Citations

The NCCN Guidelines for Biliary Tract Cancers (BTCs) provide recommendations for the evaluation and comprehensive care of patients with gallbladder cancer, intrahepatic cholangiocarcinoma, and extrahepatic cholangiocarcinoma. The multidisciplinary panel of experts is convened at least once annually to review requests from internal and external entities as well as to evaluate new data on current and emerging therapies. This manuscript focuses on the adjuvant chemotherapy and chemoradiation treatment options for BTCs as well as the systemic treatment recommendations for patients with advanced BTCs.

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.

Qualitative interviews and focus groups are commonly used methods to elicit participants’ voices in program evaluations. However, the use of these data-gathering methods can fall short of the goal; even with open-ended questions, the protocols guiding and shaping interviews and focus groups heavily reflect the evaluators’ understanding and experience of the program or intervention under consideration and its target population(s). In this paper, we describe three cases that employed a method of inquiry that is underutilized in evaluation but one that we believe holds great potential as a method to enhance interpersonal reflexivity, namely participant-generated photo-elicitation interviewing (PEI). Across three diverse settings and interventions, we readily added participant-generated PEI to our mixed methods evaluations. We found participant-generated PEI to add great value to the evaluations by complementing our other data collection methods, allowing for greater participant voice, challenging evaluators’ assumptions, enhancing dissemination efforts, and fostering our reflexivity.

INTRODUCTION: Reflux bile acids are believed to promote esophageal adenocarcinoma (EAC), but the role of systemic bile acids is unknown. This study aimed to assess associations between systemic bile acids and stages of Barrett's esophagus (BE) progression. METHODS: Subjects with and without BE were enrolled in this multicenter cross-sectional study. Targeted serum bile acid profiling was performed, and a subset of subjects completed a validated food frequency questionnaire. RNA sequencing was performed on BE or gastric cardia tissue to assess bile acid associations with gene expression. RESULTS: A total of 141 subjects were enrolled with serum bile acids profiled (49 non-BE; 92 BE: 44 no dysplasia, 25 indefinite/low grade dysplasia, 23 high-grade dysplasia/EAC). Lower Healthy Eating Index score, older age, higher body mass index, and no proton pump inhibitor use were associated with increased levels of multiple bile acids. Global bile acid pools were distinct between non-BE and stages of BE neoplasia ( P = 0.004). Increasing cholic acid was associated with high-grade dysplasia/EAC compared with non-BE, even after adjusting for EAC risk factors (adjusted odds ratio 2.03, 95% confidence interval 1.11–3.71) as was the combination of unconjugated primary bile acids (adjusted odds ratio 1.81, 95% confidence interval 1.04–3.13). High cholic acid levels were associated with tissue gene expression changes including increased DNA replication and reduced lymphocyte differentiation genes. DISCUSSION: Alterations in serum bile acids are independently associated with advanced neoplasia in BE and may contribute to neoplastic progression. Future studies should explore associated gut microbiome changes, proneoplastic effects of bile acids, and whether these bile acids, particularly cholic acid, represent potential biomarkers or viable therapeutic targets for advanced neoplasia in BE.

Background: Understanding nutrition’s role in multiple sclerosis (MS) can guide recommendations and intervention-based studies. Objective: Evaluate the association between nutrition and pediatric-onset MS outcomes. Methods: Prospective longitudinal multicenter study conducted as part of the US Network of Pediatric MS centers. Predictors were collected using a food screener estimating intake of various dietary food groups (e.g. dairy and fruits) and additional calculated indices (e.g. Healthy Eating Index (HEI)). Outcomes included time-from-enrollment to clinical relapse, new magnetic resonance imaging (MRI) T2 lesions, and Expanded Disability Status Scale (EDSS) increase. Results: 353 children with MS were enrolled (mean ± SD age 15.4 ± 2.9, follow-up 3.9 ± 2.6 years). Multivariable analysis demonstrated that increased dairy by 50% of recommended intake was associated with increased relapse risk by 41% (adjusted hazard ratio (HR) 1.41, 95% CI 1.07–1.86), and risk of T2 progression by 40% (1.40, 1.12–1.74). Increased intake of fruit or vegetable above recommended, and every five-point HEI increase decreased relapse risk by 25% (0.75, 0.60–0.95), 45% (0.55, 0.32–0.96), and 15% (0.84, 0.74–0.96), respectively. No associations were found with EDSS. Conclusion: This work supports the influence of dietary intake on MS course, particularly with dairy intake. Future prospective study is required to establish causation.