Case Report Guidelines for Authors

Practical Gastroenterology Case Report Guidelines for Authors

May 2021 • Volume XLV, Issue 5

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• The aim of Case Reports is to provide challenging yet clinically relevant and informative cases to primary care physicians.

• The Case should center around one (1) to three (3) high quality images that are completely described in the report. Images should be endoscopic, pathologic, and/or radiographic (without any patient identifiers) with clear labeling as appropriate.

• The Case must be a concise report submitted as a Word document consisting of no more than 1250 words.

• The images must be submitted as .jpg files separate from the Word document.

• There should be a brief introduction/abstract, relevant presentation of the case, relevant case discussion and conclusion.

• The conclusion should include one or two clinical pearls that the reader may apply to their practice or add to their knowledge set.

• References should be limited to 8. References should follow AMA style and journal names should be abbreviated according to Index Medicus practice. Inclusive page ranges should be indicated.

• Authors should be limited to 3 on each submission. No author photographs are necessary. All authors must provide their names, addresses, phone numbers, complete titles and affiliations.

• Case Reports must not have been published previously. Each Case Report is subject to review by members of our Editorial Board. Case Reports are subject to final editing. Upon publication, Case Reports will be copyrighted by Practical Gastroenterology Publishing, Inc.

• Please submit your Case Report to: Adrien Mahl, Editor Practical Gastroenterology practicalgastro@aol.com

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FRONTIERS IN ENDOSCOPY, SERIES #73

G-POEM: Review and Technical Update

May 2021 • Volume XLV, Issue 5
Gregory Toy,Stephanie McDonough,Douglas G. Adler

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Introduction

Gastroparesis is a chronic debilitating disorder of gastric motility. This disorder is more commonly encountered in women with an age adjusted prevalence per 100,000 persons of 37.8 in women and 9.8 in men.1 Gastroparesis has put an increasing burden on the healthcare system over time with a 300% increase in gastroparesis related hospitalizations reported from 1997 to 2013 with an annual cost of $568 million annually.2 There are many etiologies of gastroparesis but the three most common are diabetic gastroparesis, post-surgical gastroparesis, and idiopathic gastroparesis.3 The pathophysiology of gastroparesis seems to be due to loss of antral contraction and abnormal pyloric movement. One study found abnormally prolonged, high amplitude pyloric contractions, deemed a “pylorospasm.”4 Other histologic studies have shown loss of the interstitial cells of Cajal which are the pacemaker cells controlling smooth muscle contraction.5

Some common symptoms of gastroparesis include postprandial nausea, vomiting, bloating, early satiety, and abdominal pain. Treatment of gastroparesis generally begins with symptomatic management such as dietary changes and the administration of promotility medications. Metoclopramide is a widely used promotility agent but carries a risk of extrapyramidal effects such as tardive dyskinesia especially if used for longer than 12 weeks.6 Other commonly used drugs like domperidone and erythromycin have short term efficacy with the risk of tachyphylaxis.7 About 30% of patients do not respond to conservative management.6

If conservative management fails, treatment options include the injection of botulinum toxin (Botox) around the pylorus, gastro-electrical stimulators (GES), and surgery. There have been mixed results to Botox injection with one case series showing only a 43% clinical response rate while another study showed a 77% response at a higher dose.8,9 GES has also had mixed results with 1-year clinical response rates reported anywhere from 45-74% with only about a quarter of patients having sustained response for 3 years.10 In addition, few centers have experience with placement and management of GES. Laproscopic pyloromyotomy is the most invasive treatment but has shown the best results, improving symptoms in 83-86% of patients and normalizes gastric emptying in 60- 90% of patients. It is limited by the fact that many surgeons are reluctant to operate on the stomach of patients with gastroparesis and the typical adverse effects of surgery such as leaks, bleeding, and wound infections.11

G-poem Technique

Background

A recent development in the treatment of gastroparesis is the gastric peroral endoscopic myotomy procedure (G-POEM) which, as its name suggests, involves using an endoscope rather than surgery to perform a pyloromyotomy. G-POEM is a variation of the standard peroral endoscopic myotomy (POEM) procedure which is performed in the esophagus and used to treat achalasia.6 Challenges to G-POEM include the fact that the submucosal tunnel near the pylorus is curved compared to the straight esophageal tube, there is antral peristalsis causing movement which isn’t encountered in the aperistaltic esophagus, and that it is more difficult to identify the pyloric muscular ring (PMR) compared to the lower esophageal sphincter (LES).

This procedure was first described by Khashab et. al. in 2013 who performed the procedure on a 27 year old woman with diabetic gastroparesis. Twelve weeks after the procedure, she continued to report improvement of symptoms and was able to tolerate a soft diet.12

Prior to undergoing G-POEM, patients are often kept on a clear liquid diet for 2-3 days and nil per os (NPO) for 12 hours prior to the procedure to clear the stomach of retained food, improve visualization during the procedure, and to decrease the risk of procedure related infection.6 Prophylactic intravenous antibiotics are often administered. However, there is no high-quality data regarding the efficacy of these antibiotics nor is there any standardization on the type of antibiotics to be used.6 Common antibiotics that are used include 4.5g of piperacillin/tazobactam or 500mg of levofloxacin.13,14,15

Procedure Steps and Variations

The general steps that are taken in a G-POEM procedure include mucosotomy to enter the submucosal plane, submucosal dissection to create a submucosal tunnel, myotomy, and closure of the mucosal defect.6 Each of these steps have a number of variations.

The initial mucosotomy was traditionally done on the greater curvature since the endoscope would be in a more neutral position with greater maneuverability.6 However, mucosotomy is sometimes performed on the lesser curvature. Advantages to a lesser curvature mucosotomy and approach include a “shorter” scope position and length, shorter length of the submucosal tunnel, less looping of the scope in the stomach, and a non-dependent position which avoids food residue, secretions, and pooling of blood.16

There are also variations in how to identify the PMR. The conventional method is to inject a mixed solution of methylene blue and saline during submucosal tunneling causing the mucosa at and around the pylorus to appear blue. Xue et. al., whose study involved mucosotomy on the greater curvature, carried out a variation of this procedure by placing an endoscopic clip at the 9 to 11 o’clock position of the pylorus and completing the procedure under fluoroscopy. In this study, the clip served as a reference point for the submucosal tunnel entry which occurred at the 6 o’clock position.17 One study found that the PMR was better identified under fluoroscopy and that G-POEM performed with the assistance of fluoroscopy had a shorter procedure time than the conventional method. However, there was no significant difference in outcomes between these two methods.17

Although the length of the mucosal incision can be variable, one example of how this procedure is carried out is by making a mucosal incision 5cm proximal to the PMR and creating a submucosal tunnel to 1cm distal to the PMR. Then, a full thickness myotomy would be completed from a point 2-3cm proximal to the PMR to 0.5-1cm past the duodenal bulb.17,18 The mean myotomy length as reported by 6 studies was 2.7 ± 0.7 cm.19

After completing the myotomy, the mucosa can be closed via endoscopic clips or sutures. One study of 25 patients found successful complete closure in all 15 patients with sutures and 9 of 10 patients with endoclips.20 However, a review of endoscopic techniques among patients undergoing G-POEM recommends that endoscopic clips should be used as first line therapy and sutures should be used if clip closure is unable to be completed.21 Overall, endoscopic clips are widely used in practice. One pooled analysis found that clips were used in 266/285 cases while suturing was only used in 21/285 cases.19

Outcomes

Technical Success

Even though G-POEM can be a challenging procedure, reported technical success rates are high. In a pooled analysis consisting of 10 studies and 292 patients, the technical success rate was 100%.19 A meta-analysis conducted by Meybodi et. al. that included 7 studies and 196 patients also found a technical success rate of 100%.22 There may be a component of publication or reporting bias.6 Although the technical success is around 100%, there is a large range in mean procedural time from 40-120 minutes which possibly can be due to the learning curve for this procedure.6 Notably, procedure time has dropped quite a bit from the 119 ± 23 minutes reported by an early study.3

Symptoms Before and After G-POEM

One measure of clinical success is the Gastroparesis Cardinal Symptom Index (GCSI), which is based on three subscales which evaluate post-prandial fullness/early satiety, nausea/vomiting, and bloating. In a meta-analysis consisting of 10 studies and 281 patients conducted by Uemura et. al, the pooled mean difference in GCSI before and after the procedure was 1.76, which was a significant difference. These GCSI differences were durable. When using the longest follow up period for each study which ranged from 3-18 months, the mean difference in GCSI was 1.84 which was also statistically significant.23 Meybodi et. al. also reported a similar significant difference in GCSI before and after G-POEM of 1.57 in their metaanalysis.22 Of note, one symptom that is not asked about in the GCSI is abdominal pain, although many patients with gastroparesis complain of abdominal pain, especially in the post-prandial setting. Various studies have reported improvement of abdominal pain in 56-73% of patients following G-POEM.6

Gastric Emptying Scans Before and After G-POEM

Another measure of clinical success that is often used is the Gastric Emptying Scan (GES). In the GES 4-h test, a patient will eat a liquid egg white meal with radiolabeled material, and the amount of food left in the stomach after 4 hours will be measured by scintigraphy. Uemura et. al. found that there was a significant 26.28% decrease in retained food between the GES done before and 2-3 months after G-POEM.23 Meybodi et. al found a similar significant decrease of 22.3%.22 When pooling the clinical success rates based on improvement of GCSI scores, Mohan et. al. found a clinical success rate of 75.8% and when pooled by improvement in GES 4-h, the clinical success rate was 85.1%.24

Quality of Life Outcome Measures

Some studies examined improvement in quality of life as measured by the SF-36 form. The SF-36 form is a validated, patient reported survey which reports a patient’s health and quality of life in eight different subsections. One study examining long term outcomes of G-POEM found that at a mean follow up time of 16 months, there was a significant improvement in quality of life as measured by the SF-36.25 Improvement in SF36 scores have been found in 70-78% of patients with significant improvements specifically in the domains of vitality, general health, mental health, and social functioning.6 Additionally, emergency room visits, gastroparesis-related hospitalizations, and anti-emetic medication use were found to be significantly lower post G-POEM as compared to controls.6

Changes in Pyloric Function

Endoscopic functional luminal imaging probe (Endo-FLIP, Medtronic, Minneapolis, USA) technology can give some useful information about patient outcomes following G-POEM. Endo-FLIP can assess pyloric function by measuring the length, pressure, cross sectional area (CSA), and distensibility of the pylorus. Malik et. al. took Endo-FLIP measurements of the pylorus before and after G-POEM. They found that after G-POEM there was increased length, CSA, and distensibility of the pylorus. Along with this, there was decreased average pyloric pressure. However, only the increase in CSA had a statistically significant correlation with better clinical outcomes.3

Adverse Events

The three most common adverse events were GI bleeding (32%), abdominal pain (30%), and pneumoperitoneum (24%) with other adverse events like pulmonary embolism, abscess, and stricture occurring less than 5% of the time.23 GI bleeding is usually controlled with endoscopic intervention or medications like proton pump inhibitors. Mohan et. al. found a pooled adverse event rate of 11% in a meta-analysis consisting of 332 patients in 11 studies.24 Meybodi et. al. found only 12/196 (6.1%) had an adverse event in their meta-analysis.22

Several studies have reported pyloric ulcers at the incision site of the procedure. A causal relationship between the pyloric ulcer and bleeding has been established in some studies but not in others.6 Pneumoperitoneum, on the other hand, is often managed conservatively and resolves on its own. In severe cases, needle decompression can be used for treatment.6 No deaths have been reported due to G-POEM. Two studies of G-POEM have reported patient deaths. However, in both cases, autopsy revealed that the death was not due to the procedure.23

Analysis

Predictors of Clinical Success

With G-POEM being one of many possible interventions for gastroparesis, it becomes useful to know which patients may benefit from the procedure prior to offering it to them. Unfortunately, predictive factors for clinical success are disputed. A 2017 study by Gonzalez et. al. found efficacy rates after 3 months to be 93% for idiopathic gastroparesis, 57% for gastroparesis secondary to diabetes, 80% for post-operative gastroparesis, and 50% for scleroderma-induced gastroparesis. At 6 months, the rates were 92%, 43%, 50%, and 50% respectively. They found that diabetes as the etiology of gastroparesis and female gender were significantly associated with worse outcomes.26 Another study also showed patients with idiopathic and postoperative gastroparesis to have the best response to G-POEM with those with diabetes complicated by advanced macrovascular disease having the worst outcomes.27

On the other hand, Jacques et. al. found favorable outcomes when using Endo-FLIP to analyze diabetic patients after G-POEM.28 Mekaroonkamol et. al. conducted a single center, retrospective study with 25 diabetic and 15 nondiabetic patients and found no significant difference in GSCI scores or degree of improvement between the diabetic and non-diabetic groups. Additionally, within the diabetic group, baseline HbA1c level did not correlate with clinical response.7 This study also investigated whether the duration of the patient’s gastroparesis before G-POEM had any effect on G-POEM outcomes. There was no difference in outcome at the one or six month follow up. However, at the 12 month follow up, it was found that longer duration of disease was associated with worse outcomes as measured by GSCI score.7 Other predictive factors that have been associated with poorer outcomes include higher BMI, history of psychiatric medication use, and history of pain medication use.25 This may be due to the fact that both psychiatric medications and pain medications can often be anticholinergic.

Given the novelty of G-POEM, it has been hypothesized that there is a learning curve involved with the procedure and that operator experience could lead to better outcomes. One study found that it took 18 procedures to reach procedural efficiency, defined as completing the procedure in less than 60 minutes.29 Other studies have investigated the association between provider experience with G-POEM outcomes, but have not shown a clear correlation. One study divided a provider’s first ten cases and the rest of their cases into two groups. Another study divided the first half and second half of cases performed by the same provider. Neither of these studies found any correlation between provider experience and outcomes.7,30

Comparison of G-POEM to other Treatments for Gastroparesis

When compared to GES, G-POEM was associated with a better long term clinical response with a 60% lower risk of clinical recurrence at a median follow up time of 27.7 months. Additionally, G-POEM was more versatile; it is effective in patients with both idiopathic and non-idiopathic causes of gastroparesis while GES was not effective in patients with idiopathic gastroparesis.10

Landreaneau et. al. conducted a study which propensity matched patients undergoing G-POEM with those undergoing laparoscopic pyloroplasty (LP) and found similar clinical efficacy. G-POEM, however, performed better when it came to operative time, length of hospital stay, estimated blood loss and complication rate.31 Mohan et. al. also found similar clinical efficacy between the procedures. In their study, G-POEM was found to have a shorter procedure time, but hospital length of stay was not significantly different between the procedures.24

Conclusion

Management of gastroparesis has been and remains a clinical challenge. A durable cure has long eluded medical providers as medications come with side effects and procedures such as Botox injection and GES placement have less than perfect success rates and do not always produce a sustained response. G-POEM has been introduced as another treatment to refractory gastroparesis which is less invasive than surgery and more effective than the methods listed above. The procedure has many variations but generally involves mucosotomy, submucosal dissection, myotomy, and mucosal closure. Technical success rates have been reported to be 100% across many studies. Patients undergoing G-POEM have also shown significantly improved GCSI, GES 4h, and quality of life scores along with trends towards improvement in EndoFLIP scores. Adverse events have occurred in about 5-10% of patients but are often managed conservatively or with non-invasive interventions. G-POEM performs well when compared to GES and similarly to surgery. However, it does have the advantage of being less invasive and having a shorter procedure time than surgery. With these findings, G-POEM should be a consideration for patients with refractory gastroparesis at any facility with the capabilities to perform this procedure.

References

  1. Bharucha, A. E. (2015). Epidemiology and natural history of gastroparesis. Gastroenterology Clinics, 44(1), 9-19.
  2. Wadhwa, V., Mehta, D., Jobanputra, Y., Lopez, R., Thota, P. N., & Sanaka, M. R. (2017). Healthcare utilization and costs associated with gastroparesis. World journal of gastroenterology, 23(24), 4428.
  3. Malik, Z., Kataria, R., Modayil, R., Ehrlich, A. C., Schey, R., Parkman, H. P., & Stavropoulos, S. N. (2018). Gastric per oral endoscopic myotomy (G-POEM) for the treatment of refractory gastroparesis: early experience. Digestive diseases and sciences, 63(9), 2405-2412.
  4. Mearin, F., Camilleri, M., & Malagelada, J. R. (1986). Pyloric dysfunction in diabetics with recurrent nausea and vomiting. Gastroenterology, 90(6), 1919-1925.
  5. Rodriguez, J. H., Haskins, I. N., Strong, A. T., Plescia, R. L., Allemang, M. T., Butler, R. S., & Kroh, M. D. (2017). Per oral endoscopic pyloromyotomy for refractory gastroparesis: initial results from a single institution. Surgical endoscopy, 31(12), 5381-5388.
  6. Mekaroonkamol, P., Shah, R., & Cai, Q. (2019). Outcomes of per oral endoscopic pyloromyotomy in gastroparesis worldwide. World journal of gastroenterology, 25(8), 909.
  7. Mekaroonkamol, P., Patel, V., Shah, R., Li, B., Luo, H., Shen, S.,& Cai, Q. (2019). Association between duration or etiology of gastroparesis and clinical response after gastric per-oral endoscopic pyloromyotomy. Gastrointestinal endoscopy, 89(5), 969-976.
  8. Bromer, M. Q., Friedenberg, F., Miller, L. S., Fisher, R. S., Swartz, K., & Parkman, H. P. (2005). Endoscopic pyloric injection of botulinum toxin A for the treatment of refractory gastroparesis. Gastrointestinal endoscopy, 61(7), 833-839.
  9. Coleski, R., Anderson, M. A., & Hasler, W. L. (2009). Factors associated with symptom response to pyloric injection of botulinum toxin in a large series of gastroparesis patients. Digestive diseases and sciences, 54(12), 2634-2642.
  10. Shen, S., Luo, H., Vachaparambil, C., Mekaroonkamol, P., Abdelfatah, M. M., Xu, G., & Cai, Q. (2020). Gastric peroral endoscopic pyloromyotomy versus gastric electrical stimulation in the treatment of refractory gastroparesis: a propensity score-matched analysis of long term outcomes. Endoscopy, 52(05), 349-358.
  11. Shada, A. L., Dunst, C. M., Pescarus, R., Speer, E. A., Cassera, M., Reavis, K. M., & Swanstrom, L. L. (2016). Laparoscopic pyloroplasty is a safe and effective firstline surgical therapy for refractory gastroparesis. Surgical endoscopy, 30(4), 1326-1332.
  12. Khashab, M. A., Stein, E., Clarke, J. O., Saxena, P., Kumbhari, V., Roland, B. C., & Inoue, H. (2013). Gastric peroral endoscopic myotomy for refractory gastroparesis: first human endoscopic pyloromyotomy (with video). Gastrointestinal endoscopy, 78(5), 764-768.
  13. Dacha, S., Mekaroonkamol, P., Li, L., Shahnavaz, N., Sakaria, S., Keilin, S., & Cai, Q. (2017). Outcomes and quality-of-life assessment after gastric per-oral endoscopic pyloromyotomy (with video). Gastrointestinal endoscopy, 86(2), 282-289.
  14. Koul, A., Dacha, S., Mekaroonkamol, P., Li, X., Li, L., Shahnavaz, N., & Cai, Q. (2018). Fluoroscopic gastric peroral endoscopic pyloromyotomy (G-POEM) in patients with a failed gastric electrical stimulator. Gastroenterology report, 6(2), 122-126.
  15. Mekaroonkamol, P., Li, L. Y., Dacha, S., Xu, Y., Keilin, S. D., Willingham, F. F., & Cai, Q. (2016). Gastric peroral endoscopic pyloromyotomy (G-POEM) as a salvage therapy for refractory gastroparesis: a case series of different subtypes. Neurogastroenterology & Motility, 28(8), 1272-1277.
  16. Petrov, R. V., Bakhos, C. T., Abbas, A. E., Malik, Z., & Parkman, H. P. (2020). Endoscopic and Surgical Treatments for Gastroparesis: What to Do and Whom to Treat?. Gastroenterology Clinics, 49(3), 539-556.
  17. Xue, H. B., Fan, H. Z., Meng, X. M., Cristofaro, S., Mekaroonkamol, P., Dacha, S., & Cai, Q. (2017). Fluoroscopy-guided gastric peroral endoscopic pyloromyotomy (G-POEM): a more reliable and efficient method for treatment of refractory gastroparesis. Surgical endoscopy, 31(11), 4617-4624.
  18. Xu, J., Chen, T., Elkholy, S., Xu, M., Zhong, Y., Zhang, Y., & Zhou, P. (2018). Gastric peroral endoscopic myotomy (G-POEM) as a treatment for refractory gastroparesis: long-term outcomes. Canadian Journal of Gastroenterology and Hepatology, 2018.
  19. Spadaccini, M., Maselli, R., Chandrasekar, V. T., Anderloni, A., Carrara, S., Galtieri, P. A., & Repici, A. (2020). Gastric peroral endoscopic pyloromyotomy for refractory gastroparesis: a systematic review of early outcomes with pooled analysis. Gastrointestinal endoscopy, 91(4), 746-752.
  20. Hustak, R., Vackova, Z., Krajciova, J., Spicak, J., &Martinek, J. (2020). Endoscopic Clips Versus Endoscopic Suture for Mucosal Closure after Per-Oral Endoscopic Pyloromyotomy: A Prospective Study. Endoscopy, 52(S 01), OP288.
  21. Parsa, N., & Khashab, M. A. (2019). Endoscopic techniques for myotomy of the lower esophageal sphincter and pylorus. Current opinion in gastroenterology, 35(5), 416-423.
  22. Meybodi, M. A., Qumseya, B. J., Shakoor, D., Lobner, K., Vosoughi, K., Ichkhanian, Y., & Khashab, M. A. (2019). Efficacy and feasibility of G-POEM in management of patients with refractory gastroparesis: a systematic review and meta-analysis. Endoscopy international open, 7(3), E322.
  23. Uemura, K. L., Chaves, D., Bernardo, W. M., Uemura, R. S., de Moura, D. T. H., & de Moura, E. G. H. (2020). Peroral endoscopic pyloromyotomy for gastroparesis: a systematic review and meta-analysis. Endoscopy International Open, 8(7), E911.
  24. Mohan, B. P., Chandan, S., Jha, L. K., Khan, S. R., Kotagiri, R., Kassab, L., Adler, D. G. (2020). Clinical efficacy of gastric per-oral endoscopic myotomy (G-POEM) in the treatment of refractory gastroparesis and predictors of outcomes: a systematic review and meta-analysis using surgical pyloroplasty as a comparator group. Surgical endoscopy, 34(8), 3352-3367.
  25. Abdelfatah, M. M., Noll, A., Kapil, N., Shah, R., Li, L., Nustas, R., Cai, Q. (2020). Long-Term Outcome of Gastric Per-Oral Endoscopic Pyloromyotomy in Treatment of Gastroparesis. Clinical Gastroenterology and Hepatology.
  26. Gonzalez, J. M., Benezech, A., Vitton, V., & Barthet, M. (2017). G-POEM with antro-pyloromyotomy for the treatment of refractory gastroparesis: mid-term follow-up and factors predicting outcome. Alimentary pharmacology & therapeutics, 46(3), 364-370.
  27. Rodriguez, J. H., Haskins, I. N., Strong, A. T., Plescia, R. L., Allemang, M. T., Butler, R. S., & Kroh, M. D. (2017). Per oral endoscopic pyloromyotomy for refractory gastroparesis: initial results from a single institution. Surgical endoscopy, 31(12), 5381-5388.
  28. Jacques, J., Pagnon, L., Hure, F., Legros, R., Crepin, S., Fauchais, A. L., & Monteil, J. (2019). Peroral endoscopic pyloromyotomy is efficacious and safe for refractory gastroparesis: prospective trial with assessment of pyloric function. Endoscopy, 51(01), 40-49.
  29. Suresh, S., Tyberg, A., Martínez, M. G., Zamarripa, F., Lambroza, A., Gaidhane, M., & Kahaleh, M. (2018). Su1280 gastric peroral endoscopic myotomy: a specific learning curve. Gastrointestinal Endoscopy, 87(6), AB309-AB310.
  30. Abdelfatah, M. M., Li, B., Kapil, N., Noll, A., Li, L., Luo, H., & Cai, Q. (2020). Short-term outcomes of double versus single pyloromyotomy at peroral endoscopic pyloromyotomy in the treatment of gastroparesis (with video). Gastrointestinal endoscopy, 92(3), 603-609.
  31. Landreneau, J. P., Strong, A. T., El-Hayek, K., Tu, C., Villamere, J., Ponsky, J., Rodriguez, J. H. (2019). Laparoscopic pyloroplasty versus endoscopic per-oral pyloromyotomy for the treatment of gastroparesis. Surgical endoscopy, 33(3), 773-781.

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NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #209

Enteral Nutrition in the Adult Short Bowel Patient: A Potential Path to Central Line Freedom

April 2021 • Volume XLV, Issue 4
Carol Rees Parrish,Andrew P. Copland

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Short bowel syndrome/intestinal failure (SBS/IF) is characterized by patients who have lost absorptive surface area in the gut either due to structural (e.g. surgical) or functional (e.g. mucosal disease) changes and demonstrate an inability to maintain both hydration and nutritional wellbeing while eating and drinking a normal diet. While the use of enteral nutrition is part of primary therapy in the pediatric SBS population, it is underutilized in adult patients trying to transition off parenteral nutrition. Instead, adult SBS patients are sometimes left on chronic parenteral hydration or nutrition. This article will address how one institution orchestrates an enteral feeding trial in the adult SBS patient trying to achieve enteral autonomy from parenteral support.

Introduction

Short bowel syndrome/intestinal failure (SBS/IF) is best defined as an inability to maintain adequate nutrition and/or hydration through oral intake due to insufficient gut surface area either from surgical resection or a significantly defunctionalized bowel surface (e.g. radiation injury, etc.). Many patients require parenteral nutrition (PN) or hydration due to the severity of malabsorption and/or dehydration present. Not only does this pose significant lifestyle and financial challenges, but the medical risks of catheter infection, thrombosis, and gradual loss of vascular access are also significant. Effective and aggressive care of the SBS patient requires a thoughtful approach to maximizing GI tract function and eliminating the need for parenteral support whenever possible.

While enteral nutrition (EN) is widely used in pediatric SBS patients1-4 in an attempt to transition from PN to enteral autonomy, it appears to be rarely used in adult SBS patients. Getting the most out of a shortened bowel means not only providing luminal nutrients to maximize absorption and the adaptation process,5 but also means incorporating creative strategies such as using the GI tract at a time when it would normally be in disuse (i.e., during sleep). This allows delivery of nutrients at a slower pace for gradual absorption without overwhelming the vulnerable GI tract. This article will address how one institution orchestrates an EN trial in the adult SBS patient trying to achieve enteral autonomy from parenteral support.

Adaptation Phase After Loss of Bowel

After a massive loss of bowel, the remaining bowel attempts to boost absorption of nutrients and fluids through hypertrophy of the villous mucosa. While maximal adaptation is usually reached within the first 6 months after resection, some bowel adaptation will continue for up to two years. During the adaptation phase, enteral nutrients directly stimulate:

  • Enteral blood flow
  • Epithelial cells
  • Production of trophic hormones
  • Pancreaticobiliary secretions

In so doing, mucosal atrophy is prevented, mucosal barrier function is preserved, and the mucosal immune system is downregulated.5-7 Recognizing that nutrients in the GI tract stimulate this process is key to understanding intestinal adaptation. To maximize intestinal adaptation, it is important to provide early introduction of whole, enterally delivered nutrients (either as food or polymeric formula). Whole nutrients help maximize the functional workload of the intestinal epithelium which drives intestinal adaptation (think use it or lose it). Utilizing the gut overnight may have the added benefit of avoiding overstimulation of the bowel by presenting nutrients slowly via a pump maximizing uptake at the brush border.

It is absolutely critical in caring for the newly minted SBS patient to allow time for adaptation before committing a patient to “long-term or PERMANENT TPN.” Patients may see significant improvements in bowel function as the adaptation window closes which could facilitate weaning of previously necessary parenteral support. As with any post-op GI patient, oral/enteral nutrients should be started as soon as feasible, to initiate the intestinal adaption process, even if oral intake is not sufficient, or needs to be kept to a minimum to prevent high output. Oral intake enlists the cephalic phase of digestion activating salivary glands and stimulation of epidermal growth factor secretion and other trophic agents in saliva that also may play a role in adaptation.2,8 Finally, oral intake is a very important component in the quality of life of our patients. For our institution’s written SBS diet education materials for patients go to: med.virginia.edu/ginutrition/patient-education.

Enteral Feeding Considerations in the Adult Short Bowel Patient

Available supportive evidence for using EN in adult SBS patients with varying lengths of small bowel consists of case reports, case series and small observational studies.9-20

Feeding Route

Gastric delivery is favored over jejunal feeding, not only to stimulate pancreaticobiliary secretions to assimilate nutrients, but to encompass the greatest amount of surface area for absorption and to better regulate flow across the pylorus into the small bowel. Jejunal feeding should be reserved for those patients with functional or mechanical gastric outlet obstruction, severe ongoing gastric reflux, or anatomy that prevents gastric feeding. However, this would only be appropriate in those patients with adequate jejunal/ileal surface area below the jejunal feeding tube ports to absorb infused nutrients.

Continuous vs. Bolus Enteral Infusion

Pump feeding is preferred to bolus feeding to present nutrients slowly over time to maximize nutrient contact and saturation of mucosal receptors resulting in overall improved absorption per unit length of small bowel.1 Delivery of EN via a pump is vastly slower than the slowest/smallest amount of food or fluid taken orally; consider: 60mL/ hour = 1mL/minute (a teaspoon [5mL] infused over 5 minutes). Several studies have shown improved outcomes (nutrient absorption, weight gain, less diarrhea, less divalent cation loss), with continuous infusion in both pediatric and adult SBS populations.4,13-16,18,21,22 In the patient consuming a short bowel diet over the course of the day, nocturnal pump feedings over 8-12 hours at night have the advantage of using the GI tract when there is no competition for the mucosal receptors, leaving nutrients their very own contact time. For those who want to infuse during the day and tolerate the increased daytime enteral workload, an enteral backpack can be used to carry the infusion pump so patients can continue their normal activities as desired (“infuse and cruise” as it were).

Enteral Product Selection

In the early studies of enteral feeding in pediatric SBS, elemental or semi-elemental formulas were often used based on the assumption that the injured, shortened intestinal tract needed help to absorb nutrients by having them partially or fully broken down. While there is evidence in animal studies that more complex nutrients promote adaptation, human studies have been small, hence clear benefit of polymeric vs. elemental formulas is not available at this time.13,14,20,23,24 Elemental-type formulas tend to be more osmotic and costly. The whole nutrients in polymeric formulas also provide the necessary “workload” to maximally stimulate adaptation.5 See Table 1 for a comparison of various standard polymeric vs. elemental-type formulas.

Fiber-containing products may be useful in those SBS patients with a colon segment as colon metabolism generates useful free fatty acids. However, patients with concurrent small intestinal bacterial overgrowth may find that fiber exacerbates gas and distension. This can be worsened in some patients by the addition of fructo-oligosaccharides (FOS) in some of the enteral products.25,26

As enteral formulas are known to be relatively low in sodium content, SBS patients with end jejunostomies or ileostomies may need additional salt added directly to their EN prior to infusion27 if they do not get enough salt in their diet. Those with a colon should not need this as even a small colon segment avidly absorbs sodium from the gut.

Finally, there may be a few patients who only need hydration rather than additional nutrition support. Oral rehydration infused over time via a gastrostomy tube may effectively hydrate and allow freedom from the risks of a central line.28

Blended Whole Food Formulas

In a small study of 10 pediatric patients with intestinal failure (80% with colon in continuity), transition from an elemental to a commercial blended formula (Compleat Pediatric®) resulted in more formed stools and appropriate weight gain after one year.24

Lower Fat Formulas Might be Worth a Try in Some Patients (especially those with a colon)

In general, avoid restricting fat intake because of the caloric density fat provides. However, some patients with SBS have significant fat malabsorption, which may be worsened by a coexisting bile salt insufficiency, or the increasingly more common pancreatic exocrine asynchrony from altered upper gut anatomy such as a Roux en y gastric bypass. Using a lower total fat formula in these cases may improve overall absorption, particularly in patients with colon in continuity. Case in point:

32 year-old male with history of SBS due to necrotizing enterocolitis as an infant (~ 30cm proximal SB anastomosed to ~ 50cm of distal colon); transferred to the adult service when he was 24 years of age. Therapy at that time included: PN, nocturnal semi-elemental EN via gastrostomy tube, and an oral short bowel diet (followed fairly well). His usual body weight fluctuated for years between 95-105 lbs (height 4’ 10”). After numerous central line septic episodes, he was transitioned off PN to daily nocturnal IV fluids/electrolytes alone (he could not hydrate himself without), nocturnal EN, and optimized oral SBS diet and fluids during the day. When teduglutide became available, he was started on it in an effort to get him off IV fluids. His weight increased over time to an all-time high of 124 lbs (goal weight was 110 lbs., but patient started working out and wanted to weigh 120 lbs.). Urine and stool output averaged 900-1100mL (never a kidney stone), and 1500-2000mL, respectively. Given his weight gain, and the fact it was over goal, it was decided to switch him from Peptamen® 1.5 @ 110mL/hr x 6 cans for years to a lower fat polymeric formula: Replete @ 110mL/hr x 6 cans. While this dropped his total daily EN calories from 2250kcal to 1500kcal, it also reduced the total fat content from 84g to 50g/ day; his weight stabilized at 120 lbs and he experienced a decrease in his 24-hour stool output, demonstrating improved absorption on less total fat.

Be wary of exchanging medium chain triglycerides (MCT) for long chain triglycerides (LCT). Too much MCT can overwhelm a SBS patient’s ability to passively absorb it and still result in significant fat malabsorption. In our experience, the use of MCTs should be reserved for SBS patients with colon in continuity, and then only if clear clinical benefit is demonstrated in an individual patient.

In a patient with SBS, lower osmolality products may be helpful, but this benefit is often minimal given the extensive dilution effect of both baseline gastric and intestinal secretions with any gastric formula infused. The bottom line is any enteral product that clearly drives stool/ostomy output above what is tenable for an individual patient is not sustainable.

Additionally, poorly absorbed osmoles are significant contributors to diarrhea in any patient, especially patients with SBS. Liquid medications containing sugar alcohols (see Table 2) and enteral products containing FOS have been shown to increase stool volume.25,26,29

Who Needs an Enteral Feeding Trial?

Once out of the adaptation phase, every SBS patient that is PN-dependent as well as every SBS patient that is struggling with nutrition/hydration on oral intake alone, should be considered for novel approaches to maximize current function of their GI tract.

Although there are some patients that have a low probability of success, there is no downside to trying to liberate a patient from PN or IV fluids and central line access. Situations that may be considered relative “contraindications” are high output fistula on maximum medication therapy (antidiarrheals, antisecretory, etc.), chronic dysmotility, chronic obstruction, and severe (> 2000mL/day) diarrhea output.

Indications for an enteral feeding trial begins with a careful examination of the patient and their gut function. The patient is assessed to ensure that they:

  1. Are willing to undergo an enteral feeding trial
  2. Do not have potential contraindications or complexities associated with enteral access
  3. Do not have other untreated GI disorders (e.g. significant dysmotility, bowel fistula, active Crohn’s disease, etc.)

We then assess gut function via:

  • 72 hour fecal fat – to assess degree of malabsorption
  • Small bowel follow through – to assess transit time and gross assessment of bowel anatomy if unknown
  • 24hr I and O – to assess baseline oral fluid intake, stool/ostomy and urine output

Patients with the Highest Potential for Success:

  1. Eating and drinking a very high calorie short bowel diet and despite this, cannot gain weight
  2. Stool output increases considerably if patient tries to eat or drink more
  3. Too full to eat or drink the amount they need in order to meet needs or gain weight
  4. Cannot maintain consistent high calorie intake (> 3000kcal/day) day after day as it consumes the entire day leaving no time to have a life, and a grocery bill that may not be sustainable

Based on above information along with patient centered decision making, we embark on a formal enteral feeding trial. This is often conducted in an inpatient setting to ensure adequate measurements, facilitate rapid changes if needed, and to monitor for clinical issues such as refeeding syndrome.

The Architecture of an Inpatient Enteral Feeding Trial

Conducting an EN trial is often a challenge to orchestrate given the unpredictability and fast pace of modern inpatient medicine. Despite this, with careful planning and appropriate communication, it can be executed smoothly and efficiently. A 3-4 day hospitalization is usually expected, although caution the patient that this could be shorter or longer depending on the circumstances. For smooth initiation of an EN trial, complete as much as possible prior to admission such as a small bowel follow through and baseline 24-hour urine and stool outputs for comparison purposes when enteral trial begins (see Table 3).

Planning and coordination is everything. It is important to be very clear with the involved teams that ALL intake (food, fluid, fluid with medications) and output (urine, stool, external drains) should be accounted for; also that urine and stool should be measured separately (for some female patients this is difficult and might require temporary placement of a Foley catheter). In our experience, more than one patient has reported high ostomy/stool output only to find out they were unable to separate urine and stool and the volume recorded/reported was a high percentage of urine volume and not stool/ ostomy output.

The EN regimen initiated is a nocturnal run with a lower fat, standard polymeric formula or a semi-elemental product (see Table 1) via a pump, which can be delivered slowly over time to maximize absorption. Typically, a set volume of 2-3 cans (~ 500-1000 calories) over 10-14 hours is infused. A conservative volume is chosen initially to avoid drastically increasing the stool volume; only increase rate once tolerance is demonstrated ensuring the patient is not up all-night stooling/ emptying ostomy appliance. Monitoring any alteration to laboratory values is necessary as well. While refeeding syndrome is a serious clinical issue that is often evident in the lab work, significant diarrhea can also result in electrolyte changes and biochemical signs of volume depletion (e.g. rising BUN/Creatinine ratio).

It is not uncommon to see an increase in stool output requiring escalation of antidiarrheal agents (e.g. crushed loperamide, codeine, etc.), especially at the start of nocturnal EN infusion. If the stool volume increases such that a patient’s ability to sleep or generally function is compromised, then the EN plan is untenable.

During the EN trial, the goal is to maintain a stool output of ideally less than 1500mL and a urine output of greater than 1200mL, without evidence of metabolic disarray or progressive volume depletion. If success is achieved, proceed with a more permanent form of enteral access (e.g. gastrostomy tube) ideally prior to discharge. Some patients may require continued PN for a time with a plan to wean as home EN continues to be advanced. See section below on EN coverage options.

Enteral Access after Successful Enteral Feeding Trial

The principles behind enteral access in the SBS patient emphasize maximizing the length of gut involved in enteral feeding. For most patients, this means consideration of a gastrostomy tube. We recommend avoiding jejunostomy extension arms and jejunostomy tubes if possible since they:

  1. Divert past valuable mucosal surface area
  2. Bypass the important function of the stomach to control emptying into the duodenum
  3. Cause asynchrony of EN infused with normal pancreaticobiliary secretions

Placement of a gastrostomy tube depends on local expertise, but most hospitals have access to teams from GI endoscopy, surgery, or radiology, who can safely perform these procedures. In general, we attempt to endoscopically place a gastrostomy tube prior to discharge if long-term EN is the plan.

If there is hesitation on the part of the patient or the medical team, a reasonable plan at the time of discharge would be a short-term trial at home with a nasogastric tube to clearly demonstrate the enteral feeding/hydration plan is successful before placing more permanent access. This is a temporary option given the risk of displacement of the nasogastric tube, the discomfort associated, and the risk of injury to the sinuses associated with a longer-term NG tube.

If at First You Don’t Succeed…Pitfalls Encountered That Alter Success of Plan

  • Make sure all orders (medications, diet, fluid, I & O’s, etc.) go in correctly the first time and are carefully followed
  • Appropriate labs are scheduled at opportune times
  • Can patient separate urine and stool when voiding?
    If not, patient may need a urinary catheter to accurately measure stool/ ostomy output during trial

The Converse: Some patients are very unlikely to succeed with an enteral trial

There are certainly cases where an enteral trial is quite unlikely to succeed. We utilize the clinical history and baseline data from studies such as fecal fat collections to help patients understand the likelihood of success. For example:

65 year old, 6’ 2”, 142# male presented to GI nutrition clinic with malnutrition, failure to thrive, and depression with a history significant for: pseudomyxoma peritoni with heated intraperitoneal chemotherapy; exploratory laparotomy with radical intra-abdominal tumor debulking and bowel resection. He was constantly hungry, ate all day long, yet suffered significant osmotic diarrhea despite a 6 month effort to maximize diet and narcotic gut slowing. Neither his hydration status nor his weight had meaningfully improved. A 48 fecal fat collection was completed while he ingested a 100-gram fat diet with the following results: 5220mL total stool volume (2610mL/ daily) and 85 g fat lost per day. This degree of fat malabsorption made the likelihood of success with an EN trial extremely low. After reassurance regarding the risk of PN which had previously been explained to him by another provider as quite dire, he was started on PN. In follow-up his quality of life was markedly improved back to travelling and deep-sea fishing with a weight of 165 lbs.

Insurance Coverage of Enteral Feeding in SBS

Insurance coverage of EN can vary widely; it is helpful to acquire approval PRIOR to permanent gastrostomy tube placement if needed. Medicare requires patients to have a permanent (>3 months) functional impairment of the upper GI tract making EN via a tube necessary. In patients making the transition from PN, not all insurance carriers will cover both modalities at the same time to facilitate a safe transition.

Getting both EN and PN covered at the same time:
• Medicare patients not possible as definitive criteria exists for each therapy

• Commercial plans: Patient, prescriber and home provider will have to clear the patient’s plan to assess if both EN and PN can be covered. There may or may not be a case manager to work with at the plan and a prior authorization may be required

• The payer may not cover a hospitalization for a trial or initiation of enteral feeding. Check to see if a “home trial” is possible with strong outpatient support

• If patient is weaning off PN and not in any danger of doing a trial at home, discontinue PN temporarily and monitor the EN trial and the patient’s clinical status closely

• Some private insurers will not cover the cost of enteral formula but will cover enteral pump and supplies. Insurance and benefits should always be cleared prior to initiating therapy so the patient and family are clear on what the financial responsibility will be

• Medicaid or managed Medicaid plans: Every state is different. Again, benefits should be cleared with the patient’s plan prior to initiating therapy to assure the patient will have full EN coverage and there will be a provider willing to take the patient’s case

• Consider soliciting product donations from EN manufacturers for at least the trial period

• Oley Foundation Equipment/Supply Exchange Program: (oley.org/page/ Equipment_Exchange), however, if shipping is involved, it costs a flat rate of ~$20/case

• Patient is willing to self-pay (for formula and supplies)

Conclusion

Clinicians should consider enteral feeding for SBS patients for the maintenance and/or improvement of nutritional status, improvement of residual bowel function (adaptation), freedom from a central line, and improvement of quality of life. EN therapy is not without risk, but it may be a viable, less costly alternative for some patients while minimizing the risks and complexity associated with central venous access and PN therapy. A carefully planned enteral trial often includes brief hospitalization, if covered, clinical monitoring, utilization of polymeric EN formulas, and judicious use of bowel slowing agents. A summary table of considerations when enterally feeding the adult SBS patient can be found in Table 3.

References

  1. Avitzur Y, Courtney-Martin G. Enteral approaches in malabsorption. Best Pract Res Clin Gastroenterol. 2016;30(2):295- 307.
  2. Olieman J, Kastelijn W. Nutritional Feeding Strategies in Pediatric Intestinal Failure. Nutrients. 2020 ;12(1). Pii : E177.
  3. Mezoff EA, Cole CR, Cohran VC. Etiology and Medical Management of Pediatric Intestinal Failure. Gastroenterol Clin North Am. 2019;48(4):483-498.
  4. Weizman Z, Schmueli A, Deckelbaum RJ. Continuous nasogastric drip elemental feeding. Alternative for prolonged parenteral nutrition in severe prolonged diarrhea. Am J Dis Child. 1983;137(3):253-5.
  5. Tappenden KA. Intestinal adaptation following resection. JPEN J Parenter Enteral Nutr. 2014;38(1 Suppl):23S-31S.
  6. de Laffolie J, Naim HY, Rudloff S, et al. Starch Tolerance and the Short Bowel. J Pediatr Gastroenterol Nutr. 2018;66 Suppl 3:S68-S71.
  7. Tappenden KA. Pathophysiology of short bowel syndrome: considerations of resected and residual anatomy. JPEN J Paren ter Enteral Nutr. 2014;38(1 Suppl):14S-22S.
  8. DiBaise JK, Decker GA. Enteral access options and management in the patient with intestinal failure. J Clin Gastroenterol. 2007;41(7):647–56.
  9. Kinney JM, Goldwyn RM, Barr Jr JS, et al. Loss of the entire jejunum and ileum, and the ascending colon. Management of a patient. JAMA. 1962;179:529-32.
  10. Rodriguez DJ, Clevenger FW. Successful enteral refeeding after massive small bowel resection. West J Med. 1993;159(2):192-4.
  11. Simko V, Linscheer WG. Absorption of different elemental diets in a short-bowel syndrome lasting 15 years. Am J Dig Dis. 1976;21(6):419-25.
  12. Borges VC, Teixeira da Silva ML, Gonçalves Dias MC, et al. Long-term nutritional assessment of patients with severe short bowel syndrome managed with home enteral nutrition and oral intake. Nutr Hosp. Jul-Aug 2011;26(4):834-42.
  13. Joly F, Dray X, Corcos O, et al. Tube feeding improves intestinal absorption in short bowel syndrome patients. Gastroenterology. 2009;136(3):824–31.
  14. Levy E, Frileux P, Sandrucci S, et al. Continuous enteral nutrition during the early adaptive stage of the short bowel syndrome. Br J Surg. 1988;75(6):549–53.
  15. Gong JF, Zhu WM, Yu WK, et al. Role of enteral nutrition in adult short bowel syndrome undergoing intestinal rehabilitation: the long-term outcome. Asia Pac J Clin Nutr. 2009;18(2):155-63.
  16. McIntyre PB, Wood SR, Powell-Tuck J, et al. Nocturnal nasogastric tube feeding at home. Postgrad Med J. 1983;59(698):767- 9.
  17. Cosnes J, Gendre JP, Evard D, et al. Compensatory enteral hyperalimentation for management of patients with severe short bowel syndrome. Am J Clin Nutr. 1985;41(5):1002-9.
  18. Heymsfield SB, Smith-Andrews JL, Hersh T. Home nasoenteric feeding for malabsorption and weight loss refractory to conventional therapy. Ann Intern Med. 1983;98(2):168–70.
  19. Cosnes J, Evard D, Beaugerie L, et al. Improvement in protein absorption with a small-peptide-based diet in patients with high jejunostomy. Nutrition. 1992;8(6):406-11.
  20. McIntyre PB, Fitchew M, Lennard-Jones JE. Patients with a high jejunostomy do not need a special diet. Gastroenterology. 1986;91(1):25–33.
  21. Parker P, Stroop S, Greene H. A controlled comparison of continuous versus intermittent feeding in the treatment of infants with intestinal disease. J Pediatr. 1981;99(3):360-4.
  22. Cosnes J, Parquet M, Gendre JP, et al. [Continuous enteral feeding to reduce diarrhea and steatorrhea following ileal resection (author’s transl)]. Gastroentérology Clin Biol. 1980;4(10):695– 9.
  23. Ksiazyk J, Piena M, Kierkus J, et al. Hydrolyzed versus nonhydrolyzed protein diet in short bowel syndrome in children. J Pediatr Gastroenterol Nutr. 2002;35(5):615-8.
  24. Samela K, Mokha J, Emerick K, et al. Transition to a Tube Feeding Formula with Real Food Ingredients in Pediatric Patients with Intestinal Failure. Nutr Clin Pract. 2017;32(2):277-281.
  25. Halmos EP. Role of FODMAP content in enteral nutrition-associated diarrhea. J Gastroenterol Hepatol. 2013;28 Suppl 4:25–8.
  26. Barrett JS, Gearry RB, Muir JG, et al. Dietary poorly absorbed, short-chain carbohydrates increase delivery of water and fermentable substrates to the proximal colon. Aliment Pharmacol Ther. 2010;31(8):874–82.
  27. Nightingale J, Woodward JM; Small Bowel and Nutrition Committee of the British Society of Gastroenterology. Guidelines for management of patients with a short bowel. Gut. 2006;55 Suppl 4(Suppl 4):iv1-12.
  28. Nauth J, Chang CW, Mobarhan S, et al. A therapeutic approach to wean total parenteral nutrition in the management of short bowel syndrome: three cases using nocturnal enteral rehydration. Nutr Rev. 2004;62(5):221-31.
  29. Liauw S, Saibil F. Sorbitol: Often forgotten cause of osmotic diarrhea. Can Fam Physician. 2019 Aug;65(8):557-558

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FRONTIERS IN ENDOSCOPY, SERIES #72

Over the Scope Clips: Current Indications, Uses and Outcomes

April 2021 • Volume XLV, Issue 4
Gregory Toy,Douglas G. Adler

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Introduction

In 2007, Kirschniak et al. first described treating 11 patients with so-called over the scope clips (OTSC) for a variety of GI conditions such as bleeding, deep wall lesions, and perforations. These devices are supplied on caps that fit over the end of a flexible endoscope and are much larger than traditional through the scope (TTS) clips. Since then, OTSC use has taken off worldwide and has even spread to new indications including, but not limited to, stent anchoring and endoscopic full thickness resections.

One OTSC (Ovesco Endoscopy GmbH, Tübingen, Germany) system consists of an applicator cap with mounted clip, hand wheel, thread retriever. The clip is deployed when a hand wheel is turned which pulls the thread connected to the applicator cap. This system is quite intuitive to a GI physician as it is similar to the devices used to band esophageal varices. The clip is made of nitinol which is a biocompatible, MRI conditional alloy. The jaws of the clip are supplied open at 90 degrees in contrast to the closed jaws of the TTS clips. This allows for the strong compression force when the jaws of the clip are closed. The OTSC system has two auxiliary forceps which are the twin grasper (TG) and anchor (AC) forceps. The TG forceps allow approximation of both sides of a lesion as it has two arms that close separately from each other. The AC forceps are tri-pronged with three needles that can simultaneously grab a lesion.2

Another OTSC is the Padlock ClipTM (Aponos Medical, Kingston, NH). This clip is a nitinol ring with six pre-affixed dagger-shaped needles pointing towards each other. The clip is preassembled in an open position and loaded onto an applicator cap. The design of the cap allows for efficient suction and adhesion of the tissue to the instrument cap, avoiding the need for other instrumentation. The trigger wire used to deploy the clip does not go through the working channel of the endoscope and is instead outside of the endoscope along the shaft and is connected to a trigger handle. Pressing the trigger causes the wire to be pushed within the cable. This causes release to the clip by the delivery systemTM (Aponos Medical, Kingston, NH). Once the clip is deployed, it goes back to its original form, an 11mm hexagonal ring. The prongs of the six dagger-shaped needles penetrate and pull the tissue inwards. The tissue controllers (the crossguards of the daggers) moderate penetration depth and tissue-on-tissue pressure.5

Device and Accessory Selection

Choosing the equipment for OTSC placement is important for clinical success. Asokkumar et al.3 reported using a therapeutic endoscope (3.7mm) and water jet or CO2 insufflation to visualize a target before placing an OTSC. This author also reported adjusting the cap depth onto the tip of the endoscope based on the amount of tissue needed to be grasped. A cap depth of 3mm is appropriate for most types of targeted tissue as it potentially avoids excessive tissue capture.3 For GI perforations or lesions that need additional tissue to be grasped a 6mm cap depth may be more appropriate. Usually the OTSC will be deployed using the suction technique, but an accessory like the forceps described above may be needed for additional traction.

Indications

GI Bleeding (Non-Variceal)

One common use of the OTSC system is to treat patients with non-variceal GI bleeding (NVGIB). While OTSC used to be used to close GI perforations, they are now being increasingly used to treat upper GI bleeding. (Figure 1) One study randomized patients into two arms, with one group receiving standard hemostasis treatment and the other an OTSC with the possibly of adjunctive treatment with epinephrine. The OTSC were shown to be superior in comparison to standard treatment in patients with recurrent GI bleeding. Immediate hemostasis was achieved in 94% of patients in the OTSC group but in only 58% of controls. Clinical success, defined as no further bleeding, was also significantly higher in the OTSC group.

OTSC are useful in treating refractory bleeding. These instances of bleeding are often associated with high risk features. One high risk feature is involvement of a large artery, either a visible large artery or bleeding along the distribution of a large artery. Another high risk feature is a lesion that has suspicion for perforation such as one that is deeply penetrating or fibrotic. In this case, thermal intervention will be harmful. According to one study, there is as high as a 40% rebleeding rate for these lesions with standard therapy. Another study found that there was a true success rate of the OTSC in 81.3% of patients which was in line with comparable smaller studies showing a success rate between 77.8% and 100%.9 The authors concluded that OTSC could be a valuable tool in both primary and rescue therapy for NVGIB.

Another variable to consider when deciding to treat a GI bleed with an OTSC is the location of the bleed. Lower success rates, especially after 30 days, were found when OTSC were deployed in the esophagus or small bowel. One theory for this is that the clip has to be deployed tangentially given the limited diameter of the GI lumen in these locations. Nonetheless, OTSC have been shown to be more effective than traditional clips in posterior duodenal lesions. OTSC are easier to apply in these situations because the cap at the end of the scope allows for good visualization and less distance is needed between the clip and tissue for application of the clip.8 There is also a difference between OTSC success rates in iatrogenic and spontaneous bleeding. Iatrogenic bleeding is defined as bleeding due to a medical procedure while spontaneous bleeding is bleeding due to other causes such as an ulcer. One study reported a lower rate of success in spontaneous bleeding.10 The reason for this could be that the tissue surrounding a spontaneous bleed is less favorable for OTSC as it contains more fibrotic and inflammatory tissue which is harder to suction neatly or approximate with forceps.

Full Thickness Resection

Another indication for OTSC is to perform full thickness resections of GI lesions including adenomas and submucosal tumors. This procedure can also be performed when a transmural wall sample is needed for pathologic analysis. This procedure can be performed with the Full Thickness Resection Device (FTRD, Ovesco Endoscopy, Tubingen, Germany). The FTRD consists of a transparent cap that is mounted over a standard endoscope. The cap is 13mm in diameter and is longer than a standard cap. When resecting a colonic lesion, this device comes with a 14mm OTSC mounted over the cap and a polypectomy snare attached to the tip of the colonoscope. Instead of putting the snare through the endoscope, this snare runs on the outer surface of the endoscope under a plastic sheath. Before attempting the full thickness resection, diagnostic endoscopy is done to identify the lesion and its lateral margins are marked with a high frequency probe (Ovesco Endoscopy). For the resection itself, either grasping forceps or an anchor device (Ovesco Endoscopy) is advanced through the scope. The lesion is grasped and pulled into the scope until the previously marked lateral margins can be seen. This creates a pseudopolyp. The OTSC is then deployed across the base of the pseudopolyp and the snare is then used to resect the target lesion. The goal is a complete full thickness resection (R0).

Standard treatment for colorectal neoplasms includes routine polypectomy, endoscopic mucosal resection (EMR), and endoscopic submucosal dissection (ESD). However, most of these techniques rely on being able to separate the submucosal layer from the underlying muscularis propria. FTRD and OTSC can be used in more difficult lesions where standard treatments are unable to remove the lesion due to technical or anatomic constraints.

The major endpoints of resection of lesions when using FTRD are technical success and R0 resection. Technical success refers to the removal of the lesion in one piece and no macroscopic residual lesion as determined by the endoscopist. An R0 resection refers to complete histological removal of the lesion with positive margins. One study of 181 patients who had colorectal lesions treated with FTRD found a technical success rate of 89.5% and a R0 resection rate of 76.9%. Comparatively, in a meta-analysis, R0 resection rates were found to be 42.3% with EMR and 80.3% with ESD. In the FTRD study, 11% of the patients had to undergo surgery due to adverse events or non-curative resection12 while 5.8 to 9.9% of patients receiving standard EMR or ESD treatment underwent additional surgical intervention.13 The majority of patients receiving FTRD treatment were considered to have lesions that were difficult to resect and would likely have needed surgical intervention if FTRD was not performed. Only 2.2% of patients receiving FTRD had to go to surgery specifically due to procedure-related adverse events.12

One limit of FTRD is lesion size as larger lesions will not fully fit into the cap. R0 resection rates in lesions less than 2cm were 81.2% while those in lesions larger than 2cm were 58.1% (p=0.0038).12 Another limit of FTRD is the long cap which has an outer diameter of 21mm. This makes it difficult to advance the endoscope to the target lesion since the cap may impair visibility and endoscope tip flexibility. Resection of the lesion is also difficult as this long cap may impair the ability to see the lateral margins of the target.12

Stent Anchoring

Esophageal self-expanding metal stents (SEMS) are used for a wide variety of benign and malignant esophageal and upper GI pathologies. Fully covered SEMS are often preferred because they have a lower rate of tissue ingrowth than partially covered or uncovered SEMS. Fully covered SEMS are also generally removable. Partially covered SEMS still can be removed but this can be technically challenging, with special maneuvers being required at times.The biggest liability of SEMS is their high migration rate. One large multicenter retrospective study found the migration rate in fully covered SEMS to be 30% in benign strictures and 23% in malignant strictures. However, the clinically relevant migration rate was 17% and 12% in benign and malignant strictures respectively. Clinically relevant migration was defined as migration that warranted reintervention with stent replacement. In comparison, a study examining the migration rate of partially covered SEMS in benign conditions found a migration rate of 11%.14

Prevention of stent migration usually takes one of two forms: either external or internal fixation. External fixation, which is only rarely performed, includes silk sutures or umbilical tape which can be used to secure the SEMS against the back of the ear or nasal septum. However, discomfort is a limiting factor for this. Internal fixation can be accomplished via the use of endoscopic full thickness suturing, TTS clips, and OTSC. Full thickness sutures can decrease the stent migration rate to 1 in 6 but can significantly add to the total procedure cost. The average procedure time with suturing has been found to be 12.5 minutes. On the other hand, securing the stent with an OTSC takes 3.5 minutes on average.14 TTS clips are rarely used to fix fully covered SEMS in place.17 The placement of TTS clips is limited by their superficial degree of attachment.

In cases where a stent needs fixation, the OTSC is advanced to the proximal end of the stent and suction is applied so that the clip will be 50% attached to the stent and 50% attached to the esophageal wall. (Figure 2) Studies examining the efficacy of OTSC in stent anchoring have generally had a small sample size but have shown positive outcomes. In a study of 13 patients, only 2 (15%) were found to have stent migration and even in those patients the median dwell time of the stent increased from 3.5 days to 32 days. This group of 13 patients notably were high risk for stent migration as all of them had previous stent migration and 8 of them had stent migration even with conventional TTS clips to anchor the stent.14 In another study examining 22 patients with Mega stents (Taewoong Medical, Seoul, Korea) and OTSC anchoring, 4 patients (18%) were found to have stent migration. Stent migration usually leads to an increased number of endoscopic procedures to retrieve or move the stent. OTSC stent anchoring lowered the number of endoscopic procedures per patient to 2.8. This is less than the 4.4 to 4.8 procedures per patient noted in the literature for stents placed without OTSC anchoring. Additionally, only 1.4 stents were used per patient which is lower than the 1.7 to 2.6 noted in the literature.18

Perforations, fistulae, leaks

Diagnostic endoscopic procedures have a low risk of perforation with an incidence of 0.01 to 0.6%. However, therapeutic endoscopic procedures have a higher risk of perforation (0.6% to upwards of 5%). Besides iatrogenic perforations, there are spontaneous perforations which occur due to wide variety of pathologies including ulcers, tumors, and Boerhaave’s syndrome. Conventional treatment for GI perforation has traditionally been surgery but this has not yielded good results with a post operative mortality rate of 7%. Other alternative treatments include hemoclip suturing and TTS clips. Hemoclip suturing involves placing multiple clips to close a perforation. Two clips will be placed at the distal ends of the perforation and additional clips in the center as necessary to further close the gap between the tissue. Hemoclip sutures are limited in that only lesions under 10mm can be successfully sutured. TTS clips are limited by the low opening width and closure strength. On the other hand, ex-vivo experiments have shown that strengths of OTSC are comparable to the gold standard of surgical suturing. Therefore, OTSC are now commonly used to close esophageal, gastric, small intestinal, and colonic perforations.

To set up the OTSC device, a nitinol clip is loaded onto a cap which is mounted on the tip of the endoscope. Clip size can range from 9 to 14mm depending on the size of the endoscope tip and/or the size of the lesion. There are three types of clips that can be used. The atraumatic clip (type a) has a blunt distal end used for tissue compression while the traumatic clip (type t) has small spikes distally used for compression and anchoring and the gastric closure clip (type gc) has large distal spikes used for tissue closure.22 The defect or perforation can be prepared for closure in a number of ways. One way is to use suction to pull the lesion into the cap, which is appropriate for adequately mobile tissue. Another device that can be used is the “twin grasper” forceps whose mechanism was described earlier. Some endoscopists prefer using accessories such as a rat toothed forceps to grasp and retract tissue. It is important to avoid excessive suction since this can cause luminal restriction and can catch structures from outside of the bowel wall.19 Examples of this include small bowel fixation during closure of a colonic fistula and ureteral capture while closing a sigmoid fistula.3 Once the clip is deployed, it exerts 8-9 N of force onto the tissue which is similar to rubber band ligation.

OTSC are widely effective in treating GI perforations and leaks. (Figure 3 and Figure 4) A meta-analysis including 301 patients from 24 publications found that the long-term overall success rate for treating GI perforations with OTSC ranged between 42% and 100% with a pooled success rate of 73%. This analysis also found a discrepancy in success rate depending on the etiology of the lesion. Endoscopic and procedural based perforations had a 90% success rate followed by post-operative perforations at 68% and chronic leaks and fistulas at 59%.23 This could be attributed to the fact that a procedural lesion, if acted on in short order, is more likely to present without fibrosis, inflammation, or other complications. The lower success rates seen in patients with fistulae have been noted in other studies. A multinational retrospective study found only a 42.9% success rate when OTSC were used for the closure of fistulae. Gastrogastric fistulae after Roux-en-y gastric bypass surgery appear to be especially challenging to close; a small study on this topic demonstrated long term success in only 33% of patients. Khater et al.,22 analyzed closure of iatrogenic perforations before and after the advent of OTSC. Technical success was achieved in 100% of cases meaning that the OTSC was deployed in all cases with successful closure of the perforation without leakage. The overall clinical success rate was 82% as 18% of patients (2/11) had to undergo surgery. These authors also found a similarly high success rate of OTSC closing iatrogenic perforations at 75- 100%. Additionally, the rate of surgeries needed dropped from 62.5% before the introduction of the OTSC system to 12.5% afterwards.22

Complications

In one meta-analysis, the overall adverse event (AE) rate for OTSC was found to be 1.3% (4/301).23 In another meta-analysis, the AE rate was found to be 1.7% with a severe AE rate of 0.6%.2 Complications can happen during device setup, endoscope insertion, OTSC deployment, endoscope removal, or in the post procedure setting. During device set up, participants have been seen to accidently release the clip into the air or onto their fingers given that there is no safety or locking mechanism to prevent inadvertent deployment. When the endoscope is inserted, resistance can be felt when navigating through any luminal narrowing. Forceful advancement of the endoscope could result in mucosal injury or even perforation.

When deploying the clip, it is important to be cognizant of technique, surrounding structures, and orientation. Misplacement or superficial placement of OTSC have been reported in instances where the entire lesion is not suctioned into the cap. Additionally, placement of OTSC in thin-walled areas of bowel can result in perforation with resulting peritonitis, pneumoperitoneum, and fistulae.

In some cases, surrounding structures have been caught with the OTSC. There has been a report of inadvertent capture of the right ureter with the gastrointestinal wall.22 Loss of orientation during OTSC deployment can also cause luminal stenosis.

Occasionally, the OTSC will fail to release if the endoscope is severely angulated even with multiple hand wheel rotations.3 Post procedurally, there have been reports of detachment of the OTSC which led to delayed surgery.23

Follow Up and Removal of OTSC

One of the biggest advantages of OTSC is that it has a powerful clamping ability and broader range for closure of GI bleeds, leaks, and fistulae. On the other hand, the OTSC does not spontaneously detach from the mucosa. Rates of spontaneous detachment range from 13% in the gastric fundus to 75% in the gastric body with a follow up time of 20 months. A systematic review reported that between 0 and 44.4% of OTSC detached with a follow up of 1-12 weeks. The FTRD includes a 14mm clip with more teeth than the standard OTSC, potentially making it even harder to detach. The low rate of OTSC detachment is generally considered a positive development. Generally, the OTSC should stay in place for 4-8 weeks. For endoscopic full thickness resection, the FTRD device should stay in place for 2-3 months.

Some indications for OTSC removal include need for further treatment, adverse events, poor healing, recovery from the initial GI condition that warranted treatment, misplacement of the clip, and patient preference. OTSC removal methods involve damaging the clip so it can be removed including endoscopic lasers, argon plasma coagulation (APC), and the remOVE system (Ovesco Endoscopy, Tubingen Germany), EMR/ ESD, and ice-cold saline solution.

In general, removal of an OTSC involves two procedure phases: clip fragmentation and fragment retrieval. The remOVE system uses a bipolar grasping device with three distal electrodes and uses DC current to burn through the clip. The DC impulse is applied to the thinnest part of the clip in order to dislodge it. The electrical current is programmed to stop when the device is no longer in contact with nitinol, which reduces risk of thermal mucosal injury.3 One study showed a pooled success rate of 97% and 89% for fragmentation and retrieval respectively. The most cited reason for failure was mucosal overgrowth where the clip was buried so deep in the tissue that it could not be fragmented or retrieved.32

OTSC removal via EMR/ESD involves cutting away the clip with the tissue it is attached to. This can only be performed in clips that are attached to the mucosal or submucosal level as major bleeding and perforation is a concern if the muscular layer is involved. The theory behind the ice-cold saline solution is that nitinol, the material OTSC is made of, changes stiffness at various temperatures. At temperatures under 10 degrees C, nitinol changes to its martensitic grid structure; this means that one can change its shape with application of low force. Therefore, at this temperature, it is easier to deform and remove the clip. This method has only been described in case reports, so its safety, efficacy, and criteria for usage is uncertain.32

Adverse events to OTSC removal tend to be mild with minor bleeding, superficial thermal damage, and superficial mucosal tears being the most common.32

Conclusion

OTSC have the potential to change management and outcomes for many patients. The mechanism for using these clips is intuitive for endoscopists as it is like the mechanism to deploy esophageal bands. OTSC also have several benefits over alternative treatments. Indications for OTSC include NVGIB, perforations, fistulae, tissue resection, and stent anchoring. AEs do occur and can include creating a perforation, fistula, or stenosis in the bowel or capture of structures outside of the bowel wall. However, the AE rate is low overall. OTSC can be removed in some situations. Overall, understanding the mechanism of OTSC and its advantages and disadvantages can help endoscopists improve their practice.

References

  1. Kirschniak, A., Kratt, T., Stüker, D., Braun, A., Schurr, M. O., & Königsrainer, A. (2007). A new endoscopic over-the-scope clip system for treatment of lesions and bleeding in the GI tract: first clinical experiences. Gastrointestinal Endoscopy, 66(1), 162-167.
  2. Kobara, H., Mori, H., Nishiyama, N., Fujihara, S., Okano, K., Suzuki, Y., & Masaki, T. (2019). Over-the-scope clip system: A review of 1517 cases over 9 years. Journal of Gastroenterology and Hepatology, 34(1), 22-30.
  3. Asokkumar, R., Chin, Y. K., & Soetikno, R. (2019). Complications with over the scope clip: how can we prevent it?. Gastrointestinal endoscopy clinics of North America, 30(1), 75-89.
  4. Goenka, M. K., Rodge, G. A., & Tiwary, I. K. (2019). Endoscopic Management with a Novel Over-The-Scope Padlock Clip System. Clinical Endoscopy, 52(6), 574.
  5. Armellini, E., Crinò, S. F., Orsello, M., Ballarè, M., Tari, R., Saettone, S., & Occhipinti, P. (2015). Novel endoscopic overthe-scope clip system. World Journal of Gastroenterology, 21(48), 13587.
  6. Dinelli, M., Omazzi, B., Andreozzi, P., Zucchini, N., Redaelli, A., & Manes, G. (2017). First clinical experiences with a novel endoscopic over-the-scope clip system. Endoscopy international open, 5(3), E151.
  7. Asokkumar, R., Kaltenbach, T., & Soetikno, R. (2016). Use of over-the-scope clip to treat bleeding duodenal ulcers. Gastrointestinal Endoscopy, 83(2), 459-460.
  8. Schmidt, A., Gölder, S., Goetz, M., Meining, A., Lau, J., von Delius, S., & Kratt, T. (2018). Over-the-scope clips are more effective than standard endoscopic therapy for patients with recurrent bleeding of peptic ulcers. Gastroenterology, 155(3), 674-686.
  9. Brandler, J., Baruah, A., Zeb, M., Mehfooz, A., Pophali, P., Song, L. W. K., & Buttar, N. (2018). Efficacy of over-the-scope clips in management of high-risk gastrointestinal bleeding. Clinical Gastroenterology and Hepatology, 16(5), 690-696.
  10. Honegger, C., Valli, P. V., Wiegand, N., Bauerfeind, P., & Gubler, C. (2017). Establishment of Over-The-Scope-Clips (OTSC®) in daily endoscopic routine. United European Gastroenterology Journal, 5(2), 247-254.
  11. Schmidt, A., Damm, M., & Caca, K. (2014). Endoscopic full-thickness resection using a novel over-the-scope device. Gastroenterology, 147(4), 740-742.
  12. Schmidt, A., Beyna, T., Schumacher, B., Meining, A., RichterSchrag, H. J., Messmann, H., & Probst, A. (2018). Colonoscopic full-thickness resection using an over-the-scope device: a prospective multicentre study in various indications. Gut, 67(7), 1280-1289.
  13. Fujiya, M., Tanaka, K., Dokoshi, T., Tominaga, M., Ueno, N., Inaba, Y., … & Kohgo, Y. (2015). Efficacy and adverse events of EMR and endoscopic submucosal dissection for the treatment of colon neoplasms: a meta-analysis of studies comparing EMR and endoscopic submucosal dissection. Gastrointestinal endoscopy, 81(3), 583-595.
  14. Irani, S., Baron, T. H., Gluck, M., Gan, I., Ross, A. S., & Kozarek, R. A. (2014). Preventing migration of fully covered esophageal stents with an over-the-scope clip device (with videos). Gastrointestinal endoscopy, 79(5), 844-851.
  15. Thomas, S., Siddiqui, A. A., Taylor, L. J., Parbhu, S., Cao, C., Loren, D., & Adler, D. G. (2019). Fully-covered esophageal stent migration rates in benign and malignant disease: a multicenter retrospective study. Endoscopy international open, 7(6), E751.
  16. Shim, C. S., Cho, Y. D., Moon, J. H., Kim, J. O., Cho, J. Y., Kim, Y. S., & Lee, M. S. (2001). Fixation of a modified covered esophageal stent: its clinical usefulness for preventing stent migration. Endoscopy, 33(10), 843-848.
  17. Law, R., Prabhu, A., Fujii-Lau, L., Shannon, C., & Singh, S. (2018). Stent migration following endoscopic suture fixation of esophageal self-expandable metal stents: a systematic review and meta-analysis. Surgical endoscopy, 32(2), 675-681.
  18. Shehab, H. M., Hakky, S. M., & Gawdat, K. A. (2016). An endoscopic strategy combining mega stents and over-the-scope clips for the management of post-bariatric surgery leaks and fistulas (with video). Obesity surgery, 26(5), 941-948.
  19. Mangiavillano, B., Caruso, A., Manta, R., Di Mitri, R., Arezzo, A., Pagano, N., & Antonucci, E. (2016). Over-the-scope clips in the treatment of gastrointestinal tract iatrogenic perforation: a multicenter retrospective study and a classification of gastrointestinal tract perforations. World Journal of Gastrointestinal Surgery, 8(4), 315.
  20. Lüning, T. H., Keemers-Gels, M. E., Barendregt, W. B., Tan, A. C. I. T. L., & Rosman, C. (2007). Colonoscopic perforations: a review of 30,366 patients. Surgical endoscopy, 21(6), 994-997.
  21. Mangiavillano, B., Viaggi, P., & Masci, E. (2010). Endoscopic closure of acute iatrogenic perforations during diagnostic and therapeutic endoscopy in the gastrointestinal tract using metallic clips: a literature review. Journal of Digestive Diseases, 11(1), 12-18.
  22. Khater, S., Rahmi, G., Perrod, G., Samaha, E., Benosman, H., Abbes, L., & Cellier, C. (2017). Over-the-scope clip (OTSC) reduces surgery rate in the management of iatrogenic gastrointestinal perforations. Endoscopy international open, 5(5), E389.
  23. Mennigen, R., Senninger, N., & Laukoetter, M. G. (2014). Novel treatment options for perforations of the upper gastrointestinal tract: endoscopic vacuum therapy and over-the-scope clips. World Journal of Gastroenterology: WJG, 20(24), 7767.
  24. Seebach, L., Bauerfeind, P., & Gubler, C. (2010). “Sparing the surgeon”: clinical experience with over-the-scope clips for gastrointestinal perforation. Endoscopy, 42(12), 1108-1111.
  25. Haito-Chavez, Y., Law, J. K., Kratt, T., Arezzo, A., Verra, M., Morino, M., & Ryan, M. B. (2014). International multicenter experience with an over-the-scope clipping device for endoscopic management of GI defects (with video). Gastrointestinal endoscopy, 80(4), 610-622.
  26. Niland, B., & Brock, A. (2017). Over-the-scope clip for endoscopic closure of gastrogastric fistulae. Surgery for Obesity and Related Diseases, 13(1), 15-20.
  27. Soetikno R, Asokkumar R, Salazar E, et al. Flipped learning in endoscopy: a time effective model to impacr change in practice culture. Gastrointest Endosc 2019;89(6):AB410–1.
  28. Asokkumar, R., Sanchez-Yague, A., & Soetikno, R. (2018). Incomplete hemostasis of high-risk adverse outcome bleeding lesions after placement of the over-the-scope clip: causes and solutions. VideoGIE, 3(5), 155-156.
  29. Hu, J., Yang, Y., Ge, N., Wang, S., Guo, J., Liu, X., … & Sun, S. (2020). Long-term assessment of over-the-scope clip (OTSC) behavior after gastric application. Minimally Invasive Therapy & Allied Technologies, 29(2), 86-89.
  30. Weiland, T., Fehlker, M., Gottwald, T., & Schurr, M. O. (2013). Performance of the OTSC System in the endoscopic closure of iatrogenic gastrointestinal perforations: a systematic review. Surgical endoscopy, 27(7), 2258-2274.
  31. Ou, Y. H., Kong, W. F., Li, L. F., Chen, P. S., Deng, S. H., He, F. J., & Yue, H. (2020). Methods for Endoscopic Removal of Over-the-Scope Clip: A Systematic Review. Canadian Journal of Gastroenterology and Hepatology, 2020.
  32. Arezzo, A., Alberto, B., Harald, F., & Morino, M. (2013). The way to remove an over-the-scope-clip (with video).

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DISPATCHES FROM THE GUILD CONFERENCE, SERIES #35

Management of Large Colon Polyps

April 2021 • Volume XLV, Issue 4
Mohammad Bilal,Aasma Shaukat

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Colorectal cancer is the third most common cancer in the United States. Pre-cancerous colon polyps are precursors to most colorectal cancers, and colonoscopy reduces the incidence of colorectal cancer by removal of these polyps. The risk of cancer is especially higher in polyps > 20 mm in size, NICE 3 or Kudos VI or VN features. Management of large colon polyps includes optimal detection and recognition especially for sessile polyps, assessment of polyp morphology and histology, endoscopist’s comfort in advanced polypectomy techniques as well as managing associated adverse events.

Introduction

Colorectal cancer (CRC) is the third most common cause of cancer-related deaths in the United States.1 Colon polyps with certain histology are the precursors to most CRCs.2 Colonoscopy with polypectomy reduces both the incidence as well as the mortality associated with CRC.3,4 Previous studies have shown that removal of adenomatous polyps during colonoscopy is associated with 50% reduction in CRC-related mortality. 3,4 Therefore, optimizing the management of colon polyps is essential. This is especially important in large polyps. When the size of polyps is larger than 20 mm, the risk of cancer in these polyps increases.5 In this review, we will discuss techniques of management of large colon polyps.

Inspection

The first step in managing large colon polyps is being able to recognize them. Flat or sessile polyps especially in the right colon can be often missed. Hence, studies have shown that a second look in the right colon whether in forward view or in retroflexion during colonoscopy can improve the detection rates of these polyps.6 Needless to add that high-quality colonoscopy is essential in recognizing polyps. This includes a good bowel preparation, adequate withdrawal time and an endoscopist with an adenoma detection rate meeting standard guidelines.7,8

Once a large polyp is identified, the next step is to carefully assess the polyp for size, location and morphology.9-11 This is important to determine whether endoscopic resection is safely possible and the optimal modality of endoscopic resection. While studies have shown that there is only moderate agreement among experts when it comes to classifying large polyps according to various classifications,12 there are several available classifications. In the US, the most commonly used are the Paris classification,13 narrow band imaging international colorectal endoscopic (NICE) classification,14 and Kudo’s classification of polyp pit pattern among others.15

Classification Systems to assess polyps

The Paris classification classifies polyps as pedunculated (1p), sessile (1s), flat (IIa, IIb, IIc) or ulcerated (III).13 For non-pedunculated polyps (Paris classification 1s and II), surface morphology should also be classified as granular or non-granular laterally spreading tumors. The NICE classification classifies lesions as type 1 (serrated class: either hyperplastic or sessile serrated polyp), type 2 (conventional adenomas) or type 3 (deep submucosal invasive cancer).14 Another classification system, especially popular in Eastern part of the world is the Kudo pit pattern classification system.15 It requires magnification during colonoscopy using chromoendoscopy and evaluation of the pit pattern of the polyps. Pits are openings for the crypts. The Kudo classification classifies pit pattern as round / normal (Type I), asteroid (Type II), tubular or round pit smaller than normal pit (Type IIIS), tubular or round pit larger than normal pit (Type IIIL), gyrus/dendritic (IV), irregular arrangement (VI), and loss of decrease of pits with amorphous structure (VN). Polyps with type I to IV pit pattern are endoscopically resectable, while those with type VI and VN are suggestive of invasion and neoplasia.

What makes a polyp unresectable?

While all the above classifications are helpful in standardizing the nomenclature of how we describe large polyps, it is important to note that reports have shown variability in agreement among experts regarding polyp classifications.12 Therefore, the most practical recommendation for endoscopists is to recognize which polyps are amenable to endoscopic resection. Histological features that are unfavorable (lymphovascular invasion, tumor budding, poor differentiation) are not always predictable before resection.16

Depth of submucosal invasion can be predicted based upon lesion morphology and pit pattern as described above. Non-granular surface particularly pseudodepressed subtype, redness, expansion, firmness and fold convergence can all be associated with submucosal invasive carcinoma.17 Areas in polyp which do not lift with submucosal injection are also worrisome for invasive cancer.18,19 Prior reports have shown that the positive predictive value for invasive cancer if non-lifting sign is present can be 80% in treatment-naïve lesions.19,20 Non-lifting sign can be seen in lesions which have been previously biopsied or endoscopic resection has been attempted, and in these cases, this does not predict submucosal invasion.

Knowing your expertise

As mentioned above, optimal and complete resection of large colon polyps is essential in preventing CRC. The United States Multi-Society Task Force (USMSTF) recommends an advanced endoscopist experienced in advanced polypectomy to manage polyps larger than > 20 mm in size.9 It is important to know your expertise and resources. This is because studies have shown that polyps which are endoscopically resectable are often sent for surgery.21According to one report, after endoscopic resection by expert endoscopists, only about 5-10% of patient subsequently require surgery.22 Therefore, resection should not be attempted unless the endoscopist is comfortable that resection will be complete. Incomplete polyp resections and biopsies cause submucosal fibrosis. Partial resections make subsequent endoscopic resection challenging, hence, the first attempt should always be aimed to complete resection.23 If an endoscopist feels a polyp will be challenging to resect or does not have available time for that, it is better to refer the patient to an endoscopist who is comfortable with advanced polypectomy techniques.

Tattoo placement

If an endoscopist deems that a polyp is unresectable, it is often advisable to place a tattoo so that polyp can be recognized easily by the endoscopist who the patient will be referred to. However, if cecal landmarks are in view, then tattoo placement is not necessary. 9 It is important to remember that tattoo placement can be problematic at times as well. Tattoo should never be placed in or under polyp itself. Carbon black spreads in the submucosa even if it is a few centimeters from the site of injection and extends beneath polyps causing submucosal fibrosis and rendering future endoscopic attempts complicated.23,24 Tattoos should be placed on an opposite wall from the polyp, or 5 cm distal to the polyp, with images depicting the lesion and its relationship to the tattoo.23,24

Endoscopic Management

Pedunculated Polyps

As mentioned above large polyps can be pedunculated or non-pedunculated. For pedunculated polyps that are greater than 10 mm in size, hot snare polypectomy is suggested.9 Attempts should be made to perform polypectomy towards the lower end of the stalk so assessment of stalk invasion can be made on histological analysis.9 For larger pedunculated polyps, consideration of epinephrine into the head or stalk of polyp can also be considered to reduce the size and make resection easier. Other strategies include using a detachable loop or placing clips at the polyp stalk before resection via hot snare. The USMSTF recommends that after resection, attempts should be made to retrieve large pedunculated polyps en-bloc so that accurate histological assessment can be made.9

Non-pedunculated polyps

The vast majority of non-pedunculated polyps can be removed using endoscopic mucosal resection (EMR). The various modalities implied in resection of large non-pedunculated polyps are described below. Algorithm for approaching management of large colon polyps is outlined in Figure 1.

Endoscopic mucosal resection

Endoscopic mucosal resection (EMR) involves submucosal injection of fluid to lift the lesion away from muscle and allow resection in single or multiple pieces. This technique has now evolved, and several sub-categories of this technique exists including hot EMR, cold EMR and underwater EMR. In expert hands, EMR is safe and effective. According to a systematic review of 50 studies, the reported rate of severe adverse events was 10% and the review also reported low rates of local recurrence (14%).25

Hot EMR

Hot snare EMR involves the use of electrocautery in polyp resection. The first step is submucosal injection. Submucosal injection can be achieved with using dye such as methylene blue with saline or there are commercially available submucosal injections available as well. Polyps which are < 20 mm in size can be removed en-bloc while polyps which are > 20 mm in size can be removed in piecemeal fashion. After submucosal injection is achieved and the lesion is adequately lifted, a snare is used to capture the tissue. After the lesion is captured in the snare, the snare is lifted up away from the mucosa and lesion is removed using electrocautery. When a polyp is removed piecemeal, ablation of the normal margins of the EMR defect using argon plasma coagulation or snare tip soft coagulation can burn microscopic residual tissue and reduce the risk of recurrence.9

Cold snare EMR

Over the past few years, another technique of EMR which has gained popularity is cold snare EMR.26,27 This technique allows for resection of large polyps without the use for electrocautery. The advantage of this technique is that it significantly reduces the adverse events associated with electrocautery such as bleeding and perforation. Initial data has been encouraging and has shown low rates of adverse events and comparable recurrence rates to hot snare EMR.28 While there is variation in technique, the basic principles involve using submucosal injection and using small diameter snare and removal of the polyp in multiple pieces.

Underwater EMR

Underwater EMR is another technique for resection of large colon polyps which allows full water immersion for polypectomy.29 It obviates the need for submucosal injection prior to polypectomy. Some experts report using argon plasma coagulation to mark the borders of the polyp.29,30

This is followed by immersing the segment of the colon polyp under water. All gas is aspirated from the colon and the mucosa and submucosa involute as folds into the colon.

Post resection considerations

Endoscopic clip placement

Bleeding is the most common adverse event after endoscopic mucosal resection. Risk factors for postpolypectomy bleeding include polyp size > 1 cm, presence of a thick stalk, use of anti-coagulation, right sided polyps and co-morbid conditions such as cardiovascular disease or renal dysfunction.31 In these cases, endoscopic clip placement after polypectomy can be considered. Endoscopic clip placement is usually not necessary after cold snare EMR since the risk of delayed bleeding is extremely low.30

Tattoo placement and surveillance

Tattoo placement should be considered when a polyp is resected in piecemeal fashion and is in a location which will be challenging to localize in the future.9 Tattoo placement is usually recommended 3-5 cm anatomically distal to the lesion.9

For large colon polyps that have been removed using piecemeal EMR, the USMSTF recommends the first surveillance colonoscopy at 6 months, and if there is no recurrence of polyp, then following examination should be performed at 1 and 3 year intervals respectively.9 Endoscopists should perform a careful exam of the resection site using high-definition white light endoscopy and narrow band imaging. Post-resection sites that demonstrate normal macroscopic and histological examination have high predictive values for long term eradication.32 If recurrence of polyp is seen on surveillance examination, attempts should be made at endoscopic resection with either repeat EMR, snare or avulsion method.9

Endoscopic Submucosal Dissection

Endoscopic submucosal dissection (ESD) allows for higher en-bloc resection rates as compared to EMR for lesions > 20 mm in size. Other instances when ESD should be considered include lesions where there is suspicion for submucosal invasion, local early carcinoma, and pseudodepressed laterally spreading tumor.33 ESD involves submucosal injection followed by use of an ESD knife to perform a mucosal incision. This is followed by trimming of the submucosal edges to facilitate access to the submucosal plane. Submucosal dissection is then performed resulting in en-bloc resection. While ESD has excellent rates of en-bloc resection, it has higher rates of adverse events compared to EMR, including perforation, hospitalization related to procedure and costs.34

Endoscopic Full-Thickness Resection

Endoscopic full-thickness resection (EFTR) is a relatively new approach which allows for removal of all layers of the colon wall.35,36 EFTR is indicated in lesions < 30 mm in size which do not lift or those which involve a diverticulum or lesions in the appendiceal orifice which are challenging to resect with traditional polypectomy methods.37 Commercially available full-thickness resection device is available (Ovesco Endoscopy AG, Tübingen, Germany) which is an over-the-scope system with a cap and a ready to use mounted clip and fitted snare.

Conclusion

Over the last decade, there has been a paradigm shift for management of large colon polyps from surgery to endoscopic resection. Optimal resection of large colon polyps is essential for preventing the incidence and mortality associated with colorectal cancer. Endoscopists should be comfortable at recognizing large colon polyps. Resection of large colon polyps should only be attempted by endoscopists who feel comfortable with advanced polypectomy techniques and if resources are not available, patients should be referred to an endoscopist who is familiar with large polyp resection.

References

  1. Siegel RL, Miller KD, Goding Sauer A, et al. Colorectal cancer statistics, 2020. CA: A Cancer Journal for Clinicians 2020;70:145-164.
  2. Vogelstein B, Fearon ER, Hamilton SR, et al. Genetic alterations during colorectal-tumor development. N Engl J Med 1988;319:525-32.
  3. Winawer SJ, Zauber AG, Ho MN, et al. Prevention of colorectal cancer by colonoscopic polypectomy. The National Polyp Study Workgroup. N Engl J Med 1993;329:1977-81.
  4. Zauber AG, Winawer SJ, O’Brien MJ, et al. Colonoscopic polypectomy and long-term prevention of colorectal-cancer deaths. N Engl J Med 2012;366:687- 96.
  5. De Ceglie A, Hassan C, Mangiavillano B, et al. Endoscopic mucosal resection and endoscopic submucosal dissection for colorectal lesions: A systematic review. Crit Rev Oncol Hematol 2016;104:138-55.
  6. Desai M, Bilal M, Hamade N, et al. Increasing adenoma detection rates in the right side of the colon comparing retroflexion with a second forward view: a systematic review. Gastrointest Endosc 2019;89:453-459.e3.
  7. Yang SY, Quan SY, Friedland S, et al. Predictive factors for adenoma detection rates: a video study of endoscopist practices. Endosc Int Open 2021;9:E216-e223.
  8. Wong WJ, Arafat Y, Wang S, et al. Colonoscopy withdrawal time and polyp/adenoma detection rate: a single-site retrospective study in regional Queensland. ANZ J Surg 2020;90:314-316.
  9. Kaltenbach T, Anderson JC, Burke CA, et al. Endoscopic Removal of Colorectal Lesions-Recommendations by the US Multi-Society Task Force on Colorectal Cancer. Gastroenterology 2020;158:1095-1129.
  10. Shaukat A, Kaltenbach T, Dominitz JA, et al. Endoscopic Recognition and Management Strategies for Malignant Colorectal Polyps: Recommendations of the US Multi-Society Task Force on Colorectal Cancer. Gastrointest Endosc 2020;92:997-1015.e1.
  11. Shaukat A, Robertson D, Rex D. Endoscopic Recognition of Malignant Polyps. Gastroenterology 2021.
  12. van Doorn SC, Hazewinkel Y, East JE, et al. Polyp morphology: an interobserver evaluation for the Paris classification among international experts. Am J Gastroenterol 2015;110:180-7.
  13. The Paris endoscopic classification of superficial neoplastic lesions: esophagus, stomach, and colon: November 30 to December 1, 2002. Gastrointest Endosc 2003;58:S3-43.
  14. Hewett DG, Kaltenbach T, Sano Y, et al. Validation of a simple classification system for endoscopic diagnosis of small colorectal polyps using narrow-band imaging. Gastroenterology 2012;143:599-607.e1.
  15. Kudo S, Tamura S, Nakajima T, et al. Diagnosis of colorectal tumorous lesions by magnifying endoscopy. Gastrointest Endosc 1996;44:8-14.
  16. Aarons CB, Shanmugan S, Bleier JI. Management of malignant colon polyps: current status and controversies. World J Gastroenterol 2014;20:16178- 83.
  17. Matsuda T, Parra-Blanco A, Saito Y, et al. Assessment of likelihood of submucosal invasion in non-polypoid colorectal neoplasms. Gastrointest Endosc Clin N Am 2010;20:487-96.
  18. Uno Y, Munakata A. The non-lifting sign of invasive colon cancer. Gastrointest Endosc 1994;40:485-9.
  19. Ishiguro A, Uno Y, Ishiguro Y, et al. Correlation of lifting versus non-lifting and microscopic depth of invasion in early colorectal cancer. Gastrointest Endosc 1999;50:329-33.
  20. Kato H, Haga S, Endo S, et al. Lifting of lesions during endoscopic mucosal resection (EMR) of early colorectal cancer: implications for the assessment of resectability. Endoscopy 2001;33:568-73.
  21. Bronzwaer MES, Koens L, Bemelman WA, et al. Volume of surgery for benign colorectal polyps in the last 11 years. Gastrointest Endosc 2018;87:552-561. e1.
  22. Moss A, Williams SJ, Hourigan LF, et al. Long-term adenoma recurrence following wide-field endoscopic mucosal resection (WF-EMR) for advanced colonic mucosal neoplasia is infrequent: results and risk factors in 1000 cases from the Australian Colonic EMR (ACE) study. Gut 2015;64:57-65.
  23. Grimm IS, McGill SK. Look, but don’t touch: what not to do in managing large colorectal polyps. Gastrointest Endosc 2019;89:479-481.
  24. Kim HG, Thosani N, Banerjee S, et al. Effect of prior biopsy sampling, tattoo placement, and snare sampling on endoscopic resection of large nonpedunculated colorectal lesions. Gastrointest Endosc 2015;81:204- 13.
  25. Hassan C, Repici A, Sharma P, et al. Efficacy and safety of endoscopic resection of large colorectal polyps: a systematic review and meta-analysis. Gut 2016;65:806-20.
  26. Choksi N, Elmunzer BJ, Stidham RW, et al. Cold snare piecemeal resection of colonic and duodenal polyps ≥1 cm. Endosc Int Open 2015;3:E508-13.
  27. Piraka C, Saeed A, Waljee AK, et al. Cold snare polypectomy for non-pedunculated colon polyps greater than 1 cm. Endosc Int Open 2017;5:E184-e189.
  28. Tutticci NJ, Hewett DG. Cold EMR of large sessile serrated polyps at colonoscopy (with video). Gastrointest Endosc 2018;87:837-842.
  29. Binmoeller KF, Weilert F, Shah J, et al. “Underwater” EMR without submucosal injection for large sessile colorectal polyps (with video). Gastrointest Endosc 2012;75:1086-91.
  30. Binmoeller KF, Hamerski CM, Shah JN, et al. Attempted underwater en bloc resection for large (2-4cm) colorectal laterally spreading tumors (with video). Gastrointest Endosc 2015;81:713-8.
  31. Buddingh KT, Herngreen T, Haringsma J, et al. Location in the right hemi-colon is an independent risk factor for delayed post-polypectomy hemorrhage: a multi-center case-control study. Am J Gastroenterol 2011;106:1119-24.
  32. Khashab M, Eid E, Rusche M, et al. Incidence and predictors of “late” recurrences after endoscopic piecemeal resection of large sessile adenomas. Gastrointest Endosc 2009;70:344-9.
  33. Tanaka S, Saitoh Y, Matsuda T, et al. Evidencebased clinical practice guidelines for management of colorectal polyps. J Gastroenterol 2015;50:252-60.
  34. Fujiya M, Tanaka K, Dokoshi T, et al. Efficacy and adverse events of EMR and endoscopic submucosal dissection for the treatment of colon neoplasms: a meta-analysis of studies comparing EMR and endoscopic submucosal dissection. Gastrointest Endosc 2015;81:583-95.
  35. Schmidt A, Bauerfeind P, Gubler C, et al. Endoscopic full-thickness resection in the colorectum with a novel over-the-scope device: first experience. Endoscopy 2015;47:719-25.
  36. Vitali F, Naegel A, Siebler J, et al. Endoscopic fullthickness resection with an over-the-scope clip device (FTRD) in the colorectum: results from a university tertiary referral center. Endosc Int Open 2018;6:E98- e103.
  37. Schmidt A, Beyna T, Schumacher B, et al. Colonoscopic full-thickness resection using an over-the-scope device: a prospective multicentre study in various indications. Gut 2018;67:1280-1289.

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MEDICAL BULLETIN BOARD

Cellmax Life and Sebela Pharmaceuticals Enter Strategic Development and Commercialization Partnership for Firstsight™ Blood Test for Detection of Colorectal Cancer and Pre-cancer

April 2021 • Volume XLV, Issue 4

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CellMax Life closes Series C financing to accelerate development and regulatory approvals of FirstSight

SUNNYVALE, CA and ROSWELL, GA (March, 2021) – CellMax Life, a molecular diagnostics company with proprietary technology for pre-cancer and cancer detection blood tests, and Sebela Pharmaceuticals, a market leader in gastroenterology, announce the closing of a strategic development and commercial collaboration agreement, as well as CellMax’s Series C financing. Participation in the financing also includes a strategic investment from new investor, Aflac Ventures, the corporate venture arm of Aflac Incorporated (NYSE: AFL), and existing investor, ArtimanVentures.

“Strategic financing from market leaders, Sebela and Aflac Ventures, is a testament to CellMax’s technology and vision,” said Atul Sharan, chief executive officer, CellMax Life. “Sebela has a leading market position in the gastroenterology field in the United States. The financing will bring to life our vision of detecting colon cancer before it occurs through a globally marketed blood test that can detect pre-cancerous polyps.”

The Series C financing will be used to accelerate the clinical development of CellMax’s multimodal liquid biopsy test, FirstSight™, for the detection of colorectal cancer and pre-cancerous polyps, also known as advanced adenomas. CellMax recently initiated a multicenter U.S. study to further optimize its proprietary algorithm and cell capture techniques. CellMax and Sebela will collaborate on completing the development of FirstSight and, following approval from the U.S. Food and Drug Administration, Sebela will commercialize the test in the United States.

“For the last several years, we have closely followed the industry’s development of colorectal cancer liquid biopsies,” said Alan Cooke, chief executive officer, Sebela Pharmaceuticals. “Sebela and our subsidiary, Braintree, have worked with gastroenterologists for over 35 years, and we expect FirstSight to play a central role in the future of colorectal cancer screening. FirstSight may not only enable the U.S. to exceed its 80% screening rate target, as set by the National Colorectal Cancer Roundtable, but can also help detect pre-cancerous adenomas early, referring patients to colonoscopy for preemptive removal.”

This partnership complements Sebela’s portfolio of market-leading gastroenterology and colonoscopy preparation products, which are utilized to facilitate colonoscopies, the “gold standard” for the prevention and detection of colorectal cancer. Colonoscopies remain the only means of removing detected pre-cancerous lesions to prevent colorectal cancer.

At the 2021 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancer Symposium, Dr. Shai Friedland, professor of medicine at Stanford University Medical Center and chief of gastroenterology at the VA Palo Alto Health Care System, presented results from a prospective study performed on 458 subjects utilizing FirstSight, a multimodal assay comprised of circulating dysplastic epithelial cells and circulating tumor DNA mutation markers, in combination with a proprietary algorithm.

“A test that detects only colorectal cancer, and not adenomas, will result in missed opportunities to prevent cancer and subject patients to invasive cancer treatments,” said Dr. Friedland. “Today, there is not a single non-invasive screening test that can accurately detect pre-cancerous polyps even nearly as effective as a colonoscopy. Our study data with the FirstSight blood test continues to show consistent ability to detect advanced adenomas with high sensitivity, enabling removal before they progress to carcinomas.”

In clinical studies performed in the U.S. and Taiwan, FirstSight has demonstrated strong performance in detecting both advanced adenomas and colorectal cancer. FirstSight has also shown the ability to detect recurrent neoplasia following polypectomy. i-v [i], [ii], [iii], [iv], [v]

Colorectal cancer represents the second deadliest cancer in the U.S., despite being one of the most preventable.[vi] Additionally, screening adherence rates have fallen short of the 80% target, as only 68.8% of adults aged 50 to 75 years, and only 63.3% of adults aged 50 to 64 years, were up to date with colorectal cancer screening as of 2018.[vii]

About CellMax Life

CellMax Life is a diagnostics company focused on cancer screening with proprietary technology for detecting precancerous and cancer cells and genomic aberrations in a single blood sample. CellMax Life is headquartered in Sunnyvale, California, and has a CLIA certified and CAP accredited laboratory at this location.

For more information, visit: cellmaxlife.com

About Sebela Pharmaceuticals®

Sebela Pharmaceuticals is a growth oriented pharmaceutical company focused in gastroenterology, colorectal cancer detection and prevention. Braintree, a part of Sebela Pharmaceuticals, is a pioneer in colonoscopy screening with a broad marketed portfolio of innovative prescription colonoscopy preparations and gastroenterology products. Braintree has multiple clinical development programs including, in collaboration with Cellmax Life, a multimodal liquid biopsy test, FirstSight™, for the detection of colorectal cancer and pre-cancerous polyps. Sebela’s core therapeutic areas also include women’s health and dermatology. In women’s health, Sebela has two next generation intra-uterine devices (IUDs) for contraception in late-stage clinical development. Sebela Pharmaceuticals has offices in Roswell, GA; Braintree, MA; and Dublin, Ireland; has annual net sales of $200-250 million; and has grown to over 300 employees through strategic acquisitions and organic growth. Please visit sebelapharma.com for more information.

About Aflac Incorporated

Aflac Incorporated (NYSE: AFL) is a Fortune 500 company helping provide protection to more than 50 million people through its subsidiaries in Japan and the U.S., where it is a leading supplemental insurer by paying cash fast when policyholders get sick or injured. For more than six decades, insurance policies of Aflac Incorporated’s subsidiaries have given policyholders the opportunity to focus on recovery, not financial stress. Aflac Life Insurance Japan is the leading provider of medical and cancer insurance in Japan where it insures 1 in 4 households. For 15 consecutive years, Aflac Incorporated has been recognized by Ethisphere as one of the World’s Most Ethical Companies. In 2021, Fortune included Aflac Incorporated on its list of World’s Most Admired Companies for the 20th time, and Bloomberg added Aflac Incorporated to its Gender-Equality Index, which tracks the financial performance of public companies committed to supporting gender equality through policy development, representation and transparency, for the second consecutive year.

To find out how to get help with expenses health insurance doesn’t cover, get to know us at: aflac.com

Forward Looking Statements

This press release and any statements made for and during any presentation or meeting contain forward-looking statements related to Sebela Pharmaceuticals under the safe harbor provisions of Section 21E of the Private Securities Litigation Reform Act of 1995 and are subject to risks and uncertainties that could cause actual results to differ materially from those projected. These statements may be identified by the use of forward-looking words such as “anticipate,” “planned,” “believe,” “forecast,” “estimated,” “expected,” and “intend,” among others. There are a number of factors that could cause actual events to differ materially from those indicated by such forward-looking statements. These factors include, but are not limited to, the development, launch, introduction and commercial potential of FirstSight™; growth and opportunity, including peak sales and the potential demand for FirstSight™, as well as its potential impact on applicable markets; market size; substantial competition; our ability to continue as a growing concern; our need for additional financing; uncertainties of patent protection and litigation; uncertainties of government or thirdparty payer reimbursement; dependence upon third parties; our financial performance and results, including the risk that we are unable to manage our operating expenses or cash use for operations, or are unable to commercialize our products, within the guided ranges or otherwise as expected; and risks related to failure to obtain FDA and/or CMS clearances or approvals and noncompliance with FDA regulations. As with any diagnostic under development, there are significant risks in the development, regulatory approval and commercialization of new products. There are no guarantees that future clinical trials discussed in this press release will be completed or successful or that any product will receive regulatory approval for any indication or prove to be commercially successful. While the list of factors presented here is considered representative, no such list should be considered to be a complete statement of all potential risks and uncertainties. Unlisted factors may present significant additional obstacles to the realization of forward-looking statements. Forwardlooking statements included herein are made as of the date hereof, and Sebela Pharmaceuticals does not undertake any obligation to update publicly such statements to reflect subsequent events or circumstances except as required by law.

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MEDICAL BULLETIN BOARD

Lilly’s Mirikizumab Helps Patients Achieve Clinical Remission and Improves Symptoms in Adults with Ulcerative Colitis in 12-week Phase 3 Induction Study

April 2021 • Volume XLV, Issue 4

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  • Patients treated with mirikizumab met the primary endpoint of clinical remission and all key secondary endpoints compared to placebo
  • LUCENT-1 is the first and only Phase 3 study of an anti-IL23p19 monoclonal antibody to demonstrate reduced bowel urgency in moderate to severe ulcerative colitis
  • Safety results in this study were consistent with that of the previous mirikizumab study in ulcerative colitis and studies with the anti-IL-23p19 antibody class

INDIANAPOLIS, March, 2021 – Eli Lilly and Company (NYSE: LLY) announced that mirikizumab met the primary and all key secondary endpoints in LUCENT-1, a 12-week Phase 3 induction study evaluating the efficacy and safety of mirikizumab for the treatment of patients with moderate to severe ulcerative colitis (UC). LUCENT-2, a multicenter, randomized, doubleblind, placebo-controlled maintenance study of mirikizumab in patients who have completed the 12-week LUCENT-1 induction study is ongoing.

UC is a chronic inflammatory disease of the large intestine, also referred to as the colon, that affects the lining of the colon and may cause small sores, or ulcers, to form. [i] This inflammation can cause abdominal pain, frequent and urgent trips to the bathroom, bloody stools and incontinence.1 UC can cause significant and debilitating disruptions in daily life. Millions of people live with UC globally.2

“There is a continued need for additional treatments that can provide people living with ulcerative colitis relief from their most challenging symptoms,” said William J. Sandborn, MD, Professor of Medicine, and Chief, Division of Gastroenterology, University of California San Diego. “Results of this study provide further clinical evidence of the potential for mirikizumab to become the first anti-IL-23p19 biologic for the treatment of ulcerative colitis.”

In LUCENT-1, mirikizumab met the primary endpoint of clinical remission at Week 12 compared to placebo (p<0.0001). Clinical remission is met when inflammation of the colon is controlled or resolved, leading to normalization or nearnormalization of symptoms such as stool frequency and bleeding.

Mirikizumab also achieved all key secondary endpoints compared to placebo at Week 12 in patients with UC with highly statistically significant p-values, including reduced bowel urgency, clinical response, endoscopic remission, symptomatic remission and improvement in endoscopic histologic inflammation. In addition, mirikizumab demonstrated rapid improvement in patient symptoms as early as four weeks after initiating treatment. Mirikizumab also reduced symptoms among patients who had previously not responded to or stopped responding to biologic and/or Janus kinase (JAK) inhibitor therapies.

In the 12-week placebo-controlled induction study of LUCENT-1, the incidence of treatmentemergent adverse events (AEs) and serious AEs among patients treated with mirikizumab was consistent with that of the previous Phase 2 mirikizumab study in UC and studies with the antiIL-23p19 antibody class. The most common AEs included nasopharyngitis, anemia and headache for both placebo and mirikizumab-treated patients.

“People living with UC often struggle to effectively manage recurring flare ups of the disease,” said Lotus Mallbris, M.D., Ph.D., vice president of immunology development at Lilly. “With these positive results, we look forward to the continuation of the maintenance study through 52 weeks in hopes of providing a new option to people living with UC.”

“Ulcerative colitis can be debilitating and unpredictable for the hundreds of thousands of people living with this chronic disease,” said Dr. Caren Heller, Chief Scientific Officer for the Crohn’s & Colitis Foundation. “We’re encouraged by these promising results for a potential new treatment that may help provide symptom relief and remission.”

About Mirikizumab

Mirikizumab is a humanized IgG4 monoclonal antibody that binds to the p19 subunit of interleukin23. Mirikizumab is being studied for the treatment of immune diseases, including psoriasis, ulcerative colitis and Crohn’s disease.

About the LUCENT Clinical Trial Program

The LUCENT Phase 3 clinical development program for mirikizumab includes LUCENT-1, LUCENT-2 and LUCENT-3. LUCENT-1 (NCT03518086) is a multicenter, randomized, double-blind, placebocontrolled, Phase 3 induction study of mirikizumab in patients with moderate to severe UC who had failed conventional and/or biologic treatments. LUCENT-2 (NCT03524092) is a multicenter, randomized, double-blind, placebo-controlled maintenance study of mirikizumab in patients who have completed the 12-week LUCENT-1 induction study. LUCENT-3 (NCT03519945) is an open label extension study for eligible patients who have participated in mirikizumab UC trials.

The program began in 2018, with full results from the induction and maintenance studies anticipated in early 2022.

About Ulcerative Colitis

Ulcerative colitis is a chronic inflammatory bowel disease that affects the colon.1 UC occurs when the immune system sends white blood cells into the lining of the intestines, where they produce chronic inflammation and ulcerations.3 There is an unmet need for additional treatment options for UC that provide meaningful symptom relief, including bowel urgency, and deliver sustained clinical remission.

About Eli Lilly and Company

Lilly is a global health care leader that unites caring with discovery to create medicines that make life better for people around the world. We were founded more than a century ago by a man committed to creating high-quality medicines that meet real needs, and today we remain true to that mission in all our work. Across the globe, Lilly employees work to discover and bring lifechanging medicines to those who need them, improve the understanding and management of disease, and give back to communities through philanthropy and volunteerism.

To learn more about Lilly, please visit us at: lilly.com and lilly.com/newsroom

This press release contains forward-looking statements (as that term is defined in the Private Securities Litigation Reform Act of 1995) about mirikizumab as a potential treatment for patients with ulcerative colitis and other diseases and reflects Lilly’s current beliefs and expectations. As with any pharmaceutical product, there are substantial risks and uncertainties in the process of drug research, development, and commercialization. Among other things, there can be no guarantee that future study results will be consistent with study results to date, that mirikizumab will prove to be a safe and effective treatment or that mirikizumab will receive regulatory approvals or be commercially successful. For further discussion of these and other risks and uncertainties, see Lilly’s most recent Form 10-K and Form 10-Q filings with the United States Securities and Exchange Commission. Except as required by law, Lilly undertakes no duty to update forward-looking statements to reflect events after the date of this release.

  1. Overview of Ulcerative Colitis. Crohn’s and Colitis Foundation Website.https://www.crohnscolitisfoundation.org/what-is-ulcerativecolitis/overview. Accessed February 2021.
  2. Adelphi Data 2017.
  3. What is Ulcerative Colitis? Crohn’s and Colitis Foundation Website. http://www.crohnscolitisfoundation.org/what-are-crohns-and-colitis/ what-is-ulcerative-colitis/. Accessed February 2021

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FROM THE PEDIATRIC LITERATURE

Teduglutide and Short Bowel Syndrome in Children

April 2021 • Volume XLV, Issue 4

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Intestinal failure due to short bowel syndrome (SBS) is disabling as well as life-threatening in children. Teduglutide is a glucagon-like peptide-2 which promotes intestinal growth and bowel adaption. There is minimal data in children regarding the efficacy of this new medication, and the authors of this prospective, multi-center study followed 17 children with SBS who were treated with teduglutide at 0.05mg/kg/day via the subcutaneous route. All included patients had less than 100 cm of remaining bowel (except for 2 patients), were on parenteral nutrition (PN), and had no surgical intervention or changes in PN for 3 months prior to teduglutide use. At each clinic visit (baseline, 3 months, 6 months, and 12 months after therapy), information on PN volume, nutritional support, recorded stool losses, plasma citrulline levels, and the presence of adverse events were recorded. Any patient with a reduction in PN by 20% was defined as a “responder”. All patients were older than one year of age, and all patients developed intestinal failure after birth. The most common cause of intestinal failure was necrotizing enterocolitis. These patients were receiving an average 55 mL/kg/day of fluid volume daily (range 8-210 mL/kg/day) and were receiving 33 kcal/k/ day of nutritional support (range 0-65 kcal/kg/ day). Their mean initial citrulline level was 20 micromoles/L (range 7.8-51 micromoles/L).

A total of 15 of the 17 patients were able to complete one year of teduglutide. By the 3-month follow up, 3 patients had achieved full enteral autonomy. This trend continued with an additional 4 patients and then 3 patients reaching full enteral autonomy at 6 months and 12 months, respectively. Most patients were able to reduce their fluid volume and nutritional support, and in total, 14 of the 15 patients who finished the therapeutic study were responders to teduglutide. A 20% or greater reduction in PN support was noted in 47%, 87%, and 93% of patients at 3, 6, and 12 months respectively, while 17%, 44%, and 60% of patients were able to wean off of PN at 3, 6, and 12 months respectively. Stool output improved and citrulline levels increased in all patients throughout the study. The most common adverse events consisted of abdominal pain occurring in 30% of patients, followed by injection-site reactions, nausea, headaches, abdominal distention, and the presence of upper respiratory tract infections. Most of these side effects were mild or moderate.

This small study demonstrates promising results regarding the efficacy of teduglutide in the treatment of pediatric intestinal failure. More research is needed for children with an even greater loss of bowel as well as determination of cost savings associated with teduglutide use.

Boluda E, Ferreiro S, Moral O, Romero R, Terradillows I, Ramos R, Diaz M, Miquel B, Pinera I, Sanchez A, Sacristan R, Barea M, Villares J. Experience with teduglutide in pediatric short bowel syndrome: first real-life data. Journal of Pediatric Gastroenterology and Nutrition 2020; 71: 734-739.

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FROM THE PEDIATRIC LITERATURE

How Common are Pediatric Feeding Disorders?

April 2021 • Volume XLV, Issue 4

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Feeding disorders in children commonly are seen in both the primary care and pediatric gastroenterology setting. There is no good epidemiologic data about the prevalence of pediatric feeding disorders in children in the United States. Thus, the authors of this study used de-identified data from the Truven Health Analytics MarketScan Commercial Claims and Encounters Database (Ann Arbor, Michigan) for patients with private insurance as well as Arizona and Wisconsin Medicaid data for patients with Medicaid covering the time period from 2009 to 2014. Children between 2 months and 18 years were included in the study, and the authors used 25 International Classification of Diseases (ICD)-9 and ICD-10 codes to identify potential study subjects as there is no specific “feeding disorder” diagnosis code for children. Children who had been diagnosed with one of these codes and not with an eating disorder were included. The authors evaluated all such patients for comorbid conditions, the presence of malnutrition/ failure to thrive, and the presence of a gastrostomy tube. Children were identified as having a complex chronic condition (CCC) based on known ICD codes if they had a medical condition expected to last at least 12 months and had at least one organ system involvement which could require pediatric subspecialty care and potential hospitalization.

The presence of feeding disorders increased in all databases during the time period with significantly more children covered by Medicaid having feeding disorders (Arizona, 16.97 per 1000 child-years; 95% CI, 16.84-17.10 and Wisconsin, 21.43 per 1000 child-years; 95% CI, 21.27-21.60) compared to children covered with private insurance (9.38 per 1000 child-years; 95% CI, 9.35-9.40). A lower prevalence of feeding disorders was present in older patients (defined as 12-18 years old), and more males had feeding disorders compared to females throughout the study. Specific patients with CCC (including children with respiratory, gastrointestinal, miscellaneous technology dependency, prematurity/neonatal risk, and organ transplantation) had higher rates of feeding disorders, and the prevalence of feeding disorders in children with a CCC increased throughout the study despite no increase in the number of children with a feeding disorder and without a CCC. Although the prevalence of malnutrition in children with a feeding disorder decreased in all databases throughout the study, children with an associated CCC had a higher prevalence of a malnutrition. The prevalence of gastrostomy tubes decreased in this population throughout the study period, and most children who had both a feeding disorder and a gastrostomy tube also had an associated CCC. This study demonstrates that pediatric feeding disorders are increasing in children in the United States, and this disorder is commonly associated with the presence of a CCC. Thus, we need early intervention as well as improved long-term treatment options for this population as well as better accuracy in ICD coding in order to track and to care for these children over time.

Kovacic K, Rein L, Szabo A, Kommareddy S, Bhagavatula P, Goday P. Pediatric feeding disorder: a nationwide prevalence study. Journal of Pediatrics 2021; 228: 126-131.

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FROM THE LITERATURE

Gastric Cancer Incidence Among Races and Ethnicities in Patients Age 50 Years and Older

April 2021 • Volume XLV, Issue 4

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To evaluate the racial and ethnic differences in the incidence of gastric adenocarcinoma worldwide and in the United States, based on a decision analysis, screening for noncardia gastric adenocarcinoma might be cost-effective for non-White individuals 50 years or older. A lack of precise contemporary information on gastric adenocarcinoma incidence in specific anatomic sites for this age group has impeded prevention and early detection programs in the U.S.

To estimate the differences in gastric adenocarcinoma incidence in specific anatomic sites among races and ethnicities in individuals 50 years or older, the California Cancer Registry data from 2011 through 2015 was evaluated to estimate incidences of gastric adenoma in specific anatomic sites for non-Hispanic White (NHW), non-Hispanic black, Hispanic and the seventh largest Asian-American populations. Calculation was carried out as to the differential incidence between non-White groups and NHW, using incidence rate ratios and 95% confidence intervals (CIs).

Compared with NHW subjects, all non-White groups had significantly higher incidences of noncardiac gastric adenocarcinoma. The incidence was highest among Korean-American men 50 years and older (70 cases per 100,000). Compared with NHW subjects 50 years and older, the risk of noncardiac gastric adenocarcinoma was 1.8-fold to 7.3-fold, higher in most non-White groups and 12- fold to 14.5-fold higher among Korean-American men and women 50 years and older, respectively.

Compared with NHW men 50 years and older, all non-White men, except Japanese and KoreanAmerican men had a significantly lower risk of cardia gastric adenocarcinoma.

There was identification of several-fold differences in evidence of gastric adenocarcinoma in specific anatomic sites among racial and ethnic groups, with significant age and sex differences. These findings should be used to develop targeted risk reduction programs for gastric adenocarcinoma.

Shah, S., McKinley, M., Gupta, S., et al. “Population-Based Analysis of Differences in Gastric Cancer Incidence Among Races and Ethnicities in Individuals Aged 50 Years and Older.” Gastroenterology 2020; Vol. 159, pp. 1705-1714.

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