[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.

[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.

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.

Transoral access for endoscopic thyroid resection.

BACKGROUND: Endoscopic neck surgery is requested by an increasing number of patients. The access trauma of the axillary, breast, and chest approaches is greater than with open or video-assisted surgery. The authors tested the feasibility of the sublingual transoral access, which they believe is the most promising minimally invasive endoscopic access to the thyroid gland from outside the neck region. METHODS: The sublingual transoral access was first evaluated in two fresh human cadavers. An experimental investigation then was performed using a porcine model. A total of 10 endoscopic transoral thyroidectomies were performed in 10 pigs using a modified axilloscope with an obturator, ultrasonic scissors, and a neuromonitoring system to identify the recurrent laryngeal nerve. RESULTS: A complete transoral thyroid resection was achieved with both the human cadavers and all the living pigs. Despite the complexity of the anatomic region, the transoral procedure was astonishingly easy to perform. In the animal study, the time from the introduction of the obturator just above the larynx to its removal was 59 s. The average overall operation time was 50 min. The neuromonitoring system permitted the regular function of the recurrent laryngeal nerves on both sides to be proved after removal of the thyroid gland. The pigs were observed for another 2 h after the operation. No complications occurred during the operation or afterward. CONCLUSIONS: Endoscopic transoral thyroid resection is possible. It proved to be a safe procedure in living pigs and astonishingly easy to perform. The results may be helpful for thyroid resections in humans using a similar access, as suggested by the thyroidectomies in human cadavers preceding this study.

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.

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.

Limited surgical resection and jejunal interposition for early adenocarcinoma of the distal esophagus.

The need for radical resection and extensive lymphadenectomy for early adenocarcinoma of the distal esophagus has recently been challenged. Limited surgical resection and endoscopic mucosal ablation techniques are increasingly proposed and used as less invasive alternatives. Available data indicate that a limited resection of the distal esophagus and esophagogastric junction with jejunal interposition is associated with less morbidity and mortality, provides similar oncologic results, and offers a better quality of life as compared with radical esophagectomy. In contrast, endoscopic ablation and mucosectomy techniques are still plagued by high tumor recurrence rates, particularly in patients with incomplete removal of the underlying Barrett's mucosa, multicentric tumors, or tumors invading into the submucosa. Attention to technical details of limited resection and jejunal interposition is, however, required to avoid complications, poor functional results, and the need for reintervention.

Flexible versus rigid endoscopy for treatment of foreign body impaction in the esophagus.

BACKGROUND: The use of either flexible endoscopy (FE) or rigid endoscopy (RE) for removal of ingested foreign bodies (FBs) impacted in the esophagus is still discussed controversially. METHODS: We report a consecutive series of 139 patients with FB impaction in the esophagus. During a 6-year period, 69 men and 70 women (median age, 64 [0.7-97] years) requiring removal of an impacted FB underwent either RE (n = 63) in the Otolaryngology Department of our hospital or FE (n = 76) in the Surgical Endoscopy Unit. RESULTS: Foreign body removal was equally effective with FE (success rate 93.4%) and RE (95.2%, p = n.s.). The cases in which foreign body removal failed (5 FE cases [6.6%] and 3 RE cases [4.8%]) were all subsequently successfully managed with "conversion" and use of the other technique. No severe complications occurred when FB removal was attempted with FE (0 of 76 cases; 0.0%), whereas RE was associated with esophageal rupture requiring immediate surgical intervention in 2 of 63 cases (3.2%; p < 0.002). Patient comfort differed significantly between the two procedures (p < 0.0001); RE was always performed under general anesthesia (100.0%), whereas only a minority of patients undergoing FE required general anesthesia (13.0%; p < 0.0001) or mild analgosedation (20.0%). The better patient comfort with FE was also reflected in a significantly lower rate of dysphagia (15%) compared to RE (48%; p < 0.0001). Rigid endoscopy was more frequently used in removal of FBs of the upper esophagus (p < 0.0001), whereas FE was the predominate approach to FBs in the lower esophagus (p < 0.0001). CONCLUSIONS: A tailored approach to treatment of FB impaction is recommended. Because of the lower rate of severe complications, better patient comfort with a lower rate of dysphagia, and lack of requirement for general anesthesia, FE should be the "first line" approach to FBs, although RE has its place as the "second line" therapy.

Prognostic significance of expression patterns of c-erbB-2, p53, p16INK4A, p27KIP1, cyclin D1 and epidermal growth factor receptor in oesophageal adenocarcinoma: a tissue microarray study.

AIMS: To correlate immunohistochemical expression patterns and prognosis in oesophageal adenocarcinoma. METHODS: The expression of c-erbB-2, p53, p16INK4A, p27KIP1, cyclin D1 and epidermal growth factor receptor (EGFR) was studied in a series of 137 primarily resected oesophageal adenocarcinoma samples. The expression analysis on protein level was performed on routine paraffin wax-embedded material, with immunohistochemical staining of the samples, assembled on a tissue microarray. The results were correlated with clinicopathological features (pT, pN and G) and survival. RESULTS: 22 (16%) tumours showed an overexpression of the c-erbB-2 oncoprotein. Expression of EGFR was observed in 72 (55%) cases, accumulation of p53 in 68 (52%) cases and of cyclin D1 in 102 (77%) cases. Loss of p16INK4A expression was observed in 101 (76%) cases and low expression of p27KIP1 in 91 (71%) cases. Expression of these proteins did not correlate with tumour stage, grade, Lauren's or World Health Organization classification or lymph node status. On univariate survival analysis, more advanced tumour stage (p = 0.002), lymph node involvement (p = 0.003), high tumour grade (p = 0.017) and lack of EGFR expression (p = 0.034) were found to be associated with poorer survival. On multiple regression analysis, only tumour stage (p = 0.03) and lymph node involvement (p = 0.004) were shown to have an association with the survival of the patient. CONCLUSION: The immunohistochemical expression of c-erbB-2 oncoprotein, cylin D1, p16INK4A, p27KIP1, p53 and EGFR in most oesophageal adenocarcinomas suggests their implication in the pathogenesis of this entity. None of the molecular markers assessed, however, was of prognostic value. Identification of any marker superior to or even approaching the prognostic value of conventional histopathological markers (pT and pN) was therefore not possible.

Immunohistochemistry and in situ hybridization of the androgen receptor in the developing human prostate.

UNLABELLED: As it is suggested that the androgen receptor mechanism is required for prostatic development, we attempted to determine the appearance, expression and distribution of the androgen receptor in embryonic, infantile and pubertal human prostate. Using mono- and polyclonal antibodies and a digoxigenin-labeled 713 bp riboprobe, the androgen receptor expression in paraffin sections of fetal, infantile, and pubertal prostates was studied at the protein and RNA level. Under highly standardized conditions, application of the polyclonal antibodies resulted in a weak cytoplasmic and nuclear labeling of the epithelium of fetal glands. No immunoreaction was obtained with monoclonal antibodies. Applying the polyclonal antibody to pubertal and adult specimens, immunoreactivity of the androgen receptor was positive in nuclei of adluminal and basal epithelial cells, in interstitial and vascular smooth muscle cells and vascular endothelium, whereas ganglionic cells and enteroendocrine cells were negative. In situ hybridization with the digoxigenin-labeled riboprobe gave clear positive results already in epithelium of very young fetal specimens. A semiquantitative visual evaluation of in situ hybridizations showed that intermediate intensity of expression was increased in pubertal and adult specimens, whereas strong expression was reduced in prostatic epithelium. CONCLUSIONS: The essential findings are: (1) an early expression of androgen receptor mRNA in the fetal prostate; (2) no immunoreaction of monoclonal antibodies against the androgen receptor in the same specimens, (3) a decrease of androgen receptor mRNA expression, but increase in immunoreactivity of the androgen receptor protein with the onset of glandular maturation during puberty.

Enucleation of submucosal tumors of the esophagus: minimally invasive versus open approach.

BACKGROUND: Surgical enucleation of submucosal tumors (SMTs) of the esophagus (mostly leiomyomas) is indicated when either the tumors are symptomatic or their biological behavior is unclear. The classic approach is a thoracotomy, but tumor enucleation can now also be performed via thoracoscopy or, for distal tumors, via laparoscopy. METHODS: We assessed our experience with the different approaches in a total of 25 patients (n = 13 minimally invasive approach and n = 12 open surgery). Enucleation of the SMT was the basic surgical principle; the choice of the approach was based on the preference of the surgeon. RESULTS: Compared to open surgery, the minimally invasive approach reduced pulmonary complications, hospital stay, and postoperative wound-related pain. The operating time was the same for both approaches. CONCLUSION: Minimally invasive approaches are suitable for the surgical enucleation of submucosal esophageal tumors. Thoracoscopic and laparoscopic techniques are recommended as standard procedures in experienced centers.

[Carcinoma of the oesophagogastric junction and Barrett's esophagus: an almost clear oncologic model?]. / Karzinom des ösophagogastralen Ubergangs und Barrett-Osophagus. Ein nahezu klares onkologisches Modell?

From a clinical and biological point of view, the term "adenocarcinoma of the esophagogastric junction" (AEG) encompasses several distinct tumor entities. The topographic anatomic classification into adenocarcinoma of the distal esophagus (AEG I), true carcinoma of the cardia (AEG II), and subcardiac gastric cancer (AEG III) also reflects differences regarding the pathogenesis of these tumors and is increasingly accepted worldwide. Associated Barrett's esophagus, which usually develops as a consequence of chronic gastroesophageal reflux, can be documented in practically all patients with AEG I tumors and constitutes the most important precancerous lesion. A metaplasia-dysplasia-carcinoma sequence has been confirmed for these tumors. Barrett's esophagus is thus considered a model for studies on carcinogenesis and the prevention of esophageal adenocarcinoma. Its pathogenetic role in AEG II and III tumors must, however, be discussed differently. Our own experience shows that pathogenetic mechanisms similar to those in AEG I tumors may be present in up to 30% of tumors classified as AEG II. The majority of AEG II tumors, however, show morphologic, biologic and pathogenetic similarities with AEG III tumors and proximal gastric cancer.

[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.

[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.