Citations

Abstract Purpose: Current endoscopy-based screening and surveillance programs have not been proven effective at decreasing esophageal adenocarcinoma (EAC) mortality, creating an unmet need for effective molecular tests for early detection of this highly lethal cancer. We conducted a genome-wide methylation screen to identify novel methylation markers that distinguish EAC and high-grade dysplasia (HGD) from normal squamous epithelium (SQ) or nondysplastic Barrett's esophagus (NDBE). Experimental Design: DNA methylation profiling of samples from SQ, NDBE, HGD, and EAC was performed using HM450 methylation arrays (Illumina) and reduced-representation bisulfate sequencing. Ultrasensitive methylation-specific droplet digital PCR and next-generation sequencing (NGS)-based bisulfite-sequencing assays were developed to detect the methylation level of candidate CpGs in independent esophageal biopsy and endoscopic brushing samples. Results: Five candidate methylation markers were significantly hypermethylated in HGD/EAC samples compared with SQ or NDBE (P < 0.01) in both esophageal biopsy and endoscopic brushing samples. In an independent set of brushing samples used to construct biomarker panels, a four-marker panel (model 1) demonstrated sensitivity of 85.0% and 90.8% for HGD and EACs respectively, with 84.2% and 97.9% specificity for NDBE and SQ respectively. In a validation set of brushing samples, the panel achieved sensitivity of 80% and 82.5% for HGD and EAC respectively, at specificity of 67.6% and 96.3% for NDBE and SQ samples. Conclusions: A novel DNA methylation marker panel differentiates HGD/EAC from SQ/NDBE. DNA-methylation–based molecular assays hold promise for the detection of HGD/EAC using esophageal brushing samples.

Current selection of different treatments for patients with gastroparesis is empiric or based on trial and error, though pyloric distensibility and diameter may predict response to pyloric interventions. High-resolution antropyloroduodenal manometry (HR-ADM) can characterize a variety of postprandial antral contractile and pyloric motility dysfunctions in patients with suspected gastroparesis. HR-ADM shows promise to provide guidance for selection and individualization of treatments such as prokinetic agents or pyloric interventions for patients with gastroparesis based on documented pathophysiology.

LINKED CONTENTThis article is linked to Khanna et al papers. To view these articles, visit https://doi.org/10.1111/apt.17065

US hospital quality rankings and ratings use disparate methodologies and are weakly correlated. This causes confusion for patients and hospital quality staff. At the authors’ institution, a Composite Hospital Quality Index (CHQI) was developed to combine hospital quality ratings. This approach is described and a calculator is shared here for other health systems to explore their performance. Among the US News and World Report Top 50 Hospitals, hospital-specific numeric summary scores were aggregated from the 2021 Centers for Medicare and Medicaid Services (CMS) Hospital Overall Star Rating, the Spring 2021 Leapfrog Safety Grade, and the April 2021 Hospital Consumer Assessment of Healthcare Providers and Systems Star Rating. The CHQI is the hospital-specific sum of the national percentile-rankings across these 3 ratings. In this example, mean (SD) percentiles were as follows: CMS Stars 74 (19), Hospital Consumer Assessment of Healthcare Providers and Systems 63 (19), Leapfrog 65 (24), with mean (SD) CHQI of 202 (49). The CHQI is used at the authors’ institution to identify improvement opportunities and ensure that high-quality care is delivered across the health system.

Abstract The primary mechanism of action for the chemotherapeutic 5-fluorouracil (5-FU) is inhibition of thymidylate synthase (TS), which leads to nucleotide imbalance and subsequent cellular death. Expression of TS has been suggested to be determined by a variable number of tandem repeats located within the TS enhancer region (TSER). TSER genotype has been inconsistently linked to 5-FU-related adverse events, including severe grade ≥3 drug-related toxicity. Our recent studies demonstrated that the number of repeats within the TSER, as well as the presence or absence of a polymorphism within each repeat, was significantly associated with 5-FU toxicity in 629 patients. Our findings are consistent with a model in which the number of upstream stimulatory factor (USF1) transcription factor binding sites in the TSER, which is determined both by repeat status and genotype within each repeat, defines TYMS expression and contributions to 5-FU toxicity risk. We present an updated nomenclature that concisely and unambiguously identifies both the number of repeats and the number of USF1 binding sites. The difficulty in obtaining clear genotypes within this highly repetitive and variable region limits the ability to integrate this biomarker into predictive tests. We present methodologies for assigning TSER genotypes using conventional and high-throughput sequencing, including whole genome sequence data. Our results are expected to promote the improved study of TSER genotype in future clinical studies and the integration of TSER status into clinical predictive tests for severe 5-FU toxicity. Citation Format: Huixing Huang, Dominic Schaerer, Remington Schmidt, Ting Zhang, Tanja K Froehlich, Kelly Bouchonville, Robert B Diasio, Ursula Amstutz, Carlo Largiadèr, Steven M Offer. Novel approach to thymidylate synthase genotype determination and utility as a biomarker of severe toxicity to 5-FU chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5805.

Abstract Genetic variants in the DPYD gene that are deleterious to dihydropyrimidine dehydrogenase (DPD) enzyme function have demonstrated clinical validity as predictive biomarkers for severe (i.e., CTCAE grade ≥3) and potentially lethal toxicity to fluorouracil (5-FU) and capecitabine chemotherapies. Variants within the coding region only explain 5-10% of 5-FU-related toxicities; and GWAS approaches have been unable to identify validated predictive biomarkers to date. Our previous studies demonstrated that DPD expression was controlled by multiple epigenetic processes; considerable variation was also noted in liver DPYD/DPD levels. Using CRISPR-interference (CRISPRi) and CRISPR-activation (CRISPRa), we identified functional enhancer regions within liver tissues and cells. Epigenetic status at these regions was shown to correlate with DPYD expression in cell models and human liver tissues. Chromosome conformation capture (3C) confirmed direct promoter-enhancer interactions. A multi-omics analysis of >1000 human liver specimens identified a proximal eQTL for DPYD expression within an enhancer, with a global minor allele frequency of 27%. This variant was subsequently shown to directly alter DPYD expression in knock-in cell line models. The variant disrupts transcription factor binding at the DPYD enhancer, leading to reduced enhancer-promoter interaction, reduced DPD expression, and increased cellular sensitivity to 5-FU. Collectively, our data suggest that the variant could represent a novel predictive biomarker for severe 5-FU toxicity. The evaluation of this marker in the clinical setting is currently underway. Citation Format: Ting Zhang, Alisa Ambrodji, Huixing Huang, Kelly Bouchonville, Amy Etheridge, Remington Schmidt, Jose Cardiel Nunez, Zoey Temesgen, Federico Innocenti, Robert Diasio, Carlo Largiadèr, Steven M. Offer. DPYD enhancer variant confers increased risk of severe toxicity in 5-FU chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5420.

AbstractSeizure is one of the manifestations of central nervous system inflammatory demyelinating diseases, which mainly include multiple sclerosis (MS), aquaporin 4 antibody‐positive neuromyelitis optica spectrum disorder (AQP4‐NMOSD), and myelin oligodendrocyte glycoprotein antibody‐associated disease (MOGAD). Acute symptomatic seizures secondary to MS/AQP4‐NMOSD/MOGAD occur in the acute phase of the diseases, and are more frequent in MOGAD. In contrast, recurrent nonprovoked seizures, mainly attributed to autoimmune‐associated epilepsy, occur in the nonacute phase of the diseases. Seizures in MS/AQP4‐NMOSD/MOGAD mostly have a focal onset. MS patients with concomitant systemic infections, earlier onset, and greater disease activity are more likely to have seizures, whereas factors such as greater MS severity, the presence of status epilepticus, and cortical damage indicate a greater risk of developing epilepsy. In MOGAD, cerebral cortical encephalitis and acute disseminated encephalomyelitis (ADEM)‐like phenotypes (predominately ADEM and multiphasic disseminated encephalomyelitis) indicate a greater seizure risk. Multiple relapses with ADEM‐like phenotypes predict epilepsy in pediatrics with MOGAD. Pathophysiologically, acute symptomatic seizures in MS are associated with neuronal hyperexcitability secondary to inflammation and demyelination. Chronic epilepsy in MS is largely due to gliosis, neuronal dysfunction, and synaptic abnormalities. The mainstay of treatment for seizures secondary to MS/AQP4‐NMOSD/MOGAD consists of immunotherapy along with antiseizure medications. This critical review discusses the most‐updated evidence on epidemiology, clinical correlates, and inflammatory mechanisms underlying seizures and epilepsy in MS/AQP4‐NMOSD/MOGAD. Treatment cautions including drug‐drug interactions and the impact of treatments on the diseases are outlined. We also highlight pitfalls and challenges in managing such patients and future research perspectives to address unsolved questions.

SummaryBackgroundTradipitant, an NK1 receptor antagonist, improved symptoms in patients with gastroparesis. It is unclear whether these effects are mediated centrally (e.g., vomiting centre) or on gastric functions. As a class, NK1 antagonists may retard gastric emptying (GE) or increase fasting and postprandial gastric volumes (GV).AimTo evaluate the effects of tradipitant relative to placebo on gastric motor functions, satiation, postprandial symptoms, and pharmacokinetics.MethodsWe conducted a randomised, double‐blind, placebo‐controlled, single‐centre study of tradipitant 85 mg or matching placebo b.i.d. for 9 consecutive days in 24 healthy volunteers. During the last 2 days of treatment, participants underwent scintigraphic measurements of GE of 320 kcal egg meal, fasting and postprandial GV by SPECT, and satiation by nutrient drink ingested to maximum tolerated volume (MTV) and symptoms 30 min later. Treatments were compared by Wilcoxon rank sum test. The study had 80% power to detect group differences of 23.6% in GV and 29.2% in GE T1/2.ResultsThe two groups of healthy participants were well balanced based on demographic features, age, and BMI. There were nonsignificant positive correlations between blood levels of tradipitant and accommodation GV and GE at 4 h. There were no significant effects of tradipitant, 85 mg b.i.d. for 9 days compared to placebo on GE, GV, satiation, or symptoms 30 min after MTV.ConclusionTradipitant, 85 mg b.i.d., does not significantly affect gastric motor functions (GV or GE). Importantly, there was no retardation of GE by tradipitant, which is important in relation to its potential use in patients with gastroparesis.Clinic trials registryClinicalTrials.gov #NCT04849559.

AbstractBackgroundRecent studies with functional endoluminal imaging probe (EndoFLIP®) measure physiologic characteristics of the pylorus. EndoFLIP® has the potential to select optimal candidates for gastric peroral endoscopic myotomy (G‐POEM). Normative values of the pylorus using EndoFLIP® have not been established.MethodsTwenty‐four healthy volunteers (20–56 years old; 15 females) underwent unsedated, transoral EndoFLIP® measurements of the pylorus after 8 h of fasting. Measurements of diameter (DM), balloon pressure, and distensibility index (DI) of the pylorus were obtained twice over 5 min at 40, 50, and 60 ml balloon distensions.Key ResultsPyloric DM at 40, 50, and 60 ml balloon distensions were 13.0 ± 2.5, 14.3 ± 1.8, and 17.2 ± 2.0 mm, respectively. DM with 60 ml distension was notably higher than with 40 and 50 ml distensions. Pyloric DI at 40, 50, and 60 ml distensions were 10.9 ± 4.8, 11.3 ± 5.8, and 11.1 ± 4.3 mm2/mm Hg, respectively (p = 0.86). Linear regression and Bland–Altman plots showed similar distribution of the DM and DI during the second minute compared with the full 5‐min measurements at 50 ml distension, as well as between two sequential measurements using 50 ml distension. With 50 ml balloon distension, intraindividual coefficients of variation (COVintra) for DM and DI were 13.8% and 29.6%, respectively, and interindividual COV (COVinter) were 12.6% and 51.3%, respectively. Similar reproducibility was obtained with 40 ml balloon distension.Conclusions and InferencesUnsedated EndoFLIP® can be used to characterize human fasting pyloric diameter and distensibility, with best performance observed with 40 ml and 50 ml distensions and data collection during the second minute. Normative values reported serve as reference values for future studies.