Barrett's esophagus and esophageal adenocarcinoma are common after treatment for achalasia.

BACKGROUND: Achalasia is characterized by esophageal aperistalsis and impaired relaxation of the lower esophageal sphincter (LES). This contrasts with an insufficient LES, predisposing to gastro-esophageal reflux and Barrett's esophagus. The co-incidence of achalasia and BE is rare. Pneumatic dilatation (PD) may lead to gastro-esophageal reflux, Barrett's esophagus development, and esophageal adenocarcinoma. AIMS: To determine the incidence of Barrett's esophagus and esophageal adenocarcinoma in achalasia patients treated with PD. METHODS: We performed a single-center cohort follow-up study of 331 achalasia patients treated with PD. Mean follow-up was 8.9 years, consisting of regular esophageal manometry, timed barium esophagram, and endoscopy. RESULTS: Twenty-eight (8.4%) patients were diagnosed with Barrett's esophagus, one at baseline endoscopy. This corresponds with an annual incidence of Barrett's esophagus of 1.00% (95% CI 0.62-1.37). Hiatal herniation was present in 74 patients and 21 developed Barrett's esophagus compared to seven of 257 patients without a hiatal hernia. Statistical analysis revealed a hazard ratio of 8.04 to develop Barrett's esophagus if a hiatal hernia was present. Post-treatment LES pressures were lower in patients with Barrett's esophagus than in those without (13.9 vs. 17.4 mmHg; p = 0.03). Two (0.6%) patients developed esophageal adenocarcinoma during follow-up. CONCLUSIONS: Barrett's esophagus is incidentally diagnosed in untreated achalasia patients despite high LES pressures, but is more common after successful treatment, especially in the presence of hiatal herniation. Patients treated for achalasia should be considered for GERD treatment and surveillance of development of Barrett's esophagus, in particular, when they have low LES pressures and a hiatal herniation.

Predictors for outcome of failure of balloon dilatation in patients with achalasia.

BACKGROUND: Pneumatic balloon dilatation (PD) is a regular treatment modality for achalasia. The reported success rates of PD vary. Recurrent symptoms often require repeated PD or surgery. OBJECTIVE: To identify predicting factors for symptom recurrence requiring repeated treatment. METHODS: Between 1974 and 2006, 336 patients were treated with PD and included in this longitudinal cohort study. The median follow-up was 129 months (range 1-378). Recurrence of achalasia was defined as symptom recurrence in combination with increased lower oesophageal sphincter (LOS) pressure on manometry, requiring repeated treatment. Patient characteristics, results of timed barium oesophagram and manometry as well as baseline PD characteristics were evaluated as predictors of disease recurrence with Kaplan-Meier curves and Cox regression analysis. RESULTS: 111 patients had symptom recurrence requiring repeated treatment. Symptoms recurred after a mean follow-up of 51 months (range 1-348). High recurrence percentages were found in patients younger than 21 years in whom the 5 and 10-year risks of recurrence were 64% and 72%, respectively. These risks were respectively 28% and 36% in patients with classic achalasia, respectively 48% and 60% in patients without complete obliteration of the balloon's waist during PD and respectively 25% and 33% in patients with a LOS pressure greater than 10 mm Hg at 3 months post-dilatation. These four predictors remained statistically significant in a multivariable Cox analysis. CONCLUSION: Although PD is an effective primary treatment in patients with primary achalasia, patients are at risk of recurrent disease, with this risk increasing during long-term follow-up. Young age at presentation, classic achalasia, high LOS pressure 3 months after PD and incomplete obliteration of the balloon's waist during PD are the most important predicting factors for the need for repeated treatment during follow-up. Patients who meet one or more of these characteristics may be considered earlier for alternative treatment, such as surgery.

Long-term esophageal cancer risk in patients with primary achalasia: a prospective study.

OBJECTIVES: Achalasia patients are considered at increased risk for esophageal cancer, but the reported relative risks vary. Identification of this risk is relevant for patient management. We performed a prospective evaluation of the esophageal cancer risk in a large cohort of achalasia patients with long-term follow-up. METHODS: Between 1975 and 2006, all patients diagnosed with primary achalasia in our hospital were treated and followed by the same protocol. After graded pneumatic dilatation, all patients were offered a fixed surveillance protocol including gastrointestinal endoscopy with esophageal biopsy sampling. RESULTS: We surveyed a cohort of 448 achalasia patients (218 men, mean age 51 years at diagnosis, range 4-92 years) for a mean follow-up of 9.6 years (range 0.1-32). Overall, 15 (3.3%) patients (10 men) developed esophageal cancer (annual incidence 0.34 (95% confidence interval 0.20-0.56)). The mean age at cancer diagnosis was 71 years (range 36-90) after a mean of 11 years (range 2-23) following initial presentation, and a mean of 24 years (range 10-43) after symptom onset. The relative hazard rate of esophageal cancer was 28 (confidence interval 17-46) compared with an age- and sex-identical population in the same timeframe. Five patients received a potential curative treatment. CONCLUSIONS: Although the gastro-esophageal cancer risk in patients with longstanding achalasia is much higher than in the general population, the absolute risk is rather low. Despite structured endoscopical surveillance, most neoplastic lesions remain undetected until an advanced stage. Efforts should be made to identify high-risk groups and develop adequate surveillance strategies.

Expression of p53 as predictor for the development of esophageal cancer in achalasia patients.

Patients with longstanding achalasia have an increased risk of developing esophageal cancer. Surveillance is hampered by chronic stasis. We investigated whether aberrant expressions of tumor suppressor gene p53 and proliferation marker ki67 are early predictors for progression to malignancy. In 399 achalasia patients, 4% died of esophageal cancer despite surveillance. We performed a cohort study, using surveillance biopsies from 18 patients (11 carcinoma, one high-grade dysplasia [HGD], and six low-grade dysplasia [LGD]) and 10 controls (achalasia patients without cancer or dysplasia development). One hundred sixty-four biopsies were re-evaluated and studied for p53 and ki67 expression using immunohistochemistry. Eighty-two percent of patients with cancer/HGD showed p53 overexpression in surveillance biopsies at a mean of 6 (1-11) years prior to cancer development. In 67% of patients with LGD and only in 10% of the controls p53 overexpression was present. The proportion of samples with p53 overexpression increased with increasing grades of dysplasia. We found no difference for ki67 overexpression. p53 overexpression may identify achalasia patients at increased risk of developing esophageal carcinoma. Further study is needed to determine if patients with p53 overexpression would benefit from intensive surveillance to detect esophageal neoplasia at a potential curable stage.

Achalasia and associated esophageal cancer risk: What lessons can we learn from the molecular analysis of Barrett's-associated adenocarcinoma?

Idiopathic achalasia and Barrett's esophagus (BE) are preneoplastic conditions of the esophagus. BE increases the risk of esophageal adenocarcinoma (EAC), while achalasia is associated with both EAC and esophageal squamous cell carcinoma (ESCC). However, while the molecular mechanisms underlying the transformation of esophageal epithelial cells in BE are relatively well characterized, less is known regarding these processes in achalasia. Nevertheless, both conditions are associated with chronic inflammation and BE can occur in achalasia patients, and it is likely that similar processes underlie cancer risk in both diseases. The present review will discuss possible lessons that we can learn from the molecular analysis of BE for the study of achalasia-associated cancer and contrast findings in BE with those in achalasia. First, we will describe cellular fate during development of BE, EAC, and ESCC, and consider the inflammatory status of the epithelial barrier in BE and achalasia in terms of its contribution to carcinogenesis. Next, we will summarize current data on genetic alterations and molecular pathways involved in these processes. Lastly, the plausible role of the microbiota in achalasia-associated carcinogenesis and its contribution to abnormal lower esophageal sphincter (LES) functioning, the maintenance of chronic inflammatory status and influence on the esophageal mucosa through carcinogenic by-products, will be discussed.

Oesophagitis is common in patients with achalasia after pneumatic dilatation.

BACKGROUND: Achalasia, an oesophageal motor disease, is associated with functional oesophageal obstruction. Food stasis can predispose for oesophagitis. Treatment aims at lowering of the lower oesophageal sphincter pressure, enhancing the risk of gastro-oesophageal reflux. Nevertheless, the incidence of oesophagitis after achalasia treatment is unknown. AIM: To investigate the incidence and severity of oesophagitis in achalasia patients treated with pneumatic dilatation. METHODS: A cohort of 331 patients with achalasia were treated with pneumatic dilatation and followed. Oesophagitis and stasis were assessed by endoscopy and inflammation was graded by histology. RESULTS: 251 patients were followed for a mean values of 8.4 years (range: 1-26). The average number of endoscopies with biopsy sample sets per patient was 4 (range: 1-17). Three patients had no histological signs of oesophagitis throughout follow-up, 139 had oesophagitis grade 1, 49 oesophagitis grade 2 and 60 grade 3. Specialized intestinal metaplasia was found in 37 patients. The association between endoscopic food stasis and histological inflammation was significant. The association between endoscopic signs of oesophagitis and histological inflammation was poor. CONCLUSIONS: Forty percent of the achalasia patients develop chronic active or ulcerating oesophagitis after treatment. Inflammation was associated with food stasis. Because the sensitivity of endoscopy to detect inflammation is low, surveillance endoscopy with biopsy sampling and assessment of stasis is warranted to detect early neoplastic changes.

Recovery of chronic hepatitis by treatment of concomitant hyperthyroidism.

A 15-year-old boy presented with biochemical and histological hepatic abnormalities consistent with chronic aggressive hepatitis and concomitant hyperthyroidism. After treatment with antithyroid therapy not only the hyperthyroidism subsided but also the hepatic function normalized. Two years later, the hyperthyroidism and liver function disorders relapsed in combination with a striking vitiligo and once again the liver function normalized after treating the hyperthyroidism. The liver biopsy sample taken in remission showed a normal picture without signs of hepatitis, fibrosis or cirrhosis. The diagnosis of a polyglandular syndrome was made, of which three types have been described. At this moment the patient fits best in type 3, which is a rather heterogenic group. Recovery of chronic hepatitis by treatment of concomitant hyperthyroidism has never been described before.

[Melioidosis]. / Melioidosis.

A 34-year-old woman presented two weeks after a visit to Burma with fever peaking up to 39 degrees C, chills, non-productive cough, headache, muscle pain, shortness of breath and a painful swelling on the left lower leg. She was treated immediately with intravenous amoxycillin-clavulanic acid. The Gram negative causative agent of melioidosis, Burkholderia (previously Pseudomonas) pseudomallei, was cultured from samples taken beforehand. The patient then received ceftazidime. She recovered. In view of the risk of relapse she was treated with amoxycillin-clavulanic acid for a further six months. Melioidosis is endemic in Southeast Asia and Northern Australia. It is rarely seen outside these areas. The clinical spectrum of the disease is wide and varies from fulminating sepsis to a subclinical disease and may affect any organ system, usually the lungs. The mortality of the septicaemic form after adequate treatment is 40%. Surviving patients have a high relapse rate (4-20%). Melioidosis can become chronic with formation of abscesses or can remain subclinical for many years, probably because the microorganism can survive within phagocytic cells with a risk of reactivation at moments of immunosuppression. The optimal treatment consists of ceftazidime intravenously for at least two weeks followed by an eradication phase consisting of oral antibiotics for at least 3 months.

Proton pump inhibitor therapy in gastro-oesophageal reflux disease decreases the oesophageal immune response but does not reduce the formation of DNA adducts.

BACKGROUND: Chronic oesophageal inflammation and related oxidative stress are important in the pathogenesis of erosive oesophagitis (EO) and its malignant progression. AIM: To study the effect of proton pump inhibitors (PPIs) on oesophageal cellular immune response and oxidative damage in EO patients. METHODS: Forty gastro-oesophageal reflux disease (GERD) patients [non-erosive reflux disease (NERD): 15, EO: 25] were included, after 7 days off antisuppressive drugs. EO patients were randomized to 20-mg rabeprazole once daily for either 4 or 8 weeks with baseline and follow-up endoscopy with distal oesophageal biopsies. T lymphocytes, macrophages and mast cells were quantified by immunohistochemistry. DNA adducts were measured by analysis of 8-oxo-deoxyguanosine levels. RESULTS: Erosive oesophagitis patients had more T lymphocytes and CD8(+) T lymphocytes in squamous epithelium than NERD patients (P = 0.001, P = 0.002, respectively). Levels of DNA adducts between both groups were, however, not different (P = 0.99). Four- and eight-week rabeprazole treatment in EO patients resulted in a significant decrease in number of T lymphocytes and CD8(+) T lymphocytes (all P < 0.05). PPIs did not, however, affect levels of DNA adducts. CONCLUSIONS: Short-term PPI therapy in EO patients reduces the oesophageal cellular immune response, but does not change oxidative damage. PPI therapy may therefore not be effective in reducing the risk of oesophageal cancer in GERD patients.