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INTRODUCTION
Current guidelines advise esophagectomy for submucosal esophageal adenocarcinoma (T1b EAC). However, data from retrospective studies suggest that endoscopic follow-up (FU) may be a valid alternative in patients without signs of lymph node metastases (LNM) at baseline. In this international multicenter, prospective cohort study (NCT03222635), we aim to evaluate the safety of a watchful waiting strategy with regular endoscopic FU in patients treated endoscopically for T1b EAC.

METHODS
This ongoing prospective study is conducted in 19 hospitals in Europe and Australia, and aims to include 141 patients with 5-year FU. After radical endoscopic resection of T1b EAC, patients are re-staged with endoscopic ultrasound (EUS) and CT/PET. In the absence of LNM or distant metastases (N0M0), and upon consent for endoscopic FU, patients are included and undergo strict endoscopic FU with gastroscopy and EUS every 3 months during year 1 and 2, every 6 months during year 3 and 4, and at year 5. CT/PET is repeated after 1 year. We divided our cohort into two groups: high-risk (submucosal invasion ≥500um, a/o poorly/undifferentiated tumor (G3-4), a/o lymphovascular invasion (LVI+)), and low-risk if high risk features are absent. Primary outcome parameters are 5-year disease specific survival and overall survival; secondary outcome parameters are rate of LNM and local recurrence.

RESULTS
Since July 2017, 120 patients (100 men, median 68 yrs) were included with a median FU of 22 (IQR 10-32) months: 80 high-risk and 40 low-risk patients. 6 patients (5% [95CI 1.0-9.0]) were diagnosed with LNM (table 1) after median FU of 8 (IQR 5-16) months. Of these 6 patients, 2/6 were referred for neoadjuvant chemo(radio)therapy with esophagectomy (ypT0N0M0, ypT0N1M0), 1/6 underwent esophagectomy only (pT0N2M0), 3/6 underwent selective surgical resection of the tumor-positive LN.

7 patients (6% [95CI 2.0-10.0] were diagnosed with an intra-luminal tumor recurrence not eligible for endoscopic re-treatment after median FU of 7 (IQR 6-15) months. 5 had initial ESD and 2 cap-based EMR. Of these 7 patients, 2/7 underwent esophagectomy (pT1bN0M0, pTisN0M0), 1/7 had neoadjuvant chemoradiotherapy and esophagectomy (ypT1aN0M0), 2/7 underwent chemoradiotherapy only, 1/7 had palliative radiotherapy, 1/7 refused additional treatment. No distant metastases were diagnosed during FU in both cohorts. 6 patients died, all non EAC-related deaths. 3 patients discontinued FU due to old age. 2 patients were lost to FU.

CONCLUSION
The interim analysis from our ongoing prospective study suggest that in patients with radically removed high- or low-risk T1b EAC, without LNM at baseline, a strict endoscopic follow-up protocol is feasible and curative therapy remains possible in those patients who develop LNM (5%) or a local intra-luminal recurrence (6%) during FU. Most patients demonstrate uneventful FU.

Background: Objective assessments of esophageal varices (EVs) are inadequate. The recurrence of variceal bleeding after endoscopic variceal ligation (EVL) is associated with residual blood flow underlying EVL or incomplete treatment of perforating veins connecting to the EVs. To overcome these problems, we established the novel through-the-scope Doppler probe method (DOP), which has advantages in managing EVs (Fig. 1). This study aimed to develop a strategy for managing EVs and validate it.
Methods: The first study included 54 varices of 20 patients with a history of esophageal variceal rupture from June 2019 to December 2020 who underwent DOP at a tertiary hospital. Variceal velocities were compared based on the size and endoscopic variceal findings. In addition, we assessed the effectiveness of our strategy to reduce the recurrence of variceal bleeding in twelve patients with EVs from January 2021 to July 2021.
Results: Doppler imaging was observed in all 54 varices. The velocity of varices (cm/s) was significantly higher in EVs with a larger size (y = 1.567x – 1.329, R²= 0.826), greater form (F1, 4.03 ± 1.22; F2, 8.75 ± 1.91; F3, 10.75 ± 2.87; P=0.02), blue color (blue 7.68 ± 2.94 vs white 4.04 ± 1.54; P<0.001), and red color sign positive (RC-positive 9.33 ± 2.40 vs. RC-negative 4.22 ± 1.31; P<0.001). We developed the strategy for managing EVs based on the results (Fig. 2). The cutoff value for EV velocity (>5 cm/s to treat) was correlated with EV color (blue vs. white; the area under the curve was 0.89). In the validation study, perforating veins were identified in nine out of twelve patients who underwent DOP. Repeat EVL was performed until the variceal velocity reached decreased value (≤5 cm/s). No recurrence of variceal bleeding occurred during the follow-up period (mean 11.7 ± 3.2 months). No adverse events associated with DOP were observed.
Conclusion: This was the first study on the evaluation of the hemodynamics of EVs using DOP. EV velocities were related to the variceal size, form, blue color, and red color sign positive. The Developed strategy using DOP may be an objective and effective treatment for EVs. Further large-scale, long-term comparative studies are warranted.

Benefits of DOP: (<b>1</b>) Risk stratification according to variceal velocities, (<b>2</b>) Identification of perforating veins, (<b>3</b>) Confirmation of reduced blood flow after EVL, and (<b>4</b>) avoiding EVL for downhill cases. Each red arrow means blood stream of varices. Black bar represents the band after EVL.

Benefits of DOP: (1) Risk stratification according to variceal velocities, (2) Identification of perforating veins, (3) Confirmation of reduced blood flow after EVL, and (4) avoiding EVL for downhill cases. Each red arrow means blood stream of varices. Black bar represents the band after EVL.

A flow chart of the management of esophageal varices

A flow chart of the management of esophageal varices

Katsuyuki Fukuda

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