Tools to Measure the Impact of Structural Racism and Discrimination on Gastrointestinal and Hepatology Disease Outcomes: A Scoping Review.

BACKGROUND & AIMS: Structural racism and discrimination (SRD) are important upstream determinants of health perpetuated by discriminatory laws and policies. Therefore, measuring SRD and its impact on health is critical to developing interventions that address resultant health disparities. We aimed to identify gastrointestinal (GI) or liver studies that report measures of SRD or interventions to achieve health equity in these domains by addressing upstream determinants of health. METHODS: We conducted a scoping review according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses scoping reviews guidelines. Studies that used an SRD measure or examined an upstream intervention in GI or liver disease were included. Studies that described health disparities in GI or liver conditions without mentioning SRD were excluded. Study characteristics, findings, and limitations were extracted. RESULTS: Forty-six articles (19 studies using SRD measures and 27 studies of upstream interventions) were identified. Measures of residential racial segregation were reported most frequently. SRD was associated with poorer health outcomes for racial and ethnic minority populations. Although upstream intervention studies focused primarily on policies related to colon cancer screening and organ graft allocation, racial and ethnic disparities often persisted post-intervention. CONCLUSIONS: To achieve health equity in GI and liver conditions, there is an urgent need for research that goes beyond describing health disparities to incorporating measures of SRD and implementing interventions that address this understudied determinant of health.

Opioid-Related Constipation.

Opioid-related constipation encompasses constipation directly caused by opioid use (opioid-induced constipation [OIC]) as well as pre-existing constipation worsened by opioid use (opioid-exacerbated constipation [OEC]). Over-the-counter laxatives should be used as first-line agents for both OIC and OEC, given their efficacy, low cost, and high safety profiles. Symptoms of OIC and responses to therapy can be assessed with the Bowel Function Index. Individuals with OIC refractory to laxatives may be responsive to peripherally acting µ-opioid receptor antagonists. Although data supporting the superiority of one prescription agent over another is lacking, all have proven effective for the treatment of OIC.

Review article: current and future treatment approaches for IBS with constipation.

BACKGROUND: Multiple efficacious therapies are currently available for treating irritable bowel syndrome with constipation (IBS-C). IBS-C specific survey tools that assess symptom relief, treatment satisfaction, and quality of life are important for gauging real-world effectiveness. AIMS/METHODS: This article reviews clinical trial efficacy data as well as survey data on adequate relief and quality of life from pivotal trials for lubiprostone, linaclotide, plecanatide, tenapanor, and tegaserod. A brief discussion of agents in development with novel mechanisms of action is also provided. RESULTS/CONCLUSIONS: Quality of life and symptom metrics should be standardized and continue to be represented in future IBS-C trials. The choice of agent should be tailored to probability of improving symptoms, safety, tolerability, and cost.

Efficacy and Safety of Neostigmine and Decompressive Colonoscopy for Acute Colonic Pseudo-Obstruction: A Single-Center Analysis.

BACKGROUND: Acute colonic pseudo-obstruction (ACPO) is characterized by acute colonic dilation in the absence of anatomical obstruction. Neostigmine is an acetylcholinesterase inhibitor recommended as first-line salvage therapy for uncomplicated ACPO. Decompressive colonoscopy is recommended if neostigmine is contraindicated or unsuccessful. There is a need to better characterize relative efficacy and factors impacting treatment choice. The aim of the study was to examine the use, efficacy, and safety of neostigmine and decompressive colonoscopy in the management of ACPO at a single academic center. METHODS: Patients ≥ 18 years of age meeting established criteria for uncomplicated ACPO and with cecal diameter ≥ 10 cm on imaging between 1999 and 2019 were identified. Individuals were categorized as having received supportive care alone or subsequent trials of neostigmine or decompressive colonoscopy. Demographics and pre- and post-intervention data were collected, including indication and contraindication to intervention used, time to intervention, initial response, and adverse events. RESULTS: In 46 cases of ACPO (N = 42 patients), all but one individual received initial supportive care. Seven responded to conservative measures alone. Of the patients failing supportive care, 15 cases were initially treated with neostigmine (response rate 86.7%) and 24 initially underwent decompressive colonoscopy (response rate 95.8%) (P = 0.390). One episode of transient bradycardia, resolved with atropine, occurred in the neostigmine group. One patient experienced respiratory instability during colonoscopy. CONCLUSIONS: Both neostigmine and decompressive colonoscopy appear effective for treating uncomplicated ACPO in individuals failing conservative therapy. Adverse events were infrequent in both cohorts. Future prospective studies examining treatment for ACPO should focus on whether either intervention is superior to the other.

Focus on Pharmacotherapy for Irritable Bowel Syndrome with Constipation.

Irritable bowel syndrome with constipation is a common disorder that significantly impairs quality of life. There are now multiple classes of therapeutics that have been shown via rigorous clinical testing to improve the abdominal and bowel symptoms attributed to irritable bowel syndrome with constipation. These include the secretagogues (lubiprostone, linaclotide, plecanatide, tenapenor) and the prokinetic agent tegaserod. This article highlights the pivotal evidence for these agents and most recent treatment guidance from the major North American gastroenterological societies. When pharmaceuticals are used, a patient-specific approach based on efficacy, safety, tolerability, access, and affordability is recommended.

Naldemedine for the treatment of opioid-induced constipation in adults with chronic noncancer pain.

This review aims to summarize the efficacy data for naldemedine, a member of the novel peripherally acting µ-opioid receptor antagonists (PAMORAs), which gained US FDA approval for the treatment of opioid-induced constipation in adults with chronic noncancer pain-related syndromes in 2017. In Phase III trials, patients receiving naldemedine were significantly more likely to meet the primary end point ≥3 spontaneous bowel movements/week and an increase of ≥1 spontaneous bowel movement/week from baseline for at least 9/12 weeks compared to placebo (p < 0.0001). The most frequent adverse events were abdominal pain (8%) and diarrhea (7%). Based on available data, naldemedine appears to be an effective and safe first-line therapy for the treatment of opioid-induced constipation in adults with chronic noncancer pain.

Further Defining the 2012 Multi-Society Task Force Guidelines for Surveillance of High-risk Adenomas: Is a 3-Year Interval Needed for All Patients?

GOALS: We set out to determine whether variation from this 3-year follow-up interval was associated with the finding of subsequent high-risk adenoma (HRA). BACKGROUND: HRAs include the following: (1) an adenoma measuring ≥10 mm, (2) ≥3 adenomas found during a single procedure, and (3) an adenoma with high-grade dysplasia or villous architecture. The current Multi-Society Task Force guideline for timing of surveillance colonoscopy after removal of a HRA is 3 years. STUDY: In 2016, we analyzed 495 patients who had a HRA removed during a 2008 colonoscopy. We compared the frequency of finding another HRA at follow-up intervals. We used the current guidelines as our referent group and performed logistical regression to identify whether any patient characteristics, procedural factors, or type of HRA predicted the development of HRAs on follow-up colonoscopy. RESULTS: Individuals who followed-up at a median of 4.5 years did not have more HRA on follow-up compared with those who followed-up at 3 years (25.2% vs. 21.0%, P=0.062). These groups had similar baseline characteristics. Older individuals, male gender, having a history of polyps, and piecemeal resection of an HRA predicted future HRAs. The removal of ≥3 adenomas in 2008 as well as a combination of multiple, large, and advanced polyps showed a higher risk of future HRAs. CONCLUSIONS: The 2012 Multi-Society Task Force recommendation of 3-year follow-up after removal of HRAs may not apply to all patients. We showed that a combination of patient demographics, procedural factors, and pathology best determines the surveillance colonoscopy interval.

Posttransplant Lymphoproliferative Disorder Isolated to the Adrenal Gland in a Liver Transplant Patient.

Posttransplant lymphoproliferative disorder (PTLD) is a serious complication that accounts for up to 20% of malignancies after solid organ transplantation. We describe a rare case of isolated PTLD in the adrenal gland occurring 7 months after liver transplant in a patient who developed a primary Epstein-Barr virus infection. He was treated with rituximab and his immunosuppression regimen was minimized. We review the incidence, pathogenesis, presentation, and management of PTLD in the liver-transplant population. Our case highlights the variation in the presentation of PTLD and the importance of a high index of suspicion among the at-risk group.

Reactive oxygen species is essential for cycloheximide to sensitize lexatumumab-induced apoptosis in hepatocellular carcinoma cells.

This study aims to investigate apoptosis induced by lexatumumab (Lexa) in hepatocellular carcinoma (HCC) cells. We assessed the sensitivity of HCC cell lines and normal human hepatocytes to Lexa and explored the sensitization of HCC cells to Lexa-induced apoptosis by cycloheximide (CHX). Our data indicated that CHX sensitized HCC cell lines to Lexa-induced apoptosis, whereas treatment using solely CHX or Lexa was ineffective. The sequential treatment of CHX followed by Lexa dramatically induced caspase-dependent apoptosis in HCC cells and had synergistically increased intracellular rates of reactive oxygen species (ROS). Additionally, when ROS production was blocked by N-acetyl-L-cysteine (NAC), HCC cells were protected against Lexa and CHX combination treatment-induced apoptosis. ROS generation induced by combination treatment of Lexa and CHX triggered pro-apoptotic protein Bax oligomerization, conformation change, and translocation to mitochondria, which resulted in the release of cytochrome c and subsequent cell death. Furthermore, HSP90 was involved in mediating Lexa and CHX combination treatment-induced ROS increase and apoptotic death. More importantly, we observed that combination treatment of Lexa and CHX did not cause apoptotic toxicity in normal human primary hepatocytes. These results suggest that Lexa and CHX combination treatment merits investigation for the development of therapies for patients with HCC.