Barrett esophagus (BE) is a pre-malignant, metaplastic alteration of the normal esophageal epithelium cell characterized by the conversion of the normal esophageal squamous epithelium into the metaplastic columnar epithelium with an increased risk of developing low-grade dysplasia to high-grade dysplasia subsequently to adenocarcinoma to esophageal adenocarcinoma that is detected on endoscopic examination and pathologically confirmed by the presence of intestinal metaplasia on biopsy.
Barrett’s esophagus occurs when the normal squamous epithelium of the distal esophagus changes to columnar-lined intestinal-type cells, a transition known as intestinal metaplasia. Its importance lies in that it is the only known precursor to esophageal adenocarcinoma.[rx] The transition occurs when the esophagus is repeatedly exposed to gastric acid, which in turn causes mucosal inflammation. When intestinal metaplasia occurs, the normal esophageal mucosa will take on a salmon-colored appearance when viewed endoscopically.
Causes of Barrett Esophagus
Barrett’s metaplasia occurs as a result of prolonged tissue injury in the esophagus due to chronic gastroesophageal reflux disease (GERD). One of the risk factors of GERD and its complications has been the increase in obesity, especially central adiposity. The underlying mechanism may be linked to an increase in intra-abdominal pressure and elevated serum levels of pro-proliferative hormones. Cigarette smoking is a risk factor for both Barrett’s metaplasia and esophageal adenocarcinoma, but the association with alcohol is weak.
There are two large case-control studies of twins suggesting that the development of Barrett’s esophagus in GERD is genetically predisposed.
Having GERD increases your chances of developing Barrett’s esophagus. GERD is a more serious, chronic form of gastroesophageal reflux, a condition in which stomach contents flow back up into your esophagus. Refluxed stomach acid that touches the lining of your esophagus can cause heartburn and damage the cells in your esophagus.
Between 10 and 15 percent of people with GERD develop Barrett’s esophagus.
Obesity—specifically high levels of belly fat—and smoking also increase your chances of developing Barrett’s esophagus. Some studies suggest that your genetics, or inherited genes, may play a role in whether or not you develop Barrett’s esophagus.
Having a Helicobacter pylori (H. pylori) infection may decrease your chances of developing Barrett’s esophagus. Doctors are not sure how H. pylori protects against Barrett’s esophagus. While the bacteria damage your stomach and the tissue in your duodenum, some researchers believe the bacteria make your stomach contents less damaging to your esophagus if you have GERD.
Researchers have found that other factors may decrease the chance of developing Barrett’s esophagus, including
- Gastroesophageal reflux – The most important pathogenetic factor for the development of BE is showed to be reflux disease. Because only a minority of patients (around 10–15%) with reflux esophagitis have BE, additional factors that play important roles in determining the apparently sudden development of BE must concur [rx]. Several systemic factors, which may predispose to columnar metaplastic healing of the previously squamous esophageal mucosa, have been identified. Notable among these are the retinoic acid status and the effects of genetic heterogeneity, including the expression of different types of insulin growth factor, and differences between BE patients and controls in CDX2 expression in the squamous mucosa in response to acid and bile salt-induced injury [rx–rx] [rx].
- Nitrates – Nitrate-induced injury is another theory that has recently emerged in the pathogenesis of BE. After a nitrate-rich diet, nitrates are found in abundance in human saliva and are also present in high concentrations at the ESO-gastric junction [rx]. On contact with acid, nitrates are converted to nitrites and so they become even more carcinogenic. This occurs at the gastroesophageal junction that conforms to the appearance of Barrett’s esophagus at the junctional level. Due to the industrialization of commercial farming, the widespread use of nitrate fertilizers mirrors the increased incidence in esophageal adenocarcinoma [rx].[rx].
- Obesity – has been known to increase the risk for developing BE, but there is an ongoing debate on whether obesity’s contribution comes from visceral adiposity versus the overall increase in body mass index (BMI). IL6 and IL8, cytokines released by adipocytes have been found to be important in the internalization process [rx]. Waist circumference can have some modest independent association with the risk of Barrett’s esophagus according to some studies, more than BMI. This finding can represent partial support for the hypothesis that abdominal obesity increases gastro-esophageal reflux and thus, indirectly the risk for Barrett esophagus [rx].
- Age, race, sex, and HH – Another frequent association with Barrett’s esophagus, together with chronic gastroesophageal reflux, is represented by an increased age, Caucasian race, male sex, and hiatal hernia. A rare finding in children, BE mean age of diagnose in Europe is in the 60s [rx]. A recognized risk factor for the development of Barrett’s esophagus is represented by the hiatal hernia and the length of the metaplasia segment is increased in patients with larger hiatal defect. Up to 90% of the patients with BE have an associated hiatal hernia, the latter being responsible, along with the other factors, for the reflux of the gastric juice in the esophagus [rx].
- Alcohol and smoking – Some diet and lifestyle factors, like alcohol and smoking, seem to be implicated in the development of Barrett’s esophagus. Later studies showed that cigarette smoking, besides being implicated in the development of esophageal adenocarcinoma, is also a risk factor for Barrett’s esophagus [rx]. Alcohol seems not to be involved in the development of Barrett’s esophagus and there are even some studies that found a protective role of moderate wine consumption (<40g/week) in the development of Barrett’s esophagus and esophageal adenocarcinoma [rx].
- Helicobacter Pylori – The relationship between Barrett’s esophagus and the infection with Helicobacter Pylori is controversial, even if the bacterial role in the gastric carcinogenesis is well known; most of the studies found a protective role of the bacteria in the development of intestinal metaplasia, probably because of the reduced gastric secretion that it determines [rx].
- Familial transmission – Some patients present a familial transmission of BE, some genetic modifications independent of smoking or BMI being observed in the same family [rx].
- The Cellular Origin of BE – An issue that needs to be resolved as it will have implications for the putative molecular mechanisms underlying the metaplastic process is represented by the cellular origin of BE. The inability of researchers to determine the cellular origin of BE is in part due to the inability to observe the process of metaplastic conversion in vivo and the lack of reliable physiological animal models [rx].
Symptoms of Barrett’s esophagus?
While Barrett’s esophagus itself doesn’t cause symptoms, many people with Barrett’s esophagus have gastroesophageal reflux disease (GERD), which does cause symptoms.
Experts don’t know the exact cause of Barrett’s esophagus. However, some factors can increase or decrease your chance of developing Barrett’s esophagus.
Diagnosis of Barrett’s Esophagus
Doctors diagnose Barrett’s esophagus with an upper gastrointestinal (GI) endoscopy and a biopsy. Doctors may diagnose Barrett’s esophagus while performing tests to find the cause of a patient’s gastroesophageal reflux disease (GERD) symptoms.
Medical history
Your doctor will ask you to provide your medical history. Your doctor may recommend testing if you have multiple factors that increase your chances of developing Barrett’s esophagus.
Upper GI endoscopy and biopsy
In an upper GI endoscopy, a gastroenterologist, surgeon, or other trained health care provider uses an endoscope to see inside your upper GI tract, most often while you receive light sedation. The doctor carefully feeds the endoscope down your esophagus and into your stomach and duodenum. The procedure may show changes in the lining of your esophagus.
The doctor performs a biopsy with the endoscope by taking a small piece of tissue from the lining of your esophagus. You won’t feel the biopsy. A pathologist examines the tissue in a lab to determine whether Barrett’s esophagus cells are present. A pathologist who has expertise in diagnosing Barrett’s esophagus may need to confirm the results.
Barrett’s esophagus can be difficult to diagnose because this condition does not affect all the tissue in your esophagus. The doctor takes biopsy samples from at least eight different areas of the lining of your esophagus.
Chromo-endoscopy
Chromo-endoscopy is founded on the current use of acetic acid to stain abnormal tissues during an examination of the cervix to whiten immature (young) and dysplastic cells. When acetic acid is used in the gastrointestinal tract via a spray catheter in the endoscope, both the oesophageal and gastric mucosae turn white (as in the cervix) but once a few minutes have passed, normal mucosa remains white whereas Barrett’s mucosa transiently turns red, as does gastric columnar mucosa[rx]. Its use can be improved by the addition of indigo carmine to better visualize early gastric cancer and as a mucolytic to remove mucus obscuring the mucosa[rx]. Dysplasia may be found where there are areas of surface irregularity, changes in the vascular pattern, or variability of staining.
Narrowband imaging
Narrowband imaging (NBI) is an alternative technique where lights of specific blue (wavelength = 440-460 nm) and green (wavelength = 540-560 nm) wavelengths are used to enhance the detail of the mucosa and blood vessels. This works because the wavelengths correlate with the peak light absorption of hemoglobin hence will appear very dark thus improving their visibility and easing the identification of neighboring structures.
The other methods which can be employed for surveillance of Barrett’s esophagus include endosonography [endoscopic ultrasound (EUS)], optical coherence tomography (OCT), confocal microendoscopy, auto-fluorescence endoscopy, and computed virtual chromo-endoscopy (CVC).
Endoscopic ultrasound
Studies have shown that EUS to screen patients with Barrett’s esophagus is neither justified nor cost-effective but does play a role when there is high-grade dysplasia or intramucosal carcinoma[rx]. Conversely, in terms of superiority, OCT is above EUS as its resolution is better as once can see the layers of the oesophageal wall can be visualized with good correlation to histologic structures thus allowing endoscopists to detect high-grade dysplasia earlier. The sensitivity of detecting dysplasia was 68% and specificity was 28%[rx].
Computed virtual chromo-endoscopy
CVC enhances mucosal surface contrasts and vascular pattern variability without the use of dye as is standard in chromo-endoscopy. Its utility was demonstrated in a randomized control trial where 57 patients with Barrett’s esophagus and history of high-grade intraepithelial neoplasia/early cancer were allocated to undergo acetic acid chromo-endoscopy or CVC with re-examination after 4-6 wk with the other procedure. The positive predictive value for the former was 39% and 37% for the latter with comparable sensitivities at 83% and 92% respectively[rx]. The study thus shows that CVC is not only useful as an adjunct but provides comparable results to conventional chromo-endoscopy in the detection of high-grade dysplasia/early cancer.
Auto-fluorescence
Auto-fluorescence endoscopy is a technique incorporating a real-time wide-angle view allowing the endoscopist to rapidly go from standard white lighting to auto-fluorescence and to very quickly examine large areas of the gastrointestinal mucosa. However, there was no clear superiority over conventional white-light imaging (whether or not it is used in conjunction with NBI)[rx]. On the other hand, confocal microendoscopy is where the resolution and contrast of imaging is augmented by eliminating out-of-focus light by the addition of a spatial pinhole at the confocal plane of the lens. A study determined that this method is very accurate and reliable (sensitivity 88% and specificity 96%) for the diagnosis of neoplasia[rx].
Who should be screened for Barrett’s esophagus?
Your doctor may recommend screening for Barrett’s esophagus if you are a man with chronic—lasting more than 5 years—and/or frequent—happening weekly or more—symptoms of GERD and two or more risk factors for Barrett’s esophagus. These risk factors include
- being age 50 and older
- being Caucasian
- having high levels of belly fat
- being a smoker or having smoked in the past
- having a family history of Barrett’s esophagus or esophageal adenocarcinoma
Treatment for Barrett’s Esophagus
Your doctor will talk about the best treatment options for you based on your overall health, whether you have dysplasia, and its severity. Treatment options include medicines for GERD, endoscopic ablative therapies, endoscopic mucosal resection, and surgery.
Periodic surveillance endoscopy
Your doctor may use upper gastrointestinal endoscopy with a biopsy periodically to watch for signs of cancer development. Doctors call this approach surveillance.
Experts aren’t sure how often doctors should perform surveillance endoscopies. Talk with your doctor about what level of surveillance is best for you. Your doctor may recommend endoscopies more frequently if you have high-grade dysplasia rather than low-grade or no dysplasia. Read whether people with Barrett’s esophagus are more likely to develop cancer.
Medicines
If you have Barrett’s esophagus and gastroesophageal reflux disease (GERD), your doctor will treat you with acid-suppressing medicines called proton pump inhibitors (PPIs). These medicines can prevent further damage to your esophagus and, in some cases, heal existing damage.
PPIs include
- omeprazole(Prilosec, Zegerid)
- lansoprazole (Prevacid)
- pantoprazole (Protonix)
- rabeprazole (AcipHex)
- esomeprazole (Nexium)
- dexlansoprazole (Dexilant)
All of these medicines are available by prescription. Omeprazole and lansoprazole are also available in over-the-counter strength.
Your doctor may consider anti-reflux surgery if you have GERD symptoms and don’t respond to medicines. However, research has not shown that medicines or surgery for GERD and Barrett’s esophagus lower your chances of developing dysplasia or esophageal adenocarcinoma.
Aspirin and other NSAIDs have been proposed as chemoprotective agents against adenocarcinoma development in patients with Barrett’s esophagus. This data is based on in-vitro and animals based studies. Epidemiological studies have also shown a decreased risk of esophageal adenocarcinoma with NSAID use. Serious gastrointestinal (GI) and cardiovascular side effects associated with NSAIDs may outweigh potential benefits. Therefore, routine use of these drugs is not recommended.
Endoscopic ablative therapies
Endoscopic ablative therapies use different techniques to destroy the dysplasia in your esophagus. After the therapies, your body should begin making normal esophageal cells.
A doctor, usually a gastroenterologist or surgeon, performs these procedures at certain hospitals and outpatient centers. You will receive local anesthesia and a sedative. The most common procedures are the following
- Photodynamic therapy – Photodynamic therapy uses a light-activated chemical called porfimer (Photofrin), an endoscope, and a laser to kill precancerous cells in your esophagus. A doctor injects porfimer into a vein in your arm, and you return 24 to 72 hours later to complete the procedure.
Endoscopic mucosal resection
In endoscopic mucosal resection, your doctor lifts Barrett’s tissue, injects a solution underneath or applies suction to the tissue, and then cuts the tissue off. The doctor then removes the tissue with an endoscope. Gastroenterologists perform this procedure at certain hospitals and outpatient centers. You will receive local anesthesia to numb your throat and a sedative to help you relax and stay comfortable.
Before performing an endoscopic mucosal resection for cancer, your doctor will do an endoscopic ultrasound.
Complications can include bleeding or tearing of your esophagus. Doctors sometimes combine endoscopic mucosal resection with photodynamic therapy.
Surgery
Surgery called esophagectomy is an alternative to endoscopic therapies. Many doctors prefer endoscopic therapies because these procedures have fewer complications.
Esophagectomy is the surgical removal of the affected sections of your esophagus. After removing sections of your esophagus, a surgeon rebuilds your esophagus from part of your stomach or large intestine. The surgery is performed at a hospital. You’ll receive general anesthesia, and you’ll stay in the hospital for 7 to 14 days after the surgery to recover.
Surgery may not be an option if you have other medical problems. Your doctor may consider the less-invasive endoscopic treatments or continued frequent surveillance instead.
Endoscopic eradication therapies
Endoscopic eradication therapies have become the mainstay of treatment for patients with Barrett’s esophagus with dysplasia. This can be achieved using the application of heat through laser, radiofrequency, argon plasma coagulation, cold cryotherapy, or photodynamic therapy (PDT) to destroy the abnormal epithelium. Due to comparable efficacy and beneficial side effect profile, radiofrequency ablation is the preferred mode of endoscopic therapy compared to PDT. Cryotherapy can be substituted depending on local expertise. Ablation therapies are indicated for flat lesions. Any nodular lesions should be removed using endoscopic mucosal resection, which also provides a substantial sample for determining the depth of invasion. Endoluminal therapy is not recommended in cases of submucosal invasion because it is associated with a much higher risk of metastatic spread.
Esophagectomy
Esophagectomy was previously the treatment of choice for high-grade dysplasia and intramucosal carcinoma in Barrett’s disease. It is associated with prolonged hospital stay, short and long-term complications with a poor quality of life in the immediate post-operative period, and is no longer the first-line treatment. It can be considered on an individual basis in patients with high-grade dysplasia or carcinoma-in-situ if endoluminal therapy is not feasible or unable to eradicate the neoplastic disease.
Lasers
Light amplification by stimulated emission of radiation (LASER) beam is directed against the lesion and destroys it. There are various types of lasers: argon, neodymium:yttrium-aluminum-garnet, potassium titanyl phosphate (KTP), and KTP: YAG with different wavelength emissions. Gossner and colleagues studied 10 patients (LGD = 4, HGD = 4, early EC=2) using a (Nd:YAG) KTP laser system.[rx] After a mean follow-up of 10.6 months a complete response was observed in all. In two patients Barrett’s submucosa was identified. Weston et al also presented the results of 14 patients with BE and HGD/IMC treated with an Nd: YAG contacts laser.[rx] They reported successful elimination of HGD and or cancer in all patients. Eleven of 14 achieved complete histological ablation of Barrett’s tissue, and no buried columnar epithelial tissue was observed. Odynophagia and early dysphagia were reported in 30.6% and 16.3% of the patients, respectively.
Photodynamic Therapy (PDT)
The basis for PDT is the administration of a photosensitizer [porfimer sodium (iv), 5-aminolevulinic acid (per os)] that has properties to bind the neoplastic area through an unknown mechanism. After exposure to intense laser light, vascular thrombosis and cell necrosis are caused. Overholt and colleagues studied 100 patients with a mean follow-up of 19 months.[rx] Elimination of BE and HGD was observed in 43% and 88% of the patients, respectively. Progression or failure was found in 21 patients. Complications observed were stricture (34%) and subsquamous Barrett’s esophagus (6%). An international randomized phase III trial was also conducted by Overholt et al[rx] that studied 208 patients to compare PDT using porfimer sodium (POR) plus omeprazole vs. omeprazole only. There was a significant difference (P < .0,001) in favor of PORPDT compared with omeprazole in complete eradication of HGD at any time during the follow-up period. The occurrence of EAC in the PORPDT group was 13% and significantly lower compared with the omeprazole group, being 28% (P < .006).
Multipolar Electrocoagulation (MPEC)
Two or more electrodes of the MPEC probe allow the delivery of thermal energy to the desired area and destroy tissue. In a multicenter trial, patients were studied, and after a follow-up of six months, 78% of the patients had a complete response. One patient developed stricture and the most common side effect was chest pain (19/58).[rx] Kovacs et al studied 27 patients with BE treated with MPEC and lansoprazole with an intention to reverse histology.[rx] Twenty-two patients had a successful reversal, and the most common side effect was dysphagia (41%).
Argon Plasma Coagulation (APC)
Through the flow of ionized argon gas, a high-frequency monopolar current is directed to the neoplastic tissues. Attwood et al studied 29 patients with HGD with a mean follow-up of 37 months.[rx] . No patients in the intervention group progressed to HGD. On the contrary, 2/20 in the surveillance group progressed. Two patients treated with APC developed a stricture but could be managed endoscopically.
Radiofrequency Ablation (RFA)
This technique requires the application of a balloon with circular electrodes delivering radio-frequency energy in the circumferential way (HALO360). In addition, for focal lesions, a plate device can be used (HALO90). Roorda et al studied 13 patients (6 with BE, 4 with LGD, and 3 with HGD).[rx] After a mean follow-up of 12 months, eradication of BE was observed in 6 patients (46%) and eradication of dysplasia in 5 out of 7 (71%). Fleischer et al presented their data on 61 patients with intramucosal carcinoma.[rx] A complete remission was observed in 98% of patients after a median follow-up of 30 months. In both studies, no complications were reported. Shaheen and co-researchers reported on a randomized, multicenter prospective trial comparing RFA with a sham procedure in BE with dysplasia.[rx] One hundred and twenty-seven patients (LGD = 64, HGD = 63) with a 12-month follow-up were studied. Complete eradication of LGD and HGD occurred in 90.5% and 81% in the ablation group (P < .001). On the other hand, complete elimination of LGD and HGD occurred in 22.7% and 19% in the control group (P < .001). A clear superiority for RFA was observed. Furthermore, this superiority was also significant for eradication of BE with 77.4% (RFA group) as compared with 2.3% of those in the control group (P < .001). Patients in the ablation group had fewer cancers (1.2% vs. 9.3%, P = .045) and less disease progression (3.6% vs. 16.3%, P = .03). Six percent of patients treated with RFA developed a stricture, and one had gastrointestinal bleeding.
Endoscopic Mucosal Resection (EMR)
In EMR, local, endoscopic resection is performed after the injection of fluid to separate the mucosal and muscle layers. Ell et al reported their experience with EMR in BE patients with dysplasia or IMC.[rx] They studied 64 BE patients with HGD or IMC. Thirty-five patients belonged to the low-risk group and 29 to the high-risk group according to histological grade, lesion size, and macroscopic appearance. BE eradication was observed in 97% and 59% in low- and high-risk groups, respectively, after a mean follow-up of 12 months. Recurrence or metachronous lesions incidence was 13.6% and 17.1%, respectively.
Larghi et al also reported their results with this technique in 24 BE patients with HGD or IMC after a mean follow-up of 28 months.[rx] Complete eradication was observed in 87.5% of the patients (21 out of 24). Complications were observed in five patients (two with bleeding and three with stricture). Persistence or de novo BE, developing underneath the newly formed squamous mucosa (subsquamous), was identified in two patients (8%).
Cryo-Spray Ablation (CSA)
Through the application of liquid nitrogen gas or CO2, cold temperatures (−196°C, −70° respectively) generated can freeze the tissues, and ischemic necrosis can occur. Furthermore, cryo-ablation induces apoptosis and immune stimulation. A prospective trial evaluating the safety and efficacy of CSA in patients with BE and HGD or IMCA by Dumont and colleagues was reported in 30 patients with a median follow-up of 12 months. At the last follow-up, responses persisted in 68% for HGD and 80% for IMCA.[rx] Greenwald et al presented results of parallel prospective treatment studies at four tertiary care medical centers.[rx] Seventy-seven patients (BE = 7, BE with HGD = 45, BE with IMCA = 13, EC = 10, and severe squamous dysplasia = 2) were treated. Out of 23 patients completing therapy, in 17 patients with HGD, there was a complete response in 94% and complete elimination of BE in 53%. In all four patients with IMC, a complete response was noted for cancer and 75% of BE eradication. In all three patients with esophageal cancer (inoperable or refused surgery, ineligible or refused radiation or systemic therapy) a complete response was observed for cancer and 67% of BE elimination. One major complication occurred during their study, consisting of a gastric perforation caused by gastric distention due to nitrogen gas. The most common side effect in procedures was chest pain (17.6%) and dysphagia (13.3%).
Ablation therapy in Barrett’s esophagus
| Ablation modalities | Description of the technique | Outcome | |
| RFA | RFA uses a balloon-based circumferential array of closely spaced electrodes to deliver radiofrequency energy to the esophageal mucosa. With this technique, the mucosa is ablated to the submucosal level. A smaller, endoscope-mounted, radiofrequency catheter ablation device could be used for the focal ablation of metaplasia that could remain after treatment with the circumferential system. Follow-up endoscopy is at 3 mo when any remaining metaplasia is ablated, with a further follow-up endoscopy at 1 yr | A landmark large, multicentre, randomized trial showed that RFA can eliminate HGD, reducing the risk of EAC compared with a sham procedure. Overall, the eradication rates for HGD range from 79% to 90% and from 69% and 97% for NDBE/LGD patients RFA is safer and easier to administer, and it causes fewer major complications, particularly stricture formation, than PDT | |
| APC | APC produces a flow of ionized argon plasma that generates a high-frequency monopolar current to the BE surface under direct vision | Different eradication rates for NDBE and LGD in the short term ranged from 36% to 100% for NDBE and rates of recurrence between 62% and 100% for LGD patients | |
| PDT | PDT is based on the injection of a light sensitizing drug (e.g., porfimer sodium) into the patient and then the exposure of a portion of the esophagus to the light of a specific wavelength, which would lead to dysplasia cell death. Once the photosensitizer is activated by the light, it generates oxygen free radicals that result in cytotoxicity to the mucosal cells | The eradication rates for HGD range from 77% to 100% and those for NDBE/LGD range from 50%-100% of patients The limitations include the cost of the intravenous agent, the prolonged period (weeks) of photosensitivity following exposure, and an appreciable post-treatment stricture rate | |
| CRY | CRY is a non-contact method of cryotherapy that involves an endoscopically directed spray of liquid nitrogen at -196 °C directly onto Barrett’s mucosa The advantage is a lack of contact with mucosa and hence can be applied to irregularity, which would make the application of contact therapies such as RFA challenging | The rates of complete eradication are approximately 68%-97% for HGD and 57% for NDBE The current literature is inadequate to assess the ability of CRY to achieve sustained reversion of the metaplastic mucosa to the normal-appearing squamous epithelium in subjects at any stage of BE. Further longitudinal studies are needed | |
| MPEC | MPEC uses an endoscopic multipolar electrical probe, which is used to control gastrointestinal hemorrhage that applies electrical energy at 50 W so that all BE surfaces are treated | Complete eradication in 65%-100% of NDBE. This technique is very much operator dependent and causes dysphagia as the most common side effect |
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