Recent advances in early esophageal cancer: diagnosis and treatment based on endoscopy.

Esophageal cancer (EC) often cannot be discovered in time because of its asymptomatic or symptom-atypical characteristics in early stage. The risk and probability of lymph node metastasis and distant metastasis increase correspondingly as the cancer aggressively invades deeper layers. Treatment regimens may be shifted to surgery and chemoradiotherapy (CRT) from endoscopic eradication therapy (EET) with poor quality of life and prognosis. It is imperative to identify dysplasia and EC early and enable early curative endoscopic treatments. Newer methods have been attempted in the clinical setting to achieve early detection at a more microscopic and precise level. Newer imaging techniques and artificial intelligence (AI) technology have been involved in targeted biopsies and will gradually unveil the visualization of pathology in the future. Early detection and diagnosis are the prerequisite to choose personal and precise treatment regimens. EET has also been undergoing development and improvement to benefit more patients as the first option or the firstly chosen alternative therapy, when compared with esophagectomy. More clinical studies are needed to provide more possibilities for EET.

Dysplasia in Random Biopsies from Barrett's Surveillance Is an Important Marker for More Severe Pathology.

BACKGROUND AND AIM: Although endoscopic recognition of dysplasia in Barrett's esophagus is difficult, experience in recognition of early neoplastic lesions is supposed to increase the detection of early neoplastic lesions. The aim of this study was to assess the significance of dysplasia in random biopsies in Barrett's esophagus, in the absence of reported visible lesions as well as the difference in final outcome of pathology. METHODS: We retrospectively identified all patients with Barrett's esophagus with suspicion of dysplasia or early adenocarcinoma who were referred to our center between February 2008 and April 2016. We analyzed all endoscopy reports, pathology reports, and referral letters from 19 different hospitals. Patients were divided into two groups, based on the presence or absence of visible lesions reported upon referral. RESULTS: In total, 170 patients diagnosed with dysplasia or adenocarcinoma were referred to our tertiary center. Ninety-one of these referred patients were referred with dysplasia or adenocarcinoma in random biopsies, without a reported lesion during endoscopy in the referral center. During endoscopic work-up at our center, a visible lesion was detected in 44 of these 91 patients (48.4%). After endoscopic work-up and treatment, adenocarcinoma was found in an additional 21 patients. Two of these patients were initially referred with low-grade dysplasia, and 19 patients were initially referred with high-grade dysplasia. The final pathology was upstaged in 35.8% of the patients. CONCLUSIONS: The presence of any grade of dysplasia in random biopsies during surveillance in referral centers is a marker for more severe final pathology. Training in recognition of early neoplastic lesions in Barrett's esophagus imaging is recommended for endoscopists performing Barrett's surveillance.

Does Risk of Progression from Barrett's Esophagus to Esophageal Adenocarcinoma Change Based on the Number of Non-dysplastic Endoscopies?

BACKGROUND: There is a large Barrett's esophagus patient population undergoing endoscopic surveillance. Methods to stratify patients into higher and lower risk groups may enable more varied surveillance intervals for patients with non-dysplastic Barrett's esophagus that could optimize use of endoscopy resources. OBJECTIVE: We aimed to assess whether risk of progression to esophageal adenocarcinoma differed in patients with multiple endoscopic biopsies negative for dysplasia. METHODS: We conducted a retrospective cohort study among individuals from the population-based Northern Ireland Barrett's register with a histologically confirmed diagnosis of non-dysplastic Barrett's esophagus (with intestinal metaplasia) between 1993 and 2010, who had at least one endoscopic biopsy conducted at least 12 months after diagnosis. We used Poisson regression to estimate incidence rate ratios (IRR) and 95% confidence intervals (CI) for the association between number of successive endoscopies showing non-dysplastic Barrett's esophagus and risk of esophageal adenocarcinoma alone, and combined with high-grade dysplasia, at the next endoscopy. RESULTS: We identified 1761 individuals who met our eligibility criteria. Subsequent risk of progression to esophageal adenocarcinoma was lower at the next endoscopy following two endoscopies showing non-dysplastic Barrett's esophagus (IRR 0.26, 95% CI 0.10-0.66) than following one endoscopy showing non-dysplastic Barrett's esophagus. Similar findings were apparent for risk of progression to esophageal adenocarcinoma or high-grade dysplasia (IRR 0.41, 95% CI 0.22-0.79). CONCLUSION: The lower risk of malignant progression in individuals with persistent non-dysplastic Barrett's esophagus over two consecutive endoscopic biopsies but not for longer term persistence does not support hypotheses of persistence being an indicator of less biologically aggressive lesions. Instead, the initial difference may be attributable to post-endoscopy cancers and support the necessity of adhering to robust quality standards for endoscopic procedures.

Trends in Treatment of T1N0 Esophageal Cancer.

OBJECTIVE: The purpose of this study was to explore nationwide trends in treatment and outcomes of T1N0 esophageal cancer. BACKGROUND: Endoscopic treatment has become an accepted option for early-stage esophageal cancer, but nationwide utilization rates and outcomes are unknown. METHODS: T1N0 esophageal cancers were identified in the National Cancer Database from 2004 to 2014. We assessed trends in treatment; compared endoscopic therapy, esophagectomy, chemoradiation, and no treatment; and performed a subgroup analysis of T1a and T1b patients from 2010 to 2014 (AJCC 7). RESULTS: A total of 12,383 patients with clinical T1N0 esophageal cancer were analyzed. Over a decade, use of endoscopic therapy increased from 12.7% to 33.6%, whereas chemoradiation and esophagectomy decreased, P < 0.01. The rise in endoscopic treatment of T1a disease from 42.7% to 50.6% was accompanied by a decrease in esophagectomies from 21.7% to 12.8% (P < 0.01). For T1b disease, the rise in endoscopic treatment from 16.9% to 25.1% (P = 0.03) was accompanied by decreases in no treatment and chemoradiation, whereas the rate of esophagectomies remained approximately 50%. Unadjusted median survival was longer for patients undergoing resection: esophagectomy, 98.6 months; endoscopic therapy, 77.7 months; chemoradiation, 17.3 months; no treatment, 8.2 months; P < 0.01. Risk-adjusted Cox modeling showed esophagectomy was associated with improved survival [hazard ratio (HR): 0.85], and chemoradiation (HR: 1.79) and no treatment (HR: 3.57) with decreased survival, compared to endoscopic therapy (P < 0.01). CONCLUSIONS: Use of endoscopic therapy for T1 esophageal cancer has increased significantly: for T1a, as an alternative to esophagectomy; and for T1b, as an alternative to no treatment or chemoradiation. Despite upfront risks, long-term survival is highest for patients who can undergo esophagectomy.

The Present Status and Future of Barrett's Esophageal Adenocarcinoma in Japan.

BACKGROUND: The incidence of esophageal adenocarcinoma in Europe and the United States rapidly increased from the latter half of the 1970s and exceeded that of esophageal squamous cell carcinoma in the latter half of the 1990s, currently accounting for approximately 60% of all esophageal carcinomas. Recently, its incidence has also increased in Japan, raising concerns that it will follow a course similar to that in Europe and the United States. SUMMARY: The incidence of esophageal adenocarcinoma in Japan was about 2% until the 1990s, but in recent years, it has risen to 6.5-7.1%. Causes include the increase in the incidence of obesity due to changes in eating habits with resultant increases in the incidence of hiatal hernia and reflux esophagitis, a decrease in the rate of Helicobacter pylori infection, and the increased interest of physicians in the gastroesophageal junction. The number of gastroesophageal reflux disease patients in Japan rapidly increased from the 1990s, which accordingly increased the number of Barrett's esophageal adenocarcinoma patients from the latter half of the 1990s. Tabulation and analysis of 1,794 reported cases of Barrett's esophageal adenocarcinoma in Japan showed that superficial cancers accounted for 77.6%, and that the concomitant rates of hiatal hernia and reflux esophagitis were high at 87 and 70% respectively. Key Message: The future trend in the incidence of Barrett's esophageal adenocarcinoma in Japan will depend on the increase in the incidence of reflux esophagitis, which is essential for the development of Barrett's esophagus and Barrett's esophageal carcinoma. The obesity rate is lower in Japan than that in Europe and the United States, and the incidence and severity of reflux esophagitis are low. We expect that the incidence of Barrett's esophageal adenocarcinoma in Japan will not rise as high as in Europe and the United States, and will remain below 10%.

Outcome and follow-up of patients requiring emergency oesophagoscopy for food bolus obstruction over a 5-year period.

INTRODUCTION: OFBO is a common occurrence in the emergency setting. Endoscopic removal via rigid or flexible oesophagoscopy is only performed following failure to pass the obstruction after a period of observation and medical management. Despite recommendations from the ESGE, there is currently a lack of high-quality evidence to support the diagnostic work-up of these patients. PURPOSE: The purpose of this single centre study was to assess the outcome and follow-up of this population over a 5-year period. We retrospectively collected data regarding all patients undergoing emergency oesophagoscopy between 2012-2017 and recorded their outcomes and subsequent follow-up. R esults: We found that only 33% of patients had diagnostic investigations performed post-operatively and oesophageal pathology was detected in 44% of those investigated. Eosinophilic oesophagitis was the most common diagnosis and OGD was more likely to detect pathology compared to other modalities. C onclusion: Our study suggests that our findings could have been higher had all our patients underwent further investigation. Therefore, we would recommend a diagnostic work-up in all patients following a discussion of the risks associated with an endoscopic examination. We thoroughly support further large-scale collaborative research which can shed better light of evidence on the topic.

Advances in Management of Esophageal Motility Disorders.

The widespread adoption of high-resolution manometry (HRM) has led to a restructuring in the classification of esophageal motility disorder classification summarized in the Chicago Classification, currently in version 3.0. It has become apparent that the cardinal feature of achalasia, impaired lower esophageal sphincter relaxation, can occur in several disease phenotypes: without peristalsis, with premature (spastic) distal esophageal contractions, with panesophageal pressurization, or even with preserved peristalsis. Furthermore, despite these advances in diagnostics, no single manometric pattern is perfectly sensitive or specific for idiopathic achalasia and complimentary assessments with provocative maneuvers during HRM or interrogating the esophagogastric junction with the functional luminal imaging probe during endoscopy can be useful in clarifying equivocal or inexplicable HRM findings. Using these tools, we have come to conceptualize esophageal motility disorders as characterized by obstructive physiology at the esophagogastric junction, smooth muscle esophagus, or both. Recognizing obstructive physiology as a primary target of therapy has become particularly relevant with the development of a minimally invasive technique for performing a calibrated myotomy of the esophageal circular muscle, the POEM procedure. Now and going forward, optimal management is to render treatment in a phenotype-specific manner: e.g. POEM calibrated to patient-specific physiology for spastic achalasia and spastic disorders of the smooth muscle esophagus, more conservative strategies (pneumatic dilation) for the disorders limited to the sphincter.

Novel Developments in Endoscopic Mucosal Imaging.

Endoscopic techniques such as high-definition and optical-chromoendoscopy have had enormous impact on endoscopy practice. Since these techniques allow assessment of most subtle morphological mucosal abnormalities, further improvements in endoscopic practice lay in increasing the detection efficacy of endoscopists. Several new developments could assist in this. First, web based training tools could improve the skills of the endoscopist for enhancing the detection and classification of lesions. Secondly, incorporation of computer aided detection will be the next step to raise endoscopic quality of the captured data. These systems will aid the endoscopist in interpreting the increasing amount of visual information in endoscopic images providing real-time objective second reading. In addition, developments in the field of molecular imaging open opportunities to add functional imaging data, visualizing biological parameters, of the gastrointestinal tract to white-light morphology imaging. For the successful implementation of abovementioned techniques, a true multi-disciplinary approach is of vital importance.

Recent advances in diagnostic testing for gastroesophageal reflux disease.

INTRODUCTION: Gastroesophageal reflux disease (GERD) has a large economic burden with important complications that include esophagitis, Barrett's esophagus, and adenocarcinoma. Despite endoscopy, validated patient questionnaires, and traditional ambulatory pH monitoring, the diagnosis of GERD continues to be challenging. Areas covered: This review will explore the difficulties in diagnosing GERD with a focus on new developments, ranging from basic fundamental changes (histology and immunohistochemistry) to direct patient care (narrow-band imaging, impedance, and response to anti-reflux surgery). We searched PubMed using the noted keywords. We included data from full-text articles published in English. Further relevant articles were identified from the reference lists of review articles. Expert commentary: Important advances in novel parameters in intraluminal impedance monitoring such as baseline impedance monitoring has created some insight into alternative diagnostic strategies in GERD. Recent advances in endoscopic assessment of esophageal epithelial integrity via mucosal impedance measurement is questioning the paradigm of prolonged ambulatory testing for GERD. The future of reflux diagnosis may very well be without the need for currently employed technologies and could be as simple as assessing changes in epithelia integrity as a surrogate marker for GERD. However, future studies must validate such an approach.

Current Status and Future Prospects for Esophageal Cancer Treatment.

The local control effect of esophagectomy with three-field lymph node dissection (3FLD) is reaching its limit pending technical advancement. Minimally invasive esophagectomy (MIE) by thoracotomy is slowly gaining acceptance due to advantages in short-term outcomes. Although the evidence is slowly increasing, MIE is still controversial. Also, the results of treatment by surgery alone are limiting, and multimodality therapy, which includes surgical and non-surgical treatment options including chemotherapy, radiotherapy, and endoscopic treatment, has become the mainstream therapy. Esophagectomy after neoadjuvant chemotherapy (NAC) is the standard treatment for clinical stages II/III (except for T4) esophageal cancer, whereas chemoradiotherapy (CRT) is regarded as the standard treatment for patients who wish to preserve their esophagus, those who refuse surgery, and those with inoperable disease. CRT is also usually selected for clinical stage IV esophageal cancer. On the other hand, with the spread of CRT, salvage esophagectomy has traditionally been recognized as a feasible option; however, many clinicians oppose the use of surgery due to the associated unfavorable morbidity and mortality profile. In the future, the improvement of each treatment result and the establishment of individual strategies are important although esophageal cancer has many treatment options.

Novel insights into esophageal diagnostic procedures.

The 21st century offers new advances in diagnostic procedures and protocols in the management of esophageal diseases. This review highlights the most recent advances in esophageal diagnostic technologies, including clinical applications of novel endoscopic devices, such as ultrathin endoscopy and confocal laser endomicroscopy for diagnosis and management of Barrett's esophagus; novel parameters and protocols in high-resolution esophageal manometry for the identification and better classification of motility abnormalities; innovative connections between esophageal motility disorder diagnosis and detection of gastroesophageal reflux disease (GERD); impedance-pH testing for detecting the various GERD phenotypes; performance of distensibility testing for better pathophysiological knowledge of the esophagus and other gastrointestinal abnormalities; and a modern view of positron emission tomography scanning in metastatic disease detection in the era of accountability as a model for examining other new technologies. We now have better tools than ever for the detection of esophageal diseases and disorders, and emerging data are helping to define how well these tools change management and provide value to clinicians. This review features novel insights from multidisciplinary perspectives, including both surgical and medical perspectives, into these new tools, and it offers guidance on the use of novel technologies in clinical practice and future directions for research.

Management of esophageal perforation in the endoscopic era: Is operative repair still relevant?

BACKGROUND: With the introduction of new treatment paradigms for esophageal perforation, the management of this highly morbid condition is evolving. We reviewed our experience to investigate the modern management and outcomes of esophageal perforations with a focus on operatively repaired patients. METHODS: A retrospective review of all esophageal perforations was conducted between August 2003 and January 2016. RESULTS: A total of 48 patients were identified, with iatrogenic injury in 19 (40%), spontaneous perforation in 18 (38%), and traumatic/foreign body causes in 11 (23%). The distal esophagus was the site of perforation in 63% of the patients, and the duration of time between perforation and treatment was <24 hours in 60%. Nonoperative management was employed in 18 (38%) and operative repair in 30 (primary operative repair = 20, drainage = 4, esophagectomy = 6). Iatrogenic and traumatic perforations were more likely to be treated nonoperatively (68%), while all spontaneous perforations were treated by operative intervention. There were no complications or mortalities in the nonoperative group and only a 5% reintervention rate. In the operative group, complications occurred in 10 (33%), reinterventions in 13 (43%), and mortality in 2 (7%) patients. CONCLUSION: Our study highlights the importance of considering the etiology of a perforation when planning management and the success of nonoperative treatment with careful patient selection. In addition, operative repair in septic patients yielded excellent outcomes and should be the standard for comparison in future studies exploring endoscopic approaches.

Endoscopic Options for Gastroesophageal Reflux: Where Are We Now and What Does the Future Hold?

Early in the twenty-first century, novel endoscopic techniques were introduced for the management of gastroesophageal reflux disease, providing minimally invasive ways to eliminate pharmacologic acid inhibition and avoid the need for anti-reflux surgery. These techniques do not significantly alter the anatomy of the gastroesophageal junction, minimizing short- and long-term adverse effects, such as dysphagia and bloating. After extensive clinical testing, many endoscopic therapies were abandoned due to either lack of durable efficacy or unfavorable safety profile. Today, only four such therapies remain clinically available, each with variable levels of clinical validation and market penetration. This review will provide an assessment of these endoscopic therapies, highlighting their respective strengths and weaknesses and their present and future applicability to patients with gastroesophageal reflux disease.

Current treatment options for esophageal diseases.

Exciting new developments-pharmacologic, endoscopic, and surgical-have arisen for the treatment of many esophageal diseases. Refractory gastroesophageal reflux disease presents a therapeutic challenge, and several new options have been proposed to overcome an insufficient effectiveness of proton pump inhibitors. In patients with distal esophageal spasm, drugs and endoscopic treatments are the current mainstays of the therapeutic approach. Treatment with proton pump inhibitors (or antireflux surgery) should be considered in patients with Barrett's esophagus, since a recent meta-analysis demonstrated a 71% reduction in risk of neoplastic progression. Endoscopic resection combined with radiofrequency ablation is the standard of care in patients with early esophageal adenocarcinoma. Mucosal squamous cancer may also be treated endoscopically, preferably with endoscopic submucosal dissection. Patients with upper esophageal cancer often refrain from surgery. Robot-assisted, thoracolaparoscopic, minimally invasive esophagectomy may be an appropriate option for these patients, as the robot facilitates a good overview of the upper mediastinum. Induction chemoradiotherapy is currently considered as standard treatment for patients with advanced squamous cell carcinoma, while the role of neoadjuvant therapy for adenocarcinoma remains controversial. A system for defining and recording perioperative complications associated with esophagectomy has been recently developed and may help to find predictors of mortality and morbidity.

Population-based cohort study of the management and survival of patients with early-stage oesophageal adenocarcinoma in England.

BACKGROUND: Until recently, oesophagectomy was the treatment of choice for early oesophageal cancer. Endoscopic treatment has been introduced relatively recently. This observational national database study aimed to describe how endoscopic therapy has been introduced in England and to examine the safety of this approach. METHODS: A population-based cohort study was undertaken of patients diagnosed with oesophageal adenocarcinoma between October 2007 and June 2009 using three linked national databases. Patients with early-stage disease (T1 tumours with no evidence of spread) were identified, along with the primary treatment modality where treatment intent was curative. Short-term outcomes after treatment and 5-year survival were evaluated. RESULTS: Of 5192 patients diagnosed with oesophageal adenocarcinoma, 306 (5·9 per cent) were considered to have early-stage disease before any treatment, of whom 239 (79·9 per cent of 299 patients with data on treatment intent) were managed with curative intent. Of 175 patients who had an oesophagectomy, 114 (65·1 (95 per cent c.i. 57·6 to 72·7) per cent) survived for 5 years. Among these, 47 (30·3 per cent of 155 patients with tissue results available) had their disease upstaged after pathological staging; this occurred more often in patients who did not have staging endoscopic ultrasonography before surgery. Of 41 patients who had an endoscopic resection, 27 (66 (95 per cent c.i. 49 to 80) per cent) survived for 5 years. Repeat endoscopic therapy was required by 23 (56 per cent) of these 41 patients. CONCLUSION: Between 2007 and 2009, oesophagectomy remained the initial treatment of choice (73·2 per cent) among patients with early-stage oesophageal cancer treated with curative intent; one in five patients were managed endoscopically, and this treatment was more common in elderly patients. Although the groups had different patient characteristics, 5-year survival rates were similar.

Capsule endoscopy: current practice and future directions.

Capsule endoscopy (CE) has transformed investigation of the small bowel providing a non-invasive, well tolerated means of accurately visualising the distal duodenum, jejunum and ileum. Since the introduction of small bowel CE thirteen years ago a high volume of literature on indications, diagnostic yields and safety profile has been presented. Inclusion in national and international guidelines has placed small bowel capsule endoscopy at the forefront of investigation into suspected diseases of the small bowel. Most commonly, small bowel CE is used in patients with suspected bleeding or to identify evidence of active Crohn's disease (CD) (in patients with or without a prior history of CD). Typically, CE is undertaken after upper and lower gastrointestinal flexible endoscopy has failed to identify a diagnosis. Small bowel radiology or a patency capsule test should be considered prior to CE in those at high risk of strictures (such as patients known to have CD or presenting with obstructive symptoms) to reduce the risk of capsule retention. CE also has a role in patients with coeliac disease, suspected small bowel tumours and other small bowel disorders. Since the advent of small bowel CE, dedicated oesophageal and colon capsule endoscopes have expanded the fields of application to include the investigation of upper and lower gastrointestinal disorders. Oesophageal CE may be used to diagnose oesophagitis, Barrett's oesophagus and varices but reliability in identifying gastroduodenal pathology is unknown and it does not have biopsy capability. Colon CE provides an alternative to conventional colonoscopy for symptomatic patients, while a possible role in colorectal cancer screening is a fascinating prospect. Current research is already addressing the possibility of controlling capsule movement and developing capsules which allow tissue sampling and the administration of therapy.

Endoscopic diagnosis of early Barrett's neoplasia: perspectives for advanced endoscopic technology.

Barrett's esophagus (BE) is a metaplastic condition that occurs secondary to gastroesophageal reflux disease. BE is also a precursor to esophageal adenocarcinoma, which, although still rare in Japan, is one of the most rapidly increasing cancers in Western countries. However, the prevalence of gastroesophageal reflux disease has increased significantly over the past few decades in Japan, possibly leading to an incremental rise in BE and the associated inherent risk of adenocarcinoma. Given the poor prognosis of advanced-stage Barrett's adenocarcinoma, endoscopic surveillance is recommended for subjects with BE to detect early neoplasias including dysplasia. However, endoscopic identification of dysplastic lesions is still not sufficiently reliable or subjective, making targeted therapy extremely difficult. Over the past few years, improvements in image resolution, image processing software, and optical filter technology have enabled identification of dysplasia and early cancer in BE patients. We retrieved as many studies on advanced endoscopic technologies in BE as possible from MEDLINE and PubMed. The present review focuses on the emergent clinically available technologies to provide an overview of the technologies, their practical applicability, current status, and future challenges.