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1.  Evaluation of a Minimally Invasive Cell Sampling Device Coupled with Assessment of Trefoil Factor 3 Expression for Diagnosing Barrett's Esophagus: A Multi-Center Case–Control Study 
PLoS Medicine  2015;12(1):e1001780.
Background
Barrett's esophagus (BE) is a commonly undiagnosed condition that predisposes to esophageal adenocarcinoma. Routine endoscopic screening for BE is not recommended because of the burden this would impose on the health care system. The objective of this study was to determine whether a novel approach using a minimally invasive cell sampling device, the Cytosponge, coupled with immunohistochemical staining for the biomarker Trefoil Factor 3 (TFF3), could be used to identify patients who warrant endoscopy to diagnose BE.
Methods and Findings
A case–control study was performed across 11 UK hospitals between July 2011 and December 2013. In total, 1,110 individuals comprising 463 controls with dyspepsia and reflux symptoms and 647 BE cases swallowed a Cytosponge prior to endoscopy. The primary outcome measures were to evaluate the safety, acceptability, and accuracy of the Cytosponge-TFF3 test compared with endoscopy and biopsy.
In all, 1,042 (93.9%) patients successfully swallowed the Cytosponge, and no serious adverse events were attributed to the device. The Cytosponge was rated favorably, using a visual analogue scale, compared with endoscopy (p < 0.001), and patients who were not sedated for endoscopy were more likely to rate the Cytosponge higher than endoscopy (Mann-Whitney test, p < 0.001). The overall sensitivity of the test was 79.9% (95% CI 76.4%–83.0%), increasing to 87.2% (95% CI 83.0%–90.6%) for patients with ≥3 cm of circumferential BE, known to confer a higher cancer risk. The sensitivity increased to 89.7% (95% CI 82.3%–94.8%) in 107 patients who swallowed the device twice during the study course. There was no loss of sensitivity in patients with dysplasia. The specificity for diagnosing BE was 92.4% (95% CI 89.5%–94.7%). The case–control design of the study means that the results are not generalizable to a primary care population. Another limitation is that the acceptability data were limited to a single measure.
Conclusions
The Cytosponge-TFF3 test is safe and acceptable, and has accuracy comparable to other screening tests. This test may be a simple and inexpensive approach to identify patients with reflux symptoms who warrant endoscopy to diagnose BE.
Editors' Summary
Background
Barrett's esophagus is a condition in which the cells lining the esophagus (the tube that transports food from the mouth to the stomach) change and begin to resemble the cells lining the intestines. Although some people with Barrett's esophagus complain of burning indigestion or acid reflux from the stomach into the esophagus, many people have no symptoms or do not seek medical advice, so the condition often remains undiagnosed. Long-term acid reflux (gastroesophageal reflux disease), obesity, and being male are all risk factors for Barrett's esophagus, but the condition's exact cause is unclear. Importantly, people with Barrett's esophagus are more likely to develop esophageal cancer than people with a normal esophagus, especially if a long length (segment) of the esophagus is affected or if the esophagus contains abnormally growing “dysplastic” cells. Although esophageal cancer is rare in the general population, 1%–5% of people with Barrett's esophagus develop this type of cancer; about half of people diagnosed with esophageal cancer die within a year of diagnosis.
Why Was This Study Done?
Early detection and treatment of esophageal cancer increases an affected individual's chances of survival. Thus, experts recommend that people with multiple risk factors for Barrett's esophagus undergo endoscopic screening—a procedure that uses a small camera attached to a long flexible tube to look for esophageal abnormalities. Once diagnosed, patients with Barrett's esophagus generally enter an endoscopic surveillance program so that dysplastic cells can be identified as soon as they appear and removed using endoscopic surgery or “radiofrequency ablation” to prevent cancer development. However, although endoscopic screening of everyone with reflux symptoms for Barrett's esophagus could potentially reduce deaths from esophageal cancer, such screening is not affordable for most health care systems. In this case–control study, the researchers investigate whether a cell sampling device called the Cytosponge coupled with immunohistochemical staining for Trefoil Factor 3 (TFF3, a biomarker of Barrett's esophagus) can be used to identify individuals who warrant endoscopic investigation. A case–control study compares the characteristics of patients with and without a specific disease. The Cytosponge is a small capsule-encased sponge that is attached to a string. The capsule rapidly dissolves in the stomach after being swallowed, and the sponge collects esophageal cells for TFF3 staining when it is retrieved by pulling on the string.
What Did the Researchers Do and Find?
The researchers enrolled 463 individuals attending 11 UK hospitals for investigational endoscopy for dyspepsia and reflux symptoms as controls, and 647 patients with Barrett's esophagus who were attending hospital for monitoring endoscopy. Before undergoing endoscopy, the study participants swallowed a Cytosponge so that the researchers could evaluate the safety, acceptability, and accuracy of the Cytosponge-TFF3 test for the diagnosis of Barrett's esophagus compared with endoscopy. Nearly 94% of the participants swallowed the Cytosponge successfully, there were no adverse effects attributed to the device, and those participants that swallowed the device generally rated the experience as acceptable. The overall sensitivity of the Cytosponge-TFF3 test (its ability to detect true positives) was 79.9%. That is, 79.9% of the individuals with endoscopically diagnosed Barrett's esophagus were identified as having the condition using the new test. The sensitivity of the test was greater among patients who had a longer length of affected esophagus and importantly was not reduced in patients with dysplasia. Compared to endoscopy, the specificity of the Cytosponge-TFF3 test (its ability to detect true negatives) was 92.4%. That is, 92.4% of people unaffected by Barrett's esophagus were correctly identified as being unaffected.
What Do These Findings Mean?
The case–control design of this study means that its results are not generalizable to a primary care population. Also, the study used only a single measure of the acceptability of the Cytosponge-TFF3 test, Nevertheless, these findings indicate that this minimally invasive test for Barrett's esophagus is safe and acceptable, and that its accuracy is similar to that of colorectal cancer and cervical cancer screening tests. The Cytosponge-TFF3 test might, therefore, provide a simple, inexpensive way to identify those patients with reflux symptoms who warrant endoscopy to diagnose Barrett's esophagus, although randomized controlled trials of the test are needed before its routine clinical implementation. Moreover, because most people with Barrett's esophagus never develop esophageal cancer, additional biomarkers ideally need to be added to the test before its routine implementation to identify those individuals who have the greatest risk of esophageal cancer, and thereby avoid overtreatment of Barrett's esophagus.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001780.
The US National Institute of Diabetes and Digestive and Kidney Diseases provides detailed information about Barrett's esophagus and gastroesophageal reflux disease
The US National Cancer Institute provides information for patients and health professionals about esophageal cancer (in English and Spanish)
Cancer Research UK (a non-profit organization) provides detailed information about Barrett's esophagus (including a video about having the Cytosponge test and further information about this study, the BEST2 Study) and about esophageal cancer
The UK National Health Service Choices website has pages on the complications of gastroesophageal reflux and on esophageal cancer (including a real story)
Heartburn Cancer Awareness Support is a non-profit organization that aims to improve public awareness and provides support for people affected by Barrett's esophagus; the organization's website explains the range of initiatives to promote education and awareness as well as highlighting personal stories of those affected by Barrett's esophagus and esophageal cancer
The British Society of Gastroenterology has published guidelines on the diagnosis and management of Barrett's esophagus
The UK National Institute for Health and Care Excellence has published guidelines for gastroesophageal reflux
The Barrett's Esophagus Campaign is a UK-based non-profit organization that supports research into the condition and provides support for people affected by Barrett's esophagus; its website includes personal stories about the condition
In a multi-center case-control study, Rebecca Fitzgerald and colleagues examine whether a minimally invasive cell sampling device could be used to identify patients who warrant endoscopy to diagnose Barrett's esophagus.
doi:10.1371/journal.pmed.1001780
PMCID: PMC4310596  PMID: 25634542
2.  A case of esophageal squamous cell intraepithelial neoplasia with positivity for type 16 human papillomavirus successfully treated with radiofrequency ablation 
Esophageal cancer is the eight most common cancer worldwide and the sixth cause of cancer related death with squamous cell carcinoma (SCC) accounting for almost half of all esophageal cancers. Persistent human papilloma virus (HPV) infection has been suspected to play an active role in esophageal carcinogenesis but a clear association has not still been proven and no specific indications or guidelines for possible endoscopic and surgical therapeutic approaches to this clinical scenario are available. We report a case of a 62-year-old woman with histological diagnosis of high-grade intraepithelial squamous neoplasia of distal esophagus associated with cytological modifications resembling cervical HPV infection and with a positive INNO-LiPA assay for genotype 16 HPV. A single session of radiofrequency ablation (RFA) was performed on the dysplastic esophageal area with complete endoscopic eradication as confirmed by the following endoscopic, histologic and microbiologic examinations. Our report might give further strength to the hypothesis of an etiological role of HPV in selected cases of esophageal carcinogenesis and opens a discussion on the possible use of Radio Frequency Ablation as an effective and safe endoscopic treatment for both early squamous cell neoplasia and HPV esophageal colonization.
doi:10.3978/j.issn.2078-6891.2014.005
PMCID: PMC3999629  PMID: 24772344
Esophagus; squamous cell neoplasia; human papilloma virus (HPV); radiofrequency ablation (RFA)
3.  Outcomes from a prospective trial of endoscopic radiofrequency ablation of early squamous cell neoplasia of the esophagus 
Gastrointestinal endoscopy  2011;74(6):1181-1190.
Background
Radiofrequency ablation (RFA) is safe and effective for eradicating neoplasia in Barrett’s esophagus.
Objective
Evaluate RFA for eradicating early esophageal squamous cell neoplasia (ESCN) defined as moderate- and high-grade squamous intraepithelial neoplasia (MGIN, HGIN) and early flat-type esophageal squamous cell carcinoma (ESCC).
Design
Prospective cohort study.
Setting
Tertiary referral center.
Patients
Esophageal unstained lesions (USLs) were identified using Lugol’s chromoendoscopy. Inclusion: at least 1 flat (type 0-IIb) USL ≥3cm, USL-bearing esophagus ≤12 cm, and a consensus diagnosis of MGIN, HGIN, or ESCC by two expert GI pathologists. Exclusion: prior endoscopic resection or ablation, stricture, or any non-flat mucosa.
Interventions
Circumferential RFA creating a continuous treatment area (TA) including all USLs. At 3-month intervals thereafter, chromoendoscopy with biopsies, followed by focal RFA of USLs, if present.
Main outcome measures
Complete response (CR) at 12 months, defined as absence of MGIN, HGIN or ESCC in TA; CR after one RFA session; neoplastic progression from baseline; and adverse events.
Results
29 patients (14 male, mean age 60.3 years) with MGIN (18), HGIN (10), or ESCC (1) participated. Mean USL length was 6.2 cm (TA 8.2 cm). At 3-months, after one RFA session, 86% of patients (25/29) were CR. At 12-months, 97% (28/29) of patients were CR. There was no neoplastic progression. There were 4 strictures, all dilated to resolution.
Limitations
Single center study with limited number of patients.
Conclusions
In patients with early ESCN (MGIN, HGIN, flat-type ESCC), RFA was associated with a high rate of histological complete response (97% of patients), no neoplastic progression, and an acceptable adverse event profile.
doi:10.1016/j.gie.2011.05.024
PMCID: PMC3505032  PMID: 21839994
4.  Magnified Endoscopy Combined with Narrow Band Imaging of Minimal Superficial Esophageal Neoplasia—Indicators to Differentiate Intraepithelial Neoplasias 
Purpose
Clinical application of narrow band imaging facilitates diagnosis of esophageal neoplasia. However, no previous investigation has been conducted on magnifying endoscopy combined with narrow band imaging in detection of minimal superficial esophageal neoplasia, which is defined as neoplasia <10 mm in diameter. The aim of this retrospective study was to evaluate the usefulness of this combined technique in the differential diagnosis of minimal superficial esophageal neoplasia.
Methods
Between January 2005 and November 2011, 53 minimal superficial esophageal neoplasias in 40 patients were diagnosed by screening upper gastrointestinal endoscopy with narrow band imaging at our hospital. We investigated findings including brownish dots, brownish epithelium, and demarcation line of minimal superficial esophageal neoplasia diagnosed histopathologically as low-grade intraepithelial neoplasia, high-grade intraepithelial neoplasia, and squamous cell carcinoma.
Results
Significantly more brownish dots (P < 0.05) and brownish epithelium (P < 0.005) were observed in intraepithelial papillary capillary loops in high-grade neoplasia compared with low-grade neoplasia. When minimal superficial esophageal neoplasia was diagnosed as high-grade intraepithelial neoplasia or squamous cell carcinoma, sensitivity, specificity, positive predictive value, and negative predictive value were 88.9, 42.9, 44.4, and 88.2 %, respectively, for brownish dots; 94.4, 51.4, 50.0, and 94.7 %, respectively, for brownish epithelium; and 66.7, 62.9, 48.0, and 78.6 %, respectively, for demarcation line.
Conclusions
The combined technique was useful in the differential diagnosis of minimal superficial esophageal neoplasia.
doi:10.1007/s12029-012-9395-0
PMCID: PMC3523113  PMID: 22618519
Endoscopy; Esophageal neoplasms; Carcinoma; Squamous cell carcinoma; Narrow band imaging; Magnifying endoscopy
5.  Long-term follow-up after complete ablation of Barrett’s esophagus with argon plasma coagulation 
AIM: To report the long-term outcome of patients after complete ablation of non-neoplastic Barrett’s esophagus (BE) with respect to BE relapse and development of intraepithelial neoplasia or esophageal adenocarcinoma.
METHODS: In 70 patients with histologically proven non-neoplastic BE, complete BE ablation was achieved by argon plasma coagulation (APC) and high-dose proton pump inhibitor therapy (120 mg omeprazole daily). Sixty-six patients (94.4%) underwent further surveillance endoscopy. At each surveillance endoscopy four-quadrant biopsies were taken from the neo-squamous epithelium at 2 cm intervals depending on the pre-treatment length of BE mucosa beginning at the neo-Z-line, and from any endoscopically suspicious lesion.
RESULTS: The median follow-up of 66 patients was 51 mo (range 9-85 mo) giving a total of 280.5 patient years. A mean of 6 biopsies were taken during surveillance endoscopies. In 13 patients (19.7%) tongues or islands suspicious for BE were found during endoscopy. In 8 of these patients (12.1%) non-neoplastic BE relapse was confirmed histologically giving a histological relapse rate of 3% per year. In none of the patients, intraepithelial neoplasia nor an esophageal adenocarcinoma was detected. Logistic regression analysis identified endoscopic detection of islands or tongues as the only positive predictor of BE relapse (P = 0.0004).
CONCLUSION: The long-term relapse rate of non-neoplastic BE following complete ablation with high-power APC is low (3% per year).
doi:10.3748/wjg.v11.i8.1182
PMCID: PMC4250710  PMID: 15754401
Barrett’s esophagus; Argon plasma coagulation; Esophageal adenocarcinoma
6.  Endoscopic assessment and management of early esophageal adenocarcinoma 
Esophageal carcinoma affects more than 450000 people worldwide and the incidence is rapidly increasing. In the United States and Europe, esophageal adenocarcinoma has superseded esophageal squamous cell carcinoma in its incidence. Esophageal cancer has a high mortality rates secondary to the late presentation of most patients at advanced stages. Endoscopic screening is recommended for patients with multiple risk factors for cancer in Barrett’s esophagus. These risk factors include chronic gastroesophageal reflux disease, hiatal hernia, advanced age, male sex, white race, cigarette smoking, and obesity. The annual risk of esophageal cancer is approximately 0.25% for patients without dysplasia and 6% for patients with high-grade dysplasia. Twenty percent of all esophageal adenocarcinoma in the United States is early stage with disease confined to the mucosa or submucosa. The significant morbidity and mortality of esophagectomy make endoscopic treatment an attractive option. The American Gastroenterological Association recommends endoscopic eradication therapy for patients with high-grade dysplasia. Endoscopic modalities for treatment of early esophageal adenocarcinoma include endoscopic resection techniques and endoscopic ablative techniques such as radiofrequency ablation, photodynamic therapy and cryoablation. Endoscopic therapy should be precluded to patients with no evidence of lymphovascular invasion. Local tumor recurrence is low after endoscopic therapy and is predicted by poor differentiation of tumor, positive lymph node and submucosal invasion. Surgical resection should be offered to patients with deep submucosal invasion.
doi:10.4251/wjgo.v6.i8.275
PMCID: PMC4133795  PMID: 25132925
Esophageal adenocarcinoma; High grade dysplasia, endoscopic ultrasound; Gastroesophageal reflux; Barrett’s esophagus; Chromoendoscopy; Narrow band imaging; Endoscopic mucosal resection; Radiofrequency ablation
7.  Usefulness of Non-Magnifying Narrow-Band Imaging in Screening of Early Esophageal Squamous Cell Carcinoma: A Prospective Comparative Study Using Propensity Score Matching 
OBJECTIVES:
The usefulness of non-magnifying endoscopy with narrow-band imaging (NBI; NM-NBI) in the screening of early esophageal squamous cell carcinoma (SCC) and high-grade intraepithelial neoplasia (HGIN) remains unclear. Here, we aimed to compare NM-NBI and chromoendoscopy with iodine staining (CE-Iodine) in terms of the diagnostic performance, and to evaluate the usefulness of NM-NBI in detecting early esophageal SCC.
METHODS:
We prospectively enrolled 202 consecutive patients (male/female=180/22; median age, 67 years) with high-risk factors for esophageal SCC. All patients received endoscopic examination with NM-NBI and CE-Iodine to screen for early esophageal SCC or HGIN. We conducted the examinations sequentially, and calculated the accuracy, sensitivity, and specificity through a per-lesion-based analysis. A propensity score matching analysis was performed to reduce the effects of selection bias, and we compared the respective outcomes according to NM-NBI and CE-Iodine after matching.
RESULTS:
The accuracy, sensitivity, and specificity of NM-NBI were 77.0, 88.3, and 75.2%, respectively, and those for unstained areas by CE-Iodine were 68.0, 94.2, and 64.0, respectively. The accuracy and specificity of NM-NBI were superior to those of CE-Iodine (P=0.03 and P=0.01, respectively). However, the sensitivity did not significantly differ between NM-NBI and CE-Iodine (P=0.67). The accuracy and specificity of NM-NBI before matching were superior to those of CE-Iodine after matching (P=0.04 and P=0.03).
CONCLUSIONS:
NM-NBI was useful and reliable for the diagnosis of esophageal SCC and can be a promising screening strategy for early esophageal SCC.
doi:10.1038/ajg.2014.94
PMCID: PMC4050526  PMID: 24751580
8.  Limiting esophageal temperature in radiofrequency ablation of left atrial tachyarrhythmias results in low incidence of thermal esophageal lesions 
Background
Atrio-esophageal fistula formation following radiofrequency ablation of left atrial tachyarrhythmias is a rare but devastating complication. Esophageal injuries are believed to be precursors of fistula formation and reported to occur in up to 47% of patients. This study investigates the incidence of esophageal lesions when real time esophageal temperature monitoring and temperature limitation is used.
Methods
184 consecutive patients underwent open irrigated radiofrequency ablation of left atrial tachyarrhythmias. An esophageal temperature probe consisting of three independent thermocouples was used for temperature monitoring. A temperature limit of 40°C was defined to interrupt energy delivery. All patients underwent esophageal endoscopy the next day.
Results
Endoscopy revealed ulcer formation in 3/184 patients (1.6%). No patient developed atrio-esophageal fistula. Patient and disease characteristics had no influence on ulcer formation. The temperature threshold of 40°C was reached in 157/184 patients. A temperature overshoot after cessation of energy delivery was observed frequently. The mean maximal temperature was 40.8°C. Using a multiple regression analysis creating a box lesion that implies superior- and inferior lines at the posterior wall connecting the right and left encircling was an independent predictor of temperature. Six month follow-up showed an overall success rate of 78% documented as sinus rhythm in seven-day holter ECG.
Conclusion
Limitation of esophageal temperature to 40°C is associated with the lowest incidence of esophageal lesion formation published so far. This approach may contribute to increase the safety profile of radiofrequency ablation in the left atrium.
doi:10.1186/1471-2261-10-52
PMCID: PMC2987899  PMID: 20977747
9.  Radiofrequency ablation for early oesophageal squamous neoplasia: Outcomes form United Kingdom registry 
AIM: To report outcomes on patients undergoing radiofrequency ablation (RFA) for early oesophageal squamous neoplasia from a National Registry.
METHODS: A Prospective cohort study from 8 tertiary referral centres in the United Kingdom. Patients with squamous high grade dysplasia (HGD) and early squamous cell carcinoma (ESCC) confined to the mucosa were treated. Visible lesions were removed by endoscopic mucosal resection (EMR) before RFA. Following initial RFA treatment, patients were followed up 3 monthly. Residual flat dysplasia was treated with RFA until complete reversal dysplasia (CR-D) was achieved or progression to invasive Squamous cell cancer defined as infiltration into the submucosa layer or beyond. The main outcome measures were CR-D at 12 mo from start of treatment, long term durability, progression to cancer and adverse events.
RESULTS: Twenty patients with squamous HGD/ESCC completed treatment protocol. Five patients (25%) had EMR before starting RFA treatment. CR-D was 50% at 12 mo with a median of 1 RFA treatment, mean 1.5 (range 1-3). Two further patients achieved CR-D with repeat RFA after this time. Eighty per cent with CR-D remain dysplasia free at latest biopsy, with median follow up 24 mo (IQR 17-54). Six of 20 patients (30%) progressed to invasive cancer at 1 year. Four patients (20%) required endoscopic dilatations for symptomatic structuring after treatment. Two of these patients have required serial dilatations thereafter for symptomatic dysphagia with a median of 4 dilatations per patient. The other 2 patients required only a single dilatation to achieve an adequate symptomatic response. One patient developed cancer during follow up after end of treatment protocol.
CONCLUSION: The role of RFA in these patients remains unclear. In our series 50% patients responded at 12 mo. These figures are lower than limited published data.
doi:10.3748/wjg.v19.i36.6011
PMCID: PMC3785622  PMID: 24106401
Squamous neoplasia; Oesophageal cancer; Endoscopic mucosal resection; High-grade dysplasia; Radiofrequency ablation
10.  Changes in Screening, Prognostication and Therapy for Esophageal Adenocarcinoma in Barrett’s Esophagus 
Purpose of review
Significant changes in concepts of managing Barrett’s esophagus have led to change in the recommendations concerning screening, surveillance, biomarkers, and therapies in this condition over the past several years. We summarize the important changes in this regard.
Recent findings
Narrow band imaging and esophageal capsule endoscopy are alternative methods to screen for Barrett’s esophagus. Narrow band imaging provides clear visualization of the mucosal pit patterns and vascular patterns, which improve the diagnostic value for specialized intestinal mataplasia. Esophageal capsule endoscopy is a new potential tool which allows a direct noninvasive visualization of esophagus. Research efforts are currently directed towards risk stratification of patients and biomarkers have been developed to predict development of esophageal adenocarcinoma. Recent studies have reported that frequent loss of heterozygosity (LOH) as well as allelic imbalances in chromosomes in esophageal adenocarcinoma. Fluorescent in situ hybridization technique which uses fluorescently labeled DNA probes to detect chromosomal alterations in cells obtained from cytology specimens has been developed. It showed more sensitive and specific for abnormalities than PCR based techniques. Currently, many studies support the concept of endoscopic elimination of dysplastic lesions in the esophagus by a mucosal ablation therapy. Photodynamic therapy and radiofrequency ablation are recently developed, emerging techniques.
Summary
Recent advances in screening, prognostication and therapy for esophageal adenocarcinoma in Barrett’s Esophagus have brought a significant new insight in clinical practices and will eventually ensure better patients outcomes.
doi:10.1097/MOG.0b013e32832c148f
PMCID: PMC3762463  PMID: 19461512
narrow band imaging; esophageal capsule endoscopy; fluorescent in situ hybridization; photodynamic therapy; radiofrequency ablation
11.  Detection of Esophageal Squamous Cell Carcinoma by Cathepsin B Activity in Nude Mice 
PLoS ONE  2014;9(3):e92351.
Background and Objective
Despite great progress in treatment, the prognosis for patients with esophageal squamous cell carcinoma (ESCC) remains poor, highlighting the importance of early detection. Although upper endoscopy can be used for the screening of esophagus, it has limited sensitivity for early stage disease. Thus, development of new diagnosis approach to improve diagnostic capabilities for early detection of ESCC is an important need. The aim of this study was to assess the feasibility of using cathepsin B (CB) as a novel imaging target for the detection of human ESCC by near-infrared optical imaging in nude mice.
Methods
Initially, we examined specimens from normal human esophageal tissue, intraepithelial neoplasia lesions, tumor in situ, ESCC and two cell lines including one human ESCC cell line (Eca-109) and one normal human esophageal epithelial cell line (HET-1A) for CB expression by immunohistochemistry and western blot, respectively. Next, the ability of a novel CB activatable near-infrared fluorescence (NIRF) probe detecting CB activity presented in Eca-109 cells was confirmed by immunocytochemistry. We also performed in vivo imaging of tumor bearing mice injected with the CB probe and ex vivo imaging of resected tumor xenografts and visceral organs using a living imaging system. Finally, the sources of fluorescence signals in tumor tissue and CB expression in visceral organs were identified by histology.
Results
CB was absent in normal human esophageal mucosa, but it was overexpressed in ESCC and its precursor lesions. The novel probe for CB activity specifically detected ESCC xenografts in vivo and in vitro.
Conclusions
CB was highly upregulated in human ESCC and its precursor lesions. The elevated CB expression in ESCC allowed in vivo and in vitro detection of ESCC xenografts in nude mice. Our results support the usefulness of CB activity as a potential imaging target for the detection of human ESCC.
doi:10.1371/journal.pone.0092351
PMCID: PMC3950293  PMID: 24618814
12.  Safety, tolerability, and efficacy of endoscopic low-pressure liquid nitrogen spray cryotherapy in the esophagus 
SUMMARY
Endoscopic cryotherapy is a new technique for ablation of esophageal dysplasia and neoplasia. Preliminary studies have shown it to be safe and effective for this indication. The objective of this study is to characterize safety, tolerability, and efficacy of low-pressure liquid nitrogen endoscopic spray cryotherapy ablation in a large cohort across multiple study sites. Parallel prospective treatment studies at four tertiary care academic medical centers in the U.S. assessed spray cryotherapy in patients with Barrett’s esophagus with or without dysplasia, early stage esophageal cancer, and severe squamous dysplasia who underwent cryotherapy ablation of the esophagus. All patients were contacted between 1 and 10 days after treatment to assess for side effects and complications of treatment. The main outcome measurement was the incidence of serious adverse events and side effects from treatment. Complete response for high-grade dysplasia (HGD) (CR-HGD), all dysplasia (CR-D), intestinal metaplasia (CR-IM) and cancer (CR-C) were assessed in patients completing therapy during the study period. A total of 77 patients were treated for Barrett’s high-grade dysplasia (58.4%), intramucosal carcinoma (16.9%), invasive carcinoma (13%), Barrett’s esophagus without dysplasia (9.1%), and severe squamous dysplasia (2.6%). Twenty-two patients (28.6%) reported no side effects throughout treatment. In 323 procedures, the most common complaint was chest pain (17.6%) followed by dysphagia (13.3%), odynophagia (12.1%), and sore throat (9.6%). The mean duration of any symptoms was 3.6 days. No side effects were reported in 48% of the procedures (155/323). Symptoms did not correlate with age, gender, diagnosis, or to treatment early versus late in the patient’s or site’s experience. Logit analysis showed that symptoms were greater in those with a Barrett’s segment of 6 cm or longer. Gastric perforation occurred in one patient with Marfan’s syndrome. Esophageal stricture developed in three, all successfully treated with dilation. In 17 HGD patients, cryotherapy produced CR-HGD, CR-D, and CR-IM of 94%, 88%, and 53%, respectively. Complete regression of cancer and HGD was seen in all seven patients with intramucosal carcinoma or stage I esophageal cancer. Endoscopic spray cryotherapy ablation using low-pressure liquid nitrogen in the esophagus is safe, well-tolerated, and efficacious.
doi:10.1111/j.1442-2050.2009.00991.x
PMCID: PMC3144029  PMID: 19515183
Barrett esophagus; catheter ablation; cryosurgery; cryotherapy; esophageal neoplasm; safety
13.  Targeted imaging of esophageal neoplasia with a fluorescently labeled peptide: First in-human results 
Science translational medicine  2013;5(184):10.1126/scitranslmed.3004733.
Esophageal adenocarcinoma is rising rapidly in incidence, and usually develops from Barrett’s esophagus, a precursor condition commonly found in patients with chronic acid reflux. Pre-malignant lesions are challenging to detect on conventional screening endoscopy because of their flat appearance. Molecular changes can be used to improve detection of early neoplasia. We have developed a peptide that binds specifically to high-grade dysplasia and adenocarcinoma. We first applied the peptide ex vivo to esophageal specimens from 17 patients to validate specific binding. Next, we performed confocal endomicroscopy in vivo in 25 human subjects after topical peptide administration and found 3.8-fold greater fluorescence intensity for esophageal neoplasia compared with Barrett’s esophagus and squamous epithelium with 75% sensitivity and 97% specificity. No toxicity was attributed to the peptide in either animal or patient studies. Therefore, our first-in-humans results show that this targeted imaging agent is safe, and may be useful for guiding tissue biopsy and for early detection of esophageal neoplasia and potentially other cancers of epithelial origin, such as bladder, colon, lung, pancreas, and stomach.
doi:10.1126/scitranslmed.3004733
PMCID: PMC3859345  PMID: 23658246
14.  Cerebral Air Emboli With Atrial-Esophageal Fistula Following Atrial Fibrillation Ablation 
The Neurohospitalist  2011;1(3):128-132.
Background: Atrial-esophageal fistula (AEF) is a rare and early complication of radiofrequency ablation for medically refractory atrial fibrillation, but has devastating consequences when the diagnosis is delayed or difficult to make. Methods: Single case in a neurosciences critical care center. Results: A 69-year-old man with significant cardiac and neurologic medical history who underwent atrial fibrillation ablation 50 days prior to admission to the neurocritical care unit presented with acute left-sided weakness and gram-positive bacterial sepsis. This is an exceptional case discussing the need for early detection of AEF presenting with sepsis, neurologic deficit along with complicated decision-making in the neurocritical care setting. His hospital course was complicated by acute stroke, left ventricular (LV) aneurysm with thrombus, gastrointestinal (GI) bleed discovered to be from left atrial esophageal fistula, and subsequent cerebral air emboli leading to death. Conclusions: This is the most delayed presentation of AEF following atrial fibrillation ablation reported in the literature to date. We emphasize the need for awareness of this complication even after such an unexpected time-frame postprocedure as well as the unintended complications of cerebral air emboli following upper endoscopy.
doi:10.1177/1941875211399582
PMCID: PMC3726131  PMID: 23983846
atrial fibrillation; atrial esophageal fistula; AEF; left ventricular aneurysm; cerebral air emboli
15.  Measuring telomere length for the early detection of precursor lesions of esophageal squamous cell carcinoma 
BMC Cancer  2013;13:578.
Background
Esophageal cancer is the sixth leading cause of cancer death worldwide; current early detection screening tests are inadequate. Esophageal balloon cytology successfully retrieves exfoliated and scraped superficial esophageal epithelial cells, but cytologic reading of these cells has poor sensitivity and specificity for detecting esophageal squamous dysplasia (ESD), the precursor lesion of esophageal squamous cell carcinoma (ESCC). Measuring telomere length, a marker for chromosomal instability, may improve the utility of balloon cytology for detecting ESD and early ESCC.
Methods
We examined balloon cytology specimens from 89 asymptomatic cases of ESD (37 low-grade and 52 high-grade) and 92 age- and sex-matched normal controls from an esophageal cancer early detection screening study. All subjects also underwent endoscopy and biopsy, and ESD was diagnosed histopathologically. DNA was extracted from the balloon cytology cells, and telomere length was measured by quantitative PCR. A receiver operating characteristic (ROC) curve was plotted for telomere length as a diagnostic marker for high-grade dysplasia.
Results
Telomere lengths were comparable among the low- and high-grade dysplasia cases and controls, with means of 0.96, 0.96, and 0.92, respectively. The area under the ROC curve was 0.55 for telomere length as a diagnostic marker for high-grade dysplasia. Further adjustment for subject characteristics, including sex, age, smoking, drinking, hypertension, and body mass index did not improve the use of telomere length as a marker for ESD.
Conclusions
Telomere length of esophageal balloon cytology cells was not associated with ESCC precursor lesions. Therefore, telomere length shows little promise as an early detection marker for ESCC in esophageal balloon samples.
doi:10.1186/1471-2407-13-578
PMCID: PMC3882883  PMID: 24308314
Esophageal squamous cell carcinoma; Esophageal squamous dysplasia; Early detection; Screening; Balloon cytology; Telomeres
16.  Esophagitis may not be a Major Precursor Lesion for Esophageal Squamous Cell Carcinoma in a High Incidence Area in North-Eastern Iran 
BACKGROUND
Esophageal squamous cell carcinoma (ESCC) is usually detected in advanced stages resulting in a very poor prognosis. Early diagnosis needs identification of clinically relevant precancerous lesions which could become the target of screening and early treatment. Our aim was to check whether esophagitis could serve as a relevant histological precursor of ESCC in Northern Iran.
METHODS
During 2001–2005, all adult patients who were referred to Atrak clinic for upper gastrointestinal endoscopy and biopsy were enrolled. Atrak clinic is a major center for upper gastrointestinal cancer research in eastern Golestan. All subjects had been complaining of upper GI symptoms and were under further investigation to rule out cancer. Biopsies from the endoscopically normal mid-esophagus and also just above the esophago-gastric junction were obtained in all subjects whose esophagus appeared normal during endoscopy and from endoscopically normal appearing mucosa at the proximal vicinity of any detected mass. Microscopic examinations for the verification of the presence or absence of esophagitis was performed by independant histological examination of the samples by two pathologists. All the discrepant diagnoses were resolved in joint diagnostic sessions.
RESULTS
During the study period 836 patients were enrolled including 419 non cancer patients (endoscopy clinic controls), 387 cancer patients, and 30 subjects with clinical diagnosis of malignancy referred for histological reconfirmation of diagnosis by repeated biopsy. Mild or marked mid-esophagitis was diagnosed in 39 (9.3%), 47 (12.5%) and 12 (40%) of endoscopy clinic controls, cancer patients and those who were suspicious for upper gastrointestinal malignancies.
CONCLUSION
Our observation does not show evidence for esophagitis to be a predisposing factor for ESCC in Gonbad region In North Eastern Iran.
PMCID: PMC4154925  PMID: 25197529
Esophagus; Squamous cell carcinoma; Esophagitis
17.  Recurrent oesophageal intramucosal squamous carcinoma treated by endoscopic mucosal resection and subsequent radiofrequency ablation using HALO system 
BMJ Case Reports  2010;2010:bcr0820103211.
The method of radiofrequency ablation (RFA) is currently used for the treatment of high-grade dysplasia in Barrett's oesophagus. It has theoretical potential also for the use in squamous epithelial neoplasias. The authors present a case report of an early diagnosis of squamous cancer in a high-risk patient, its endoscopic treatment and follow-up, and successful RFA of recurrent neoplasia. RFA can expand our therapeutic possibilities for the management of recurrent neoplastic lesions after endoscopic treatment of squamous oesophageal cancer.
doi:10.1136/bcr.08.2010.3211
PMCID: PMC3027413  PMID: 22802374
18.  Endoscopy in screening for digestive cancer 
The aim of this study is to describe the role of endoscopy in detection and treatment of neoplastic lesions of the digestive mucosa in asymptomatic persons. Esophageal squamous cell cancer occurs in relation to nutritional deficiency and alcohol or tobacco consumption. Esophageal adenocarcinoma develops in Barrett’s esophagus, and stomach cancer in chronic gastric atrophy with Helicobacter pylori infection. Colorectal cancer is favoured by a high intake in calories, excess weight, low physical activity. In opportunistic or individual screening endoscopy is the primary detection procedure offered to an asymptomatic individual. In organized or mass screening proposed by National Health Authorities to a population, endoscopy is performed only in persons found positive to a filter selection test. The indications of primary upper gastrointestinal endoscopy and colonoscopy in opportunistic screening are increasingly developing over the world. Organized screening trials are proposed in some regions of China at high risk for esophageal cancer; the selection test is cytology of a balloon or sponge scrapping; they are proposed in Japan for stomach cancer with photofluorography as a selection test; and in Europe, America and Japan; for colorectal cancer with the fecal occult blood test as a selection test. Organized screening trials in a country require an evaluation: the benefit of the intervention assessed by its impact on incidence and on the 5 year survival for the concerned tumor site; in addition a number of bias interfering with the evaluation have to be controlled. Drawbacks of screening are in the morbidity of the diagnostic and treatment procedures and in overdetection of none clinically relevant lesions. The strategy of endoscopic screening applies to early cancer and to benign adenomatous precursors of adenocarcinoma. Diagnostic endoscopy is conducted in 2 steps: at first detection of an abnormal area through changes in relief, in color or in the course of superficial capillaries; then characterization of the morphology of the lesion according to the Paris classification and prediction of the risk of malignancy and depth of invasion, with the help of chromoscopy, magnification and image processing with neutrophil bactericidal index or FICE. Then treatment decision offers 3 options according to histologic prediction: abstention, endoscopic resection, surgery. The rigorous quality control of endoscopy will reduce the miss rate of lesions and the occurrence of interval cancer.
doi:10.4253/wjge.v4.i12.518
PMCID: PMC3536848  PMID: 23293721
Esophagus; Stomach; Colon; Adenoma; Adenocarcinoma; Endoscopy; Screening
19.  MicroRNA Expression Differentiates Squamous Epithelium from Barrett’s Esophagus and Esophageal Cancer 
Digestive diseases and sciences  2013;58(11):3178-3188.
Background
Current strategies fail to identify most patients with esophageal adenocarcinoma (EAC) before the disease becomes advanced and incurable. Given the dismal prognosis associated with EAC, improvements in detection of early-stage esophageal neoplasia are needed.
Aims
We sought to assess whether differential expression of microRNAs could discriminate between squamous epithelium, Barrett’s esophagus (BE), and EAC.
Methods
We analyzed microRNA expression in a discovery cohort of human endoscopic biopsy samples from 36 patients representing normal squamous esophagus (n=11), BE (n=14), and high-grade dysplasia (HGD)/EAC (n=11). RNA was assessed using microarrays representing 847 human microRNAs followed by qRT-PCR verification of nine microRNAs. In a second cohort (n=18), qRT-PCR validation of five miRNAs was performed. Expression of 59 microRNAs associated with BE/EAC in the literature was assessed in our training cohort. Known esophageal cell lines were used to compare miRNA expression to tissue miRNAs.
Results
After controlling for multiple comparisons, we found 34 miRNAs differentially expressed between squamous esophagus and BE/EAC by microarray analysis. However, miRNA expression did not reliably differentiate non-dysplastic BE from EAC. In the validation cohort, all five microRNAs selected for qRT-PCR validation differentiated between squamous samples and BE/EAC. Microarray results supported 14 of the previously reported microRNAs associated with BE/EAC in the literature. Cell lines did not generally reflect miRNA expression found in vivo.
Conclusions
These data indicate that miRNAs differ between squamous esophageal epithelium and BE/EAC, but do not distinguish between BE and EAC. We suggest prospective evaluation of miRNAs in patients at high risk for EAC.
doi:10.1007/s10620-013-2806-7
PMCID: PMC4180409  PMID: 23925817
Barrett esophagus; esophageal neoplasms; microarray analysis; microRNAs
20.  Safety and Efficacy of Endoscopic Mucosal Therapy with Radiofrequency Ablation for Patients with Neoplastic Barrett’s Esophagus 
Background& Aims
The goal of radiofrequency ablation (RFA) for patients with Barrett’s esophagus (BE) is to eliminate dysplasia and metaplasia. The efficacy and safety of RFA for patients with BE and neoplasia are incompletely characterized.
Methods
We performed a retrospective study of 244 patients treated with RFA for BE with dysplasia or intramucosal carcinoma. Efficacy outcomes were complete eradication of intestinal metaplasia (CEIM), complete eradication of dysplasia (CED), total treatments, and RFA sessions. Safety outcomes included death, perforation, stricture, bleeding, and hospitalization. We identified factors associated with incomplete EIM and stricture formation.
Results
CEIM was achieved in 80% of the patients, and CED in 87%; disease progressed in 4 patients. A higher percentage of patients with incomplete EIM were female (40%) than those with CEIM (20%, P=.045); patients with incomplete EIM also had a longer segment of BE (5.5 vs 4.0 cm, P=.03), incomplete healing between treatment sessions (45% vs 15%, P=0.004), and underwent more treatment sessions (4 vs 3, P=.007). Incomplete healing was independently associated with incomplete EIM. Twenty-three patients (9.4%) had a treatment-related complication during 777 treatment sessions (3.0%), including strictures (8.2%), post-procedural hemorrhages (1.6%), and hospitalizations (1.6%). Patients that developed strictures were more likely to use non-steroidal anti-inflammatory drugs (NSAID) than those without strictures (70% vs 45%, P=.04), have undergone antireflux surgery (15% vs 3%, P=.04), or had erosive esophagitis (35% vs 12%, P=.01).
Conclusions
RFA is highly effective and safe for treatment of BE with dysplasia or early-stage cancer. Strictures were the most common complications. Incomplete healing between treatment sessions was associated with incomplete EIM. NSAID use, prior anti-reflux surgery, and a history of erosive esophagitis predicted stricture formation.
doi:10.1016/j.cgh.2012.10.028
PMCID: PMC3660497  PMID: 23103824
Barrett’s esophagus; radiofrequency ablation; esophageal cancer; epidemiology
21.  Barrett’s esophagus: review of diagnosis and treatment 
Gastroenterology Report  2013;1(1):9-18.
Barrett's esophagus (BE) is an acquired condition characterized by replacement of stratified squamous epithelium by a cancer predisposing metaplastic columnar epithelium. Endoscopy with systemic biopsy protocols plays a vital role in diagnosis. Technological advancements in dysplasia detection improves outcomes in surveillance and treatment of patients with BE and dysplasia. These advances in endoscopic technology radically changed the treatment for dysplastic BE and early cancer from being surgical to organ-sparing endoscopic therapy. A multimodal treatment approach combining endoscopic resection of visible and/or raised lesions with ablation techniques for flat BE mucosa, followed by long-term surveillance improves the outcomes of BE. Safe and effective endoscopic treatment can be either tissue acquiring as in endoscopic mucosal resection and endoscopic submucosal dissection or tissue ablative as with photodynamic therapy, radiofrequency ablation and cryotherapy. Debatable issues such as durability of response, recognition and management of sub-squamous BE and optimal management strategy in patients with low-grade dysplasia and non-dysplastic BE need to be studied further. Development of safer wide field resection techniques, which would effectively remove all BE and obviate the need for long-term surveillance, is another research goal. Shared decision making between the patient and physician is important while considering treatment for dysplasia in BE.
doi:10.1093/gastro/got015
PMCID: PMC3941437  PMID: 24759662
Barrett’s esophagus; endoscopic mucosal resection; endoscopic submucosal dissection
22.  Esophageal early basaloid squamous carcinoma with unusual narrowband imaging magnified endoscopy findings 
World Journal of Gastroenterology : WJG  2014;20(35):12673-12677.
Basaloid squamous carcinoma (BSC) is a rare variant of esophageal cancer. There are very few reports of “early” BSC. Here we report a case of early BSC with unusual findings by narrowband imaging magnified endoscopy (NBI-ME). A 70-year-old man with a middle thoracic esophageal tumor was referred to our hospital. White-light endoscopy revealed a reddish depressed lesion 5 mm in diameter having a subepithelial tumor-like prominence with a gentle rising slope. NBI-ME revealed irregular loop-shaped microvessels coexistent with thick irregularly branched non-looped vessels. Iodine staining revealed a pale brown lesion. We performed endoscopic submucosal dissection for diagnostic treatment. Histologic examination showed the proliferation of basal cell-like hyperchromatic tumor cells in the lamina propria and with slight invasion into the submucosa at a depth of 320 μm. The tumor cells formed solid nests and microcystic structures, containing an Alcian blue-positive mucoid matrix. The surface was covered with squamous epithelium without cellular atypia. Thin vessels were observed in the intra-epithelial papilla and thick vessels were observed around the solid nests beneath the epithelium. Based on these findings together, we diagnosed the lesion as BSC. In this case, the NBI-ME findings differed from those of typical squamous cell carcinoma in that both non-invasive cancer-like irregular loop-shaped microvessels coexisted with massively invasive cancer-like thick non-looped vessels. We speculate that the looped and non-looped vessels observed by NBI-ME histologically corresponded to thin vessels in the intra-epithelial papilla and thick vessels around the tumor nests, respectively. These NBI-ME findings might be a feature of early esophageal BSC.
doi:10.3748/wjg.v20.i35.12673
PMCID: PMC4168107  PMID: 25253974
Basaloid squamous carcinoma; Narrowband imaging; Esophagus; Endoscopic submucosal dissection
23.  COX2 (PTGS2) gene methylation in epithelial, subepithelial lymphocyte and stromal tissue compartments in a spectrum of esophageal squamous neoplasia 
Cancer detection and prevention  2008;32(2):135-139.
Background
Previous studies have shown important effects of stromal elements in carcinogenesis. To explore the tumor-stromal relationship in esophageal neoplasia, we examined methylation of COX-2 (PTGS2), a gene etiologically associated with the development of gastrointestinal cancers, in adjacent foci of epithelium, subepithelial lymphocytes and non-lymphocytic stromal cells found in sections of normal squamous epithelium, squamous dysplasia and invasive esophageal squamous cell carcinoma.
Methods
Adjacent foci of epithelium, subepithelial lymphocytic aggregates and non-lymphocytic stromal tissues were laser microdissected from six fully embedded, ethanol fixed, esophagectomy samples from Shanxi, China, a high-risk region for esophageal cancer. Promoter CpG site-specific hypermethylation status of COX-2 was determined using real-time methylation specific PCR (qMS-PCR) based on Taqman Chemistry. The methylation status of a subset of samples was confirmed by pyrosequencing.
Results
Forty-nine microdissected foci were analyzed. COX-2 gene methylation was significantly more common in subepithelial lymphocytes (12/16 (75% of all foci)) than in epithelial foci (3/16 (19%)) or foci of non-lymphocytic stromal tissues (3/17 (18%)) (Fisher’s Exact p=0.05). Two of three epithelial samples and all three stromal samples that showed COX-2 methylation were adjacent to foci of methylated subepithelial lymphocytes. Pyrosequencing confirmed the methylation status in a subset of samples.
Conclusions
In these esopohageal cancer patients, COX-2 gene methylation was more common in subepithelial lymphocytes than in adjacent epithelial or stromal cells in both grades of dysplasia and in foci of invasive cancer. These findings raise the possibility that methylation of subepithelial lymphocytes may be important for tumorigenesis. Future studies of gene methylation should consider separate evaluation of epithelial and non-epithelial cell populations.
Condensed abstract
COX2 (PTGS2) gene methylation increases with disease severity and is more common in subepithelial lymphocytes than in adjacent epithelial or stromal cells in dysplastic and early invasive esophageal squamous cell cancer foci.
doi:10.1016/j.cdp.2008.05.001
PMCID: PMC2629649  PMID: 18632220
esophagus; neoplasms; cancer; cyclooxgenase-2; precancerous conditions; methylation; lymphocytes; squamous cell cancer
24.  Advanced Electrophysiologic Mapping Systems 
Executive Summary
Objective
To assess the effectiveness, cost-effectiveness, and demand in Ontario for catheter ablation of complex arrhythmias guided by advanced nonfluoroscopy mapping systems. Particular attention was paid to ablation for atrial fibrillation (AF).
Clinical Need
Tachycardia
Tachycardia refers to a diverse group of arrhythmias characterized by heart rates that are greater than 100 beats per minute. It results from abnormal firing of electrical impulses from heart tissues or abnormal electrical pathways in the heart because of scars. Tachycardia may be asymptomatic, or it may adversely affect quality of life owing to symptoms such as palpitations, headaches, shortness of breath, weakness, dizziness, and syncope. Atrial fibrillation, the most common sustained arrhythmia, affects about 99,000 people in Ontario. It is associated with higher morbidity and mortality because of increased risk of stroke, embolism, and congestive heart failure. In atrial fibrillation, most of the abnormal arrhythmogenic foci are located inside the pulmonary veins, although the atrium may also be responsible for triggering or perpetuating atrial fibrillation. Ventricular tachycardia, often found in patients with ischemic heart disease and a history of myocardial infarction, is often life-threatening; it accounts for about 50% of sudden deaths.
Treatment of Tachycardia
The first line of treatment for tachycardia is antiarrhythmic drugs; for atrial fibrillation, anticoagulation drugs are also used to prevent stroke. For patients refractory to or unable to tolerate antiarrhythmic drugs, ablation of the arrhythmogenic heart tissues is the only option. Surgical ablation such as the Cox-Maze procedure is more invasive. Catheter ablation, involving the delivery of energy (most commonly radiofrequency) via a percutaneous catheter system guided by X-ray fluoroscopy, has been used in place of surgical ablation for many patients. However, this conventional approach in catheter ablation has not been found to be effective for the treatment of complex arrhythmias such as chronic atrial fibrillation or ventricular tachycardia. Advanced nonfluoroscopic mapping systems have been developed for guiding the ablation of these complex arrhythmias.
The Technology
Four nonfluoroscopic advanced mapping systems have been licensed by Health Canada:
CARTO EP mapping System (manufactured by Biosense Webster, CA) uses weak magnetic fields and a special mapping/ablation catheter with a magnetic sensor to locate the catheter and reconstruct a 3-dimensional geometry of the heart superimposed with colour-coded electric potential maps to guide ablation.
EnSite System (manufactured by Endocardial Solutions Inc., MN) includes a multi-electrode non-contact catheter that conducts simultaneous mapping. A processing unit uses the electrical data to computes more than 3,000 isopotential electrograms that are displayed on a reconstructed 3-dimensional geometry of the heart chamber. The navigational system, EnSite NavX, can be used separately with most mapping catheters.
The LocaLisa Intracardiac System (manufactured by Medtronics Inc, MN) is a navigational system that uses an electrical field to locate the mapping catheter. It reconstructs the location of the electrodes on the mapping catheter in 3-dimensional virtual space, thereby enabling an ablation catheter to be directed to the electrode that identifies abnormal electric potential.
Polar Constellation Advanced Mapping Catheter System (manufactured by Boston Scientific, MA) is a multielectrode basket catheter with 64 electrodes on 8 splines. Once deployed, each electrode is automatically traced. The information enables a 3-dimensional model of the basket catheter to be computed. Colour-coded activation maps are reconstructed online and displayed on a monitor. By using this catheter, a precise electrical map of the atrium can be obtained in several heartbeats.
Review Strategy
A systematic search of Cochrane, MEDLINE and EMBASE was conducted to identify studies that compared ablation guided by any of the advanced systems to fluoroscopy-guided ablation of tachycardia. English-language studies with sample sizes greater than or equal to 20 that were published between 2000 and 2005 were included. Observational studies on safety of advanced mapping systems and fluoroscopy were also included. Outcomes of interest were acute success, defined as termination of arrhythmia immediately following ablation; long-term success, defined as being arrhythmia free at follow-up; total procedure time; fluoroscopy time; radiation dose; number of radiofrequency pulses; complications; cost; and the cost-effectiveness ratio.
Quality of the individual studies was assessed using established criteria. Quality of the overall evidence was determined by applying the GRADE evaluation system. (3) Qualitative synthesis of the data was performed. Quantitative analysis using Revman 4.2 was performed when appropriate.
Quality of the Studies
Thirty-four studies met the inclusion criteria. These comprised 18 studies on CARTO (4 randomized controlled trials [RCTs] and 14 non-RCTs), 3 RCTs on EnSite NavX, 4 studies on LocaLisa Navigational System (1 RCT and 3 non-RCTs), 2 studies on EnSite and CARTO, 1 on Polar Constellation basket catheter, and 7 studies on radiation safety.
The quality of the studies ranged from moderate to low. Most of the studies had small sample sizes with selection bias, and there was no blinding of patients or care providers in any of the studies. Duration of follow-up ranged from 6 weeks to 29 months, with most having at least 6 months of follow-up. There was heterogeneity with respect to the approach to ablation, definition of success, and drug management before and after the ablation procedure.
Summary of Findings
Evidence is based on a small number of small RCTS and non-RCTS with methodological flaws.
Advanced nonfluoroscopy mapping/navigation systems provided real time 3-dimensional images with integration of anatomic and electrical potential information that enable better visualization of areas of interest for ablation
Advanced nonfluoroscopy mapping/navigation systems appear to be safe; they consistently shortened the fluoroscopy duration and radiation exposure.
Evidence suggests that nonfluoroscopy mapping and navigation systems may be used as adjuncts to rather than replacements for fluoroscopy in guiding the ablation of complex arrhythmias.
Most studies showed a nonsignificant trend toward lower overall failure rate for advanced mapping-guided ablation compared with fluoroscopy-guided mapping.
Pooled analyses of small RCTs and non-RCTs that compared fluoroscopy- with nonfluoroscopy-guided ablation of atrial fibrillation and atrial flutter showed that advanced nonfluoroscopy mapping and navigational systems:
Yielded acute success rates of 69% to 100%, not significantly different from fluoroscopy ablation.
Had overall failure rates at 3 months to 19 months of 1% to 40% (median 25%).
Resulted in a 10% relative reduction in overall failure rate for advanced mapping guided-ablation compared to fluoroscopy guided ablation for the treatment of atrial fibrillation.
Yielded added benefit over fluoroscopy in guiding the ablation of complex arrhythmia. The advanced systems were shown to reduce the arrhythmia burden and the need for antiarrhythmic drugs in patients with complex arrhythmia who had failed fluoroscopy-guided ablation
Based on predominantly observational studies, circumferential PV ablation guided by a nonfluoroscopy system was shown to do the following:
Result in freedom from atrial fibrillation (with or without antiarrhythmic drug) in 75% to 95% of patients (median 79%). This effect was maintained up to 28 months.
Result in freedom from atrial fibrillation without antiarrhythmic drugs in 47% to 95% of patients (median 63%).
Improve patient survival at 28 months after the procedure as compared with drug therapy.
Require special skills; patient outcomes are operator dependent, and there is a significant learning curve effect.
Complication rates of pulmonary vein ablation guided by an advanced mapping/navigation system ranged from 0% to 10% with a median of 6% during a follow-up period of 6 months to 29 months.
The complication rate of the study with the longest follow-up was 8%.
The most common complications of advanced catheter-guided ablation were stroke, transient ischemic attack, cardiac tamponade, myocardial infarction, atrial flutter, congestive heart failure, and pulmonary vein stenosis. A small number of cases with fatal atrial-esophageal fistula had been reported and were attributed to the high radiofrequency energy used rather than to the advanced mapping systems.
Economic Analysis
An Ontario-based economic analysis suggests that the cumulative incremental upfront costs of catheter ablation of atrial fibrillation guided by advanced nonfluoroscopy mapping could be recouped in 4.7 years through cost avoidance arising from less need for antiarrhythmic drugs and fewer hospitalization for stroke and heart failure.
Expert Opinion
Expert consultants to the Medical Advisory Secretariat noted the following:
Nonfluoroscopy mapping is not necessary for simple ablation procedures (e.g., typical flutter). However, it is essential in the ablation of complex arrhythmias including these:
Symptomatic, drug-refractory atrial fibrillation
Arrhythmias in people who have had surgery for congenital heart disease (e.g., macro re-entrant tachycardia in people who have had surgery for congenital heart disease).
Ventricular tachycardia due to myocardial infarction
Atypical atrial flutter
Advanced mapping systems represent an enabling technology in the ablation of complex arrhythmias. The ablation of these complex cases would not have been feasible or advisable with fluoroscopy-guided ablation and, therefore, comparative studies would not be feasible or ethical in such cases.
Many of the studies included patients with relatively simple arrhythmias (e.g., typical atrial flutter and atrial ventricular nodal re-entrant tachycardia), for which the success rates using the fluoroscopy approach were extremely high and unlikely to be improved upon using nonfluoroscopic mapping.
By age 50, almost 100% of people who have had surgery for congenital heart disease will develop arrhythmia.
Some centres are under greater pressure because of expertise in complex ablation procedures for subsets of patients.
The use of advanced mapping systems requires the support of additional electrophysiologic laboratory time and nursing time.
Conclusions
For patients suffering from symptomatic, drug-refractory atrial fibrillation and are otherwise healthy, catheter ablation offers a treatment option that is less invasive than is open surgical ablation.
Small RCTs that may have been limited by type 2 errors showed significant reductions in fluoroscopy exposure in nonfluoroscopy-guided ablation and a trend toward lower overall failure rate that did not reach statistical significance.
Pooled analysis suggests that advanced mapping systems may reduce the overall failure rate in the ablation of atrial fibrillation.
Observational studies suggest that ablation guided by complex mapping/navigation systems is a promising treatment for complex arrhythmias such as highly symptomatic, drug-refractory atrial fibrillation for which rate control is not an option
In people with atrial fibrillation, ablation guided by advanced nonfluoroscopy mapping resulted in arrhythmia free rates of 80% or higher, reduced mortality, and better quality of life at experienced centres.
Although generally safe, serious complications such as stroke, atrial-esophageal, and pulmonary vein stenosis had been reported following ablation procedures.
Experts advised that advanced mapping systems are also required for catheter ablation of:
Hemodynamically unstable ventricular tachycardia from ischemic heart disease
Macro re-entrant atrial tachycardia after surgical correction of congenital heart disease
Atypical atrial flutter
Catheter ablation of atrial fibrillation is still evolving, and it appears that different ablative techniques may be appropriate depending on the characteristics of the patient and the atrial fibrillation.
Data from centres that perform electrophysiological mapping suggest that patients with drug-refractory atrial fibrillation may be the largest group with unmet need for advanced mapping-guided catheter ablation in Ontario.
Nonfluoroscopy mapping-guided pulmonary vein ablation for the treatment of atrial fibrillation has a significant learning effect; therefore, it is advisable for the province to establish centres of excellence to ensure a critical volume, to gain efficiency and to minimize the need for antiarrhythmic drugs after ablation and the need for future repeat ablation procedures.
PMCID: PMC3379531  PMID: 23074499
25.  Esophageal squamous cell carcinoma - precursor lesions and early diagnosis 
Squamous cell carcinoma of the esophagus (SCCE) carries a poor prognosis due to late diagnosis. Early detection is highly desirable, since surgical and endoscopic resection offers the only possible cure for esophageal cancer. Population screening should be undertaken in high risk areas, and in low or moderate risk areas for people with risk factors (alcoholics, smokers, mate drinkers, history of head and neck cancer, achalasia and lye stricture of the esophagus). Esophageal balloon cytology is an easy and inexpensive sampling technique, but the current methods are insufficient for primary screening due to sampling errors. Conventional endoscopy with biopsy remains the standard procedure for the identification of pre-malignant and early malignant changes in esophageal mucosa and endoscopic detection. It may be enhanced by several techniques such as dye and optic chromoendoscopy, magnifying endoscopy, and optical-based spectroscopic and imaging modalities. Since more than 80% of SCCE deaths occur in developing countries, where expensive techniques such as narrow band imaging (NBI) and autofluorescence imaging are unavailable, the most cost-effective tool for targeting biopsies may be Lugol dye chromoendoscopy, since it is easy, accurate, inexpensive and available worldwide. In ideal conditions, or in developed countries, is it reasonable to think that optimal detection will require a combination of techniques, such as the combination of Lugol’s chromoendoscopy and NBI to identify esophageal areas that require further characterization by a high resolution technique. The efficacy and cost-effectiveness will determine whether these modalities will become part of standard endoscopy practice.
doi:10.4253/wjge.v4.i1.9
PMCID: PMC3262175  PMID: 22267978
Autofluorescence endoscopy; Early diagnosis; Esophageal cancer; Esophageal squamous cell carcinoma; Lugol’s solution; Narrow-band imaging endoscopy

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