[Diagnostics and therapy of achalasia]. / Diagnostik und Therapie der Achalasie.

The low incidence (1:100,000) makes primary idiopathic achalasia a problem of special importance. Patients often have a long medical history of suffering before the diagnosis is established and adequate therapy provided. Surgeons who perform antireflux surgery must be certain of detecting achalasia patients within their collective of gastroesophageal reflux disease (GERD) patients to avoid contraindicated fundoplication. The current gold standard for establishing the diagnosis of achalasia is manometry. Especially in early stages, symptom evaluation, endoscopy and barium swallow lack adequate sensitivity. High-resolution manometry (HRM) is increasingly used and allows characterization of different achalasia types (i.e. type I classical achalasia, type II panesophageal pressurization and type III spasmodic achalasia) and differentiation from other motility disorders (e.g. distal esophageal spasm, jackhammer esophagus and nutcracker esophagus). For patients over 45 years of age additional endoscopic ultrasound and computed tomography are recommended to exclude pseudoachalasia. A curative treatment restoring normal esophageal function does not exist; however, there are good options for symptom control. Therapy aims are abolishment of dysphagia, improvement of esophageal clearance, prevention of reflux and abolishment of chest pain. The current standard treatment is cardiomyotomy, which was first described 100 years ago by the German surgeon Ernst Heller and has been shown to be clearly superior when compared to endoscopic treatment (e.g. botox injection and balloon dilatation). Heller's myotomy procedure is preferentially performed via the laparoscopic route and combined with partial fundoplication. Currently, an alternative to performing Heller's myotomy via the endoscopic route is under intensive investigation in several centers worldwide. The peroral endoscopic myotomy (POEM) procedure has shown very promising initial results and warrants further clinical evaluation.

[Peroral endoscopic myotomy for treatment of achalasia. Literature review and own initial experience]. / Perorale endoskopische Myotomie zur Therapie der Achalasie. Literaturüberblick und eigene initiale Erfahrung.

Peroral endoscopic myotomy (POEM) is a new, purely endoscopic procedure for treatment of achalasia. Due to the lack of incisions POEM can be regarded as a true NOTES procedure. With POEM a myotomy is created in a similar fashion to the previous standard treatment, laparoscopic Heller myotomy (LHM). The relatively free choice of length and localization of the myotomy may be regarded as advantages of POEM. The procedure starts with a mucosal incision (mucosal entry) followed by preparation of a submucosal tunnel crossing the esophagogastric junction and creation of a myotomy in an antegrade direction before the mucosal access is closed with endoscopic clip placement. Since the first description of the application of POEM in humans in 2010 by the pioneer Haruhiro Inoue, Yokohama, Japan, it has been used increasingly and investigated in some centers in Asia, the U.S.A. and also Europe. The results are very promising. Although the procedure is technically demanding it can be performed safely with low complication rates. The POEM procedure achieves very good control of dysphagia and gastroesophageal reflux witch is only a rare side-effect witch is well-controllable with proton pump inhibitors (PPI). We review the currently available data from the literature and present our own initial series of 14 patients treated with POEM.

[Colonic diverticulosis and its complications: pathogenesis, classification and clinical implications]. / Die Kolondivertikulose und ihre Komplikationen: Pathogenese, Klassifikation und Klinische Implikationen.

Current understanding of the pathogenesis of colonic diverticulosis and its complications has certain implications for current therapy concepts, which are summarised here. Colonic diverticula in the Western world are pseudodiverticula predominating in the sigmoid colon. Pathogenesis is multifactorial and includes low-fibre diet, dysmotility, increased intraluminal pressure and morphological changes. Uncomplicated diverticulitis results from microperforations, contradicting the hypothesis of the "abscessed diverticulum". Administration of antibiotics for treatment is controversial. Complicated sigmoid diverticulitis is characterised by an intensive inflammatory infiltrate with macrophages. Immunosuppression and especially steroid intake are identified as risk factors. Nowadays, elective or emergency resection is generally recommended as therapy of first choice. However, contrary concepts with merely conservative treatment or drainage--even for perforated diverticulitis--are emerging. The pathogenesis of chronically recurrent diverticulitis is poorly understood and concepts are changing. Resection after the second episode is replaced by a risk-adapted strategy. Diverticular bleeding occurs due to rupture of a vas rectum at the fundus of the diverticulum. Conservative and endoscopic management is the first line and surgical resection plays a role as salvage-strategy in case of recurrent and life-threatening bleeding. Localising the bleeding, i.e., with angiography, is crucial prior to surgery. The pathophysiology of colonic diverticulosis is complex and incompletely understood and linked with several controversial issues, regarding treatment strategies.

Glucocorticoid-induced tumour necrosis factor receptor expression: a potential molecular link between steroid intake and complicated diverticulitis?

AIM: Immunosuppression and steroid medication have been identified as risk factors for complicated sigmoid diverticulitis. The underlying molecular mechanisms have not yet been elucidated. We hypothesized that glucocorticoid-induced tumour necrosis factor receptor (GITR) and matrix metalloproteinase-9 (MMP-9) might play a role. METHOD: GITR and MMP-9 were analysed at protein [immunohistochemistry/immunofluorescence (IF)] and messenger RNA level (real-time polymerase chain reaction) in surgical specimens with complicated and non-complicated diverticulitis (n=101). IF double staining and regression analysis were performed for both markers. GITR expression was correlated with clinical data and its usefulness as a diagnostic test was investigated. RESULTS: High GITR expression (≥41%) was observed in the inflammatory infiltrate in complicated diverticulitis, in contrast to non-complicated diverticulitis where GITR expression was low (P<0.001). High GITR expression was significantly associated with steroid use and pulmonary diseases (both P<0.001). MMP-9 expression correlated with GITR expression (R(2) =0.7268, P<0.0001, r=0.85) as demonstrated with IF double-staining experiments. Co-labelling of GITR with CD68, but not CD15, suggested that GITR-expressing cells in diverticulitis are macrophages. GITR expression was superior to C-reactive protein (CRP), white cell count and temperature in distinguishing complicated and non-complicated diverticulitis. CONCLUSIONS: Our results suggest that GITR expression in inflammatory cells might potentially indicate a molecular link between steroid use and complicated forms of acute sigmoid diverticulitis. Increased MMP-9 expression by GITR signalling might explain the morphological changes in the colonic wall of perforated and phlegmonous diverticulitis. Analysis of soluble GITR might be a promising strategy for future research.

[Newly recognized side-effects of proton pump inhibitors. Arguments in favour of fundoplication for GERD?]. / Neu erkannte Nebenwirkungen von Protonenpumpeninhibitoren. Argumente Pro Fundoplicatio bei GERD?

Among other indications proton pump inhibitors (PPIs) are used as medical treatment of gastroesophageal reflux disease (GERD) and are the most frequently prescribed and most frequently used drugs in gastroenterology. Until recently PPIs were regarded as very safe and associated with very few side-effects. However, during recent years study results have revealed many severe adverse events associated especially with long-term PPI use. We review the currently available evidence, regarding the side-effects of PPIs and discuss the potential impact on treatment strategies for GERD (conservative treatment vs. antireflux surgery). Currently available data suggest that PPIs are associated with osteoporosis-related fractures, Clostridium difficile associated diarrhea (CDAD), community and hospital-acquired pneumonia, pharmacologic interaction with clopidogrel and acetylsalicylic acid with subsequent increased rate of cardiovascular events, refractory hypomagnesemia and rebound reflux symptoms etc. The risk-benefit ratio of PPIs is increasingly recognized as being less favourable. This leads to a more critical viewpoint and raises the question whether the side-effects of PPIs may outweigh the benefits, especially with long-term use. The side-effects of PPIs seem to make a strong argument in favour of laparoscopic fundoplication in the treatment of GERD.

[Quality of life after fast track colorectal surgery]. / Lebensqualität nach Kolonchirurgie unter "Fast Track"-Bedingungen.

BACKGROUND: Fast track (enhanced recovery) surgery is a standardized concept of perioperative management, which is applied independently of the disease and the operative procedure. The implementation of this concept adjusts the quality of medical results and allows to analyse different factors and their impact on quality of life (QoL). The aim of this investigation was to assess the QoL of patients after elective colorectal surgery undergoing standardized perioperative fast track rehabilitation. MATERIAL AND METHODS: From December 2004 to May 2006 all patients undergoing elective colorectal surgery and fast track rehabilitation were included in this study. Quality of life was evaluated prospectively using the Gastrointestinal Quality of Life Index (GIQLI) according to Eypasch. QoL was analyzed pre- and postoperatively. Subgroup analyses were performed regarding age, malignant or non-malignant colorectal disease and surgical approach. Follow-up was performed three months postoperatively. RESULTS: 124 patients underwent elective resection within a fast track program (age 64±10 years, 55 with benign disease, 69 with colorectal carcinoma; 67 men and 57 women). 62 patients (50 %) completed the follow-up examination (QoL evaluation three months postoperatively). Pre- and postoperative QoL did not differ significantly (98 [92-104] and 103 [98-109] points, respectively). Subgroup analyses revealed that patients having undergone colorectal resection for benign disease had significantly improved quality of life after surgery, but not so the patients treated for colorectal cancer. The QoL was 14 (2-26) and -1 (-9 - 5), respectively. Patients' age and surgical approach (minimally invasive or open) did not influence their QoL. CONCLUSION: Postoperative QoL after standarized fast track perioperative management was influenced mainly by the patients' disease (with potential QoL improvement in benign disorders), whereas age and the operative approach (minimally invasive or open) had little impact in this respect.

Tumor necrosis factor-α is associated with positive lymph node status in patients with recurrence of colorectal cancer-indications for anti-TNF-α agents in cancer treatment.

INTRODUCTION: The progressive growth of malignancies is accompanied by a decline in the immune response through mechanisms which are poorly understood. Apoptosis and induction of inflammation by tumor released cytokines as tumor escape mechanisms have been proposed to play an important role in colorectal carcinogenesis. METHODS: Expression of Tumor necrosis factor-alpha (TNF-α) was analyzed in colorectal cancer specimen and the cancer cell line HT-29 by immunohistochemistry and RT-PCR. TNF-α expression on protein and mRNA level were correlated with clinical characteristics and impact on survival. TNFR-1 was co-labelled with TNF-α and CD8+ cytotoxic T cells in immunofluorescence double staining experiments. RESULTS: 94% (n = 98/104) of the patients with CRC expressed TNF-α. High TNF-α expression was significantly associated with positive lymph node stage and recurrence of the tumor. Multivariate analysis revealed high TNF-α expression as an independent prognostic factor. Immunohistochemistry was correlated with RT-PCR results (т = 0.794). Immunofluorescence double staining experiments revealed increased TNFR-1 expression by CD8+ cells. CONCLUSIONS: TNF-α expression by tumor cells may be an efficient immunological escape mechanism by inflammation-enhanced metastases and probably by induction of apoptosis in tumor-infiltrating CD8+ immune cells resulting in a down regulation of the tumoral immune response. Our data support the role of tumor-derived TNF-α expression as an important promoter of tumoral immune escape mechanisms and malignant progression, and suggest that analysis on either protein (immunohistochemistry) or RNA level (RT-PCR) can be used effectively in this respect. Targeting TNF-α may be a promising option, especially in cases with high TNF-α expression and positive lymph node metastases.

[Cost analysis of the fast track concept in elective colonic surgery]. / Kostenanalyse des Fast-Track-Konzeptes bei elektiver Kolonchirurgie.

INTRODUCTION: Fast track (FT) is a modern concept to enhance postoperative recovery after elective surgery. It has been approved during the last years. Beside its medical benefits, fast-track (FT) concepts may provide an economic incentive, although a cost-benefit analysis in the daily clinical routine has not yet been realised. In addition to this an elevated consumption of resources is postulated. PATIENTS AND METHODS: In 2007 we prospectively studied the implementation of the FT concept for elective colonic surgery in the daily clinical routine at the Department of General Surgery of Nuremberg Hospital. In a representative subgroup of patients studied, we performed a cost-cost analysis by comparing these patients to a retrospectively analysed group that had been treated in a conventional traditional manner in 2002. RESULTS: 369  patients were included and treated according to the FT concept. Discharge criteria were met at the 4(th) postoperative day in median (SD 3.9  days, minimum  1, maxiumum 29  days). The rate of general postoperative complications was 24.4 % (16 % minor complications) for all patients and 6.6 % in the group of patients who were discharged within 9 postoperative days or less (n=182). With respect to the main FT items, implementation of the FT concept was considered as effective. Cost-cost analyses showed a cost reduction of 32 % in favour of patients treated with the FT concept. CONCLUSION: This study clearly shows the clinical and economic benefits of the FT concept considering health services research. Therefore further clinical implementation of the FT concept seems beneficial, not only in the view of medical aspects, but also for economic reasons.

Tumor necrosis factor-α is associated with positive lymph node status in patients with recurrence of colorectal cancer--indications for anti-TNF-α agents in cancer treatment.

INTRODUCTION: The progressive growth of malignancies is accompanied by a decline in the immune response through mechanisms which are poorly understood. Apoptosis and induction of inflammation by tumor released cytokines as tumor escape mechanisms have been proposed to play an important role in colorectal carcinogenesis. METHODS: Expression of Tumor necrosis factor-alpha (TNF-α) was analyzed in colorectal cancer specimen and the cancer cell line HT-29 by immunohistochemistry and RT-PCR. TNF-α expression on protein and mRNA level were correlated with clinical characteristics and impact on survival. TNFR-1 was co-labelled with TNF-α and CD8+ cytotoxic T cells in immunofluorescence double staining experiments. RESULTS: 94% (n=98/104) of the patients with CRC expressed TNF-α. High TNF-α expression was significantly associated with positive lymph node stage and recurrence of the tumor. Multivariate analysis revealed high TNF-α expression as an independent prognostic factor. Immunohistochemistry was correlated with RT-PCR results (τ=0.794). Immunofluorescence double staining experiments revealed increased TNFR-1 expression by CD8+ cells. CONCLUSIONS: TNF-α expression by tumor cells may be an efficient immunological escape mechanism by inflammation-enhanced metastases and probably by induction of apoptosis in tumor-infiltrating CD8+ immune cells resulting in a down regulation of the tumoral immune response. Our data support the role of tumor-derived TNF-α expression as an important promoter of tumoral immune escape mechanisms and malignant progression, and suggest that analysis on either protein (immunohistochemistry) or RNA level (RT-PCR) can be used effectively in this respect. Targeting TNF-α may be a promising option, especially in cases with high TNF-α expression and positive lymph node metastases.

The effect of ultrasound dissection in thyroid surgery.

BACKGROUND: One of the most important aspects of thyroid surgery is hemostasis. The ultrasonically activated scalpel is described as a very useful instrument in thyroid surgery for the dissection and sealing of vessels. Our study compares the short-term results of endocrine surgery, with and without the use of ultrasonic devices. METHODS: In a prospectively randomized trial, 96 patients with endemic goiter were operated by the same surgeon, one study group (n = 54 patients) being operated with the ultrasonic scalpel as an additional instrument. We measured the operating time, the number of ligatures needed as well as intraoperative and postoperative bleeding as surrogate markers for improvement of the surgical technique. RESULTS: The ultrasound dissection technique significantly reduces surgery time (p = 0.048; ultrasound procedure average 68 min, conventional procedure average 83 min), intraoperative bleeding (p = 0.028) and the number of ligatures (p = 0.008; ultrasound procedure average 8.2, conventional procedure average 26.4). CONCLUSIONS: The use of an ultrasonically activated scalpel significantly improves bleeding control during thyroid resections and may also be beneficial with respect to cost reduction. Clinical application and further studies to characterize its role are justified.

Critical reappraisal of current surveillance strategies for Barrett's esophagus: analysis of a large German Barrett's database.

Endoscopic surveillance is recommended for patients with Barrett's esophagus (BE). Based on a large database, gathered from predominantly community-based practices in Germany, we aimed to investigate the time-course of malignant progression and apply these findings to current clinical practice. Data of 1438 patients with BE from a large German BE database were analyzed. Patients with at least one follow-up endoscopy/biopsy were included. Detection of 'malignant Barrett' (either high-grade intra-epithelial neoplasia or invasive adenocarcinoma) was considered as study end-point. Of 1438 patients with BE, 57 patients had low-grade intra-epithelial neoplasia (LG-IN) on initial biopsy and 1381 exhibited non-neoplastic BE. 'Malignant Barrett' was detected in 28 cases (1.9%) during a median follow-up period of 24 months (1-255), accounting for an incidence of 0.95% per patient year of follow-up. The frequency of 'malignant Barrett' was significantly higher (P < 0.001, chi(2)-test) in the LG-IN group (n = 11, 19.3%) compared with the non-neoplastic BE group (n = 17, 1.2%). In the non-neoplastic BE group, 'malignant Barrett' was predominantly found during re-endoscopy within the first year of follow-up (12 of 17; 70.6%), in contrast to the LG-IN group, in which 'malignant Barrett' was observed predominantly after a time exceeding 12 months (8 of 11, 72.7%; P = 0.05, Fisher's exact test). Initial endoscopic evaluations seem to play the most crucial role in managing BE. After 1 year of follow-up, endoscopic surveillance should be focused on patients with LG-IN. In patients with repeatedly proven non-neoplastic BE, elongation of the follow-up intervals to the upper limit of current guidelines, that is, 5 years, might be justified.

Expression of prostaglandin E synthase in Barrett's cancer.

Expression of prostaglandin E synthase (PGES) - an enzyme of the prostaglandin biosynthetic pathway with suspected impact on carcinogenesis--was studied in Barrett's cancer to determine its pathogenetic role and prognostic impact in this entity. Expression analysis of PGES was performed on mRNA level (quantitative reverse transcription polymerase chain rection [RT-PCR]) in a large surgical series of 123 primary resected adenocarcinomas of the distal esophagus (Barrett's cancer). Gene expression results were correlated with clinical parameters, overall survival and expression levels of previously analyzed target genes of the cyclooxygenase (COX) pathway (COX-1, COX-2) and mediators of angiogenesis (vascular endothelial growth factor [VEGF]-A) and lymphangiogenesis [VEGF-C]. Expression of PGES was demonstrated in all 123 tumors (100%) on mRNA level (quantitative RT-PCR). Relative mRNA expression levels were highly variable between different cases. Gene expression showed a strong positive correlation with both COX isoforms (COX-1: r = 0.502, P < 0.001; COX-2: r = 0.679, P < 0.001), with the angiogenetic VEGF-A (r = 0.583, P < 0.001) and with the lymphangiogentic VEGF-C (r = 0.465, P < 0.001). PGES mRNA expression showed no significant correlation with clinicopathologic parameters (i.e. pTNM categories, UICC stage, survival). Variable overexpression of PGES seems to be potentially implicated in Barrett's carcinogenesis. Gene expression of PGES is strongly correlated with other mediators of the prostaglandin biosynthetic pathway, that is both COX isoforms (COX-1 and COX-2). However, no impact on patients' outcome in relation to PGES expression was found.