Upper Gastrointestinal Endoscopy and Gastrointestinal Biopsy

Number: 0738

Table Of Contents

Policy

Scope of Policy

This Clinical Policy Bulletin addresses upper gastrointestinal endoscopy and gastrointestinal biopsy.

1. Medical Necessity

   Aetna considers the following interventions medically necessary:

   1. Esophagogastroduodenoscopy (EGD)/upper endoscopy for high-risk screening in any of the following:

      1. Persons with chronic (5 years or more) gastro-esophageal reflux disease (GERD) at risk for Barrett's esophagus (BE) Note: After a negative screening EGD, further screening EGD is not indicated;
      2. Persons with symptomatic pernicious anemia (e.g., anemia, fatigue, pallor, red tongue, shortness of breath, as well as tingling and numbness in the hands and feet) to identify prevalent lesions (e.g., carcinoid tumors, gastric cancer);
      3. Persons with cirrhosis and portal hypertension but no prior variceal hemorrhage, especially those with platelet counts less than 140,000/mm3, or Child's class B or C disease;

   2. Diagnostic EGD in any of the following:

      1. Evaluation of dyspepsia symptoms in persons who have undergone non-invasive testing for H. pylori, and whose symptoms persist despite eradication of H. pylori and have failed an appropriate therapeutic trial (e.g., proton pump inhibitor [PPI], with/without prokinetic, antidepressant);
      2. Evaluation of dyspepsia in persons who are H. pylori negative and who have undergone an appropriate trial of PPI therapy (appropriate trial of therapy is a 2-4 week course of standard dose, once daily proton pump inhibitor);
      3. Evaluation of dyspepsia symptoms associated with multiple or progressive alarm signs (e.g., anorexia, anemia and weight loss) in persons younger than 60 years of age;
      4. Evaluation of dyspepsia in persons over 60 years of age;
      5. Evaluation of dysphagia or odynophagia;
      6. Evaluation of esophageal reflux symptoms that are persistent or recurrent despite appropriate therapy (appropriate therapy consists of an 8 week trial of standard dose once daily PPI; in patients with partial response, the dose may be increased to twice daily);
      7. Evaluation of esophageal masses and for directing biopsies for diagnosing esophageal cancer;
      8. Evaluation of persons with signs or symptoms of loco-regional recurrence after resection of esophageal cancer;
      9. Evaluation of persistent vomiting of unknown cause;
      10. Evaluation of other diseases in which the presence of upper gastro-intestinal (GI) pathological conditions might modify other planned management (e.g., persons who have a history of ulcer or GI bleeding who are scheduled for organ transplantation, long-term anti-coagulation, or long-term non-steroidal anti-inflammatory drug therapy for arthritis, and those with cancer of the head and neck);
      11. Evaluation of familial adenomatous polyposis syndromes;
      12. Confirmation and specific histological diagnosis of radiologically demonstrated lesions:
          
          
          1. Gastric or esophageal ulcer;
          2. Suspected neoplastic lesion;
          3. Upper GI tract stricture or obstruction;

      13. Evaluation of GI bleeding:

          1. For persons with active or recent bleeding;
          2. For presumed chronic blood loss and for iron deficiency anemia when the clinical situation suggests an upper GI source or when colonoscopy results are negative;
      14. Sampling of upper GI tissue or fluid;
      15. Evaluation of persons with suspected portal hypertension to document or treat esophageal varices;
      16. Evaluation of acute injury after caustic ingestion;
      17. Evaluation of dyspepsia when any of the following is present:
          
          
          1. Chronic GI bleeding;
          2. Crohn’s disease with persistent dyspepsia;
          3. Epigastric mass;
          4. Iron deficiency anemia;
          5. Persistent vomiting;
          6. Progressive difficulty swallowing;
          7. Progressive unintentional weight loss;
          8. Suspicious barium meal (upper GI series);
      18. Evaluation of chronic dyspepsia and/or abdominal pain when other studies (e.g., colonoscopy, enteroscopy, ileoscopy, and flexible sigmoidoscopy) have negative results;
      19. Differentiation of Crohn's disease from ulcerative colitis in indeterminate colitis;

   3. Therapeutic EGD in any of the following:

      1. Banding or sclerotherapy of varices;
      2. Dilation of stenotic lesions (e.g., with trans-endoscopic balloon dilators or dilation systems using guide wires);
      3. Management of achalasia by means of botulinum toxin, balloon dilation;
      4. Palliative treatment of stenosing neoplasms by means of laser, multi-polar electrocoagulation, stent placement;
      5. Per-oral endoscopic myotomy (POEM) for the treatment of type III (spastic) achalasia;
      6. Placement of feeding or drainage tubes (per-oral, trans-nasal, percutaneous endoscopic gastrostomy, percutaneous endoscopic jejunostomy);
      7. Removal of foreign bodies or selected polypoid lesions;
      8. Treatment of bleeding lesions such as ulcers, tumors, and vascular abnormalities by means of electrocoagulation, heater probe, laser photocoagulation, or injection therapy;
      9. Local injection of steroid into an anastomotic esophageal stricture at the time of endoscopic dilation for prevention of stricture;

   4. Sequential or periodic EGD in any of the following:

      1. Surveillance of persons with BE without dysplasia - for persons with established BE of any length and with no dysplasia, after 2 consecutive examinations within 1 year, an acceptable interval for additional surveillance is every 3 years;
      2. Surveillance of persons with BE and low-grade dysplasia (LGD) at 6 months - if LGD is confirmed, then surveillance at 12 months and yearly thereafter as long as dysplasia persists;
      3. Surveillance of persons with BE and high-grade dysplasia every 3 months for at least 1 year - after 1 year of no cancer detection, the interval of surveillance may be lengthened if there are no dysplastic changes on 2 subsequent endoscopies performed at 3-month intervals;
      4. Surveillance of persons with a severe caustic esophageal injury every 1 to 3 years beginning 15 to 20 years after the injury;
      5. Surveillance of persons with tylosis every 1 to 3 years beginning at 30 years of age;
      6. Surveillance of recurrence of adenomatous polyps in synchronous and metachronous sites at 3- to 5-year intervals;
      7. Surveillance of persons with familial adenomatous polyposis starting around the time of colectomy or after age of 30 years;
      8. Surveillance of persons with hereditary non-polyposis colorectal cancer;

   5. Biopsy of the upper gastrointestinal tract for the following indications:

      1. Gastroesophageal reflux disease (GERD), biopsies directed to irregularities of the mucosa;
      2. Barrett’s esophagus - Seattle Protocol;
         
         
         1. Without dysplasia - 4 quadrant biopsies each 2 cm;
         2. With low grade dysplasia - 4 quadrant biopsies each 1-2 cm;
         3. With high grade dysplasia - 4 quadrant biopsies each 1 cm;
      3. Eosinophilic esophagitis - up to 8 biopsies of the esophagus, plus biopsies of the gastric antrum and duodenum if there is suspicion of eosinophilic gastroenteritis;
      4. Infectious esophagitis:
         
         
         1. CMV infection - biopsies from the base of the ulcers;
         2. HSV infection - biopsies from the edges of the ulcers;
         3. Esophageal candidiasis - biopsies from affected areas plus exfoliative cytology;
      5. Helicobacter pylori - up to 5 biopsies (Sidney protocol);
      6. Metaplastic (chronic) atrophic gastritis;
         
         
         1. Environmental metaplastic atrophic gastritis - up to 12 biopsies;
         2. Autoimmune atrophic metaplastic gastritis (AMAG) - biopsies of ulcers, nodules, polyps, and masses to rule out neoplasia;
      7. Gastric polyps - number of medically necessary biopsies determined by the number of polyps;
      8. Peptic ulcer disease - 8 or more biopsies, from the base and edges if there is suspicion of malignancy;
      9. Celiac disease - up to 2 biopsies of the duodenal bulb and 4 or more biopsies of the distal duodenum;
      10. Inflammatory bowel disease, diagnosis - Two or more biopsies from the esophagus, stomach and duodenum (see also indications for biopsy in lower endoscopy, below);
      11. Acute graft versus host disease - In case of non-diagnostic flexible sigmoidoscopy, an upper endoscopy should be performed with four or more biopsies from the gastric body, antrum and duodenum;

   6. Endoscopic submucosal dissection (ESD) for the treatment of BE when any of the following criteria is met:

      1. Barrett’s esophagus with high-grade dysplasia (HGD) with a visible lesion of greater than 1.5 cm; or
      2. Early esophageal cancer by endoscopic ultrasonography (EUS) with a negative PET scan; or
      3. Esophageal polyps unable to be removed by snare techniques; or
      4. Recurrent HGD (visible lesion(s)); or
      5. Submucosal esophageal adenocarcinoma (T1b) with low-risk features (less than 500-μm invasion in the submucosa [sm1], good-to-moderate differentiation, and no lymphatic invasion); or
      6. Submucosal masses of greater than 2.0 cm.

2. Experimental, Investigational, or Unproven

   Aetna considers the following interventions experimental, investigational, or unproven because the effectiveness of these approaches has not been established:

   1. EGD (screening, diagnostic, therapeutic, or sequential/periodic) for any of the following:

      1. EGD before bariatric surgery in asymptomatic individuals;
      2. EGD for confirming placement of gastric band;
      3. EGD for diagnosing laryngopharyngeal reflux;
      4. EGD for routine screening;
      5. Evaluation of symptoms that are considered functional in origin (there are exceptions in which an EGD may be done once to rule out organic disease, especially if symptoms are unresponsive to therapy);
      6. Evaluation of metastatic adenocarcinoma of unknown primary site when the results will not alter management;
      7. Repeat EGD for persons with a prior normal EGD if symptoms remain unchanged;
      8. Routine evaluation of abdominal pain in children (i.e., without other signs and symptoms suggestive of serious organic disease);
      9. Evaluation of radiographical findings of:
         
         
         1. Asymptomatic or uncomplicated sliding hiatal hernia;
         2. Deformed duodenal bulb when symptoms are absent or respond adequately to ulcer therapy;
         3. Uncomplicated duodenal ulcer that has responded to therapy;
      10. Surveillance for malignancy in persons with gastric atrophy, pernicious anemia, or prior gastric operations for benign disease (e.g., partial gastrectomy for peptic ulcer disease);
      11. Surveillance of healed benign disease (e.g., esophagitis or duodenal/gastric ulcer);
      12. Surveillance during repeated dilations of benign strictures unless there is a change in status;
      13. Surveillance of persons with achalasia;
      14. Surveillance of persons with previous aerodigestive squamous cell cancer;
      15. Surveillance of persons with gastric intestinal metaplasia;
      16. Surveillance of persons following adequate sampling or removal of non-dysplastic gastric polyps.

   2. Endoscopic functional luminal imaging probe (EndoFLIP) (impedance planimetry) for the management of the following (not an all-inclusive list):

      1. Achalasia;
      2. Dysphagia;
      3. Esophagitis;
      4. Esophagogastric junction outflow obstruction;
      5. Fecal incontinence;
      6. Gastro-esophageal reflux disease (GERD);
      7. Gastroparesis;
      8. Prediction of clinical response to flexible endoscopy in Zenker's diverticulotomy;
      9. Upper gastro-intestinal tract stenosis (including guiding therapy for esophageal stenosis).
   3. Screening upper endoscopy. No current guidelines of leading medical professional organizations or Federal public health agencies recommend routine upper endoscopy screening of asymptomatic persons;
   4. Drug-coated balloons for the treatment of esophageal strictures.

3. Related Policies

   • CPB 0396 - Gastrointestinal Function: Selected Tests
   • CPB 0588 - Capsule Endoscopy
   • CPB 0616 - Gastrointestinal Manometry
   • CPB 0625 - Dysphagia Therapy
   • CPB 0667 - Esophageal and Airway pH Monitoring

Background

Esophagogastroduodenoscopy (EGD), also known as upper gastro-intestinal (GI) endoscopy, upper endoscopy, or gastroscopy, refers to examination of the esophagus, stomach, and upper duodenum (first part of the small intestine) by means of a flexible fiber-optic endoscope.  It has been employed for investigating the cause(s) of abdominal pain, dysphagia (difficulty swallowing), gastro-esophageal reflux disease (GERD), hematemesis (vomiting up blood), persistent nausea and vomiting, as well as occult and obscure GI bleeding.  It can also be used in diagnosing esophagitis (inflammation of the esophagus), Schatzki's ring (also known as esophagogastric ring and lower esophageal ring), Mallory-Weiss syndrome (tear in the mucous membrane where the esophagus connects to the stomach), gastritis (inflammation of the stomach), duodenitis (inflammation of the duodenum), GI ulcer and polyps (growth of tissue), diverticula (abnormal pouches in the lining of the intestines), as well as obstruction, stricture (abnormal narrowing), and tumors of the esophagus, stomach, and upper duodenum.

Concha and colleagues (2007) stated that patients with obscure-occult GI bleeding presenting with IDA who have previously undergone upper endoscopy and colonoscopy and who do not respond to iron replacement should undergo a repeat upper endoscopy or enteroscopy and colonoscopy.  In obscure-overt GI bleeding, if the patient is not actively bleeding (intermittent melena or hematochezia requiring repeated blood transfusions), a repeat upper endoscopy and colonoscopy is recommended.  If negative, push enteroscopy is the next diagnostic step.  If negative and if no further bleeding, the patient should undergo wireless capsule endoscopy.

The American Society for Gastrointestinal Endoscopy (ASGE)'s guideline on the role of endoscopy in the assessment and treatment of esophageal cancer (Jacobson et al, 2003) stated that endoscopy is pivotal in the diagnosis and management of this malignancy.  Standard upper endoscopy remains the primary method for visualizing esophageal masses and for directing biopsies.  Patients presenting with signs or symptoms of loco-regional recurrence after resection of esophageal cancer should undergo endoscopy as part of their evaluation.

The following recommendations on EGD are provided by the ACG (Moayyedi, 2017) and ASGE (Cohen et al, 2006).

Esophagogastroduodenoscopy is generally indicated for the evaluation of:

• Dyspepsia symptoms in individuals younger than age 60 who have been evaluated with a noninvasive test for H. pylori infection, and:

  • The test is negative; or
  • The test was positive, and if the symptoms have persisted despite treatment for infection and confirmation of eradication;
    
    
• Dyspepsia symptoms that persist despite an appropriate trial of therapy;
• Dyspepsia symptoms not suggestive of pancreaticobiliary origin, associated with >1 alarm symptoms or signs suggesting serious organic disease (e.g., anorexia and weight loss) in individuals younger than age 60;
• Dyspepsia in patients greater than 60 years of age;
• Dysphagia or odynophagia;
• Progressive or significant (more than 20 lbs) weight loss;
• Esophageal reflux symptoms that are persistent or recurrent despite appropriate therapy;
• Persistent vomiting of unknown cause;
• Other diseases in which the presence of upper GI pathological conditions might modify other planned management (e.g., patients who have a history of ulcer or GI bleeding who are scheduled for organ transplantation, long-term anti-coagulation, or long-term non-steroidal anti-inflammatory drug therapy for arthritis, and those with cancer of the head and neck);
• Familial adenomatous polyposis syndromes;
• For confirmation and specific histological diagnosis of radiologically demonstrated lesions:
   
  • Suspected neoplastic lesion
  • Gastric or esophageal ulcer
  • Upper tract stricture or obstruction;
    
    

• Gastrointestinal bleeding:

  • In patients with active or recent bleeding
  • For presumed chronic blood loss and for IDA when the clinical situation suggests an upper GI source or when colonoscopy results are negative;
    
    
• When sampling of tissue or fluid is indicated;
• In patients with suspected portal hypertension to document or treat esophageal varices;
• To assess acute injury after caustic ingestion;
• Treatment of bleeding lesions such as ulcers, tumors, vascular abnormalities (e.g., electrocoagulation, heater probe, laser photocoagulation, or injection therapy);
• Banding or sclerotherapy of varices;
• Removal of foreign bodies;
• Removal of selected polypoid lesions;
• Placement of feeding or drainage tubes (per-oral, percutaneous endoscopic gastrostomy, percutaneous endoscopic jejunostomy);
• Dilation of stenotic lesions (e.g., with transendoscopic balloon dilators or dilation systems using guide wires);
• Management of achalasia (e.g., botulinum toxin, balloon dilation);
• Palliative treatment of stenosing neoplasms (e.g., laser, multi-polar electrocoagulation, stent placement).

Esophagogastroduodenoscopy is generally not indicated for the evaluation of:

• Symptoms that are considered functional in origin (there are exceptions in which an endoscopic examination may be done once to rule out organic disease, especially if symptoms are unresponsive to therapy);
• Metastatic adenocarcinoma of unknown primary site when the results will not alter management;
• Radiographical findings of:
   
  • Asymptomatic or uncomplicated sliding hiatal hernia
  • Uncomplicated duodenal ulcer that has responded to therapy
  • Deformed duodenal bulb when symptoms are absent or respond adequately to ulcer therapy.

Sequential or periodic EGD may be indicated for:

• Surveillance for malignancy in patients with pre-malignant conditions such as Barrett's esophagus (a condition that increases the risk for developing esophageal cancer).

Sequential or periodic EGD is generally not indicated for:

• Surveillance for malignancy in patients with gastric atrophy, pernicious anemia, or prior gastric operations for benign disease;
• Surveillance of healed benign disease such as esophagitis or gastric or duodenal ulcer;
• Surveillance during repeated dilations of benign strictures unless there is a change in status.

The ASGE guideline on the role of endoscopy in the surveillance of pre-malignant conditions of the upper GI tract (Hirota et al, 2006) provided the following recommendations:

• Patients with chronic GERD at risk for Barrett's esophagus should be considered for endoscopic screening (B).
• In patients with Barrett's esophagus without dysplasia, the cost effectiveness of surveillance endoscopy is controversial. If surveillance is performed, an interval of 3 years is acceptable (C).
• Although an increased cancer risk has not been established in patients with Barrett's esophagus and low-grade dysplasia, endoscopy at 6 months and yearly thereafter should be considered (C).
• Patients with Barrett's esophagus with confirmed high-grade dysplasia should be considered for surgery or aggressive endoscopic therapy (B).
• Patients with high-grade dysplasia who elect endoscopic surveillance should be followed up closely (i.e., every 3 months) for at least 1 year. If no further high-grade dysplasia is confirmed, then the interval between follow-ups may be lengthened (B).
• There are insufficient data to recommend routine surveillance for patients with achalasia (C).
• Patients with a severe caustic esophageal injury should undergo surveillance every 1 to 3 years beginning 15 to 20 years after the injury (C).
• Patients with tylosis should undergo surveillance endoscopy every 1 to 3 years beginning at age 30 years (C).
• There are insufficient data to support routine endoscopic surveillance for patients with previous aerodigestive squamous cell cancer (C).
• Adenomatous gastric polyps should be resected because of the risk for malignant transformation (B).
• Adenomatous polyps may recur in synchronous and metachronous sites, and surveillance endoscopies should be performed at 3- to 5-year intervals (C).
• Endoscopic surveillance for gastric intestinal metaplasia has not been extensively studied in the U.S. and therefore cannot be routinely recommended (C). However, there may be a subgroup of high-risk patients who will benefit from endoscopic surveillance (B).
• Patients with confirmed gastric high-grade dysplasia should be considered for gastrectomy or local resection because of the high incidence of prevalent carcinoma (B).
• Patients with pernicious anemia may be considered for a single screening endoscopy, particularly if symptomatic, but there are insufficient data to recommend ongoing surveillance (C).
• There are insufficient data to support routine endoscopic surveillance in patients with previous partial gastrectomy for peptic ulcer disease (C).
• Patients with familial adenomatous polyposis should undergo regular surveillance endoscopy using both end-viewing and side-viewing endoscopes, starting around the time of colectomy or after age 30 years (B).
• Patients with hereditary non-polyposis colorectal cancer have an increased risk of gastric and small-bowel cancer (B). Surveillance should be strongly considered (C).

Definitions:

1. Prospective controlled trials
2. Observational studies
3. Expert opinion

The North of England Dyspepsia Guideline Development Group (2004) recommended that "[u]rgent specialist referral or endoscopic investigation (to be seen within 2 weeks) is indicated for patients of any age with dyspepsia when presenting with any of the following: chronic gastrointestinal bleeding, progressive unintentional weight loss, progressive difficulty swallowing, persistent vomiting, iron deficiency anaemia, epigastric mass, or suspicious barium meal....Routine endoscopic investigation of patients of any age, presenting with dyspepsia and without alarm signs, is not necessary.  However, for patients over 55, when symptoms persist despite Helicobacter pylori (H. pylori) testing and acid suppression therapy, consider endoscopic referral for any of the following: previous gastric ulcer or surgery; continuing need for NSAID treatment; or raised risk of gastric cancer or anxiety about cancer".

The ASGE guidelines on the role of endoscopy in the management of variceal hemorrhage (Qureshi et al, 2005) recommended that screening EGD should be performed in patients with established cirrhosis, especially in those with platelet counts less than 140,000/mm³, or Child's class B or C disease.

The ASGE guideline on the role of endoscopy in the patient with lower GI bleeding (Davila et al, 2005) stated that nasogastric-tube placement and/or upper endoscopy to look for an upper GI source of bleeding should be considered if a source is not identified on colonoscopy, especially if there is a history of upper GI symptoms or anemia.

The ASGE guideline on endoscopy in the diagnosis and treatment of inflammatory bowel disease (IBD) (Leighton et al, 2006) stated that EGD or enteroscopy may be helpful for diagnosing IBD when other studies have negative results and for differentiating Crohn's disease from ulcerative colitis in indeterminate colitis.  Note: ASGE does not recommend routine EGD in all patients suspected of having Crohn's disease.

The American College of Gastroenterology's guidelines for the diagnosis and treatment of GERD (DeVault and Castell, 2005) stated that "[i]f the patient's history is typical for uncomplicated GERD, an initial trial of empirical therapy (including lifestyle modification) is appropriate.  Endoscopy at presentation should be considered in patients who have symptoms suggesting complicated disease, those at risk for Barrett's esophagus ... Endoscopy is the technique of choice used to identify suspected Barrett's esophagus and to diagnose complications of GERD.  Biopsy must be added to confirm the presence of Barrett's epithelium and to evaluate for dyspepsia".

The American College of Gastroenterology Guidelines for the Diagnosis and Management of Gastroesophageal Reflux Disease (Katz, Gerson and Vela, 2013) states: "An 8-week course of PPIs is the therapy of choice for symptom relief and healing of erosive esophagitis; There are no major differences in efficacy between the different PPIs; PPI therapy should be initiated at once a day dosing, before the first meal of the day. For patients with partial response to once daily therapy, tailored therapy with adjustment of dose timing and / or twice daily dosing should be considered; Non-responders to PPI should be referred for evaluation."

Dughera et al (2007) noted that GERD is known to cause erosive esophagitis, Barrett's esophagus (BE), and has been linked to the development of adenocarcinoma of the esophagus.  Currently, endoscopy is the main clinical tool for visualizing esophageal lesions, but the majority of GERD patients do not have endoscopic visible lesions and other methods are required.  Ambulatory esophageal pH monitoring is the gold standard in diagnosing GERD, since it measures distal esophageal acid exposure and demonstrates the relationship between symptoms and acid reflux.

According to the University of Michigan Health System's guideline on GERD (2007), no gold standard exists for the diagnosis of this disease.  Although pH probe is accepted as the standard with a sensitivity of 85 % and specificity of 95 %, false positives and false negatives still exist.  Endoscopy lacks sensitivity in determining pathological reflux.  Barium radiology has limited usefulness in the diagnosis of GERD and is not recommended.  Furthermore, If symptoms remain unchanged in a patient with a prior normal endoscopy, repeating endoscopy has no benefit and is not recommended.

The ACG guideline on the management of dyspepsia (Moayyedi 2017) recommends that "dyspepsia patients under the age of 60 should have a non-invasive test for H. pylori, and therapy for H. pylori if present." Hence, endoscopy should not be pursued in individuals younger than age 60 if H. pylori testing has not been performed. The guideline further states : "we do not suggest endoscopy to investigate alarm features for dyspepsia patients under the age of 60 to exclude upper GI neoplasia." The rationale for his recommendation is: "the risk of a person < 60 years old having malignancy is typically very low so, even with an alarm feature, the risk is still much <1% and it is very unlikely that endoscopy of all young patients with alarm features would be cost-effective." The guidelines go on to clarify that "a minority of patients <60 years of age with alarm features would warrant endoscopy, particularly if the feature was prominent (e.g., weight loss > 20 lb or rapidly progressive dysphagia) or if a combination of features were present." The guideline further clarifies that it does not govern pain that has features of pancreaticobiliary pain, or the occurrence of symptoms such as dysphagia or weight loss in the absence of dyspeptic symptoms.

The randomized clinical trials of PPI that are referenced in the guidelines ranged between 2-6 weeks in duration, but most studies a 4-week course of PPI therapy. The doses ranged between 10 mg to 40 mg, and most utilized once daily dosing.

The ACG guidelines (Chey 2017) have also updated the treatment regimens for H. pylori. While clarithromycin-based triple therapy remains a first line of therapy, the guidelines acknowledge the high rates of clarithromycin resistance by recommending the use of this regimen in regions with clarithromycin resistance lower than 15%, and in patients without prior macrolide exposure. While detailed data on regional prevalence is unavailable, the data that is currently present suggests that prevalence of clarithromycin resistance exceeds 15% in many parts of North America.   The guidelines acknowledge that better data on regional antibiotic resistance is needed, and that the lack of tests to determine antibiotic sensitivity "remains an unfortunate barrier to making evidence-based treatment recommendations." Given the concern for clarithromycin resistance, multiple additional therapies have been designated to be first-line options:

"Bismuth quadruple therapy consisting of a PPI, bismuth, tetracycline, and a nitroimidazole for 10–14 days is a recommended first-line treatment option. Bismuth quadruple therapy is particularly attractive in patients with any previous macrolide exposure or who are allergic to penicillin (strong recommendation; low quality of evidence).

Concomitant therapy consisting of a PPI, clarithromycin, amoxicillin and a nitroimidazole for 10–14 days is a recommended first-line treatment option (strong recommendation; low quality of evidence (for duration: very low quality of evidence)).

Sequential therapy consisting of a PPI and amoxicillin for 5–7 days followed by a PPI, clarithromycin, and a nitroimidazole for 5–7 days is a suggested first-line treatment option (conditional recommendation; low quality of evidence (for duration: very low quality of evidence)).

Hybrid therapy consisting of a PPI and amoxicillin for 7 days followed by a PPI, amoxicillin, clarithromycin and a nitroimidazole for 7 days is a suggested first-line treatment option (conditional recommendation; low quality of evidence (For duration: very low quality of evidence)).

Levofloxacin triple therapy consisting of a PPI, levofloxacin, and amoxicillin for 10–14 days is a suggested first-line treatment option (conditional recommendation; low quality of evidence (For duration: very low quality of evidence)).

Fluoroquinolone sequential therapy consisting of a PPI and amoxicillin for 5–7 days followed by a PPI, fluoroquinolone, and nitroimidazole for 5–7 days is a suggested first-line treatment option (conditional recommendation; low quality of evidence (for duration: very low quality of evidence))."

In a systemic review on EGD in children with abdominal pain, Thakkar et al (2007) stated that the diagnostic yield of EGD in children with unclear abdominal pain is low; however, existing studies are inadequate.  The effect of EGD on change in treatment, quality of life, improvement of abdominal pain, and cost-effectiveness is unknown.  The predictors of significant findings are unclear.  These findings suggested that a large multi-center study examining clinical factors, biopsy reports, and addressing patient outcomes is needed to further clarify the value of EGD in children with abdominal pain.

Absolute contraindications to EGD include shock, peritonitis, fulminant colitis, perforated viscus (e.g., esophagus, stomach, intestine), severe cardiac decompensation, and acute myocardial infarction (unless active, life-threatening hemorrhage is present).  Relative contraindications include an obtunded or uncooperative subject, coma (unless the patient is intubated), and cardiac arrhythmias or recent myocardial ischemia (Merck 2005; Cerulli, 2006).

Kawai et al (2010) reported that ultra-thin trans-nasal EGD (TN-EGD) reduces pharyngeal discomfort and is more tolerable for the patients.  Ultra-thin transnasal endoscopy has been reported as inferior to transoral conventional EGD (TO-EGD) in terms of image quality, suction, air insufflation and lens washing, due to the smaller endoscope caliber; TN-EGD should be conducted slowly, with short distance observation, and also with image-enhanced endoscopy.  With reference to image-enhanced endoscopy, chromoendoscopy method (indigocarmine) is suitable for gastric neoplasm.  On the other hand, optical digital method (NBI) and digital method (i-scan, FICE) is suitable for esophageal neoplasm.  TN-EGD is applied in various GI procedures such as percutaneous endoscopic gastrostomy, naso-enteric feeding tube placement, endoscopic retrograde cholangiopancreaticography with naso-biliary drainage, long intestinal tube placement in small bowel obstruction, as well as esophageal manometry.

Zhang and colleagues (2012) evaluated the feasibility and efficacy of small-caliber TN-EGD for the placement of naso-enteric feeding tubes (NET) in patients with severe upper GI diseases.  Between January 2007 and March 2010, a total of 51 patients underwent trans-nasal endoscopy for the placement of NET in Peking University Third Hospital.  Indications for NET included esophageal stricture or gastric outlet obstruction because of corrosive esophagitis or gastritis, partial obstruction due to malignancy, stenosis in stoma or efferent loop, gastroparesis, metallic stent in upper GI tract, tracheo-esophageal fistula, severe acute pancreatitis, anorexia nervosa and intensive care patients.  The tubes were endoscopically placed using the guidewire technique.  The position of the tube was confirmed by the immediate second endoscopy or abdominal X-ray.  If the initiate placement was incorrect, an adjustment or a second placement was conducted immediately.  Initial post-pyloric placement of NET was achieved in 43 of 51 patients (84.3 %), but the total success rate reached 98.0 % (50/51) after the second placement.  The time required for the procedure ranged from 10 to 35 mins, with a median time of 20.4 mins.  Epistaxis occurred in 2 patients.  There were no complications of hemorrhage, perforation or aspiration.  The authors concluded that trans-nasal endoscopic placement of NET was feasible in patients with upper GI diseases, especially in those with changed anatomy.

Kwon et al (2011) stated that laryngopharyngeal reflux (LPR) is a subset of GERD and given its own identity, because the main symptomatic regions are the larynx and pharynx.  Accurate diagnosis and effective treatment of LPR has been challenging.  Much research has been dedicated to the elucidation of its complex pathophysiology and the development of accurate diagnostic modalities and effective treatment.

Vardar and associates (2012) noted that the techniques used in the diagnosis of GERD have insufficient specificity and sensitivity in diagnosing LPR.  These investigators evaluated the role of EGD and laryngological examination in the diagnosis of LPR.  A total of 684 diagnosed GERD and suspected LPR patients were prospectively scored by the reflux finding score (RFS).  A total of 484 patients with GERD who had RFS greater than or equal to 7 were accepted as having LPR; 248 patients with GERD plus LPR on whom an endoscopic examination was performed were evaluated.  As a control group, results from 82 patients with GERD who had RFS less than 7 were available for comparison.  The GERD symptom score (RSS) was counted according to the existence of symptoms (heartburn/regurgitation) and frequency, duration, and severity.  The reflux symptom index (RSI) was also evaluated.  The relationship between esophageal endoscopic findings, RSS, RFS and RSI was investigated.  Mean age was 46 +/- 12 (19 to 80).  The mean values of RSS, RFS, and RSI were 18.9 +/- 7.7, 10 +/- 2.2, 16.6 +/- 11.9, respectively.  Erosive esophagitis was detected in 75 cases (30 %).  Hiatus hernia was observed in 32 patients (13 %).  There was no correlation between RSS and RFS, RSI.  The severity of esophagitis did not correlate with the severity of the laryngeal findings.  The authors concluded that LPR should be suspected when the history and laryngoscopy findings are suggestive of the diagnosis; and EGD has no role in the diagnosis of LPR.

UpToDate reviews on "Endoscopy in patients who have undergone bariatric surgery" (Huang, 2013) and "Overview of upper gastrointestinal endoscopy (esophagogastroduodenoscopy)" (Greenwald and Cohen, 2013) do not mention confirmation of gastric band placement as an indication of endoscopy/upper gastrointestinal endoscopy.

De Palma and Forestieri (2014) stated that obesity is an increasingly serious health problem in nearly all Western countries.  It represents an important risk factor for several GI diseases, such as GERD, erosive esophagitis, hiatal hernia, BE, esophageal adenocarcinoma, H. pylori infection, colorectal polyps and cancer, non-alcoholic fatty liver disease, cirrhosis, and hepato-cellular carcinoma.  Surgery is the most effective treatment to date, resulting in sustainable and significant weight loss, along with the resolution of metabolic comorbidities in up to 80 % of cases.  Many of these conditions can be clinically relevant and have a significant impact on patients undergoing bariatric surgery.  There is evidence that the chosen procedure might be changed if specific pathological upper GI findings, such as large hiatal hernia or BE, are detected pre-operatively.  The value of a routine endoscopy before bariatric surgery in asymptomatic patients (screening EGD) remains controversial.

Schigt and colleagues (2014) noted that Roux-Y gastric bypass (RYGB) is a frequently used technique in bariatric surgery.  Post-operative anatomy is altered by exclusion of the stomach, which makes this organ inaccessible for future EGD.  The value of pre-operative assessment of the stomach is unclear.  Some institutions choose to investigate the future remnant stomach by EGD, others do not.  These investigators quantified the yield of pre-operative EGD in their institution.  Patients, planned for primary laparoscopic RYGB (LRYGB) or laparoscopic sleeve gastrectomy from December 2007 until August 2012, were screened by EGD in advance.  Results of EGD and patient characteristics were retrospectively analyzed and categorized according to a classification system based on intervention needed.  A total of 523 patients (122 males, 401 females, mean age of 44.3 years, average body mass index [BMI] of 46.6) underwent pre-operative EGD.  In 257 patients (48.9 %) no abnormality was found (group A), 117 patients (17.2 %) had abnormalities without treatment consequences (B1), 84 patients (of the 326 tested [comment #1, reviewer #1, 26.8 %] were H. pylori positive (B2), in 75 (14.3 %) treatment with proton pump inhibitors was required (B3), 6 (1.1 %) required follow-up EGD before surgery (C).  For 1 patient (0.2 %) the operation was canceled because pre-operative EGD presented with Barrett's esophagus with carcinoma (D).  When all abnormalities were taken into account, baselines did show a significant difference for age, gender and reflux symptoms.  The authors concluded that standard pre-operative assessment by EGD in patients who are planned for bariatric surgery is not indicated.  The number needed to screen to find clinically significant abnormalities is high.

Aurora et al (2012) noted that sleeve gastrectomy has become a popular stand-alone bariatric procedure with comparable weight loss and resolution of co-morbidities to that of laparoscopic gastric bypass.  The simplicity of the procedure and the decreased long-term risk profile make this surgery more appealing.  Nonetheless, the ever present risk of a staple-line leak is still of great concern and needs further investigation.  An electronic literature search of MEDLINE database plus manual reference checks of articles published on laparoscopic sleeve gastrectomy for morbid obesity and its complications was completed.  Keywords used in the search were "sleeve gastrectomy" OR "gastric sleeve" AND "leak".  These researchers analyzed 29 publications, including 4,888 patients.  They analyzed the frequency of leak after sleeve gastrectomy and its associated risks of causation.  The risk of leak after sleeve gastrectomy in all comers was 2.4 %.  This risk was 2.9 % in the super-obese [body mass index (BMI) greater than 50 kg/m(2)] and 2.2 % for BMI less than 50 kg/m(2).  Staple height and use of buttressing material did not affect leak rate.  The use of a size 40-Fr or greater bougie was associated with a leak rate of 0.6 % compared with those who used smaller sizes whose leak rate was 2.8 %.  Leaks were found at the proximal third of the stomach in 89 % of cases.  Most leaks were diagnosed after discharge.  Endoscopic management is a viable option for leaks and was documented in 11 % of cases as successful.  The authors concluded that sleeve gastrectomy has become an important surgical option for the treatment of the ever growing morbidly obese population.  The risk of leak is low at 2.4 %.  Attention to detail specifically at the esophago-gastric junction cannot be stressed enough.  Careful patient selection (BMI less than 50 kg/m(2)) and adopting the use of a 40-Fr or larger bougie may decrease the risk of leak.  Vigilant follow-up during the first 30 days is critical to avoid catastrophe, because most leaks will happen after patient discharge.  This study did not mention the use of upper GI endoscopy for detection of leak following sleeve gastrectomy.

Sakran and colleagues (2013) stated that laparoscopic sleeve gastrectomy (LSG) remains under scrutiny as a stand-alone bariatric procedure.  The most feared complication after LSG is staple line leak.  Eight bariatric centers in Israel participated in this study.  A retrospective analysis was performed by querying all the LSG cases performed between June 2006 and June 2010.  The data collected included patient demographics, anthropometrics, and operative and peri-operative parameters.  Among the 2,834 patients who underwent LSG, 44 (1.5 %) with gastric leaks were identified.  Of these 44 patients, 30 (68 %) were women.  The patients had a mean age of 41.5 years and a BMI of 45.4 kg/m(2).  Intra-operative leak tests and routine post-operative swallow studies were performed with 33 patients, and all but 1 patient (3 %) failed to detect the leaks.  Leaks were diagnosed at a median of 7 days post-operatively: early (0 to 2 days) in 9 cases (20 %), intermediately (3 to 14 days) in 32 cases (73 %), and late (greater than 14 days) in 3 cases (7 %).  For 38 patients (86 %), there was clinical suspicion, later confirmed by imaging or operative findings.  Computed tomography, swallow studies, and methylene blue tests were performed for 37, 21, and 15 patients, respectively, and the results were positive, respectively, for 31 (84 %), 11 (50 %), and 9 (60 %) of these patients.  Re-operation was performed for 27 of the patients (61 %).  Other treatment methods included percutaneous drainage (n = 28, 63.6 %), endoscopic placement of stents (n = 11, 25 %), clips (n = 1, 2.3 %), and fibrin glue (n = 1, 2.3 %).  In 33 of the patients (75 %), the leak site was found in the upper sleeve near the gastro-esophageal junction.  The median time to leak closure was 40 days (range of 2 to 270 days), and the overall leak-related mortality rate was 0.14 % (4/2,834).  The authors concluded that gastric leak is the most common cause of major morbidity and mortality after LSG.  Routine tests to rule out leaks seem to be superfluous.  Rather, selective utilization is recommended.  Management options vary, depending mainly on patient disposition.  An accepted algorithm for the diagnosis and treatment of gastric leak has yet to be proposed.

Abou Rached et al (2014) noted that gastric sleeve gastrectomy has become a frequent bariatric procedure.  Its apparent simplicity hides a number of serious, sometimes fatal, complications.  This is more important in the absence of an internationally adopted algorithm for the management of the leaks complicating this operation.  The debates exist even regarding the definition of a leak, with several classification systems that can be used to predict the cause of the leak, and also to determine the treatment plan.  Causes of leak are classified as mechanical, technical and ischemic causes.  After defining the possible causes, the authors went into suggesting a number of preventive measures to decrease the leak rate, including gentle handling of tissues, staple line reinforcement, larger bougie size and routine use of methylene blue test peri-operatively.  These investigators noticed that the most important clinical sign or symptom in patients with gastric leaks are fever and tachycardia, which mandate the use of an abdominal computed tomography, associated with an upper GI series and/or gastroscopy if no leak was detected.  After diagnosis, the management of leak depends mainly on the clinical condition of the patient and the onset time of leak.  It varies between prompt surgical intervention in unstable patients and conservative management in stable ones in whom leaks present lately.  The management options include also endoscopic interventions with closure techniques or more commonly exclusion techniques with an endoprosthesis.  This review did not mention the use of routine upper GI endoscopy for evaluation of leak following sleeve gastrectomy.

Also, the American Association of Clinical Endocrinologists, Obesity Society, American Society for Metabolic & Bariatric Surgery’s clinical practice guidelines on "The perioperative nutritional, metabolic, and nonsurgical support of the bariatric surgery patient" (Mechanick et al, 2013) states that "Clinically significant gastrointestinal symptoms should be evaluated before bariatric surgery with imaging studies, upper gastrointestinal (UGI) series, or endoscopy (Grade D)".  It does not mention use of imaging studies following bariatric surgery.

The American Gastroenterological Association (AGA)’s guideline on "The role of upper gastrointestinal biopsy to evaluate dyspepsia in the adult patient in the absence of visible mucosal lesions" (Yang et al, 2015) stated that "In patients undergoing esophagogastroduodenoscopy (EGD) for dyspepsia as the sole indication, the AGA recommends against obtaining routine biopsies of the normal-appearing esophagus or gastroesophageal (GE) junction regardless of immune status".

Pre-Operative Upper Endoscopy Before Bariatric Surgery

Bennett et al (2016) noted that the necessity of routine pre-operative EGD before bariatric surgery is controversial. These investigators performed a systematic review and meta-analysis to determine the proportion and scope of clinical findings discovered at pre-operative EGD.  They performed a search of Medline, Embase, and Cochrane databases included MeSH terms "bariatric surgery", "endoscopy", and "preoperative".  Inclusion criteria were any case series, cohort study, or clinical trial describing results of pre-operative EGD for any bariatric surgery.  Exclusion criteria were studies with less than 10 patients, patients less than 18 years of age, or revisional operations.  Changes in surgical and medical management and proportions of pathologic findings were extracted and combined in a meta-analysis using the random effects model.  Initial search identified 532 citations; 48 were included after full text review.  Included studies comprised 12,261 patients with a mean (SD) age of 40.5 (1.3) years and BMI of 46.3 (1.5) kg/m2.  The majority of patients (77.1 %) were female.  The proportion of EGDs resulting in a change in surgical management was 7.8 %.  After removing benign findings with controversial impact on management (hiatal hernia, gastritis, peptic ulcer), this was found to be 0.4 %. Changes in medical management were seen in 27.5 %, but after eliminating H. pylori eradication, this was found to be 2.5 %.  The authors concluded that pre-operative EGD in average-risk, asymptomatic bariatric surgery patients should be considered optional, as the proportion of EGDs that resulted in important changes in management was low.

Parikh et al (2016) stated that there is debate regarding pre-operative EGD in patients undergoing bariatric surgery. Some centers perform EGD routinely in all patients; others perform EGD selectively.  These investigators performed a systematic review and meta-analysis of the existing literature to estimate how frequently pre-operative EGD changes management.  The review yielded 28 studies encompassing 6,616 patients.  Baseline characteristics including age and BMI were included.  Patients were grouped based on EGD findings into 2 groups: Group 1 – findings that did not significantly change management (e.g., mild/moderate duodenitis, Grade A/B esophagitis, mild/moderate gastritis, H. pylori infection, hiatal hernia less than 2 cm); and Group 2 – findings that delayed, altered, or cancelled surgery (e.g., severe duodenitis, Grade C/D esophagitis, gastric varices, hiatal hernia greater than 2 cm, mass/carcinoma).  A general estimating equation (GEE) model accounting for the correlated data within each study was used to calculate confidence intervals (Cis) around the estimate of how frequently surgery was delayed or altered.  Mean age was 41.4 ± 2.9 years, the majority was women, and mean pre-operative BMI was 47 ± 3.2 kg/m2.  Overall, 92.4 % (n = 6,112) had a normal EGD or findings that did not change clinical management and 7.6 % (n = 504) (95 % confidence interval [CI]: 4.6 to 12.4 %) had findings that delayed/altered surgery.  The revised estimate was 20.6 %; 95 % CI: 14.5 to 28.2 %] if all esophagitis (regardless of grade) were categorized into Group 2.  The approximate incidence of BE and carcinoma were 0.1 and 0.08 %, respectively.  The authors concluded that a selective approach to pre-operative EGD may be considered, based on the patients' symptoms, risk factors, and type of procedure planned.

Endoscopic Functional Luminal Imaging Probe (EndoFLIP) (Impedance Planimetry)

According to Michigan Health Lab, endoluminal functional lumen imaging probe (EndoFLIP; Crospon Ltd, Galway, Ireland) is a new, minimally invasive device created to complement traditional diagnostic tests, such as high resolution esophageal manometry and barium esophagram.  EndoFLIP uses a balloon mounted on a thin catheter placed trans-orally at the time of a sedated endoscopy.  In comparison to the traditional diagnostic tests, EndoFLIP offers the additional capability of measuring the cross-sectional area (CSA) and intra-luminal pressure of the esophagus while under distension (as if a solid bolus was present).  The technology uses impedance planimetry to estimate CSA. 

Familiari et al (2014) noted that per-oral endoscopic myotomy (POEM) has been recently introduced in clinical practice for the treatment of achalasia.  The EndoFLIP) system uses impedance planimetry for the real-time measurement of the diameter of the EGJ.  These researchers prospectively evaluated the effect of POEM on the EGJ using EndoFLIP.  All the patients who underwent POEM in a single center between April and July 2013 were enrolled in the study.  EndoFLIP was used intra-operatively, immediately before and after POEM.  During follow-up, patients underwent esophagogastroduodenoscopy, esophageal pH monitoring and manometry.  Clinical outcomes were compared with the diameter of the EGJ after POEM.  A total of 23 patients (12 men, mean age of 51.7 years) were enrolled, and 21 underwent POEM successfully.  Pre-operative mean basal lower esophageal sphincter pressure was 42.1 mmHg (± 17.6).  Before POEM, the mean EGJ diameter and CSA were 6.3 mm (± 1.8) and 32.9 mm2 (± 23.1), respectively.  After treatment, the mean diameter and CSA of the EGJ were 11.3 mm (± 1.7 SD) and 102.38 mm2 (± 28.2 SD), respectively.  No complications occurred during a mean follow-up of 5 months.  Median post-operative Eckardt score was 1; 3 patients (14.3 %) reported heartburn.  Follow-up studies revealed GERD in 57.1 % of patients and esophagitis in 33.3 %.  No correlations were observed between the diameter of EGJ after POEM and symptoms relief, GERD incidence and lower esophageal sphincter pressure.  The authors concluded that the diameter of EGJ substantially increased after POEM.  They stated that EndoFLIP is a reliable method for the intra-operative evaluation of EGJ diameter; however, the real usefulness of this technology after POEM remains controversial.  The authors stated that additional studies with follow-up are needed to evaluate the true utility of this system during POEM.

Malik et al (2015) stated that pyloric dysfunction has been associated with gastroparesis, especially diabetic gastroparesis.  EndoFLIP uses 16 sensors inside a balloon that is inflated inside a sphincter to evaluate physiologic characteristics.  These researchers measured the pressure, diameter, CSA, and distensibility of the pylorus using EndoFLIP in patients with gastroparesis.  In addition, the relationship between pyloric pathophysiology with gastroparesis etiology, symptoms, and gastric emptying was assessed.  EndoFLIP was performed in 54 patients (39 idiopathic gastroparesis, 15 diabetic gastroparesis).  The EndoFLIP catheter was passed endoscopically so that the balloon straddled the pylorus.  Pressure, diameter, CSA, and distensibility of the pylorus were measured at 20, 30, 40, and 50 cc balloon volume.  Pyloric sphincter contour was seen best at 40 cc balloon distension (diameter 12.2 ± 0.44 mm, CSA 125.2 ± 9.15 mm(2), pressure 18.0 ± 1.23 mmHg, length 1.59 ± 0.34 cm, distensibility 10.7 ± 2.57 mm(2)/mmHg).  There was a wide range seen in diameter (5.6 to 22.1 mm) and distensibility (1 to 55 mm(2)/mmHg) of the pylorus.  Symptoms of early satiety and post-prandial fullness were inversely correlated with pyloric sphincter diameter and CSA.  No significant difference was seen between diabetic and idiopathic gastroparetics.  The authors concluded that EndoFLIP is a novel technique that can be used to assess pyloric physiologic characteristics.  Early satiety and post-prandial fullness were inversely correlated with diameter and CSA of the pyloric sphincter.  No significant differences were seen comparing diabetic and idiopathic gastroparetics.  They stated that this technology may be of benefit to help select patients with pyloric sphincter abnormalities.

Smeets et al (2015) examined the value of the EndoFLIP technique in GERD patients treated by transoral incisionless fundoplication (TIF).  A total of 42 GERD patients underwent EGJ distensibility measurement before TIF using the EndoFLIP technique.  In a subgroup of 25 patients, EndoFLIP measurement was repeated both post-operative and at 6 months follow-up.  Treatment outcome was assessed according to esophageal acid exposure time (AET; objective outcome) and symptom scores (clinical outcome) 6 months after TIF.  Multiple logistic regression analysis showed that pre-operative EGJ distensibility (odds ratio [OR], 0.16; 95 % CI: 0.03 to 0.78; p = 0.023) and pre-operative AET (OR, 0.62; 95 % CI: 0.42 to 0.90; p = 0.013) were independent predictors for objective treatment outcome but not for clinical outcome after TIF.  The best cut-off value for objective outcome was 2.3 mm(2)/mmHg for pre-operative EGJ distensibility and 11 % for pre-operative AET; EGJ distensibility decreased direct post-operative from 2.0 (1.2 to 3.3) to 1.4 (1.0 to 2.2) mm(2)/mmHg (p = 0.014), but increased to 2.2 (1.5 to 3.0) at 6 months follow-up (p = 0.925, compared to pre-operative).  The authors concluded that pre-operative EGJ distensibility and pre-operative AET were independent predictors for objective treatment outcome but not for clinical outcome after TIF.  They stated that according to these findings, the EndoFLIP technique has no added value either in the pre-operative diagnostic work-up or in the post-procedure evaluation of endoluminal anti-reflux therapy.

Pitt et al (2017) noted that the EndoFLIP can be used to evaluate dimensions and distensibility of the upper and lower esophageal sphincter.  The null hypotheses for this study were that EndoFLIP variables would be stable between anesthetic episodes and would not be affected by body position when evaluating the upper and lower esophageal sphincters in healthy dogs.  During each of 3 consecutive general anesthesia episodes administered to 8 healthy adult research colony dogs with a standardized protocol, the EndoFLIP catheter was positioned to measure CSA, intra-bag pressure, upper and lower esophageal sphincter length at 2 different balloon fill volumes (30 and 40 ml) and 2 body positions (lateral and dorsal recumbency).  From these measured variables, a DI was also calculated.  Mixed effect analysis of variance was used to evaluate the fixed marginal and interaction effects of anesthesia episode, body position, and balloon volume on measured and calculated variables.  For the upper esophageal sphincter significant interactions were present between anesthetic episode and body position for all variables except intra-bag pressure; adjusting for body position significant differences were present between anesthetic episodes for all variables except DI; adjusting for anesthetic episode CSA, intra-bag pressure, upper esophageal sphincter length and DI were all affected by body position.  For the lower esophageal sphincter DI was the only variable where a significant interaction between anesthesia episode and body position occurred; CSA, intra-bag pressure, and lower esophageal length were not significantly affected by anesthesia episode when adjusting for body position; DI was the only variable significantly affected by body position.  Measurements of the geometry of the lower esophageal sphincter as measured by the EndoFLIP device were consistent under conditions of general anesthesia.  Similar measurements taken at the upper esophageal sphincter displayed greater variability between anesthetic episodes and were affected to a greater extent by body position.  The authors concluded that body position should be standardized in studies using the EndoFLIP to assess geometric and functional characteristics of the upper and lower esophageal sphincters.

Ata-Lawenko and Lee (2017) stated that gastro-intestinal sphincters play a vital role in gut function and motility by separating the gut into functional segments.  Traditionally, function of sphincters including the EGJ is studied using endoscopy and manometry.  However, due to its dynamic biomechanical properties, data on distensibility and compliance may provide a more accurate representation of the sphincter function.  The EndoFLIP system can provide data on tissue distensibility and geometric changes in the sphincter as measured through resistance to volumetric distention with real-time images.  With the advent of EndoFLIP studies, EGJ dysfunction and other disorders of the stomach and bowels may be better evaluated.  It may be utilized as a tool in predicting effectiveness of endoscopic and surgical treatments as well as patient outcomes. 

Wu and colleagues (2017) noted that chemoradiotherapy for head and neck cancer (HNC) with/without laryngectomy commonly causes dysphagia.  Pharyngo-esophageal junction (PEJ) stricturing is an important contributor.  These researchers examined the EndoFLIP system as a tool for quantitating pre-treatment PEJ distensibility and treatment-related changes in HNC survivors with dysphagia and assessed the diagnostic accuracy of EndoFLIP-derived distensibility in detecting PEJ strictures.  These investigators studied 34 consecutive HNC survivors with long-term (greater than 12 months) dysphagia who underwent endoscopic dilation for suspected strictures; 20 non-dysphagic patients undergoing routine endoscopy served as controls; PEJ distensibility was measured at endoscopy with the EndoFLIP system pre- and post-dilation.  PEJ stricture was defined as the presence of a mucosal tear post-dilation.  PEJ stricture was confirmed in 22/34 HNC patients (65 %).  During distension up to 60 mmHg, the mean EndoFLIP-derived narrowest CSA (nCSA) in HNC patients with strictures, without strictures, and in controls were 58 mm2 (95 % CI: 22 to 118), 195 mm2 (95 % CI: 129 to 334), and 227 mm2 (95 % CI: 168 to 316), respectively.  A cut-off of 114 mm2 for the nCSA at the PEJ had perfect diagnostic accuracy in detecting strictures (area under the receiver operating characteristic curve = 1).  In patients with strictures, a single session of dilation increased the nCSA by 29 mm2 (95 % CI: 20 to 37; p  < 0.001).  In patients with no strictures, dilation caused no change in the nCSA (mean difference of 13 mm2 [95 % CI: -4 to 30]; p  = 0.13).  The authors concluded that EndoFLIP is a highly accurate technique for the detection of PEJ strictures.  They stated that EndoFLIP may complement conventional diagnostic tools in the detection of pharyngeal outflow obstruction.

Commenting on "the AGA Clinical Practice Update: Using FLIP to assess upper GI tract", Chitnis (2017) states that this approach is still in "murky territory – review authors concluded that more study still needs to be done to ascertain exactly what FLIP is capable of and when it can be used to greatest effect.  In addition to evaluating its benefit in patients with GERD, research should focus on how to make data obtained via FLIP easier to interpret and put to use". 

Furthermore, there is a clinic trial – "EndoFLIP Use in Upper GI Tract Stenosis (EndoFLIP)" – that is currently recruiting subjects (last verified January 2017).

Kim and colleagues (2018) noted that EndoFLIP can provide real time information about characteristics of the gastro-esophageal junction.  These investigators performed retrospective analysis of prospectively collected data on the use of EndoFLIP during minimally invasive hiatal hernia repair to tailor the size of the crural closure and size of the fundoplication.  They then examined if it provided good reflux control without significant dysphagia.  A total of 40 patients underwent minimally invasive hiatal hernia repair with fundoplication.  After fundoplication, the average minimal diameter (Dmin) decreased to 5.97 ± 0.6 from 8.92 ± 1.93 mm, and distensibility index decreased to 1.26 ± 0.38 from 2.88 ± 1.55 mm/mm Hg (p < 0.0001).  After 1 month, none of the patients had reflux or significant dysphagia.  The authors concluded that EndoFLIP could be used to tailor fundoplication with good functional outcome.  Moreover, they stated that further studies are needed to understand the long-term consequences of tailored fundoplication.

Saadi and associates (2018) stated that pyloric sphincter abnormalities may be detected in gastroparesis.  Botulinum toxin A (BoNT/A) injection into the pylorus has been used to treat gastroparesis with varying results.  These investigators examined if pyloric sphincter characteristics using the EndoFLIP with impedance planimetry in patients with gastroparesis correlated with symptoms, gastric emptying, and therapeutic response to pyloric sphincter BoNT/A injection.  EndoFLIP study was performed on patients undergoing gastroparesis treatment with BoNT/A.  The gastroparesis cardinal symptom index (GCSI) was applied prior to treatment and at post-treatment weeks 2, 4, 8, and 12.  A total of 44 patients were enrolled (30 with idiopathic gastroparesis, 14 with diabetic gastroparesis).  Smaller pyloric diameter, CSA, and distensibility correlated with worse vomiting and retching severity at baseline.  Greater gastric retention tended to correlate with decreased CSA and pyloric distensibility.  BoNT/A treatment resulted in a significant decrease in the GCSI score at 2 and 4 weeks after treatment, but not at post-treatment weeks 8 or 12.  Nausea, early satiety, post-prandial fullness, and upper abdominal pain improved up to 12 weeks, whereas loss of appetite, stomach fullness, and stomach visibly larger improved only up to 4 weeks.  Retching and vomiting failed to improve.  Greater pyloric compliance at baseline correlated with greater improvement in early satiety and nausea at 8 weeks and greater pyloric distensibility correlated with improvement in upper abdominal pain.  The authors concluded that EndoFLIP characteristics of the pylorus provided important pathophysiologic information in patients with gastroparesis, in relation to symptoms, gastric emptying, and predicting the response to treatment directed at the pylorus.  The main drawbacks of this study were its relative small sample size (n = 44) with mixed types of gastroparesis as well as short-term follow-up (maximum of 12 weeks).

Ng and colleagues (2020) stated that pediatric esophageal stenosis can be challenging to manage due to post-dilation tissue response involving fibroblast activity resulting in scar reformation. The FLIP uses high-resolution impedance planimetry to measure key luminal parameters during a volume-controlled distension.  In a retrospective chart review, these researchers examined the safety as well as possible settings of EndoFLIP and EsoFLIP in the pediatric population.  They reviewed patients that had EndoFLIP (with and without balloon dilation) or EsoFLIP performed between July 2017 and May 2018.  A total of 18 patients were identified and 19 FLIP procedures were performed during EGD (10 EndoFLIP, 6 EndoFLIP + traditional balloon dilation, 3 EsoFLIP).  Median age for the population was 13.7 years.  Dysphagia was the most common chief complaint prior to endoscopic intervention.  EndoFLIP measurements were most commonly taken at 20 ml and/or 30 ml of infusion.  Diameter, compliance, CSA, and distensibility index were similar between infusion volumes.  Median procedure time of the EndoFLIP + traditional balloon dilation group was longer (60.5 mins) than the median procedure time of the EsoFLIP group (35 mins, p = 0.12).  Median fluoroscopy time of the EndoFLIP + traditional balloon dilation group was 0.6 min and the median fluoroscopy time of the EsoFLIP group was 0.5 min (p = 0.79).  EndoFLIP + traditional balloon dilation was associated with a smaller diameter increase compared to EsoFLIP (2.2 mm versus 4 mm; p = 0.09).  There were no complications.  The authors concluded that FLIP could safely provide important luminal measurements in pediatric patients with esophageal stenosis, and may guide therapy.  These researchers stated that esophageal dilation using EsoFLIP may yield a larger diameter change and may potentially reduce procedure time when compared to traditional balloon dilation.  These preliminary findings need to be validated by well-designed studies.

Carlson and associates (2019) FLIP panometry provides a comprehensive evaluation of esophageal functional at the time of endoscopy, including assessment of esophageal distensibility and distension-induced esophageal contractility.  However, the few and inconsistent findings from healthy individuals pose challenges to the application of FLIP to research and clinical practice.  These investigators performed FLIP panometry in asymptomatic volunteers.  They carried out a prospective study of 20 asymptomatic volunteers (aged 23 to 44 years; 14 women) who were evaluated with 16-cm FLIP positioned across the EGJ and distal esophagus (and in 8 subjects also repositioned at the proximal esophagus) during sedated upper endoscopy.  FLIP data were analyzed with a customized program that generated FLIP panometry plots and calculated the EGJ-DI and distensibility plateaus (DP) of distal and proximal esophageal body.  Distension-induced esophageal contractility was also assessed.  The median EGJ-DI was 5.8 mm2/mm Hg (interquartile range [IQR], 4.9 to 6.7 mm2/mm Hg); all 20 subjects had an EGJ-DI greater than 2.8 mm2/mm Hg.  The median DP values from all subjects tested were 20.2 mm (IQR, 19.8 to 20.8 mm) at the distal body, 21.1 mm (IQR, 20.3 to 22.9 mm) at the proximal body, and greater than 18 mm at both locations.  Repetitive antegrade contractions (RACs) were observed in all 20 subjects; in 19 of 20 (95 %) subjects, the RAC pattern persisted for 10 or more consecutive antegrade contractions.  The authors concluded that normal parameters of FLIP panometry were EGJ-DI greater than 2.8 mm2/mm Hg, DP greater than 18 mm, and antegrade contractions that occurred in a repetitive pattern (RACs); these could be used as normal findings for esophageal distensibility and distension-induced contractility.  These values could be used in comparative studies of esophageal diseases, such as achalasia and eosinophilic esophagitis, and would facilitate application of FLIP panometry to clinical practice.  Moreover, these researchers stated that although future studies evaluating esophageal disease states are still needed to further validate the clinical utility of esophageal distensibility and distension-induced motility evaluation, these values enhance the normative reference to aid application of FLIP panometry in scientific and clinical evaluation of esophageal disease.

The authors stated that this study had several drawbacks.  Effects on esophageal motility associated with opiates and benzodiazepines have been reported, thus concerns have been voiced regarding the potential effects of sedating agents on the esophageal motility impression when assessed at the time of sedated endoscopy.  By evaluating this asymptomatic cohort with FLIP panometry during conscious sedation, these data supported that these FLIP findings were associated with normal manometry and would serve as a reliable reference for patients studied under similar conditions.  Although these investigators have not observed significant differences in FLIP parameters among clinical FLIP studies performed using propofol, further study is needed to clarify the potential effects of sedating agents.  The generalizability of these findings may be limited by the sample size (although the consistency of results within this cohort was reassuring), as well as by the relatively young age and low BMI of this cohort.  The generalizability of this FLIP panometry analysis techniques with the reliance on customized MATLAB software also may pose a limitation.  However, broader application may be facilitated by the recent commercial availability of the real-time FLIP topography display (Medtronic, Inc.), especially through its depiction of the contractile response to distension.  Application to clinical practice hopefully will be improved further by incorporation of the authors’ paradigms into analysis software associated with this evolving technology.

Vosoughi and colleagues (2020) stated that EndoFLIP is an imaging tool that measures the physiologic characteristics of GI sphincters.  These investigators used EndoFLIP to examine the association between the pyloric physiologic measurements and the clinical outcomes of gastric POEM (G-POEM) in patients with refractory gastroparesis.  A total of 37 patients from 5 centers who underwent G-POEM for management of refractory gastroparesis and had EndoFLIP measurements were evaluated; CSA, balloon pressure, and the DI of the pylorus were evaluated by EndoFLIP at 40 ml and 50 ml balloon fills before and after G-POEM.  One-year clinical success and change in gastric emptying study 3 months after the G-POEM procedure were compared with the EndoFLIP measurements.  Clinical success was achieved in 26 (70 %) patients.  Post-G-POEM CSA and DI were significantly higher in the clinical success group with both 40-ml volume distension (CSA: 89.9 ± 64.8 versus 172.5 ± 71.9 mm2, p = 0.003; DI: 5.8 ± 4.4 versus 8.8 ± 6.1 mm2/mm Hg, p = 0.043) and 50-ml volume distention (CSA: 140.1 ± 89.9 versus 237.5 ± 80.3 mm2, p = 0.003; DI: 5.6 ± 3.3 versus 9.9 ± 6.6 mm2/mm Hg, p = 0.049).  CSA using 40-ml volume distention with an area under the curve (AUC) of 0.83 yielded a specificity of 91 % and a sensitivity of 71 % at a cut-off point of 154 mm2.  The authors concluded that post-G-POEM CSA of the pylorus was associated with clinical success and improvement in a gastric emptying scan after G-POEM.  These researchers stated that EndoFLIP measurements of the pylorus have the potential to be used as a tool to predict the clinical outcome of G-POEM.

Holmstrom and associates (2021) examined if the intra-operative measurement of DI using FLIP was associated with improved clinical outcomes following POEM for achalasia when compared with procedures in which FLIP was not utilized.  Patients undergoing POEM from 2012 to 2017 at a single institution by a single surgeon were studied.  Use of FLIP during this time period was based on catheter and technician availability, resulting in 2 patient cohorts.  In patients in whom FLIP was used, operative video recordings were reviewed to determine when DI measurements led to the performance of additional myotomy.  Post-operative Eckardt symptom scores (ES) at 12 months and post-operative physiologic studies were compared between patients with and without intra-operative FLIP.  Associations were assessed using Mann-Whitney U and Chi-square tests.  A total of 143 patients were included in the analysis (61 with intra-operative FLIP and 82 without FLIP).  Video recordings were available for 85 % of the FLIP cohort.  Review of these operative recordings showed that 65 % of patients who underwent FLIP had additional myotomy performed following the initial post-myotomy FLIP measurement.  At 12 months after POEM, the FLIP cohort had significantly more clinical successes (defined as ES of less than or equal to 3) than patients in whom FLIP was not used (93 % versus 81 %, p < 0.05).  The authors concluded that the use of intra-operative FLIP during POEM resulted in the surgeon performing additional myotomy in over 50 % of cases and was associated with improved clinical outcomes.  This study demonstrated the potential for a FLIP-tailored myotomy to improve outcomes in patients undergoing surgical myotomy for achalasia.

Bianca and co-workers (2020) noted that the FLIP system is an Food and Drug Administration (FDA)-approved tool for dynamic evaluation of the EGJ.  Even though commercially available since 2009, FLIP utilization remains low, partly due to lack of consensus in methodology and interpretation.  In a single-center study, these researchers analyzed the influence of concurrent endoscopy on FLIP measurements.  They reviewed data from 93 patients undergoing FLIP for symptomatic esophageal motility disorders between 2016 and 2018.  During sedated endoscopy, these investigators measured luminal values (distensibility, CSA, and balloon pressure) at the EGJ and distal esophagus using 30-, 40-, and 50-ml distension volumes, with and without concurrent endoscope presence.  All recorded values were compared at the various distension volumes between the 2 measurements using a Wilcoxon rank sum test.  There was a significant difference in distensibility and CSA with index distension volume (40 ml) at the EGJ comparing the 2 measurements: Lower median distensibility was 2.1 mm2 mm Hg-1 in the group with concurrent inserted endoscope, respectively, 3.4 mm2 mm Hg-1 without endoscope (p < 0.001), and median CSA was 86.0 resp. 110.0 mm2 (p < 0.001).  No significant difference could be found in the measurements of the distal esophagus.  The authors concluded that these findings showed a significant difference in FLIP measurements with and without endoscope presence.  This underlined the importance of establishing a consensus of a standardized FLIP protocol to define normal luminal values and guiding future FLIP diagnostic studies.

EndoFLIP (Impedance Planimetry) for Achalasia

Carlson and colleagues (2021) noted that achalasia subtypes on high-resolution manometry (HRM) prognosticate therapeutic response and aid in directing management plan.  In a retrospective study, these researchers used parameters of distension-induced contractility and pressurization on FLIP panometry and machine learning to predict HRM achalasia subtypes.  A total of 108 adult patients with treatment-naïve achalasia defined by HRM per Chicago Classification (40 type I, 99 type II, 41 type III achalasia) who underwent FLIP panometry were included: 140 patients were used as the training cohort and 40 patients as the test cohort.  FLIP panometry studies performed with 16-cm FLIP assemblies were analyzed to evaluate distensive pressure and distension-induced esophageal contractility.  Correlation analysis, single tree, and random forest were adopted to develop classification trees to identify achalasia subtypes.  Intra-balloon pressure at 60-ml fill volume, and proportions of patients with absent contractile response, repetitive retrograde contractile pattern, occluding contractions, sustained occluding contractions (SOC), contraction-associated pressure changes of greater than 10 mm Hg all differed between HRM achalasia subtypes and were used to build the decision tree-based classification model.  The model identified spastic (type III) versus non-spastic (types I and II) achalasia with 90 % and 78 % accuracy in the train and test cohorts, respectively.  Achalasia subtypes I, II, and III were identified with 71 % and 55 % accuracy in the train and test cohorts, respectively.  The authors concluded that using a supervised machine learning process, a preliminary model was developed that distinguished type III achalasia from non-spastic achalasia with FLIP panometry.  Moreover, these researchers stated that further refinement of the measurements and more experience (data) may improve its ability for clinically relevant application.

EndoFLIP (Impedance Planimetry) for Gastro-Esophageal Reflux Disease

Lee and colleagues (2021) examined the usefulness of EndoFLIP for the diagnosis of GERD compared to normal controls.  These researchers analyzed EndoFLIP data from 204 patients with erosive reflux disease (ERD), 310 patients with non-ERD (NERD), and 277 normal subjects.  EndoFLIP uses impedance planimetry to measure 16 CSAs in conjunction with the corresponding intra-bag pressure within a 4.6-cm cylindrical segment of a fluid-filled bag.  The EGJ distensibility was assessed using 40-ml volume-controlled distensions.  The mean DI values were 13.98 mm2/mm Hg in ERD patients, 11.42 mm2/mm Hg in NERD patients, and 9.1 mm2/mm Hg in normal subjects.  There were significant differences in EGJ distensibility among the 3 groups (p < 0.001).  Furthermore, the CSAs were significantly higher in the ERD (291.03 ± 160.77 mm2) and NERD groups (285.87 ± 155.47 mm2) than in the control group (249.78 ± 144.76 mm2, p = 0.004).  These investigators determined the DI cut-off value of EGJ as 10.95 for the diagnosis of GERD by receiver operating characteristic curve (ROC) analysis.  The authors concluded that the EGJ distensibilities of GERD patients were higher than those of normal subjects, regardless of the presence of reflux esophagitis; therefore, the measurement of EGJ distensibility using the EndoFLIP system could be useful in the diagnosis of GERD.

The authors stated that this study had several drawbacks.  First, these researchers did not examine the presence of hiatal hernias, which could alter the pressure when the low esophageal sphincter (LES) enters the thorax.  It is important to control for the presence of hiatal hernias when measuring the DI among the groups.  However, hiatal hernias were difficult to objectify via endoscopic reviews.  Second, these investigators divided patients into ERD and NERD groups based on typical reflux symptoms that responded to proton pump inhibitors (PPIs) as in the previous study.  By this definition, the NERD group could include reflux hypersensitivity.  In this study, the mean values of the DeMeester score of the ERD and NERD groups was less than 14.7 points.  The authors inferred that defining GERD patients based on symptoms might lead to false positive patients, whereas the DeMeester score can lead to highly false negative patients considering that the sensitivity of pH monitoring is 70 % to 80 %.  When diagnosing based on symptoms, some GERD patients showed a low DeMeester score.  Therefore, in this study, ERD group was defined according to typical reflux symptoms and endoscopic findings, and NERD was defined according to typical reflux symptoms, endoscopic findings and response to PPI.  Control group was defined according to non-specific abdominal symptoms, endoscopic findings and pH monitoring.  The classification of ERD, NERD, and control group in this study may be confusing.  Third, there was a relatively large variability among the patients, and, despite repeating the measurements 3 times, the real-time recording may have led to variation during intra-procedural changes.  However, since a significant difference was observed between the controls and the patients with GERD, these researchers concluded that EndoFLIP could provide additional information via the measurement of EGJ function.  Fourth, in this study, these investigators only used a 40-ml volume-controlled distension.  Although there is no established volume distension during the EndoFLIP procedure, 30-ml and 40-ml volumes appeared to be the most clinically relevant based on previously published data.  However, in this study, these researchers standardized the volume to 40 ml and measured the parameters in a 40-ml volume distension, which may serve to reduce the bias among the study groups.

EndoFLIP (Impedance Planimetry) for Prediction of Clinical Response to Flexible Endoscopy in Zenker's Diverticulotomy

Sondhi and colleagues (2021) noted that various techniques have been described for flexible endoscopic therapy for Zenker's diverticulum (ZD); however, objective methods to evaluate the effectiveness of myotomy are lacking.  In a single-center, pilot study, these researchers examined the use of impedance planimetry in flexible endoscopic ZD therapies and correlation with a validated symptom score.  Patients undergoing endoscopic therapy for symptomatic ZD from February 2019 to March 2020 were included.  Intra-procedural impedance planimetry was carried out pre- and post-myotomy to evaluate esophageal diameter and DI.  Eating Assessment Tool (EAT)-10 scores were evaluated pre-intervention and post-intervention.  Descriptive statistics were calculated.  A total of 13 patients (46 % women; mean age of 80 years; 77 % POEM technique) were included.  Technical and clinical success was 100 %.  No adverse events (AEs) occurred.  At 40-ml and 50-ml, the diameter improved (mean of 2.3 mm and 2.6 mm, respectively).  At 40-ml and 50-ml, the DI improved (mean of 1.0 mm2/mmHg and 1.8 mm2/mmHg, respectively).  EAT-10 scores improved by a mean of 15 points.  Mean follow-up was 97 days.  The authors concluded that intra-procedural impedance planimetry may provide objective data to define success for flexible endoscopic ZD.  Moreover, these researchers stated that further research in a larger sample size is needed to corroborate these findings, evaluate for a possible minimum change in impedance planimetry to achieve clinical response, and compare the efficacy of conventional flexible endoscopic cricopharyngeal (CP) myotomy versus the Z-POEM approach.  The authors stated that this pilot study had several drawbacks, including a small sample size (n = 13) from a single tertiary-care institution.  Furthermore, all procedures were carried out by a single endoscopist.  This may limit generalizability.

Zhang and associates (2021) stated that flexible endoscopic cricopharyngeal myotomy (FECM) allows minimally invasive treatment of patients with ZD; however, re-treatment rates are substantial.  These researchers hypothesized that the functional lumen imaging probe (FLIP) may provide insight into ZD pathophysiology and serve as an intra-procedural guide to adequacy of myotomy.  They prospectively evaluated 11 ZD patients undergoing FECM and compared the baseline CP distensibility with 16 control subjects.  Intra-procedural CP distensibility was measured immediately pre- and post-myotomy.  The CP-DI was defined as a ratio of the nCSA and the corresponding intra-bag pressure at 40-ml distension.  Same procedure myotomy extension was performed in a subgroup if threshold distensibility changes were not met.  ZD patients had reduced baseline nCSA and CP-DI compared with control subjects, (169.6 versus 227.5 mm2 [p < 0.001] and 3.8 versus 7.6 mm2/mm Hg [p < 0.001], respectively).  After CP myotomy, both nCSA and CP-DI increased significantly by an average of 74.2 mm2 (95 % CI: 35.1 to 113.3; p = 0.002) and 2.2 mm2/mm Hg (95 % CI: 0.6 to 3.8; p = 0.01), respectively.  In the subgroup with no significant change in CP distensibility after initial myotomy (n = 6), myotomy extension resulted in significant increases in both mean nCSA and CP-DI of 66.6 mm2 (95 % CI: 16.4 to 116.8; p = 0.03) and 1.9 mm2/mm Hg (95 % CI: 0.4 to 3.3; p = 0.015), respectively; and there were no AEs.  The authors concluded that CP distensibility was reduced in ZD patients and was partially reversible by FECM.  An intra-procedural FLIP CP distensibility measurement was safe and sensitive in detecting myotomy-induced changes.  These researchers stated that these findings support using FLIP to optimize FECM outcome; however, further studies are needed to derive precise metrics predictive of clinical response.

Endoscopic Submucosal Dissection (ESD) for the Treatment of Barrett's Esophagus

The American Gastroenterological Association (AGA) clinical practice on “Endoscopic submucosal dissection in the United States” (Draganov et al, 2019) noted the following:

• Endoscopic submucosal dissection (ESD) may be considered in selected patients with BE with the following features: large or bulky area of nodularity, lesions with a high likelihood of superficial submucosal invasion, recurrent dysplasia, endoscopic mucosal resection specimen showing invasive carcinoma with positive margins, equivocal pre-procedural histology, and intra-mucosal carcinoma

The AGA’s updated clinical practice update on “Endoscopic treatment of Barrett's esophagus with dysplasia and/or early cancer” (Sharma et al, 2020) provided the following information:

• Both Barrett's endoscopic therapy (BET) and continued surveillance are reasonable options for the management of BE patients with confirmed and persistent LGD.
• Barrett's endoscopic therapy (BET) is the preferred treatment for BE patients with HGD.
• BET should be preferred over esophagectomy for BE patients with intramucosal esophageal adenocarcinoma (T1a).
• BET is a reasonable alternative to esophagectomy in patients with submucosal esophageal adenocarcinoma (T1b) with low-risk features (less than 500-μm invasion in the submucosa [sm1], good-to-moderate differentiation, and no lymphatic invasion) especially in those who are poor surgical candidates.
• The approach to recurrent disease is similar to that of the initial therapy; visible recurrent nodular lesions require endoscopic resection, whereas flat areas of columnar mucosa in the tubular esophagus can be treated with mucosal ablation.

Han and Sun (2021) noted that ESD has been developed to overcome the limitations of EMR; however, the potential for EMR should not be ignored.  In a systematic review and meta-analysis, these researchers compared the safety and effectiveness of ESD and EMR in the treatment of superficial esophageal carcinoma (SEC).  All relevant articles were retrieved from electronic databases.  The primary outcomes included en bloc resection, curative resection, R0 resection, and local recurrence rates.  Secondary outcomes included procedure time, rates of perforation, bleeding, and post-operative stricture.  Subgroup analyses based on histologic types and lesion sizes were carried out; and a total of 22 studies were included in this analysis.  Overall results showed higher en bloc, curative, and R0 resection rate, and lower recurrence rate in ESD compared with EMR.  ESD was significantly more time-consuming and induced more perforations than EMR procedure.  In subgroup analyses of SCC and BE-associated neoplasia and EAC subtypes, ESD also excelled in en bloc, curative, R0 resection and local recurrence rates.  However, in subgroup analysis stratifying outcomes according to lesion sizes, the superior effect of ESD in en bloc resection, curative resection, and local recurrence rate only manifested when lesion size greater than 2.0 cm.  Overall, ESD appeared to have superior effectiveness and similar safety profiles compared to EMR in treating SCC, BE-associated neoplasia and EAC.  Nevertheless, the selection of ESD or EMR should take lesion size into consideration -- EMR is appropriate when lesion size 1.0 cm or less, EMR and ESD are both applicable for lesion between 1.1 and 2.0 cm, and ESD is preferable for lesions greater than 2.0 cm.

Barret (2022) stated that endoscopic therapy has replaced esophagectomy for the management of early Barrett's neoplasia, allowing for the curative treatment of intra-mucosal adenocarcinoma, dysplastic BE, and the prevention of metachronous recurrences.  The author noted that endoscopic therapy relies on the resection of any visible lesion, suspicious of harboring cancer, followed by the eradication of the residual BE, potentially harboring dysplastic foci.  Currently, EMR using the multi-band mucosectomy technique is the gold standard for the resection of visible lesions; ESD is feasible with comparable complication rates to EMR, but longer procedural times.  It is still limited to EMR failures or suspected submucosal adenocarcinoma.  Eradication of residual BE relies mainly on RFA, with over 90 % effectiveness in expert centers.  Despite initial complete eradication of BE, intestinal metaplasia and dysplasia recur in time, justifying prolonged endoscopic surveillance.  The author concluded that the 1st step of the therapeutic endoscopy for BE is a careful diagnostic evaluation, searching for visible(s) lesion(s).  EMR is the recommended resection technique for visible lesions; and ESD has not demonstrated its superiority on EMR in routine practice.  Endoscopic follow-up after Barrett's eradication therapy is mandatory.

Perez et al (2022) noted that the difference in clinical outcomes following ESD) and EMR for early BE neoplasia remains unclear.  In a retrospective study, these investigators compared the recurrence/residual tissue rates, resection outcomes, and AEs following ESD and EMR for early BE neoplasia.  They included patients who underwent EMR or ESD for BE-associated HGD or T1a EAC at 8 academic hospitals.  These researchers compared demographic, procedural, and histologic characteristics, and follow-up data.  A time-to-event analysis was carried out to examine recurrence/residual disease and a Kaplan-Meier curve was used to compare the groups.  A total of 243 patients (150 EMR; 93 ESD) were included.  EMR had lower en bloc (43 % versus 89 %; p < 0.001) and R0 (56 % versus 73 %; p = 0.01) rates than ESD.  There was no difference in the rates of perforation (0.7 % versus 0; p > 0.99), early bleeding (0.7 % versus 1 %; p > 0.99), delayed bleeding (3.3 % versus 2.1 %; p = 0.71), and stricture (10 % versus 16 %; p = 0.16) between EMR and ESD.  Patients with non-curative resections who underwent further therapy were excluded from the recurrence analysis.  Recurrent/residual disease was 31.4 % [44/140] for EMR and 3.5 % [3/85] for ESD during a median (inter-quartile range [IQR]) follow-up of 15.5 (6.75 to 30) and 8 (2 to 18) months, respectively.  Recurrence-/residual disease-free survival (DFS) was significantly higher in the ESD group.  More patients required additional endoscopic resection procedures to treat recurrent/residual disease after EMR (EMR 24.2 % versus ESD 3.5 %; p < 0.001).  The authors concluded that ESD was safe and resulted in more definitive treatment of early BE neoplasia, with significantly lower recurrence/residual disease rates and less need for repeat endoscopic treatments than with EMR.

The European Society of Gastrointestinal Endoscopy (ESGE)’s updated guideline on “Endoscopic submucosal dissection for superficial gastrointestinal lesions” (Pimentel-Nunes et al, 2022) provided the following:

• For BE-associated lesions, ESGE suggests the use of ESD for lesions suspicious of submucosal invasion (Paris type 0-Is, 0-IIc), for malignant lesions greater than 2.0 cm, and for lesions in scarred/fibrotic areas.

Fibrin Glue for the Prevention of Bleeding After Gastric Endoscopic Submucosal Dissection

In an open-label, multi-center, randomized controlled trial (RCT),  Lee et al (2023) examined the effectiveness of fibrin glue for the prevention of bleeding after ESD in high-risk patients (expected iatrogenic ulcer size of 40 mm or larger, or receiving anti-thrombotic therapy).  This trial was carried out at 4 tertiary medical centers in South Korea between July 1, 2020, and June 22, 2022.  Patients with gastric neoplasm and a high-risk of post-ESD bleeding were enrolled and allocated at 1:1 to a control group (standard ESD) or a fibrin glue group (fibrin glue applied to iatrogenic ulcers after standard ESD).  The primary outcome was overall bleeding events within 4 weeks; and the secondary outcomes were acute bleeding (within 48 hours post-ESD) and delayed bleeding (48 hours to 4 weeks post-ESD).  A total of 254 patients were randomized, and 247 patients were included in the modified intention-to-treat (ITT) population (125 patients in the fibrin glue group and 122 patients in the control group).  Overall bleeding events occurred in 12.0 % (15/125) of the fibrin glue group and 13.1 % (16/122) of the control group (p = 0.791).  Acute bleeding events were significantly less common in the fibrin glue group than in the control group (1/125 versus 7/122, p = 0.034).  Delayed bleeding events occurred in 11.2 % (14/125) in the fibrin glue group and 7.3 % (9/122) in the control group (p = 0.301).  The authors concluded that this RCT failed to show a preventive effect of fibrin glue on overall post-ESD bleeding in high-risk patients; however, the secondary outcomes suggested a potential sealing effect of fibrin glue during the acute period.

Drug-Coated Balloons for the Treatment of Esophageal Strictures

Wang et al (2023) noted that benign esophageal strictures can result in dysphagia and decreased quality of life (QOL).  A novel drug-coated balloon (DCB; ProTractX3 DCB, GIE Medical Inc, Plymouth, MN) for dilation was developed to dilate strictures while concurrently delivering paclitaxel (PTX) to reduce recurrence.  These investigators presented initial pre-clinical histologic and pharmacokinetic (PK) data in addition to first-in-human pilot data.  A total of 39 healthy swine were treated by using 3 different PTX dosing regimens or a bare balloon.  Paclitaxel PK elimination profile in plasma and tissue as well as local tissue responses were evaluated.  A total of 9 adult human subjects were treated and followed-up for up to 2 years with dysphagia scores, safety, and imaging.  In the animal studies, histologic and PK analysis revealed PTX present in treated tissues through 28 days post-procedure, whereas plasma levels were minimal (1 ng/ml at 155 mg total drug dose).  No local or systemic drug toxicity was found.  A total of 9 human subjects with an average initial stricture diameter of 6.4 mm and an average Ogilvie Dysphagia Score of 2.2 were treated.  No major treatment-related AEs were observed.  The re-treatment rate through 2 years was 11 %; 5 subjects completed 2-year follow-up, with an average 2-year Ogilvie Dysphagia Score of 0.  Stricture diameter improved to 19.4 +/- 0.9 mm at 1 year (n = 5).  authors concluded that the animal studies showed that DCB treatment of esophageal mucosa appeared to be safe with PTX still present in tissue after 1 month, but at minimal plasma levels.  Initial results in humans indicated DCB could be safely used with clinically relevant increases in esophageal lumen at 1 year with symptomatic improvement.  Moreover, these researchers stated that a future RCT in a larger population will provide additional information on the safety and effectiveness of the ProTractX3 DCB in the treatment of benign esophageal strictures and is currently enrolling participants.  Primary dilatation of the stricture with the CRE designed ProTract DCB balloon is a future objective but will need to await the results of the randomized study.

The authors stated that the drawbacks of this early-phase clinical study included a small sample size (n = 9 human subjects) and an excessive lost to follow-up rate (unfortunately related to the occurrence of the COVID-19 pandemic).  The lack of a control group made comparison to the broader clinical outcomes after standard dilation difficult; however, patient characteristics in this trial represented a known difficult patient population.  The INGEST Trial was designed as a 1st-in-human study to gain preliminary safety and effectiveness data on a novel device.  PK and histologic data collected in a healthy porcine model provided insight into local tissue response to treatment, although the translation of these findings to human applications remains uncertain.

Ren et al (2024) stated that most patients with benign esophageal stenosis require multiple or even continuous balloon dilation treatments to achieve symptom relief.  In this study, a total of 18 rabbits were used to establish an esophageal benign stenosis model; they were divided into a control group (n = 6), a balloon group (n = 6), and a PTX-coated balloon group (n = 6) to examine the feasibility and effectiveness of PTX-coated balloons for the rabbit esophageal benign stenosis model.  The weight and esophageal diameter were recorded every 2 weeks until 8 weeks post-surgery.  Hematoxylin-eosin staining, Masson's trichrome staining, as well as immunohistochemical staining were carried out for pathological analysis.  Four weeks post-operation, there was a significant difference in weight between the control group and the balloon group (p = 0.01) and between the control group and the PTX-coated balloon group (p = 0.01).  There was a significant difference in the esophageal diameter between the balloon group and the PTX-coated balloon group at 8 weeks post-operation (p = 0.02).  Four weeks post-operation, the degree of inflammatory cell infiltration in the PTX-coated balloon group was significantly lower than that in the control group (p = 0.002) and balloon group (p = 0.001).  The degree of collagen deposition in the PTX-coated balloon group was significantly lower than that in the control group (p = 0.002) and balloon group (p = 0.03).  Eight weeks post-operation, the percentage of cells positive for transforming growth factor-beta (TGF-β) (p < 0.001), the degree of inflammatory cell infiltration (p = 0.02), and the degree of collagen deposition (p = 0.02) in the PTX-coated balloon group were significantly lower than those in the balloon group; thus, PTX-coated balloons may alleviate the local inflammatory response and collagen deposition when used during dilation treatment of benign esophageal stenosis.

The authors stated that this study had several drawbacks.  First, its small sample size (n = 6 in the PTX-coated balloon group) may have affected the significance of the findings; however, these findings could guide further, more detailed research.  Second, the follow-up duration of 8 weeks may not have been enough to observe changes throughout the whole process, as was the case for patients with benign esophageal stenosis.  Third, the mechanism of occurrence and recurrence of benign esophageal strictures was not studied in depth.

A phase-III clinical trial entitled “Paclitaxel Coated Balloon for the Treatment of Chronic Benign Stricture - Esophagus (PATENT-E)” is currently recruiting subjects.  The objective of this trial is to examine the safety and effectiveness of the ProTractX3 DCB for the treatment of benign esophageal strictures (Last updated May 2, 2024).  

Furthermore, an UpToDate review on “Endoscopic interventions for nonmalignant esophageal strictures in adults” (Gelrud and Fang, 2024) does not mention drug-coated balloon as a management / therapeutic option.

Local Injection of Steroid for Prevention of Esophageal Stricture

Sakaguchi et al (2023) noted that post-operative stricture and refractory stricture are severe adverse events (AEs) that occur following expansive esophageal endoscopic submucosal dissection (ESD).  In a retrospective, cohort study, these researchers examined the effectiveness of steroid injection, polyglycolic acid (PGA) shielding, and of additional steroid injection thereafter for the prevention of refractory esophageal stricture.  A total of 816 consecutive cases of esophageal ESD were carried out between 2002 and 2021 at the University of Tokyo Hospital.  After 2013, all patients with a diagnosis of superficial esophageal carcinoma covering over 50 % the esophageal circumference underwent preventive treatment immediately after ESD with either "PGA shielding", "steroid injection", or "steroid injection + PGA shielding".  Additional steroid injection was carried out for high-risk patients after 2019.  The risk of refractory stricture was especially high in the cervical esophagus (OR 24.77, p = 0.002) and after total circumferential resection (OR 894.04, p < 0.001).  "Steroid injection + PGA shielding" was the only method significantly effective in preventing stricture occurrence (OR 0.36; 95 % CI: 0.15 to 0.83, p = 0.012).  This method also lowered the risk of refractory stricture (OR 0.38; 95 % CI: 0.10 to 1.28, p = 0.096); however, additional steroid injection was the only significantly effective method for prevention of refractory stricture (OR 0.42; 95 % CI: 0.14 to 0.98, p = 0.029).  The authors concluded that combining steroid injection and PGA shielding was effective for preventing post-ESD stricture and refractory stricture; additional steroid injection was a viable option for patients at high-risk for refractory stricture.

In a retrospective study, Okimoto et al (2024) examined the use of intensive triamcinolone acetonide (TA) injections following extensive esophageal ESD.  This trial included 27 lesions in 27 consecutive patients who underwent ESD (ulcers encompassing 3/4 or more of the esophageal circumference) and received TA injections without oral steroid administration.  Groups A and B included patients undergoing ESD with and without complete circumferential resection, respectively.  All patients received TA injections (100 mg/session) immediately after ESD.  In Group A, weekly based TA injections were carried out until near-complete ulcer epithelialization.  In Group B, patients did not receive additional injections or received weekly or bi-weekly TA injections.  The primary outcome was stricture rate, and the secondary outcomes were the proportion of patients requiring endoscopic balloon dilation (EBD) and the number of TA injections.  Group A included 7 lesions, and Group B included 20 lesions.  The median (range) tumor lengths were 40 (30 to 90) mm, and 45 (30 to 110) mm in Groups A and B, respectively.  In Group A, the median circumferential resection diameter was 40 (20 to 80) mm.  The stricture rate and the proportion of patients requiring EBD were 0 (0 %) in Group A, and 1 (5.0 %) in Group B.  The number of TA injection sessions was significantly higher in Group A than in Group B (8 [5 to 25] versus 1.5 [1 to 3]; p < 0.001).  The authors concluded that intensive weekly or bi-weekly based TA injections might aid in preventing post-ESD stricture, and the need for EBD in patients undergoing extensive resection entailing the entire esophageal circumference.

In a retrospective study, Martinez Diaz et al (2024) examined the effectiveness of intralesional steroid treatment in refractory caustic esophageal stricture.  This trial included patients (n = 5) receiving intralesional steroid treatment with triamcinolone acetonide as a result of refractory caustic esophageal stricture.  Demographic variables, stricture characteristics, number of dilations, steroid injections, and dilation score (number of dilations/follow-up period in months) pre- and post-treatment were collected.  Stricture characteristics (diameter and length) and dilation score pre- and post-treatment were compared using the T-Test or Wilcoxon test.  Median age of subjects was 5 years (17 months to 7 years).  Follow-up: 6.60 ± 2.70 years.  Swallowed products included NaOH, KOH, and ClH.  Zargar classification at follow-up initiation was IIb (n= 2), IIIa (n= 1), and 2 chronic strictures.  A total of 6.6 ± 9.23 esophageal dilations were carried out before steroid treatment initiation.  The mean number of intralesional therapy sessions was 11.20 ± 6.14.  Stricture length decreased by 3.60 ± 2.63 cm (t = 3.06; p = 0.019).  No differences were found in terms of diameter increase: -1.60 ± 3.58 mm (t = -1.00; p= 0.187).  The dilation score diminished from 1.47 ± 0.86 to 0.47 ± 0.18 dilations per month of follow-up (Z = -2.02; p = 0.043).  The authors concluded that even though there was limited evidence available in the pediatric population, intralesional triamcinolone treatment appeared to be useful in the treatment of refractory caustic esophageal stricture, since it reduced length and dilation score.

Ando et al (2024) noted that there is a high incidence of stricture following ESD for cervical esophageal cancer.  In a retrospective study, these researchers examined the risk factors for stricture and assessed the effectiveness of steroid injection for stricture prevention in the cervical esophagus.  They analyzed 100 patients who underwent ESD for cervical esophageal cancer to identify the factors associated with stricture among patients who did not receive steroid injection; and compare the incidence of stricture between patients with and without steroid injection.  Among 48 patients who did not receive steroid injection, there were significant differences in tumor size (p = 0.026), resection time (p = 0.028), and circumferential extent of the mucosal defect (p = 0.005) between patients with stricture (n = 5) and without stricture (n = 43).  Compared with patients without steroid injection, patients with steroid injection had a significantly lower incidence of stricture when the post-ESD mucosal defect was less than 3/4 and greater than or equal to 1/2 (40 % versus 8 %, p = 0.039).  As for the patients with a post-ESD mucosal defect of greater than or equal to 3/4 (n = 13), local steroid injection was performed for all the patients, and 6 patients (46 %) developed stricture.  The authors concluded that patients who underwent greater than or equal to 1/2 circumferential resection were at high-risk of cervical esophageal stricture.  Steroid injection had a stricture-prevention effect in patients with less than 3/4 and greater than or equal to 1/2 circumferential resection, but appeared to be insufficient in preventing stricture in patients with greater than or equal to 3/4 circumferential resection.

Carpentier et al (2024) stated that extensive esophageal ESDs without preventive measures carry a high risk of stricture.  Oral steroids and local injection of triamcinolone acetonide have proven to be effective in Asia for the prevention of esophageal stricture.  In a retrospective review, these investigators examined the effectiveness of a systematic steroid administration protocol for stricture prevention in a Western center.  This study was performed of all esophageal ESDs performed at H.U.B. Erasme Hospital, Brussels between 2016 and 2022 . Injection of triamcinolone was carried out for mucosal defects between 50 % and 89 % of the circumference.  These researchers added oral corticosteroids for patients with resections of 90 % or more of the circumference.  The primary outcome was the incidence of symptomatic stenosis at 3 months.  Secondary outcomes included the cumulative stricture rate assessed by endoscopy within 6 months of ESD.  Potential risk factors of stricture were evaluated with uni-variate and multi-variate analysis.  A total of 111 patients underwent 130 esophageal ESDs, with 59 patients receiving triamcinolone acetonide local injection and 8 receiving local and oral corticosteroids.  The primary outcome showed a stricture incidence of 8.4 %.  The cumulative stricture rate assessed by endoscopy within 6 months of ESD was 10.4 %.  A mucosal defect of 60 mm of greater in length was associated with a 15-fold increased risk of stricture, with circumferential extent also identified as being an independent prognostic factor for stricture.  The authors concluded that their protocol resulted in a low stricture rate, even after extensive resection.  As a single session treatment without systemic side effects, triamcinolone injection could provide benefits as a preventive method after large esophageal resections.

Furthermore, an UpToDate review on “Endoscopic interventions for nonmalignant esophageal strictures in adults” (Gelrud and Fang, 2024) states that “For initial treatment of refractory nonmalignant esophageal strictures, we typically perform glucocorticoid injection into the stricture and endoscopic dilation during one endoscopic session … Glucocorticoid injection of refractory strictures resulted in lower risk of stricture recurrence and fewer dilation sessions.  In a meta-analysis of 6 trials (most of which were non-blinded) including 176 patients with refractory esophageal strictures, triamcinolone injection plus endoscopic dilation resulted in lower risk of stricture recurrence (risk ratio 0.64, 95 % CI 0.51-0.81) and fewer endoscopic dilation sessions (mean difference -1.06, 95 % CI -1.80 to -0.31) compared with dilation alone.  No significant differences in dysphagia-free intervals or in complication rates were found between the groups”.

References