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.).

[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.

[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.

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.

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.

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.

How complicated is complicated diverticulitis?--phlegmonous diverticulitis revisited.

PURPOSE: The purpose of this study is to elucidate the accuracy of a clinical classification system for acute diverticulitis with special regard to "phlegmonous diverticulitis". METHODS: A consecutive patient series (n = 318; General Hospital Nuremberg, 1/2004-12/2006) was classified preoperatively (imaging with 4/16-slice spiral CT scanner) according to the Hansen and Stock (H&S) classification which is commonly used in Germany and evaluated based on histopathology. RESULTS: Pre-treatment classification grouped 30 patients (9.4%) as uncomplicated diverticulitis (type I according to H&S), for whom treatment was merely conservative. One hundred twelve patients (35.2%) were classified as phlegmonous diverticulitis (type IIA), 84 (26.4%) as "covered perforations" (type IIB) and 27 (8.5%) as "free perforations" (type IIC), and 54 (17.0%) as chronically recurrent diverticulitis (type III, 17.0%). The remaining 11 patients (3.5%) were not staged preoperatively. Accuracy of staging of complicated diverticulitis differed significantly between type IIC (100.0%), type IIB (91.0%), and type IIA (36.1%). The latter group was frequently understaged as it concealed a substantial number of patients (n = 44; 53.0%) with IIB disease. Neither laboratory tests (CRP/WBC) nor clinical parameters allowed distinction of correctly and falsely staged patients with type IIA disease. CONCLUSIONS: Patients with phlegmonous diverticulitis (type IIA) represent the most challenging group among patients with acute diverticulitis as they are frequently understaged and conceal cases with covered perforations (type IIB). This may support the view to subsume phlegmonous diverticulitis (type IIA) under complicated diverticulitis.

Association of steroid use with complicated sigmoid diverticulitis: potential role of activated CD68+/CD163+ macrophages.

BACKGROUND: Immunosupression and, especially, intake of steroids have previously been identified as risk factors for complicated types of sigmoid diverticulitis. However, little is known about the underlying molecular and cellular mechanisms. We aimed to elucidate the potential role of activated macrophages in this respect. METHODS: A consecutive series of n = 101 patients having undergone surgical resection for sigmoid diverticulitis at our institution was analyzed regarding the inflammatory infiltrate and prevalence of comorbid diseases as well as risk factors, including steroid use. Fifty-seven patients had complicated types of diverticulitis with severe inflammation (group A). Forty-four patients had moderate inflammation, most of whom had been operated for chronically recurrent diverticulitis (group B). Randomly selected 50 patients (n = 20/group A/n = 30 group B) underwent immunolabelling against CD68 and CD163. RESULTS: Using immunofluorescence double labeling experiments we found a strong positive correlation of CD68 expression with CD163 expression (т = 0.934). High CD68 expression (x ≥ 23%) and high CD163 expression (x ≥ 22%) within stromal cells of the lamina propria was significantly associated with steroid use (CD68, p = 0.012 and CD163, p = 0.004, respectively) and complicated sigmoid diverticulitis with severe inflammation (CD68, p = 0.0001 and CD163, p = 0.001, respectively). CONCLUSIONS: Inflammation, especially mediated by activated (CD68+/CD163+) macrophages in histopathological specimen might resemble the cellular link between steroid use and complicated types of sigmoid diverticulitis. Macrophages might be a suitable target for future supportive/preventive therapies. However, as long as we are lacking such strategies, we must bear in mind that steroid intake is a risk factor for complicated diverticulitis, especially when indicating surgical resection.

MMP-1 is a (pre-)invasive factor in Barrett-associated esophageal adenocarcinomas and is associated with positive lymph node status.

BACKGROUND: Esophageal adenocarcinomas (EACs) arise due to gastroesophageal reflux, with Barrett's esophagus (BE) regarded as precancerous lesion. Matrix metalloproteinases (MMPs) might play a role during the multistep carcinogenetic process. METHODS: Expression of MMP-1 and -13 was analyzed in esophageal cancer (n = 41 EAC with BE, n = 19 EAC without BE, and n = 10 esophageal squamous-cell carcinomas, ESCC), furthermore in BE without intraepithelial neoplasia (IN) (n = 18), and the cell line OE-33. MMP-1 was co-labelled with Ki-67 (proliferation), Cdx-2 (marker for intestinal metaplasia, BE) and analyzed on mRNA level. MMP-1 staining results were correlated with clinicopathological parameters. RESULTS: On protein level, MMP-1 expression was found in 39 of 41 (95%) EAC with BE, in 19 of 19 (100%) EAC without BE, in 6 of 10 (60%) ESCC, and in 10 of 18 (56%) BE without IN. No expression of MMP-13 was found in these specimens. Quantification showed 48% MMP-1 positive cells in EAC with BE, compared to 35% in adjacent BE (p < 0.05), 44% in EAC without BE, 32% in ESCC, and 4% in BE without IN. Immunofluorescence double staining experiments revealed increased MMP-1 expressing in proliferating cells (MMP-1+/Ki-67+) (r = 0.943 for BE and r = 0.811 for EAC). On mRNA-level, expression of MMP-1 was significantly higher in EAC compared to BE (p = 0.01) and confirmed immunohistochemical staining results. High MMP-1 levels were associated with lymph node metastases but not with poorer survival (p = 0.307). CONCLUSIONS: Our findings suggest that MMP-1 plays a role as preinvasive factor in BE-associated EAC. Expression of MMP-1 in proliferating BE and EAC cells suggest malignant proliferation following the clonal expansion model.

Thyroid artery erosion by esophageal cancer: management with interventional radiology.

Management of upper gastrointestinal bleeding because of erosion of vessels by esophageal cancer may be challenging. We present herein the angiographic images of a 49-year-old patient who was admitted with massive bleeding from a tumor-eroded inferior thyroid artery. Attempts to control the bleeding by means of flexible endoscopy and insertion of a Sengstaken-Blakemore tube had failed. The diagnosis was impressively demonstrated by multislice computed tomography with intravenous contrast in the arterial phase and multiplanar reconstructions (computed tomography angiography) and by digital subtraction angiography. The bleeding was successfully treated with superselective catheterization and coiling of the eroded vessel.

Coexpression of cyclooxygenases (COX-1, COX-2) and vascular endothelial growth factors (VEGF-A, VEGF-C) in esophageal adenocarcinoma.

Cyclooxygenases (COX), especially COX-2, are considered to be involved in carcinogenesis. Our study was initiated to test whether expression of COX isoforms (COX-1 and COX-2) is linked to expression of potent inducers of angiogenesis [vascular endothelial growth factor (VEGF)-A] and lymphangiogenesis (VEGF-C) in esophageal adenocarcinoma. One hundred twenty-three esophageal adenocarcinomas were investigated by means of quantitative reverse transcription-PCR for expression of COX-1, COX-2, VEGF-A, and VEGF-C. Additionally, COX-2 protein expression was determined using immunohistochemistry. Three esophageal cancer cell lines (OE-33, OSC-1, and OSC-2) were treated with COX-inhibiting substances (diclofenac, rofecoxib, and SC-560) and the effect on expression of the four genes was determined. COX-2 protein expression was found in all carcinomas under analysis. RNA expression levels of COX-1 and COX-2 varied markedly in carcinoma tissues and correlated significantly with each other (P < 0.001, r = 0.726). Furthermore, COX expression correlated with expression of VEGF-A (COX-1: P < 0.001, r = 0.753; COX-2: P < 0.001, r = 0.764) and VEGF-C (COX-1: P < 0.001, r = 0.778; COX-2: P < 0.001; r = 0.613). Exposure of esophageal cancer cell lines OE-33, OSC-1, and OSC-2 with three COX-inhibiting substances (diclofenac, rofecoxib, and SC-560) resulted in significantly reduced expression of VEGF-A and VEGF-C. In conclusion, our data suggest that both COX isoforms may be involved in the pathogenesis of esophageal adenocarcinoma, as they are linked to the expression of important modulators of angiogenesis (VEGF-A) and lymphangiogenesis (VEGF-C).

Lymphatic vessel invasion as a prognostic factor in patients with primary resected adenocarcinomas of the esophagogastric junction.

PURPOSE: To evaluate the value of lymphatic vessel invasion (LVI) as a predictor of survival in patients with primary resected adenocarcinomas of the esophagogastric junction (AEG). PATIENTS AND METHODS: We prospectively evaluated 459 patients undergoing primary surgical resection for tumors of the esophagogastric junction at our institution between 1992 and 2000 (180 adenocarcinomas of the distal esophagus, AEG I; 140 carcinomas of the cardia, AEG II; and 139 subcardial gastric cancers, AEG III). Median follow-up was 36.8 months. The prevalence of LVI was evaluated by two independent pathologists. Univariate and multivariate analysis of prognostic factors was performed. RESULTS: The total rate of LVI was 49.9%, with a significant difference between AEG I (38.9%) and AEGII/III (57.0%, P = .0002). Univariate analysis showed a significant correlation between LVI and T category (P < .0001), N category (P < .0001), and resection status (R [residual tumor] category; P < .0001). This was shown for the group of all AEG tumors, as well as for the subgroups AEG I and AEG II/III. On multivariate analysis, LVI was identified as a significant and independent prognostic factor (P = .050) in the population of all patients and in patients with AEG II/III, but not in the subgroup with AEG I. CONCLUSION: These data demonstrate the prognostic significance of LVI in patients with AEG tumors, with marked differences between the subgroups AEG I versus AEG II/III. The lower prevalence and lack of prognostic significance of LVI in AEG I might be explained by inflammation involved in the pathogenesis of this entity.

Esophageal squamous cell carcinoma with entirely intramural growth pattern.

Esophageal cancers are predominantly carcinomas, which are-due to their origin from the epithelial lining-visible by endoluminal view. We report in this study about the rare case of an esophageal squamous cell cancer with an unusual, entirely intramural growth pattern. The diagnosis could only be established postoperatively, because all preoperative biopsies had failed to demonstrate the tumor. The entirely intramural growth pattern of esophageal squamous cell cancer is an exceedingly rare variant, with only one previously reported case. Nevertheless, clinicians, radiologists, and pathologists should be aware of the potential existence of this condition, especially when clinical and imaging results suggest a malignant tumor that cannot be proven on biopsies. Surgical exploration must be considered under these circumstances.

Surgical management of esophagogastric junction tumors.

Surgical resection with lymphadenectomy is the mainstay of treatment for all resectable esophagogastric junction tumors, prior to systemic generalization of the disease. This makes accurate pre-treatment staging and classification of the tumors most demanding. A well-established and internationally accepted classification for adenocarcinomas of the esophagogastric junction (AEG) helps to choose the appropriate surgical approach and to make results from different institutions comparable. Distal esophageal adenocarcinomas (AEG I) are distinguished from true cardia carcinomas (AEG II) and subcardiac gastric cancers (AEG III). Substantial advancements in this surgical field during the preceding decades have clearly revealed that individualization of the surgical strategy is the key to successfully approaching these entities. In this review we discuss the surgical management of esophagogastric junction tumors with a tailored surgical strategy.

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.

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.

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.