Erik Johnsson

Mucosal FOXP3-expressing CD4+ CD25high regulatory T cells in Helicobacter pylori-infected patients

ABSTRACT Helicobacter pylori chronically colonizes the stomach and duodenum and causes peptic ulcers or gastric adenocarcinoma in 10 to 20% of infected individuals. We hypothesize that the inability of patients to clear H. pylori infections is a consequence of active suppression of the immune response. Here we show that H. pylori-infected individuals have increased frequencies of CD4+ CD25high T cells in both the stomach and duodenal mucosa compared to uninfected controls. These cells have the phenotype of regulatory T cells, as they express FOXP3, a key gene for the development and function of regulatory T cells, as well as high levels of the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) protein. In contrast, mucosal CD4+ CD25low and CD4+ CD25− cells express little FOXP3 mRNA and low levels of the CTLA-4 protein. Mucosal CD4+ CD25high T cells are present in individuals with asymptomatic H. pylori infections as well as in duodenal ulcer patients. The frequencies of CD4+ CD25high cells are also increased in the stomachs of H. pylori-infected patients with gastric adenocarcinoma, particularly in cancer-affected tissues. These findings suggest that regulatory T cells may suppress mucosal immune responses and thereby contribute to the persistence of H. pylori infections.

Pneumatic dilatation or laparoscopic cardiomyotomy in the management of newly diagnosed idiopathic achalasia. Results of a randomized controlled trial.

BackgroundThe most effective therapeutic strategy in newly diagnosed achalasia is yet to be established. Therefore we designed a study in which pneumatic dilatation was compared to laparoscopic cardiomyotomy to which was added a partial posterior fundoplication.Patients and ResultsA series of 51 patients (24 males, mean age 44 years) were randomly allocated to the therapeutic modalities (dilatation = 26, surgery = 25). All patients were followed for at least 12 months, and during that period the pneumatic dilatations strategy had significantly more treatment failures (P = 0.04). Only minor differences emerged between the study groups when symptoms, dysphagia scorings, and quality-of-life assessments were evaluated 12 months after initiation of therapy.ConclusionsLaparoscopic myotomy was found to be superior to an endoscopic balloon dilatation strategy in the treatment of achalasia when studied during the first 12 months after treatment.

Palliation of Malignant Gastroduodenal Obstruction with Open Surgical Bypass or Endoscopic Stenting: Clinical Outcome and Health Economic Evaluation

Gastroduodenal outlet obstruction is a complication of advanced gastrointestinal malignant disease. In the past it was usually treated by an open surgical bypass procedure. During the last decade, endoscopic self-expandable stents (SEMS) have been used. The aim of this study was to compare these two palliative strategies concerning clinical outcome and health economy. A series of 36 patients with incurable malignant disease and gastroduodenal outlet obstruction syndrome were treated in a prospective study. According to the attending hospital and endoscopist on duty, 21 of the 36 patients were endoscopically treated with SEMS and 15 underwent an open surgical gastroenteroanastomosis. Health economic evaluation was based on the monetary charges for each patient associated with the procedure, postoperative care, and hospital stay. The hospital stay was 7.3 days for the stented group compared with 14.7 days for the open surgery group (p > 0.05). The survivals were 76 and 99 days, respectively (NS). In the stented group all 15 patients (100%) alive after 1 month were able to eat or drink, and 11 (73%) of them tolerated solid food. In the surgical bypass group,9 out of 11 (81%) patients alive after 1 month could eat or drink, and 5 of them (45%) could eat solid food. The mean charges (U.S. dollars) during the hospital stay were

An antireflux stent versus conventional stents for palliation of distal esophageal or cardia cancer: a randomized clinical study

7215 for the stented group and

Supportive nutrition on recovery of metabolism, nutritional state, health-related quality of life, and exercise capacity after major surgery: a randomized study.

10,190 for the open surgery group (p < 0.05). Palliation of the gastroduodenal obstruction in patients with malignant disease were at least as good, and the charges were lower for the endoscopic stenting procedure than for an open surgical bypass.

Health economic evaluation of therapeutic strategies in patients with idiopathic achalasia: results of a randomized trial comparing pneumatic dilatation with laparoscopic cardiomyotomy

BackgroundSelf-expandable metal stents placed across the esophagogastric junction for palliative treatment of malignant strictures may lead to gastroesophageal reflux and pulmonary aspiration. This study compared the effects of a Dua antireflux stent with those of a conventional stent.MethodsPatients with incurable cancer of the distal esophagus or gastric cardia were randomly assigned to receive an antireflux stent (n = 19) or a standard stent (n = 22) at nine Swedish hospitals during the period September 1, 2003 to July 31, 2005. Complications were recorded at clinical follow-up visits. Survival rates were assessed through linkage to the Population Register. Dysphagia, reflux symptoms, esophageal pain, dyspnea, and global quality of life were assessed as changes in mean scores between baseline and 1 month after stent insertion through validated questionnaires.ResultsNo technical problems occurred during stent placement in the 41 enrolled patients. Fewer patients with complications were observed in the antireflux stent group (n = 3) than in the standard group (n = 8), but no statistically significant difference was shown (p = 0.14). The survival rates were similar in the two groups (p = 0.99; hazard ratio, 1.0; 95% confidence interval, 0.5–2.0). The groups did not differ significantly in terms of studied esophageal or respiratory symptoms or quality of life. Clinically relevant improvement in dysphagia occurred in both groups. Dyspnea decreased after antireflux stent insertion (mean score change, –11), and increased after insertion of standard stent (mean score change, +21).ConclusionsAntireflux stents may be used without increased risk of complications, mortality, esophageal symptoms, or reduced global quality of life. These results should encourage large-scale randomized trials that can establish potentially beneficial effects of antireflux stents.

Health economic evaluation of stent or endoluminal brachytherapy as a palliative strategy in patients with incurable cancer of the oesophagus or gastro-oesophageal junction: results of a randomized clinical trial.

BACKGROUND & AIMS The aim of this study was to investigate whether specialized supportive enteral and parenteral feeding have superior effects compared to oral nutrition on recovery during long-term postoperative treatment of cancer patients with preoperative weight loss and reduced maximum exercise capacity. METHODS One hundred twenty-six patients referred for resection of the esophagus (n = 48), stomach (n = 28), or pancreas (n = 50) were considered to be included before operation. Included patients (n = 80) received supportive enteral or parenteral nutrition postoperatively at home corresponding to 1000 kcal/d until the patients did not wish to continue with artificial nutrition for any reason. Patients randomized to oral nutrition only served as control subjects. Caloric intake, body composition (dual-energy x-ray absorptiometry), and respiratory gas exchanges at rest and during exercise were measured including health-related quality of life. RESULTS Survival and hospital stay did not differ among the groups, whereas overall complications were higher on artificial nutrition (P < .05). Changes in resting energy expenditure and biochemical tests did not differ during follow-up among the groups. Body weight and whole body fat declined similarly over time in all groups (P < .005), whereas lean body mass was unchanged during follow-up compared to preoperative values. Maximum exercise capacity and maximum oxygen consumption were normalized within 6 months postoperatively in all groups. There was no difference in recovery of food intake among the groups. Parenteral feeding was associated with the highest rate of nutrition-related complications, whereas enteral feeding reduced quality of life most extensively. CONCLUSION After major surgery, specialized supportive enteral and parenteral nutrition are not superior to oral nutrition only when guided by a dietitian.

CD4+CD25high regulatory T cells reduce T cell transendothelial migration in cancer patients

BackgroundWe have prospectively collected information concerning the costs incurred during the management of patients allocated to either forceful dilatation or to an immediate laparoscopic operation because of newly diagnosed achalasia.MethodsFifty-one patients with newly diagnosed achalasia were randomized to either pneumatic dilatation to a diameter of 30–40 mm or to a laparoscopic myotomy to which was added a posterior partial fundoplication. Follow-ups were scheduled at 1, 3, 6, and 12 months after inclusion. At each follow-up visit a study nurse interviewed the patients regarding symptoms and their quality of life (QoL) and a health economic questionnaire was completed. In the latter questionnaire, patients were asked to report the presence and character of contacts with the healthcare system since the last visit.ResultsIn the dilatation group six patients (23%), including the patient who was operated on because of perforation, were classified as failures during the first 12 months of follow-up compared to one (4%) in the myotomy group (p = 0.047). Five of those classified as failures in the dilatation group subsequently had a surgical myotomy and the sixth patient was treated with repeated dilatations. The patient classified as failure in the myotomy group was treated with endoscopic dilatation. The initial treatment cost and the total costs were significantly higher for laparoscopic myotomy compared to a pneumatic dilatation-based strategy (p = 0.0002 and p = 0.0019, respectively) When the total costs were subdivided into the different resources used, we found that the single largest cost item for pneumatic dilatation was that for hospital stay and that for laparoscopic myotomy was the actual operative treatment (operating room time) The cost-effectiveness analysis, relating to the actual treatment failures, revealed that the cost to avoid one treatment failure (incremental cost-effectiveness ratio) amounted to €9239.ConclusionThe current prospective, controlled clinical trial shows that despite a higher level of clinical efficacy of laparoscopic myotomy to prevent treatment failure in newly diagnosed achalasia, the cost effectiveness of pneumatic dilatation is superior, at least when a reasonable time horizon is applied.

Antireflux stent versus conventional stent in the palliation of distal esophageal cancer. A randomized, multicenter clinical trial

Objective To relieve dysphagia is the main goal in palliative treatment of patients with incurable cancer of the oesophagus or the gastro-oesophageal junction. The aim of this prospective, randomized multicentre study was to compare stent placement and brachytherapy regarding health economy and clinical outcomes. Methods Patients with incurable cancer of the oesophagus or gastro-oesophageal junction were randomized to receive a self-expandable metallic stent or 3×7 Gy brachytherapy. At clinical follow-up visits, dysphagia was scored and health care consumptions were recorded. Costs were based on hospital debits. Total lifetime healthcare consumption costs and costs for the initial treatments were calculated and a sensitivity analysis was conducted. Results Thirty patients were randomized to each treatment group. There was no difference in survival or complication rates between the two treatment strategies. There was a significant difference in the change of dysphagia scores between the time of inclusion and the 1-month follow-up visit, in favour of the stented group (P=0.03). This difference had disappeared at 3 months. Median total lifetime costs were &U20AC;17 690 for the stented group compared with &U20AC;33 171 for the brachytherapy group (P=0.005). This difference was due to higher costs for the initial treatment (&U20AC;4615 versus &U20AC;23 857, P<0.0001). Sensitivity analyses showed that the charges for a brachytherapy session had to be reduced from &U20AC;6092 to &U20AC;4222 (31%) to make this therapeutic concept cost-competitive. Conclusion Stenting is currently more cost-effective compared with fractionated 3×7 Gy brachytherapy for patients with incurable cancer of the oesophagus and gastro-oesophageal junction.

Preoperative adjuvant radiochemotherapy may increase the risk in patients undergoing thoracoabdominal esophageal resections.

Cell‐mediated immunity is thought to be the main mechanism of anti‐tumour responses of the host, but it is not known if cancer disease affects T cell recruitment from blood to tissues. Therefore, we compared Heliobacter pylori‐induced T cell transendothelial migration (TEM) in H. pylori‐infected gastric carcinoma patients, colon and lung carcinoma patients and healthy volunteers. H. pylori induced significant T cell migration from all groups. However, there was a dramatic reduction of T cell TEM in gastric carcinoma patients (80%) compared to healthy individuals. A similarly reduced transmigration was also seen in colon and lung carcinoma patients. We found significantly increased frequencies of Treg cells in the blood of gastric carcinoma patients compared to healthy individuals, and depletion of Treg cells from the blood of these patients prior to TEM restored T cell migration. The effect of Treg cells was largely dependent on cell‐cell contact, but not on IL‐10 or TGF‐β. In addition, the presence of Treg cells led to reduced T cell attachment to endothelium and decreased production of T cell‐recruiting chemokines during TEM. In conclusion, Treg cell‐mediated reduction of T cell TEM may reduce T cell recruitment in patients with epithelial malignancies, thereby hampering anti‐tumour responses.