Eso-Sponge® for anastomotic leakage after oesophageal resection or perforation: outcomes from a national, prospective multicentre registry.

BACKGROUND: Anastomotic leakage (AL) after oesophagectomy and oesophageal perforations are associated with significant morbidity and mortality. Minimally invasive endoscopy is often used as first-line treatment, particularly endoluminal vacuum therapy (EVT). The aim was to assess the performance of the first commercially available endoluminal vacuum device (Eso-Sponge®) in the management of AL and perforation of the upper gastrointestinal tract (GIT). METHODS: The Eso-Sponge® registry was designed in 2014 as a prospective, observational, national, multicentre registry. Patients were recruited with either AL or perforation within the upper GIT. Data were collected with a standardized form and transferred into a web-based platform. Twenty hospitals were enrolled at the beginning of the study (registration number NCT02662777; http://www.clinicaltrials.gov). The primary endpoint was successful closure of the oesophageal defect. RESULTS: Eleven out of 20 centres recruited patients. A total of 102 patients were included in this interim analysis; 69 patients with AL and 33 with a perforation were treated by EVT. In the AL group, a closure of 91 per cent was observed and 76 per cent was observed in the perforation group. The occurrence of mediastinitis (P = 0.002) and the location of the defect (P = 0.008) were identified as significant predictors of defect closure. CONCLUSIONS: The Eso-Sponge® registry offers the opportunity to collate data on EVT with a uniform, commercially available product to improve standardization. Our data show that EVT with the Eso-Sponge® is an option for the management of AL and perforation within the upper GIT.

Genome-wide association analysis of diverticular disease points towards neuromuscular, connective tissue and epithelial pathomechanisms.

OBJECTIVE: Diverticular disease is a common complex disorder characterised by mucosal outpouchings of the colonic wall that manifests through complications such as diverticulitis, perforation and bleeding. We report the to date largest genome-wide association study (GWAS) to identify genetic risk factors for diverticular disease. DESIGN: Discovery GWAS analysis was performed on UK Biobank imputed genotypes using 31 964 cases and 419 135 controls of European descent. Associations were replicated in a European sample of 3893 cases and 2829 diverticula-free controls and evaluated for risk contribution to diverticulitis and uncomplicated diverticulosis. Transcripts at top 20 replicating loci were analysed by real-time quatitative PCR in preparations of the mucosal, submucosal and muscular layer of colon. The localisation of expressed protein at selected loci was investigated by immunohistochemistry. RESULTS: We discovered 48 risk loci, of which 12 are novel, with genome-wide significance and consistent OR in the replication sample. Nominal replication (p<0.05) was observed for 27 loci, and additional 8 in meta-analysis with a population-based cohort. The most significant novel risk variant rs9960286 is located near CTAGE1 with a p value of 2.3×10-10 and 0.002 (ORallelic=1.14 (95% CI 1.05 to 1.24)) in the replication analysis. Four loci showed stronger effects for diverticulitis, PHGR1 (OR 1.32, 95% CI 1.12 to 1.56), FAM155A-2 (OR 1.21, 95% CI 1.04 to 1.42), CALCB (OR 1.17, 95% CI 1.03 to 1.33) and S100A10 (OR 1.17, 95% CI 1.03 to 1.33). CONCLUSION: In silico analyses point to diverticulosis primarily as a disorder of intestinal neuromuscular function and of impaired connective fibre support, while an additional diverticulitis risk might be conferred by epithelial dysfunction.

Treatment of Complicated Anal Fistula by an Endofistular Polyurethane-Sponge Vacuum Therapy: A Pilot Study.

BACKGROUND: Treatment of supra- and transsphincteric anal fistulas remains a clinical challenge because current treatment results are variable and potentially endanger sphincter function. OBJECTIVE: Based on positive results of endoluminal polyurethane-sponge vacuum therapy in the upper and lower GI tract, a new system for endofistular vacuum therapy was developed for anal fistulas to utilize vacuum therapy to remove the endofistular pseudoepithelium and to induce granulation in the fistula tract. DESIGN: This study is based on a prospective case series. PATIENTS: Seven patients with complicated anal fistulas (3 associated with Crohn's disease and 4 of cryptoglandular origin) longer than 4 cm were treated. Initially, the fistula was curettaged and the first endofistular vacuum therapy sponge was positioned in the fistula tract. The inner fistula opening was closed by suture. A 125 mm Hg constant vacuum was applied to the sponge, and the endofistular vacuum therapy sponge was changed a median of 3 (3-5) times after each 48 to 72 hours of constant vacuum therapy. After final removal, the fistulas were reevaluated every other week for 3 months. MAIN OUTCOME MEASURE: The main outcome measured was the closure of the fistula. RESULTS: All patients tolerated the therapy well and no adverse events were observed. Fistula tract closure was demonstrated within 4 weeks after the termination of vacuum therapy. One patient with cryptoglandular fistula developed a recurrence within the follow-up of 3 months. LIMITATIONS: This was an observational study that had no control arm. CONCLUSION: In this pilot case series, the results are encouraging. Because endoluminal vacuum therapy would be a new and sphincter-sparing therapy, this concept warrants further investigation in controlled trials.

Long-term quality of life after endovac-therapy in anastomotic leakages after esophagectomy.

BACKGROUND: Endoluminal vacuum therapy (EVT) has been successfully established with promising survival rates in the treatment of anastomotic leakages after esophagectomy. It is still unclear how this therapy affects health related quality of life (HRQOL). METHODS: HRQOL was prospectively assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) questionnaire. Assessment was carried out prior to surgery, after discharge, 6 months and 12 months after surgery. We compared HRQOL after EVT (n=23) to patients without anastomotic leakages as a control group (n=50). Investigated parameters included age, sex, and localization of anastomosis, number of EVT sessions, length of ICU and hospital stay, therapy failure, anastomotic stricture, tumour stage, neoadjuvant and adjuvant treatment, sepsis. RESULTS: After esophagectomy HRQOL increased within 12 months. Compared to patients without leakages the EVT-group showed significantly better HRQOL-scores for pain, social and emotional functioning after discharge and 6 months after surgery. In the long-term follow up HRQOL was comparable between the groups. After EVT age, advanced tumour stage, tumour recurrence, anastomotic strictures, length of ICU and hospital stay and length of EVT had a significant influence on HRQOL. CONCLUSIONS: EVT is a promising therapeutic option in leakages after esophagectomy. In the long-term, HRQOL of EVT-treated patients is comparable to patients, who did not suffer from postsurgical leakages.

Metabolic biomarker signature to differentiate pancreatic ductal adenocarcinoma from chronic pancreatitis.

OBJECTIVE: Current non-invasive diagnostic tests can distinguish between pancreatic cancer (pancreatic ductal adenocarcinoma (PDAC)) and chronic pancreatitis (CP) in only about two thirds of patients. We have searched for blood-derived metabolite biomarkers for this diagnostic purpose. DESIGN: For a case-control study in three tertiary referral centres, 914 subjects were prospectively recruited with PDAC (n=271), CP (n=282), liver cirrhosis (n=100) or healthy as well as non-pancreatic disease controls (n=261) in three consecutive studies. Metabolomic profiles of plasma and serum samples were generated from 477 metabolites identified by gas chromatography-mass spectrometry and liquid chromatography-tandem mass spectrometry. RESULTS: A biomarker signature (nine metabolites and additionally CA19-9) was identified for the differential diagnosis between PDAC and CP. The biomarker signature distinguished PDAC from CP in the training set with an area under the curve (AUC) of 0.96 (95% CI 0.93-0.98). The biomarker signature cut-off of 0.384 at 85% fixed specificity showed a sensitivity of 94.9% (95% CI 87.0%-97.0%). In the test set, an AUC of 0.94 (95% CI 0.91-0.97) and, using the same cut-off, a sensitivity of 89.9% (95% CI 81.0%-95.5%) and a specificity of 91.3% (95% CI 82.8%-96.4%) were achieved, successfully validating the biomarker signature. CONCLUSIONS: In patients with CP with an increased risk for pancreatic cancer (cumulative incidence 1.95%), the performance of this biomarker signature results in a negative predictive value of 99.9% (95% CI 99.7%-99.9%) (training set) and 99.8% (95% CI 99.6%-99.9%) (test set). In one third of our patients, the clinical use of this biomarker signature would have improved diagnosis and treatment stratification in comparison to CA19-9.

Endoscopic endoluminal vacuum therapy in esophageal perforation.

BACKGROUND: Esophageal perforation is a serious disease with a high morbidity and mortality rate. Endoscopic vacuum therapy (EVT) is a new endoscopic treatment option, which is used to treat anastomotic leakages after rectal and esophageal resections. We report on 10 patients treated with EVT for esophageal perforation. METHODS: Clinical and therapy-related data such as age, sex, duration of intensive care stay, length of hospital stay, reasons for perforation, EVT-associated complications, mortality, need for alternative treatment options, and course of infectious variables were analyzed. RESULTS: Ten patients were treated with 54 vacuum sponges that were placed in upper gastrointestinal defects. Causes for perforation were iatrogenic, spontaneous, or foreign body-associated. Mean number of sponge insertions was 5.4 (range, 2 to 12) with a mean period of 19 ± 14.26 days. Successful therapy was achieved in 9 of 10 patients. After successful primary treatment, 1 patient died during therapy as a result of general failure of the cardiovascular system. In 1 patient, surgical resection was necessary after repeated Mallory-Weiss lesions and minor perforations during the course of immunosuppressive therapy. In a third patient an endoscopic stent was inserted in the clean wound cavity after primary EVT. CONCLUSIONS: In this small trial EVT has been shown to be a safe and feasible therapy option for perforations of the upper gastrointestinal tract. If necessary, EVT can be combined with operative revision for better control of the local septic focus or used as a bridging procedure for wound conditioning before aggressive surgical treatment.

Metabolic signature of electrosurgical liver dissection.

BACKGROUND AND AIMS: High frequency electrosurgery has a key role in the broadening application of liver surgery. Its molecular signature, i.e. the metabolites evolving from electrocauterization which may inhibit hepatic wound healing, have not been systematically studied. METHODS: Human liver samples were thus obtained during surgery before and after electrosurgical dissection and subjected to a two-stage metabolomic screening experiment (discovery sample: N = 18, replication sample: N = 20) using gas chromatography/mass spectrometry. RESULTS: In a set of 208 chemically defined metabolites, electrosurgical dissection lead to a distinct metabolic signature resulting in a separation in the first two dimensions of a principal components analysis. Six metabolites including glycolic acid, azelaic acid, 2-n-pentylfuran, dihydroactinidiolide, 2-butenal and n-pentanal were consistently increased after electrosurgery meeting the discovery (p<2.0 × 10(-4)) and the replication thresholds (p<3.5 × 10(-3)). Azelaic acid, a lipid peroxidation product from the fragmentation of abundant sn-2 linoleoyl residues, was most abundant and increased 8.1-fold after electrosurgical liver dissection (preplication = 1.6 × 10(-4)). The corresponding phospholipid hexadecyl azelaoyl glycerophosphocholine inhibited wound healing and tissue remodelling in scratch- and proliferation assays of hepatic stellate cells and cholangiocytes, and caused apoptosis dose-dependently in vitro, which may explain in part the tissue damage due to electrosurgery. CONCLUSION: Hepatic electrosurgery generates a metabolic signature with characteristic lipid peroxidation products. Among these, azelaic acid shows a dose-dependent toxicity in liver cells and inhibits wound healing. These observations potentially pave the way for pharmacological intervention prior liver surgery to modify the metabolic response and prevent postoperative complications.

Endoscopic endoluminal vacuum therapy is superior to other regimens in managing anastomotic leakage after esophagectomy: a comparative retrospective study.

BACKGROUND: Anastomotic leakage after esophagectomy is a life-threatening complication. No comparative outcome analyses for the different treatment regimens are yet available. METHODS: In a single-center study, data from all esophagectomy patients from January 1995 to January 2012, including tumor characteristics, surgical procedure, postoperative anastomotic leakage, leakage therapy regimens, APACHE II scores, and mortality, were collected, and predictors of patient survival after anastomotic leakage were analyzed. RESULTS: Among 366 resected patients, 62 patients (16 %) developed an anastomotic leak, 16 (26 %) of whom died. Therapy regimens included surgical revision (n = 18), endoscopic endoluminal vacuum therapy (n = 17), endoscopic stent application (n = 12), and conservative management (n = 15). APACHE II score at the initiation of treatment for leakage was the strongest predictor of in-hospital mortality (p < 0.0017). Conservatively managed patients showed mild systemic illness (mean APACHE II score 5) and no mortality. In systemically ill patients matched for APACHE II scores (mean, 14.4), endoscopic endoluminal vacuum therapy patients had lower mortality (12 %) compared to surgically treated (50 %, p = 0.01) cases and patients managed by stent placement (83 %, p = 00014, log rank test). No other clinical or laboratory parameters significantly influenced patient survival. CONCLUSIONS: Endoscopic endoluminal vacuum therapy was the best treatment of anastomotic leakage in systemically ill patients after esophagectomy in this retrospective analysis. It should therefore be considered an important instrument in the management of this disorder.

Genetic and functional identification of the likely causative variant for cholesterol gallstone disease at the ABCG5/8 lithogenic locus.

UNLABELLED: The sterolin locus (ABCG5/ABCG8) confers susceptibility for cholesterol gallstone disease in humans. Both the responsible variant and the molecular mechanism causing an increased incidence of gallstones in these patients have as yet not been identified. Genetic mapping utilized patient samples from Germany (2,808 cases, 2,089 controls), Chile (680 cases, 442 controls), Denmark (366 cases, 766 controls), India (247 cases, 224 controls), and China (280 cases, 244 controls). Analysis of allelic imbalance in complementary DNA (cDNA) samples from human liver (n = 22) was performed using pyrosequencing. Transiently transfected HEK293 cells were used for [(3) H]-cholesterol export assays, analysis of protein expression, and localization of allelic constructs. Through fine mapping in German and Chilean samples, an ∼250 kB disease-associated interval could be defined for this locus. Lack of allelic imbalance or allelic splicing of the ABCG5 and ABCG8 transcripts in human liver limited the search to coding single nucleotide polymorphisms. Subsequent mutation detection and genotyping yielded two disease-associated variants: ABCG5-R50C (P = 4.94 × 10(-9) ) and ABCG8-D19H (P = 1.74 × 10(-10) ) in high pairwise linkage disequilibrium (r(2) = 0.95). [(3) H]-cholesterol export assays of allelic constructs harboring these genetic candidate variants demonstrated increased transport activity (3.2-fold, P = 0.003) only for the ABCG8-19H variant, which was also superior in nested logistic regression models in German (P = 0.018), Chilean (P = 0.030), and Chinese (P = 0.040) patient samples. CONCLUSION: This variant thus provides a molecular basis for biliary cholesterol hypersecretion as the mechanism for cholesterol gallstone formation, thereby drawing a link between "postgenomic" and "pregenomic" pathophysiological knowledge about this common complex disorder. (HEPATOLOGY 2012).

Clinical outcomes and health-related quality of life after thoracoscopic talc pleurodesis.

OBJECTIVES: Thoracoscopic pleurodesis is a safe and effective method of palliative care for patients suffering from malignant pleural effusion. Health-related quality of life (QOL) is an important factor in palliative therapy; however, we are not aware of any studies that have examined the QOL of patients following thoracoscopic pleurodesis. METHODS: A total of 123 patients underwent thoracoscopic pleurodesis between January 2006 and February 2009. A total of 45 patients agreed to take part at the QOL assessment and were enrolled in our prospective study. In addition to clinical outcome, the patients' QOL data were assessed prior to thoracoscopic pleurodesis and for 12 months after surgery using the European Organization for Research and Treatment of Cancer (EORTC) QLQ C-30 questionnaire. We compared the patients' QOL scores at each time point with their preoperative scores and analyzed these data relative to the scores of a healthy age-matched population. RESULTS: Due to the advanced clinical status of the patients in our study, the overall median survival time was 7.5 months versus 10.2 months for patients' QOL data. Following discharge from the hospital, most functional scales (with exception of emotional function, p=0.035) did not significantly differ from preoperative scores. Throughout the study period, patients experienced statistically and clinically significant improvements in functional scales. Global health values increased after surgery throughout the entire study period. There was a clear decline in dyspnea upon discharge, followed by a continuous remote increase throughout the subsequent months. QOL of the study population remained lower than that of the healthy cohort. CONCLUSIONS: Our data are consistent with clinical findings that pleurodesis decreases respiratory symptoms, but does not alleviate impairments in the patient's general condition.

Distinct DNA methylation patterns in cirrhotic liver and hepatocellular carcinoma.

Abberrant DNA methylation is one of the hallmarks of cancerogenesis. Our study aims to delineate differential DNA methylation in cirrhosis and hepatic cancerogenesis. Patterns of methylation of 27,578 individual CpG loci in 12 hepatocellular carcinomas (HCCs), 15 cirrhotic controls and 12 normal liver samples were investigated using an array-based technology. A supervised principal component analysis (PCA) revealed 167 hypomethylated loci and 100 hypermethylated loci in cirrhosis and HCC as compared to normal controls. Thus, these loci show a "cirrhotic" methylation pattern that is maintained in HCC. In pairwise supervised PCAs between normal liver, cirrhosis and HCC, eight loci were significantly changed in all analyses differentiating the three groups (p < 0.0001). Of these, five loci showed highest methylation levels in HCC and lowest in control tissue (LOC55908, CELSR1, CRMP1, GNRH2, ALOX12 and ANGPTL7), whereas two loci showed the opposite direction of change (SPRR3 and TNFSF15). Genes hypermethylated between normal liver to cirrhosis, which maintain this methylation pattern during the development of HCC, are depleted for CpG islands, high CpG content promoters and polycomb repressive complex 2 (PRC2) targets in embryonic stem cells. In contrast, genes selectively hypermethylated in HCC as compared to nonmalignant samples showed an enrichment of CpG islands, high CpG content promoters and PRC2 target genes (p < 0.0001). Cirrhosis and HCC show distinct patterns of differential methylation with regards to promoter structure, PRC2 targets and CpG islands.

Lack of CCR7 expression is rate limiting for lymphatic spread of pancreatic ductal adenocarcinoma.

CCR7 expression on tumor cells promotes lymphatic spread in several malignant tumors. However, a comprehensive characterization of the CCL19/CCL21-CCR7 axis in pancreatic ductal adenocarcinoma (PDAC), which is known for its high rates of lymph-node metastases, is still lacking. CCR7 mRNA and CCR7 protein were found to be expressed in spheroid cultures of all six examined PDAC cell lines. In migration assays, CCR7 expressing PDAC cells showed enhanced migration toward CCL19 and CCL21, the two ligands of CCR7. In an orthotopic nude mouse model, CCR7-transfected PT45P1 cells gave rise to significantly larger tumors and showed a higher frequency of lymph vessel invasion and lymph-node metastases than mock-transfected cells. In an analysis using quantitative real-time PCR, CCR7 showed fourfold overexpression in microdissected PDAC cells compared to normal duct cells. Moderate-to-strong immunohistochemical CCR7 expression, found in 58 of 121 well-characterized human PDACs, correlated with high rates of lymph vessel invasion. Conversely, PDACs completely lacking CCR7 expression showed only low rates of lymph vessel invasion and lymph-node metastases. The evaluation of CCL21 expression by immunofluorescence staining revealed a significant upregulation of CCL21 in peritumoral and intratumoral lymph vessels compared to lymph vessels in disease-free pancreata. In conclusion, our study revealed strong evidence that lack of CCR7 impairs the metastatic potential of PDAC. Lymph vessel invasion by CCR7 expressing PDAC cells may be additionally enhanced by upregulation of CCL21 in tumor-associated lymph vessels, representing a previously unknown factor of lymphatic spread.

Preoperative risk evaluation of postoperative morbidity in IBD patients--impact of the POSSUM score.

BACKGROUND: The aim of this study was to assess the morbidity and mortality of patients undergoing surgery for inflammatory bowel disease (IBD) with special focus of the predictive value of the Physiological and Operative Severity Score for the Enumeration of Mortality and Morbidity (POSSUM) scoring system for preoperative risk adjustment of postoperative morbidity. METHODS: The operative notes and hospital files of 191 patients with IBD were analyzed. The POSSUM scoring system was used to predict morbidity rates after surgery. The physiological sub-score of the POSSUM score was analyzed with regard to its ability to predict postoperative complications. RESULTS: The overall complication rate was 27.7%, and the mortality was 0.5%. The morbidity rate predicted by POSSUM was 28.4% and the mortality rate 7.2%. The mean POSSUM-phys sub-score in patients without the major complications (anastomotic leakages, peritonitis, bleeding) was significant lower compared to patients with at least one of these complications (14.7 vs. 18.6; p < 0.001). Regarding the major complications separately, there were significant differences in the POSSUM-phys scores in patients developing a sepsis (14.1 vs. 23.4; p < 0.001) and/or a peritonitis (14.8 vs. 19.2; p = 0.05), whereas patients developing an anastomotic leakage/suture dehiscence or a postoperative bleeding did not differ significantly. CONCLUSION: POSSUM was an accurate predictor of morbidity in IBD patients and overpredicted mortality. The POSSUM-phys score is a promising instrument for identifying patients at increased risk of developing major postoperative complications after surgery for IBD.

A new technique for bedside placement of enteral feeding tubes: a prospective cohort study.

INTRODUCTION: To accomplish early enteral feeding in the critically ill patient a new transnasal endoscopic approach to the placement of postpyloric feeding tubes by intensive care physicians was evaluated. METHODS: This was a prospective cohort study in 27 critically ill patients subjected to transnasal endoscopy and intubation of the pylorus. Attending intensive care physicians were trained in the handling of the new endoscope for transnasal gastroenteroscopy for two days. A jejunal feeding tube was advanced via the instrument channel and the correct position assessed by contrast radiography. The primary outcome measure was successful postpyloric placement of the tube. Secondary outcome measures were time needed for the placement, complications such as bleeding and formation of loops, and the score of the placement difficulty graded from 1 (easy) to 4 (difficult). Data are given as mean values and standard deviation. RESULTS: Out of 34 attempted jejunal tube placements, 28 tubes (82%) were placed correctly in the jejunum. The duration of the procedure was 28 ± 12 minutes. The difficulty of the tube placement was judged as follows: grade 1: 17 patients, grade 2: 8 patients, grade 3: 7 patients, grade 4: 2 patients. In three cases, the tube position was incorrect, and in another three cases, the procedure had to be aborted. In one patient bleeding occurred that required no further treatment. CONCLUSIONS: Fast and reliable transnasal insertion of postpyloric feeding tubes can be accomplished by trained intensive care physicians at the bedside using the presented procedure. This new technique may facilitate early initiation of enteral feeding in intensive care patients.

Elevated L1CAM expression in precursor lesions and primary and metastastic tissues of pancreatic ductal adenocarcinoma.

The promigratory molecule L1CAM is overexpressed in various tumors, often representing an unfavorable prognostic marker. Recently, we identified L1CAM expression in pancreatic ductal adenocarcinoma (PDAC) cells accounting for chemoresistance and increased cell migration. Thus, the present study aims at further elucidating the role of L1CAM in a larger cohort of PDAC specimens including precursor lesions and metastasis. L1CAM expression was determined by immunohistochemistry in tissues of 123 patients including tissues of 110 primary PDACs, 15 lymph node metastases and 14 liver metastases. The immunohistochemical analyses revealed L1CAM expression in 92.7% of primary PDACs, 80% of lymph node metastases and 100% of liver metastases. Furthermore, we have investigated PDAC precursors, pancreatic intraepithelial neoplasia (PanIN) lesions, revealing a significant increase of L1CAM expression with the PanIN grade (6.4 and 6.8% in PanIN 1A and B, 35% in PanIN 2 and 20% in PanIN 3). The elevated expression of L1CAM already found in PanINs points to a role of L1CAM quite early in tumorigenesis of PDAC. Furthermore, its broad expression in primary tumors as well as in metastases of PDAC patients provide a rationale to further explore the value of L1CAM as a therapeutic target in the treatment of this highly malignant tumor.

Evaluation of the POSSUM score in surgical treatment of cholangiocarcinoma.

BACKGROUND/AIMS: The surgical treatment for cholangiocarcinoma (CCC) is still a challenge. The aim of this study was to evaluate the POSSUM scoring system for preoperative physiological risk adjustment and for the operative risk of postoperative morbidity and mortality. METHODOLOGY: The operative notes and hospital files of 171 patients with CCC were analyzed retrospectively. The POSSUM scoring system was used to predict morbidity and mortality rates after surgery. The physiological sub score and the operative sub score of the POSSUM score were analyzed with regard to their ability to predict major postoperative complications. RESULTS: The overall complication rate was 40.9% and the mortality was 11.2%. The morbidity predicted by POSSUM was 63.5% and the prediction for postoperative mortality was 23.7%. Both rates are much higher than the observed morbidity and mortality. High operative severity sub scores correlate with the occurrence of major complications. CONCLUSION: The POSSUM scoring system over predicts morbidity and mortality in surgery for CCC. Operative severity and intraoperative parameters have a greater influence on postoperative mortality and morbidity rates than the physiological parameters represented in the POSSUM physiological score. Prospective studies will have to show whether POSSUM can be modified or whether it is necessary to develop a new score for assessing morbidity and mortality in surgery for CCC.

Age-related impairment of quality of life after lung resection for non-small cell lung cancer.

BACKGROUND: Health-related quality of life (QOL) after resection of non-small cell lung cancer (NSCLC) is of primary interest to clinicians, secondary to clinical outcome. However, few studies have explored QOL following lung resection and, to our knowledge, no studies have specifically examined the QOL of elderly patients. METHODS: A total of 131 patients with NSCLC underwent surgical resection (lobectomy or bilobectomy) between January 1998 and December 2004 and were enrolled in our prospective study. The patients' QOL and clinical data were assessed prior to resection and for up to 24 months after surgery using the EORTC QLQ C-30 questionnaire and the lung-specific questionnaire, QLQ-LC13. Quality of life was then calculated and the QOL of patients younger than 70 years was compared with that of patients aged 70 years or older. RESULTS: The overall 5-year survival rate was 47%, and the rate of complications did not differ significantly between the groups. Overall, most QOL indicators, including physical function (p<0.001), pain (p=0.025), and dyspnea (p<0.001) were significantly impaired after surgery and remained so for up to 24 months. Elderly patients survived for an average of 39 months, while younger patients survived for an average of 49 months (p=0.18). The QOL of younger patients returned to preoperative levels significantly faster than did the QOL of elderly patients. CONCLUSIONS: Elderly patients who underwent lung resection for NSCLC failed to make a complete recovery. They showed a decreased tendency to achieve the preoperative level of QOL compared to younger patients.

Investigation of the colorectal cancer susceptibility region on chromosome 8q24.21 in a large German case-control sample.

Human chromosome 8q24.21 has been implicated as a susceptibility region for colorectal cancer (CRC) as a result of genome-wide association and candidate gene studies. To assess the impact of molecular variants at 8q24.21 upon the CRC risk of German individuals and to refine the disease-associated region, a total of 2,713 patients with operated CRC (median age at diagnosis: 63 years) were compared with 2,718 sex-matched control individuals (median age at inclusion: 65 years). Information on microsatellite instability in tumors was available for 901 patients. Association analysis of SNPs rs10505477 and rs6983267 yielded allelic p-values of 1.42 x 10(-7) and 2.57 x 10(-7), respectively. For both polymorphisms, the odds ratio was estimated to be 1.50 (95% CI: 1.29-1.75) under a recessive disease model. The strongest candidate interval, outside of which significance dropped by more than 4 orders of magnitude, was delineated by SNPs rs10505477 and rs7014346 and comprised 17 kb. In a subgroup analysis, the disease association was found to be more pronounced in MSI-stable tumors (odds ratio: 1.71). Our study confirms the role of genetic variation at 8q24.21 as a risk factor for CRC and localizes the corresponding susceptibility gene to a 17 kb candidate region.

The extent of lung parenchyma resection significantly impacts long-term quality of life in patients with non-small cell lung cancer.

BACKGROUND: Secondary to clinical outcome, health-related quality of life (QOL) after resection of non-small cell lung cancer (NSCLC) is of particular interest. However, few studies have explored QOL following lung resection. METHODS: Between January 1998 and December 2004, a total of 159 patients with NSCLC underwent surgical resection and were enrolled in this prospective study. QOL and clinical data were assessed prior to resection and for up to 24 months after surgery by applying the European Organization for Research and Treatment of Cancer core questionnaire and the lung-specific questionnaire, the European Organization for Research and Treatment of Cancer lung-specific module. QOL was calculated, and QOL following bilobectomy/lobectomy was compared with QOL after pneumonectomy. RESULTS: Overall, the 5-year survival rate was 42%. Mean survival of the pneumonectomy group was slightly lower than that of the bilobectomy/lobectomy group, although the difference was not statistically significant (p = 0.058). The rate of complications was not significantly different between the two groups. After a postoperative drop, most QOL indicators remained near baseline for up to 24 months, with the exception of physical function (p < 0.001), pain (p = 0.034), and dyspnoea (p < 0.001), which remained significantly impaired. QOL was significantly better (difference > 10 points) after bilobectomy/lobectomy than after pneumonectomy. However, differences were statistically significant only with regards to physical function (at 3 months), social function (at 3 and 6 months), role function (at 3, 6, and 12 months), global health (at 3 and 6 months), and pain (at 6 months). CONCLUSIONS: Patients who underwent lung resection for NSCLC failed to make a complete recovery after 24 months. Patients who underwent pneumonectomy had significantly worse QOL values and a decreased tendency to recover, compared with patients who underwent bilobectomy/lobectomy. Therefore, major lung resection has a much more serious impact on the QOL of affected patients than does major visceral surgery.

Dexamethasone reduces tumor recurrence and metastasis after pancreatic tumor resection in SCID mice.

BACKGROUND: Glucocorticoids are among the most potent anti-inflammatory agents that act by inhibiting the synthesis of almost all known cytokines and influencing multiple transduction pathways. Inflammation accompanies most solid cancers including pancreatic ductal adenocarcinoma (PDAC), one of the most fatal cancers with surgery being the only potential curative therapeutic. In the present work we investigated the influence of glucocorticoids on PDAC cells in vitro as well as in vivo in a pancreatic carcinoma resection mouse model. METHODS: The influence of dexamethasone (DEX), a synthetic glucocorticoid, on proliferation and IL8 secretion in pancreatic cells (BxPC3, Colo357, PancTuI) was analyzed by cell counting and ELISA. NFkappaB-activity of PancTuI cells treated with DEX was determined by electrophoretic mobility shift assay (EMSA). Furthermore, effects of DEX on the invasiveness were studied by a fibroblast-based invasion assay. In the mouse resection model subtotal pancreatectomy was performed after orthotopic inoculation of human PDAC cells. DEX was administered after resection as an adjuvant treatment regime and 4 weeks later, local recurrent tumor sizes as well as number of liver and spleen metastases were analyzed. RESULTS: In vitro, DEX did not have an anti-proliferative effect on PDAC cells, but strongly reduced the invasiveness well as the activation of NFkappaB. The secretion of IL-8 into the supernatant of the tumor cells correlated inversely with the reduced activation of NFkappaB. In vivo, we observed a significant reduction of the local recurrent tumor volume and the number of liver and spleen metastases. CONCLUSIONS: DEX has a profound influence on the malignant phenotype of PDAC tumor cells in vitro in terms of inhibition of invasiveness and pro-inflammatory signaling. This was approved in vivo by reduced metastasizing capacity and reduced size of local tumor recurrence. Therefore, DEX-treatment appears to be an interesting therapeutical option in an adjuvant setting after pancreatic cancer resection.