An Analysis of the Impact of COVID-19 Pandemic-related Lockdown Measures on a Large Gastrointestinal Pathology Service in the United States.

BACKGROUND/AIM: The coronavirus disease 2019 (COVID-19) pandemic prompted global recommendations to delay non-urgent endoscopic procedures to limit the spread of SARS-COV-2, but such delays had unprecedented impact on the delivery of healthcare. Being a large specialty GI Pathology service, we sought to analyze the effect of the pandemic on the frequency of GI malignancies in our department. PATIENTS AND METHODS: Based on the electronic search of departmental pathology records, we compared the total numbers of cancer diagnoses (primary and metastatic) from various GI biopsy sites during the 12-month pre- and post-pandemic periods. We summarized patient demographics and analyzed pertinent histopathologic data. RESULTS: For all GI biopsy sites, the number of intramucosal/invasive malignancies reported during the one-year pre-COVID-19 pandemic (pre-COVID) and post-COVID-19 pandemic national lockdown (post-COVID) observation periods were 146 and 218, respectively. Among these, 32 and 70 malignancies were reported for the first quarter (representing the earliest post-lockdown period), 29 and 53 for the second, 41 and 54 for the third, and 44 and 41 for the fourth quarter. During the first two quarters of the post-COVID observation period, the increase in malignant diagnoses was most profound, showing 119% post-COVID increase compared to the pre-COVID levels. Of the two main primary histologic types of large intestinal carcinomas [adenocarcinoma (ADC) and squamous cell carcinoma (SCC)], the most profound post-COVID increase was noted in SCCs (136% vs. 58% for ADCs). CONCLUSION: Compared to the pre-pandemic baseline, the COVID-19 pandemic caused a major increase in biopsy diagnoses of GI cancers in our department. The most plausible explanations for this trend include inevitable lockdowns to minimize the spread of SAR-COV2, which affected GI endoscopy procedure schedules/re-schedules as well as patient response and adaptation to emerging post-COVID GI healthcare patterns. The COVID-19 pandemic's long-term impact on the health of GI cancer patients will need to be determined through systematic analyses by multi-disciplinary teams.

Aldafermin in patients with non-alcoholic steatohepatitis (ALPINE 2/3): a randomised, double-blind, placebo-controlled, phase 2b trial.

BACKGROUND: Non-alcoholic steatohepatitis (NASH) is characterised by hepatic steatosis, inflammation, and injury, and is associated with an increased risk of liver transplantation and death. NASH affects more than 16 million people in the USA, and there is no approved therapy. The aim of this study was to evaluate the safety and efficacy of aldafermin, an engineered analogue of the gut hormone fibroblast growth factor 19 (FGF19). METHODS: In this randomised, double-blind, placebo-controlled, phase 2b study (ALPINE 2/3) in patients with biopsy-confirmed NASH and stage 2 or 3 fibrosis, we randomly assigned patients stratified by fibrosis stage in a 1:1:1:1 ratio to receive placebo, aldafermin 0·3 mg, 1·0 mg, or 3·0 mg once daily for 24 weeks at 30 study sites in the USA. Patients, investigators, the funder, and all other staff, were masked to treatment assignment throughout the study. The primary endpoint was an improvement in liver fibrosis of at least one stage with no worsening of NASH at week 24. Analyses were done by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT03912532, and has been completed. FINDINGS: Between May 16, 2019, and Sept 4, 2020, 786 patients were screened, of whom 171 were randomly assigned to a treatment group and included in the intention-to-treat population: 43 in the 0·3 mg aldafermin group, 42 in the 1·0 mg group, 43 in the 3·0 mg group, and 43 in the placebo group. In total, 145 (85%) of patients completed treatment. At week 24, among patients with biopsies at both baseline and week 24, was seven (19%) of 36 patients in the placebo group, 11 (31%) of 36 in the 0·3 mg aldafermin group (difference 90% CI 12% [-9 to 33]; p=0·11), five (15%) of 34 patients in the 1·0 mg group (difference -5% [-24 to 13]; p=0·80), and 11 (30%) of 37 patients in the 3·0 mg group (difference 10% [-9 to 30]; p=0·12) had an improvement in liver fibrosis of at least one stage with no worsening of NASH, without meeting the prespecified significance for dose response (p=0·55). Adverse events were mostly mild or moderate in severity. Diarrhoea occurred in six (14%) of 43 patients in the placebo group, three (7%) of 43 patients in the 0·3 mg aldafermin group, five (12%) of 41 patients in the 1·0 mg group, and ten (23%) of 43 patients in the 3·0 mg group. Incidences of serious adverse events and discontinuations owing to adverse events were similar between groups. INTERPRETATION: Aldafermin was generally well tolerated but did not produce a significant dose response on fibrosis improvement of at least one stage with no worsening of NASH, despite positive effects on a number of secondary endpoints. The findings of this trial may have implications for the design of future NASH trials. FUNDING: NGM Biopharmaceuticals.

CDX-2 Expression in Esophageal Biopsies Without Goblet Cell Intestinal Metaplasia May Be Predictive of Barrett's Esophagus.

BACKGROUND: CDX-2 is a nuclear homeobox transcription factor not normally expressed in esophageal and gastric epithelia, reported to highlight intestinal metaplasia (IM) in the esophagus. Pathological absence of goblet cells at initial screening via hematoxylin and eosin (HE) and alcian blue (AB) staining results in patient exclusion from surveillance programs. AIMS: This study aimed to determine whether non-goblet cell IM, as defined by CDX-2 positivity, can be considered to be a precursor to Barrett's esophagus (BE). METHODS: This study received IRB approval (17,284). Patients with gastroesophageal reflux disease (n = 181) who underwent upper-gastrointestinal endoscopy with biopsies of the distal esophagus to rule out BE using HE/AB staining and CDX-2 immunostaining were followed for 3 years. Initial and follow-up staining results were evaluated for age/sex. RESULTS: Differences between development of goblet cell IM in CDX-2-negative and CDX-2-positive groups were evaluated. A Kaplan-Meier curve showed that, out of the 134 patients initially positive for CDX-2, 25 (18.7%) had developed goblet cell IM after 2 years and 106 (79.1%) after 3 years. Conversely, of the 47 patients initially negative for CDX-2, 8 (17.9%) developed goblet cell IM after 24 months and only 11 (23.8%) after 40 to 45 months (P = .049; age-adjusted Cox proportional hazard regression model). CONCLUSION: In cases that are initially AB negative and CDX-2 positive, CDX-2 was demonstrated to have a potential prognostic utility for early detection of progression to BE. CDX-2 expression is significantly predictive for risk of goblet cell IM development 40 to 45 months after initial biopsy.