Endoscopic resection for residual oesophageal neoplasia after definitive chemoradiotherapy.

Definitive chemoradiation is the recommended treatment for locally advanced, irresectable oesophageal cancer and a valid alternative to neoadjuvant chemoradiotherapy (CRT) with surgery in oesophageal squamous cell cancer (OSCC) patients. In case of locoregional recurrence, salvage treatment can be considered in fit and resectable patients. Salvage surgery is a valid option but associated with significant morbidity. Therefore, for tumors confined to the mucosa or submucosal layers endoscopic resection is a good and less-invasive alternative. Over the last decade several case-series have demonstrated a high technical success rate of endoscopic treatment after definitive CRT. In this review we summarize the clinical outcomes and challenges of endoscopic treatment of early recurrence after definitive CRT in oesophageal cancer.

Categorizing Risks within Barrett's Esophagus To Guide Surveillance and Interception; Suggesting a New Framework.

Barrett's esophagus is a precancerous condition that can progress in a stepwise manner to dysplasia and eventually esophageal adenocarcinoma (EAC). Once diagnosed, patients with Barrett's esophagus are kept on surveillance to detect progression so that timely intervention can occur with endoscopic therapy. Several demographic and clinical risk factors are known to increase progression toward EAC, such as longer Barrett's segments, and these patients are kept on tighter surveillance. While p53 IHC has been advocated as an adjunct to histopathologic diagnosis, use of this biomarker is variable, and no other molecular factors are currently applied. Given the new evidence available, it is time to consider whether other risk factors or tools could be applied in clinical practice to decide on closer or attenuated surveillance. In this commentary, we summarize the most relevant risk factors for Barrett's esophagus progression, highlight the most promising novel risk stratification tools-including nonendoscopic triage and commercial biomarker panels, and propose a new framework suggesting how to incorporate risk stratification into clinical practice.

Adequacy of endoscopic recognition and surveillance of gastric intestinal metaplasia and atrophic gastritis: A multicentre retrospective study in low incidence countries.

BACKGROUND: Gastric atrophy (GA) and gastric intestinal metaplasia (GIM) are precursor conditions to gastric adenocarcinoma (GAC) and should be monitored endoscopically in selected individuals. However, little is known about adherence to recommendations in clinical practice in low-risk countries. OBJECTIVE: The aim of this study was to evaluate endoscopic recognition and adequacy of surveillance for GA and GIM in countries with low GAC prevalence. METHODS: We retrospectively analysed patients diagnosed with GIM or GA in three centers in The Netherlands and UK between 2012 and 2019. Cases with GIM and/or GA diagnosis at index endoscopy were retrieved through systematic search of pathology databases using 'gastric' and 'intestinal metaplasia' or 'atrophy' keywords. Endoscopy reports were analysed to ascertain accuracy of endoscopic diagnoses. Adequacy of surveillance was assessed following histological diagnosis at the index endoscopy based on ESGE guidelines published in 2012. RESULTS: We included 396 patients with a median follow-up of 57.2 months. Mean age was 66 years and the rates of antrum-predominant versus extensive GIM were comparable (37% vs 38%). Endoscopic recognition rates were 48.5% for GA and 16.3% for GIM. Surveillance was adequately carried out in 215 of 396 patients (54.3%). CONCLUSION: In countries with a low incidence of GAC, the rate of endoscopic recognition of gastric pre-cancerous lesions and adherence to surveillance recommendation are low. Substantial improvement is required in endoscopic training and awareness of guidelines recommendation in order to optimise detection and management of pre-malignant gastric conditions.

Endoscopic surveillance with systematic random biopsy for the early diagnosis of hereditary diffuse gastric cancer: a prospective 16-year longitudinal cohort study.

BACKGROUND: Hereditary diffuse gastric cancer, generally caused by germline pathogenic variants in CDH1, presents with early-onset signet ring cell carcinoma. Prophylactic total gastrectomy is the definitive treatment. Endoscopic surveillance can inform the timing of prophylactic total gastrectomy through detection of microscopic signet ring cell carcinoma foci. However, evidence is scarce about the optimal endoscopic sampling technique and characterisation of signet ring cell carcinoma foci in hereditary diffuse gastric cancer. We aimed to formally assess the diagnostic yield of different sampling strategies and to identify criteria for the characterisation of endoscopic lesions. METHODS: For this prospective longitudinal cohort study, we included individuals aged 18 years or older at the Cambridge University Hospitals National Health Service (NHS) Foundation Trust who fulfilled testing criteria for hereditary diffuse gastric cancer between June 1, 2005, and July 31, 2021. The primary outcome was detection of intramucosal signet ring cell carcinoma foci. We assessed the detection rate and anatomical location of signet ring cell carcinoma in random biopsy samples taken according to a systematic protocol compared with biopsies targeted to endoscopic findings. Endoscopic lesions were examined with white-light and narrow band imaging with magnification to assess the likelihood of cancerous foci. FINDINGS: 145 individuals were included, of whom 68 (47%) were male and 92 (63%) carried the CDH1 pathogenic variant. 58 (40%) patients were diagnosed with invasive signet ring cell carcinoma over a median follow-up time of 51 months (IQR 18-80). The first diagnosis of signet ring cell carcinoma was most commonly made from random biopsies (29 [50%] of 58 patients), rather than targeted biopsies (15 [26%] patients). The anatomical distribution of signet ring cell carcinoma foci detected by random biopsies more accurately reflected those identified in prophylactic total gastrectomy specimens than did targeted biopsies. Omitting random biopsies in our cohort would have led to an under-diagnosis rate of 42%. Using a novel panel of endoscopic criteria, gastric lesions containing signet ring cell carcinoma were predicted with a sensitivity of 67·3% and a specificity of 90·2%. INTERPRETATION: Random biopsies enhance the early detection of signet ring cell carcinoma and are complementary to targeted biopsies in surveillance of hereditary diffuse gastric cancer. This sampling method should be the standard of care when performing all surveillance endoscopies for individuals with hereditary diffuse gastric cancer. FUNDING: UK Medical Research Council.

Endosheath ultrathin transnasal endoscopy is a cost-effective method for screening for Barrett's esophagus in patients with GERD symptoms.

BACKGROUND AND AIMS: Barrett's esophagus (BE) screening is currently not considered to be cost effective in the general population but may be effective in high-risk subgroups, such as 50-year-old white men with chronic reflux disease (GERD). A new modality for screening is unsedated transnasal endoscopy using endosheath technology (uTNE), which has been shown to be safe and effective in clinical practice. In this study, we determined the cost-utility of uTNE in a high-risk subgroup compared with no screening or screening with standard endoscopy. METHODS: A Markov model was used to simulate screening of 50-year-old white men with symptoms of GERD with either uTNE or standard endoscopy compared with no screening, over a lifetime horizon. Input variables were based on the literature and recent data on uTNE screening for BE. The study was designed from a healthcare payer perspective by using direct costs. Primary outcome measures were costs, quality-adjusted life years (QALYs), and the incremental cost-utility ratio (ICUR) of uTNE and standard endoscopy compared with no screening. Sensitivity analysis was performed for several factors, such as prevalence of BE. RESULTS: Costs of uTNE, standard endoscopy, and no screening were estimated at, $2495, $2957, and $1436, respectively. Compared with no screening, uTNE screening resulted in an overall QALY increase of 0.039 (95% percentile 0.018; 0.063) and an ICUR of $29,446 per QALY gained (95% confidence interval [CI], 18.516-53.091), whereas standard endoscopy compared with no screening resulted in a QALY increase of 0.034 (95% CI, 0.015-0.056) and an ICUR of $47,563 (95% CI, 31,036-82,970). CONCLUSION: Both uTNE and standard endoscopy seem to be cost-effective screening methods in a screening cohort of 50-year-old white men with GERD at a willingness-to-pay cutoff of $50,000.

Incidence of Progression of Persistent Nondysplastic Barrett's Esophagus to Malignancy.

BACKGROUND & AIMS: The risk of esophageal adenocarcinoma (EAC) in patients with non-dysplastic Barrett's esophagus (NDBE) is low, so there is debate over the role of ongoing surveillance for patients with NDBE. It is important to identify patients at low risk for progression. We assessed cancer risk based on the subsequent number of endoscopies showing persistence of NDBE in a nationwide study in the Netherlands. METHODS: In a population-based study, patients with a first diagnosis of NDBE were selected from the Dutch nationwide registry of histopathology. We calculated incidence rates and incidence rate ratios (IRR) for high-grade dysplasia (HGD) and EAC to determine whether the number of endoscopies negative for dysplasia and the persistence of NDBE over time associate with progression to malignancy. RESULTS: We identified 12,728 patients with NDBE during 2003 and 2013. HGD or EAC developed in 436 patients (3.4%) during 64,537 person-years of follow up (median, 4.9 years). The rate of progression to HGD or EAC was 0.68 (95% CI, 0.61-0.74) per 100 person-years. In patients with 2 consecutive endoscopies showing NDBE, the rate of progression to HGD or EAC decreased to 0.55 (95% CI, 0.46-0.64) per 100 person-years (IRR, 0.72; 95% CI, 0.60-0.87). Overall, the incidence of HGD or EAC decreased by 14% for each year of progression-free follow-up (IRR, 0.86; 95% CI, 0.81-0.92). CONCLUSION: In a population-based study in the Netherlands, we found patients with stable NDBE to have a low risk of progression to HGD or EAC. These findings indicate that surveillance intervals might be lengthened or even discontinued in subgroups patients with persistent NDBE.

CD44, SHH and SOX2 as novel biomarkers in esophageal cancer patients treated with neoadjuvant chemoradiotherapy.

BACKGROUND AND PURPOSE: Neoadjuvant chemoradiotherapy (nCRT) improves survival in esophageal cancer (EC) patients, but the response to treatment is heterogeneous and little is known regarding prognostic and predictive markers in these patients. CD44, SOX2 and SHH have been implicated in resistance to CRT, possibly through an association with a cancer stem cell phenotype. MATERIAL AND METHODS: 101 EC patients treated with nCRT and surgery were included. Sufficient pre-treatment biopsy material was present in 71 patients, of which 53 patients were non-complete responders on nCRT (nCR). Protein expression was examined using immunohistochemistry (IHC). Prognostic factors were determined using Cox regression analysis for disease free survival (DFS) and cause specific survival (CSS) in the complete cohort, the pre-treatment biopsies group and post-treatment nCR group. RESULTS: Low CD44 expression in the nCR group was an independent prognostic factor for both DFS and CSS (DFS HR 2.81, p=0.002 and CSS HR 3.48, p=0.002). Absent SOX2 expression in pretreatment biopsies was related to systemic recurrence (p=0.029) while low SHH in pretreatment biopsies was an independent prognostic factor for a poor DFS (HR 2.27, p=0.036). No relation between marker expression and response to nCRT was observed. CONCLUSIONS: Low expression of CD44 and SHH are associated with a poor survival outcome in EC patients treated with nCRT.

GATA6 expression in Barrett's oesophagus and oesophageal adenocarcinoma.

BACKGROUND: Barrett's oesophagus can progress towards oesophageal adenocarcinoma through a metaplasia-dysplasia-carcinoma sequence, but the underlying mechanisms are poorly understood. The transcription factor GATA6 is known to be involved in columnar differentiation and proliferation, and GATA6 gene amplification was recently linked with poor survival in oesophageal adenocarcinoma. AIM: To study the expression of GATA6 during Barrett's oesophagus development and malignant transformation. To determine the prognostic value of GATA6 in oesophageal adenocarcinoma. METHODS: Two retrospective cohorts were derived from the pathological archive of the University Medical Center Groningen. The first cohort contained 130 tissue samples of normal squamous epithelium, metaplasia, dysplasia and oesophageal adenocarcinoma. The second cohort consisted of a tissue microarray containing tissue from 92 oesophageal adenocarcinoma patients. Immunohistochemistry was used to examine GATA6 protein expression and to correlate GATA6 expression in oesophageal adenocarcinoma with overall and disease-free survival. RESULTS: The percentage of GATA6-positive cells was low in squamous epithelium (10%) but increased progressively in Barrett's oesophagus (30%, P < 0.001) and high-grade dysplasia (82%, P = 0.005). GATA6 expression was not associated with overall or disease-free survival in oesophageal adenocarcinoma patients (P = 0.599 and P = 0.700 respectively). CONCLUSION: GATA6 expression is progressively increased during Barrett's oesophagus development and its malignant transformation. However, no prognostic value of GATA6 expression could be found in oesophageal adenocarcinoma.

Loss of CD44 and SOX2 expression is correlated with a poor prognosis in esophageal adenocarcinoma patients.

BACKGROUND: It has been suggested that markers associated with cancer stem cells (CSC) may play a role in esophageal cancer. Our aim was to investigate the expression pattern of proposed CSC markers ALDH1, Axin2, BMI1, CD44, and SOX2 in esophageal adenocarcinoma (EAC) and to relate their expression to survival. METHODS: In this study we included 94 EAC patients and examined the expression of the above-mentioned markers by using immunohistochemistry on tissue microarrays. Expression was scored as positive or negative or categorized as low or high in terms of an immunoreactivity score (IRS). Expression rates were related to clinicopathologic characteristics and overall and disease-free survival (DFS). RESULTS: In a multivariate analysis, negative expression of CD44 and of SOX2 were both significant prognostic factors for DFS [hazard ratio (HR), 1.73; 95 % confidence interval (CI), 1.00-2.96; P = 0.046 and HR, 2.06; 95 % CI 1.14-3.70 P = 0.016). When CD44 and SOX2 expression were analyzed together, negative SOX2 expression was an independent prognostic factor for DFS (HR, 1.91; 95 % CI 1.05-3.46; P = 0.034). Low IRS scores for ALDH1 or Axin2 were associated with a reduced median survival (12.8 vs. 28.7 and 12.1 vs. 25.5 months, respectively). However, these markers and BMI1 were not prognostic factors for survival. CONCLUSIONS: Loss of CD44 expression and loss of SOX2 expression are prognostic factors of poor survival in EAC patients. This suggests a role of these proteins in EAC that requires further investigation.

A critical appraisal of circumferential resection margins in esophageal carcinoma.

BACKGROUND: In esophageal cancer, circumferential resection margins (CRMs) are considered to be of relevant prognostic value, but a reliable definition of tumor-free CRM is still unclear. The aim of this study was to appraise the clinical prognostic value of microscopic CRM involvement and to determine the optimal limit of CRM. METHODS: To define the optimal tumor-free CRM we included 98 consecutive patients who underwent extended esophagectomy with microscopic tumor-free resection margins (R0) between 1997 and 2006. CRMs were measured in tenths of millimeters with inked lateral margins. Outcome of patients with CRM involvement was compared with a statistically comparable control group of 21 patients with microscopic positive resection margins (R1). RESULTS: A cutoff point of CRM at < or = 1.0 mm and > 1.0 mm appeared to be an adequate marker for survival and prognosis (both P < 0.001). The outcome in patients with CRMs < or = 1.0 and > 0 mm was equal to that in patients with CRM of 0 mm (P = 0.43). CRM involvement was an independent prognostic factor for both recurrent disease (P = 0.001) and survival (P < 0.001). Survival of patients with positive CRMs (< or = 1 mm) did not significantly differ from patients with an R1 resection (P = 0.12). CONCLUSION: Involvement of the circumferential resection margins is an independent prognostic factor for recurrent disease and survival in esophageal cancer. The optimal limit for a positive CRM is < or = 1 mm and for a free CRM is >1.0 mm. Patients with unfavorable CRM should be approached as patients with R1 resection with corresponding outcome.

Routine or on demand radiological contrast examination in the diagnosis of anastomotic leakage after esophagectomy.

BACKGROUND: To detect anastomotic leakage after esophagectomy in esophageal carcinoma patients, many surgeons perform a radiological contrast examination routinely. The aim of this retrospective study is to determine the clinical relevance of a routine contrast examination after esophagectomy and to evaluate criteria for contrast examination on demand. METHODS: Data were obtained from 211 patients with cancer of the esophagus or gastro-esophageal junction who underwent an esophagectomy during the period 1991-2004. Retrospectively, we analyzed patients regarding anastomosis-related characteristics and clinical signs including sepsis, fever > or = 39.0 degrees C, leukocytosis > or = 20 x 10(9)/ml and pleural effusion. RESULTS: Anastomotic leakage had appeared in 35 of the 211 patients. The clinical signs sepsis (odds ratio (OR) 6.72: 95% confidence interval (CI) (2.57-17.56); P < 0.0001), leukocytosis (OR 2.62 (1.10-6.22); P < 0.030), and fever (OR 2.34 (1.01-5.42); P < 0.047) were significantly related to anastomotic leakage. Pleural effusion was not significantly related to anastomotic leakage (OR 2.83 (0.98-8.13); P = 0.054). CONCLUSION: Our study suggests that the clinical value for a routinely performed contrast examination is debatable. We recommend performing a contrast examination based on clinical suspicion and clinical signs of anastomotic leakage including sepsis, fever > or = 39.0 degrees C and leukocytosis > or = 20 x 10(9)/ml.