Trends in Incidence and Prevalence of Specialized Intestinal Metaplasia,Barrett’s Esophagus,and Adenocarcinoma of the Gastroesophageal Junction

Most available information on the epidemiology of Barretts esophagus (BE) relates to patients with long segments (> 3 cm) of specialized intestinal metaplasia (SIM). Its prevalence is 3% in patients undergoing endoscopy for reflux symptoms and 1% in those undergoing endoscopy for any clinical indication. The latter prevalence is similar to the 1% found in autopsy series. A silent majority with BE remain unrecognized in the general population. BE is more common in men, and the prevalence rises with age. Recent endoscopic series document a rise in the diagnosis of endoscopically apparent short segments (< 3 cm) of BE (SSBE). The prevalence of SSBE in both unselected and reflux patients is 8% to 12%. Specialized intestinal metaplasia at the cardia, below a normal-appearing squamocolumnar junction, has been reported to vary from 6% to 25% in patients presenting for upper endoscopy. Unlike patients with long segment Barretts esophagus (LSBE), the role of gastroesophageal reflux disease in the pathogenesis of SSBE and SIM of the cardia is controversial. Recent data suggest that the etiology of SIM of the cardia might be secondary to Helicobacter pylori infection, although the role of other environmental factors cannot be ruled out. The incidence of adenocarcinoma of the esophagus and esophagogastric juction (EGJ) has been increasing over the past 15 years in Western countries. Surgical series and population-based studies show that by 1994 adenocarcinomas of the esophagus accounted for half of all esophageal cancer among white men. LSBE and SSBE predispose to the development of adenocarcinoma of the esophagus and EGJ. The role of SIM of the cardia as a precursor lesion for EGJ adenocarcinoma is still unclear. The prevalences of dysplasia in LSBE and SSBE are around 6% and 8%, respectively. The incidence of adenocarcinoma in patients with LSBE is about 1 in 100 patient-years. Cancer risk for SSBE and SIM at the cardia is unknown. Smoking and obesity increase the risk for esophageal and EGJ adenocarcinomas.     

Surgical Approach to Invasive Adenocarcinoma of the Distal Esophagus (Barrett’s Cancer)

Barretts carcinoma, usually arising in the distal esophagus, must be considered a separate entity from squamous cell esophageal cancer. Epidemiology, etiology, patients risk profiles, biology of metastases, and prognosis differ markedly between these two major esophageal tumor types. The preoperative work-up of patients with Barretts cancer is primarily directed toward assessing the chances for R0 resection and estimating the risk of the patient to survive an esophagectomy. If R0 resection appears likely and the surgical risk is acceptable, the indication for an operative approach is given. From the oncologic point of view there is no difference between a radical transmediastinal approach and a transthoracic approach. A possible advantage of a transthoracic approach is the extension of lymphadenectomy to the upper mediastinum. Lymph node metastases in the upper mediastinum, however, usually indicate advanced lymphatic and subclinical systemic tumor dissemination, i.e., a poor prognosis even with extended surgery. Consequently the controversies about the surgical approach are reduced to technical and functional aspects. A better swallowing function argues for an intrathoracic anastomosis; the lower morbidity, for a cervical approach. We prefer transthoracic en bloc esophagectomy with an intrathoracic anastomosis in patients with moderate risk and early tumor stages. In all other patients radical transmediastinal esophagectomy with a cervical anastomosis is the procedure of choice. The overall 5-year survival rate of more than 40%, which is superior to most published data, supports this therapeutic strategy.     

Barrett’s Esophagus: Model of Neoplastic Progression

Human cancer progression is characterized by clonal expansion of cells with accumulated genetic errors. Invasive carcinomas contain all the genetic errors that were acquired during neoplastic progression and then continue to accumulate further abnormalities, leading to tumor heterogeneity. Many investigations of human cancer have given valuable insights in genetic abnormalities important for tumor biology. Early events responsible for neoplastic progression, however, are often impossible to investigate in invasive cancers because the premalignant tissue in which the tumors develop are often overgrown and the premalignant conditions cannot be studied in vivo because they are either not detected owing to lack of symptoms or are removed before cancer develops. Unlike many other premalignant conditions Barretts esophagus is often associated with symptoms leading to diagnosis at an early stage before cancer develops, and the premalignant epithelium is seldom removed at an early stage of cancer progression. Furthermore, in patients who present with invasive carcinoma the tumor is often surrounded by premalignant epithelium, which is available for further investigations. Therefore Barretts esophagus is an excellent model in which to study the early events of neoplastic progression. It may not only contribute to a better understanding of the neoplastic process but also provide a base for safer assessment of cancer risk during surveillance for early detection of esophageal adenocarcinoma.     

Barrett’s Esophagus: Environmental Influences in the Progression of Dysplasia

Barretts esophagus (BE) is composed of multiple lineages including Paneth cells and endocrine cells in addition to gastric and intestinal cells. Although the origin of the BE stem cell is a matter of conjecture, the stem cells are clearly multipotent, and therefore the phenotype is restricted by genomic imprinting (termed restricted potency). Recent evidence suggests that the microenvironment may select various lineages. In this regard the proportion of gastric and specialized intestinal metaplastic cells has been attributed to the composition of the refluxate, acid or bile, respectively. Experimental evidence also implicates specific xenobiotics in this process, including bile acids. In particular we discuss the potential biologic roles of bile acids in epithelial adaptation from in vivo and in vitro models.     

Activation of the BMP4 Pathway and Early Expression of CDX2 Characterize Non-specialized Columnar Metaplasia in a Human Model of Barrett’s Esophagus

Background

A human model of gastroesophageal reflux disease was used to examine the contribution of a non-specialized columnar type of metaplasia (NSCM) and key molecular events (BMP4 and CDX2) in the development of Barrett??s esophagus.

Methods

Biopsies of the remnant esophagus from 18 patients undergoing esophagectomy with gastric preservation were taken at 6?C36-month intervals postoperatively and examined for activation of the BMP pathway (BMP4/P-Smad 1/5/8) and CDX2 and CDX1 expression by imunohistochemistry, quantitative real-time PCR, Western blot, and in situ hybridization.

Results

A short segment (mean 15.6?mm) of NSCM was detected in 10 (56%) patients, with an increasing prevalence from 17% at 6?months to 62% at 36?months. Nuclear expression of P-Smad 1/5/8 in the squamous epithelium close to the anastomosis with strong expression in all epithelial cells of NSCM areas was found. Forty-eight (63%) biopsies with NSCM showed scattered nuclear expression of CDX2. Two cases showed isolated glands at 18, 24, and 36?months that fully expressed CDX2 and co-expressed CDX1. BMP4 mRNA and CDX2 mRNA levels were significantly greater in NSCM than in squamous epithelium.

Conclusions

BMP4 activation in NSCM and early expression of CDX2 are involved in the columnar epithelial differentiation of Barrett??s esophagus.     

Results of Surgical Therapy in Patients with Barrett’s Adenocarcinoma

The incidence of adenocarcinoma arising from Barretts esophagus is dramatically increasing in Western countries. The purpose of this study was to report our experience in the surgical management of these patients. Between November 1992 and December 2000, 330 consecutive patients with adenocarcinoma of the esophagogastric junction were observed in our institution. Of these, 105 (31.8%) had Barretts carcinoma. In 12 individuals (11.4%) adenocarcinoma was discovered during endoscopic surveillance for Barretts esophagus. Twelve patients with doubtful cleavage planes at preoperative investigation were treated with neoadjuvant chemotherapy. Overall, 80 patients (76.2%) underwent esophagectomy without operative mortality. The Ivor Lewis approach was used in 70 patients; of these, 31 underwent extended mediastinal lymph node dissection. Seventy-four patients (92.5%) had R0 resection. The overall 5-year survival rate was 48%. Survival was significantly associated with stage, lymph node status, and completeness of resection. Early diagnosis remains the prerequisite for curative treatment of esophageal carcinoma. An extended mediastinal lymphadenectomy does not increase morbidity, allows precise tumor staging, and may prove effective in preventing local recurrences. Neoadjuvant therapy requires major improvement before it can be unconditionally recommended outside clinical trials.     

Prevention of Adenocarcinoma by Reversing Barrett’s Esophagus with Mucosal Ablation

The ultimate goal of therapy in patients with Barretts esophagus (BE) is to reduce the risk of developing adenocarcinoma of the esophagus. Neither pharmacologic nor surgical therapy has been documented to reduce this risk. There is preliminary evidence that many forms of mucosal ablation combined with acid reduction therapy result in restitution of normal squamous epithelium in patients with BE. Acid reduction can be accomplished with high-dose proton pump inhibitor therapy or antireflux surgery. Endoscopic ablation can be accomplished with photodynamic therapy, laser, multipolar electrocoagulation, a heater probe, and argon plasma coagulation. These techniques require further study so the complication rates can be compared. The success of reversing BE must be evaluated in a standard way utilizing large-capacity biopsy forceps through a therapeutic endoscope. Ideally, patients at high risk of developing adenocarcinoma of the esophagus can be treated with ablation therapy and followed to document a reduction in the development of adenocarcinoma of the esophagus. A validated biomarker would help select high risk patients appropriate for reversal therapy. Currently, patients who are at prohibitive risk for surgery or who refuse surgery are candidates for combination therapy including mucosal ablation to reverse their BE. This therapy offers the promise of less morbidity and greater quality of life than resection.     

Significance of Nissen fundoplication after endoscopic radiofrequency ablation of Barrett’s esophagus

Objective

HALO radiofrequency ablation (RFA) has been proven as safe and efficient in eradication of both non- and dysplastic Barrett’s esophagus (BE). Definitive post-RFA treatment is yet to be determined.

Methods

RFA was performed in 56 patients with BE, 38 with intestinal metaplasia (IM) and 18 with low-grade dysplasia (LGD), and repeated in case of residual BE. Length of the BE was classified according to C&M criteria. Follow-up included regular upper GI endoscopies with biopsies 6 months, 1 and 2 years after the complete resolution of BE. Patients were divided into two groups regarding post-RFA treatment: those maintaining proton pump inhibitors (PPI) daily and those submitted to laparoscopic Nissen fundoplication (LNF) at least 3 months after BE eradication or synchronous with RFA.

Results

There were no perforations or strictures related to RFA. Complete endoscopic resolution of BE was observed in 83.92 % patients (86.84 % IM and 77.77 % LGD), in 25 that maintained PPI and 22 in whom LNF was done. In PPI group, 2-year follow-up revealed BE recurrence in biopsy samples in 20 % of patients, while in LNF group 9.1 % of patients had recurrent IM. In overall sample of patients, no difference was noted regarding the influence of post-RFA treatment (p < 0.423). LNF proved superiority over PPI treatment in patients with long-segment BE (cutoff C > 4 cm, p < 0.021).

Conclusion

HALO RFA is a safe procedure, with high rate of success in complete eradication of BE in symptomatic GERD patients. LNF provides good protection for neosquamous epithelium and in selected group of patients could be offered as a first line of treatment after HALO RFA.

     

Efficacy and safety of Hybrid-APC for the ablation of Barrett’s esophagus

Background and study aim

After thermal ablation of Barrett’s esophagus (BE), stricture formation is reported in 5 to over 10 % of patients. The question arises whether submucosal fluid injection prior to ablation may lower the risk of stricture formation. The aim of the present study was to evaluate the efficacy and safety of the new technique of Hybrid-APC which combines submucosal injection with APC.

Patients and methods

Patients who had a residual BE segment of at least 1 cm after endoscopic resection of early Barrett’s neoplasia underwent thermal ablation of BE by Hybrid-APC. Prior to thermal ablation, submucosal injection of sodium chloride 0.9 % was carried out using a flexible water-jet probe (Erbejet 2; Erbe Elektromedizin, Tuebingen, Germany). Check-up upper GI endoscopy was carried out 3 months after macroscopically complete ablation including biopsies from the neo-Z-line and the former BE segment, and recording of stricture formation.

Results

From May 2011 to November 2012, a total of 60 patients (pt) were included in the study [55 pt male (92 %); mean age 62 ± 9 years, range 42–79]. Ten patients were excluded from the study. In the remaining 50 pt, Hybrid-APC ablation and check-up endoscopy at 3 months were carried out. Forty-eight out of 50 pt (96 %; ITT: 49/60, 82 %) achieved macroscopically complete remission after a median of 3.5 APC sessions [SD 2.4; range 1–10]. Freedom from BE was histopathologically observed in 39/50 patients (78 %). There was one treatment-related stricture (2 %). Minor adverse events of Hybrid-APC were observed in 11 patients (22 %).

Conclusions

According to this pilot series, Hybrid-APC was effective and safe for BE ablation in a tertiary referral center. The rate of stricture formation was only 2 %. Further studies are required to confirm the present results.

German Clinical Trials Register

DRKS00003369.

     

From Heartburn to Barrett’s Esophagus,and Beyond

Background

Gastroesophageal reflux disease (GERD) affects an estimated 20% of the population in the USA, and its prevalence is increasing worldwide. About 10–15% of patients with GERD will develop Barrett’s esophagus (BE).

Aims

The aims of this study were to review the available evidence of the pathophysiology of BE and the role of anti-reflux surgery in the treatment of this disease.

Results

The transformation of the squamous epithelium into columnar epithelium with goblet cells is due to the chronic injury produced by repeated reflux episodes. It involves genetic mutations that in some patients may lead to high-grade dysplasia and cancer. There is no strong evidence that anti-reflux surgery is associated with resolution or improvement in BE, and its indications should be the same as for other GERD patients without BE.

Conclusions

Patients with BE without dysplasia require endoscopic surveillance, while those with low- or high-grade dysplasia should have consideration of endoscopic eradication therapy followed by surveillance. New endoscopic treatment modalities are being developed, which hold the promise to improve the management of patients with BE.

     

Vascular Endothelial Growth Factor Expression and Neovascularization in Barrett’s Carcinoma

Angiogenesis is essential for tumor growth and metastasis. An association between microvessel density, a measure of tumor angiogenesis, and conventional prognostic variables has been shown for many tumor entities. For Barretts carcinoma, the results are controversial. Immature vessels formed in tumors are structurally and functionally different from those in mature vessels. The relation between mature and immature vessels as a prognostic factor for Barretts carcinoma has not been assessed. Specimens from 45 R0-resected Barretts carcinomas were immunostained for vascular endothelial growth factor (VEGF), CD 31, and smooth muscle -actin to discriminate between mature and immature vessels. VEGF staining was evaluated quantitatively by measuring optical density with a new computer-based program and expressed as a percentage of the staining (juvenile placental tissue) on control slides. The neovascularization coefficient (i.e., the relation between mature and immature vessels) was estimated with an interactive analytic computer program. The median survival of the study group was 45.7 months. The neovascularization coefficient correlated with the histopathologic classification (p < 0.001). Survival time in patients with a low neovascularization coefficient was significantly better than the survival time in patients with a high neovascularization coefficient (p = 0.021). VEGF expression did not correlate with clinicopathologic data (p > 0.05) or with patient survival (p > 0.05). The tumors with a high neovascularization coefficient did not have significantly elevated VEGF expression. Based on a strong quantitative computer evaluation program, the present study indicates that neovascularization has an important impact on the survival of patients with Barretts carcinoma. However, VEGF does not appear to be the vascular growth factor stimulating neovascularization in Barretts carcinoma patients.     

Results of a Multimodal Therapy in Patients with Stage IV Barrett’s Adenocarcinoma

Background  Locally advanced and metastatic Barrett’s carcinomas account for the majority of this tumor entity at the time of diagnosis. Many studies have shown that a multimodal therapy concept consisting of neoadjuvant chemotherapy followed by resection can result in improved long-term survival in patients responding to chemotherapy. The benefit of a multimodal therapy concept in patients with stage IV disease remains unclear. Methods  A total of 178 patients with Barrett’s carcinoma who underwent multimodal therapy with resection of the tumor were reviewed. The pathological staging and the clinical course of patients with metastatic disease, who were treated equally, were compared to patients with locally advanced tumors. Results  As expected, postoperative pathological staging showed that patients with metastatic disease have a more advanced T- and N-status. Moreover, the histopathological response according to Becker showed a chemoresistence in 84% of cases with metastatic disease, whereas 54% of patients with locally advanced carcinomas had a good response rate. Overall survival was poor, with 9 months in the metastatic group. Conclusions  This is the first study to compare the outcome of a modern multimodal therapy concept in patients with metastatic Barrett’s carcinoma in comparison to patients with the locally advanced form of the disease. There are profound differences in the two groups with regard to survival time and response rates. Because of the poor outcome to date, multimodal therapy with resection of the tumor in stage IV disease cannot be recommended.     

Approach to Early Barrett’s Cancer

Because of effective surveillance programs in patients with known Barretts esophagus, adenocarcinoma of the distal esophagus is increasingly diagnosed at early stages. With the introduction of limited surgical and endoscopic treatment modalities, the need for radical esophagectomy and extensive lymphadenectomy in such patients has been questioned. When selecting the approach to early Barretts cancer, the precancerous nature of the underlying Barretts esophagus, the frequent multicentricity of neoplastic alterations within the Barrett mucosa, the inaccuracy of current staging modalities, and the presence of lymph node metastases should be taken into account. Invasiveness and morbidity of the procedures, as well as quality of life aspects, should also be considered. From an oncologic point of view the minimum extent of a resection for early Barretts cancer should include a full-thickness removal of the entire segment of the distal esophagus covered by intestinal metaplasia together with a regional lymphadenectomy. In appropriately selected patients this can be achieved by a limited surgical procedure involving transhiatal resection of the distal esophagus, but not by endoscopic mucosal ablation or endoscopic mucosa resection. Our experience with 49 limited surgical resections with regional lymphadenectomy indicates that this procedure is oncologically adequate and safe. Reconstruction with an interposed jejunal loop prevents postoperative gastroesophageal reflux and is associated with good quality of life. In contrast, endoscopic interventions are plagued by a high tumor recurrence rate, probably from persistence of Barretts mucosa and gastroesophageal reflux.     

Barrett’s Esophagus: A Review of the Literature

Barrett’s esophagus (BE) is the premalignant lesion of esophageal adenocarcinoma (EAC) defined as specialized intestinal metaplasia of the tubular esophagus that results from chronic gastroesophageal reflux. Which patients are at risk of having BE and which are at further risk of developing EAC has yet to be fully established. Many aspects of the management of BE have changed considerably in the past 5 years alone. The aim of this review is to define the critical elements necessary to effectively manage individuals with BE. The general prevalence of BE is estimated at 1.6–3% and follows a demographic distribution similar to EAC. Both short-segment (<3 cm) and long-segment (≥3 cm) BE confer a significant risk for EAC that is increased by the development of dysplasia. The treatment for flat high-grade dysplasia is endoscopic radiofrequency ablation therapy. The benefits of ablation for non-dysplastic BE and BE with low-grade dysplasia have yet to be validated. By understanding the intricacies of the development, screening, surveillance, and treatment of BE, new insights will be gained into the prevention and early detection of EAC that may ultimately lead to a reduction in morbidity and mortality in this patient population.     

Modelling the Progression of Competitive Performance of an Academy’s Soccer Teams

Progression of a team’s performance is a key issue in competitive sport, but there appears to have been no published research on team progression for periods longer than a season. In this study we report the game-score progression of three teams of a youth talent-development academy over five seasons using a novel analytic approach based on generalised mixed modelling. The teams consisted of players born in 1991, 1992 and 1993; they played totals of 115, 107 and 122 games in Asia and Europe between 2005 and 2010 against teams differing in age by up to 3 years. Game scores predicted by the mixed model were assumed to have an over-dispersed Poisson distribution. The fixed effects in the model estimated an annual linear pro-gression for Aspire and for the other teams (grouped as a single opponent) with adjustment for home-ground advantage and for a linear effect of age difference between competing teams. A random effect allowed for different mean scores for Aspire and opposition teams. All effects were estimated as factors via log-transformation and presented as percent differences in scores. Inferences were based on the span of 90% confidence intervals in relation to thresholds for small factor effects of x/÷1.10 (+10%/-9%). Most effects were clear only when data for the three teams were combined. Older teams showed a small 27% increase in goals scored per year of age difference (90% confidence interval 13 to 42%). Aspire experienced a small home-ground advantage of 16% (-5 to 41%), whereas opposition teams experienced 31% (7 to 60%) on their own ground. After adjustment for these effects, the Aspire teams scored on average 1.5 goals per match, with little change in the five years of their existence, whereas their opponents’ scores fell from 1.4 in their first year to 1.0 in their last. The difference in progression was trivial over one year (7%, -4 to 20%), small over two years (15%, -8 to 44%), but unclear over >2 years. In conclusion, the generalized mixed model has marginal utility for estimating progression of soccer scores, owing to the uncertainty arising from low game scores. The estimates are likely to be more precise and useful in sports with higher game scores.

Key points

• A generalized linear mixed model is the approach for tracking game scores, key performance indicators or other measures of performance based on counts in sports where changes within and/or between games/seasons have to be considered.
• Game scores in soccer could be useful to track performance progression of teams, but hundreds of games are needed.
• Fewer games will be needed for tracking performance represented by counts with high scores, such as game scores in rugby or key performance indicators based on frequent events or player actions in any team sport.

Key words: Association football, generalised mixed model, key performance indicators, performance trends