Individual risk calculator to predict lymph node metastases in patients with submucosal (T1b) esophageal adenocarcinoma: a multicenter cohort study.

BACKGROUND: Lymph node metastasis (LNM) is possible after endoscopic resection of early esophageal adenocarcinoma (EAC). This study aimed to develop and internally validate a prediction model that estimates the individual risk of metastases in patients with pT1b EAC. METHODS: A nationwide, retrospective, multicenter cohort study was conducted in patients with pT1b EAC treated with endoscopic resection and/or surgery between 1989 and 2016. The primary end point was presence of LNM in surgical resection specimens or detection of metastases during follow-up. All resection specimens were histologically reassessed by specialist gastrointestinal pathologists. Subdistribution hazard regression analysis was used to develop the prediction model. The discriminative ability of this model was assessed using the c-statistic. RESULTS: 248 patients with pT1b EAC were included. Metastases were seen in 78 patients, and the 5-year cumulative incidence was 30.9 % (95 % confidence interval [CI] 25.1 %-36.8 %). The risk of metastases increased with submucosal invasion depth (subdistribution hazard ratio [SHR] 1.08, 95 %CI 1.02-1.14, for every increase of 500 µm), lymphovascular invasion (SHR 2.95, 95 %CI 1.95-4.45), and for larger tumors (SHR 1.23, 95 %CI 1.10-1.37, for every increase of 10 mm). The model demonstrated good discriminative ability (c-statistic 0.81, 95 %CI 0.75-0.86). CONCLUSIONS: A third of patients with pT1b EAC experienced metastases within 5 years. The probability of developing post-resection metastases was estimated with a personalized predicted risk score incorporating tumor invasion depth, tumor size, and lymphovascular invasion. This model requires external validation before implementation into clinical practice.

Nonthermal resection device for ablation of Barrett's esophagus: a feasibility and safety study.

BACKGROUND: Several techniques exist for the eradication of Barrett's esophagus (BE); however, all have limitations regarding successful conversion to squamous epithelium and a complication profile. We aimed to assess the feasibility and safety of a new nonthermal device, the EndoRotor, for the eradication of BE as a first-line ablation technique. METHODS: Patients with BE were prospectively included at two tertiary referral centers in The Netherlands. INCLUSION CRITERIA: BE length 2-5 cm, with low grade dysplasia, high grade dysplasia, or residual BE after endoscopic resection (ER) of a lesion containing early neoplasia. EXCLUSION CRITERIA: previous ER > 50 % circumference, or previous ablation therapy. Follow-up endoscopy was performed 3 months after ablation therapy. Outcomes were the percentage of endoscopically visible BE surface regression and complications. RESULTS: 30 patients were included (age 66 years, interquartile range [IQR] 59-73, median BE C0M3, 25 male). Overall, 18 patients underwent ER prior to ablation. Median percentage BE ablated was 100 % (IQR 94 %-100 %). Median visual BE surface regression at 3-month follow-up was 80 % (IQR 68 %-95 %). Multiple residual Barrett's islands were commonly seen. Six patients (20 %) had a treatment-related complication requiring intervention, including one perforation (3 %), one postprocedural hemorrhage (3 %), and four strictures (13 %). Post-procedural pain was reported in 18 patients (60 %). CONCLUSIONS: Endoscopic ablation of BE using this novel nonthermal device was found to be technically demanding, with a longer procedure time compared with established ablation techniques and a high complication rate. Based on these results, we do not recommend its use as a first-line ablation technique for the eradication of BE.

Lymphovascular invasion quantification could improve risk prediction of lymph node metastases in patients with submucosal (T1b) esophageal adenocarcinoma.

AIM: To quantify lymphovascular invasion (LVI) and to assess the prognostic value in patients with pT1b esophageal adenocarcinoma. METHODS: In this nationwide, retrospective cohort study, patients were included if they were treated with surgery or endoscopic resection for pT1b esophageal adenocarcinoma. Primary endpoint was the presence of metastases, lymph node metastases, or distant metastases, in surgical resection specimens or during follow-up. A prediction model to identify risk factors for metastases was developed and internally validated. RESULTS: 248 patients were included. LVI was distributed as follows: no LVI (n = 196; 79.0%), 1 LVI focus (n = 16; 6.5%), 2-3 LVI foci (n = 21; 8.5%) and ≥4 LVI foci (n = 15; 6.0%). Seventy-eight patients had metastases. The risk of metastases was increased for tumors with 2-3 LVI foci [subdistribution hazard ratio (SHR) 3.39, 95% confidence interval (CI) 2.10-5.47] and ≥4 LVI foci (SHR 3.81, 95% CI 2.37-6.10). The prediction model demonstrated a good discriminative ability (c-statistic 0.81). CONCLUSION: The risk of metastases is higher when more LVI foci are present. Quantification of LVI could be useful for a more precise risk estimation of metastases. This model needs to be externally validated before implementation into clinical practice.

Olfactomedin 4 (OLFM4) expression is associated with nodal metastases in esophageal adenocarcinoma.

To date no informative biomarkers exist to accurately predict presence of lymph node metastases (LNM) in esophageal adenocarcinoma (EAC). We studied the discriminative value of Olfactomedin 4 (OLFM4), an intestinal stem cell marker, in EAC. Patients who had undergone esophagectomy as single treatment modality for both advanced (pT2-4) and early (pT1b) adenocarcinoma of the esophagus or gastro-esophageal junction were selected for this study from an institutional database (Erasmus MC University Medical Center, Rotterdam, The Netherlands). Surgical resection specimens of 196 advanced and 44 early EAC were examined. OLFM4 expression was studied by immunohistochemistry and categorized as low (<30%) or high (> = 30%) expression. Low OLFM4 was associated with poor differentiation grade in both advanced (60% vs. 34.8%, p = 0.001) and early EAC (39.1% vs. 9.5%, p = 0.023). LNM were present in 161 (82.1%) of advanced and 9 (20.5%) of early EAC respectively. Low OLFM4 was independently associated with the presence of LNM in advanced EAC in multivariable analysis (OR 2.7; 95% CI, 1.16-6.41; p = 0.022), but not in early EAC (OR 2.1; 95% CI, 0.46-9.84; p = 0.338). However, the difference in association with LNM between advanced (OR 2.7; 95% CI, 1.18-6.34; p = 0.019) and early (OR 2.3; 95% CI, 0.47-11.13; p = 0.302) EAC was non-significant (p = 0.844), suggesting that the lack of significance in early EAC is due to the small number of patients in this group. OLFM4 was not of significance for the disease free and overall survival. Overall, low expression of intestinal stem cell marker OLFM4 was associated with the presence of LNM. Our study suggests that OLFM4 could be an informative marker with the potential to improve preoperative assessment in patients with EAC. Further studies are needed to confirm the value of OLFM4 as a biomarker for LNM.

Do pathologists agree with each other on the histological assessment of pT1b oesophageal adenocarcinoma?

Background: In early (T1) oesophageal adenocarcinoma (OAC), the histological profile of an endoscopic resection specimen plays a pivotal role in the prediction of lymph node metastasis and the potential need for oesophagectomy with lymphadenectomy. Objective: To evaluate the inter-observer agreement of the histological assessment of submucosal (pT1b) OAC. Methods: Surgical and endoscopic resection specimens with pT1b OAC were independently reviewed by three gastrointestinal pathologists. Agreement was determined by intraclass correlation coefficient for continuous variables, and Fleiss' kappa (κ) for categorical variables. Bland-Altman plots of the submucosal invasion depth were made. Results: Eighty-five resection specimens with pT1b OAC were evaluated. The agreement was good for differentiation grade (κ=0.77, 95% confidence interval (CI) 0.68-0.87), excellent for lymphovascular invasion (κ=0.88, 95% CI 0.76-1.00) and moderate for submucosal invasion depth using the Paris and Pragmatic classifications (κ=0.60, 95% CI 0.49-0.72 and κ=0.42, 95% CI 0.33-0.51, respectively). Systematic mean differences between pathologists were detected for the measurement of submucosal invasion depth, ranging from 297 µm to 602 µm. Conclusions: A substantial discordance was found between pathologists for the measurement of submucosal invasion depth in pT1b OAC. Differences may lead to an over- or underestimation of the lymph node metastasis risk, with grave implications for the treatment strategy. Review by a second gastrointestinal pathologist is recommended to improve differentiating between a favourable and an unfavourable histological profile.

Self-sizing radiofrequency ablation balloon for eradication of Barrett's esophagus: results of an international multicenter randomized trial comparing 3 different treatment regimens.

BACKGROUND AND AIMS: Recently, the 360 Express radiofrequency ablation balloon catheter (360 Express, Medtronic, Minneapolis, Minn, USA) has replaced the traditional system for circumferential radiofrequency ablation (RFA) of Barrett's esophagus (BE). The aim was to compare 3 different ablation regimens for the 360 Express. METHODS: An international multicenter noninferiority randomized controlled trial was conducted in which patients with a BE (2-15 cm) with dysplasia or early cancer were randomly assigned to the standard (1 × 10 J/cm2-clean-1 × 10 J/cm2), simple-double (2 × 10 J/cm2-no clean), or simple-single ablation regimen (1 × 10 J/cm2-no clean). The primary outcome was the percentage endoscopically visual BE regression at 3 months. Secondary outcomes were procedure time, adverse events, and patient discomfort. RESULTS: Between September 2015 and October 2017, 104 patients were enrolled. The simple-double ablation arm was closed prematurely because of a 21% stenosis rate. The trial continued with the standard (n = 37) and simple-single arm (n = 38). Both arms were comparable at baseline. Noninferiority of the simple-single arm could not be demonstrated: BE regression was 73% in the simple-single arm versus 85% in the standard arm; the median difference was 13% (95% confidence interval, 5%-23%). The procedure time was significantly longer in the standard arm (31 vs 17 minutes, P < .001). Both groups were comparable with regard to adverse events and patient discomfort. CONCLUSIONS: This randomized trial shows that circumferential RFA with the 360 Express using the simple-double ablation regimen results in an unacceptable high risk of stenosis. Furthermore, the results suggest that a single ablation at 10 J/cm2 results in inferior BE regression at 3 months. We therefore advise using the standard ablation regimen (1 × 10 J/cm2-clean-1 × 10 J/cm2) for treatment of BE using the 360 Express. (Clinical trial registration number: NTR5191.).

Exploring diagnostic and therapeutic implications of endoscopic mucosal resection in EUS-staged T2 esophageal adenocarcinoma.

Background and study aims Treatment strategies for clinical (c)T2N0M0 esophageal adenocarcinoma (EAC) are subject to debate owing to the relative inaccuracy of tumor staging by endoscopic ultrasound (EUS), with profound implications in overstaged patients. We aimed to evaluate the final histological diagnosis of patients initially staged as having a cT2 tumor by EUS, and to assess the value of endoscopic reassessment by an interventional endoscopist, followed by an endoscopic resection when deemed feasible. Patients and methods Two distinct cohorts of patients with cT2 EAC as determined by EUS were included: a retrospective surgical cohort of patients treated by primary esophagectomy, and a prospective cohort of patients who underwent an endoscopic reassessment by an interventional endoscopist. The main outcome measure was the final pathological (p)T stage. Results We identified 134 patients with stage T2 EAC from the surgical cohort. In 72 patients treated by primary esophagectomy, 32/72 (44 %) were downstaged to a pT1 tumor. In 12/72 (17 %), the surgical resection specimen showed tumor characteristics that fulfilled the current criteria for a curative endoscopic resection. In 13 prospectively identified patients with cT2N0M0 EAC, an expert endoscopic reassessment was done. In 11/13 (85 %) the lesion appeared endoscopically resectable and a complete endoscopic resection was performed. Histology revealed a pT1 tumor in all 11 patients, with 5/13 (38 %) fulfilling current criteria for a curative endoscopic resection. Conclusions In this study, 44 % of cT2 EACs were in fact pT1 tumors. Curative treatment by endoscopic resection was achieved in more than a third of these cases. To avoid an unnecessary esophagectomy, an endoscopic reassessment by an interventional endoscopist is recommended for all patients with cT2N0M0 EAC.