Qin, Yi

Abstract Background: Discovery of methylated DNA markers (MDM) of esophageal squamous cell carcinoma (ESCC) has sparked interest in assessing these markers in tissue. We evaluated MDMs in ESCC from three geographically and ethnically distinct populations, and explored the feasibility of assaying MDMs from DNA obtained by swallowed balloon devices. Methods: MDMs were assayed in ESCC and normal tissues obtained from the populations of United States, Iran, and China, and from exfoliative cytology specimens obtained by balloons in a Chinese population. Areas under the receiver operating curve (AUC) of MDMs discriminating ESCC from normal tissues were calculated. Random forest prediction models were built, trained on U.S. cases and controls, and calibrated to U.S.-only controls (model 1) and three-country controls (model 2). Statistical tests were used to assess the relationship between dysplasia and MDM levels in balloons. Results: Extracted DNA from 333 ESCC and 322 normal tissues was analyzed, in addition to archival DNA from 98 balloons. For ESCC, model 1 validated in Iranian and Chinese tissues with AUCs of 0.90 and 0.87, and model 2 yielded AUCs of 0.99, 0.96, and 0.94 in tissues from the United States, Iran, and China, respectively. In Chinese balloons, MDMs showed a statistically significant trend of increasing levels with increasing grades of dysplasia (P < 0.004). Conclusions: MDMs accurately discriminate ESCC from normal esophagus in tissues obtained from high- and low-incidence countries. Preliminary data suggest that levels of MDMs assayed in DNA from swallowed balloon devices increase with dysplasia grade. Larger studies are needed to validate these results. Impact: MDMs coupled with minimally invasive collection methods have the potential for worldwide application in ESCC screening.

Abstract Risk stratification in Barrett's esophagus may allow aggressive management of those at “high risk” and reduction in surveillance in at “low” risk. Davison et al. report the results of the independent validation of a multibiomarker panel (TissueCypher assay) performed on biopsy tissue, in a case control study. “High-risk” patients progressed 5 times more than those at “low risk.” Sensitivity and specificity for “high-risk” patients were 29% and 86% with a positive predictive value of 23%. A negative predictive value of a “low-risk” score was 96%. These findings may allow more intensive surveillance in those at “high risk.” Despite some limitations, this assay is a potentially major advance in the management of Barrett's esophagus patients without dysplasia.

Abstract Purpose: The burden of esophageal cancer continues to rise, and noninvasive screening tools are needed. Methylated DNA markers (MDM) assayed from plasma show promise in detection of other cancers. For esophageal cancer detection, we aimed to discover and validate MDMs in tissue, and determine their feasibility when assayed from plasma. Experimental Design: Whole-methylome sequencing was performed on DNA extracted from 37 tissues (28 EC; 9 normal esophagus) and 8 buffy coat samples. Top MDMs were validated by methylation specific PCR on tissue from 76 EC (41 adeno, 35 squamous cell) and 17 normal esophagus. Quantitative allele-specific real-time target and signal amplification was used to assay MDMs in plasma from 183 patients (85 EC, 98 controls). Recursive partitioning (rPART) identified MDM combinations predictive of esophageal cancer. Validation was performed in silico by bootstrapping. Results: From discovery, 23 candidate MDMs were selected for independent tissue validation; median area under the receiver operating curve (AUC) for individual MDMs was 0.93. Among 12 MDMs advanced to plasma testing, rPART modeling selected a 5 MDM panel (FER1L4, ZNF671, ST8SIA1, TBX15, ARHGEF4) which achieved an AUC of 0.93 (95% CI, 0.89–0.96) on best-fit and 0.81 (95% CI, 0.75–0.88) on cross-validation. At 91% specificity, the panel detected 74% of esophageal cancer overall, and 43%, 64%, 77%, and 92% of stages I, II, III, and IV, respectively. Discrimination was not affected by age, sex, smoking, or body mass index. Conclusions: Novel MDMs assayed from plasma detect esophageal cancer with moderate accuracy. Further optimization and clinical testing are warranted.

SummaryBackgroundCurrent management of refractory benign oesophageal strictures with endoscopic dilations and stenting leads to resolution of dysphagia in only 30% of patients. Oesophageal self‐dilation may be an alternative.AimTo evaluate the efficacy and safety of oesophageal self‐dilation at a tertiary referral centre.MethodsWe conducted a retrospective review of patients with refractory benign oesophageal strictures who participated in oesophageal self‐dilation at Mayo Clinic (Rochester, MN, USA) between 2003 and 2017. Clinical data including stricture characteristics, Dakkak and Bennett Dysphagia Score, number and dates of endoscopies, and complications were collected. A two‐tailed paired Student's t test was used to compare the measures of efficacy, with differences considered significant at a 5% probability level.ResultsWe identified 52 patients with refractory strictures treated with self‐dilation. The median number of endoscopic interventions was reduced from 9.5 (range 5‐30) to 0 (range 0‐3) within 12 months before and after self‐dilation, respectively (P < 0.0001). A median intervention‐free interval of 417 days (IQR 256‐756 days) was observed. The mean dysphagia score at baseline was 2.5 (95% CI 2.2‐2.8) and 0.33 (95% CI 0.11‐0.53) after self‐dilation. 23 of 27 (85%) patients who received enteral nutrition prior to self‐dilation had their feeding tubes removed.ConclusionsOesophageal self‐dilation is an effective way of maintaining oesophageal patency in refractory benign oesophageal strictures, with safety comparable to current standard of care. Prospective studies are needed to further validate the role of self‐dilation in treatment of refractory benign oesophageal strictures.