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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

Background: Endoscopic radiofrequency ablation (RFA) has shown good efficacy and safety in eradicating flat-type early esophageal squamous cell neoplasia (ESCN). However, post-RFA stricture is still a major concern, especially when treating long-segment early ESCNs. The aim of this study was to investigate the efficacy and safety of oral prednisolone to prevent post-RFA stricture.
Methods: We prospectively enrolled 48 patients treated with balloon-type RFA who had Lugol-unstained or mosaic-like flat-type ESCNs with an expected treatment area more than 10 cm. Oral prednisolone was started at a dose of 30 mg/day on the third day after RFA and continued for 4 weeks. The results were compared to a historical control group of 25 patients who received RFA without oral steroids (Figure 1). The primary endpoint was the frequency of post-RFA stricture (Figure 2 A-D). Secondary endpoints were the number of balloon dilation sessions and the adverse event rate.
Results: There were no significant differences in the worst pathology grade at baseline, length of unstained lesions between the two groups. The complete response rates after 1 session of RFA were 73% and 72%, respectively. Compared to the control group, the oral prednisolone group had a significantly lower stricture rate (4%, 2/48 patients vs. 44%, 11/25 patients; P<0.0001) and a lower number of balloon dilation sessions (median 0, range 0-4 vs. median 6, range 0-10). There were two cases of asymptomatic candida esophagitis in the study group, and no severe adverse effects.
Conclusions: The oral administration of prednisolone showed promising results in preventing post-RFA stricture (Figure 2 E-H) for long-segment early ESCNs.

Background: Endoscopic submucosal dissection (ESD) for Barrett’s esophageal adenocarcinoma (EAC) is increasingly supported by societal guidance. While definitions of pathologically curative vs. non-curative ESD exist, data concerning how these definitions operate, as well as rates of recurrent malignancy over long periods of surveillance, are lacking. We hypothesize that ESD of EAC fulfilling criteria for pathologically curative resection will result in low rates of local/distant recurrence.

Methods: A multicenter retrospective study (including 6 academic centers from a larger collaborative in North America) was performed that included only patients who underwent ESD of EAC with endoscopic ± imaging surveillance for ≥1 year or until recurrence. We assessed demographic and procedural outcomes including rates of pathologically curative resection (R0, moderately/well differentiated, lack of lymphovascular invasion, and if T1b with submucosal invasion <500 µm). Primary outcomes included rates of recurrence, development of a metachronous lesion, and location of recurrence (i.e., local or distant/metastatic).

Results: 112 patients underwent ESD for EAC. Patients were predominantly male and Caucasian with median age of 70 years (Table 1A). Median tumor size on pathology was 26 mm, and 98% of tumors were located in the distal esophagus. 74 (66%) EACs were T1a, 37 (33%) were T1b, and 1 was unspecified T1. En bloc resection was achieved in 96% and complete histologic resection (R0) was achieved in 77%. 54 patients (48%) met criteria for curative resection and had endoscopic surveillance. 39 (35%) patients underwent endoscopic surveillance due to patient preference or comorbidities precluding surgery. The remaining 19 patients (17%) underwent surgical resection. Median follow-up was 35 months (IQR 20-50 months), which included a median of 3 endoscopies and 1 imaging study. Recurrences were less likely to occur in the curative resection group compared to non-curative resections followed endoscopically (11% vs. 28%, P=0.04), which was supported by multivariate analysis (OR 3.0 for non-curative, CI [1.0, 9.4], P=0.05; Table 1B). Median time to local or metastatic recurrence was 4-5 months in both groups. There was no significant difference in recurrence over time for patients with curative resection vs. those with non-curative resection who then underwent surgical resection (Figure 1).

Discussion: ESD of EAC with a pathologically curative resection results in very low rates of local or metastatic recurrence (2%) when performed in North American centers. Recurrence rates were significantly higher in those who did not achieve curative resection and were unwilling or unfit for surgery, which indicates that closer surveillance may be warranted in this population. As more patients undergo ESD for EAC, such data will help inform surveillance strategies.

Table 1

Figure 1

Introduction:
Dysphagia is a common complaint seen by gastroenterologists. The prevalence of dysphagia is around 10-22% in Americans aged 50 and over. Dysphagia is often due to obstructive etiologies but in a subset of patients no etiology is identified, and endoscopy is found to be normal. The guidelines are well defined on the management of dysphagia using dilation techniques in obvious mechanical obstruction. However, although empiric dilation is commonly performed on non-obstructive dysphagia, there are conflicting data as to its benefit. The aim of this study is to assess outcomes of empiric esophageal Savary dilation in patients with non-obstructive dysphagia.
Methods:
This is a retrospective case series at a single, tertiary care center. Patients who had an esophagogastroduodenoscopy (EGD) for dysphagia from 2011-2021, and who had empiric dilation using wire-guided Savary dilators were included. Patients with obstructive dysphagia or known esophageal dysmotility were excluded. Baseline characteristics recorded were age, gender, race, beginning and end diameter of dilator, number of additional dilations, and interval between first and second EGD for dilation. Primary outcome was to assess for improvement in dysphagia ascertained from patient reports during clinic follow up visits or phone encounter. Secondary outcomes included admissions within 12 months related to dysphagia or food impactions, change in weight, and post-procedure adverse events.
Results:
A total of 132 patients were included in the cohort as described in Table 1. The mean age was 63.8 years (19-97 years), 91/132 (68.9%) were female and 112/132 (84.8%) of patients were white. The mean beginning and end diameter of dilator in the initial EGD was around 19 mm. There were 72/132 (54.5%) patients who reported that their dysphagia improved after dilation and 18/132 (13.6%) reported no improvement after dilation, with 42/132 (31.8%) who failed to follow up. Also, 41/73 (56.2%) were noted to have weight gain at 9-15 months after initial dilation, and 32/73 (43.8%) lost weight but the majority was non-significant (< 5% of total body weight). Furthermore, 101/132 (76.5%) of patients did not have any additional dilations, while 31/132 (23.5%) required at least one additional dilation. One patient was admitted to the hospital within 12 months after dilation for a food impaction, and one patient for dysphagia. No procedure-related adverse events were reported.
Conclusion:
Given that most of our patients reported improvement in their dysphagia, and given the lack of adverse events related to dilation, it can be concluded that empiric esophageal dilation using wire-guided Savary dilators is safe, and can offer benefit in non-obstructive dysphagia.

Background: In a preliminary study, we documented complete response (CR) rate > 50% with a single session of liquid nitrogen spray cryotherapy (LNSC) administered prior to chemoradiation (CRT). LNSC is hypothesized to stimulate an anti-tumor immune response. Our aim was to assess safety, maximally tolerated dose (MTD), and immune effects of LNSC during neoadjuvant CRT in locally advanced esophageal cancer.

Methods: Eligible adult patients with locally advanced esophageal cancer were prospectively enrolled in this 3 + 3 + 3 Phase 1 dose frequency escalation study (Figure 1). Patients were contacted 48 hours and 1-week post-procedure to evaluate for procedure related toxicities and change in dysphagia and quality of life (QOL) using the Mellow-Pinkas and EORTC QLQ-OES18 instruments respectively. The relationship of an adverse event to LNSC and its severity was adjudicated by an independent data safety monitoring committee. We measured high mobility group box 1 (HMGB1) protein levels on enzyme linked immunosorbent assay (ELISA) of peripheral blood obtained at baseline and 2 weeks after LNSC (before CRT). HMGB1 acts on Toll Like Receptor 4 to present antigens from dying tumor cells, and inversely correlates with response to anti-cancer immunotherapy.

Results: 14 patients were prospectively enrolled. 3 patients completed 2 sessions of LNSC, and 6 completed 3 sessions of LNSC (Figure 2). No patients experienced grade 2 toxicity (G2T) or G3T. The most common adverse event was self-limited chest pain, which occurred in 8/14 patients during at least one session of LNSC (all classified as grade 1). One patient reported hemoptysis without any drop in hemoglobin level (grade 1). There was no cryotherapy related toxicity that resulted in delay or discontinuation of chemoradiation. Mean dysphagia score improved compared to baseline by 0.4, 0.7, and 0.6 at one week following the 1^st, 2^nd, and 3^rd sessions of LNSC respectively. QoL score improved from 37 at baseline to 31, 29, and 34 at 1 week after the 1^st, 2^nd, and 3^rd session respectively (p-value 0.001, 0.008, and 0.3 respectively). Only 2 patients required a feeding tube during CRT, and no patients received an esophageal stent. 50% of patients who completed at least 2 sessions of LNSC had a complete CR after CRT. HMGB1 decreased by >25% in ~40% of patients.

Discussion: 3 sessions of LNSC in the neoadjuvant chemoXRT setting did not result in any G2T or G3T. When administered prior to chemoXRT, LNSC significantly improved QoL, and clinical CR was more common than reported with current standard of care (SoC) neoadjuvant regimens. LNSC may enhance response to CRT by stimulating immune cell death. Our results provide a compelling rationale to conduct a larger randomized trial comparing 2-3 sessions of LNSC + neoadjuvant SoC vs. neoadjuvant SoC alone in locally advanced esophageal cancer.

Figure 1: Schematic of dose escalation and de-escalation criteria

Figure 1: Schematic of dose escalation and de-escalation criteria

Figure 2: Eligibility criteria, reasons for withdrawal after enrollment

Figure 2: Eligibility criteria, reasons for withdrawal after enrollment

Background: A tumor-positive vertical margin (R1v) is considered a risk factor for residual cancer after endoscopic resection (ER) of early neoplasia in Barrett’s esophagus (BE). Additional surgery is advocated after an R1v resection, but often no residual tumor is detected in the surgical resection specimen. We aimed to assess the risk of local residual cancer in patients with a histologically confirmed R1v after ER.

Methods: We included patients treated with ER for BE neoplasia since 2008 in the Dutch Barrett Expert Centers, with documented R1v. Digital pathology slides of the resection specimens were re-assessed by 4 expert pathologists until consensus was reached regarding the vertical margin. Vertical R1 resections were defined as cancer cells touching the vertical margin. The primary outcome was the presence of residual cancer.

Results: 110 patients were included, which were treated with EMR (n=74) and ESD (n=36) for T1a (n=19) and T1b (n=91) cancer. The ER specimens of 108 (98%) patients were re-assessed, revealing confirmation of R1v in 78 (72%) patients and Rx/R0 in 30 patients (28%). Reasons for doubtful or not assessable (Rx) vertical margins included tangential cutting (20%), suboptimal embedding (12%), curled lateral margins (9%), and cauterization artefacts (8%). Seven patients with confirmed R1v had no follow-up. Among remaining confirmed R1v (n=71), residual cancer was present in 29 (41%) patients, either detected in the surgical specimen (n=10), during endoscopic scar assessment after ER (n=13), or both (n=8) (Figure 1). Endoscopic scar assessment detected all residual cancers in patients treated with additional surgery after ER (n=6). The risk of residual cancer was higher but not significantly increased with increasing tumor width in the vertical margin (OR 1.44, 95% CI 0.95-2.18 for every increase of 1000µm).

Conclusion: No residual cancer was present in 59% of the patients with a confirmed vertical R1 margin after endoscopic resection. The pathological assessment of vertical R1 margins appears challenging, as only 72% of documented vertical R1 cases were confirmed during re-assessment. The tumor width in the vertical margin might be useful to identify patients at highest risk of residual cancer after ER with R1v.

P.J.F. De Jonge

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