Introduction

Patients with Barrett’s esophagus (BE) have an increased risk of developing esophageal adenocarcinoma (EAC) and therefore surveillance is necessary. However, lesion detection with high-definition white light endoscopy (HD-WLE) and narrow-band imaging (NBI) is hampered by high miss rates. Previous phase II studies have confirmed the great potential of quantitative fluorescence molecular endoscopy (qFME) in combination with topically administered fluorescent tracers for lesion detection in BE. However, incubation time after topical tracer administration prolongs the procedure time by five minutes. In this ongoing clinical study, oral administration of bevacizumab-800CW, targeting vascular endothelial growth factor A (VEGFA), and cetuximab-800CW, targeting epidermal growth factor receptor (EGFR), is evaluated to improve both lesion detection and the clinical implementation of qFME.

Aims & Methods

A total of 30 patients with BE scheduled for a diagnostic and/or therapeutic endoscopy will be included. First 5 – 10 patients receive 4.5 mg and/or 9 mg oral bevacizumab-800CW before qFME. Subsequently, five patients will be included who receive 4.5 mg cetuximab-800CW orally before the diagnostic endoscopy, before their therapeutic endoscopy they receive a dose of 9 mg. The patients drink the tracer in two sips in an upright position ten minutes before qFME. qFME consisted of in vivo fluorescence signal visualization and quantification by multi-diameter single fiber reflectance / single fiber fluorescence (MDSFR/SFF) spectroscopy measurements on the mucosa. Additionally, biopsies are collected from non-dysplastic Barrett tissue and (suspected) dysplastic tissue and ex vivo analysis will be performed.

Results

Nine patients received 4.5 mg and/or 9 mg bevacizumab-800CW and five patients received 4.5 mg cetuximab-800CW. Oral administration of both tracers was well tolerated by all patients. No incubation time is needed after oral administration after the procedure. A higher fluorescence signal was seen in all visible lesions in vivo. 16 out of 17 endoscopically visible lesions were detected by qFME with bevacizumab-800CW or cetuximab-800CW and were pathologically confirmed to be dysplastic. We will conduct further analysis to evaluate target-to-background ratios and/or contrast-to-noise ratios in vivo. Additionally, quantitative in vivo fluorescence based on MDSFR/SFF spectroscopy will be assessed.

Conclusion

Our preliminary results show that qFME with oral administration of bevacizumab-800CW and cetuximab-800CW is feasible and, compared to topical administration, seems promising for shortening the procedure time, while remaining adequate in lesion detection. After completion of the cetuximab-800CW cohort, the optimal dosis and tracer will be determined and compared to combined administration of both tracers. Lastly, depending on what achieves the best in vivo results, either the optimal tracer or a combination of both tracers will be administered to five patients with non-dysplastic Barrett’s esophagus to test the specificity of our tracers.

Introduction

Esophageal squamous cell carcinoma (ESCC) often develops the synchronous or metachronous multiple ESCC. Although the Japanese guideline recommended endoscopic examination as surveillance at least once a year after endoscopic resection (ER) of ESCC, the optimal surveillance modality was not specified. In clinical practice, image-enhanced endoscopy (IEE) followed by Lugol chromoendoscopy (LCE) is commonly performed. While LCE reduces the proportion of missed lesion, it has low specificity and causes severe discomfort to the patients, so attempts have been made to omit Lugol's staining. It is unknown what lesions may be missed at this time point by omitting LCE in surveillance after esophageal ER.

Aims & Methods

Thus, this study aimed to clarify clinicopathological characteristics of synchronous or metachronous multiple ESCCs missed by IEE but detected by LCE in surveillance endoscopy after esophageal ER. We retrospectively analyzed the consecutive lesions that fulfilled all of the following inclusion criteria: (1) treated with endoscopic submucosal dissection (ESD) or endoscopic mucosal resection (EMR) at our institution between April 2021 and March 2022; (2) newly detected during surveillance endoscopy after ER or during preoperative endoscopy for other ESCC; (3) underwent narrow-band imaging (NBI) or blue laser imaging (BLI) observation followed by LCE observation in the esophagus using a high-definition endoscope at the endoscopic examination of lesion detection; and (4) biopsy-proven or strongly suspected squamous cell carcinoma. Patients with a history of chemotherapy, radiotherapy, or surgery for esophageal cancer were excluded. Lesions were classified into the IEE group (detected by NBI/BLI) and the LCE group (detected only after Lugol staining). The lesion in the IEE group were defined when the lesion was clearly visualized and in focus on the endoscopic images with NBI or BLI, or the endoscopic report described that it was detected with NBI/BLI. We evaluated the features of the lesions in the LCE group by comparing the clinicopathological characteristics between the lesions in the IEE group and LCE group. The endpoints were proportion of　LCE detected lesion and the proportion of target ESCC, defined as ESCC with pathological invasion depth of the muscularis mucosae (pT1a-MM) or deeper and/or positive lymphovascular invasion (LVI) on histological evaluation after ER.

Results

A total of 122 lesions in 96 patients were included. The IEE group comprised 99 lesions (81.1%) in 75 patients, while the LCE group comprised 23 lesions (18.9%) in 21 patients, thus proportion of LCE detected lesion was 18.9%. Most patients (92.7%, 89/96) had grade C of Lugol voiding staining. The median lesion size was 15 mm (range: 4-60 in the IEE group, which was higher than that in the LCE group at 10 mm (5-30). The lesions located on the anterior (23.5%) and left wall (31.3%) tended to be more frequently detected by LCE than those on the right (10.8%) and posterior wall (13.9%). Finally, 26 lesions were treated with EMR and 96 with ESD. The pathological diagnosis was pT1a-MM in 5 lesions and pT1b-SM1 in 2, resulting in the proportion of target ESCC of 5.7% (7/122). By group, the proportions of target ESCC were 7.1% (7/99) in the IEE group and 0% in the LCE group.

Conclusion

The characteristics of missed lesions in IEE observation tended to be small and located on the left or anterior wall of esophagus at surveillance endoscopy. Furthermore, all of these lesions were curatively resected with ER, resulting pT1a-EP/LPM without LVI in the pathological diagnosis.

Introduction

Quantitative fluorescence molecular endoscopy (qFME) enables real-time in vivo visualization and quantification of fluorescence and can thereby highlight tumor tissue. qFME has proven its potential in detection of lesions and residual disease but is limited to the mucosal side only^1,2. Ultrasound guided needle biopsy (USNB/SFF) single fiber fluorescence spectroscopy may enable assessment of lymph nodes and all tissue layers of the esophageal wall. This pilot study evaluated the clinical impact of USNB/SFF spectroscopy using the fluorescent tracer bevacizumab-800CW for the identification of residual tumor in patients with esophageal cancer.

Aims & Methods

Patients diagnosed with locally advanced esophageal adenocarcinoma scheduled for neoadjuvant chemoradiotherapy followed by surgery were included. Patients were intravenously injected with either 4.5, 10 or 25 mg bevacizumab-800CW 2-3 days prior to the qFME to establish the optimal dose. FME collected real-time white light and fluorescence images of the primary tumor site and normal esophageal tissue. Quantitative fluorescent measurements were acquired superficially using multi-diameter single fiber reflectance / single fiber fluorescence (MDSFR/SFF) and inside the esophageal wall and within lymph nodes using USNB-SFF spectroscopy. Additionally, the reduced scattering coefficient and absorption coefficient were determined from the MDSFR/SFF data.

Results

Fifteen patients were included in the dose-escalation, where 25 mg showed the best differentiation between primary tumor site and normal tissue and was extended with 3 additional patients (TBR: 2.63±0.60, p=0.0002). VEGF immunohistochemistry confirmed the higher uptake of VEGF at the primary tumor site. USNB was evaluated in 6/8 patients from the 25mg cohort. The primary tumor site (p=0.071) and lymph nodes (p=0.090) showed higher fluorescence intensity compared to normal tissue. Fluorescence measurements of normal tissue were comparable between the luminal MDSFR/SFF and USNB/SFF measurements. In 33% of all patients residual tumor was found only below a tumor-free mucosa signifying the need to analyze the deeper tissue layers. Last, the optical properties, the reduced scattering coefficient and absorption coefficient. The combination of the intrinsic fluorescence, absorption and scattering coefficient was converted into the new variable omega and improved the differentiation between tumor and normal tissue even further.

Conclusion

We showed the potential of bevacizumab-800CW combined with qFME and USNB/SFF for response monitoring in esophageal cancer. This combination allows for both in vivo superficial and deeper tissue measurements to ensure that partial responders with a tumor-free mucosa are also adequately selected. A phase II study should establish its value for stratification of patients for active surveillance or surgery.

References

1. Tjalma JJJ, Koller M, Linssen MD, Hartmans E, de Jongh S, Jorritsma-Smit A, et al. Quantitative fluorescence endoscopy: an innovative endoscopy approach to evaluate neoadjuvant treatment response in locally advanced rectal cancer. Gut. 2020;69(3):406-10.
2. Nagengast WB, Hartmans E, Garcia-Allende PB, Peters FTM, Linssen MD, Koch M, et al. Near-infrared fluorescence molecular endoscopy detects dysplastic oesophageal lesions using topical and systemic tracer of vascular endothelial growth factor A. Gut. 2019;68(1):7-10.

Disclosure

Nothing to disclose

Introduction

Early detection of esophageal squamous cell carcinoma (ESCC) significantly improves patient quality of life and outcomes. Nevertheless, there is currently no reliable, convenient, and efficient method to achieve a high detection rate of early ESCC and high-grade intraepithelial neoplasia (HGIN). Non-endoscopic detection of HGIN/ESCC using sponge-based methylated DNA markers (MDMs) are promising approaches amenable to wider application ^1-4. We previously described a 2-MDM panel for ESCC non-invasive diagnosis ^5-6. Furthermore, we have demonstrated excellent performance in ESCC screening using a redesigned cell collection device (CCD) in conjunction with machine learning-assisted cytology ⁷.

Aims & Methods

We aimed to train and validate a predictive algorithm using MDMs based on encapsulated sponge cell CCD samples. CCD samples in the training set (n=120) were taken from 2 medical centers and in the validation set (n=70) were prospectively collected from another medical center. The case group contained a diverse range of esophageal high-grade lesions, including HGIN (n=20), early ESCC (n=40), and advanced ESCC (n=10). The algorithms were trained in the training set and blocked to evaluate diagnostic performance in the prospective validation set.

Results

The MDMs model was constructed by logistic regression with two MDMs (OTOP2, KCNA3). The areas under the receiver operating characteristic curves (AUCs) were 0.933 (95%CI 0.881 to 0.986) and 0.911 (95%CI 0.841 to 0.981) in training and validation sets, respectively. The overall sensitivity was 90.0% at a specificity of 91.4% in the training set. As shown in Table 1, the sensitivity was 90.0%, 95.0%, and 90.0% for HGIN, early ESCC, and advanced ESCC in the training set, respectively. The sensitivity and specificity were 87.5% and 86.7% in the validation set, respectively. Notably, the MDMs model achieved a combined detection rate of 92.5% (95%CI, 79.6% to 98.4%) and 86.7% (95%CI, 69.3% to 96.2%) for HGIN and early ESCC in the training and validation sets, respectively. The AUCs for the complex model that included the two MDMs and age were 0.961(95%CI, 0.920 to 1.000) and 0.940 (95%CI, 0.889 to 0.990) in the training and validation sets, respectively.

Conclusion

The assay of MDMs in CCD samples offers a highly accurate method of predicting HGIN/ESCC, thereby providing the potential for early diagnosis and screening for HGIN/ESCC.

References

1. Iyer PG, et al. Accurate Nonendoscopic Detection of Barrett's Esophagus by Methylated DNA Markers: A Multisite Case Control Study. AM J GASTROENTEROL 2020;115:1201–9.
2. Iyer PG, et al. Validation of a methylated DNA marker panel for the nonendoscopic detection of Barrett’s esophagus in a multisite case-control study. GASTROINTEST ENDOSC 2021;94:498–505.
3. Iyer PG, et al. Algorithm Training and Testing for a Nonendoscopic Barrett’s Esophagus Detection Test in Prospective Multicenter Cohorts. CLIN GASTROENTEROL H 2024;22:1596-1604.e4.
4. Moinova HR, et al. Multicenter, Prospective Trial of Nonendoscopic Biomarker-Driven Detection of Barrett’s Esophagus and Esophageal Adenocarcinoma. AM J GASTROENTEROL 2024;119:2206–14.
5. Bian Y, et al. Genome-wide methylation profiling identified methylated KCNA3 and OTOP2 as promising diagnostic markers for esophageal squamous cell carcinoma. CHIN MED J (Engl) 2024;137:1724-1735
6. Bian Y, et al. Non-invasive diagnosis of esophageal cancer by a simplified circulating cell-free DNA methylation assay targeting OTOP2 and KCNA3: a double-blinded, multicenter, prospective study. J HEMATOL ONCOL 2020;17:47.
7. Gao Y, et al. Machine learning-based automated sponge cytology for screening of oesophageal squamous cell carcinoma and adenocarcinoma of the oesophagogastric junction: a nationwide, multicohort, prospective study. LANCET GASTROENTEROL HEPATOL 2023;8:432–45.

Introduction

Esophageal stricture remains a challenging complication following extensive endoscopic submucosal dissection (ESD) for superficial neoplastic lesions. Oral steroid therapy has been reported to effectively prevent post-ESD stricture. However, its efficacy in preventing luminal stenosis after total circumferential ESD has been disappointing.

Aims & Methods

This study aimed to compare the effectiveness of oral prednisolone alone versus a combination of oral prednisolone and nasogastric tube (NGT) placement in preventing esophageal stricture after circumferential ESD.
We retrospectively collected clinical data from patients with extensive superficial esophageal neoplastic lesions who underwent total circumferential ESD. Patients were categorized into two groups: the steroid group (receiving only oral prednisolone) and the steroid+NGT group (receiving oral prednisolone combined with NGT placement). The incidence of esophageal stricture was analyzed and compared between the two groups.

Results

From June 2010 to December 2024, 29 circumferential lesions in 27 patients underwent esophageal ESD. Of these, 13 lesions in 12 patients received oral steroid therapy alone, while 16 lesions in 15 patients received a combination of oral steroids and NGT placement. There was no significant difference in the characteristics of the patients between the two groups. The overall esophageal stricture rate was 72.4% (21/29). No adverse events were observed in either group. The stricture rate was significantly higher in the steroid group compared to the steroid+NGT group (12/13, 92.3% v.s. 9/16, 56.3%; p=0.044. Table 1). Multivariate logistic regression analysis revealed that longitudinal length of post-ESD mucosal defect (OR 1.12; 95% CI 1.01-1.25; P=0.026) was the independent risk factor. NG placement had a potential preventive effect (OR 0.05; 95% CI 0.00-1.14; P=0.06).

Conclusion

The combination of oral steroid and NGT placement is safe and potentially more effective in preventing esophageal stricture than oral steroid therapy alone following total circumferential ESD. Further randomized controlled trials are needed to confirm these findings.

References

1. Jing Wang, et al. Surgical Endoscopy 2023; 37: 8892-8900.
2. Lihong Teng, et al. Turk J Gastroenterol 2024; 35: 481-487.
3. Kadota T. et al. Esophagus 2020; 17: 440-447.
4. Mizutani T. et al. Jpn J Clin Oncol 2015; 45: 1087-1090.
5. Abe S. et al. Gastrointest Endosc 2017; 86: 779-791.
6. Chu Y. et al. Surg Endosc 2019; 33: 1244-1251.