Real-life Indications and Outcome of Electrocautery-enhanced Lumen-apposing Metal Stents in a Tertiary Center.

PURPOSE: Electrocautery-enhanced lumen-apposing stents (EC-LAMS) were originally designed for the drainage of the gallbladder, bile duct, and pancreas pseudocysts. Throughout the years, several off-label indications were established. This study aims to evaluate the indication, safety, efficacy, and outcome of all LAMS implanted in a single tertiary referral center. METHODS: From April 2016 to April 2022, all patients undergoing LAMS placement in a single tertiary center were included. We present a detailed analysis of indications, success rates, and complications based on a retrospective analysis of our prospectively maintained database. RESULTS: A total of 86 stents were placed in 77 patients between April 2016 and April 2022. Indications were walled-off pancreatic necrosis (25.6%), bile duct obstructions (16.3%), acute cholecystitis (15.1%), pancreas pseudocysts (15.1%), postoperative collections (10.5%), postoperative pancreatic fistulas (9.3%), and gastro-gastrostomy/jejunostomy (8.1%) to enable to perform an endoscopic retrograde cholangiopancreatography in patients with gastric bypass. Technical success was 97.7% (84 out of 86). A total of 10 (11.7%) adverse events were observed. In 3 patients (3.5%), severe complications occurred, which required acute surgery; one displacement was closed through clips. In 7 patients (8.2%), bleedings occurred during necrosectomy or from mucosal erosions at the stent side, respectively, that were treated with endoclips. CONCLUSIONS: EC-LAMS are safe and show a high technical success rate in all indications. In everyday clinical practice, the main indications are hepato-pancreato-biliary, and therefore an hepato-pancreato-biliary-surgical department should have EC-LAMS in their armamentarium.

Impact of the COVID-19 pandemic lockdown on the utilization of acute surgical care in the State of Salzburg, Austria: retrospective, multicenter analysis.

BACKGROUND: Some medical disciplines have reported a strong decrease of emergencies during the coronavirus disease 2019 (COVID-19) pandemic; however, the effect of the lockdown on general surgery emergencies remains unclear. METHODS: This study is a retrospective, multicenter analysis of general surgery emergency operations performed during the period from 1 March to 15th 2020 lockdown and in the same time period of 2019 in three medical centers providing emergency surgical care to the area Salzburg-North, Austria. RESULTS: In total 165 emergency surgeries were performed in the study period of 2020 compared to 287 in 2019. This is a significant decrease of 122 (42.5%) emergency surgeries during the COVID-19 lockdown (p = 0.005). The length of hospital stay was reduced to 3 days in 2020 compared to 4 in 2019. Appendectomy remained the most performed emergency surgery for both periods; however the number of surgeries was reduced to less than a half, with 72 cases in 2019 and 33 cases in 2020 (p = 0.118). Emergency colon surgery observed the strongest decrease of 75% from 17 cases in 2019 to 4 in 2020. In addition, the emergency abdominal wall hernia, cholecystectomies for acute cholecystitis, small surgeries and proctological emergencies recorded drops of 70%, 39%, 33% and 47% respectively. The strongest reduction in frequencies of emergency surgeries was reported from the designated COVID center in the examined region. CONCLUSIONS: Emergency general surgery is an essential service that continues to run under all circumstances. Our data show that COVID-19-related restrictions have resulted in a significant decrease in the utilization of acute surgical care.

[Reflux Symptoms - No Difference in Severity and Intensity in Patients with and without Functional Verified Gastroesophageal Reflux Disease]. / Refluxsymptomatik ­ kein Unterschied in Ausprägung und Schweregrad bei Patienten mit und ohne funktionell bewiesene gastroösophageale Refluxerkrankung.

BACKGROUND: Patients with gastroesophageal reflux disease (GERD) often suffer greatly from their symptoms. The aim of this study was to determine if there is a difference in quality of life and gastrointestinal symptom complexes between patients with purely functional complaints and patients with objective GERD. MATERIAL AND METHODS: We included all patients with typical reflux symptoms, who had a GERD examination in 2017 at our department. All patients underwent high resolution manometry, 24-h-pH-metry impedance measurement and gastroscopy. Quality of life was assessed using the Gastrointestinal Quality of Life Index (GIQLI) and gastrointestinal symptoms were rated by a symptom checklist (SCL), assessing the severity and intensity of 14 different symptoms. Based on the results of the 24-h-pH-metry impedance measurement, patients were divided into 2 groups: patients with functional reflux symptoms and patients with true GERD. These two groups were compared. RESULTS: Complete data were available in 162 patients, of whom 86 (52.2%) were objectively suffering from reflux (DeMeester score mean: 37.85; SD ± 29.11) and 76 (46.1%) had a normal DeMeester score (Mean: 7.01; SD ± 4.09). No significant difference in quality of life was found between the two groups (mean GIQLI of GERD patients: 94.81, SD ± 22.40, and mean GIQLI of patients with functional reflux symptoms: 95.26, SD ± 20.33, p = 0.988). Furthermore, no significant difference could be found in the evaluated symptoms (mean general SCL score of GERD patients: 46.97; SD ± 29.23; patients with functional reflux symptoms: 48.03; SD ± 29.17, p = 0.827). CONCLUSION: Patients with functional complaints suffer just as much from their symptoms as patients with objectively diagnosed GERD. Differentiation between gastroesophageal reflux disease and functional reflux symptoms is only possible by means of functional diagnostic testing.

[Planning and Design of a Prospective Randomised Multi-Centre Trial on the Repair of Large Hiatal Hernias with Sutures vs. Pledgeted Sutures vs. Absorbable Mesh]. / Vorstellung einer prospektiv randomisierten Multicenterstudie zum Vergleich der Hiatusplastik mit Nähten vs. Nähte mit Pledgets vs. resorbierbares Netz bei großen Hiatushernien.

BACKGROUND: The hernia recurrence rate after surgical treatment of large hiatal hernias is still very high. The optimal technique to reduce the recurrence rate is still under debate. The aim of this work is to clarify whether pledgeted reinforced sutures or a resorbable mesh can reduce the recurrence rate compared to hiatus closure with only sutures. MATERIALS AND METHODS: An Austria-wide, multi-centre, prospective, randomised study was planned. The study protocol was prepared by the main test centre (University Clinic for General, Visceral and Thoracic Surgery, Paracelsus Medical University Salzburg). The study includes patients who are scheduled to undergo laparoscopic or robot-assisted surgery for a large symptomatic hiatal hernia. A large hiatal hernia is defined as > 5 cm in manometry or gastroscopy or at least ⅓ of the stomach lying intrathoracically. The primary study endpoint is defined as the hernia recurrence rate, objectively assessed by gastroscopy. After inclusion in the study, patients will be followed up for 6 months, 1 year, 3 years and 5 years after the operation, using standardised questionnaires and gastroscopy. The power calculation showed a requirement of 55 patients per group. Preoperative randomisation and data management are software-based. RESULTS: The study approval by the leading ethics committee is currently pending and the study itself has been registered on ClinicalTrials.gov since October 2020. The Clinical Trials Registration Number is NCT04591860. Five clinics are participating in the study at the moment and all centres are actively enrolling patients. The duration of the study is set until January 2027. CONCLUSION: This study is the world's first prospective randomised study that examines the value of pledgets and resorbable mesh to reduce the recurrence rate after treatment of large hiatal hernias. The results will help to find the optimal technique to close the hiatus of large hiatal hernias.

Impedance planimetry values for predicting clinical response following peroral endoscopic myotomy.

BACKGROUND: There is growing interest in developing impedance planimetry as a tool to enhance the clinical outcomes for endoscopic and surgical management of achalasia. The primary aim of this study was to determine whether impedance planimetry measurements can predict clinical response and reflux following peroral endoscopic myotomy (POEM). METHODS: A multicenter cohort study of patients with achalasia undergoing POEM was established from prospective databases and retrospective chart reviews. Patients who underwent impedance planimetry before and after POEM were included. Clinical response was defined as an Eckardt score of ≤ 3. Tenfold cross-validated area under curve (AUC) values were established for the different impedance planimetry measurements associated with clinical response and reflux development. RESULTS: Of the 290 patients included, 91.7 % (266/290) had a clinical response and 39.4 % (108/274) developed reflux following POEM. The most predictive impedance planimetry measurements for a clinical response were: percent change in cross-sectional area (%ΔCSA) and percent change in distensibility index (%ΔDI), with AUCs of 0.75 and 0.73, respectively. Optimal cutoff values for %ΔCSA and %ΔDI to determine a clinical response were a change of 360 % and 272 %, respectively. Impedance planimetry values were much poorer at predicting post-POEM reflux, with AUCs ranging from 0.40 to 0.62. CONCLUSION: Percent change in CSA and distensibility index were the most predictive measures of a clinical response, with a moderate predictive ability. Impedance planimetry values for predicting reflux following POEM showed weak predictive capacity.

Endoscopic or Surgical Myotomy in Patients with Idiopathic Achalasia.

BACKGROUND: Pneumatic dilation and laparoscopic Heller's myotomy (LHM) are established treatments for idiopathic achalasia. Peroral endoscopic myotomy (POEM) is a less invasive therapy with promising early study results. METHODS: In a multicenter, randomized trial, we compared POEM with LHM plus Dor's fundoplication in patients with symptomatic achalasia. The primary end point was clinical success, defined as an Eckardt symptom score of 3 or less (range, 0 to 12, with higher scores indicating more severe symptoms of achalasia) without the use of additional treatments, at the 2-year follow-up; a noninferiority margin of -12.5 percentage points was used in the primary analysis. Secondary end points included adverse events, esophageal function, Gastrointestinal Quality of Life Index score (range, 0 to 144, with higher scores indicating better function), and gastroesophageal reflux. RESULTS: A total of 221 patients were randomly assigned to undergo either POEM (112 patients) or LHM plus Dor's fundoplication (109 patients). Clinical success at the 2-year follow-up was observed in 83.0% of patients in the POEM group and 81.7% of patients in the LHM group (difference, 1.4 percentage points; 95% confidence interval [CI], -8.7 to 11.4; P = 0.007 for noninferiority). Serious adverse events occurred in 2.7% of patients in the POEM group and 7.3% of patients in the LHM group. Improvement in esophageal function from baseline to 24 months, as assessed by measurement of the integrated relaxation pressure of the lower esophageal sphincter, did not differ significantly between the treatment groups (difference, -0.75 mm Hg; 95% CI, -2.26 to 0.76), nor did improvement in the score on the Gastrointestinal Quality of Life Index (difference, 0.14 points; 95% CI, -4.01 to 4.28). At 3 months, 57% of patients in the POEM group and 20% of patients in the LHM group had reflux esophagitis, as assessed by endoscopy; at 24 months, the corresponding percentages were 44% and 29%. CONCLUSIONS: In this randomized trial, POEM was noninferior to LHM plus Dor's fundoplication in controlling symptoms of achalasia at 2 years. Gastroesophageal reflux was more common among patients who underwent POEM than among those who underwent LHM. (Funded by the European Clinical Research Infrastructure Network and others; ClinicalTrials.gov number, NCT01601678.).

Multicenter Evaluation of Clinical Efficacy and Safety of Per-oral Endoscopic Myotomy in Children.

OBJECTIVES: Per-oral endoscopic myotomy (POEM) is a recommended treatment modality for achalasia, but there is little published data for its use in children. The objective of the present study was to evaluate whether POEM is clinically effective and safe for children. METHODS: International multicenter retrospective study conducted in 14 tertiary centers that included consecutive children who underwent POEM between January 2012 and August 2018. Outcomes, such as clinical response were assessed whenever available. Adverse events and factors associated with clinical failure were also investigated. RESULTS: A total of 117 patients (mean ±â€ŠSD age: 14.2 ±â€Š3.7 years) underwent POEM for achalasia (type I, n = 36; type II n=66; type III, n=8). Among these, 30 (26%) were pretreated (botulinum injection and/or pneumatic dilatation). Mean ±â€ŠSD baseline Eckardt score was 7.5 ±â€Š2.0. Clinical success was achieved in 90.6% of cases (95%CI [83.8%;95.2%]) in the intention-to-treat analysis. The mean ±â€ŠSD Eckardt score post-POEM was 0.9 ±â€Š1.2 (P < 0.001). The mean duration of follow-up time 545 days (range: 100-1612). A total of 7 adverse events occurred (4 mucosotomies, 2 subcutaneous emphysema, 1 esopleural fistula). Gastroesophageal reflux symptoms were seen in 17 patients (15%); missing data for 10 patients (9%). There was a trend towards more frequent clinical failure in achalasia associated with genetic disorders (40% vs 8%, P = 0.069). CONCLUSIONS: POEM in pediatric patients appears to be effective and safe, although there was a trend towards more frequent clinical failure achalasia associated with genetic disorders. Further studies are needed to assess the long-term outcomes, especially the consequences of GERD.

[Current Treatment of Achalasia 2019]. / Aktuelle Therapie der Achalasie 2019.

Treatment of primary idopathic achalasia, the most common of the rare oesophageal motility disorders, is currently changing. The therapeutic priciple of Heller's myotomy is increasingly accepted as standard. In 1913, the German surgeon Ernst Heller described the cardiomyotomy named after him, faciliating excellent symptom control. Meta-analyses of randomised trials (level 1A evidence) demonstrate superiority of laparoscopic Heller myotomy (LHM) over endoscopic pneumatic dilatation (PD). However, some surgeons still advocate the PD strategy, based on the results of the randomised European Multicenter study PD vs. LHM, suggesting that the two procedures achieve similar symptom control after 2 and 5 years. However, an initial series of PDs was excluded from "intention-to-treat" analysis, as the oesophageal perforation rate was unacceptably high (33.3%). To prevent postoperative gastroesophageal reflux (GER) after LHM, addition of a fundoplication is established as standard. The anterior 180° Dor is the wrap type of choice. This standard (LHM + Dor procedure) has now been challenged: Peroral endoscopic myotomy (POEM) was introduced into clinical practice by Harihiro Inoue in 2010, and has now been intensively investigated in specialised centres worldwide. This allows creation of a "Heller myotomy" through the endoscopic route. Complication rates are low, symptom control is excellent and systematic reviews of published series show similar or slightly superior dysphagia control with POEM than with LHM. Advantages of POEM are the possibility to perform a long-myotomy (of the entire length of the oesophagus if necessary) and the relatively free choice of the localisation of the myotomy (anterior/posterior POEM). The disadvantage is the increased postoperative GER after POEM; however this sequel is managed with PPI in most cases, or a laparoscopic fundoplication, if necessary. Preliminary results of two prospectively randomised trials show the superiority of POEM over PD, as well as the non-inferiority to LHM, but increased postoperative GER. The author uses a tailored approach, with preference of POEM for achalasia type III and type II with chest pain and LHM + Dor for sigmoid achalasia and other associated morphological changes. The procedure in all other patients is depends on individual personal preferences.

Comprehensive Analysis of Adverse Events Associated With Per Oral Endoscopic Myotomy in 1826 Patients: An International Multicenter Study.

OBJECTIVES: The safety of peroral endoscopic myotomy (POEM) is still debated since comprehensive analysis of adverse events (AEs) associated with the procedure in large multicenter cohort studies has not been performed. To study (1) the prevalence of AEs and (2) factors associated with occurrence of AEs in patients undergoing POEM. METHODS: Patients who underwent POEM at 12 tertiary-care centers between 2009 and 2015 were included in this case-control study. Cases were defined by the occurrence of any AE related to the POEM procedure. Control patients were selected for each AE case by matching for age, gender, and disease classification (achalasia type I and II vs. type III/spastic esophageal disorders). RESULTS: A total of 1,826 patients underwent POEM. Overall, 156 AEs occurred in 137 patients (7.5%). A total of 51 (2.8%) inadvertent mucosotomies occurred. Mild, moderate, and severe AEs had a frequency of 116 (6.4%), 31 (1.7%), and 9 (0.5%), respectively. Multivariate analysis demonstrated that sigmoid-type esophagus (odds ratio (OR) 2.28, P=0.05), endoscopist experience <20 cases (OR 1.98, P=0.04), use of a triangular tip knife (OR 3.22, P=0.05), and use of an electrosurgical current different than spray coagulation (OR 3.09, P=0.02) were significantly associated with the occurrence of AEs. CONCLUSIONS: This large study comprehensively assessed the safety of POEM and highly suggests POEM as a relatively safe procedure when performed by experts at tertiary centers with an overall 7.5% prevalence of AEs. Severe AEs are rare. Sigmoid-type esophagus, endoscopist experience, type of knife, and current used can be considered as predictive factors of AE occurrence.

Original article: role of adjuvant chemotherapy in a perioperative chemotherapy regimen for gastric cancer.

BACKGROUND: Multimodal treatment strategies - perioperative chemotherapy (CTx) and radical surgery - are currently accepted as treatment standard for locally advanced gastric cancer. However, the role of adjuvant postoperative CTx (postCTx) in addition to neoadjuvant preoperative CTx (preCTx) in this setting remains controversial. METHODS: Between 4/2006 and 12/2013, 116 patients with locally advanced gastric cancer were treated with preCTx. 72 patients (62 %), in whom complete tumor resection (R0, subtotal/total gastrectomy with D2-lymphadenectomy) was achieved, were divided into two groups, one of which receiving adjuvant therapy (n = 52) and one without (n = 20). These groups were analyzed with regard to survival and exclusion criteria for adjuvant therapy. RESULTS: Postoperative complications, as well as their severity grade, did not correlate with fewer postCTx cycles administered (p = n.s.). Long-term survival was shorter in patients receiving postCTx in comparison to patients without postCTx, but did not show statistical significance. In per protocol analysis by excluding two patients with perioperative death, a shorter 3-year survival rate was observed in patients receiving postCTx compared to patients without postCTx (3-year survival: 71.2 % postCTx group vs. 90.0 % non-postCTx group; p = 0.038). CONCLUSION: These results appear contradicting to the anticipated outcome. While speculative, they question the value of post-CTx. Prospectively randomized studies are needed to elucidate the role of postCTx.

Comprehensive epidemiological and genotype-phenotype analyses in a large European sample with idiopathic achalasia.

BACKGROUND AND AIM: Although an eight-residue insertion in HLA-DQß1 has been recently identified as a genetic risk factor for idiopathic achalasia, other risk factors are still unknown. In the present study, we carried out an epidemiological survey and a genotype-phenotype (G×P) analysis to gain further insights into the etiology of achalasia. METHODS: We obtained medical data from 696 achalasia patients and 410 controls, as well as their first-degree relatives (2543 of patients and 1497 of controls). For the G×P analysis, we stratified the patients into HLA-DQß1 insertion carriers and noncarriers. RESULTS: Our data show that patients are more often affected by viral infections before achalasia onset (P<0.0001, most significantly for varicella zoster virus infections). In addition, allergic (P=0.0005) and autoimmune disorders (P=0.0007, most significantly for psoriasis and Sjögren's syndrome) represent comorbid disease conditions. First-degree relatives of patients also show higher prevalence rates of allergic disorders (P=0.0007) and psoriasis (P=0.016) compared with control relatives. Moreover, the G×P analysis reveals that achalasia is triggered by pregnancies in female HLA-DQß1 insertion carriers (P=0.031). CONCLUSION: Our data point to a role of viral infections in the development of achalasia. In addition, they provide evidence for a relationship between achalasia and allergic, as well as autoimmune, disorders. Furthermore, pregnancy seems to be a disease-triggering factor in female HLA-DQß1 insertion carriers, which points to hormonal and/or immunosuppressive factors influencing disease development.

The HLA-DQß1 insertion is a strong achalasia risk factor and displays a geospatial north-south gradient among Europeans.

Idiopathic achalasia is a severe motility disorder of the esophagus and is characterized by a failure of the lower esophageal sphincter to relax due to a loss of neurons in the myenteric plexus. Most recently, we identified an eight-amino-acid insertion in the cytoplasmic tail of HLA-DQß1 as strong achalasia risk factor in a sample set from Central Europe, Italy and Spain. Here, we tested whether the HLA-DQß1 insertion also confers achalasia risk in the Polish and Swedish population. We could replicate the initial findings and the insertion shows strong achalasia association in both samples (Poland P=1.84 × 10(-04), Sweden P=7.44 × 10(-05)). Combining all five European data sets - Central Europe, Italy, Spain, Poland and Sweden - the insertion is achalasia associated with Pcombined=1.67 × 10(-35). In addition, we observe that the frequency of the insertion shows a geospatial north-south gradient. The insertion is less common in northern (around 6-7% in patients and 2% in controls from Sweden and Poland) compared with southern Europeans (~16% in patients and 8% in controls from Italy) and shows a stronger attributable risk in the southern European population. Our study provides evidence that the prevalence of achalasia may differ between populations.

Intraoperative measurement of esophagogastric junction cross-sectional area by impedance planimetry correlates with clinical outcomes of peroral endoscopic myotomy for achalasia: a multicenter study.

BACKGROUND: Peroral endoscopic myotomy (POEM) has been introduced as an endoscopic alternative to surgical myotomy. The endoluminal functional lumen imaging probe (endoFLIP) evaluates esophagogastric junction (EGJ) distensibility based on cross-sectional area and pressure in response to volume distension. The aim of this study was to evaluate whether there is a correlation between endoFLIP measurements during POEM and postoperative clinical outcomes in terms of symptom relief and development of post-procedure reflux. METHODS: We conducted a retrospective review of achalasia patients who underwent POEM and intraoperative endoFLIP at three tertiary centers. Patients were divided into two groups based on clinical response measured by Eckardt score (ES): good response (ES < 3) or poor response (ES ≥ 3). Post-procedure reflux was defined as the presence of esophagitis and/or abnormal pH study. EGJ diameter, cross-sectional area, and distensibility measured by endoFLIP were compared. RESULTS: Of the 63 treated patients, 50 had good and 13 had poor clinical response. The intraoperative final EGJ cross-sectional area was significantly higher in the good-response group versus poor-response group; median (interquartile range): 89.0 (78.5-106.7) versus 72.4 (48.8-80.0) mm(2) [p = 0.01]. The final EGJ cross-sectional area was also significantly higher in patients who had reflux esophagitis after POEM: 99.5 (91.2-103.7) versus 79.3 (57.1-94.2) mm(2) [p = 0.02]. CONCLUSION: Intraoperative EGJ cross-sectional area during POEM for achalasia correlated with clinical response and post-procedure reflux. Impedance planimetry is a potentially important tool to guide the extent and adequacy of myotomy during POEM.

Incidence, time course and independent risk factors for metachronous peritoneal carcinomatosis of gastric origin--a longitudinal experience from a prospectively collected database of 1108 patients.

BACKGROUND: Comprehensive evidence on the incidence, time course and independent risk factors of metachronous peritoneal carcinomatosis (metaPC) in gastric cancer patients treated with curative intent in the context of available systemic combination chemotherapies is lacking. METHODS: Data from a prospectively collected single-institutional Center Cancer Registry with 1108 consecutive patients with gastric adenocarcinoma (GC), clinical, histological and survival data were analyzed for independent risk factors and prognosis with focus on the development of metaPC. Findings were then stratified to the time periods of treatment with surgery alone, 5-Fluorouracil-only and contemporary combined systemic perioperative chemotherapy strategies, respectively. RESULTS: Despite R0 D2 gastrectomy (n = 560), 49.6% (±5.4%) of the patients were diagnosed with tumour recurrence and 15.5% (±1.8%) developed metaPC after a median time of 17.7 (15.1-20.3) months after surgery resulting in a tumour related mortality of 100% with a median survival of 3.0 months (2.1 - 4.0). Independent risk factors for the development of metaPC were serosa positive T-category, nodal positive-status, signet cell and undifferentiated gradings (G3/G4). Contemporary systemic combination chemotherapy did not improve the incidence and prognosis of metaPC (p = 0.54). CONCLUSIONS: Despite significant improvements in the overall survival for the complete cohort with gastric cancer over time, those patients with metaPC did not experience the same benefits. The lack of change in the incidence, and persistent poor prognosis of metaPC after curative surgery expose the need for further prevention and/or improved treatment options for this devastating condition.

Common variants in the HLA-DQ region confer susceptibility to idiopathic achalasia.

Idiopathic achalasia is characterized by a failure of the lower esophageal sphincter to relax due to a loss of neurons in the myenteric plexus. This ultimately leads to massive dilatation and an irreversibly impaired megaesophagus. We performed a genetic association study in 1,068 achalasia cases and 4,242 controls and fine-mapped a strong MHC association signal by imputing classical HLA haplotypes and amino acid polymorphisms. An eight-residue insertion at position 227-234 in the cytoplasmic tail of HLA-DQß1 (encoded by HLA-DQB1*05:03 and HLA-DQB1*06:01) confers the strongest risk for achalasia (P=1.73×10(-19)). In addition, two amino acid substitutions in the extracellular domain of HLA-DQα1 at position 41 (lysine encoded by HLA-DQA1*01:03; P=5.60×10(-10)) and of HLA-DQß1 at position 45 (glutamic acid encoded by HLA-DQB1*03:01 and HLA-DQB1*03:04; P=1.20×10(-9)) independently confer achalasia risk. Our study implies that immune-mediated processes are involved in the pathophysiology of achalasia.

Ten-year follow-up of a prospective trial for the targeted therapy of gastric cancer with the human monoclonal antibody PAT-SC1.

The fully human monoclonal antibody PAT-SC1 is specific for an isoform of CD55 (decay-accelerating factor) designated CD55PAT-SC1. This antigen is expressed in the majority (80%) of gastric cancers (GCs), and the antibody induces tumour cell-specific apoptosis in vitro as well as in vivo. PAT-SC1, therefore, has been deemed promising as a therapeutic agent. Here, we describe the results of an academic clinical study performed in a neoadjuvant setting with resectable GC patients. Patients undergoing treatment for GC between 1997 and 2001 were tested for CD55PAT-SC1 expression. Fifty-one resectable patients that tested positively received a single administration of 20 mg PAT-SC1 48 h prior to surgery. They underwent standard surgery with either subtotal or total gastrectomy with bursectomy, omentectomy and a modified D2-lymphadenectomy, aimed at R0 resection. Primary endpoints of the present study were to evaluate side-effects of the PAT-SC1 antibody treatment and to evaluate histopathological effects such as tumour regression and induction of apoptosis. Long-term survival was a secondary endpoint. Administration of PAT-SC1 appeared safe with only reversible side-effects according to WHO grade I and II. Despite the low­dose of the antibody, 81.6% of the patients showed signs of increased apoptosis within the primary tumour and 60% showed signs of tumour cell regression. Comparison of the 10-year survival rates of the R0-resected CD55PAT-SC1-positive patients treated with the PAT-SC1 antibody with a historical collective of R0-resected CD55PAT-SC1-positive patients not treated with PAT-SC1 indicated a survival benefit in the treated patients. Furthermore, comparison of the patient survival of CD55PAT­SC1-positive vs. CD55PAT-SC1-negative groups suggested that CD55PAT-SC1 antigen expression is an independent predictor of poor survival in a Cox regression analysis. Antibody PAT-SC1 may be a useful additive therapeutic agent in the treatment of patients with CD55PAT-SC1-expressing GCs. In combination with radical standard surgery, PAT-SC1 given as an adjuvant or neoadjuvant immunotherapeutic agent induces apoptosis in tumour cells which may improve survival of these patients. Because of the human origin and its specific binding to the CD55PAT-SC1 antigen, PAT-SC1 was well tolerated in this trial.

Pathogenesis of colonic diverticular disease.

PURPOSE: This paper aims to review the current evidence regarding pathogenesis of colonic diverticular disease and its complications, which are a major health problem in the Western world. METHODS: Based on selective Medline searches, relevant literature was indentified regarding pathogenesis of (1) diverticulosis/formation of diverticula, (2) diverticulitis/inflammation of diverticula, (3) complicated diverticulitis/perforation, and (4) diverticular bleeding. RESULTS: Pathogenesis of colonic diverticula is regarded as a multifactorial process, involving dietary factors (Western low-fiber diet), structural changes of the colonic wall (altered musculature, collagen, elastin, etc.) and functional changes (motility disorder, increased intraluminal pressure). Genetic changes are also discussed and aging is also a key factor. Pathogenesis of inflammation (diverticulosis) is regarded as a result of "microperforations" at the fundus of the diverticulum, and not an "abscessed diverticulum" due to an impacted fecolith. Histamine and its receptors do also seem to play a role, corresponding with the promising prophylactic approach with probiotics. Pathogenesis of complicated diverticulitis is characterized by perforation, which is the cardinal feature. Furthermore, an intensive inflammatory infiltrate with macrophages is found in surgical specimens, even after antibiotic pretreatment. Steroid intake and immunosuppression are risk factors and only recently a glucocorticoid-induced tumor necrosis factor-receptor has been suggested to resemble the molecular link. Diverticular bleeding is a distinct disease process-which does usually take place without diverticulitis-and is due to eccentric rupture of the vas rectum. CONCLUSIONS: The pathophysiology of diverticular disease is multifactorial. Some of the current evidence has important implications for clinical practice, e.g., the suggested role of steroid intake and immunosuppression for complicated diverticulitis.

Allergic predisposition, histamine and histamine receptor expression (H1R, H2R) are associated with complicated courses of sigmoid diverticulitis.

BACKGROUND: We aimed to evaluate our hypothesis that allergic predisposition and expression of histamine receptors might contribute to complicated courses of sigmoid diverticulitis. METHODS: Expression of histamine and histamine receptors (H1R, H2R) was analysed on protein level (immunohistochemistry/immunofluorescence (IF)) as well as mRNA level (reverse transcription-PCR (RT-PCR) in surgical specimen of patients (n = 101) having undergone resection for sigmoid diverticulits (n = 57 complicated diverticulitis/n = 44 non-complicated diverticulitis). RESULTS: The mean number of comorbid diseases per patient was 1.76 ± 1.25. Thirty-nine of 101 patients (38.6%) exhibited allergic predisposition (grass poll, food, drug, pets, etc.). Comorbid diseases were significantly associated with complicated diverticulitis (p = 0.027). Complicated sigmoid diverticulitis was significantly associated with high H1R and H2R expression (p < 0.001). Furthermore, an association of complicated diverticulitis with allergic predisposition was found (odds ratio = 3.2, p = 0.0097). IF double-labelling experiments showed a strong correlation of increased histamine expression with expression of H1R and H2R on intestinal enterocytes (histamine/H1R, rho = 0.841, p < 0.0001 and histamine/H2R, rho = 0.806, p < 0.0001). The results of increased H1R and H2R expression in complicated sigmoid diverticulitis were also detected on mRNA level in a subset of patients (RT-PCR, p = 0.009). CONCLUSIONS: Our findings suggest that allergic predisposition might be another important risk factor for complicated courses of acute sigmoid diverticulitis and linked with histamine receptor expression. Supportive therapies with antihistaminic drugs might become an option. Allergic predisposition might be worth considering when indicating surgery for sigmoid diverticulitis.