Pseudoachalasia as First Manifestation of a Malignancy.

Pseudoachalasia is a condition in which symptoms, radiologic, endoscopic, and manometric findings mimick idiopathic achalasia. About 4% of patients with a typical constellation for idiopathic achalasia will turn out to have pseudoachalasia, posing a major diagnostic challenge. A large spectrum of underlying causes of pseudoachalasia has been described. However, in about 70% of affected patients, this condition is caused by a malignancy (mostly adenocarcinoma of the esophagogastric junction or cardia). We describe a 16-year-old high school student referred for management of achalasia who turned out to have pseudoachalasia due to adenocarcinoma of the cardia. He was cured with preoperative chemotherapy followed by radical surgery. Therapy of pseudoachalasia secondary to neoplasia is directed against the tumor or may be palliative to keep the lumen open. Other causes of pseudoachalasia include esophageal motility disturbances as a paraneoplastic phenomenon (e.g., with small cell lung cancer), post fundoplication or post bariatric surgery, in association with a thoracic aortic aneurysm, or with sarcoidosis or amyloidosis. Therapy is directed accordingly to eliminate or correct the underlying cause.

Involvement of EP2 and EP4 Receptors in Eosinophilic Esophagitis: A Pilot Study.

BACKGROUND: The prostaglandin D2 receptor DP2 has been implicated in eosinophil infiltration and the development of eosinophilic esophagitis (EoE). AIMS AND METHODS: In this study, we investigated an involvement of PGE2 (EP1-EP4) and PGD2 (DP1) receptors in EoE by measuring their expression in peripheral blood eosinophils and esophageal mucosal biopsies of EoE patients and by performing migration and adhesion assays with eosinophils from healthy donors. RESULTS: Expression of EP2 and EP4, but not EP1 and EP3, was decreased in blood eosinophils of patients with EoE vs. control subjects. Adhesion of eosinophils to esophageal epithelial cells was decreased by EP2 receptor agonist butaprost and EP4 agonist ONO-AE1-329, whereas DP1 agonist BW245C increased adhesion. In chemotaxis assays with supernatant from human esophageal epithelial cells, only ONO-AE1-329 but not butaprost or BW245C inhibited the migration of eosinophils. Expression of EP and DP receptors in epithelial cells and eosinophils was detected in sections of esophageal biopsies from EoE patients by immunohistochemistry. qPCR of biopsies from EoE patients revealed that gene expression of EP4 and DP1 was the highest among PGE2 and PGD2 receptors. Esophageal epithelial cells in culture showed high gene expression for EP2 and EP4. Activation of EP2 and EP4 receptors decreased barrier integrity of esophageal epithelial cells in impedance assays. CONCLUSIONS: Activation of EP2 and EP4 receptors may inhibit eosinophil recruitment to the esophageal mucosa. However, their activation could negatively affect esophageal barrier integrity suggesting that eosinophilic rather than epithelial EP2 and EP4 have a protective role in EoE.

Secondary tumors of the GI tract: origin, histology, and endoscopic findings.

BACKGROUND AND AIMS: The GI tract is rarely affected by secondary tumors. Patients often present at an advanced stage of the disease, and prognosis is dismal. This study aimed to analyze the clinical, endoscopic, and pathologic features of secondary tumors that had been diagnosed endoscopically. METHODS: We conducted a retrospective database analysis of 217 patients with secondary tumors of the GI tract. Endoscopic findings and histologic diagnoses were systematically re-evaluated. RESULTS: Malignant melanoma (n = 33, 15%), breast cancer (n = 32, 15%), and pancreatic cancer (n = 27, 12%) were the most common corresponding primaries. About one-third of secondary tumors were detected in the stomach (n = 76, 35%), followed by small intestine (n = 54, 25%) and rectum (n = 53, 24%). The median time between the diagnoses of primary and secondary tumors was 19 months (mean, 31; range, 0-251), and this time was particularly long for renal cell carcinoma and breast cancer (median, 38 and 45 months, respectively). Direct invasion from extra-GI malignancies was more common (56%) than vascular cancer spread (44%) and depended on both sites of tumor involvement and corresponding primary. The lesions presented with various endoscopic patterns. In patients for whom a definitive diagnosis of cancer was known before the examination (n = 168), a secondary tumor was included in the differential diagnosis in only 48% of lesions. It is of note that the remaining cases were diagnosed endoscopically as primary tumors and rarely also as nonneoplastic change. CONCLUSIONS: Secondary tumors may affect all parts of the GI tract. Malignant melanoma and breast and pancreatic cancer represent the most common primaries. Diagnosis based on examination of biopsy specimens is crucial to avoid misclassification.

Cardiac mucosa at the gastro-oesophageal junction: indicator of gastro-oesophageal reflux disease? Data from a prospective central European multicentre study on histological and endoscopic diagnosis of oesophagitis (histoGERD trial).

AIMS: The origin and significance of cardiac mucosa at the gastro-oesophageal junction are controversial. In the prospective Central European multicentre histoGERD trial, we aimed to assess the prevalence of cardiac mucosa, characterized by the presence of glands composed of mucous cells without parietal cells, and to relate its presence to features related to gastro-oesophageal reflux disease (GORD). METHODS AND RESULTS: One thousand and seventy-one individuals (576 females and 495 males; median age 53 years) were available for analysis. Overall, in biopsy specimens systematically taken from above and below the gastro-oesophageal junction, cardiac mucosa was observed in 713 (66.6%) individuals. Its presence was associated with patients' symptoms and/or complaints (P = 0.0025), histological changes of the squamous epithelium (P < 0.001) indicative of GORD, intestinal metaplasia (P < 0.001), and an endoscopic diagnosis of oesophagitis (P < 0.001). No association with an endoscopic diagnosis of Barrett's oesophagus or with gastric pathology, particularly Helicobacter infection, was observed. CONCLUSIONS: Cardiac mucosa is a common finding in biopsy specimens taken from the gastro-oesophageal junction. Its association with reflux symptoms, histological changes indicating GORD and the endoscopic diagnosis of oesophagitis suggests that injury and repair related to GORD contribute to its development and/or expansion.

Management of gastroesophageal reflux disease: lifestyle modification and alternative approaches.

The first step in the management of gastroesophageal reflux disease (GERD) is lifestyle modification, with dietary recommendations such as increasing fiber intake and lowering dietary fat. While there is some physiological evidence that various foods as well as alcohol and tobacco affect the pressure of the lower esophageal sphincter (LES), targeted interventions have not shown any benefit in clinical trials. The general recommendation is for the patient to avoid foods and beverages that in his or her experience trigger GERD symptoms. The only measures that have been shown with some degree of scientific evidence to be beneficial are weight loss on the part of obese patients and elevation of the head of the bed. We, in contrast, developed a training program that induces a change from thoracic to abdominal breathing. We hypothesized that this change in breathing actively trains the diaphragm, and so potentially strengthens the LES. In a randomized trial using breathing exercises as the intervention, we found an improvement in gastroesophageal reflux symptoms, assessed by quality of life, pH-metry and proton pump inhibitor use. Most patients would prefer to take proton pump inhibitors than to do exercises, but at least for a subgroup of highly motivated patients who would prefer an alternative to medication, structured physical exercises could offer new help with their GERD.

EndoBarrier™ Implantation Rapidly Improves Insulin Sensitivity in Obese Individuals with Type 2 Diabetes Mellitus.

The EndoBarrier™ medical device is a duodenal-jejunal bypass liner designed to mimic the effects of gastric bypass surgery to induce weight loss and glycaemic improvement. In this study, 10 participants with type 2 diabetes mellitus (T2DM), a mean body mass index (BMI) of 43.3 ± 5.0 (kg/m2) and a mean glycated haemoglobin A1c (HbA1c) of 60.6 ± 8.6 mmol/mol were examined at baseline (before implantation of EndoBarrier™), 4 weeks after implantation, at 36 weeks (right before explantation) and 24 weeks after the removal of the device to explore the short and long-term effects on glucose metabolism. Besides a significant reduction in body weight and fat mass, EndoBarrier™ treatment significantly improved insulin sensitivity during Botnia clamp investigations after four weeks of implantation. The beneficial effects decreased over time but remained significant 24 weeks after removal of the device.

Helpful, albeit hazardous! Esophageal stem-cell injection in systemic sclerosis.

BACKGROUND: Over 90% of patients with systemic sclerosis suffer from gastroesophageal reflux. Esophageal motility disturbances are associated with a reduced life quality and may force interstitial lung disease progression. We wanted to determine whether we can improve gastroesophageal reflux in these patients by esophageal stem-cell injection. METHODS: We performed a pilot study including eights patients with systemic sclerosis and symptomatic gastroesophageal reflux. Sampling of adipose tissue was performed by an experienced plastic surgeon under local anesthesia. The collected fat was injected into the submucosa of the distal esophagus, each time 1 ml in all four quadrants starting 2, 4 and 6 cm proximal to the Z line (ending up to a total volume of 12 ml). Before the intervention, 3, 6 and finally 12 months after the procedure, patients answered the Gastroesophageal Reflux Disease Health-Related Quality of Life Questionnaire (GERD HRQL) and a high-resolution manometry was performed to quantify changes in motility function. RESULTS: All patients showed an improvement in the GERD HRQL score after the stem-cell injection and a lower dosage of proton-pump inhibitors. The manometric findings showed no change throughout the time. A serious adverse event occurred, as one patient developed multiple cerebellar embolic infarcts. CONCLUSION: Because of the favorable effect in all patients, a safe route for esophageal fat injection needs to be developed.

Impact of Duodeno-Jejunal Bypass Liner (EndoBarrierTM) Implantation on Insulin Sensitivity in Patients with Type 2 Diabetes Mellitus (T2DM): A Study Protocol for a Pilot Trial.

INTRODUCTION: A 60-cm endoscopically implantable duodenal-jejunal bypass liner (Endobarrier™, GI Dynamics, Lexington, MA, USA) has been introduced as a therapeutic option to support weight loss for a selected group of obese subjects with type 2 diabetes mellitus (T2DM). The sleeve prevents contact between chyme and the intestinal mucosa of the upper gastrointestinal tract. The primary aim of this study is to elucidate the changes in insulin sensitivity and beta-cell function after EndoBarrier™ implantation in obese patients with T2DM; changes in gut permeability and gut microbiome are also to be examined. METHODS: This is an open, single-center, prospective trial in which ten obese subjects with T2DM and suboptimal glycemic control (glycosylated hemoglobin A1c (HbA1c) level > 48 mmol/mol) are investigated with regards to EndoBarrier™ implantation. The Endobarrier™ is implanted shortly after baseline and left in situ for a period of 36 weeks. Dual-energy X-ray absorptiometry measurement, assessment of beta-cell function and insulin sensitivity as measured by a Botnia clamp procedure, and a mixed-meal tolerance test are performed prior to implantation and at 4, 36, and 64 weeks after implantation. The composition of the gut microbiota is characterized from stool using 454 pyrosequencing of 16S rRNA genes. Gut permeability is assessed by a differential sugar absorption method. PLANNED OUTCOME: This study will give mechanistic insights in particulr into changes of insulin sensitivity, beta-cell function or microbiome changes over time in subjects implanted with an EndobarrierTM device. TRIAL REGISTRATION: NCT02769728, Registered 12 May 2016. Current Protocol Date/Version: 04 September 2017/Version 1.9.

The incidence of gastroesophageal reflux after transthoracic esophagocardio-myotomy without fundoplication: a long term follow-up.

OBJECTIVE: Evaluation of the long term results of Heller's myotomy performed over a lateral thoracotomy without additional fundoplication. METHODS: Forty patients (17 males, 23 females; mean age 43.2 years; range: 14-63 years) were operated between 1985 and 2000. Preoperative evaluation included clinical scoring of symptoms, esophagogram, endoscopy, manometry and 24-h ph-metry. At the follow-up investigation, the preoperative evaluation was repeated in all patients, adding a histological workup of the distal esophageal mucosa. The mean duration of follow-up after surgery was 10.3 years, ranging from 3-16 years. RESULTS: The clinical scores improved significantly: Excellent relief from dysphagia was present in 86%, little or no regurgitation was found in 79%, little or no retrosternal spasms were reported by 72% of the patients. Esophagogram showed an overall esophageal dilatation in all patients but no significant obstruction at the esophagogastric junction. Endoscopically, 2.5% had candida-esophagitis, 5% showed signs of a GERD I, 92.5% had a macroscopically insuspect esophageal mucosa. Histologically, 53% showed a mild chronic inflammation. Manometry demonstrated distinct hypomotility of the esophagus in all cases, yet no elevated pressure of the lower sphincter; pH-metry showed moderate reflux in 46%. CONCLUSIONS: Transthoracic cardiomyotomy is a valid method for the treatment of achalasia, but it will not improve the esophageal motility, which slowly deterioriates in these cases. The patient's subjective assessment of the postoperative result was positive in the majority of cases. Although fundoplication was not done in any of these patients, none of them showed signs of clinically relevant reflux.

Annoying vacation souvenir: Fish tapeworm (Diphyllobothrium sp.) infestation in an Austrian fisherman.

Diphyllobothriosis is infestation with the fish tapeworm. Although the worldwide incidence has decreased in recent decades, increased travel and the new popularity of dishes involving raw fish (e.g. sushi) may provide a higher risk of infestation in formerly low-risk areas. We report an Austrian fisherman who passed a 75 cm tapeworm segment in his stool. Infestation presumably occurred 14 months earlier during a fishing tour in Alaska. At presentation, the patient was asymptomatic, reported no weight loss and showed neither anaemia nor eosinophilia. He was cured with a single dose of 10 mg/kg body weight praziquantel.

Are dyspeptic symptoms linked to Helicobacter pylori? A prospective cohort study among medical students.

OBJECTIVE AND DESIGN: In Austria, the prevalence of Helicobacter pylori (Hp) infection in healthy people with or without symptoms of dyspepsia has not yet been assessed systematically. We conducted a prospective cohort study among medical students during their rotation in internal medicine to determine whether or not dyspeptic symptoms are linked to Hp infection. Symptoms were assessed before testing for Hp so that knowledge of Hp status could not influence symptom-reporting behavior. METHODS: From February 2000 to February 2001 we invited 242 medical students to participate in this trial. Abdominal symptoms were assessed by a questionnaire. Dyspeptic symptoms were defined according to the Rome II criteria: heartburn was not considered a dyspeptic symptom. Severity of symptoms was assessed using the Glasgow dyspepsia severity score (GDSS). After determination of symptoms, students underwent a 13C-urea breath test for Hp. RESULTS: Of 242 students (103 male, 139 female, mean age 26 years, range 21-39 years), 23 tested positive for Hp (10%). Of 34 participants reporting dyspeptic symptoms (14%, GDSS-range 1-11), four were Hp positive (12%). Of the 208 asymptomatic students, 19 were Hp positive (9%). Statistical analysis did not show a significant difference in the frequency of Hp infection between asymptomatic students and students reporting dyspeptic symptoms. CONCLUSION: Hp prevalence in Austrian medical students is similar to that in other western countries. There was no significant difference in Hp prevalence between dyspeptic students and asymptomatic students.

Short-term therapeutic trial of proton pump inhibitors in suspected extraesophageal reflux.

Pharyngoesophageal gastric acid reflux is thought to initiate chronic posterior laryngitis. The gold standard for measuring gastric reflux is dual-channel 24-hour pH monitoring. This is a time-consuming, inconvenient, expensive method that is not available in all areas. New therapeutic regimes that make use of proton pump inhibitors (PPIs) have proven to be therapeutically efficient for control of acid reflux. Twenty-four consecutive patients with chronic voice disorders and signs of posterior laryngitis were selected for therapy. Twenty-four hour pH monitoring was performed independently before the therapy. The trial therapy consisted of all patients receiving pantoprazole, 40 mg once daily for 6 weeks. Immediately following the therapy a statistically significant (p < 0.05) improvement was observed in all patients. This improvement was analyzed retrospectively by comparison with the results of 24-hour pH monitoring. In 71% of the patients the 24-hour pH-monitoring gave a positive result showing a high number of patients with extraesophageal reflux in our study group. Patients with positive results of pH-monitoring responded in a statistically significant manner (p < 0.05) to the pantoprazole therapy, whereas those patients without detected reflux did not. A 3-month follow-up of the patients with a positive result of the pH-monitoring confirmed the improvement. No patients reported adverse effects. A 6-week treatment with pantoprazole can be clinically justified. It helps to save time and reduce costs, allows for selection of reflux-negative patients for alternative therapy, and may prevent inadequate treatment of patients with false-negative pH monitoring. Twenty-four hour pH monitoring is still recommended for patients unresponsive to this trial therapy.

Evolving patterns in the diagnosis of reactive gastropathy: data from a prospective Central European multicenter study with proposal of a new histologic scoring system.

Histologic examination of gastric biopsies is crucial for determining the cause of gastritis. This prospective multicenter study was undertaken to investigate different histologic parameters arguing in favor or against the diagnosis of reactive gastropathy and to correlate findings with patient's symptoms and endoscopic findings. A total of 1123 individuals aged 15-93 years participated in a prospective multicenter study (histoGERD trial). Diagnosis of Helicobacter gastritis was made following the Updated Sydney System. Diagnosis of reactive gastropathy was based upon Dixon's parameters of foveolar hyperplasia, smooth muscle fibers in the lamina propria and vasodilatation and congestion of mucosal capillaries. Including paucity of acute and chronic inflammatory cells in analysis, a new score with visual analog scales for the diagnosis of reactive gastropathy was developed. All three histologic parameters in favor of the diagnosis of reactive gastropathy were positively associated with the endoscopic diagnosis of gastritis (p < 0.001), yet negatively with Helicobacter infection (p < 0.001). In contrast, presence of acute and chronic inflammatory cells in lamina propria was positively associated with Helicobacter infection (p < 0.001), yet not with the endoscopic diagnosis of gastritis. Our score demonstrated strong association between histologic and endoscopic diagnoses (p < 0.001), yet not with patient's symptoms. In conclusion, our data prove foveolar hyperplasia, smooth muscle fibers and vasodilatation and congestion as key histologic parameters for the diagnosis of reactive gastropathy. The proposed score may enhance the diagnostic accuracy. It should be validated in future studies.

Multilayered epithelium at the gastroesophageal junction is a marker of gastroesophageal reflux disease: data from a prospective Central European multicenter study (histoGERD trial).

Multilayered epithelium is defined as hybrid epithelium with characteristics of both squamous and columnar epithelia. Our aim was to evaluate the clinicopathological significance of the lesion by relating its presence to various histological and clinical and/or endoscopic features indicating gastroesophageal reflux disease (GERD). A total of 1,071 individuals participated in a prospective cross-sectional study (576 females and 495 males; median age 53 years). Biopsy material was systematically sampled from the gastroesophageal junction. The histological diagnosis of esophagitis was made according to the Esohisto consensus guidelines. The endoscopic diagnosis of esophagitis was made according to the modified Los Angeles classification and the diagnosis of Barrett's esophagus according to Prague's C & M criteria, respectively. Multilayered epithelium was identified in 103 (9.6 %) individuals, frequently within or adjacent to the ducts of esophageal glands. Its presence was associated with increasing age (p < 0.001), high BMI (p = 0.026), hiatal hernia (p < 0.001), and the endoscopic diagnoses of esophagitis (p = 0.002) and Barrett's esophagus (p < 0.001). Upon histology, multilayered epithelium was associated with features of the squamous epithelium indicating GERD, particularly intercellular space dilation (p = 0.005), and presence of cardiac mucosa (<0.001). For intestinal metaplasia, a trend was noted (p = 0.094). In conclusion, multilayered epithelium was observed in about every tenth individual undergoing upper gastrointestinal endoscopy. The association with histological and clinical features indicating GERD advocates the lesion as a promising new marker for reflux esophagitis. The association with cardiac mucosa and Barrett's esophagus suggests multilayered epithelium to be an intermediate step in the development of columnar metaplasia and, ultimately, Barrett's esophagus.

Validation study of the Esohisto consensus guidelines for the recognition of microscopic esophagitis (histoGERD Trial).

In patients with gastroesophageal reflux disease (GERD), histology is generally believed to be a tool of limited diagnostic value. Our study aimed to assess the prevalence of microscopic esophageal lesions as defined by the Esohisto consensus guidelines, which have proven high interobserver agreement in previous studies. In the prospective Central European multicenter histoGERD trial, we recruited 1071 individuals (576 females and 495 males; median age, 53 years; range, 15-93 years) undergoing gastroscopy for nonselected reasons. Biopsy material was systematically sampled from above and below the gastroesophageal junction. Overall, histologic diagnosis of mild and severe esophagitis was made in 423 (39.5%) and 296 (27.6%) individuals, respectively, whereas the squamous mucosa of 352 individuals (32.9%) was normal upon histology or showed only insignificant findings. Proliferative changes of the squamous epithelium, in particular basal cell layer hyperplasia, papillary elongation, and intercellular space dilation, were more common than inflammatory cell infiltration. The presence of microscopic esophagitis was associated with male sex (P = .009), patients' symptoms (P = .003), history of proton pump inhibitor intake (P < .001), and the endoscopic diagnosis of esophagitis (P < .001). Notably, among the 450 patients with no endoscopic signs of esophagitis (Los Angeles Category N), 41.8% and 17.1% were identified with mild and severe (microscopic) esophagitis, respectively, indicating higher sensitivity of histologic diagnosis. In conclusion, our data illustrate the value of histology in the workup of patients with reflux disease. We suggest that biopsies should routinely be obtained when patients undergo upper gastrointestinal endoscopy for evaluation of GERD and may particularly be beneficial in patients with nonerosive reflux disease.

Changing prevalence patterns in endoscopic and histological diagnosis of gastritis? Data from a cross-sectional Central European multicentre study.

BACKGROUND AND AIMS: Traditionally, Helicobacter infection is considered to be the most common cause of gastritis. In the cross-sectional Central European histoGERD trial, we assessed the prevalence of different types of gastritis, correlating histological and endoscopic diagnoses. METHODS: A total of 1123 individuals participated in an observational multicentre study. Endoscopists classified individuals as positive or negative for gastritis and rendered the putative cause. Pathologists evaluated biopsy specimens based upon the Updated Sydney System. RESULTS: Histological diagnosis of gastritis was made in 639 (56.9%) participants. In all, 210 (18.7%) individuals were diagnosed with Helicobacter gastritis, 215 (19.1%) with post Helicobacter gastritis, 234 (20.8%) with reactive gastropathy, 26 (2.3%) with autoimmune gastritis, and 6 (0.5%) with focally enhanced gastritis related to Crohn's disease. In 46 out of 639 (7.2%) individuals diagnosed with gastritis, combinations of different histological subtypes were noted the most common being reactive gastropathy and post Helicobacter gastritis. Endoscopic diagnosis of gastritis was made in 534 (47.6%) individuals. CONCLUSIONS: Reactive gastropathy was more common than active Helicobacter gastritis, and the majority of cases attributable to Helicobacter infection were no longer ongoing, i.e. post Helicobacter gastritis. Agreement between histological and endoscopic diagnoses was better in reactive gastropathy than in Helicobacter gastritis.