Page 20 – Practical Gastro

FRONTIERS IN ENDOSCOPY, SERIES #79

Updates to Colorectal Cancer Screening Recommendations and Future Implications

March 2022 • Volume XLVI, Issue 3

Colorectal cancer (CRC) remains the second leading cause of cancer death in the United States, although there have been significant improvements in CRC incidence and mortality over time. Despite robust efforts in CRC screening, roughly one-third of eligible adults are not up to date with CRC screening. Trends in CRC incidence and mortality show an alarming increase in individuals below the age of 50, prompting the U.S. Preventive Services Task Force to update their 2016 recommendations on CRC screening. This update now recommends initiation of CRC screening at age 45 years instead of age 50 years for all average-risk adults. This review addresses the rationale for this update, highlights the recommended modalities for screening, discusses the role of programmatic screening, and posits the implications of this update to the gastroenterology community.

INTRODUCTION

Colorectal cancer (CRC) is the third most recommendations for screening and methods commonly diagnosed cancer and the second to increase adherence.^2,3 The U.S. Preventive leading cause of cancer death in the U.S. It Services Task Force (USPSTF), along with several is estimated that almost 147,950 individuals were professional societies, publish recommendations for colorectal cancer screening, which were most recently updated in May 2021. The most remarkable update from the USPSTF 2016 recommendations is the endorsement of initiating colorectal cancer screening for average risk individuals beginning at age 45 years.⁴ This recommendation is in response to the body of evidence that rates of colorectal cancer are increasing among individuals younger than 50 years. While other societies had also previously recommended initiation of CRC screening at age 45, the USPSTF recommendations specifically inform insurance coverage and waiver of cost sharing for preventive services. This recommendation may improve CRC outcomes in younger adults, but may also impact access to care or further widen racial or ethnic disparities in screening and outcomes.

Incidence and Risk Factors

CRC affects approximately 4.4% of men and 4.1% of women in their lifetime.1 Age is in most cases the most important risk factor for CRC. The incidence rate roughly doubles for each five-year age group up until the age of 50 years, at which point it increases by about 30% for each subsequent 5-year period.⁵ The median age for diagnosis of CRC has been steadily declining, currently at 66 years, down from 72 years in the early 2000s, and nearly one-third of rectal cancers are diagnosed in those younger than 55 years. This downward shift in age is likely multifactorial, with CRC incidence decreasing in older age groups due to increased uptake of screening, and increasing incidence in younger adults.^5,6 Overall, rates of CRC incidence have been slowly increasing in females while rates are declining in males. However, death rates from CRC have been substantially declining, with a large decline from 2000 to the present, correlating with increased uptake of colonoscopy (Figure 1).

Importantly, there are significant racial disparities in CRC incidence and mortality,

with highest rates among Non-Hispanic Blacks, followed by American Indians and Alaska Natives. In these ethnic groups, CRC incidence rates and death rates are 20% and 40 % respectively higher than those in Non-Hispanic Whites.⁷ These disparities are multifactorial, but in large part reflect socioeconomic status in the form of prevalence of risk factors and access to health care.8-10 Figure 2.
Modifiable risk factors for CRC include lifestyle and behavioral factors such as heavy alcohol intake, smoking, obesity, and a diet rich in red and processed meat. Nonmodifiable factors that increase risk include hereditary factors, a personal or family history of adenomas or CRC, and a personal history of inflammatory bowel disease.

Rates of CRC Incidence and Mortality Over Time

CRC incidence rates have been declining gradually since the mid-1980s, with an acceleration in the decline starting in the early 2000s, due to a positive change in modifiable risk factors and the widespread adoption of colonoscopy for screening. However, since the mid-1990s, incidence of CRC in younger adults (those aged less than 50 years) has been increasing, accounting for 11% of colon cancers and 15% of rectal cancers in 2020 compared to 5% and 9%, respectively, in 2010.^1,11 These alarming trends provide the foundation for the change in recommendations for CRC screening.

New Screening Recommendations

The USPSTF relies on a panel of experts to provide evidence-based recommendations on a variety of clinical preventive services including preventive care, counseling, and screening. In May 2021, the USPSTF updated their 2016 guidelines for CRC screening, in part due to the growing body of data demonstrating increasing rates of CRC in younger adults. The USPSTF recommends screening for colorectal cancer in all adults aged 50 to 75 years, with a grade A strength of recommendation, indicating substantial net benefit. The USPSTF recommends screening for CRC in adults aged 45 to 49 years, with a grade B recommendation, indicating moderate net benefit. Additionally, the USPSTF recommends that clinicians offer CRC screening in adults aged 76 to 85 years, after consideration of the patient’s overall health, screening history, and preferences, with a grade C recommendation, indicating a small net benefit.⁴

The key update to the 2021 recommendation was to begin average risk CRC screening at age 45 years rather than at age 50 years. This recommendation was not based on clinical trials that would be expensive and taken years to perform, but rather microsimulation modeling studies that estimated the benefits of CRC screening beginning at age 45. These simulation studies used known cancer incidence and mortality data to provide updated model-based estimates of the benefits, burden, and harms of CRC screening strategies and to identify those that may provide an efficient balance of lifeyears gained (LYG) versus colonoscopy burden.¹² Six widely accepted methods for CRC screening were used in the model: fecal immunochemistry testing (FIT), multitarget stool DNA testing, flexible sigmoidoscopy with or without FIT, CT colonography, or colonoscopy.

Two important assumptions were made in these models:

all persons with an abnormal result on a non-colonoscopy screening test would subsequently undergo colonoscopy and
full adherence with all procedures.

The modeling analysis demonstrated 49 strategies that were considered efficient options, and 41 of those strategies indicated screening starting at age 45 years. Lowering the age to commence screening at age 45 versus 50 was estimated to result in 5 additional LYG (22 vs. 27 LYG), 623 additional colonoscopies (161 vs. 784), and a minimal increase in complications.¹² Keeping in mind that these models assumed 100% adherence, in real life the authors estimated that the true LYG would be diminished by between 4% and 25%. The long-term outcomes from the models may also help inform patients and clinicians to determine the best strategy for that particular patient, balancing LYG for risks and hassle of undergoing colonoscopy compared to more modest LYG with stool-based tests and colonoscopy minimization.

Recommended Colorectal
Cancer Screening Strategies

Although CRC screening by colonoscopy is by far the most common method for CRC screening in the U.S., randomized controlled trials have only shown a mortality benefit with the use of fecal occult blood testing (FOBT) followed by colonoscopy if FOBT is abnormal and flexible sigmoidoscopy with subsequent colonoscopy if polyps are detected.¹³ The effectiveness of colonoscopy in reducing mortality from both right and left-sided colon cancers has been demonstrated in observational studies.^14,15 The USPSTF recommends seven different methods for CRC screening: 1) High-sensitivity gFOBT every year; 2) FIT every year; 3) stool DNA test with FIT (sDNA-FIT) every 1 to 3 years; 4) colonoscopy every 10 years; 5) CT colonography every 5 years; 6) flexible sigmoidoscopy every 5 years; and 7) flexible sigmoidoscopy every 10 years with FIT every year. The stool-based tests are considered two-step tests because any abnormal result requires a follow-up colonoscopy. Of the stool-based tests, annual FIT or annual sDNA-FIT provides a greater LYG than either annual high-sensitivity gFOBT or sDNA-FIT every 3 years. Further, modeling studies demonstrate that annual screening with sDNA-FIT would result in more colonoscopies than annual screening with FIT.^4,16 Overall, colonoscopy every 10 years yielded the greatest LYG and CRC cases averted compared to the other methods, whether screening begins at age 50 years or at age 45 years, but this benefit was followed closely by sDNAFIT annually and flexible sigmoidoscopy every 10 years plus annual FIT.¹²

Given the challenges with CRC screening adherence, the main benefit of endorsing a variety of screening methods is that it allows ordering clinicians and patients to engage in shared decision making about patient-centered approaches to CRC screening while also acknowledging local variation in availability of endoscopy services. While CRC screening among individuals aged 50 years and older increased from 38% in 2000 to 66.8% in 2018, screening rates are still well below the U.S. Department of Health and Human Services Healthy People goal of 74.4%, and far short of prior goals set by the American Cancer Society of 80% by 2020.¹⁰ Each of the included screening tests comes with advantages and disadvantages. Some of the main issues regarding colonoscopy include access to facilities and physicians that perform colonoscopy in an appropriate time frame, the need for fasting and bowel preparation, potentially time off work plus a responsible person to provide transportation, need for sedation or anesthesia, risks associated with an invasive procedure, and up until recently, added costs associated with polypectomy. The main advantage of colonoscopy is the ability to remove any polyps at the time of the procedure, and determination of an appropriate surveillance interval based on the number, size, and pathology of those polyps. Conversely, stoolbased or two-step tests may often be performed in the privacy of one’s home, require no bowel prep, are non-invasive, but typically require annual adherence. Further, those with an abnormal stoolbased test then require a colonoscopy to complete the screening occurrence. Currently, that followup colonoscopy may be associated with significant out-of-pocket expenses.

Population-Based
Approaches to CRC Screening

In order to achieve the CRC mortality benefit suggested by the USPSTF modelling studies, population-based approaches to CRC screening that are not dependent on an individual’s insurance status or access to primary care are needed. CRC screening in the U.S. is largely an opportunistic process, with patients typically offered CRC screening in the context of a primary care office visit. Given that 25% of U.S. adults did not have an identified source of primary care in 2015, our current approach to CRC screening is unlikely to get us to desired screening targets.¹⁷ Studies have shown that patients who are older, more educated, earn more money, see a health care provider regularly, and have health insurance are more likely to be up to date with CRC screening.¹⁰ Additionally, certain racial and ethnic groups are disproportionately affected by this approach.¹⁰ The inclusion of stool-based tests in the paradigm for CRC screening allows for the implementation of population-based screening programs that provide the ability to systematically offer screening to all eligible members of population with standardized counseling, access, support, and monitoring. Levin and colleagues implemented an organized CRC screening program for Kaiser Permanente Northern California health plan beneficiaries using FIT and colonoscopy for eligible individuals aged 50 – 75 years and followed them for 15 years. Up-to-date status of screening more-than doubled from 38.9% in 2000 to 82.7% in 2015, and was associated with a 25.5% reduction in annual CRC incidence and a 52.4% reduction in cancer mortality.¹⁸ Other countries that have initiated programmatic screening have also shown reductions in CRC incidence and mortality.^19,20

Anticipated Impact of 2021 USPSTF
Recommendations on Screening and
Access to Colonoscopy and Unintended Consequences

Although the USPSTF recommends several accepted approaches to CRC screening, colonoscopy is by far the most commonly employed method. Expanding CRC screening to begin at age 45 could lead to significantly increased demand for colonoscopies, with an additional 20 million Americans now eligible for CRC screening. Continued dependence on colonoscopy as the primary tool for screening will further strain our currently limited endoscopy resources, especially in rural and other areas where endoscopy services are scarce. Further work is needed to better understand whether screening with colonoscopy should be reserved for older patients who will have higher likelihood of polyps and CRC, and if other screening modalities, such as stool-based screening, should be encouraged in younger individuals. An unfortunate unintended consequence of the USPSTF update would be if colonoscopy resources are diverted to younger patients, resulting in decreased screening and CRC detection in older, higher risk individuals where CRC screening has been shown to have the greatest impact on LYG, CRC incidence, and CRC mortality. Endoscopists should plan how to be best positioned for these changes. This could mean increasing endoscopy capacity and access, and/or be prepared for more therapeutic procedures that will be required following positive stool- or imaging-based screening tests. As larger polyps are found on colonoscopies that follow stoolbased tests, the skills and therapeutic capabilities of endoscopists and their facilities will also need to expand. Our professional societies can play an important role in providing this education for endoscopists in practice, while our trainees in gastroenterology will benefit from this exposure during their standard fellowship.

The Patient Protection and Affordable Care Act (ACA) required most health plans to cover evidence-based preventive services that have been recommended by the USPSTF, including CRC screening. This important legislation has made CRC screening more affordable to many more people; however, health plans stop short by only covering the first screening test itself. If a positive stool-based test leads to a recommendation for a colonoscopy, that colonoscopy is considered diagnostic and subject to out-of-pocket costs that typically range from $99-$231.²¹ Patients who may have otherwise opted for a stool-based screening strategy may choose screening colonoscopy instead to avoid unpredictable cost sharing that may be associated with follow-up diagnostic testing. Even worse, we expect individuals in resource poor locations will forgo CRC screening altogether, further worsening health disparities. Unless followup colonoscopies are considered to be part of the screening process that is covered without cost sharing, cost will continue to be a barrier to patient acceptance of non-colonoscopy screening methods.

In addition, we support population-based approaches to CRC screening that do not rely on an individual’s insurance status, access to primary care, or geographic region. While programs instituted within individual primary care practices, health systems, and health plans will certainly help, population-based approaches that engage individuals both in and out of the traditional health care system are needed. Without populationbased approaches, recommendations to begin CRC screening at age 45 will threaten to worsen health care disparities as those well-positioned to access screening colonoscopies at age 45 will limit availability of screening in patients historically disadvantaged, including older patients. In summary, we agree that the evidence supports the USPSTF recommendations to commence CRC screening at age 45. However, due to already limited endoscopy resources, the updated recommendations may not result in the intended benefit of decreasing CRC mortality if not associated with other interventions. In geographic areas that cannot support the anticipated demand for colonoscopies, we support studying whether starting with non-colonoscopy-based screening strategies in younger individuals may be preferred. We also advocate for policy changes to recommend follow-up colonoscopies following positive screening tests be covered as part of CRC screening. Finally, institution of population-based CRC screening approaches are needed to ensure that we do not further widen access between individuals already engaged in healthcare and those that are not, which would lead to unintended consequences of worsening health disparities in CRC mortality.

References

^{Siegel RL, Miller KD, Goding Sauer A, et al. Colorectal cancer statistics, 2020. CA Cancer J Clin. 05 2020;70(3):145-164. doi:10.3322/caac.21601}
^{Whitlock EP, Lin JS, Liles E, Beil TL, Fu R. Screening for colorectal cancer: a targeted, updated systematic review for the U.S. Preventive Services Task Force. Ann Intern Med. Nov 04 2008;149(9):638-58. doi:10.7326/0003-4819-149-9-200811040-00245}
^{Lin JS, Perdue LA, Henrikson NB, Bean SI, Blasi PR. Screening for Colorectal Cancer: An Evidence Update for the U.S. Preventive Services Task Force. 2021.}
^{Davidson KW, Barry MJ, Mangione CM, et al. Screening for Colorectal Cancer: US Preventive Services Task Force Recommendation Statement. JAMA. 05 18 2021;325(19):1965-1977. doi:10.1001/jama.2021.6238 5. Society AC. Colorectal Cancer Facts & Figures 20202022. Atlanta: American Cancer Society; 2020.}

^{Siegel RL, Fedewa SA, Anderson WF, et al. Colorectal
Cancer Incidence Patterns in the United States, 19742013. J Natl Cancer Inst. 08 01 2017;109(8)doi:10.1093/ jnci/djw322}
^{Sherman R, Firth R, De P, et al. Cancer in North America: 2012-2016. Volume One: Combined Cancer Incidence for the United States, Canada and North America. North American Association of Central Cancer Registries, Inc.; 2019.}
^{Fedewa SA, Flanders WD, Ward KC, et al. Racial and Ethnic Disparities in Interval Colorectal Cancer Incidence: A Population-Based Cohort Study. Ann Intern
Med. Jun 20 2017;166(12):857-866. doi:10.7326/M16-
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^{Doubeni CA, Laiyemo AO, Major JM, et al.
Socioeconomic status and the risk of colorectal cancer: an analysis of more than a half million adults in the National Institutes of Health-AARP Diet and Health Study. Cancer. Jul 15 2012;118(14):3636-44. doi:10.1002/cncr.26677}
^{Joseph DA, King JB, Dowling NF, Thomas CC,
Richardson LC. Vital Signs: Colorectal Cancer Screening Test Use – United States, 2018. MMWR Morb Mortal Wkly Rep. Mar 13 2020;69(10):253-259. doi:10.15585/ mmwr.mm6910a1}
^{Bailey CE, Hu CY, You YN, et al. Increasing disparities in the age-related incidences of colon and rectal cancers in the United States, 1975-2010. JAMA Surg. Jan 2015;150(1):17-22. doi:10.1001/jamasurg.2014.1756}
^{Knudsen AB, Rutter CM, Peterse EFP, et al. Colorectal Cancer Screening: An Updated Modeling Study for the US Preventive Services Task Force. JAMA. 05 18 2021;325(19):1998-2011. doi:10.1001/jama.2021.5746}
^{Jodal HC, Helsingen LM, Anderson JC, Lytvyn L, Vandvik PO, Emilsson L. Colorectal cancer screening with faecal testing, sigmoidoscopy or colonoscopy: a systematic review and network meta-analysis. BMJ Open. 10 02 2019;9(10):e032773. doi:10.1136/bmjopen-2019-032773}
^{Doubeni CA, Corley DA, Quinn VP, et al. Effectiveness of screening colonoscopy in reducing the risk of death from right and left colon cancer: a large community based study. Gut. 02 2018;67(2):291-298. doi:10.1136/ gutjnl-2016-312712}
^{Wang K, Ma W, Wu K, et al. Long-Term Colorectal Cancer Incidence and Mortality After Colonoscopy Screening According to Individuals’ Risk Profiles. J Natl Cancer Inst. Sep 04 2021;113(9):1177-1185. doi:10.1093/jnci/djab041}
^{Knudsen AB, Rutter CM, Peterse EFP, et al. Colorectal Cancer Screening: An Updated Decision Analysis for the U.S. Preventive Services Task Force. 2021.}
^{Levine DM, Linder JA, Landon BE. Characteristics of Americans With Primary Care and Changes Over Time,
2002-2015. JAMA Intern Med. 03 01 2020;180(3):463-doi:10.1001/jamainternmed.2019.6282}
^{Levin TR, Corley DA, Jensen CD, et al. Effects of Organized Colorectal Cancer Screening on Cancer Incidence and Mortality in a Large Community-Based
Population. Gastroenterology. 11 2018;155(5):1383-
1391.e5. doi:10.1053/j.gastro.2018.07.017}
^{Zorzi M, Fedeli U, Schievano E, et al. Impact on colorectal cancer mortality of screening programmes based on the faecal immunochemical test. Gut. May
2015;64(5):784-90. doi:10.1136/gutjnl-2014-307508}
^{Siegel RL, Torre LA, Soerjomataram I, et al. Global patterns and trends in colorectal cancer incidence in young adults. Gut. 12 2019;68(12):2179-2185. doi:10.1136/ gutjnl-2019-319511}
^{Fendrick AM, Princic N, Miller-Wilson LA, Wilson K, Limburg P. Out-of-Pocket Costs for Colonoscopy After Noninvasive Colorectal Cancer Screening Among US Adults With Commercial and Medicare Insurance. JAMA Netw Open. 12 01 2021;4(12):e2136798. doi:10.1001/ jamanetworkopen.2021.36798}

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FROM THE PEDIATRIC LITERATURE

Pediatric Patients Who Have Celiac Disease and Inflammatory Bowel Disease

March 2022 • Volume XLVI, Issue 3

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Celiac disease (CD) can occur concomitantly in patients with inflammatory bowel disease (IBD); however, there is limited data regarding both of these diseases occurring in children. The authors of this study performed a multi-center, retrospective, observational study to evaluate such patients using data from the IBD Registry of the Italian Society of Pediatric Gastroenterology, Hepatology and Nutrition (SIGENP). All patients were 17 years of age or younger, and IBD was diagnosed using the Porto criteria while CD was diagnosed using standard antibody tests for CD in addition to findings of villous atrophy on duodenal biopsy per the guidelines of the European Society of Pediatric Gastroenterology Hepatology and Nutrition (ESPGHAN). Patients with IBD and CD were compared to a control group of 98 patients with the sole diagnosis of IBD.

Patients with both IBD and CD comprised 49 patients from an eligible pool of 2,800 patients. Crohn disease was present in 26 patients (53.1%) while ulcerative colitis was present in 23 patients (46.9%). Females made up 53.1% of the study subjects. CD was diagnosed before IBD in 75.5% of patients (median interval 4.2 years). The median age at diagnosis for CD was 7.5 years while the median age at diagnosis for IBD was 11.5 years. When compared to patients with IBD alone, patients with CD and IBD were statistically more likely to have other associated autoimmune disease mainly consisting of thyroiditis (OR, 2.81; 95% CI, 0.97–8.37; P = 0.04). No difference was present between patients with IBD and CD versus IBD alone regarding immune suppression treatment regimens, surgery, or hospitalizations. Ileocolonic disease was less common in patients with CD and Crohn disease compared to control patients solely with Crohn disease. The risk of colectomy was significantly higher in patients with CD and ulcerative colitis compared to patients with ulcerative colitis alone (P=0.03). Growth delay was present at time of diagnosis in 7 patients (14.3%) with CD and IBD compared to 16 patients just with IBD (16.3%) (OR, 0.72; 95% CI, 0.26–1.98; P = 0.53). There was no statistical difference in reaching pubertal age between patients with CD and IBD compared to patients with IBD alone; however, patients with CD and IBD were significantly more likely to have pubertal delay (3.2%; OR, 5.24; 95% CI, 1.13–33.0; P = 0.02). Univariate analysis determined that growth delay and a younger age at IBD diagnosis were associated with pubertal delay. CD associated with IBD, intestinal surgery, and a higher number of hospitalizations also were associated with pubertal delay. Although pubertal delay was present, final heights of both male and female patients were similar between patients in the two groups

This study describes a unique phenotype in pediatric patients with CD and IBD and understanding the risk factors for development of other autoimmune disease as well as growth delay / pubertal delay is important, especially when explaining health outcomes to such patients and their families.

^{Bramuzzo M, Lionetti P, Miele E, Romano C, Arrigo S, Cardile S, Di Nardo G, Illiceto M, Pastore M, Felici E, Fuoti M, Banzato C, Citrano M, Congia M, Norsa L, Pozzi E, Zuin G, Agrusti A, Bianconi M, Grieco C, Guidici F, Aloi M, Alvisi P, on the behalf of the SIGENP IBD Group. Phenotype and Natural History of Children with Coexistent Inflammatory Bowel Disease and Celiac Disease. Inflammatory Bowel Diseases 2021; 27: 1881-1888.}

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FROM THE LITERATURE

A Marker for Assessment of Prospective Risk in Barrett’s Esophagus

April 2022 • Volume XLVI, Issue 4

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To identify the small group with Barrett’s esophagus (BE) who will progress to advanced disease from the many who will not, assessment of p53 status has promise as a predictive biomarker, but analytic limitations and lack of validation has precluded its use. To develop a robust criteria for grading abnormal immunochemical (IHC) expression of p53 and to test its utility as a biomarker for progression in BE, the following was carried out.

Criteria for abnormal IHC of p53 were developed in BE biopsies and validated with sequencing to assess TP53 mutations. The utility of p53 IHC as a biomarker for progression of BE was tested retrospectively in 561 patients with BE, with or without known progression. The findings were prospectively validated in a clinical practice setting in 1487 patients with BE.

Abnormal p53 IHC highly correlated with TP53 mutation status (90.6% agreement), and was strongly associated with neoplastic progression in retrospective cohort, regardless of histologic diagnosis.

In a retrospective cohort, abnormal p53 was associated with a hazard ratio of 5.03 and hazard ratio of 5.27 for patients with exclusively nondysplastic disease before progression.

In a prospective validation cohort, p53 IHC predicted progression among nondysplastic BE, indefinite for dysplasia and low-grade dysplasia.

It was concluded that p53 IHC identifies patients with BE at higher risk of progression, including in patients without evidence of dysplasia. P53 IHC is inexpensive, easily integrated into routine practice, and should be considered in biopsy of all BE patients without high-grade dysplasia or cancer.

^{Redston, M., Noffsinger, A., Kim, A., et al. “Abnormal TP53 Predicts Risk of Progression in Patients with Barrett’s Esophagus Regardless of a Diagnosis of Dysplasia.” Gastroenterology 2022; Vol. 162, pp. 468-481, February 2022.}

^{Murray H. Cohen, DO, “From} ^{the Literature” Editor, is on the Editorial Board of Practical Gastroenterology.}

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FROM THE LITERATURE

Surgery vs. Chemoradiotherapy in Esophageal Squamous Cell Carcinoma

April 2022 • Volume XLVI, Issue 4

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A trial was carried out to investigate the noninferiority of CRT (chemoradiotherapy) relative to surgery for T1bN0M0 (ESCC) esophageal squamous cell carcinoma. The primary endpoint was overall survival, which was determined using inverse probability weighting with propensity scoring. Surgery consisted of an esophagectomy with 2- or 3-field lymph node dissection. CRT consisted of 2 courses of 5-FU on days 1-4 and cisplatin on day 1, every 4 weeks, with concurrent radiation.

From December 20, 2006 to February 5, 2013, a total of 368 patients were enrolled in a nonrandomized portion of the study. The patient characteristics in surgery arm and CRT arm, respectively, were as follows: Median age 62 and 65 years; proportion of males 82.8% and 88.1%; proportion of performance status 0, 99.5% and 98.1%. Comparisons were made using nonrandomized groups.

The 5-year overall survival rate was 86.5% in the surgery arm and 85.5% in the CRT arm. The complete response rate in the CRT arm was 87.3%. The 5-year progression-free survival was 81.7% in the surgery arm and 71.6% in the CRT arm. Treatment-related deaths occurred in 2 patients in the surgery arm and none in the CRT arm.

It was concluded that CRT is noninferior to surgery and should be considered for the treatment of T1bN0M0 (ESCC).

^{Kato, K., Ito, Y., Nozaki, I., et al for the Japan Esophageal Oncology Group of the Japan Clinical Oncology Group. “ParallelGroup Control Trial of Surgery Versus Chemoradiotherapy in Patients with Stage 1 Esophageal Squamous Cell Carcinoma.” Gastroenterology 2021; Vol. 161, pp 1878-1886}.

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FROM THE LITERATURE

Evaluation of Pancreatic Neoplasm in Intraductal Location

April 2022 • Volume XLVI, Issue 4

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The International Consensus Guidelines that were updated in 2017 recommended surgery to all main duct intraductal papillary mucinous neoplasms (MD-IPMNs), with the main pancreatic duct (MPD) of 10 mm of more and those with mural nodules, regardless of size. To identify predictors of malignancy in MD-IPMN among preoperative factors, including MPD and mural nodule size, 26 benign MD-IPMNs (7 resected and 19 nonresected), and 32 malignant MD-IPMNs (31 resected and 1 nonresected), were included in this study.

MRCP, CT, EUS and cytology were performed using pancreatic juice collected by ERCP. Resected IPMNs were classified as benign or malignant by histologic examination and nonresected MDIPMNs by imaging, cytology, and observation. Cutoff values of candidate parameters were determined by receiver operating characteristic curves. Univariate and multivariate analyses by regression model were performed.

MPD and mural nodule size, as well as cytology results differed significantly between benign and malignant groups. Cutoff values of MPD and mural nodule sizes were 15 mm and 10

mm with areas under the curve of 0.66 and 0.86, respectively. Mural nodules of 10 mm or more (OR 8.32), and positive cytology (OR 42.5), were shown to be independent predictors of malignancy on multivariate analysis. When MD-IPMNs with either predictor were diagnosed to be malignant, sensitivities, specificities and overall accuracy for malignancy were 94%, 85%, and 90%, respectively. It was concluded that mural nodules of 10 mm or more and positive cytology were independent predictors of malignancy in MD-IPMN.

^{“Predictors of Malignancy in Main Duct Intraductal Papillary Mucinous Neoplasm of the Pancreas.” Uehara, H., Abe, Y., Kai, Y., et al. Gastroenterology 2022; 95:291-296.}

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FRONTIERS IN ENDOSCOPY, SERIES #78

Endo-Mucosal Full-Thickness Resection

January 2022 • Volume XLVI, Issue 1

Douglas G. Adler

BACKGROUND

Polypectomy, endoscopic mucosal resection, and endoscopic submucosal dissection are endoscopic procedures performed to remove superficial tumors involving the mucosa and submucosa of the gastrointestinal system (GI).¹ The efficacy and safety of these techniques are hampered in the presence of non-lifting epithelial lesions due to severe fibrosis and scarring, subepithelial lesions (SELs) emerging from muscularis propria (MP), and complex lesions that are difficult to approach endoscopically or at high risk for complications such as bleeding and/or perforation.²

Endoscopic full-thickness resection (EFTR) has emerged as an endoscopic resection technique for removing deep submucosal tumors (SMTs) in the GI wall.³

Suzuki and Ikeda were the first to describe EFTR in 2001.⁴ There are three EFTR techniques: clip-assisted EFTR, standard (direct) resection of the lesion followed by defect closure (“exposed” EFTR), and lesion resection by submucosal tunneling (non-exposed EFTR).² In this manuscript, we will discuss the technical characteristics, indications, safety, and outcomes of EFTR.

Full-Thickness Resection Device

The FTRD (Full-thickness resection device) system consists of a plastic cap (13 x 23mm) preloaded with an FTRD clip and a 14-mm poly filament polypectomy snare, as well as accessory equipment including a tissue grasper and a high-frequency marking device or probe (see Figure1). Before endo-mucosal full-thickness resection with FTRD, the marking probe is used. This high-frequency marking probe is used to tag the target lesion before applying the FTRD, enabling detection and complete excision of the target tissue easier (see Figures 2 & 3). In contrast to the majority of endoscopic polypectomy snares, the FTRD system’s snare does not progress through the working channel; instead, the shaft runs along the scope’s exterior side, protected by a plastic sheath, leaving the working channel available for instrumentation.⁵

1. Clip-Assisted EFTR

Standard EFTR approaches entail the excision of a lesion followed by the closure of the defect with mechanical clips or endoscopic suturing devices. However, over-the-scope clip (OTSC) assisted EFTR is a newly developed “close then cut” technique for complete excision of epithelial and subepithelial lesions throughout the GI tract. This approach offers a potentially safer alternative that involves stabilizing and affixing the defect prior to resection of the target lesion.

Indications

Non-lifting epithelial lesions (e.g., adenoma) linked with significant fibrosis from earlier resection attempts, as well as SELs, such as neuroendocrine tumors, leiomyomas, some pancreatic rests, and gastrointestinal stromal tumors (GISTs) are potential indications for clip-assisted EFTR.⁶

Technique

After identifying the target lesion, the circumference of each lesion is pre-marked with a high-definition marking probe using the coagulation setting. Following that, the scope is withdrawn, and the FTRD system is attached to it. After re-inserting the scope, the lesion is pulled inside the distal plastic cap using the appropriate grasper with the intention to pull all layers of the stomach or bowel wall. The FTRD clip is then deployed, and the electrocautery snare is engaged with monopolar current and used in a standard manner to excise the clip-captured tissue in full-thickness. The specimen is subsequently removed, leaving the intestinal wall closed by the OTSC.⁵ (see Figures 4 and 5).

Safety and Efficacy

In a recent meta-analysis involving eighteen studies with 730 patients, Brewer Gutierrez et al. reported a pooled overall histological full resection rate (R0) of 82%. Lesions included in this study were difficult/residual colorectal adenomas, adenomas that involved a diverticulum or the appendiceal orifice, early cancers, colorectal SELs, and upper gastrointestinal lesions. Perforation and hemorrhage occurred in 0.1 and 2% of patients, respectively. There were no EFTR-related deaths.⁶

In a prospective multicenter study involving 181 participants, the efficacy and safety of the FTRD system for the removal of colorectal lesions were reported. EFTR was technically successful in 89.5%, with a 76.9% R0 resection rate. The R0 resection rate was 77.7% in 127 individuals with complicated adenomas and benign histology. Unsuspected cancer was found in 14 of the lesions, while 15 of the lesions were primarily known as malignancies. R0 resection was achieved in 72.4% of the cases, while 8 more instances exhibited profound submucosal infiltration >1000 m. As a result, only 13/29 patients were able to have curative resection (44.8%). R0 resection rate was 87.0% in the subgroup with subepithelial tumors (SETs) (n=23). In general, lesions < 2 cm had a greater R0 resection rate than lesions >2 cm (81.2 % vs. 58.1 %, p=0.0038). The rate of adverse events was 10%. Out of 181 patients, 10 experienced procedure-related moderate adverse events, such as hemorrhage, post-polypectomy syndrome which is defined as development of abdominal pain, fever, leukocytosis, and peritoneal inflammation in the absence of frank perforation, appendicitis (which was conservatively handled), and recurrent abdominal pain of unclear origin (5.5 percent ). 8 patients out of total 181 (4.5% ) developed severe adverse events which include perforation, appendicitis required laparoscopic appendectomy and enterocolonic fistula after EFTR.⁷ Benjamin Meier et al. in a multicenter retrospective study including 1,178 colorectal FTRD procedures reported an 80% R0 resection rate for difficult adenomas, early carcinomas, and subepithelial tumors. Full-thickness excision (visible of all layers of the colonic wall, including serosa, within the resection material) was histologically confirmed in 89.9% of the cases in the whole cohort. Compared to the rectum, the colon had a considerably greater rate of full-thickness resection (92.0 % vs. 83.3 %, P=0.0001). Histologically complete resection (R0) was accomplished in 80.0 % of the whole cohort. There was no significant difference in

R0 resection between the colon and the rectum (78.9% vs. 83.6%, P= 0.11) or between the lesions < 20 and > 20 mm (77.6 % vs. 81.0%, P =0.2). Compared to the overall cohort, R0 resection for SETs was considerably higher (97.1% vs. 80.0 %, P=0.0001). In addition, SET was a single significant independent predictor of R0 resection in multivariable analysis (P=0.009).

Procedure-related adverse events were reported in 142 patients (12.1%). Complications that necessitated additional surgical intervention, perforations, and obstructive stenosis are among the major side effects (3.1%). Minor side effects include bleeding, perforation, inflammation and infection and others which include stenosis after FTRD clip, misplacement of FTRD clip, clipping of grasping device (9.0%). Adverse events requiring surgical intervention include perforation, delayed perforation, appendicitis, and delayed bleeding.⁸

2. Standard EFTR (Exposed EFTR)

In contrast to clip-assisted EFTR, the standard EFTR approach is a “cut and then close” procedure that is generally utilized to remove gastric SELs from the MP. However, limited working space, limited mobility for defect closure, and substantial morbidity are associated with adverse events, including mediastinitis and fistula formation. Similarly, the use of traditional EFTR use in the colon is restricted due to an increased risk of perforation and inadequate defect closure.

Indication

Standard EFTR is best suited for gastric SELs < 3 cm arising from the MP. Although EFTR is technically viable for lesions larger than 3 cm, their extraction through the esophagus following en bloc resection can be harrowing, and the resulting esophageal wall defects may be difficult, if not impossible, to seal, increasing the risk of perforation.⁹

Standard EFTR Technique

The procedure begins with lesion marking utilizing high-definition marking probe to place coagulation dots along the lesion’s periphery, followed by peripheral incision and lesion enucleation with breach of MP. Finally, an endoscopic suturing device is used to close the defect.

Safety and Efficacy

In a retrospective analysis, Jian G. et al.’s colleagues included 100 gastric SMTs excised using EFTR. Efficacy of EFTR was measured in terms of rates of en bloc resection and was achieved in 98 cases (98 %). Ten patients (9.9%) experienced adverse events. Two patients developed intraoperative bleeding, one delayed bleeding, and seven patients had peritonitis. EFTR was ceased in one patient due to massive intraoperative bleeding, and conversion to laparoscopic surgery was necessary. One patient required laparoscopic surgery due to delayed bleeding, and other minor complications were resolved with conservative management. Overall tumor size > 3 cm was associated with difficult EFTR, which was defined as a procedure time ≥ 120 minutes and/or the occurrence of major adverse events, such as significant bleeding, abdominal pain, or peritonitis.¹⁰ Antonino G. et al., in their recent systematic review, evaluated 15 studies, mainly from Asia, reported 750 exposed-EFTR treated gastric SMTs. The complete resection and surgical conversion rate was 98.8% and 0.8%, respectively. The rate of major adverse events, including delayed bleeding, perforation, peritonitis, and infection, was 1.6%, 0.5%, 0.1%, and 0.9%, respectively. The rate of successful exposed EFTR and effective endoscopic defect closure was 98.3%.¹¹

Another retrospective study by Ye L.P et al. included a series of 726 patients who underwent resection of 733 upper subepithelial lesions (1-4cm in size) originating from the muscularis propria via exposed EFTR and EFTR through submucosal tunneling. Adverse events including perforation (12.1%), immediate bleeding (1.8%), peritonitis (0.7%) and delayed bleeding (0.1%). Most lesions were leiomyomas (63%) and GISTs (34%) without residual lesions and a mean follow-up of 28 months. The major risk factors for incomplete resection were an extensive connection to the muscularis propria (p=0.007) and extraluminal growth (p=0.04).

Risk factors for perioperative perforation were large tumor size (p=0.04), extensive connection to muscularis propria (p=0.01) and extraluminal growth (p=0.04).¹² Although conventional EFTR has been reported for resection of SELs in the colon, its safety profile limits its widespread usage at the moment, in large part due to the inability to consistently close the resection defect.¹³Submucosal Tunneling Endoscopic Resection

(STER)

STER Technique

STER is a combination of peroral endoscopic myotomy and endoscopic submucosal dissection techniques.¹⁴ In this technique, a submucosal tunnel is constructed to serve as a working area for endoscope insertion and tumor excision. When compared to ESD, this method has a lesser chance of perforation since the integrity of the GI mucosa is preserved; it also provides better wound healing and a lower risk of infection. Furthermore, due to the deeper tumor origin, this technique is better suited for cancers coming from the muscularis propria layer, for which ESD resection is problematic.¹⁵

Indications

STER is appropriate for tumors arising from the MP with an intact overlying mucosa and no highrisk EUS characteristics. STER is usually effective for lesions less than 3.5 cm in diameter.¹⁹ Resection of larger lesions can be associated with technical problems, a lower probability of en bloc resection, and a higher risk of adverse events, including bleeding, mucosal laceration, and perforation.²⁰

Contraindications

STER should not be performed if the mucosa is ulcerated.¹⁵ SMTs with irregular borders are more likely to be malignant and more challenging to resect using STER.¹⁶ There is a significant risk of perforation, persistent fistula development, and secondary infection when removing lesions involving a deep part of the muscularis propria.¹⁶

The Steps Involved in STER

1. Identification of Tumor

The first step of STER involves tumor identification. Injection of indigo carmine or methylene blue may be performed to help locate the tumor and guide the direction of subsequent tunneling.¹⁶

2. Submucosal Injection

A fluid cushion is subsequently generated through a submucosal injection of fluid, usually a saline solution with indigo carmine or methylene blue, 2-5cm from the SMT.¹⁷ Sometimes, epinephrine is added to the solution.

3. Generating Tunnel Entry

To create an entrance to the submucosal tunnel, a mucosectomy is performed, with the orientation of the incision being left to the operator.

4. Tunnel Generation

An electrosurgical knife is used to guide the endoscope through the incision. To further distinguish the submucosal and muscularis layers, a dye such as indigo carmine or methylene blue with or without epinephrine with saline as an injectate is utilized as the scope progresses to prevent damage while expanding the tunnel mucosa. To provide enough working area, the tunnel should be extended approximately 2 cm beyond the distal edge of the SMT.

5. Tumor Dissection and Removal

Various electrosurgical knives may be employed for a partial or full-thickness resection, depending on the degree of attachment of the lesion to the muscularis propria. It is recommended to avoid unnecessary breach of the adventitia or the serosal layer during an en bloc excision.¹⁸ The resected tumor is then extracted using a retraction device such as an endoscopic anchoring device, a rat-tooth forceps, or a retrieval net.

Efficacy and Safety

Chen et al., in a retrospective study, evaluated 180 patients with upper gastrointestinal submucosal tumors undergoing STER and reported a 90.6% en bloc resection rate. The overall complication rate was 8.3%. Pneumothorax and hydrothorax occurred in 10 patients (5.5%), clinically significant bleeding occurred in 2 patients (1.1%), the mucosal injury occurred in 2 patients (1.1%), and an esophagealpleural fistula occurred in 1 patient (0.6%).²¹ Xiu-He Lv et al. published a meta-analysis showing pooled complete resection and en bloc resection rates for SMTs undergoing STER was 95.5% and 94.6%, respectively. The most common complications related to STER were pneumothorax and bowel perforation. The pooled rate of subcutaneous emphysema and pneumomediastinum was 14.8%. The rate for pneumothorax was 6.1% and 6.8% for pneumoperitoneum. Additionally, the pooled rate of perforation was 5.6%. Only a few cases of bleeding were reported in only two studies.²²

Li et al. found a 98.6% en bloc resection rate in their retrospective study of 74 patients who underwent STER for esophageal SMTs lesions. Perforation was reported in only one patient as an intraoperative adverse event. Pneumothorax and pneumoperitoneum were postoperative complications noted in 9 individuals.²³ Mao et al., in their prospective study of 56 patients, reported a 100% rate of en bloc resection. Only 9 patients experienced adverse events, including pneumothorax, pleural effusion, and pneumoperitoneum.²⁴ Chen et al., in their retrospective study of 290 patients with upper gastrointestinal SMTs treated by STER, reported an 89.3% en bloc resection rate. The overall incidence of complications was 23.4% (68/290).10.0 % of procedures (29/290) required intervention for complications. Major bleeding occurred in 5 patients (1.7%). Pleural effusion occurred in 49 patients, including 9 patients who developed pneumothorax.²⁵ Wang et al., in their prospective study of 80 patients undergoing STER, reported a 97.6% en bloc resection rate. Complications included chest pain, subcutaneous emphysema, and pneumothorax in 8.75% (7/80) of cases, and all of them resolved with conservative therapy.²⁶

CONCLUSION

Although EFTR technology is still in development, it is a less invasive technique when compared to surgery for specific neoplastic lesions. The development of reliable closure devices and the adoption of appropriate indications will continue to make EFTR more feasible. In addition, it will help patients minimize their financial, physical, and psychological burdens. Although the published results to date are encouraging, prospective comparative studies are required to determine the long-term effectiveness and safety of EFTR.

References

^{Schmidt, A., B. Meier, and K. Caca, Endoscopic fullthickness resection: Current status. World journal of gastroenterology, 2015. 21(31): p. 9273-9285.}
^{Rajan, E. and LMWK. Song, Endoscopic full thickness resection. Gastroenterology, 2018. 154(7): p. 1925-1937. e2.}
^{Cai, M.Y., F. Martin Carreras-Presas, and P.H. Zhou, Endoscopic full-thickness resection for gastrointestinal submucosal tumors. Digestive Endoscopy, 2018. 30: p. 17-24.}
^{Suzuki, H. and K. Ikeda, Endoscopic mucosal resection and full thickness resection with complete defect closure for early gastrointestinal malignancies. Endoscopy, 2001. 33(05): p. 437-439.}
^{Wedi, E., et al., Full-Thickness Resection Device for Complex Colorectal Lesions in High-Risk Patients as a Last-Resort Endoscopic Treatment: Initial Clinical Experience and Review of the Current Literature. Clinical endoscopy, 2018. 51(1): p. 103-108.}
^{Brewer Gutierrez, O.I., et al., Endoscopic full-thickness resection using a clip non-exposed method for gastrointestinal tract lesions: a meta-analysis. Endoscopy international open, 2020. 8(3): p. E313-E325}
^{Schmidt, A., et al., Colonoscopic full-thickness resection using an over-the-scope device: a prospective multicentre study in various indications. Gut, 2018. 67(7): p. 12801289.}
^{Meier, B., et al., Efficacy and Safety of Endoscopic FullThickness Resection in the Colorectum: Results From the German Colonic FTRD Registry. Am J Gastroenterol, 2020. 115(12): p. 1998-2006.}
^{Lu, J., et al., Endoscopic management of upper gastrointestinal submucosal tumors arising fromuscularis propria. J Clin Gastroenterol, 2014. 48(8): p. 667-73.}
^{Jian, G., et al., Factors that predict the technical difficulty during endoscopic full-thicknessresection of a gastric submucosal tumor. Rev Esp Enferm Dig, 2021. 113(1): p. 35-40.}
^{Antonino, G., et al., Efficacy and safety of gastric exposed endoscopic full-thickness resection without laparoscopic assistance: a systematic review. Endosc Int Open, 2020. 8(9): p. E1173-e1182.}
^{Ye, L.P., et al., Safety of Endoscopic Resection for Upper Gastrointestinal Subepithelial Tumors Originating from the Muscularis Propria Layer: An Analysis of 733 Tumors. Am J Gastroenterol, 2016. 111(6): p. 788-96.}
^{Brigic, A., et al., A systematic review regarding the feasibility and safety of endoscopic full thickness resection (EFTR) for colonic lesions. Surg Endosc, 2013. 27(10): p. 3520-9.}
^{Xu, M.-D., et al., Submucosal tunneling endoscopic resection: a new technique for treating upper GI submucosal tumors originating from the muscularis propria layer (with videos). Gastrointestinal endoscopy, 2012. 75(1): p. 195-199.}
^{Du, C., et al., Submucosal tunneling endoscopic resection: An effective and safe therapy for upper gastrointestinal submucosal tumors originating from the muscularis propria layer. World journal of gastroenterology, 2019. 25(2): p. 245-257.}
^{Yoshizumi, F., et al., Submucosal tunneling using endoscopic submucosal dissection for peritoneal access and closure in natural orifice transluminal endoscopic surgery: a porcine survival study. Endoscopy, 2009. 41(8): p. 707-11.}
^{Wang, H., et al., Submucosal tunneling endoscopic resection for upper gastrointestinal submucosal tumors originating from the muscularis propria layer. European Journal of Gastroenterology & Hepatology, 2015. 27(7): p. 776-780.}
^{Wang, H., et al., Submucosal tunneling endoscopic resection for upper gastrointestinal submucosal tumors originating from the muscularis propria layer. European Journal of Gastroenterology & Hepatology, 2015. 27(7): p. 776-780.}
^{Liu, B.R. and JT Song, Submucosal Tunneling Endoscopic Resection (STER) and Other Novel Applications of Submucosal Tunneling in Humans. Gastrointest Endosc Clin N Am, 2016. 26(2): p. 271-282.}
^{Chen, T., et al., Submucosal Tunneling Endoscopic Resection vs. Thoracoscopic Enucleation for Large Submucosal Tumors in the Esophagus and the Esophagogastric Junction. J Am Coll Surg, 2017. 225(6): p. 806-816.}
^{Chen, T., et al., Long-term Outcomes of Submucosal Tunneling Endoscopic Resection for Upper Gastrointestinal Submucosal Tumors. Annals of Surgery, 2017. 265(2).}
^{Lv, XH, C.H. Wang, and Y. Xie, Efficacy and safety of submucosal tunneling endoscopic resection for upper gastrointestinal submucosal tumors: a systematic review and meta-analysis. Surg Endosc, 2017. 31(1): p. 49-63.}
^{Li, Q.-y., et al., Comparison of endoscopic submucosal tunneling dissection and thoracoscopic enucleation for the treatment of esophageal submucosal tumors. Gastrointestinal Endoscopy, 2017. 86(3): p. 485-491.}
^{Mao, X.-L., et al., Submucosal tunneling endoscopic resection using methylene-blue guidance for cardial subepithelial tumors originating from the muscularis propria layer. Diseases of the Esophagus, 2017. 30(4): p. 1-7.}
^{Chen, T., et al., Management of the complications of submucosal tunneling endoscopic resection for upper gastrointestinal submucosal tumors. Endoscopy, 2016. 48(2): p. 149-55.}
^{Wang, H., et al., Submucosal tunneling endoscopic resection for upper gastrointestinal submucosal tumors}
^{originating from the muscularis propria layer. Eur J Gastroenterol Hepatol, 2015. 27(7): p. 776-80.}

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NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #218

Nutritional Management of Infants with Necrotizing Enterocolitis

January 2022 • Volume XLVI, Issue 1

Patti H. Perks,

Stephen M. Borowitz,

Jonathan R. Swanson

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Necrotizing enterocolitis (NEC) is an inflammatory disorder of the gastrointestinal (GI) tract that primarily occurs in premature infants, contributing to infant morbidity and mortality. Term infants are also at risk of NEC, particularly infants with congenital heart disease (CHD), although the pathophysiology differs from that in preterm infants. Optimal nutritional management, both during and following NEC, is imperative for the developing infant. Options for parenteral and enteral nutrition have expanded, necessitating this update to a previously published article on Nutritional Management of the Infant with Necrotizing Enterocolitis.

INTRODUCTION

Necrotizing enterocolitis (NEC) is an inflammatory disorder of the gastrointestinal (GI) tract that primarily occurs in premature infants. NEC represents the culmination of pathological processes involving dysfunction of the gut epithelium, immune and hemodynamic systems, and intestinal dysbiosis.¹ NEC is a leading cause of morbidity and mortality in the neonatal intensive care unit (NICU) and is associated with an increased risk of neurodevelopmental delay.^2,3

A meta-analysis published in 2020 reported the global incidence of NEC in very low birth weight (VLBW) infants (birth weight < 1500 g) at 7%.⁴ Term infants are also at risk of NEC, particularly infants with congenital heart disease (CHD), yet the pathophysiology differs from that of preterm infants.^2,3,5 Optimal nutritional management during and following NEC is imperative for the developing infant.

The pathophysiology of NEC is multifactorial,⁷ and shares overlapping clinical features with other acquired neonatal intestinal diseases.^8,9 Risk factors predisposing to NEC include maternal and in utero factors as well as infant perinatal and postnatal factors.^2,3,8,10-14 (Table 1)

The incidence of NEC in preterm infants peaks around 31 weeks post-menstrual age (PMA) with 95% of cases occurring by 34 weeks (PMA).^2,15 Preterm infants have decreased immunocompetence coupled with an immature GI tract and dysmotility. Mature peristaltic patterns do not develop until 34-36 weeks’ PMA. Preterm intestinal defense systems against pathogens and toxins are underdeveloped. These systems include digestion, production of gastric acid, a mucin lining, and reduction of intestinal permeability.¹⁶ Nutrient maldigestion and malabsorption coupled with reduced GI contractility may predispose to stasis, small intestinal bacterial overgrowth (SIBO), dysbiosis, and ischemic damage to the premature bowel.¹⁶ Translocation of bacteria across the intestinal barrier precipitates an inflammatory cascade that can result in intestinal necrosis.^2,11 The pathophysiology of NEC in late preterm or term infants is primarily the result of diminished perfusion of the intestinal tract that occurs with hypoxic-ischemic encephalopathy, placental insufficiency, certain forms of congenital heart disease such as hypoplastic left heart syndrome and single ventricle defects, or polycythemia and associated hyperviscosity.

Prevention strategies proposed for both preterm and term infants include early human milk feeding,^2,14 antibiotic stewardship, probiotics,¹¹ avoidance of acid inhibitors, infection prevention, avoidance of anemia, and adherence to feeding protocols.²

Clinical Presentation and Medical and Surgical Management

The clinical presentation of NEC varies from one infant to another. Disease severity is based on clinical markers. Non-surgical NEC includes mild ileus to moderate illness with focal pneumatosis intestinalis and dilated loops with or without portal venous gas. Medical management is indicated in these conditions. Surgery is typically indicated if the clinical condition worsens, which can be marked by:

hemodynamic instability
severe thrombocytopenia
disseminated intravascular coagulopathy (DIC)

peritonitis or pneumoperitoneum.⁷

Although commonly used as a definition, Bell’s criteria were not meant as a means of diagnosing NEC, but rather as a means of grading the severity of the NEC. There have been at least six more recent definitions of NEC, nearly all of which have better sensitivity and specificity than Bell’s criteria alone.^17,18 The severity of the disease process determines which medical and/or surgical interventions are indicated.¹² (Table 2)

NEC can present with abdominal distention, feeding intolerance, emesis, grossly bloody stools, diarrhea, and/or abdominal wall erythema. Differential diagnoses include sepsis-induced ileus, spontaneous intestinal perforation (SIP), meconium peritonitis, Hirschsprung-associated enterocolitis, food protein enterocolitis, malrotation with volvulus, or intestinal obstruction. Similar symptoms may result in misdiagnosis. Accurate diagnosis can impact reintroduction of feeds, particularly if cow’s milk protein or other dietary proteins need to be excluded from the infant’s or mother’s diet. SIP typically occurs within the first 10 days after birth in very preterm VLBW infants and requires surgical intervention. The perforation is usually isolated in the terminal ileum and the remainder of the bowel is healthy. Feeding intolerance is typically demonstrated by increased gastric retention, abdominal distention or fullness, inadequate stooling, and/or increased apnea, all of which can be seen in NEC.⁹

Identification of pneumatosis intestinalis in conjunction with previously mentioned clinical symptoms is diagnostic for NEC, and the diagnosis is supported by thrombocytopenia, neutropenia, DIC, elevated lactic acid levels, and/ or hyperkalemia and hyponatremia. With severe NEC, infants may develop generalized edema due to capillary leak and poor vascular tone, necessitating aggressive fluid resuscitation and inotropic support. Hyponatremia may occur, requiring significant sodium in

parenteral nutrition (PN). Acidosis from tissue injury and necrosis often mandates more acetate in PN. An infant with rapidly worsening NEC is at risk for poor renal perfusion and hyperkalemia; PN potassium delivery should be limited and requires close monitoring. Poor hepatic perfusion or excessive glucose delivery may impair fatty acid oxidation; lipid delivery may need to be temporarily reduced during hypertriglyceridemia²⁴ which in infants may be defined as levels over 200-250 mg/dL. Clinical complications dictate nutritional adjustments. (Table 3)

In the post-acute catabolic phase, PN must then be optimized to provide 100% of estimated nutritional needs to support recovery and minimize lean tissue loss while continuing to promote growth.²⁵ Adequate PN delivery requires central venous access unless fluid volumes greater than 140 mL/kg are provided.²⁴ PN energy needs are generally estimated to be 10%–15% lower than enteral nutrition (EN) needs due to reduced stool losses and due to the absence of the thermic effect of food or the energy required for digestion and absorption. Energy needs of the sedated infant during the acute phase of NEC or post-surgery are lower and the timing of moving from catabolism to anabolism remains unclear.²⁶ PN provision of ~ 75-80 kcal/kg with mean protein delivery of 3.5 gm/kg in the first week after surgery in infants < 32 weeks’ gestational age with NEC has been associated with improved head circumference growth without negative impacts.²⁷ PN energy needs during the subsequent recovery phase need to be increased to support growth.

Enteral Nutrition Management Following NEC

Non-nutritive sucking during bowel rest, if feasible, can promote motility and mesenteric blood flow;²⁴ wiping or swabbing the baby’s mouth (oral care) with colostrum or mom’s milk can provide the benefits of human milk.²⁸ EN should be initiated as soon as clinically feasible following NEC to mitigate the negative impact of lack of GI stimulation and prolonged PN such as sepsis, cholestasis, SIBO, impaired growth, impaired neurocognitive development, and increased length of stay.^24,29 Feeds can be safely started when there is evidence of return of GI function, demonstrated by stable vital signs and resolving thrombocytopenia⁷ reduction (not necessarily cessation) of nasogastric output, an improving abdominal exam, and normalization of abdominal x-rays or ultrasound.^29,30,31 In several retrospective cohort studies, earlier re-initiation of EN (< 5-7 days) as compared to later re-initiation of EN (> 7 days) was associated with a lower risk of recurrent NEC and/or post-NEC strictures.³² Moreover, the risk of central line-associated bloodstream infection (CLABSI) was lower, likely the result of improved intestinal barrier function, and full feeds were reached sooner in the early EN group.³²

Potential benefits of early feeding after GI surgery using human milk include digestibility, the delivery of immunoglobulins, and prebiotics (which may decrease the risk of infection), the delivery of mucin, and growth factors (which may promote intestinal adaptation), motility, and colonization with beneficial GI bacteria.^1,25,29,33 For VLBW infants, early feeding with human milk, both mother’s own milk or pasteurized donor human milk (PDHM) as compared to intact cow’s milk protein formulas may promote intestinal maturation and decrease the risk of intestinal inflammation.¹ Small cohorts of infants recovering from NEC experienced an increase in cytokine response with exposure to cow’s milk beta-lactoglobulin and casein.⁷

Initial EN volume of 10 or 20 mL/kg/d for the infant recovering from medical or less severe surgical NEC is reasonable, and an advance of 20 mL/kg/d has been shown to be tolerated without negative outcomes.^30,31 Feeds should be advanced cautiously and fortified to meet protein and mineral needs. Feeding advances are tailored to the severity of illness and extent of surgical resection, if applicable, while monitoring clinical responses to advancing volumes. Quantification of ostomy output, if applicable, should be used to direct the rate of feeding advances and determine whether bolus versus continuous delivery of feeds is better tolerated. Bolus feeds may better stimulate intestinal adaptation than continuous feedings,⁷ however, continuous feeds allow for slower nutrient delivery which may facilitate improved absorption and feeding tolerance, especially in infants with short bowel syndrome (SBS).⁷ Overnight continuous

feedings with small daytime boluses facilitate PO trials during the day. Continuous delivery via gastric or small bowel access may promote tolerance of goal EN volumes when dysmotility or malabsorption are present,²⁴ allowing the reduction or discontinuation of PN. Concentrating PN as feeds are advanced can optimize the delivery of energy, protein, and micronutrients until feeds can be fortified and advanced sufficiently to eliminate the need for PN.²⁵

If mother’s own milk or PDHM are unavailable or limited, formula choice post-NEC will depend on whether cow’s milk protein intolerance is suspected. Some infants demonstrating cow’s milk protein intolerance do not improve with extensivelyhydrolyzed protein formulas and in such cases, an amino acid-based formula is appropriate. Infants with SBS may benefit from initial feeds with breast milk; if malabsorption with advancing volumes results in poor growth, dehydration, or electrolyte disarray, an extensively-hydrolyzed or amino acid containing formula containing medium chain triglycerides may aid absorption of nutrients, although evidence is limited and more research is needed.^1,7

Human milk fortification or formula choice and concentration are tailored to the infant’s gestational age and energy and protein needs to support recovery and growth. Achieving a conservative protein goal of 2.5 g/kg/d requires enteral intake of over 200 mL/kg/d of unfortified breast milk, rarely feasible for young infants. Fortification is therefore needed. Human milk-based fortifiers provide increased nutrition while preserving many of the beneficial effects of human milk for preterm infants.³⁴ Liquid cow’s milk-based fortifiers contain hydrolyzed protein and can be effectively used

to meet the nutritional needs of preterm infants when human milk-based fortifiers are not available. Fortification of human milk is often needed for term infants recovering from GI disease and the appropriate formula powder and/or modulars can be used to reach the needed calorie goal if human milk-based fortifiers designed for term infants are not available. Modulars are less frequently needed due to improved human milk fortifiers and formulas but may include a human milk-based calorie fortifier, protein modulars, medium chain triglycerides (MCT), or other oils, or a combination dextrose/MCT powder.

Preterm infants generally can absorb intact milk proteins; however, absorption may be impaired if pancreatic secretion is inadequate. Hydrolyzed protein, whether extensively or partially hydrolyzed, may promote protein absorption in the setting of pancreatic insufficiency. In the absence of cow’s milk protein intolerance or allergy, formulas containing intact protein may be well-tolerated if human milk is unavailable. Human milk contains some peptides which may contribute to its digestibility.¹ Extensively hydrolyzed and elemental formulas do not contain lactose which is an important prebiotic. Undigested lactose in the large bowel undergoes fermentation which produces short-chain fatty acids (SCFAs), gas, and contributes to immune function and gut epithelial health.¹ Infants with SBS may produce less lactase initially due to loss of bowel surface area as well as immature bowel mucosa and may have increased abdominal distention related to increased gas production and rapid intestinal transit. This may result in increased stoma output or excoriated perineal areas.¹ This does not mean lactose needs to be eliminated; gradual introduction of lactosecontaining feeds may promote mucosal adaptation and production of the lactase enzyme. However, when concentrating formula, lactose content may be an important factor to consider based on GI symptoms.

Amino acid-based formulas contain glucose polymers instead of lactose and some proportion of MCT instead of long chain triglycerides (LCT). While intended for infants with cow’s milk sensitivity refractory to extensively hydrolyzed protein formulas, these are often used initially for infants recovering from NEC despite a lack of evidence to support this practice.¹ MCTs may be more efficiently absorbed than long chain triglycerides among infants with SBS, however, the optimal amount of MCT and the duration of use remains unclear.¹ LCT are important for production of docosahexaenoic and arachidonic acid, vital for eye and brain development¹ and potentially instrumental in intestinal adaptation after bowel resection.⁷

Complications of NEC

Complications secondary to NEC are varied and can range from strictures occurring weeks after diagnosis, to the most serious complication of short-bowel syndrome due to loss of small intestinal length with or without intact colon. Post-NEC strictures may result in partial or total bowel obstruction; more common symptoms are intermittent or persistent abdominal distension, feeding intolerance, and/or intermittent or recurrent vomiting, and chronic or recurrent diarrhea that is sometimes bloody. Persistent or intermittent SIBO caused by intestinal stasis above the stricture produce some of these same symptoms.¹⁹

Infants who have lost the distal ileum as a result of surgical NEC are at risk of developing vitamin B₁₂ deficiency, fat malabsorption, and bile acid malabsorption which may result in steatorrhea as well as watery diarrhea. Loss of the ileocecal valve also increases the risk for rapid intestinal transit and SIBO.

SIBO may exacerbate malabsorption and diarrhea and can cause vomiting, bloating, and abdominal distension, feeding intolerance, recurrent abdominal pain, weight loss, and occasionally fever.³⁴ Diagnostic tests can be employed to diagnose SIBO, however, they are all poorly reproducible, and hence this largely remains a clinical diagnosis. Treatment is largely empiric, and a wide variety of antibiotics can be used. Recurring SIBO can be associated with chronic intestinal inflammation. Treatment with intermittent or rotating antibiotics may improve feeding tolerance, decrease the incidence of catheter associated infections, and decrease the risk of parenteral nutrition-associated liver disease.³⁶ SBS describes a loss of functional bowel length which can occur following medical NEC and more commonly occurs following surgical NEC.

Key articles and resources can guide clinicians in managing short bowel syndrome. (Table 4)

Micronutrient Supplementation

Vitamin and mineral supplementation is an important component of EN support. If SBS, cholestasis, or fat malabsorption exist, a watermiscible form of the fat-soluble vitamins A, D, E, and K will be required. Additional vitamin D supplementation may be indicated when cholestasis and/or indications of metabolic bone disease are present.³⁷ A serum 25-hydroxy vitamin D level can help determine what level of vitamin D supplementation is needed and for how long. Prematurity and GI fluid losses such as enterostomy output contribute to frequent need for additional zinc above the recommended daily enteral intake of 1.42.5 mg/kg/d.³⁸ Zinc sulfate (10 mg/mL elemental zinc) suspension may be an option. Iron is absorbed in the duodenum and proximal jejunum. Adequate supplemental iron is needed if not provided by the formula or fortifier, or if absorption is impaired due to intestinal resection. Typically, a liquid iron such as Fer-in-sol^R at 2-4 mg/kg/d will meet iron requirements, taking into account enteral sources. Split dosing may promote better absorption.³⁷ Calcium and phosphorous intake through adequate fortification and/or formula intake is ideal, but if calcium and phosphorus supplements are required due to malabsorption and metabolic bone disease, doses must be carefully calculated and given at separate times with close monitoring for enteral intolerance as well as potential hypercalcemia or hyperphosphatemia.³⁹

Infants with ileostomies are at high risk of excessive fluid and sodium losses in their ileostomy effluent, resulting in total body sodium depletion, metabolic acidosis, and growth failure. Assessment of total body sodium via urine sodium measurement and adequate sodium supplementation are essential to promote growth.⁴⁰

CONCLUSION

Successful nutritional management post-NEC requires teamwork and thoughtful attention to clinical signs and symptoms, growth, and GI tolerance with frequent problem-solving to reach nutritional goals. With current products and cautious advancements after early reintroduction of EN, it is possible to optimize nutritional and hydration status, as well as improve overall development.

References

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^{Overman RE, Criss CN, Gadepalli SK. Necrotizing enterocolitis in term infants: A different disease process? J Pediatr Surg. 2019;54:1143-1146.}
^{Perks P, Abad-Jorge, A. Nutritional management of the infant with necrotizing enterocolitis. Pract Gastroenterol. Feb 2008;59:46-60.}
^{Ou J, Courtney CM, Steinberger AE, et al: Nutrition in Necrotizing Enterocolitis and Following Intestinal Resection. Nutrients. 2020 Feb 18;12(2):520.}
^{Gordon PV, Swanson JR, MacQueen BC, et al: A critical question for NEC researchers: Can we create a consensus definition of NEC that facilitates research progress? Semin Perinatol. 2017;41:714.}
^{Gordon PV, Swanson JR, Attridge JT, et al: Emerging trends in acquired neonatal intestinal disease: is it time to abandon Bell’s criteria? J of Perinatol.. 2007;1-11.}
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^{Ellis CL, Rutledge JC, Underwood MA. Intestinal microbiota and blue baby syndrome. Gut Microbes. 2010;1;6:359-366.}
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^{Lucas A, Boscardin J, Abrams SA. Preterm infants fed cow’s milk-derived fortifier had adverse outcomes despite a base diet of only mother’s own milk. Breastfeed Med. 2020;15(5):297-303.}
^{Gordon PV, Clark R, Swanson JR, et al. Can a national dataset generate a nomogram for necrotizing enterocolitis onset? J Perinatol. 2014; 34(10):732-5. PMID 25078862}
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^{Lueschow SR, Boly TJ, Jasper E, et al. Pediatr Res. 2021; May 21.}
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^{Bazacliu C, Neu J. Necrotizing Enterocolitis: Long Term Complications. Curr Pediatr Rev, 2019; 15, 115-124.}
^{Khan FA, Mitchell PD, Fisher JG, et al. Magnitude of surgical burden associated with pediatric intestinal failure: a multicenter cohort analysis. J Pediatr Surg 2014;49(12):1795-1798.}
^{Ganapathy, V., Hay, J.W., Kim, J.H., et al. Long term healthcare costs of infants who survived neonatal necrotizing enterocolitis: a retrospective longitudinal study among infants enrolled in Texas Medicaid. BMC Pediatr 2013;13:127.}
^{Halbrich M, Ben-Shoshan M, Rex G. Friend or foe? Figuring out the difference between FPIES, IgE-mediated allergy and food intolerance. BMJ Case Rep. April 2014}
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^{Garofalo, N. A., & Caplan, M. S. Oropharyngeal Mother’s Milk: State of the Science and Influence on Necrotizing Enterocolitis. Clin Perinatol. W.B.
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^{Hock, A. M., Chen, Y., Miyake, H., Koike, Y., Seo, S., & Pierro, A. Initiation of Enteral Feeding after Necrotizing Enterocolitis. Eur J Pediatr Surg, 2018;28(1), 44–50.}
^{Bohnhorst B, Muller S. et al. Early Feeding after Necrotizing Enterocolitis in Preterm Infants. J Pediatr. 2003;Vol 143(4),pp 484-487.}
^{Brotschi B, Baenziger O, Frey B, et al: Early enteral feeding in conservatively managed stage II necrotizing enterocolitis is associated with a reduced risk of catheter-related sepsis. J Perinat Med. 2009; 37:701-705.}
^{Patel EU, Wilson DA, Brennan EA, et al: Earlier re-initiation of enteral feeding after necrotizing enterocolitis decreases recurrence or stricture: a systematic review and meta-analysis. J Perinatol. 2020;40:1679-1687.}
^{Brindle ME, McDiarmid C, Short K, et al: Consensus guidelines for perioperative care in neonatal intestinal surgery: enhanced recovery after surgery (ERAS®) society recommendations. World J Surg. 2020;44:2482-2492.}
^{Arslanoglu S, Boquien C, King C, et al. Fortification of Human Milk for Preterm Infants: Update and Recommendations of the European Milk Bank Association (EMBA) Working Group on Human Milk Fortification. Front. Pediatr., 2019;22 March.}
^{McGrath, K.H., Pitt, J., Bines, J.E. Small intestinal overgrowth in children with intestinal failure on home parenteral nutrition. JGH Open 2019;3(5):394-399.}
^{Kaufman, SS, Loseke CA, Lupo JV, et al. Influence of bacterial overgrowth and intestinal inflammation on duration of parenteral nutrition in children with short bowel syndrome. J Pediatr 1997;131(3):356-361.}
^{Groh-Wargo S, Sapsford A. Enteral Nutrition Support of the Preterm Infant in the Neonatal Intensive Care Unit. Nutr Clin Pract.
2009;l24(3):363-376.}
^{Domellof, M. Nutritional Care of Premature Infants: Microminerals. In: Koletzko B, Poindexter B, Uauy R (eds): Nutritional Care of Preterm Infants: Scientific Basis and Practical Guidelines. World Rev Nutr Diet. Basel, Karger, 2014;110:121-139.}
^{Bhatia J, Griffin I, Anderson D, Neelam K, Domellof M. Selected Macro/Micronutrient Needs of the Routine Preterm Infant. J Pediatr 2013;162:S48-55.}
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Medical Bulletin Board

New Lilly Study Reveals Underappreciation of Bowel Urgency as a Symptom of Ulcerative Colitis and Highlights Communication Gap Between Healthcare Providers and Patients

January 2022 • Volume XLVI, Issue 1

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Findings from the CONFIDE Study show bowel urgency was the second most commonly reported symptom experienced by people with moderately-toseverely active ulcerative colitis, but many patients don’t feel comfortable reporting it to healthcare providers.

More than 60 percent of those patients who don’t feel comfortable reporting bowel urgency to their healthcare providers cite embarrassment as the top reason

Findings will be presented at the Advances in Inflammatory Bowel Diseases (AIBD) conference, taking place in Orlando and virtually December 9-11, 2021, with additional CONFIDE results presented at future congresses in 2022

INDIANAPOLIS, December 9, 2021 – Eli Lilly and Company (NYSE: LLY) today announced results from the CONFIDE Study (Communicating Needs and Features of IBD Experiences) that show bowel urgency – defined as the sudden or immediate need for a bowel movement – is the second most commonly reported symptom suffered by study respondents living with moderately-to-severely active ulcerative colitis (UC), regardless of whether or not they were receiving an advanced therapy (biologic or novel oral therapy). In this study, only one in four healthcare providers perceived bowel urgency as one of the top three most reported symptoms by their patients.

The CONFIDE Study examines the experience of those living with moderately-to-severely active UC and Crohn’s disease and aims to advance the understanding of the burden, barriers and care experience of individuals with inflammatory bowel disease (IBD) and how they communicate with their healthcare providers. These U.S.specific data were collected from a cross-sectional survey of healthcare professionals and adults with moderately-to-severely active UC and Crohn’s disease in the U.S., Europe and Japan.

“Bowel urgency is a disruptive, often underreported symptom of ulcerative colitis and can be embarrassing and difficult for many people to talk about,” said David T. Rubin, M.D., professor of medicine, chief, Section of Gastroenterology, Hepatology and Nutrition, University of Chicago Medicine and scientific advisor to the CONFIDE Study. “It is essential for those who care for people with inflammatory bowel disease to create an environment where they can have an open and trusting conversation about bowel urgency, especially considering this symptom is significantly associated with many patients’ perceived disease severity.”

In the CONFIDE Study, respondents living with moderately-to-severely active UC were asked which symptoms they experienced in the last month, as well as symptoms they had ever experienced, respectively. Diarrhea (experienced over the last month: 62.5%; have ever experienced: 74.0%), bowel urgency (experienced over the last month: 47.0%; have ever experienced: 61.5%) and increased stool frequency (experienced over the last month: 38.5%; have ever experienced: 57.5%) were reported as the top three symptoms suffered among respondents.

When asked to rank the top three symptoms they felt were most reported by their patients, three out of four healthcare providers (76.0%) did not identify bowel urgency, noting instead that the top three symptoms reported to them included diarrhea (73.5%), blood in stool (69.0%) and increased stool frequency (37.5%).

Of the respondents living with moderatelyto-severely active UC who experienced bowel urgency, only two out of five (38.2%) felt completely comfortable reporting bowel urgency to their healthcare provider. For those who were not comfortable discussing bowel urgency with their healthcare provider, more than 60 percent reported that the top reason for not doing so was they were embarrassed to talk about it.

“The first findings from the CONFIDE Study shed light on an important conversation that may not be happening between healthcare providers and people living with ulcerative colitis. Many patients still feel embarrassed or struggle to explain symptoms like bowel urgency, a common experience that can take a toll on a person’s day-today life,” said Melodie Narain-Blackwell, founder, Color of Crohn’s and Chronic Illness.

Notably, when respondents with moderately-toseverely active UC were asked about their perceived disease severity, bowel urgency was significantly associated with those who considered their disease activity to be severe (62.9%) when compared with those that reported mild-to-moderately active disease (42.9%). Among the overall patient population surveyed, three-quarters (76.5%) of people were receiving advanced therapies (biologic or novel oral therapy), however; bowel urgency was still being currently experienced by almost one-half (46.4%) of respondents.

“One of the most important aspects of accurate diagnosis and treatment is to ensure that patients feel completely comfortable talking about their symptoms with their provider,” said Cem Kayhan, M.D., gastroenterology indications medical leader at Lilly. “These initial results from the CONFIDE Study help advance our understanding of the realworld experience of those living with and treating moderately-to-severely active ulcerative colitis, including those who are receiving advanced therapies and still experiencing bowel urgency. We look forward to sharing additional insights from the CONFIDE Study in the near future.” About The CONFIDE Study

The CONFIDE Study is a global, cross-sectional survey of healthcare professionals and people with moderately-to-severely active UC or Crohn’s disease in the U.S., Europe and Japan. The study looks at the experience and impact of symptoms and aims to provide further understanding of the burden, barriers and care experience of those living with these diseases. The global CONFIDE Study includes more than 1,600 adults living with UC or Crohn’s disease and more than 800 healthcare providers from the U.S., Europe and Japan. This specific U.S. disclosure included a total of 200 healthcare provider respondents and 200 adults living with ulcerative colitis.

About the CONFIDE Scientific Advisory Panel*

The CONFIDE study was conducted by Adelphi Real World on behalf of Eli Lilly and Company, with expert guidance provided by some of the leading voices in UC research today, including (in alphabetical order):

Marla Dubinsky, Co-Director, Susan and Leonard Feinstein Inflammatory Bowel Disease Clinical Center, U.S.

Toshifumi Hibi, Professor, Kitasato University, Kitasato Institute Hospital, Japan

Remo Panaccione, Professor of Medicine,

University of Calgary Cumming School of Medicine, Canada

David T. Rubin, Professor of Medicine, Chief, Section of Gastroenterology, Hepatology and Nutrition, University of Chicago Medicine, U.S.

Stefan Schreiber, Director of Internal Medicine,

University Hospital Schleswig-Holstein, Germany

Simon Travis, Professor of Clinical

Gastroenterology, Nuffield Department of Medicine, University of Oxford, U.K.

About Ulcerative Colitis

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

About Eli Lilly and Company

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

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

*Members of the scientific advisory board serve as consultants and have received honoraria from Eli Lilly and Company.

P-LLY

Lilly Forward-Looking Statement

This press release contains forward-looking statements (as that term is defined in the Private Securities Litigation Reform Act of 1995) about the treatment of patients with ulcerative colitis and/or Crohn’s disease and reflects Lilly’s current beliefs and expectations. However, as with any disease treatment, there are substantial risks and uncertainties. Among other things, there can be no guarantee that future study results would be consistent with the study results reported. For further discussion of these and other risks and uncertainties, see Lilly’s most recent Form 10-K and Form 10-Q filings with the United States Securities and Exchange Commission. Except as required by law, Lilly undertakes no duty to update forward-looking statements to reflect events after the date of this release.

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Medical Bulletin Board

Redhill Biopharma: Concerning Rates of Clarithromycin Prescribing for H. Pylori, Despite Increasing Antibiotic Resistance, Uncovered in New Digestive Diseases & Sciences Publication

January 2022 • Volume XLVI, Issue 1

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Despite increasing resistance to, and suboptimal H. pylori eradication rates with, clarithromycin, a new study, published in Digestive Diseases and Sciences, indicates that over 80% of all prescriptions for H. pylori infection contain clarithromycin

In addition, this analysis highlighted a nearly 40% failure rate for clarithromycin-based triple therapies in treatment-naïve patients; Study also showed a more than 80% failure rate in CYP2C19 rapid metabolizers, accounting for approximately 30% of Americans

Talicia, an FDA-approved therapy, is intended for first-line H. pylori eradication therapy

RALEIGH, N.C. and TEL-AVIV, Israel, December 9, 2021, RedHill Biopharma Ltd. (Nasdaq: RDHL) (“RedHill” or the “Company”), a specialty biopharmaceutical company, today announced the publication in the journal Digestive Diseases and Sciences of a new study entitled “Pitfalls of Physician-Directed Treatment of Helicobacter pylori: Results from Two Phase 3 Clinical Trials and Real-World Prescribing Data”, revealing concerning rates of widespread, physician-directed prescribing of clarithromycin-based regimens for patients with persistent H. pylori infection despite rising rates of antibiotic resistance and prior patient macrolide use.

“The failure rate of clarithromycin-based therapy is alarming enough on its own. More alarming still is that more than 80% of all prescriptions for H. pylori infection are clarithromycin-based therapies – despite clear ACG recommendations to avoid clarithromycin triple therapy in patients with any prior macrolide use or in regions where the resistance rate is known to be 15% or above (or where resistance levels are not known),” said Dr. Colin W. Howden, MD, Professor Emeritus, Chief of the Division of Gastroenterology, University of Tennessee Health Science Center. “Such failure rates and resistance have not been seen with Talicia. Since it does not contain clarithromycin, Talicia can be prescribed first-line without having to be concerned about local clarithromycin resistance, prior macrolide use, or patient CYP2C19 status.”

This study assessed prescribing patterns and associated cure rates of physician-directed therapy for subjects with persistent H. pylori infection after participation in either of two Phase 3 clinical trials

(ERADICATE Hp and ERADICATE Hp2). The study also conducted CYP2C19 genotype analysis of subjects who were prescribed clarithromycinbased triple therapy. The most frequently selected treatments for physician-directed therapy from ERADICATE Hp and Hp2 were clarithromycinbased triple regimens (71.7%). Clarithromycinbased triple therapies across these studies showed eradication rates of approximately 60%, while rapid CYP2C19 metabolizers had eradication rates of less than 20%. This is clinically relevant because roughly one third of Americans have either rapid or ultra-rapid CYP2C19 metabolizer status[i]. Additionally, the study analyzed real world H. pylori retail prescription data, which revealed that the most frequently selected treatments for physician-directed therapy were clarithromycinbased triple regimens, accounting for more than 80% of prescriptions.

“This study highlights the need for a change in prescribing habits for H. pylori given rising resistance and the suboptimal eradication rates seen with clarithromycin-based regimens. This study demonstrated an approximately 60% eradication rate for clarithromycin-based therapies in treatment naïve patients[ii], which is consistent with recently published eradication rates[iii],” said Dr. June Almenoff, MD, Ph.D., RedHill’s Chief Medical Officer. “Conversely, efficacy data from the two Phase 3 studies demonstrated eradication rates of approximately 89% in the ERADICATE Hp mITT population and 90% in the ERADICATE Hp2 adherent population for Talicia in treatmentnaïve subjects, identified no primary or acquired resistance to rifabutin and found that cure rates were largely unaffected by CYP2C19 metabolic status.”

About Talicia^®

Talicia^® is the only rifabutin-based therapy approved for the treatment of H. pylori infection and is designed to address the high resistance of H. pylori bacteria seen with other antibiotics. The high rates of H. pylori resistance to clarithromycin have led to significant rates of treatment failure with clarithromycin-based therapies and are a strong public health concern, as highlighted by the ACG, FDA and the World Health Organization (WHO) in recent years.

Talicia^® is a novel, fixed-dose, all-in-one oral capsule combination of two antibiotics (amoxicillin and rifabutin) and a proton pump inhibitor (PPI) (omeprazole). In November 2019, Talicia^® was approved by the U.S. FDA for the treatment of H. pylori infection in adults. In the pivotal Phase 3 study, Talicia^® demonstrated 84% eradication of H. pylori infection in the intent-to-treat (ITT) group vs. 58% in the active comparator arm (p<0.0001). Minimal to zero resistance to rifabutin, a key component of Talicia^®, was detected in RedHill’s pivotal Phase 3 study. Further, in an analysis of data from this study, it was observed that subjects who were confirmed adherent[iv] to their therapy had response rates of 90.3% in the Talicia^® arm vs. 64.7% in the active comparator arm[v]. Talicia^® is eligible for a total of eight years of U.S. market exclusivity under its Qualified Infectious Disease Product (QIDP) designation and is also covered by U.S. patents which extend patent protection until 2034 with additional patents and applications pending and granted in various territories worldwide.

About H. pylori

H. pylori is a bacterial infection that affects approximately 35%[vi] of the U.S. population, with an estimated two million patients treated annually[vii]. Worldwide, more than 50% of the population has H. pylori infection, which is classified by the WHO as a Group 1 carcinogen. It remains the strongest known risk factor for gastric cancer[viii] and a major risk factor for peptic ulcer disease[ix] and gastric mucosa-associated lymphoid tissue (MALT) lymphoma[x]. More than 27,000 Americans are diagnosed with gastric cancer annually[xi]. Eradication of H. pylori is becoming increasingly difficult, with current therapies failing in approximately 25-40% of patients who remain H. pylori-positive due to high resistance of H. pylori to antibiotics – especially clarithromycin – which is still commonly used in standard combination therapies[xii].

About RedHill Biopharma

RedHill Biopharma Ltd. (Nasdaq: RDHL) is a specialty biopharmaceutical company primarily focused on gastrointestinal and infectious diseases. RedHill promotes the gastrointestinal drugs, Movantik^® for opioid-induced constipation in adults[xiii], Talicia^® for the treatment of Helicobacter pylori (H. pylori) infection in adults[xiv], and Aemcolo^® for the treatment of travelers’ diarrhea in adults[xv]. RedHill’s key clinical late-stage development programs include: (i) RHB-204, with an ongoing Phase 3 study for pulmonary nontuberculous mycobacteria (NTM) disease; (ii) opaganib (ABC294640), a firstin-class, oral SK2 selective inhibitor targeting multiple indications with a Phase 2/3 program for COVID-19 and Phase 2 studies for prostate cancer and cholangiocarcinoma ongoing; (iii) RHB-107 (upamostat), an oral serine protease inhibitor in a U.S. Phase 2/3 study as treatment for symptomatic COVID-19, and targeting multiple other cancer and inflammatory gastrointestinal diseases; (iv) RHB-104, with positive results from a first Phase 3 study for Crohn’s disease; (v) RHB-102, with positive results from a Phase 3 study for acute gastroenteritis and gastritis and positive results from a Phase 2 study for IBS-D; and (vi) RHB106, an encapsulated bowel preparation.

More information about the company is available at: www.redhillbio.com https://twitter.com/RedHillBio

About Talicia^®

(omeprazole magnesium, amoxicillin and rifabutin)

INDICATION AND USAGE

Talicia is a three-drug combination of omeprazole, a proton pump inhibitor, amoxicillin, a penicillinclass antibacterial, and rifabutin, a rifamycin antibacterial , indicated for the treatment of Helicobacter pylori infection in adults. 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 bacteria.

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 rilpivirine-containing products.

Talicia is contraindicated in patients receiving delavirdine or voriconazole.

Serious and occasionally fatal hypersensitivity reactions have been reported with omeprazole, amoxicillin and rifabutin.

Severe cutaneous adverse reactions (SCAR) (e.g. Stevens-Johnson syndrome (SJS), Toxic epidermal necrolysis (TEN)) have been reported with rifabutin, amoxicillin, and omeprazole. Additionally, drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported with rifabutin.

Acute Tubulointerstitial Nephritis has been Clostridioides difficile-associated diarrhea observed in patients taking PPIs and penicillins.

Clostridioides difficile-associated diarrhea observed in patients taking PPIs and penicillins.

Clostridioides difficile-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. Talicia may reduce the efficacy of hormonal 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.

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.

To report SUSPECTED ADVERSE REACTIONS, contact RedHill Biopharma INC. at: 1-833-ADRHILL (1-833-237-4455) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Full prescribing information for Talicia is available at: Talicia.com

This press release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995. Such statements may be preceded by the words “intends,” “may,” “will,” “plans,” “expects,” “anticipates,” “projects,” “predicts,” “estimates,” “aims,” “believes,” “hopes,” “potential” or similar words. Forward-looking statements are based on certain assumptions and are subject to various known and unknown risks and uncertainties, many of which are beyond the Company’s control and cannot be predicted or quantified, and consequently, actual results may differ materially from those expressed or implied by such forward-looking statements. Such risks and uncertainties associated with (i) the initiation, timing, progress and results of the Company’s research, manufacturing, pre-clinical studies, clinical trials, and other therapeutic candidate development efforts, and the timing of the commercial launch of its commercial products and ones it may acquire or develop in the future; (ii) the Company’s ability to advance its therapeutic candidates into clinical trials or to successfully complete its pre-clinical studies or clinical trials or the development of a commercial companion diagnostic for the detection of MAP; (iii) the extent and number and type of additional studies that the Company may be required to conduct and the Company’s receipt of regulatory approvals for its therapeutic candidates, and the timing of other regulatory filings, approvals and feedback; (iv) the manufacturing, clinical development, commercialization, and market acceptance of the Company’s therapeutic candidates and Talicia^®; (v) the Company’s ability to successfully commercialize and promote Talicia^®, and Aemcolo^® and Movantik^®; (vi) the Company’s ability to establish and maintain corporate collaborations; (vii) the Company’s ability to acquire products approved for marketing in the U.S. that achieve commercial success and build its own marketing and commercialization capabilities; (viii) the interpretation of the properties and characteristics of the Company’s therapeutic candidates and the results obtained with its therapeutic candidates in research, pre-clinical studies or clinical trials; (ix) the implementation of the Company’s business model, strategic plans for its business and therapeutic candidates; (x) the scope of protection the Company is able to establish and maintain for intellectual property rights covering its therapeutic candidates and its ability to operate its business without infringing the intellectual property rights of others; (xi) parties from whom the Company licenses its intellectual property defaulting in their obligations to the Company; (xii) estimates of the Company’s expenses, future revenues, capital requirements and needs for additional financing; (xiii) the effect of patients suffering adverse experiences using investigative drugs under the Company’s Expanded Access Program; (xiv) competition from other companies and technologies within the Company’s industry; and (xv) the hiring and employment commencement date of executive managers. More detailed information about the Company and the risk factors that may affect the realization of forward-looking statements is set forth in the Company’s filings with the Securities and Exchange Commission (SEC), including the Company’s Annual Report on Form 20-F filed with the SEC on March 18, 2021. All forwardlooking statements included in this press release are made only as of the date of this press release. The Company assumes no obligation to update any written or oral forward-looking statement, whether as a result of new information, future events or otherwise unless required by law.

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From the Pediatric Literature

Can We Predict Severity of Pancreatitis in Children?

January 2022 • Volume XLVI, Issue 1

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The incidence of acute pancreatitis (AP) in children has been increasing over time, and better modeling is needed to predict severe AP in this population. In this study, children with AP were recruited prospectively at a tertiary children’s hospital in the United States. AP was defined as occurring when a child had two of the following three criteria: abdominal pain consistent with AP, serum amylase or lipase level greater than 3 times the upper limit of normal, and imaging consistent with AP. A “derivation cohort” consisted of patients presenting with AP between 2016 and 2018 while a “validation cohort” consisted of patients diagnosed with AP between 2018 and 2019. Blood sampling was obtained within 48 hours of hospital admission for AP which then underwent analysis for the presence of multiple protein biomarkers (via the Luminex^®assay), and C-reactive protein (CRP) levels were measured as well. Severity of pediatric pancreatitis was determined by pre-existing North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) guidelines.

The derivation cohort consisted of 46 patients with AP and 20 control patients while the validation cohort consisted of 25 patients with AP and 10 control patients. No significant difference in age, sex, body mass index, etiology of AP, or AP severity was present between groups. Heatmap analysis demonstrated 48 biomarkers that were statistically significant when comparing patients with AP with controls. Specifically, Interleukin-6 (IL-6) and monocyte chemotactic protein-1 (MCP-1) levels were significantly higher in patients with severe AP in the derivation cohort compared to patients with mild AP and with controls. This testing was repeated in the validation cohort, and again, IL-6 and MCP-1 levels were significantly elevated in patients with severe AP compared to patients with mild AP as well as with controls. CRP levels were significantly higher in both the derivation cohort and validation cohort for patients with severe AP compared to patients with mild AP and controls. The absolute neutrophil count, absolute lymphocyte count, and absolute monocyte count were significantly higher in the validation cohort for patients with severe AP compared to patients with mild AP and to control patients. Interestingly, ROC modeling demonstrated that blood urea nitrogen (BUN) levels were statistically correlated with severity of AP with a good area under the receiver operating characteristic (AUROC 0.72 [95% CI 0.57-0.87], P = .003), and BUN combined with CRP improved the model to a greater degree (AUROC 0.79 [95% CI 0.64-0.94]). Similar significant findings were noted when BUN was combined independently with IL-6 and MCP-1.

This study suggests that CRP levels are helpful in predicting severity in pediatric patients with acute recurrent pancreatitis which can then help guide therapy. IL-6 and MCP-1 are novel proteins that may prove to be useful as additional biomarkers for future studies.

^{Farrell P, Jones E, Hornung L, Thompson T, Patel J, Lin T, Nathan J, Vitale D, Habtezion A, Abu-El-Haija M. Cytokine profile elevations on admission can determine risks of severe acute pancreatitis in children. Journal of Pediatrics 2021; 238: 33-41.}

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