Uma M. Sachdeva

SUMMARY: The peri-operative period surrounding esophagectomy is challenging for patients to navigate. In this study, we describe the implementation of a digital health pathway to provide peri-operative education and track patient reported outcomes (PRO) after esophagectomy. This single-center study involved adults who underwent esophagectomy between 2021 and 2024. Educational emails, PRO surveys, and quality of life (QOL) questionnaires were delivered via a mobile health (mHealth) platform (CareSense; MedTrak Inc). Pathway data were combined with outcome data. Primary outcome was the rate of post-operative complications. Secondary outcomes included enrollment rate, PRO, and QOL scores. Fisher’s exact test, Pearson Chi-square test, Kruskal–Wallis test, and logistic regressions were utilized for statistical analyses. Of 168 eligible patients, 136 (80.9%) enrolled in the pathway. There were no significant differences in demographic characteristics between patients who enrolled and those who did not. Enrollment was not associated with post-operative complication rate. Patients activated the pathway a median of 26 days (19–36) before their operation. They received a median of 23 emails (22, 30), 14 surveys, and 6 questionnaires; only 8 patients did not complete any of the daily surveys (5.9%). Median pre-operative anxiety score was 51 (43–56) after peri-operative education, indicating little to no anxiety. Median score change in global QOL at the 2-year time-point was +17 (0, 21). The majority of eligible patients enrolled in the pathway and patient satisfaction was high. There were no differences in post-operative complications based on enrollment. Enrolled patients had low pre-operative anxiety following peri-operative education and clinically significant QOL improvement at 2 years.

Supplementary Figure Legends 1-4

ERK1/2 signaling pathway in CCL5 knockout cells.

Loss of tumor-derived CCL5 reduces tumor cell proliferation in TE-1 cells.

Targeted CCR5 inhibition replicates CCL5 loss with reduced tumor cell proliferation in vitro and in vivo.

Confirmation of CCL5 knockout clones.

Background: Eosinophilic oesophagitis (EoE) is a food allergen-induced inflammatory disorder characterised by interleukin (IL)-13-mediated oesophageal inflammation and epithelial basal cell hyperplasia (BCH). The role of mitochondria in EoE pathogenesis remains elusive. Design: Prompted by single cell transcriptomics data, we interrogated the role of mitochondria in EoE pathobiology using patient biopsies, EoE-mouse models and oesophageal epithelial cells grown in monolayer and three-dimensional (3D) organoid cultures treated with EoE-relevant cytokines. 3D organoids and EoE-bearing mice were treated with omeprazole—a proton-pump inhibitor used as first-line EoE therapy. We performed CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) interference in mouse organoids to identify the key mitochondrial regulatory genes whose depletion may lead to BCH. We analysed mitochondrial membrane potential, mass and superoxide production by flow cytometry, cellular oxygen consumption by respirometry, mitochondrial structures and perturbation of cellular energy homeostasis by immunoblotting. Results : Mitochondrial dysfunction appeared to be a hallmark of EoE-related BCH where mitochondrial structural damage was associated with impaired oxidative respiratory capacity, elevation of mitochondrial superoxide and decreased adenosine triphosphate (ATP) production, as corroborated by activation of the adenosine monophosphate (AMP) -activated protein kinase and suppression of mammalian target-of-rapamycin signalling. Depletion of PGC1A, the master regulator of mitochondria biogenesis, recapitulated EoE-related BCH, suggesting that mitochondrial dysfunction drives BCH. Further, omeprazole alleviated mitochondrial damage and dysfunction in EoE-related BCH modelled in mice and patient-derived organoids. Conclusion: Mitochondrial dysfunction is tightly linked to perturbation of redox homeostasis in EoE-related BCH, which is promoted by IL-13 and reversible with omeprazole treatment.

Barrett’s esophagus (BE) is a common precancerous lesion that can progress to esophageal adenocarcinoma (EAC). There are significant alterations in the esophageal microbiome in the progression from healthy esophagus to BE to EAC, including an increased abundance of a variety of lactate-producing bacteria and an increase of lactate in the tumor microenvironment, as predicted by metabolic modeling. The role of bacterial lactate in EAC is unknown. Here, we utilize patient-derived organoid (PDO) models of EAC and demonstrate that lactate inhibits the growth and proliferation of EAC PDOs through alterations in the tumor NADH/NAD+ redox state. Further RNA sequencing of EAC PDOs identifies ID1 and RSAD2 as potential regulatory molecules crucial in mediating lactate’s ability to suppress glycolysis and proliferation. Gene ontology analysis also identifies the activation of inflammatory and immunological pathways in addition to alterations in the metabolic pathways in EAC PDOs exposed to lactate, suggesting a multi-faceted role for lactate in the pathogenesis of EAC.