Sawas, Tarek

INTRODUCTION: The adjunctive use of p53 immunohistochemistry has been proposed as a potential tool to improve risk stratification in Barrett's esophagus (BE) with conflicting results. We performed a systematic review and meta-analysis to evaluate the performance of p53 in predicting progression to advanced neoplasia (high-grade dysplasia [HGD] and esophageal adenocarcinoma [EAC]) among patients with BE. METHODS: We searched multiple databases for studies that evaluated the use of aberrant p53 in esophageal biopsies among patients with BE and reported progression rates to HGD/EAC. The outcomes were p53 test characteristics and incidence and risk ratio (RR) for progression to HGD/EAC in patients with and without aberrant p53 using random effects models. RESULTS: Among the 27 included studies, the proportion of patients with aberrant p53 expression at baseline was 20% (95% CI: 14%, 27%). The rate of progression with and without aberrant p53 was 8 per 100 person-years (95% CI: 6, 11) and 0.3 per 100 person-years (95% CI: 0.1, 0.6), respectively. Compared with patients without aberrant p53 expression, those with aberrant p53 had a higher risk for progression to HGD/EAC in cohort studies (RR = 10.2 [95% CI: 6.9, 15.0]) and case control studies (RR = 3.3 [95% CI: 2.5, 4.4]). The sensitivity for progression for non-dysplastic Barrett's esophagus and low-grade dysplasia/indefinite for dysplasia was 42% and 77% and specificity was 96% and 76%, respectively. DISCUSSION: While aberrant p53 expression has been associated with an increased risk of progression to advanced neoplasia in patients with BE undergoing surveillance, the diagnostic characteristics are suboptimal precluding uniform clinical adoption. Prospective studies with standardized grading protocols are needed to determine whether p53-guided surveillance strategies can meaningfully improve patient outcomes.

Summary Central obesity is a risk factor for esophageal adenocarcinoma (EAC) independent of acid reflux. However, about a quarter of patients with Barrett’s esophagus (BE) and EAC have a normal body mass index (BMI). One hypothesis is that chronic systemic inflammation is as critical to the cancer pathway than the BMI alone. Therefore, we hypothesized that lean patients with BE/EAC would have a high prevalence of metabolic diseases. We aimed to compare metabolic diseases among lean patients with BE/EAC and overweight/obese BE/EAC and lean control without BE/EAC. We performed a propensity score–matched case–control study including patients with BE/EAC and a control group without BE/EAC from the Rochester Epidemiology Project (REP). The groups were compared using chi-square χ 2 and Student t-test as appropriate. Adjusted logistic regression models were used to compare the association with metabolic diseases. We included a total of 2504 patients (631 EAC, 621 BE, and 1252 controls). A quarter of patients (24.6%) with BE/EAC were lean. When compared to controls without BE/EAC, lean patients with BE were more likely to have diabetes (32.2% vs. 11.2%, P < 0.001) and hyperlipidemia (76.2% vs. 53%, P < 0.001). When comparing lean EAC patients to controls without BE/EAC, lean patients had a higher association with smoking (73.3% vs. 58.6%, P: 0.002) and diabetes (18.7% vs. 11.2%, P: 0.03). When compared to overweight/obese BE patients, lean BE were less likely to have NASH (7.7% vs. 20.3%, P: 0.001), diabetes (32.3% vs. 42.1%, P: 0.03), hyperlipidemia (77.2% vs. 87%, P: 0.003), and metabolic syndrome (24% vs. 54%, P < 0.001). Similarly, when compared to overweight/obese patients with EAC, lean EAC patients were less likely to have NASH (0% vs. 15.5%, P < 0.001), diabetes (18.7% vs. 34.1%, P < 0.001), hyperlipidemia (37.3% vs. 51.8%, P: 0.002), hypertension (37.3% vs. 55.3%, P < 0.001), and metabolic syndrome (8% vs. 37.6%, P < 0.001). A quarter of patients with BE/EAC are lean. Although lean BE/EAC patients have a more favorable metabolic profile compared to overweight/obese BE/EAC patients, diabetes and smoking are more common among lean patients with EAC compared to lean controls. The higher association with smoking and diabetes among lean EAC challenges traditional risk factor paradigms, suggesting a significant role for insulin resistance and chronic inflammation in EAC pathogenesis, especially in patients without typical risk factors. BMI-determined obesity may need to be supplemented with inflammatory metabolic diseases to improve assessment of BE/EAC risk in lean patients.

INTRODUCTION: Current guidelines recommend endoscopic surveillance of Barrett's esophagus (BE) but do not account for competing mortality unrelated to esophageal cancer (EC). We conducted a systematic review and meta-analysis to estimate EC and non-EC mortality risk in BE patients. METHODS: We searched multiple databases for studies reporting mortality in BE. We included population-based studies providing standardized mortality ratio (SMR). The primary outcome was SMR from all causes and EC and non-EC etiologies. SMR was calculated by dividing the observed mortality over the expected mortality. Logarithmic form of SMRs was pooled using random-effects model. RESULTS: Our search yielded 2,826 articles, of which 7 studies (n = 34,454) were included. All-cause mortality was elevated in BE patients compared with population controls (pooled SMR 1.24, 95% confident interval [CI] 1.01–1.53) driven in part by increased EC mortality risk (SMR 8.98, 95 CI 5.12–15.77). The mortality risk was still increased but attenuated after excluding EC mortality (SMR 1.21, 95% CI 1–1.46). There was no increased mortality risk of non-EC malignancies (SMR 1.22, 95% CI 0.82–1.82) or mortality due to noncancer etiologies (SMR 1.13, 95% CI 0.90–1.43). Death due to cardiovascular diseases was higher in BE (SMR 1.16, 95% CI 1.02–1.33). BE patients were 10 times more likely to die from noncancer etiologies than EC (risk ratio 10.71, 95% CI 5.98–19.16). Subgroup analysis of studies that excluded prevalent EC at baseline (3 studies) also showed increased all-cause (SMR 1.12, 95% CI 1.07–1.18) and EC mortality (SMR 4.7, 95% CI 3.58–6.17) among BE patients. DISCUSSION: BE patients exhibit a higher all-cause mortality, driven in part by risk of EC mortality. A personalized approach to surveillance, mitigating risk of EC while recognizing the broader mortality risks, is warranted.

Objective: We report the development and validation of a combined DNA/RNA next-generation sequencing (NGS) platform to improve the evaluation of pancreatic cysts. Background and Aims: Despite a multidisciplinary approach, pancreatic cyst classification, such as a cystic precursor neoplasm, and the detection of high-grade dysplasia and early adenocarcinoma (advanced neoplasia) can be challenging. NGS of preoperative pancreatic cyst fluid improves the clinical evaluation of pancreatic cysts, but the recent identification of novel genomic alterations necessitates the creation of a comprehensive panel and the development of a genomic classifier to integrate the complex molecular results. Methods: An updated and unique 74-gene DNA/RNA-targeted NGS panel (PancreaSeq Genomic Classifier) was created to evaluate 5 classes of genomic alterations to include gene mutations (e.g., KRAS, GNAS, etc.), gene fusions and gene expression. Further, CEA mRNA (CEACAM5) was integrated into the assay using RT-qPCR. Separate multi-institutional cohorts for training (n=108) and validation (n=77) were tested, and diagnostic performance was compared to clinical, imaging, cytopathologic, and guideline data. Results: Upon creation of a genomic classifier system, PancreaSeq GC yielded a 95% sensitivity and 100% specificity for a cystic precursor neoplasm, and the sensitivity and specificity for advanced neoplasia were 82% and 100%, respectively. Associated symptoms, cyst size, duct dilatation, a mural nodule, increasing cyst size, and malignant cytopathology had lower sensitivities (41–59%) and lower specificities (56–96%) for advanced neoplasia. This test also increased the sensitivity of current pancreatic cyst guidelines (IAP/Fukuoka and AGA) by >10% and maintained their inherent specificity. Conclusions: PancreaSeq GC was not only accurate in predicting pancreatic cyst type and advanced neoplasia but also improved the sensitivity of current pancreatic cyst guidelines.

AimsBarrett's oesophagus with indefinite for dysplasia (BE‐IND) is a subjective diagnosis with a low interobserver agreement (IOA) among pathologists and uncertain clinical implications. This study aimed to assess the utility of p53 immunohistochemistry (p53‐IHC) in assessing BE‐IND specimens.Methods and resultsArchive endoscopic biopsies with a BE‐IND diagnosis from two academic centres were analysed. First, haematoxylin and eosin‐stained slides (H&E) were reviewed by four expert gastrointestinal (GI) pathologists allocated into two groups (A and B). After a washout period of at least 8 weeks, H&E slides were reassessed side‐to‐side with p53‐IHC available. We compared the rate of changed diagnosis and the IOA for all BE grades before and after p53‐IHC. We included 216 BE‐IND specimens from 185 patients, 44.0 and 32.9% of which were confirmed after H&E slide revision by groups A and B, respectively. More than half the cases were reclassified to a non‐dysplastic BE (NDBE), while 5.6% of cases in group A and 7.4% in group B were reclassified to definite dysplasia. The IOA for NDBE, BE‐IND, low‐grade dysplasia (LGD) and high‐grade dysplasia (HGD)/intramucosal cancer (IMC) was 0.31, 0.21, −0.03 and −0.02, respectively. Use of p53‐IHC led to a >40% reduction in BE‐IND diagnoses (P < 0.001) and increased IOA for all BE grades [κ = 0.46 (NDBE), 0.26 (BE‐IND), 0.49 (LGD), 0.35 (HGD/IMC)]. An aberrant p53‐IHC pattern significantly increased the likelihood of reclassifying BE‐IND to definite dysplasia (odds ratio = 44.3, 95% confidence interval = 18.8–113.0).ConclusionP53‐IHC reduces the rate of BE‐IND diagnoses and improves the IOA among pathologists when reporting BE with equivocal epithelial changes.

AbstractBackground and study aims Endoscopic submucosal dissection (ESD) is technically challenging, difficult to learn, and carries a substantial risk of perforation, all of which remain significant barriers to its adoptability. We aimed to determine whether use of a novel scissor-type knife improved efficacy and safety among novice performers of ESD.Materials and methods Following a brief didactic session on ESD, participants performed ESD of two lesions (2 cm diameter) in an ex vivo porcine gastric model. One resection was performed with a conventional knife and the other with the scissor knife (order of knife randomized). We recorded procedure time, successful en bloc resection, and adverse events (including full-thickness perforation and muscle injury) for each dissection. Participants completed a post-study survey.Results 10 endoscopists (8 trainees, 2 staff) considered novices in ESD participated. Compared with the conventional knife, use of the scissor knife was associated with a significantly shorter time to completion of submucosal dissection (mean 6.2 [SD 5.6] vs. 15.6 [SD 15.6] minutes; P = 0.04) and total procedure time was not significantly different (22.1 [SD 13.3] vs. 24.9 [SD 26.5] minutes; P = 0.65). Scissor knife use was also associated with a significantly lower proportion of perforation and/or muscle injury (10.0 % vs. 70.0 %; P < 0.01) and proportion of muscle injury alone (10.0 % vs. 60.0 %; P = 0.02).Conclusions Among novices performing ESD on an ex vivo animal model, use of a scissor knife was associated with a significantly lower proportion of adverse events without prolonging procedure time. Scissor-type knives may improve ESD safety, at least among novices.

Abstract Background and aims Endoscopic resections are associated with bleeding and perforation and may be managed with through-the-scope (TTS) clips, over-the-scope clips and endoscopic suturing. The aim of this preclinical study was to compare technical success of closure using a novel TTS tissue helix tack and suture device (X-Tack) to TTS clips in a porcine model. Materials and methods Four subjects underwent 40 mucosal resections, diameter range 25–50 mm, in the stomach (n = 24) and colon (n = 16). Closures were randomized to X-Tack (n = 24) or clip (n = 16). Animals underwent weekly endoscopic follow-up for 4 weeks. Results Technical closure with X-Tack was successful in 24 of 24 (100 %) cases and with clips in 13 of 16 cases (81.3 %) (P = 0.0001). One colonic perforation occurred and was successfully managed using X-Tack. The rate of healing was not statistically different between the groups, and all sites healed at 4 weeks including the perforation and were confirmed by histology. Conclusions Compared to TTS clip, X-Tack is superior for effecting large mucosal defect closure, including durable sealing of full-thickness perforation. There was no difference in rate of healing between devices.

AbstractBackground:Esophageal adenocarcinoma is a lethal cancer with rising incidence. There are limited data in younger (&lt;50 years) patients with esophageal adenocarcinoma. We aimed to assess time trends in the incidence and outcomes of “young-onset” esophageal adenocarcinoma using a population-based database.Methods:We queried the Surveillance, Epidemiology, and End Results 9 database to identify patients with esophageal adenocarcinoma between 1975 and 2015. Patients were stratified into three age strata: &lt;50, 50 to 69, and ≥70 years. Staging was stratified as localized, regional, and distant. Trends in incidence, disease stage, and survival were assessed in three periods (1975–89, 1990–99, and 2000–2015). Univariate and multivariate models were created to identify predictors of mortality.Results:Esophageal adenocarcinoma incidence has increased in patients &lt;50 years of age, with an annual percentage change of 2.9% (95% confidence interval, 1.4%–4.4%) from 1975 to 2015. Young-onset esophageal adenocarcinoma presented at more advanced stages (regional + distant) compared with older patients (84.9% vs. 67.3%; P &lt; 0.01), with increasing proportion of advanced stages over the study period. These patients also experienced poorer 5-year esophageal adenocarcinoma–free survival compared with older patients (22.9%% vs. 29.6%; P &lt; 0.01), although this finding was attenuated on stage-stratified analysis.Conclusions:Young-onset esophageal adenocarcinoma, while uncommon, is rising in incidence. Concerningly, the proportion of advanced disease continues to increase. Young-onset esophageal adenocarcinoma also presents at more advanced stages, resulting in poorer esophageal adenocarcinoma–free survival.Impact:Patients with esophageal adenocarcinoma younger than 50 years present at more advanced stages with higher esophageal adenocarcinoma–specific mortality compared with older peers. Current diagnostic and management strategies for young-onset esophageal adenocarcinoma may need to be reevaluated.