designed longitudinal studies of incident BE are needed to clarify existing associations of serum adipokines and insulin with BE.

SOX2 Expression Testing for Prediction of Neoplastic Progression in BE

van Olphen et al (2015) evaluated the predictive value (PV) of SOX2 expression for neoplastic progression in BE patients. These researchers conducted a case-control study within a prospective cohort of 720 BE patients.  Patients with neoplastic progression, defined as the development of HGD or EAC, were classified as cases and patients without neoplastic progression were classified as controls.  SOX2 expression was determined by immunohistochemistry in more than 12,000 biopsies from 635 patients; these results were combined with the authors’ previous p53 immunohistochemical data.  Non-dysplastic BE showed homogeneous nuclear staining for SOX2, whereas SOX2 was progressively lost in dysplastic BE.  Loss of SOX2 was seen in only 2 % of biopsy series without dysplasia, in contrast to 28 % in LGD and 67 % in HGD/EAC.  Loss of SOX2 expression was associated with an increased risk of neoplastic progression in BE patients after adjusting for gender, age, BE length, and esophagitis (adjusted relative risk 4.8; 95 % CI: 3.2 to 7.0).  The positive PV for neoplastic progression increased from 16 % with LGD alone to 56 % with concurrent loss of SOX2 and aberrant p53 expression.  The authors concluded that SOX2 expression is lost during transition from non-dysplastic BE to HGD/EAC, and it is associated with an increased risk of neoplastic progression.  The highest PV is achieved by concurrent loss of SOX2 and aberrant p53 expression in BE patients with LGD.  They stated that the use of these markers has the potential to significantly improve risk stratification of Barrett surveillance.

Markers of Intestinal Phenotype, Mucin Glycoprotein Immunostains, and p53

Srivastava and colleagues (2017) noted that BE is a known risk factor for the development of esophageal adenocarcinoma.  Pathologists play a critical role in confirming the diagnosis of BE and BE-associated dysplasia.  As these diagnoses are not always straight-forward on routine hematoxylin and eosin-stained slides, numerous ancillary stains have been used in an attempt to help pathologists confirm the diagnosis.  On the basis of an in-depth review of the literature, the Rodger C. Haggitt Gastrointestinal Pathology Society provided recommendations regarding the use of ancillary stains in the diagnosis of BE and BE-associated dysplasia.  The authors stated that because goblet cells are almost always identifiable on routine hematoxylin and eosin-stained sections, there is insufficient evidence to justify reflexive use of Alcian blue (at pH 2.5) and/or periodic-acid Schiff stains on all esophageal biopsies to diagnose BE.  In addition, the use of mucin glycoprotein immunostains and markers of intestinal phenotype (CDX2, Das-1, villin, Hep Par 1, and SOX9) are not indicated to aid in the diagnosis of BE at this time.  A diagnosis of dysplasia in BE remains a morphologic diagnosis, and hence, ancillary stains are not recommended for diagnosing dysplasia.  Although p53 is a promising marker for identifying high-risk BE patients, it is not recommended for routine use at present; additional studies are needed to address questions regarding case selection, interpretation, integration with morphologic diagnosis, and impact on clinical outcome.

Cryotherapy for Persistent Barrett's Esophagus after Radiofrequency Ablation

Visrodia and colleagues (2018) stated that a small but significant proportion of patients with BE have persistent dysplasia or IM after treatment with RFA. These investigators examined the efficacy of 2nd-line cryotherapy in patients with BE who have persistent dysplasia or IM after RFA by conducting a systematic review and meta-analysis  They performed a systematic literature search of PubMed, Embase, and Web of Science through September 1, 2017.  Articles were included for meta-analysis based on the following inclusion criteria: greater than or equal to 5 patients with BE treated with RFA had persistent dysplasia or IM; they subsequently underwent greater than or equal to 1 session of cryotherapy with follow-up endoscopy; the proportions of patients achieving complete eradication of dysplasia (CE-D) and/or IM (CE-IM) were reported.  The main outcomes were pooled proportions of CE-D and CE-IM by using a random effects model.  A total of 11 studies making up 148 patients with BE treated with cryotherapy for persistent dysplasia or IM after RFA were included.  The pooled proportion of CE-D was 76.0 % (95 % CI: 57.7 to 88.0), with substantial heterogeneity (I2 = 62 %).  The pooled proportion of CE-IM was 45.9 % (95 % CI: 32.0 to 60.5) with moderate heterogeneity (I2 = 57 %).  Multiple pre-planned sub-group analyses did not sufficiently explain the heterogeneity; adverse effects were reported in 6.7 % of patients.  The authors concluded that cryotherapy successfully achieved CE-D in 3/4 and CE-IM in 50 % of patients with BE who did not respond to initial RFA. They stated that considering its favorable safety profile, cryotherapy may be a viable 2nd-line option for this therapeutically challenging cohort of patients with BE, however, higher-quality studies are needed to validate these findings.

The authors stated that this meta-analysis had several potential limitations.  All included studies were relatively small and observational, and most studies were single-center series published in abstract form alone, amounting to a limited set of data from which these investigators derived the earlier conclusions.  This was not surprising given that the vast majority of patients would respond to RFA.  Because there is no uniformly accepted definition for RFA-refractory BE, criteria for proceeding to cryotherapy varied among institutions.  However, 5 studies had a reported minimum number of RFA sessions, and most studies reported a mean-median 2 to 3 RFA sessions before cryotherapy was initiated.  These researchers recognized that it is not uncommon for patients to require greater than 2 to 3 RFA sessions to achieve CE-D or CE-IM, and so switching to a 2nd-line therapy at this juncture may be considered premature.  However, these investigators suspected this was done in select patients who had a very poor initial response to RFA, and additional RFA was deemed low yield, but they could not be sure.  Furthermore, long-term follow-up was not reported in the majority of studies, limiting conclusions regarding the risk of recurrence or progression in this seemingly higher risk cohort.  The authors encountered moderate-to-substantial heterogeneity that could not be explained by several pre-planned subgroup analyses.  However, such heterogeneity was not uncommon in studies of prevalence and/or proportion, and conceptually the studies were similar based on the strict inclusion and exclusion criteria.

Mohan and colleagues (2019) noted that RFA is the preferred therapeutic option for BE to achieve CE-D, and CE-IM.  Cryotherapy, using liquid nitrogen (LNC), is a cold-induced tissue-injury technique option for the ablation of BE.  These investigators performed a systematic review and meta-analysis to evaluate the overall safety and efficacy of LNC in the treatment of BE.  They carried out a search of multiple electronic databases and conference proceedings from inception through June 2018.  The primary outcome was to estimate the pooled rates of CE-IM, CE-D, and CE-HGD.  The secondary outcome was to estimate the risk of adverse events (AEs) and recurrence of disease following LNC.  A total of 9 studies reported 386 patients who were treated with LNC.  The pooled rate of CE-IM was 56.5 % (95 % CI: 48.5 to 64.2, I2 = 47), pooled rate of CE-D was 83.5 % (95 % CI: 78.3 to 87.7, I2 = 22.8), and pooled rate of CE-HGD was 86.5 % (95 % CI: 64.4 to 95.8, I2 = 88.1).  Rate of AEs was 4.7% , and the risk of BE recurrence was 12.7 %.  On subgroup analysis, the pooled rate of CE-IM with LNC in patients who failed RFA was 58.4 % (95 % CI: 47.2 to 68.8, I2 = 32.5), and the pooled rate of CE-D in the same population was 81.9 % (95 % CI: 72.5 to 88.6, I2 = 5.9).  CE-D rates with LNC were comparable to RFA while CE-IM rates appeared to be lower than the rates achievable with RFA; CE-IM rate in RFA failed patients was 58.4 %.  The authors concluded that  LNC was a rescue option to consider in RFA-failed BE patients.  At this time, data are lacking to say if LNC is inferior or superior to RFA in treatment-naive patients.  The quality of available data is weak with regards to cryotherapy as compared to RFA in treatment-naïve patients.  Hence with current available data, cryotherapy cannot be recommended as 1st-line treatment in BE.  Novel methods of cryogen delivery, like the nitrous-oxide cryo-balloon are promising and may soon make cryotherapy as acceptable 1rst-line treatment in BE.  These researchers stated that more prospective, well-conducted randomized studies are needed to answer this question.

The authors stated that this review/meta-analysis had several limitations.  The included studies were not entirely representative of the general population and community practice, with most studies being retrospective and performed in tertiary-care referral centers.  They did not include a comparator-group in their analysis against LNC.  These investigators were unable to identify a high-risk subset of patients undergoing the procedure who were likely to experience success, with minimal risk to AEs.  These researchers could not examine the influence of nodular-BE, and BE-length on the reported outcomes.  Patient related characteristics such as age, smoking, previous attempts and procedures, need to be accounted for in identifying this high-risk subset that may benefit from LNC in the treatment of BE.

Hamade and co-workers (2019) noted that cryotherapy has been used as salvage therapy; however, its efficacy as 1st-line treatment in patients with BE neoplasia has not been well studied.  In a systematic review, these researchers examined the efficacy of cryotherapy as the primary treatment of BE.  An electronic database search was performed (PubMed, Embase, Cochrane, and Google Scholar) to search for studies with cryotherapy as the initial primary modality of ablation in patients with BE neoplasia.  Studies that included patients with other prior forms of therapy were excluded.  The primary outcomes were the pooled rates of CE-IM and CE-N.  Secondary outcomes were recurrence rates of neoplasia and intestinal metaplasia (IM) and AEs.  The statistical software OpenMetaAnalyst was used for analysis with pooled estimates reported as proportions (%) with 95% CI with heterogeneity (I2) among studies.  The search revealed 6 eligible studies with a total of 282 patients (91.5 % men, average age of 65.3 years) with 459 person years of follow-up; 69.35 % (95 % CI: 52.1 % to 86.5 %) of patients achieved CE-IM and 97.9 % (95 % CI: 95.5 % to 100 %) had CE-N; 7.3 % of patients had persistent dysplasia with 4 % progressing to cancer.  The recurrence rate of neoplasia was 10.4 and that of IM was 19.1 per 100 patient years of follow-up.  The overall rate of stricture formation was 4.9 %.  There were scarce data on the use of cryotherapy as the primary modality for the treatment of BE dysplasia.  The authors concluded that the published data demonstrated efficacy rates of 69 % and 98 % for complete eradication of metaplasia and neoplasia, respectively.   Moreover, these researchers stated that these findings need to be evaluated in prospective, comparative trials with other forms of therapy; higher quality studies and head-to-head comparison trials are still needed to better define the true efficacy of cryotherapy and enhance the generalizability of results.  Data on the safety and efficacy of the next-generation cryo-balloon devices are awaited.

The authors stated that this study had several drawbacks.  First, none of the included studies was RCTs; most studies were performed in single centers with tertiary level of care, which could affect the generalizability of the results.  Procedures were probably performed by expert endoscopists with experience in cryotherapy and management of BE.  Furthermore, the retrospective nature of the studies may have led to an under-estimation of the rates of AEs.  There was also significant heterogeneity among the studies, which could be from methodological and clinical variation.  Unfortunately, this heterogeneity could not be examined due to inherent limitations of the nature of the analysis and scope of the paper.  Also, these investigators were unable to determine the baseline length of BE in the studies, which was of importance since a longer BE would likely lead to more failed treatment, increased recurrence, and increased stricture rates.  Due to lack of information from the included studies, these researchers were unable to stratify AEs based on confounders.  Finally, only 6 studies with small sample size were available for analysis, which increased risk of bias.  These researchers stated that findings of this pooled analysis should be further confirmed in a RCT comparing cryotherapy against standard of care in patients who are ablation naive.

In a meta-analysis, Westerveld and colleagues (2020) examined the feasibility, safety and effectiveness of balloon cryoablation (BC) for the treatment of BE neoplasia.  Several databases were searched for relevant articles (PubMed, Web of Science, Google Scholar, Embase) as well as abstracts of recent gastroenterology meetings.  Data extraction was carried out by 2 investigators using standardized forms, including age, gender, length of BE segment, prior treatments, procedural time and number ablation sessions, technical feasibility, AEs, and eradication rates of intestinal metaplasia (CE-IM) and dysplasia (CE-D) at follow-up.  Quality of the studies was evaluated using a modified Newcastle Ottawa Scale.  A total of 7 studies met inclusion criteria for 548 ablation sessions in 272 patients.  The most common histopathology reported prior to BC was HGD (n = 131), followed by LGD (n = 75), and intra-mucosal adenocarcinoma (n = 52).  The pooled rate for technical feasibility was 95.8 % (95 % CI: 93.6 to 97.5 %; I2  = 13.2 %; p  = 0.3).  Pooled rates of CE-IM and CE-D were 85.8 % (95 % CI: 77.8 to 92.2 %, I2  = 55.5 %; p = 0.04) and 93.8 % (95 % CI: 85.5 to 98.7 %, I2  = 74.2 %; p  = 0.001), respectively.  The overall AE rate was 12.5 % (34 out of 272 patients), of which stricture formation was the most common (5.8 %), followed by mucosal laceration (0.7 %), perforation (0.4 %), and bleeding (0.4 %).  All AEs were successfully managed endoscopically.  The authors concluded that the cryoablation balloon is a novel, portable, easy-to-use device that may be suitable for primary and secondary treatment of patients with BE.  Moreover, these researchers stated that larger prospective, and preferably comparative trials are needed to further define the role of BC in the treatment algorithm of patients with BE-associated neoplasia.

The authors stated that this meta-analysis had several drawbacks.  Given the relative novelty of BC for the treatment of BE, all of the included studies were relatively small, observational, and many had only been published in abstract form alone.  As previously noted, the pooled proportions of CE-IM and CE-D included both treatment naive as well as RFA-refractory patients with BE, which contributed to the heterogeneity noted in the analysis and the possibility of confounding of the effectiveness outcome.  Moreover, performing a meta-analysis of observational studies presented challenges in interpreting the study outcome due to the inherent biases in the included studies.  In this study confounding biases may include the afore-mentioned lack of reporting of patient treatment with RFA in 2 studies and reporting of treatment duration to name a few.  Publication bias, as in the selection of publications based on their cohort size and language of publication should also be considered.  This study reported funnel plots to aid in detection of publication bias, however, the lack of sensitivity analysis for confounders presented a limitation of this study.  Furthermore, many of the studies assessed clinical outcomes following only 1 session of BC.  The relatively short follow-up precluded any definitive conclusions on the effectiveness of BC in maintaining CE-IM and CE-D and the potential rate of incomplete treatment versus recurrence rates.  Nonetheless, this meta-analysis of the current available literature on BC is promising, albeit underscored the need for high-quality studies.

van Munster and colleagues (2020) stated that most guidelines for BE recommend RFA as 1st-choice option for dysplastic BE, or after endoscopic resection of early cancer.  Numerous high-quality (randomized) studies have demonstrated that RFA for these indications is safe and effective.  In recent years, an increasing number of studies appeared, examining the use of new ablation techniques such as cryo-spray ablation, cryo-balloon ablation (CBA) and (hybrid) argon plasma coagulation (APC).  These investigators noted that Westerveld et al (2020) reported the findings of a systematic review that examined the rates of CE-IM and CE-D following CBA.  The meta-analysis included 7 clinical studies with a total of 272 patients.  The pooled rates for all outcomes were: feasibility (95.8 %), CE-IM (85.8 %) and CE-D (93.8 %), defined as the proportion of patients that achieved clearance of IM/dysplasia.  The overall AE rate was 12.5 %.  Based on these results, Westerveld et al concluded that CBA is a safe and effective ablation technique for treatment of BE neoplasia.  van Munster et al (2020) stated that a new ablation tool first needs several small studies to prove that it is feasible and these should be followed by at least 1 prospective, large, single-arm study to prove that the technique is mature.  Before that, systematic reviews do not provide reliable evidence for safety and efficacy of the technology.

Extracellular microRNAs (miRNAs) as Biomarkers of Barrett’s Esophagus

Clark and colleagues (2018) stated that esophageal adenocarcinoma (EAC) is a highly aggressive malignancy that develops from BE.  MicroRNAs (miRNAs), short non-coding regulatory RNAs, are frequently dysregulated in BE and are thought to play key roles in the onset of BE and its progression to EAC; thus, miRNAs have potential diagnostic and prognostic value and are increasingly being used as cancer biomarkers.  In a systematic review, these investigators summarized the current literature related to miRNAs that are dysregulated in BE within the context of Hedgehog, Notch, MAPK, NF kappa-B, Wnt and epithelial-mesenchymal transition (EMT) signaling, which are thought to drive BE onset and progression.  This comprehensive analysis of miRNAs and their associated signaling in the regulation of BE provided an overview of vital discoveries in this field and highlighted gaps in the understanding of BE pathophysiology that warrant further investigation.  The authors concluded that identification of clinically reliable early miRNA biomarkers of BE will require extensive validation and a deeper understanding of the cellular signaling events that drive BE development.  Of the miRNAs discussed, it remains unclear which miRNAs have the potential to serve as biomarkers specific to BE and which are broad spectrum cancer biomarkers.  They stated that further studies into the mechanisms by which circulating miRNAs become differentially expressed are needed to identify those miRNAs of real clinical importance.  A number of technical challenges remain that have hindered current efforts at identifying miRNA biomarkers including low miRNA yield from serum samples, lack of suitable endogenous miRNA controls, and a lack of strategies to deal with normal variation in circulating miRNA levels.  These researchers noted that improved early detection of BE and other cancers will only occur by overcoming these technical challenges and by obtaining a more detailed understanding of miRNA signaling network.

Inokuchi and colleagues (2020) stated that EAC, the major histologic type of esophageal cancer (EC) in Western countries, is a disease with a poor prognosis, primarily due to usual diagnosis at an advanced stage.  The prevalence of EAC has increased in recent years, both in Western countries and in Asia.  Barrett's esophagus (BE) is a precursor lesion of EAC; thus, early detection and proper management of BE and EAC is important to improve prognosis.  In a systematic review, these investigators examined the available evidence regarding the potential use of extracellular microRNAs (miRNAs), which are thought to be non-invasive biomarkers for many diseases, for these purposes.  They carried out a search of the PubMed and Embase databases; and identified 22 papers on extracellular miRNAs that have potential use for the management of EAC.  Among them, 19 were EAC-related and 10 were BE-related; some of these addressed both conditions.  The articles included studies reporting diagnosis, prognosis, and treatment responses.  Multiple papers reported dysregulation of miR-194-5p in BE and miR-21-5p, -25-3p, and -93-5p in EAC.  The authors concluded that many miRNAs have been identified in the context of BE/EAC diagnosis and prognosis. In particular, several studies identified the same serum miRNAs (miR-21-5p, miR-25-3p, and miR93-5p) as being associated with EAC.  However, since these studies were small-scale, and the sample types, method of miRNA analysis, pathological definition of disease, study populations, and outcomes varied, it was hard to identify useful miRNAs.  These researchers stated that in order to bring miRNA analysis into clinical practice, investigators must overcome many challenges, including standardization of methodologies, improvement of diagnostic performance, and cost-effectiveness.  They stated that further investigations are needed to establish extracellular miRNAs as useful clinical biomarkers.

Barrett’s Esophagus Fluorescence In Situ Hybridization (FISH) Assay (e.g., MolDX)

According to Acupath Laboratories (2018), the Barrett’s esophagus FISH assay utilizes esophageal brushings, collected in conjunction with biopsies, to identify genetic abnormalities that enable the clinician to risk stratify patients into high and low risk groups.  The test provides objective information to use when determining the aggressiveness of treatment and addresses several important deficiencies of current biopsy methodology including sampling error, the time required to collect the recommended # of biopsies, and inter-observer variability. 

Rossi et al (2006) noted that Her-2/neu is a proto-oncogene frequently over-expressed in breast cancer, recently found to be also over-expressed in carcinoma arising on BE.  Immunohistochemistry and FISH are conventionally used for Her-2 testing in carcinomas, but a single assay is not yet accepted as a "gold standard" in BE.  These investigators evaluated the correlation between histopathology variables and gene expression/amplification in the sequence BE-low grade dysplasia (LGD)-high grade dysplasia (HGD)-adenocarcinoma.  A total of 50 esophageal specimens from patients with a diagnosis of BE (21 BE, 4 LGD, 12 HGD, and 13 adenocarcinomas) were evaluated.  Histopathologic evaluation was carried out using hematoxylin and eosin staining.  Paraffin-embedded tissues were investigated for Her-2 by immunohistochemistry (HercepTest) and FISH.  HercepTest was scored 0, 1+, 2+, and 3+ depending on the percentage (cut-off 10 %) of membrane staining, whereas gene assessment evaluated by FISH was based on the ratio between Her-2/neu and the 17 chromosome copy number.  There was a positive correlation between gene amplification and protein over-expression.  No case with HercepTest scoring 0 or 1+ displayed gene amplification, but this was present in 20 % of cases scoring 2+ and in all cases scoring 3+.  Her-2/neu amplification or over-expression was never observed in BE.  Gene amplification and over-expression was observed in more than 50 % of dysplasias and adenocarcinomas.  The authors concluded that Her-2/neu amplification/over-expression might be considered as a marker of progression from BE to dysplasia; FISH may represent a useful diagnostic tool to integrate the result of HercepTest for selecting patients for more targeted therapeutic approaches.

Rygiel et al (2007) stated that automated assessment of genetic abnormalities detected by FISH in brush cytology specimens from patients with BE may enhance the clinical applicability of this methodology.  These  researchers attempted to validate a novel, automated, proprietary system (CytoVison SPOT AX) for the assessment of FISH abnormalities in BE brush cytology and, subsequently used this automated method for screening of a BE surveillance cohort.  FISH with DNA probes for chromosomes 9, 17, and Y, and for the 9p21 (p16), 17q11.2 (Her2/neu), and 17p13.1 (p53) loci was applied on brush cytology specimens from a surveillance cohort of 151 patients with BE.  Validation of the automated system was performed by comparison of the automated FISH results with manual scores for the first 60 patients.  There was 98 % concordance between manual and automated FISH analysis with kappa values from 0.49 to 1 for the different probes.  The loss of 17p13.1 (p53) was observed in only 5 % of patients with no dysplasia (ND) and in 9 % of patients with LGD but increased to 46 % in patients with HGD (p < 0.005; Fisher exact test).  Chromosomes 9 and 17 were observed in 6 % of patients with ND, in 21 % of patients with LGD, and in 62 % of patients with HGD (p < 0.05); 10 % of patients with ND had loss of the Y chromosome, which increased to 27 % in patients with HGD (p < 0.05).  The amplification of 17q11.2 (Her2/neu) was detected in 62 % of patients with HGD (p < 0.001).  The authors concluded that the findings of this study indicated that the CytoVison SPOT AX is an objective, efficient system for the analysis of DNA-FISH on BE brush cytology and is applicable for analyzing large populations of BE patients.  In the current study cohort, the loss of 17p13.1 (p53), Y chromosome loss, and polysomy of chromosomes 17 and 9 were correlated with increasing grade of dysplasia in patients with BE.  Moreover, these researchers stated that future follow-up of the surveillance cohort are needed to prove the true predictive value of these abnormalities.  They believed that the potential of automated FISH analysis for the accurate assessment of important genetic changes can improve the effectiveness of future surveillance programs.

Fritcher et al (2008) stated that new detection methods with prognostic power are needed for early identification of dysplasia and EA in patients with BE.  These investigators evaluated the relative sensitivity and specificity of conventional cytology, DNA ploidy analysis with digital image analysis (DIA), and FISH for the detection of dysplasia and adenocarcinoma in endoscopic brushing specimens from 92 patients undergoing endoscopic surveillance for BE.  FISH used probes to 8q24 (C-MYC), 9p21 (P16), 17q12 (HER2), and 20q13; 4-quadrant biopsies taken every centimeter throughout visible Barrett's mucosa were used as the gold standard.  The sensitivity of cytology, DIA, and FISH for LGD was 5 %, 5 %, and 50 %, respectively; for HGD, 32 %, 45 %, and 82 %, respectively; and for EA, 45 %, 45 %, and 100 %, respectively.  FISH was more sensitive (p < 0.05) than cytology and DIA for LGD, HGD, and EA.  The specificity of cytology, DIA, and FISH among patients (n = 14) with tissue showing only benign squamous mucosa was 93 %, 86 %, and 100 % (p = 0.22), respectively.  All patients with a polysomic FISH result had HGD and/or EA within 6 months (n = 33).  There was a significant difference between FISH categories (negative, 9p21 loss, gain of a single locus, and polysomy) for progression to HGD/EA (p < 0.001).  The authors concluded that these findings suggested that FISH has high sensitivity for the detection of dysplasia and EA in BE patients, with the power to stratify patients by FISH abnormality for progression to HGD/EA.  Moreover, they stated that further studies in a general population are needed to determine the appropriate use of FISH results in clinical practice.  The authors noted that the main drawback of this study was that there were few patients with a histologic diagnosis of benign squamous epithelium (n = 14) at the time of the brushing because of the high prevalence of disease in this population.  This limitation may explain the fact that the specificity of “Cytology P + S + A” was unexpectedly the same as the specificity of “Cytology P + S”.  

Brankley et al (2012) noted that the progression of intestinal metaplasia to EA in patients with BE is partly driven by chromosomal alterations that activate oncogenes and inactivate tumor suppressor genes.  These researchers determined how alterations of 4 frequently affected genes correlate with the range of histopathologic lesions observed in resected esophagi of patients with BE; FISH was used to assess 83 tissue sections from 10 BE esophago-gastrectomy specimens for chromosomal alterations of 8q24 (MYC), 9p21 (CDKN2A; alias P16), 17q12 (ERBB2), and 20q13.2 (ZNF217).  Histologic lesions assessed included gastric metaplasia (n = 8), intestinal metaplasia (n = 43), low-grade dysplasia (n = 28), high-grade dysplasia (n = 25), and adenocarcinoma (n = 16). Histologic maps showing the correlation between fluorescence in situ hybridization abnormalities and corresponding histology were created for all patients.  Chromosomal abnormalities included 9p21 loss, single locus gain, and polysomy.  A greater number of chromosomal alterations were detected as the severity of histologic diagnosis increased from intestinal metaplasia to adenocarcinoma.  All patients had alterations involving the CDKN2A gene.  CDKN2A loss was the only abnormality detected in 20 (47 %) of 43 areas of intestinal metaplasia.  Polysomy, the most common abnormality in dysplastic epithelium and adenocarcinoma, was observed in 16 (57 %) of 28 LGD, 22 (88 %) of 25 HGD, and 16 (100 %) of 16 adenocarcinoma.  The authors concluded that the findings of this study improved the understanding of the role that chromosomal instability and alterations of tumor suppressor genes such as CDKN2A and oncogenes such as ERBB2 play in the progression of intestinal metaplasia to adenocarcinoma in patients with BE.  These preliminary findings need to be validated by well-designed studies.

Brankley et al (2016) stated that BE with HGD defines a group of individuals at high risk of progression to EA; and FISH has been shown to be useful for the detection of dysplasia and EA in endoscopic brushing specimens from BE patients.  These researchers examined if FISH in combination with histological findings would further identify more rapid progressors to EA.  This is a retrospective cohort study of high-risk patients, having a history of biopsy-confirmed HGD without EA, with an endoscopic brushing specimen analyzed by FISH while undergoing endoscopic surveillance and treatment between April 2003 and October 2010.  Brushing specimens were assessed by FISH probes targeting 8q24 (MYC), 9p21 (CDKN2A), 17q12 (ERBB2), and 20q13 (ZNF217) and evaluated for the presence of polysomy, defined as multiple chromosomal gains (displaying greater than or equal to 3 signals for greater than or equal to 2 probes).  Specimens containing greater than or equal to 4 cells exhibiting polysomy were considered polysomic.  HGD was confirmed by at least 2 experienced gastro-intestinal pathologists.  Of 245 patients in this study, 93 (38.0 %) had a polysomic FISH result and 152 (62.0 %) had a non-polysomic FISH result.  Median follow-up was 3.6 years (interquartile range [IQR] 2 to 5 years).  Patients with a polysomic FISH result had a significantly higher risk of developing EA within 2 years (14.2 %) compared with patients with a non-polysomic FISH result (1.4 %, p < 0.001).  The authors concluded that these findings suggested that a polysomic FISH result in BE patients with simultaneous HGD identified patients at a higher risk for developing EA compared with those with non-polysomy.  Moreover, they stated that additional multi-institutional prospective studies are needed to confirm the findings of this study and to address the role of FISH analysis in predicting risk of progression to EA in a lower-risk BE population, including patients with LGD and non-dysplastic BE.

The ACG’s clinical guideline on “Diagnosis and management of Barrett’s esophagus” (Shaheen et al, 2016) does not mention FISH as a management tool.

Poneros et al (2017) noted that preliminary single-institution data suggested that FISH may be useful for detecting HGD and EA in patients with BE.  This multi-center study aimed to validate the measurement of polysomy (gain of at least 2 loci) by FISH as a way to discriminate degrees of dysplasia in BE specimens.  Tissue specimens were collected from 4 different hospitals and read by both the local pathology department ("Site diagnosis") and a single central pathologist ("Review diagnosis") at a separate institution.  The specimens then underwent FISH analysis using probes 8q24 (MYC), 9p21 (CDKN2A), 17q12 (ERBB2), and 20q13 (ZNF217) for comparison.  A total of 46 non-BE, 42 non-dysplastic specialized intestinal metaplasia (SIM), 23 indefinite-grade dysplasia (IGD), 10 LGD, 29 HGD, and 42 EA specimens were analyzed.  These investigators found that polysomy, as detected by FISH, was the predominant chromosomal abnormality present as dysplasia increased.  Polysomy was also the best predictor for the presence of dysplasia or EA when comparing its area under the curve to that of other FISH abnormalities.  These investigators observed that if at least 10 % of cells had polysomy within a specimen, the FISH probe was able to differentiate between EA/HGD and the remaining pathologies with a sensitivity of 80 % and a specificity of 88 %.  The authors concluded that the findings of this study demonstrated that using FISH to determine the percentage of cells with polysomy can accurately and objectively aid in the diagnosis of HGD/EA in BE specimens.  These findings need to be further investigated in well-designed studies.

Furthermore, UpToDate reviews on “Barrett's esophagus: Surveillance and management” (Spechler, 2018a) and “Barrett's esophagus: Epidemiology, clinical manifestations, and diagnosis” (Spechler, 2018b) do not mention FISH/fluorescent in situ hybridization as a management tool.

Methylated DNA Markers for Detection of Barrett's Esophagus

Iyer and colleagues (2018) stated that minimally invasive methods have been described to detect BE, but are limited by subjectivity and suboptimal accuracy.  These researchers identified methylated DNA markers (MDMs) for BE in tissue and assessed their accuracy on whole esophagus brushings and capsule sponge samples.  Step 1: Unbiased whole methylome sequencing was performed on DNA from BE and normal squamous esophagus (SE) tissue.  Discriminant MDM candidates were validated on an independent patient cohort (62 BE cases, 30 controls) by quantitative methylation specific PCR (qMSP).  Step 2: Selected MDMs were further evaluated on whole esophageal brushings (49 BE cases, 36 controls); 35 previously sequenced EAC MDMs were also evaluated.  Step 3: 20 BE cases and 20 controls were randomized to swallow capsules sponges (25 mm, 10 pores or 20 pores per inch (ppi)) followed endoscopy.  DNA yield, tolerability, and mucosal injury were compared.  Best MDM assays were performed on this cohort.  Step 1: 19 MDMs with AUCs of greater than 0.85 were carried forward.  Step 2: On whole esophageal brushings, 80 % of individual MDM candidates showed high accuracy for BE (AUCs: 0.84 to 0.94).  Step 3: The capsule sponge was swallowed and withdrawn in 98 % of subjects.  Tolerability was superior with the 10 ppi sponge with minimal mucosal injury and abundant DNA yield.  A 2-marker panel (VAV3 + ZNF682) yielded excellent BE discrimination (AUC = 1).  The authors concluded that identified MDMs discriminated BE with high accuracy; BE detection appeared safe and feasible with a capsule sponge.  Moreover, they stated that corroboration in larger studies is needed.

EsoGuard is an esophageal methylated DNA biomarker test for detecting BE.  There is a lack of evidence regarding the effectiveness of this assay/test.

An UpToDate review on “Barrett's esophagus: Epidemiology, clinical manifestations, and diagnosis” (Spechler, 2019a) does not mention the use of methylated DNA biomarkers as a diagnostic tool.

Optical Coherence Tomography or Evaluation of Barrett's Esophagus

Kohli and colleagues (2017) stated that optical coherence tomography (OCT) can generate high-resolution images of the esophagus that allows cross-sectional visualization of esophageal wall layers.  These researchers conducted a systematic review to assess the utility of OCT for diagnosing of esophageal IM, BE, dysplasia, cancer and staging of early esophageal cancer.  English language human observational studies and clinical trials published in PubMed and Embase were included if they assessed any of the following:

1. in-vivo features and accuracy of OCT at diagnosing esophageal IM, sub-squamous intestinal metaplasia (SSIM), dysplasia, or cancer, and
2. accuracy of OCT in staging esophageal cancer; 21 of the 2,068 retrieved citations met inclusion criteria.  

In the 2 prospective studies that assessed accuracy of OCT at identifying IM, sensitivity was 81 % to 97 %, and specificity was 57 % to 92 %.  In the 2 prospective studies that assessed accuracy of OCT at identifying dysplasia and early cancer, sensitivity was 68 % to 83 %, and specificity was 75 % to 82 %.  Observational studies described significant variability in the ability of OCT to accurately identify SSIM; 2 prospective studies that compared the accuracy of OCT at staging early squamous cell carcinoma (SCC) to histologic resection specimens reported accuracy of greater than 90 %.  Risk of bias and applicability concerns was rated as low among the prospective studies using the QUADAS-2 questionnaire.  The authors concluded that OCT may identify intestinal metaplasia and dysplasia, but its accuracy may not meet recommended thresholds to replace 4-quadrant biopsies in clinical practice.  They stated that OCT may be more accurate than EUS at staging early esophageal cancer, but randomized trials and cost-effective analyses are lacking.

Cytosponge for Screening and Surveillance of Barrett's Esophagus

Cytosponge is a mesh surrounded by gelatin capsule attached to a string that is passed trans-orally.  Five minutes after swallowing, the capsule dissolves in the proximal stomach, expanding the mesh to a sphere of 3 cm.  The sample containing cytological specimen is stained with Trefoil Factor3 (TFF3), which is a biomarker for IM.  In addition to TFF3, Cytosponge sample can be used for detection of other additional biomarkers for BE such as TFPI2, TWIST1, ZNF345, and ZNF569, which can further improve the sensitivity.

Iqbal and colleagues (2018) noted that esophageal adenocarcinoma is an increasingly common cause of morbidity and mortality in developed countries.  Most cases are considered the consequence of chronic GERD, with subsequent Barrett's metaplasia and dysplasia.  Because progression from Barrett's metaplasia to cancer occurs over many years, endoscopic screening and surveillance programs have been established, albeit with little or no consideration for cost-effectiveness.  As an alternative to the expensive and resource-demanding endoscopic surveillance, the Cytosponge has been developed to sample the esophageal mucosa efficiently.  The device is a compressed mesh sponge encapsulated in an ingestible gelatin pill attached to a string.  After swallowing, the capsule dissolves allowing the sponge to expand in the stomach.  As it is pulled out, cells are collected from the esophagogastric junction and throughout the esophagus.  The cellular samples can be analyzed by cytology, immunohistochemistry, and molecular markers.  These researchers conducted a systematic review of all recent relevant studies to help define the role of this novel technology, including studies of screening and surveillance of BE, esophageal squamous dysplasia detection, detection of eosinophilic esophagitis, and evaluation of benign esophageal diseases.  With the major limitation that most studies were performed by a single investigative group that developed the technology, the device yielded overall impressive results against the endoscopy/biopsy gold standard.  Patient acceptability was high.  The authors concluded that if these promising early findings are validated by other investigators in other populations, the Cytosponge represents an important new advance in the detection of esophageal pathology that could potentially decrease the burden of endoscopic esophageal sampling. 

Januszewicz and associates (2019) stated that non-endoscopic methods for diagnosis and surveillance of BE and eosinophilic esophagitis are needed.  Cytosponge is a minimally invasive device for esophageal cell sampling.  These researchers evaluated the safety and acceptability of this device.  They collected data from 5 prospective trials from patients with reflux disease, BE, or eosinophilic esophagitis in primary and secondary care.  They analyzed data from 2,672 Cytosponge procedures, performed in 2,418 individuals from 2008 through 2017.  Acceptability of the Cytosponge and subsequent endoscopy were calculated using the visual analogue scale (VAS; score of 0 for the lowest and 10 for highest level of acceptability) and compared using a Mann Whitney test.  The number of attempts, failures in swallowing the device, and occurrence of AEs were analyzed.  Risk factors for failure in swallowing were analyzed using a multi-variate regression model.  There were 2 AEs related to the device: a pharyngeal bleed and 1 case of detachment (less than 1:2000).  The median acceptability score for Cytosponge was 6.0 (IQR, 5.0 to 8.0), which was higher than for endoscopy without sedation (median of 5.0, IQR, 3.0 to 7.0; p < 0.001) and lower than for endoscopy with sedation (median of 8.0, IQR, 5.0 to 9.0; p < 0.001).  Nearly all patients (96.5 %) successfully swallowed the Cytosponge, most often on the 1st swallow attempt (90.1 %).  Failure to swallow the device was more likely to occur in secondary care (odds ratio [OR], 5.13, 95 % CI: 1.48 to 17.79; p < 0.01).  The authors concluded that in this first review of clinical data on safety and acceptability of the Cytosponge, they had demonstrated that this device has a favorable safety and acceptability profile.  The relative ease of administration and the higher safety profile as compared to endoscopy made it a promising tool to be used in the primary care setting as a screening and surveillance test for esophageal disorders such as BE or eosinophilic esophagitis.  Results from the ongoing BEST3 randomized trial will be critical prior to implementing the Cytosponge test for widespread use.

The authors stated that this study had several drawbacks.  There were comparatively fewer acceptability scores recorded for endoscopy than the Cytosponge.  This was because patients enrolled onto the BEST1 trial did not have the acceptability score recorded following endoscopy.  Furthermore, the VAS scale was a crude measure of acceptability and further quantitative and qualitative interviews are needed to fully understand the patient experience.  Some of the studies included in this analysis had more complex tools to measure patients’ experience, such as Impact Event Score or Spielberger state trait anxiety inventory, however these researchers did not include it in this analysis since they were not used across all the studies.  Moreover, these researchers could not conclude whether the use of local anesthetic had any influence on the acceptability ratings of the Cytosponge test, as its use wasn’t routinely recorded and data were missing for nearly 50 % of the procedures.

Kaz and Grady (2019) stated that a major barrier to the identification of people with BE is that upper GI tract endoscopy is the only screening test available.  Although safe and accurate, endoscopy is an inconvenient and expensive screening test, which has led to controversy regarding the population health value of BE screening programs.  This has led to intense interest in the development of an inexpensive, safe and accurate BE screening test that is acceptable to patients.  To this end, a variety of techniques are being developed that are less costly and less invasive than upper endoscopy and that could be deployed on a population level.  The most mature and promising of these emerging assays are based on swallowable balloons or capsules that are tethered to a string or small tube that remains outside the patient’s mouth.  After being swallowed, the string is used to retrieve the device and collect cellular material from the esophagus for analysis.  Of the current devices, the EsophaCap and Cytosponge were the first iterations of the swallowable cytology collection devices and consist of an expandable sponge.  These investigators noted that to realize the potential impact of these emerging BE biomarker assays, larger prospective trials in targeted populations, such as the ongoing BEST3 study with the Cytosponge and clinical trials supported by the BETRNET, EDRN, and GI SPORE mechanisms, are needed to establish that these devices are safe, accurate, easy to administer, and cost-effective.  If these studies show that swallowable device-based methods are effective and more people are screened for BE, issues related to over-diagnosis and over-treatment will need to be addressed, as will the need for non-endoscopic surveillance methods that are inexpensive, accurate and safe.  There are also ongoing studies to determine the potential for molecular assays that use the swallowable devices to be used for surveillance of HGD and early EAC.

Sanghi and Thota (2019) presented various novel techniques for screening of BE such as un-sedated trans-nasal endoscopy, Cytosponge with trefoil factor-3, balloon cytology, esophageal capsule endoscopy, liquid biopsy, electronic nose, and oral microbiome.  These investigators noted that a qualitative study showed high acceptability and comfort level in patients undergoing Cytosponge procedure; VAS determined favorable acceptability (p < 0.001) in 93.9 to 99 % patients.  Brief episodes of sore throat and site abrasion with oozing blood was noted in 16.7 % of patients, which resolved without any intervention.  The authors concluded that Cytosponge with TFF3 appeared promising over endoscopy and can be utilized in the primary care clinic if applicable to the general population.  They stated that Cytosponge and Esocheck non-endoscopic balloon are being validated in larger studies before they can be implemented for clinical use.

In a multi-center RCT, Fitzgerald and associates (2020) examined if offering the Cytosponge-TFF3 to patients on medication for GERD would increase the detection of BE compared with standard management.  This study was carried out in 109 socio-demographically diverse general practice clinics in England.  Randomization was performed both at the general practice clinic level (cluster randomization) and at the individual patient level, and the results for each type of randomization were analyzed separately before being combined.  Patients were eligible if they were aged 50 years or older, had been taking acid-suppressants for symptoms of GERD for more than 6 months, and had not undergone an endoscopy procedure within the past 5 years.  General practice clinics were selected by the local clinical research network and invited to participate in the trial.  For cluster randomization, clinics were randomly assigned (1:1) by the trial statistician using a computer-generated randomization sequence; for individual patient-level randomization, patients were randomly assigned (1:1) by the general practice clinics using a centrally prepared computer-generated randomization sequence.  After randomization, subjects received either standard management of GERD (usual care group), in which subjects only received an endoscopy if required by their general practitioner, or usual care plus an offer of the Cytosponge-TFF3 procedure, with a subsequent endoscopy if the procedure identified TFF3-positive cells (intervention group).  The primary outcome was the diagnosis of BE at 12 months after enrolment, expressed as a rate per 1000 person-years, in all subjects in the intervention group (regardless of whether they had accepted the offer of the Cytosponge-TFF3 procedure) compared with all subjects in the usual care group; analyses were intention-to-treat (ITT).  Between March 20, 2017, and March 21, 2019, a total of 113 general practice clinics were enrolled; however, 4 clinics dropped out shortly after randomization.  Using an automated search of the electronic prescribing records of the remaining 109 clinics, these researchers identified 13,657 eligible patients who were sent an introductory letter with 14 days to opt out.  A total of 13 514 of these patients were randomly assigned (per practice or at the individual patient level) to the usual care group (n = 6,531) or the intervention group (n = 6,983).  Following randomization, 149 (2 %) of 6,983 subjects in the intervention group and 143 (2 %) of 6,531 subjects in the usual care group, on further scrutiny, did not meet all eligibility criteria or withdrew from the study.  Of the remaining 6,834 subjects in the intervention group, 2,679 (39 %) expressed an interest in undergoing the Cytosponge-TFF3 procedure.  Of these, 1,750 (65 %) met all of the eligibility criteria on telephone screening and underwent the procedure.  Most of these subjects (1,654 [95 %]; median age of 69 years) swallowed the Cytosponge successfully and produced a sample; 231 (3 %) of 6,834 subjects had a positive Cytosponge-TFF3 result and were referred for an endoscopy.  Patients who declined the offer of the Cytosponge-TFF3 procedure and all subjects in the usual care group only had an endoscopy if deemed necessary by their general practitioner.  During an average of 12 months of follow-up, 140 (2 %) of 6,834 subjects in the intervention group and 13 (less than 1 %) of 6,388 subjects in the usual care group were diagnosed with BE (absolute difference 18.3 per 1,000 person-years [95 % CI: 14.8 to 21.8]; rate ratio adjusted for cluster randomization 10.6 [95 % CI: 6.0 to 18.8], p < 0.0001); 9 (less than 1 %) of 6,834 subjects were diagnosed with dysplastic BE (n = 4) or stage I esophago-gastric cancer (n = 5) in the intervention group, whereas no subjects were diagnosed with dysplastic BE or stage I GE junction cancer in the usual care group.  Among 1,654 subjects in the intervention group who swallowed the Cytosponge device successfully, 221 (13 %) underwent endoscopy after testing positive for TFF3 and 131 (8 %, corresponding to 59 % of those having an endoscopy) were diagnosed with BE or cancer; 1 patient had a detachment of the Cytosponge from the thread requiring endoscopic removal, and the most common side-effect was a sore throat in 63 (4 %) of 1,654 participants.  The authors concluded that for patients with heartburn-predominant symptoms requiring acid-suppressant therapy for at least 6 months, the Cytosponge-TFF3 procedure was a feasible, safe, and generally acceptable test to administer in the general practice clinic setting.  This procedure resulted in improved detection of BE; thus, enabling a more proactive approach for the identification and minimally invasive treatment of dysplasia and early cancer.  An economic evaluation will establish the effect of this strategy, taking into account the additional number of endoscopies required as a result of the Cytosponge-TFF3 procedure.  This strategy will lead to additional endoscopies with some false positive results.

The authors stated that this study had several drawbacks.  First, those subjects who agreed to undergo the Cytosponge-TFF3 procedure might have had more problematic symptoms than those who did not accept the offer of the procedure.  These investigators eliminated this bias by analyzing the data of the whole trial as an ITT analysis.  Second, 150 (9 %) of 1,654 subjects still had a low-confidence result after the offer of a repeat test.  Work is ongoing to find out how to reduce this outcome.  Third, there were slightly more women than men agreeing to undergo the Cytosponge-TFF3 procedure, even though BE is more prevalent in men than in women.  In the future, strategies to encourage men to attend the procedure, and whether to alter the threshold for testing men versus women, should be considered.  Finally, variation in the quality of endoscopies was apparent across the 24 hospitals that participated in this trial.  These researchers carried out a central review of video images and liaised with hospitals to ensure consistency in reporting.  Presently, the TFF3 test requires manual reading by a pathologist trained in analyzing these specimens, which are much larger and more cytological in nature than endoscopic biopsies.  Work is underway to use deep machine learning to automate the quality control and assist the pathologists in their diagnosis; thus, substantially reducing the reporting time and observer bias.

Swart and colleagues (2021) noted that EAC has a very poor prognosis unless detected early.  The Cytosponge-TFF3 is a non-endoscopic test for BE, a precursor of EAC.  Randomized controlled trial data from the BEST3 Trial has shown that an offer of Cytosponge-TFF3 in the primary care setting in England to individuals on medication for acid reflux increases detection of BE 10-fold over a year compared with standard care.  This study was an economic evaluation of Cytosponge-TFF3 screening versus usual care using data from the BEST3 Trial that took place between March 20,  2017 and March 21, 2019.  A Markov model with a 1-year cycle-length and a lifetime time horizon was created, adapting previous modeling work on Cytosponge screening.  The impact of 1 round of Cytosponge screening was modeled in patients with a median age of 69 years (based on BEST3 trial population).  Cost-effectiveness was expressed as an incremental cost-effectiveness ratio (ICER).  Deterministic and probabilistic sensitivity analyses were performed on model parameters.  Per person, 1 round of Cytosponge-TFF3 screening, including confirmatory endoscopy and treatment, in the intervention arm costed £82 more than usual care and generated an additional 0.015 quality-adjusted life-years (QALYs) at an ICER of £5,500 per QALY gained.  Probabilistic sensitivity analysis gave an ICER of £5,405 (95 % CI: -£6,791 to £17,600).  The average QALY gain per person was small because the majority of patients in the model will not develop BE; thus, will have no resulting change in their utility.  However, the small proportion of patients who were identified with BE dysplasia or cancer derive large benefit.  At a willingness-to-pay threshold of £20,000 per QALY, the probability that Cytosponge-TFF3 was cost-effective was over 90 %.  The authors concluded that using data from a pragmatic randomized trial, one-off Cytosponge-TFF3 screen was cost-effective relative to usual care for patients with GERD, despite relatively low uptake and an older population in this trial setting than previously modeled.  These investigators stated that improving Cytosponge-TFF3 uptake and targeting younger patients is likely to further improve cost-effectiveness.  Moreover, these researchers stated that these findings were encouraging for the rapidly expanding research efforts to develop non-endoscopic screening strategies for BE; and paved the way for further modeling studies to examine cost-effectiveness and health benefits in various healthcare systems.

The authors concluded that the drawbacks of this study included the lack of available data on transition probabilities between stages of EAC, and lack of available data needed to estimate the standard errors of their probabilistic sensitivity analysis (PSA) parameters.  These investigators had tried to overcome this by using values that would bias against the intervention.  Updating this analysis with treatment transition probabilities for NDBE would be a recommendation for further study.  Furthermore, the model predicts 20 fewer EAC deaths in the Cytosponge-arm (although this was not the model's primary function and these researchers lacked robust data on EAC progression risk) and again this would be affected by the uptake of the test.  Micro-simulation models are needed to examine this further.  Lastly, the median age from BEST3 used here was for those who took the Cytosponge test and was skewed by more elderly persons accepting a postal invitation offer for research and having time to attend a trial test.  A screening program targeting slightly younger participants would likely see additional benefit as younger participants will accrue more QALYs as they stay in better health states for longer.  Similarly, a screening intervention focusing on male patients is likely to have a positive effect on the ICER, considering the comparatively higher risk of BE progression in males; thus, the potential gain in quality and length of life from early diagnosis and treatment.  This analysis considered only 1 round of screening for 1 cohort.  Continued monitoring of the BEST3 cohort would allow this analysis to be updated when the post-screening incidence of BE can be identified in the BEST3 cohort, and future economic modeling will help to inform whether a program of screening every 3, 5 or 10 years, for example, would be more cost-effective.  Furthermore, as evidence accrues on predictive risk scores for BE and EAC, this may help to identify the optimum group for targeted screening strategies to be cost-effective, including considering enriching the population at risk without reliance on a history of reflux.

Yusuf and Fitzgerald (2021) noted that the targeted approach adopted for BE screening is sub-optimal considering the large proportion of BE cases that are currently missed.  These investigators reviewed the literature highlighting recent technological advancements in efforts to counteract this challenge.  They also provided insights into strategies that could improve the outcomes from current BE screening practices.  The standard method for BE detection, endoscopy, is invasive and expensive; thus, inappropriate for mass screening.  On the other hand, endoscopy is more cost-effective for screening a high-risk population; however, a consensus has not been reached on who should be screened.  Risk prediction algorithms have been tested as an enrichment pre-screening tool reporting modest AUC's; but require more prospective evaluation studies.  Less invasive endoscopy methods like trans-nasal endoscopy, esophageal capsule endoscopy and non-endoscopic cell collection devices like the Cytosponge coupled with biomarker analysis have shown promise in BE detection with randomized clinical trial evidence.  The authors concluded that a 3-tier precision cancer program whereby risk prediction algorithms and non-endoscopic minimally invasive cell collection devices are used to triage test a wider pool of individuals may improve the detection rate of current screening practices with minimal cost implications.  Moreover, these researchers stated that the favorable safety profile and relative ease of the Cytosponge procedure in comparison to endoscopy makes it a promising screening tool in primary care setting.  An implementation study, called DELTA, is currently underway in the U.K. to establish the practical steps for introduction into routine clinical care and to further evaluate cost-effectiveness and patient preferences to maximize uptake.

Esophageal Microbiota for Detection of Barrett's Esophagus

Lv and colleagues (2019) stated that the incidence of EAC has increased in recent decades, and its 5-year survival rate is less than 20 %.  As a well-established precursor, patients with BE have a persistent risk of progression to EAC.  Many researchers have already identified some factors that may contribute to the development of BE and EAC, and the identified risks include GER, male sex, older age, central obesity, tobacco smoking, Helicobacter pylori (H. pylori) eradication, and the administration of PPIs and antibiotics.  The human gut harbors trillions of microorganisms, the majority of which are bacteria.  These microorganisms benefit the human host in many ways, such as helping in digestion, assisting in the synthesis of certain vitamins, promoting the development of the GI immune system, regulating metabolism and preventing invasion by specific pathogens.  In contrast, microbial dysbiosis may play important roles in various diseases, such as inflammation and cancers.  The composition of the microbiota located in the normal esophagus is relatively conserved without distinct microbial preferences in the upper, middle and lower esophagus.  Six major phyla constitute the esophageal microbiota, including Firmicutes, Bacteroides, Actinobacteria, Proteobacteria, Fusobacteria and TM7, similar to the oral microbiota.  Streptococcus dominates the esophageal microbiota.  However, the microbiota varies in different esophageal diseases compared to that in the healthy esophagus.  The type I microbiota, which is primarily composed of gram-positive bacteria, is closely associated with the normal esophagus, while type II microbiota has enriched gram-negative bacteria and is mainly associated with the abnormal esophagus.  These increased gram-negative anaerobes/microaerophiles include Veillonella, Prevotella, Haemophilus, Neisseria, Granulicatella and Fusobacterium, many of which are associated with BE.  The microbial diversity in the esophagus is decreased in EAC patients, and Lactobacillus fermentum is enriched compared to that in controls and BE patients.  Furthermore, the microbiota may be associated with BE and EAC by interacting with their risk factors, including central obesity, GER, H. pylori, administration of PPIs and antibiotics.  Thuse, a large gap in research must be bridged to elucidate the associations among these factors.  Some studies have already proposed several potential mechanisms by which the microbiota participates in human carcinogenesis by complicated interactions with the human host immune system and signaling pathways.  The activation of the LPS-TLR4-NF-κB pathway may contribute to inflammation and malignant transformation.  The authors concluded that this exciting field of GI microbiota allows researchers to unravel the mystery of carcinogenesis from another perspective.  They stated that further prospective studies with sophisticated techniques are needed to examine if the microbiota changes before or after disease onset, to improve the understanding of the pathogenesis, and to find novel targets for prevention, diagnosis and therapy, which could offer more cost-effective and relatively safe choices.

Mitochondrial DNA Deletions for Detection of Barrett's Esophagus

Keles and colleagues (2019) stated that esophageal cancer is the 8th most common cancer globally.  Esophageal adenocarcinoma (EA) and esophageal squamous-cell carcinoma (ESCC) are the 2 major types of esophageal cancer with poor prognosis.  The mechanisms of the progression of normal esophagus to BE and EA are not fully understood.  Mitochondria play a central role in generating energy, apoptosis and cell proliferation.  Mutations of mitochondrial DNA (mtDNA) have been identified in many diseases including cancers.  Mutations of mtDNA were examined as a part of carcinogenesis.  These researchers examined if the 5 kb and 7.4 kb mtDNA deletions are important in the progression of normal esophagus to BE and EA.  In this study, the frequency of the 5 kb and 7.4 kb deletions in mtDNA were studied in specimens ranging from normal esophageal tissue to BE and EA and also from ESCC; 76 paraffin-embedded tissue samples were studied; and 4 couple primers were used.  The negative control and the positive control PCR product were detected in all analyzed samples.  The fusion PCR products, which represent the presence of the deletions, were not detected in any of the samples.  The authors concluded that these mtDNA deletions were not associated with progression of normal esophagus to BE and EA and they do not have an important role in detecting esophagitis, BE, EA, and ESSC.

Volumetric Laser Endomicroscopy for Evaluation of Barrett's Esophagus

Trindade and associates (2017) noted that the incidence of EAC is on the rise despite widespread appreciation that the precursor lesion is BE.  Studies have shown that some patients known to have BE develop cancer despite their enrollment in conventional endoscopic surveillance programs.  This highlighted the need for advanced endoscopic imaging to help identify early neoplasia and prevent its progression to esophageal cancer.  Recently, a wide-field, 2nd-generation OCT endoscopic platform called volumetric laser endomicroscopy (VLE) was cleared by the FDA and made commercially available for advanced imaging in BE.  These investigators discussed current literature on VLE imaging in BE.  Based on ex-vivo studies, criteria have been established for identifying BE-associated neoplasia.  In addition, recent studies, case series, and case reports have demonstrated that VLE is well-tolerated, effective, and can target neoplasia.  The authors concluded that VLE is a new advanced imaging platform for BE with considerable promise to target BE-associated neoplasia.  The following are needed to establish VLE's clinical role: studies showing incremental yield of dysplasia detection using VLE, studies to determine VLE's in-vivo diagnostic accuracy for identifying and classifying BE-associated neoplasia, and studies on the cost-efficacy of VLE.

Aziz and Fatima (2018) stated that EAC is one of the deadliest carcinoma faced by gastroenterologists.  Any insult to esophagus that causes replacement of normal squamous epithelium with columnar intestinal epithelium is labelled as the initiating event of the metaplasia-neoplasia sequence.  Currently, endoscopically obtained biopsies are used to detect neoplastic changes in patients with BE; however, it is not cost-effective and hence a better screening modality is needed.  The authors stated that VLE has been under study for the past few years and has shown promising results to overcome the shortcoming faced in the biopsy samplings.  It is a 2nd-generation OCT that provides high-resolution cross-sectional imaging of the esophageal mucosa using near-infrared light.

Smith and colleagues (2019) noted that VLE uses OCT for real-time, microscopic cross-sectional imaging.  A US-based multi-center registry was constructed to prospectively collect data on patients undergoing upper endoscopy during which a VLE scan was performed.  The objective of this registry was to determine usage patterns of VLE in clinical practice and to estimate quantitative and qualitative performance metrics as they are applied to BE management.  All procedures utilized the NvisionVLE Imaging System (NinePoint Medical, Bedford, MA) which was used by investigators to identify the tissue types present, along with focal areas of concern.  Following the VLE procedure, investigators were asked to answer 6 key questions regarding how VLE impacted each case.  Statistical analyses including neoplasia diagnostic yield improvement using VLE was performed.  A total of 1,000 patients were enrolled across 18 U.S. trial sites from August 2014 through April 2016.  In patients with previously diagnosed or suspected BE (894/1,000), investigators used VLE and identified areas of concern not observed on WLE in 59 % of the procedures; VLE imaging also guided tissue acquisition and treatment in 71 % and 54 % of procedures, respectively; VLE as an adjunct modality improved the neoplasia diagnostic yield by 55 % beyond the standard of care practice.  In patients with no prior history of therapy, and without visual findings from other technologies, VLE-guided tissue acquisition increased neoplasia detection over random biopsies by 700 %.  Registry investigators reported that VLE improved the BE management process when used as an adjunct tissue acquisition and treatment guidance tool.  The authors concluded that this registry-based study demonstrated the potential for VLE to fill clinically relevant gaps in the ability to evaluate and manage BE.

The authors stated that the utility of this analysis is subject to several limitations.  As a post-market registry study, there was no defined protocol for imaging, image interpretation and tissue acquisition, and there was no control group for matched population comparisons.  The early experience of users on VLE image interpretation may have resulted in over-calling areas of concern.  Abnormalities located deeper in the esophageal wall could be targeted with forceps biopsies at one site, while other sites would utilize endoscopic resection techniques that are more likely to remove the target.  All of these discrepancies could affect any calculations regarding the adjunctive yield of VLE-targeted sampling.  Further analysis of the global detection rate of dysplasia by site did not reveal any statistical difference.  At the time of this study, image interpretation was performed using previously published guidelines for detection of neoplasia in BE with OCT.  Challenges with histopathological diagnosis of LGD limited the development of VLE criteria for LGD.  As such, the analyses in this study focused on neoplasia.  Current guidelines suggest that treatment of LGD is acceptable so detection of LGD with VLE should be addressed in a future study.  Additionally, the characteristic image features that maximized sensitivity and specificity of confirmatory biopsies must be optimized.  Recently, Leggett et al (2016) established an updated step-wise diagnostic algorithm to detect dysplasia based on similar VLE features used in this study.  This diagnostic algorithm achieved 86 % sensitivity, 88 % specificity, and 87 % diagnostic accuracy to detect BE dysplasia with almost perfect interobserver agreement among 3 raters (kappa = 0.86).  Further optimization of VLE image features for identifying dysplasia and neoplasia are ongoing.  Other limitations of the study included the lack of central pathology for interpretation of specimens, which could affect (positively or negatively) the reported benefit of VLE in finding dysplasia.  However, this study focused on neoplasia where there is less inter-observer variability compared to LGD.  Finally, as a non-randomized study conducted mostly at large BE referral centers with possibly higher pre-test probability of neoplasia, it was plausible that their validity in a community setting is limited.  However, the large sample size, its heterogeneity, plus variation in technique by site likely restored at least some of the external validity of the findings.

In a systematic review and meta-analysis, Rodriguez and colleagues (2019) examined the accuracy of OCT and VLE in diagnosis of intestinal metaplasia, dysplasia, and HGD, and IMCA in BE.  The primary outcome measure was diagnostic accuracy of OCT and VLE, in comparison with the gold standard.  These investigators calculated sensitivity, specificity, positive likelihood ratio (LR+), negative likelihood ratio (LR-), and diagnostic odds ratio (DOR) for both methods.  They performed analyses by patient and by lesion.  These researchers evaluated 14 studies involving a collective total of 721 patients and 1,565 lesions.  In the analysis by lesion, VLE showed a pooled sensitivity, specificity, LR+, LR-, DOR, and summary receiver operating characteristic area under the curve (SROC-AUC) of 85 %, 73 %, 3.2, 0.21, 15.0, and 0.87, respectively, for detection of HGD/IMC.  In the analysis by lesion for detection of HGD/EAC, OCT showed a pooled sensitivity, specificity, LR+, LR-, DOR, and SROC-AUC of 89 %, 91 %, 9.6, 0.12, 81.0, and 0.95, respectively.  The accuracy of OCT in identifying intestinal metaplasia showed a pooled sensitivity, specificity, LR+, LR-, and DOR of 92 %, 81 %, 5.06, 0.091, and 55.58, respectively.  The authors concluded that OCT- and VLE-guided targeted biopsies could improve detection of dysplasia and neoplasia.  Moreover, these researchers stated that further studies could examine if the use of such biopsies might replace the current protocol.

TissueCypher

Zaidi and co-workers (2014) noted that EAC is associated with a dismal prognosis.  The identification of cancer biomarkers can advance the possibility for early detection and better monitoring of tumor progression and/or response to therapy.  These researchers presented results from the development of a serum-based, 4-protein (biglycan, myeloperoxidase, annexin-A6, and protein S100-A9) biomarker panel for EAC.  A vertically integrated, proteomics-based biomarker discovery approach was used to identify candidate serum biomarkers for the detection of EAC.  Liquid chromatography-tandem mass spectrometry analysis was performed on formalin-fixed, paraffin-embedded tissue samples that were collected from across the BE-EAC disease spectrum.  The mass spectrometry-based spectral count data were used to guide the selection of candidate serum biomarkers.  Then, the serum enzyme-linked immunosorbent assay data were validated in an independent cohort and were used to develop a multi-parametric risk-assessment model to predict the presence of disease.  With a minimum threshold of 10 spectral counts, 351 proteins were identified as differentially abundant along the spectrum of BE, HGD, and EAC (p < 0.05).  A total of 11 proteins from this data set were then tested using enzyme-linked immunosorbent assays (ELISA) in serum samples, of which 5 proteins were significantly elevated in abundance among patients who had EAC compared with normal controls, which mirrored trends across the disease spectrum present in the tissue data.  By using serum data, a Bayesian rule-learning predictive model with 4 biomarkers was developed to accurately classify disease class; the cross-validation results for the merged data set yielded accuracy of 87 % and an area under the receiver operating characteristic curve (AUROC) of 93 %.  The authors concluded that serum biomarkers hold significant promise for the early, non-invasive detection of EAC.

Prichard and colleagues (2015) described a quantitative, multiplexed biomarker imaging approach termed TissueCypher that applies systems biology to anatomic pathology.  Applications of TissueCypher in understanding the tissue system of BE and the potential use as an adjunctive tool in the diagnosis of BE were described.  The TissueCypher Image Analysis Platform was used to assess 14 epithelial and stromal biomarkers with known diagnostic significance in BE in a set of BE biopsies with non-dysplastic BE with reactive atypia (RA, n = 22) and Barrett's with HGD (n = 17).  Biomarker and morphology features were extracted and evaluated in the confirmed BE HGD cases versus the non-dysplastic BE cases with RA.  Multiple image analysis features derived from epithelial and stromal biomarkers, including immune biomarkers and morphology, showed significant differences between HGD and RA.  The authors concluded that these findings demonstrated the potential of the technology as an addition to standard histopathology in the diagnosis of BE, especially in distinguishing HGD from RA, which show histologic similarities, but are distinct at the molecular and cellular level and require different clinical management.

The authors stated that the limitations of this study included the retrospective nature of the cohort, which could result in selection bias.  The cohort included patients in surveillance at academic referral centers and community practice centers and the biopsies tested had collection dates spanning a 10-year period, which prevented standardization of biopsy fixation and storage protocols.  However, the biopsies were all collected during endoscopic surveillance and thus reflected routine BE samples requiring a risk assessment.

Nieto and associates (2018) summarized studies that examined epigenetic biomarkers in patients with BE and their association with progression to EAC; BE is a precursor lesion for EAC.  There is no clinical test to predict patients who are likely to progress to EAC.  An epigenetic biomarker could predict patients who are at high risk of progression from BE to EAC that could facilitate earlier diagnosis and spare those unlikely to develop cancer from regular invasive surveillance endoscopy.  These researchers carried out a systematic search of the following databases: Medline, Medline in Process, Embase, Cochrane Central, ISI Conference Proceedings Citation Index and the British Library's ZETOC.  Studies were conducted in secondary and tertiary care settings.  All studies measuring epigenetic change in patients over 18 years old who progressed from non-dysplastic BE to EAC were included.  Genetic, in-vitro and studies that did not measure progression in the same patient cohort were excluded.  Study inclusion and risk of bias of individual eligible studies were assessed in duplicate by 2 reviewers using a modified Quality in Prognostic Studies tool.  A total of 14 studies met the inclusion criteria; 42 epigenetic markers were identified, and 5 studies developed models aiming to predict progression to EAC.  The authors concluded that the evidence from this systematic review was suggestive of a role for p16 as an epigenetic biomarker for the progression of BE to EAC.  These researchers stated that further large primary studies using current epigenetic techniques and standardized reporting are needed to inform future models to further examine the role of epigenetics in progression to HGD and EAC.

Maddalo and colleagues (2018) stated that the cost-effectiveness of surveillance in BE is still debated and the use of biomarkers in screening and surveillance still not recommended.  No information is available regarding squamous cell carcinoma antigen [SCCA-immunoglobulin (Ig)M] determination in BE.  In a phase-III clinical trial, these researchers examined the potential role of the determination of the immunocomplexed form of SCCA-immunoglobulin (Ig)M for the screening of BE and EAC.  SCCA-IgM levels were determined (by ELISA) in 231 patients prospectively recruited, 71 with BE, 53 with EAC, and 107 controls, including 42 blood donors and 65 patients with gastro-esophageal reflux.  SCCA-IgM cut-offs between BE/EAC and controls and for BE "at risk" versus short non-dysplastic BE were calculated by receiver operating characteristic curves.  Immunostaining for SCCA-IgM was obtained in a subgroup of patients.  Median SCCA-IgM values were significantly higher in BE and EAC than in controls (p = 0.0001).  Patients with SCCA-IgM levels above the cut-off had a 33 times higher relative risk of harboring BE or EAC (p = 0.0001).  Patients "at risk" with long or dysplastic BE had SCCA-IgM levels significantly higher than those with short non-dysplastic BE (p = 0.035) and patients with SCCA-IgM above the cut-off had a 8 times higher relative risk of having BE "at risk".  SCCA was expressed in Barrett mucosa but not in cardiac metaplasia.  The authors concluded that serum SCCA-IgM determination allowed the identification of patients at risk for BE/EAC and the stratification of BE patients in subgroups with different cancer risk.  Moreover, these researchers stated that because of the still limited number of controls, large, prospective studies are needed to confirm this evidence.

Furthermore, UpToDate reviews on “Barrett's esophagus: Surveillance and management” (Spechler, 2019b) and “Barrett's esophagus: Pathogenesis and malignant transformation” (Spechler, 2019c) do not mention the use of biomarkers as a management tool.

Genome-Wide Association Studies / Polygenic Risk Score for Early Intervention or Surveillance of Barrett’s Esophagus

Callahan and colleagues (2019) noted that surveillance of BE is a clinical challenge; metaplasia of the distal esophagus increases a patient's risk of EAC significantly but the actual percentage of patients who progress is low.  The current screening recommendations require frequent endoscopy and biopsy, which has inherent risk, high cost, and operator variation.  Identifying BE patients genetically who are at high risk of progressing could de-emphasize the role of endoscopic screening and create an opportunity for early therapeutic intervention.  Genetic alterations in germline DNA have been identified in other disease processes and allow for early intervention or surveillance well before disease develops.  The genetic component of BE remains mostly unknown and only a few genome-wide association studies (GWASs) exist on this topic.  The authors summarized the current literature available that examined genetic alterations in BE and EAC with a particular emphasis on clinical implications.  These researchers stated that 5 GWASs shed a tremendous amount of light on germline variants in both BE and EAC; however, there were several drawbacks that needed further discussion.  Most notable was the fact that many of these studies pulled “cases”, whether BE or EAC, from the same consortiums.  For example, 4 of the 5 studies filled at least a part of the case group from the BEACON consortium.  Taken a step further, all consortiums used were only from a handful of Caucasian-dominant nations.  Therefore, these findings may not be transferable to the entire BE/EAC population as a whole and certainly may not be accurate for specific populations alone.  Furthermore, the control groups in many of these studies exhibited variations in how they were chosen.  For example, the WTCCC2 pulled DNA from multiple populations.  In some populations, the controls were ensured to have no family history of disease or personal history of related diseases but for the majority of cohorts, these controls were really just general population controls.  In other words, these controls were not screened for BE or EAC and therefore it stood to reason that some controls may actually have the disease being studied.  Because BE and EAC are so rare and the criterion of genome-wide significance is so stringent (p < 5 × 10−8), this limitation likely has little effect on the overall results.  Lastly, Gharahkhani et al (2016) acknowledged a different limitation that applied to all of these studies as well, which was that no in-vitro or in-vivo evidence was provided for the biological function of these single nucleotide polymorphisms (SNPs).  This meant that all conclusions regarding change in function of mutated proteins due to genetic variants were inferred based on bioinformatics only.  In other words, one could not definitively say how a particular mutation in these regions actually affect the protein it codes for.  To that same end, the effect of an SNP’s mutation is being surmised by linking it to the closest previously studied gene or region.  It is unclear exactly how near or far 2 SNPs can be from each other while still having similar gene products and subsequent consequences.

These researchers noted that many of the SNPs identified are promising markers for the development of BE or EAC.  The low OR issue is common for most GWAS SNPs.  Although the individual effects of these risk-associated SNPs are modest, they could have a strong cumulative effect.  Combining all the variants into a single polygenic risk score (PRS) is the next logical step toward predicting pathology based on genetic analysis.  These investigators stated that Dong et al (2018) published the 1st study that developed a PRS to examined the risk of BE or EAC based on genetic variants.  The PRS was developed using 23 previously identified variants by assigning points proportional to ORs.  In examining the re-classification properties of adding a PRS to demographic/lifestyle-gastro-esophageal reflux symptoms, the authors compared genetic and non-genetic models for BE and EAC.  There was an overall improvement in the net risk stratification (3 % in BE, and 5.6 % in EAC), meaning that a percentage of patients were re-classified greater or lower risk based solely on the PRS.  The authors concluded that the PRS was strongly associated with risks of BE and EAC; however, the absolute difference in discriminatory ability of the combined model compared to risk models based on only non-genetic factors was insufficient to influence clinical decision-making.

Artificial Intelligence for Detection of Early Neoplasia in Barrett's Esophagus

Tan et al (2022) noted that artificial intelligence (AI) is rapidly evolving in gastro-intestinal (GI) endoscopy.  In a systematic review and meta-analysis, these researchers examined the performance of AI for detection of early Barrett's neoplasia.  They searched Medline, Embase, and Cochrane Central Register of controlled trials database from inception to the January 28, 2022 to identify studies on the detection of early Barrett's neoplasia using AI.  Study quality was evaluated using Quality Assessment of Diagnostic Accuracy Studies - 2 (QUADAS-2).  A random-effects model was used to calculate pooled sensitivity, specificity, and DOR.  Forest plots and SROC curves displayed the outcomes.  Heterogeneity was determined by I2, Tau2 statistics and p-value.  The funnel plots and Deek's test were used to examine publication bias.  A total of 12 studies entailing 1,361 patients (using 532,328 images on which the various AI models were trained) were used.  The SROC was 0.94 (95 % CI: 0.92 to 0.96).  Pooled sensitivity, specificity and DOR were 90.3 % (95 % CI: 87.1 % to 92.7 %), 84.4 % (95 % CI: 80.2 % to 87.9 %) and 48.1 (95 % CI: 28.4 to 81.5), respectively.  Subgroup analysis of AI models trained only on white light endoscopy was similar with pooled sensitivity and specificity of 91.2 % (95 % CI: 85.7 % to 94.7 %) and 85.1 % (95 % CI: 81.6 % to 88.1 %), respectively.  The authors concluded that AI was highly accurate at detecting early Barrett's neoplasia and validated for patients with at least high-grade dysplasia and above.  Moreover, these researchers stated that further prospective, well-designed RCTs of all histopathological subtypes of early Barrett's neoplasia are needed to confirm these findings.

Spadaccini et al (2022) stated that BE is a well-established risk factor for EAC.  It is recommended that patients have regular endoscopic surveillance, with the ultimate goal of detecting early-stage neoplastic lesions before they can progress to invasive carcinoma.  Detection of both dysplasia or early adenocarcinoma allows curative endoscopic treatments, and with this objective, thorough endoscopic assessment is crucial and improves outcomes.  The burden of missed neoplasia in BE is still far from being negligible, likely due to inappropriate endoscopic surveillance.  Over the past 20 years, advanced imaging techniques, moving from traditional dye-spray chromoendoscopy to more practical virtual chromoendoscopy technologies, have been introduced with the aim to enhance neoplasia detection in BE.  As witnessed in other fields, AI has revolutionized the field of diagnostic endoscopy and is set to cover a pivotal role in BE as well.  Moreover, these researchers stated that the field of AI will continue to evolve in next few years providing models that would enhance easy detection and mucosal detailing for endoscopists.  This will undergo rigorous prospective validation and testing before being available.  Ideal AI-based model should be easily taught, reproducible with accuracy and such that can be easily incorporated in community GI endoscopy centers.

Wide-Area Transepithelial Sampling for Surveillance of Barrett's Esophagus

Qumseya et al (2022) stated that wide-area transepithelial sampling (WATS) is an emerging technique that may increase dysplasia detection in BE.  In a systematic review and meta-analysis, these investigators examined the additional yield of WATS to Seattle protocol forceps biopsy sampling (FB) in patients who underwent surveillance for BE.  They searched PubMed, Embase, Web of science, and the Cochrane library, ending in January 2021.  The primary outcomes were the relative and absolute increase in dysplasia detection when adding WATS to FB.  Heterogeneity was assessed using I2 and Q statistic.  Publication bias was examined using funnel plots and classic fail-safe test.  A total of 7 studies were included totaling 2,816 patients.  FB identified 158 dysplasia cases, whereas WATS resulted in an additional 114 cases.  The pooled risk ratio (RR) of all dysplasia detection was 1.7 (1.43 to 2.03), p < 0.001, I2 = 0.  For HGD, the pooled RR was 1.88 (1.28 to 2.77), p = 0.001, I2 = 33 %.  The yield of WATS was dependent on the prevalence of dysplasia in the study population.  Among studies with high rates of dysplasia, the absolute increase in dysplasia detection (risk difference, RD) was 13 % (8 % to 18 %, p < 0.0001, number needed to treat [NNT] = 8).  The pooled RD in HGD was 9 % (2 % to 16 %), p < 0.001, NNT = 11.  For studies with a low prevalence of dysplasia, RD for all dysplasia was 2 % (1 % to 3 %), p = 0.001, NNT = 50.  For HGD, the RD was 0.6 % (0.2 % to 1.3 %), p = 0.019, NNT = 166.  The authors concluded that in populations with a high prevalence of dysplasia, adding WATS to FB led to a significant increase in dysplasia detection.  Moreover, these researchers stated that the clinical value of the increased detection rate of dysplasia for WATS needs further investigation because there are limited data regarding how various centers deal with these findings.

The authors stated that they noticed that studies evaluating the use of WATS in BE had several limitations, which included: the variable definition of dysplasia reported crypt dysplasia (CD); indefinite for dysplasia (IND), LGD, and HGD/adenocarcinoma (HGD/AC); varying indications for surveillance and inclusion criteria (surveillance post-EET, surveillance in NDBE); and the fact that most WATS studies were industry-sponsored.  A previous meta-analysis tried to synthesize WATS data but resulted in very high heterogeneity, making the results largely uninterpretable.  This study tried to control for the afore-mentioned limitations in various ways.  The 1st limitation these investigators tried to address was the heterogeneity in dysplasia definition.  Some studies included LGD, while others excluded LGD.  Similarly, some studies included IND with LGD as one category.  Other studies also included CD in the dysplasia categories; thus, trying to analyze all studies together when the outcomes were not the same was inappropriate.  This was a major hurdle in analyzing WATS data and has contributed to the significant heterogeneity reported in a previous meta-analysis with an I2 of 97 %.  Therefore, for the primary analyses, these researchers separated studies based on how dysplasia was reported.  This standardized approach was proposed a priori and was essential for this kind of data synthesis.  The 2nd limitation was the varying indication for surveillance among studies including various inclusion and exclusion criteria.  Most studies included patients undergoing surveillance for BE.  These researchers recognized that the variation in rate of dysplasia in the study population was a major source of heterogeneity.  This was not a factor when calculating relative values; however, it was a major factor when examining absolute effect estimates, i. e., RD.  A study of patients who already had dysplasia and underwent RFA before surveillance would be expected to detect far more cases of dysplasia compared to a study of patients who had mostly NDBE.  The meta-regression indicated that the prevalence of dysplasia was a significant contributor to heterogeneity in calculation of absolute increase in dysplasia detection.  In stratifying the data based on prevalence of dysplasia, these investigators were able to address heterogeneity and calculate more accurate absolute measures and NNT. 

Codipilly et al (2022) stated that FB is currently recommended for surveillance in BE; however, this approach is limited by sampling error and lack of compliance.  Wide-area transepithelial sampling with 3-dimensional analysis (WATS3D; CDx Diagnostics, Suffern, NY) is reported to increase BE dysplasia detection.  In a systematic review and meta-analysis, these investigators examined the incremental yield and clinical significance of WATS3D for dysplasia detection over FB.  They queried major scientific databases for studies using WATS3D and FB from 2000 to 2020.  The primary outcome was the incremental yield of WATS3D-detected dysplasia (defined as a composite of IND, LGD, HGD, and EAC) over FB.  Secondary outcomes were incremental yields of HGD/EAC and rate of reconfirmation of WATS3D dysplasia on subsequent FB.  Meta-analysis of 7 eligible studies demonstrated that FB diagnosed dysplasia in 15.9 % of cases, whereas the incremental yield with WATS3D was 7.2 % (95 % CI: 3.9 % to 11.5 %; I2 = 92.1 %).  Meta-analysis of 6 studies demonstrated that FB diagnosed HGD/EAC in 2.3 % of patients, whereas the incremental yield with WATS3D was 2.1 % (95 % CI: 0.4 % to 5.3 %; I2 = 92.7 %).  Notably, WATS3D was negative in 62.5 % of cases where FB identified dysplasia; 2 studies reported re-confirmation of WATS3D dysplasia with FB histology in only 20 patients.  The authors concluded that WATS3D increased dysplasia detection; however, the clinical significance of this increased dysplasia detection remains uncertain.  These investigators stated that data from endoscopic follow-up to determine FB histology in patients with dysplasia based solely on WATS3D are needed to ascertain the optimal clinical application and significance of WATS3D-only dysplasia.

Envisage Test (DNA Methylation) for Determination of Progression of Pre-Cancerous Barrett’s Esophagus to Esophageal Cancer

Jammula et al (2020) stated that EACs are heterogeneous and often preceded by BE.  Many genomic changes have been associated with development of BE and EAC; however, little is known regarding the epigenetic alterations.  In a retrospective, cohort study, these researchers carried out epigenetic analyses of BE and EAC tissues and combined these data with transcriptome and genomic data to identify mechanisms that control gene expression and genome integrity.  They collected tissue samples and clinical data from 150 BE and 285 EAC cases from the Esophageal Cancer Classification and Molecular Stratification Consortium in the U.K.  these investigators analyzed methylation profiles of all BE and EAC tissues and assigned them to subgroups using non-negative matrix factorization with k-means clustering.  Data from whole-genome sequencing and transcriptome studies were then incorporated; these researchers conducted integrative methylation and RNA-sequencing analyses to identify genes that were suppressed with increased methylation in promoter regions.  Levels of different immune cell types were computed using single-sample gene set enrichment methods.  They derived 8 organoids from 8 EAC tissues and tested their sensitivity to different drugs.  BE and EAC samples shared genome-wide methylation features, compared with normal tissues (esophageal, gastric, and duodenum; controls) from the same patients and grouped into 4 subtypes.  Subtype 1 was characterized by DNA hyper-methylation with a high mutation burden and multiple mutations in genes in cell cycle and receptor tyrosine signaling pathways.  Subtype 2 was characterized by a gene expression pattern associated with metabolic processes (ATP synthesis and fatty acid oxidation) and the lack of methylation at specific binding sites for transcription factors; 83 % of samples of this subtype were BE and 17 % were EAC.  Subtype 3 did not have changes in methylation pattern, compared with control tissue, but had a gene expression pattern that indicated immune cell infiltration; this tumor subtype was associated with the shortest time of patient survival.  Subtype 4 was characterized by DNA hypo-methylation associated with structure re-arrangements, copy number alterations, with preferential amplification of CCNE1 (cells with this gene amplification have been reported to be sensitive to CDK2 inhibitors).  Organoids with reduced levels of MGMT and CHFR expression were sensitive to temozolomide and taxane drugs.  The authors concluded that the findings of this study elucidated diversity in the methylation landscape across BE and EAC and its influence on gene expression and genome integrity, suggesting a role for DNA methylation alteration in EAC carcinogenesis.  Moreover, these researchers stated that it is worth noting that all observations made in this study were derived from only the CpG sites present on the Illumina MethylationEPIC BeadChip (EPIC) array.  This was a narrow representation of the whole genome, and may be a limiting factor, as these investigators could not draw conclusions or understand changes in other parts of the genome and their influence in tumorigenesis.  The authors stated that in the future, it would be worth examining methylation on a genome-wide scale, perhaps via whole-genome bisulfite sequencing approaches.

Ma et al (2022) noted that EC, with 544,076 deaths in 2020, includes esophageal adenocarcinoma and esophageal squamous cell carcinoma (ESCC), which comprises 90 % of esophageal cancers worldwide.  The 5-year survival rate remains poor (15 % to 25 % worldwide) because patients usually present with late disease.  Although ESCC can be diagnosed by means of EGD with biopsy, EGD is not widely available in low-income countries.  Inexpensive, safe, accessible diagnostic alternatives will likely improve diagnosis and outcome.

In a meta-analysis, Fan et al (2022) examined the association of CDH1 methylation with EC risk.  These investigators searched the PubMed, Embase, Web of Science, and Cochrane Library databases to identify relevant studies.  Pooled OR) with 95 % CI were estimated using the fixed- or random-effects models.  The pooled sensitivity and specificity were calculated to assess the diagnostic value of CDH1 methylation for EC.  The results of the meta-analysis were validated using the Cancer Genome Atlas and Gene Expression Omnibus databases.  A total of 13 studies consisting of 1,633 samples were included.  A high CDH1 methylation was significantly associated with an increased risk of EC (OR = 10.40, 95 % CI: 6.29 to 17.18).  Furthermore, CDH1 methylation status was related to tumor status, lymph node status, and metastasis.  For the diagnosis of EC, the pooled sensitivity and specificity of CDH1 methylation were 0.57 (95 % CI: 0.39 to 0.74) and 0.89 (95 % CI: 0.81 to 0.94), respectively.  Bioinformatics analysis showed that CDH1 methylation occurred more frequently in EC tissues than in normal controls, in good agreement with the results of the meta-analysis.  The authors concluded that a significant association was found between CDH1 methylation and EC risk; thus, these researchers suggested that CDH1 methylation could serve as a promising diagnostic marker for EC.

Envisage is a test to determine which patients with pre-cancerous BE will progress to esophageal cancer in the future, empowering physicians to provide rapid treatment to prevent EC.  Capsulomics' lead products use DNA methylation for the diagnosis and prognosis of the esophageal pre-cancerous BE, along with the 2 main types of EC.  Preliminary studies suggested that Capsulomics' diagnostics could detect more esophageal diseases, including early cancers, and predict progression more accurately than all existing EC or pre-cancer diagnostics currently available.

Sheikh et al (2023) stated that EC is the 9th most common cancer and the 6th leading cause of cancer deaths globally; ESCC and EAC are the 2 main histological subtypes with distinct epidemiological and clinical features.  While the global incidence of ESCC is declining, the incidence of EAC is increasing in many countries.  Epidemiologic studies have identified distinct environmental exposures for ESCC and EAC subtypes.  Recent advent in the genomic aspects of EC have advanced the understanding of EC causes and resulted in the use of specific genomic alterations in EC tumors as biomarkers for early diagnosis, treatment, and prognosis of this cancer.  However, the prognosis of EC is still poor, with a 5-year survival rate of less than 20 %.  For therapy and early detection, topical studies that have used chemo-prevention methods, such as using aspirin and proton pump inhibitors (PPIs), and early detection methods, such as using Cytosponge and biomarker assays among symptomatic or high-risk individuals, have shown promising results.  However, there are still challenges in each field that need to be addressed in future studies.  Primary prevention remains the preferred strategy for reducing the global burden of EC. 

These researchers noted that a wide range of biomarkers, including immunohistochemical markers, blood-based markers, MicroRNA markers, long noncoding RNAs, and DNA-based markers, have been identified in various studies that were suggested to have diagnostic potential for detecting ESCC and EAC.  However, each of these biomarkers has its limitations, and none have been translated into effective clinical tools.  Other limitations of the current biomarker research for the diagnosis of EC include small sample size, research design of a single population, lack of value for early diagnosis, lack of independent verification studies, and lack of pre-clinical data.  In addition to the requirement for more technologies and detection methods to settle the problem of the low abundance of some biomarkers in biological samples and further enhance the quality of detection, studies should focus on building combined detection methods to gain better diagnostic value.  Finally, more clinical studies are needed to identify the appropriate collection methods and cut-off values for the identified biomarkers for the detection of EC.

An UpToDate review on “Barrett's esophagus: Surveillance and management” (Spechler, 2023) states that “A number of molecular markers for cancer risk have been proposed as alternatives to random biopsy sampling to detect dysplasia in Barrett's esophagus.  Promising molecular markers that have been associated with carcinogenesis in Barrett's esophagus include abnormalities in p53 and cyclin D1 expression, and abnormal cellular DNA content demonstrable by flow cytometry or methylation arrays.  Additional evaluation of the markers is needed before they can be recommended for routine clinical use or to replace random biopsies.  However, some markers may serve as an adjunct to established diagnostic methods.  For example, the British Society of Gastroenterology suggests that immunostaining of esophageal biopsies for p53 may improve the reproducibility of a diagnosis of dysplasia”.

Furthermore, National Comprehensive Cancer Network’s clinical practice guideline on “Esophageal and Esophagogastric Cancers” (Version 2.2023) does not mention DNA methylation as a management tool.

Esopredict

Sato et al (2008) noted that BE predisposes to esophageal adenocarcinoma.  However, the value of endoscopic surveillance in BE has been debated because of the low incidence of esophageal adenocarcinoma in BE.  Moreover, high inter-observer and sampling-dependent variation in the histologic staging of dysplasia made clinical risk assessment problematic.  These researchers developed a 3-tiered risk stratification strategy, based on systematically selected epigenetic and clinical parameters, to improve BE surveillance efficiency.  These investigators defined HGD as endpoint of progression, and BE progressor patients as BE patients with either no dysplasia or LGD who later developed HGD or esophageal adenocarcinoma.  They analyzed 4 epigenetic and 3 clinical parameters in 118 BE tissues obtained from 35 progressor and 27 non-progressor BE patients from Baltimore Veterans Affairs Maryland Health Care Systems and Mayo Clinic.  Based on 2-year and 4-year prediction models using linear discriminant analysis (area under the receiver-operator characteristic (ROC) curve: 0.8386 and 0.7910, respectively), BE specimens were stratified into high-risk (HR), intermediate-risk (IR), or low-risk (LR) groups.  This 3-tiered stratification method retained both the high specificity of the 2-year model and the high sensitivity of the 4-year model.  Progression-free survivals (PFSs) differed significantly among the 3 risk groups, with p = 0.0022 (HR versus IR) and p < 0.0001 (HR or IR versus LR).  Incremental value analyses showed that the number of methylated genes contributed most influentially to prediction accuracy.  The authors concluded that this 3-tiered risk stratification strategy has the potential to exert a profound impact on BE surveillance accuracy and efficiency.

The authors stated that the work described in this report is now the subject of an EDRN phase-III validation study.  In preparing to proceed to phase-IV validation, these investigators developed a prediction model to stratify BE patients, validated their model, and estimated its potential clinical impact (endoscopy savings) by applying a simulation.  Because of the rarity of BE progressor specimens, the number of progressor patients and specimens was relatively small, despite collecting them from 2 centers.  These researchers stated that further studies may be needed to increase the number of BE progressor and non-progressor specimens by collecting specimens from multiple additional institutions before initiating a prospective, phase-IV trial.

Jin et al (2009) stated that esophageal adenocarcinoma risk in BE is increased 30- to 125-fold versus the general population.  Among all BE patients, however, neoplastic progression occurs only 1 per 200 patient-years; thus, molecular biomarkers are needed to risk-stratify patients for more efficient surveillance endoscopy and to improve the early detection of progression.  These investigators carried out a retrospective, double-blinded, multi-center, validation study of 8 BE progression prediction methylation biomarkers.  Progression or non-progression were determined at 2 years (tier 1) and 4 years (tier 2).  Methylation was assayed in 145 non-progressors and 50 progressors using real-time quantitative methylation-specific PCR.  Progressors were significantly older than non-progressors (70.6 versus 62.5 years; p < 0.001).  These researchers evaluated a linear combination of the 8 markers, using coefficients from a multi-variate logistic regression analysis.  Areas under the ROC curve (AUC) were high in the 2-year, 4-year, and combined data models (0.843, 0.829, and 0.840; p < 0.001, < 0.001, and < 0.001, respectively).  Furthermore, even after rigorous over-fitting correction, the incremental AUCs contributed by panels based on the 8 markers plus age versus age alone were substantial (Delta-AUC = 0.152, 0.114, and 0.118, respectively) in all 3 models.  The authors concluded that a methylation biomarker-based panel to predict neoplastic progression in BE has potential clinical value in improving both the efficiency of surveillance endoscopy and the early detection of neoplasia.  Moreover, these researchers stated that future studies should examine additional potentially predictive methylation targets, along with alternative means of evaluating methylation biomarkers (such as immunohistochemical staining for reduced biomarker expression).

Boerwinkel et al (2014) noted that in BE, the normal squamous lining of the esophagus is replaced by specialized columnar epithelium.  Endoscopic surveillance with auto-fluorescence imaging (AFI) and molecular biomarkers have been studied separately to detect early neoplasia (EN) in BE.  The combination of advanced-imaging modalities and biomarkers has not been examined; AFI may help detecting biomarkers as a risk-stratification tool.  In a retrospective study, these researchers examined a cohort of patients undergoing endoscopy for EN in BE with AFI and correlated 5 biomarkers (HPP1, RUNX3, p16, cyclin A, and p53) in tissue samples with AFI and dysplasia status.  A total of 58 samples from a previous prospective study were selected: 15 true-positive (TP: AFI-positive, EN), 21 false-positive (FP: AFI-positive, no EN), 12 true-negative (TN1; AFI-negative, no EN in sample), 10 true-negative (TN2: AFI-negative, no EN in esophagus).  Methylation-specific RT-PCR was carried out for HPP1, RUNX3, p16, and immunohistochemistry for cyclin A, p53; p < 0.05 was considered statistically significant; and Bonferroni correction was used for multiple comparisons.  P16, cyclin A, p53 correlated with dysplasia (p < 0.01, p = 0.003, p < 0.001, respectively).  Increased p16 methylation was observed between TP versus TN2 (p = 0.003) and TN1 versus TN2 (p = 0.04) subgroups, suggesting a field defect.  Only p53 correlated with AFI-status (p = 0.003).  After exclusion of EN samples, significance was lost.  Although correlation with dysplasia status was confirmed for p16, cyclin A and p53, underlining the importance of these biomarkers as an early event in neoplastic progression, none of the studied biomarkers correlated with AFI status.  The authors concluded that a prospective, larger study is needed to examine the combination of AFI and a larger panel of biomarkers to improve risk stratification in BE.

Yu et al (2022) stated that current endoscopy-based screening and surveillance programs have not been proven effective at decreasing esophageal adenocarcinoma (EAC) mortality, creating an unmet need for effective molecular tests for early detection of this highly lethal cancer.  These researchers carried out a genome-wide methylation screen to identify novel methylation markers that distinguish EAC and HGD from normal squamous epithelium (SQ) or non-dysplastic BE (NDBE).  DNA methylation profiling of samples from SQ, NDBE, HGD, and EAC was carried out using HM450 methylation arrays (Illumina) and reduced-representation bi-sulfate sequencing.  Ultra-sensitive methylation-specific droplet digital PCR and next-generation sequencing (NGS)-based bi-sulfite sequencing assays were developed to detect the methylation level of candidate CpGs in independent esophageal biopsy and endoscopic brushing samples.  A total of 5 candidate methylation markers were significantly hyper-methylated in HGD/EAC samples compared with SQ or NDBE (p < 0.01) in both esophageal biopsy and endoscopic brushing samples.  In an independent set of brushing samples used to construct biomarker panels, a 4-marker panel (model 1) demonstrated sensitivity of 85.0 % and 90.8 % for HGD and EACs, respectively, with 84.2 % and 97.9 % specificity for NDBE and SQ, respectively.  In a validation set of brushing samples, the panel achieved sensitivity of 80 % and 82.5 % for HGD and EAC, respectively, at specificity of 67.6 % and 96.3 % for NDBE and SQ samples.  The authors concluded that a novel DNA methylation marker panel differentiated HGD/EAC from SQ/NDBE.  These researchers stated that DNA-methylation-based molecular assays hold promise for the detection of HGD/EAC using esophageal brushing samples.  These researchers stated that these findings laid the molecular foundation for further trials of a DNA methylation-based tests for the detection of HGD and EAC.

The authors stated that the drawbacks of this study included the lack of a pre-specified sample size at discovery and the relatively small sample size of the training and validation sets of esophageal brushing samples; therefore, requires further validation in larger cohorts.  In addition, given the emerging technical advances in swallowable collection devices, these investigators plan to validate the DNA-methylation based molecular assay in esophageal balloon collected samples, as this sample collection method appeared to have a high likelihood of near-term adoption into clinical practice for at least BE screening.  Furthermore, these researchers stated that it was worth noting that the primary objective of this study was to identify and develop methylation markers that distinguish EAC/HGD from normal squamous epithelium or NDBE.  These findings raised the question of whether these biomarkers could be used to identify HGD patients who will develop EAC in the future.  Although intriguing, the current study design and sample collections precluded the assessment of the BE progression biomarkers, which was beyond the scope of this study.

Gong et al (2022) characterized the use of a gene methylation-based biomarker test that has been validated to predict progression towards EAC.  Barrett esophagus is a precursor condition for EAC with somewhat variable approaches among gastroenterologists toward managing neoplastic progression risk.  Capsulomics has developed a validated multi-gene DNA methylation-based biomarker assay performed on BE biopsies designed to address this variability by classifying BE patients into progression risk groups.  In this study, a survey was administered to practicing gastroenterologists to examine the potential impact of this assay on clinical practice.  In this context, 89 % (95 % Cl: 85.4 % to 92.6%) of surveyed physicians felt strongly that the multi-gene BE test helped resolve uncertainties and optimize care of patients with BE by impacting their decisions on surveillance intervals and use of active treatments, such as ablation.  The assay significantly impacted surveillance intervals for both high-risk (22.0 no assay versus 12.3 months with assay; p = 1.7E-8) and low-risk (7.9 no assay versus 11.4 months with assay, p = 8.8E-4) stratified case results.  Finally, the assay also significantly impacted decisions to pursue active ablation treatments in both high-risk (5 % recommending ablation without assay versus 42 % with assay; p = 3.7E-11) and low-risk (42 % recommending ablation without assay versus 29 % with assay; p = 0.049) stratified case results.  Results demonstrated a strong effect of the assay on clinical decision-making, even in conjunction with established clinical guidelines. 

The authors stated that drawbacks of this study included the open-ended questioning and the limited timeframe during which the survey was completed.  These researchers were also unable to simulate the patient encounter, something that may have considerable effect on the care regimen.  These investigators stated that further investigations are needed to confirm benefits in care offered to patients in real-world clinical practice.

Maity et al (2022) noted that early detection of esophageal cancer is critical to improve survival.  While studies have identified biomarkers, their interpretation and validity is often confounded by cell-type heterogeneity.  These investigators employed systems-epigenomic and cell-type deconvolution algorithms to a discovery set encompassing RNA-Seq and DNA methylation data from EAC patients and matched normal-adjacent tissue, to identify robust biomarkers, free from the confounding effect posed by cell-type heterogeneity.  They identified 12 gene-modules that were epigenetically deregulated in EAC; and were able to validate all 12 modules in 4 independent EAC cohorts.  These researchers demonstrated that the epigenetic deregulation was present in the epithelial compartment of EAC-tissue.  By means of single-cell RNA-Seq data, these researchers demonstrated that 1 of these modules, a proto-cadherin module centered around CTNND2, was inactivated in BE, a precursor lesion to EAC.  By measuring DNA methylation in saliva from EAC cases and controls, these investigators identified a chemokine module centered around CCL20, whose methylation patterns in saliva correlated with EAC status.

The authors concluded that given the observations that a CCL20 chemokine network was over-activated in EAC tissue and saliva from EAC patients, and that in independent studies CCL20 has been found to be over-activated in EAC tissue infected with the bacterium F. nucleatum, a bacterium that normally inhabits the oral cavity, these findings highlighted the possibility of using DNA methylation measurements in saliva as a proxy for changes occurring in the esophageal epithelium.  They noted that both the CTNND2/CCL20 modules represent novel promising network biomarkers for EAC that merit further investigation.

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References