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1.  Outcomes from a prospective trial of endoscopic radiofrequency ablation of early squamous cell neoplasia of the esophagus 
Gastrointestinal endoscopy  2011;74(6):1181-1190.
Radiofrequency ablation (RFA) is safe and effective for eradicating neoplasia in Barrett’s esophagus.
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).
Prospective cohort study.
Tertiary referral center.
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.
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.
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.
Single center study with limited number of patients.
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.
PMCID: PMC3505032  PMID: 21839994
2.  Magnified Endoscopy Combined with Narrow Band Imaging of Minimal Superficial Esophageal Neoplasia—Indicators to Differentiate Intraepithelial Neoplasias 
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.
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.
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.
The combined technique was useful in the differential diagnosis of minimal superficial esophageal neoplasia.
PMCID: PMC3523113  PMID: 22618519
Endoscopy; Esophageal neoplasms; Carcinoma; Squamous cell carcinoma; Narrow band imaging; Magnifying endoscopy
3.  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.
PMCID: PMC3785622  PMID: 24106401
Squamous neoplasia; Oesophageal cancer; Endoscopic mucosal resection; High-grade dysplasia; Radiofrequency ablation
4.  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.
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.
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.
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.
PMCID: PMC3950293  PMID: 24618814
5.  Limiting esophageal temperature in radiofrequency ablation of left atrial tachyarrhythmias results in low incidence of thermal esophageal lesions 
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.
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.
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.
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.
PMCID: PMC2987899  PMID: 20977747
6.  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.
PMCID: PMC3027413  PMID: 22802374
7.  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.
PMCID: PMC3859345  PMID: 23658246
8.  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.
PMCID: PMC3941437
Barrett’s esophagus; endoscopic mucosal resection; endoscopic submucosal dissection
9.  Safety, tolerability, and efficacy of endoscopic low-pressure liquid nitrogen spray cryotherapy in the esophagus 
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.
PMCID: PMC3144029  PMID: 19515183
Barrett esophagus; catheter ablation; cryosurgery; cryotherapy; esophageal neoplasm; safety
10.  Measuring telomere length for the early detection of precursor lesions of esophageal squamous cell carcinoma 
BMC Cancer  2013;13:578.
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.
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.
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.
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.
PMCID: PMC3882883  PMID: 24308314
Esophageal squamous cell carcinoma; Esophageal squamous dysplasia; Early detection; Screening; Balloon cytology; Telomeres
11.  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.
PMCID: PMC3262175  PMID: 22267978
Autofluorescence endoscopy; Early diagnosis; Esophageal cancer; Esophageal squamous cell carcinoma; Lugol’s solution; Narrow-band imaging endoscopy
12.  Argon plasma coagulation for superficial esophageal squamous-cell carcinoma in high-risk patients 
AIM: To evaluate the usefulness and safety of argon plasma coagulation (APC) for superficial esophageal squamous-cell carcinoma (SESC) in high-risk patients.
METHODS: We studied 17 patients (15 men and 2 women, 21 lesions) with SESC in whom endoscopic mucosal resection (EMR), endoscopic submucosal dissection (ESD), and open surgery were contraindicated from March 1999 through February 2009. None of the patients could tolerate prolonged EMR/ESD or open surgery because of severe concomitant disease (e.g., liver cirrhosis, cerebral infarction, or ischemic heart disease) or scar formation after EMR/ESD and chemoradiotherapy. After conventional endoscopy, an iodine stain was sprayed on the esophageal mucosa to determine the lesion margins. The lesion was then ablated by APC. We retrospectively studied the treatment time, number of APC sessions per site, complications, presence or absence of recurrence, and time to recurrence.
RESULTS: The median duration of follow-up was 36 mo (range: 6-120 mo). All of the tumors were macroscopically classified as superficial and slightly depressed type (0-IIc). The preoperative depth of invasion was clinical T1a (mucosal cancer) for 19 lesions and clinical T1b (submucosal cancer) for 2. The median treatment time was 15 min (range: 10-36 min). The median number of treatment sessions per site was 2 (range: 1-4). The median hospital stay was 14 d (range: 5-68 d). Among the 17 patients (21 lesions), 2 (9.5%) had recurrence and underwent additional APC with no subsequent evidence of recurrence. There were no treatment-related complications, such as bleeding or perforation.
CONCLUSION: APC is considered to be safe and effective for the management of SESC that cannot be resected endoscopically because of underlying disease, as well as for the control of recurrence after EMR and local recurrence after chemoradiotherapy.
PMCID: PMC3471110  PMID: 23082058
Argon plasma coagulation; Superficial esophageal cancer; Squamous-cell carcinoma; High-risk patient; Endoscopic therapy
13.  Esophageal squamous cell carcinoma presenting with extensive skin lesions: a case report 
Esophageal squamous cell carcinoma (ESCC) is the most common histological subtype of cancer in the upper and middle esophagus and is characterized by a high rate of mortality. The incidence of esophageal cancer varies greatly among regions of the world and occurs at a high frequency in Asia and South America.
Case presentation
In our department, a 51-year-old man was diagnosed with ESCC after presenting with extensive disseminated skin nodules. Biopsy of the nodules showed metastatic ESCC. Cutaneous manifestations of esophageal neoplasia are very rare and are mainly described for esophageal adenocarcinoma (EADC). Here we report a very uncommon case of extensive skin metastases of ESCC.
Early biopsies of suspicious skin lesions are important and should be performed in patients with unclear symptoms such as weight loss or dysphagia and especially in patients with a history of cancer, since they can reveal the existence of a distant malignant disease leading to diagnosis and prompt therapy.
PMCID: PMC2365965  PMID: 18426583
14.  Optical Imaging of Periostin Enables Early Endoscopic Detection and Characterization of Esophageal Cancer in Mice 
Gastroenterology  2012;144(2):294-297.
Imaging strategies that detect early-stage esophageal squamous cell carcinoma (ESCC) could improve clinical outcomes, combined with endoscopic approaches. Periostin is an integrin-binding protein that is important in the tumor microenvironment. We created a fluorescent-labeled antibody that recognizes periostin and binds specifically to ESCC xenograft tumors in mice. In L2-cre;p120ctnLoxP/LoxP mice, which develop squamous cell cancers that resemble human ESCC, we visualized the probe in preneoplastic and neoplastic esophageal lesions using near-infrared fluorescent imaging with upper gastrointestinal endoscopy. Periostin might be a biomarker of the esophageal tumor microenvironment that can be used to detect preneoplastic lesions.
PMCID: PMC3624041  PMID: 23085486
mouse model; neoplasm; extracellular matrix; POSTN
15.  High-risk esophageal varices in patients treated with locoregional therapy for hepatocellular carcinoma: Assessment with liver computed tomography 
AIM: To assess the diagnostic performance of follow-up liver computed tomography (CT) for the detection of high-risk esophageal varices in patients treated with locoregional therapy for hepatocellular carcinoma (HCC).
METHODS: We prospectively enrolled 100 patients with cirrhosis who underwent transcatheter arterial chemoembolization, radiofrequency ablation or both procedures for HCCs. All patients underwent upper endoscopy and subsequently liver CT. Three radiologists independently evaluated the presence of high-risk esophageal varices with transverse images alone and with three orthogonal multiplanar reformation (MPR) images, respectively. With endoscopic grading as the reference standard, diagnostic performance was assessed by using receiver operating characteristic (ROC) curve analysis.
RESULTS: The diagnostic performances (areas under the ROC curve) of three observers with transverse images alone were 0.947 ± 0.031, 0.969 ± 0.024, and 0.916 ± 0.038, respectively. The mean sensitivity, specificity, positive predicative value (PPV), and negative predicative value (NPV) with transverse images alone were 90.1%, 86.39%, 70.9%, and 95.9%, respectively. The diagnostic performances, mean sensitivity, specificity, PPV, and NPV with three orthogonal MPR images (0.965 ± 0.025, 0.959 ± 0.027, 0.938 ± 0.033, 91.4%, 89.5%, 76.3%, and 96.6%, respectively) were not superior to corresponding values with transverse images alone (P > 0.05), except for the mean specificity (P = 0.039).
CONCLUSION: Our results showed excellent diagnostic performance, sensitivity and NPV to detect high-risk esophageal varices on follow-up liver CT after locoregional therapy for HCC.
PMCID: PMC3447273  PMID: 23002363
Liver computed tomography; High-risk esophageal varices; Locoregional therapy; Hepatocellular carcinoma; Multiplanar reformation images
16.  Defective Barrier Function in Neosquamous Epithelium 
The American journal of gastroenterology  2013;108(3):10.1038/ajg.2012.440.
Radiofrequency ablation (RFA) of Barrett’s esophagus (BE) is a common strategy for the prevention of esophageal adenocarcinoma (EAC). After RFA, the ablated esophagus heals on acid suppressive therapy, and is re-populated with a stratified squamous epithelium, referred to as ‘neosquamous epithelium (NSE).’ Because the ability of the NSE to protect the underlying tissue from recurrent insult by reflux is unclear, we assessed the barrier function of NSE by comparing it to that of the native upper squamous epithelium (USE) in subjects having undergone RFA.
At varying intervals following RFA, the barrier function of NSE and USE were assessed in endoscopic biopsies by light and electron microscopy, and by measurement of electrical resistance (RT) and fluorescein flux in mini-Ussing chambers. Chamber results were further compared with results from control biopsies (healthy distal esophagus). A claudin expression profile in the tight junctions (TJ) of NSE and USE was determined using qRT-PCR. Differential expression of claudin 4 between NSE and USE was assayed by immunoblots.
USE was histologically normal while NSE showed dilated intercellular spaces and marked eosinophilia. NSE was also more permeable than USE and healthy controls, having lower mean RT and higher fluorescein fluxes. Abnormally low RT values for NSE were unrelated to the time period following RFA (or number of prior RFA sessions), being abnormal even 26 months after RFA. Abnormal permeability in NSE was associated with significantly lower values for claudin-4 and claudin-10 than in USE.
NSE commonly exhibits defective barrier function. Since this defect will make it vulnerable to injury, inflammation and destruction by acidic and weakly acidic refluxates, it may in part explain incidences of recurrence of BE following ablation.
PMCID: PMC3838860  PMID: 23318477
17.  Radiofrequency ablation in the management of Barrett's esophagus – preliminary own experience 
Barrett's esophagus develops as a result of chronic injury of esophagus epithelium from gastroesophageal reflux disease. It is defined when metaplastic columnar epithelium replaces the stratified squamous epithelium which normally lies in the distal esophagus. The condition represents a risk factor for esophageal adenocarcinoma. The aim of the radiofrequency ablation (RFA) method is to destroy metaplastic epithelium with radiofrequency electric current and to stimulate reappearance of the flat multilayer epithelium in the distal esophagus.
To evaluate the efficiency and safety of the RFA technique, newly introduced in Poland, in the management of Barrett's esophagus.
Material and methods
Twelve patients were treated with the RFA method. Patients with Barrett's esophagus confirmed in the histopathological report were qualified for treatment. Two RFA techniques were applied using a BARRX® device: circular based on the balloon HALO360 system or focal based on the HALO90 system mounted to the endoscopic ending. The procedures were performed at 2-month intervals. The macroscopic and microscopic effects of RFA therapy, the patients’ treatment tolerance as well as potential complications were evaluated.
In the group of 12 patients subjected to RFA therapy, 10 completed the therapeutic cycle. A total of 37 procedures were performed: 5 HALO360 and 32 HALO90. In all patients eradication of the abnormal metaplastic esophageal epithelium was achieved, as confirmed in both endoscopic and histopathological evaluation. In 2 patients with ongoing therapy progressive eradication of metaplastic epithelium was observed. No significant RFA-related complications were reported.
Based on our preliminary results we consider this method to be promising, free of significant complications and well tolerated by patients. In most patients it results in successful eradication of metaplastic epithelium in the distal esophagus.
PMCID: PMC3699765  PMID: 23837094
Barrett's esophagus; metaplasia; radiofrequency ablation
18.  Prevalence and predictors of recurrent neoplasia after ablation of Barrett's esophagus  
Gastrointestinal endoscopy  2009;71(4):697-703.
The incidence and risk factors for recurrence of dysplasia after ablation of Barrett's esophagus (BE) have not been well defined.
To determine the rate and predictors of dysplasia/neoplasia recurrence after photodynamic therapy (PDT) in BE.
Retrospective analysis of a prospective cohort of BE patients seen at a specialized BE unit.
Patients underwent a standard protocol assessment with esophagogastroduodenoscopy and 4-quadrant biopsies every centimeter at 3-month intervals after ablation. Recurrence was defined as the appearance of any grade of dysplasia or neoplasia after 2 consecutive endoscopies without dysplasia. Entry histology, demographics, length of BE, presence and length of diaphragmatic hernia, EMR, stricture formation, nonsteroidal anti-inflammatory drug use, smoking, and the presence of nondysplastic BE or squamous epithelium were assessed for univariate associations. Time-to-recurrence analysis was done by using Cox proportional hazards regression. A multivariate model was constructed to establish independent associations with recurrence.
A total of 363 patients underwent PDT with or without EMR. Of these, 261 patients were included in the final analysis (44 lost to follow-up, 46 had residual dysplasia, and 12 had no dysplasia at baseline). Indication for ablation was low-grade dysplasia (53 patients, 20%), high-grade dysplasia (152 patients, 58%), and intramucosal cancer (56 patients, 21%). Median follow-up was 36 months (interquartile range 18-79 months). Recurrence occurred in 45 patients. Median time to recurrence was 17 months (interquartile range 8-45 months). Significant predictors of recurrence on the multivariate model were older age (hazard ratio [HR] 1.04, P=.029), presence of residual nondysplastic BE (HR 2.88, P=.012), and a history of smoking (HR 2.68, P=.048).
Possibility of missing prevalent dysplasia despite aggressive surveillance.
Recurrence of dysplasia/neoplasia after PDT ablation is associated with advanced age, smoking, and residual BE.
PMCID: PMC2981349  PMID: 19959164
19.  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.
PMCID: PMC3536848  PMID: 23293721
Esophagus; Stomach; Colon; Adenoma; Adenocarcinoma; Endoscopy; Screening
20.  Multi-susceptibility genes associated with the risk of the development stages of esophageal squamous cell cancer in Feicheng County 
BMC Gastroenterology  2011;11:74.
The purpose of this study was to evaluate the association of multi-genotype polymorphisms with the stepwise progression of esophageal squamous cell cancer (ESCC) and the possibility of predicting those at higher risk.
A total of 1,004 subjects were recruited from Feicheng County, China, between Jan. 2004 and Dec. 2007 and examined by endoscopy for esophageal lesions. These subjects included 270 patients with basal cell hyperplasia (BCH), 262 patients with esophageal squamous cell dysplasia (ESCD), 226 patients with ESCC, and 246 controls with Lugol-voiding area but diagnosed as having normal esophageal squamous epithelial cells by histopathology. The genotypes for CYP2E1 G1259C, hOGG1 C326G, MTHFR C677T, MPO G463A, and ALDH2 allele genes were identified in blood samples collected from all participants.
The alleles ALDH2 and MTHFR C677T were critical for determining individual susceptibility to esophageal cancer. Compared to the ALDH 1*1 genotype, the ALDH 2*2 genotype was significantly associated with increased risks of BCH, ESCD, and ESCC. However, the TT genotype of MTHFR C677T only increased the risk of ESCC. Further analysis revealed that the combination of the high-risk genotypes 2*2/1*2 of ALDH 2 and TT/TC of MTHFR C677T increased the risk of BCH by 4.0 fold, of ESCD by 3.7 fold, and ESSC by 8.72 fold. The generalized odds ratio (ORG) of the two combined genotypes was 1.83 (95%CI: 1.55-2.16), indicating a strong genetic association with the risk of carcinogenic progression in the esophagus.
The study demonstrated that the genotypes ALDH2*2 and MTHFR 677TT conferred elevated risk for developing esophageal carcinoma and that the two susceptibility genotypes combined to synergistically increase the risk.
PMCID: PMC3141752  PMID: 21672255
21.  A laterally-spreading tumor in a colonic interposition treated by endoscopic submucosal dissection 
Herein we describe an early colonic carcinoma which developed in a colonic interposition 14 years after surgery for esophageal cancer, which was successfully treated by endoscopic submucosal dissection (ESD). An 80-year-old man underwent colonic interposition between the upper esophagus and stomach after surgery for an early esophageal squamous cell carcinoma in 1994. He received a surveillance endoscopy, and a laterally-spreading tumor of granular type, approximately 20 mm in size, was identified in the colonic interposition. An endoscopic biopsy revealed moderately differentiated adenocarcinoma histologically, however, we diagnosed the lesion as an intramucosal carcinoma based on the endoscopic findings. The lesion was safely and completely removed en bloc by ESD using a bipolar knife. Histologically, the lesion was an intramucosal moderately differentiated adenocarcinoma in a tubular adenoma.
PMCID: PMC2807963  PMID: 20082488
Colonic interposition; Early colonic carcinoma; Endoscopic submucosal dissection
22.  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.
PMCID: PMC3726131  PMID: 23983846
atrial fibrillation; atrial esophageal fistula; AEF; left ventricular aneurysm; cerebral air emboli
23.  Preoperative Iodine Staining May Complicate the Demarcation of Esophageal Carcinoma 
Gut and Liver  2013;7(4):492-496.
A 53-year-old man was suspected of having an esophageal neoplasm. An endoscopic examination including Lugol chromoendoscopy suggested an esophageal squamous cell neoplasm limited to the lamina propria. A targeted biopsy showed atypical squamous cells, and an endoscopic submucosal dissection was performed 22 days after the previous endoscopy. Although a single 40 mm unstained area was observed by preoperative Lugol chromoendoscopy, intraoperative endoscopy revealed a 25 mm iodine-unstained area, with small unstained areas scattered on the oral side. We included the small unstained areas in the extent of the resection through assessment by preoperative endoscopy. Histopathologically, the tumor extent appeared to coincide with the preoperative assessment. Tumor cells were found in the basal-parabasal layers of the mucosa, in which small unstained areas were scattered, although the superficial layers exhibited well-differentiated cells containing glycogen in the cytoplasm. Although Lugol chromoendoscopy, which can induce chemical esophagitis, is widely used, re-epithelialization after mucosal damage by preoperative iodine staining may complicate the intraoperative demarcation of tumors.
PMCID: PMC3724041  PMID: 23898393
Lugol chromoendoscopy; Esophageal squamous cell neoplasm; Re-epithelialization
24.  Era of Barrett’s surveillance: Does equipment matter? 
Barrett’s esophagus is a consequence of long standing gastro-esophageal reflux disease and predisposes to the development of esophageal adenocarcinoma. Regular surveillance endoscopies can detect curable early neoplasia in asymptomatic patients, which in turn could improve the prognosis compared to symptomatic cancer. Early neoplastic lesions, which are amenable for local therapy, could be treated endoscopically, avoiding a major surgery. However, in the absence of obvious mucosal lesions, random four quadrant biopsies are done, which is associated with significant sampling error. Newer imaging modalities, such as autofluorescence endoscopy, are helpful in detecting subtle lesions that could be examined in detail with narrow band imaging to characterize and target biopsies. This has the potential benefit of reducing the number of random biopsies with a better yield of dysplasia. Confocal endomicroscopy provides “optical biopsies” and is a valuable tool in targeting biopsies to improve dysplasia detection; however, this is technically challenging. Fuji intelligent chromoendoscopy and I-Scan are recent additions to the imaging armamentarium that have produced notable early results. While all these additional new imaging techniques are promising, a thorough examination by high resolution white light endoscopy after clearing the mucosa with mucolytics should be the minimum standard to improve dysplasia detection during Barrett’s surveillance.
PMCID: PMC2951513  PMID: 20872963
Barrett’s esophagus; Endoscopy; Autofluorescence imaging; Narrowband imaging; Early diagnosis of cancer
25.  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.
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.
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.
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.
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.
PMCID: PMC2629649  PMID: 18632220
esophagus; neoplasms; cancer; cyclooxgenase-2; precancerous conditions; methylation; lymphocytes; squamous cell cancer

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