Gastroenterology and Endoscopy News ( October 2020 )

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@=206.9 216A6<; Annual Supplement to Gastroenterology & Endoscopy News â&#x20AC;˘ 2020

From the News: Eosinophilic Disorders From the News: Inflammatory Bowel Disease The Role of Biomarkers In the Management Of Barrettâ&#x20AC;&#x2122;s Esophagus Cases From the Frontiers Of Therapeutic Ultrasound in 2020 Pancreatic Cystic Lesions: Diagnosis, Evaluation, And Management Updated Evidence for Optimal Management of C. diff Infection From the News: Endoscopic Resection Determinants of Bowel Preparation Quality for Colonoscopy Helicobacter pylori: An Update Ancillary Services and Practice Management

Investigate all 3 domains together to uncover the hidden signs of chronic inflammation in EoE.1-4

Symptoms, such as dysphagia, may be masked by adaptive

behaviors that patients unknowingly develop1,5

Endoscopy can miss complications such as strictures caused by

Ç&#x2030;ÇŚČ&#x2013;Č&#x2026;ǿNJÇ&#x2030; ÇŠÇżĐ&#x153; ĆşÇžÇžĆşČ ÇŠČ&#x2026;Çż ÇŠÇż Č&#x2026; Ç?ČŁÇ&#x201C; Č Č&#x2026; Č ÇŚÇ&#x201C; Ç?ÇŠČ&#x2122;Ç&#x201C;ĆşČ&#x2122;Ç&#x201C;ŕ§?Č&#x2122; Č&#x2019;ĆşČ Ç&#x2030;ÇŚÎĄ ÇżĆşČ ČŁČ&#x2013;Ç&#x201C; 1-4,6,7

Histopathology may help confirm a suspected diagnosis, but esophageal eosinophilia with â&#x2030;Ľ15 eos/hpf can be a sign of various Ç&#x201C;Č&#x2122;Č&#x2026;Č&#x2019;ÇŚĆşÇ Ç&#x201C;ƺǚ Ç?ÇŠČ&#x2122;Ç&#x201C;ĆşČ&#x2122;Ç&#x201C;Č&#x2122; Ç&#x2C6;Ç&#x201C;Č&#x2122;ÇŠÇ?Ç&#x201C;Č&#x2122; Č&#x2026; 2,3

Learn more at revealEoE.com

;ovơ;ovbmor_bŃ´vĸ _r=ơ_b]_Ĺ&#x160;roÂ&#x2030;;u C ;Ń´7Äş References: 1. Â&#x2020;bu ġ uoÂ&#x2030;mĹ&#x160;)_b|;_oum $ġ o7Â&#x2030;bm ġ ;| -Ń´Äş Clin Exp GastroenterolÄş Ć&#x2018;Ć?Ć?Ć&#x2013;ĸĆ?Ć&#x2018;ÄšĆ&#x2019;Ć&#x2013;Ć?Ĺ&#x160;Ć&#x2019;Ć&#x2013;Ć&#x2013;Äş 2. ;Ń´Ń´om "ġ b-1oÂ&#x2020;u-v ġ oŃ´bm-Ĺ&#x160; m=-m|; ġ ;| -Ń´Äş GastroenterologyÄş Ć&#x2018;Ć?Ć?ќĸĆ?Ć&#x201D;Ć&#x201D;Ĺ?Ć&#x201C;Ĺ&#x2018;ÄšĆ?Ć?Ć&#x2018;Ć&#x2018;Ĺ&#x160;Ć?Ć?Ć&#x2019;Ć&#x2019;Äş;Ć?Ć?Äş 3. Â&#x2020;1;m7o ġ oŃ´bm-Ĺ&#x160; m=-m|; ġ ub-v ġ ;| -Ń´Äş United European Gastroenterol JÄş Ć&#x2018;Ć?Ć?Ć&#x2022;ĸĆ&#x201D;Ĺ?Ć&#x2019;Ĺ&#x2018;ÄšĆ&#x2019;Ć&#x2019;Ć&#x201D;Ĺ&#x160;Ć&#x2019;Ć&#x201D;ќĺ 4. "-=uom;;Â&#x2C6;- ġ "|u-Â&#x2020;l-mm ġ ovŃ´oÂ&#x2C6;vhÂ&#x2039; ġ ;| -Ń´Äş GastroenterologyÄş Ć&#x2018;Ć?Ć?ѾĸĆ?Ć&#x201D;Ć?Ĺ?Ć&#x2019;Ĺ&#x2018;ÄšĆ&#x201D;ŃśĆ?Ĺ&#x160;Ć&#x201D;Ć&#x2013;Ć?Äş;Ć&#x201C;Äş 5. bu-mo ġ Â&#x2020;uÂ&#x2020;|- $Äş GastroenterologyÄş Ć&#x2018;Ć?Ć&#x2018;Ć?ĸĆ?Ć&#x201D;ŃśĹ?Ć&#x201C;Ĺ&#x2018;ĚќĆ&#x201C;Ć?Ĺ&#x160;ŃśĆ&#x201D;Ć?Äş 6. bu-mo Äş GastroenterologyÄş Ć&#x2018;Ć?Ć?ќĸĆ?Ć&#x201D;Ć&#x201D;ĚѾĆ?Ć?Ĺ&#x160;ŃľĆ?Ѿĺ 7. "-@ -ub ġ ;|;uvom ġ -m] ġ ;| -Ń´Äş J Allergy Clin ImmunolÄş Ć&#x2018;Ć?Ć?Ć&#x2018;ĸĆ?Ć&#x2019;Ć?Ĺ?Ć&#x2019;Ĺ&#x2018;ÄšĆ&#x2022;Ć&#x2013;ŃśĹ&#x160;ŃśĆ?Ć?Äş ĹĄĆ&#x2018;Ć?Ć&#x2018;Ć? $-h;7- _-ul-1;Â&#x2020;ŕŚ&#x17E; 1-Ń´v &Äş"Äş Äş m1Äş Ń´Ń´ ub]_|v u;v;uÂ&#x2C6;;7Äş $ -m7 |_; $ o]o -u; |u-7;l-uhv ou u;]bv|;u;7 |u-7;l-uhv o= $-h;7- _-ul-1;Â&#x2020;ŕŚ&#x17E; 1-Ń´ olr-mÂ&#x2039; blb|;7Äş $_; " o o]o bv - |u-7;l-uh o= "_bu; (buo _-ul- ġ - $-h;7- 1olr-mÂ&#x2039;Äş &"Ĺ&#x160; Ĺ&#x160;Ć?Ć&#x2018;Ć&#x201C;Ć&#x2013;Â&#x2C6;Ć?ÄşĆ? Ć?ŃśĹ&#x2020;Ć&#x2018;Ć?

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@=206.9 216A6<; Annual Supplement to Gastroenterology & Endoscopy News • 2020

8 16 31 37

Cases From the Frontiers of Therapeutic Ultrasound in 2020

57 65 76

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From the News: Inflammatory Bowel Disease The Role of Biomarkers in the Management of Barrett’s Esophagus

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From the News: Eosinophilic Disorders

Ashton Ellison, MB ChB • Vani Konda, MD

Andrew C. Storm, MD • Michael J. Levy, MD

Pancreatic Cystic Lesions: Diagnosis, Evaluation, and Management Antonio R. Cheesman, MD • Gaurav Kakked, MD Christopher J. DiMaio, MD

Updated Evidence for Optimal Management of C. diff Infection Mark H. Wilcox, MD, FRCPath

From the News: Endoscopic Resection Determinants of Bowel Preparation Quality For Colonoscopy: The Role of Modifiable And Nonmodifiable Factors Shashank Sarvepalli, MD, MS • Zunirah Ahmed, MD Yousaf Zafar, MD • Carol A. Burke, MD

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Helicobacter pylori: An Update

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Ancillary Services and Practice Management

Frederick B. Peng, MD • David Y. Graham, MD Mimi C. Tan, MD, MPH

GASTROENTEROLOGIST† RECOMMENDED Brands for Digestive Health

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DAILY PROBIOTIC SUPPLEMENT Recommend ALIGN® to help with occasional:* · Abdominal discomfort · Gas · Bloating

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Metamucil®: OTC Therapeutic Fiber category. Align®: Probiotic Category. ^ It’s possible while taking Prilosec OTC. Use as directed for 14 days to treat frequent heartburn. May take 1-4 days for full effect. * THESE STATEMENTS HAVE NOT BEEN EVALUATED BY THE FOOD AND DRUG ADMINISTRATION. THIS PRODUCT IS NOT INTENDED TO DIAGNOSE, TREAT, CURE, OR PREVENT ANY DISEASE.

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IBD Patients Are More Likely To Have Eosinophilic Esophagitis

E

osinophilic esophagitis has been found to be

four times more common in patients with inflammatory bowel disease than the general population.

The increased risk is associated with both Crohn’s disease and ulcerative colitis, according to researchers led by Thomas Sferra, MD, the chief of the Division of Pediatric Gastroenterology, Hepatology and Nutrition at UH Rainbow Babies & Children’s Hospital, in Cleveland.

“You have to be aware these two diseases could coexist, and patients presenting with appropriate symptoms should be evaluated for eosinophilic esophagitis and treated differently than for their

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inflammatory bowel disease,” Dr. Sferra said. “For IBD, you primarily use several different medications that affect different regions of the GI tract, and some of these medications are not indicated therapies for eosinophilic esophagitis and would not be sufficient for treatment of this disease.”

EoE is becoming more prevalent and increasingly is recognized as being associated with other medical conditions, including autoimmune-mediated diseases. Dr. Sferra, who also is a professor of

Table. Clinical Comparison of Patients With and Without EoE Condition

Patients With EoE, % Patients Without EoE, %

History of dysphagia

P Value

46

8.6

<0.0001

Gastroesophageal reflux disease

64.5

35.4

<0.0001

Atopic IgE-mediated allergic disorders

37.9

20.09

<0.0001

pediatrics at Case Western Reserve University School therapies confer a risk for EoE, Dr. Sferra said. Disease of Medicine, in Cleveland, and his colleagues decided awareness by the managing gastroenterologist might to undertake the study after seeing an increase in the also be a factor. Further study is needed to determine number of children with IBD who met the criteria for a if there are differences between children and adults, diagnosis of EoE. he said.

The researchers used the Explorys database to iden“We need to do more studies, single-center and protify a cohort of children and adults with EoE and IBD, spective studies, to try to identify what is causing this Crohn’s disease and ulcerative coliincrease of eosinophilic esophatis, between 2014 and 2019. Explogitis in inflammatory bowel disrys integrates de-identified elecease,” Dr. Sferra said. “Is it the distronic health records from 26 ease itself or is it a consequence ‘You have to be aware these health care systems in the United of any of the therapies that we are States, spanning more than 360 using for inflammatory bowel distwo diseases could coexist, hospitals. At the time of data ease that may increase the risk of extraction, the database included eosinophilic esophagitis?” and patients presenting with 36,857,870 patients, of whom Miguel Regueiro, MD, the appropriate symptoms should chair of the Department of 400,040 (1.08%) with IBD and 28,670 (0.8%) with EoE. Gastroenterology, Hepatology and be evaluated for eosinophilic The investigators found that Nutrition, and a professor of medpatients with IBD had a significine at Cleveland Clinic in Ohio, esophagitis and treated icantly higher prevalence of said the fact that there is such a differently than for their EoE compared with the genhigh prevalence of EoE in IBD was eral population (0.31% vs. 0.08%; surprising. “I think that when you inflammatory bowel disease,’ P<0.0001), or 4.1 times higher look at EoE and IBD and the global odds of having the dual diagincreases in both, it really speaks —Thomas Sferra, MD nosis (2019 annual meeting of to environmental factors that are UH Rainbow Babies & Children’s the North American Society for changing,” said Dr. Regueiro, who Hospital, Cleveland Pediatric Gastroenterology, Hepwas not involved with the research. atology and Nutrition; abstract “These diseases can’t be due to 307). The prevalence of EoE was genetics only because genetics similar in patients with Crohn’s disease and ulcertakes thousands of years to change, and you would see ative colitis (0.35% vs. 0.32%; P=0.33). Compared with it clustered in patients differently. My opinion is that patients who did not have EoE, patients with the conEoE and IBD are probably going to turn out to be somedition more frequently had a history of dysphagia, gasthing in the diet, based on the fact that it is affecting troesophageal reflux disease and atopic IgE-mediated the GI tract in two different places—the esophagus and allergic disorders (Table). the intestine and bowel.”

The finding that IBD patients with EoE are more Dr. Regueiro said he didn’t know “whether the assolikely to have proximal gastrointestinal tract symptoms ciation of EoE with IBD without symptoms means we and IgE-mediated allergic disorders provides clues as should look for EoE in IBD patients right now, but the to which IBD patients also might have EoE, accordabstract really leads to the question of should we in the ing to Dr. Sferra. The reason EoE is more common in future.”

IBD is unclear. It is possible that pathology associated —Kate O’Rourke with IBD, such as increased intestinal permeability or Drs. Regueiro and Sferra reported no relevant financial conflicts of interest. an altered microbiome, or perhaps the use of specific

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Novel Method Promising For Diagnosing Fibrosis in EoE

F

or some children with eosinophilic esophagitis, fibrosis of the

lamina propria can be a significant complication of the condition. But clinicians have struggled to diagnose the condition because available tools for taking biopsies of the affected tissue are not particularly effective.

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New research involving a novel biopsy forceps and and digital quantification of the total fluorescence immunofluorescence imaging could change that. In a signal. The cost of CHP imaging is similar to that of pilot study, the combination showed promise for diagtypical immunostaining, with rapid clinical turnaround nosing lamina propria fibrosis in (eight to 24 hours), according to children with EoE. Dr. Robson.

“Lamina propria fibrosis can A pathologist graded whether lead to notable symptoms in kids, lamina propria fibrosis was present ‘Lamina propria fibrosis such as trouble swallowing or and scored its severity on a 1-3 even food getting stuck. It is quite scale (1=not fibrotic, 2=moderate can lead to notable tricky to diagnose lamina propria fibrosis, and 3=features of notable fibrosis because our typical endofibrosis). All biopsies had at least symptoms in kids, such scopic biopsies do not reliably one section with adequate tissue yield adequate lamina propria tisfor evaluation. as trouble swallowing or sue for evaluation,” said lead inves“Our main finding was that we tigator Jacob Robson, MD, MS, an were able to safely and reliably even food getting stuck.’ assistant professor in the Division obtain lamina propria for evaluation of Pediatric Gastroenterology at under the microscope,” Dr. Robson —Jacob Robson, MD, MS the University of Utah School of said. “Second, we were able to use University of Utah School of Medicine, in Salt Lake City. collagen hybridizing peptides to Medicine, Salt Lake City “From this small study, it show the degree of fibrosis within appears we are able to safely and the tissue. We were able to use a reliably obtain lamina propria for special tissue stain to make the evaluation. We are very excited to deeper tissue fibrosis light up. study this further, because we think it could have a Our study is one of the first to look at lamina propria major impact in the care of children with EoE,” he said. fibrosis in children with EoE just using the commercially Despite the increasing incidence of EoE, many available biopsy forceps.” Larger, prospective cohort aspects of the condition remain poorly understood, studies are needed to further investigate the issue, he particularly the occurrence of lamina propria fibrosis in said. children. To date, fibrosis has not been part of an activ“For a long time, we said we are not able to reliably ity index for EoE because clinicians are able to obtain assess lamina propria fibrosis in children with EoE, so adequate tissue samples to determine a diagnosis in we will track other disease metrics,” Dr. Robson said. fewer than 50% of cases, and taking multiple biop“I think this [new technology] gives us an opportunity sies to overcome this hurdle is not ideal (Gastrointest to put more weight on lamina propria fibrosis assessEndosc 2018;87[5]:1207-1214). Peak esophageal eosinment, and it allows us to do a better job of understandophil counts per high-power field are the benchmark ing if some of the children’s symptoms are driven by for EoE disease activity, but they correlate poorly with this fibrosis.” symptoms after treatment. Fibrosis may correlate betEdaire Cheng, MD, an assistant professor of pediter with certain EoE symptoms, such as dysphagia and atrics and the medical research director of the Dallas food impactions, according to Dr. Robson.

Eosinophilic GI Diseases and Esophagitis Program at In a study of adults with EoE by Bussmann et al, the University of Texas Southwestern Medical Center, the use of static jaw, side-opening forceps (Olympus said the forceps appeared to be safe to use in children. model FB-45Q-1) enabled procurement of target tissue Dr. Cheng was not involved in the study. in 90% of cases, with no adverse events (Endoscopy “It’s a small study, but the main thing I take away is 2016;48[12]:1069-1075). that using the side-opening forcep is consistent with In the new study, the researchers presented their what was seen in the [Bussmann et al] study in adults. experience with the reusable forceps and novel immuSo far, it seems like the forcep might be safe to use nofluorescence imaging techniques in a pilot samin pediatric patients. The amount of lamina propria ple of three children with EoE (2019 meeting of the obtained by the forcep is impressive, and the quality North American Society for Pediatric Gastroenterology, of the lamina propria will need to be further evaluHepatology and Nutrition; abstract 508). ated,” Dr. Cheng said. “At this point, I think the sideThey used collagen hybridizing peptides (CHPs) opening forceps will likely be further examined in the and immunofluorescence signal measurements academic setting. The CHP staining is novel and will for fibrosis quantification. CHPs can be added to likely require several steps in research and development fresh/frozen or formalin-fixed tissue specimens, where before reaching clinical practice. I look forward to future they bind unfolded collagen chains by forming a findings by the investigators.” collagen-specific triple helical structure. CHPs can —Kate O’Rourke be labeled with fluorescent 5-FAM or other such Drs. Robson and Cheng reported no relevant financial conflicts of interest. common dyes, to allow for fluorescence imaging

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In Pediatric UC and Crohnâ&#x20AC;&#x2122;s, Presentation of EoE May Differ

E

osinophilic esophagitis appears to be more common in patients with ulcerative colitis than

Crohnâ&#x20AC;&#x2122;s disease, according to a study by researchers in Cleveland.

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The study also found that for people with Crohn’s, induction of disease remission with infliximab appears to be associated with development of the esophageal condition—a connection to which clinicians should be alert.

“If you have a patient who has Crohn’s disease and they are showing signs of dysphagia after they have been on treatment with infliximab and their disease seems under control, you need to think of EoE and do an upper endoscopy,” said Judy Splawski, MD, a pediatric gastroenterologist at UH Rainbow Babies and Children’s Hospital, in Cleveland, who helped conduct the new study. “I think the study demonstrates that ulcerative colitis and Crohn’s disease really do have different immune profiles.”

EoE has been associated with celiac disease and other autoimmune conditions. Ulcerative colitis and Crohn’s disease have different clinical presentations and immune profiles. The first is more associated with Th2 cytokines, whereas Crohn’s is more related to Th1 cytokines. The Cleveland researchers hypothesized that there might be differences in the association of EoE with different forms of inflammatory bowel disease.

Using billing codes, the researchers generated lists of pediatric patients with the diagnosis of IBD and a diagnosis of EoE, defined as any esophageal biopsy with greater than 15 eosinophils per high power field (eos/hpf). They collected demographic, clinical, laboratory, endoscopic and histologic data.

The investigators found that 8.2% of pediatric IBD patients also had a diagnosis of EoE (2019 annual meeting of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition; abstract 568). Of that group, 56.7% had ulcerative colitis and 43.3% had Crohn’s. These findings differed from those from another study presented at the meeting (abstract 307), which showed that the prevalence of EoE was similar in patients with Crohn’s and those with ulcerative colitis.

“Our study had a higher incidence of EoE than has previously been reported. However, in reviewing the pathology reports, there were a significant number of IBD patients who were not coded as having EoE even though they had more than 15 eos/hpf,” Dr. Splawski

told Gastroenterology & Endoscopy News.

“In ulcerative colitis patients, most of the time EoE was present at the time of diagnosis, but the Crohn’s disease patients were more often diagnosed with EoE after their diagnosis of inflammatory bowel disease, on a follow-up scope,” Dr. Splawski said.

All 10 of the patients with Crohn’s disease and EoE who were diagnosed with EoE after their diagnosis of IBD were on infliximab before EoE was diagnosed.

Most of these patients had mild disease or were in remission at the time of EoE diagnosis, whereas the majority of the patients with ulcerative colitis and EoE had active disease at the time of their EoE diagnosis.

“All 10 of the Crohn’s disease patients diagnosed with EoE on follow-up were on infliximab, and when we looked at their disease activity, they had mild disease or they were in remission and had nearly normal labs and endoscopies at the time they were diagnosed with EoE,” Dr. Splawski said. “We don’t know if the development of EoE in Crohn’s disease is related to an effect of [the drug] on the immune profile or if it is specific to infliximab or whether we will see this effect with other biologics that have different immune targets.”

Miguel Regueiro, MD, the chair of the Department of Gastroenterology, Hepatology and Nutrition, and a professor of medicine at Cleveland Clinic in Ohio, said clinicians have been wondering whether eosinophils on biopsy signal a patient who is harder to treat and might require more surgery.

“The fact that they are actually picking up eosinophilic esophagitis at higher rates in patients with ulcerative colitis also makes you wonder, given the biologic necessity of infliximab, whether it represents a more aggressive course,” said Dr. Regueiro, who was not involved with the research. “If you have a patient with ulcerative colitis who is not responding the way you think they should to milder treatment, and they have the EoE, I would use that as a potential predictor of more severe course that would probably prompt me to think about using biologic or more aggressive therapy earlier.”

—Kate O’Rourke Drs. Regueiro and Splawski reported no relevant financial conflicts of interest.

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Antibody in Phase 3 Trial Might Be First Therapy For Eosinophilic Gastritis

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novel drug alleviated inflammation and symptoms of eosinophilic gastritis and eosinophilic duodenitis

in a randomized, double-blind trial. Antolimab (Allakos), a monoclonal antibody targeting siglec-8, is on track to become the first therapy indicated for eosinophilia below the esophagus in the GI tract.

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In the phase 2 study, called ENIGMA, antolimab “met all prespecified end points, demonstrating significant histologic and symptomatic improvement,” Evan S. Dellon, MD, a professor of medicine and epidemiology at the University of North Carolina at Chapel Hill, said.

In the trial, 65 patients with eosinophilic gastritis or eosinophilic duodenitis were randomized to one of two doses of antolimab or placebo. The primary end point was mean percentage change in eosinophils.

Four doses of the study drugs were administered four weeks apart. A biopsy and symptom assessment obtained two weeks after the last dose were compared with baseline measures, said Dr. Dellon, whose group submitted the findings to the 2020 Digestive Disease Week (abstract 932).

Eosinophil counts, which were approximately 75 per high-power field at baseline, fell by more than 90% from baseline with either the high or low doses of antolimab (P<0.0001), according to the researchers.

Eosinophil counts rose by 10% in the placebo group.

On a secondary responder end point that included at least a 30% improvement in a prespecified Total Symptom Score (TSS) and at least a 75% reduction in eosinophil counts, the response rates were 70%, 68% and 5% in the high-dose (P=0.0009), low-dose (P=0.0019), and placebo groups, respectively.

Response rates solely on the basis of the TSS, which measured eight symptoms, were 58%, 49% and 24%, in the high-dose (P=0.0012), low-dose (P=0.015), and placebo groups, respectively. Median reductions were substantial for all eight of the symptoms contained in the TSS, ranging from 47% for bloating and 55% for diarrhea to 79% for nausea and 100% for vomiting, the researchers reported.

The most common adverse events with antolimab were mild to moderate reactions related to the infusion, Dr. Dellon said.

In an exploratory analysis of the 25 patients in this study who had concomitant eosinophilic esophagitis (EoE), 93% of those randomized to antolimab versus 11% of placebo patients achieved an eosinophil count of 6 or fewer per high-power field.

In an open-label extension of the study, 58 of the 59 eligible participants from the randomized trial, including those switched from placebo, were followed long term on the higher dose of antolimab. Nirmala Gonsalves, MD, a professor of gastroenterology and hepatology at the Feinberg School of Medicine of Northwestern University, in Chicago, and Kathryn A. Peterson, MD, an associate professor at the University of Utah, in Salt Lake City, submitted these data separately (abstract 228).

The extension data indicated a greater reduction in symptoms with a longer period of treatment. The relative mean change from baseline in TSS rose from 51% in patients with at least 13 weeks of exposure to 53% in those with at least 29 weeks of exposure, according to the researchers.

In the subgroup of 30 patients with at least 52 weeks of antolimab exposure, the median improvements were 80% or greater for seven of the eight symptoms. The exception was bloating, with a median score reduction of 57%, the study found.

The large, and in many cases, complete depletion of eosinophils observed in the randomized trial was sustained in the extension, Dr. Gonsalves said. Antolimab was well tolerated in the randomized trial, and no new or unexpected adverse events occurred in the extension arm, she reported.

The target of antolimab, siglec-8, is a receptor on the mast cells and eosinophils. Blocking the receptor depletes both types of cells, which appears to be the mechanism of action of the drug’s anti-inflammatory effect. The target is being evaluated in the control of other diseases mediated by these cells, including urticaria, asthma and allergic conjunctivitis.

A phase 3 pivotal trial with antolimab for eosinophilic gastritis and eosinophilic duodenitis with a planned enrollment of 160 patients has been announced, as has a randomized trial for eosinophilic esophagitis.

The FDA has yet to approve a treatment for EoE, a better-studied eosinophilic inflammation of the upper GI tract. A positive phase 3 trial with budesonide suspension was completed last year, so a licensed therapy might be coming, but Stuart J. Spechler, MD, the chief of gastroenterology at Baylor University Medical Center, in Dallas, said these eosinophilic diseases are distinct.

“The incidence of EoE has increased dramatically over the past two decades to the point that gastroenterologists are seeing these patients with some regularity. In contrast, eosinophilic gastritis and eosinophilic duodenitis remain rare GI disorders that a general gastroenterologist might not encounter in a lifetime of practice,” Dr. Spechler told Gastroenterology & Endoscopy News.

Yet, “allergy-related eosinophilic GI disorders may well be increasing in frequency,” and effective treatments are welcome, Dr. Spechler said. In patients with symptomatic eosinophilia in the stomach and duodenum, the findings for antolimab provide “good news,” but this patient population remains small.

—Ted Bosworth Dr. Dellon reported financial relationships with Abbott, Adare, Aimmune, Allakos, AstraZeneca, Biorasi, Calypso, Celgene, Eli Lilly, EsoCap, GlaxoSmithKline, Regeneron, Robarts, Salix and Shire/Takeda. Dr. Gonsalves reported no relevant financial conflicts of interest.

Dr. Peterson reported financial relationships with Allakos, AstraZeneca, Eli Lilly, Nexeos and Takeda. Dr. Spechler reported financial relationships with Frazier Management, Interpace Diagnostics, Ironwood Pharmaceuticals and Phatom Pharmaceuticals.

Allakos funded both studies.

G AST R O E N T E R O LO GY & E N D O S CO PY N E WS S P E C I A L E D I T I O N • O C TO B E R 2 02 0

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Building a Medical Home for IBD? Here’s What You Need to Know

T

he patient-centered medical home model of

treatment, with its emphasis on comprehensive, patient-oriented care, is well suited to severe inflammatory bowel disease.

In this model, patients receive care from a medical team that addresses all of the patient’s needs, both physical and psychological, around a disease state. For IBD, this might include a psychologist, psychiatrist, dietitian and social worker, who help the patients to manage their daily lives. The gastroenterologist and primary care physician provide the foundation for their team members, attending to the patient’s disease status and overall physical health. The IBD medical home need not be physical; the providers on a team might choose to collaborate electronically using telehealth resources, such as secure email, video chats and phone calls.

But a medical home that operates under a single roof offers the advantages of closer communication and collaboration among providers and, ultimately, a more closely-knit team. (The threat of COVID-19 has prompted medical homes to turn to telehealth for the duration of the crisis.)

Starting and running a medical home for IBD take coordination, resources and a network of like-minded medical practitioners. Establishing one can seem like a daunting task. We asked three doctors with knowledge of the IBD medical home model for tips on how to build a robust medical home for IBD. Here are a few things to consider.

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G AST R O E N D O N E WS .CO M

Building a Comprehensive Team Teams are the “secret sauce” of any successful medical home, Miguel Regueiro, MD, the chair of gastroenterology and hepatology at Cleveland Clinic in Cleveland, said. “The IBD home is really a multispecialty group that includes a dietitian; psychosocial care, which may include a psychologist, a social worker and a psychiatrist; a gastroenterologist; a surgeon; and a pharmacist, and is where the principal care for ulcerative colitis and Crohn’s disease occur,” he said. “It’s a one-stop shop, but beyond that, you’re looking at the whole person, not just their disease, but issues with stress, paying for medications, diet questions and so on.”

“You have to find people who are willing to work within a team and change their approach to a patient based on the team’s priorities, not their own,” Laurie Keefer, PhD, the director of psychobehavioral research within the Division of Gastroenterology at Mount Sinai Hospital, in New York City, said. “For example, it is not uncommon for the mental health provider to choose to focus on depression and the nutritionist to focus on malnutrition; the patient is prescribed multiple tasks for each, when really the depression and malnutrition are directly related and the two expert providers need to set up the treatment plan together.”

Dr. Regueiro added that while building a full team is challenging, the rewards are worth it. “In this model, we all work together to care for patients and to care for each other, and in that process we almost become a family. It’s a powerful thing, and it may reduce burnout and improve job satisfaction and engagement.”

Money and Space Dr. Regueiro said ensuring that providers get paid fairly is the “biggest problem” with the medical home model. “One way is to work in a hospital system where you can work from the top down to focus on patientcentered care, and the Cleveland Clinic is a great example of that,” he said. “Another way is to work with insurance companies and show them how they’ll actually save money in the end, by preventing ER visits and hospital utilization.”

Raymond Cross, MD, the co-director of the Digestive Health Center at the University of Maryland School of Medicine, in Baltimore, said the university network has “many of the components” of the IBD medical home,

such as a diverse array of specialists, but the payment model remains more traditional. He added that this is true in “a lot” of clinics, particularly those in networks with many payors relative to the number of providers. While the payment model of the medical home exists, he said, it is rarely used, but things will change given time.

“The concept of multidisciplinary care is starting to gain traction in the health care system, but the payment model of the subspecialty home is in its very early stages,” Dr. Cross said. “We at Maryland have 10 different payors, which makes it more complicated than at someplace like the University of Pittsburgh Medical Center, where they only have one.”

Dr. Cross added that building a medical home rooted in a single location carries a significant up-front cost and requires substantial space.

“For a patient to be able to see multiple providers from different disciplines at the same visit, it requires physical space to move patients through the visit,” he said. “You probably need at least six exam rooms and see IBD Home, page 18

G AST R O E N T E R O LO GY & E N D O S CO PY N E WS S P E C I A L E D I T I O N • O C TO B E R 2 02 0

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Microvilli Height Predicts Biologic Treatment Response Microvilli may be small, but they tell many tales.

The height of ileal epithelial microvilli can predict the likelihood that a patient with Crohn’s disease will respond to biologic therapy, according to studies by researchers from two US centers. Experts said the findings could lead to improvements in how clinicians manage patients with inflammatory bowel disease by optimizing drug treatment.

In one study (late-breaking abstract 3), Thaddeus Stappenbeck, MD, PhD, a professor of pathology and immunology at Washington University School of Medicine in St. Louis, and his colleagues retrospectively analyzed pre- and post-treatment histologic, endoscopic and clinical data from 95 people with Crohn’s disease who received either ustekinumab (Stelara, Janssen) or placebo as part of the UNITI-2 trial (2019 United European Gastroenterology Week [UEG]; late-breaking abstract 3).

“What we found was that the greatest therapeutic effect and the greatest difference between treatment and placebo responders was seen in those with microvilli at least 1.7 microns in length,” Dr. Stappenbeck said.

The rate of clinical response in the entire study population for ustekinumab and placebo was 65% and 39% at eight weeks, respectively. By subgroup, the rate among patients with microvilli height at least 1.7 microns was 85% and 20%, respectively (P=0.02). Conversely, among those with shorter microvilli, the gap in response was

IBD Home continued from page 17

additional workspace for this to run smoothly unless the home is virtual and connected via telemedicine.

You also need a conference room where the group can meet comfortably to discuss patients.”

Telehealth—Now More Than Ever Like most institutions, Mount Sinai has responded to the COVID-19 pandemic by greatly expanding its telehealth efforts, according to Dr. Keefer. Telehealth already comprised about 50% of visits for patients with IBD before the outbreak, but now is being used to receive referrals and continue with care.

“Most of our sessions are COVID-related—either anxiety around immunosuppression, family members not heeding quarantines ... or concerns about food security and maintaining nutrition,” Dr. Keefer said. “A

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G AST R O E N D O N E WS .CO M

narrower, at 59% and 46% for ustekinumab and placebo recipients, respectively.

Patients with longer microvilli also had a numerically, but not significantly, higher likelihood of endoscopic response to ustekinumab at eight weeks (ustekinumab, 75%; placebo, 20%) than those with shorter microvilli (ustekinumab, 65%; placebo, 48%).

“Using an ileal biopsy and measuring microvilli

few patients have also lost their jobs during [the pandemic], so we have been working to preserve their health insurance and make sure there are no lapses in care. Some patients are switching their medications to home infusion,” she said, adding that college students also may need prescriptions transferred, depending no whether they are remote learning or not.”

Dr. Cross noted that the University of Maryland health system is trying to convert “nearly all” visits to telehealth until the COVID-19 crisis resolves.

At Cleveland Clinic, Dr. Regueiro said all in-person visits are being changed to telehealth or virtual visits, adding that this was already the plan. “We were headed toward a future of more medical home visits being virtual visits, and this COVID-19 pandemic has accelerated our time line to provide this care within weeks, not over years,” he said. “With so many people sheltering at home, we have found that scheduling telehealth visits and the acceptance of these visits are quite high.”

—Ajai Raj

length at baseline would be a helpful and easy-toadopt predictor of clinical and endoscopic response,” Dr. Stappenbeck said.

In a separate study also presented at UEG Week (latebreaking abstract 4), combining ileal microvilli height with ileal epithelial cell death strongly identified responders to the biologic agent vedolizumab (Entyvio, Takeda).

The work followed on previous research by Julia Liu, MD, a staff physician at the University of Arkansas for Medical Sciences, in Little Rock, whose group found that death of ileal epithelial cells predicted response to vedolizumab, although specificity was low.

In the new study, Dr. Liu and her colleagues analyzed both cell death, defined as less than 14 activated caspase-positive cells per 1,000 intestinal epithelial cells, and microvilli height in 43 men and women with Crohn’s disease who were treated with vedolizumab at several centers.

Baseline demographic, medication and disease characteristics did not differ between the 58% of responders and the nonresponders. However, like Dr. Stappenbeck’s team, Dr. Liu’s group found that microvilli predicted response: 82% of patients with a mean height of ileal microvilli of 1.35 to 1.55 microns experienced a clinical response, compared with 44% of those with microvilli shorter than 1.35 microns and 40% of those with microvilli longer than 1.55 microns.

“We did expect that because vedolizumab and ustekinumab have different mechanisms of action, the optimal microvilli length range or cutpoints would be different,” Dr. Liu said, referring to the results of Dr. Stappenbeck’s study.

When Dr. Liu’s team focused on patients who met both the microvilli height and the definition of ileal epithelial

cell death, they found that sensitivity was slightly lower but specificity rose: 78% of the patients meeting the two conditions experienced clinical response, compared with 25% of those not meeting either criterion.

“It would be interesting to examine whether altering microvilli length through diet or other approaches could help improve response to treatment,” Dr. Liu said, noting that a high-fat diet has been shown to reduce microvilli height in animals (J Nutr Sci Vitaminol 1994;40[2]:127-136).

Ashwin Ananthakrishnan, MD, MPH, an associate professor of medicine at Massachusetts General Hospital, in Boston, who was not involved in the studies, praised the investigators. “These are two very promising studies that contribute to an important area of research, namely being able to predict response to the expanding number of therapies with distinct mechanisms of action in IBD,” Dr. Ananthakrishnan told Gastroenterology & Endoscopy News.

Dr. Ananthakrishnan said future studies should try “to determine whether microvillus length is a predictor of response after adjusting for prior treatments and refractoriness to those treatments, which may themselves impact microvillus length.”

He added that further studies should analyze any correlations of microvilli height with other biomarkers, such as C-reactive protein and albumin, which sometimes are used to predict response to treatment.

—David Wild Dr. Ananthakrishnan reported no relevant financial conflicts of interest. Dr. Liu reported holding a patent on an ileal pyroptosis stain assay. Dr. Stappenbeck reported research funding from Boehringer Ingelheim and Janssen.

G AST R O E N T E R O LO GY & E N D O S CO PY N E WS S P E C I A L E D I T I O N • O C TO B E R 2 02 0

19

For your appropriate adult patients with moderately to severely active UC for whom other therapies have not worked well enough or cannot be tolerated

Entyvio works through a gut-selective MOA by specifically binding to the α4β7 integrin and blocking its interaction with MAdCAM-1, which is mainly expressed on gut endothelial cells.1 Remission was evaluated at Week 52.1 Individual results may vary.

INDICATIONS

IMPORTANT SAFETY INFORMATION

Adult Ulcerative Colitis (UC)

(continued)

ENTYVIO (vedolizumab) is indicated in adults for the treatment of moderately to severely active UC.

• Patients treated with ENTYVIO are at increased risk for developing infections. Serious infections have been reported in patients treated with ENTYVIO, including anal abscess, sepsis (some fatal), tuberculosis, salmonella sepsis, Listeria meningitis, giardiasis, and cytomegaloviral colitis. ENTYVIO is not recommended in patients with active, severe infections until the infections are controlled. Consider withholding ENTYVIO in patients who develop a severe infection while on treatment with ENTYVIO. Exercise caution in patients with a history of recurring severe infections. Consider screening for tuberculosis (TB) according to the local practice.

Adult Crohn’s Disease (CD) ENTYVIO (vedolizumab) is indicated in adults for the treatment of moderately to severely active CD.

IMPORTANT SAFETY INFORMATION • ENTYVIO (vedolizumab) for injection is contraindicated in patients who have had a known serious or severe hypersensitivity reaction to ENTYVIO or any of its excipients.

• Infusion-related reactions and hypersensitivity reactions including anaphylaxis, dyspnea, bronchospasm, urticaria, flushing, rash, and increased blood pressure and heart rate have been reported. These reactions may occur with the first or subsequent infusions and may vary in their time of onset from during infusion or up to several hours post-infusion. If anaphylaxis or other serious infusion-related or hypersensitivity reactions occur, discontinue administration of ENTYVIO immediately and initiate appropriate treatment.

• Progressive multifocal leukoencephalopathy (PML), a rare and often fatal opportunistic infection of the central nervous system (CNS), has been reported with systemic immunosuppressants, including another integrin receptor antagonist. PML is caused by the John Cunningham (JC) virus and typically only occurs in patients who are immunocompromised. One case of PML in an ENTYVIO-treated patient with multiple contributory factors has been reported in the postmarketing setting (e.g., human immunodeficiency virus [HIV]

ENTYVIO is a trademark of Millennium Pharmaceuticals, Inc., registered with the U.S. Patent and Trademark Office and is used under license by Takeda Pharmaceuticals America, Inc. All other trademarks are the property of their respective owners. ©2020 Takeda Pharmaceuticals U.S.A., Inc. All rights reserved. Printed in U.S.A. US-VED-0385v1.0 08/20

For your appropriate adult patients with moderately to severely active UC

ONLY ENTYVIO COMBINES

RAPID RESPONSE & LONG-TERM REMISSION1,8

GUT SELECTIVITY2-7 Entyvio helps address inflammation where it occurs—in the gut1 Entyvio specifically binds to the α4β7 integrin and blocks the interaction between the α4β7 integrin and MAdCAM-1, which is mainly expressed on the GI tract endothelial cells

SAFETY FOR THE LONG TERM1,9

UC patients achieved response at Week 6 and remission at Week 52 vs placebo in study populations that included bio-naïve and anti-TNFα–experienced patients1,8 Individual results may vary

Clinical trials evaluated safety in more than 3300 patients (UC and CD).1 A 5-year analysis, which included an open-label continuation study (UC and CD), has demonstrated consistent results across safety parameters9

ONLY ENTYVIO OFFERS RESULTS FROM

IS THE

FASTEST GROWING FIRST-LINE BIOLOGIC

HEAD-TO-HEAD STUDY ENTYVIO HUMIRA®

OF BIOLOGICS IN MODERATE TO SEVERE UC8,10 ‡

FORUC UCAND ANDCD CDPATIENTS PATIENTS8*COMBINED8* FOR

(vedolizumab)

Biologics included Entyvio, Humira®, Remicade® (infliximab), and Stelara® (ustekinumab)†

(adalimumab)

*Based on an analysis of data in SHA database comparing patient counts from year-to-year absolute growth information from January 2018 to December 2019 with “first-line” defined as a new start in patients with UC or CD who had no UC or CD biologic drug claims for the past 3 years. †Humira® (AbbVie Inc. Chicago, IL); Remicade® (Janssen Biotech, Inc. Horsham, PA); Stelara® (Janssen Biotech, Inc. Horsham, PA). ‡Humira® (AbbVie Inc. North Chicago, IL). For information related to Humira, please see AbbVie.com.

IMPORTANT SAFETY INFORMATION

IMPORTANT SAFETY INFORMATION

(continued)

(continued)

infection with a CD4 count of 300 cells/mm and prior and concomitant immunosuppression). Although unlikely, a risk of PML cannot be ruled out. Monitor patients for any new or worsening neurological signs or symptoms. Typical signs and symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes. If PML is suspected, withhold dosing with ENTYVIO and refer to a neurologist; if confirmed, discontinue ENTYVIO dosing permanently.

3

• There have been reports of elevations of transaminase and/or bilirubin in patients receiving ENTYVIO. ENTYVIO should be discontinued in patients with jaundice or other evidence of significant liver injury.

• Prior to initiating treatment with ENTYVIO, all patients should be brought up to date with all immunizations according to current immunization guidelines. Patients receiving ENTYVIO may receive non-live vaccines and may receive live vaccines if the benefits outweigh the risks.

• Most common adverse reactions (incidence ≥3% and ≥1% higher than placebo): nasopharyngitis, headache, arthralgia, nausea, pyrexia, upper respiratory tract infection, fatigue, cough, bronchitis, influenza, back pain, rash, pruritus, sinusitis, oropharyngeal pain, and pain in extremities.

Please see brief summary of Prescribing Information on adjacent pages.

CD = Crohn's disease; GI = gastrointestinal; MAdCAM-1 = mucosal addressin cell adhesion molecule-1; MOA = mechanism of action; TNFα = tumor necrosis factor alpha; UC = ulcerative colitis.

References: 1. Entyvio (vedolizumab) prescribing information. Takeda Pharmaceuticals.

2. Briskin M, Winsor-Hines D, Shyjan A, et al. Am J Pathol. 1997;151(1):97-110. 3. Fedyk E, Wyant T, Yang LL, et al. Inflamm Bowel Dis. 2012;18(11):2107-2119. 4. Milch C, Wyant T, Xu J, et al. J Neuroimmunol. 2013;264:123-126. 5. Soler D, Chapman T, Yang LL, et al.

J Pharmacol Exp Ther. 2009;330(3):864-875. 6. Wyant T, Fedyk E, Abhyankar B. J Crohns Colitis. 2016;10(12):1437-1444. 7. Wyant T, Leach T, Sankoh S, et al. Gut. 2015;64(1):77-83. 8. Data on file. Takeda Pharmaceuticals. 9. Colombel JF, Sands BE, Rutgeerts P, et al. Gut. 2017;66(5):839-851. 10. Sands BE, Peyrin-Biroulet L, Loftus EV Jr, et al. N Engl J Med. 2019;381(13):1215-1226.

For more information on how you can help your patients, visit EntyvioHCP.com.

ADVERSE REACTIONS The following topics are also discussed in detail in the Warnings and Precautions section: • Infusion-Related Reactions and Hypersensitivity Reactions [see Warnings and Precautions] • Infections [see Warnings and Precautions] • Progressive Multifocal Leukoencephalopathy [see Warnings and Precautions] • Liver Injury [see Warnings and Precautions]

BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION ENTYVIO (vedolizumab) for injection, for intravenous use FULL PRESCRIBING INFORMATION INDICATIONS AND USAGE ENTYVIO is indicated in adults for the treatment of: • moderately to severely active ulcerative colitis.

• moderately to severely active Crohn’s disease.

CONTRAINDICATIONS ENTYVIO is contraindicated in patients who have had a known serious or severe hypersensitivity reaction to ENTYVIO or any of its excipients (such as dyspnea, bronchospasm, urticaria, flushing, rash and increased heart rate) [see Warnings and Precautions].

FP

O

WARNINGS AND PRECAUTIONS Infusion-Related Reactions and Hypersensitivity Reactions Infusion-related reactions and hypersensitivity reactions have been reported, including anaphylaxis, dyspnea, bronchospasm, urticaria, flushing, rash, and increased blood pressure and heart rate [see Adverse Reactions]. These reactions may occur with the first or subsequent infusions of ENTYVIO and may vary in their time of onset from during infusion or up to several hours post-infusion.

If anaphylaxis or other serious infusion-related or hypersensitivity reactions occur, discontinue administration of ENTYVIO immediately and initiate appropriate treatment.

Infections Patients treated with ENTYVIO are at increased risk for developing infections [see Adverse Reactions]. The most commonly reported infections in clinical trials occurring at a rate greater on ENTYVIO than placebo involved the upper respiratory and nasal mucosa (e.g., nasopharyngitis, upper respiratory tract infection). Serious infections have also been reported in patients treated with ENTYVIO, including anal abscess, sepsis (some fatal), tuberculosis, salmonella sepsis, Listeria meningitis, giardiasis and cytomegaloviral colitis.

ENTYVIO is not recommended in patients with active, severe infections until the infections are controlled. Consider withholding treatment in patients who develop a severe infection while on treatment with ENTYVIO. Exercise caution when considering the use of ENTYVIO in patients with a history of recurring severe infections. Consider screening for tuberculosis (TB) according to the local practice. For progressive multifocal leukoencephalopathy (PML), see Warnings and Precautions.

Progressive Multifocal Leukoencephalopathy PML, a rare and often fatal opportunistic infection of the central nervous system (CNS), has been reported with systemic immunosuppressants, including another integrin receptor antagonist. PML is caused by the John Cunningham (JC) virus and typically only occurs in patients who are immunocompromised.

One case of PML in an ENTYVIO-treated patient with multiple contributory factors has been reported in the postmarketing setting (e.g., human immunodeficiency virus [HIV] infection with a CD4 count of 300 cells/mm3 and prior and concomitant immunosuppression). Although unlikely, a risk of PML cannot be ruled out.

Monitor patients on ENTYVIO for any new onset, or worsening, of neurological signs and symptoms. Typical signs and symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes. The progression of deficits usually leads to death or severe disability over weeks or months. If PML is suspected, withhold dosing with ENTYVIO and refer to a neurologist; if confirmed, discontinue dosing permanently.

Liver Injury There have been reports of elevations of transaminase and/or bilirubin in patients receiving ENTYVIO. In general, the combination of transaminase elevations and elevated bilirubin without evidence of obstruction is generally recognized as an important predictor of severe liver injury that may lead to death or the need for a liver transplant in some patients. ENTYVIO should be discontinued in patients with jaundice or other evidence of significant liver injury [see Adverse Reactions].

Live and Oral Vaccines Prior to initiating treatment with ENTYVIO, all patients should be brought up to date with all immunizations according to current immunization guidelines.

Patients receiving ENTYVIO may receive non-live vaccines (e.g., influenza vaccine injection) and may receive live vaccines if the benefits outweigh the risks. There are no data on the secondary transmission of infection by live vaccines in patients receiving ENTYVIO [see Adverse Reactions].

Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described below reflect exposure to ENTYVIO in 3,326 patients and healthy volunteers in clinical trials, including 1,396 exposed for greater than one year, and 835 exposed for greater than two years.

The safety data described in Table 2 are derived from four controlled Phase 3 trials (UC Trials I and II, and CD Trials I and III); data from patients receiving open-label ENTYVIO treatment at Weeks 0 and 2 (prior to entry into UC Trial II and CD Trial III) and from Weeks 6 to 52 (non-responders at Week 6 of UC Trial I and CD Trial I) are included.

In these trials, 1,434 patients received ENTYVIO 300 mg for up to 52 weeks, and 297 patients received placebo for up to 52 weeks. Of these, 769 patients had ulcerative colitis and 962 patients had Crohn’s disease. Patients were exposed for a mean duration of 259 days (UC Trials I and II) and 247 days (CD Trials I and III).

Adverse reactions were reported in 52% of patients treated with ENTYVIO and 45% of patients treated with placebo (UC Trials I and II: 49% with ENTYVIO and 37% with placebo; CD Trials I and III: 55% with ENTYVIO and 47% with placebo). Serious adverse reactions were reported in 7% of patients treated with ENTYVIO compared to 4% of patients treated with placebo (UC Trials I and II: 8% with ENTYVIO and 7% with placebo; CD Trials I and III: 12% with ENTYVIO and 9% with placebo).

The most common adverse reactions (reported by ≥3% of patients treated with ENTYVIO in the UC Trials I and II and CD Trials I and III combined group and ≥1% higher than in combined placebo group) were nasopharyngitis, headache, arthralgia, nausea, pyrexia, upper respiratory tract infection, fatigue, cough, bronchitis, influenza, back pain, rash, pruritus, sinusitis, oropharyngeal pain and pain in extremities (Table 2).

Table 2. Adverse Reactions in ≥3% of ENTYVIO-Treated Patients and ≥1% Higher than in Placebo (UC Trials I and II* and CD Trials I and III*) ENTYVIO† (N=1434)

Placebo‡ (N=297)

Nasopharyngitis Headache

13% 12%

7% 11%

Arthralgia

12%

10%

Nausea

9%

8%

Pyrexia

9%

7%

Upper respiratory tract infection

7%

6%

Fatigue

6%

3%

Cough

5%

3%

Bronchitis

4%

3%

Influenza

4%

2%

Adverse Reaction

Back pain

4%

3%

Rash

3%

2%

Pruritus

3%

1%

Sinusitis

3%

1%

Oropharyngeal pain

3%

1%

Pain in extremities

3%

1%

*Data from patients receiving open-label ENTYVIO treatment at Weeks 0 and 2 (prior to entry into UC Trial II and CD Trial III) and from Weeks 6 to 52 (non-responders at Week 6 of UC Trial I and CD Trial I) are included. † Patients who received ENTYVIO for up to 52 weeks. ‡ Patients who received placebo for up to 52 weeks.

Safety data for patients (n=279) in UC Trials I and II and CD Trials I and III who received ENTYVIO at Weeks 0 and 2 and were then randomized to placebo at Week 6 for up to 52 weeks, and for patients (n=416) in CD Trial II, a 10 week Crohn’s disease trial, are similar to those listed in Table 2.

breast cancer (n=1), carcinoid tumor of the appendix (n=1) and squamous cell carcinoma (n=1). Malignancy was reported in one of 297 (0.3%) patients treated with placebo (squamous cell carcinoma).

Malignancies (excluding dysplasia and basal cell carcinoma) observed during the ongoing open-label long-term extension trial included B-cell lymphoma, breast cancer, colon cancer, malignant hepatic neoplasm, malignant lung neoplasm, malignant melanoma, lung cancer of primary neuroendocrine carcinoma, renal cancer and squamous cell carcinoma. Overall, the number of malignancies in the clinical trials was small; however, long-term exposure was limited.

Live and Oral Vaccines There are no data on the secondary transmission of infection by live vaccines in patients receiving ENTYVIO. In a placebo-controlled study of healthy volunteers, 61 subjects were given a single ENTYVIO 750 mg dose (2.5 times the recommended dose), and 62 subjects received placebo followed by intramuscular vaccination with Hepatitis B surface antigen and oral cholera vaccine. After intramuscular vaccination with three doses of recombinant Hepatitis B surface antigen, those treated with ENTYVIO did not have lower rates of protective immunity to Hepatitis B virus. However, those exposed to ENTYVIO did have lower seroconversion rates and anti-cholera titers relative to placebo after receiving the two doses of a killed, oral cholera vaccine. The impact on other oral vaccines and on nasal vaccines in patients is unknown.

Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to vedolizumab in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

In UC Trials I and II and CD Trials I and III, in patients who received ENTYVIO, the frequency of antibodies detected in patients was 13% at 24 weeks after the last dose of study drug (greater than five half-lives after last dose). During treatment, 56 of 1,434 (4%) of patients treated with ENTYVIO had detectable anti-vedolizumab antibody at any time during the 52 weeks of continuous treatment. Nine of 56 patients were persistently positive (at two or more study visits) for anti-vedolizumab antibody and 33 of 56 patients developed neutralizing antibodies to vedolizumab. Among eight of these nine subjects with persistently positive anti-vedolizumab antibody and available vedolizumab concentration data, six had undetectable and two had reduced vedolizumab concentrations. None of the nine subjects with persistently positive anti-vedolizumab antibody achieved clinical remission at Weeks 6 or 52 in the controlled trials.

Postmarketing Experience The following adverse reactions have been identified during post-approval use of ENTYVIO. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Immune system disorders: Anaphylaxis [see Warnings and Precautions]

FP

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Infusion-Related Reactions and Hypersensitivity Reactions Serious infusion-related reactions and hypersensitivity reactions including anaphylaxis have been reported following ENTYVIO administration in clinical trials [see Warnings and Precautions]. In UC Trials I and II and Crohn’s Trials I and III, one case of anaphylaxis [one out of 1,434 patients treated with ENTYVIO (0.07%)] was reported by a Crohn’s disease patient during the second infusion (symptoms reported were dyspnea, bronchospasm, urticaria, flushing, rash and increased blood pressure and heart rate) and was managed with discontinuation of infusion and treatment with antihistamine and intravenous hydrocortisone.

In UC Trials I and II and CD Trials I and III, 4% of patients treated with ENTYVIO and 3% of patients treated with placebo experienced an infusion-related reaction (IRR). The most frequently observed IRR in the patients treated with ENTYVIO (reported more than twice) were nausea, headache, pruritus, dizziness, fatigue, infusion-related reaction, pyrexia, urticaria and vomiting (each of these adverse reactions occurred in <1% in all patients treated with ENTYVIO) and no individual adverse reaction reported occurred at a rate above 1%. These reactions generally occurred within the first two hours after the infusion and resolved with no treatment or following antihistamine and/or IV hydrocortisone treatment. Less than 1% of patients treated with ENTYVIO had IRRs assessed by the investigator as severe, and IRRs requiring discontinuation of study treatment occurred in <1%.

In clinical trials, for patients with mild IRRs or hypersensitivity reactions, physicians were allowed to pretreat with standard medical treatment (e.g., antihistamine, hydrocortisone and/or acetaminophen) prior to next infusion.

Infections In UC Trials I and II and CD Trials I and III, the rate of infections was 0.85 per patient-year in the patients treated with ENTYVIO and 0.7 per patient-year in the patients treated with placebo [see Warnings and Precautions]. The infections consisted primarily of nasopharyngitis, upper respiratory tract infection, sinusitis and urinary tract infection. Two percent of patients discontinued ENTYVIO due to infections.

In UC Trials I and II and CD Trials I and III, the rate of serious infections was 0.07 per patient-year in patients treated with ENTYVIO and 0.06 per patient-year in patients treated with placebo. Serious infections were more common in Crohn’s disease patients than ulcerative colitis patients, and anal abscesses were the most frequently reported serious adverse reaction in Crohn’s disease patients. Over 48 months, there was no increase in the rate of serious infections.

In controlled- and open-label long-term extension trials in adults treated with ENTYVIO, serious infections have been reported, including anal abscess, sepsis (some fatal), tuberculosis, salmonella sepsis, Listeria meningitis, giardiasis and cytomegaloviral colitis.

In UC Trials I and II and CD Trials I and III, sepsis, including bacterial sepsis and septic shock, was reported in four of 1,434 (0.3%) patients treated with ENTYVIO and in two of 297 patients treated with placebo (0.7%). During these trials, two Crohn’s disease patients treated with ENTYVIO died due to reported sepsis or septic shock; both patients had significant comorbidities and a complicated hospital course that contributed to the deaths. In an open-label, long-term extension trial, additional cases of sepsis (some fatal), including bacterial sepsis and septic shock, were reported. The rate of sepsis in patients with ulcerative colitis or Crohn’s disease receiving ENTYVIO was two per 1,000 patient-years.

In clinical trials, all patients were screened for tuberculosis. One case of latent, pulmonary tuberculosis was diagnosed during the controlled trials with ENTYVIO. Additional cases of pulmonary tuberculosis were diagnosed during the open-label trial. All of these observed cases occurred outside the United States, and none of the patients had extrapulmonary manifestations.

Liver Injury There have been reports of elevations of transaminase and/or bilirubin in patients receiving ENTYVIO [see Warnings and Precautions]. In UC Trials I and II and CD Trials I and III, three patients reported serious adverse reactions of hepatitis, manifested as elevated transaminases with or without elevated bilirubin and symptoms consistent with hepatitis (e.g., malaise, nausea, vomiting, abdominal pain, anorexia). These adverse reactions occurred following two to five ENTYVIO doses; however, based on case report information it is unclear if the reactions indicated drug-induced or autoimmune etiology. All patients recovered following discontinuation of therapy with some requiring corticosteroid treatment. In controlled trials, the incidence of ALT and AST elevations ≥3x ULN was <2% in patients treated with ENTYVIO and in patients treated with placebo. In the open-label trial, one additional case of serious hepatitis was observed.

Malignancies In UC Trials I and II and CD Trials I and III, malignancies (excluding dysplasia and basal cell carcinoma) were reported in six of 1,434 (0.4%) patients treated with ENTYVIO, including colon cancer (n=2), transitional cell carcinoma (n=1),

DRUG INTERACTIONS Natalizumab Because of the potential for increased risk of PML and other infections, avoid the concomitant use of ENTYVIO with natalizumab.

TNF Blockers Because of the potential for increased risk of infections, avoid the concomitant use of ENTYVIO with TNF blockers.

Live Vaccines Live vaccines may be administered concurrently with ENTYVIO only if the benefits outweigh the risks [see Warnings and Precautions].

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ENTYVIO during pregnancy. Information about the registry can be obtained by calling 1-877-TAKEDA7 (1-877-825-3327).

Risk Summary Available pharmacovigilance data, data from the ongoing pregnancy registry, and data from published case reports and cohort studies in pregnant women have not identified an ENTYVIO associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There are risks to the mother and the fetus associated with inflammatory bowel disease in pregnancy (see Clinical Considerations). No fetal harm was observed in

animal reproduction studies with intravenous administration of vedolizumab to rabbits and monkeys at dose levels 20 times the recommended human dosage (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and miscarriage is 15 to 20%, respectively.

Clinical Considerations Disease-associated maternal and embryo/fetal risk Published data suggest that the risk of adverse pregnancy outcomes in women with inflammatory bowel disease (IBD) is associated with increased disease activity. Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2,500 g) infants, and small for gestational age at birth.

Fetal/Neonatal adverse reactions ENTYVIO administered during pregnancy could affect immune responses in the in utero exposed newborn and infant. The clinical significance of low levels of ENTYVIO in utero-exposed infants is unknown. The safety of administering live or live-attenuated vaccines in exposed infants is unknown.

Data Animal Data A reproduction study has been performed in pregnant rabbits at single intravenous doses up to 100 mg/kg administered on gestation Day 7 (about 20 times the recommended human dosage) and has revealed no evidence of impaired fertility or harm to the fetus due to vedolizumab. A pre- and post-natal development study in monkeys showed no evidence of any adverse effect on pre- and post-natal development at intravenous doses up to 100 mg/kg (about 20 times the recommended human dosage).

Lactation Risk Summary Available published literature suggests the presence of vedolizumab in human milk. The effects of local gastrointestinal exposure and expected low systemic exposure to vedolizumab on the breastfed infant are unknown. There are no data on the effects of vedolizumab on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ENTYVIO and any potential adverse effects on the breastfed infant from ENTYVIO or from the underlying maternal condition.

Pediatric Use Safety and effectiveness of ENTYVIO in pediatric patients have not been established.

Geriatric Use Clinical trials of ENTYVIO did not include sufficient numbers of subjects aged 65 and over (46 Crohn’s and ulcerative colitis patients aged 65 and over were treated with ENTYVIO during controlled Phase 3 trials) to determine whether they respond differently from younger subjects. However, no overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients.

Manufactured by: Takeda Pharmaceuticals America, Inc. Deerfield, IL 60015 U.S. License No. 1898 Revised: March 2020 ENTYVIO is a trademark of Millennium Pharmaceuticals Inc. and is used under license by Takeda Pharmaceuticals America, Inc. All other trademark names are the property of their respective owners. ©2014 – 2020 Takeda Pharmaceuticals America, Inc. For more information, go to www.ENTYVIO.com or call 1-877-TAKEDA-7 (1-877-825-3327).

VMB245 R4_Brf04/20

For Better Clinical Trials, Engage Patients

S

andra Zelinsky is an expert patient. Diagnosed with Crohn’s disease at age 19, and breast cancer in 2019 at 36, Ms. Zelinsky has

been living with life-altering illnesses for more than a quarter-century.

Not long after she received her diagnosis of breast cancer, her Crohn’s destabilized and she was admitted for surgery. Following a serious infection after surgery and ongoing complications with the healing process, Ms. Zelinsky sold her business, and she and her husband moved from a small rural town in British Columbia back to her hometown of Calgary, Alberta.

During her recovery, she received an email inviting her to take part in a course called “Patients and Community Engagement Research” (PaCER) at the University of Calgary. The course led her to research and patient advocacy. Today Ms. Zelinsky has published studies and national and international conferences on her curriculum vitae.

“Things just kind of snowballed,” Ms. Zelinsky said of her transition from patient to patient engagement researcher. “I couldn’t have planned it if I tried.”

Ms. Zelinsky presented a study at this year’s Crohn’s & Colitis Congress in Austin, Texas, titled “IBD Partnerships: Understanding Patients vs. Clinicians’ Perspectives of IBD Treatment Options to Improve Shared Decision-Making” (abstract P002).

The pilot study consisted of 21 patients, split into three focus groups. Led by Ms. Zelinsky, the groups worked together to articulate and rank their priorities related to biologic therapy. The study was externally validated by several gastroenterologists.

The three groups were divided according to where they lived, where they were treated, and how informed they were about IBD research and advocacy. The first group consisted of patients from rural areas being treated by community physicians; the second of patients from urban areas receiving treatment at tertiary care centers; and the third of “very informed patients” familiar with advocacy and research, also from urban areas.

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In a novel study design, the groups worked in a series, with the data from the first group analyzed by the second group, and the data from the first two groups analyzed by the third group, Ms. Zelinsky said. Each group generated discussion topics, sorted and themed their concerns and, ultimately, defined and ranked their priorities when choosing a biologic therapy. The voting on priorities was anonymous to mitigate group bias.

The data in this study consisted of thoughts and ideas generated by patient discussion.

“I had patients write down one question, comment or concern per sticky note, and we put those sticky notes on the wall,” Ms. Zelinsky said. “Then they had to work through the process of dividing those notes into groups and naming those categories. So, it’s their work, not my work; their lens, not mine.”

The findings indicated that IBD patients value risk reduction over efficacy when evaluating biologic treatments, in contrast to the “previously demonstrated” priorities of clinicians. They will inform the development of the nationwide patient and clinician surveys that will comprise the next phase of the research, and its final discussion phase.

The project is being conducted by IMAGINE SPOR in collaboration with the University of Calgary, with funding from Takeda’s Canadian division. IMAGINE stands for Inflammation, Microbiome, and Alimentation: Gastro-Intestinal and Neuropsychiatric Effects, and SPOR for Strategy for Patient-Oriented Research.

IMAGINE is a chronic disease research network within SPOR, with a focus on the impact of diet and microbiome in IBD and irritable bowel syndrome. It is currently conducting a trial that seeks to recruit 8,000 patients to study how genetics, diet and mental health each affect the gut microbiome in IBD and IBS, and the overall effect on the course of disease. The study is called MAGIC (Mind And Gut Interactions Cohort). In addition, IMAGINE is recruiting for 13 smaller studies.

Getting Multiple Perspectives Is Crucial This kind of patient-oriented research is emphasized by the Patient-Centered Outcomes Research Institute (PCORI). Kristin Carman, PhD, MA, PCORI’s director of Public and Patient Engagement for the, said her group’s approach is rooted in designing studies to address realworld problems with multiple stakeholders.

“The key is diversity, and diversity means identifying the communities and perspectives who are going to have to be at the table to contribute to effective problem solving for a given research project,” Dr. Carman said. “If we’re testing a treatment that’s going to eat up a lot of time for the clinician, for example, we need a clinician’s voice at the table.”

Disseminating research findings to the people who will benefit is another fundamental concern of PCORI, Dr. Carman said. “You need to know, when the results come out on the other side, that there’s going to be someone who will be interested in implementing them, whether it’s the patient, the clinician or the payor,” she said.

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PCORI publishes guidance and funding for those looking to do co-produced research, and hosts an annual meeting each year, with the 2020 meeting scheduled for September in Arlington, Va. “We showcase a lot of work that we’re doing, and we bring our stakeholder communities together to share approaches and methodologies, to network, and to find great ideas,” Dr Carman said. “PCORI is one of the largest funders of comparative effectiveness research, and what makes us unique is the depth and breadth of stakeholder involvement, as well as our fascinating laboratory of engaged research.”

PCORI’s online database contains more than 2,400 citations of research funded by the organization, with links to full articles where available. PCORI has funded 20 trials in IBD since 2016, Dr. Carman said.

Encountering Doubters Both Ms. Zelinsky and Dr. Carman said they have faced skepticism about getting patients involved in research.

“I presented at a quality-of-life conference in Berlin in 2014, and during the question-and-answer session after my presentation, a doctor essentially said he didn’t see why patients should get involved,” Ms. Zelinsky said. “In my head, I was trying to understand this visceral reaction. It’s my health, my health care.

Why wouldn’t I want to be involved?”

Dr. Carman said PCORI responds to skepticism by providing guidance and oversight while letting principal investigators work out the details for themselves.

“The way PCORI implemented engagement was to say, ‘We’re not going to tell you how to do your study,’” she said. “We are going to require that you engage with stakeholders at every stage of the life cycle, but other than that, we want to give projects that have won funding from us the opportunity to innovate.”

Paul Moayyedi, MD, PhD, MPH, the joint coordinating editor of the Upper GI and Pancreatic Disease Cochrane Review Group, and IMAGINE’s principal investigator, cautioned that clinicians who do conduct patient-oriented research must be vigilant to avoid “tokenism”—or conducting nominally patient-oriented studies—while doing things the same way they always have.

“Sometimes you’re leading the way, sometimes you’re a contributor, but it’s important to really listen to patients every step of the way,” Dr. Moayyedi said. “It’s also important, when choosing patients, to gather as broad of a set of perspectives as possible in the disease area you’re studying. Don’t choose someone from your own clinic, for example, or someone who’s narrowly focused on a cause or pet treatment, like someone who’s super into acupuncture, for example.”

Dr. Moayyedi said he expects patient-oriented research to become an “obvious” idea in the future.

“Doctors in the 18th and 19th centuries believed in bloodletting,” he said. “Hopefully, in the next 50 to 100 years, we’ll look back and wonder why patientoriented research took so long to arrive.”

—Ajai Raj

Simple Interventions Can Help Military IBD Patients Transition to VA Care

T

he transition from active military service to civilian life can be

challenging for veterans, especially those diagnosed with a chronic illness.

In the early 1990s, the Department of Defense (DOD) established the Transition Assistance Program (TAP) to prepare veterans for life after military service, primarily in the form of career support. The program does not prepare veterans for their transition to Veterans Affairs health care, nor does it provide disease-specific support for those diagnosed with a chronic illness, such as inflammatory bowel disease, for whom continuity of care is at risk during this transition.

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Interruptions in therapy can cause complications and flares, so veterans with IBD need help to take charge of managing their disease during transitions of care, said Anish Patel, MD, of Brooke Army Medical Center, in San Antonio.

“Many of these patients are medically discharged due to regulations that limit duty status because of IBD,” Dr. Patel said. “As a result, many soldiers are expedited through the transition process without having a mental/ logical grasp on their disease and/or management. Since the transition process focuses on the masses, individuals with chronic diseases need more focal attention to assure proper transition and continuity of care.”

A First-of-Its-Kind Transition Clinic To improve the process, Dr. Patel and his colleagues have created the first DOD transition clinic to deliver self-efficacy interventions to veterans with chronic diseases.

Self-efficacy—which has been shown to predict health outcomes—describes a patient’s confidence in their ability to manage the demands of living with a chronic disease.

To evaluate the feasibility of these interventions, Dr. Patel partnered with Laurie Keefer, PhD, of the Mount Sinai Health System, in New York City, who has studied transitions from pediatric to adult care for patients with IBD. They shared their findings at the 2019 Advances in Inflammatory Bowel Diseases meeting.

“We demonstrated that applying some techniques to help with health literacy and resiliency will provide soldiers with a better idea of how to navigate the system and manage their disease and improve health literacy,” Dr. Patel said.

Dr. Patel’s group enrolled 50 active-duty service members with IBD who were in remission and going through TAP. All participants completed the Transition Readiness Assessment Questionnaire (TRAQ), a survey developed to evaluate adolescent readiness for transition to adult care. Participants also completed the IBD Self-Efficacy Scale (IBD-SES), which evaluates a patient’s ability to manage stress and emotions, medical care, symptoms and disease, and maintaining remission.

Half of the patients were randomly assigned to undergo educational and behavioral interventions based on TRAQ categories that were delivered during routine clinical visits and by a mobile app called Care Zone. The rest received standard TAP support. Outcomes were assessed before, and four and 12 weeks after, discharge from the military.

The interventions improved medication and appointment management, tracking and managing health issues, and communicating with providers (P<0.001).

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Self-efficacy and self-management also improved for up to three months after discharge (P<0.001). Depression and anxiety improved slightly, Dr. Patel said.

“The key to success was to provide simple interventions, but focused on the soldier’s perceived limitations rather than a global intervention,” he said.

Delays in Care While the primary aim of the study was to assess improvements in self-efficacy, Dr. Patel and his colleagues described secondary findings of poor outcomes tied to delays in care—an ongoing problem within the VA health system despite reported improvements.

Study participants had to wait 3.5 months on average for their first primary care visit and 5.4 months for their first appointment with a gastroenterologist. As a result, more than 60% had to discontinue therapy and half had a disease flare, the researchers found.

“The gap in transition to the VA led many of our patients to start having symptoms, some requiring multiple [emergency department] visits and a few surgeries, that otherwise may have been mitigated with timely transition,” Dr. Patel said. “Many patients that had a delay in care switched medical therapy, despite having control on a prior therapy.”

This study “sheds light on an often-overlooked transition within U.S. health care,” but self-efficacy did not improve wait times or clinical outcomes, said Jordan Shapiro, MD, of the Houston VA Center for Innovations in Quality, Effectiveness and Safety. “This may be due to the small sample size but may reflect that systemlevel measures are not likely to be affected by improved patient self-efficacy alone.”

He also questioned the validity of TRAQ in the context of the VA. Unlike IBD-SES, TRAQ has not been studied outside of pediatric transitions, although TRAQ scores predict IBD-SES scores.

“The absence of a consistently used definition of high-quality transition care makes it difficult to determine which interventions are meaningful for improving patient outcomes,” Dr. Shapiro said. “Use of specific patient, provider and system-level measures may help [us] to better understand more concrete goals for transition programs.”

Despite these uncertainties, Dr. Patel said he hoped to expand these interventions to improve self-efficacy among patients in the VA. “Though we focused on IBD, such processes can be implemented to most chronic diseases that limit duty for soldiers, including cancer and rheumatoid arthritis,” he said. “Currently, we are the only location in the DOD that employs the transition clinic, and we are in the process of formalizing the process to be used at other institutions.”

—Adam Leitenberger

Academic Request for Proposals The Crohn’s & Colitis Foundation has issued an international request for proposals (RFP) for academic researchers to gain access to IBD Plexus® resources.

IBD Plexus provides researchers with access to clinical and patient-reported data linked to biosamples and genetic and molecular data from diverse research cohorts, real-world clinical care settings, and patients’ experiences. Through this RFP, for the first time, researchers will also have the opportunity to gain access to data and biosamples collected from the SHP647 (Ontamalimab) clinical trials, a recent enhancement to IBD Plexus data.

Submission details and requirements are outlined within the RFP.

Learn more at crohnscolitisfoundation.org/PlexusRFP. This RFP was made possible with the support of The Leona M. and Harry B. Helmsley Charitable Trust and Takeda Pharmaceutical Company Limited.

LucidDX.com

The Role of Biomarkers In the Management Of Barrett’s Esophagus Potential to optimize therapy, surveillance, and screening ASHTON ELLISON, MB CHB Department of Medicine Baylor University Medical Center Dallas, Texas

VANI KONDA, MD Department of Medicine Baylor University Medical Center Baylor Scott and White Center of Esophageal Diseases Dallas, Texas

I

t is well established that selected patients with high-grade dysplasia (HGD)/ esophageal adenocarcinoma (EAC) benefit from endoscopic therapy with an acceptable risk profile, but we have yet to develop selection criteria to

determine which patients with Barrett’s esophagus and either no evidence of dysplasia or low-grade dysplasia (LGD) would benefit from treatment.

It is plausible that a subset of these patients may benefit from therapy, whereas others may enjoy longer surveillance intervals. However, we lack the proper tools to confidently direct patients to a rigorous or a relaxed approach. In addition, current screening and surveillance approaches for Barrett’s esophagus are imperfect.

Although it is not cost-effective to screen the entire population, the majority of patients who develop esophageal cancer are missed using the current standards.

Clinicians have used clinical parameters to help riskstratify patients with Barrett’s esophagus. For example, a clinical model that has been proposed for this purpose includes male sex, smoking, length of the lesion, and LGD at baseline (vs HGD or no dysplasia) to determine

if patients are at low, intermediate, or high risk for progression.1 However, better tools are needed to improve risk stratification. For years, biomarkers in Barrett’s esophagus were enticing but remained on the horizon.

The advent of recent work on many fronts now suggests that clinical incorporation of biomarkers is within our grasp and potentially allows us to tailor treatments, intervene at earlier stages, lengthen surveillance periods for those at low risk, and identify more patients at risk by offering broader population screening.

Confirming the Promise of Prediction Common techniques to look for biomarkers in the laboratory include immunohistochemistry (IHC), which

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exploits antibodies binding to specific antigens in tissues, and fluorescence in situ hybridization, which highlights specific DNA/RNA sequences. Promising investigations also have demonstrated valuable information related to epigenetic events, with much attention recently focused on DNA methylation.

This idea of a reliable biomarker already was proven and is in widespread use to aid in the early detection of other malignancies, such as breast and prostate cancers. Testing for the BRCA gene can help individuals understand their risk for breast cancer and guide preventive treatment plans, and prostate-specific antigen can help direct individual screening for prostate cancer.

Metaplastic Barrett’s esophagus tissue specimens have been shown to acquire gene modifications that can lead to cancer even before demonstrating histologic features of dysplasia.2 Nondysplastic Barrett’s esophagus has a high frequency of somatic mutations, from 1.3 to 5.4 mutations per megabase of DNA, more than those found in cancers of the prostate and breast.3 This finding suggests that reliable biomarker(s) could help in the clinical management of Barrett’s esophagus that is nondysplastic, indefinite for dysplasia, or with LGD. Tumor suppressor genes are the cell’s mechanism to stop cell cycle replication. Mutations in these genes can lead to uncontrolled cell replication and, hence, cancer.

Early promising biomarkers for progression in Barrett’s esophagus were alterations resulting in inactivation of 2 tumor suppressor genes, p16 and p53. Both genes have a role in arresting G1 cell cycle progression.3 However, only a minority of tumors progress along this pathway, which involved an accumulation of alterations in p53 and p16.4 The majority of Barrett’s esophagus–associated tumors (62.5%) develop through the genomedoubling pathway.3 This pathway starts with mutation in the p53 tumor suppressor gene, which is followed by a doubling of the cell’s whole genome, predisposing the cell to genomic instability and oncogene amplification.5 Aberrations in p53 and their contribution to cancer progression in Barrett’s esophagus are well established. In a recent meta-analysis, Snyder et al showed that aberrant p53 (absent or increased expression) was significantly associated with risk for progression to HGD or EAC in patients with Barrett’s esophagus. The metaanalysis indicated that with p53 aberrancy, the odds ratio (OR) for Barrett’s esophagus to exhibit neoplastic progression was 3.84 (95% CI, 2.79-5.27; P<0.001) in 8 retrospective case-control studies, and the relative risk was 17.31 (95% CI, 9.35-32.08; P<0.001) in 7 cohort studies.6 Despite the identification of these specific genetic aberrations, it is generally thought that a panel of several biomarkers will be the means to develop a clinically useful test. In a nested case-control study, LGD diagnosis, abnormal expression of p53, and abnormal expression of Aspergillus oryzae lectin were independent predictors for progression to HGD/EAC; when combined into a multivariate biomarker panel, they demonstrated an area under the receiver operating curve (AUC) of 0.73.7 In a Dutch surveillance cohort,

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a prediction model combined clinical factors including age, circumferential length of the Barrett’s segment, and clonicity features across chromosomes 7, 17, 20q, and c-MYC.8 This model resulted in an AUC of 0.88, a sensitivity of 0.91, and a specificity of 0.38. Additional aberrations, such as single nucleotide polymorphisms, or in microRNA, which functions primarily to inhibit gene expression, have been associated with progression in patients with Barrett’s esophagus and may be worthy of further study.9,10 Furthermore, epigenetic events that affect regulation and expression of genes have been investigated as potential biomarkers in risk stratification in Barrett’s esophagus. There has been much interest in DNA methylation profiles, with certain profiles associated with progression.11,12 Biomarker panels also may be more promising with stratification along genomic, transcriptomic, and epigenetic profiles. Jammula et al demonstrated this potential by measuring DNA methylation data with genomic and transcriptomic information. They found 4 different subtypes in tissue samples of over 400 cases with Barrett’s esophagus and EAC; each subgroup was associated with different patient outcomes, dysplasia status, and grade.13 They went on to demonstrate in vitro how different subtypes may respond to specific therapeutic pathways and how biomarkers may help indicate specific types of targeted therapy for patients with esophageal cancer.

The current guidelines from the American Gastroenterological Association, American College of Gastroenterology, and American Society for Gastrointestinal Endoscopy for the diagnosis and management of Barrett’s esophagus all suggest that biomarkers show promise but are not recommended for risk stratification.14-16 Although promising biomarkers and pathways have been identified, ultimately, these markers have to be feasible for clinical integration, provide reliably reproducible results, and be validated for meaningful clinical use.

The TissueCypher Barrett’s Esophagus Assay (Cernostics) is an automated, quantitative assay that is well poised for consideration for clinical use. This commercially available assay uses formalin-fixed and paraffin-embedded tissue from endoscopic biopsies for multiplexed immunofluorescence for p53, p16, AMACR, HER2, cytokeratin-20, CD68, COX-2, HIF-1 alpha, and CD45RO and analyzes a scanned whole slide to extract data of 15 features. Risk scores are then compiled, assigning low, intermediate, and high risk for progression based on previous investigations.17,18 A recent independent, blinded study by Davison et al validated the performance of the prediction model for identifying patients with Barrett’s esophagus who have a higher risk for neoplastic progression.19 They assessed performance of the test in 210 nonprogressors and 58 progressors at 2 institutions and demonstrated predictive power independent of clinical variables. Among patients with nondysplastic Barrett’s esophagus, the positive predictive value for a high-risk score was 26%.

A

B

Figure. These images show molecular biomarkers that can be assessed in the context of the histology. This high-risk pattern was demonstrated in nondysplastic Barrett’s esophagus tissue in a patient who subsequently progressed to high-grade dysplasia.

A. Overexpression of p53 (yellow) and AMACR (red) and loss of p16. B. Infiltration of lymphoctyes (red) and HIF-1 alpha-expressing cells (green). Nuclei are stained blue.

Images printed with permission from Cernostics, Inc.

The hazard ratio of high versus low risk by the assay test was 3.68 (95% CI, 1.67-8.11; P=0.0112); this result outperforms expert pathologic review, for which the diagnosis of LGD versus nondysplasia is 1.64 (95% CI, 0.68-3.95; P=0.27). This test suggested a similar probability of progression for patients who had nondysplastic Barrett’s esophagus on biopsy but scored as high risk and those who were diagnosed by expert pathologic review as having LGD. Additionally, the costeffectiveness profile of such an assay recently was investigated in a hypothetical model. The model demonstrated the assay was cost-effective within 5 years, with a 16.6% reduction in endoscopies for low-risk patients, a 58.4% increase in endoscopic treatments for high-risk patients, and a theoretically decreased incidence of HGD and EAC.20

On the Horizon for Screening: Nonendoscopic Methods The key to capturing more patients at risk for developing esophageal cancer is to include a broader population for testing. However, an endoscopic screening approach for the entire population is not cost-effective, worth the risk, or feasible.21 If there was a nonendoscopic screening device that could be administered in an office-based setting, it could enable identification

of patients who would benefit from an endoscopy to assess for Barrett’s esophagus and associated neoplasia.

A variety of nonendoscopic screening tools are under investigation that essentially employ a tethered device for a patient to ingest for collection of cells in the esophagus. In addition to cytology, these devices can acquire tissue for IHC and DNA methylation.

The Cytosponge (Medtronic) is an encapsulated tethered sponge that can be swallowed, released from the capsule, and then withdrawn to collect cells from the esophagogastric junction and esophagus. These cells can be stained for Trefoil factor 3, which identifies the presence of intestinal metaplasia. In a casecontrol study across 11 sites and 1,110 subjects (647 with Barrett’s esophagus, the rest with dyspepsia or reflux), 93.9% of the subjects swallowed the device successfully.22 Sensitivity for the diagnosis of Barrett’s esophagus was 79.9% (95% CI, 76.4%-83.0%). Sensitivity increased for patients with long segments of Barrett’s esophagus (≥3 cm) to 87.2% (95% CI, 83.0%-90.6%).

A randomized controlled trial in the primary care setting is underway to assess whether centers that offer the Cytosponge will be able to detect more cases of Barrett’s esophagus than the usual care practice.23 There is the opportunity to incorporate additional biomarkers, such as hypermethylation of TFPI2, TWIST1,

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ZNF345, and ZNF569, which also have shown potential on cytology-based samples obtained from Cytosponge in the diagnosis of Barrett’s esophagus.24 A model analyzing Cytosponge samples followed by endoscopic confirmation showed it is a cost-effective strategy.25 Another sponge on a string device under investigation, EsophaCap (Capnostics), serves as a vehicle to examine DNA methylation markers. One study looking at discriminant DNA methylation markers found a 2-marker panel (VAV3 plus ZNF682) that demonstrated the ability to detect Barrett’s esophagus (AUC, 1).26 Another study looked at methylation markers p16, HPP1, NELL1, TAC1, and AKAP12 with high accuracy for Barrett’s esophagus and found an AUC of 0.929 (95% CI, 0.810-1.0; P<0.001).27 Another study used a balloon-based device (EsoCheck/EsoGuard, Lucid Diagnostics) that examined molecular assays of CCNA1 plus VIM DNA methylation on cytologic specimens and detected Barrett’s esophagus metaplasia with 90.3% sensitivity and 91.7% specificity.28

An even less invasive platform is being investigated with an electronic nose device, Aeonose (The eNose Company), which uses a breath test for volatile organic compound signatures to screen for Barrett’s esophagus and esophageal cancer.29 A recent study in 402 patients was able to identify volatile organic compounds associated with Barrett’s esophagus, with a sensitivity of 91% and specificity of 74%.30

Conclusion There is an unmet need to identify which patients may benefit from endoscopic therapy, closer surveillance intervals, or a screening endoscopy. Although additional larger validation studies are required, recent activity in the development and validation of biomarkers is paving the way from the laboratory setting to the clinical arena. This promising body of data demonstrates that biomarker panels have the potential to be clinically integrated in an accessible and acceptable manner into treatment, surveillance, and screening paradigms for Barrett’s esophagus.

References 1.

Parasa S, et al. Gastroenterology. 2018;154(5):1282-1289.e2.

2.

Souza RF, et al. CA Cancer J Clin. 2005;55(6):334-351.

3.

Stachler MD, et al. Nat Genet. 2015;47(9):1047-1055.

4.

Souza RF, et al. Aliment Pharmacol Ther. 2001;15(8):1087-1100.

5.

Nones K, et al. Nat Commun. 2014;5:5224.

17.

Critchley-Thorne RJ, et al. Cancer Epidemiol Biomark Prev.

2016;25(6):958-968.

18.

Critchley-Thorne RJ, et al. Cancer Epidemiol Biomark Prev.

2017;26(2):240-248.

19.

Davison JM, -et al. Am J Gastroenterol. 2020 Feb 18. [Epub ahead of print]. doi: 10.14309/ajg.0000000000000556.

6.

Snyder P, et al. Dig Dis Sci. 2019;64(5):1089-1097.

20.

Hao J, et al. Clinicoecon Outcomes Res. 2019;11:623-635.

7.

Duits LC, et al. Dis Esophagus. 2019;32(1):doy102.

21.

Inadomi JM, et al. Dig Dis Sci. 2018;63(8):2094-2104.

8.

Hoefnagel SJM, et al. PLoS One. 2020;15(4):e0231419.

22.

Ross-Innes CS, et al. PLoS Med. 2015;12(1):e1001780.

9.

Sepulveda JL, et al. Int J Cancer. 2019;145(10):2754-2766.

23.

Offman J, et al. BMC Cancer. 2018;18(1):784.

10.

Craig MP, et al. Clin Transl Gastroenterol. 2020;11(1):e00125.

24.

Chettouh H, et al. Gut. 2018;67(11):1942Ð1949.

25.

Heberle CR, et al. Clin Gastroenterol Hepatol.

2017;15(9):1397-1404.e7.

Iyer PG, et al. Am J Gastroenterol. 2018;113(8):1156-1166.

11.

Nieto T, et al. BMJ Open. 2018;8(6):e020427.

12.

Dilworth MP, et al. Ann Surg. 2019;269(3):479-485.

13.

Jammula S, et al. Gastroenterology. 2020;158(6):1682-1697.

26.

14.

Shaheen N, et al. Am J Gastroenterol. 2016;111(1):30-50.

27.

Wang Z, et al. Clin Cancer Res. 2019;25(7):2127-2135.

15.

American Gastroenterological Association, et al.

Gastroenterology. 2011;140(3):1084-1091.

28.

Moinova HR, et al. Sci Transl Med. 2018;10(424):eaao5848.

29.

Chan DK, et al. Gastroenterology. 2017;152(1):24-26.

16.

ASGE Standards of Practice Committee, et al. Gastrointest Endosc. 2019;90(3):335-359.

30.

Peters Y, et al. Gut. 2020 Feb 25. [Epub ahead of print]

Dr Ellison reported no relevant financial conflicts of interest.

Dr Konda reported receiving grant support from Ironwood Pharmaceuticals.

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THE IMAGING YOU EXPECTED. THE MANEUVERABILITY YOU DIDN'T.

Cases From the Frontiers Of Therapeutic Endoscopic Ultrasound in 2020 ANDREW C. STORM, MD MICHAEL J. LEVY, MD Division of Gastroenterology and Hepatology Mayo Clinic College of Medicine and Science Rochester, Minnesota

.

H

istorically, endoscopic ultrasound (EUS) was a diagnostic procedure used to enhance tumor staging and characterize mucosal and submucosal lesions. More recently, the roles of EUS have been

expanded to an alternative, and increasingly primary, role in the guidance of therapeutic intervention across a broad spectrum of gastrointestinal and non-gastrointestinal disorders. Herein, we present selected patients in whom EUS provided a novel approach from the frontiers of EUS-guided patient care.

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Pancreatic Tumor Ablation With EUS-Guided Radiofrequency Ablation A 72-year-old woman with multiple comorbid illnesses and an enlarging nonfunctioning pancreatic neuroendocrine tumor presented for therapy. The enhancing tumor was visualized by CT (Figure 1A), MRI (Figure 1B), and EUS (Figure 1C). The patient was evaluated in our multidisciplinary Pancreas Clinic after referral for possible pancreatic resection.

All options were considered, including pancreatic resection, locally ablative therapy, and observation alone. The patient and medical team opted for local ablation, and she was referred for EUS-guided radiofrequency ablation (RFA). During therapy, the RFA probe is pictured within the tumor by fluoroscopy (Figure 1D).

The typical hyperechoic changes associated with ablation are noted during EUS (Figure 1E). After therapy, CT showed ablation of the tumor, partly based on the decrease in tumor size but more so on the complete loss of enhancement (Figure 1F).

The success of therapy was further demonstrated by contrast-enhanced EUS, which revealed complete absence of blood flow in the lesion (Figure 1G). The lesion has remained stable without evidence of tumor growth in the subsequent 12-month follow-up.

This case highlights a long-awaited application of therapeutic EUS, namely to allow endoscopically directed pinpoint ablative therapy beyond the lumen of the gastrointestinal tract. Data on ideal patient selection, tumor type, and use of the device are still preliminary and inconclusive, with reported adverse events including pancreatitis, bowel perforation, and pancreatic ductal stenosis,1 but it is likely that over the coming years EUSdirected ablation will continue to evolve into a mature and highly used tool for minimally invasive tumor therapy.

Figure 1A, B, C.

Figure 1D, E.

Figure 1F, G.

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An EUS-Guided Shortcut for Surgically Altered Anatomy ERCPs: The EDEE Procedure A 62-year-old woman who had received a liver transplant with Rouxen-Y hepaticojejunostomy presented with cholangitis and jaundice suggestive of recurrence of anastomotic strictures. Two years previously, after failed single-balloon enteroscopeassisted endoscopic retrograde cholangiopancreatography (ERCP) procedures, the strictures were managed with percutaneous transhepatic biliary drains. Given that 2 separate biliary anastomoses (right and left hepaticojejunostomy) were created, and both had stenosis, she unfortunately required 2 percutaneous drains. She preferred to avoid reinsertion of the drains, which had caused skin infection and irritation and required frequent manipulations. Given the previous difficulty with altered anatomy ERCP, and her preference to avoid percutaneous drainage, she was offered an EUSdirected transenteric ERCP (EDEE) procedure. In this procedure, a lumenapposing metal stent (LAMS) is placed from the stomach or duodenum into the Roux limb, making a shortcut to the biliary anastomoses (Figure 2A). A small retrospective multicenter series

of EDEE procedures recently was reported, showing high rates of technical and clinical success.2 In this case, the Roux limb of the jejunum was visualized on EUS, and a 19-gauge needle was used to inject contrast and saline into the jejunum to serve as a target for EUS-guided stent placement. With a freehand technique, a 15-mm electrocautery-enhanced LAMS was advanced through the duodenal bulb and into the Roux limb (Figure 2B). (The LAMS stent is not yet FDA approved for this indication.) Cre- Figure ation of this duodenumto-Roux limb anastomosis facilitated forward-viewing single-channel therapeutic endoscopic access to the biliary anastomoses, which were each stented with two 10 Fr plastic stents (Figure 2C). Note that with enteroscope-assisted ERCP, 7 Fr stents generally are the largest that can be placed. The patient underwent 2 stent exchanges for a total of 6 months of stenting, at which time her Figure stents, as well as the LAMS, were removed. The fistula from the duodenum to the Roux limb was maintained for future ease of access with a soft plastic doublepigtail stent (Figure 2D).

This case highlights the use of EUS-guided access to facilitate ERCP in nonâ&#x20AC;&#x201C;gastric bypass Roux anatomy, which often is technically challenging and further limited by the lack of tools that can be used and deployed Figure through a small enteroscope working channel.

2B.

2C.

2D.

Figure 2A. G AST R O E N T E R O LO GY & E N D O S CO PY N E WS S P E C I A L E D I T I O N â&#x20AC;˘ O C TO B E R 2 02 0

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Gelfoam and Coil Embolization of Gastric Varices A 68-year-old man with alcoholic cirrhosis presented with melena and hematemesis. He underwent an upper endoscopy in the ICU, which revealed blood in the stomach and multiple large clots in the cardia, limiting views of this area (Figure 3A). After 24 hours on an octreotide infusion, a repeat endoscopy was performed, revealing large type 1 gastroesophageal varices as the likely source of hemorrhage (Figure 3B). The endoscope was exchanged for EUS, which confirmed a large cluster of gastric varices (Figure 3C). The diameters of the variceal lumens were measured, and then appropriately sized vascular embolization coils deployed. A transesophageal 22-gauge needle puncture was performed, and 5 coils were placed successfully into different areas of the varices to act as scaffolding. Absorbable gelatin sponge (Gelfoam, Pfizer) was cut into small pieces (Figure 3D) and suspended in a slurry of sterile saline and contrast for injection. A total of 6 mL of this suspension was injected into and around the previously placed coils (Figure 3E), resulting in thrombosis and diminishment of flow in the previously identified varices, as confirmed by Doppler examination (Figure 3F).

Figure 3C.

Figure 3D.

Figure 3A.

Figure 3B.

This product may allow avoidance of some of the limitations of cyanoacrylate glue injection, such as symptomatic embolization, scope damage, and varix unroofing, as suggested by a pilot study of 10 patients who underwent Gelfoam obliteration of gastric varices at Brigham and Women’s Hospital, in Boston, Massachusetts.3 Cyanoacrylate glue injection, which is not FDA approved for therapy of gastric varices but is guideline recommended by various societies, may result in glue embolization to the lungs in up to 50% of patients— including asymptomatic cases—and may be associated with more serious adverse events, including arterial embolization leading to stroke.4 If cyanoacrylate glue is used, our protocol calls for exclusion of gastroor splenorenal shunts and PFO before injection of any substance into gastric varices to avoid potentially fatal arterial embolization. The use of vascular coils as a scaffold for the glue also may reduce this risk.

Another issue with cyanoacrylate glue is the potential for damage to the distal end of the echoendoscope. We prefer to access gastric varices through the esophageal wall, when feasible, to prevent bringing glue back into the distal end of the scope, which typically is what causes scope damage. This also has the benefit over direct vascular puncture in the stomach of avoiding “unroofing” of a varix, if the glue does not immediately separate from the needle tip on withdrawal.

Figure 3E.

Figure 3F.

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EUS Reversal of Symptomatic Vertical Banded Gastroplasty Stenosis: LAMS Gastrogastrostomy A 79-year-old woman with a history of obesity treated by open vertical banded gastroplasty (VBG) nearly 35 years previously presented with several years of dysphagia, which was leading to weight loss and failure to thrive. Her surgical report was not available, but it was anticipated that the gastroplasty was performed using a Marlex mesh, given the absence of a silastic type band on CT scan of the abdomen.

Upper endoscopy revealed stenosis of the mid-stomach at the VBG (Figure 4A). An attempt to internally migrate the mesh was undertaken using luminal stenting for 4 weeks. This exposed the ingrown mesh material but did not allow its endoscopic removal. Her dysphagia persisted; however, given her comorbid conditions and poor nutritional status, surgical intervention was not considered to be an option.

As an alternative, EUS-guided

Figure 4A.

Figure 4B.

bypass of the strictured gastroplasty was conducted. A nasobiliary tube was placed over a wire into the distal stomach across the stricture of the VBG, and a mixture of contrast and water was injected through it to fill the distal stomach. From the proximal gastric pouch, the distal stomach was visualized on EUS (Figure 4B); it was punctured using an electrocauteryenhanced LAMS catheter, and a 15-mm LAMS was deployed across the new gastrogastrostomy tract (Figure 4C). After deployment, the stent was dilated to 15 mm. The stent is shown from the proximal stomach (Figure 4D) and in the distal portion of the stomach in scope retroflexion from the VBG pathway (Figure 4E). Figure 4C. The patientâ&#x20AC;&#x2122;s dysphagia improved significantly after this procedure, and she was able to gain weight.

Although not yet FDA approved for any indication beyond pancreatic pseudocyst drainage, LAMS are increasingly used to create novel luminal anastomoses. This case demonstrates yet another opportunity for therapeutic EUS to provide minimally invasive therapeutic options for patients, par- Figure 4D. ticularly when surgery is not a viable option.

Figure 4E.

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EUS-Guided Drainage of a Duodenal Wall Intramural Abscess A 58-year-old man developed acute cholecystitis (Figure 5A) that, due to multiple comorbidities and the lack of availability of an experienced endoscopist, was managed in the referring hospital with cholecystostomy tube placement (Figure 5B). The cholecystogram demonstrated a patent cystic duct. Although the initial CT scan demonstrated an enlarged gallbladder and pericholecystic fluid, after symptom resolution and removal Figure 5A. of the cholecystostomy tube, follow-up CT revealed a shrunken and contracted gallbladder with minimal periduodenal inflammatory changes.

One month later, the patient presented with right upper quadrant pain, nausea, vomiting, and early satiety. Repeat CT again demonstrated the small and contracted gallbladder, but now an intramurally confined abscess was viewed in the second portion of the duodenum, resulting in gastroduodenal outlet obstruc- Figure 5B. tion (Figure 5C). Options for surgical drainage were considered, but due to the unresolved comorbidities, the patient was referred for EUS-guided drainage. EUS-guided fine needle injection of contrast revealed the duodenal wall intramural abscess. To provide drainage and bypass, a LAMS and nasojejunal feeding tube were placed (Figure 5D-F). There was rapid resolution of the mechanical obstruction and associated symptoms. Ten days later, the LAMS and nasojejunal feeding tube were removed.

Extramural abscesses and Figure 5C. fluid collections are common applications for LAMS in todayâ&#x20AC;&#x2122;s therapeutic EUS procedures. Successful management of an intramural gastric hematoma using a LAMS has

42

G AST R O E N D O N E WS .CO M

Figure 5D.

Figure 5E.

Figure 5F. been reported.5 Our case likewise demonstrates that an intramural abscess also may be managed easily with this technology.

Remember Your Diagnostic Skills A 49-year-old woman presented with painless obstructive jaundice. CT, MRI, ERCP, and EUS identified no evidence of pathology, and the patient was referred to our center for further evaluation. At EUS, a 1.5-cm isoechoic ampullary mass was identified (Figure 6A). The cytology was interpreted as positive for adenocarcinoma (Figure 6B). However, at EUS, we also identified disparate pancreatic tail changes indicative of coexisting autoimmune pancreatitis (AIP) (Figure 6C). EUS-guided core biopsies taken from the pancreatic tail indicated the absence of malignancy and presence of AIP. Subsequent pylorus-preserving pancreaticoduodenectomy was performed, confirming the presence of invasive (grade 2 of 4) ampullary adenocarcinoma with mucinous features (1.5×1.5×0.9 cm), with focal pancreatic head extension. Immunohistochemistry was compatible with an intestinal phenotype. The resection margin was negative for malignancy and confirmed the presence of storiform fibrosis and lymphocytic phlebitis (Figure 6D), thereby confirming the presence of AIP. Her postoperative recovery was uneventful. The patient received systemic chemotherapy. Given the lack of clinical and radiographic evidence of pancreatic inflammation, corticosteroid therapy for AIP was not administered.

The findings from this case demonstrate the potential for the simultaneous presence of pancreatic ductal adenocarcinoma and AIP, the latter of which may have hindered early detection of malignancy, which was discovered early and successfully resected. Cases like these highlight the critical importance of maintaining diagnostic EUS skills when there often is greater interest in interventional EUS.

Figure 6A, B, C, D.

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References 1.

Barthet M, Giovannini M, Lesavre N, et al. Endoscopic ultrasoundguided radiofrequency ablation for pancreatic neuroendocrine tumors and pancreatic cystic neoplasms: a prospective multicenter study. Endoscopy. 2019;51(9):836-842.

4.

Romero-Castro R, Ellrichmann M, Ortiz-Moyano C, et al. EUSguided coil versus cyanoacrylate therapy for the treatment of gastric varices: a multicenter study (with videos). Gastrointest Endosc. 2013;78(5):711-721.

2.

Ichkhanian Y, Yang J, James TW, et al. EUS-directed transenteric ERCP in non-Roux-en-Y gastric bypass surgical anatomy patients (with videos). Gastrointest Endosc. 2020;91(5):1188-1194.

5.

Bakheet N, Strauss AT, Ichkhanian Y, et al. Lumen-apposing metal stent for the management of intramural hematoma of the GI tract. VideoGIE. 2019;4(7):328-330.

3.

Bazarbashi AN, Wang TJ, Thompson CC, et al. Endoscopic ultrasound-guided treatment of gastric varices with coil embolization and absorbable hemostatic gelatin sponge: a novel alternative to cyanoacrylate. Endosc Int Open.

2020;8(2):E221-E227.

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Dr Storm reported receiving research support from Boston Scientific.

Dr Levy reported no relevant financial conflicts of interest.Disclosures: Dr Storm reported receiving research support from Boston Scientific.

Dr Levy reported no relevant financial conflicts of interest

For daily news, videos and more from GastroEndoNews, like us on Facebook at facebook.com/gastroendonews.

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Samples collected with Moray micro forceps provided a diagnosis in 75% of the patients vs. cytology which provided a diagnosis in 15.9% patients.1

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Microscopic view of mucinous epithelium2

For more information, visit www.steris.com 1. DiMaio, Christopher, MD, et all. Impact of EUS-guided microforceps biopsy sampling and needle-based confocal laser endomicroscopy on the diagnostic yield and clinical management of pancreatic cystic lesions. Gastrointestinal Endoscopy. Volume 91, No. 5 : 2020.

2. Pham, Khanh Do-Cong. Case Report Series 4 – Moray micro forceps. Data on file at STERIS Endoscopy. ©2020 STERIS Endoscopy. All Rights Reserved.

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Pancreatic Cystic Lesions: Diagnosis, Evaluation, and Management ANTONIO R. CHEESMAN, MD GAURAV KAKKED, MD CHRISTOPHER J. DIMAIO, MD Icahn School of Medicine at Mount Sinai New York, New York

P

ancreatic cystic lesions (PCLs) are increasingly encountered incidentally due to the widespread use of abdominal cross-sectional imaging.

The behavior and malignant potential of specific PCL types differ significantly. Given the limitations in our understanding of the natural history of certain types of lesions and the diagnostic accuracy of available tests, management of PCLs is controversial and often anxiety provoking.

Epidemiology The prevalence of PCLs in asymptomatic patients may vary between 2.4% and 13.5%,1,2 and it appears to increase sharply with age,1,3 with PCLs being identified in up to 40% of adults aged older than 70 years.2 The number of patients evaluated for these lesions has increased over the past few decades—by up to 8% annually4—without a parallel increase in pancreatic cancer incidence or related mortality, highlighting the effect of increased diagnostic scrutiny resulting in PCL detection.5

Most Common Cyst Types Lesions can be classified as nonneoplastic (pseudocysts) or neoplastic (the majority of PCLs), with the latter divided further based on their malignant potential.

The differential diagnosis of PCLs includes over 20 pathologic types.6 However, in clinical practice only a handful of subtypes are encountered commonly (Table 1). This review focuses on the 6 most commonly encountered PCLs: nonneoplastic pancreatic pseudocysts; benign serous cystadenomas (SCAs); and potentially malignant mucinous cystic neoplasms (MCNs), solid pseudopapillary neoplasms (SPNs), cystic neuroendocrine tumors (NETs), and intraductal papillary mucinous neoplasms (IPMNs).

Nonneoplastic Cysts Pancreatic pseudocysts are fluid collections resulting from acute pancreatitis or pancreatic duct leaks that can be caused by trauma, surgical complications, or chronic pancreatitis. They occur at any age,

predominantly in men (75%). Patients may be asymptomatic or present with abdominal pain, infection, and luminal or biliary obstruction.

Pancreatic pseudocysts, as defined by the revised Atlanta classification,7 are mature fluid collections that develop at least 4 weeks after a primary insult, have a well-defined wall formed by adjacent organ structures, and may have intra- or peripancreatic involvement (Figure 1). They usually occur as a single (unifocal) lesion without compartments (unilocular) and lack solid or calcified components. Pancreatic duct communication is common, and associated pancreatic duct abnormalities may be present (dilation, strictures, or stones).

Fluid aspirates on fine needle aspiration (FNA) frequently are brown, carcinoembryonic antigen (CEA) level is low (<5 to 20 ng/mL), and amylase level is elevated (>250 U/L).8 Cytology may reveal histiocytes, macrophages, and neutrophils.

Therapeutic cyst drainage typically is limited to patients who have associated abdominal pain, early satiety, obstructive jaundice, or secondary infection.

Neoplastic Cysts Neoplastic cysts trigger episodes of pancreatitis (20%). Thus, an alternative diagnosis and further testing should be pursued in patients who do not have a contributory history, or who have unusual-appearing cysts or cysts that occur before or concurrently with acute pancreatitis.9 Benign Without Malignant Potential SCAs. These cysts account for approximately 25% of all neoplastic PCLs; they typically are identified in the fifth to seventh decades of life and occur more commonly in women (75%).9,10 Most lesions are found incidentally on cross-sectional imaging obtained for other purposes, but patients occasionally may present with symptoms due to mass effect.

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Table 1. Characteristics of Most Common Pancreatic Cysts Cyst Type

Pancreatic Pseudocysts

Serous Cystadenomas

Mucinous Cystic Solid Neoplasms Pseudopapillary Neoplasms

Cystic NETs

BD-IPMNs

Patient Age

Any

Fifth to seventh decade

Fifth to seventh decade

Second to third decade

Fifth to sixth decade

Fifth to seventh decade

Patient Sex

Men, 75%

Women, 75%

Women, >95%

Women, >90%

Similar frequency in men and women

Similar frequency in men and women

Associations

History of pancreatitis or PD disruption preceding PCL formation

von Hippel-Lindau

Multiple endocrine neoplasia type 1

Can cause pancreatitis

Typical Clinical Asymptomatic; Asymptomatic pain; luminal Presentation

Asymptomatic; pain

Pain

Asymptomatic Asymptomatic (largely nonfunctioning)

Unifocal unilocular or oligolocular lesion in the body or tail of the pancreas (>90%); no PD communication

Unifocal solid, cystic, or mixed lesion in the body or tail of the pancreas

Unifocal solid, cystic, or mixed lesion

Multifocal (40%), multicystic (â&#x20AC;&#x153;cluster of grapesâ&#x20AC;?) lesion; presence of PD communication

Viscous

Bloody

Bloody

Viscous

or biliary obstruction Unifocal Typical unilocular Imaging Characteristics lesion; no solid

Unifocal multilocular microcystic components; lesion common PD (honeycomb communication pattern), central scar (sunburst calcification); no PD communication

Brown Aspirate Characteristics

Thin, straw-colored

Cytology

Histiocytes, Glycogen-rich macrophages, cuboidal cells and neutrophils

Mucin-rich columnar cells with variable atypia supported by ovarian-like stroma

Branching papillae with myxoid stroma

NET cells

Mucin-rich columnar cells with variable atypia

Fluid Analysis

CEA <5 to 20 ng/mL; amylase >250 U/L

CEA <5 to 20 ng/mL; amylase <250 U/L

CEA >192 ng/mL; amylase <250 U/L

Not characteristic

Not characteristic

CEA >192 ng/mL; amylase >250 U/L

Malignant Potential

None

Negligible

Moderate

Moderate to high

Variable

Variable

Management

No surveillance; No surveillance; cyst drainage if surgical symptomatic resection if symptomatic

Surgical resection; no need for postoperative surveillance, unless invasive cancer

Surgical resection; postoperative surveillance needed

Surgical vs expectant (small, lowgrade, low proliferative index nonfunctioning lesions)

Surveillance vs surgical resection, depending on cyst features

BD-IPMNs, branch-duct intraductal papillary mucinous neoplasms; CEA, carcinoembryonic antigen; NETs, neuroendocrine tumors; PCL, pancreatic cystic lesion; PD, pancreatic duct

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SCAs typically occur as solitary lesions anywhere in the pancreas. Multiple lesions with or without associated NETs may be seen in patients with underlying von Hippel-Lindau (VHL) disease.11 Classic SCAs are multilocular and have numerous microcystic compartments in a honeycomb pattern that can mimic a solid mass (Figure 2). When a central scar or “sunburst” calcification is seen (30%), it is considered pathognomonic.

Less commonly, lesions may be oligolocular with larger cystic compartments and can be difficult to distinguish from other neoplastic lesions (ie, branch-duct IPMNs or MCNs). SCAs do not communicate with the pancreatic duct, which may help differentiate them.

The diagnostic yield of FNA in SCAs is limited because aspirates often are dry and acellular due to the microcystic morphology of these lesions.12,13 Cystic fluid typically is thin and straw-colored. Levels of CEA (<5 to 20 ng/mL) and amylase are low.8,14 Cytology reveals characteristic glycogen-rich cuboidal epithelial cells that line the cyst and stain positive for alpha-inhibin.13,15 Analysis of DNA shows somatic loss-of-function mutations in the VHL tumor suppressor gene.

SCAs are slow growing and symptoms are related to cyst enlargement. Only a handful of case reports of malignant transformation exist in the literature.10,16 Thus, no surveillance or treatment is needed when the diagnosis of SCA is certain, and surgery is indicated only for symptomatic patients.9,17 The presence of a single honeycomb-appearing lesion with central calcification on radiological evaluation in an asymptomatic patient is sufficient to establish the diagnosis.9 However, when the diagnosis is unclear or if symptoms develop, MRI surveillance or endoscopic ultrasound (EUS) with or without FNA can be pursued.

Benign With Malignant Potential MCNs. Usually identified in the fifth to seventh decades of life, MCNs occur almost exclusively in women (>95%).9,18 Lesions can be found incidentally or due to complications from mass effect or malignant degeneration.

MCNs typically occur as a unifocal lesion in the body or tail of the pancreas (>90%) and do not communicate with the pancreatic duct.18,19 They are unilocular or oligolocular septated lesions that may present with eccentric rim “eggshell” calcifications (15%) (Figure 3).

High-risk features for underlying malignancy include a cyst diameter of at least 5 cm, wall thickening or calcification, and internal solid components.19,20 On FNA, cystic fluid appears viscous, CEA levels typically are high (>192 ng/mL), and amylase levels are low (<250 U/L).8,14 Cytology can reveal mucin-rich columnar cells with variable atypia in the epithelial lining of the cyst that are supported by characteristic ovarian-like stroma, which differentiate MCNs from IPMNs.19 Aspirates from solid components have a high diagnostic yield when malignancy is present. Analysis of DNA may reveal mutations in KRAS.8 MCNs have moderate malignant potential, and

Figure 1. Pancreatic pseudocyst that developed after an attack of alcohol-induced pancreatitis.

Figure 2. Serous cystadenoma with classic honeycomb microcystic appearance. approximately 10% to 40% of resected lesions exhibit high-grade dysplasia (HGD) or cancer.19-21 The prevalence of malignancy appears to be very low for lesions less than 3 cm in diameter without mural nodules or serum carbohydrate antigen 19-9 (CA 19-9) abnormalities.21 However, resection traditionally has been recommended for all patients with an acceptable surgical risk,17,22,23 given that most MCNs occur at a young age, can be resected by distal pancreatectomy, do not require postoperative surveillance even when lesions harbor HGD,9,24 and have excellent cure rates in cases of noninvasive malignancy.

Surveillance still can be considered for lesions less than 3 cm in diameter without other high-risk features.9 For resected lesions harboring invasive cancer, postoperative surveillance should be continued.9 SPNs. Usually discovered in the second to third decades of life, SPNs are more common in women (90%).25 They can be found incidentally but frequently present with abdominal pain (60%),25 and in children, a palpable mass may be noted.

SPNs appear as unifocal lesions, most commonly in the body or tail of the pancreas. They can be solid,

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Figure 3. Mucinous cystic neoplasm with “eggshell” calcifications.

Figure 4. Solid pseudopapillary tumor with typical mixed solid/cystic appearance. cystic, or have mixed components due to tumor necrosis, occasionally with irregular calcifications (20%) (Figure 4).26 A larger cyst diameter (≥5 cm) is associated with an increased risk for underlying malignancy.27 When available, cystic fluid typically is bloody. Levels of CEA are not characteristic. Cytology frequently is diagnostic (75%), particularly when obtained from solid components, revealing branching papillae with myxoid stroma.26 Special staining for E-cadherin, betacatenin, and CD10 can help differentiate these lesions from NETs,28,29 whereas DNA analysis can reveal CTNNB1 mutations that are specific.

SPNs have moderate to high malignant potential, and approximately 15% of resected lesions harbor high-grade malignancy.25,27,30 Resection always is recommended in patients with an acceptable risk,9,17 and postoperative surveillance should be continued in all patients for at least 5 years.9 When malignancy is present, complete excision or debulking for metastatic disease leads to a high cure rate or prolonged survival, respectively.25,31 NETs. These rare, largely nonfunctioning (>50%) tumors usually are identified in the fifth to sixth decades

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of life, with similar frequency in men and women. They can occur sporadically or be associated with multiple endocrine neoplasia type 1 (MEN1). The presence of anterior pituitary or parathyroid gland disorders should raise suspicion.

Pancreatic NETs, except MEN1-associated NETs, typically appear as unifocal lesions. They can be solid (>85%), cystic (Figure 5), or have mixed components due to tumor necrosis. When available, cystic fluid is bloody, and CEA and amylase levels are low. Cytology can reveal NET cells, and various stains can help establish the diagnosis.

NETs exhibit a wide spectrum of clinical behavior that appears to be unchanged for lesions with cystic degeneration.32 Their management is controversial and beyond the scope of this review, but an expectant approach may be considered for small (<1 cm), low-grade/low proliferative index nonfunctioning lesions without evidence of local invasion or distant metastases.33 IPMNs. These lesions are classified into main duct (MD-IPMN), branch duct (BD-IPMN), or mixed according to their level of pancreatic duct involvement. MD-IPMN and mixed lesions have a high risk for malignant degeneration and should be surgically resected. BD-IPMNs are, perhaps, the most important PCLs encountered in clinical practice; they are the most common incidental cysts and have an estimated prevalence of 2.5% in the United States,1,3 with variable risk for malignant progression and evolving management recommendations.

BD-IPMNs typically are discovered incidentally in the fifth to seventh decades of life and are distributed evenly between men and women.34 Patients occasionally present with unexplained pancreatitis due to pancreatic duct obstruction, which may be recurrent.

BD-IPMNs often appear as multifocal lesions (40%)9,35 anywhere in the pancreas, and they can be unilocular or multicystic (“cluster of grapes”) (Figure 6). BDIPMNs arise from the pancreatic ductal system and, thus, pancreatic duct communication is pathognomonic but may not always be recognizable. Segmental or diffuse pathognomonic dilation can occur from direct ductal involvement (mixed/MD-IPMN) or mucin-related obstruction. Features suggestive of underlying malignancy include a cyst diameter greater than 30 mm and irregular thick septae and mural nodules greater than 10 mm (Figure 7).36,37 On FNA, fluid aspirates are viscous, and levels of CEA (>192 ng/mL) and amylase (>250 U/L) are elevated.8,14 The use of cystic fluid glucose with a threshold less than 50 mg/dL recently also was advocated as an adjunct diagnostic marker to differentiate mucinous lesions due to its increased sensitivity, although with lower specificity than CEA.38-40 Stains are positive for mucin (<50%), and cytology can reveal mucin-rich columnar cells with variable atypia that conform to the epithelial lining of the cyst. Aspirates from solid components have a high diagnostic yield when malignancy is present. Analysis of DNA may reveal GNAS mutations, in addition to

abnormalities in KRAS, as seen in MCNs.8 BD-IPMNs have variable malignant potential. Management involves surveillance and, in selected cases, surgical resection based on cyst characteristics (morphologic features, cyst location) and patient-related factors (life expectancy, patient preference). Several clinical guidelines have been developed9,17,22,23,41,42; however, recommendations are based largely on expert opinion, given the low quality of data available. The 2017 revised Fukuoka41 and 2018 American College of Gastroenterology (ACG)9 guidelines are the most recent and are well accepted.

The Fukuoka guidelines stratify the morphologic features of BD-IPMNs into 2 categories: high risk and worrisome (Figure 8; Table 2).41 Surgical resection is recommended for BD-IPMNs with any high-risk features, whereas EUS with or without FNA should be pursued if worrisome features are present. Surgical resection is recommended if high-risk stigmata are identified on EUS or if FNA is positive for HGD or cancer. Depending on cyst size, BD-IPMNs not meeting any of these criteria can undergo surveillance by CT/MRI (lesions <2 cm), repeat EUS alternating with MRI, or surgery in selected cases (lesions >2 cm).

The ACG guidelines highlight high-risk features for presumed mucinous cysts (IPMN and MCN), which indicate the need for EUS with or without FNA, if not already obtained, and referral to a multidisciplinary group for further management. The features include jaundice or acute pancreatitis attributable to the cyst, main pancreatic duct dilation greater than 5 mm, or abrupt change in the main pancreatic duct with upstream atrophy, a cyst diameter of at least 3 cm, an increase in cyst size of at least 3 mm per year, mural nodules, an otherwise unexplained elevation of CA 19-9, and evidence of HGD/cancer on cytology.

A recent meta-analysis including over 3,700 patients evaluated the performance of the revised Fukuoka (pooled sensitivity, 0.67; specificity, 0.64; area under the curve, 0.78) and AGA (pooled sensitivity, 0.59; specificity, 0.77; area under the curve, 0.79) guidelines for predicting advanced neoplasia in surgically resected and histologically confirmed PCLs, showing similar but unsatisfactory diagnostic accuracy.43 In this context, it is important to understand the malignancy risk profile of BD-IPMNs. Studies have shown that for low-risk lesions, the short-term risk for malignant transformation (HGD/cancer) is low (1%-2% at a median follow-up of 3 years)44,45 and modestly increases with time (3%-5% at a median follow-up of 5-7 years),46-48 with an estimated annual risk of 0.7%.46 For BD-IPMNs with worrisome or high-risk features, however, the risk for malignancy varies from 4% to 50% at 5 years.49 Thus, long-term surveillance is reasonable, provided the patient remains an appropriate surgical candidate and is amenable to pursuing surgery if suspicion regarding cancer arises. The high morbidity (30%) and mortality (2%) associated with surgical resection must

Figure 5. Cystic NET. NET, neuroendocrine tumor

Figure 6. Multifocal BD-IPMN. BD-IPMN, branch-duct intraductal papillary mucinous neoplasm

Figure 7. BD-IPMN with features suggestive of underlying malignancy.

BD-IPMN, branch-duct intraductal papillary mucinous neoplasm

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Are any of the following “high-risk stigmata” of malignancy present?

• Obstructive jaundice in a patient with a cystic lesion of the head of the pancreas • Enhancing mural nodule ≥5 mm • Main pancreatic duct ≥10 mm

Yes Consider surgery if clinically appropriate

Clinical: • Pancreatitisa

Yes

No

Are any of the following “worrisome features” present?

Imaging: • Cyst ≥3 cm • Abrupt change in caliber of pancreatic • Enhancing mural nodule <5 mm duct with distal pancreatic atrophy • Thickened/enhancing cyst walls • Lymphadenopathy • Main duct size 5-9 mm • Increased serum level of CA 19-9 • Cyst growth rate ≥5 mm in 2 y

Yes Perform endoscopic ultrasound No Are any of the following features present?

• Definite mural nodule(s) ≥5 mmb • Main duct features suspicious for involvementc • Cytology: suspicious or positive for malignancy

No

What is the size of the largest cyst?

Inconclusive >3 cm • Close surveillance alternating MRI with EUS every 3-6 mo • Strongly consider surgery in young, fit patients

2-3 cm

1-2 cm

• EUS in 3-6 mo, then lengthen interval up to 1 y, alternating MRI with EUS • Consider surgery in young, fit patients with need for prolonged surveillance

• CT/MRI every 6 mo× 1 y, yearly for 2 y, then up to 2 y if no change

<1 cm • CT/MRI in 6 mo, then every 2 y if no change

Figure 8. Algorithm for the management of suspected BD-IPMNs according to the revised Fukuoka guidelines. a b

c

Pancreatitis may be an indication for surgery for relief of symptoms.

Differential diagnosis includes mucin. Mucin can move with change in patient position, may be dislodged on cyst lavage, and does not have Doppler flow. Features of true tumor nodule include lack of mobility, presence of Doppler flow, and FNA of nodule showing tumor tissue.

Presence of thickened walls, intraductal mucin, or mural nodules is suggestive of main duct involvement.

In their absence, main duct involvement is inconclusive.

BD-IPMNs, branch-duct intraductal papillary mucinous neoplasms; CA 19-9, carbohydrate antigen 19-9; EUS, endoscopic ultrasound; FNA, fine needle aspiration Reprinted from reference 41, with permission from Elsevier.

be considered.9 Various clinical scores have been used to evaluate the risk for death from factors other than pancreatic cancer in these patients,50,51 which can help guide individualized discussions on the need for surveillance and surgery.

Finally, postoperative surveillance is necessary despite resection, given the risk for recurrence or development of a “concomitant” cancer (20%)48 in the remaining pancreatic parenchyma.52 In patients with a resected IPMN with HGD or cancer, MRI/EUS is recommended every 6 months, whereas for those who have low-grade dysplasia lesions resected, surveillance is performed every 2 years or sooner, as dictated by features of coexisting IPMNs, if present.9

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Diagnostic Evaluation The main goals and challenges in the diagnostic evaluation of PCLs include identifying lesions that do not require surveillance, tailoring the management of those with malignant potential according to their specific risk profile, and achieving early detection of HGD or cancer if present, while avoiding subjecting patients to repetitive expensive and invasive testing.

Cross-Sectional Imaging This technique typically is used for unrelated reasons and leads to the incidental discovery of PCLs. Specific morphologic features sometimes can help distinguish specific PCL types. Although CT is relatively inexpensive

and readily available, contrast-enhanced MRI and magnetic resonance cholangiopancreatography (MRCP) are preferred for their improved resolution allowing for evaluation of pancreatic duct communication, septae, and mural nodules.9,53 For differentiating IPMNs from other cyst types, MRI/MRCP particularly outperform CT. However, the diagnostic accuracy of MRI/MRCP for determining PCL type and differentiating lesions harboring high-grade pathology is only 40% to 50% and 55% to 76%, respectively.54 A dedicated pancreatic protocol of contrast-enhanced CT can be used in patients unable to undergo MRI/MRCP.

Table 2. Risk Stratification of BD-IPMNs According to Revised Fukuoka Guidelines High-Risk Features Worrisome Features • Jaundice

• Main PD dilation • Rapid growth rate >5 mm in 2 y ≥10 mm • Enhancing mural nodule <5 mm • Enhancing • Thickened and enhancing cyst intramural wall nodule ≥5 mm • Main PD dilation of 5-9 mm

Endoscopic Ultrasound EUS provides high-quality image resolution and allows for sampling of pancreatic lesions. However, when used solely as an imaging modality (without FNA), EUS has not shown to be superior to cross-sectional imaging for characterization of cyst type or identification of high-grade (65%-67%) or invasive pathology.55-58 EUS, preferentially with FNA, is indicated for PCLs with high-risk or worrisome features and for uncharacterized lesions greater than 2 cm in diameter.

EUS-Guided FNA Typically used for chemical (amylase, glucose, CEA) and cytologic analysis, FNA leads to improved cyst characterization and identification of high-grade pathology, with high specificity but suboptimal sensitivity.

Low amylase levels (<250 U/L) can be used to exclude pseudocysts. Particular importance lies in the differentiation of mucinous from nonmucinous lesions.

For this purpose, glucose levels lower than 50 mg/dL are highly sensitive for mucinous cysts (89%-92%; specificity, 86%-87%),38,39 whereas CEA levels greater than 192 ng/mL are highly specific (88%; sensitivity, 63%) and values less than 5 ng/mL virtually exclude them.14 Cytologic analysis shows similar results (specificity, 93%; sensitivity, 54%).14 The major limitations in FNA techniques result from insufficient fluid for biochemical analysis (51%) and inadequate cellularity (69%).59 In addition, CEA levels do not correlate with, or help with the recognition of, HGD or cancer.60,61 Furthermore, cytology only is able to identify advanced pathologic grade in 64.8% of malignant IPMNs.62 To improve on this, newer molecular tests and ancillary EUS techniques are being investigated.

As previously reviewed, various molecular markers (KRAS, GNAS, VHL, CTNNB1) can assist in the characterization of PCLs.63-65 In particular, KRAS/GNAS mutations and proteomic mucin profiling may help distinguish mucinous lesions. Mutations in TP53, PIK3CA, and PTEN can help identify malignancy, but further studies are required to validate molecular markers and determine their clinical utility and place in the diagnostic algorithm of PCLs. For example, a meta-analysis showed poor outcomes of PCL fluid KRAS mutation analysis in identifying both premalignant cysts (including mucinous PCLs) and malignant lesions compared with CEA levels and cytology.66

• Cyst diameter ≥3 cm

• Abrupt change in PD caliber with distal atrophy • Lymphadenopathy • Elevated serum CA 19-9 level CA 19-9, carbohydrate antigen 19-9; PD, pancreatic duct Based on reference 41.

EUS-Guided Needle-Based Confocal Laser Endomicroscopy EUS-guided needle-based confocal laser endomicroscopy (nCLE) allows for real-time in vivo microscopic evaluation of the cyst wall through a 19-gauge endoscopic needle. Various epithelial and vascular patterns have been described for PCL types.67 A prospective validation study of nCLE demonstrated better diagnostic performance than EUS morphology and CEA analysis for noncommunicating PCLs in 78 patients with reference diagnoses by FNA cytology or surgical histopathology.68 A recent prospective study demonstrated nCLE was more accurate in classifying mucinous versus nonmucinous cysts than CEA and cytology in 65 patients with surgically resected PCLs.69 However, nCLE is not widely available, requires the use of fluorescein and a large-gauge needle, and diagnostic interpretations made using this technique may be affected by operator variability.

EUS-Guided Microforceps Biopsy Microforceps biopsy employs the use of a novel miniature biopsy forceps that can be inserted through a 19-gauge endoscopic needle and allows for direct pancreatic cyst wall biopsies to be obtained. Two recent meta-analyses including over 400 patients each demonstrated higher diagnostic yield for a specific cyst type than with cytology obtained by FNA; they also showed higher concordance rates with surgical pathology in addition to mucinous cyst histologic severity, with an acceptable low-risk profile.70 A recent retrospective study of patients with PCLs showed the combination of cyst fluid chemistry and cytology obtained by FNA, along with microforceps biopsy and/or nCLE, resulted in significantly higher rates of specific PCL diagnostic classification, leading to a major influence on changing clinical management

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decisions, including need for continued surveillance or surgery. It is thus proposed that the addition of microforceps biopsy and/or nCLE be considered when performing EUS-FNA of PCLs.71

Endoscopic Cyst Ablation Multiple studies have examined the role of endoscopic ablation of PCLs with ethanol alone or in combination with a chemotherapeutic agent (paclitaxel or gemcitabine). The rates of complete cyst resolution achieved vary widely (0%-75% after â&#x2030;Ľ1 ablation treatment),72-78 and there are several cases of cancer developing after ablation treatment for BD-IPMN.79,80 No data indicate that a decrease in cyst size or apparent cyst resolution reduces the risk for malignant degeneration of neoplastic cysts or development of a concomitant cancer in a patient with IPMN. Thus, PCL ablation is not recommended and should be used only in research settings.

Conclusion PCLs are a common and important clinical entity encountered in everyday practice. Potential PCLs should not be ignored because the majority of these lesions are neoplastic in nature or have the potential for malignant transformation. Proper evaluation requires careful review of a patientâ&#x20AC;&#x2122;s clinical history in combination with the use of contrast-enhanced cross-sectional imaging and/or EUS with FNA. Numerous guidelines exist for the management of the variety of PCLs. Most patients typically undergo radiographic surveillance, but a subset of patients with asymptomatic neoplastic lesions may benefit from surgical resection. Advances in cystic fluid biomarkers and improved tissue imaging and acquisition hopefully will improve preoperative identification and risk stratification for patients with PCLs.

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18

To receive your free copy of the Summer 2020 issue go to

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What is the power of the microbiome?

...and how can it be unlocked to treat disease?

UNLOCK THE POTENTIAL AT POWEROFMICROBIOME.COM Ferring is committed to exploring the crucial link between the gut microbiome and the threat of recurrent Clostridioides difficile infections. With the 2018 acquisition of Rebiotix and several other alliances, Ferring is rapidly advancing its microbiome research, developing novel therapies to address significant unmet needs in Š2020 Ferring B.V. US-MBIO-2000020

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Updated Evidence for Optimal Management of C. diff Infection MARK H. WILCOX, MD, FRCPATH Consultant and Head of Microbiology Research and Development Leeds Teaching Hospitals NHS Trust Professor of Medical Microbiology Sir Edward Brotherton Chair of Bacteriology University of Leeds Leeds, England

E

vidence continues to accumulate on the increased relative efficacy of some therapies for

Clostridioides difficile infection (CDI), especially with respect to the prevention of recurrent infection.

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There are 4 agents approved for managing CDI: 2 older antibiotics, metronidazole and vancomycin, and 2 newer options, the antibiotic fidaxomicin (Dificid, Merck) and a newer monoclonal antibody against toxin B, 1 of the 2 major C. difficile toxins (bezlotoxumab [Zinplava, Merck]). Four additional agents are in phase 1 to 3 clinical trials.

Bezlotoxumab is given along with one of the standard of care antibiotics to reduce the risk for CDI recurrence by augmenting the host endogenous antibody response against C. difficile toxin B. The antibiotics aim to stop C. difficile growth and, thus. toxin production. However, the other crucial issues are whether C. difficile persists in the gut as spores, with the potential to germinate once antibiotic administration has stopped, and the extent of microbiome disturbance that the CDI therapeutic causes on top of the existing dysbiosis. Together, these issues determine the effectiveness of the therapeutic to achieve clinical cure and prevent infection recrudescence (recurrent CDI).

Table. Patients Needed to Treat With Bezlotoxumab and Standard Of Care Antibiotic To Prevent One Recurrence of CDIa

Subgroup

NNT to Prevent A Recurrence

Patients aged ≥65 y

3.8

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4.7

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5.1

Patients aged ≥65 y who have had ≥1 previous episode in prior 6 mo

2.5

Patients who are immunocompromised and have had ≥1 previous episode in prior 6 mo

3.0

Patients who present with severe CDI and have had ≥1 previous episode in prior 6 mo

2.5

a Patients were stratified according to baseline risk factors for recurrence.

CDI, Clostridioides difficile; NNT, needed to treat

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We know that metronidazole, until recently the most common option for treating CDI, is inferior to vancomycin (and almost certainly to fidaxomicin).1-3 Thus, guidelines increasingly advocate the use of vancomycin (or fidaxomicin) rather than metronidazole, especially for the treatment of non-mild cases of CDI.4 Notably, however, fidaxomicin and bezlotoxumab have been shown convincingly to reduce the risk for recurrent CDI by 40% to 50% compared with vancomycin alone.5-7 This review focuses primarily on emerging evidence that underscores the efficacy of the newer CDI treatment options, summarizes the new agents undergoing clinical trials (phase 2 or beyond), and highlights a new focused update of the recently published CDI guideline from the Infectious Diseases Society of America.

Emerging Evidence on Fidaxomicin Efficacy A recent randomized, controlled, open-label, superiority, phase 3Ib/4 clinical trial in hospitalized adults aged ≥60 years demonstrated that an extended-pulsed dosing regimen of fidaxomicin (200 mg twice daily on days 1-5, then once every other day on days 7-25)— comprising the same total dose of antibiotic as a conventional course—can further reduce the risk for recurrent CDI compared with a standard course of vancomycin (125 mg 4 times daily on days 1-10).8 The primary end point was sustained clinical cure 30 days after the end of treatment (day 55 for extended-pulsed fidaxomicin and day 40 for vancomycin); 70% (124/177) of the extended-pulsed fidaxomicin recipients versus 59% (106/179) of the vancomycin patients achieved sustained clinical cure 30 days after the end of treatment (difference, 11%; 95% CI, 1.0%-20.7%; P=0.030; odds ratio, 1.62 [95% CI, 1.04-2.54]).

Studies in an in vitro model that simulates conditions found in the human colon, and notably the gut microbiome in the context of CDI, provided a rationale for the above-mentioned novel extended dosage of fidaxomicin.9 This gut model, which is primed with pooled fecal samples from elderly volunteers, has proven to be predictive of antibiotic behavior in patients—both whether antibiotics have high or low propensity to induce CDI and whether novel agents will treat CDI and prevent recurrent infection successfully.10 Gut model experiments showed that pulsed or tapered fidaxomicin regimens may enhance suppression of C. difficile, while allowing microbiota recovery.9 Two other key lines of evidence are pertinent to understanding why an extended dosage of fidaxomicin is particularly effective at reducing the risk for recurrent CDI. First, in both fecal samples from human volunteers and gut model contents, fidaxomicin can be detected well beyond the cessation of dosing (2-3 weeks), at levels well in excess of the minimum inhibitory concentration of fidaxomicin for C. difficile.11,12 So, extended dosage regimens likely result in persistence of fidaxomicin for longer periods than standard dosing regimens, suppressing recrudescence of C. difficile spores but allowing recovery of gut microbiota populations. Notably, no evidence of the emergence

of reduced susceptibility of C. difficile has been associated with extended dosage regimens. Second, in vitro studies show that fidaxomicin persists on C. difficile spores, whereas vancomycin does not.13 Furthermore, persistence of fidaxomicin prevented C. difficile growth and toxin production. Thus, it is possible that the continued presence of fidaxomicin in the gut after cessation of dosing, coupled with the association of antibiotic with spores, explains why this antibiotic reduced CDI recurrence. Such effects may be exploited by extended dosing of fidaxomicin.8 In a follow-up report to the phase 3b/4 clinical trial, both prespecified and post hoc subgroup analyses were presented to determine whether particular patient groups showed more benefit from the extended fidaxomicin dosage regimen.14 Prespecified subgroup categories included patient age (60-74 vs ≥75 years); cancer diagnosis (presence vs absence); CDI severity; and number of prior CDI episodes within 3 months before study participation. A post hoc subgroup efficacy analysis also was performed in relation to presence of C. difficile ribotype 027 (vs other ribotypes). The primary end point was sustained clinical cure (initial cure and absence of recurrence) 30 days after end of treatment. Sustained clinical cure rates did not differ significantly between extended dosage fidaxomicin (124/177; 70.1%) and vancomycin (106/179; 59.2%) according to age, cancer diagnosis, CDI severity, or history of CDI. However, in patients with CDI due to ribotype 027, the sustained clinical cure rate was significantly higher in extended fidaxomicin (20/25; 80%) than vancomycin (9/22; 40.9%) recipients (treatment difference, 39.1%; 95% CI, 13.2%-64.9%; P=0.006).14 Such data for a C. difficile type that is associated with poor outcomes,

albeit from a post hoc analysis, provide added confidence about the efficacy of fidaxomicin in treating CDI. In a prospective surveillance study spanning 5 years (2011-2016) across 28 European countries (40 sites) 3,499 isolates from cases of CDI were monitored for changes in antimicrobial susceptibility and ribotype distribution.15 Ribotype prevalence varied greatly between countries and between years, but the most common of the 264 ribotypes found was 027 (mean prevalence 11.4%). Metronidazole and vancomycin geometric mean MICs were 0.46 mg/L and 0.70 mg/L, respectively.

Fidaxomicin susceptibility, including in ribotype 027, was maintained post-introduction; geometric mean MIC for years 1 to 5 was 0.04 mg/L, with only one fidaxomicinresistant isolate (RT344) detected (MIC ≥4 mg/L).

Emerging Evidence for Bezlotoxumab In phase 3 trials, bezlotoxumab significantly reduced the risk for CDI recurrence in predefined groups at high risk for recurrent disease and/or poor outcome (≥65 years, previous CDI, immunocompromised, or severe CDI, but not CDI due to ribotype 027).16 Bezlotoxumab also was associated with a significant reduction in the 30-day CDI-associated readmission rate (4.0% vs 9.6%; difference, –5.7%; 95% CI, –8.8% to –2.7%).17 Recent reports have added to our understanding of the efficacy of bezlotoxumab in preventing recurrent CDI. Higher host antitoxin B, but not antitoxin A, antibody titers were associated with protection against recurrent CDI, which is consistent with the MODIFY trial outcomes (bezlotoxumab, but not actoxumab, was efficacious).18 In addition, a post hoc analysis of the efficacy rates of bezlotoxumab according to the method used to diagnose CDI in the MODIFY clinical trials found that the

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magnitude of reduction in recurrent CDI was substantially larger in participants diagnosed by toxin tests (relative difference, –46.6%) than in subjects recruited on the basis of a (toxin gene) PCR test or toxigenic culture (–29.1%).19 Hence, bezlotoxumab recipients diagnosed by toxin testing had a lower rate of CDI recurrence than those recruited by indirect toxin tests (17.6% vs 23.6%).

These data show the magnitude of reduction in recurrent CDI achieved by bezlotoxumab is probably greater than the headline rate reported in the primary publication of the MODIFY studies.6 A subsequent analysis of the modified intent-totreat population from the MODIFY studies who received bezlotoxumab or placebo (n=1,554) according to their baseline risk factors for recurrent CDI recently was published.20 These risk factors were prespecified in the statistical analysis plan: age ≥65 years, history of CDI, compromised immunity, severe CDI, and ribotype 027/078/244.

The proportion of placebo recipients who experienced recurrent CDI exceeded 30% for each risk factor compared with 20.9% of those without a risk factor. Also, the rate of recurrent CDI increased with the number of risk factors (1 risk factor, 31.3%; ≥3 risk factors, 46.1%). In a separate analysis, the number of subjects needed to treat (NNT) to prevent a CDI recurrence was calculated (Table). This shows a very low NNT of 2 to 3 patients in those who have 2 risk factors for recurrent CDI, and provide a good basis for selecting patients to consider for bezlotoxumab treatment.21 In a real-world study of 46 patients receiving bezlotoxumab in five hospitals in Finland, 71% remained recurrence-free at 3 months.22 Of particular note, 8 patients were awaiting fecal microbiota transplantation (FMT). After stopping the antibiotics that were continued to prevent CDI recurrence (and receiving bezlotoxumab), all 8 patients remained free of recurrence and did not require FMT. Given that FMT is an experimental procedure, whereas bezlotoxumab has regulatory approval for the prevention of CDI recurrence, this (uncontrolled) observation is revealing. Similarly, in the 2 registrational phase 3 (MODIFY) clinical trials, 11% of patients in the placebo group went on to receive FMT, whereas only 3% of those receiving active treatment had FMT.23 Thus, these data are consistent with the recommendation in the IDSA CDI guideline that appropriate antibiotic treatments for at least 2 recurrences (ie, 3 CDI episodes) should be tried prior to offering FMT.4 Using pooled data from MODIFY I/II, a post hoc analysis examined CDI-related outcomes in participants with inflammatory bowel disease (IBD) and CDI.24 A total of 44 participants had IBD (ulcerative colitis, 23; Crohn’s disease, 18; and non-characterized IBD, 3). Given that overall recurrent CDI results were similar for the bezlotoxumab and the actoxumab plus bezlotoxumab groups, these groups were pooled (bezlotoxumab group); similarly, the actoxumab and placebo groups were pooled (no bezlotoxumab group). This meant that 28 IBD subjects received bezlotoxumab, while 16 were in the nobezlotoxumab group (14 completed the study). There

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was a trend toward a reduced rate of initial clinical cure in IBD participants in the bezlotoxumab group versus the no-bezlotoxumab group (53.6% vs 81.3%). During a 12-week follow-up period, there was a trend toward less recurrent CDI in the bezlotoxumab group (26.7% vs 53.8%), representing a 27.2% absolute reduction (95% CI, –57.9% to 9.6%) in the incidence of recurrent CDI in participants with IBD. These data show promise for a subgroup of CDI patients for whom more evidence is needed about the efficacy of treatment options and justify the need for a prospective randomized study in this cohort with an unmet need.

A post-hoc analysis of pooled MODIFY I/II data examined recurrent CDI rates according to the type of C. difficile strain.25 A technique known as restriction endonuclease analysis was used to categorize strains.

Using this method, BI strains can be distinguished, and these are similar to the more frequently used term ribotype 027. It was shown that the recurrent CDI rate for BI strains treated with bezlotoxumab was lower than for those in the no bezlotoxumab group (23.6% vs 43.9%); by comparison, recurrent CDI rates for cases due to non-BI strains were 21.4% vs 36.1%, respectively.

Pipeline Antibiotics for CDI Noting the recent demise of surotomycin (Merck) and cadazolid (Actelion) after disappointing results in pivotal phase 3 clinical trials, there are now very few remaining novel agents in the investigational pipeline of CDI therapeutics.26-30 The only remaining late-stage (phase 3) antibiotic for CDI treatment is ridinilazole (SMT19969; Summit Therapeutics), a novel, nonabsorbable, very narrowspectrum antimicrobial.31-35 The efficacy and safety of ridinilazole were established in healthy patients and in a recently reported phase 2, randomized, doubleblind trial (CoDIFy) comparing 10 days of therapy with 200 mg of oral ridinilazole twice daily or 125 mg of oral vancomycin 4 times daily.33 Ridinilazole had a superior sustained clinical response rate (66.7%) compared with vancomycin (42.4%). The very narrow spectrum of activity and, therefore, relative avoidance of further gut microbiome dysbiosis associated with ridinilazole likely contributes significantly to its high efficacy.34,35 Phase 3 clinical trials of ridinilazole versus vancomycin have been in progress since early 2019.

Three other investigational agents to treat CDI have reached the phase 2 clinical trial stage: CRS3123 (Crestone) is a novel diaryldiamine that targets methionyl-tRNA synthetase. A randomized, doubleblind, phase 2 trial of this agent is due to start shortly.36 DNV383714/DNV3681 (also known as MCB383714/ MCB3681; Deinove) is an oxazolidinone–quinolone hybrid (similar to cadazolid). This intravenous (IV) prodrug of DNV3681 has completed a phase 1 trial,37 and has started a 2-part, open-label, phase 2 trial (ClinicalTrials. gov Identifier: NCT03824795). Ibezapolstat (Acurx; formerly known as ACX-362E) is a poorly absorbed oral antibiotic that inhibits DNA polymerase IIIC (pol IIIC) of

C. difficile. The results of a phase 1 trial were recently published,38 and an open label phase 2 study has commenced (ClinicalTrials.gov Identifier: NCT04247542). It remains too soon to know how effective these agents will be, but it is promising to have 3 candidate treatment options at phase 2 stage, in addition to ridinilazole at phase 3.

In addition, it is likely that new options may soon become available for the management of patients with recurrent CDI that are based on FMT or substitute versions thereof. Notably, Seres recently announced very positive results from its phase 3 clinical trial of SER-109 ((ClinicalTrials.gov Identifier: NCT03183128),

an oral, biologically-derived microbiome therapeutic, which met its primary end point in the treatment of patients with recurrent CDI. There was a highly statistically significant 30.2% absolute reduction in the rate of (further) CDI recurrence relative to placebo.39

Updating IDSA Guidelines on CDI Treatment A treatment-focused update of the 2017 IDSA CDI guideline is underway; the 2017 guideline (published in 2018) was limited to evidence published up to the end of 2016.4 Thus, evidence on CDI therapeutics published since 2016 will be reviewed for the update, which is hoped to be available in late 2020.

References 1.

Johnson S, Louie TJ, Gerding DN, et al. Vancomycin, metronidazole, or tolevamer for Clostridium difficile infection: results from two multinational, randomized, controlled trials. Clin Infect Dis. 2014;59(3):345-354.

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Nelson RL, Suda KJ, Evans CT. Antibiotic treatment for Clostridium difficile-associated diarrhoea in adults. Cochrane Database Syst Rev. 2017;3:CD004610.

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Vardakas KZ, Polyzos KA, Patouni K, et al. Treatment failure and recurrence of Clostridium difficile infection following treatment with vancomycin or metronidazole: a systematic review of the evidence. Int J Antimicrob Agents. 2012;40(1):1-8.

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McDonald LC, Gerding DN, Johnson S, et al. Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis. 2018;66(7):e1-e48.

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Crook DW, Walker AS, Kean Y, et al. Fidaxomicin versus vancomycin for Clostridium difficile infection: meta-analysis of pivotal randomized controlled trials. Clin Infect Dis. 2012;55(suppl 2):S93-S103.

Wilcox MH, Gerding DN, Poxton IR, et al. Bezlotoxumab for prevention of Clostridium difficile infection recurrence.

N Engl J Med. 2017;376(4):305-317.

Goldenberg SD, Brown S, Edwards L, et al. The impact of the introduction of fidaxomicin on the management of Clostridium difficile infection in seven NHS secondary care hospitals in England: a series of local service evaluations.

Eur J Clin Microbiol Infect Dis. 2016;35(2):251-259.

Guery B, Menichetti F, Anttila VJ, et al. Extended-pulsed fidaxomicin versus vancomycin for Clostridium difficile infection in patients 60 years and older (EXTEND): a randomised, controlled, open-label, phase 3b/4 trial. Lancet Infect Dis. 2018;18(3):296-307.

Chilton CH, Crowther GS, Todhunter SL, et al. Efficacy of alternative fidaxomicin dosing regimens for treatment of simulated Clostridium difficile infection in an in vitro human gut model. J Antimicrob Chemother. 2015;70(9):2598-2607.

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Chilton CH, Crowther GS, Freeman J, et al. Successful treatment of simulated Clostridium difficile infection in a human gut model by fidaxomicin first line and after vancomycin or metronidazole failure. J Antimicrob Chemother. 2014;69(2):451-462.

12. European Medicines Agency. DIFICLIR Public Assessment Report.

22 September 2011. www.ema.europa.eu/docs/en_GB/document_ library/EPAR_-_Public_assessment_report/human/002087/ WC500119707.pdf.

13. Chilton CH, Crowther GS, Ashwin H, et al. Association of fidaxomicin with C. difficile spores: effects of persistence on subsequent

spore recovery, outgrowth and toxin production. PLoS One. 2016;11(8):e0161200.

14. Cornely OA, Vehreschild MJGT, Adomakoh N, et al. Extendedpulsed fidaxomicin versus vancomycin for Clostridium difficile infection: EXTEND study subgroup analyses. Eur J Clin Microbiol Infect Dis. 2019;38(6):1187-1194.

15. Freeman J, Vernon J, Pilling S, et al. Five-year Pan-European, longitudinal surveillance of Clostridium difficile ribotype prevalence and antimicrobial resistance: the extended ClosER study. Eur J Clin Microbiol Infect Dis 2020;39(1):169-177.

16. Wilcox MH, Gerding DN, Poxton IR, et al; MODIFY I and MODIFY II Investigators. Bezlotoxumab for prevention of recurrent Clostridium difficile infection. N Engl J Med. 2017;376:305-317.

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Prabhu VS, Cornely OA, Golan Y, et al. Thirty-day readmissions in hospitalized patients who received bezlotoxumab with antibacterial drug treatment for Clostridium difficile infection.

Clin Infect Dis. 2017;65(7):1218-1221.

18. Kelly CP, Poxton IR, Shen J, et al. Effect of endogenous Clostridioides difficile toxin antibodies on recurrence of C. difficile infection. Clin Infect Dis. 2019. pii: ciz809. doi: 10.1093/cid/ciz809.

19. Wilcox MH, Rahav G, Dubberke ER, et al. Influence of diagnostic method on outcomes in phase 3 clinical trials of bezlotoxumab for the prevention of recurrent Clostridioides difficile infection: a post hoc analysis of MODIFY I/II. Open Forum Infect Dis. 2019;6. pii: ofz293.

20. Gerding DN, Kelly CP, Rahav G, et al. Bezlotoxumab for prevention of recurrent Clostridium difficile infection in patients at increased risk for recurrence. Clin Infect Dis. 2018;67(5):649-656.

21. Prabhu VS, Dubberke ER, Dorr MB, et al. Cost-effectiveness of bezlotoxumab compared with placebo for the prevention of recurrent Clostridium difficile infection. Clin Infect Dis. 2018;66(3):355-362.

22. Oksi J, Aalto A, Säilä P, et al. Real-world efficacy of bezlotoxumab for prevention of recurrent Clostridium difficile infection: a retrospective study of 46 patients in five university hospitals in Finland. Eur J Clin Microbiol Infect Dis. 2019;38(10):1947-1952.

23. FDA. Minutes of the Antimicrobial Drugs Advisory Committee, 9 June 2016. www.fda.gov/media/99345/download. Accessed October 23, 2019.

24. Kelly CP, Wilcox MH, Glerup H, et al. Bezlotoxumab for Clostridium difficile infection complicating inflammatory bowel disease.

Gastroenterology. 2018;155(4):1270-1271.

25. Johnson S, Citron DM, Gerding DN, et al. Efficacy of bezlotoxumab in trial participants infected with Clostridioides difficile strain BI associated with poor outcomes. Clin Infect Dis, 2020. In press. doi: 10.1093/cid/ciaa1035.

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26. Boix V, Fedorak RN, Mullane KM, et al. Primary outcomes from a phase 3, randomized, double-blind, active-controlled trial of surotomycin in subjects with Clostridium difficile infection.

Open Forum Infect Dis. 2017;19(4):ofw275.

35. Chang J, Kane A, Snydman D. Ridinilazole preserves major components of the intestinal microbiota during treatment of Clostridium difficile infection. Presented at: ASM Microbe 2016; June 16-20, 2016; Boston, MA. Abstract LB-116.

27. Deshpande A, Hurless K, Cadnum JL, et al. Effect of surotomycin, a novel cyclic lipopeptide antibiotic, on intestinal colonization with vancomycin-resistant enterococci and Klebsiella pneumoniae in mice. Antimicrob Agents Chemother. 2016;60(6):3333-3339.

36. Businesswire. Crestone, Inc. (Boulder) secures NIH funding for phase 2 clinical trial of novel antibiotic candidate. September 12, 2019. www.businesswire.com/news/home/20190912005834/ en/Crestone-Boulder-Secures-NIH-Funding-Phase-2. Accessed September 21, 2020.

28. Chilton CH, Crowther GS, Baines SD, et al. In vitro activity of cadazolid against clinically relevant Clostridium difficile isolates and in an in vitro gut model of C. difficile infection.

J Antimicrob Chemother. 2014;69(3):697-705.

29. Gehin M, Desnica B, Dingemanse J. Minimal systemic and high faecal exposure to cadazolid in patients with severe Clostridium difficile infection. Int J Antimicrob Agents. 2015;46(5):576-581.

30. Baldoni D, Gutierrez M, Timmer W, et al. Cadazolid, a novel antibiotic with potent activity against Clostridium difficile: safety, tolerability and pharmacokinetics in healthy subjects following single and multiple oral doses. J Antimicrob Chemother.

2014;69(3):706-714.

31. Goldstein EJ, Citron DM, Tyrrell KL, et al. Comparative in vitro activities of SMT19969, a new antimicrobial agent, against Clostridium difficile and 350 gram-positive and gram-negative aerobic and anaerobic intestinal flora isolates.

Antimicrob Agents Chemother. 2013;57(10):4872-4876.

32. Vickers R, Robinson N, Best E, et al. A randomised phase 1 study to investigate safety, pharmacokinetics and impact on gut microbiota following single and multiple oral doses in healthy male subjects of SMT19969, a novel agent for Clostridium difficile infections. BMC Infect Dis. 2015;15:91.

33. Vickers RJ, Tillotson GS, Nathan R, et al. Efficacy and safety of ridinilazole compared with vancomycin for the treatment of Clostridium difficile infection: a phase 2, randomised, doubleblind, active-controlled, non-inferiority study. Lancet Infect Dis. 2017;17(7):735-744.

34. Chang J, Kane A, McDermott L, et al. Ridinilazole preserves major components of the intestinal microbiota during treatment of Clostridium difficile infection. Presented at: ECCMID 2016; April 9-12, 2016; Amsterdam, Netherlands. Abstract LB-116.

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37. Dalhoff A, Rashid M-U, Kapsner T, et al. Analysis of effects of MCB3681, the antibacterially active substance of prodrug MCB3837, on human resident microflora as proof of principle.

Clin Microbiol Infect. 2015;21(8):767.e1-767.e4.

38. Garey KW, Begum K, Lancaster C, et al. A randomized, double blind, placebo controlled, single and multiple ascending dose phase 1 study to determine the safety, pharmacokinetics and food and faecal microbiome effects of ibezapolstat administered orally to healthy subjects. J Antimicrob Chemother. 2020 September 6. [ePub ahead of print]. doi: 10.1093/jac/dkaa364.

39. Businesswire. Seres Therapeutics announces positive topline results from SER-109 phase 3 ECOSPOR III study in recurrent C. difficile infection. August 10, 2020. www.businesswire.com/news/ home/20200810005194/en/Seres-Therapeutics-AnnouncesPositive-Topline-Results-from-SER-109-Phase-3-ECOSPOR-IIIStudy-in Recurrent-C.-difficile-Infection. Accessed September 21, 2020.

Dr. Wilcox is the lead on CDI for Public Health England; and an expert advisor to National Health Service Improvement on infection prevention and control in the United Kingdom.

Dr Wilcox reported relationships with Actelion, AG, Alere, Almirall, Astellas, bioMĂŠrieux, Crestone, Da Volterra, Enterobiotix, Merck, Meridian, MicroPharm, Morphochem, Motif Bio, NestlĂŠ, Paratek, Pfizer, Sanofi Pasteur, Seres, Singulex Micro Pharm, Summit, Synthetic Biologics, Tetraphase, Valneva, Vaxxilon, and VenatoRx.

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‘Sad Economics’ Bedevils EMR Endoscopists lament poor reimbursement for polyp removal procedure

E

ndoscopic mucosal resection of large polyps is more challenging and time-consuming than screening colonoscopy, but physicians are better

compensated if they avoid the former and opt for the latter, according to the findings of a study from Northwestern University, in Chicago.

Clinicians generally prefer EMR to surgery for the management of complex colon polyps because it is associated with lower cost and fewer adverse events.

But the increased time and complexity of EMR have raised questions about whether reimbursement rates for the technique accurately reflect the work needed to perform the procedure.

“It is less cost-effective for the endoscopist to perform colon EMR compared to doing a routine screening colonoscopy. Even though EMR is technically more complex, we are reimbursed less per minute of our time,” said Rajesh N. Keswani, MD, the study’s senior investigator and an associate professor and the medical director of quality for the Northwestern Medicine Digestive Health Center. “The consequence is that you disincentivize clinicians from doing more complex work, which

then encourages them to send patients to surgery, even though that is less cost-effective for the system.”

Time Is Money (Lost) Dr. Keswani and his colleagues identified all adults who underwent colon EMR at their center during a 21-month period ending in October 2019. Patients had been referred to one of three EMR specialists for removal of one or more polyps of at least 2 cm in size. People undergoing sigmoidoscopy, inpatient colonoscopy and/ or endoscopic submucosal dissection were excluded from the analysis. The findings were submitted to the virtual 2020 Digestive Disease Week (abstract 1183).

The investigators compared 158 patients who underwent EMR with a control group of 158 patients undergoing routine screening colonoscopy. They collected

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data for all the patients on procedure time and in-room duration, as well as charges and collections by physicians and hospitals. (Hospital charges excluded patients admitted immediately after colonoscopy.)

The primary outcome was overall reimbursement rate, defined as physician collections per procedure duration.

For the 158 patients who underwent EMR, multiple polyps larger than 2 cm were removed in 7% of patients, resulting in a total of 169 polyps removed. The mean polyp size was 29.1 mm (range, 10-90 mm); 67% were adenomas, 32% were serrated, and 1% were other types; submucosal injection was used in 89% and hot snare in 97%; location was right-sided for 67%.

Compared with the 158 screening colonoscopy procedures, EMR took a significantly longer time (52 vs. 23 minutes; P<0.0001), the researchers reported. In addition, trainees were involved in 42% of EMR cases, and the procedure time for those cases was significantly longer than for cases without trainees (59.6 vs. 47.1 minutes, P=0.0002).

Mean physician collections were significantly higher for EMR than for screening colonoscopy, at $653 versus $465 (P<0.0001). However, mean reimbursement— physician collections per time spent on the procedure— was significantly lower for EMR ($14 vs. $22 per minute; P<0.0001; Table).

The exclusion of procedures involving trainees did not alter the significant physician reimbursement differences seen between EMR cases and screening colonoscopies, according to Arnold Abud, MD, an internal medicine resident at Northwestern Medicine, who led the study team. “Our study indicates

that despite a modest increase in reimbursement for EMR compared to screening colonoscopy, this does not adequately offset the markedly greater EMR procedure times,” Dr. Abud said.

He and Dr. Keswani said reimbursement rates should reflect the increased complexity and procedure times of EMR.

Findings Reflect ‘Sad Economics’ Shyam Varadarajulu, MD, the medical director of the AdventHealth Center for Interventional Endoscopy, in Orlando, Fla., said the findings “reflect the sad economics of practicing therapeutic endoscopy in the United States.”

Dr. Varadarajulu led a study that showed significant benefits for EMR over surgery, one of which was financial (DDW 2015, abstract Sa1616). “Despite numerous studies that have clearly demonstrated superior clinical and economical outcomes for EMR in the treatment of large colon polyps, as compared to minimally invasive surgery, more large colon polyps are still being removed by surgery rather than by endoscopic techniques,” he said.

“In a health care system that values gastroenterologists by relative value units generated, it does not make logical or financial sense to perform few complex, timeconsuming endoscopies and get paid less versus churning out many simple, shorter-duration endoscopies and get paid more,” Dr. Varadarajulu added. “Our patients and the health care system are seriously disadvantaged because of this flawed policy.”

—Caroline Helwick Dr. Keswani reported consulting for Boston Scientific.

Drs. Abud and Varadarajulu reported no relevant financial conflicts of interest.

Table. Outcomes With Endoscopic Mucosal Resection Versus Screening Colonoscopy Mean Procedure Duration, Charge and Reimbursement for Large Polyp Removal Outcome

EMR (N=158)

Colonoscopy Controls (N=158)

P Value

Procedure duration, minutes

52

23

<0.0001

In-room duration, minutes

65

30

<0.0001

Physician charges, $

2,604

1,258

<0.0001

Physician collections, $

653

465

<0.0001

Hospital charges, $

12,449

5,585

<0.0001

Physician reimbursement rate, $ (collections per minute)a

14

22

<0.0001

Physician in-room reimbursement rate, $

11

17

<0.0001

Hospital charge rate, $

277

259

0.1185

Hospital in-room charge rate, $

204

201

0.6713

a

Collections or charges per total procedure or in-room minutes.

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Malignant Polyps: Optimal Course Remains Elusive

F

or patients with stage I malignant colorectal polyps, clinicians still ponder the best course of action—surgery

or observation—after endoscopic resection of the lesions.

Recent studies have not made the decision simpler.

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“This question continues to generate significant those who underwent surgical resection (P=0.016). controversy and variations in care,” said Brooks D. However, a larger study reported at the 2019 Digestive Cash, MD, the chief of gastroenterology, hepatology Disease Week (abstract 1039), based on an analysis of and nutrition at the University of Texas Health Science the National Cancer Database, showed an overall survival Center, in Houston. benefit for surgery that remained consistent after adjustThe worry, of course, is leaving cancer behind, said ing for multiple patient and tumor factors between the V. Prasad Poola, MD, an assistant professor of surgery two approaches. at Southern Illinois University, in Springfield. “If I see a “Our study suggests that polypectomy alone patient with a small invasive cancer [that] was comhas not led to improved survival in usual clinical pletely removed by polypectomy, I have two choices: practice,” said Dhruv Lowe, MBBS, who led the study operate and remove that part of the colon, including as a gastroenterology fellow at SUNY Upstate Medical lymph nodes, knowing that 7% to 10% will have a posUniversity, in Syracuse, N.Y., and is now at the Geisinger itive node that cannot be otherwise detected, or take Community Medical Center, in Scranton, Pa. the 90% chance that there is nothing in the nodes and Dr. Lowe and his colleagues identified 31,062 just watch and see. Sometimes surgery isn’t feasible, patients in the National Cancer Database with a and compliant patients will undergo regular colonosT1N0M0 invasive adenocarcinoma and negative tumor copies, but they may still have cancer in the nodes.” margins, treated between 2004 and 2015. Of this Guidelines from the National group, 28,469 (91.7%) underC o m p r e h e n s i ve Cancer went surgery and 2,593 (8.3%) Network state that patients had polypectomy followed by ‘I have two choices: operate and with pedunculated T1N0M0 observation. Despite having remove that part of the colon, lesions with favorable histoclinically node-negative dislogic characteristics and clear ease, 7% of patients had posiincluding lymph nodes, knowing margins after polypectomy can tive lymph nodes found at surthat 7% to 10% will have a positive gery—consistent with previous be observed, whereas for sessile polyps either colectomy or reports, Dr. Lowe said. node that cannot be otherwise observation is appropriate.

After a median follow-up of detected, or take the 90% chance almost four years, overall surRecurrence and Survival: vival was significantly better that there is nothing in the nodes Conflicting Studies after surgery (Table), which and just watch and see.’

A recent French study that conferred an absolute risk compared endoscopic and surreduction of 1.6% at one year —V. Prasad Poola, MD gical resection of malignant poland 5.5% at five years. As of Southern Illinois University yps in 411 patients found clear last contact, the percentage margins to be the most imporof patients still alive was 81.8% tant determinant of long-term after surgery and 74.5% with outcomes (Gut 2019;68[1]:111-117). The overall five-year observation, for an unadjusted hazard ratio of 0.66 survival rate was 81% when pathologic margins were favoring surgery. A multivariate analysis upheld the less than 1 mm and 96% when they were 1 mm or more results, Dr. Lowe reported.

(P=0.024). For patients with pedunculated polyps and Lesions in the left colon and those that were well difmargins of 1 mm or larger, the five-year recurrence rate ferentiated were likely to be treated with resection alone, was similar, regardless of treatment (P=0.230). In conwhereas patients whose polyps were moderately or trast, for those with sessile polyps, 8.6% had disease poorly differentiated or who had lymphovascular invasion recurrence in the observation arm compared with 3% of were likely to go to surgery.

Table. Overall Survival for Endoscopic Versus Surgical Resection of Polyps Overall Survival, years

Endoscopic Resection, %

Surgical Resection, %

Relative Risk for Endoscopic Resection Alone (95% CI)

1

94.2

95.8

1.37 (1.15-1.64)

5

80.6

86.1

1.39 (1.28-1.53)

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If patients who are poor surgical candidates are excluded, most patients will be helped by surgery, Dr. Lowe said. “When we take the segment out, we decrease the risk for future polyps by mitigating the field cancerization effect.”

Data Caveats Dr. Cash applauded the large sample size and the adjustment for potential confounders, and said the data “could help shape future guidelines and clinical practice.”

But Aasma Shaukat, MD, of the University of Michigan, in Ann Arbor, said although the findings were “provocative,” the comparison was not randomized “and has limitations in terms of patient selection and how outcomes were collected and reported.”

Peter Stanich, MD, an associate professor in the Division of Gastroenterology, Hepatology and Nutrition at the Ohio State University Wexner Medical Center, in Columbus, called the study “impressive” in size. But, he said, “You do lose nuance as to why these patients chose one treatment over the other.

Decisions and outcomes can be affected by patient characteristics that are not in the database.”

Harish K. Gagneja, MD, of Austin Gastroenterology and the American College of Gastroenterology governor for Southern Texas, was skeptical about the imbalance in the treatment groups. “With 91% being surgical patients and 8% endoscopic patients, you cannot compare these groups fairly. I’m not a statistician, but the results don’t sound right. We also don’t know about disease progression and cause of death,” he said. “My feeling is that if treatment were chosen appropriately, the outcomes would be equal, or even better with observation because patients would avoid surgical complications.”

Dr. Gagneja added that if this ratio of surgery to observation reflects real-world practice, “then there are a lot of patients unnecessarily going to surgery.”

A thorough understanding of the polyp is important.

However, Dr. Stanich said, “it’s often not as black and white as the guidelines suggest. The pathologist cannot always be definitive on the criteria that are used to make these decisions.”

Generally, colectomy is recommended for younger or fit individuals with unfavorable features, patients with sessile lesions showing submucosal superficial invasion, and patients with pedunculated polyps resected piecemeal or not thoroughly assessed pathologically—but the threshold varies.

Dr. Stanich stressed that the site of the polyp matters. “With right-sided lesions, surgery is relatively simple, can often be done laparoscopically, and patients are left with good quality of life.

On the flip side, cancer in the rectum is the most complicated,” he said. For clinicians who are trained in endoscopic submucosal dissection, the technique is a good approach to resecting lesions in the rectum, he added.

Dr. Cash said, “The data increase support for surgery in most circumstances of patients with T1N0M0 cancers, especially those with ominous features, and they provide more clarity to patients regarding their choices and our recommendations.” His preference is “to send someone to surgery as long as he or she can safely undergo surgery and is willing,” he said, but it is always important to individualize treatment.

Dr. Shaukat said she leans the other way: “We attempt endoscopic removal for all pedunculated polyps and the majority of sessile polyps. At the end of the day, quality of life plays a very big role in the patient’s decision, probably more than the specifics of the histology and the difference between a 2% and 10% risk of residual cancer.”

—Caroline Helwick The sources reported no relevant financial conflicts of interest. Drs. Cash and Gagneja are members of the editorial board of Gastroenterology & Endoscopy News.

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The State of Training in Advanced Endoscopy: A Conversation With Vivek Kaul, MD

V

ivek Kaul, MD, has thought a lot about the training of current and future endoscopists. He is an experienced interventional endoscopist and the Segal-Watson Professor of Medicine at the Center for Advanced Therapeutic Endoscopy in the Division of Gastroenterology & Hepatology at the University of Rochester Medical Center, in New York. Dr. Kaul has been involved in training general and advanced endoscopy fellows throughout his nearly 20-year academic career, and he frequently lectures and consults on endoscopy training issues across the United States and around the world. Gastroenterology & Endoscopy News spoke recently with Dr. Kaul about how the field has evolved, where it stands and where it needs to go.

GEN: How has advanced endoscopy training changed over the past few decades?

Dr. Kaul: The field of endoscopy has undergone revolutionary progress over the last two decades. We’ve seen transformational changes in technology and patient care algorithms, which have impacted both our approach to training and the content of that training.

Trainees and their teachers have had to embrace newer technologies, devices and patient care practices as the field has evolved.

One of the important developments we’ve seen has been the emergence of minimally invasive endoscopic treatments, which have shifted the management

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paradigm in multiple areas of gastrointestinal medicine.

Advances in therapeutic endoscopic retrograde cholangiopancreatography, the maturation of endoscopic ultrasound as an interventional platform, the coming of age of “third-space endoscopy,” and the emergence of robots and artificial intelligence in endoscopy are some of the major advances that have impacted the education of trainees and will continue to do so.

Endoscopy training has had to incorporate these changes to ensure that the new generation of gastroenterologists attains a degree of proficiency in these newer procedures that will allow them to practice successfully in the future.

GEN: What are the current goals of training and are they sufficient to ensure success after a trainee moves into practice?

Dr. Kaul: The goals of the standard three-year GI fellowship training are to ensure that the trainee graduates with competence in cognitive and procedural skill sets in general gastroenterology. This training follows a standard curriculum, and milestones and competencies are assessed using the criteria outlined by the Accreditation Council for Graduate Medical Education (ACGME). This training also prepares the individual for writing and successfully passing the American Board of Internal Medicine–run GI subspecialty board examination.

In contrast, the goal of an advanced endoscopy fellowship is to offer a one- or two-year focused, handson training experience in specialized procedures. The typical trainee is a recent graduate of a three-year program focused primarily on therapeutic endoscopy procedures or a practicing GI physician within five years of graduation. This training is not under the auspices of the ACGME, nor does it lead to any board certification at the present time.

A high-quality advanced endoscopy program needs to ensure that the trainee develops the necessary cognitive skill set to allow for complex decision making and participates in scholarly activity, while learning the technical aspects of these specialized procedures.

GEN: How important is standardization in training?

Dr. Kaul: Standardization of fellowship training is an important mission of the ACGME for the three-year general GI fellowship. However, advanced endoscopy training is not under the ACGME umbrella and the curricula vary nationally. This means the diversity and volume of procedures, academic and scholarly productivity, methodology of competency assessment, and the overall trainee experience also can be highly variable, from center to center. For this reason, there may be some variation in the skill sets acquired by different advanced endoscopy trainees across the country.

GEN: Are there adequate opportunities for advanced endoscopy training?

Dr. Kaul: Yes, there are now a significant number of opportunities for formal advanced endoscopy training. These specialized endoscopy fellowships focus on advanced endoscopic procedures and allow trainees to develop specialized skills outside of the typical threeyear general GI fellowship. Many of these positions are filled through a national match process that is conducted under the auspices of the American Society for Gastrointestinal Endoscopy. However, some positions also are filled outside the match, and several other slots

become available on an ad hoc basis in a given year at some institutions.

Several academic medical centers and all the national GI societies have developed dedicated courses and workshops aimed at enhancing endoscopy skill sets of trainees at all levels, including those who are already in practice.

The use of endoscopy simulators and “focused sabbaticals” also has allowed our trainees to acquire newer skills, as have animal labs—both live and cadaveric—and inanimate model-based learning platforms.

Our industry colleagues have also stepped up in this realm and help support training for advanced endoscopy fellows through educational grants and sponsored workshops.

GEN: How does the advanced endoscopy training process need to improve?

Dr. Kaul: It would be beneficial to develop a standardized national curriculum for advanced endoscopy.

Establishing minimum criteria for program quality, variety and volume of procedures and academic activity, as well as ensuring the use of objective tools for assessing competence, would greatly enhance the quality of the training and the trainee experience.

Greater emphasis on cognitive skill set development, guidance on critical communications, burnout avoidance and medicolegal education also should be built into the curriculum. Given the complex and highintensity nature of advanced endoscopy practice, I believe the trainee would benefit enormously in the long term if they had these tools imparted to them during their fellowship year.

Going forward, consideration also should be given to developing different pathways for advanced endoscopy training. In light of the exponential evolution of technology and endoscopic procedures, it is no longer possible to train all trainees in all the advanced procedures in a one-year time frame. Therefore, we should seriously consider creating separate pancreaticobiliary, bariatric, endoresection, third-space and other training pathways for our trainees. These tracks would allow them to master specific skill sets in the relatively limited amount of time available. Alternatively, an extended period of advanced training beyond the traditional oneyear fellowship might be required.

As the advanced endoscopy field continues to grow and become more specialized, our approach to training and education needs to evolve as well, to ensure that our trainees are set up for success in their careers and that we serve the needs of our patients in the best way possible.

—Interview by David Wild Dr. Kaul reported no relevant financial conflicts of interest. He is a member of the editorial board of Gastroenterology & Endoscopy News.

He can be reached at Vivek_Kaul@URMC.Rochester.edu.

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Esophageal Endoscopic Resection Can Be Same-Day Procedure

S

ame-day discharge is safe in selected patients following esophageal endoscopic

submucosal dissection (ESD) when done by experienced endoscopists at high-volume centers, researchers have found.

The retrospective series of 96 patients at Mayo Clinic in Rochester, Minn., showed that 41 were discharged and 55 were admitted for further observation. All but two admitted patients (96.4%) were discharged within 24 hours.

“The point of this study is that esophageal ESD does not require a blanket admission policy, and this is the first study as far as I know to show this,” Kenneth Wang, MD, the director of the Barrett’s esophagus unit at Mayo, said. “This is a particularly important message in the United States because same-day discharge lowers the cost and might make this procedure more attractive in this country. The data speak for themselves.”

Developed in Asia and now a standard of care in many parts of the world, ESD still is performed at a relatively limited number of centers in the United States despite its advantages and low complication rate in removing dysplastic and cancerous tissue, Dr. Wang said.

Although ESD is associated with fewer complications in experienced hands, it is inconsistently reimbursed in the United States, which makes strategies to reduce costs—such as limiting hospital length of stay—attractive, he said.

The new study, which was submitted to the 2020 Digestive Disease Week (abstract Mo1289), sought to evaluate whether low-risk patients can be discharged safely on the same day as their ESD procedure. The primary end point was complications at seven days.

Nearly 40% of the patients were treated for Barrett’s esophagus with dysplasia. A large proportion of the others were treated for adenocarcinoma or squamous cell carcinoma. Other findings, such as squamous dysplasia, accounted for the remainder.

Patients were admitted to the hospital on a case-bycase basis. When admitted patients were compared with those who were not, they were more likely to be taking anticoagulant or antiplatelet therapies (56.4% vs.

34.1%; P=0.01), to have undergone prolonged procedures (103.4 vs. 62 minutes; P<0.0001), and to have had larger lesions (P<0.0001). Patients who were admitted also

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were significantly more likely to have a major comorbidity, such as chronic kidney disease.

Overall, the complication rate was low even among admitted patients, but it was zero in the same-day discharge group, the researchers reported. Bleeding, which occurred in three patients, was the major complication encountered in this series. All three patients were in the group that was admitted to the hospital.

The findings validate an approach that Dr. Wang’s department has been using, but he acknowledged that same-day discharge is not a concept that has caught on even in parts of the world where ESD is used more commonly.

“This is a fairly aggressive procedure,” Dr. Wang said.

“Although complications are low at high-volume centers, patients undergoing ESD are still generally hospitalized outside the United States. We started discharging low-risk patients on the day of surgery because our data showed that patients rarely had any complication, and this allowed us to decrease the cost of the procedure.”

ESD is a first-line therapy for the management of selected neoplastic lesions not only in the esophagus but throughout the GI tract, according to Peter Draganov, MD, a professor in the Division of Gastroenterology, Hepatology & Nutrition at the University of Florida, in Gainesville.

“I agree that ESD is not as widely used in the United States as it should be, and multiple factors contribute to that,” Dr. Draganov said. Same-day discharge in appropriate patients is a step in the right direction, but several issues will need to be addressed before it becomes standard of care, he added. “We need ongoing efforts for uniform reimbursement, expanding training opportunities, procedure refinements and device improvements to facilitate the adoption of ESD in the United States.”

—Ted Bosworth Dr. Draganov reported financial relationships with Cook, Micro-Tech and Olympus. Dr. Wang reported financial relationships with Fujinon, Interscope, Ironwood, Merit Medical, Owlstone and Pentax.

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September 2018

IMPORTANT SAFETY INFORMATION SUPREP® Bowel Prep Kit (sodium sulfate, potassium sulfate and magnesium sulfate) Oral Solution is an osmotic laxative indicated for cleansing of the colon as a preparation for colonoscopy in adults. Most common adverse reactions (>2%) are overall discomfort, abdominal distention, abdominal pain, nausea, vomiting and headache.

Use is contraindicated in the following conditions: gastrointestinal (GI) obstruction, bowel perforation, toxic colitis and toxic megacolon, gastric retention, ileus, known allergies to components of the kit. Use caution when prescribing for patients with a history of seizures, arrhythmias, impaired gag reflex, regurgitation or aspiration, severe active ulcerative colitis, impaired renal function or patients taking medications that may affect renal function or electrolytes. Use can cause temporary elevations in uric acid. Uric acid fluctuations in patients with gout may precipitate an acute flare. Administration of osmotic laxative products may produce mucosal aphthous ulcerations, and there have been reports of more serious cases of ischemic colitis requiring hospitalization. Patients with impaired water handling who experience severe vomiting should be closely monitored including measurement of electrolytes. Advise all patients to hydrate adequately before, during, and after use. Each bottle must be diluted with water to a final volume of 16 ounces and ingestion of additional water as recommended is important to patient tolerance.

BRIEF SUMMARY: Before prescribing, please see Full Prescribing Information and Medication Guide for SUPREP® Bowel Prep Kit (sodium sulfate, potassium sulfate and magnesium sulfate) Oral Solution.

INDICATIONS AND USAGE: An osmotic laxative indicated for cleansing of the colon as a preparation for colonoscopy in adults. CONTRAINDICATIONS: Use is contraindicated in the following conditions: gastrointestinal (GI) obstruction, bowel perforation, toxic colitis and toxic megacolon, gastric retention, ileus, known allergies to components of the kit. WARNINGS AND PRECAUTIONS: SUPREP Bowel Prep Kit is an osmotic laxative indicated for cleansing of the colon as a preparation for colonoscopy in adults. Use is contraindicated in the following conditions: gastrointestinal (GI) obstruction, bowel perforation, toxic colitis and toxic megacolon, gastric retention, ileus, known allergies to components of the kit. Use caution when prescribing for patients with a history of seizures, arrhythmias, impaired gag reflex, regurgitation or aspiration, severe active ulcerative colitis, impaired renal function or patients taking medications that may affect renal function or electrolytes. Pre-dose and post-colonoscopy ECGs should be considered in patients at increased risk of serious cardiac arrhythmias. Use can cause temporary elevations in uric acid. Uric acid fluctuations in patients with gout may precipitate an acute flare.

Administration of osmotic laxative products may produce mucosal aphthous ulcerations, and there have been reports of more serious cases of ischemic colitis requiring hospitalization. Patients with impaired water handling who experience severe vomiting should be closely monitored including measurement of electrolytes. Advise all patients to hydrate adequately before, during, and after use. Each bottle must be diluted with water to a final volume of 16 ounces and ingestion of additional water as recommended is important to patient tolerance. Pregnancy: Pregnancy Category C. Animal reproduction studies have not been conducted. It is not known whether this product can cause fetal harm or can affect reproductive capacity. Pediatric Use: Safety and effectiveness in pediatric patients has not been established.

Geriatric Use: Of the 375 patients who took SUPREP Bowel Prep Kit in clinical trials, 94 (25%) were 65 years of age or older, while 25 (7%) were 75 years of age or older. No overall differences in safety or effectiveness of SUPREP Bowel Prep Kit administered as a split-dose (2-day) regimen were observed between geriatric patients and younger patients. DRUG INTERACTIONS: Oral medication administered within one hour of the start of administration of SUPREP may not be absorbed completely. ADVERSE REACTIONS: Most common adverse reactions (>2%) are overall discomfort, abdominal distention, abdominal pain, nausea, vomiting and headache. Oral Administration: Split-Dose (Two-Day) Regimen: Early in the evening prior to the colonoscopy: Pour the contents of one bottle of SUPREP Bowel Prep Kit into the mixing container provided. Fill the container with water to the 16 ounce fill line, and drink the entire amount. Drink two additional containers filled to the 16 ounce line with water over the next hour. Consume only a light breakfast or have only clear liquids on the day before colonoscopy. Day of Colonoscopy (10 to 12 hours after the evening dose): Pour the contents of the second SUPREP Bowel Prep Kit into the mixing container provided. Fill the container with water to the 16 ounce fill line, and drink the entire amount. Drink two additional containers filled to the 16 ounce line with water over the next hour. Complete all SUPREP Bowel Prep Kit and required water at least two hours prior to colonoscopy. Consume only clear liquids until after the colonoscopy.

STORAGE: Store at 20°-25°C (68°-77°F). Excursions permitted between 15°-30°C (59°-86°F). Rx only. Distributed by Braintree Laboratories, Inc. Braintree, MA 02185

For additional information, please call 1-800-874-6756 or visit www.suprepkit.com

©2018 Braintree Laboratories, Inc. All rights reserved.

HH27314B

September 2018

Determinants of Bowel Preparation Quality For Colonoscopy: The Role of Modifiable and Nonmodifiable Factors SHASHANK SARVEPALLI, MD, MS ZUNIRAH AHMED, MD Baylor College of Medicine Houston, Texas`

YOUSAF ZAFAR, MD University of Missouri Kansas City, Missouri

CAROL A. BURKE, MD The Cleveland Clinic Cleveland, Ohio

C

olonoscopy plays an integral role in the evaluation of the lower gastrointestinal tract by allowing for the complete visualization of the colonic mucosa.1 The procedure has been proven to be safe and effective for this purpose.2

The most common indication for colonoscopy worldwide is screening or surveillance for colorectal cancer (CRC), followed by evaluation of rectal bleeding, abdominal pain, diarrhea, and iron deficiency anemia.3-5

CRC is the third most common malignancy in the world and second most common cause of cancer death in the United States.6 Colonoscopy is an option for CRC screening and the destination modality for all positive CRC screening tests. It stands alone in its ability to be both diagnostic and therapeuticâ&#x20AC;&#x201D;with removal of polyps to prevent cancer.7-9 Colonoscopy procedures in which visualization of the colonic mucosa is poor due to inadequate bowel preparation (IBP) are associated

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with a significantly diminished diagnostic yield and rate of cecal intubation as well as greater direct and indirect costs than procedures in which bowel preparation is adequate.10,11 Therefore, several international society guidelines consider bowel preparation to be an important quality indicator for colonoscopy and call for auditing and documentation of the quality of bowel preparation.12,13 Recognizing modifiable factors associated with IBP may

help bring about individual and organizational interventions to improve quality outcomes, while an understanding of unmodifiable factors can lead to identification of high-risk patient subgroups that deserve enhanced attention. This article explores the effect of IBP on colonoscopy and reviews extant research related to unmodifiable and modifiable (Table) factors associated with IBP.

Defining Quality of Bowel Preparation The adequacy of bowel preparation is a critical determinant of the quality of colonoscopy. It is imperative to ensure suitable visualization of the colonic mucosa and optimize lesion detection for CRC screening and surveillance. The US Multi-Society Task Force (MSTF) suggests that adequate bowel preparation allows detection of colonic polyps that are 5 mm or larger.14 The task force recommends repeat colonoscopy within 1 year if bowel preparation is poor and possible repeat colonoscopy in 5 years if small tubular adenomas are detected and the preparation is fair but adequate. Two of the most important quality indexes for colonoscopy—cecal intubation rate and adenoma detection rate—are intimately related to the quality of bowel preparation.15-18 Different scales are available to rate the quality of bowel preparation19-22; two of the most widely used scales are the Aronchick Scale19 and the Boston Bowel Preparation Scale (BBPS).20 The Aronchick Scale evaluates the entire colon cleansing on a 5-point scale (excellent, good, and fair, which equate to adequate, poor, and inadequate). The BBPS has been used in many clinical studies and requires adding the scores from right, transverse, and left colon segments on a scale of 0 (unprepped) to 3 (mucosa well seen), for a total of 9 points.21,23 A total BBPS score of at least 6 and/or all segment scores of at least 2 has been suggested as adequate.

Both of the aforementioned scales have been endorsed for use.24 BBPS scores have been shown to correlate with endoscopist recommendations for followup intervals for colonoscopy. In an evaluation of 2,516 negative screening colonoscopies performed by 74 endoscopists, if the BBPS score was at least 2 in all 3 segments, follow-up colonoscopy in 10 years was recommended in 90% of cases, whereas follow-up within 1 year was recommended for 96% of examinations with total BBPS scores of less than 3.25 Another study demonstrated a significantly higher rate of missed adenomas greater than 5 mm, with BBPS segment scores of 1 versus segments with a score of 2 or 3, supporting a recommendation for early repeat colonoscopy in patients with a BBPS score of less than 2 in any colon segment.26 Minimum performance standards for adequate bowel preparation have been suggested to be at least 85% in outpatients by the MSTF12 and at least 90% in patients in clinical practice by the European Society of Gastrointestinal Endoscopy (ESGE).24 Other scoring systems to evaluate bowel preparation include

the New Jersey Bowel Preparation Scale and the Ottawa Bowel Preparation Scale, which are used less frequently.27 Bowel preparation scales traditionally rely on human endoscopists for evaluation and are fraught with significant interobserver variability. A group of researchers at Renmin Hospital in Wuhan, China, using a deep convolutional neural network, developed an artificial intelligence system, ENDOANGEL, to provide bowel preparation scores every 30 seconds during withdrawal. Overall, the system achieved over 90% accuracy in correctly evaluating bowel preparation. In a human–machine contest, ENDOANGEL was found to be better at evaluating bowel preparation quality than any human endoscopist.28 Figures 1 and 2 show adequate and inadequate bowel preparation at colonoscopy, respectively.

Health Care Burden Associated With IBP Unfortunately, approximately one-fourth of outpatient and up to 60% of inpatient colonoscopies are associated with IBP,29,30 which drives up health care costs and potentially results in clinical harm.31 Inadequate cleansing is a cited factor in 20% to 70% of incomplete colonoscopies.15,16 Adenoma miss rates (AMRs) of 42% to 48% have been reported in various studies assessing polyp detection during colonoscopy repeated due to IBP on initial colonoscopies.17,18,32 In a study of patients undergoing colonoscopy within 1 year of a baseline examination with suboptimal bowel preparation, the advanced AMR was 36%.18 Data have shown that IBP leads to repeat colonoscopy every 7.8 years in average-risk patients instead of every 10 years, demonstrating a lack of value-based care.33 Repeat colonoscopies, in addition to exposing patients

Table. Modifiable Factors Associated With Bowel Preparation Quality Factor

Strategy to Enhance Quality

Dosing of bowel prep

Split or same day

Time of day of procedure

Before noon

Diet before colonoscopy

Clear liquid; low/no residue

Runway time

Less than 2 h after prep completed

Opioid use

Avoid

Patient understanding of preparation process

Provide interpreters (as needed) and education to nurse and patient on importance of bowel prep

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to the risks for procedure complications, are associated with direct costs (procedure costs) and indirect costs (eg, the cost of transportation, loss of productivity), as well as discomfort or harm associated with the procedure.

Aborted procedures, incomplete exams, surveillance examinations performed sooner than expected, increased procedural times associated with cleaning of luminal contents and colonic mucosa, increased sedation requirements, and fewer procedures done per day also are factors contributing to the increased costs of colonoscopy.34 Poor-quality bowel preparation in hospitalized patients is associated with other disadvantages,30,35 including increased hospital length of stay and additional hospital costs.11,36 Suboptimal bowel preparation also is associated with low patient satisfaction.37

Unmodifiable Factors Some of the unmodifiable factors related to IBP include age and socioeconomic status. Older age has been implicated as an important independent predictor of IBP in several studies.38,39 Elderly patients often have multiple comorbidities, such as chronic constipation, multiple prior surgeries, and noncompliance with dietary instructions before colonoscopy.40,41 In addition, low socioeconomic status, being unmarried, and having Medicaid insurance have been shown to be independent risk factors for IBP.39,42 These factors may be surrogate markers for poor health literacy.

Chronic medical illnesses also increase the likelihood that a patient will have IBP. Several studies have reported diabetes as an independent risk factor.43 Poor gut motility in patients with diabetes was associated with increased transit time for bowel preparation, and patient-reported straining with bowel movements significantly predicted IBP.44 Of note, patients with diabetesâ&#x20AC;&#x201D;regardless of their glycemic control, diabetic complications, and use of insulinâ&#x20AC;&#x201D;have poorer bowel preparation in response to 6 L of polyethylene glycol (PEG) 3350 and electrolytes than patients without diabetes.45 Other coexisting conditions such as obesity, inflammatory bowel disease, and neurologic conditions (eg, history of cerebrovascular accident and developmental disabilities); reduced functional status; multiple daily prescriptions; level of education; income; and abdominal surgery, including appendectomy and hysterectomy, have been found to be risk factors for IBP.35,39-43,46,47 Of note, having a history of colorectal resection has not been associated with an increased risk for IBP.48

Modifiable Factors Type of Bowel Preparation One paradigm for assessing the FDA-approved bowel preparations is based on volume, that is, highvolume (4-L) PEG-based solutions or low-volume alternatives (<4 L).49 High-volume preparations include

Figure 1. Adequate bowel preparation (BBPS segment score 3; Aronchick Scale score excellent).

BBPS, Boston Bowel Preparation Scale

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PEG 3350, sodium chloride, sodium bicarbonate, and potassium chloride (Colyte, Pendopharm); PEG 3350, sodium sulfate, sodium bicarbonate, sodium chloride, and potassium chloride (Golytely, Braintree); and PEG 3350, sodium chloride, sodium bicarbonate, and potassium chloride (Nulytely, Braintree). The most commonly used low-volume bowel preparations with enhanced taste and tolerability are sodium sulfate, potassium sulfate, and magnesium sulfate (Suprep, Braintree); PEG 3350, sodium sulfate, sodium chloride, potassium chloride, ascorbic acid, and sodium ascorbate (Moviprep, Salix); sodium sulfate, potassium sulfate, magnesium sulfate, PEG 3350, sodium chloride, sodium bicarbonate, and potassium chloride (Suclear, Braintree); sodium picosulfate, magnesium oxide, and anhydrous citrate preparations (Prepopik/Clenpiq, Ferring); and PEG 3350, sodium sulfate, sodium chloride, potassium chloride, ascorbic acid, and sodium ascorbate (Plenvu, Salix).50-53 Recently, a proof-ofconcept clinical trial evaluated a 1-L PEG-based bowel preparation solution (NER1006) with 2 L of PEG with ascorbate. In addition to demonstrating clinical efficacy in achieving adequate bowel preparation, this solution was found to have a better safety profile and tolerability.54 Limited data are available on the association of commercial bowel preparations with IBP, and most studies do not show substantial differences in the effectiveness of these preparations.55,56 In a recent study of 4,339 outpatients undergoing colonoscopy, magnesium citrate,

Miralax with Gatorade, Moviprep, Osmoprep (sodium phosphate, monobasic, mono-hydrate, sodium phosphate, and dibasic anhydrous, Salix), Prepopik/Clenpiq, and Suprep were associated with significantly higher tolerability scores compared with Golytely (all P<0.05), whereas Suprep (P<0.001), Moviprep (P<0.004), and Miralax with Gatorade (P<0.001) had higher total BBPS scores than Golytely.57 Further research evaluating lowvolume preparations has demonstrated greater efficacy, satisfaction, willingness to repeat preparation, and tolerability of 1 L of PEG plus ascorbic acid with a prepackaged low-residue diet compared with a standard 2-L PEG plus ascorbic acid solution.58 In addition to traditional bowel preparations, a recent study demonstrated greater efficacy of 2-L oral lactulose solution compared with the same volume of PEG without differences in tolerability.59 Compared with a 3-L PEG solution, the addition of 30 mL of castor oil to 2 L of PEG led to increased patient compliance and satisfaction along with reduced IBP.60 Similarly, use of a bisacodyl suppository with 1 L of PEG plus ascorbic acid resulted in similar bowel preparation quality to 2 L of PEG plus ascorbic acid.61 To counteract abdominal cramping, nausea, and vomiting associated with bowel preparations, the addition of ondansetron, metoclopramide, cisapride, or ramosetron has led to reduced symptoms and better tolerability.62,63 Intraluminal bubbles are associated with lower rates of adenoma detection and advanced adenoma detection.64 Premixing bowel preparation with simethicone, by reducing

Figure 2. Inadequate bowel preparation (BBPS segment score 0; Aronchick Scale score poor/inadequate).

BBPS, Boston Bowel Preparation Scale

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intraluminal bubbles, has been found to be effective in improving the adenoma detection rate.65 The addition of oral simethicone also has been shown to improve bloating, bowel preparation quality, and tolerability of bowel preparation solutions.66

Timing of the Preparation Bowel preparation regimens have evolved from the traditional evening-before regimen to splitting the dose.

Split-dose bowel preparation is defined as consuming at least half of the bowel preparation the day of the procedure.67 Bowel cleansing quality is best if the preparation is given beginning approximately 4 to 6 hours before the procedure and completed within 2 hours before the procedure.68-72 Runway time is defined as the interval between the last ingestion of the preparation and the beginning of colonoscopy. Bowel preparation quality is found to be inversely related to this interval.73 The majority of studies have shown that regardless of the agent or volume, split-dose or same-day as colonoscopy regimens are superior to evening-before dosing in achieving adequate bowel cleansing and associated with reduced runway time.74,75 The ESGE recommends a split regimen of 4 L of PEG solution (or a same-day regimen in the case of afternoon colonoscopy) for routine bowel preparation.13 In a randomized controlled trial of low-volume bowel preparation in the outpatient setting, a split-dose regimen has been shown to be associated with a decreased intensity and duration of bowel movements, less patient inconvenience on the drive to the colonoscopy center, improved bowel preparation, and increased rates of detection of sessile serrated polyps compared with evening-before dosing.76 In another study, patients who received same-day bowel preparations reported lower rates of abdominal pain/cramping, sleep problems, and work interference than those randomized to a split-dose regimen.77 It is well known that inpatients have substantially higher rates of IBP and often require a repeat colonoscopy. A recent study identified the following factors associated with adequate bowel preparation on second colonoscopy after the first inpatient colonoscopy had IBP: performing the second colonoscopy within 2 days or before noon, or using a low-volume preparation.78

Opioid Use Opioid use has a significant effect on quality of bowel preparation.36,57,79 In a study of inpatients, Verma et al showed that methadone dependence is a risk factor for poor bowel visualization and leads to more repeat colonoscopies.80 A more recent study demonstrated that any opioid use 3 days before colonoscopy was associated with 31% increased odds of IBP.81 One study that analyzed the impact of opioids during the week before colonoscopy on colon preparation found significantly higher rates of IBP with both low-dose (<40 oral morphine equivalents [OMEs]; P=0.05) and high-dose (>40 OMEs; P=0.039) opioid use compared with that seen

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in patients not taking opioids.82 Moreover, patients on long-term opioids (>12 weeks) had a longer procedure.83

Diet Type Before Colonoscopy Diet composition before colonoscopy significantly affects the quality of bowel preparation.84-86 A clearliquid diet and low-fiber/fiber-free diets are the most commonly employed types. The ESGE recommends a low-fiber diet on the day before colonoscopy.13 An observational study of 101 patients showed that a clear-liquid diet 2 days before the procedure substantially improved the quality of bowel preparation compared with a regular diet.84 Another study that evaluated 4 L of PEG the evening before the procedure combined with either a clearliquid or fiber-free diet on the day before the procedure showed a higher percentage of satisfactory bowel preparation quality in the fiber-free group.71 Multiple factors were cited, including a greater ability to finish the preparation and fewer side effects.

In a study evaluating an FDA-approved, split-dose, low-volume sulfate solution (Suprep), investigators randomly assigned 230 outpatients to a liquid or lowresidue diet of specified foods on the day before colonoscopy. The low-residue diet for each meal could be chosen from 3 options: easy to prepare, healthy, or restaurant.85 There was no significant difference in the BBPS between the 2 groups. Moreover, the group taking the clear-liquid diet was more likely than the lowresidue group to cancel the procedure.

Among hospitalized patients, however, being on nonâ&#x20AC;&#x201C;clear-liquid diet on the day before the hospitalization was associated with 37% increased odds of IBP.81

Patient Education Educating patients about bowel preparation is crucial, and studies have shown that an inability to follow the instructions on consuming bowel preparation is an independent predictor of IBP.86,87 One study showed that 1 of the 4 biggest contributors to poor bowel preparation was the need for an interpreter.42 A study in the United Kingdom found that comprehension of a written bowel preparation leaflet was generally low among more than 700 patients from different sociodemographic backgrounds, with health literacy being an independent predictor of comprehension.88 Instruction on preparing and drinking cleansing agents is essential and can help patients learn how they can help increase the success of the procedure.

Education can be imparted in multiple ways, including visual/audio cues and a detailed description of the preparation process, either verbally or through handouts.87 Educational booklets specifically designed with images have been shown to achieve improved bowel preparation compared with regular written instructions.89,90 Showing educational videos to patients also has been shown to have a positive effect on bowel preparation.91,92 Studies have shown improvement in bowel preparation with the

use of telephone and mobile phone messages to reinforce diet instructions and schedules for ingestion of bowel preparation agents.93,94 Tailored education is particularly helpful for patients with language barriers, for whom the use of educational materials in their native language has been shown to not only increase the percentage of patients undergoing screening but also is associated with an increased detection of polyps on colonoscopy.95 A recent metaanalysis also found that patients who received enhanced instructions had significantly better bowel preparation quality.96 In resource-limited settings, targeted education to groups with greater pre-test probability of IBP appears to be an effective strategy.97 Given the widespread use of smartphones, multiple studies have evaluated the use of smartphone applications and short message services to deliver tailored patient instructions and timely preparation reminders; these studies showed these strategies result in notable improvements in adequacy of bowel preparation, cancellation rates, and adenoma detection rates.98-103 Bowel preparation is poorer in hospitalized patients than in outpatients; thus, outpatient colonoscopy is

preferred, if possible.104 A randomized study demonstrated that inpatients receiving a 5-minute counseling session in addition to standardized written instructions before colonoscopy achieved significantly better bowel cleanliness scores on a 5-point scale than those who did not receive the counseling session.105 The benefit of education is not restricted to patients.

It has been shown that when ward nurses are educated about the procedure, there seems to be improvement in the quality of bowel preparation.106 The importance of providing adequate information to patients and nurses about colonoscopy,89,90,107 bowel preparation, and following the recommended schedule cannot be overstated.

Conclusion The efficacy of colonoscopy depends on the quality of bowel preparation. Unmodifiable and modifiable factors are associated with bowel preparation quality.

Split-dose or same-day bowel preparation, short runway time, a clear-liquid or low-residue diet ingested the day before the procedure, avoidance of exposure to opioids, and patient education can be targeted to positively influence the quality of bowel preparation.

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G AST R O E N T E R O LO GY & E N D O S CO PY N E WS S P E C I A L E D I T I O N • O C TO B E R 2 02 0

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BRIEF SUMMARY OF PRESCRIBING INFORMATION TALICIA® (omeprazole magnesium, amoxicillin and rifabutin) delayed-release capsules, for oral use 1 INDICATIONS AND USAGE 1.1 Helicobacter pylori Infection TALICIA is indicated for the treatment of Helicobacter pylori infection in adults.

1.2 Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of TALICIA and other antibacterial drugs, TALICIA should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

2 DOSAGE AND ADMINISTRATION Administer four (4) TALICIA capsules every 8 hours for 14 days with food. Instruct patients to swallow the TALICIA capsules whole, with a full glass of water (8 ounces). Each dose (4 capsules) of TALICIA includes rifabutin 50 mg, amoxicillin 1,000 mg and omeprazole 40 mg. Do not crush or chew TALICIA capsules. Do not take TALICIA with alcohol.

If a dose is missed, patients should continue the normal dosing schedule until the medication is completed. Do not take two doses at one time to make up for a missed dose.

4 CONTRAINDICATIONS 4.1 Hypersensitivity Reactions TALICIA is contraindicated in patients with known hypersensitivity to the components of TALICIA: amoxicillin [or other ß-lactam antibacterial drugs (e.g., penicillins and cephalosporins)], omeprazole (or other benzimidazoles [e.g. proton pump inhibitors (PPIs) and anthelmintics]), rifabutin (or any other rifamycins), or to any other component of TALICIA. Hypersensitivity reactions may include anaphylaxis or Stevens Johnson Syndrome, anaphylactic shock, angioedema, bronchospasm, interstitial nephritis, rash and urticaria [see Warnings and Precautions (5.1), Adverse Reactions (6.1)].

4.2 Rilpivirine-containing Products Proton pump inhibitors (PPIs), including omeprazole (a component of TALICIA), are contraindicated in patients receiving rilpivirine-containing products [see Drug Interactions (7.1)].

4.3 Delavirdine The use of rifabutin (a component of TALICIA), is contraindicated in patients receiving delavirdine [see Drug Interactions (7.1)].

4.4 Voriconazole The use of rifabutin (a component of TALICIA), is contraindicated in patients receiving voriconazole [see Drug Interactions (7.1)].

5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Reactions Serious and fatal hypersensitivity reactions, e.g. anaphylaxis, angioedema, erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, toxic epidermal necrolysis, acute generalized exanthematous pustulosis, hypersensitivity vasculitis, interstitial nephritis, and serum sickness have been reported with the components of TALICIA: omeprazole, amoxicillin and rifabutin.

Signs and symptoms of these reactions may include hypotension, urticaria, angioedema, acute bronchospasm, conjunctivitis, thrombocytopenia, neutropenia or flu-like syndrome (weakness, fatigue, muscle pain, nausea, vomiting, headache, fever, chills, aches, rash, itching, sweats, dizziness, shortness of breath, chest pain, cough, syncope, palpitations).

There have been reports of individuals with a history of penicillin hypersensitivity who have experienced severe reactions when treated with cephalosporins.

Before initiating therapy with TALICIA, inquire about history of hypersensitivity reactions to penicillins, cephalosporins, rifamycins, or PPIs. Discontinue TALICIA and institute immediate therapy, if hypersensitivity reactions occur.

5.2 Clostridioides difficile-Associated Diarrhea Clostridioides difficile-associated diarrhea (CDAD) has been reported with use of omeprazole, a component of TALICIA and nearly all antibacterial agents, including amoxicillin and rifabutin, which are components of TALICIA and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

CDAD must be considered in all patients who present with diarrhea following proton pump inhibitor and or antibacterial use.

Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is confirmed, TALICIA should be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial drug treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

5.3 Reduced Efficacy of Hormonal Contraceptives TALICIA may reduce the efficacy of hormonal contraceptives.

Therefore, an additional non-hormonal highly effective method of contraception should be used while taking TALICIA [see Drug Interactions (7.1)].

5.4 Acute Interstitial Nephritis Acute interstitial nephritis (AIN) has been observed in patients taking PPIs including omeprazole as well as in patients taking penicillins such as amoxicillin, a component of TALICIA. Acute interstitial nephritis may occur at any point during PPI therapy and is generally attributed to an idiopathic hypersensitivity reaction. Discontinue TALICIA if AIN develops [see Contraindications (4.1)].

5.5 Risk of Adverse Reactions or Loss of Efficacy Due to Drug Interactions Components of TALICIA have the potential for clinically important drug interactions [see Contraindications (4) and Drug Interactions (7)].

Avoid concomitant use of TALICIA with other CYP2C19 or CYP3A4 inducers (e.g. St. John’s Wort, rifampin) as they can substantially decrease omeprazole concentrations. Avoid concomitant use of TALICIA with CYP2C19 and/or CYP3A4 inhibitors (e.g. fluconazole, itraconazole) as it may significantly increase the plasma concentration of component (s) of TALICIA. Depending on the protease inhibitor, the concomitant use of TALICIA should be avoided (e.g. amprenavir, indinavir) or dose adjustments for a concomitantly administered protease inhibitor(s) may be required. Concomitant use of PPIs with methotrexate (primarily at high dose) may elevate and prolong serum levels of methotrexate and/or its metabolite, possibly leading to methotrexate toxicities. Avoid TALICIA in patients on high-dose methotrexate. Concomitant use of clopidogrel and omeprazole reduces the pharmacological activity of clopidogrel. Avoid TALICIA in patients on clopidogrel. When using TALICIA, consider alternative anti-platelet therapy [see Drug Interactions (7)].

5.6 Cutaneous and Systemic Lupus Erythematosus Cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE) have been reported in patients taking PPIs, including omeprazole. These events have occurred as both new onset and an exacerbation of existing autoimmune disease. The majority of PPI-induced lupus erythematosus cases were CLE. If signs or symptoms consistent with CLE or SLE develop in patients receiving TALICIA, discontinue the drug and evaluate as appropriate.

5.7 Rash in Patients with Mononucleosis A high percentage of patients with mononucleosis who receive amoxicillin develop an erythematous skin rash. Avoid TALICIA in patients with mononucleosis.

5.8 Uveitis Due to the possible occurrence of uveitis, patients should be carefully monitored when rifabutin, a component of TALICIA, is given in combination with clarithromycin (or other macrolides) and/or fluconazole and related compounds. If uveitis is suspected, refer for an ophthalmologic evaluation and, if considered necessary, suspend treatment with rifabutin [see Adverse Reactions (6.2)].

5.9 Interactions with Diagnostic Investigations for Neuroendocrine Tumors Serum chromogranin A (CgA) levels increase secondary to drug-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors. Assess CgA levels at least 14 days after TALICIA treatment and consider repeating the test if initial CgA levels are high [see Drug Interactions (7)].

5.10 Development of Drug-Resistant Bacteria Prescribing TALICIA either in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in labeling:

• Hypersensitivity Reactions [see Warnings and Precautions (5.1)] • Clostridioides difficile-Associated Diarrhea [see Warnings and Precautions (5.2)] • Acute Interstitial Nephritis [see Warnings and Precautions (5.4)] • Cutaneous and Systemic Lupus Erythematosus [see Warnings and Precautions (5.6)] • Rash in Patients with Mononucleosis [see Warnings and Precautions (5.7)] • Uveitis [see Warnings and Precautions (5.8)] 6.1 Clinical Trials Experience with TALICIA Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of TALICIA was assessed in adult patients who were screened and found to be positive for H. pylori infection in one active-controlled (Study 1) and one placebo-controlled (Study 2) clinical trial. Patients received TALICIA, amoxicillin and omeprazole, or placebo every eight hours for 14 consecutive days taken with food. A total of 305 patients received TALICIA in Studies 1 and 2, 227 patients received amoxicillin and omeprazole (as omeprazole magnesium) in Study 1, and 41 patients received placebo in Study 2. These patients had a mean age of 46.4 years (range 18 to 70 years); 62.3% were female, 80.3% were white with 64.2% Hispanic or Latino.

Adverse Reactions Leading to Discontinuation Treatment discontinuation due to an adverse reaction occurred in 1% (4/305) of patients receiving TALICIA, <1% (1/227) of patients receiving amoxicillin and omeprazole, and 2% (1/41) of patients receiving placebo. Adverse reactions leading to discontinuation of TALICIA were nausea and vomiting, nausea, nasal congestion, and nasopharyngitis, in one patient each.

Most Common Adverse Reactions Selected adverse reactions occurring in *1% of patients receiving TALICIA in Study 1 and 2 are described in Table 1.

Table 1: Selected Adverse Reactions Occurring in 1% or Greater of Patients Receiving TALICIA in Studies 1 and 2

Adverse Reaction

TALICIA (N=228) n (%)

Study 1 Amoxicillin and Omeprazole (N=227) n (%) 18 (7.9) 16 (7.0) 12 (5.3) 11 (4.8) 0 2 (0.9) 3 (1.3) 5 (2.2) 2 (0.9) 5 (2.2)

Study 2 TALICIA (N=77) n (%)

Placebo (N=41) n (%)

Diarrhea 23 (10.1) 11 (14.3) 4 (9.8) Headachea 17 (7.5) 12 (15.6) 4 (9.8) Nausea 11 (4.8) 3 (3.9) 1 (2.4) 8 (3.5) 3 (3.9) 2 (4.9) Abdominal painb Chromaturiac 0 10 (13.0) 1 (2.4) 6 (2.6) 4 (5.2) 0 Rashd 5 (2.2) 1 (1.3) 0 Dyspepsiae Vomiting 5 (2.2) 1 (1.3) 2 (4.9) Oropharyngeal pain 2 (0.9) 3 (3.9) 0 Vulvovaginal candidiasisf 5 (2.2) 0 0 a Headache includes: headache and migraine. b Abdominal pain includes: abdominal pain, abdominal pain upper, and abdominal pain lower. c Riboflavin was administered in Study 1 to prevent unintentional unblinding and may have contributed to under-reporting of chromaturia. d Rash includes: rash, rash maculo-papular, rash morbilliform, and urticaria. e Dyspepsia includes: dyspepsia and epigastric discomfort. f Vulvovaginal candidiasis includes: vulvovaginal candidiasis, vulvovaginal mycotic infection, fungal infection, and vaginal discharge + vulvovaginal burning sensation + vulvovaginal pruritus.

6.2 Other Important Adverse Reactions from the Labeling of the Individual Components of TALICIA Additional adverse reactions that occurred in 1% or greater of patients treated with omeprazole or rifabutin alone in clinical trials were as follows: Omeprazole Flatulence, acid regurgitation, upper respiratory infection, constipation, dizziness, asthenia, back pain, and cough.

Rifabutin Flatulence, asthenia, chest pain, fever, pain, leucopenia, anemia, anorexia, eructation, myalgia, insomnia, and taste perversion.

The following selected adverse reactions occurred in less than 1% of patients treated with rifabutin alone: flu-like syndrome, hepatitis, hemolysis, arthralgia, myositis, dyspnea, skin discoloration, thrombocytopenia, pancytopenia, and jaundice.

6.3 Post-Marketing Experience with Components of TALICIA Because these reactions are voluntarily reported from a population of uncertain size, it is not always possible to reliably estimate their actual frequency or establish a causal relationship to drug exposure.

Omeprazole Cardiovascular: angina, tachycardia, bradycardia, palpitations, elevated blood pressure, peripheral edema Endocrine: gynecomastia Gastrointestinal: pancreatitis including fatal pancreatitis, anorexia, irritable colon, fecal discoloration, mucosal atrophy of the tongue, stomatitis, abdominal swelling, dry mouth, microscopic colitis, fundic gland polyps, gastroduodenal carcinoids in patients with Zollinger-Ellison syndrome on long-term treatment as a manifestation of the underlying condition associated with such tumors Hepatic: fatal hepatic failure or necrosis, hepatic encephalopathy, hepatocellular disease, cholestatic disease, mixed hepatitis, jaundice Metabolism and Nutritional disorders: hypoglycemia, hypomagnesemia, with or without hypocalcemia and/or hypokalemia, hyponatremia, weight gain Musculoskeletal: muscle weakness, myalgia, muscle cramps, joint pain, leg pain, bone fracture.

Nervous System/Psychiatric: depression, agitation, aggression, hallucinations, confusion, insomnia, nervousness, apathy, somnolence, anxiety, dream abnormalities, tremors, paresthesia, vertigo Respiratory: epistaxis Skin: photosensitivity, urticaria, pruritus, petechiae, purpura, alopecia, dry skin, hyperhidrosis Special Senses: tinnitus, taste perversion Ocular: optic atrophy, optic neuritis, dry eye syndrome, ocular irritation, blurred vision, double vision Urogenital: hematuria, proteinuria, elevated serum creatinine, microscopic pyuria, urinary tract infection, glycosuria, urinary frequency, testicular pain Hematologic: Agranulocytosis, hemolytic anemia, pancytopenia, neutropenia, anemia, thrombocytopenia, leukopenia, leukocytosis Amoxicillin Gastrointestinal: black hairy tongue Liver: hepatic dysfunction, cholestatic jaundice, cholestasis, acute cytolytic hepatitis Renal: crystalluria

Hemic and Lymphatic Systems: anemia, hemolytic anemia, thrombocytopenia, thrombocytopenic purpura, eosinophilia, leukopenia, and agranulocytosis Central Nervous System: hyperactivity, agitation, anxiety, insomnia, confusion, convulsions, behavioral changes, and/or dizziness Rifabutin Blood and lymphatic system disorders: agranulocytosis, lymphopenia 7 DRUG INTERACTIONS 7.1 Interactions with Other Drugs and Diagnostics Drug interaction studies with TALICIA have not been conducted.

The drug interaction information described here is based on the prescribing information of individual TALICIA components: omeprazole, amoxicillin, and rifabutin.

Rifabutin is a substrate and inducer of cytochrome P450 (CYP) 3A enzymes. Omeprazole is a substrate and an inhibitor of CYP2C19, and a substrate of CYP3A4. Co-administration of TALICIA and other drugs that are substrates, inhibitors, or inducers of these enzymes may alter concentrations of rifabutin/omeprazole or other co-administered drugs [See Table 2 below].

Omeprazole magnesium is a PPI. Refer to the prescribing information of the drugs used concomitantly with TALICIA for further information on their interactions with PPIs. Table 2: Interactions with TALICIA When Co-Administered with Other Drugs and Diagnostics CYP2C19 or CYP3A4 Inducers Clinical Impact Decreased exposure of omeprazole when used concomitantly with strong inducers.

Prevention or St. John’s Wort, rifampin: Avoid concomitant use with TALICIA [see Warnings and Precautions (5.5)].

Management Ritonavir-containing products: See prescribing information for specific drugs.

CYP2C19 or CYP3A4 Inhibitors Clinical Impact Increased blood levels of omeprazole and rifabutin.

Voriconazole: Concomitant use with TALICIA is contraindicated [see Contraindications (4)].

Prevention or Fluconazole, posaconazole, and itraconazole: Avoid concomitant use with TALICIA. If Management coadministration cannot be avoided, monitor patients for rifabutin associated adverse events, and lack of anti-fungal efficacy.

CYP2C19 Substrates (e.g., Clopidogrel, citalopram, cilostazol, phenytoin, diazepam) plasma concentrations of CYP2C19 substrate drugs or decreased/increased plasma Clinical Impact Increased concentrations of its active metabolite(s).

Prevention or Clopidogrel: Consider use of alternative anti-platelet therapy [see Warnings and Precautions (5.5)].

Management Avoid concomitant use with TALICIA. Antiretrovirals/Protease Inhibitors Antiretrovirals/protease inhibitors may increase rifabutin blood levels.

The effect of PPIs (such as omeprazole in TALICIA) on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known.

• Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir, and nelfinavir) when used concomitantly with omeprazole may reduce antiviral effect and promote the development Clinical Impact of drug resistance.

• Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with omeprazole may increase toxicity.

There are other antiretroviral drugs which do not result in clinically relevant interactions with omeprazole.

Delavirdine: Combination treatment with TALICIA and delavirdine is contraindicated [see Contraindications (4)].

Rilpivirine-containing products: Concomitant use with TALICIA is contraindicated [see Prevention or Contraindications (4)].

Management Avoid concomitant use of TALICIA with amprenavir, indinavir, lopinavir/ritonavir, saquinavir/ritonavir, ritonavir, tipranavir/ritonavir, fosamprenavir/ritonavir, or nelfinavir [see Warnings and Precautions (5.5)].

Other antiretrovirals: See prescribing information for specific antiretroviral drugs.

Probenecid Clinical Impact Increased and prolonged blood levels of amoxicillin.

Allopurinol Increase in the incidence of rashes is reported in patients receiving both allopurinol and amoxicillin Clinical Impact together compared to patients receiving amoxicillin alone. It is not known whether this potentiation of amoxicillin rashes is due to allopurinol or the hyperuricemia present in these patients.

Prevention or Discontinue allopurinol at the first appearance of skin rash. Assess benefit-risk of continuing TALICIA Management treatment.

Warfarin, and Other Oral Anticoagulants Abnormal prolongation of prothrombin time (increased international normalized ratio [INR]) has been in patients receiving amoxicillin and oral anticoagulants and in patients receiving PPIs, Clinical Impact reported including omeprazole, and warfarin concomitantly.

Increases in INR and prothrombin time may lead to abnormal bleeding and even death.

Prevention or Monitor INR and prothrombin time and adjust the dose of warfarin or other oral anticoagulants to Management maintain the desired level of anticoagulation.

Methotrexate Concomitant use of omeprazole with methotrexate (primarily at high doses) may elevate and Clinical Impact prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities [see Warnings and Precautions (5.5)].

Prevention or Avoid concomitant use of TALICIA in patients receiving high-dose methotrexate.

Management Digoxin Clinical Impact Potential for increased digoxin blood levels.

Prevention or Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug Management concentrations. See digoxin prescribing information.

Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole) can alter the absorption of other drugs due to its effect of reducing intragastric acidity Clinical Impact Omeprazole thereby increasing gastric pH.

Prevention or Management Tacrolimus

Mycophenolate mofetil (MMF): Use TALICIA with caution in transplant patients receiving MMF. See the prescribing information of other drugs dependent on gastric pH for absorption.

Potential for increased tacrolimus blood levels, especially in patients who are intermediate or poor metabolizers of CYP2C19.

Prevention or Monitor tacrolimus whole blood levels and adjust dose as per the prescribing information for Management tacrolimus.

Drugs Metabolized via the CYP450 Enzymes (e.g., cyclosporine, disulfiram) Clinical Impact Interactions are reported with omeprazole and other drugs metabolized via the CYP450 enzymes.

Prevention or Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when Management taken concomitantly with TALICIA. Oral Contraceptives Concomitant use of amoxicillin and rifabutin with hormonal contraceptives may lead to loss of its Clinical Impact efficacy due to lower estrogen reabsorption and decreased ethinylestradiol and norethindrone concentrations, respectively [see Warnings and Precautions (5.3)].

Prevention or Patients should be advised to use additional or alternative non-hormonal methods of contraception.

Management Diagnostic Investigations for Neuroendocrine Tumors PPI-induced decrease in gastric acidity may lead to increased serum chromogranin A (CgA) levels, Clinical Impact which may cause false positive results in diagnostics for neuroendocrine tumors [see Warnings and Precautions (5.9)].

CgA levels at least 14 days after stopping TALICIA treatment and consider repeating the test Prevention or Assess initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial Management iflaboratory should be used for testing, as reference ranges between tests may vary.

Clinical Impact

Urine Glucose Test Clinical Impact

High urine concentrations of ampicillin or amoxicillin may result in false-positive reactions when using glucose tests based on the Benedict’s copper reduction reaction that determines the amount of reducing substances like glucose in the urine.

Prevention or Management Glucose tests based on enzymatic glucose oxidase reactions should be used.

Interaction with Secretin Stimulation Test in gastrin secretion in response to secretin stimulation test may falsely suggest Clinical Impact Hyper-response gastrinoma.

Prevention or Test should be performed at least 14 days after stopping TALICIA treatment to allow gastrin levels Management to return to baseline.

False Positive Urine Tests for Tetrahydrocannabinol (THC) Clinical Impact There have been reports of false positive urine screening tests for THC in patients receiving PPIs. Prevention or Management An alternative confirmatory method should be considered to verify positive results.

Other Laboratory Tests Following administration of ampicillin or amoxicillin to pregnant women, a transient decrease Clinical Impact in plasma concentration of total conjugated estriol, estriol-glucuronide, conjugated estrone, and estradiol has been noted.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Based on animal reproduction studies, TALICIA may cause fetal harm when administered to pregnant women. There are no adequate and well controlled studies of amoxicillin, omeprazole, or rifabutin (used separately or together) in pregnant women.

Use of TALICIA is generally not recommended for use in pregnancy. If TALICIA is used during pregnancy, advise pregnant women of the potential risk to a fetus.

8.2 Lactation Risk Summary Data from a published clinical lactation study reports that amoxicillin is present in human milk. Published adverse effects with amoxicillin exposure in the breast-fed infant include diarrhea.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for TALICIA and any potential adverse effects on the breast-fed child from TALICIA or from the underlying condition.

8.3 Females and Males of Reproductive Potential Contraception Both rifabutin and amoxicillin components of TALICIA interact with hormonal contraceptives resulting in lower levels of these contraceptives. Therefore, female patients taking hormonal contraceptives should use an additional non-hormonal highly effective method of contraception while taking TALICIA. 8.5 Geriatric Use Clinical studies of TALICIA did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger adult patients.

8.6 Renal Impairment It is recommended to avoid the use of TALICIA in patients with severe renal impairment (GFR < 30 mL/min). Amoxicillin is primarily eliminated by the kidney.

8.7 Hepatic Impairment It is recommended to avoid the use of TALICIA in patients with hepatic impairment. In patients with hepatic impairment (Child-Pugh Class A, B, or C) exposure to omeprazole substantially increased compared to healthy subjects.

10 OVERDOSAGE No information is available on accidental overdosage of TALICIA in humans.

In case of an overdose, patients should contact a physician, poison control center, or emergency room.

TALICIA is distributed by RedHill Biopharma Inc. Raleigh, NC TALICIA is manufactured in Sweden for RedHill Biopharma Ltd. Tel Aviv, Israel TALICIA is a trademark registered with the U.S. Patent and Trademark Office and used under license by RedHill Biopharma Inc. ©2020 RedHill Biopharma Ltd. All rights reserved. TAL/0050 04/2020

For the treatment of +HOLFREDFWHU S\ORUL infection in adults

Outsmart Resistance.

Eradicate H. pylori.

High rates of H. pylori eradication â&#x20AC;˘ 84% eradication overall â&#x20AC;˘ 90% HUDGLFDWLRQ LQ SDWLHQWV ZLWK FRQŕ˘&#x2030; UPHG blood levels of any Talicia component at day 131 Eradication Starts Here

Zero-to-minimal H. pylori resistance Favorable safety and tolerability All three medications in an all-in-one capsule Dosed as 4 capsules q8h with food for 14 days â&#x20AC;˘ Please see adjacent Brief Summary for full dosing instructions

www.talicia.com

IMPORTANT SAFETY INFORMATION

Talicia contains omeprazole, a proton pump inhibitor (PPI), amoxicillin, a penicillin-class antibacterial, and rifabutin, a rifamycin antibacterial. It is contraindicated in patients with known hypersensitivity to any of these medications, any other components of the formulation, any other beta-lactams or any other rifamycin.

Talicia is contraindicated in patients receiving rilpivirinecontaining products.

Talicia is contraindicated in patients receiving delavirdine or voriconazole.

Serious and occasionally fatal hypersensitivity reactions have been reported with omeprazole, amoxicillin and rifabutin. &ORVWULGLRLGHV GLŕ˘&#x201E; FLOH-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents and may range from mild diarrhea to fatal colitis.

Talicia may cause fetal harm. Talicia is not recommended for use in pregnancy.

7DOLFLD PD\ UHGXFH WKH Hŕ˘&#x2021; FDF\ RI KRUPRQDO contraceptives. An additional non-hormonal method of contraception is recommended when taking Talicia.

Talicia should not be used in patients with hepatic impairment or severe renal impairment.

Acute Interstitial Nephritis has been observed in patients taking PPIs and penicillins.

Cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE) have been reported in patients taking PPIs. These events have occurred as both new onset and exacerbation of existing autoimmune disease.

The most common adverse reactions (*1%) were diarrhea, headache, nausea, abdominal pain, chromaturia, rash, dyspepsia, oropharyngeal pain, vomiting, and vulvovaginal candidiasis.

Please see Brief Summary of Prescribing Information on adjacent pages.

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Helicobacter pylori: An Update

FREDERICK B. PENG, MD Department of Medicine

DAVID Y. GRAHAM, MD MIMI C. TAN, MD, MPH Section of Gastroenterology and Hepatology Department of Medicine Baylor College of Medicine Houston, Texas

G

astroenterology was forever changed in 1982, when Drs. Barry Marshall and Robin Warren successfully isolated Helicobacter pylori from a

70-year-old man with frequently bleeding gastric and duodenal ulcers.1,2

Their success was somewhat serendipitous because cultures from similar patients were negative after being incubated for 48 hours. Examination of this patientâ&#x20AC;&#x2122;s culture was delayed because of the Easter holiday, and the later examination revealed a large number of colonies of gram-negative, spiral organisms.1 In their seminal investigation, Marshall and Warren demonstrated that all 13 patients with duodenal ulcers and 18 of 22 patients with gastric ulcers were infected with H. pylori.3 These findings were published subsequently as a letter to The Lancet in 1984.2 The research community remained skeptical about its significance; it required at least another decade before the hypothesis that a bacterial infection was the cause of peptic ulcer was widely accepted.4

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A Nobel Prize: H. pylori, Gastritis, And Peptic Ulcer Disease In an effort to fulfill Koch’s postulates (for inferring causation) that the bacteria must be isolated from an infected patient and the disease reproduced when a bacterial culture is inoculated into a healthy host, Marshall undertook a self-investigation that confirmed the association between gastritis and H. pylori.5 He drank a broth containing a heavy inoculum from a 4-day-old culture plate of H. pylori isolated from a patient with non-ulcer dyspepsia. His pre-inoculation endoscopic evaluation revealed healthy gastric mucosa without evidence of colonization with H. pylori.5 Following ingestion, Marshall developed dyspepsia by the third day, as well as nausea and achlorhydric vomiting with halitosis from days 5 to 8. A repeat endoscopy on day 10 showed extensive gastritis with spiral bacteria. A Gram stain and cultures were consistent with H. pylori.1,5 This experiment was

published in the Medical Journal of Australia in 1985, and eventually led to a paradigm shift in understanding the pathophysiology of gastritis and peptic ulcer disease.5 These collective investigations formed the foundation for the future of H. pylori research and culminated in the awarding of the Nobel Prize in Physiology or Medicine to Warren and Marshall in 2005.6

Epidemiology of H. pylori Infection with H. pylori causes gastritis and the gastritis-related diseases, gastric B-cell lymphoma, peptic ulcer disease, and stomach cancer.7,8 Most H. pylori infections are acquired in childhood, and the infection is present in almost half of the world’s population.9 Prevalence varies based on geography, with the highest estimated prevalence in Africa (79%), Latin America and the Caribbean (63%), and Asia (54%), and the lowest prevalence in North America (37%).10 Disease

Table. Tests to Evaluate for Active Helicobacter pylori Infection Test

Advantages

Disadvantages

Serology

• Accessible, widely available • Least expensive • Does not require drug modifications before testing

• Does not reliably differentiate between active and previous infection • Cannot be used to confirm eradication

Stool antigen test

• High negative and positive predictive values • Can be used to test for active infection and evaluate for eradication

• Stool sample needed, patient aversion • Requires prior discontinuation of antibiotics, bismuth products, and PPIs to reduce risk for false-negative results

Urea breath test

• High negative and positive predictive values • Can be used to test for active infection and evaluate for eradication

• Resources and trained personnel needed to reliably reproduce test • Requires prior discontinuation of antibiotics, bismuth products, and PPIs to reduce risk for false-negative results

Noninvasive

Endoscopic

Culture

• Excellent specificity • Offers opportunity to test for antibiotic susceptibilities

Histology

• Good sensitivity and specificity • Provides additional information, such as degree of inflammation and associated pathology (intestinal metaplasia, atrophic gastritis) • Can be used to test for infection and evaluate for eradication

• Endoscopy needed • Trained personnel needed to stain and interpret specimen • Longer turnaround time • Higher cost • Interobserver variability among pathologists

Ureasebased testsa

• Good sensitivity and specificity • Rapid • Inexpensive

• Requires prior discontinuation of antibiotics, bismuth products, and PPIs to reduce risk for false-negative results

a

Tests include rapid urease test or Campylobacter-like organism test.

PPI, proton pump inhibitor

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• Not widely available • Variable sensitivity • Requires trained personnel and properly equipped laboratory facilities

transmission typically occurs via fecal/oral or oral/oral routes, with intrafamilial aggregation of the infection.

The most common risk factors include poor household hygiene and sanitation, exemplified by high housing density, a lack of running water, increased number of siblings, overcrowding, and bed sharing in childhood.11-14 The bacterium colonizes both the gastric antrum and corpus. Urease produced by the organism converts urea to ammonia and facilitates protection from stomach acidity. H. pylori burrows through the gastric mucus layer and attaches to the gastric epithelium, where the pH is closer to 4.5 to 6.5, compared with the gastric lumen’s average pH of 2.0.15 Inflammation associated with attachment to the gastric mucosa results in histologic changes that may lead to the stepwise cascade of superficial/chronic gastritis, atrophic gastritis, intestinal metaplasia, intraepithelial neoplasia (previously

referred to as dysplasia), and, eventually, invasive gastric carcinoma—currently the fifth-leading cause of cancer death worldwide.16

Gastric Cancer In 1994, H. pylori was designated a Group 1 human carcinogen, and it is etiologically responsible for the majority of gastric cancers.8,17,18 The EUROGAST study, which evaluated 17 populations from 13 different countries (Europe, Japan, United States), identified a 6-fold increased risk for gastric adenocarcinoma in H. pylori– infected populations compared with uninfected populations.19 The World Health Organization estimates that 89% of all gastric cancer is attributed to H. pylori (population attributable fraction), which likely is an underestimation.20 In the United States, the incidence of gastric cancer parallels that of H. pylori infection, wherein

Susceptibility Testing Available?

14-day Clarithromycin triple therapy

Yes

Yes

No or testing refused

Susceptibility tests

Empiric therapy

Clarithromycin susceptible?

Triple resistant

No

14-day Metronidazole triple therapy

Yes

Locally proven effective regimensa

Clarithromycin resistant/metronidazole susceptible?

No

14-day Levofloxacin triple therapy

Yes

Examples: 14-day Bismuth quadruple therapies

Clarithromycin and metronidazole resistant/ levofloxacin susceptible?

No

Possibly 14-day rifabutincontaining therapies Failures

Figure. First-line treatment algorithm for guiding Helicobacter pylori therapy. a

Use only antibiotics rarely associated with resistance or with resistance that can be overcome.

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Initially, H. pylori is confined largely to the antrum as antral-predominant gastritis. In the antrum, inflammation stimulates G cells to increase the release of gastrin and acid secretion from the parietal cells in the fundus.31,32 The subsequent acid load damages the underlying duodenal mucosa, contributing to development of gastric metaplasia in the duodenum, which provides sites where H. pylori can colonize and induce a duodenal ulcer. Eradication of infection leads to cure of duodenal ulcer disease in patients whose ulcers are not associated with use of nonsteroidal anti-inflammatory drugs.33 When H. pylori extends into the corpus and causes pangastritis or corpus-predominant gastritis, acid secretion is suppressed, resulting in hypochlorhydria. This condition leads to the optimal milieu for gastric ulceration, atrophic gastritis, and carcinoma.34

management approach.42 The Houston Consensus Conference on H. pylori testing in the United States confirmed the recommendation to treat all patients with active H. pylori infection (grade 1A) and to search for the infection in high-risk patients, such as those with a current or past history of peptic ulcer disease (grade 1A), uninvestigated dyspepsia (grade 1A), reflux symptoms if high risk for H. pyloriâ&#x20AC;&#x201C;related disease (grade 1C), gastric MALT lymphoma (grade 1B), and family history of gastric cancer (grade 1B).43 Testing should be considered in patients who are first-generation immigrants from high-prevalence areas (grade 1B), are Hispanic or black (grade 2C), have idiopathic thrombocytopenia (grade 1B), use proton pump inhibitors (PPI) for longer than 1 month (grade 2C), or have a family history of peptic ulcer disease (grade 1B); testing also should be considered in family members residing in the same household as patients with proven H. pylori infection (grade 1B).43 Serology (immunoglobulin G) has low specificity and cannot reliably differentiate between active and past H. pylori infection (grade 1A) (Table).8,43 If serology is used, the clinician should confirm the presence of an active infection with a reliable test, such as a urea breath test (UBT) or H. pylori stool antigen test (HpSAg), before deciding to treat. Both tests are recommended first-line for detection of active infection (grade 1A).43 PPIs, bismuth, and antibiotics should be discontinued 2 to 4 weeks before UBT or HpSAg testing (grade 1B) (Table). For symptomatic patients, antacids and H2 blockers can be continued or substituted for PPIs because neither affects the accuracy of UBT or HpSAg testing (grade 1A).43 If endoscopy is performed, biopsies should be taken from the antrum, corpus, and incisura according to the updated Sydney system (grade 1A).44 Immunohistochemical staining for H. pylori is recommended for confirmation of the infection.7 If endoscopy is required for other reasons, histology is an acceptable alternative to confirm clearance of infection (grade 1A).43

Gastric MALT Lymphoma

Treatment of H. Pylori Infection

In addition, H. pylori is associated with the development of gastric mucosaâ&#x20AC;&#x201C;associated lymphoid tissue tumors, also known as MALToma, MALT lymphoma, or extranodal marginal zone B-cell lymphoma.35,36 Although the specific mechanism of pathogenesis has not been elucidated, several theories exist, including the hypothesis that H. pyloriâ&#x20AC;&#x201C;induced pangastritis leads to the infiltration of immune cells (ie, B cells, T cells, and macrophages) to clear the infection.37-39 The resulting chronic infiltration promotes accumulation of these cells, especially lymphocytes, and is associated with organized lymphoid tissue.36 Studies have shown remission of tumors after eradication of H. pylori.39-41

The principles of antimicrobial stewardship have contributed to a complete rethinking about H. pylori therapy.

In the United States, the frequent use of macrolide and fluoroquinolone antibiotics for various infectious diseases has resulted in H. pylori becoming increasingly resistant to these antibiotics.45 The prevalence of clarithromycin and levofloxacin resistance has risen to the point that neither should be used as empiric therapy for H. pylori infection; their use should be restricted to patients proven to have susceptible infections.46 Guidelines written before the current emphasis on responsible use of antibiotics recommended a 4-drug regimen (a PPI, amoxicillin, clarithromycin, and metronidazole) for 14 days.7,47,48 Even double antibiotic coverage incorporates at least one unnecessary antibiotic, with an estimated minimum of 15.4 tons of unnecessary clarithromycin and/or metronidazole administered per 1 million prescriptions.49

minority groups (ie, blacks, Hispanics, Asians) are disproportionately afflicted with a higher disease burden.21,22 In Texas, the incidence of gastric cancer among Hispanics is more than 2-fold that of non-Hispanic whites (11.4 vs. 4.7 per 100,000 in 2005-2009).23 Although a majority of gastric cancers are associated with H. pylori infection, relatively few infected patients experience progression to gastric adenocarcinoma through the pathway of gastric mucosal atrophy and development of a metaplastic epithelium.24 Detection and eradication of the bacterium before development of irreversible damage and gastric mucosal genetic instability prevents or markedly reduces the risk for cancer.17,25 In high-risk patients who already have progressed to atrophic gastritis, cure of H. pylori still can reduce the risk for gastric cancer substantially relative to untreated people or those who do not respond to treatment.26 However, patients with a high-risk phenotype may benefit from endoscopic surveillance (eg, Operative Link on Gastritis Assessment [OLGA] or Operative Link on Gastritis Assessment based on Intestinal Metaplasia [OLGIM] grades 3 or 4).27-30

Peptic Ulcer Disease

H. Pylori Testing: Indications and Methods The recognition of H. pylori as an infectious cause of peptic ulcer disease markedly changed the

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Although microbiology laboratories are routinely available in clinics and hospitals, H. pylori susceptibility testing rarely is offered. It has long been recommended that all treated patients undergo a test of cure at least weeks after the end of therapy to assess for eradication; treatment failures provide an early indication of increasing local antibiotic resistance.7,47,48 Susceptibility testing is available at some of the large national laboratories and from Mayo Clinic. Molecular testing of gastric biopsies (fresh or paraffin-embedded) also is an alternative (eg, American Molecular Laboratories). Before the recognition that principles of antimicrobial stewardship should be applied to H. pylori therapy, culture or molecular testing was recommended only for patients who failed 2 treatment regimens.50 This approach combined with the overall high rate of treatment failures made H. pylori therapy a significant contributor to widespread antimicrobial resistance.51 Thus, the updated management algorithm should first delineate whether susceptibility testing is available in a provider’s community. If it is unavailable, clinicians should use only regimens based on local antimicrobial susceptibility patterns or therapies proven to be highly effective locally, such as bismuth quadruple therapy— bismuth subcitrate, metronidazole, and tetracycline (commercially available as Pylera from Axcan) with twice-daily PPI therapy.7,17,43 However, a notable caveat is that Pylera is packaged for 10 days, whereas the ideal regimen is 14 days. Optimal prescribing practices necessitate that pharmacies break down or sell two packages, which limits the delivery of high-value care. It often is cheaper to prescribe the individual components. However, tetracycline may be difficult to obtain, and some pharmacies try to substitute doxycycline,52 which is markedly less effective and should not be used.53 The dose of PPI should be at least 40 mg of omeprazole or an equivalent (eg, 20 mg of rabeprazole or esomeprazole, 45 mg of lansoprazole) to create the gastric environment needed for eradication.54 An alternative effective regimen, soon to be released, is the rifabutin-triple therapy ( Talicia, RedHill)—a combination capsule containing omeprazole, amoxicillin, and rifabutin at a dose of 10 mg/250 mg/12.5 mg.55 Recommended dosing is 4 capsules to achieve 40 mg/1,000 mg/50 mg of omeprazole-amoxicillin-rifabutin. Both bismuth quadruple therapy and the rifabutin combination are effective despite resistance to clarithromycin and metronidazole. Clinical experience with rifabutin-triple therapy will be required to determine its role as a firstchoice regimen.

If susceptibility testing is available, the algorithm presented in this review is recommended (Figure). Patients with clarithromycin-susceptible strains of H. pylori should be prescribed a 14-day course of clarithromycin triple therapy. For strains resistant to clarithromycin but susceptible to metronidazole, 14 days of metronidazole triple therapy should be used. In cases of resistance to clarithromycin and metronidazole but susceptibility

to levofloxacin, 14 days of levofloxacin triple therapy should be given. If triple resistance is present or susceptibility testing is unavailable, then one must fall back on locally proven combination regimens.

Potential Adverse Effects to Consider Despite the benefits of therapy, prescribers should be cognizant of potential adverse effects of these antibiotic regimens. For instance, a large cohort study from Hong Kong evaluated patients prescribed clarithromycin for outpatient H. pylori eradication and found a 3-fold increase in the risk for myocardial infarction (incidence rate ratio, 3.38; 95% CI, 1.89-6.04) and a 5-fold increase in cardiac arrhythmias (incidence rate ratio, 5.07; 95% CI, 2.19-11.72) during and immediately after clarithromycin use.56 Similarly, the 10-year CLARICOR (Effect of Clarithromycin on Mortality and Morbidity in Patients with Ischemic Heart Disease) randomized controlled trial evaluated 500 mg of clarithromycin daily compared with placebo for treatment of Chlamydia pneumoniae in patients with stable coronary artery disease. The clarithromycin group had higher all-cause and cardiovascular mortality at 2.6 years, with the highest rates in patients not taking statins.57 The FDA subsequently issued a warning in February 2018 to consider an alternative antibiotic in patients with known cardiovascular disease.58 In December 2018, the FDA issued a separate warning for fluoroquinolones, which double the risk for rupture and dissection of aortic aneurysms, and cautioned prescribers to avoid this class of antibiotics in patients with hypertension and vascular disease.59,60

Primary and Secondary Prevention Of Gastric Cancer in the United States Although it seems intuitive to advocate for global treatment of an infectious disease implicated in the pathogenesis of cancer, debate continues in the United States about H. pylori screening and endoscopic screening for precancerous lesions in people infected with H. pylori. Despite the high global burden, gastric cancer is the 15th most common type of neoplasm in the United States and its overall incidence has declined steadily over time. It is estimated that there are 27,510 new cases and 11,140 deaths annually from gastric cancer in the United States; these numbers are relatively small compared with those for breast cancer, which affects nearly 10 times as many people and results in 4 times as many deaths annually.61 However, rates of gastric cancer are rising among Americans older than 50 years, especially Hispanics.62,63 This trend likely is due to immigration patterns and an influx of immigrants from countries with a high prevalence of gastric cancer (Latin America, Asia). Asian American, black, and Hispanic populations within the United States remain at high risk for gastric cancer, with incidences up to 55 per 100,000.64,65 Population-wide H. pylori screening and subsequent endoscopic screening for precancerous lesions (atrophic gastritis or gastric intestinal

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metaplasia) is likely not cost-effective in this country.

Instead, a screening strategy based on risk stratification, in which only populations identified as having high risk (eg, older age, nonwhite race, smokers) undergo H. pylori testing and then endoscopic screening for precancerous lesions, may be cost-effective.66 Efforts to reduce the burden from gastric cancer would need to focus on primary (H. pylori testing and treatment) and secondary (endoscopic screening and surveillance of precancerous lesions) prevention strategies.

Conclusion The discovery of the pathogenic properties of H. pylori revolutionized the medical community’s understanding

and management of its associated diseases, which include gastritis, peptic ulcer disease, MALT lymphoma, and gastric adenocarcinoma. Clinicians should understand the indications for and interpretation of various tests to evaluate for active infection. Recognition of local resistance patterns and patient comorbidities has clinically significant implications for successful eradication and minimization of treatment-related adverse outcomes. Indeed, the treatment algorithm delineated here is successful in sustaining disease cure if applied in the appropriate clinical scenarios. However, whether population-based screening for H. pylori is feasible and cost-effective in the United States remains to be seen.

References 17.

Chey WD. Helicobacter pylori: when we should treat….

Am J Gastroenterol. 2019;114(12):1829-1832.

18.

No authors listed. Schistosomes, liver flukes and Helicobacter pylori. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Lyon, 7-14 June 1994. IARC Monogr Eval Carcinog Risks Hum. 1994;61:1-241.

Marshall BJ, Warren JR. Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration.

Lancet. 1984;1(8390):1311-1315.

19.

Forman D, Coleman M, De Backer G, et al. An international association between Helicobacter pylori infection and gastric cancer.

Lancet. 1993;341(8857):1359-1363.

4.

No authors listed. NIH Consensus Conference. Helicobacter pylori in peptic ulcer disease. NIH Consensus Development Panel on Helicobacter pylori in Peptic Ulcer Disease. JAMA. 1994;272(1):65-69.

20.

Plummer M, Franceschi S, Vignat J, et al. Global burden of gastric cancer attributable to Helicobacter pylori. Int J Cancer.

2015;136(2):487-490.

21.

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Marshall BJ, Armstrong JA, McGechie DB, et al. Attempt to fulfill Koch’s postulates for pyloric campylobacter. Med J Aust.

1985;142(8):436-439.

Graham DY, Malaty HM, Evans DG, et al. Epidemiology of Helicobacter pylori in an asymptomatic population in the United States. Effect of age, race, and socioeconomic status.

Gastroenterology. 1991;100(6):1495-1501.

6.

Pincock S. Nobel Prize winners Robin Warren and Barry Marshall.

Lancet. 2005;366(9495):1429.

22.

7.

Chey WD, Leontiadis GI, Howden CW, et al. ACG Clinical Guideline: Treatment of Helicobacter pylori Infection. Am J Gastroenterol. 2017;112(2):212-238.

Peng FB, Nguyen TH, Emelogu I, et al. Contemporary prevalence and predictors of Helicobacter pylori infection in a U.S. population. Am J Gastroenterol. 2019;114:S677-S678. Abstract.

23.

Ramirez AG, Thompson IM, Vela L. The South Texas Health Status Review: a health disparities roadmap. New York, NY: Springer; 2013.

1.

Marshall BJ. Helicobacter connections. Nobel Lecture, December 8, 2005. www.nobelprize.org/uploads/2018/06/marshall-lecture. pdf. Accessed January 22, 2020.

2.

Warren JR, Marshall BJ. Unidentified curved bacilli on gastric epithelium in active chronic gastritis. Lancet.

1983;321(8336):1273-1275.

3.

8.

McColl KEL. Helicobacter pylori infection. N Engl J Med. 2010;362(17):1597-1604.

24.

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Zamani M, Ebrahimtabar F, Zamani V, et al. Systematic review with meta-analysis: the worldwide prevalence of Helicobacter pylori infection. Aliment Pharmacol Ther. 2018;47(7):868-876.

Uemura N, Okamoto S, Yamamoto S, et al. Helicobacter pylori infection and the development of gastric cancer. N Engl J Med. 2001;345(11):784-789.

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Wong BCY, Lam SK, Wong WM, et al. Helicobacter pylori eradication to prevent gastric cancer in a high-risk region of China: a randomized controlled trial. JAMA. 2004;291(2):187-194.

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Brown LM. Helicobacter pylori: Epidemiology and routes of transmission. Epidemiol Rev. 2000;22(2):283-297.

Moss SF. The clinical evidence linking Helicobacter pylori to gastric cancer. Cell Mol Gastroenterol Hepatol. 2017;3(2):183-191.

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Pimentel-Nunes P, Libânio D, Marcos-Pinto R, et al. Management of epithelial precancerous conditions and lesions in the stomach (MAPS II): European Society of Gastrointestinal Endoscopy (ESGE), European Helicobacter and Microbiota Study Group (EHMSG), European Society of Pathology (ESP), and Sociedade Port. Endoscopy. 2019;51(4):365-388.

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Rugge M, Genta RM, Fassan M, et al. OLGA gastritis staging for the prediction of gastric cancer risk: a long-term follow-up study of 7436 patients. Am J Gastroenterol. 2018;113(11):1621-1628.

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Webb PM, Knight T, Greaves S, et al. Relation between infection with Helicobacter pylori and living conditions in childhood: Evidence for person to person transmission in early life. BMJ. 1994;308(6931):750.

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Perry S, Sanchez MDLL, Yang S, et al. Gastroenteritis and transmission of Helicobacter pylori infection in households.

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Ansari S, Yamaoka Y. Survival of Helicobacter pylori in gastric acidic territory. Helicobacter. 2017;22(4):e12386.

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Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin.

2018;68(6):394-424.

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Garcia N, Leavitt J, McCarty CL. Use of Helicobacter pylori antibiotic resistance testing on paraffin embedded gastric biopsy tissue. Am J Gastroenterol. 2018;113:S1512-S1513. Abstract.

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Graham DY, Dore MP. Helicobacter pylori therapy: a paradigm shift. Expert Rev Anti Infect Ther. 2016;14(6):577-585.

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Graham DY, Lee SY. How to effectively use bismuth quadruple therapy: the good, the bad, and the ugly. Gastroenterol Clin N Am. 2015;44(3):537-563.

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Axon ATR, O’Moráin CA, Bardhan KD, et al. Randomised double blind controlled study of recurrence of gastric ulcer after treatment for eradication of Helicobacter pylori infection.

BMJ. 1997;314(7080):565-568.

Graham DY, Lu H, Dore MP. Relative potency of proton-pump inhibitors, Helicobacter pylori cure rates, and meaning of double-dose PPI. Helicobacter. 2019;24(1):e12554.

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Wotherspoon AC, Ortiz-Hidalgo C, Falzon MR, et al. Helicobacter pylori-associated gastritis and primary B-cell gastric lymphoma.

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Graham DY, Canaan Y, Maher J, et al. Rifabutin (RHB-105) based triple therapy for Helicobacter pylori (HP) infection eradication: results of pivotal phase 3 multicenter study (ERADICATE Hp2).

Am J Gastroenterol. 2019;114:S674. Abstract.

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BMJ. 2016;352:h6926.

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Lee CC, Gabriel Lee MT, Chen YS, et al. Risk of aortic dissection and aortic aneurysm in patients taking oral fluoroquinolone.

JAMA Intern Med. 2015;175(11):1839-1847.

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1989;42(12):1269-1271.

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Carlson SJ, Yokoo H, Vanagunas A. Progression of gastritis to monoclonal B-cell lymphoma with resolution and recurrence following eradication of Helicobacter pylori.

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40. Wotherspoon AC, Diss TC, Pan L, et al. Regression of primary low-grade B-cell gastric lymphoma of mucosa-associated lymphoid tissue type after eradication of Helicobacter pylori.

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60. Richards GA, Brink AJ, Feldman C. Rational use of the fluoroquinolones. South African Med J. 2019;109(6):378-381.

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Steinbach G, Ford R, Glober G, et al. Antibiotic treatment of gastric lymphoma of mucosa-associated lymphoid tissue: an uncontrolled trial. Ann Intern Med. 1999;131(2):88-95.

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44. Dixon MF, Genta RM, Yardley JH, et al. Classification and grading of gastritis. The updated Sydney System. International Workshop on the Histopathology of Gastritis, Houston 1994. Am J Surg Pathol. 1996;20(10):1161-1181.

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Shiota S, Reddy R, Alsarraj A, et al. Antibiotic resistance of Helicobacter pylori among male United States veterans.

Clin Gastroenterol Hepatol. 2015;13(9):1616-1624.

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Shiotani A, Lu H, Dore MP, et al. Treating Helicobacter pylori effectively while minimizing misuse of antibiotics. Cleve Clin J Med. 2017;84(4):310-318.

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Fallone CA, Chiba N, van Zanten SV, et al. The Toronto Consensus for the Treatment of Helicobacter pylori Infection in Adults.

Gastroenterology. 2016;151(1):51-69.e14.

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Malfertheiner P, Megraud F, O’Morain CA, et al. Management of Helicobacter pylori infection – The Maastricht IV/ Florence consensus report. Gut. 2012;61(5):646-664.

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Graham DY, Dang BN, el-Serag HB. Helicobacter pylori Infection.

N Engl J Med. 2019;381(6):587-588.

Drs. Peng and Tan reported no relevant financial conflicts of interest.

Dr. Graham reported financial relationships with RedHill Biopharma and Phathom Pharmaceuticals.

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EHRs May Hold Keys To Practice Survival In the COVID Era

Data Mining

By Disease State

T

he development of ancillary services is a crucial consideration for

IBS Outsourcing to ModifyHealth to help patients with the low-FODMAP diet; ancillary income between $100 and $150 per patient enrolled

gastroenterology practices thinking about

Fatty Liver

of the COVID-19 pandemic. What service

FibroScan (Echosens) in office; ancillary income roughly $30 to $40 per patient but activates at-risk patients for additional screening and potential clinical research protocols

NASH Clinical research; having formal clinical research entity or joint venture research entity. Ancillary income ranges between $100,000 and $500,000 annually or more, based on number of protocols and enrollment numbers. Joint venture structures are with ObjectiveGI and ideal for smaller groups

Hemorrhoids In-office banding or ablation, with ancillary income ranges that are substantial and dependent on treatment frequencies and severity of hemorrhoids

Advanced Imaging Cellvizio (Mauna Kea Technologies) in the ambulatory surgery center as an adjunct to esophagogastroduodenoscopy with biopsy nets $600 to $650 additional facility fee for patients with high-grade dysplasia Source: Scott Fraser.

diversifying, particularly in the trying times line should you develop? The answer may lie in the contents of your electronic health records (EHRs).

Although often bemoaned as a bane of modern medical practice, the EHR holds a gold mine of patient data that can help practices identify ancillary service lines tailored to their patients. These data, properly used, also can identify gaps in care and drive significant improvement in patient outcomes.

“Most groups still really don’t understand that EHRs contain a tremendous repository of data that can be used to identify subsets of patients who would benefit from specific ancillary services,” according to Scott Fraser, MBA, the managing director of Fraser Healthcare LLC, in Malvern, Pa.

Safeguard Against Uncertainty Ancillary lines could help build resilience in a specialty that often derives the bulk of its revenue from procedural productivity, a business model whose vulnerabilities the COVID-19 pandemic starkly revealed.

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“We’re seeing an uptick in some patients returning to physician offices, but I would argue that most patients still have COVID-19–related reservations about entering a health care facility,” Mr. Fraser said. “If you combine that with the projected fall wave of infections, we could see another severe drop. That trend will reverse once we have a vaccine. In the interim, I think it’s critical for groups to mine their EHRs for other clinical service lines they can offer.”

Reed Hogan, MD, is a gastroenterologist with GI Associates and Endoscopy Center in Jackson, Miss., a practice that relies heavily on its ancillary services.

Dr. Hogan credits that diversity of revenue sources for keeping his group afloat lately. “We never closed. Some places closed their endoscopy centers and are just now reopening, which is hard—next to impossible,” he said.

With broad training in irritable bowel disease, inflammatory bowel diseases, nutrition, and hepatology, gastroenterologists are well suited to diversify beyond screening for colorectal cancer, which, although important, is elective, Mr. Fraser said. “It’s critical for groups to understand their vulnerability, and to identify potential patient populations who may warrant follow-up, screening or treatment” for other conditions, he said.

As an example, mining the EHR for data on patients with hepatitis B and C infections, alcoholism, and fatty liver disease could identify those at high risk for nonalcoholic steatohepatitis, who can be screened easily in the office with FibroScan (Echosens).

“The reimbursement isn’t substantial, but it identifies your at-risk patients for surveillance at appropriate intervals,” Mr. Fraser said. “Or you can enroll them into clinical trials for the 30-plus new NASH drugs in development. This means establishing a separate research organization or partnering with a research group to create a joint venture research organization. It can be a lucrative ancillary line and is a huge value-add for your patients.”

Dietary management and hemorrhoid treatment are also services that, if warranted by your patient population, are easy to establish, he added.

Independent Revenue Stream Patient data, if extracted and de-identified, could prove attractive to third parties willing to pay for the information, according to Ian Strug, a co-founder of Virgo, a company that develops automation and artificial intelligence (AI) for endoscopy. “A patient’s medical history and the ways they’ve interacted with the health care system are valuable to health care firms working with technology. There are a number of players,” Mr. Strug said.

In pharmaceutical development, for example, EHR data may help companies evaluate phase 2 drugs in patients currently taking them, potentially speeding the path to a randomized controlled trial. “That sort of evidence has been considered anecdotal, but we haven’t had the computing power to look at hundreds of thousands of patients in one consolidated model,” Mr. Strug said.

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Insurance companies could use the data to better gauge the health of patients for actuarial purposes.

Developers of AI technologies see EHR systems as a source for harvesting the immense volume of data they need to build their algorithms. “To get that data, you need a product that either feeds you that data or you need to buy it,” Mr. Strug said.

In addition, entities involved in public health may be looking for ways to access EHRs for their own initiatives. “Any private company interested in building software that helps manage population health needs data,” he said. “For public health departments, it would be good to have access to data that goes beyond your Medicare/Medicaid population.”

Dr. Hogan said he wasn’t aware of any practices selling their EHR data. “But it’s a smart idea—I like it. Our data banks are an intelligent resource. I’d be curious to learn how you would convert that into useful, revenuegenerating information,” he said.

A first step in figuring out what data to extract and how to extract them is to work with a technology representative. “Whoever sold you the software will be the best resource to help you start building customized reports, or point you in the direction of en suite software tools available to get that information,” Mr. Strug said.

Formatting and packaging data sets may not be much of an issue. “The parties interested will help define the necessary data elements and format; the goal is to provide a holistic data set containing all the data points your consumer would want,” Mr. Strug said.

A concern that people have is that their data could fall into the wrong hands. “Could someone reveal everyone in the data set? Theoretically, yes. But if you can ensure that you’ve anonymized a data set so that there is no string of data that can identify an individual, that seems unlikely,” Mr. Strug said.

Other issues are up-front costs and finding a buyer.

“Do I hire a salesperson? Do it myself? All of these things take time and resources,” Mr. Strug said.

At this point, however, capitalizing on patient data in this way may be more hypothetical than practical.

“I’ve talked with pharmaceutical companies about exchanging data, but there are a lot of legal implications, kickback implications,” said Jim Leavitt, MD, the president of Gastro Health, in Miami. “I’m not saying there’s no future for this data, but there are a lot of landmines. If you’re mining data for the right reasons—to develop programs to find and treat populations—then maybe, down the road, profiting from that data could be a byproduct. But to think of developing and selling big data primarily as an ancillary service is perverse.”

The ethics of data sharing and the murkiness of HIPAA requirements could be off-putting to physicians, Mr. Strug acknowledged. “Folks are squeamish about it.”

—Monica J. Smith

Hemorrhoids: Something For the Bottom Line

G

astroenterologists have been

GLENN LITTENBERG, MD

performing procedural therapy

Coding Advisor American Society for Gastrointestinal tinal Endoscopy Chair of ASGE Reimbursement Committee.

Chief Medical Officer inSite Digestive Health Care Managing Partner Gastroenterology Associates Branch inSite Digestive Health Care Pasadena, Calif.

for hemorrhoids for many years.

Recently available banding techniques via anoscopy have become a staple of the treatment repertoire. However, some confusion persists regarding how non-

surgeon gastroenterologists can bill for the different types of hemorrhoidal therapies they are likely to perform. In thiss column, I will review the Current Procedural Terminology (CPT) codes for these procedures.

Endoscopic Treatment Flexible sigmoid (45350) (sigmoidoscopy, flexible, with band ligation(s) [eg, hemorrhoids]) and colonoscopy with banding (45398) use banding techniques that are essentially identical to those used to treat esophageal varices, but these procedures are performed in retroflex view within the rectum. If other diagnostic or therapeutic modalities are performed during the same procedure, the other procedures (biopsy, polypectomy) can be reported with separate CPT codes using the 59 modifier to indicate that a separate technique was employed or a different site or lesion was treated.

Typically, the extra reimbursement reflects the difference between the therapeutic code and the base 45330 or 45378 code, with usual full reimbursement for the CPT code of hemorrhoid management. This has a zero-day global

period. Control of bleeding cannot be reported separately from these codes; however, if control of bleeding is the primary procedure and it happens to be performed by banding, report 45382 (control of bleeding). The total facility relative value unit (RVU) for 45398 is 7.22, compared with, for example, 7.88 for 45385 (colonoscopy with polypectomy).

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Non-Endoscopic Treatment Most commonly, we perform 46221 (hemorrhoidectomy, internal) by rubber band ligation. This procedure is not reported with 46600 for anoscopy since anoscopy is included, nor is it reported with an endoscopy code for banding—although potentially a screening colonoscopy might be performed the same day as 46221. The non-facility RVU is 8.66, and it is generally a separate office procedure with a 10-day global period.

Private payors often want some justification for doing more than one such procedure a few weeks after the initial treatment. Persistent symptoms or findings should be documented in the chart to support more than a follow-up anoscopy. Unless an initial evaluation and management (E/M) visit occurs during which a decision is made to perform rubber band ligation the same day—typically during the performance of 46221—a separate E/M visit is not reported for incidental assessment of interim symptoms, incidental exam, and follow-up instructions.

Much less commonly, gastroenterologists are trained to ligate without rubber bands, for which 2 codes

(46945 for single hemorrhoid column/group and 46946 for 2 or more hemorrhoid columns/groups) may be reported. The non-facility RVU is 7.21 for the simpler procedure. Incision of a thrombosed external hemorrhoid is reported with 46083, which generally involves a separate procedure unless a surgeon performs some type of excision the same day.

A variety of codes (46250-46262, 46320) exist for excision, which gastroenterologists seldom do. New for 2020, 46948 (hemorrhoidectomy, internal, by transanal hemorrhoidal dearterialization, two or more hemorrhoid columns/groups, including ultrasound guidance, with mucopexy, when performed) can be used as a category 3 code.

Hemorrhoids can be injected—code 46500, and sometimes thermal energy is applied with an infrared or radiofrequency device (46930). The non-facility RVU total is 676, which has a 90-day global period.

Cryosurgery is reported with unlisted code 45999.

Note: The stated RVUs are for Medicare coverage in the Los Angeles area, with most regions being 5% to 10% less.

From the Inbox

Q:

Is there a CPT code for performing an endoscopic pancreatic necrosectomy?

There is no CPT code for endoscopic necrosectomy. Code 43240 covers drainage of pancreatic pseudocysts under endoscopic ultrasound guidance. The establishment of a tract with a stent and then subsequent (usually repeated) necrosectomy would be reported with unlisted pancreas service code 48999. Submitting a detailed report with clear description of work, time involved, and likely submitting literature describing the procedure and a cover letter suggesting 1 or 2 CPT codes with work RVUs that you think are comparable would be helpful. In the cover letter, I’d suggest you indicate this should be paid as a zero-day service, meaning it isn’t global to include subsequent visits or other services. There might not be any comparable endoscopic CPT code, given the long duration of some of these services. The American Society for Gastrointestinal Endoscopy has materials about unlisted service billing that might be useful.

Q:

I’ve been fighting with Blue Cross of Mississippi to get coverage in full for precolonoscopy consultations. Where can I find the rule or regulation that directs commercial insurers to cover this service in full?

The US Department of Labor issued regulations in 2015. They state:

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The plan or issuer may not impose cost sharing with respect to a required consultation prior to the screening procedure if the attending provider determines that the pre-procedure consultation would be medically appropriate for the individual, because the preprocedure consultation is an integral part of the colonoscopy. As with any invasive procedure, the consultation before the colonoscopy can be essential in order for the consumer to obtain the full benefit of the colonoscopy safely. The medical provider examines the patient to determine if the patient is healthy enough for the procedure and explains the process to the patient, including the required preparation for the procedure, all of which are necessary to protect the health of the patient.

• Because the Department’s prior guidance may reasonably have been interpreted in good faith as not requiring coverage without cost sharing of consultation prior to a colonoscopy screening procedure, the Department will apply this clarifying guidance for plan years (or in the individual market, policy years) beginning on or after the date that is 60 days after publication. Effective Date: 12-27-2015 • On July 1, 2016, HCPCS code S0285 was established. This code was approved by Aetna, Anthem, Cigna, Humana, United Healthcare and some other major payors. Some Blue Cross Blue Shield plans also cover this code. The only approved diagnosis codes are Z12.11, Z80.0, and Z83.71.

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